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Mol Cancer. 2024 Mar 16;23(1):56. doi: 10.1186/s12943-024-01952-w.
ABSTRACT
One of the major hurdles that has hindered the success of chimeric antigen receptor (CAR) T cell therapies against solid tumors is on-target off-tumor (OTOT) toxicity due to sharing of the same epitopes on normal tissues. To elevate the safety profile of CAR-T cells, an affinity/avidity fine-tuned CAR was designed enabling CAR-T cell activation only in the presence of a highly expressed tumor associated antigen (TAA) but not when recognizing the same antigen at a physiological level on healthy cells. Using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution, and flow cytometry, we identified high carbonic anhydrase IX (CAIX) density on clear cell renal cell carcinoma (ccRCC) patient samples and low-density expression on healthy bile duct tissues. A Tet-On doxycycline-inducible CAIX expressing cell line was established to mimic various CAIX densities, providing coverage from CAIX-high skrc-59 tumor cells to CAIX-low MMNK-1 cholangiocytes. Assessing the killing of CAR-T cells, we demonstrated that low-affinity/high-avidity fine-tuned G9 CAR-T has a wider therapeutic window compared to high-affinity/high-avidity G250 that was used in the first anti-CAIX CAR-T clinical trial but displayed serious OTOT effects. To assess the therapeutic effect of G9 on patient samples, we generated ccRCC patient derived organotypic tumor spheroid (PDOTS) ex vivo cultures and demonstrated that G9 CAR-T cells exhibited superior efficacy, migration and cytokine release in these miniature tumors. Moreover, in an RCC orthotopic mouse model, G9 CAR-T cells showed enhanced tumor control compared to G250. In summary, G9 has successfully mitigated OTOT side effects and in doing so has made CAIX a druggable immunotherapeutic target.
PMID:38491381 | DOI:10.1186/s12943-024-01952-w
Parasitol Res. 2024 Mar 16;123(3):161. doi: 10.1007/s00436-024-08184-3.
ABSTRACT
Opisthorchis viverrini infection and the subsequent bile duct cancer it induces remains a significant public health problem in Southeast Asia. Opisthorchiasis has been reported to cause reduced plasma glucose levels among infected patients. The underlying mechanism for this phenomenon is unclear. In the present study, evidence is presented to support the hypothesis that O. viverrini exploits host cholangiocyte glucose transporters (GLUTs) in a similar manner to that of rodent intestinal nematodes, to feed on unabsorbed glucose in the bile for survival. GLUT levels in a cholangiocyte H69 cell line co-cultured with excretory-secretory products of O. viverrini were examined using qPCR and immunoblotting. GLUT 8 mRNA and expressed proteins were found to be downregulated in H69 cells in the presence of O. viverrini. This suggests that O. viverrini alters glucose metabolism in cells within its vicinity by limiting transporter expression resulting in increased bile glucose that it can utilize and potentially explains the previously reported anti-insulin effect of opisthorchiasis.
PMID:38491300 | DOI:10.1007/s00436-024-08184-3
Medicine (Baltimore). 2024 Mar 15;103(11):e37460. doi: 10.1097/MD.0000000000037460.
ABSTRACT
Cholangiocarcinoma (CHOL) is a race malignant cancer arising from bile duct epithelial cells in clinical practice. C-X-C motif chemokine ligand 3 (CXCL3) is a member of chemokines family, which participates in the pathogenesis of various tumors. However, the association between CXCL3 and CHOL is unclear. This present study was to assess the role of CXCL3 expression in the progress of CHOL. TIMER, GEPIA, UALCAN, GSCA, LinkedOmics, Metascape and STRING databases were performed to evaluate the clinical and biological significances for CXCL3 with CHOL patients including expression, clinicopathological factors, immune cell infiltration, GO enrichment and KEGG pathway analyses, as well as PPI network analysis. The immunohistochemistry analysis of tissue microarray was conducted to detect the protein expression level, subcellular localization, clinicopathological factors and prognosis of CXCL3 in CHOL. The mRNA and protein expression levels of CXCL3 were markedly increased in CHOL tissues. The overexpression of CXCL3 was strongly associated with maximum tumor diameter of patients with CHOL. Additionally, there were negative correlations between the expression of CXCL3 and monocyte as well as Th17. Low infiltration of neutrophil indicated significantly shorter cumulative survival in CHOL patients. And CXCL3 was significantly associated with arm-level deletion of CD8+ T cell. Furthermore, functional network analysis suggested that CXCL3 and its associated genes were mainly enriched for chemotaxis, secretory granule membrane, cytokine activity and IL-17 signaling pathway. CXCL3 might potentially participate in the carcinogenesis of CHOL, which provided a direction for future research on the mechanism of CXCL3 in CHOL.
PMID:38489741 | PMC:PMC10939667 | DOI:10.1097/MD.0000000000037460
Updates Surg. 2024 Mar 14. doi: 10.1007/s13304-024-01752-3. Online ahead of print.
ABSTRACT
Intrabiliary growth (IG) is an unusual modality for colorectal metastases to spread. Relatively little is known about this condition because large series are lacking. The aim of the study was to compare the surgical and oncological outcomes of patients with or without IG. From 01/2010 to 12/2020, 999 patients underwent hepatectomy for colorectal metastases. Clinicopathological variables were retrospectively analyzed from a prospective-collected database of patients with or without IG. A propensity score matched (PSM) analysis to compare OS and DFS was performed. At first hepatectomy, 29 patients (2.9%) had IG: 7 isolated IG and 22 mixed-type (mass-forming lesion with IG). 4 patients presented IG at repeat hepatectomy for recurrence, of whom 3 had no biliary invasion at initial surgery. IG resulted to be more common in older patients (median age 70 in IG vs 60 years of no-IG, p = 0.004). Mean time from colorectal tumor was longer in IG (20.4 months) than no-IG (12.9 months), p = 0.038. Major hepatectomies (55.2% IG vs 29.7% no-IG, p = 0.003) and anatomic resections (89.7% vs 58.2%, p = 0.001) were more frequently required to treat IG. In 5 (17%) of IG, a resection of main bile duct was performed. Overall postoperative mortality and complications were similar in the two groups, while bile leak was 17.2% IG vs 5.6% no-IG (p = 0.024). Median margin width was comparable in IG (1.4 mm) and no-IG (2 mm). Five-year overall survival (IG 45.9% vs no-IG 44.5%) and Disease-Free Survival (IG 35.9% vs no-IG 36.6%) were similar in the two groups. According to PSM, 145 patients with no-IG were compared to 29 of IG group. After PSM, OS and DFS did not show any statistically significant difference. IG has similar oncological outcomes of resected colorectal metastases without IG, although it affects surgical management.
PMID:38483785 | DOI:10.1007/s13304-024-01752-3
J Pathol. 2024 Mar 14. doi: 10.1002/path.6265. Online ahead of print.
ABSTRACT
The molecular mechanisms underpinning the development of metachronous tumors in the remnant bile duct following surgical resection of primary biliary tract carcinomas (BTCs) are unknown. This study aimed to elucidate these mechanisms by evaluating the clinicopathologic features of BTCs, the alterations to 31 BTC-related genes on targeted sequencing, and the aberrant expression of p53, p16, SMAD4, ARID1A and β-catenin on immunohistochemistry. Twelve consecutive patients who underwent resection of metachronous BTCs following primary BTC resection with negative bile duct margins were enrolled. Among the 12 metachronous tumors, six exhibited anterograde growth in the lower portion and six exhibited retrograde growth in the upper portion of the biliary tree. Surgical resection of metachronous BTCs resulted in recurrence-free survival in seven, local recurrence in five, and death in two patients. Nine achieved 5-year overall survival after primary surgery. Molecular analyses revealed that recurrently altered genes were: TP53, SMAD4, CDKN2A, ELF3, ARID1A, GNAS, NF1, STK11, RNF43, KMT2D and ERBB3. Each of these was altered in at least three cases. A comparison of the molecular features between 12 paired primary and metachronous BTCs indicated that 10 (83%) metachronous tumors developed in clonal association with corresponding primary tumors either successionally or phylogenically. The remaining two (17%) developed distinctly. The successional tumors consisted of direct or evolved primary tumor clones that spread along the bile duct. The phylogenic tumors consisted of genetically unstable clones and conferred a poor prognosis. Metachronous tumors distinct from their primaries harbored fewer mutations than successional and phylogenic tumors. In conclusion, over 80% of metachronous BTCs that develop following primary BTC resection are probably molecularly associated with their primaries in either a successional or a phylogenetic manner. Comparison between the molecular features of a metachronous tumor and those of a preceding tumor may provide effective therapeutic clues for the treatment of metachronous BTC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
PMID:38482714 | DOI:10.1002/path.6265
VideoGIE. 2023 Oct 28;9(3):154-157. doi: 10.1016/j.vgie.2023.10.011. eCollection 2024 Mar.
ABSTRACT
Video 1A case of bile and pancreatic duct injury with duodenal perforation during endoscopic submucosal dissection for superficial duodenal epithelial neoplasia.
PMID:38482477 | PMC:PMC10927496 | DOI:10.1016/j.vgie.2023.10.011
Ann Surg Oncol. 2024 Mar 13. doi: 10.1245/s10434-024-15161-8. Online ahead of print.
ABSTRACT
BACKGROUND: Currently, an effective tracer technique for lymphatic drainage during laparoscopic surgery has not been established. This study aimed to elucidate a new fluorescence, imaging technique targeting the hepatic lymphatic drainage area, using indocyanine green (ICG).
METHODS: A patient diagnosed with intrahepatic cholangiocarcinoma (ICC) located in segment 8 of the liver was injected with ICG into the connective tissue of the Glisson pedicle supplied by the lesion's liver segment, avoiding the bile duct, portal vein, and hepatic artery. This was performed under the guidance of laparoscopic ultrasonographic localization to trace the lymph nodes.
RESULTS: The lymphatic drainage area traced intraoperatively by ICG was consistent with the definition of the right regional lymph nodes for ICC. The lymph nodes were dissected, followed by addition of a fluorescence tracer.
CONCLUSIONS: Mastering intraoperative ultrasonic puncture technology can enable effective and accurate tracing of the lymph nodes of the liver segment where the lesion is located. However, the technical standards for this methodology need to be established through further studies.
PMID:38480563 | DOI:10.1245/s10434-024-15161-8
Cancer Sci. 2024 Mar 12. doi: 10.1111/cas.16143. Online ahead of print.
ABSTRACT
Cholangiocarcinoma often remains undetected until advanced stages due to the lack of reliable diagnostic markers. Our goal was to identify a unique secretory protein for cholangiocarcinoma diagnosis and differentiation from other malignancies, benign hepatobiliary diseases, and chronic liver conditions. We conducted bulk RNA-seq analysis to identify genes specifically upregulated in cholangiocarcinoma but not in most other cancers, benign hepatobiliary diseases, and chronic liver diseases focusing on exocrine protein-encoding genes. Single-cell RNA sequencing examined subcellular distribution. Immunohistochemistry and enzyme-linked immunosorbent assays assessed tissue and serum expression. Diagnostic performance was evaluated via receiver-operating characteristic (ROC) analysis. Inter-alpha-trypsin inhibitor heavy chain family member five (ITIH5), a gene encoding an extracellular protein, is notably upregulated in cholangiocarcinoma. This elevation is not observed in most other cancer types, benign hepatobiliary diseases, or chronic liver disorders. It is specifically expressed by malignant cholangiocytes. ITIH5 expression in cholangiocarcinoma tissues exceeded that in nontumorous bile duct, hepatocellular carcinoma, and nontumorous hepatic tissues. Serum ITIH5 levels were elevated in cholangiocarcinoma compared with controls (hepatocellular carcinoma, benign diseases, chronic hepatitis B, and healthy individuals). ITIH5 yielded areas under the ROC curve (AUCs) from 0.839 to 0.851 distinguishing cholangiocarcinoma from controls. Combining ITIH5 with carbohydrate antigen 19-9 (CA19-9) enhanced CA19-9's diagnostic effectiveness. In conclusion, serum ITIH5 may serve as a novel noninvasive cholangiocarcinoma diagnostic marker.
PMID:38475675 | DOI:10.1111/cas.16143
Cells. 2024 Feb 20;13(5):366. doi: 10.3390/cells13050366.
ABSTRACT
The term cholangiocarcinoma (CCA) defines a class of epithelial malignancies originating from bile ducts. Although it has been demonstrated that CCA patients with perineural invasion (PNI) have a worse prognosis, the biological features of this phenomenon are yet unclear. Our data show that in human intrahepatic CCA specimens with documented PNI, nerve-infiltrating CCA cells display positivity of the epithelial marker cytokeratin 7, lower with respect to the rest of the tumor mass. In an in vitro 3D model, CCA cells move towards a peripheral nerve explant allowing contact with Schwann cells (SCs) emerging from the nerve. Here, we show that SCs produce soluble factors that favor the migration, invasion, survival and proliferation of CCA cells in vitro. This effect is accompanied by a cadherin switch, suggestive of an epithelial-mesenchymal transition. The influence of SCs in promoting the ability of CCA cells to migrate and invade the extracellular matrix is hampered by a specific TGFβ receptor 1 (TGFBR1) antagonist. Differential proteomic data indicate that the exposure of CCA cells to SC secreted factors induces the upregulation of key oncogenes and the concomitant downregulation of some tumor suppressors. Taken together, these data concur in identifying SCs as possible promoters of a more aggressive CCA phenotype, ascribing a central role to TGFβ signaling in regulating this process.
PMID:38474330 | PMC:PMC10930666 | DOI:10.3390/cells13050366
Dalton Trans. 2024 Mar 12. doi: 10.1039/d4dt00118d. Online ahead of print.
ABSTRACT
BOLD-100 (formerly IT-139, KP1339), a well-established chemotherapeutic agent, is currently being investigated in clinical trials for the treatment of gastric, pancreatic, colorectal, and bile duct cancer. Despite numerous studies, the exact mode of action is still the subject of discussions. Radiolabeled BOLD-100 could be a powerful tool to clarify pharmacokinetic pathways of the compound and to predict therapy responses in patients using nuclear molecular imaging prior to the therapy. In this study, the radiosyntheses of carrier-added (c.a.) [97/103Ru]BOLD-100 were performed with the two ruthenium isotopes ruthenium-103 (103Ru; β-, γ) and ruthenium-97 (97Ru; EC, γ), of which in particular the latter isotope is suitable for imaging by single-photon emission computed tomography (SPECT). To identify the best tumor-to-background ratio for diagnostic imaging, biodistribution studies were performed with two different injected doses of c.a. [103Ru]BOLD-100 (3 and 30 mg kg-1) in Balb/c mice bearing CT26 allografts over a time period of 72 h. Additionally, ex vivo autoradiography of the tumors (24 h p.i.) was conducted. Our results indicate that the higher injected dose (30 mg kg-1) leads to more unspecific accumulation of the compound in non-targeted tissue, which is likely due to an overload of the albumin transport system. It was also shown that lower amounts of injected c.a. [103Ru]BOLD-100 resulted in a relatively higher tumor uptake and, therefore, a better tumor-to-background ratio, which are encouraging results for future imaging studies using c.a. [97Ru]BOLD-100.
PMID:38470348 | DOI:10.1039/d4dt00118d
Front Oncol. 2024 Feb 26;14:1329986. doi: 10.3389/fonc.2024.1329986. eCollection 2024.
ABSTRACT
PURPOSE: Mounting evidence has revealed the anti-cancer activity of various anti-viral drugs. Oseltamivir phosphate (OP), namely Tamiflu®, is routinely used to combat influenza infections. Although evidence has indicated the anti-cancer effects of OP in vitro and in vivo, little information is known about the effect of OP use on cancers in humans.
METHODS: A nationwide population-based cohort study involving 13,977,101 cases with 284,733 receiving OP was performed to examine the association between OP use and cancers using the National Health Insurance Research Database in Taiwan between 2009 and 2018.
RESULTS: The cohort study found that OP users showed a significantly lower incidence of lung cancer, colon cancer, liver, and intrahepatic bile duct cancer, oral cancer, pancreas cancer, esophagus cancer, stomach cancer, and prostate cancer. Additionally, OP users exhibited a lower risk of cancer-related mortality (adjusted HR=0.779; 95% confidence interval [CI] 0.743-0.817; p<0.001) and a reduced risk of developing liver cancer (adjusted HR=0.895; 95% CI 0.824-0.972; p=0.008), esophagus cancer (adjusted HR=0.646; 95% CI 0.522-0.799; p<0.001) and oral cancer (adjusted HR=0.587; 95% CI 0.346-0.995; p=0.048). Notably, OP users had a significant reduction in liver cancer occurrence over a 10-year period follow-up and a lower cancer stage at liver cancer diagnosis.
CONCLUSION: These findings first suggest the beneficial effects and therapeutic potential of OP use for certain cancers, especially liver cancer.
PMID:38469236 | PMC:PMC10925756 | DOI:10.3389/fonc.2024.1329986
World J Gastrointest Surg. 2024 Feb 27;16(2):503-510. doi: 10.4240/wjgs.v16.i2.503.
ABSTRACT
BACKGROUND: Although en bloc dissection of hepatic hilum lymph nodes has many advantages in radical tumor treatment, the feasibility and safety of this approach for laparoscopic pancreaticoduodenectomy (LPD) require further clinical evaluation and investigation.
AIM: To explore the application value of the "five steps four quadrants" modularized en bloc dissection technique for accessing hepatic hilum lymph nodes in LPD patients.
METHODS: A total of 52 patients who underwent LPD via the "five steps four quadrants" modularized en bloc dissection technique for hepatic hilum lymph nodes from April 2021 to July 2023 in our department were analyzed retrospectively. The patients' body mass index (BMI), preoperative laboratory indices, intraoperative variables and postoperative complications were recorded. The relationships between preoperative data and intraoperative lymph node dissection time and blood loss were also analyzed.
RESULTS: Among the 52 patients, 36 were males and 16 were females, and the average age was 62.2 ± 11.0 years. There were 26 patients with pancreatic head cancer, 16 patients with periampullary cancer, and 10 patients with distal bile duct cancer. The BMI was 22.3 ± 3.3 kg/m², and the median total bilirubin (TBIL) concentration was 57.7 (16.0-155.7) µmol/L. All patients successfully underwent the "five steps four quadrants" modularized en bloc dissection technique without lymph node clearance-related complications such as postoperative bleeding or lymphatic leakage. Correlation analysis revealed significant associations between preoperative BMI (r = 0.3581, P = 0.0091), TBIL level (r = 0.2988, P = 0.0341), prothrombin time (r = 0.3018, P = 0.0297) and lymph node dissection time. Moreover, dissection time was significantly correlated with intraoperative blood loss (r = 0.7744, P < 0.0001). Further stratified analysis demonstrated that patients with a preoperative BMI ≥ 21.9 kg/m² and a TIBL concentration ≥ 57.7 μmol/L had significantly longer lymph node dissection times (both P < 0.05).
CONCLUSION: The "five steps four quadrants" modularized en bloc dissection technique for accessing the hepatic hilum lymph node is safe and feasible for LPD. This technique is expected to improve the efficiency of hepatic hilum lymph node dissection and shorten the learning curve; thus, it is worthy of further clinical promotion and application.
PMID:38463365 | PMC:PMC10921220 | DOI:10.4240/wjgs.v16.i2.503
J Hepatol. 2024 Mar 7:S0168-8278(24)00149-1. doi: 10.1016/j.jhep.2024.02.030. Online ahead of print.
ABSTRACT
BACKGROUND & AIMS: In the developing liver, bipotent epithelial progenitor cells known as hepatoblasts undergo lineage segregation to form the two major epithelial cell types, hepatocytes that constitute the bulk of the liver parenchyma and biliary epithelial cells (cholangiocytes) which comprise the bile duct, a complex tubular network which is critical for normal liver function. Notch and TGFβ signalling promote the formation of a sheet of biliary epithelial cells, the ductal plate that organises into discontinuous tubular structures. How these structures elongate and connect to form a continuous duct remains undefined. We aimed to define the mechanisms by which the ductal plate transitions from simple sheet of epithelial cells to a complex and connected bile duct.
METHODS: By combining single cell RNA sequencing from embryonic mouse livers with genetic tools and organoid models we functionally dissected the role of planar cell polarity in duct patterning.
RESULTS: We show that the planar cell polarity protein, VANGL2 is expressed late in intrahepatic bile duct development and patterns the formation of cell-cell contacts between biliary cells. The patterning of these cell contacts regulates the normal polarisation of the actin cytoskeleton within biliary cells and loss of Vangl2-function results in the abnormal distribution of cortical actin remodelling resulting in the failure of bile duct formation.
CONCLUSIONS: Planar cell polarity is a critical step in the post-specification sculpture of the bile duct and is essential for establishing normal tissue architecture.
IMPACT AND IMPLICATIONS: Human disease and mouse models have allowed us to define how the mammalian biliary lineage is specified during liver development. Once this relatively simple epithelium has formed though, how it undergoes morphogenesis to form a complex and branched structure is not clear. Similar to other branched tissues such as the liver and kidney the bile ducts use planar cell polarity signalling to coordinate cell movements; however how these biochemical signals are linked to ductular patterning remains unclear. Here we show that the core planar cell polarity protein, VANGL2 patterns how cell-cell contacts form in the mammalian bile duct and how ductular cells transmit confluent mechanical changes along the length of a duct. This work sheds light on how biological tubes are pattered across mammalian tissues (including within the liver) and will be important in how we promote ductular growth in patients where the duct is mis-patterned or poorly formed.
PMID:38460794 | DOI:10.1016/j.jhep.2024.02.030
J Hepatol. 2024 Mar 7:S0168-8278(24)00151-X. doi: 10.1016/j.jhep.2024.02.031. Online ahead of print.
ABSTRACT
BACKGROUND AND AIMS: Syndromic biliary atresia is a cholangiopathy characterized by fibro-obliterative changes in the extrahepatic bile duct (EHBD) and congenital malformations including laterality defects. The aetiology remains elusive and faithful animal models are lacking. Genetic syndromes provide important clues for underlying pathogenic mechanisms of disease. We investigated the role of the gene Pkd1l1 in syndromic biliary atresia pathophysiology.
METHODS: Constitutive and conditional Pkd1l1 knockout mice were generated to explore genetic pathology as a cause of syndromic biliary atresia. We assessed for congenital malformations, EHBD and liver pathology, EHBD gene expression, and biliary epithelial cell turnover. Biliary drainage was functionally assessed with cholangiography. Histology and serum chemistries were assessed after 3,5-diethoxycarbony l-1,4-dihydrocollidine (DDC) diet treatment and inhibition of the ciliary signalling effector GLI1.
RESULTS: Pkd1l1-deficient mice exhibited congenital anomalies including malrotation and heterotaxy. Pkd1l1-deficient EHBD were hypertrophic and fibrotic. Pkd1l1-deficient EHBD were patent, but displayed delayed biliary drainage. Pkd1l1-deficient livers exhibited ductular reaction and periportal fibrosis. After DDC treatment, Pkd1l1-deficient mice exhibited EHBD obstruction and advanced liver fibrosis. Pkd1l1-deficient mice had increased expression of fibrosis and extracellular matrix remodeling genes (Tgfα, Cdkn1a, Hb-egf, Fgfr3, Pdgfc, Mmp12, and Mmp15) and decreased expression of genes mediating ciliary signalling (Gli1, Gli2, Ptch1, and Ptch2). Primary cilia were reduced on biliary epithelial cells and altered expression of ciliogenesis genes occurred in Pkd1l1-deficient mice. Small molecule inhibition of the ciliary signalling effector GLI1 with Gant61 recapitulated Pkd1l1-deficiency.
CONCLUSIONS: Pkd1l1 loss causes both laterality defects and fibro-proliferative EHBD transformation through disrupted ciliary signalling, phenocopying syndromic biliary atresia. Pkd1l1-deficient mice function as an authentic genetic model to study biliary atresia pathogenesis.
IMPACT AND IMPLICATIONS: The syndromic form of biliary atresia is characterized by fibro-obliteration of extrahepatic bile ducts and is often accompanied by laterality defects. The aetiology is unknown, but Pkd1l1 was identified as a potential genetic candidate for syndromic biliary atresia. We found that loss of the ciliary gene Pkd1l1 contributes to hepatobiliary pathology in biliary atresia, exhibited by bile duct hypertrophy, reduced biliary drainage, and liver fibrosis in Pkd1l1-deficient mice. Pkd1l1-deficient mice serve as a genetic model of biliary atresia and reveals ciliopathy as an aetiology of biliary atresia. This model will help scientists uncover new therapeutic approaches for patients with biliary atresia and validate screening for PKD1L1 variants by paediatric hepatologists for diagnostic evaluation.
PMID:38460793 | DOI:10.1016/j.jhep.2024.02.031
J Hepatol. 2024 Mar 7:S0168-8278(24)00152-1. doi: 10.1016/j.jhep.2024.02.032. Online ahead of print.
ABSTRACT
BACKGROUND & AIMS: NOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSECs-expressed POFUT1 in liver fibrosis.
METHODS: Endothelial-specific Pofut1 knockout mice were generated and subjected to experimental liver fibrosis by chronic carbon tetrachloride exposure or by common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA-seq, qPCR, and Western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSECs cultures. Liver single-cell RNA-seq data sets from cirrhotic patients and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies.
RESULTS: POFUT1 loss promoted injury-induced LSECs capillarization and HSC activation, leading to aggravated liver fibrosis. RNA-seq analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of cirrhotic patients. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to treatment with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling.
CONCLUSIONS: Endothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen which function as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/NOTCH/HES1/STAT3/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases.
PMID:38460791 | DOI:10.1016/j.jhep.2024.02.032
Endoscopy. 2024 Dec;56(S 01):E225-E226. doi: 10.1055/a-2253-0948. Epub 2024 Mar 8.
NO ABSTRACT
PMID:38458238 | PMC:PMC10923627 | DOI:10.1055/a-2253-0948
Cancer Med. 2024 Feb;13(4):e6892. doi: 10.1002/cam4.6892.
ABSTRACT
BACKGROUND AND AIMS: Cholangiocarcinoma (CCA), a rare and aggressive hepatobiliary malignancy, presents significant clinical management challenges. Despite rising incidence and evolving treatment options, prognosis remains poor, motivating the exploration of real-world data for enhanced understanding and patient care.
METHODS: This multicenter study analyzed data from 120 metastatic CCA patients at three institutions from 2016 to 2023. Kaplan-Meier curves assessed overall survival (OS), while univariate and multivariate analyses evaluated links between clinical variables (age, gender, tumor site, metastatic burden, ECOG performance status, response to first-line chemotherapy) and OS. Genetic profiling was conducted selectively.
RESULTS: Enrolled patients had a median age of 68.5 years, with intrahepatic tumors predominant in 79 cases (65.8%). Among 85 patients treated with first-line chemotherapy, cisplatin and gemcitabine (41.1%) was the most common regimen. Notably, one-third received no systemic treatment. After a median 14-month follow-up, 81 CCA-related deaths occurred, with a median survival of 13.1 months. Two clinical variables independently predicted survival: response to first-line chemotherapy (disease control vs. no disease control; HR: 0.27; 95% CI: 0.14-0.50; p < 0.0001) and metastatic involvement (>1 site vs. 1 site; HR: 1.99; 95% CI: 1.04-3.80; p = 0.0366). The three most common genetic alterations involved the ARID1A, tp53, and CDKN2A genes.
CONCLUSIONS: Advanced CCA displays aggressive clinical behavior, emphasizing the need for treatments beyond chemotherapy. Genetic diversity supports potential personalized therapies. Collaborative research and deeper CCA biology understanding are crucial to enhance patient outcomes in this challenging malignancy.
PMID:38457226 | PMC:PMC10923031 | DOI:10.1002/cam4.6892
Signal Transduct Target Ther. 2024 Mar 8;9(1):63. doi: 10.1038/s41392-024-01761-z.
ABSTRACT
Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells. Cancer cells could exhibit a "neural addiction" property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis. Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment. However, whether intrahepatic cholangiocarcinoma (ICC) could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown. Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that ICC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes ICC metastasis by inducing epithelial-mesenchymal transition (EMT). Acetylcholine promoted ICC metastasis through interacting with its receptor, alpha 5 nicotine acetylcholine receptor subunits (CHRNA5). Furthermore, acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca2+-mediated activation of Ca/calmodulin-dependent protein kinases (CAMKII). In addition, acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor (BDNF), which formed a feedforward acetylcholine-BDNF axis to promote ICC progression. KN93, a small-molecule inhibitor of CAMKII, significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells. Above all, Acetylcholine/CHRNA5 axis increased the expression of β-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKII/GSK3β signaling, and the CAMKII inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.
PMID:38453934 | PMC:PMC10920868 | DOI:10.1038/s41392-024-01761-z
Zhonghua Nei Ke Za Zhi. 2024 Mar 1;63(3):291-294. doi: 10.3760/cma.j.cn112138-112138-20231106-00299.
ABSTRACT
Objective: Quantified MRCP imaging data was used as a reference for design and preparation of a modified percutaneous transhepatic cholangio drainage (PTCD) tube. Methods: 3.0 T upper abdominal MR and MRCP imaging data of 2 300 patients treated from July 2015 to July 2020 at the Department of Radiology of the Affiliated Cancer Hospital of Zhengzhou University were screened and a total of 381 patients diagnosed with biliary duct structures were identified. Causative etiologies among these patients included pancreatic adenocarcinoma (pancreatic head), cholangiocarcinoma, ampullary carcinoma, as well as intrahepatic and/or extrahepatic bile duct dilation. An improved PTCD tube was designed based on MRCP quantification of left and right hepatic and common hepatic duct length. Results: In the setting of biliary obstruction caused by malignancy, the distance of the left hepatic duct from its origin to the point of left and right hepatic duct confluence was 15.9±3.8 mm, while the distance of the right hepatic duct from its origin to the point of left and right hepatic duct confluence was 12.4±3.2 mm; the length of the bile duct from its origin to the point of left and right hepatic duct confluence was 34.0±8.1 mm. The improved PTCD tube design incorporated an altered length of the drainage orifice. Conclusion: MRCP imaging of the biliary tract is effective for measuring biliary tract length in the setting of pathological dilation. Based on our biliary tract measurements, a modified PTCD tube was designed to more effectively meet drainage requirements and manage biliary obstruction caused by Bismuth-Corlette type Ⅱ and Ⅲ malignancies.
PMID:38448193 | DOI:10.3760/cma.j.cn112138-112138-20231106-00299
J Gastrointest Surg. 2024 Feb;28(2):191-192. doi: 10.1016/j.gassur.2023.11.015. Epub 2024 Feb 5.
NO ABSTRACT
PMID:38445944 | DOI:10.1016/j.gassur.2023.11.015
J Gastrointest Surg. 2024 Feb;28(2):132-140. doi: 10.1016/j.gassur.2023.12.010. Epub 2024 Feb 5.
ABSTRACT
BACKGROUND: This study aimed to develop a tool based on preoperative factors to predict the risk of perioperative complications based on the Comprehensive Complication Index (CCI) and long-term survival outcomes after liver resection for primary liver cancer.
METHODS: Patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) undergoing curative-intent hepatectomy between 1990 and 2020 were identified using a multi-institutional international database.
RESULTS: Among 1411 patients who underwent curative-intent hepatic resection (HCC: 997, 70.7%; ICC: 414, 29.3%), median patient age was 66.0 years (IQR, 57.0-73.0), and most patients were male (n = 1001, 70.9%). In the postoperative setting, 699 patients (49.5%) experienced a complication; moreover, 112 patients (7.9%) had major complications. Although most patients had a favorable risk complication-overall survival (CompOS) profile (CCI score > 40 risk of <30% and median survival of >5 years: n = 778, 55.1%), 553 patients (39.2%) had an intermediate-risk profile, and 80 patients (5.7%) had a very unfavorable risk profile (CCI score > 40 risk of ≥30% and/or median survival of ≤1.5 years). The areas under the curve of the test and validation cohorts were 0.73 and 0.76, respectively.
CONCLUSION: The CompOS risk model accurately stratified patients relative to short- and long-term risks, identifying a subset of patients at a high risk of major complications and poor overall survival.
PMID:38445934 | DOI:10.1016/j.gassur.2023.12.010
Front Immunol. 2024 Feb 19;15:1357333. doi: 10.3389/fimmu.2024.1357333. eCollection 2024.
ABSTRACT
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the first and second most common primary liver cancer (PLC). For decades, systemic therapies consisting of tyrosine kinase inhibitors (TKIs) or chemotherapy have formed the cornerstone of treating advanced-stage HCC and CCA, respectively. More recently, immunotherapy using immune checkpoint inhibition (ICI) has shown anti-tumour reactivity in some patients. The combination regimen of anti-PD-L1 and anti-VEGF antibodies has been approved as new first-line treatment of advanced-stage HCC. Furthermore, gemcibatine plus cisplatin (GEMCIS) with an anti-PD-L1 antibody is awaiting global approval for the treatment of advanced-stage CCA. As effective anti-tumour reactivity using ICI is achieved in a minor subset of both HCC and CCA patients only, alternative immune strategies to sensitise the tumour microenvironment of PLC are waited for. Here we discuss immune checkpoint stimulation (ICS) as additional tool to enhance anti-tumour reactivity. Up-to-date information on the clinical application of ICS in onco-immunology is provided. This review provides a rationale of the application of next-generation ICS either alone or in combination regimen to potentially enhance anti-tumour reactivity in PLC patients.
PMID:38440738 | PMC:PMC10910082 | DOI:10.3389/fimmu.2024.1357333
BMC Cancer. 2024 Mar 4;24(1):286. doi: 10.1186/s12885-024-11949-9.
ABSTRACT
BACKGROUNDS: Ampullary adenocarcinoma (AMPAC) is a rare malignancy, treated as pancreatic or intestinal cancer based on its histologic subtype. Little is known about the genomic features of Chinese patients with AMPAC.
MATERIALS AND METHODS: We enrolled 145 Chinese AMPAC patients in our local cohort and performed a compressive somatic and germline genetic testing using a 156 gene panel. Expression of PD-L1 (clone 28 - 8) was also assessed in tumor specimens from 64 patients.
RESULTS: The frequency of genetic alterations (GAs) in Chinese patients with AMPAC was found to be distinctive, with TP53, KRAS, SMAD4, APC, CTNNB1, ARID1A, and CDKN2A emerged as the most frequently mutated genes. Comparing with Western patients, significant differences were observed in the prevalence of PIK3CA and ARID2. Furthermore, the incidence of MSI-H was lower in the Chinese cohort, with only two patients identified as MSI-H. Conversely, 11 patients (8.27%) had pathogenic/likely pathogenic germline alterations, all of which were in the DNA damage response (DDR) pathway. In our cohort, 34.48% (22/64) of patients exhibited positive PD-L1 expression in tumor cells, and this expression was associated with GAs in CTNNB1 and BLM. Importantly, over three-fourths of Chinese AMPAC patients in our study had at least one actionable GA, with more than one-fifth of them having actionable GAs classified as Level 3. These actionable GAs were primarily involved in the DDR and PI3K pathways. Notably, GAs in the DDR pathway were detected in both Chinese and Western patients, and regardless of their functional impact, these alterations demonstrated enhanced overall survival rates and higher tumor mutational burden (TMB) levels.
CONCLUSION: These findings underscore the distinct genomic landscape of Chinese AMPAC patients and highlight the potential for targeted therapies based on the identified GAs.
PMID:38439030 | PMC:PMC10910796 | DOI:10.1186/s12885-024-11949-9
BMC Cancer. 2024 Mar 4;24(1):297. doi: 10.1186/s12885-024-12068-1.
ABSTRACT
BACKGROUD: We aimed to develop a novel preoperative nomogram to predict lymph node metastasis (LNM) in perihilar cholangiocarcinoma (pCCA) patients.
METHODS: 160 pCCA patients were enrolled at Lihuili Hospital from July 2006 to May 2022. A novel nomogram model was established to predict LNM in pCCA patients based on the independent predictive factors selected by the multivariate logistic regression model. The precision of the nomogram model was evaluated through internal and external validation with calibration curve statistics and the concordance index (C-index). Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to evaluate and determine the clinical utility of the nomogram.
RESULTS: Multivariate logistic regression demonstrated that age (OR = 0.963, 95% CI: 0.930-0.996, P = 0.030), CA19-9 level (> 559.8 U/mL vs. ≤559.8 U/mL: OR = 3.162, 95% CI: 1.519-6.582, P = 0.002) and tumour diameter (OR = 1.388, 95% CI: 1.083-1.778, P = 0.010) were independent predictive factors of LNM in pCCA patients. The C-index was 0.763 (95% CI: 0.667-0.860) and 0.677 (95% CI: 0.580-0.773) in training cohort and validation cohort, respectively. ROC curve analysis indicated the comparative stability and adequate discriminative ability of nomogram. The sensitivity and specificity were 0.820 and 0.652 in training cohort and 0.704 and 0.649 in validation cohort, respectively. DCA revealed that the nomogram model could augment net benefits in the prediction of LNM in pCCA patients.
CONCLUSIONS: The novel prediction model is useful for predicting LNM in pCCA patients and showed adequate discriminative ability and high predictive accuracy.
PMID:38438912 | PMC:PMC10913359 | DOI:10.1186/s12885-024-12068-1
J Laparoendosc Adv Surg Tech A. 2024 Mar;34(3):207-213. doi: 10.1089/lap.2023.0360. Epub 2024 Feb 22.
ABSTRACT
Objective: To introduce laparoscopic neo-pancreaticogastrostomy (neo-PG) and investigate its application potential in total laparoscopic pancreaticoduodenectomy (TLPD). Materials and Methods: We performed a single-center prospective single-arm trial to evaluate the feasibility and safety of neo-PG for its initial application in TLPD. The first 50 patients who were operated by a single surgeon and who underwent TLPD with neo-PG at our institution were recruited. The pre/intra/postoperation data were collected and analyzed. Results: Twenty-nine male patients and 21 female patients from May 2022 to March 2023 were included. The mean operation time was 272.60 ± 47.30 minutes. The median PG time was 16 (15, 23) minutes. Six patients had delayed gastric emptying (DGE), and all underwent standard LPD. None of the patients had Grade B/C postoperative pancreatic fistula (POPF) or postoperative hemorrhage, or underwent reoperation. The median length of post-LPD hospital stay was 6 (6, 8) days. None of the patients died within 90 days after surgery. Nineteen cases were pathologically classified as pancreatic lesion, 6 cases as bile duct lesion, 18 cases as duodenal lesion, and 7 cases as ampullary lesion. Conclusion: The laparoscopic neo-PG is a simple, safe, and feasible pancreatic anastomosis that can be applied in TLPD. Pylorus-preserving LPD may decrease DGE rate. Further studies involving more surgeons are warranted to prove that our new technique may terminate POPF in TLPD.
PMID:38386987 | DOI:10.1089/lap.2023.0360
Ann Surg Oncol. 2024 Mar 5. doi: 10.1245/s10434-024-15117-y. Online ahead of print.
ABSTRACT
BACKGROUND: There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. Supporting evidence for use comes mainly from the small SWOG S0809 trial, which demonstrated an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer.
METHODS: Using the National Cancer Database, we selected patients from 2004 to 2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival (OS). We examined OS in a cohort of patients mimicking the SWOG S0809 protocol as a large validation cohort. Lastly, we compared patients who received chemotherapy only with patients who received adjuvant chemotherapy and radiation using entropy balancing propensity score matching.
RESULTS: Overall, 4997 patients with gallbladder or extrahepatic bile duct adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected, 469 of whom received both adjuvant chemotherapy and radiotherapy. Median OS in patients undergoing chemoradiation was 36.9 months, and was not different between primary sites (p = 0.841). In a propensity score matched cohort, receipt of adjuvant chemoradiation had a survival benefit compared with adjuvant chemotherapy only (hazard ratio 0.86, 95% confidence interval 0.77-0.95; p = 0.004).
CONCLUSION: Using a large national database, we support the findings of SWOG S0809 with a similar median OS in patients receiving chemoradiation. These data further support the consideration of adjuvant multimodal therapy in resected biliary cancers.
PMID:38443700 | DOI:10.1245/s10434-024-15117-y
Pediatr Transplant. 2024 Mar;28(2):e14732. doi: 10.1111/petr.14732.
ABSTRACT
BACKGROUND: Neuroendocrine tumors (NETs) are rare epithelial neoplasms that arise most commonly from the gastrointestinal tract. In pediatrics, the most common site of origin is in the appendix, with the liver being the most common site of metastasis. Neuroendocrine tumors arising from the biliary tract are extremely rare.
METHODS: We describe a case of a nine-year-old girl who presented with obstructive cholestasis and was found to have multiple liver masses identified on biopsy as well-differentiated neuroendocrine tumor with an unknown primary tumor site.
RESULT: The patient underwent extensive investigation to identify a primary tumor site, including endoscopy, endoscopic ultrasound, and capsule endoscopy. The patient ultimately underwent definitive management with liver transplant, and on explant was discovered to have multiple well-differentiated neuroendocrine tumors, WHO Grade 1, with extensive infiltration into the submucosa of bile duct, consistent with primary biliary tract neuroendocrine tumor.
CONCLUSION: Identifying the site of the primary tumor in NETs found within the liver can be challenging. To determine if an extrahepatic primary tumor exists, workup should include endoscopy, EUS, and capsule endoscopy. Children with well-differentiated hepatic NETs, with no identifiable primary tumor, and an unresectable tumor, are considered favorable candidates for liver transplantation.
PMID:38433619 | DOI:10.1111/petr.14732
Zhonghua Wai Ke Za Zhi. 2024 Mar 1;62(4):265-272. doi: 10.3760/cma.j.cn112139-20240129-00058. Online ahead of print.
ABSTRACT
The incidence of gallbladder cancer has been increasing. Radial resection is still the most promising curable treatment for patients with gallbladder cancer. Although the techniques required for laparoscopic radical resection of gallbladder cancer have matured, the number of reports is also on the rise, and laparoscopic radical resection of gallbladder cancer is still controversial. To standardize laparoscopic radical resection of gallbladder cancer, the Biliary Surgery Branch, Chinese Society of Surgery, Chinese Medical Association, together with the Chinese Medical Doctor Association in Chinese Committee of Biliary Surgeons, gathered experts to formulate recommendations and consensus on laparoscopic radical resection of gallbladder cancer. This consensus includes several parts: safety, preoperative evaluation, indications, surgical team, positioning of patient and trocars, intraoperative frozen examination, lymph node dissection, liver resection,bile duct resection, etc. Furthermore, suggestions on the principle of treatment, surgical procedures, and precautions were also provided for patients with delayed diagnoses of gallbladder cancer undergoing resection. This consensus aims to offer valuable suggestions for the standardization of laparoscopic radical resection of gallbladder cancer.
PMID:38432666 | DOI:10.3760/cma.j.cn112139-20240129-00058
J Hepatol. 2024 Feb 28:S0168-8278(24)00138-7. doi: 10.1016/j.jhep.2024.02.018. Online ahead of print.
ABSTRACT
BACKGROUND & AIMS: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aim to evaluate the role of PTEN in the pathogenesis of eCCA and find novel therapies for this disease.
METHODS: The Pten gene in the biliary epithelial cells were genetically deleted using the Cre-loxp system. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry (IHC), RT-PCR, cell culture, and RNAseq. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. Experimental therapy was tested using an Aurka inhibitor.
RESULTS: We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as one month old. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated the disease progression, potentially through downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expressions of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression.
CONCLUSIONS: Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum through an Aurka-dependent manner. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA.
IMPACT AND IMPLICATIONS: The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition (EMT), cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted the disease progression. This model shall be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis.
PMID:38428643 | DOI:10.1016/j.jhep.2024.02.018
Indian J Gastroenterol. 2024 Mar 1. doi: 10.1007/s12664-024-01518-0. Online ahead of print.
ABSTRACT
Biliary tract cancers are malignant neoplasms arising from bile duct epithelial cells. They include cholangiocarcinomas and gallbladder cancer. Gallbladder cancer has a marked geographical preference and is one of the most common cancers in women in northern India. Biliary tract cancers are usually diagnosed at an advanced, unresectable stage. Hence, the prognosis is extremely dismal. The five-year survival rate in advanced gallbladder cancer is < 5%. Hence, early detection and radical surgery are critical to improving biliary tract cancer prognoses. Radiological imaging plays an essential role in diagnosing and managing biliary tract cancers. However, the diagnosis is challenging because the biliary tract is affected by many diseases that may have radiological appearances similar to cancer. Artificial intelligence (AI) can improve radiologists' performance in various tasks. Deep learning (DL)-based approaches are increasingly incorporated into medical imaging to improve diagnostic performance. This paper reviews the AI-based strategies in biliary tract cancers to improve the diagnosis and prognosis.
PMID:38427281 | DOI:10.1007/s12664-024-01518-0
World J Gastrointest Oncol. 2024 Feb 15;16(2):557-562. doi: 10.4251/wjgo.v16.i2.557.
ABSTRACT
BACKGROUND: Hyperbilirubinemia with hepatic metastases is a common complication and a poor prognostic factor for colorectal cancer (CRC). Effective drainage is often impossible before initiating systemic chemotherapy, owing to the liver's diffuse metastatic involvement. Moreover, an appropriate chemotherapeutic approach for the treatment of hyperbilirubinemia is currently unavailable.
CASE SUMMARY: The patient, a man in his 50s, presented with progressive fatigue and severe jaundice. Computed tomography revealed multiple hepatic masses with thickened walls in the sigmoid colon, which was pathologically confirmed as a well-differentiated adenocarcinoma. No RAS or BRAF mutations were detected. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was 2. Biliary drainage was impossible due to the absence of a dilated bile duct, and panitumumab monotherapy was promptly initiated. Subsequently, the bilirubin level decreased and then normalized, and the patient's PS improved to zero ECOG score after four cycles of therapy without significant adverse events.
CONCLUSION: Anti-EGFR antibody monotherapy is a safe and effective treatment for RAS wild-type CRC and hepatic metastases with severe hyperbilirubinemia.
PMID:38425406 | PMC:PMC10900148 | DOI:10.4251/wjgo.v16.i2.557
Technol Cancer Res Treat. 2024 Jan-Dec;23:15330338241234798. doi: 10.1177/15330338241234798.
ABSTRACT
Objectives: This study aimed to explore the role of inhibin subunit beta A (INHBA) in the progression of cervical cancer (CCa) and investigate its potential as a therapeutic target. Specifically, the objectives were to assess the expression levels of INHBA in CCa, examine its correlation with patient survival, and elucidate its impact on CCa cell proliferation, cell cycle regulation, migration, invasion, and in vivo tumor growth and metastasis. Methods: To achieve the objectives, we conducted a comprehensive set of experimental methods. INHBA expression in CCa was analyzed, and its association with patient survival was assessed using clinical data. In vitro experiments involved the investigation of INHBA's effects on CCa cell proliferation, cell cycle dynamics, migration, and invasion through the epithelial-mesenchymal transition (EMT) process. Additionally, in vivo experiments were performed to evaluate the influence of INHBA on CCa growth and lung metastasis. Results: The results of this study revealed upregulated expression of INHBA in CCa, with a significant association between high INHBA expression and poor patient survival. Functionally, INHBA was found to promote the proliferation of CCa cells, regulate the cell cycle, and enhance migration and invasion through the EMT process in vitro. Moreover, in vivo experiments demonstrated that INHBA facilitated the growth and lung metastasis of CCa. Conclusion: In conclusion, our findings suggest that INHBA plays a crucial role in the progression of cervical cancer. The upregulation of INHBA is associated with poor patient survival, and its involvement in promoting key aspects of cancer progression makes it a potential therapeutic target for CCa treatment. These results provide valuable insights into the molecular mechanisms underlying CCa and offer a foundation for further exploration of targeted therapeutic interventions.
PMID:38419562 | PMC:PMC10903216 | DOI:10.1177/15330338241234798
PLoS Negl Trop Dis. 2024 Feb 29;18(2):e0011362. doi: 10.1371/journal.pntd.0011362. eCollection 2024 Feb.
ABSTRACT
Opisthorchis viverrini is a parasitic liver fluke contracted by consumption of raw fish, which affects over 10 million people in Southeast Asia despite sustained control efforts. Chronic infections are a risk factor for the often fatal bile duct cancer, cholangiocarcinoma. Previous modeling predicted rapid elimination of O. viverrini following yearly mass drug administration (MDA) campaigns. However, field data collected in affected populations shows persistence of infection, including heavy worm burden, after many years of repeated interventions. A plausible explanation for this observation is systematic adherence of individuals in health campaigns, such as MDA and education, with some individuals consistently missing treatment. We developed an agent-based model of O. viverrini which allows us to introduce various heterogeneities including systematic adherence to MDA and education campaigns at the individual level. We validate the agent-based model by comparing it to a previously published population-based model. We estimate the degree of systematic adherence to MDA and education campaigns indirectly, using epidemiological data collected in Lao PDR before and after 5 years of repeated MDA, education and sanitation improvement campaigns. We predict the impact of interventions deployed singly and in combination, with and without the estimated systematic adherence. We show how systematic adherence can substantially increase the time required to achieve reductions in worm burden. However, we predict that yearly MDA campaigns alone can result in a strong reduction of moderate and heavy worm burden, even under systematic adherence. We predict latrines and education campaigns to be particularly important for the reduction in overall prevalence, and therefore, ultimately, elimination. Our findings show how systematic adherence can explain the observed persistence of worm burden; while emphasizing the benefit of interventions for the entire population, even under systematic adherence. At the same time, the results highlight the substantial opportunity to further reduce worm burden if patterns of systematic adherence can be overcome.
PMID:38422118 | PMC:PMC10931503 | DOI:10.1371/journal.pntd.0011362
Clin Endosc. 2024 Feb 29. doi: 10.5946/ce.2023.271. Online ahead of print.
ABSTRACT
Therapeutic endoscopic ultrasonography (EUS) procedures using the forward-viewing convex EUS (FV-EUS) have been reviewed based on the articles reported to date. The earliest reported procedure is the drainage of pancreatic pseudocysts using FV-EUS. However, the study on drainage of pancreatic pseudocysts focused on showing that drainage is possible with FV-EUS rather than leveraging its features. Subsequently, studies describing the characteristics of FV-EUS have been reported. By using FV-EUS in EUS-guided choledochoduodenostomy, double punctures in the gastrointestinal tract can be avoided. In postoperative modified anatomical cases, using the endoscopic function of FV-EUS, procedures such as bile duct drainage from anastomosis, pancreatic duct drainage from the afferent limb, and abscess drainage from the digestive tract have been reported. When a perpendicular puncture to the gastrointestinal tract is required or when there is a need to insert the endoscope deep into the gastrointestinal tract, FV-EUS is considered among the options.
PMID:38419166 | DOI:10.5946/ce.2023.271
Dis Model Mech. 2024 Jun 1;17(6):dmm050358. doi: 10.1242/dmm.050358. Epub 2024 Feb 28.
ABSTRACT
Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA - including Kras, Tp53, Arid1a and Smad4 - as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFβ/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.
PMID:38415925 | PMC:PMC10924230 | DOI:10.1242/dmm.050358
Asian Pac J Cancer Prev. 2024 Feb 1;25(2):537-546. doi: 10.31557/APJCP.2024.25.2.537.
ABSTRACT
BACKGROUND: Cholangiocarcinoma (CCA) is experiencing a global increase, particularly in Northeast Thailand, which has the highest global incidence rates. However, there is a paucity of studies on CCA screening, especially in high-risk populations. This study aimed to investigate the distribution and spatial patterns of CCA in Northeast Thailand over a ten-year screening period.
METHODS: The study included CCA patients from the Cholangiocarcinoma Screening and Care Program (CASCAP) between 2013 and 2022, which encompasses 20 provinces and 282 districts in Northeast of Thailand. CCA data were based on pathological diagnosis to determine the distribution and spatial patterns.
RESULTS: Of the 2,515 CCA patients, approximately two-thirds were males (63.98%), and the majority were aged over 55 years (72.72%), with a mean age of 61.12 ± 9.13 years. The highest percentage of CCA cases occurred in 2014 at 19.01% of all patients, followed by 2018 at 15.23%. The overall CCA incidence rate in Northeast Thailand over ten years was 32 per 100,000 population. Hotspot statistical analysis identified high-scoring geographic clusters in the upper and middle regions, showing a tendency to expand from hotspot areas into nearby areas.
CONCLUSION: The distribution of CCA in Northeast Thailand has continued to rise over the past decade, particularly in the upper and middle regions. Targeted screening in high-risk areas and increased awareness of CCA risks are crucial to mitigate its impact.
PMID:38415540 | DOI:10.31557/APJCP.2024.25.2.537
Korean J Radiol. 2024 Mar;25(3):243-256. doi: 10.3348/kjr.2023.0295.
ABSTRACT
OBJECTIVE: We aimed to investigate whether 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) can aid in evaluating the risk of malignancy in ampullary tumors detected by endoscopy.
MATERIALS AND METHODS: This single-center retrospective cohort study analyzed 155 patients (79 male, 76 female; mean age, 65.7 ± 12.7 years) receiving 2-[18F]FDG PET/CT for endoscopy-detected ampullary tumors 5-87 days (median, 7 days) after the diagnostic endoscopy between June 2007 and December 2020. The final diagnosis was made based on histopathological findings. The PET imaging parameters were compared with clinical data and endoscopic features. A model to predict the risk of malignancy, based on PET, endoscopy, and clinical findings, was generated and validated using multivariable logistic regression analysis and an additional bootstrapping method. The final model was compared with standard endoscopy for the diagnosis of ampullary cancer using the DeLong test.
RESULTS: The mean tumor size was 17.1 ± 7.7 mm. Sixty-four (41.3%) tumors were benign, and 91 (58.7%) were malignant. Univariable analysis found that ampullary neoplasms with a blood-pool corrected peak standardized uptake value in early-phase scan (SUVe) ≥ 1.7 were more likely to be malignant (odds ratio [OR], 16.06; 95% confidence interval [CI], 7.13-36.18; P < 0.001). Multivariable analysis identified the presence of jaundice (adjusted OR [aOR], 4.89; 95% CI, 1.80-13.33; P = 0.002), malignant traits in endoscopy (aOR, 6.80; 95% CI, 2.41-19.20; P < 0.001), SUVe ≥ 1.7 in PET (aOR, 5.43; 95% CI, 2.00-14.72; P < 0.001), and PET-detected nodal disease (aOR, 5.03; 95% CI, 1.16-21.86; P = 0.041) as independent predictors of malignancy. The model combining these four factors predicted ampullary cancers better than endoscopic diagnosis alone (area under the curve [AUC] and 95% CI: 0.925 [0.874-0.956] vs. 0.815 [0.732-0.873], P < 0.001). The model demonstrated an AUC of 0.921 (95% CI, 0.816-0.967) in candidates for endoscopic papillectomy.
CONCLUSION: Adding 2-[18F]FDG PET/CT to endoscopy can improve the diagnosis of ampullary cancer and may help refine therapeutic decision-making, particularly when contemplating endoscopic papillectomy.
PMID:38413109 | PMC:PMC10912498 | DOI:10.3348/kjr.2023.0295
World J Clin Cases. 2024 Feb 16;12(5):913-921. doi: 10.12998/wjcc.v12.i5.913.
ABSTRACT
BACKGROUND: Intrahepatic duct (IHD) stones are among the most important risk factors for cholangiocarcinoma (CCC). Approximately 10% of patients with IHD stones develop CCC; however, there are limited studies regarding the effect of IHD stone removal on CCC development.
AIM: To investigate the association between IHD stone removal and CCC development.
METHODS: We retrospectively analyzed 397 patients with IHD stones at a tertiary referral center between January 2011 and December 2020.
RESULTS: CCC occurred in 36 of the 397 enrolled patients. In univariate analysis, chronic hepatitis B infection (11.1% vs 3.0%, P = 0.03), carbohydrate antigen 19-9 (CA19-9, 176.00 vs 11.96 II/mL, P = 0.010), stone located in left or both lobes (86.1% vs 70.1%, P = 0.042), focal atrophy (52.8% vs 26.9%, P = 0.001), duct stricture (47.2% vs 24.9%, P = 0.004), and removal status of IHD stone (33.3% vs 63.2%, P < 0.001) were significantly different between IHD stone patients with and without CCC. In the multivariate analysis, CA19-9 > upper normal limit, carcinoembryonic antigen > upper normal limit, stones located in the left or both lobes, focal atrophy, and complete removal of IHD stones without recurrence were independent factors influencing CCC development. However, the type of removal method was not associated with CCC risk.
CONCLUSION: Complete removal of IHD stones without recurrence could reduce CCC risk.
PMID:38414601 | PMC:PMC10895623 | DOI:10.12998/wjcc.v12.i5.913
Gut Liver. 2024 Mar 15;18(2):358-364. doi: 10.5009/gnl230163. Epub 2024 Feb 27.
ABSTRACT
BACKGROUND/AIMS: : Peroral cholangioscopy (POC) has been used to assess intrahepatic duct (IHD) lesions but with a limited role. A new multibending (MB) ultraslim endoscope has been designed to improve POC performance. We evaluated the usefulness of POC using the MB ultraslim endoscope for the management of IHD lesions.
METHODS: : Between March 2017 and March 2020, 22 patients underwent direct POC using the MB ultraslim endoscope for IHD lesions documented by previous imaging or cholangiopancreatography. The primary outcome was technical success of POC, and secondary outcomes were technical success of POC-guided interventions, median procedure time, and POC-related adverse events.
RESULTS: : The technical success rate for POC using the MB ultraslim endoscope for IHD lesions was 95.5% (21/22). Free-hand insertion was successful in 95.2% (20/21). The overall technical success rate for POC-guided intervention was 100% (21/21), including nine diagnostic and 12 therapeutic procedures (eight direct stone removal and four intraductal lithotripsies). The median procedure time was 29 minutes (range, 9 to 79 minutes). There were no procedure-related adverse events.
CONCLUSIONS: : Direct POC using the MB ultraslim endoscope allows direct visualization of IHD lesions and may be useful for diagnosis and therapeutic management in selected patients.
PMID:38409663 | PMC:PMC10938146 | DOI:10.5009/gnl230163
Langenbecks Arch Surg. 2024 Feb 27;409(1):75. doi: 10.1007/s00423-024-03267-2.
ABSTRACT
PURPOSE: Cholelithiasis occurs often after gastrectomy. However, no consensus has been established regarding the difference in the incidence of postgastrectomy cholelithiasis with different reconstruction methods. In this study, we examined the frequency of cholelithiasis after two major reconstruction methods, namely Billroth-I (B-I) and Roux-en-Y (R-Y) following laparoscopic distal gastrectomy (LDG) for gastric cancer.
METHODS: Among 696 gastric cancer patients who underwent LDG between April 2000 and March 2017, after applying the exclusion criteria, 284 patients who underwent B-I and 310 who underwent R-Y were examined retrospectively. The estimated incidence of cholelithiasis was compared between the methods, and factors associated with the development of cholelithiasis in the gallbladder and/or common bile duct were investigated.
RESULTS: During the median follow-up of 61.2 months, 52 patients (8.8%) developed cholelithiasis postgastrectomy; 12 patients (4.2%) after B-I and 40 (12.9%) after R-Y (p = 0.0002). Among them, choledocholithiasis was more frequent in patients who underwent R-Y (n = 11, 27.5%) vs. B-I (n = 1, 8.3%) (p = 0.0056). Univariate and multivariate analyses revealed that male sex, body mass index > 22.5 kg/m2, and R-Y reconstruction were significant predictors of the development of postLDG cholelithiasis.
CONCLUSION: Regarding cholelithiasis development, B-I reconstruction should be preferred whenever possible during distal gastrectomy.
PMID:38409456 | DOI:10.1007/s00423-024-03267-2
J Vis Exp. 2024 Feb 9;(204). doi: 10.3791/66251.
ABSTRACT
Minimally invasive pancreatic resections are gaining popularity despite being technically demanding. However, in contrast to laparoscopic pancreatoduodenectomy (LPD), laparoscopic duodenum-preserving pancreatic head resection (LDPPHR) has not yet obtained wide acceptance. This could be attributed to the technical challenges involved in preserving the blood supply of the duodenum and bile duct. This study describes and demonstrates all the steps of LDPPHR. A 48-year-old woman was diagnosed with a 3.0 cm x 2.5 cm pancreatic head cystic mass, which was detected unexpectedly. The surgery was performed using the 3D laparoscopy via an inferior infracolic approach. The operation lasted approximately 310 min with 100 mL of blood loss. Postoperatively, the patient experienced no complications and was discharged 5 days later. Pathology revealed intraductal papillary mucinous neoplasms. LDPPHR via an inferior infracolic approach is feasible and safe when performed by experienced surgeons in selected patients with thin mesenteric fat layers. The described technique for LDPPHR via inferior infracolic approach should be well standardized and performed at high-volume centers with experienced surgeons in both open and laparoscopic pancreatology.
PMID:38407329 | DOI:10.3791/66251
Cureus. 2024 Jan 25;16(1):e52951. doi: 10.7759/cureus.52951. eCollection 2024 Jan.
ABSTRACT
Humoral hypercalcemia of malignancy (HHM) is often reported in cancers derived from the squamous epithelium; however, there are very few reports of HHM in patients with gallbladder cancer. We report a case of a parathyroid hormone-related protein (PTHrP)-producing gallbladder cancer presenting with HHM. A 43-year-old woman presented with appetite loss, nausea, and brown-colored urine. Blood tests revealed that she had hypercalcemia, high serum bilirubin, and high serum parathyroid hormone. Contrast-enhanced computed tomography revealed a gallbladder tumor, liver metastasis, and bile duct obstruction caused by the gallbladder tumor in the hilar region. No bone metastasis was observed. Endoscopic retrograde cholangiopancreatography revealed pancreaticobiliary maljunction. Metal biliary stents were placed, and a transpapillary biopsy of the gallbladder tumor revealed a pathological diagnosis of adenocarcinoma. The patient was diagnosed with HHM due to gallbladder cancer with liver metastasis. Although her hypercalcemia and jaundice improved, her appetite loss and nausea did not improve. Subsequently, the patient developed disseminated intravascular coagulation, and her general condition gradually deteriorated. Due to her poor general condition, chemotherapy could not be administered. The patient died six weeks after visiting our hospital. Although rare, some gallbladder cancers cause HHM due to PTHrP production.
PMID:38406045 | PMC:PMC10894057 | DOI:10.7759/cureus.52951
Front Immunol. 2024 Feb 8;15:1339207. doi: 10.3389/fimmu.2024.1339207. eCollection 2024.
ABSTRACT
BACKGROUND: Previous studies have reported associations of Crohn's disease (CD) and ulcerative colitis (UC) with the risks of extraintestinal cancers, but the causality remains unclear.
METHODS: Using genetic variations robustly associated with CD and UC extracted from genome-wide association studies (GWAS) as instrumental variables. Nine types of extraintestinal cancers of European and Asian populations were selected as outcomes. We used the inverse variance weighted method as the primary approach for two-sample Mendelian randomization analysis. Sensitivity analyses were carried out to evaluate the reliability of our findings.
RESULTS: In the European population, we found that CD showed a potential causal relationship with pancreatic cancer (OR: 1.1042; 95% CI: 1.0087-1.2088; P=0.0318). Meanwhile, both CD (outliers excluded: OR: 1.0208; 95% CI: 1.0079-1.0339; P=0.0015) and UC (outliers excluded: OR: 1.0220; 95% CI: 1.0051-1.0393; P=0.0108) were associated with a slight increase in breast cancer risk. Additionally, UC exhibited a potential causal effect on cervical cancer (outliers excluded: OR: 1.1091; 95% CI: 1.0286-1.1960; P=0.0071). In the East Asian population, CD had significant causal effects on pancreatic cancer (OR: 1.1876; 95% CI: 1.0741-1.3132; P=0.0008) and breast cancer (outliers excluded: OR: 0.9452; 95% CI: 0.9096-0.9822; P=0.0040). For UC, it exhibited significant causal associations with gastric cancer (OR: 1.1240; 95% CI: 1.0624-1.1891; P=4.7359×10-5), bile duct cancer (OR: 1.3107; 95% CI: 1.0983-1.5641; P=0.0027), hepatocellular carcinoma (OR: 1.2365; 95% CI: 1.1235-1.3608; P=1.4007×10-5) and cervical cancer (OR: 1.3941; 95% CI: 1.1708-1.6599; P=0.0002), as well as a potential causal effect on lung cancer (outliers excluded: OR: 1.1313; 95% CI: 1.0280-1.2449; P=0.0116).
CONCLUSIONS: Our study provided evidence that genetically predicted CD may be a risk factor for pancreatic and breast cancers in the European population, and for pancreatic cancer in the East Asian population. Regarding UC, it may be a risk factor for cervical and breast cancers in Europeans, and for gastric, bile duct, hepatocellular, lung, and cervical cancers in East Asians. Therefore, patients with CD and UC need to emphasize screening and prevention of site-specific extraintestinal cancers.
PMID:38404590 | PMC:PMC10885353 | DOI:10.3389/fimmu.2024.1339207
Sci Rep. 2024 Feb 23;14(1):4466. doi: 10.1038/s41598-024-53883-7.
ABSTRACT
Prognostic features in advanced perihilar cholangiocarcinoma (pCCA) patients who received first-line hepatic arterial infusion chemotherapy (HAIC) are unknown. The purpose of our study was to develop an applicable score based on serum inflammatory-tumor biomarkers to predict the survival of advanced pCCA patients who received first-line HAIC. In total, 106 advanced pCCA patients were enrolled as the training cohort. The optimal cutoff values of baseline variables were defined by the receiver operating characteristic method or according to previous publications. According to the results of Cox regression analysis, baseline neutrophil-to-lymphocyte ratio (NLR) > 3.19, carcinoembryonic antigen (CEA) > 10 ng/mL, and carbohydrate antigen 19-9 (CA19-9) > 200 U/mL were identified as independent survival predictors, which were used to develop the NLCECA score (NLR, CEA, and CA19-9). When including the NLCECA score in the multivariate analysis, the NLCECA score was the only independent predictor of survival. The risk of survival decreased by 111.9% for each 1-point increase in the NLCECA score. Additionally, the NLCECA score could also predict survival in another 33 patients in the validation cohort (P < 0.001). In summary, the NLCECA score is a potential biomarker system for predicting the survival of advanced pCCA patients who received first-line HAIC.
PMID:38395994 | PMC:PMC10891088 | DOI:10.1038/s41598-024-53883-7
Biol Direct. 2024 Feb 23;19(1):16. doi: 10.1186/s13062-024-00453-6.
ABSTRACT
BACKGROUND: Cholangiocarcinoma (CCA) is a biliary epithelial malignant tumor with an increasing incidence worldwide. Therefore, further understanding of the molecular mechanisms of CCA progression is required to identify new therapeutic targets.
METHODS: The expression of RPL35A in CCA and para-carcinoma tissues was detected by immunohistochemical staining. IP-MS combined with Co-IP identified downstream proteins regulated by RPL35A. Western blot and Co-IP of CHX or MG-132 treated CCA cells were used to verify the regulation of HSPA8 protein by RPL35A. Cell experiments and subcutaneous tumorigenesis experiments in nude mice were performed to evaluate the effects of RPL35A and HSPA8 on the proliferation, apoptosis, cell cycle, migration of CCA cells and tumor growth in vivo.
RESULTS: RPL35A was significantly upregulated in CCA tissues and cells. RPL35A knockdown inhibited the proliferation and migration of HCCC-9810 and HUCCT1 cells, induced apoptosis, and arrested the cell cycle in G1 phase. HSPA8 was a downstream protein of RPL35A and overexpressed in CCA. RPL35A knockdown impaired HSPA8 protein stability and increased HSPA8 protein ubiquitination levels. RPL35A overexpression promoted CCA cell proliferation and migration. HSPA8 knockdown inhibited CCA cell proliferation and migration, and reversed the promoting effect of RPL35A. Furthermore, RPL35A promoted tumor growth in vivo. In contrast, HSPA8 knockdown suppressed tumor growth, while was able to restore the effects of RPL35A overexpression.
CONCLUSION: RPL35A was upregulated in CCA tissues and promoted the progression of CCA by mediating HSPA8 ubiquitination.
PMID:38395908 | PMC:PMC10885515 | DOI:10.1186/s13062-024-00453-6
JCO Precis Oncol. 2024 Feb;8:e2300534. doi: 10.1200/PO.23.00534.
ABSTRACT
PURPOSE: Intrahepatic cholangiocarcinoma (ICCA) is characterized by significant phenotypic and clinical heterogeneities and poor response to systemic therapy, potentially related to underlying heterogeneity in oncogenic alterations. We aimed to characterize the genomic heterogeneity between primary tumors and advanced disease in patients with ICCA.
METHODS: Biopsy-proven CCA specimens (primary tumor and paired advanced disease [metastatic disease, progressive disease on systemic therapy, or postoperative recurrence]) from two institutions were subjected to targeted next-generation sequencing. Overall concordance (oncogenic driver mutations, copy number alterations, and fusion events) and mutational concordance (only oncogenic mutations) were compared across paired samples. A subgroup analysis was performed on the basis of exposure to systemic therapy. Patients with extrahepatic CCA (ECCA) were included as a comparison group.
RESULTS: Sample pairs from 65 patients with ICCA (n = 54) and ECCA (n = 11) were analyzed. The median time between sample collection was 19.6 months (range, 2.7-122.9). For the entire cohort, the overall oncogenic concordance was 49% and the mutational concordance was 62% between primary and advanced disease samples. Subgroup analyses of ICCA and ECCA revealed overall/mutational concordance rates of 47%/58% and 60%/84%, respectively. Oncogenic concordance was similarly low for pairs exposed to systemic therapy between sample collections (n = 50, 53% overall, 68% mutational). In patients treated with targeted therapy for IDH1/2 alterations (n = 6) or FGFR2 fusions (n = 3), there was 100% concordance between the primary and advanced disease specimens. In two patients, FGFR2 (n = 1) and IDH1 (n = 1) alterations were detected de novo in the advanced disease specimens.
CONCLUSION: The results reflect a high degree of heterogeneity in ICCA and argue for reassessment of the dominant driver mutations with change in disease status.
PMID:38394469 | PMC:PMC10901433 | DOI:10.1200/PO.23.00534
Curr Med Imaging. 2024;20:1-8. doi: 10.2174/0115734056253270231117113002.
ABSTRACT
BACKGROUND: Extrahepatic cholangiocarcinoma (EHCC), an exceedingly malignant neoplasm, often eludes early detection, culminating in a dire prognosis. Accurate cancer staging systems and pathological differentiation are designed to guide adjuvant interventions and predict postoperative prognoses.
OBJECTIVE: This study sought to investigate the predictive capacity of DW-MRI in discerning T stages, lymph node metastasis, and pathological differentiation grades in patients with EHCC.
METHODS: Eighty-five patients were pathologically diagnosed with EHCC and underwent abdominal MRI within two weeks before surgery at our hospital from Aug 2011 to Aug 2021. Tumor axial maximum area (AMA) and apparent diffusion coefficient (ADC) values for diverse T stages, N stages, and differentiation grades were retrospectively analyzed.
RESULTS: The Mann-Whitney U test displayed significantly higher lesion AMA values (P =0.006) and lower tumor ADC values (P = 0.001) in the nodepositive group (median ADC and AMA value: 1.220×10-3 mm2/s, 82.231 mm2) than in the node-negative group (median ADC and AMA value: 1.316×10-3 mm2/s, 51.174 mm2). A tumor ADC value<1.249×10-3 mm2/s from the receiver operating characteristic curve (AUC=0.725, P=0.001) exhibited the capability to predict node-positive EHCC with a sensitivity of 64.29%, and specificity of 73.68%. Furthermore, a progressive decrease in the degree of EHCC differentiation was associated with a reduction in the tumor ADC value (P=0.000).
CONCLUSION: The N stage and differentiation of EHCC can be evaluated non-invasively using diffusion-weighted MRI.
PMID:38389346 | DOI:10.2174/0115734056253270231117113002
Intern Med. 2024 Feb 26. doi: 10.2169/internalmedicine.3178-23. Online ahead of print.
ABSTRACT
A 70-year-old woman presented with stage III pancreatic head cancer. After endoscopic sphincterotomy, a fully covered self-expandable metallic stent (FCSEMS) was placed in the common bile duct to manage jaundice. The patient developed a fever and abdominal pain 40 days after stent placement, with a suspected diagnosis of infected pancreatic pseudocyst. Purulent discharge from the papilla was observed during FCSEMS removal, and pancreatography revealed a pseudocyst connected to the main pancreatic duct. The pancreatic pseudocyst resolved after transpapillary drainage. Pancreatic pseudocysts should be suspected after biliary FCSEMS placement, and prompt removal and endoscopic drainage of the FCSEMS should be considered.
PMID:38403761 | DOI:10.2169/internalmedicine.3178-23
Radiol Case Rep. 2024 Feb 17;19(5):1781-1790. doi: 10.1016/j.radcr.2024.01.068. eCollection 2024 May.
ABSTRACT
This case report presents a 62-year-old male who had previously undergone curative colectomy and neoadjuvant chemotherapy in 2005 for colorectal cancer. He presented with jaundice, which was initially attributed to choledocholithiasis. After cholecystectomy and repeat ERCPs, hyperbilirubinemia persisted. There was persistent dilation of the right posterior duct on imaging, concerning for biliary stricture, possibly due to cholangiocarcinoma or intraductal papillary neoplasm. During a right posterior hepatectomy, a peripheral liver lesion was found in association with the dilated bile duct. On frozen evaluation, the lesion was found to be invasive adenocarcinoma. The final pathology was compatible with a metastatic mucinous adenocarcinoma of colonic origin. A repeat colonoscopy was done with no recurrence or new lesion in the colon. This case underscores the challenges associated with diagnosing biliary issues and assessing liver lesions in patients with a remote history of cancer. It raises the question of when and whether, after primary cancer treatment, it becomes safe to explore alternative diagnoses without immediately suspecting metastasis. Another significant challenge arises in ascertaining the most suitable therapeutic approaches for these patients. This is because these extremely late recurrences might be linked to an indolent, slow-growing type of tumor, but also have been linked to cancer stem cells, and as any recurrence, demands attention.
PMID:38390428 | PMC:PMC10883780 | DOI:10.1016/j.radcr.2024.01.068
Cancer Immunol Immunother. 2024 Feb 22;73(3):58. doi: 10.1007/s00262-023-03609-x.
ABSTRACT
B cells possess anti-tumor functions mediated by granzyme B, in addition to their role in antigen presentation and antibody production. However, the variations in granzyme B+ B cells between tumor and non-tumor tissues have been largely unexplored. Therefore, we integrated 25 samples from the Gene Expression Omnibus database and analyzed the tumor immune microenvironment. The findings uncovered significant inter- and intra-tumoral heterogeneity. Notably, single-cell data showed higher proportions of granzyme B+ B cells in tumor samples compared to control samples, and these levels were positively associated with disease-free survival. The elevated levels of granzyme B+ B cells in tumor samples resulted from tumor cell chemotaxis through the MIF- (CD74 + CXCR4) signaling pathway. Furthermore, the anti-tumor function of granzyme B+ B cells in tumor samples was adversely affected, potentially providing an explanation for tumor progression. These findings regarding granzyme B+ B cells were further validated in an independent clinic cohort of 40 liver transplant recipients with intrahepatic cholangiocarcinoma. Our study unveils an interaction between granzyme B+ B cells and intrahepatic cholangiocarcinoma, opening up potential avenues for the development of novel therapeutic strategies against this disease.
PMID:38386050 | PMC:PMC10884120 | DOI:10.1007/s00262-023-03609-x
Int J Biol Sci. 2024 Feb 4;20(4):1492-1508. doi: 10.7150/ijbs.90774. eCollection 2024.
ABSTRACT
Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in cholangiocarcinoma (CCA) has not been explored. Herein, based on The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) databases, we found that ubiquitin-specific protease 21 (USP21) was upregulated in CCA, high USP21 level was associated with poor prognosis. In vivo and in vitro, we identified USP21 as a master regulator of CCA growth and maintenance, which directly interacted with deubiquitinates and stabilized the heat shock protein 90 (HSP90) through K48-linked deubiquitination, and in turn, this stabilization increased HIF1A expression, thus upregulating key glycolytic enzyme genes ENO2, ENO3, ALDOC, ACSS2, and then promoted aerobic glycolysis, which provided energy for CCA cell proliferation. In addition, USP21 could directly stabilize alpha-Enolase 1 (ENO1) to promote aerobic glycolysis. Furthermore, increased USP21 level enhanced chemotherapy resistance to the gemcitabine-based regimen. Taken together, we identify a USP21-regulated aerobic glycolysis mechanism that involves the USP21/HSP90/HIF1A axis and USP21/ENO1 axis in CCA tumorigenesis, which could serve as a potential target for the treatment of CCA.
PMID:38385089 | PMC:PMC10878141 | DOI:10.7150/ijbs.90774
Front Immunol. 2024 Feb 7;15:1260191. doi: 10.3389/fimmu.2024.1260191. eCollection 2024.
ABSTRACT
BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with a dismal prognosis and few effective therapeutic approaches. This study aimed to investigate the efficacy, safety, and predictive biomarkers of hepatic arterial infusion chemotherapy (FOLFOX-HAIC) in combination with lenvatinib and PD-1 inhibitor for patients with advanced iCCA.
METHODS: Locally advanced or metastatic iCCA patients receiving the triple combination therapy of lenvatinib, PD-1 inhibitor, and FOLFOX-HAIC were included in this retrospective study. Primary endpoint was the progression-free survival, evaluated using the RECIST criterion. The secondary endpoints included overall survival, objective response rate, and safety. Whole exome and RNA sequencing of tumor biopsy tissues were performed for biomarker exploration.
RESULTS: Between May, 2019 and December 2022, a total of 46 patients were included in this study. The primary endpoint showed a median progression-free survival of 9.40 months (95% CI: 5.28-13.52), with a 6-month progression-free survival rate of 76.1%. The median overall survival was 16.77 months (95% CI, 14.20-19.33), with an objective response rate of 47.8% and disease control rate of 91.3% per RECIST. In addition, 4.3% and 8.7% of patients achieved complete response of all lesions and intrahepatic target lesions per mRECIST, respectively. The most common treatment-related adverse events were neutropenia, thrombocytopenia, elevated aspartate aminotransferase and alanine aminotransferase level. Furthermore, integrated analysis of genetic, transcriptomic, and immunohistochemistry data revealed that pre-existing immunity (high expression level of immune-related signatures and intra-tumoral CD8+ T cell density) in baseline tumor tissues was associated with superior clinical benefits. However, the evaluation of tumor mutation burden did not show potential predictive value in this triple combination.
CONCLUSION: FOLFOX-HAIC in combination with lenvatinib and PD-1 inhibitor demonstrated a promising antitumor activity with manageable safety profiles in patients with advanced iCCA. Moreover, our study also revealed new perspectives on potential biomarkers for clinical efficacy.
PMID:38384459 | PMC:PMC10880187 | DOI:10.3389/fimmu.2024.1260191
Eur J Cancer. 2024 Mar;200:113587. doi: 10.1016/j.ejca.2024.113587. Epub 2024 Feb 6.
ABSTRACT
BACKGROUND: Pemigatinib is approved for patients with pretreated, locally advanced or metastatic CCA harboring FGFR2 rearrangements or fusions. We aim to assess the effectiveness and safety of pemigatinib in real-world setting.
MATERIAL AND METHODS: A joint analysis of two multicentre observational retrospective cohort studies independently conducted in France and Italy was performed. All consecutive FGFR2-positive patients affected by CCA and treated with pemigatinib as second- or further line of systemic treatment in clinical practice, within or outside the European Expanded Access Program, were included.
RESULTS: Between July 2020 and September 2022, 72 patients were treated with pemigatinib in 14 Italian and 25 French Centres. Patients had a median age of 57 years, 76% were female, 81% had ECOG-PS 0-1, 99% had intrahepatic CCA, 74% had ≥ 2 metastatic sites, 67% had metastatic disease at diagnosis, while 38.8% received ≥ 2 previous lines of systemic treatment. At data cut-off analysis (April 2023), ORR and DCR were 45.8% and 84.7%, respectively. Median DoR was 7 months (IQR: 5.8-9.3). Over a median follow-up time of 19.5 months, median PFS and 1-year PFS rate were 8.7 months and 32.8%. Median OS and 1-year OS rate were 17.1 months and 60.6%. Fatigue (69.4%), ocular toxicity (68%), nail toxicities (61.1%), dermatologic toxicity (41.6%) hyperphosphataemia (55.6%), stomatitis (48.6%), and diarrhea (36.1%) were the most frequent, mainly G1-G2 AEs. Overall incidence of G3 AEs was 22.2%, while no patient experienced G4 AE. Dose reduction and temporary discontinuation were needed in 33.3% and 40.3% of cases, with 1 permanent discontinuation due to AEs.
CONCLUSIONS: These results confirm the effectiveness and safety of pemigatinib in a real-world setting.
PMID:38340384 | DOI:10.1016/j.ejca.2024.113587
Int J Clin Oncol. 2024 Mar;29(3):297-308. doi: 10.1007/s10147-023-02466-z. Epub 2024 Feb 6.
ABSTRACT
BACKGROUND: Studies have demonstrated a prognostic role of sarcopenia (i.e., loss of skeletal muscle volume and functionality) in patients with various cancer types. In patients with biliary tract cancer, the quantity and quality of skeletal muscles and their serial changes have not been fully investigated in relation to survival outcomes.
METHODS: We identified 386 patients with unresectable or recurrent biliary tract cancer and calculated skeletal muscle index (SMI) and skeletal muscle density (SMD) to estimate muscular quantity and quality, respectively, based on computed tomography images. Using the Cox regression model with adjustment for potential confounders, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) according to skeletal muscle status and its serial change.
RESULTS: Compared to patients without sarcopenia, patients with sarcopenia were associated with shorter PFS (multivariable HR, 1.60; 95% CI, 1.15-2.22; P = 0.005), but not with OS (P = 0.027) at the adjusted α level of 0.013. SMD at baseline was associated with OS (multivariable HR comparing the extreme quartiles, 1.52; 95% CI, 1.07-2.14; Ptrend = 0.012), but not with PFS (Ptrend = 0.13). A reduction in SMI rather than that in SMD was associated with OS. Progressive disease was a risk factor for reductions in SMI and SMD.
CONCLUSIONS: Skeletal muscle quantity and quality and their serial changes were associated with survival outcomes in patients with advanced biliary tract cancer. Our data highlight the importance of designing nutritional and physical interventions for improvements in skeletal muscle status.
PMID:38319509 | PMC:PMC10884055 | DOI:10.1007/s10147-023-02466-z
Medicine (Baltimore). 2024 Feb 23;103(8):e37187. doi: 10.1097/MD.0000000000037187.
ABSTRACT
The improvement of digestive cancer survival results in increased morbidity of noncancerous comorbidities. This study aimed at clarifying causes of death (COD) and predicting overall survival (OS) in patients diagnosed with liver cancer, gallbladder cancer, cholangiocarcinoma, and pancreatic cancer. We used the Surveillance, Epidemic, and End Results database to extract information. Nomograms of multivariate Cox regression was used to predict OS of cancer patients. The models were evaluated using the concordance indexes (C-indexes), the receiver operating characteristic curves and calibration curves. Respectively 58,895, 15,324, 30,708, and 109,995 cases with cancer of liver, gallbladder, bile duct or pancreas were retrieved between 2000 and 2020. Approximately 80% deaths occurred within 1 years after cancer diagnosis. Sequence in noncancerous COD proportion was diverse, while diseases of heart always accounted for a great part. Risks of death from most noncancerous COD were significantly higher than that of the cancer-free population. Nomograms were developed by predictors of interest such as age, therapy and TNM stage. The concordance indexes of nomograms were 0.756, 0.729, 0.763, and 0.760 respectively, well-calibrating to the reality. The 0.5-, 1-, and 2-year areas under the receiver operating characteristic curve were about 0.800, indicating good reliability and accuracy. Noncancerous COD accounted for larger part in gallbladder cancer and cholangiocarcinoma. Noncancerous COD showed an upward trend as follow-up time extended and the majorities were diseases of heart, cerebrovascular disease, chronic liver disease and cirrhosis. The novel OS-nomograms can provide personalized prognosis information with satisfactory accuracy.
PMID:38394524 | DOI:10.1097/MD.0000000000037187
Eur J Radiol Open. 2024 Feb 16;12:100554. doi: 10.1016/j.ejro.2024.100554. eCollection 2024 Jun.
ABSTRACT
PURPOSE: This study examines periductal infiltration in intrahepatic mass-forming cholangiocarcinoma (IMCC), focusing on its importance for differentiating hepatic tumors and its influence on post-surgical survival in IMCC patients.
METHODS: Eighty-three consecutive patients with IMCC (n = 43) and liver cancer whose preoperative images showed intrahepatic bile duct dilatation adjacent to the tumor for differential diagnosis from hepatocellular carcinoma (HCC) [n = 21], metastatic liver cancer (MLC) [n = 16] and combined hepatocellular-cholangiocarcinoma (cHCC-CC) [n = 3] were enrolled. CT and MRI findings of simple bile duct compression, imaged periductal infiltration, and imaged intrabiliary growth adjacent to the main tumor were reviewed. Clinicopathological and imaging features were compared in each group. The sensitivity, specificity, and odds ratio were calculated for each imaging finding of IMCC versus the other tumor groups. Overall survival was compared between cases of IMCC with and without imaged periductal infiltration.
RESULTS: Simple bile duct compression and imaged intrabiliary growth were more frequently observed in HCC than in the others (p < 0.0001 and 0.040, respectively). Imaged periductal infiltration was observed more often in histopathologically confirmed large-duct type IMCC than in the small-duct type IMCC (p = 0.034). Multivariable analysis demonstrated that only imaged periductal infiltration (odds ratio, 50.67) was independently correlated with IMCC. Patients with IMCC who had imaged periductal infiltration experienced a poorer prognosis than those without imaged periductal infiltration (p = 0.0034).
CONCLUSION: Imaged periductal infiltration may serve as a significant marker for differentiating IMCC from other liver cancers. It may also have the potential to predict post-surgical outcomes in patients with IMCC.
PMID:38390438 | PMC:PMC10881313 | DOI:10.1016/j.ejro.2024.100554
J Cancer Res Ther. 2023 Oct 1;19(7):2060-2063. doi: 10.4103/jcrt.jcrt_1891_21. Epub 2022 Sep 3.
ABSTRACT
Pancreatic and bile duct metastases from esophageal cancer are extremely rare. We report a case of advanced esophageal cancer successfully treated with chemotherapy, selected on the basis of an accurate pathologic diagnosis. A 69-year-old man with chronic renal dysfunction presented with persistent abdominal pain and anorexia. Upper gastrointestinal endoscopy revealed an irregular-shaped tumor in the lower esophagus. Computed tomography and ultrasonography revealed swollen para-aortic lymph nodes, a pancreatic mass, and distal bile duct stenosis. Histopathological examination showed that all of the lesions were squamous cell carcinoma with unique immunohistochemical characteristics of p40+ and cytokeratin 7+. The final diagnosis was esophageal squamous cell carcinoma accompanied by lymph node, pancreas, and bile duct metastases. Taking his renal dysfunction into consideration, modified FOLFOX was administered as the first-line chemotherapy. The patient survived for 15 months since his first presentation. The favorable outcome was attributed to the accurate diagnosis based on comprehensive tissue sampling.
PMID:38376319 | DOI:10.4103/jcrt.jcrt_1891_21
Diagn Interv Radiol. 2024 Feb 20. doi: 10.4274/dir.2024.232601. Online ahead of print.
ABSTRACT
PURPOSE: To examine the diagnostic performance for the longitudinal extent of extrahepatic bile duct (EHD) cancer on computed tomography (CT) after biliary drainage (BD) and investigate the appropriate timing of magnetic resonance imaging (MRI) acquisition.
METHODS: This retrospective study included patients who underwent curative-intent surgery for EHD cancer and CT pre- and post-BD between November 2005 and June 2021. The biliary segment-wise longitudinal tumor extent was evaluated according to the 2019 Korean Society of Abdominal Radiology consensus recommendations, with pre-BD CT, post-BD CT, and both pre- and post-BD CT. The performance for tumor detectability was compared using GEEs. When preoperative MRI was performed, patients were divided into two subgroups according to the timing of MRI with respect to BD, and the performance of MRI obtained pre- and post-BD was compared.
RESULTS: In 105 patients (mean age: 67 ± 8 years; 74 men and 31 women), the performance for tumor detectability was superior using both CT scans compared with using post-BD CT alone (reader 1: sensitivity, 72.6% vs. 64.6%, P < 0.001; specificity, 96.9% vs. 94.8%, P = 0.063; reader 2: sensitivity, 77.2% vs. 72.9%, P = 0.126; specificity, 97.5% vs. 94.2%, P = 0.003), and it was comparable with using pre-BD CT alone. In biliary segments with a catheter, higher sensitivity and specificity were observed using both CT scans than using post-BD CT (reader 1: sensitivity, 74.4% vs. 67.5%, P = 0.006; specificity, 92.4% vs. 88.0%, P = 0.068; reader 2: sensitivity, 80.5% vs. 74.4%, P = 0.013; specificity, 94.3% vs. 88.0%, P = 0.016). Post-BD MRI (n = 30) exhibited a comparable performance to pre-BD MRI (n = 55) (reader 1: sensitivity, 77.9% vs. 75.0%, P = 0.605; specificity, 97.2% vs. 94.9%, P = 0.256; reader 2: sensitivity, 73.2% vs. 72.6%, P = 0.926; specificity, 98.4% vs. 94.9%, P = 0.068).
CONCLUSION: Pre-BD CT provided better diagnostic performance in the preoperative evaluation of EHD cancer. The longitudinal tumor extent could be accurately assessed with post-BD MRI, which was similar to pre-BD MRI.
CLINICAL SIGNIFICANCE: The acquisition of pre-BD CT could be beneficial for the preoperative evaluation of EHD cancer when BD is planned. Post-BD MRI would not be significantly affected by BD in terms of the diagnostic performance of the longitudinal tumor extent.
PMID:38375768 | DOI:10.4274/dir.2024.232601
World J Surg Oncol. 2024 Feb 19;22(1):58. doi: 10.1186/s12957-024-03327-3.
ABSTRACT
BACKGROUND/PURPOSE: This study compared the clinical efficacy and safety of laparoscopic versus open resection for hilar cholangiocarcinoma (HCCA) and analyzed potential prognostic factors.
METHODS: The study included patients who underwent HCCA resection at our center from March 2012 to February 2022. Perioperative complications and postoperative prognosis were compared between the laparoscopic surgery (LS) and open surgery (OS) groups.
RESULTS: After screening 313 HCCA patients, 68 patients were eligible for the study in the LS group (n = 40) and OS group (n = 28). Kaplan-Meier survival curve analysis revealed that overall survival > 2 years and 3-year disease-free survival (DFS) were more common in the LS than OS group, but the rate of 2-year DFS was lower in the LS group than OS group. Cox multivariate regression analysis revealed age (< 65 years), radical resection, and postoperative adjuvant therapy were associated with reduced risk of death (hazard ratio [HR] = 0.380, 95% confidence interval [CI] = 0.150-0.940, P = 0.036; HR = 0.080, 95% CI = 0.010-0.710, P = 0.024 and HR = 0.380, 95% CI = 0.150-0.960, P = 0.040), whereas preoperative biliary drainage was an independent factor associated with increased risk of death (HR = 2.810, 95% CI = 1.130-6.950, P = 0.026). Perineuronal invasion was identified as an independent risk factor affecting DFS (HR = 5.180, 95% CI = 1.170-22.960, P = 0.030).
CONCLUSIONS: Compared with OS, laparoscopic HCCA resection does not significantly differ in terms of clinical efficacy. Age (<65 years), radical resection, and postoperative adjuvant therapy reduce the risk of death, and preoperative biliary drainage increases the risk of death.
PMID:38369496 | PMC:PMC10875844 | DOI:10.1186/s12957-024-03327-3
Gastrointest Endosc. 2024 Mar;99(3):323-325. doi: 10.1016/j.gie.2023.11.035.
NO ABSTRACT
PMID:38368041 | DOI:10.1016/j.gie.2023.11.035
Mol Cancer. 2024 Feb 17;23(1):35. doi: 10.1186/s12943-024-01950-y.
ABSTRACT
BACKGROUND: circular RNAs (circRNAs) have been reported to exert important effects in the progression of numerous cancers. However, the functions of circRNAs in intrahepatic cholangiocarcinoma (ICC) are still unclear.
METHODS: circPCNXL2 (has_circ_0016956) were identified in paired ICC by circRNA microarray. Then, we assessed the biological functions of circPCNXL2 by CCK8, EdU, clone formation, transwell, wound healing assays, and xenograft models. RNA pull-down, mass spectrometry, and RNA immunoprecipitation (RIP) were applied to explore the interaction between cirrcPCNXL2 and serine-threonine kinase receptor-associated protein (STRAP). RNA pull-down, RIP and luciferase reporter assays were used to investigate the sponge functions of circPCNXL2. In the end, we explore the effects of circPCNXL2 and trametinib (a MEK1/2 inhibitor) in vivo.
RESULTS: circPCNXL2 was upregulated in ICC tissues and cell lines, which promoted the proliferation and metastasis of ICC in vitro and in vivo. In terms of the mechanisms, circPCNXL2 could directly bind to STRAP and induce the interaction between STRAP and MEK1/2, resulting in the tumor promotion in ICC by activation of ERK/MAPK pathways. Besides, circPCNXL2 could regulate the expression of SRSF1 by sponging miR-766-3p and subsequently facilitated the growth of ICC. Finally, circPCNXL2 could partially inhibit the anti-tumor activity of trametinib in vivo.
CONCLUSION: circPCNXL2 played a crucial role in the progression of ICC by interacting with STRAP to activate the ERK signaling pathway, as well as by modulating the miR-766-3p/SRSF1 axis. These findings suggest that circPCNXL2 may be a promising biomarker and therapeutic target for ICC.
PMID:38365721 | PMC:PMC10873941 | DOI:10.1186/s12943-024-01950-y
BMC Cancer. 2024 Feb 16;24(1):227. doi: 10.1186/s12885-024-11976-6.
ABSTRACT
BACKGROUND: Most patients with intrahepatic cholangiocarcinoma (ICC) have developed distant metastasis at the time of diagnosis, while there is rear related nomogram to predict the prognosis.
METHODS: Clinical data of patients pathologically diagnosed of ICC with distant metastasis were retrospectively collected from the Surveillance, Epidemiology, and End Results (SEER) database during 2005 to 2019. Finally, patients diagnosed as ICC in the Second Affiliated Hospital of Nanchang University from 2014 to 2019 were collected for external verification. All data were divided into training cohort and validation cohort in a ratio of 7:3. The nomogram was established based on independent prognostic factors using Cox univariate and multivariate analyses. The area under the receiver operating characteristic (ROC) curves (AUC), the calibration curve and the decision curve analysis (DCA) were used to determine the prediction accuracy of the nomogram.
RESULTS: This study finally included 572 ICC with distant metastasis patients, another 32 patients collected by the author's hospital were used as external verification. Results showed that age, surgery, radiotherapy and chemotherapy were independent prognostic factors, and nomogram was established. The AUC of predicting 3, 6, 9-month overall survival were 0.866, 0.841 and 0.786. The ROC curves and calibration curves showed that the nomogram had good predictive accuracy, and DCA showed that the nomogram had good clinical applicability.
CONCLUSIONS: The nomogram has good accuracy in predicting prognosis of DM-ICC patients, which would be of good significance to improve the prognosis of these patients.
PMID:38365630 | PMC:PMC10874087 | DOI:10.1186/s12885-024-11976-6
Endoscopy. 2024 Dec;56(S 01):E153-E155. doi: 10.1055/a-2253-1069. Epub 2024 Feb 15.
NO ABSTRACT
PMID:38359887 | PMC:PMC10869228 | DOI:10.1055/a-2253-1069
Ann Med. 2024 Dec;56(1):2310196. doi: 10.1080/07853890.2024.2310196. Epub 2024 Feb 15.
ABSTRACT
Cholangiocarcinoma (CCA) is a malignant tumor originating in the bile duct and its branching epithelium. Due to its high heterogeneity, there are no specific clinical indications at the early stage, the diagnosis is often in advanced CCA. With surgical resection, the 5-year postoperative survival rate (long-term survival rate) is very poor. The regimen of gemcitabine combined with platinum has been used as the first-line chemotherapy for advanced patients. In recent years, targeted therapy for a variety of malignant tumors has made great progress, showing good efficacy and safety in advanced CCA. However, the current targeted therapy of CCA still has many challenges, such as adverse reactions, drug resistance, and individual differences. Therefore, the researches need to further explore the targeted therapy mechanism of CCA malignancies in depth, develop more effective and safe drugs, and accurately formulate plans based on patient characteristics to further improve patient prognosis in the future. This article reviews the recent progress of targeted therapy for CCA, aiming to provide a strategy for the research and clinical work of targeted therapy for CCA.
PMID:38359439 | PMC:PMC10877652 | DOI:10.1080/07853890.2024.2310196
Radiographics. 2024 Mar;44(3):e230109. doi: 10.1148/rg.230109.
ABSTRACT
Biliary abnormalities in children are uncommon, and the spectrum of biliary disorders is broader than in adult patients. Unlike in adults, biliary disorders in children are rarely neoplastic and are more commonly rhabdomyosarcoma rather than cholangiocarcinoma. Pediatric biliary disorders may be embryologic or congenital, such as anatomic gallbladder anomalies, anomalous pancreaticobiliary tracts, various cholestatic processes, congenital cystic lesions, or genetic conditions. They may also be benign, such as biliary filling anomalies, biliary motility disorders, and biliary inflammatory and infectious disorders. Distinguishing these entities with a single imaging modality is challenging. US is the primary imaging modality for initial evaluation of biliary abnormalities in children, due to its wide availability, lack of ionizing radiation, and low cost and because it requires no sedation. Other examinations such as MRI, CT, and nuclear medicine examinations may provide anatomic and functional information to narrow the diagnosis further. Hepatobiliary-specific contrast material with MRI can provide better assessment of biliary anatomy on delayed images than can traditional MRI contrast material. MR cholangiopancreatography (MRCP) allows visualization of the intra- and extrahepatic biliary ducts, which may not be possible with endoscopic retrograde cholangiopancreatography (ERCP). Suspected biliary atresia requires multiple modalities for diagnosis and timely treatment. Determining the type of choledochal cyst calls for a combination of initial US and MRCP. Many benign and malignant biliary masses require biopsy for definitive diagnosis. Knowledge of the imaging appearances of different pediatric biliary abnormalities is necessary for appropriate imaging workup, providing a diagnosis or differential diagnosis, and guiding appropriate management. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.
PMID:38358937 | DOI:10.1148/rg.230109
Biol Pharm Bull. 2024;47(2):427-433. doi: 10.1248/bpb.b23-00655.
ABSTRACT
It has recently been reported that cholangiocyte organoids can be established from primary human hepatocytes. The purpose of this study was to culture the organoids in monolayers on inserts to investigate the biliary excretory capacity of drugs. Cholangiocyte organoids prepared from hepatocytes had significantly higher mRNA expression of CK19, a bile duct epithelial marker, compared to hepatocytes. The organoids also expressed mRNA for efflux transporters involved in biliary excretion of drugs, P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP). The subcellular localization of each protein was observed. These results suggest that the membrane-cultured cholangiocyte organoids are oriented with the upper side being the apical membrane side (A side, bile duct lumen side) and the lower side being the basolateral membrane side (B side, hepatocyte side), and that each efflux transporter is localized to the apical membrane side. Transport studies showed that the permeation rate from the B side to the A side was faster than from the A side to the B side for the substrates of each efflux transporter, but this directionality disappeared in the presence of inhibitor of each transporter. In conclusion, the cholangiocyte organoid monolayer system has the potential to quantitatively evaluate the biliary excretion of drugs. The results of the present study represent an unprecedented system using human cholangiocyte organoids, which may be useful as a screening model to directly quantify the contribution of biliary excretion to the clearance of drugs.
PMID:38369341 | DOI:10.1248/bpb.b23-00655
Phytomedicine. 2024 Feb 16:155405. doi: 10.1016/j.phymed.2024.155405. Online ahead of print.
NO ABSTRACT
PMID:38368134 | DOI:10.1016/j.phymed.2024.155405
Gastrointest Endosc. 2024 Mar;99(3):477-478. doi: 10.1016/j.gie.2023.11.001.
NO ABSTRACT
PMID:38368049 | DOI:10.1016/j.gie.2023.11.001
Cancer. 2024 Feb 15. doi: 10.1002/cncr.35249. Online ahead of print.
ABSTRACT
BACKGROUND AND AIMS: The incidence of biliary tract cancers (BTC) appears to be increasing worldwide. We analyzed the characteristics of BTC-related hospitalizations under medical services across 28 hospitals in Ontario, Canada.
METHODS: This study uses data collected by GEMINI, a hospital research data network. BTC-related hospitalizations from 2015 to 2021 under the Department of Medicine or intensive care unit were captured using the International Classification of Diseases, 10th revision, codes for intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma, and gallbladder cancers.
RESULTS: A total of 4596 BTC-related hospitalizations (2720 iCCA, 1269 extrahepatic cholangiocarcinoma, 607 gallbladder cancers) were analyzed. The number of unique patients with BTC-related hospitalizations increased over time. For iCCA-related hospitalizations, the total number of hospitalizations increased (from 385 in 2016 to 420 in 2021, p = .005), the hospital length of stay decreased over the study period (mean 10 days [SD, 12] in 2016 to 9 days [SD, 8] in 2021, p = .04), and the number of in-hospital deaths was stable (from 68 [18%] in 2016 to 55 [13%] in 2021, p = .62). Other outcomes such as 30-day readmissions, medical imaging tests, intensive care unit-specific hospitalizations, and length of stay were stable over time for all cohorts. The cost of hospitalization for the BTC cohort increased from median $8203 CAD (interquartile range, 5063-15,543) in 2017 to $8507 CAD (interquartile range, 5345-14,755) in 2021.
CONCLUSIONS: This real-world data analysis showed a rising number of patients with BTC-related hospitalizations and rising number of iCCA-related hospitalizations across 28 hospitals in Ontario between 2015 and 2021.
PMID:38361443 | DOI:10.1002/cncr.35249
World J Gastrointest Surg. 2024 Jan 27;16(1):67-75. doi: 10.4240/wjgs.v16.i1.67.
ABSTRACT
BACKGROUND: Bile leakage is a common and serious complication of open hepatectomy for the treatment of biliary tract cancer.
AIM: To evaluate the incidence, risk factors, and management of bile leakage after open hepatectomy in patients with biliary tract cancer.
METHODS: We retrospectively analyzed 120 patients who underwent open hepatectomy for biliary tract cancer from February 2018 to February 2023. Bile leak was defined as bile drainage from the surgical site or drain or the presence of a biloma on imaging. The incidence, severity, timing, location, and treatment of the bile leaks were recorded. The risk factors for bile leakage were analyzed using univariate and multivariate logistic regression analyses.
RESULTS: The incidence of bile leak was 16.7% (20/120), and most cases were grade A (75%, 15/20) according to the International Study Group of Liver Surgery classification. The median time of onset was 5 d (range, 1-14 d), and the median duration was 7 d (range, 2-28 d). The most common location of bile leakage was the cut surface of the liver (70%, 14/20), followed by the anastomosis site (25%, 5/20) and the cystic duct stump (5%, 1/20). Most bile leaks were treated conservatively with drainage, antibiotics, and nutritional support (85%, 17/20), whereas some required endoscopic retrograde cholangiopancreatography with stenting (10%, 2/20) or percutaneous transhepatic cholangiography with drainage (5%, 1/20). Risk factors for bile leakage include male sex, hepatocellular carcinoma, major hepatectomy, blood loss, and blood transfusion.
CONCLUSION: Bile leakage is a frequent complication of open hepatectomy for biliary tract cancer. However, most cases are mild and can be conservatively managed. Male sex, hepatocellular carcinoma, major hepatectomy, blood loss, and blood transfusion were associated with an increased risk of bile leak.
PMID:38328317 | PMC:PMC10845266 | DOI:10.4240/wjgs.v16.i1.67
World J Surg Oncol. 2024 Feb 7;22(1):48. doi: 10.1186/s12957-024-03329-1.
ABSTRACT
INTRODUCTION: Explorative laparotomy without subsequent curative-intent liver resection remains a major clinical problem in the treatment of perihilar cholangiocarcinoma (pCCA). Thus, we aimed to identify preoperative risk factors for non-resectability of pCCA patients.
MATERIAL AND METHODS: Patients undergoing surgical exploration between 2010 and 2022 were eligible for the analysis. Separate binary logistic regressions analyses were used to determine risk factors for non-resectability after explorative laparotomy due to technical (tumor extent, vessel infiltration) and oncological (peritoneal carcinomatosis, distant nodal or liver metastases)/liver function reasons.
RESULTS: This monocentric cohort comprised 318 patients with 209 (65.7%) being surgically resected and 109 (34.3%) being surgically explored [explorative laparotomy: 87 (27.4%), laparoscopic exploration: 22 (6.9%)]. The median age in the cohort was 69 years (range 60-75) and a majority had significant comorbidities with ASA-Score ≥ 3 (202/318, 63.5%). Statistically significant (p < 0.05) risk factors for non-resectability were age above 70 years (HR = 3.76, p = 0.003), portal vein embolization (PVE, HR = 5.73, p = 0.007), and arterial infiltration > 180° (HR = 8.05 p < 0.001) for technical non-resectability and PVE (HR = 4.67, p = 0.018), arterial infiltration > 180° (HR = 3.24, p = 0.015), and elevated CA 19-9 (HR = 3.2, p = 0.009) for oncological/liver-functional non-resectability.
CONCLUSION: Advanced age, PVE, arterial infiltration, and elevated CA19-9 are major risk factors for non-resectability in pCCA. Preoperative assessment of those factors is crucial for better therapeutical pathways. Diagnostic laparoscopy, especially in high-risk situations, should be used to reduce the amount of explorative laparotomies without subsequent liver resection.
PMID:38326854 | PMC:PMC10851609 | DOI:10.1186/s12957-024-03329-1
Cell Commun Signal. 2024 Feb 8;22(1):103. doi: 10.1186/s12964-024-01500-5.
ABSTRACT
Neutrophil extracellular traps (NETs) have garnered attention for their dual role in host defense and tumor promotion. With their involvement documented across a spectrum of tumors, their influence on the progression of cholangiocarcinoma (CCA) is of paramount interest. We employed immunohistochemistry and immunofluorescence to detect NET deposition in CCA tissues. Through in vitro and in vivo investigation, including CCA organoid and transposon-based models in PAD4 KO mice, we explored the effects of NETs on cell proliferation and metastasis. Molecular insights were gained through RNA sequencing, enzyme linked immunosorbent assay, and chromatin immunoprecipitation. Elevated intratumoral NET deposition within CCA tissues was associated with poor survival. The influence of NETs on CCA proliferation, migration and invasion was primarily mediated by NET-DNA. RNA sequencing unveiled the activation of the NFκB signaling pathway due to NET-DNA stimulation. NET-DNA pull-down assay coupled with mass spectrometry revealed the interaction between NET-DNA and αV integrin (ITGAV), culmination in the activation of the NFκB pathway. Furthermore, NET-DNA directly upregulated the expression of VEGF-A in cancer cells. The study unequivocally establishes NETs as facilitators of CCA progression, orchestrating proliferation, metastasis, and angiogenesis through ITGAV/NFκB pathway activation. This novel insight positions NETs as prospective therapeutic targets for managing CCA patients. By implementing a variety of methodologies and drawing intricate connections between NETs, DNA interactions, and signaling pathways, this research expands our comprehension of the complex interplay between the immune system and cancer progression, offering promising avenues for intervention.
PMID:38326837 | PMC:PMC10851487 | DOI:10.1186/s12964-024-01500-5
Sci Rep. 2024 Feb 7;14(1):3095. doi: 10.1038/s41598-024-53754-1.
ABSTRACT
Differentiation between adenocarcinomas is sometimes challenging. The promising avenue for discovering new biomarkers lies in bioinformatics using DNA methylation analysis. Utilizing a 2853-sample identification dataset and a 782-sample independent verification dataset, we have identified diagnostic DNA methylation biomarkers that are hypermethylated in cancer and differentiate between breast invasive carcinoma, cholangiocarcinoma, colorectal cancer, hepatocellular carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma and stomach adenocarcinoma. The best panels for cancer type exhibit sensitivity of 77.8-95.9%, a specificity of 92.7-97.5% for tumors, a specificity of 91.5-97.7% for tumors and normal tissues and a diagnostic accuracy of 85.3-96.4%. We have shown that the results can be extended from the primary cancers to their liver metastases, as the best panels diagnose and differentiate between pancreatic adenocarcinoma liver metastases and breast invasive carcinoma liver metastases with a sensitivity and specificity of 83.3-100% and a diagnostic accuracy of 86.8-91.9%. Moreover, the panels could detect hypermethylation of selected regions in the cell-free DNA of patients with liver metastases. At the same time, these were unmethylated in the cell-free DNA of healthy donors, confirming their applicability for liquid biopsies.
PMID:38326602 | PMC:PMC10850119 | DOI:10.1038/s41598-024-53754-1
Sci Rep. 2024 Feb 7;14(1):3136. doi: 10.1038/s41598-024-52991-8.
ABSTRACT
FGFR inhibitors have been developed to inhibit FGFR activation and signal transduction; notwithstanding, currently the selection of intrahepatic cholangiocarcinoma (iCCA) patients for these drugs only relies on the detection of FGFR2 genetic alterations (GAs) in tumor tissues or circulating tumor DNAs, without concomitant assessment of FGFR2 signalling status. Accordingly, we performed multi-omic analyses of FGFR2 genes and FGFR2 signalling molecules in the tissue samples from 36 iCCA naïve patients. Gain-of-function FGFR2 GAs were detected in 7 patients, including missense mutations (n = 3; p.F276C, p.C382R and p.Y375C), translocations (n = 1) and copy number gain (n = 4; CNV ≥ 4). In contrast, among 29 patients with wild-type FGFR2, 4 cases showed activation of FGFR2 signalling, as they expressed the FGFR2 ligand FGF10 and phosphorylated FGFR2/FRS2α proteins; the remaining 25 cases resulted negative for activated FGFR2 signalling, as they lacked FGFR2 (n = 8) or phosphorylated FRS2α (n = 17) expression. Overall, we found that activation of FGFR2 signalling occurs not only in iCCA naïve patients with FGFR2 GAs, but also in a subgroup carrying wild-type FGFR2. This last finding entails that also this setting of patients could benefit from FGFR targeted therapies, widening indication of these drugs for iCCA patients beyond current approval. Future clinical studies are therefore encouraged to confirm this hypothesis.
PMID:38326380 | PMC:PMC10850506 | DOI:10.1038/s41598-024-52991-8
Curr Opin Gastroenterol. 2024 Mar 1;40(2):92-98. doi: 10.1097/MOG.0000000000001005. Epub 2024 Feb 8.
ABSTRACT
PURPOSE OF REVIEW: This review discusses evidence regarding progenitor populations of the biliary tree in the tissue regeneration and homeostasis, and the pathobiology of cholangiopathies and malignancies.
RECENT FINDINGS: In embryogenesis biliary multipotent progenitor subpopulation contributes cells not only to the pancreas and gall bladder but also to the liver. Cells equipped with a constellation of markers suggestive of the primitive endodermal phenotype exist in the peribiliary glands, the bile duct glands, of the intra- and extrahepatic bile ducts. These cells are able to be isolated and cultured easily, which demonstrates the persistence of a stable phenotype during in vitro expansion, the ability to self-renew in vitro, and the ability to differentiate between hepatocyte and biliary and pancreatic islet fates.
SUMMARY: In normal human livers, stem/progenitors cells are mostly restricted in two distinct niches, which are the bile ductules/canals of Hering and the peribiliary glands (PBGs) present inside the wall of large intrahepatic bile ducts. The existence of a network of stem/progenitor cell niches within the liver and along the entire biliary tree inform a patho-biological-based translational approach to biliary diseases and cholangiocarcinoma since it poses the basis to understand biliary regeneration after extensive or chronic injuries and progression to fibrosis and cancer.
PMID:38320197 | DOI:10.1097/MOG.0000000000001005
Methods Mol Biol. 2024;2769:129-141. doi: 10.1007/978-1-0716-3694-7_10.
ABSTRACT
Tissue-resident and recruited immune cells are essential mediators of natural and therapy-induced immunosurveillance of liver neoplasia. This idea has been recently reinforced by the clinical approval of immune checkpoint inhibitors for the immunotherapy of hepatocellular carcinoma and cholangiocarcinoma. Such research progress relies on the in-depth characterization of the immune populations that are present in pre-neoplastic and neoplastic hepatic lesions. A convenient technology for advancing along this path is high-dimensional cytometry.In this chapter, we present a protocol to assess the subtype and differentiation state of hepatic lymphocyte populations by multicolor immunofluorescence staining and flow cytometry. We detail the steps required for viability assessment and immune cell phenotyping of single-cell suspensions of liver cells by means of surface and intracellular staining of more than a dozen markers of interest. This protocol does not require prior removal of debris and dead cells and allows to process multiple samples in parallel. The procedure includes the use of a fixative-resistant viability dye that allows cell fixation and permeabilization after cell surface staining and before intracellular staining and data acquisition on a flow cytometer. Moreover, we provide a panel of fluorochrome-labeled antibodies designed for the characterization of lymphocytic subsets that can be adapted to distinct experimental settings. Finally, we present an overview of the post-staining pipeline, including data acquisition on a flow cytometer and tools for post-acquisition analyses.
PMID:38315394 | DOI:10.1007/978-1-0716-3694-7_10
Methods Mol Biol. 2024;2769:99-108. doi: 10.1007/978-1-0716-3694-7_8.
ABSTRACT
Cholangiocarcinoma (CCA) is a malignancy affecting the epithelial cells that line the bile ducts. This cancer shows a poor prognosis and current treatments remain inefficient. Orthotopic CCA mouse models are useful for the development of innovative therapeutic strategies. Here, we describe an orthotopic model of intrahepatic CCA that can be easily induced in mice within 5 weeks at a high incidence. It is achieved by expressing two oncogenes, namely, (i) the intracellular domain of the Notch1 receptor (NICD) and (ii) AKT, in hepatocytes by means of the sleeping beauty transposon system. These plasmid vectors are delivered by hydrodynamic injection into the tail vein. The present chapter also describes how to perform magnetic resonance imaging (MRI) of the livers to visualize intrahepatic CCA nodules.
PMID:38315392 | DOI:10.1007/978-1-0716-3694-7_8
World J Clin Cases. 2024 Jan 16;12(2):367-373. doi: 10.12998/wjcc.v12.i2.367.
ABSTRACT
BACKGROUND: Intraductal papillary neoplasms of the bile duct (IPNBs) are rare and characterized by papillary growth within the bile duct lumen. IPNB is similar to obstructive biliary pathology. In this report, we present an unexpected case of asymptomatic IPNB and consolidate our findings with the relevant literature to augment our understanding of this condition. Integrating relevant literature contributes to a more comprehensive understanding of the disease.
CASE SUMMARY: A 66-year-old Chinese male patient was admitted to our hospital for surgical intervention after gallstones were discovered during a routine physical examination. Preoperative imaging revealed a lesion on the left side of the liver, which raised the suspicion of IPNB. A laparoscopic left hemihepatectomy was performed, and subsequent histopathological examination confirmed the diagnosis of IPNB. At the 3-mo postoperative follow-up, the patient reported good recovery and no metastasis. IPNB can manifest both latently and asymptomatically. Radical surgical resection is the most effective treatment for IPNB.
CONCLUSION: Hepatic and biliary masses, should be considered to diagnose IPNB. Prompt surgery and vigilant follow-up are crucial in determining prognosis.
PMID:38313650 | PMC:PMC10835693 | DOI:10.12998/wjcc.v12.i2.367
Trop Biomed. 2023 Dec 1;40(4):383-391. doi: 10.47665/tb.40.4.002.
ABSTRACT
The southeast Asian fluke Opisthorchis viverrini remains endemic, particularly in Thailand, Lao PDR, Cambodia, Vietnam, and Myanmar. However, there is a lack of data on the prevalence of liver fluke infection in Kratie Province in northeastern Cambodia. The present study aimed to detect O. viverrini DNA in fecal specimens by using the internal transcribed spacer 2 (ITS2) region of ribosomal DNA (rDNA) based on polymerase chain reaction (PCR). The prevalence and percentage of O. viverrini infection were described by data analysis. Bivariate binary logistic regression analysis was used to look at the related prevalence of O. viverrini infection. A total of 6.89% from 377 fecal samples were found positive of O. viverrini DNA. The prevalence of O. viverrini infection was found to be higher in men (8.92%) than in women (5.45%), and to be associated more frequently with younger age groups (13.40%), illiteracy (8.74%), participation in other careers (non-specific occupations) (11.63%), and residence in the Trapaing Srae village (9.94%) of the Snuol district, Kratie Province. Age groups under 20 years old were significantly linked with O. viverrini infection, with ORadj=0.601, 95% CI=0.410-0.882, p=0.009 and significant value established at (P<0.05). This study demonstrates that O. viverrini infection is distributed in rural areas located near freshwater reservoirs. Therefore, active surveillance, clinical examination of association with hepatobiliary, cholangiocarcinoma, and health education are needed.
PMID:38308824 | DOI:10.47665/tb.40.4.002
ANZ J Surg. 2024 Feb 2. doi: 10.1111/ans.18893. Online ahead of print.
ABSTRACT
BACKGROUND: The purpose of this study is to examine and analyse the outcomes and patient experiences associated with laparoscopic central pancreatectomy.
METHODS: The perioperative data of 16 patients who underwent laparoscopic central pancreatectomy were retrospectively analysed at Ningbo Medical Center Lihuili Hospital (Xingning Branch and Eastern Branch) from September 2017 to July 2023.
RESULTS: All surgical procedures were completed without the need for intraoperative conversion to open surgery. In two cases, intraoperative cholangiography was performed, while in four cases, intraoperative fluoroscopic laparoscopic assistance was utilized. The duration of the operations varied from 160 to 360 min, with an average of 281.75 min. The estimated volume of intraoperative bleeding ranged from 50 to 300 mL, with an average of 113.75 mL. The postoperative pathology results revealed that there were two cases of intraductal papillary mucinous neoplasm, six cases of serous cystic neoplasms, one case of mucinous cystic neoplasm, five cases of solid pseudopapillary neoplasms, and two cases of neuroendocrine tumours. The maximum diameter of the tumours ranged from 3.0 to 5.0 cm, with an average of 3.67 cm. There were no instances of postoperative common bile duct stenosis or biliary leakage. Among the cases, five did not exhibit pancreatic fistula, six experienced biochemical leakage, three had grade B pancreatic fistula, and two had grade C pancreatic fistula.
CONCLUSION: Laparoscopic central pancreatectomy, as a method to preserve pancreatic function, entails specific surgical risks and a notable likelihood of postoperative pancreatic fistula, necessitating the expertise of seasoned surgeons for its execution.
PMID:38308435 | DOI:10.1111/ans.18893
Anticancer Res. 2024 Feb;44(2):613-619. doi: 10.21873/anticanres.16850.
ABSTRACT
BACKGROUND/AIM: Cell-free and concentrated ascites reinfusion therapy (CART) was established for refractory ascites and renovated CART (Keisuke Matsusaki (KM) -CART) has been recently developed especially for malignant ascites; however, the actual clinical efficacy of KM-CART has been rarely reported.
PATIENTS AND METHODS: We performed 226 KM-CART procedures in 104 patients with malignant ascites in three hospitals from August 2013 to September 2018. Medical records were retrospectively reviewed for ascites data, related complications, symptoms before and after each CART and prognosis after the first CART. The modified Glasgow Prognostic Score (mGPS) was reviewed before every procedure, as an indicator of nutritional status.
RESULTS: Pancreatic cancer was the most common indication for the KM-CART procedure, followed by gastric cancer, hepatocellular carcinoma, ovarian cancer, and cholangiocarcinoma (five major diseases). The 50% survival times of these five major diseases after the first procedure were 25, 39, 31, 49, and 33 days, respectively. The mean survival time for all patients was 73.5 days, and 75.6 days for those with the five major diseases. All patients experienced symptomatic relief, and complications were rare. Repeated KM-CART was performed in 47.1% of the patients, most often in those with ovarian cancer (66.7%). Regarding the mGPS at the first CART procedure, 89% of patients were in the group with the poorest nutritional status. Patients who underwent KM-CART three or more times had longer survival than those who were treated once or twice.
CONCLUSION: Repeated KM-CART provides a survival benefit for patients with malignant ascites, even in cases of poor nutritional status.
PMID:38307557 | DOI:10.21873/anticanres.16850
AJOG Glob Rep. 2024 Jan 11;4(1):100310. doi: 10.1016/j.xagr.2024.100310. eCollection 2024 Feb.
ABSTRACT
BACKGROUND: Gallstone disease in pregnancy is one of the most common indications for nonobstetrical surgery during pregnancy. National-level data on contemporary surgical practice and outcomes are limited.
OBJECTIVE: This study aimed to assess the clinical characteristics and outcomes of patients undergoing cholecystectomy during pregnancy.
STUDY DESIGN: This cross-sectional study examined the Healthcare Cost and Utilization Project's 2 nationwide databases in the United States: the National Inpatient Sample and the Nationwide Ambulatory Surgery Sample. The study population included 18,630 patients who had cholecystectomy during pregnancy from January 2016 to December 2020. The exposure was gestational age, grouped sequentially into the following 5 groups: first trimester (<14 weeks), early second trimester (14-20 weeks), late second trimester (21-27 weeks), early third trimester (28-36 weeks), and late third trimester (≥37 weeks). The main outcomes were clinical demographics, medical comorbidities, surgical information, and pregnancy characteristics and outcomes, assessed by gestational age.
RESULTS: Cholecystectomy was most common in the early second trimester (32.1%), followed by the first trimester (25.2%), late second trimester (23.1%), early third trimester (12.4%), and late third trimester (7.2%). Patients in the first-trimester group were more likely to be aged ≥35 years, to smoke, and to have acute cholecystitis, severe hyperemesis gravidarum including metabolic disturbance, pregestational diabetes, multifetal gestation, and sepsis/shock (P<.001). Patients in the early-third-trimester group were more likely to be obese and have gestational diabetes, Charlson Comorbidity Index of ≥1, premature rupture of membranes, and intrauterine growth restriction, whereas those in the late-third-trimester group were more likely to have gallstone pancreatitis, biliary colic, chorioamnionitis, gestational hypertension, preeclampsia, and severe maternal morbidity including sepsis (P<.001). At the cohort level, a laparoscopic approach was used in most cholecystectomy procedures (97.5%), and bile duct injury was uncommon (<0.1%). Delivery during the admission occurred in 0.3%, 0%, 0.6%, 17.8%, and 60.6% in the 5 gestational age groups, respectively (P<.001). Among the cases that had delivery in the early- and late-third-trimester groups, the delivery event preceded cholecystectomy in 61.4% and 86.2%, respectively, whereas both delivery and cholecystectomy occurred on the same day in 34.3% and 13.8%, respectively.
CONCLUSION: This nationwide analysis suggests that clinical and pregnancy characteristics and outcomes of patients undergoing cholecystectomy differ by pregnancy stage with a bimodal distribution. Although patients in the first and third trimesters have distinct medical conditions, more clinically significant pregnancy and maternal outcomes were found in both groups compared with patients in the second trimester.
PMID:38304305 | PMC:PMC10830852 | DOI:10.1016/j.xagr.2024.100310
Gan To Kagaku Ryoho. 2023 Dec;50(13):1630-1632.
ABSTRACT
A 73-year-old, male patient presented with the chief complaint of epigastric pain and received the diagnosis of extensive cholangiocarcinoma after a close examination. Extensive extension of the malignancy into the right and left hepatic ducts precluded a curative resection, and the patient received GC therapy. After 11 courses of GC over about 1 year, no new lesions or tumor progression was observed, and a bile duct mapping biopsy was performed to investigate the possibility of resection conversion. The results showed a marked decrease in atypia, and reactive atypia was diagnosed. A pancreaticoduodenectomy was performed, and histopathologically negative margins were obtained. The response to treatment was Grade Ⅱa according to the Evans classification. At 23 months after the start of treatment and 12 months after surgery, the patient is recurrence-free without adjuvant chemotherapy. Although the evidence for conversion surgery for biliary tract cancer has not been established, the long-term outcomes may be favorable.
PMID:38303364
Gan To Kagaku Ryoho. 2023 Dec;50(13):1627-1629.
ABSTRACT
During the postoperative follow-up for adrenal tumor for a 78-year-old male patient, a contrast-enhanced computed tomography scan revealed wall thickness with contrast effect in the cystic duct, enlarged lymph nodes along the ileocecal artery, and nodal shadow in the lower lobe of the left lung. First, the collected bile juice at ERC was submitted to cytology multiple times however, no malignant findings were noted. Next, a staging laparoscopy was performed; but the pathological findings of the enlarged lymph nodes and the abdominal lavage cytology showed no malignancy. A nodule in the lower lobe of the left lung was resected for diagnostic and therapeutic purposes, and the pathological diagnosis was primary adenocarcinoma of the lung. Finally the patient underwent exploratory laparotomy for diagnostic purposes. An intraoperative ultrasound- guided needle biopsy for mass lesion located in the medial section of the left liver was performed, and malignant lymphoma was suspected by the intraoperative pathological diagnosis. Cholecystectomy was performed to confirm the histological type, leading to the diagnosis of diffuse large B cell lymphoma. After surgery, the patient underwent 6 courses of rituximab plus CHOP therapy, and the bile duct stricture was improved.
PMID:38303363
Gan To Kagaku Ryoho. 2023 Dec;50(13):1609-1611.
ABSTRACT
An 88-year-old woman had been diagnosed with hilar cholangiocarcinoma for 3 years since she received metallic stents for malignant biliary obstruction, and observed without any aggressive medical treatment. She was admitted to our hospital for further investigation of her abdominal pain. Abdominal CT showed an enlarged gallbladder, fluid collection in the right paracolic gutter, and swollen appendix. Laboratory tests showed high-grade inflammation. She was diagnosed with acute perforated appendicitis with acute cholecystitis. Laparoscopic cholecystectomy and appendectomy were performed. Perforation was confirmed intraoperatively in the appendix wall and accumulation of pus was found in the right paracolic gutter. There were no macroscopic findings of metastasis and peritoneal dissemination. Microscopic examination of the resected appendix showed adenocarcinoma cells positive for CK7 and negative for CK20 and CDX2, and were predominantly infiltrated from the muscular layer to the serosa of the appendix wall, with a diagnosis of appendiceal metastasis from hilar cholangiocarcinoma. Metastatic appendiceal carcinoma is rare, and appendiceal metastasis from hilar cholangiocarcinoma is extremely rare. Herein, we report a rare case of metastatic appendiceal carcinoma from hilar bile duct cancer with acute perforated appendicitis and cholecystitis along with findings of previous literature.
PMID:38303357
Gan To Kagaku Ryoho. 2023 Dec;50(13):1563-1565.
ABSTRACT
A 77-year-old man visited a clinic because of nausea and chest discomfort. On blood test, hepatobiliary enzymes were elevated, and he referred to our hospital. Contrast-enhanced CT revealed stenosis of the extrahepatic bile duct and brush cytology of the bile duct showed adenocarcinoma. We therefore performed pancreatoduodenectomy for extrahepatic bile duct cancer. Pathological diagnosis was small cell neuroendocrine carcinoma, pT3N2M0, Stage ⅢA. The patient did not receive adjuvant chemotherapy and 3 months later contrast-enhanced CT and MRI showed multiple liver metastases. The patient was treated with cisplatin plus irinotecan in the first-line, cisplatin plus etoposide in the second-line, and amrubicin in the third-line and accordingly he died 1 year and 3 months after the surgery. Chemotherapy for neuroendocrine carcinoma of the bile duct is recommended as in small cell lung cancer, but the prognosis is extremely poor. We report this case with a review of some of the literature.
PMID:38303342
Gan To Kagaku Ryoho. 2023 Dec;50(13):1453-1455.
ABSTRACT
Chemotherapy is the standard therapy for unresectable intrahepatic cholangiocarcinoma(ICC), but chemotherapy is not efficacious. Proton beam therapy(PBT)has been covered by Japanese health insurance for ICC since 2022, and the number of cases is expected to increase. In some cases, irradiation is difficult due to the close proximity of the gastrointestinal tract to the tumor. We report our management of a patient with ICC close to the gastrointestinal tract. The patient was a 69-year- old woman with a history of distal gastrectomy and Billroth-Ⅰ reconstruction for gastric cancer. A CT scan showed a tumor in liver S3; a biopsy revealed ICC. Because the tumor was in contact with the gastroduodenal anastomosis, we placed an absorbable spacer and performed PBT. After the treatment, the tumor shrank slightly. Although the liver is anatomically adjacent to the digestive tract, the placement of absorbable spacers facilitates performing PBT without adverse events, and is thus considered a useful treatment.
PMID:38303305
Gan To Kagaku Ryoho. 2023 Dec;50(13):1962-1964.
ABSTRACT
A 73-year-old female was diagnosed with gallbladder cancer, but the future liver remnant volume was deemed insufficient for curative resection. Consequently, transileocolic portal vein embolization was performed. During laparotomy, multiple nodules were palpable on the peritoneal surface of the pelvic floor. Subsequently, staging laparoscopy confirmed the pathological diagnosis of adenocarcinoma in the resected nodules, indicating peritoneal dissemination of gall bladder cancer. Due to this peritoneal dissemination, surgical resection was deemed inappropriate, and the patient was initiated on systemic chemotherapy consisting of gemcitabine and cisplatin. Following 22 courses of chemotherapy, contrast-enhanced computed tomography demonstrated no significant changes in the size of the primary tumor or its location relative to the main vessels, although a small metastatic lesion was identified in the gallbladder bed. At the second staging laparoscopy, any nodules suggesting peritoneal dissemination were observed. Based on these findings, we decided to perform curative resection. The surgical procedure involved right hepatectomy plus segment 4a resection, extrahepatic bile duct resection, and hepaticojejunostomy. Pathological examination revealed ypT3bN0M1(HEP), ypStage ⅣB, with the achievement of R0 resection. The patient survived with no recurrences for 40 months after surgery. These results suggest that aggressive therapeutic strategies, including conversion surgery following systemic chemotherapy, may be beneficial for patients initially deemed unresectable due to gallbladder cancer.
PMID:38303265
Gan To Kagaku Ryoho. 2023 Dec;50(13):1953-1955.
ABSTRACT
We report a case of biliary cystadenocarcinoma in which long-term survival was achieved after 2 operations for intrahepatic recurrence. A 72-year-old man with biliary cystadenocarcinoma located mainly in segment 3 of the liver underwent left hepatectomy, extrahepatic bile duct resection, and lymph node dissection. Seven years and 9 months after the initial resection, he underwent partial liver resection(segment 5)for intrahepatic recurrence detected by computed tomography. Fifteen years and 7 months after the initial resection, he underwent repeat partial resection of the liver(segment 5)for intrahepatic recurrence. Histologically, these tumors were confirmed to be recurrence of biliary cystadenocarcinoma. He remains alive and well with no further recurrence 21 years and 6 months after the initial resection. This case and a literature review suggest that hepatic resection is a useful treatment option for intrahepatic recurrence of biliary cystadenocarcinoma.
PMID:38303262
Gan To Kagaku Ryoho. 2023 Dec;50(13):1878-1880.
ABSTRACT
A female in her 70s underwent right hepatectomy with resection of caudate lobe and extrahepatic bile duct for perihilar cholangiocarcinoma(T2aN0M0, Stage Ⅱ: Biliary Cancer Treatment Regulations, 7th edition). On the 4th postoperative day, the patient had impaired consciousness, which worsened to almost coma on the 5th postoperative day. On the same day, a blood test showed high ammonia level, thus the state was thought to be hepatic encephalopathy. Contrast -enhanced CT on the same day showed thrombus from the main trunk of the portal vein to the remnant left branch, narrowing of the lumen of the vessel. Simultaneously, enlarged portosystemic shunt in the pelvic floor due to portal hypertension induced by the thrombosis. Plasmapheresis was performed, and anticoagulation with sodium heparin and antithrombin Ⅲ were started. Then, the portal vein thrombus was reduced, and encephalopathy was improved. She was discharged from the hospital on postoperative day 48. She was treated with edoxaban as an outpatient, and anticoagulation therapy was terminated after a CT scan 6 months after surgery, which confirmed no recurrence of thrombus. She is now alive without recurrence of thrombus or tumor for about 2 years after the surgery.
PMID:38303238
Gan To Kagaku Ryoho. 2023 Dec;50(13):1875-1877.
ABSTRACT
Tumor mutation burden(TMB)-High is known to potentially elicit a favorable response to immune checkpoint inhibitors. In this report, we present a case of recurrent hilar cholangiocarcinoma with TMB-High, in which we performed comprehensive treatment including immune checkpoint inhibitor pembrolizumab. The patient was a 58-year-old male diagnosed with hilar cholangiocarcinoma who underwent extended right hepatectomy, caudate lobe resection, bile duct excision, and bile duct reconstruction. Postoperatively, peritoneal seeding recurrence and liver metastasis were observed, indicating TMB-High. Therefore, pembrolizumab therapy was administered. The tumor marker CA19-9 significantly decreased, and the peritoneal seeding and liver metastatic lesions disappeared on imaging. In this case, we experienced the use of pembrolizumab monotherapy for TMB-High recurrent bile duct cancer with early postoperative peritoneal seeding recurrence. Further accumulation of cases is needed, but pembrolizumab monotherapy holds promise as a treatment option for TMB-High bile duct cancer at the hepatic hilum.
PMID:38303237
Gan To Kagaku Ryoho. 2023 Dec;50(13):1872-1874.
ABSTRACT
A 58-year-old woman presented with a complaint of weight loss. Abdominal computed tomography showed dilatation of the biliary and pancreatic ducts and a mural nodule in the pancreatic duct. The diagnosis was intraductal papillary mucinous neoplasm(IPMN). Endoscopic retrograde cholangiopancreatography(ERCP)and cholangioscopy revealed a fistula between the common bile duct and the IPMN. A sudden increase in hepatobiliary enzymes was noted preoperatively. ERCP showed that the common bile duct was obstructed by mucus. A nasobiliary drainage tube was inserted into the bile duct endoscopically and kept open by daily tube washing, and the liver dysfunction improved. Total pancreatectomy, splenectomy, and regional lymph node dissection were performed. Histological examination confirmed that the primary tumor was mixed invasive intraductal papillary mucinous adenocarcinoma. The patient remains alive and well with no evidence of recurrence 18 months after resection.
PMID:38303236
Gan To Kagaku Ryoho. 2023 Dec;50(13):1795-1797.
ABSTRACT
We report a case of local recurrence of intrahepatic bile duct cancer that was successfully treated using chemotherapy and radiation therapy. A man in his 80s underwent hepatic resection for intrahepatic cholangiocarcinoma, and abdominal CT 11 months after surgery revealed local recurrence around the dissected surface. He was diagnosed with a local recurrence of intrahepatic cholangiocarcinoma and started systemic chemotherapy(GEM plus CDDP plus S-1). After 11 courses of chemotherapy, stereotactic body radiation therapy(SBRT)was administered to the same site at 50 Gy/10 Fr, as the local recurrence area had increased, although no distant metastases were detected on imaging. The patient was then started on chemotherapy( GEM plus S-1), but after 2 courses, 8 courses of GEM alone were administered at the patient's request. No increase in tumor markers was observed, but an increase in the low-absorption area was observed on imaging. Thereafter, the regimen was changed to S-1. Three months later, the same area was reduced in size and obscured on imaging evaluation. The patient is still taking it 12 months later. No recurrence has been observed since 2 years and 7 months after the start of treatment for local recurrence. This case suggested that multidisciplinary therapy might be useful for local recurrence of intrahepatic cholangiocarcinoma.
PMID:38303210
Gan To Kagaku Ryoho. 2023 Dec;50(13):1753-1755.
ABSTRACT
A 66-year-old man was referred to our hospital with fever and abdominal pain. CT showed a mass in the intrapancreatic bile duct but no wall thickness in the perihilar bile ducts. Neither regional lymphadenopathy nor distant metastasis was observed. Biliary cytology showed adenocarcinoma. The diagnosis was distal cholangiocarcinoma, and pancreatoduodenectomy was performed. Intraoperative frozen section examination of the ductal resection margins at the right and left hepatic ducts was positive for carcinoma in situ, and the operation ultimately completed with R1 resection. Histological examination confirmed a diagnosis of cholangiocarcinoma with superficial spread and a single positive lymph node. Adjuvant chemotherapy with S-1 was administered for 1 year. Anastomotic recurrence at the hepaticojejunostomy was found 5 years after resection; biopsy specimens revealed adenocarcinoma. Thereafter, S-1 chemotherapy was resumed, and the patient remains alive and well 9 years and 1 month after resection.
PMID:38303196
Hum Pathol. 2024 Jan 30;144:46-52. doi: 10.1016/j.humpath.2024.01.011. Online ahead of print.
ABSTRACT
Enteroblastic carcinoma is clinically characterized by an elevated serum level of alpha-fetoprotein (AFP) and is histologically characterized by cancer cells with a clear cytoplasm and 'blastic' coarse chromatin. It sometimes has an element of hepatoid carcinoma; therefore, these two neoplasms are often regarded as sister entities. Although hepatoid carcinoma in the biliary tree has been reported, enteroblastic cholangiocarcinoma is extremely uncommon. In the present study, four cases of enteroblastic cholangiocarcinoma were examined. Tumors were located inside the liver (n = 2) or common bile duct (n = 2). The two intrahepatic cases had a history of primary sclerosing cholangitis, and serum AFP levels were elevated in both. One unresectable case was diagnosed by needle liver biopsy, while the remaining three underwent surgical resection. Histologically, all cases showed similar microscopic features. Cuboidal or polygonal cancer cells with the characteristic clear cytoplasm and subnuclear vacuoles were arranged in a papillary, micropapillary, tubular, or solid architecture. One case had an element of pancreatobiliary-type adenocarcinoma, while a hepatoid carcinoma element was not observed in any cases. All cases were positive for AFP, glypican 3, and SALL4, with SALL4 being the most widely expressed. Heppar-1 and arginase-1 were negative, except for one case, which was positive for Heppar-1. In conclusion, enteroblastic cholangiocarcinoma is an uncommon subtype of biliary tract malignancy. These cases may have been categorized as 'clear cell' cholangiocarcinoma. Although enteroblastic cholangiocarcinoma seems to occur more commonly in extrahepatic regions, including the gallbladder, it may also develop in the liver, particularly in patients with primary sclerosing cholangitis.
PMID:38301963 | DOI:10.1016/j.humpath.2024.01.011
Proc Natl Acad Sci U S A. 2024 Feb 6;121(6):e2317756121. doi: 10.1073/pnas.2317756121. Epub 2024 Feb 1.
ABSTRACT
Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures. In this study, aided by analysis of protein dynamics, we designed a selective, covalent FGFR2 inhibitor. In a key initial step, analysis of long-timescale molecular dynamics simulations of the FGFR1 and FGFR2 kinase domains allowed us to identify differential motion in their P-loops, which are located adjacent to the orthosteric site. Using this insight, we were able to design orthosteric binders that selectively and covalently engage the P-loop of FGFR2. Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2-altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.
PMID:38300868 | PMC:PMC10861881 | DOI:10.1073/pnas.2317756121
J Cancer Res Clin Oncol. 2024 Feb 1;150(2):66. doi: 10.1007/s00432-023-05532-1.
ABSTRACT
OBJECTIVE: The tumor microenvironment (TME) in cholangiocarcinoma (CHOL) is typically characterized by a low level of immune infiltration, which accounts for the dismal prognosis of this patient population. This study sought to investigate the mechanisms underlying the reduced infiltration of immune cells into the CHOL TME.
METHODS: We constructed a Least Absolute Shrinkage and Selection Operator (LASSO) regression model to identify prognosis-related differentially expressed genes (DEGs). The 'Corrplot' package was employed to analyze the correlation between dermatopontin (DPT) and immune infiltration in CHOL. The Tumor and Immune System Interaction Database (TISIDB) was used to evaluate the association between DPT and immunology. Single-cell analysis was conducted to localize CCL19 secretions. Western blot and qPCR were utilized to detect DPT expression, while immunofluorescence was performed to investigate the cellular localization of DPT. Additionally, ELISA analysis was employed to assess the alteration in CCL19 secretion in cancer-associated fibroblasts (CAFs) and macrophages.
RESULTS: Our findings revealed that CHOL patients with low DPT expression had a poorer prognosis. Enrichment analysis demonstrated a positive correlation between DPT levels and the infiltration of immunomodulators and immune cells. Moreover, high DPT levels were associated with enhanced anti-PD-1/PD-L1 immunotherapeutic responses. Furthermore, DPT expression impacted the landscape of gene mutations, showing a negative association with tumor grade, stage, and lymph node metastasis. Based on the results of protein peptides analysis and cell experiments, it was inferred that the downregulation of DPT in CHOL cells effectively suppressed the secretion of CCL19 in macrophages.
CONCLUSIONS: DPT is a novel prognosis-related biomarker for CHOL patients, and this study provides preliminary insights into the mechanism by which DPT promotes the infiltration of immune cells into the CHOL TME.
PMID:38300311 | PMC:PMC10834663 | DOI:10.1007/s00432-023-05532-1
Integr Cancer Ther. 2024 Jan-Dec;23:15347354231223967. doi: 10.1177/15347354231223967.
ABSTRACT
BACKGROUND: A statistical model is essential in determining the appropriate predictive indicators for therapies in many types of cancers. Predictors have been compared favorably to the traditional systems for many cancers. Thus, this study has been proposed as a new standard approach. A recent study on the clinical efficacy of Atractylodes lancea (Thunb) DC. (AL) revealed the higher clinical benefits in patients with advanced-stage intrahepatic cholangiocarcinoma (ICC) treated with AL compared with standard supportive care. We investigated the relationships between clinical efficacy and pharmacokinetic parameters of serum bioactivity of AL and its active constituent atractylodin and determined therapeutic ranges.
METHODS: Group 1 of advanced-stage ICC patients received daily doses of 1000 mg of standardized extract of the capsule formulation of AL (CMC-AL) for 90 days. Group 2 received daily doses of 1000 mg of CMC-AL for 14 days, followed by 1500 mg for 14 days, and 2000 mg for 62 days. Group 3 (control group) received palliative care. Cox proportional hazard model and Receiver Operating Characteristic (ROC) were applied to determine the cut-off values of AUC0-inf, Cmax, and Cavg associated with therapeutic outcomes. Number needed to treat (NNT) and relative risk (RR) were also applied to determine potential predictors.
RESULTS: The AUC0-inf of total AL bioactivity of >96.71 µg hour/ml was identified as a promising predictor of disease prognosis, that is, progression-free survival (PFS) and disease control rate (DCR). Cmax of total AL bioactivity of >21.42 was identified as a predictor of the prognosis of survival. The therapeutic range of total AL bioactivity for PFS and DCR is 14.48 to 65.8 µg/ml, and for overall survival is 10.97 to 65.8 µg/ml. Conclusions: The predictors of ICC disease prognosis were established based on the pharmacokinetics of total AL bioactivity. The information could be exploited to improve the clinical efficacy of AL in patients with advanced-stage ICC. These predictors will be validated in a phase 2B clinical study.
TRIAL REGISTRATION: TCTR20210129007 (TCTR: www.clinicaltrials.in.th).
PMID:38291969 | PMC:PMC10832411 | DOI:10.1177/15347354231223967
Endoscopy. 2024 Dec;56(S 01):E85-E86. doi: 10.1055/a-2234-4355. Epub 2024 Jan 30.
NO ABSTRACT
PMID:38290706 | PMC:PMC10827524 | DOI:10.1055/a-2234-4355
Front Immunol. 2024 Jan 15;14:1286771. doi: 10.3389/fimmu.2023.1286771. eCollection 2023.
ABSTRACT
OBJECTIVES: To evaluate the efficacy and safety of biliary stenting implantation with iodine-125 seed strand (SI) followed by hepatic artery infusion chemotherapy (HAIC) plus lenvatinib (Len) with programmed death-1 (PD-1) inhibitor for patients diagnosed with extrahepatic cholangiocarcinoma (ECC) and malignant obstructive jaundice (MOJ).
METHODS: In this single-center retrospective study, the data of ECC patients with MOJ from March 2015 to January 2023 was assessed. Using probability score matching (PSM), the selection bias of patients was reduced. Primary study outcomes included overall survival (OS) and progression-free survival (PFS). The OS and PFS were performed using the Kaplan-Meier method and evaluated with the log-rank test.
RESULTS: A total of 104 patients were enrolled finally, including 52 patients treated with interventional therapy (SI+HAIC) plus Len with PD-1 inhibitor (SI+HAIC+Len+P group) and 52 patients treated with interventional therapy (SI+HAIC) plus lenvatinib (SI+HAIC+Len group). 26 pairs of patients were matched after PSM analysis. After PSM analysis, the median OS and PFS in the SI+HAIC+Len+P group were significantly longer compared to those in the SI+HAIC+Len group (OS:16.6 vs. 12.3 months, P = 0.001; PFS:12.6 vs 8.5 months, P = 0.004). The DCR was significantly different between groups (P = 0.039), while ORR not (P = 0.548). The addition of PD-1 inhibitor was generally well tolerated without treatment-associated mortality.
CONCLUSION: Interventional therapy (SI+HAIC) plus Len with PD-1 inhibitor was effective for ECC patients accompanied by MOJ with a manageable safety profile.
PMID:38288113 | PMC:PMC10822914 | DOI:10.3389/fimmu.2023.1286771
Eur J Cancer. 2024 Mar 13;202:114000. doi: 10.1016/j.ejca.2024.114000. Online ahead of print.
ABSTRACT
INTRODUCTION: This document is a summary of the French intergroup guidelines of the management of biliary tract cancers (BTC) (intrahepatic, perihilar and distal cholangiocarcinomas, and gallbladder carcinomas) published in September 2023, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org).
METHODS: This collaborative work was conducted under the auspices of French medical and surgical societies involved in the management of BTC. Recommendations were graded in three categories (A, B and C) according to the level of scientific evidence until August 2023.
RESULTS: BTC diagnosis and staging is mainly based on enhanced computed tomography, magnetic resonance imaging and (endoscopic) ultrasound-guided biopsy. Treatment strategy depends on BTC subtype and disease stage. Surgery followed by adjuvant capecitabine is recommended for localised disease. No neoadjuvant treatment is validated to date. Cisplatin-gemcitabine chemotherapy combined to the anti-PD-L1 inhibitor durvalumab is the first-line standard of care for advanced disease. Early systematic tumour molecular profiling is recommended to screen for actionable alterations (IDH1 mutations, FGFR2 rearrangements, HER2 amplification, BRAFV600E mutation, MSI/dMMR status, etc.) and guide subsequent lines of treatment. In the absence of actionable alterations, FOLFOX chemotherapy is the only second-line standard-of-care. No third-line chemotherapy standard is validated to date.
CONCLUSION: These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice. Each individual BTC case should be discussed by a multidisciplinary team.
PMID:38493667 | DOI:10.1016/j.ejca.2024.114000
Drug Discov Today. 2024 Mar 14:103949. doi: 10.1016/j.drudis.2024.103949. Online ahead of print.
ABSTRACT
Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme that regulates proliferating cell metabolism. The role of PKM2 in common diseases has been well established, but its role in rare diseases (RDs) is less well understood. Over the past few years, PKM2 has emerged as a crucial player in RDs, including, neoplastic, respiratory, metabolic, and neurological disorders. Herein, we summarize recent findings and developments highlighting PKM2 as an emerging key player in RDs. We also discuss the current status of PKM2 modulation in RDs with particular emphasis on preclinical and clinical studies in addition to current challenges in the field. Teaser: The review underscores recent discoveries that solidify PKM2 as a crucial player in the rare disease realm.
PMID:38492882 | DOI:10.1016/j.drudis.2024.103949
Cell Signal. 2024 Mar 14:111141. doi: 10.1016/j.cellsig.2024.111141. Online ahead of print.
ABSTRACT
Cholangiocarcinoma (CCA) is a malignancy with an extremely poor prognosis, and much remains unknown about its pathogenesis and treatment modalities. Circular RNA (circRNA) has been proven to play regulatory roles in various tumorigenesis, yet its potential function and mechanism in cholangiocarcinoma require further investigation. This study is the first to identify the aberrant expression and functional role of a novel circRNA, circ_0007534, derived from the DDX42 gene, in cholangiocarcinoma. Compared to the normal control group, the expression of circ_0007534 was significantly elevated in the tissues and cells with CCA and that high expression correlated with lymph node invasion and poor prognosis. Functional experiments indicated that downregulating circ_0007534 markedly inhibited the proliferation, migration, invasion, stemness, and anti-anoikis ability of CCA cells, as well as the tumor growth and liver and lung metastasis in nude mice. Mechanistic studies revealed that DDX42, as the parent gene of circ_0007534, can mutually regulate each other's expression. Predominantly located in the cytoplasm, circ_0007534 can form a complex with the RNA-binding protein DDX3X, which enhances the stability of DDX42 mRNA, thereby upregulating the expression of DDX42. This creates a positive feedback loop among the three, collectively promoting the progression of cholangiocarcinoma. In conclusion, this study sheds light on the pivotal role and molecular mechanism of circ_0007534 in the development of CCA, offering potential new targets for early diagnosis and treatment.
PMID:38492624 | DOI:10.1016/j.cellsig.2024.111141
Inflammation. 2024 Mar 16. doi: 10.1007/s10753-024-02003-8. Online ahead of print.
ABSTRACT
Advanced intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by limited response to standard therapeutic modalities, such as radiotherapy, chemotherapy, and targeted therapy. The prognosis for patients with advanced ICC is exceedingly bleak, with an overall survival of less than 1 year. In recent years, personalized neoantigen vaccines have emerged as a promising approach to augment the immune response against tumors. Clinical investigations are currently underway to evaluate the efficacy of neoantigen-based peptide, DNA, and dendritic cell vaccines. Herein, we present a noteworthy case of advanced ICC patients who experienced disease progression following relapse and subsequently received immunotherapy with a personalized neoantigen nanovaccine. This innovative treatment strategy involved the administration of a custom-designed neoantigen-based peptide nanovaccine tailored to the patient's specific gene mutation profile subsequent to failure of first-line therapy. The clinical efficacy and anti-tumor immune responses were evaluated using various methods, including imaging, interferon-γ ELISPOT assay, and intracellular cytokine staining. Notably, the neoantigen nanovaccine elicited a robust and specific tumor-killing effect mediated by T cells, resulting in a durable response lasting up to 25 months. These findings highlight the potential of neoantigen-based immunotherapy as a novel therapeutic avenue for the management of advanced ICC.
PMID:38492185 | DOI:10.1007/s10753-024-02003-8
J Visc Surg. 2024 Mar 14:S1878-7886(24)00026-2. doi: 10.1016/j.jviscsurg.2024.03.001. Online ahead of print.
NO ABSTRACT
PMID:38490829 | DOI:10.1016/j.jviscsurg.2024.03.001
J Vasc Interv Radiol. 2024 Mar 13:S1051-0443(24)00211-2. doi: 10.1016/j.jvir.2024.03.005. Online ahead of print.
ABSTRACT
PURPOSE: To assess the safety and effectiveness of using modified radiation lobectomy (mRL) to treat primary hepatic tumors located in the right hepatic lobe (segments V-VIII) and determine future liver remnant (FLR) hypertrophy.
METHODS: A retrospective review was performed at a single institution to include 19 consecutive patients (7 Female, 12 Male) who underwent single-session mRL for right sided primary hepatic tumors: 15 received segmentectomy plus lobectomy (segmental dose >190 Gy and lobar dose >80 Gy); 4 were treated with the double-segmental approach (dominant segments >190 Gy and non-dominant segments > 80 Gy). Treated tumors included 13 hepatocellular carcinoma (HCC), 4 cholangiocarcinoma (CCA), and 2 mixed-type HCC-CCA with a median dominant tumor size of 5.3 cm (Interquartile range [IQR]: 3.7-7.3cm). FLR of the left hepatic lobe was measured at baseline, T1 (4-8 weeks), T2 (2-4 months), T3 (4-6 months), and T4 (9-12 months).
RESULTS: Objective tumor response and tumor control were achieved in 17/19 (89.5%) and 18/19 (94.7%) patients, respectively. FLR hypertrophy was observed at T1 (median 47.8%, p=0.0245), T2 (median 48.4%, p=0.0120), T3 (median 50.4%, p=0.0147), and T4 (median 59.1%, p=0.00023). Non-cirrhotic patients demonstrated greater hypertrophy by 6-month (median 55.8% vs 47.2%, p=0.0310). One patient developed a grade 3 adverse event (ascites requiring paracentesis) at 1-month follow-up. Grade 2 or above serum toxicities are associated with worse baseline Child-Pugh Score, serum albumin, and total bilirubin (p<0.05). Among 7 patients who underwent neoadjuvant mRL, two underwent resection and one received liver transplant.
CONCLUSION: mRL appears safe and effective for treatment of right-sided primary hepatic tumors with the benefit of promoting FLR hypertrophy.
PMID:38490364 | DOI:10.1016/j.jvir.2024.03.005
Medicine (Baltimore). 2024 Mar 15;103(11):e37460. doi: 10.1097/MD.0000000000037460.
ABSTRACT
Cholangiocarcinoma (CHOL) is a race malignant cancer arising from bile duct epithelial cells in clinical practice. C-X-C motif chemokine ligand 3 (CXCL3) is a member of chemokines family, which participates in the pathogenesis of various tumors. However, the association between CXCL3 and CHOL is unclear. This present study was to assess the role of CXCL3 expression in the progress of CHOL. TIMER, GEPIA, UALCAN, GSCA, LinkedOmics, Metascape and STRING databases were performed to evaluate the clinical and biological significances for CXCL3 with CHOL patients including expression, clinicopathological factors, immune cell infiltration, GO enrichment and KEGG pathway analyses, as well as PPI network analysis. The immunohistochemistry analysis of tissue microarray was conducted to detect the protein expression level, subcellular localization, clinicopathological factors and prognosis of CXCL3 in CHOL. The mRNA and protein expression levels of CXCL3 were markedly increased in CHOL tissues. The overexpression of CXCL3 was strongly associated with maximum tumor diameter of patients with CHOL. Additionally, there were negative correlations between the expression of CXCL3 and monocyte as well as Th17. Low infiltration of neutrophil indicated significantly shorter cumulative survival in CHOL patients. And CXCL3 was significantly associated with arm-level deletion of CD8+ T cell. Furthermore, functional network analysis suggested that CXCL3 and its associated genes were mainly enriched for chemotaxis, secretory granule membrane, cytokine activity and IL-17 signaling pathway. CXCL3 might potentially participate in the carcinogenesis of CHOL, which provided a direction for future research on the mechanism of CXCL3 in CHOL.
PMID:38489741 | PMC:PMC10939667 | DOI:10.1097/MD.0000000000037460
Trop Dis Travel Med Vaccines. 2024 Mar 15;10(1):6. doi: 10.1186/s40794-023-00215-8.
ABSTRACT
Hepatitis B and C virus, Opisthorchis viverrini and Clonorchis sinensis, are all individually known to put a person at increased risk for cholangiocarcinoma and hepatocellular carcinoma. This paper seeks to determine if there is any interaction between liver flukes and hepatitis virus infection that are known to put a person at an increased risk for cholangiocarcinoma and hepatocellular carcinoma collectively. This paper seeks to determine whether there is any publicly available articles in English that determine if having a hepatitis viral co-infection along with liver flukes would influence the risk of developing liver cancer. We followed PRISMA systematic review guidelines to conduct a literature review. Three manuscripts fit the search criteria. Two presented evidence in support of a synergistic relationship between liver fluke and viral hepatitis infection while the other found no relationship. One manuscript determined that the interaction between hepatitis B and C. sinensis did not have any significant risk of liver cancer. Studies found that HBV affected progression of co-infection to liver cancer but may have its own disease state worsened by presence of liver flukes. Only one paper was found that presented data on HCV, therefore no conclusion can be drawn due to the lack of evidence discovered. Of the studies, the conclusions and strength of the data were mixed. However, the stronger studies suggested a synergistic relationship between liver flukes and HBV to increase the risk of progressing to liver cancer.
PMID:38486298 | PMC:PMC10941421 | DOI:10.1186/s40794-023-00215-8
Cancers (Basel). 2024 Feb 23;16(5):899. doi: 10.3390/cancers16050899.
ABSTRACT
This international multicenter cohort study included 30 centers. Patients with duodenal adenocarcinoma (DAC), intestinal-type (AmpIT) and pancreatobiliary-type (AmpPB) ampullary adenocarcinoma, distal cholangiocarcinoma (dCCA), and pancreatic ductal adenocarcinoma (PDAC) were included. The primary outcome was 30-day or in-hospital mortality, and secondary outcomes were major morbidity (Clavien-Dindo 3b≥), clinically relevant post-operative pancreatic fistula (CR-POPF), and length of hospital stay (LOS). Results: Overall, 3622 patients were included in the study (370 DAC, 811 AmpIT, 895 AmpPB, 1083 dCCA, and 463 PDAC). Mortality rates were comparable between DAC, AmpIT, AmpPB, and dCCA (ranging from 3.7% to 5.9%), while lower for PDAC (1.5%, p = 0.013). Major morbidity rate was the lowest in PDAC (4.4%) and the highest for DAC (19.9%, p < 0.001). The highest rates of CR-POPF were observed in DAC (27.3%), AmpIT (25.5%), and dCCA (27.6%), which were significantly higher compared to AmpPB (18.5%, p = 0.001) and PDAC (8.3%, p < 0.001). The shortest LOS was found in PDAC (11 d vs. 14-15 d, p < 0.001). Discussion: In conclusion, this study shows significant variations in perioperative mortality, post-operative complications, and hospital stay among different periampullary cancers, and between the ampullary subtypes. Further research should assess the biological characteristics and tissue reactions associated with each type of periampullary cancer, including subtypes, in order to improve patient management and personalized treatment.
PMID:38473260 | PMC:PMC10930966 | DOI:10.3390/cancers16050899
Cancers (Basel). 2024 Feb 22;16(5):879. doi: 10.3390/cancers16050879.
ABSTRACT
First-line chemotherapy has been established for advanced biliary tract cancer (BTC). However, few treatment options are available as second-line treatment. Advances in comprehensive genomic analysis revealed that nearly half of patients with BTC harbor targetable genetic alterations such as fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), BRAF, human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI)-high, neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), and poly (adenosine diphosphate-ribose) polymerase (PARP). This review summarizes currently available options in precision medicine and clinical trials for patients with advanced BTC.
PMID:38473240 | PMC:PMC10931393 | DOI:10.3390/cancers16050879
Diagnostics (Basel). 2024 Feb 24;14(5):490. doi: 10.3390/diagnostics14050490.
ABSTRACT
Cholangiocarcinoma (CCA) is an adenocarcinoma originating from the epithelial cells of the bile ducts/hepatocytes or peribiliary glands. There are three types of cholangiocarcinoma: intrahepatic, perihilar and distal. CCA represents approximately 3% of the gastrointestinal malignancies. The incidence of CCA is higher in regions of the Eastern world compared to the Western countries. There are multiple risk factors associated with cholangiocarcinoma such as liver fluke, primary sclerosing cholangitis, chronic hepatitis B, liver cirrhosis and non-alcoholic fatty liver disease. Endoscopy plays an important role in the diagnosis and management of cholangiocarcinoma. The main endoscopic methods used for diagnosis, biliary drainage and delivering intrabiliary local therapies are endoscopic retrograde cholangiopancreatography and endoscopic ultrasound. The purpose of this review is to analyze the current data found in literature about cholangiocarcinoma, with a focus on the actual diagnostic tools and endoscopic management options.
PMID:38472961 | PMC:PMC10931405 | DOI:10.3390/diagnostics14050490
Ann Surg Oncol. 2024 Mar 12. doi: 10.1245/s10434-024-15115-0. Online ahead of print.
ABSTRACT
BACKGROUND: A right- or left-sided liver resection can be considered in about half of patients with perihilar cholangiocarcinoma (pCCA), depending on tumor location and vascular involvement. This study compared postoperative mortality and long-term survival of right- versus left-sided liver resections for pCCA.
METHODS: Patients who underwent major liver resection for pCCA at 25 Western centers were stratified according to the type of hepatectomy-left, extended left, right, and extended right. The primary outcomes were 90-day mortality and overall survival (OS).
RESULTS: Between 2000 and 2022, 1701 patients underwent major liver resection for pCCA. The 90-day mortality was 9% after left-sided and 18% after right-sided liver resection (p < 0.001). The 90-day mortality rates were 8% (44/540) after left, 11% (29/276) after extended left, 17% (51/309) after right, and 19% (108/576) after extended right hepatectomy (p < 0.001). Median OS was 30 months (95% confidence interval [CI] 27-34) after left and 23 months (95% CI 20-25) after right liver resection (p < 0.001), and 33 months (95% CI 28-38), 27 months (95% CI 23-32), 25 months (95% CI 21-30), and 21 months (95% CI 18-24) after left, extended left, right, and extended right hepatectomy, respectively (p < 0.001). A left-sided resection was an independent favorable prognostic factor for both 90-day mortality and OS compared with right-sided resection, with similar results after excluding 90-day fatalities.
CONCLUSIONS: A left or extended left hepatectomy is associated with a lower 90-day mortality and superior OS compared with an (extended) right hepatectomy for pCCA. When both a left and right liver resection are feasible, a left-sided liver resection is preferred.
PMID:38472674 | DOI:10.1245/s10434-024-15115-0
Cancer Res. 2024 Mar 12. doi: 10.1158/0008-5472.CAN-23-3298. Online ahead of print.
ABSTRACT
Intrahepatic cholangiocarcinoma (iCCA) is the second most prevalent primary liver cancer. While the genetic characterization of iCCA has led to targeted therapies for treating tumors with FGFR2 alterations and IDH1/2 mutations, only a limited number of patients can benefit from these strategies. Epigenomic profiles have emerged as potential diagnostic and prognostic biomarkers for improving treatment of cancers. In this study, we conducted whole-genome bisulfite sequencing on 331 iCCAs integrated with genetic, transcriptomic, and proteomic analyses, demonstrating the existence of four DNA methylation subtypes of iCCAs (S1-S4) that exhibited unique post-operative clinical outcomes. The S1 group was an IDH1/2-mutation-specific subtype with moderate survival. The S2 subtype was characterized by the lowest methylation level and the highest mutational burden among the four subtypes and displayed upregulation of a gene expression pattern associated with cell cycle/DNA replication. The S3 group was distinguished by high inter-patient heterogeneity of tumor immunity, a gene expression pattern associated with carbohydrate metabolism, and an enrichment of KRAS alterations. Patients with the S2 and S3 subtypes had the shortest survival among the four subtypes. Tumors in the S4 subtype, which had the best prognosis, showed global methylation levels comparable to normal controls, increased FGFR2 fusions/BAP1 mutations, and the highest copy number variant burdens. Further integrative and functional analyses identified GBP4 demethylation, which is highly prevalent in the S2 and S3 groups, as an epigenetic oncogenic factor that regulates iCCA proliferation, migration, and invasion. Together, this study identifies prognostic methylome alterations and epigenetic drivers in iCCA.
PMID:38471085 | DOI:10.1158/0008-5472.CAN-23-3298
Am J Physiol Gastrointest Liver Physiol. 2024 Mar 12. doi: 10.1152/ajpgi.00263.2023. Online ahead of print.
ABSTRACT
BACKGROUND AND AIMS: Tissue-specific gene manipulations are widely used in genetically engineered mouse models. A single recombinase system, such as the one using Alb-Cre, has been commonly used for liver-specific genetic manipulations. However, most diseases are complex, involving multiple genetic changes and various cell types. A dual recombinase system is required for conditionally modifying different genes sequentially in the same cell or inducing genetic changes in different cell types within the same organism.
METHODS: A FlpO cDNA was inserted between the last exon and 3'-UTR of the mouse albumin gene in a bacterial artificial chromosome (BAC-Alb-FlpO). The founders were crossed with various reporter mice to examine the efficiency of recombination. Liver cancer tumorigenesis was investigated by crossing the FlpO mice with FSF-KrasG12D mice and p53frt mice (KPF mice).
RESULTS: BAC-Alb-FlpO mice exhibited highly efficient recombination capability in both hepatocytes and intrahepatic cholangiocytes. No recombination was observed in the duodenum and pancreatic cells. BAC-Alb-FlpO-mediated liver-specific expression of mutant KrasG12D and conditional deletion of p53 gene caused the development of liver cancer. Remarkably, liver cancer in these KPF mice manifested a distinctive mixed hepatocellular carcinoma and cholangiocarcinoma phenotype.
CONCLUSIONS: A highly efficient and liver-specific BAC-Alb-FlpO mouse model was developed. In combination with other Cre lines, different genes can be manipulated sequentially in the same cell, or distinct genetic changes can be induced in different cell types of the same organism.
PMID:38469630 | DOI:10.1152/ajpgi.00263.2023
J Clin Imaging Sci. 2024 Feb 13;14:4. doi: 10.25259/JCIS_59_2023. eCollection 2024.
ABSTRACT
OBJECTIVES: Cholangiocarcinoma (CCA) is the second-most common primary hepatic malignancy with an increasing incidence over the past two decades. CCA arises from the epithelial cells lining the bile ducts and can be classified as intrahepatic, perihilar, or distal based on the site of origin in the biliary tree. Surgical resection is the definitive curative therapy for early-stage intrahepatic CCA; however, only a minority of patients may be ideal surgical candidates. Percutaneous microwave ablation (MWA) is a minimally invasive procedure widely used for hepatocellular carcinoma and colorectal cancer metastases to the liver. Growing evidence suggests MWA can play a role in the management of patients with early-stage intrahepatic CCA. In this study, we aim to describe the safety and efficacy of MWA for the management of intrahepatic CCA.
MATERIAL AND METHODS: A retrospective review of patients with intrahepatic CCA treated with MWA at our tertiary referral medical center was performed. Eight patients were treated between 2014 and 2019. Diagnosis of CCA was made based on histopathological studies of samples obtained by surgical resection or percutaneous liver biopsy. All procedures were performed under computed tomography (CT) guidance using a high-power single antenna MWA system. General anesthesia was used for all procedures. Patient medical history, procedural technical information, outcomes, and follow-up data were reviewed. Progression-free survival was estimated with a Kaplan-Meier curve.
RESULTS: A total of 25 tumors with an average size of 2.2 ± 1.7 cm (range 0.5-7.8) were treated with MWA. Our cohort consisted of eight patients (4 males and 4 females) with an average age of 69.3 ± 5.7 years (range 61-79). Three out of eight (3/8, 37.5%) patients were treated initially with surgical resection. NASH-related cirrhosis was documented in 3/8 (37.5%) patients, while 1/8 (12.5%) had alcoholic cirrhosis; the remaining 4 patients (4/8, 50%) did not have cirrhosis. All patients were discharged within 24 h after ablation. Average total follow-up time was 10.6 ± 11.8 months (range 0-41). The incomplete ablation rate and local recurrence rate were 4% (1/25 lesions) and 12% (3/25 lesions), respectively.
CONCLUSION: In patients who do not qualify for surgical resection, MWA is a safe alternative therapy for the treatment of intrahepatic CCA.
PMID:38469173 | PMC:PMC10927040 | DOI:10.25259/JCIS_59_2023
BMC Genomics. 2024 Mar 11;25(1):269. doi: 10.1186/s12864-023-09814-3.
ABSTRACT
BACKGROUND: Polymorphisms of Plasmodium falciparum chloroquine resistance transporter (pfcrt), Plasmodium falciparum multi-drug resistance 1 (pfmdr1) and Plasmodium falciparum kelch 13-propeller (pfk13) genes are accepted as valid molecular markers of quinoline antimalarials and artemisinins. This study investigated the distribution patterns of these genes in P. falciparum isolates from the areas along the Thai-Myanmar border during the two different periods of antimalarial usage in Thailand.
RESULTS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to detect pfcrt mutations at codons 76, 220, 271, 326, 356, and 371 as well as pfmdr1 mutation at codon 86. The prevalence of pfcrt mutations was markedly high (96.4-99.7%) in samples collected during both periods. The proportions of mutant genotypes (number of mutant/total isolate) at codons 76, 220, 271, 326, 356 and 371 in the isolates collected during 1993-1998 (period 1) compared with 2002-2008 (period 2) were 97.9% (137/140) vs. 97.1% (401/413), 97.9% (140/143) vs. 98.8% (171/173), 97.2% (139/143) vs. 97.1% (333/343), 98.6% (140/142) vs. 99.7% (385/386), 96.4% (134/139) vs. 98.2% (378/385) and 97.8% (136/139) vs. 98.9% (375/379), respectively. Most isolates carried pfmdr1 wild-type at codon 86, with a significant difference in proportions genotypes (number of wild type/total sample) in samples collected during period 1 [92.9% (130/140)] compared with period 2 [96.9% (379/391)]. Investigation of pfmdr1 copy number was performed by real-time PCR. The proportions of isolates carried 1, 2, 3 and 4 or more than 4 copies of pfmdr1 (number of isolates carried correspondent copy number/total isolate) were significantly different between the two sample collecting periods (65.7% (90/137) vs. 87.8% (390/444), 18.2% (25/137) vs. 6.3%(28/444), 5.1% (7/137) vs. 1.4% (6/444) and 11.0% (15/137) vs. 4.5% (20/444), for period 1 vs. period 2, respectively). No pfk13 mutation was detected by nested PCR and nucleotide sequencing in all samples with successful analysis (n = 68).
CONCLUSIONS: The persistence of pfcrt mutations and pfmdr1 wild-types at codon 86, along with gene amplification in P. falciparum, contributes to the continued resistance of chloroquine and mefloquine in P. falciparum isolates in the study area. Regular surveillance of antimalarial drug resistance in P. falciparum, incorporating relevant molecular markers and treatment efficacy assessments, should be conducted.
PMID:38468205 | PMC:PMC10929098 | DOI:10.1186/s12864-023-09814-3
Cancer Gene Ther. 2024 Mar 11. doi: 10.1038/s41417-024-00754-y. Online ahead of print.
ABSTRACT
Intrahepatic cholangiocarcinoma (ICC) is a primary epithelial carcinoma known for its aggressive nature, high metastatic potential, frequent recurrence, and poor prognosis. Heparanase (HPSE) is the only known endogenous β-glucuronidase in mammals. In addition to its well-established enzymatic roles, HPSE critically exerts non-catalytic function in tumor biology. This study herein aimed to investigate the non-enzymatic roles of HPSE as well as relevant regulatory mechanisms in ICC. Our results demonstrated that HPSE was highly expressed in ICC and promoted the proliferation of ICC cells, with elevated HPSE levels implicating a poor overall survival of ICC patients. Notably, HPSE interacted with Bcl-2-associated factor 1 (BCLAF1) to upregulate the expression of Bcl-2, which subsequently activated the PERK/eIF2α-mediated endoplasmic reticulum (ER) stress pathway to promote anti-apoptotic effect of ICC. Moreover, our in vivo experiments revealed that concomitant administration of gemcitabine and the Bcl-2 inhibitor navitoclax enhanced the sensitivity of ICC cells with highly expressed HPSE to chemotherapy. In summary, our findings revealed that HPSE promoted the development and drug resistance of ICC via its non-enzymatic function. Bcl-2 may be considered as an effective target with therapeutic potential to overcome ICC chemotherapy resistance induced by HPSE, presenting valuable insights into the development of novel therapeutic strategies against ICC.
PMID:38467765 | DOI:10.1038/s41417-024-00754-y
HPB (Oxford). 2024 Feb 28:S1365-182X(24)00053-4. doi: 10.1016/j.hpb.2024.02.016. Online ahead of print.
ABSTRACT
BACKGROUND: Although post-hepatectomy liver failure (PHLF) can accurately predict short-term mortality of liver resection for perihilar cholangiocarcinoma (pCCA), its significance in predicting long-term overall survival (OS) is still uncertain.
METHODS: Retrospective analysis was performed on patients with pCCA who underwent liver resection between October 2013 and December 2018. The patients were divided into 3 groups; No PHF, PHLF (all grade) and grade B/C PHLF according to The International Study Group of Liver Surgery (ISGLS) criteria.
RESULTS: A total of 177 patients were enrolled, 65 (36.7%) had PHLF; 25 (14.1%) had grade A, and 40 (22.6%) had grade B/C. Prior to surgery, patients with PHLF showed significantly greater bilirubin levels and CA 19-9 level than those without (11.5 vs 6.7 mg/dL, p = 0.002 and 232.4 vs 85.9 U/mL, p = 0.005, respectively). Additionally, pre-operative future liver remnant volume in PHLF group was lower than no PHLF group significantly (39.6% vs 43.5%, p = 0.006). Major complication and 90-day mortality were higher in PHLF group than no PHLF group (69.2% vs 20.5%, p < 0.001 and 29.2% vs 3.6%, p < 0.001, respectively). The OS in both grade A PHLF and grade B/C PHLF was significantly worse compared to no PHLF, with median survival times of 8.4, 3.3, and 19.2 months, respectively (p < 0.001 and p < 0.001, respectively). Multivariable analysis revealed that PHLF was independently prognostic factor for long-term survival.
CONCLUSION: To achieve negative resection margin, the surgical resection in pCCA was aggressive, however this increased the risk of PHLF, which also affects the OS. Consequently, it is necessary for establishing a balance between aggressive surgery and PHLF.
PMID:38467530 | DOI:10.1016/j.hpb.2024.02.016
Eur J Surg Oncol. 2024 Mar 7:108248. doi: 10.1016/j.ejso.2024.108248. Online ahead of print.
ABSTRACT
Intrahepatic and peri-hilar cholangiocarcinoma are life threatening disease with poor outcomes despite optimal treatment currently available (5-year overall survival following resection 20-35%, and <10% cured at 10-years post resection). The insidious onset makes diagnosis difficult, the majority do not have a resection option and the high recurrence rate post-resection suggests that occult metastatic disease is frequently present. Advances in perioperative management, such as ipsilateral portal vein (and hepatic vein) embolisation methods to increase the future liver remnant volume, genomic profiling, and (neo)adjuvant therapies demonstrate great potential in improving outcomes. However multiple areas of controversy exist. Surgical resection rate and outcomes vary between centres with no global consensus on how 'resectable' disease is defined - molecular profiling and genomic analysis could potentially identify patients unlikely to benefit from resection or likely to benefit from targeted therapies. FDG-PET scanning has also improved the ability to detect metastatic disease preoperatively and avoid futile resection. However tumours frequently invade major vasculo-biliary structures, with resection and reconstruction associated with significant morbidity and mortality even in specialist centres. Liver transplantation has been investigated for very selected patients for the last decade and yet the selection algorithm, surgical approach and both value of both neoadjuvant and adjuvant therapies remain to be clarified. In this review, we discuss the contemporary management of intrahepatic and peri-hilar cholangiocarcinoma.
PMID:38467524 | DOI:10.1016/j.ejso.2024.108248
Cell Cycle. 2024 Mar 11:1-14. doi: 10.1080/15384101.2024.2318949. Online ahead of print.
ABSTRACT
Cholangiocarcinoma (CCA) is a common gastrointestinal malignancy characterized by a poor prognosis. Considering its prevalence, exploring its underlying molecular biological mechanisms is of paramount clinical importance. In this study, bioinformatics techniques were utilized to analyze CCA sample data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The analysis revealed a notable upregulation in FUT4 expression in CCA samples. To further investigate the functional implications of FUT4, in vivo and in vitro experiments were conducted, which demonstrated that FUT4 overexpression significantly enhances the proliferative and migratory capabilities of tumor cells. Subsequent sequencing analysis unveiled a correlation between FUT4 and epithelial-mesenchymal transition (EMT). Indeed, the pioneering discovery of elevated FUT4 expression in CCA was highlighted in this study. Further investigations into the function of FUT4 in CCA provided initial insights into its role in driving cancer progression via EMT. These findings present promising avenues for the diagnosis and treatment of CCA.[Figure: see text].
PMID:38466946 | DOI:10.1080/15384101.2024.2318949
Clin Nucl Med. 2024 Feb 29. doi: 10.1097/RLU.0000000000005133. Online ahead of print.
ABSTRACT
DOTA-ibandronic acid (IBA) is a novel precursor targeting bone metastasis. It can be radiolabeled with 68Ga for the diagnosis of bone metastases. However, extraosseous lesions can also show increased DOTA-IBA uptake. We report the 68Ga-DOTA-IBA PET/CT findings in a case with cholangiocarcinoma with multiple bone metastases. 68Ga-DOTA-IBA PET/CT revealed increased uptake of DOTA-IBA in bone metastases. Besides, symmetrical and diffuse increased DOTA-IBA uptake in bilateral salivary glands was observed. 99mTcO4- salivary gland scintigraphy showed impaired salivary gland function.
PMID:38465977 | DOI:10.1097/RLU.0000000000005133
Clin Nucl Med. 2024 Mar 7. doi: 10.1097/RLU.0000000000005112. Online ahead of print.
ABSTRACT
PURPOSE: In this study, we evaluated and compared the diagnostic performances of 68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT for primary and metastatic cholangiocarcinoma (CCA) lesions. We also investigated the performance of PET/MR for visualizing and characterizing CCA and liver metastasis lesions.
PATIENTS AND METHODS: Forty-four patients with suspected CCA were recruited and underwent 68Ga-FAPI-04 and 18F-FDG PET/CT within 1 week, including 30 patients who underwent simultaneous abdominal 68Ga-FAPI-04 PET/MR scanning. The findings were confirmed by histopathology or radiographic follow-up.
RESULTS: Compared with 18F-FDG PET/CT, 68Ga-FAPI-04 PET/CT showed higher sensitivity (94.3% vs 88.6%) and the same accuracy (86.4% vs 86.4%) in evaluating primary tumors. However, its specificity was lower (55.6% vs 77.8%). 68Ga-FAPI-04 PET was superior to 18F-FDG PET in both patient-based and lesion-based evaluations except for metastatic lesions in the liver and bone. For intrahepatic CCA, 68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT (100% vs 100%) had similar detection rates, with similar uptake levels between tracers (P > 0.05). However, for extrahepatic CCA, 68Ga-FAPI-04 PET/CT had a higher detection rate (89.5% vs 78.9%), and 68Ga-FAPI-04 had a higher uptake (P < 0.05). PET/MR was more effective than PET/CT in terms of lesion conspicuity and diagnostic confidence for primary tumors and liver metastases. In addition, multisequence MRI identified more liver metastases than 68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT.
CONCLUSIONS: Compared with 18F-FDG PET/CT, 68Ga-FAPI-04 PET/CT showed a higher sensitivity in detecting primary CCA tumors, involved lymph nodes, and peritoneal metastases. Compared with 68Ga-FAPI-04 PET/CT, PET/MR detected primary and liver metastatic lesions more accurately. For extrahepatic CCA, the combination of 68Ga-FAPI-04 PET/CT and abdominal PET/MRI may replace 18F-FDG PET/CT.
PMID:38465929 | DOI:10.1097/RLU.0000000000005112
Am J Transl Res. 2024 Feb 25;16(2):690-699. eCollection 2024.
ABSTRACT
To clarify the mechanism underlying the development and poor prognosis of combined hepatocellular-cholangiocarcinoma (cHCC-CCA), we characterized liver cancer driver mutations and poor prognostic markers in both the HCC and intrahepatic CCA (iCCA) components of a cHCC-CCA tumor. The telomerase reverse transcriptase (TERT) promoter mutation C228T was quantified by digital polymerase chain reaction using DNA from multiple microdissected cancer components of a single cHCC-CCA nodule. The protein expression of cancer-related markers, including TERT, was examined by serial thin-section immunohistochemistry and double-staining immunofluorescence. TERT promoter mutation and TERT protein expression were detected in all cancer components but not in noncancer regions. TERT promoter mutation frequencies were similar among components; those of TERT protein-positive cancer cells were higher in iCCA and mixed components than in HCC. The frequencies of Ki67- and p53-positive cells were similarly higher in iCCA and mixed components than in HCC. However, double-positive cells for the three proteins were unexpectedly rare; single-positive cells dominated, indicating phenotypic microheterogeneity in cancer cells within a component. Interestingly, HCC and CCA marker protein immunohistochemistry suggested dedifferentiation of HCC and transdifferentiation from HCC to iCCA in HCC and iCCA components, respectively. Such phenotypic intercomponent heterogeneity and intracomponent microheterogeneity were detected in a tumor nodule of cHCC-CCA uniformly carrying the early HCC driver mutation. Moreover, poor prognostic markers were randomly expressed without a regular pattern, consistent with the poor prognosis.
PMID:38463590 | PMC:PMC10918120
SAGE Open Med Case Rep. 2024 Mar 8;12:2050313X241237612. doi: 10.1177/2050313X241237612. eCollection 2024.
ABSTRACT
Hyponatraemia is an uncommon complication of external biliary drainage. We report on a 62-year-old male with hilar cholangiocarcinoma who developed refractory severe hyponatraemia despite sodium replacement during preoperative external biliary drainage. Nasojejunal bile refeeding restored sodium levels to normal.
PMID:38463452 | PMC:PMC10924539 | DOI:10.1177/2050313X241237612
World J Gastrointest Surg. 2024 Feb 27;16(2):289-306. doi: 10.4240/wjgs.v16.i2.289.
ABSTRACT
BACKGROUND: Phospholipase A2 (PLA2) enzymes are pivotal in various biological processes, such as lipid mediator production, membrane remodeling, bioenergetics, and maintaining the body surface barrier. Notably, these enzymes play a significant role in the development of diverse tumors.
AIM: To systematically and comprehensively explore the expression of the PLA2 family genes and their potential implications in cholangiocarcinoma (CCA).
METHODS: We conducted an analysis of five CCA datasets from The Cancer Genome Atlas and the Gene Expression Omnibus. The study identified differentially expressed genes between tumor tissues and adjacent normal tissues, with a focus on PLA2G2A and PLA2G12B. Gene Set Enrichment Analysis was utilized to pinpoint associated pathways. Moreover, relevant hub genes and microRNAs for PLA2G2A and PLA2G12B were predicted, and their correlation with the prognosis of CCA was evaluated.
RESULTS: PLA2G2A and PLA2G12B were discerned as differentially expressed in CCA, manifesting significant variations in expression levels in urine and serum between CCA patients and healthy individuals. Elevated expression of PLA2G2A was correlated with poorer overall survival in CCA patients. Additionally, the study delineated pathways and miRNAs associated with these genes.
CONCLUSION: Our findings suggest that PLA2G2A and PLA2G12B may serve as novel potential diagnostic and prognostic markers for CCA. The increased levels of these genes in biological fluids could be employed as non-invasive markers for CCA, and their expression levels are indicative of prognosis, underscoring their potential utility in clinical settings.
PMID:38463362 | PMC:PMC10921223 | DOI:10.4240/wjgs.v16.i2.289
J Gastroenterol. 2024 Mar 10. doi: 10.1007/s00535-024-02090-2. Online ahead of print.
ABSTRACT
BACKGROUND: The tumor microbiome has been characterized in several malignancies; however, no previous studies have investigated its role in intrahepatic cholangiocarcinoma (ICC). Hence, we explored the tumor microbiome and its association with prognosis in ICC.
METHODS: One hundred and twenty-one ICC tumor samples and 89 adjacent normal tissues were profiled by 16S rRNA sequencing. Microbial differences between tumor and adjacent nontumoral liver tissues were assessed. Tumor microbial composition was then evaluated to detect its association with prognosis. Finally, a risk score calculated by the tumor microbiota was accessed by the least absolute shrinkage and selector operator method (Lasso) to predict prognosis of ICC.
RESULTS: The tumor microbiome displayed a greater diversity than that in adjacent nontumoral liver tissues. Tumor samples were characterized by a higher abundance of Firmicutes, Actinobacteria, Bacteroidetes, and Acidobacteriota. Higher tumor microbial α diversity was associated with lymph node metastasis and predicted shortened overall survival (OS) and recurrence-free survival (RFS). A total of 11 bacteria were selected to generate the risk score by Lasso. This score showed potential in predicting OS, and was an independent risk factor for OS.
CONCLUSION: In conclusion, our study characterized the tumor microbiome and revealed its role in predicting prognosis in ICC.
PMID:38461467 | DOI:10.1007/s00535-024-02090-2
HPB (Oxford). 2024 Feb 28:S1365-182X(24)00052-2. doi: 10.1016/j.hpb.2024.02.015. Online ahead of print.
ABSTRACT
BACKGROUND: This study aimed to develop a predictive score for intrahepatic cholangiocarcinoma (ICC) in patients without lymph node metastasis (LNM) using preoperative factors.
METHODS: A retrospective analysis of 113 ICC patients who underwent liver resection with systemic lymph node dissection between 2002 and 2021 was conducted. A multivariate logistic regression analysis was used as a predictive scoring system for node-negative patients based on the β coefficients of preoperatively available factors.
RESULTS: LNM was observed in 36 patients (31.9%). Four factors were associated with LNM: suspicion of LNM on MDCT (odds ratio [OR] 13.40, p < 0.001), low-vascularity tumor (OR 6.28, p = 0.005), CA19-9 ≥500 U/mL (OR 5.90, p = 0.010), and tumor location in the left lobe (OR 3.67, p = 0.057). The predictive scoring system was created using these factors (assigning 3 points for suspected LNM on MDCT, 2 points for CA19-9 ≥500 U/mL, 2 points for low vascularity tumor, and 1 point for tumor location in the left lobe). A score cutoff value of 4 resulted in 0.861 sensitivity and a negative predictive value of 0.922 for detecting LNM. Notably, no patients with peripheral tumors and a score of ≤3 had LNM.
CONCLUSION: The developed scoring system may effectively help identify ICC patients without LNM.
PMID:38461071 | DOI:10.1016/j.hpb.2024.02.015
J Transl Med. 2024 Mar 8;22(1):254. doi: 10.1186/s12967-024-04976-4.
ABSTRACT
BACKGROUND: Although hepatitis B virus (HBV) infection is a major risk factor for hepatic cancer, the majority of HBV carriers do not develop this lethal disease. Additional molecular alterations are thus implicated in the process of liver tumorigenesis. Since phosphatase and tensin homolog (PTEN) is decreased in approximately half of liver cancers, we investigated the significance of PTEN deficiency in HBV-related hepatocarcinogenesis.
METHODS: HBV-positive human liver cancer tissues were checked for PTEN expression. Transgenic HBV, Alb-Cre and Ptenfl/fl mice were inter-crossed to generate WT, HBV, Pten-/- and HBV; Pten-/- mice. Immunoblotting, histological analysis and qRT-PCR were used to study these livers. Gp73-/- mice were then mated with HBV; Pten-/- mice to illustrate the role of hepatic tumor biomarker golgi membrane protein 73 (GP73)/ golgi membrane protein 1 (GOLM1) in hepatic oncogenesis.
RESULTS: Pten deletion and HBV transgene synergistically aggravated liver injury, inflammation, fibrosis and development of mixed hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). GP73 was augmented in HBV; Pten-/- livers. Knockout of GP73 blunted the synergistic effect of deficient Pten and transgenic HBV on liver injury, inflammation, fibrosis and cancer development.
CONCLUSIONS: This mixed HCC-ICC mouse model mimics liver cancer patients harboring HBV infection and PTEN/AKT signaling pathway alteration. Targeting GP73 is a promising therapeutic strategy for cancer patients with HBV infection and PTEN alteration.
PMID:38459588 | PMC:PMC10924424 | DOI:10.1186/s12967-024-04976-4
Gut. 2024 Mar 8:gutjnl-2023-331715. doi: 10.1136/gutjnl-2023-331715. Online ahead of print.
ABSTRACT
OBJECTIVE: The correlation between cholangiocarcinoma (CCA) progression and bile is rarely studied. Here, we aimed to identify differential metabolites in benign and malignant bile ducts and elucidate the generation, function and degradation of bile metabolites.
DESIGN: Differential metabolites in the bile from CCA and benign biliary stenosis were identified by metabonomics. Biliary molecules able to induce mast cell (MC) degranulation were revealed by in vitro and in vivo experiments, including liquid chromatography-mass spectrometry (MS)/MS and bioluminescence resonance energy transfer assays. Histamine (HA) receptor expression in CCA was mapped using a single-cell mRNA sequence. HA receptor functions were elucidated by patient-derived xenografts (PDX) in humanised mice and orthotopic models in MC-deficient mice. Genes involved in HA-induced proliferation were screened by CRISPR/Cas9.
RESULTS: Bile HA was elevated in CCA and indicated poorer prognoses. Cancer-associated fibroblasts (CAFs)-derived stem cell factor (SCF) recruited MCs, and bile N,N-dimethyl-1,4-phenylenediamine (DMPD) stimulated MCs to release HA through G protein-coupled receptor subtype 2 (MRGPRX2)-Gαq signalling. Bile-induced MCs released platelet-derived growth factor subunit B (PDGF-B) and angiopoietin 1/2 (ANGPT1/2), which enhanced CCA angiogenesis and lymphangiogenesis. Histamine receptor H1 (HRH1) and HRH2 were predominantly expressed in CCA cells and CAFs, respectively. HA promoted CCA cell proliferation by activating HRH1-Gαq signalling and hastened CAFs to secrete hepatocyte growth factor by stimulating HRH2-Gαs signalling. Solute carrier family 22 member 3 (SLC22A3) inhibited HA-induced CCA proliferation by importing bile HA into cells for degradation, and SLC22A3 deletion resulted in HA accumulation.
CONCLUSION: Bile HA is released from MCs through DMPD stimulation and degraded via SLC22A3 import. Different HA receptors exhibit a distinct expression profile in CCA and produce different oncogenic effects. MCs promote CCA progression in a CCA-bile interplay pattern.
PMID:38458750 | DOI:10.1136/gutjnl-2023-331715
J Hepatol. 2024 Mar 6:S0168-8278(24)00127-2. doi: 10.1016/j.jhep.2024.02.008. Online ahead of print.
ABSTRACT
BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a poorly immunogenic malignancy with limited survival. Syngeneic, immunocompetent mouse models of CCA are an essential tool to elucidate the tumor immune microenvironment (TIME), understand mechanisms of tumor immune evasion, and test novel immunotherapeutic strategies. The scope of this study was to develop and characterize immunocompetent CCA models with distinct genetic drivers, and correlate tumor genomics, immunobiology, and therapeutic response.
METHODS: A multifaceted approach including scRNA-seq, CITE-seq, whole exome and RNA sequencing was employed. FDA-approved PD-1/PD-L1 antibodies were tested in humanized PD-1/PD-L1 mice (HuPD-H1).
RESULTS: A genetic mouse model of intrahepatic CCA (iCCA) driven by intrabiliary transduction of Fbxw7ΔF/Akt that mimics human iCCA was generated. From the Fbxw7ΔF/Akt tumors, a murine cell line (FAC) and syngeneic model with genetic and phenotypic characteristics of human iCCA were developed. Established SB1 (YAP/Akt) and KPPC (KrasG12Dp53L/L) models were compared to the FAC model. Although the models had transcriptomic similarities, they had substantial differences as well. Mutation patterns of SB1, KPPC, and FAC cells matched different mutation signatures in Western and Japanese CCA patient cohorts. KPPC tumors had a high tumor mutation burden. FAC tumors had a T cell-infiltrated TIME, while SB1 tumors had a preponderance of suppressive myeloid cells. SB1, FAC, and KPPC tumors matched different immune signatures in human iCCA cohorts. Moreover, SB1, KPPC, and FAC tumor-bearing HuPD-H1 mice had differential responses to nivolumab or durvalumab.
CONCLUSIONS: Syngeneic iCCA models display a tumor genotype-immune microenvironment phenotype correlation with differential responses to FDA-approved immunotherapy. This study underscores the importance of leveraging multiple preclinical models to understand immunotherapy response in different genetic subsets of human CCA.
PMID:38458319 | DOI:10.1016/j.jhep.2024.02.008
Int J Biol Macromol. 2024 Mar 6;264(Pt 2):130657. doi: 10.1016/j.ijbiomac.2024.130657. Online ahead of print.
ABSTRACT
Gelatin-based hydrogels are extensively used for 3D cell culture, bioprinting, and tissue engineering due to their cell-adhesive nature and tunable physio-chemical properties. Gelatin hydrogels for 3D cell culture are often developed using high-gelatin content (frequently 10-15 % w/v) to ensure fast gelation and improved stability. While highly stable, such matrices restrict the growth of encapsulated cells due to creating a dense, restrictive environment around the encapsulated cells. Hydrogels with lower polymer content are known to improve 3D cell growth, yet fabrication of ultra-low concentration gelatin hydrogels is challenging while ensuring fast gelation and stability. Here, we demonstrate that physical gelation and photo-crosslinking in gelatin results in a fast-gelling hydrogel at a remarkably low gelatin concentration of 1 % w/v (GelPhy/Photo). The GelPhy/Photo hydrogel was highly stable, allowed uniform 3D distribution of cells, and significantly improved the spreading of encapsulated 3T3 fibroblast cells. Moreover, human cholangiocarcinoma (HuCCT-1) cells encapsulated in 1 % GelPhy/Photo matrix grew and self-assembled into epithelial cysts with lumen, which could not be achieved in a traditional high-concentration gelatin hydrogel. These findings pave the way to significantly improve existing gelatin hydrogels for 3D cell culture applications.
PMID:38458282 | DOI:10.1016/j.ijbiomac.2024.130657
Cancer Med. 2024 Feb;13(4):e6892. doi: 10.1002/cam4.6892.
ABSTRACT
BACKGROUND AND AIMS: Cholangiocarcinoma (CCA), a rare and aggressive hepatobiliary malignancy, presents significant clinical management challenges. Despite rising incidence and evolving treatment options, prognosis remains poor, motivating the exploration of real-world data for enhanced understanding and patient care.
METHODS: This multicenter study analyzed data from 120 metastatic CCA patients at three institutions from 2016 to 2023. Kaplan-Meier curves assessed overall survival (OS), while univariate and multivariate analyses evaluated links between clinical variables (age, gender, tumor site, metastatic burden, ECOG performance status, response to first-line chemotherapy) and OS. Genetic profiling was conducted selectively.
RESULTS: Enrolled patients had a median age of 68.5 years, with intrahepatic tumors predominant in 79 cases (65.8%). Among 85 patients treated with first-line chemotherapy, cisplatin and gemcitabine (41.1%) was the most common regimen. Notably, one-third received no systemic treatment. After a median 14-month follow-up, 81 CCA-related deaths occurred, with a median survival of 13.1 months. Two clinical variables independently predicted survival: response to first-line chemotherapy (disease control vs. no disease control; HR: 0.27; 95% CI: 0.14-0.50; p < 0.0001) and metastatic involvement (>1 site vs. 1 site; HR: 1.99; 95% CI: 1.04-3.80; p = 0.0366). The three most common genetic alterations involved the ARID1A, tp53, and CDKN2A genes.
CONCLUSIONS: Advanced CCA displays aggressive clinical behavior, emphasizing the need for treatments beyond chemotherapy. Genetic diversity supports potential personalized therapies. Collaborative research and deeper CCA biology understanding are crucial to enhance patient outcomes in this challenging malignancy.
PMID:38457226 | PMC:PMC10923031 | DOI:10.1002/cam4.6892
Signal Transduct Target Ther. 2024 Mar 8;9(1):63. doi: 10.1038/s41392-024-01761-z.
ABSTRACT
Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells. Cancer cells could exhibit a "neural addiction" property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis. Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment. However, whether intrahepatic cholangiocarcinoma (ICC) could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown. Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that ICC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes ICC metastasis by inducing epithelial-mesenchymal transition (EMT). Acetylcholine promoted ICC metastasis through interacting with its receptor, alpha 5 nicotine acetylcholine receptor subunits (CHRNA5). Furthermore, acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca2+-mediated activation of Ca/calmodulin-dependent protein kinases (CAMKII). In addition, acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor (BDNF), which formed a feedforward acetylcholine-BDNF axis to promote ICC progression. KN93, a small-molecule inhibitor of CAMKII, significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells. Above all, Acetylcholine/CHRNA5 axis increased the expression of β-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKII/GSK3β signaling, and the CAMKII inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.
PMID:38453934 | PMC:PMC10920868 | DOI:10.1038/s41392-024-01761-z
Cell Signal. 2024 Mar 5;118:111126. doi: 10.1016/j.cellsig.2024.111126. Online ahead of print.
ABSTRACT
Cancer stem-like cells (CSLCs) and anoikis resistance play crucial roles in the metastasis of cancers. However, it remains unclear whether CSLCs are related to anoikis resistance in intrahepatic cholangiocarcinoma (ICC). Here we identified a group of stemness-related anoikis genes (SRAGs) via bioinformatic analysis of public data. Accordingly, a novel anoikis-related classification was established and it divided ICC into C1 and C2 type. Different type ICC displayed distinct prognosis, molecular as well immune characteristics. Furthermore, we found one key SRAGs via several machine learning algorithms. HK2 was up-regulated in tumor-repopulating cells (TRCs) of ICC, a kind of CSLCs with a potent resistance to anoikis. Its up-regulation may be caused by the activation of MTORC1 signaling in ICC-TRCs. And inhibition of HK2 significantly increased anoikis and decreased migration as well invasion in ICC-TRCs. Our studies provide an insight into the molecular mechanism underlying the resistance of ICC-TRCs to anoikis and enhance the evidences for targeting HK2 in ICC.
PMID:38453126 | DOI:10.1016/j.cellsig.2024.111126
Pathol Res Pract. 2024 Feb 23;256:155223. doi: 10.1016/j.prp.2024.155223. Online ahead of print.
ABSTRACT
Evidence suggests that long non-coding RNAs (lncRNAs) play a pivotal role in the carcinogenesis and progression of various human malignancies including gastrointestinal malignancies. This comprehensive review reports the functions and mechanisms of the lncRNA maternally expressed gene 3 (MEG3) involved in gastrointestinal malignancies. It summarizes its roles in mediating the regulation of cellular proliferation, apoptosis, migration, invasiveness, epithelial-to-mesenchymal transition, and drug resistance in several gastrointestinal cancers such as colorectal cancer, gall bladder cancer, pancreatic cancer, gastric cancer, esophageal cancer, cholangiocarcinoma, gastrointestinal stromal tumors and most importantly, hepatocellular carcinoma. In addition, the authors briefly highlight its implicated mechanistic role and interactions with different non-coding RNAs and oncogenic signaling cascades. This review presents the rationale for developing non coding RNA-based anticancer therapy via harnessing the power of MEG3 in gastrointestinal malignancies.
PMID:38452587 | DOI:10.1016/j.prp.2024.155223
Phys Med. 2024 Mar 6;120:103322. doi: 10.1016/j.ejmp.2024.103322. Online ahead of print.
ABSTRACT
PURPOSE: This study aimed to evaluate the ability of MRI-based intratumoral and peritumoral radiomics features of liver tumors to differentiate between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) and to predict ICC differentiation.
METHODS: This study retrospectively collected 87 HCC patients and 75 ICC patients who were confirmed pathologically. The standard region of interest (ROI) of the lesion drawn by the radiologist manually shrank inward and expanded outward to form multiple ROI extended regions. A three-step feature selection method was used to select important radiomics features and convolution features from extended regions. The predictive performance of several machine learning classifiers on dominant feature sets was compared. The extended region performance was assessed by area under the curve (AUC), specificity, sensitivity, F1-score and accuracy.
RESULTS: The performance of the model is further improved by incorporating convolution features. Compared with the standard ROI, the extended region obtained better prediction performance, among which 6 mm extended region had the best prediction ability (Classification: AUC = 0.96, F1-score = 0.94, Accuracy: 0.94; Grading: AUC = 0.94, F1-score = 0.93, Accuracy = 0.89).
CONCLUSION: Larger extended region and fusion features can improve tumor predictive performance and have potential value in tumor radiology.
PMID:38452430 | DOI:10.1016/j.ejmp.2024.103322
Heliyon. 2024 Feb 28;10(5):e27217. doi: 10.1016/j.heliyon.2024.e27217. eCollection 2024 Mar 15.
ABSTRACT
Trilobolide-6-O-isobutyrate exhibits significant antitumor effects on cholangiocarcinoma (CCA) cells by effectively inhibiting the JAK/STAT3 signaling pathway. This study aims to investigate the mechanisms underlying the antitumor properties of trilobolide-6-O-isobutyrate, and to explore its potential as a therapeutic agent for CCA. This study illustrates that trilobolide-6-O-isobutyrate efficiently suppresses CCA cell proliferation in a dose- and time-dependent manner. Furthermore, trilobolide-6-O-isobutyrate stimulates the production of reactive oxygen species, leading to oxidative stress and initiation of apoptosis via the activation of the mitochondrial pathway. Data from xenograft tumor assays in nude mice confirms that TBB inhibits tumor growth, and that there are no obvious toxic effects or side effects in vivo. Mechanistically, trilobolide-6-O-isobutyrate exerts antitumor effects by inhibiting STAT3 transcriptional activation, reducing PCNA and Bcl-2 expression, and increasing P21 expression. These findings emphasizes the potential of trilobolide-6-O-isobutyrate as a promising therapeutic candidate for the treatment of CCA.
PMID:38449612 | PMC:PMC10915568 | DOI:10.1016/j.heliyon.2024.e27217
Ther Adv Med Oncol. 2024 Mar 5;16:17588359241235799. doi: 10.1177/17588359241235799. eCollection 2024.
ABSTRACT
Biliary tract cancers (BTCs), consisting of intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, are an aggressive, heterogeneous malignancy. They are most often diagnosed in the locally advanced or metastatic setting, at which point treatment consists of systemic therapy or best supportive care. Our understanding of the tumor microenvironment and the molecular classification has led to the identification of targetable mutations, such as isocitrate dehydrogenase 1 and fibroblast growth factor receptor 2. Despite the identification of these genomic alterations, until recently, little advancement had been made in the first-line setting for advanced BTC. While immunotherapy (IO) has revolutionized the treatment of many malignancies, the use of IO in BTC had yielded limited results prior to TOPAZ-1. In this review, we discuss the systemic therapeutic advances for BTC over the past decade, the rationale for immunotherapy in BTC, prior trials utilizing IO in BTC, and current and emerging immune-based therapeutic options. We further analyze the culmination of these advances, which resulted in the approval of durvalumab with gemcitabine and cisplatin for the first-line treatment of BTC per TOPAZ-1. We also discuss the results of KEYNOTE-966, which similarly reported improved clinical outcomes with the use of pembrolizumab in combination with gemcitabine and cisplatin.
PMID:38449562 | PMC:PMC10916472 | DOI:10.1177/17588359241235799
Ann Surg Oncol. 2024 Mar 6. doi: 10.1245/s10434-024-15156-5. Online ahead of print.
NO ABSTRACT
PMID:38448738 | DOI:10.1245/s10434-024-15156-5
Zhonghua Nei Ke Za Zhi. 2024 Mar 1;63(3):291-294. doi: 10.3760/cma.j.cn112138-112138-20231106-00299.
ABSTRACT
Objective: Quantified MRCP imaging data was used as a reference for design and preparation of a modified percutaneous transhepatic cholangio drainage (PTCD) tube. Methods: 3.0 T upper abdominal MR and MRCP imaging data of 2 300 patients treated from July 2015 to July 2020 at the Department of Radiology of the Affiliated Cancer Hospital of Zhengzhou University were screened and a total of 381 patients diagnosed with biliary duct structures were identified. Causative etiologies among these patients included pancreatic adenocarcinoma (pancreatic head), cholangiocarcinoma, ampullary carcinoma, as well as intrahepatic and/or extrahepatic bile duct dilation. An improved PTCD tube was designed based on MRCP quantification of left and right hepatic and common hepatic duct length. Results: In the setting of biliary obstruction caused by malignancy, the distance of the left hepatic duct from its origin to the point of left and right hepatic duct confluence was 15.9±3.8 mm, while the distance of the right hepatic duct from its origin to the point of left and right hepatic duct confluence was 12.4±3.2 mm; the length of the bile duct from its origin to the point of left and right hepatic duct confluence was 34.0±8.1 mm. The improved PTCD tube design incorporated an altered length of the drainage orifice. Conclusion: MRCP imaging of the biliary tract is effective for measuring biliary tract length in the setting of pathological dilation. Based on our biliary tract measurements, a modified PTCD tube was designed to more effectively meet drainage requirements and manage biliary obstruction caused by Bismuth-Corlette type Ⅱ and Ⅲ malignancies.
PMID:38448193 | DOI:10.3760/cma.j.cn112138-112138-20231106-00299
Dig Surg. 2024 Mar 6. doi: 10.1159/000535995. Online ahead of print.
ABSTRACT
BACKGROUND: Prognosis of peri-hilar cholangiocarcinoma (PHCC) is poor and curative-intent resection is the most effective treatment associated with long-term survival. Surgery is technically demanding since it involves a major hepatectomy with en-bloc resection of caudate lobe and extrahepatic bile duct. Furthermore, to achieve negative margins, it may be necessary to perform concomitant vascular resection or pancreatoduodenectomy. Despite this aggressive approach, recurrence is often observed considering 5-year RFS below 15%, and 5-year OS that barely exceeds 40%.
SUMMARY: The literature reports that survival rates are better in patients with negative margins and surprisingly R0 resections range between 19% and 95%. This variability is probably due to different surgical strategies and the pathologist's expertise with specimens. In fact, a proper pathological examination of residual disease should take into consideration both the ductal and the radial margin (RM) status. Currently, detailed pathological reports are lacking and there is a likelihood of misinterpreting residual disease status due to the missing of RM description and the utilization of various definitions for surgical margins.
KEY MESSAGES: The aim of PHCC surgery is to achieve negative margins including RM. More clarity in reporting on RM is needed to define true radical resection and consistent design of oncological studies for adjuvant treatments.
PMID:38447545 | DOI:10.1159/000535995
HPB (Oxford). 2024 Feb 1:S1365-182X(24)00016-9. doi: 10.1016/j.hpb.2024.01.014. Online ahead of print.
ABSTRACT
BACKGROUND: Anatomical sectionectomy based on Takasaki's segmentation has shown advantages in hepatocellular carcinoma. However, whether this approach improves the survival of intrahepatic cholangiocarcinoma (ICC) remains unknown.
METHODS: A series of 248 consecutive patients with solitary ICCs who underwent hepatectomy were studied retrospectively. The patients were classified into the groups of anatomical sectionectomy based on Takasaki's segmentation (TS group) and non-Takasaki's hepatectomy (NTH group). The bias between the two groups was minimized using propensity score matching (PSM). Recurrence-free survival (RFS) and overall survival (OS) were evaluated with Kaplan-Meier analysis. The Cox proportional hazards model was performed to determine the adverse risk factors associated with survival.
RESULTS: After PSM, 67 pairs of patients were compared. Both the RFS and OS rates in the TS group were significantly better than those in the NTH group (23.2 % vs. 16.5 %, and 40.4 % vs. 27.3 %, P = 0.035 and 0.032, respectively). Multivariate analysis showed that NTH was independently associated with worse RFS and OS than TS. The stratified analysis demonstrated that the RFS and OS rates in the TS group with tumor stage I and tumor size ≥3 cm were significantly better than those in the NTH group, while the survival rates for ICC with stage I and tumor size <3 cm or stage II-III showed no significant difference.
CONCLUSION: TS was associated with improved RFS and OS in patients with solitary ICC even after PSM. TS may be preferred particularly in patients with tumor stage I and tumor size ≥3 cm.
PMID:38485565 | DOI:10.1016/j.hpb.2024.01.014
J Pharmacol Sci. 2024 Apr;154(4):301-311. doi: 10.1016/j.jphs.2024.02.012. Epub 2024 Feb 24.
ABSTRACT
Amino acid transporter LAT1 is highly upregulated in various cancer types, including cholangiocarcinoma (CHOL), and contributes to the rapid proliferation of cancer cells and disease progression. However, the molecular mechanisms underlying the pathological upregulation of LAT1 remain largely unknown. This study pursued the possibility of miRNA-mediated regulation of the LAT1 expression in CHOL cells. Using online target prediction methods, we extracted five candidate miRNAs commonly predicted to regulate the LAT1 expression. Three of them, miR-194-5p, miR-122-5p, and miR-126-3p, were significantly downregulated in CHOL cancer compared to normal tissues. Correlation analysis revealed weak-to-moderate negative correlations between the expression of these miRNAs and LAT1 mRNA in CHOL cancer tissues. We selected miR-194-5p and miR-122-5p for further analyses and found that both miRNAs functionally target 3'UTR of LAT1 mRNA by a luciferase-based reporter assay. Transfection of the miRNA mimics significantly suppressed the LAT1 expression at mRNA and protein levels and inhibited the proliferation of CHOL cells, with a trend of affecting intracellular amino acids and amino acid-related signaling pathways. This study indicates that the decreased expression of these LAT1-targeting tumor-suppressive miRNAs contributes to the upregulation of LAT1 and the proliferation of CHOL cells, highlighting their potential for developing novel cancer therapeutics and diagnostics.
PMID:38485348 | DOI:10.1016/j.jphs.2024.02.012
Eur J Surg Oncol. 2024 Mar 4;50(4):108246. doi: 10.1016/j.ejso.2024.108246. Online ahead of print.
ABSTRACT
BACKGROUND: Sarcopenia is associated with adverse prognosis of intrahepatic cholangiocarcinoma (iCCA) after surgery.
METHODS: 321 patients with iCCA undergoing surgery were retrospectively recruited and assigned to training and validation cohort. Skeletal muscle index (SMI) was assessed to define sarcopenia. Logistic regression and cox regression analysis were used to identify risk factors. A novel sarcopenia-based nomogram was constructed and validated by ROC curves, calibration curves, and DCA curves.
RESULTS: 260 patients were included for analysis. The median age was 63.0 years and 161 patients (61.9%) were diagnosed with sarcopenia. Patients with sarcopenia exhibited a higher rate of postoperative complications, a worse OS and RFS than patients without sarcopenia. Sarcopenia, low albumin and intraoperative blood transfusion were independent risk factors of postoperative complications, while sarcopenia and low albumin were risk factors of high CCI≥26.2. Sarcopenia, high PS score, low-undifferentiated differentiation, perineural invasion, TNM stage III-IV were risk factors of OS, and a novel nomogram based on these five factors was built to predict the 12-, 24-, and 36-months OS, with the mean AUC > 0.6.
CONCLUSION: Sarcopenia is negatively associated with both postoperative complications and survival prognosis of iCCA undergoing hepatectomy.
PMID:38484491 | DOI:10.1016/j.ejso.2024.108246
Chirurgia (Bucur). 2024 Mar;119(Ahead of print):1-13. doi: 10.21614/chirurgia.2945.
ABSTRACT
Introduction: intrahepatic cholangiocarcinoma (ICCA) are rare, aggressive cancers that develop in second order or smaller bile ducts. The aim of this review is to systematically review the most important prognostic factors affecting the long-term outcomes of these patients. Material and Methods: articles conducted on this issue, written in English, published between from January 2000 to December 2023 in Cochrane Library, PubMed, Embase, MedLine, Web of Science, Elsevier, Google Scholar were systematically researched and reviewed. Results: ICCA are usually late diagnosed cancers because of the asymptomatic character, and curative procedures are often not feasible, only 20 to 30% of patients being fit for surgery. With the prognostic of this aggressive malignancy being baleful, the most important risk factors but also prognosis factors seem to be represented by socioeconomic factors, morphological presentation, dimensions, number and extension of the tumor as well as resection margins. Conclusions: once these factors are widely recognized and identified in each case, the clinician will be able to find the best treatment for these patients in order to improve the long-term outcomes.
PMID:38484362 | DOI:10.21614/chirurgia.2945
J Gastrointest Oncol. 2024 Feb 29;15(1):485-490. doi: 10.21037/jgo-23-815. Epub 2024 Jan 16.
ABSTRACT
BACKGROUND: Cholangiocarcinoma (CCA) is a rare and aggressive gastrointestinal cancer. Unfortunately, 60% to 70% of early-stage CCA patients experience disease recurrence after curative resection and standard adjuvant therapy. Currently, there is no reliable tool to identify CCA recurrence before radiographic detection. Longitudinal monitoring of circulating tumor DNA (ctDNA) has shown promising value in molecular identification of relapse prior to conventional surveillance in other solid tumors. However, there is a scarcity of data on ctDNA in CCA after curative surgery.
CASE DESCRIPTION: An 81-year-old male with stage 3A intrahepatic CCA achieved radiographic remission after curative resection and was started on standard adjuvant capecitabine on post-operative day (POD) 50. Tumor-informed ctDNA tested positive on two consecutive occasions, with the titer increasing from 0.16 mean tumor molecule (MTM)/mL on POD 92 to 0.80 MTM/mL on POD 183, despite being on capecitabine. carbohydrate antigen 19-9 (CA19-9) also continued to increase from 175.6 U/mL on POD 92 to 7,594.9 U/mL on POD 217. Notably, surveillance computed tomography (CT) scans showed no evidence of disease (NED) on POD 126, 186, and 211. Molecular profiling and next-generation sequencing (NGS) panels from CCA tissue revealed microsatellite instability-high (MSI-H). After extensive discussions with the patient regarding the rising ctDNA titer despite being on capecitabine for nearly 6 months, we initiated pembrolizumab on POD 224 prior to radiographic recurrence. Given the tumor is MSI-H, and the preferred toxicity profile compared to the front-line chemotherapy option for CCA, we started pembrolizumab. ctDNA became undetectable, and CA19-9 returned to the reference range with pembrolizumab. As of the last follow-up on POD 876, the patient has continued pembrolizumab without noticeable side effects, and imaging continues to show NED, with persistent negative ctDNA and normal CA19-9 levels.
CONCLUSIONS: This case demonstrates the potential utility of tumor-informed ctDNA in CCA as (I) an early detection tool before radiographic recurrence; (II) a response monitoring tool as a surrogate biomarker that can guide therapy optimization; and (III) shows that early intervention with immunotherapy or potentially targeted agents based on ctDNA may lead to improved survival outcomes.
PMID:38482231 | PMC:PMC10932665 | DOI:10.21037/jgo-23-815
J Gastrointest Oncol. 2024 Feb 29;15(1):478-484. doi: 10.21037/jgo-23-139. Epub 2024 Feb 1.
ABSTRACT
BACKGROUND: Small molecule fibroblast growth factor receptor (FGFR) inhibitors, such as pemigatinib, have been developed for the treatment of cholangiocarcinoma (CCA) with rearrangements or fusions in the FGFR2. FGFR inhibitors (FGFRis) have dermatologic side effects such as dry skin or nail bed damage. However, in very rare instances, a life-threatening vascular calcification disease known as calciphylaxis has been linked to these therapies.
CASE DESCRIPTION: We report a patient with metastatic CCA, who developed calciphylaxis following the start of their pemigatinib treatment. Calciphylaxis is associated with skin lesions and affects the dermal microvasculature in addition to the vascular calcification. This case focuses on the management strategy used for this rare adverse event (AE) as well as the pathology and complicated mechanism of calciphylaxis. We highlight the unclear pathophysiology behind this disease by identifying key players in the signaling and molecular pathways in the microenvironment that are needed to trigger this pathology.
CONCLUSIONS: Calciphylaxis is normally associated with advanced renal failure in the setting of high phosphate and calcium. However, the patient we present here did not have advanced renal failure or high calcium levels and calcium dysregulation. As FGFRi use becomes more widespread, the more important it becomes to identify and have a treatment strategy for this rare AE.
PMID:38482230 | PMC:PMC10932651 | DOI:10.21037/jgo-23-139
Ann Gastroenterol. 2024 Mar-Apr;37(2):133-141. doi: 10.20524/aog.2024.0861. Epub 2024 Feb 14.
ABSTRACT
Integrating artificial intelligence (AI) into gastrointestinal (GI) endoscopy heralds a significant leap forward in managing GI disorders. AI-enabled applications, such as computer-aided detection and computer-aided diagnosis, have significantly advanced GI endoscopy, improving early detection, diagnosis and personalized treatment planning. AI algorithms have shown promise in the analysis of endoscopic data, critical in conditions with traditionally low diagnostic sensitivity, such as indeterminate biliary strictures and pancreatic cancer. Convolutional neural networks can markedly improve the diagnostic process when integrated with cholangioscopy or endoscopic ultrasound, especially in the detection of malignant biliary strictures and cholangiocarcinoma. AI's capacity to analyze complex image data and offer real-time feedback can streamline endoscopic procedures, reduce the need for invasive biopsies, and decrease associated adverse events. However, the clinical implementation of AI faces challenges, including data quality issues and the risk of overfitting, underscoring the need for further research and validation. As the technology matures, AI is poised to become an indispensable tool in the gastroenterologist's arsenal, necessitating the integration of robust, validated AI applications into routine clinical practice. Despite remarkable advances, challenges such as operator-dependent accuracy and the need for intricate examinations persist. This review delves into the transformative role of AI in enhancing endoscopic diagnostic accuracy, particularly highlighting its utility in the early detection and personalized treatment of GI diseases.
PMID:38481787 | PMC:PMC10927620 | DOI:10.20524/aog.2024.0861
Trop Med Int Health. 2024 Mar 14. doi: 10.1111/tmi.13983. Online ahead of print.
ABSTRACT
BACKGROUND: Cholangiocarcinoma (CCA) caused by Opisthorchis viverrini is a well-known and significant public health issue in northeastern Thailand; however, a link between pesticide exposure (PE) and CCA risk has not yet been established. Therefore, our research objective was to investigate the relationship between PE and CCA risk.
METHODS: A hospital-based matched case-control study was carried out. All cases (in-patients) and controls (out-patients) were volunteers at a tertiary hospital in northeast Thailand. Between 2015 and 2019, 178 incident cases of pathologically-confirmed CCA and 356 controls were selected from the check-up clinic from the Srinagarind Hospital outpatient database (two controls per case). The recruited controls were individually-matched to the CCA cases based on sex, age (±5 years) and admission date (±3 months). During face-to-face interviews, a standardised pre-tested questionnaire was used to collect data. Multivariable conditional logistic regression was used to analyse the data.
RESULTS: The respective frequency of PE between the 178 CCA cases and 356 controls was 77.0% versus 87.6% for never used, 14.6% versus 5.3% for have used but stopped and 8.4% versus 7.0% for currently using. After adjusting for the highest educational attainment, smoking behaviour, alcohol use and family history of cancer, PE was not significantly associated with CCA (p-value = 0.086). Using volunteers who have never used PE as the reference group, the respective odds of developing CCA for those who have ever used but have since stopped and are currently using was 2.04 (adjusted OR = 2.04; 95% CI: 1.03-4.04) versus 0.83 (adjusted OR = 0.83; 95% CI: 0.39-1.76) times more likely to develop CCA than those who had never used PE.
CONCLUSION: There is no association between PE and the risk of CCA. Notwithstanding the finding, future research should focus on enhancing PE assessment methods that consider complex chemical mixtures, chemicals of interest, historical exposure and exposure pathways. Moreover, there is need for more extensive and longer population-based cohort studies that include younger, non-occupationally exposed individuals during periods of developmental susceptibility.
PMID:38481371 | DOI:10.1111/tmi.13983
Ann Surg Oncol. 2024 Mar 13. doi: 10.1245/s10434-024-15161-8. Online ahead of print.
ABSTRACT
BACKGROUND: Currently, an effective tracer technique for lymphatic drainage during laparoscopic surgery has not been established. This study aimed to elucidate a new fluorescence, imaging technique targeting the hepatic lymphatic drainage area, using indocyanine green (ICG).
METHODS: A patient diagnosed with intrahepatic cholangiocarcinoma (ICC) located in segment 8 of the liver was injected with ICG into the connective tissue of the Glisson pedicle supplied by the lesion's liver segment, avoiding the bile duct, portal vein, and hepatic artery. This was performed under the guidance of laparoscopic ultrasonographic localization to trace the lymph nodes.
RESULTS: The lymphatic drainage area traced intraoperatively by ICG was consistent with the definition of the right regional lymph nodes for ICC. The lymph nodes were dissected, followed by addition of a fluorescence tracer.
CONCLUSIONS: Mastering intraoperative ultrasonic puncture technology can enable effective and accurate tracing of the lymph nodes of the liver segment where the lesion is located. However, the technical standards for this methodology need to be established through further studies.
PMID:38480563 | DOI:10.1245/s10434-024-15161-8
Cancer Sci. 2024 Mar 13. doi: 10.1111/cas.16140. Online ahead of print.
ABSTRACT
Cholangiocarcinoma (CCA) is one of the most difficult malignancies to treat as the therapeutic options are limited. Although several driver genes have been identified, most remain unknown. In this study, we identified a failed axon connection homolog (FAXC), whose function is unknown in mammals, by analyzing serially passaged CCA xenograft models. Knockdown of FAXC reduced subcutaneous tumorigenicity in mice. FAXC was bound to annexin A2 (ANXA2) and c-SRC, which are tumor-promoting genes. The FAXC/ANXA2/c-SRC complex forms in the mitochondria. FAXC enhances SRC-dependent ANXA2 phosphorylation at tyrosine-24, and the C-terminal amino acid residues (351-375) of FAXC are required for ANXA2 phosphorylation. Transcriptome data from a xenografted CCA cell line revealed that FAXC correlated with epithelial-mesenchymal transition, hypoxia, and KRAS signaling genes. Collectively, these findings advance our understanding of CCA tumorigenesis and provide candidate therapeutic targets.
PMID:38480477 | DOI:10.1111/cas.16140
Cancer Lett. 2024 Mar 11;588:216799. doi: 10.1016/j.canlet.2024.216799. Online ahead of print.
ABSTRACT
As two major types of primary liver cancers, the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have been well studied separately. However, a systemic assessment of the similarities and differences between the TIME of HCC and ICC is still lacking. In this study, we pictured a landscape of combined TIME of HCC and ICC by sequencing and integrating 41 single-cell RNA-seq samples from four different tissue types of both malignancies. We found that T cells in HCC tumors generally exhibit higher levels of immunosuppression and exhaustion than those in ICC tumors. Myeloid cells in HCC and ICC tumors also exhibit distinct phenotypes and may serve as a key factor driving the differences between their TIMEs. Besides, we identified a cluster of EGR1+ macrophages specifically enriched in HCC tumors. Together, our study provides new insights into cellular composition, states and interactions in the TIMEs of HCC and ICC, which could pave the way for the development of future therapeutic targets for liver cancers.
PMID:38479553 | DOI:10.1016/j.canlet.2024.216799
Cancer Sci. 2024 Mar 12. doi: 10.1111/cas.16143. Online ahead of print.
ABSTRACT
Cholangiocarcinoma often remains undetected until advanced stages due to the lack of reliable diagnostic markers. Our goal was to identify a unique secretory protein for cholangiocarcinoma diagnosis and differentiation from other malignancies, benign hepatobiliary diseases, and chronic liver conditions. We conducted bulk RNA-seq analysis to identify genes specifically upregulated in cholangiocarcinoma but not in most other cancers, benign hepatobiliary diseases, and chronic liver diseases focusing on exocrine protein-encoding genes. Single-cell RNA sequencing examined subcellular distribution. Immunohistochemistry and enzyme-linked immunosorbent assays assessed tissue and serum expression. Diagnostic performance was evaluated via receiver-operating characteristic (ROC) analysis. Inter-alpha-trypsin inhibitor heavy chain family member five (ITIH5), a gene encoding an extracellular protein, is notably upregulated in cholangiocarcinoma. This elevation is not observed in most other cancer types, benign hepatobiliary diseases, or chronic liver disorders. It is specifically expressed by malignant cholangiocytes. ITIH5 expression in cholangiocarcinoma tissues exceeded that in nontumorous bile duct, hepatocellular carcinoma, and nontumorous hepatic tissues. Serum ITIH5 levels were elevated in cholangiocarcinoma compared with controls (hepatocellular carcinoma, benign diseases, chronic hepatitis B, and healthy individuals). ITIH5 yielded areas under the ROC curve (AUCs) from 0.839 to 0.851 distinguishing cholangiocarcinoma from controls. Combining ITIH5 with carbohydrate antigen 19-9 (CA19-9) enhanced CA19-9's diagnostic effectiveness. In conclusion, serum ITIH5 may serve as a novel noninvasive cholangiocarcinoma diagnostic marker.
PMID:38475675 | DOI:10.1111/cas.16143
Cells. 2024 Feb 20;13(5):366. doi: 10.3390/cells13050366.
ABSTRACT
The term cholangiocarcinoma (CCA) defines a class of epithelial malignancies originating from bile ducts. Although it has been demonstrated that CCA patients with perineural invasion (PNI) have a worse prognosis, the biological features of this phenomenon are yet unclear. Our data show that in human intrahepatic CCA specimens with documented PNI, nerve-infiltrating CCA cells display positivity of the epithelial marker cytokeratin 7, lower with respect to the rest of the tumor mass. In an in vitro 3D model, CCA cells move towards a peripheral nerve explant allowing contact with Schwann cells (SCs) emerging from the nerve. Here, we show that SCs produce soluble factors that favor the migration, invasion, survival and proliferation of CCA cells in vitro. This effect is accompanied by a cadherin switch, suggestive of an epithelial-mesenchymal transition. The influence of SCs in promoting the ability of CCA cells to migrate and invade the extracellular matrix is hampered by a specific TGFβ receptor 1 (TGFBR1) antagonist. Differential proteomic data indicate that the exposure of CCA cells to SC secreted factors induces the upregulation of key oncogenes and the concomitant downregulation of some tumor suppressors. Taken together, these data concur in identifying SCs as possible promoters of a more aggressive CCA phenotype, ascribing a central role to TGFβ signaling in regulating this process.
PMID:38474330 | PMC:PMC10930666 | DOI:10.3390/cells13050366
Cancers (Basel). 2024 Mar 6;16(5):1070. doi: 10.3390/cancers16051070.
ABSTRACT
BACKGROUND: ALPPS leads to fast and effective liver hypertrophy. This enables the resection of extended tumors. Conventional ALPPS is associated with high morbidity and mortality. MILS reduces morbidity and the robot adds technical features that make complex procedures safe.
MATERIAL AND METHODS: The MD-MILS was screened for patients who underwent rALPPS. Demographic and perioperative data were evaluated retrospectively. Ninety days postoperative morbidity was scored according to the CD classification. The findings were compared with the literature.
RESULTS: Since November 2021, five patients have been identified. The mean age and BMI of the patients were 50.0 years and 22.7 kg/m2. In four cases, patients suffered from colorectal liver metastases and, in one case, intrahepatic cholangiocarcinoma. Prior to the first operation, the mean liver volume of the residual left liver was 380.9 mL with a FLR-BWR of 0.677%. Prior to the second operation, the mean volume of the residual liver was 529.8 mL with a FLR-BWR of 0.947%. This was an increase of 41.9% of the residual liver volume. The first and second operations were carried out within 17.8 days. The mean time of the first and second operations was 341.2 min and 440.6 min. The mean hospital stay was 27.2 days. Histopathology showed the largest tumor size of 39 mm in diameter with a mean amount of 4.7 tumors. The mean tumor-free margin was 12.3 mm. One complication CD > 3a occurred. No patient died during the 90-day follow up.
CONCLUSION: In the first German series, we demonstrated that rALPPS can be carried out safely with reduced morbidity and mortality in selected patients.
PMID:38473426 | PMC:PMC10930461 | DOI:10.3390/cancers16051070
Cancers (Basel). 2024 Mar 5;16(5):1050. doi: 10.3390/cancers16051050.
ABSTRACT
Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.
PMID:38473407 | PMC:PMC10930726 | DOI:10.3390/cancers16051050
Cancers (Basel). 2024 Feb 28;16(5):977. doi: 10.3390/cancers16050977.
ABSTRACT
(1) Background: Previous studies have raised concerns about a potential increase in pancreaticobiliary cancer risk after cholecystectomy, but few studies have focused on patients who undergo cholecystectomy after receiving endoscopic retrograde cholangiopancreatography (ERCP) for choledocholithiasis. This study aims to clarify cancer risks in these patients, who usually require cholecystectomy, to reduce recurrent biliary events. (2) Methods: We conducted a nationwide cohort study linked to the National Health Insurance Research Database, the Cancer Registry Database, and the Death Registry Records to evaluate the risk of pancreaticobiliary cancers. All patients who underwent first-time therapeutic ERCP for choledocholithiasis from 2011 to 2017 in Taiwan were included. We collected the data of 13,413 patients who received cholecystectomy after endoscopic retrograde cholangiopancreatography and used propensity score matching to obtain the data of 13,330 patients in both the cholecystectomy and non-cholecystectomy groups with similar age, gender, and known pancreaticobiliary cancer risk factors. Pancreaticobiliary cancer incidences were further compared. (3) Results: In the cholecystectomy group, 60 patients had cholangiocarcinoma, 61 patients had pancreatic cancer, and 15 patients had ampullary cancer. In the non-cholecystectomy group, 168 cases had cholangiocarcinoma, 101 patients had pancreatic cancer, and 49 patients had ampullary cancer. The incidence rates of cholangiocarcinoma, pancreatic cancer, and ampullary cancer were 1.19, 1.21, and 0.3 per 1000 person-years in the cholecystectomy group, all significantly lower than 3.52 (p < 0.0001), 2.11 (p = 0.0007), and 1.02 (p < 0.0001) per 1000 person-years, respectively, in the non-cholecystectomy group. (4) Conclusions: In patients receiving ERCP for choledocholithiasis, cholecystectomy is associated with a significantly lower risk of developing pancreaticobiliary cancer.
PMID:38473337 | PMC:PMC10930920 | DOI:10.3390/cancers16050977
Cancers (Basel). 2024 Feb 25;16(5):927. doi: 10.3390/cancers16050927.
ABSTRACT
INTRODUCTION: Circulating tumor DNA (ctDNA) is emerging as a promising, non-invasive diagnostic and surveillance biomarker in solid organ malignancy. However, its utility before and after liver transplant (LT) for patients with primary and secondary liver cancers is still underexplored.
METHODS: Patients undergoing LT for hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and colorectal liver metastases (CRLM) with ctDNA testing were included. CtDNA testing was conducted pre-transplant, post-transplant, or both (sequential) from 11/2019 to 09/2023 using Guardant360, Guardant Reveal, and Guardant360 CDx.
RESULTS: 21 patients with HCC (n = 9, 43%), CRLM (n = 8, 38%), CCA (n = 3, 14%), and mixed HCC/CCA (n = 1, 5%) were included in the study. The median follow-up time was 15 months (range: 1-124). The median time from pre-operative testing to surgery was 3 months (IQR: 1-4; range: 0-5), and from surgery to post-operative testing, it was 9 months (IQR: 2-22; range: 0.4-112). A total of 13 (62%) patients had pre-transplant testing, with 8 (62%) having ctDNA detected (ctDNA+) and 5 (32%) not having ctDNA detected (ctDNA-). A total of 18 (86%) patients had post-transplant testing, 11 (61%) of whom were ctDNA+ and 7 (33%) of whom were ctDNA-. The absolute recurrence rates were 50% (n = 5) in those who were ctDNA+ vs. 25% (n = 1) in those who were ctDNA- in the post-transplant setting, though this difference was not statistically significant (p = 0.367). Six (29%) patients (HCC = 3, CCA = 1, CRLM = 2) experienced recurrence with a median recurrence-free survival of 14 (IQR: 6-40) months. Four of these patients had positive post-transplant ctDNA collected following diagnosis of recurrence, while one patient had positive post-transplant ctDNA collected preceding recurrence. A total of 10 (48%) patients had sequential ctDNA testing, of whom n = 5 (50%) achieved ctDNA clearance (+/-). The remainder were ctDNA+/+ (n = 3, 30%), ctDNA-/- (n = 1, 10%), and ctDNA-/+ (n = 1, 11%). Three (30%) patients showed the acquisition of new genomic alterations following transplant, all without recurrence. Overall, the median tumor mutation burden (TMB) decreased from 1.23 mut/Mb pre-transplant to 0.00 mut/Mb post-transplant.
CONCLUSIONS: Patients with ctDNA positivity experienced recurrence at a higher rate than the ctDNA- patients, indicating the potential role of ctDNA in predicting recurrence after curative-intent transplant. Based on sequential testing, LT has the potential to clear ctDNA, demonstrating the capability of LT in the treatment of systemic disease. Transplant providers should be aware of the potential of donor-derived cell-free DNA and improved approaches are necessary to address such concerns.
PMID:38473290 | PMC:PMC10930708 | DOI:10.3390/cancers16050927
Ann Surg Oncol. 2024 Mar 5. doi: 10.1245/s10434-024-15117-y. Online ahead of print.
ABSTRACT
BACKGROUND: There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. Supporting evidence for use comes mainly from the small SWOG S0809 trial, which demonstrated an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer.
METHODS: Using the National Cancer Database, we selected patients from 2004 to 2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival (OS). We examined OS in a cohort of patients mimicking the SWOG S0809 protocol as a large validation cohort. Lastly, we compared patients who received chemotherapy only with patients who received adjuvant chemotherapy and radiation using entropy balancing propensity score matching.
RESULTS: Overall, 4997 patients with gallbladder or extrahepatic bile duct adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected, 469 of whom received both adjuvant chemotherapy and radiotherapy. Median OS in patients undergoing chemoradiation was 36.9 months, and was not different between primary sites (p = 0.841). In a propensity score matched cohort, receipt of adjuvant chemoradiation had a survival benefit compared with adjuvant chemotherapy only (hazard ratio 0.86, 95% confidence interval 0.77-0.95; p = 0.004).
CONCLUSION: Using a large national database, we support the findings of SWOG S0809 with a similar median OS in patients receiving chemoradiation. These data further support the consideration of adjuvant multimodal therapy in resected biliary cancers.
PMID:38443700 | DOI:10.1245/s10434-024-15117-y
Abdom Radiol (NY). 2024 Mar 5. doi: 10.1007/s00261-024-04192-0. Online ahead of print.
ABSTRACT
PURPOSE: To explore factors associated with overall survival (OS) and progression-free survival (PFS) of intrahepatic cholangiocarcinoma (iCCA) after ultrasound-guided ablation and establish a model for survival risk evaluation.
METHODS: Data from 54 patients with 86 iCCAs between August 2008 and October 2022 were retrospectively analyzed. Cox regression were used to analyze the effects of clinical features on OS and PFS. Based on the variables screened by multivariable analysis, a model was established to predict the survival of the patients. Time-dependent receiver operating characteristic (timeROC) curve was constructed to evaluate the performance of this model. The model was further verified by bootstrap validation. The clinical usefulness of the model was evaluated by the decision curve analysis (DCA).
RESULTS: During follow up, 39 patients died and 49 patients developed recurrence. Pre-ablation CA199 level > 140 U/ml was the only independent predictor of poor PFS. Age > 70 years, early recurrence, maximal diameter of tumor size > 1.5 cm and pre-ablation CA199 level > 140 U/ml were significantly associated with poor OS. Then a model was established based on the above four variables. The areas under the timeROC curve (AUC) for 1-year, 2-year, 3-year, 5-year were 0.767, 0.854, 0.791 and 0.848, respectively. After bootstrapping for 1000 repetitions, the AUCs were similar to the initial model. DCA also demonstrated that the model had good positive net benefits.
CONCLUSION: The established model in this study could predict the survival outcomes of the patients with iCCA after thermal ablation, but further research was needed to validate the results.
PMID:38443551 | DOI:10.1007/s00261-024-04192-0
Front Immunol. 2024 Feb 19;15:1357333. doi: 10.3389/fimmu.2024.1357333. eCollection 2024.
ABSTRACT
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the first and second most common primary liver cancer (PLC). For decades, systemic therapies consisting of tyrosine kinase inhibitors (TKIs) or chemotherapy have formed the cornerstone of treating advanced-stage HCC and CCA, respectively. More recently, immunotherapy using immune checkpoint inhibition (ICI) has shown anti-tumour reactivity in some patients. The combination regimen of anti-PD-L1 and anti-VEGF antibodies has been approved as new first-line treatment of advanced-stage HCC. Furthermore, gemcibatine plus cisplatin (GEMCIS) with an anti-PD-L1 antibody is awaiting global approval for the treatment of advanced-stage CCA. As effective anti-tumour reactivity using ICI is achieved in a minor subset of both HCC and CCA patients only, alternative immune strategies to sensitise the tumour microenvironment of PLC are waited for. Here we discuss immune checkpoint stimulation (ICS) as additional tool to enhance anti-tumour reactivity. Up-to-date information on the clinical application of ICS in onco-immunology is provided. This review provides a rationale of the application of next-generation ICS either alone or in combination regimen to potentially enhance anti-tumour reactivity in PLC patients.
PMID:38440738 | PMC:PMC10910082 | DOI:10.3389/fimmu.2024.1357333
BMC Cancer. 2024 Mar 4;24(1):297. doi: 10.1186/s12885-024-12068-1.
ABSTRACT
BACKGROUD: We aimed to develop a novel preoperative nomogram to predict lymph node metastasis (LNM) in perihilar cholangiocarcinoma (pCCA) patients.
METHODS: 160 pCCA patients were enrolled at Lihuili Hospital from July 2006 to May 2022. A novel nomogram model was established to predict LNM in pCCA patients based on the independent predictive factors selected by the multivariate logistic regression model. The precision of the nomogram model was evaluated through internal and external validation with calibration curve statistics and the concordance index (C-index). Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to evaluate and determine the clinical utility of the nomogram.
RESULTS: Multivariate logistic regression demonstrated that age (OR = 0.963, 95% CI: 0.930-0.996, P = 0.030), CA19-9 level (> 559.8 U/mL vs. ≤559.8 U/mL: OR = 3.162, 95% CI: 1.519-6.582, P = 0.002) and tumour diameter (OR = 1.388, 95% CI: 1.083-1.778, P = 0.010) were independent predictive factors of LNM in pCCA patients. The C-index was 0.763 (95% CI: 0.667-0.860) and 0.677 (95% CI: 0.580-0.773) in training cohort and validation cohort, respectively. ROC curve analysis indicated the comparative stability and adequate discriminative ability of nomogram. The sensitivity and specificity were 0.820 and 0.652 in training cohort and 0.704 and 0.649 in validation cohort, respectively. DCA revealed that the nomogram model could augment net benefits in the prediction of LNM in pCCA patients.
CONCLUSIONS: The novel prediction model is useful for predicting LNM in pCCA patients and showed adequate discriminative ability and high predictive accuracy.
PMID:38438912 | DOI:10.1186/s12885-024-12068-1
Clin Cancer Res. 2024 Mar 4. doi: 10.1158/1078-0432.CCR-23-3588. Online ahead of print.
ABSTRACT
PURPOSE: FGFR2 and FGFR3 show oncogenic activation in many cancer types, often through chromosomal fusion or extracellular domain mutation. FGFR2 and FGFR3 alterations are most prevalent in intrahepatic cholangiocarcinoma (ICC) and bladder cancers, respectively, and multiple selective reversible and covalent pan-FGFR tyrosine kinase inhibitors (TKIs) have been approved in these contexts. However, resistance, often due to acquired secondary mutations in the FGFR2/3 kinase domain, limits efficacy. Resistance is typically polyclonal, involving a spectrum of different mutations that most frequently affect the molecular brake and gatekeeper residues (N550 and V565 in FGFR2).
EXPERIMENTAL DESIGN: Here we characterize the activity of the next-generation covalent FGFR inhibitor, KIN-3248, in preclinical models of FGFR2 fusion+ ICC harboring a series of secondary kinase domain mutations, in vitro and in vivo. We also test select FGFR3 alleles in bladder cancer models.
RESULTS: KIN-3248 exhibits potent selectivity for FGFR1-3 and retains activity against various FGFR2 kinase domain mutations, in addition to being effective against FGFR3 V555M and N540K mutations. Notably, KIN-3248 activity extends to the FGFR2 V565F gatekeeper mutation, which causes profound resistance to currently approved FGFR inhibitors. Combination treatment with EGFR or MEK inhibitors potentiates KIN-3248 efficacy in vivo, including in models harboring FGFR2 kinase domain mutations.
CONCLUSIONS: Thus, KIN-3248 is a novel FGFR1-4 inhibitor whose distinct activity profile against FGFR kinase domain mutations highlights its potential for the treatment of ICC and other FGFR-driven cancers.
PMID:38437671 | DOI:10.1158/1078-0432.CCR-23-3588
Liver Int. 2024 Mar 4. doi: 10.1111/liv.15886. Online ahead of print.
ABSTRACT
INTRODUCTION: The effectiveness of percutaneous radiofrequency ablation (RFA) in intrahepatic cholangiocarcinomas (iCCA) remains insufficiently studied.
METHODS: We conducted a retrospective study including patients with histologically proven iCCA within Milan criteria treated by percutaneous RFA from 2000 to 2022. The primary outcome was overall survival in treatment-naive patients and secondary outcomes included ablation completeness, adverse events, local and distant recurrence. A total of 494 patients with hepatocellular carcinoma (HCC) on cirrhosis treated by RFA were included as a comparison group. Oncological events were analysed using Kaplan-Meier, log-rank and univariate/multivariate Cox models.
RESULTS: The main population included 71 patients, mostly cirrhotic (80%) with solitary tumours (66%) of a median size of 24 mm. Local recurrence was 45% at 5 years, lower in multibipolar versus monopolar RFA (22% vs. 55%, p = .007). In treatment-naive patients (n = 45), median overall and recurrence-free survivals were 26 and 11 months, respectively. Tumour size (p = .01) and Child-Pugh B (p = .001) were associated with death. The rate of distant recurrence was 59% at 5 years significantly lower for single tumours of less than 2 (p = .002) or 3 cm (p = .02). In cirrhotic patients naïve of previous treatment (n = 40), overall survival was shorter than in HCC (26 vs 68 months, p < .0001), with more local recurrences (p < .0001). Among distant recurrences, 50% were extrahepatic metastases compared to 12% in HCC (p < .001).
CONCLUSION: Multibipolar RFA provides better results in terms of tumour recurrence than monopolar RFA and could be used to treat small iCCA (<3 cm). Adjuvant chemotherapy should be discussed due to the frequent extra-hepatic metastasis at recurrence.
PMID:38436538 | DOI:10.1111/liv.15886
Cureus. 2024 Feb 1;16(2):e53394. doi: 10.7759/cureus.53394. eCollection 2024 Feb.
ABSTRACT
Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is an aggressive hepatic cancer that has characteristics of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). For resectable disease, liver resection is the preferred first treatment option. As for the advanced or metastatic setting, and due to its rarity, there is still no consensus on which is the optimal systemic treatment. As such, regimens used in both HCC and CC have often been used as first-line treatment options. We report a case of a male patient in his 50s, diagnosed with a cHCC-CC with lymph node and adrenal metastasis, with an extensive portal vein tumour thrombosis, that started treatment with a multikinase inhibitor - lenvatinib.
PMID:38435222 | PMC:PMC10908305 | DOI:10.7759/cureus.53394
Clin Cancer Res. 2024 Mar 4:OF1-OF8. doi: 10.1158/1078-0432.CCR-23-0633. Online ahead of print.
ABSTRACT
PURPOSE: NCI-MATCH assigned patients with advanced cancer and progression on prior treatment, based on genomic alterations in pretreatment tumor tissue. Arm J (EAY131-J) evaluated the combination of trastuzumab/pertuzumab (HP) across HER2-amplified tumors.
PATIENTS AND METHODS: Eligible patients had high levels of HER2 amplification [copy number (CN) ≥7] detected by central next-generation sequencing (NGS) or through NCI-designated laboratories. Patients with breast/gastroesophageal adenocarcinoma and those who received prior HER2-directed therapy were excluded. Enrollment of patients with colorectal cancer was capped at 4 based on emerging data. Patients received HP IV Q3 weeks until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS).
RESULTS: Thirty-five patients were enrolled, with 25 included in the primary efficacy analysis (CN ≥7 confirmed by a central lab, median CN = 28). Median age was 66 (range, 31-80), and half of all patients had ≥3 prior therapies (range, 1-11). The confirmed ORR was 12% [3/25 partial responses (colorectal, cholangiocarcinoma, urothelial cancers), 90% confidence interval (CI) 3.4%-28.2%]. There was one additional partial response (urothelial cancer) in a patient with an unconfirmed ERBB2 copy number. Median PFS was 3.3 months (90% CI 2.0-4.1), and median OS 9.4 months (90% CI 5.0-18.9). Treatment-emergent adverse events were consistent with prior studies. There was no association between HER2 CN and response.
CONCLUSIONS: HP was active in a selection of HER2-amplified tumors (non-breast/gastroesophageal) but did not meet the predefined efficacy benchmark. Additional strategies targeting HER2 and potential resistance pathways are warranted, especially in rare tumors.
PMID:38433347 | DOI:10.1158/1078-0432.CCR-23-0633
Intern Med. 2024 Mar 4. doi: 10.2169/internalmedicine.3071-23. Online ahead of print.
ABSTRACT
Combined hepatocellular cholangiocarcinoma is a rare and challenging primary liver malignancy that lacks any established standard treatments for unresectable cases. We herein present the first known case of a 49-year-old woman diagnosed with unresectable combined hepatocellular-cholangiocarcinoma, who underwent novel chemotherapy involving durvalumab plus tremelimumab combination therapy. The treatment was temporarily discontinued owing to immune-related adverse events, such as rash, and the patient was subsequently managed with systemic steroid therapy; however, the disease progressed after two courses of this treatment. Further studies are needed to validate the efficacy and safety of immune checkpoint inhibitors such as durvalumab and tremelimumab for the treatment of unresectable combined hepatocellular cholangiocarcinoma.
PMID:38432964 | DOI:10.2169/internalmedicine.3071-23
Zhonghua Wai Ke Za Zhi. 2024 Mar 1;62(4):346-352. doi: 10.3760/cma.j.cn112139-20230911-00111. Online ahead of print.
ABSTRACT
Intrahepatic cholangiocarcinoma(ICC) refers to cholangiocarcinomas originating from the secondary bile ducts within the liver and their branches.As a prevalent malignancy of the liver,the diagnosis and treatment of ICC pose significant challenges due to the high heterogeneity of the tumor and its propensity to develop drug resistance.Traditional drug screening and tumor mechanism studies have been confined to two-dimensional cell line cultures and patient-derived xenograft(PDX) models.However,cell lines cannot fully recapitulate the tumor heterogeneity,and PDX models have limitations such as high costs and time consumption,making them less practical for widespread clinical application.To address the limitations of these models,organoid models have been developed based on two-dimensional cell cultures.Organoid models combine the advantages of both aforementioned culture methods and offer unique strengths in cancer research.They provide a new perspective for studying the development and treatment of tumors. In this review, the focus is primarily on the latest advances in the field of organoids of ICC,with a particular emphasis on existing culture protocols and their potential applications in precision medicine and the establishment of biobanks.
PMID:38432677 | DOI:10.3760/cma.j.cn112139-20230911-00111
Zhonghua Wai Ke Za Zhi. 2024 Mar 1;62(4):331-337. doi: 10.3760/cma.j.cn112139-20231215-00274. Online ahead of print.
ABSTRACT
Intrahepatic cholangiocarcinoma (ICC) is a type of primary liver cancer, which has shown an increasing trend in incidence and mortality in recent years, with a poor prognosis. The clinical diagnosis and treatment of ICC currently face the challenges of low detection rate, high mortality rate, poor treatment outcome, and urgently need more in-depth research to promote the improvement of clinical diagnosis and treatment level. In recent years, ICC diagnosis and treatment related research has made new progress in many aspects, and the knowledge about these new clinical diagnosis and treatment advances should be updated in a timely manner. This article reviewed the latest research results in recent years, summarized some new views on ICC typing, prevention and diagnosis staging that have been proposed recently, as well as the new progress made in surgical treatment and systemic treatment, and briefly discussed the potential of ICC individualized precision treatment and the occurrence of rare complications caused by combined treatment.
PMID:38432675 | DOI:10.3760/cma.j.cn112139-20231215-00274
Zhonghua Wai Ke Za Zhi. 2024 Mar 1;62(4):316-323. doi: 10.3760/cma.j.cn112139-20231215-00276. Online ahead of print.
ABSTRACT
Objectives: To analyze the survival benefit of intrahepatic cholangiocarcinoma (ICC) radical resection based on single cell omics. Methods: This is a retrospective case-series study. ICC single-cell sequencing was integrated from four data sets in the Gene Expression Omnibus Database, with a total of 46 patients undergoing radical resection, to explore the characteristics of the microenvironment. Microarray data of 100 ICC cases was analyzed in the EMBI database with survival data. The infiltration abundance of each epithelial cell cluster was calculated in each microarray data sample using the ssGSEA algorithm. The key epithelial cell cluster associated with poor patient outcomes was explored. The clinical value of key marker genes in this subgroup was studied. Prognostic marker genes were selected using the univariate and multivariate Cox proportional hazards(CoxPH) model. The The CoxPH model was constructed by the target genes and a nomogram was drawn. Kaplan-Meier survival analysis was used to verify the relationship between score and prognosis of patients. The predictive power of the model was evaluated by receiver operating characteristic(ROC) curves, calibration curves, and decision curve analysis (DCA). Results: Epithelial cell clusters infiltrated almost exclusively in tumor tissue. The mt2a+ epithelial cell subset was associated with a poorer prognosis for patients with a high invasion abundance and patients characterized by infiltration of this group were defined as antioxidant. After screening Marker genes in this cluster using a univariate and multivariate CoxPH model, the following genes were found to be independent prognostic factors: filpil, nfkbia, peg10, serpinb5. The CoxPH model was constructed using the four gene expression levels, and the survival rate of patients in the high-risk group was significantly lower than those in the low-risk group (all P<0.05). The constructed nomogram had good discrimination and validity. The ROC curve showed that the predicted area under the curve was 0.779, 0.844 and 0.845 at 1, 3 and 5 years, respectively. Compared to clinical indicators, the model had better predictive power using the calibration curve and the DCA test. Conclusions: The mt2a+ epithelial cell group may be associated with the prognosis of patients with ICC, and the concept of ICC tissue typing of antioxidant and non-antioxidant types is proposed. The type of antioxidant may predict the poor prognosis of the patients, and postoperative adjuvant therapy and other means could be considered to improve the survival of the patients.
PMID:38432673 | DOI:10.3760/cma.j.cn112139-20231215-00276
Zhonghua Wai Ke Za Zhi. 2024 Mar 1;62(4):309-315. doi: 10.3760/cma.j.cn112139-20231214-00271. Online ahead of print.
ABSTRACT
Objective: To explore the efficacy and safety of hepatic arterial infusion chemotherapy(HAIC) for unresectable hepatitis B-related intrahepatic cholangiocarcinoma(ICC). Methods: This is a retrospective controlled study. Data from 140 unresectable ICC patients who received HAIC treatment at Sun Yat-sen University Cancer Center from March 2015 to June 2023 were retrospectively collected, including 72 patients in the hepatitis B surface antigen(HBsAg)negative group (43 males and 29 females, aged (59.6±9.5)years(range: 34 to 81 years)), 68 cases in the HBsAg-positive group (48 males, 20 females, aged (53.4±11.4)years(range: 29 to 82 years)). HAIC treatment used the FOLFOX regimen combined with oxaliplatin, leucovorin,and fluorouracil. The differences in effects, prognosis,and adverse reactions between the two groups of patients after HAIC treatment were analyzed. All variables were expressed as categorical data. The χ2 test or Fisher's exact probability method was used to compare between groups. The Kaplan-Meier method was used to draw survival curves. The difference of survival curve between groups were compared through the Log-rank test. Results: According to the Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1,the objective response rate(ORR) of the HBsAg-negative group was 23.2%(16/69),and the ORR of the HBsAg-positive group was 40.3%(25/62). The difference in ORR between the two groups was statistically significant(χ2=4.459,P=0.035). According to the modified RECIST(mRECIST) criteria,the ORR of the HBsAg-negative group was 27.5%(19/69),and the ORR of the HBsAg-positive group was 45.2%(28/62). The difference in ORR between the two groups was statistically significant(χ2=4.410,P=0.036). The median progression-free survival(PFS) of the HBsAg-negative group and the positive group were 7.1 months(95%CI: 5.8 to 13.2 months) and 7.3 months (95%CI: 5.7 to 10.3 months), respectively, and the median overall survival(OS) were 16.3 months (95%CI: 12.5 to 33.9 months) and 15.9 months (95%CI: 9.2 to 20.7 months) respectively. There were no statistically significant differences in PFS and OS between the two groups (both P>0.05). The main serious adverse reactions of the two groups of patients included increased AST, increased ALT, thrombocytopenia,and neutropenia. There were no statistically significant differences in various adverse reactions between the two groups after HAIC treatment (all P>0.05). Conclusion: Patients with HBsAg-positive unresectable ICC are more likely to benefit from HAIC treatment.
PMID:38432672 | DOI:10.3760/cma.j.cn112139-20231214-00271
Zhonghua Wai Ke Za Zhi. 2024 Mar 1;62(4):290-301. doi: 10.3760/cma.j.cn112139-20231221-00296. Online ahead of print.
ABSTRACT
Objective: To investigate the surgical treatment effect and prognostic factors of hilar cholangiocarcinoma. Methods: This study is an ambispective cohort study. From August 2005 to December 2022,data of 510 patients first diagnosed with hilar cholangiocarcinoma and underwent surgical resection at the Hepatobiliary Center of the First Affiliated Hospital of Nanjing Medical University were retrospectively collected. In the cohort,there were 324 males and 186 females,with an age of (M (IQR)) 63(13)years (range:25 to 85 years). The liver function at admission was Child-Pugh A (343 cases,67.3%) and Child-Pugh B (167 cases,32.7%). Three hundred and seventy-two(72.9%) patients had jaundice symptoms and the median total bilirubin was 126.3(197.6) μmol/L(range: 5.4 to 722.8 μmol/L) at admission. Two hundred and fourty-seven cases (48.4%) were treated with percutaneous transhepatic cholangial drainage or endoscopic nasobiliary drainage before operation. The median bilirubin level in the drainage group decreased from 186.4 μmol/L to 85.5 μmol/L before operation. Multivariate Logistic regression was used to identify the influencing factors for R0 resection,and Cox regression was used to construct multivariate prediction models for overall survival and disease-free survival. Results: Among 510 patients who underwent surgical resection,Bismuth Ⅲ-Ⅳ patients accounted for 71.8%,among which 86.1% (315/366) underwent hemi-hepatectomy,while 81.9% (118/144) underwent extrahepatic biliary duct resection alone in type Ⅰ-Ⅱ patients. The median OS was 22.8 months,and the overall survival rates at 1-,3-,5-and 10-year were 72.2%,35.6%,24.8% and 11.0%,respectively. The median DFS was 15.2 months,and the disease-free survival rate was 66.0%,32.4%,20.9% and 11.0%,respectively. The R0 resection rate was 64.5% (329/510),and the overall survival rates of patients with R0 resection at 1-,3-,5-and 10-year were 82.5%,48.6%,34.4%,15.2%,respectively. The morbidity of Clavien-Dindo grade Ⅲ-Ⅴ complications was 26.1%(133/510) and the 30-day mortality was 4.3% (22/510). Multivariate Logistic regression indicated that Bismuth type Ⅰ-Ⅲ (P=0.009),hemi-hepatectomy and extended resection (P=0.001),T1 and T2 patients without vascular invasion (T2 vs. T1:OR=1.43 (0.61~3.35),P=0.413;T3 vs. T1:OR=2.57 (1.03~6.41),P=0.010;T4 vs. T1,OR=3.77 (1.37~10.38),P<0.01) were more likely to obtain R0 resection. Preoperative bilirubin,Child-Pugh grade,tumor size,surgical margin,T stage,N stage,nerve infiltration and Edmondson grade were independent prognostic factors for OS and DFS of hilar cholangiocarcinoma patients without distant metastasis. Conclusions: Radical surgical resection is necessary to prolong the long-term survival of hilar cholangiocarcinoma patients. Hemi-hepatectomy and extended resection,regional lymph node dissection and combined vascular resection if necessary,can improve R0 resection rate.
PMID:38432670 | DOI:10.3760/cma.j.cn112139-20231221-00296
Zhonghua Wai Ke Za Zhi. 2024 Mar 1;62(4):284-289. doi: 10.3760/cma.j.cn112139-20231218-00283. Online ahead of print.
ABSTRACT
Due to the unique location and aggressive tumor biology,hilar cholangiocarcinoma,intrahepatic cholangiocarcinoma,and gallbladder cancer often present with obstructive jaundice and require extensive liver resection,also exhibit high rates of recurrence and metastasis after radical excision. Therefore,surgeons should make treatment decisions based on the biliary anatomy of patients and the biological characteristics of tumors as it significantly affects patient's prognosis. Treatment strategy should be made to ensure the successful implementation of radical resection for biliary tract malignant tumors while maximizing the survival benefits of patients. Firstly,conversion of liver function by relieving jaundice technology and conversion of tumor biological characteristics through systematic therapy,followed by the conversion of future liver remnant. Currently,there are still controversies surrounding indications,methods,standards of relieving jaundice,and treatment plans,cycles,evaluation of therapeutic effects for systematic conversion therapy,and the standards and techniques of conversion therapy for future liver remnant.This article discusses these issues through literature analysis and the author's experience in the hope of resonating with colleagues.
PMID:38432669 | DOI:10.3760/cma.j.cn112139-20231218-00283
Surg Oncol. 2024 Feb 29;53:102058. doi: 10.1016/j.suronc.2024.102058. Online ahead of print.
ABSTRACT
BACKGROUND: Intrahepatic cholangiocarcinoma is the second most common primary liver cancer after hepatocellular carcinoma with an increasing incidence worldwide. Surgical resection is still the only potential cure, and survival rates are dismal due to disease relapse after resection and/or metastatic disease. Positive resection margins are associated with recurrence, with conflicting studies regarding the benefits of wide resection margins to reduce recurrence rates.
METHODS: 126 patients with an R0 resection treated with hepatic surgery for intrahepatic cholangiocarcinoma at the Surgical Department at the Medical University Centre Essen, Germany were identified in a database and retrospectively analysed. Patients were grouped into three groups according to margin width, <1 mm (very narrow margin width) 1-5 mm (narrow margin width) and >5 mm (wide margin width). Epidemiological as well as perioperative data was analysed, and a univariate analysis as well as Kaplan-Meier plots carried out to investigate recurrence-free and overall survival.
RESULTS: Wider resection margins did not lead to better recurrence-free survival. A wider resection margin >5 mm was not significantly associated with improved overall survival. Positive lymph nodes (HR 2.50, 95% CI 1.11-5.61, p=0.027) and non-anatomic resections (HR 2.06, 95% CI 1.13-3.75, p=0.019) are significantly associated with poorer overall survival. Regarding recurrence-free survival, V2 vascular invasion was the only risk factor statistically significantly associated with poorer recurrence-free survival (HR 8.83, 95% CI 0.85-2.83, p=0.005).
CONCLUSION: Resection margins did not have a significant impact on disease free survival or overall survival following hepatic resection for intrahepatic cholangiocarcinoma. Non-anatomical resections, lymph node and vascular invasion all significantly impacted oncological outcomes.
PMID:38431994 | DOI:10.1016/j.suronc.2024.102058
Cancer Cell Int. 2024 Mar 2;24(1):92. doi: 10.1186/s12935-024-03251-2.
ABSTRACT
BACKGROUND: Cholangiocarcinoma represents a malignant neoplasm originating from the hepatobiliary tree, with a subset of tumors developing inside the liver. Intrahepatic cholangiocarcinomas (ICC) commonly exhibit an asymptomatic presentation, rendering both diagnosis and treatment challenging. Cuproptosis, an emerging regulated cell death pathway induced by copper ions, has garnered attention recently. As cancer cells show altered copper metabolism and comparatively higher copper needs, cuproptosis may play a role in the development of ICC. However, studies investigating this possibility are currently lacking.
METHODS: Single-cell and bulk RNA sequence data were analyzed, and correlations were established between the expression of cuproptosis-related molecules and ICC patient survival. Genes with predicting survival were used to create a CUPT score using Cox and LASSO regression and tumor mutation burden (TMB) analysis. The CIBERSORT software was employed to characterize immune cell infiltration within the tumors. Furthermore, immune infiltration prediction, biological function enrichment, and drug sensitivity analyses were conducted to explore the potential implications of the cuproptosis-related signature. The effects of silencing solute carrier family 39 member 4 gene (SLC39A4) expression using siRNA were investigated using assays measuring cell proliferation, colony formation, and cell migration. Key genes of cuproptosis were detected by western blotting.
RESULTS: The developed CUPT score divided patients into high and low CUPT score groups. Those with a low score had significantly better prognosis and longer survival. In contrast, high CUPT scores were associated with worse clinical outcomes and significantly higher TMB. Comparisons of the two groups also indicated differences in the immune infiltrate present in the tumors. Finally, we were able to identify 95 drugs potentially affecting the cuproptosis pathway. Some of these might be effective in the treatment of ICC. The in vitro experiments revealed that suppressing the expression of SLC39A4 in ICC cell lines resulted in reduced cell proliferation, colony formation, and cell migration. It also led to an increase in cell death and the upregulation of key genes associated with cuproptosis, namely ferredoxin 1 (FDX1) and dihydrolipoyl transacetylase (DLAT). These findings strongly suggest that this cuproptosis-associated molecule may play a pivotal role in the development and metastasis of ICC.
CONCLUSIONS: Changes in the expression of a cuproptosis-related gene signature can predict the clinical prognosis of ICC with considerable accuracy. This supports the notion that cuproptosis influences the diversity and complexity of the immune microenvironment, mutational landscape, and biological behavior of ICC. Understanding this pathway better may hold promise for the development of innovative strategies in the management of this disease.
PMID:38431620 | PMC:PMC10908169 | DOI:10.1186/s12935-024-03251-2
Cell Mol Gastroenterol Hepatol. 2024 Feb 28:S2352-345X(24)00036-5. doi: 10.1016/j.jcmgh.2024.02.008. Online ahead of print.
NO ABSTRACT
PMID:38431266 | DOI:10.1016/j.jcmgh.2024.02.008
Hepatol Res. 2024 Mar 2. doi: 10.1111/hepr.14031. Online ahead of print.
ABSTRACT
BACKGROUND AND AIM: Autotaxin (ATX) is an extracellular lysophospholipase D that catalyzes the hydrolysis of lysophosphatidylcholine into lysophosphatidic acid (LPA). Recent accumulating evidence indicates the biological roles of ATX in malignant tumors. However, the expression and clinical implications of ATX in human cholangiocarcinoma (CCA) remain elusive.
METHODS: In this study, the expression of ATX in 97 human CCA tissues was evaluated by immunohistochemistry. Serum ATX levels were determined in CCA patients (n = 26) and healthy subjects (n = 8). Autotaxin expression in cell types within the tumor microenvironment was characterized by immunofluorescence staining.
RESULTS: High ATX expression in CCA tissue was significantly associated with a higher frequency of lymph node metastasis (p = 0.050). High ATX expression was correlated with shorter overall survival (p = 0.032) and recurrence-free survival (RFS) (p = 0.001) than low ATX expression. In multivariate Cox analysis, high ATX expression (p = 0.019) was an independent factor for shorter RFS. Compared with low ATX expression, high ATX expression was significantly associated with higher Ki-67-positive cell counts (p < 0.001). Serum ATX levels were significantly higher in male CCA patients than in healthy male subjects (p = 0.030). In the tumor microenvironment of CCA, ATX protein was predominantly expressed in tumor cells, cancer-associated fibroblasts, plasma cells, and biliary epithelial cells.
CONCLUSIONS: Our study highlights the clinical evidence and independent prognostic value of ATX in human CCA.
PMID:38430513 | DOI:10.1111/hepr.14031
J Hepatol. 2024 Feb 28:S0168-8278(24)00138-7. doi: 10.1016/j.jhep.2024.02.018. Online ahead of print.
ABSTRACT
BACKGROUND & AIMS: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aim to evaluate the role of PTEN in the pathogenesis of eCCA and find novel therapies for this disease.
METHODS: The Pten gene in the biliary epithelial cells were genetically deleted using the Cre-loxp system. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry (IHC), RT-PCR, cell culture, and RNAseq. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. Experimental therapy was tested using an Aurka inhibitor.
RESULTS: We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as one month old. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated the disease progression, potentially through downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expressions of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression.
CONCLUSIONS: Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum through an Aurka-dependent manner. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA.
IMPACT AND IMPLICATIONS: The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition (EMT), cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted the disease progression. This model shall be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis.
PMID:38428643 | DOI:10.1016/j.jhep.2024.02.018
Indian J Gastroenterol. 2024 Mar 1. doi: 10.1007/s12664-024-01518-0. Online ahead of print.
ABSTRACT
Biliary tract cancers are malignant neoplasms arising from bile duct epithelial cells. They include cholangiocarcinomas and gallbladder cancer. Gallbladder cancer has a marked geographical preference and is one of the most common cancers in women in northern India. Biliary tract cancers are usually diagnosed at an advanced, unresectable stage. Hence, the prognosis is extremely dismal. The five-year survival rate in advanced gallbladder cancer is < 5%. Hence, early detection and radical surgery are critical to improving biliary tract cancer prognoses. Radiological imaging plays an essential role in diagnosing and managing biliary tract cancers. However, the diagnosis is challenging because the biliary tract is affected by many diseases that may have radiological appearances similar to cancer. Artificial intelligence (AI) can improve radiologists' performance in various tasks. Deep learning (DL)-based approaches are increasingly incorporated into medical imaging to improve diagnostic performance. This paper reviews the AI-based strategies in biliary tract cancers to improve the diagnosis and prognosis.
PMID:38427281 | DOI:10.1007/s12664-024-01518-0
Abdom Radiol (NY). 2024 Mar 1. doi: 10.1007/s00261-024-04194-y. Online ahead of print.
ABSTRACT
PURPOSE: To analyze and compare the differences in MRI features between combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) and intrahepatic cholangiocarcinoma (iCCA) with arterial phase peripheral enhancement, so as to provide valuable references for preoperative differential diagnosis.
METHODS: Seventy cHCC-CCA patients and 74 iCCA patients confirmed by pathology were included in this study. Their contrast-enhanced MRI showed rim arterial phase hyperenhancement (Rim APHE). The differences of clinicopathological data and MRI features between cHCC-CCA and iCCA were compared. Then, the sensitivity, specificity, and area under curve (AUC) were also analyzed and compared.
RESULTS: Seventy cHCC-CCA patients (mean age, 55.7 ± 10.6 years) and 74 iCCA patients (mean age, 61.1 ± 10.5 years) were evaluated. In this study, univariable and multivariable regression analysis showed that AFP > 20 ng/ml (OR = 5.824, p = 0.006), enhancing capsule (OR = 7.252, p = 0.001), and mosaic architecture (OR = 32.732, p < 0.001) were independent risk factors of cHCC-CCA with Rim APHE. However, only hepatic capsule retraction (OR = 0.091, p < 0.001) was an independent predictor of iCCA. In addition, combining AFP > 20 ng/ml with enhancing capsule (96.7% vs. 79.2%, p < 0.001) and/or mosaic architecture (96.4% vs. 94.7%, p < 0.001) can improve the sensitivity of differentiating cHCC-CCA (vs. iCCA) with Rim APHE.
CONCLUSION: The combination of elevated AFP and MRI features, such as enhancing capsule and mosaic architecture, will help in preoperative differential diagnosis of cHCC-CCA and iCCA with Rim APHE.
PMID:38427077 | DOI:10.1007/s00261-024-04194-y
Clin Transl Radiat Oncol. 2024 Feb 18;45:100749. doi: 10.1016/j.ctro.2024.100749. eCollection 2024 Mar.
ABSTRACT
BACKGROUND: Scarce evidence exists for clinical target volume (CTV) definitions of regional lymph nodes (LNs) in intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We investigated the mapping pattern of nodal recurrence after surgery for iCCA and cHCC-CCA and provided evidence for the nodal CTV definition.
METHODS: We retrospectively reviewed the medical records of patients with iCCA or cHCC-CCA who underwent surgery between 2010 and 2020. Eligibility criteria included patients pathologically diagnosed with iCCA or cHCC-CCA after surgery and a first recurrent event in regional LNs during follow-up. All recurrent LNs were registered onto reference computed tomography images based on the vascular structures to reconstruct the node mapping. Fifty-three patients were eligible. LN regions were classified into four risk groups.
RESULTS: Hepatic hilar and portal vein-vena cava were the most common recurrent regions, with recurrence rates of 62.3 % and 39.6 % (high-risk regions), respectively. Recurrence rates in the left gastric, diaphragmatic, common hepatic, superior mesenteric vessels, celiac trunk, and paracardial regions ranged from 15.1 % to 30.2 % (intermediate-risk regions). There were fewer recurrences in the para-aortic (16a1, a2, b1) and splenic artery and hilum regions, with rates <10 % (low-risk regions). No LN recurrence was observed in the para-oesophageal or para-aortic region (16b2) (very low-risk regions). Based on node mapping, the CTV should include high- and intermediate-risk regions for pathologically negative LN patients during postoperative radiotherapy. Low-risk regions should be included for pathologically positive LN patients.
CONCLUSION: We provide evidence for CTV delineation in patients with iCCA and cHCC-CCA based on recurrent LN mapping.
PMID:38425471 | PMC:PMC10904232 | DOI:10.1016/j.ctro.2024.100749
World J Gastrointest Oncol. 2024 Feb 15;16(2):255-258. doi: 10.4251/wjgo.v16.i2.255.
ABSTRACT
Enhanced recovery after surgery (ERAS) programs have been widely applied in liver surgery since the publication of the first ERAS guidelines in 2016 and the new recommendations in 2022. Liver surgery is usually performed in oncological patients (liver metastasis, hepatocellular carcinoma, cholangiocarcinoma, etc.), but the real impact of liver surgery ERAS programs in oncological outcomes is not clearly defined. Theoretical advantages of ERAS programs are: ERAS decreases postoperative complication rates and has been demonstrated a clear relationship between complications and oncological outcomes; a better and faster postoperative recovery should let oncologic teams begin chemotherapeutic regimens on time; prehabilitation and nutrition actions before surgery should also improve the performance status of the patients receiving chemotherapy. So, ERAS could be another way to improve our oncological results. We will discuss the literature about liver surgery ERAS focusing on its oncological implications and future investigations projects.
PMID:38425397 | PMC:PMC10900164 | DOI:10.4251/wjgo.v16.i2.255
Technol Cancer Res Treat. 2024 Jan-Dec;23:15330338241234798. doi: 10.1177/15330338241234798.
ABSTRACT
Objectives: This study aimed to explore the role of inhibin subunit beta A (INHBA) in the progression of cervical cancer (CCa) and investigate its potential as a therapeutic target. Specifically, the objectives were to assess the expression levels of INHBA in CCa, examine its correlation with patient survival, and elucidate its impact on CCa cell proliferation, cell cycle regulation, migration, invasion, and in vivo tumor growth and metastasis. Methods: To achieve the objectives, we conducted a comprehensive set of experimental methods. INHBA expression in CCa was analyzed, and its association with patient survival was assessed using clinical data. In vitro experiments involved the investigation of INHBA's effects on CCa cell proliferation, cell cycle dynamics, migration, and invasion through the epithelial-mesenchymal transition (EMT) process. Additionally, in vivo experiments were performed to evaluate the influence of INHBA on CCa growth and lung metastasis. Results: The results of this study revealed upregulated expression of INHBA in CCa, with a significant association between high INHBA expression and poor patient survival. Functionally, INHBA was found to promote the proliferation of CCa cells, regulate the cell cycle, and enhance migration and invasion through the EMT process in vitro. Moreover, in vivo experiments demonstrated that INHBA facilitated the growth and lung metastasis of CCa. Conclusion: In conclusion, our findings suggest that INHBA plays a crucial role in the progression of cervical cancer. The upregulation of INHBA is associated with poor patient survival, and its involvement in promoting key aspects of cancer progression makes it a potential therapeutic target for CCa treatment. These results provide valuable insights into the molecular mechanisms underlying CCa and offer a foundation for further exploration of targeted therapeutic interventions.
PMID:38419562 | PMC:PMC10903216 | DOI:10.1177/15330338241234798
Nat Rev Clin Oncol. 2024 Feb 29. doi: 10.1038/s41571-024-00869-z. Online ahead of print.
ABSTRACT
Fibroblast growth factor (FGF) signalling via FGF receptors (FGFR1-4) orchestrates fetal development and contributes to tissue and whole-body homeostasis, but can also promote tumorigenesis. Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. Erdafitinib is approved for patients with urothelial carcinoma harbouring FGFR2/3 alterations, and futibatinib and pemigatinib are approved for patients with cholangiocarcinoma harbouring FGFR2 fusions and/or rearrangements. Clinical benefit from these agents is in part limited by hyperphosphataemia owing to off-target inhibition of FGFR1 as well as the emergence of resistance mutations in FGFR genes, activation of bypass signalling pathways, concurrent TP53 alterations and possibly epithelial-mesenchymal transition-related isoform switching. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence.
PMID:38424198 | DOI:10.1038/s41571-024-00869-z
Hematol Oncol Clin North Am. 2024 Feb 28:S0889-8588(24)00005-4. doi: 10.1016/j.hoc.2024.01.005. Online ahead of print.
ABSTRACT
Biliary tract cancers continue to increase in incidence and have a high mortality rate. Most of the patients present with advanced-stage disease. The discovery of targetable genomic alterations addressing IDH, FGFR, HER2, BRAFV600 E, and others has led to the identification and validation of novel therapies in biliary cancer. Recent advances demonstrating an improved outcome with the addition of immune checkpoint inhibitors to chemotherapy have established a new first-line care standard. In case of contraindications to the use of checkpoint inhibitors and the absence of targetable alterations, chemotherapy remains to be the standard of care.
PMID:38423933 | DOI:10.1016/j.hoc.2024.01.005
PLoS Negl Trop Dis. 2024 Feb 29;18(2):e0011362. doi: 10.1371/journal.pntd.0011362. Online ahead of print.
ABSTRACT
Opisthorchis viverrini is a parasitic liver fluke contracted by consumption of raw fish, which affects over 10 million people in Southeast Asia despite sustained control efforts. Chronic infections are a risk factor for the often fatal bile duct cancer, cholangiocarcinoma. Previous modeling predicted rapid elimination of O. viverrini following yearly mass drug administration (MDA) campaigns. However, field data collected in affected populations shows persistence of infection, including heavy worm burden, after many years of repeated interventions. A plausible explanation for this observation is systematic adherence of individuals in health campaigns, such as MDA and education, with some individuals consistently missing treatment. We developed an agent-based model of O. viverrini which allows us to introduce various heterogeneities including systematic adherence to MDA and education campaigns at the individual level. We validate the agent-based model by comparing it to a previously published population-based model. We estimate the degree of systematic adherence to MDA and education campaigns indirectly, using epidemiological data collected in Lao PDR before and after 5 years of repeated MDA, education and sanitation improvement campaigns. We predict the impact of interventions deployed singly and in combination, with and without the estimated systematic adherence. We show how systematic adherence can substantially increase the time required to achieve reductions in worm burden. However, we predict that yearly MDA campaigns alone can result in a strong reduction of moderate and heavy worm burden, even under systematic adherence. We predict latrines and education campaigns to be particularly important for the reduction in overall prevalence, and therefore, ultimately, elimination. Our findings show how systematic adherence can explain the observed persistence of worm burden; while emphasizing the benefit of interventions for the entire population, even under systematic adherence. At the same time, the results highlight the substantial opportunity to further reduce worm burden if patterns of systematic adherence can be overcome.
PMID:38422118 | DOI:10.1371/journal.pntd.0011362
J Ultrason. 2024 Feb 27;24(96):20240005. doi: 10.15557/jou.2024.0005. eCollection 2024 Feb.
ABSTRACT
Intrahepatic cholangiocarcinoma (ICC) is a rare, heterogeneous, highly lethal tumor of the biliary tract. Due to the lack of effective treatments, an early identification of ICC is essential to achieve the best outcome in terms of therapy and prognosis aiming for a curative intent. ICC may arise on a normal liver or with an underlying liver disease, making the diagnosis more difficult and complex. Contrast-enhancement ultrasound (CEUS) is an accurate procedure able to detect ICC-specific contrast vascular pattern, and thus facilitating the correlation between radiological and histopathological findings with high specificity and sensitivity. CEUS has been shown to have a high diagnostic potential in the diagnosis of ICC thanks to the possibility of studying in real time the intralesional microcirculation and evaluating the precocity of the enhancement of the lesion during the arterial phase. All these features allow to differentiate the ICC from hepatocarcinoma (HCC) with high sensitivity and specificity. Furthermore, CEUS is a rapid, non-invasive, non-nephrotoxic or non-allergenic tool. The only limitations CEUS may have are related to the disease site and patient characteristics (obesity) and compliance, including the operator's experience. A clinical evaluation of the patient, together with tumor markers and biochemical tests assessment, to differentiate ICC from HCC are highly suggested.
PMID:38419841 | PMC:PMC10897370 | DOI:10.15557/jou.2024.0005
Asian Pac J Cancer Prev. 2024 Feb 1;25(2):365. doi: 10.31557/APJCP.2024.25.2.365.
NO ABSTRACT
PMID:38415518 | DOI:10.31557/APJCP.2024.25.2.365
Ecancermedicalscience. 2023 Nov 27;17:1641. doi: 10.3332/ecancer.2023.1641. eCollection 2023.
ABSTRACT
BACKGROUND: The most common types of primary malignant liver tumours are hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Treatment options for patients who are inoperable/advanced, or recurring are challenging. Cyclin D1, epidermal growth factor (EGFR) and vascular endothelial growth factor (VEGR) are common carcinogenic proteins that have potential therapeutic targets in various cancers. They have been implicated in the development of HCC and CCA. In this study, we aimed to evaluate the oncogenic function expression of cyclin D1, EGFR and VEGF in HCC and CCA of Egyptian patients. This could help to validate their therapeutic potential.
MATERIAL AND METHODS: Tumour cases were selected from 82 cases of primary liver carcinomas, with 58 cases being from HCC and 24 cases from CCA compared to 51 non-tumour adjacent liver cases and 18 from normal liver tissue. The immunohistochemical study of cyclin D1, EGFR and VEGR was conducted.
RESULTS: Cyclin D1, EGFR and VEGF are overexpressed in HCC and CCA as compared to the control group (p < 0.001). Cyclin D1 was related to well-differentiated grade and early pathologic stage in HCC (p = 0.016 and p = 0.042, respectively). The well-differentiated grade showed significantly higher VEGF levels (p = 0.04). In the CCA group, however, EGFR was strongly related to high tumour size (p = 0.047). EGFR and VEGF were overexpressed in HCC raised in the non-cirrhotic liver compared to those developed in post-hepatitic liver cirrhosis (p = 0.003 and p = 0.014).
CONCLUSION: Cyclin D1, EGFR and VEGF shared significant overexpression in HCC and CCA. EGFR and VEGF may play an oncogenic function in the development of HCC in non-cirrhotic liver. Furthermore, cyclin D1 and VEGF may play a good prognostic function in HCC, but EGFR may play a bad prognostic role in CCA.
PMID:38414954 | PMC:PMC10898887 | DOI:10.3332/ecancer.2023.1641
World J Clin Cases. 2024 Feb 16;12(5):913-921. doi: 10.12998/wjcc.v12.i5.913.
ABSTRACT
BACKGROUND: Intrahepatic duct (IHD) stones are among the most important risk factors for cholangiocarcinoma (CCC). Approximately 10% of patients with IHD stones develop CCC; however, there are limited studies regarding the effect of IHD stone removal on CCC development.
AIM: To investigate the association between IHD stone removal and CCC development.
METHODS: We retrospectively analyzed 397 patients with IHD stones at a tertiary referral center between January 2011 and December 2020.
RESULTS: CCC occurred in 36 of the 397 enrolled patients. In univariate analysis, chronic hepatitis B infection (11.1% vs 3.0%, P = 0.03), carbohydrate antigen 19-9 (CA19-9, 176.00 vs 11.96 II/mL, P = 0.010), stone located in left or both lobes (86.1% vs 70.1%, P = 0.042), focal atrophy (52.8% vs 26.9%, P = 0.001), duct stricture (47.2% vs 24.9%, P = 0.004), and removal status of IHD stone (33.3% vs 63.2%, P < 0.001) were significantly different between IHD stone patients with and without CCC. In the multivariate analysis, CA19-9 > upper normal limit, carcinoembryonic antigen > upper normal limit, stones located in the left or both lobes, focal atrophy, and complete removal of IHD stones without recurrence were independent factors influencing CCC development. However, the type of removal method was not associated with CCC risk.
CONCLUSION: Complete removal of IHD stones without recurrence could reduce CCC risk.
PMID:38414601 | PMC:PMC10895623 | DOI:10.12998/wjcc.v12.i5.913
World J Gastroenterol. 2024 Feb 7;30(5):471-484. doi: 10.3748/wjg.v30.i5.471.
ABSTRACT
BACKGROUND: Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment options. Recombinant adeno-associated virus (rAAV) provides a promising platform for gene therapy on such kinds of diseases. A microRNA (miRNA) let-7a has been reported to be associated with the progress of PSC but the potential therapeutic implication of inhibition of let-7a on PSC has not been evaluated.
AIM: To investigate the therapeutic effects of inhibition of a miRNA let-7a transferred by recombinant adeno-associated virus 8 (rAAV8) on a xenobiotic-induced mouse model of sclerosing cholangitis.
METHODS: A xenobiotic-induced mouse model of sclerosing cholangitis was induced by 0.1% 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC) feeding for 2 wk or 6 wk. A single dose of rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo into mice onset of DDC feeding. Upon sacrifice, the liver and the serum were collected from each mouse. The hepatobiliary injuries, hepatic inflammation and fibrosis were evaluated. The targets of let-7a-5p and downstream molecule NF-κB were detected using Western blot.
RESULTS: rAAV8-mediated anti-let-7a-5p sponges can depress the expression of let-7a-5p in mice after DDC feeding for 2 wk or 6 wk. The reduced expression of let-7a-5p can alleviate hepato-biliary injuries indicated by serum markers, and prevent the proliferation of cholangiocytes and biliary fibrosis. Furthermore, inhibition of let-7a mediated by rAAV8 can increase the expression of potential target molecules such as suppressor of cytokine signaling 1 and Dectin1, which consequently inhibit of NF-κB-mediated hepatic inflammation.
CONCLUSION: Our study demonstrates that a rAAV8 vector designed for liver-specific inhibition of let-7a-5p can potently ameliorate symptoms in a xenobiotic-induced mouse model of sclerosing cholangitis, which provides a possible clinical translation of PSC of human.
PMID:38414587 | PMC:PMC10895596 | DOI:10.3748/wjg.v30.i5.471
In Vivo. 2024 Mar-Apr;38(2):785-793. doi: 10.21873/invivo.13502.
ABSTRACT
BACKGROUND/AIM: Metabolic syndrome (MetS) stands as a significant risk for developing various severe health problems. Therefore, the discovery of biomarkers capable of predicting the progression of metabolic conditions is crucial for improving overall health outcomes. Recently, we reported that coiled-coil domain containing 25 (CCDC25) might be associated with key proteins involved in metabolic pathways, by bioinformatics analysis. Thus, we assumed that serum CCDC25 levels might have an association with MetS status.
PATIENTS AND METHODS: In this study, based on the modified National Cholesterol Education Program-Adult Treatment Panel III (modified NCEP-ATP III) criteria, the participants who had three or more of abnormal criteria were defined as MetS, and those who had 1 or 2 abnormal criteria as pre-MetS groups; those who had no abnormal criteria were classified as the healthy control (HC) group. Serum CCDC25 levels were measured using the dot blot assay.
RESULTS: The results showed that serum CCDC25 levels of the MetS group (0.072±0.026 ng/μl) were significantly higher (p<0.001) than that of pre-MetS (0.031±0.011 ng/μl) or HC groups (0.018±0.007 ng/μl). We can discern a consistent trend indicating that serum CCDC25 level is well correlated with the number of abnormal criteria of MetS of each participant. Although serum CCDC25 levels correlated with the distribution of all 5 MetS criteria, the highest correlation was seen in serum CCDC25 levels and triglyceride (TG) levels, with r=0.563, followed by systolic blood pressure (SBP) levels (r=0.557) and high-density lipoprotein-cholesterol (HDL-C) levels (r=-0.545).
CONCLUSION: CCDC25 showed correlations with all MetS parameters, particularly with TG, SBP, and HDL-C. This prompts speculation that heightened CCDC25 levels may indicate the development and/or progression of those MetS-associated diseases.
PMID:38418150 | PMC:PMC10905474 | DOI:10.21873/invivo.13502
Surg Laparosc Endosc Percutan Tech. 2024 Feb 26. doi: 10.1097/SLE.0000000000001270. Online ahead of print.
ABSTRACT
OBJECTIVE: To comparatively analyze the clinical efficacy and safety of unilateral radioactive stent (RS) insertion versus bilateral normal stent (NS) insertion in patients with inoperable hilar cholangiocarcinoma (HC).
PATIENTS AND METHODS: Patients with inoperable HC were treated in our hospital from January 2016 to December 2020. The treatment approach included the insertion of either unilateral RS or bilateral NS, evaluating the efficacy and safety of therapy in 2 distinct groups.
RESULTS: A total of 58 individuals experienced the insertion of a unilateral RS, whereas 57 patients underwent the insertion of bilateral NS. No statistically significant difference between the unilateral RS and bilateral NS groups was seen in the technical success rates (98.3% vs 94.7%, P = 0.598) and clinical success rates (98.2% vs 100%, P = 0.514). While there is no statistically significant difference in the rates of stent restenosis (19.3% vs 9.3%, P = 0.132) between the two groups, the unilateral RS group demonstrated substantially longer stent patency (202 vs 119 d, P = 0.016) and overall survival (229 vs 122 d, P = 0.004) compared with the bilateral NS group. Moreover, 8 patients (14.0%) in the unilateral RS group and 14 patients (25.9%) in the bilateral NS group had postoperative complications with no significant difference (P = 0.116).
CONCLUSION: When inserting stents for inoperable HC, both unilateral RS and bilateral NS insertion procedures have demonstrated favorable therapeutic efficacy. Nevertheless, inserting a unilateral RS provided a longer duration of stent patency and overall survival than implantation of bilateral NS.
PMID:38417125 | DOI:10.1097/SLE.0000000000001270
Hum Cell. 2024 Feb 28. doi: 10.1007/s13577-024-01032-7. Online ahead of print.
ABSTRACT
This study aimed to investigate the expression of protein regulator of cytokinesis 1 (PRC1) in cholangiocarcinoma (CHOL) and elucidate its potential impact as well as the underlying mechanisms governing the progression of CHOL. In this study, we used CHOL cells (HUCCT1, RBE, and CCLP1) and conducted a series of experiments, including qRT-PCR, cell counting kit-8 assays, EdU assays, flow cytometry, wound healing assays, Transwell assays, western blotting, double luciferase assays, and ELISA. Subsequently, a mouse model was established using cancer cell injections. Haematoxylin-eosin staining, along with Ki67 and TUNEL assays, were employed to assess tissue histopathology, cell proliferation, and apoptosis. Our findings revealed significantly elevated PRC1 expression in CHOL. According to bioinformatics analysis, it was found that the increased PRC1 level is correlated with the high tumour grades, metastases, and unfavourable prognoses. Notably, PRC1 knockdown inhibited cell viability, proliferation, migration, and invasion while promoting apoptosis in CHOL cells. Analysing TCGA-CHOL data and utilising transcription factor prediction tools (hTFtarget and HumanTFDB), we identified that genes positively correlated with PRC1 in TCGA-CHOL intersect with predicted transcription factors, revealing the activation of PRC1 by forkhead box protein M1 (FOXM1). Moreover, PRC1 was found to exert regulatory control over glycolysis and the mammalian target of rapamycin complex 1 (mTORC1) pathway in the context of CHOL based on KEGG and GSEA analysis. Collectively, these results underscore the pivotal role of PRC1 in CHOL progression, wherein it modulates glycolysis and the mTORC1 pathway under the regulatory influence of FOXM1.
PMID:38416277 | DOI:10.1007/s13577-024-01032-7
BMB Rep. 2024 Feb;57(2):123.
ABSTRACT
[Retraction to: BMB Rep. 2022 June 30; 55(6): 299-304.] Retraction: "Inhibition of ClC-5 suppresses proliferation and induces apoptosis in cholangiocarcinoma cells through the Wnt/β-catenin signaling pathway," by Zhe Shi, Liyuan Zhou, Yan Zhou, Xiaoyan Jia, Xiangjun Yu, Xiaohong An and Yanzhen Han, BMB Rep. 2022; 55(6) 299-304: The above article, published online on 30 June 2022 in BMB Reports [https:] BMBRep.2022.55.6.044), has been retracted by agreement between the authors and the journal's Editor in Chief. The authors unable to replicate certain results presented in the article and have therefore made the difficult decision to withdraw it. Editorial Board, BMB Reports.
PMID:38416114 | PMC:PMC10910095
Dis Model Mech. 2024 Jun 1;17(6):dmm050358. doi: 10.1242/dmm.050358. Epub 2024 Feb 28.
ABSTRACT
Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA - including Kras, Tp53, Arid1a and Smad4 - as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFβ/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.
PMID:38415925 | DOI:10.1242/dmm.050358
Asian Pac J Cancer Prev. 2024 Feb 1;25(2):537-546. doi: 10.31557/APJCP.2024.25.2.537.
ABSTRACT
BACKGROUND: Cholangiocarcinoma (CCA) is experiencing a global increase, particularly in Northeast Thailand, which has the highest global incidence rates. However, there is a paucity of studies on CCA screening, especially in high-risk populations. This study aimed to investigate the distribution and spatial patterns of CCA in Northeast Thailand over a ten-year screening period.
METHODS: The study included CCA patients from the Cholangiocarcinoma Screening and Care Program (CASCAP) between 2013 and 2022, which encompasses 20 provinces and 282 districts in Northeast of Thailand. CCA data were based on pathological diagnosis to determine the distribution and spatial patterns.
RESULTS: Of the 2,515 CCA patients, approximately two-thirds were males (63.98%), and the majority were aged over 55 years (72.72%), with a mean age of 61.12 ± 9.13 years. The highest percentage of CCA cases occurred in 2014 at 19.01% of all patients, followed by 2018 at 15.23%. The overall CCA incidence rate in Northeast Thailand over ten years was 32 per 100,000 population. Hotspot statistical analysis identified high-scoring geographic clusters in the upper and middle regions, showing a tendency to expand from hotspot areas into nearby areas.
CONCLUSION: The distribution of CCA in Northeast Thailand has continued to rise over the past decade, particularly in the upper and middle regions. Targeted screening in high-risk areas and increased awareness of CCA risks are crucial to mitigate its impact.
PMID:38415540 | DOI:10.31557/APJCP.2024.25.2.537
Clin Radiol. 2024 Feb 13:S0009-9260(24)00093-X. doi: 10.1016/j.crad.2024.02.001. Online ahead of print.
ABSTRACT
AIM: To establish a machine-learning model based on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to differentiate combined hepatocellular-cholangiocarcinoma (cHCC-CC) from hepatocellular carcinoma (HCC) before surgery.
MATERIALS AND METHODS: Clinical and MRI data of 194 patients with histopathologically diagnosed cHCC-CC (n=52) or HCC (n=142) were analysed retrospectively. ITK-SNAP software was used to delineate three-dimensional (3D) lesions and extract high-throughput features. Feature selection was carried out based on Pearson's correlation coefficient and least absolute shrinkage and selection operator (LASSO) regression analysis. A radiomics model (radiomics features), a clinical model (i.e., clinical-image features), and a fusion model (i.e., radiomics features + clinical-image features) were established using six machine-learning classifiers. The performance of each model in distinguishing between cHCC-CC and HCC was evaluated with the receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC), sensitivity, and specificity.
RESULTS: Significant differences in liver cirrhosis, tumour number, shape, edge, peritumoural enhancement in the arterial phase, and lipid were identified between cHCC-CC and HCC patients (p<0.05). The AUC of the fusion model based on logistic regression was 0.878 (95% CI: 0.766-0.949) in the arterial phase in the test set, and the sensitivity/specificity was 0.844/0.714; however, the AUC of the clinical and radiomics models was 0.759 (95% CI: 0.663-0.861) and 0.838 (95% CI: 0.719-0.921) in the test set, respectively.
CONCLUSION: The fusion model based on DCE-MRI in the arterial phase can significantly improve the diagnostic rate of cHCC-CC and HCC as compared with conventional approaches.
PMID:38413354 | DOI:10.1016/j.crad.2024.02.001
J Biosci Bioeng. 2024 Feb 26:S1389-1723(24)00037-9. doi: 10.1016/j.jbiosc.2024.01.017. Online ahead of print.
ABSTRACT
Estimation of the biliary clearance of drugs and their metabolites in humans is crucial for characterizing hepatobiliary disposition and potential drug-drug interactions. Sandwich-cultured hepatocytes, while useful for in vitro bile analysis, require cell destruction for bile recovery, limiting long-term or repeated dose drug effect evaluations. To overcome this limitation, we investigated the feasibility of coculturing a human hepatic carcinoma cell line (HepG2-NIAS cells) and a human cholangiocarcinoma cell line (TFK-1 cells) using the collagen vitrigel membrane in a variety of coculture configurations. The coculture configuration with physiological bile flow increased the permeability of fluorescein-labeled bile acids (CLF) across the HepG2-NIAS cell layer by approximately 1.2-fold compared to the HepG2-NIAS monoculture. This enhancement was caused by paracellular leakage due to the loosened tight junctions of HepG2-NIAS, confirmed by the use of an inhibitor for bile acid transporters, the increase of permeability of dextran, and the decrease of the transepithelial electrical resistance (TEER) value. Based on the results of loosening hepatic tight junctions via coculture with TFK-1 in the CLF permeability assay, we next attempted to collect the CLF accumulated in the bile canaliculi of HepG2-NIAS. The recovery of the CLF accumulated in the bile canaliculi was increased 1.4 times without disrupting hepatic tight junctions by the coculture of HepG2-NIAS cells and TFK-1 cells compared to the monoculture of HepG2-NIAS cells. This non-destructive bile recovery has the potential as a tool for estimating the biliary metabolite and provides valuable insights to improve in vitro bile analysis.
PMID:38413317 | DOI:10.1016/j.jbiosc.2024.01.017
Histopathology. 2024 Feb 26. doi: 10.1111/his.15162. Online ahead of print.
ABSTRACT
AIMS: The histological subtype of intrahepatic cholangiocarcinoma (iCCA) is associated with different mutational characteristics that impact clinical management. So far, data are lacking on the presence of small duct iCCA (SD-iCCA) and large duct iCCA (LD-iCCA) in a single patient. The aim of the current study was to determine the presence and degree of intratumoural heterogeneity of SD- and LD-iCCA features in different tumour regions.
METHODS AND RESULTS: All patients treated with surgically resected iCCA at Frankfurt University Hospital between December 2005 and March 2023 were retrospectively analysed. Histomorphological features of SD- and LD-iCCA were evaluated by an expert hepatobiliary pathologist. Tissue samples suspicious for subtype heterogeneity were further investigated. Immunohistochemistry for N-cadherin, S100P, MUC5AC, MUC6, TFF1 and AGR2 and mutational profiling with the Illumina TruSight Oncology 500 (TSO500) assay were performed separately for the SD- and LD-iCCA regions. Of 129 patients with surgically resected iCCA, features of either SD- or LD-iCCA were present in 67.4% (n = 87) and 24.8% of the patients (n = 32), respectively; 7.8% (n = 10) had histomorphological features of both SD- and LD-iCCA, seven patients (5.4%) of which had sufficient formalin-fixed, paraffin-embedded tissue for further analysis. Heterogeneity of both subtypes could be confirmed with immunohistochemistry. In five of seven (71.4%) patients, molecular profiling revealed intratumoural differences in genetic alterations between the SD- and LD-iCCA region. In one patient, a BRAF mutation (p.V600E) was found in the SD-iCCA but not in the LD-iCCA region of the tumour.
CONCLUSIONS: A marked portion of patients with iCCA exhibits both SD- and LD-iCCA in different tumour regions. In case of the presence of histopathological heterogeneity, mutational profiling should be considered to avoid missing therapeutically relevant genetic alterations.
PMID:38409827 | DOI:10.1111/his.15162