Rare Cancer News & Clinical Trials

Hepatoblastoma (225 unread)

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Evaluation of Lung Metastases Based on Ultrashort Echo Time MRI

Posted: March 10th, 2023, 3:00pm GMT

Conditions: Hepatoblastoma; Radiology
Intervention:
Sponsor: RenJi Hospital
Recruiting

Sodium Thiosulfate Otoprotection During Salvage Cisplatin Therapy

Posted: March 6th, 2023, 3:00pm GMT

Condition: Ototoxicity, Drug-Induced
Intervention: Drug: Sodium Thiosulfate
Sponsor: Children's Hospital Medical Center, Cincinnati
Recruiting

$Permalink for 'Relapsed and Refractory Hepatoblastoma: A Prospective Registry and Liver Tumor Research Consortium Initiative'$

Relapsed and Refractory Hepatoblastoma: A Prospective Registry and Liver Tumor Research Consortium Initiative

Posted: September 27th, 2022, 2:00am GMT

Conditions: Relapsed Hepatoblastoma; Refractory Hepatoblastoma
Interventions: Other: Biospecimen collection
Sponsors: Children's Hospital Medical Center, Cincinnati
Recruiting

$Permalink for 'Neoadjuvant Dual Checkpoint Inhibition and Cryoablation in Relapsed/Refractory Pediatric Solid Tumors'$

Neoadjuvant Dual Checkpoint Inhibition and Cryoablation in Relapsed/Refractory Pediatric Solid Tumors

Posted: March 31st, 2022, 2:00am GMT

Conditions: Osteosarcoma; Ewing Sarcoma; Rhabdomyosarcoma; Relapsed Pediatric Solid Tumor; Refractory Pediatric Solid Tumor; Melanoma; Hepatoblastoma; Hepatocellular Carcinoma; Neuroblastoma; Wilms Tumor
Interventions: Procedure: Cryoablation Therapy; Drug: Nivolumab; Drug: Ipilimumab
Sponsors: Children's National Research Institute; Bristol-Myers Squibb
Active, not recruiting

B7-H3-Specific Chimeric Antigen Receptor Autologous T-Cell Therapy for Pediatric Patients With Solid Tumors (3CAR)

Posted: May 21st, 2021, 2:00pm GMT

Conditions: Pediatric Solid Tumor; Osteosarcoma; Rhabdomyosarcoma; Neuroblastoma; Ewing Sarcoma; Wilms Tumor; Adrenocortical Cancer; Desmoplastic Small Round Cell Tumor; Germ Cell Cancer; Rhabdoid Tumor; Clear Cell Sarcoma; Hepatoblastoma; Melanoma; Carcinoma; Malignant Peripheral Nerve Sheath Tumors; Soft Tissue Sarcoma
Interventions: Drug: Fludarabine; Drug: Cyclophosphamide; Drug: MESNA; Drug: B7-H3 CAR T cells
Sponsor: St. Jude Children's Research Hospital
Recruiting

$Permalink for 'Tegavivint for the Treatment of Recurrent or Refractory Solid Tumors, Including Lymphomas and Desmoid Tumors'$

Tegavivint for the Treatment of Recurrent or Refractory Solid Tumors, Including Lymphomas and Desmoid Tumors

Posted: April 20th, 2021, 2:00pm GMT

Conditions: Colorectal Carcinoma; Endometrial Carcinoma; Melanoma; Neuroblastoma; Ovarian Carcinoma; Pancreatic Ductal Adenocarcinoma; Recurrent Desmoid Fibromatosis; Recurrent Ewing Sarcoma; Recurrent Hepatoblastoma; Recurrent Hepatocellular Carcinoma; Recurrent Malignant Solid Neoplasm; Recurrent Non-Hodgkin Lymphoma; Recurrent Osteosarcoma; Refractory Desmoid Fibromatosis; Refractory Ewing Sarcoma; Refractory Hepatoblastoma; Refractory Hepatocellular Carcinoma; Refractory Malignant Solid Neoplasm; Refractory Non-Hodgkin Lymphoma; Refractory Osteosarcoma; Solid Pseudopapillary Neoplasm of the Pancreas; Wilms Tumor
Interventions: Procedure: Biospecimen Collection; Procedure: Dual X-ray Absorptiometry; Drug: Tegavivint; Procedure: X-Ray Imaging
Sponsors: Children's Oncology Group; National Cancer Institute (NCI)
Recruiting

A Multi-institutional Study for Treatment of Children With Newly Diagnosed Hepatoblastoma Using a Modified PHITT Strategy

Posted: July 20th, 2020, 2:00pm GMT

Conditions: Hepatoblastoma
Interventions: Drug: Sodium Thiosulfate Injection; Procedure: Primary surgery resection; Drug: mono CDDP-Group A2; Drug: Cisplatin, 5-Fluorouracil, Vincristine, Doxorubicin-Group C; Procedure: Biopsy; Procedure: Resection or transplant; Procedure: Resection of pulmonary nodules; Drug: mono CDDP- Group B; Drug: Block 1 to 3 (Cisplatin, Doxorubicin) Group D; Drug: Consolidation (Carboplatin, Doxorubicin) -Group D1; Drug: Consolidation (Carboplatin +Doxorubicin/Vincristine + Irinotecan)-Group D2
Sponsors: Shanghai Children's Medical Center; Shanghai Children's Hospital
Recruiting

Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With Temozolomide for Treatment of Recurrent Pediatric Solid Tumors

Posted: April 7th, 2020, 2:00pm GMT

Conditions: Solid Tumors; Neuroblastoma; Rhabdomyosarcoma; Ewing Sarcoma; Hepatoblastoma; Medulloblastoma
Interventions: Drug: VAL-413; Drug: Temozolomide
Sponsor: Valent Technologies, LLC
Recruiting

Yttrium-90 (TARE-Y90) in Children, Adolescents, and Young Adults With Liver Tumors

Posted: March 20th, 2020, 2:00pm GMT

Conditions: Hepatoblastoma; Hepatocellular Carcinoma; Rhabdoid Tumor of Liver; Undifferentiated (Embryonal) Sarcoma of the Liver; Pediatric Liver Cancer; Liver Tumors
Interventions: Behavioral: Quality of Life Assessment; Radiation: Transarterial Radioembolization
Sponsors: Nemours Children's Clinic; Alfred I. duPont Hospital for Children
Recruiting

$Permalink for 'Vorinostat in Combination With Chemotherapy in Relapsed/Refractory Solid Tumors and CNS Malignancies'$

Vorinostat in Combination With Chemotherapy in Relapsed/Refractory Solid Tumors and CNS Malignancies

Posted: March 16th, 2020, 2:00am GMT

Conditions: Ewing Sarcoma; Rhabdomyosarcoma; Wilms Tumor; Neuroblastoma; Hepatoblastoma; Germ Cell Tumor
Interventions: Drug: Vorinostat
Sponsors: New York Medical College
Recruiting

Molecular Basis of Pediatric Liver Cancer

Posted: May 22nd, 2019, 2:00pm GMT

Conditions: Childhood Liver Cancer; Liver Malignant Tumors; Embryonal Sarcoma of Liver (Disorder); Hepatoblastoma; Hepatocellular Carcinoma; Rhabdoid Tumor of Liver
Intervention:
Sponsor: University of Pittsburgh
Recruiting

Permalink for 'Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)'

Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)

Posted: October 9th, 2018, 2:00am GMT

Conditions: Advanced Malignant Solid Neoplasm; Recurrent Ependymal Tumor; Recurrent Ewing Sarcoma; Recurrent Glioma; Recurrent Hepatoblastoma; Recurrent Histiocytic and Dendritic Cell Neoplasm; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Germ Cell Tumor; Recurrent Malignant Solid Neoplasm; Recurrent Medulloblastoma; Recurrent Neuroblastoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Osteosarcoma; Recurrent Peripheral Primitive Neuroectodermal Tumor; Recurrent Primary Malignant Central Nervous System Neoplasm; Recurrent Rhabdoid Tumor; Recurrent Rhabdomyosarcoma; Recurrent Soft Tissue Sarcoma; Refractory Ependymoma; Refractory Ewing Sarcoma; Refractory Glioma; Refractory Hepatoblastoma; Refractory Histiocytic and Dendritic Cell Neoplasm; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Germ Cell Tumor; Refractory Malignant Solid Neoplasm; Refractory Medulloblastoma; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Refractory Osteosarcoma; Refractory Peripheral Primitive Neuroectodermal Tumor; Refractory Primary Malignant Central Nervous System Neoplasm; Refractory Rhabdoid Tumor; Refractory Rhabdomyosarcoma; Refractory Soft Tissue Sarcoma; Wilms Tumor
Interventions: Other: Pharmacokinetic Study; Drug: Ulixertinib
Sponsors: National Cancer Institute (NCI)
Active, not recruiting

$Permalink for 'EGFR806 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults'$

EGFR806 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults

Posted: August 7th, 2018, 2:00pm GMT

Conditions: Pediatric Solid Tumor; Germ Cell Tumor; Retinoblastoma; Hepatoblastoma; Wilms Tumor; Rhabdoid Tumor; Carcinoma; Osteosarcoma; Ewing Sarcoma; Rhabdomyosarcoma; Synovial Sarcoma; Clear Cell Sarcoma; Malignant Peripheral Nerve Sheath Tumors; Desmoplastic Small Round Cell Tumor; Soft Tissue Sarcoma; Neuroblastoma
Interventions: Biological: second generation 4-1BBζ EGFR806-EGFRt; Biological: second generation 4-1BBζ EGFR806-EGFRt and a second generation 4 1BBζ CD19-Her2tG
Sponsor: Seattle Children's Hospital
Recruiting

Permalink for 'Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery'

Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery

Posted: May 23rd, 2018, 2:00pm GMT

Conditions: Childhood Hepatocellular Carcinoma; Childhood Malignant Liver Neoplasm; Fibrolamellar Carcinoma; Hepatoblastoma; Hepatocellular Malignant Neoplasm, Not Otherwise Specified
Interventions: Drug: Carboplatin; Drug: Cisplatin; Drug: Doxorubicin; Drug: Etoposide; Drug: Fluorouracil; Drug: Gemcitabine; Drug: Irinotecan; Other: Laboratory Biomarker Analysis; Drug: Oxaliplatin; Other: Patient Observation; Procedure: Resection; Drug: Sorafenib; Drug: Vincristine Sulfate
Sponsors: Children's Oncology Group; National Cancer Institute (NCI)
Recruiting

$Permalink for 'Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)'$

Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)

Posted: May 16th, 2018, 2:00am GMT

Conditions: Advanced Malignant Solid Neoplasm; Recurrent Childhood Ependymoma; Recurrent Ewing Sarcoma; Recurrent Glioma; Recurrent Hepatoblastoma; Recurrent Kidney Wilms Tumor; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Germ Cell Tumor; Recurrent Malignant Glioma; Recurrent Medulloblastoma; Recurrent Neuroblastoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Osteosarcoma; Recurrent Peripheral Primitive Neuroectodermal Tumor; Recurrent Rhabdoid Tumor; Recurrent Rhabdomyosarcoma; Recurrent Soft Tissue Sarcoma; Refractory Ependymoma; Refractory Ewing Sarcoma; Refractory Glioma; Refractory Hepatoblastoma; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Germ Cell Tumor; Refractory Malignant Glioma; Refractory Medulloblastoma; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Refractory Osteosarcoma; Refractory Peripheral Primitive Neuroectodermal Tumor; Refractory Rhabdoid Tumor; Refractory Rhabdomyosarcoma; Refractory Soft Tissue Sarcoma
Interventions: Other: Laboratory Biomarker Analysis; Drug: Palbociclib; Other: Pharmacological Study
Sponsors: National Cancer Institute (NCI)
Active, not recruiting

$Permalink for 'Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)'$

Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)

Posted: July 28th, 2017, 2:00am GMT

Conditions: Advanced Malignant Solid Neoplasm; Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma; Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma; Low Grade Glioma; Malignant Glioma; Recurrent Childhood Central Nervous System Neoplasm; Recurrent Childhood Ependymoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Glioma; Recurrent Hepatoblastoma; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Solid Neoplasm; Recurrent Medulloblastoma; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Refractory Childhood Malignant Germ Cell Tumor; Refractory Ependymoma; Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Refractory Glioma; Refractory Hepatoblastoma; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Glioma; Refractory Malignant Solid Neoplasm; Refractory Medulloblastoma; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Refractory Osteosarcoma; Refractory Primary Central Nervous System Neoplasm; Refractory Rhabdomyosarcoma; Refractory Soft Tissue Sarcoma; Rhabdoid Tumor; Wilms Tumor
Interventions: Drug: Olaparib
Sponsors: National Cancer Institute (NCI)
Active, not recruiting

$Permalink for 'Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)'$

Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)

Posted: July 18th, 2017, 2:00am GMT

Conditions: Advanced Malignant Solid Neoplasm; Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma; Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma; Ependymoma; Ewing Sarcoma; Hepatoblastoma; Langerhans Cell Histiocytosis; Malignant Germ Cell Tumor; Malignant Glioma; Osteosarcoma; Peripheral Primitive Neuroectodermal Tumor; Recurrent Childhood Central Nervous System Neoplasm; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Malignant Solid Neoplasm; Recurrent Neuroblastoma; Refractory Malignant Solid Neoplasm; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Refractory Primary Central Nervous System Neoplasm; Rhabdoid Tumor; Rhabdomyosarcoma; Soft Tissue Sarcoma; Wilms Tumor
Interventions: Other: Laboratory Biomarker Analysis; Drug: Vemurafenib
Sponsors: National Cancer Institute (NCI)
Active, not recruiting

$Permalink for 'Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)'$

Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)

Posted: July 11th, 2017, 2:00am GMT

Conditions: Advanced Malignant Solid Neoplasm; Ann Arbor Stage III Hodgkin Lymphoma; Ann Arbor Stage III Non-Hodgkin Lymphoma; Ann Arbor Stage IV Hodgkin Lymphoma; Ann Arbor Stage IV Non-Hodgkin Lymphoma; Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Low Grade Glioma; Recurrent Ependymoma; Recurrent Ewing Sarcoma; Recurrent Glioma; Recurrent Hepatoblastoma; Recurrent Hodgkin Lymphoma; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Germ Cell Tumor; Recurrent Malignant Glioma; Recurrent Malignant Solid Neoplasm; Recurrent Medulloblastoma; Recurrent Neuroblastoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Osteosarcoma; Recurrent Peripheral Primitive Neuroectodermal Tumor; Recurrent Primary Central Nervous System Neoplasm; Recurrent Rhabdoid Tumor; Recurrent Rhabdomyosarcoma; Recurrent Soft Tissue Sarcoma; Refractory Hodgkin Lymphoma; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Germ Cell Tumor; Refractory Malignant Glioma; Refractory Malignant Solid Neoplasm; Refractory Medulloblastoma; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Refractory Osteosarcoma; Refractory Peripheral Primitive Neuroectodermal Tumor; Refractory Rhabdoid Tumor; Refractory Soft Tissue Sarcoma; Rhabdoid Tumor; Stage III Soft Tissue Sarcoma AJCC v7; Stage IV Soft Tissue Sarcoma AJCC v7; Wilms Tumor
Interventions: Drug: Tazemetostat
Sponsors: National Cancer Institute (NCI); Children's Oncology Group
Active, not recruiting

$Permalink for 'Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)'$

Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)

Posted: July 7th, 2017, 2:00am GMT

Conditions: Advanced Malignant Solid Neoplasm; Recurrent Childhood Ependymoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Childhood Osteosarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Hepatoblastoma; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Glioma; Recurrent Malignant Solid Neoplasm; Recurrent Neuroblastoma; Recurrent Primary Central Nervous System Neoplasm; Recurrent Rhabdoid Tumor; Refractory Childhood Malignant Germ Cell Tumor; Refractory Childhood Osteosarcoma; Refractory Childhood Rhabdomyosarcoma; Refractory Childhood Soft Tissue Sarcoma; Refractory Ependymoma; Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Refractory Hepatoblastoma; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Glioma; Refractory Malignant Solid Neoplasm; Refractory Medulloblastoma; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Refractory Primary Central Nervous System Neoplasm; Refractory Rhabdoid Tumor; Wilms Tumor
Interventions: Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration and Biopsy; Procedure: Bone Scan; Procedure: Computed Tomography; Drug: Erdafitinib; Other: Laboratory Biomarker Analysis; Procedure: Magnetic Resonance Imaging; Other: Pharmacological Study; Procedure: Positron Emission Tomography; Procedure: Radionuclide Imaging; Procedure: X-Ray Imaging
Sponsors: National Cancer Institute (NCI)
Active, not recruiting

Combined Modality Therapy in Hepatoblastoma: South Egypt Cancer Institute Experience

Posted: September 23rd, 2015, 2:00pm GMT

Condition: Hepatoblastoma
Intervention:
Sponsor: Assiut University
Recruiting

$Permalink for 'A Phase I Dose Finding Study in Children With Solid Tumors Recurrent or Refractory to Standard Therapy'$

A Phase I Dose Finding Study in Children With Solid Tumors Recurrent or Refractory to Standard Therapy

Posted: March 12th, 2014, 2:00am GMT

Conditions: Pediatric Oncology
Interventions: Drug: Regorafenib (BAY73-4506); Drug: Vincristine (Cellcristin®); Drug: Irinotecan (Irinotecan Cell pharm®)
Sponsors: Bayer
Active, not recruiting

Reduced Intensity Haploidentical BMT for High Risk Solid Tumors

Posted: March 5th, 2013, 3:00pm GMT

Condition: Refractory and/or Relapsed Metastatic Solid Tumors
Interventions: Drug: Cyclophosphamide; Drug: Fludarabine; Radiation: low dose total body irradiation; Drug: Melphalan; Drug: Tacrolimus
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Recruiting

Auto Transplant for High Risk or Relapsed Solid or CNS Tumors

Posted: January 6th, 2012, 3:00pm GMT

Conditions: Ewing's Family Tumors; Renal Tumors; Hepatoblastoma; Rhabdomyosarcoma; Soft Tissue Sarcoma; Primary Malignant Brain Neoplasms; Retinoblastoma; Medulloblastoma; Supra-tentorial Primative Neuro-Ectodermal Tumor (PNET); Atypical Teratoid/Rhabdoid Tumor (AT/RT); CNS Tumors; Germ Cell Tumors
Interventions: Drug: Ifosfamide; Drug: Etoposide; Drug: Mesna; Biological: G-CSF; Drug: Busulfan; Drug: Melphalan; Drug: Thiotepa; Biological: Autologous stem cell infusion; Radiation: Radiation; Drug: Carboplatin; Drug: Paclitaxel; Procedure: Leukapheresis; Drug: Anti-seizure prophylaxis; Drug: Ursodiol
Sponsor: Masonic Cancer Center, University of Minnesota
Recruiting

Risk-Based Therapy in Treating Younger Patients With Newly Diagnosed Liver Cancer

Posted: September 21st, 2009, 2:00am GMT

Conditions: PRETEXT I Hepatoblastoma; PRETEXT II Hepatoblastoma; PRETEXT III Hepatoblastoma; PRETEXT IV Hepatoblastoma
Interventions: Drug: Cisplatin; Drug: Dexrazoxane; Drug: Doxorubicin Hydrochloride; Drug: Fluorouracil; Drug: Irinotecan Hydrochloride; Other: Laboratory Biomarker Analysis; Procedure: Liver Transplantation; Drug: Temsirolimus; Procedure: Therapeutic Conventional Surgery; Drug: Vincristine Sulfate
Sponsors: National Cancer Institute (NCI)
Active, not recruiting

Permalink for 'Sodium Thiosulfate in Preventing Hearing Loss in Young Patients Receiving Cisplatin for Newly Diagnosed Germ Cell Tumor, Hepatoblastoma, Medulloblastoma, Neuroblastoma, Osteosarcoma, or Other Malignancy'

Sodium Thiosulfate in Preventing Hearing Loss in Young Patients Receiving Cisplatin for Newly Diagnosed Germ Cell Tumor, Hepatoblastoma, Medulloblastoma, Neuroblastoma, Osteosarcoma, or Other Malignancy

Posted: July 16th, 2008, 2:00am GMT

Conditions: Brain Tumor; Central Nervous System Tumor; Childhood Germ Cell Tumor; Extragonadal Germ Cell Tumor; Liver Cancer; Neuroblastoma; Ototoxicity; Ovarian Cancer; Sarcoma
Interventions: Drug: sodium thiosulfate; Procedure: examination
Sponsors: Children's Oncology Group; National Cancer Institute (NCI)
Completed

Reappraisal of anatomical liver resection for hepatoblastoma in children

Fetched: December 1st, 2023, 5:02am GMT by Masaki Honda

Surg Open Sci. 2023 Nov 20;16:215-220. doi: 10.1016/j.sopen.2023.11.009. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: The principle of hepatoblastoma (HB) treatment is complete resection. The removal of tumor-bearing section(s) or hemiliver is widely accepted. However, neither the standardized anterior approach for right hepatectomy nor parenchymal sparing anatomical liver resection has been described for HB.

METHODS: We retrospectively reviewed the clinical course of two pediatric HB patients who underwent extended right hepatectomy using the anterior approach with the liver hanging maneuver and one who underwent parenchymal sparing anatomical liver resection of S4 apical+S8 ventral/dorsal+S7. The critical aspects of surgical techniques are described in detail.

RESULTS: In all three patients, R0 resection was achieved without complications and are currently alive without recurrence after an average follow-up of 23 months. Intraoperative cardiac hemodynamics were stable, even in a trisomy 18 patient with cardiac disease.

CONCLUSIONS: Our findings suggest that these innovative techniques established in adults are safe and feasible for HB in children. These techniques also allow optimal anatomical liver resection to accomplish curative surgery while maintaining the functional reserve of the remnant liver.

PMID:38035224 | PMC:PMC10687054 | DOI:10.1016/j.sopen.2023.11.009

Key Modulation of ROS and HSP for Effective Therapy Against Hypoxic Tumor with Multifunctional Nanosystem

Fetched: December 1st, 2023, 5:02am GMT by Bangzhen Ma

Int J Nanomedicine. 2023 Nov 18;18:6829-6846. doi: 10.2147/IJN.S432928. eCollection 2023.

ABSTRACT

BACKGROUND: Though nanomedicine-based photothermal therapy (PTT) has demonstrated promising prospect in tumor treatment due to its high therapeutic efficiency and controllable range, the overexpression of heat shock proteins (HSPs) during PTT can lead to intracellular thermal resistance and reduce its effectiveness. Reactive oxygen species (ROS), followed by the application of chemodynamic therapy (CDT) and photodynamic therapy (PDT), can eliminate HSPs and overcome thermal resistance. However, the tumor microenvironment, including hypoxia and glutathione (GSH) overexpression, impedes the production of ROS and therapeutic efficacy of CDT and PDT. Therefore, we proposed a multifunctional nanoplatform (HMPB@TCPP-Cu) driving PTT/ PDT/ CDT synergistic therapy for tumor treatment via modulating ROS and HSPs.

METHODS AND RESULTS: In this work, a novel nanoplatform (HMPB@TCPP-Cu) composed of O2/PTT supplier HMPB (hollow mesoporous Prussian blue) and the loaded PDT/CDT agent (TCPP-Cu²⁺) was prepared. HMPB acts as an photothermal converter, effectively raising the tumor temperature and inducing apoptosis. HMPB is also a potent catalase-like nanozyme, which can catalyze hydrogen peroxide into oxygen and reduce tumor hypoxia, thus elevating the efficiency of ROS production and the effectiveness of PDT with the wing of sonosensitizer-TCPP. The intracellular glutathione(GSH) was depleted by Cu²⁺ and •OH was generated along with the Cu²⁺/Cu⁺ converting and Cu⁺-mediated Fenton-like reaction. Subsequently, the increased levels of ROS effectively eliminate intratumoral thermal resistance. The HMPB@TCPP-Cu has achieved synergistic PTT/PDT/CDT for hepatoblastoma treatment and significant inhibition of tumor growth was detected both in vitro and in vivo.

CONCLUSION: This study presents a multifunctional nanoplatform that combines photothermal/ chemodynamic/ photodynamic therapy for efficient hepatoblastoma treatment via modulating ROS and HSPs. Collectively, this study provides an appealing strategy in the cleavage of thermal resistance and a novel assistance and enhancement on thermal-related therapies.

PMID:38026539 | PMC:PMC10664717 | DOI:10.2147/IJN.S432928

Brevundimonas spp. infection in immunocompromised children: Two case reports

Fetched: December 1st, 2023, 5:02am GMT by Andreé Altamirano-Beltrán

Germs. 2023 Mar 31;13(1):72-79. doi: 10.18683/germs.2023.1369. eCollection 2023 Mar.

ABSTRACT

INTRODUCTION: Brevundimonas spp. are rare and opportunistic pathogens which may cause infections in patients who are immunocompromised or have underlying disease.

CASE REPORT: Two cases with a microbiological diagnosis of Brevundimonas aurantiaca and Brevundimonas spp. are presented. Both occurred in immunocompromised patients with post-chemotherapy febrile neutropenia for B-type acute lymphoblastic leukemia and hepatoblastoma. Antibiogram findings showed resistance to quinolones, ceftazidime, and intermediate resistance to cefepime, being susceptible to carbapenems and aminoglycosides. The cases responded favorably to the administration of carbapenem.

CONCLUSIONS: The identification of the species and antimicrobial susceptibility profile favor response to infection, denoting the importance of species identification and the performance of an antibiogram to determine the different susceptibility profiles described in the literature on this emerging pathogen.

PMID:38023950 | PMC:PMC10659748 | DOI:10.18683/germs.2023.1369

Establishment of a patient-derived xenograft humanized mouse model for hepatoblastoma in children

Fetched: November 29th, 2023, 5:02am GMT by H M Hu

Zhonghua Gan Zang Bing Za Zhi. 2023 Oct 20;31(10):1075-1080. doi: 10.3760/cma.j.cn501113-20220218-00075.

ABSTRACT

Objective: To establish a patient-derived xenograft (PDX) humanized mouse model for hepatoblastoma in children. In addition, compare the biological consistency between successfully modeled PDX tumors and primary tumors in children while comparing and analyzing the influence of PDX model modeling success as a key factor. Methods: A PDX tumor model was constructed from fresh tumor tissue samples from 39 children with hepatoblastoma. The tumor growth time and volume size were recorded in detail. Simultaneously, 39 children's data were collected for experimental and clinical analysis. The difference in tumorigenesis rate between different parameters was analyzed by χ (2) test (categorical variable). Continuous variables with a normal distribution were compared using the t-test. Results: After cell passage and pathological diagnosis, 21 cases of hepatoblastoma PDX models were successfully constructed, with a success rate of 53.8% (21/39). Tumor samples from each generation of successfully modeled PDX models had pathology results that were consistent with those of the corresponding primary tumors. The analysis of the key factors affecting the tumor formation rate of PDX revealed that the metastasis rate was more successful in primary tumors than in liver in situ tumors (7/8 vs. 14/31, P = 0.049). However, there was no significant difference between tumor formation rates and pathological subtypes. According to the PDX tumor formation group comparison between the primary tumor and the metastatic tumor, there was no statistically significant difference between the two groups in terms of tumor formation time and tumor volume. Hematoxylin-eosin staining in hepatoblastoma's PDX mouse was consistent with the primary tumor. Immunohistochemistry positivity rates of four proteins, namely hepatocyte antigen (Hepatocyte), phosphatidylinositol glycan 3, β-catenin, and alpha-fetoprotein, in primary tumor tissues and PDX mouse models were 100% vs. 100%, 100% vs. 95.24%, 100% vs. 100%, and 95.24% vs. 85.71%, respectively. Conclusion: A PDX mouse model for hepatoblastoma has been successfully established in children. The tumor formation rate is high, with metastatic tumors having a higher tumor formation rate than primary tumors and transplanted tumors retaining the biological characteristics of primary tumors.

PMID:38016773 | DOI:10.3760/cma.j.cn501113-20220218-00075

Molecular analysis of the human cytoglobin mRNA isoforms

Fetched: November 29th, 2023, 5:02am GMT by Elena Porto

J Inorg Biochem. 2023 Nov 15;251:112422. doi: 10.1016/j.jinorgbio.2023.112422. Online ahead of print.

ABSTRACT

Multiple functions have been proposed for the ubiquitously expressed vertebrate globin cytoglobin (Cygb), including nitric oxide (NO) metabolism, lipid peroxidation/signalling, superoxide dismutase activity, reactive oxygen/nitrogen species (RONS) scavenging, regulation of blood pressure, antifibrosis, and both tumour suppressor and oncogenic effects. Since alternative splicing can expand the biological roles of a gene, we investigated whether this mechanism contributes to the functional diversity of Cygb. By mining of cDNA data and molecular analysis, we identified five alternative mRNA isoforms for the human CYGB gene (V-1 to V-5). Comprehensive RNA-seq analyses of public datasets from human tissues and cells confirmed that the canonical CYGB V-1 isoform is the primary CYGB transcript in the majority of analysed datasets. Interestingly, we revealed that isoform V-3 represented the predominant CYGB variant in hepatoblastoma (HB) cell lines and in the majority of analysed normal and HB liver tissues. CYGB V-3 mRNA is transcribed from an alternate upstream promoter and hypothetically encodes a N-terminally truncated CYGB protein, which is not recognized by some antibodies used in published studies. Little to no transcriptional evidence was found for the other CYGB isoforms. Comparative transcriptomics and flow cytometry on CYGB^+/+ and gene-edited CYGB^-/- HepG2 HB cells did not unveil a knockout phenotype and, thus, a potential function for CYGB V-3. Our study reveals that the CYGB gene is transcriptionally more complex than previously described as it expresses alternative mRNA isoforms of unknown function. Additional experimental data are needed to clarify the biological meaning of those alternative CYGB transcripts.

PMID:38016326 | DOI:10.1016/j.jinorgbio.2023.112422

Modern-era successful liver transplantation outcomes in children with hepatic undifferentiated embryonal sarcoma

Fetched: November 29th, 2023, 5:02am GMT by Priya S Rolfes

Pediatr Transplant. 2023 Nov 27:e14645. doi: 10.1111/petr.14645. Online ahead of print.

ABSTRACT

BACKGROUND: Hepatic undifferentiated embryonal sarcoma (HUES) is the third most common primary hepatic malignancy in children. If unresectable, liver transplantation (LT) is the only curative option. Historically, HUES LT outcomes were not favorable; however, modern-era data are lacking. We aimed to describe LT outcomes in children with HUES and compared with LT outcomes in children transplanted for hepatoblastoma (HBL) and non-malignancy indications.

METHODS: Children 18 years or younger with HUES who underwent LT from 1987 to 2021 were identified from the Scientific Registry of Transplant Recipients database. Graft and patient survival were studied in HUES and LT recipients with HBL and non-malignancy indications using Kaplan-Meier analysis. Cox regression was used to compare patient and graft survival among groups, controlling for confounders.

RESULTS: Twenty-one children with HUES underwent LT during the study period with a median age at LT of 10 years (IQR: 8-12 years). One and five-year patient survival for HUES recipients was not significantly different from that of recipients with HBL (p = .3) or non-malignancy diagnoses (p = .6). There were no deaths due to HUES recurrence. In multivariable Cox regression, HUES did not increase risk of either patient or graft loss as compared to HBL (HR 2.36, p = .2) or non-malignancy indications (HR 0.74, p = .7).

CONCLUSION: LT outcomes are more favorable in patients with HUES than historically described, and similar to LT outcomes of patients with HBL and non-malignancy indications. Transplant should be considered for HUES patients with unresectable localized tumors.

PMID:38013236 | DOI:10.1111/petr.14645

Critical elements of pediatric liver cancer surgery

Fetched: November 27th, 2023, 5:02am GMT by Zachary J Kastenberg

Semin Pediatr Surg. 2023 Nov 21;32(5):151340. doi: 10.1016/j.sempedsurg.2023.151340. Online ahead of print.

ABSTRACT

The appropriate management of pediatric liver malignancies, primarily hepatoblastoma and hepatocellular carcinoma, requires an in depth understanding of contemporary preoperative risk stratification, experience with advanced hepatobiliary surgery, and a good relationship with one's local or regional liver transplant center. While chemotherapy regimens have become more effective, operative indications more well-defined, and overall survival improved, the complexity of liver surgery in small children provides ample opportunity for protocol violation, inadequate resection, and iatrogenic morbidity. These guidelines represent the distillation of contemporary literature and expert opinion as a means to provide a framework for preoperative planning and intraoperative decision-making for the pediatric surgeon.

PMID:38008042 | DOI:10.1016/j.sempedsurg.2023.151340

Molecular Characteristics of Cisplatin-Induced Ototoxicity and Therapeutic Interventions

Fetched: November 26th, 2023, 5:02am GMT by Winston J T Tan

Int J Mol Sci. 2023 Nov 20;24(22):16545. doi: 10.3390/ijms242216545.

ABSTRACT

Cisplatin is a commonly used chemotherapeutic agent with proven efficacy in treating various malignancies, including testicular, ovarian, cervical, breast, bladder, head and neck, and lung cancer. Cisplatin is also used to treat tumors in children, such as neuroblastoma, osteosarcoma, and hepatoblastoma. However, its clinical use is limited by severe side effects, including ototoxicity, nephrotoxicity, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, and retinal toxicity. Cisplatin-induced ototoxicity manifests as irreversible, bilateral, high-frequency sensorineural hearing loss in 40-60% of adults and in up to 60% of children. Hearing loss can lead to social isolation, depression, and cognitive decline in adults, and speech and language developmental delays in children. Cisplatin causes hair cell death by forming DNA adducts, mitochondrial dysfunction, oxidative stress, and inflammation, culminating in programmed cell death by apoptosis, necroptosis, pyroptosis, or ferroptosis. Contemporary medical interventions for cisplatin ototoxicity are limited to prosthetic devices, such as hearing aids, but these have significant limitations because the cochlea remains damaged. Recently, the U.S. Food and Drug Administration (FDA) approved the first therapy, sodium thiosulfate, to prevent cisplatin-induced hearing loss in pediatric patients with localized, non-metastatic solid tumors. Other pharmacological treatments for cisplatin ototoxicity are in various stages of preclinical and clinical development. This narrative review aims to highlight the molecular mechanisms involved in cisplatin-induced ototoxicity, focusing on cochlear inflammation, and shed light on potential antioxidant and anti-inflammatory therapeutic interventions to prevent or mitigate the ototoxic effects of cisplatin. We conducted a comprehensive literature search (Google Scholar, PubMed) focusing on publications in the last five years.

PMID:38003734 | PMC:PMC10671929 | DOI:10.3390/ijms242216545

Sedanolide Activates KEAP1-NRF2 Pathway and Ameliorates Hydrogen Peroxide-Induced Apoptotic Cell Death

Fetched: November 26th, 2023, 5:02am GMT by Yosuke Tabei

Int J Mol Sci. 2023 Nov 20;24(22):16532. doi: 10.3390/ijms242216532.

ABSTRACT

Sedanolide is a bioactive compound with anti-inflammatory and antitumor activities. Although it has been recently suggested that sedanolide activates the nuclear factor E2-related factor 2 (NRF2) pathway, there is little research on its effects on cellular resistance to oxidative stress. The objective of the present study was to investigate the function of sedanolide in suppressing hydrogen peroxide (H2O2)-induced oxidative damage and the underlying molecular mechanisms in human hepatoblastoma cell line HepG2 cells. We found that sedanolide activated the antioxidant response element (ARE)-dependent transcription mediated by the nuclear translocation of NRF2. Pathway enrichment analysis of RNA sequencing data revealed that sedanolide upregulated the transcription of antioxidant enzymes involved in the NRF2 pathway and glutathione metabolism. Then, we further investigated whether sedanolide exerts cytoprotective effects against H2O2-induced cell death. We showed that sedanolide significantly attenuated cytosolic and mitochondrial reactive oxygen species (ROS) generation induced by exposure to H2O2. Furthermore, we demonstrated that pretreatment with sedanolide conferred a significant cytoprotective effect against H2O2-induced cell death probably due to preventing the decrease in the mitochondrial membrane potential and the increase in caspase-3/7 activity. Our study demonstrated that sedanolide enhanced cellular resistance to oxidative damage via the activation of the Kelch-like ECH-associated protein 1 (KEAP1)-NRF2 pathway.

PMID:38003720 | PMC:PMC10671709 | DOI:10.3390/ijms242216532

Targeting oncogenic TERT promoter variants by allele-specific epigenome editing

Fetched: November 24th, 2023, 5:02am GMT by Alexandra G Kouroukli

Clin Epigenetics. 2023 Nov 22;15(1):183. doi: 10.1186/s13148-023-01599-2.

ABSTRACT

BACKGROUND: Activation of dominant oncogenes by small or structural genomic alterations is a common driver mechanism in many cancers. Silencing of such dominantly activated oncogenic alleles, thus, is a promising strategy to treat cancer. Recently, allele-specific epigenome editing (ASEE) has been described as a means to reduce transcription of genes in an allele-specific manner. In cancer, specificity to an oncogenic allele can be reached by either targeting directly a pathogenic single-nucleotide variant or a polymorphic single-nucleotide variant linked to the oncogenic allele. To investigate the potential of ASEE in cancer, we here explored this approach by targeting variants at the TERT promoter region. The TERT promoter region has been described as one of the most frequently mutated non-coding cancer drivers.

RESULTS: Sequencing of the TERT promoter in cancer cell lines showed 53% (41/77) to contain at least one heterozygous sequence variant allowing allele distinction. We chose the hepatoblastoma cell line Hep-G2 and the lung cancer cell line A-549 for this proof-of-principle study, as they contained two different kinds of variants, namely the activating mutation C228T in the TERT core promoter and the common SNP rs2853669 in the THOR region, respectively. These variants were targeted in an allele-specific manner using sgRNA-guided dCas9-DNMT3A-3L complexes. In both cell lines, we successfully introduced DNA methylation specifically to the on-target allele of the TERT promoter with limited background methylation on the off-target allele or an off-target locus (VEGFA), respectively. We observed a maximum CpG methylation gain of 39% and 76% on the target allele when targeting the activating mutation and the common SNP, respectively. The epigenome editing translated into reduced TERT RNA expression in Hep-G2.

CONCLUSIONS: We applied an ASEE-mediated approach to silence TERT allele specifically. Our results show that the concept of dominant oncogene inactivation by allele-specific epigenome editing can be successfully translated into cancer models. This new strategy may have important advantages in comparison with existing therapeutic approaches, e.g., targeting telomerase, especially with regard to reducing adverse side effects.

PMID:37993930 | PMC:PMC10666398 | DOI:10.1186/s13148-023-01599-2

Comparative Clinicopathological and Genomic Analysis of Hepatocellular Neoplasm, NOS and Hepatoblastoma

Fetched: November 23rd, 2023, 5:03am GMT by Shengmei Zhou

Mod Pathol. 2023 Nov 20:100385. doi: 10.1016/j.modpat.2023.100385. Online ahead of print.

ABSTRACT

Accurate diagnosis and treatment of hepatocellular neoplasm, not otherwise specified (HCN-NOS), poses significant challenges. Our study aimed to investigate the clinicopathological and genomic similarities and differences between HCN-NOS and hepatoblastoma (HB) to guide diagnostic and treatment strategies. The clinicopathological characteristics of 16 patients with HCN-NOS and 23 patients with HB were compared. Molecular studies, including the OncoKids® DNA and RNA-based next-generation sequencing panel, chromosomal microarray, and targeted Sanger sequencing analyses of CTNNB1 and TERT promoter, were employed. We found that patients with HCN-NOS were older (p<0.001) and more frequently classified as high-risk (p<0.01), yet they showed no significant differences in alpha-fetoprotein (AFP) levels or survival outcomes compared to those with HB. HCN-NOS and HB had a comparable frequency of sequence variants, with CTNNB1 mutations being predominant in both groups. Notably, TERT promoter mutations (37.5%) and rare clinically significant variants (BRAF, NRAS, and KMT2D) were exclusive to HCN-NOS. HCN-NOS demonstrated a higher prevalence of gains in 1q, encompassing the MDM4 locus (17/17 vs. 11/24, p<0.001), as well as loss/loss of heterozygosity (LOH) of 1p (11/17 vs. 6/24, p<0.05) and chromosome 11 (7/17 vs. 1/24, p<0.01) when compared to HB. Furthermore, recurrent loss/LOH of chromosome 3, 4p, 9, 15q, and Y were only observed in HCN-NOS. However, no significant differences were noted in gains of chromosomes 2, 8, and 20, or loss/LOH of 4q and 11p between the two groups. Notably, no clinically significant gene fusions were detected in either group. In conclusion, our study reveals that HCN-NOS exhibits high-risk clinicopathological features and greater structural complexity compared to HB. However, patients with HCN-NOS exhibit comparable AFP levels at diagnosis, CTNNB1 mutation rates, and survival outcomes when subjected to aggressive treatment, as compared to those with HB. These findings have the potential to enhance diagnostic accuracy and inform more effective treatments for HCN-NOS.

PMID:37992967 | DOI:10.1016/j.modpat.2023.100385

EZH2 is a key component of hepatoblastoma tumor cell growth

Fetched: November 23rd, 2023, 5:03am GMT by Kathryn Glaser

Pediatr Blood Cancer. 2023 Nov 21:e30774. doi: 10.1002/pbc.30774. Online ahead of print.

ABSTRACT

BACKGROUND: Enhancer of zeste homolog 2 (EZH2) catalyzes the trimethylation of histone H3 at lysine 27 via the polycomb recessive complex 2 (PRC2) and plays a time-specific role in normal fetal liver development. EZH2 is overexpressed in hepatoblastoma (HB), an embryonal tumor. EZH2 can also promote tumorigenesis via a noncanonical, PRC2-independent mechanism via proto-oncogenic, direct protein interaction, including β-catenin. We hypothesize that the pathological activation of EZH2 contributes to HB propagation in a PRC2-independent manner.

METHODS AND RESULTS: We demonstrate that EZH2 promotes proliferation in HB tumor-derived cell lines through interaction with β-catenin. Although aberrant EZH2 expression occurs, we determine that both canonical and noncanonical EZH2 signaling occurs based on specific gene-expression patterns and interaction with SUZ12, a PRC2 component, and β-catenin. Silencing and inhibition of EZH2 reduce primary HB cell proliferation.

CONCLUSIONS: EZH2 overexpression promotes HB cell proliferation, with both canonical and noncanonical function detected. However, because EZH2 directly interacts with β-catenin in human tumors and EZH2 overexpression is not equal to SUZ12, it seems that a noncanonical mechanism is contributing to HB pathogenesis. Further mechanistic studies are necessary to elucidate potential pathogenic downstream mechanisms and translational potential of EZH2 inhibitors for the treatment of HB.

PMID:37990130 | DOI:10.1002/pbc.30774

Permalink for 'Computed tomography imaging phenotypes of hepatoblastoma identified from radiomics signatures are associated with the efficacy of neoadjuvant chemotherapy'

Computed tomography imaging phenotypes of hepatoblastoma identified from radiomics signatures are associated with the efficacy of neoadjuvant chemotherapy

Fetched: November 22nd, 2023, 5:02am GMT by Yingqian Chen

Pediatr Radiol. 2023 Nov 20. doi: 10.1007/s00247-023-05793-5. Online ahead of print.

ABSTRACT

BACKGROUND: Though neoadjuvant chemotherapy has been widely used in the treatment of hepatoblastoma, there still lacks an effective way to predict its effect.

OBJECTIVE: To characterize hepatoblastoma based on radiomics image features and identify radiomics-based lesion phenotypes by unsupervised machine learning, intended to build a classifier to predict the response to neoadjuvant chemotherapy.

MATERIALS AND METHODS: In this retrospective study, we segmented the arterial phase images of 137 cases of pediatric hepatoblastoma and extracted the radiomics features using PyRadiomics. Then unsupervised k-means clustering was applied to cluster the tumors, whose result was verified by t-distributed stochastic neighbor embedding (t-SNE). The least absolute shrinkage and selection operator (LASSO) regression was used for feature selection, and the clusters were visually analyzed by radiologists. The correlations between the clusters, clinical and pathological parameters, and qualitative radiological features were analyzed.

RESULTS: Hepatoblastoma was clustered into three phenotypes (homogenous type, heterogenous type, and nodulated type) based on radiomics features. The clustering results had a high correlation with response to neoadjuvant chemotherapy (P=0.02). The epithelial ratio and cystic components in radiological features were also associated with the clusters (P=0.029 and 0.008, respectively).

CONCLUSIONS: This radiomics-based cluster system may have the potential to facilitate the precise treatment of hepatoblastoma. In addition, this study further demonstrated the feasibility of using unsupervised machine learning in a disease without a proper imaging classification system.

PMID:37982901 | DOI:10.1007/s00247-023-05793-5

2 years is a reasonable age cut-off level for prognostic assessment of children with hepatoblastoma

Fetched: November 19th, 2023, 5:01am GMT by Y-B Lin

Eur Rev Med Pharmacol Sci. 2023 Nov;27(21):10553-10562. doi: 10.26355/eurrev_202311_34333.

ABSTRACT

OBJECTIVE: We aimed to elucidate the prognostic significance of age in hepatoblastoma patients.

PATIENTS AND METHODS: Data from 783 patients with hepatoblastoma were obtained from the Surveillance, Epidemiology and End Results database (2000-2018). The best age cut-off level was determined by X-tile, and the Kaplan-Meier method was used to estimate overall survival (OS) and cancer-specific survival (CSS). The results of the X-tile were verified by selecting the appropriate cut-off value to maximize the difference in survival outcomes at intervals of 1 year. The Cox regression model was used to determine the prognostic impact of risk factors and age.

RESULTS: X-tile analysis determined that 2 years was the best cut-off age for OS and CSS. The overall prognosis in the ≥ 2 years group was worse than that in the < 2 years group (OS: p = 0.00017; CSS: p < 0.0001). In Cox univariate analysis, when 2 years was used as the standard group, the numbers of patients in the two groups were similar, with high hazard ratio (HR) value and narrow 95% confidence interval (CI) (OS: HR, 1.834; 95% CI, 1.329 - 2.532; p < 0.001; CSS: HR, 1.988; 95% CI, 1.410 - 2.801; p < 0.001), which was consistent with the age cut-off point determined by X-tile. Cox multivariate analysis showed that age ≥ 2 years, black ethnicity, no surgery, no chemotherapy, distant metastasis, and tumor size ≥ 5 cm were independent predictors of poor OS and CSS. On subgroup analysis, patients aged ≥ 2 years had worse survival if they were Caucasian, had elevated alpha-fetoprotein, tumor size ≥ 5 cm, or distant metastasis.

CONCLUSIONS: Age is an important prognostic factor for hepatoblastoma. Age ≥ 2 years at diagnosis may predict poor prognosis and more active treatment measures can be implemented.

PMID:37975379 | DOI:10.26355/eurrev_202311_34333

Permalink for 'Whole-genome Sequencing and RNA Sequencing Analysis Reveals Novel Risk Genes and Differential Expression Patterns in Hepatoblastoma'

Whole-genome Sequencing and RNA Sequencing Analysis Reveals Novel Risk Genes and Differential Expression Patterns in Hepatoblastoma

Fetched: November 19th, 2023, 5:01am GMT by Wuqian Wang

Gene. 2023 Nov 14:147991. doi: 10.1016/j.gene.2023.147991. Online ahead of print.

ABSTRACT

Hepatoblastoma (HB) is an uncommon malignant liver cancer primarily affecting infants and children, characterized by the presence of tissue that resembling fetal hepatocytes, mature liver cells or bile duct cells. The primary symptom in affected children is abdominal lumps. HB constitutes approximately 28% of all liver tumors and two-thirds of liver malignancies in the pediatric and adolescent population. Despite its high prevalence, the underlying mechanism of HB pathogenesis remain largely unknown. To reveal the genetic alternations associated with HB, we conducted a comprehensive genomic study using whole-genome sequencing (WGS) and RNA sequencing (RNA-seq) techniques on five HB patients. We aimed to use WGS to identify somatic variant loci associated with HB, including single nucleotide polymorphisms (SNPs), insertions and deletions (Indels), and copy number variations (CNVs). Notably, we found deleterious mutation in CTNNB1, AXIN2 and PARP1, previously implicated in HB. In addition, we discovered multiple novel genes potentially associated with HB, including BRCA2 and GPC3 which require further functional validation to reveal their contributions to HB development. Furthermore, the American College of Medical Genetics and Genomics (ACMG) analysis identified the ABCC2 gene was the pathogenic gene as a potential risk gene linked with HB. To study the gene expression patterns in HB, we performed RNA-seq analysis and qPCR validation to reveal differential expression of four candidate genes (IGF1R, METTL1, AXIN2, and TP53) in tumors compared to nonneoplastic liver tissue in HB patients (P-Val<0.01). These findings shed lights on the molecular mechanisms underlying HB development and facilitate to advance future personalized diagnosis and therapeutic interventions of HB.

PMID:37972697 | DOI:10.1016/j.gene.2023.147991

A Case Report and a Review of Pediatric Hepatoblastoma

Fetched: November 17th, 2023, 5:02am GMT by Anthony D DeRenzi

HCA Healthc J Med. 2023 Oct 30;4(5):377-382. doi: 10.36518/2689-0216.1095. eCollection 2023.

ABSTRACT

INTRODUCTION: Hepatoblastoma is a rare pediatric cancer. Approximately 100 cases of hepatoblastoma are reported per year. Due to the limited incidence of this disorder an internationally agreed-upon criteria was developed to classify patients as standard or high-risk. Studies involving chemotherapeutic agents, surgery, and liver transplants have been demonstrated to improve the disease-free survival rate. The combination of chemotherapeutic agents and surgery demonstrated the ability of these regimens to downgrade the initial diagnostic staging of tumors and transform previously unresectable tumors into resectable tumors.

CASE PRESENTATION: The following case of hepatoblastoma presents a 4-year-old male who presented to the emergency department with an upper respiratory infection symptom and was found to have hepatomegaly. The patient was later classified as high-risk, unresectable hepatoblastoma.

CONCLUSION: Hepatoblastoma is a rare liver cancer in children with an annual incidence of 1.5 cases per million. With PRETEXT staging criterion, therapeutic options such as cisplatin/doxorubicin combination, radiotherapy, and lobectomy, have become the standard of care for this condition. Many trials have demonstrated these therapeutic options to successfully improve the survivability rate of patients affected by hepatoblastoma, downgrading tumors from advanced PRETEXT stages and enabling previously unresectable tumors to be considered resectable.

PMID:37969848 | PMC:PMC10635700 | DOI:10.36518/2689-0216.1095

Genetic ablation of C/EBPα-p300 pathway blocks development of obese pregnancy associated liver disorders in offspring

Fetched: November 16th, 2023, 5:02am GMT by Margaret A Hanlon

Cell Mol Gastroenterol Hepatol. 2023 Nov 14:S2352-345X(23)00201-1. doi: 10.1016/j.jcmgh.2023.11.006. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: The obesity-associated nonalcoholic fatty liver disease represents a common cause of pediatric liver diseases, including the pediatric liver cancer hepatoblastoma. The mechanisms behind the development of fatty liver in children are not yet known. We examined the role of the C/EBPα-p300 pathway in the development of maternal obesity-associated fatty liver phenotype in offspring.

METHODS: Because the ability of C/EBPα to promote fatty liver phenotype is enhanced by CDK4-mediated phosphorylation of C/EBPα at Ser193 and subsequent formation of C/EBPα-p300 complexes, we used wild-type (WT) and C/EBPα-S193D and C/EBPα-S193A mutant mice to study the effects of maternal high-fat diet (HFD) on the liver health of offspring. The females of these mouse lines were fed an HFD before mating, and the pups were further subjected to either an HFD or a normal diet for 12 weeks.

RESULTS: WT female mice on the HFD before and during pregnancy and their subsequent offspring on the HFD had severe fatty liver, fibrosis, and an increased rate of liver proliferation. However, the HFD in C/EBPα-S193A mice did not cause development of these disorders. In HFD-HFD treated WT mice, C/EBPα is phosphorylated at Ser193 and forms complexes with p300, which activate expression of genes involved in development of fatty liver, fibrosis, and proliferation. However, S193A-C/EBPα mice do not have complexes of C/EBPα-S193A with p300, leading to a lack of activation of genes of fatty liver, fibrosis, and proliferation. The mutant C/EBPα-S193D mice have accelerated cdk4-dependent pathway and have developed steatosis at early stages.

CONCLUSIONS: These studies identified the epigenetic cause of obese pregnancy-associated liver diseases and suggest a potential therapy based on inhibition of cdk4-ph-S193-C/EBPα-p300 pathway.

PMID:37967813 | DOI:10.1016/j.jcmgh.2023.11.006

Permalink for 'LASS2 enhances p53 protein stability and nuclear import to suppress liver cancer progression through interaction with MDM2/MDMX'

LASS2 enhances p53 protein stability and nuclear import to suppress liver cancer progression through interaction with MDM2/MDMX

Fetched: November 15th, 2023, 5:03am GMT by Qingqing Zhao

Cell Death Discov. 2023 Nov 14;9(1):414. doi: 10.1038/s41420-023-01709-2.

ABSTRACT

LASS2 functions as a tumor suppressor in hepatocellular carcinoma (HCC), the most common type of primary liver cancer, but the underlying mechanism of its action remains largely unknown. Moreover, details on its role and the downstream mechanisms in Cholangiocarcinoma (CCA) and hepatoblastoma (HB), are rarely reported. Herein, LASS2 overexpression was found to significantly inhibit proliferation, migration, invasion and induce apoptosis in hepatoma cells with wild-type (HB cell line HepG2) and mutated p53 (HCC cell line HCCLM3 and CCA cell line HuCCT1). Gene set enrichment analysis determined the enrichment of the differentially expressed genes caused by LASS2 in the p53 signaling pathway. Moreover, the low expression of LASS2 in HCC and CCA tumor tissues was correlated with the advanced tumor-node-metastasis (TNM) stage, and the protein expression of LASS2 positively correlated with acetylated p53 (Lys373) protein levels. At least to some extent, LASS2 exerts its tumor-suppressive effects in a p53-dependent manner, in which LASS2 interacts with MDM2/MDMX and causes dual inhibition to disrupt p53 degradation by MDM2/MDMX. In addition, LASS2 induces p53 phosphorylation at ser15 and acetylation at lys373 to promote translocation from cytoplasm to nucleus. These findings provide new insights into the LASS2-induced tumor suppression mechanism in liver cancer and suggest LASS2 could serve as a potential therapeutic target for liver cancer.

PMID:37963859 | PMC:PMC10646090 | DOI:10.1038/s41420-023-01709-2

Navigating relapsed hepatoblastoma: Predictive factors and surgical treatment strategy

Fetched: November 15th, 2023, 5:03am GMT by Andres F Espinoza

Cancer Med. 2023 Nov 14. doi: 10.1002/cam4.6705. Online ahead of print.

ABSTRACT

OBJECTIVE: Hepatoblastoma (HB) is the most common primary hepatic malignancy in childhood. Relapse occurs in more than 50% of high-risk patients with a high mortality due to ineffective salvage therapies. The purpose of this study is to identify risk factors for relapsed HB and predictors of survival in a single tertiary referral center.

METHODS: A retrospective chart review showed 129 surgically treated HB patients from October 2004 to July 2020. Of the cohort, 22 patients presented with relapsed HB. Relapse was defined as re-appearance of malignancy after 4 weeks of normalized AFP and disappearance of all tumors on imaging.

RESULTS: Patients with relapsed HB had a 5-year overall survival (OS) of 45.4% compared to 93.1% in those without relapse (p = 0.001). When comparing PRETEXT IV, microvascular invasion, metastatic disease, and age on multivariate logistic regression, only PRETEXT IV was an independent risk factor for relapsed HB with an OR of 2.39 (95% CI: 1.16-4.96; p = 0.019). Mixed epithelial and mesenchymal HB (12/19, 63.2%) was the most common histology of primary tumors while pure epithelial HB (13/15, 86.6%) was the most common relapsed histology. Combination of surgical and medical therapy for relapsed disease was predictive of survival with an HR of 16.3 (95% CI: 1.783-149.091; p = 0.013) compared to only chemotherapy.

CONCLUSIONS: This study demonstrates that PRETEXT IV staging is an independent predictor of relapsed disease. The most common relapsed histology was epithelial, suggesting a potential selection or resistance of this component. Surgical resection is a critical component of multimodal therapy for relapsed HB.

PMID:37962078 | DOI:10.1002/cam4.6705

Permalink for 'Characterisation of Aberrant Metabolic Pathways in Hepatoblastoma Using Liquid Chromatography and Tandem Mass Spectrometry (LC-MS/MS)'

Characterisation of Aberrant Metabolic Pathways in Hepatoblastoma Using Liquid Chromatography and Tandem Mass Spectrometry (LC-MS/MS)

Fetched: November 15th, 2023, 5:03am GMT by Alison Whitby

Cancers (Basel). 2023 Oct 28;15(21):5182. doi: 10.3390/cancers15215182.

ABSTRACT

Hepatoblastoma (HB) is a rare childhood tumour with an evolving molecular landscape. We present the first comprehensive metabolomic analysis using untargeted and targeted liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-MS/MS) of paired tumour and non-tumour surgical samples in HB patients (n = 8 pairs). This study demonstrates that the metabolomic landscape of HB is distinct from that of non-tumour (NT) liver tissue, with 35 differentially abundant metabolites mapping onto pathways such as fatty acid transport, glycolysis, the tricarboxylic acid (TCA) cycle, branched-chain amino acid degradation and glutathione synthesis. Targeted metabolomics demonstrated reduced short-chain acylcarnitines and a relative accumulation of branched-chain amino acids. Medium- and long-chain acylcarnitines in HB were similar to those in NT. The metabolomic changes reported are consistent with previously reported transcriptomic data from tumour and non-tumour samples (49 out of 54 targets) as well as metabolomic data obtained using other techniques. Gene set enrichment analysis (GSEA) from RNAseq data (n = 32 paired HB and NT samples) demonstrated a downregulation of the carnitine metabolome and immunohistochemistry showed a reduction in CPT1a (n = 15 pairs), which transports fatty acids into the mitochondria, suggesting a lack of utilisation of long-chain fatty acids in HB. Thus, our findings suggest a reduced metabolic flux in HB which is corroborated at the gene expression and protein levels. Further work could yield novel insights and new therapeutic targets.

PMID:37958356 | PMC:PMC10648437 | DOI:10.3390/cancers15215182

miR-181b-5p/SOCS2/JAK2/STAT5 axis facilitates the metastasis of hepatoblastoma

Fetched: November 14th, 2023, 5:02am GMT by Yong Lv

Precis Clin Med. 2023 Oct 20;6(4):pbad027. doi: 10.1093/pcmedi/pbad027. eCollection 2023 Dec.

ABSTRACT

INTRODUCTION: Hepatoblastoma (HB) is a malignant liver tumor predominantly found in children and tumor metastasis is one of the main causes of poor prognosis in affected patients. The precise molecular mechanisms responsible for HB metastasis remain incompletely understood. However, there is evidence suggesting a connection between the dysregulation of microRNAs (miRNAs) and the progression of tumor metastasis in HB.

METHODS: The study utilized weighted gene co-expression network analysis (WGCNA) to analyze a miRNA microarray dataset of HB. The expression of miR-181b-5p in HB tissues and cells was detected using quantitative real-time PCR. The impact of miR-181b-5p on the metastatic capacity of HB was evaluated through scratch and Transwell assays. The effects of exogenously expressing miR-181b on the metastatic phenotypes of HB cells were evaluated in vivo. Furthermore, a luciferase reporter assay was performed to validate a potential target of miR-181b-5p in HB.

RESULTS: We found that miR-181b-5p was highly expressed in HB tissues and HB cell lines. Overexpression of miR-181b enhanced scratch healing, cell migration, and invasion abilities in vitro, as well as enhancing HB lung metastasis potential in vivo. Dual-luciferase reporter assays showed that Suppressor Of Cytokine Signaling 2 (SOCS2) was a direct target of miR-181b. The overexpression of miR-181b resulted in the suppression of SOCS2 expression, subsequently activating the epithelial-mesenchymal transition and JAK2/STAT5 signaling pathways. The rescue experiment showed that SOCS2 overexpression attenuated the effects of miR-181b on HB cells.

CONCLUSION: Our study showed that miR-181b promotes HB metastasis by targeting SOCS2 and may be a potential therapeutic target for HB.

PMID:37955014 | PMC:PMC10639105 | DOI:10.1093/pcmedi/pbad027

Children's Oncology Group's 2023 blueprint for research: Surgery

Fetched: November 12th, 2023, 5:02am GMT by Kenneth W Gow

Pediatr Blood Cancer. 2023 Nov 10:e30766. doi: 10.1002/pbc.30766. Online ahead of print.

ABSTRACT

Surgery plays a crucial role in the treatment of children with solid malignancies. A well-conducted operation is often essential for cure. Collaboration with the primary care team is important for determining if and when surgery should be performed, and if performed, an operation must be done in accordance with well-established standards. The long-term consequences of surgery also need to be considered. Indications and objectives for a procedure vary. Providing education and developing and analyzing new research protocols that include aims relevant to surgery are key objectives of the Surgery Discipline of the Children's Oncology Group. The critical evaluation of emerging technologies to ensure safe, effective procedures is another key objective. Through research, education, and advancing technologies, the role of the pediatric surgeon in the multidisciplinary care of children with solid malignancies will continue to evolve.

PMID:37950538 | DOI:10.1002/pbc.30766

The effect of donor graft type on survival after liver transplantation for hepatoblastoma in children

Fetched: November 11th, 2023, 5:01am GMT by Ioannis A Ziogas

Pediatr Transplant. 2023 Nov 9:e14641. doi: 10.1111/petr.14641. Online ahead of print.

ABSTRACT

BACKGROUND: Liver transplantation (LT) is the only potentially curative option for children with unresectable hepatoblastoma (HBL). Although post-transplant outcomes have improved in the contemporary era, the impact of donor graft type on survival remains unclear.

METHODS: Using the United Network for Organ Sharing database (02/2002-06/2021), demographics, clinical characteristics, and patient and graft survival were analyzed in children (<18 years) who underwent LT for HBL according to donor graft type. The Kaplan-Meier method, log-rank tests, and Cox regression modeling were used to evaluate the effect of whole, partial, and split deceased donor liver transplantation (DDLT) and living donor liver transplantation (LDLT) on patient and graft survival.

RESULTS: A total of 590 pediatric HBL LT recipients (344 whole graft DDLT; 62 partial graft DDLT; 139 split graft DDLT; 45 LDLT) were included. During 2012-2021 the proportion of LDLTs for HBL decreased to about 5% compared with about 11% during 2002-2011. No significant differences were identified by donor graft type in either patient survival (log-rank test, p = .45) or graft survival (log-rank test, p = .69). The results remained similar during the 2002-2011 era, while during the 2012-2021 era, split graft DDLT was associated with decreased graft loss risk versus whole graft DDLT (hazard ratio: 0.48, 95% confidence interval: 0.23-0.99, p = .046) without any other significant between-group differences.

CONCLUSIONS: Utilizing non-whole liver grafts can increase access to LT in children with unresectable HBL while ensuring favorable outcomes. LDLT is underutilized in children with HBL in the United States, and efforts to explore LDLT options should be undertaken.

PMID:37946593 | DOI:10.1111/petr.14641

Individualized chemotherapy and efficacy analysis of hepatoblastoma in children

Fetched: November 9th, 2023, 5:02am GMT by Huimin Hu

Pediatr Blood Cancer. 2024 Jan;71(1):e30693. doi: 10.1002/pbc.30693. Epub 2023 Nov 7.

ABSTRACT

PURPOSE: We aimed to assess the clinical utility of the mini patient-derived xenograft (MiniPDX) model in screening individualized chemotherapy regimens for pediatric hepatoblastoma.

MATERIALS AND METHODS: We included 31 children with hepatoblastoma who had unsatisfactory decreases in alpha-fetoprotein levels during neoadjuvant chemotherapy or poor clinical control of recurrence with or without metastasis. We established a MiniPDX model using surgically resected tumor tissue specimens. The sensitivities of five chemotherapeutic regimens were tested to determine the one with the lowest tumor proliferation rate, which was then set as the experimental group. We compared the clinical characteristics and efficacy with those of conventional chemotherapy regimens.

RESULTS: The median follow-up period for the experimental group was 27 months, with a complete remission (CR) rate of 80.64%. Among stage IV cases, there was a significant between-group difference in CR rate (experimental [73.68%] vs. control [37.5%]) and 3-year event-free survival rate (79.3% vs. 26.7%). The most effective individualized chemotherapy regimens were ifosfamide + pirarubicin + etoposide + carboplatin (54.84%), followed by pirubicin + cyclophosphamide + cisplatin (16.13%), ifosfamide + carboplatin + etoposide (12.90%), cisplatin + 5-fluorouracil + vincristine + adriamycin (12.90%), and vincristine + irinotecan + cyclophosphamide + cisplatin (3.23%).

CONCLUSION: Using the MiniPDX model to screen individualized chemotherapy regimens for pediatric hepatoblastoma can significantly improve the CR rate.

PMID:37937320 | DOI:10.1002/pbc.30693

Management of Macroglossia Secondary to Beckwith-Weidmann Syndrome in a Pediatric Patient: A Case Report

Fetched: November 8th, 2023, 5:02am GMT by Dhruvi Solanki

Cureus. 2023 Oct 6;15(10):e46579. doi: 10.7759/cureus.46579. eCollection 2023 Oct.

ABSTRACT

Beckwith-Wiedemann syndrome (BWS) is a rare genetic disorder, distinguished by the following characteristics: macrosomia, macroglossia, abdominal wall deformities such as omphalocele, visceromegaly, hemihypertrophy and elevated risk of developing tumors such as nephroblastoma or hepatoblastoma. A 2.5-year-old female patient came to the Department of Pediatric and Preventive Dentistry with a complaint of abnormally large tongue along with difficulty in swallowing and slurred speech. On clinical examination, the built of the patient was greater than normal. Intraoral examination revealed an enlarged tongue that led to the inability to close her mouth. Preliminary tests like blood tests, ECG, etc., were done before proceeding further to correct the enlarged tongue surgically under general anesthesia. The patient was intubated nasally, and a keyhole incision pattern was marked on the dorsum of the tongue at the central part. Reduction glossectomy was performed using electrocautery and the two parts were thereafter sutured with 5-0 vicryl sutures. The patient was kept under observation for one week and then discharged. Satisfactory healing was observed. Early diagnosis, close monitoring by healthcare specialists, and a thorough treatment plan that includes speech therapy, food support, and dental care can help manage the issues associated with BWS macroglossia.

PMID:37933371 | PMC:PMC10625723 | DOI:10.7759/cureus.46579

Preneoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma

Fetched: November 7th, 2023, 5:02am GMT by Jill Pilet

Nat Commun. 2023 Nov 6;14(1):7122. doi: 10.1038/s41467-023-42418-9.

ABSTRACT

Pediatric liver tumors are very rare tumors with the most common diagnosis being hepatoblastoma. While hepatoblastomas are predominantly sporadic, around 15% of cases develop as part of predisposition syndromes such as Beckwith-Wiedemann (11p15.5 locus altered). Here, we identify mosaic genetic alterations of 11p15.5 locus in the liver of hepatoblastoma patients without a clinical diagnosis of Beckwith-Wiedemann syndrome. We do not retrieve these alterations in children with other types of pediatric liver tumors. We show that mosaic 11p15.5 alterations in liver FFPE sections of hepatoblastoma patients display IGF2 overexpression and H19 downregulation together with an alteration of the liver zonation. Moreover, mosaic livers' microenvironment is enriched in extracellular matrix and angiogenesis. Spatial transcriptomics and single-nucleus RNAseq analyses identify a 60-gene signature in 11p15.5 altered hepatocytes. These data provide insights for 11p15.5 mosaicism detection and its functional consequences during the early steps of carcinogenesis.

PMID:37932266 | PMC:PMC10628292 | DOI:10.1038/s41467-023-42418-9

SGLT2 is upregulated to acquire cisplatin resistance and SGLT2 inhibition reduces cisplatin resistance in hepatoblastoma

Fetched: November 7th, 2023, 5:02am GMT by Sunao Fujiyoshi

J Hepatobiliary Pancreat Sci. 2023 Nov 5. doi: 10.1002/jhbp.1391. Online ahead of print.

ABSTRACT

BACKGROUND: Cancer cells can alter glucose metabolism and regulate the expression of glucose transporters. Hepatoblastoma patients undergo cisplatin-based chemotherapy; however, 22.3% of patients develop cisplatin resistance and thus face a poor prognosis. We hypothesized that glucose transporters are associated with acquiring cisplatin resistance with increasing sugar intake inhibiting glucose transporters could reduce cisplatin resistance in hepatoblastoma patients.

METHODS: We established cisplatin-resistant HepG2 and HuH6 cells by continuous treatment with cisplatin. We evaluated the relationship between cisplatin resistance and glucose uptake. We used an expression array to select cisplatin-resistant associated glucose transporters and selected sodium-glucose cotransporter 2 (SGLT2). We used dapagliflozin as an SGLT2 inhibitor and evaluated glucose uptake and IC50 after dapagliflozin treatment in wild-type and resistant hepatoblastoma cells in vitro and in vivo.

RESULTS: We found a strong relationship between cisplatin resistance and glucose uptake. Additionally, SGLT2 was upregulated in resistant cells after cisplatin treatment. After dapagliflozin treatment, glucose uptake and cisplatin resistance decreased in resistant cells.

CONCLUSIONS: Cisplatin-resistant hepatoblastoma cells exhibited upregulated SGLT2 expression and activated glucose uptake to survive under cisplatin stress. SGLT2 inhibition decreased cellular resistance to cisplatin. SGLT2 inhibition with cisplatin therapy could be a novel therapeutic strategy for cisplatin-resistant hepatoblastoma patients.

PMID:37927142 | DOI:10.1002/jhbp.1391

Thyrotoxicosis and Impending Thyroid Storm: A Rare Paraneoplastic Syndrome in an Infant With Hepatoblastoma

Fetched: November 2nd, 2023, 5:02am GMT by Neha Vyas

JCEM Case Rep. 2023 Jun 15;1(3):luad051. doi: 10.1210/jcemcr/luad051. eCollection 2023 May.

ABSTRACT

Graves' disease is the most common cause of pediatric hyperthyroidism and thyrotoxicosis. Thyroid storm is a rare initial manifestation of Graves' disease and represents an endocrine emergency. We report a case of transient hyperthyroidism, possibly a paraneoplastic syndrome presenting as impending thyroid storm in a patient with undiagnosed hepatoblastoma. To our knowledge, this is the first case of this association reported in children. A previously healthy 21-month-old male presented with abdominal pain and unremitting tachycardia. He was managed for thyrotoxicosis and impending thyroid storm. He subsequently was found to have hepatomegaly leading to a diagnosis of hepatoblastoma. Autoimmune markers for Graves' disease were negative, along with a negative human chorionic gonadotropin. After initiation of neoadjuvant chemotherapy, he had complete resolution of thyrotoxicosis. Paraneoplastic syndromes may occur with any tumor. We present a unique case of a patient developing human chorionic gonadotropin-negative hyperthyroidism, possibly as a paraneoplastic syndrome from hepatoblastoma.

PMID:37908577 | PMC:PMC10580456 | DOI:10.1210/jcemcr/luad051

Multiple Fractures in an Infant With Hepatoblastoma and Beckwith-Wiedemann Syndrome

Fetched: November 2nd, 2023, 5:02am GMT by Toni Eimicke

JCEM Case Rep. 2023 Sep 27;1(5):luad110. doi: 10.1210/jcemcr/luad110. eCollection 2023 Sep.

ABSTRACT

Children with hepatoblastoma have an increased incidence of fractures, but data are limited. Previous reports document an average of 4 fractures per child with hepatoblastoma. We present a severe case of a premature 4-month-old with multiple fractures in the setting of Beckwith-Wiedemann syndrome and hepatoblastoma. Although prematurity is a known risk for metabolic bone disease, it did not entirely explain the severity. Our patient underwent chemotherapy and surgical resection of his hepatoblastoma. Once deemed stable, he received a dose of zoledronic acid (ZA). One month post treatment with ZA, a skeletal survey revealed healing of the rib and femoral fractures and no new fractures. Five months post ZA, the skeletal survey revealed no new fractures and motor development was appropriate. An extensive search revealed scant literature on the rate or cause of pathologic fractures in patients with newly diagnosed hepatoblastoma. A better understanding of fracture risk in this population may guide prevention strategies, screening, and treatment. In our case, prematurity and substantial chronic illness may have compounded the known fracture risk associated with hepatoblastoma and may provide insight into the pathophysiology and prevention of fractures in this setting.

PMID:37908208 | PMC:PMC10612471 | DOI:10.1210/jcemcr/luad110

Permalink for 'Diet-induced rewiring of the Wnt gene regulatory network connects aberrant splicing to fatty liver and liver cancer in DIAMOND mice'

Diet-induced rewiring of the Wnt gene regulatory network connects aberrant splicing to fatty liver and liver cancer in DIAMOND mice

Fetched: November 2nd, 2023, 5:02am GMT by Ana López-Pérez

Sci Rep. 2023 Oct 31;13(1):18666. doi: 10.1038/s41598-023-45614-1.

ABSTRACT

Several preclinical models have been recently developed for metabolic associated fatty liver disease (MAFLD) and associated hepatocellular carcinoma (HCC) but comprehensive analysis of the regulatory and transcriptional landscapes underlying disease in these models are still missing. We investigated the regulatory and transcriptional landscape in fatty livers and liver tumours from DIAMOND mice that faithfully mimic human HCC development in the context of MAFLD. RNA-sequencing and ChIP-sequencing revealed rewiring of the Wnt/β-catenin regulatory network in DIAMOND tumours, as manifested by chromatin remodelling and associated switching in the expression of the canonical TCF/LEF downstream effectors. We identified splicing as a major mechanism leading to constitutive oncogenic activation of β-catenin in a large subset of DIAMOND tumours, a mechanism that is independent on somatic mutations in the locus and that has not been previously shown. Similar splicing events were found in a fraction of human HCC and hepatoblastoma samples.

PMID:37907668 | PMC:PMC10618177 | DOI:10.1038/s41598-023-45614-1

Modulating the Unfolded Protein Response with ISRIB Mitigates Cisplatin Ototoxicity

Fetched: November 1st, 2023, 5:01am GMT by Jiang Li

bioRxiv. 2023 Oct 17:2023.10.17.562797. doi: 10.1101/2023.10.17.562797. Preprint.

ABSTRACT

Cisplatin is a common chemotherapy drug with a nearly universal side effect of ototoxicity. The cellular mechanisms underlying cisplatin ototoxicity are poorly understood. Efforts in drug development to prevent or reverse cisplatin ototoxicity have largely focused on pathways of oxidative stress and apoptosis. An effective treatment for cisplatin ototoxicity, sodium thiosulfate, is associated with reduced survival in disseminated hepatoblastoma, highlighting the need for more specific drugs. The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways have been shown to be involved in the pathogenesis of noise-induced hearing loss and cochlear synaptopathy in vivo , and these pathways have been implicated broadly in cisplatin cytotoxicity. This study sought to determine whether the UPR can be targeted to prevent cisplatin ototoxicity. Neonatal cochlear cultures and HEK cells were exposed to cisplatin and UPR-modulating drugs, and UPR marker gene expression and cell death measured. Treatment with ISRIB, a drug that activates eif2B and downregulates the pro-apoptotic PERK/CHOP pathway of the UPR, was tested in an in vivo mouse model of cisplatin ototoxicity and well as a head and neck squamous cell carcinoma (HNSCC) cell-based assay of cisplatin cytotoxicity. Cisplatin exhibited a biphasic, non-linear dose-response of cell death and apoptosis that correlated with different patterns of UPR marker gene expression in HEK cells and cochlear cultures. ISRIB treatment protected against cisplatin-induced hearing loss and hair-cell death, but did not impact cisplatin's cytotoxic effects on HNSCC cell viability. These findings demonstrate that targeting the pro-apoptotic PERK/CHOP pathway with ISRIB can mitigate cisplatin ototoxicity without reducing anti-cancer cell effects, suggesting that this may be a viable strategy for drug development.

PMID:37905009 | PMC:PMC10614842 | DOI:10.1101/2023.10.17.562797

Permalink for 'Molecular Profiling of a Hepatocellular Neoplasm Not Otherwise Specified (HCN-NOS) Demonstrates Distinct Molecular Features in Hepatoblastoma and HCC-Like Components'

Molecular Profiling of a Hepatocellular Neoplasm Not Otherwise Specified (HCN-NOS) Demonstrates Distinct Molecular Features in Hepatoblastoma and HCC-Like Components

Fetched: October 31st, 2023, 5:02am GMT by Yan Chen Wongworawat

Pediatr Dev Pathol. 2023 Oct 30:10935266231204788. doi: 10.1177/10935266231204788. Online ahead of print.

ABSTRACT

Hepatoblastomas (HB) are embryonal tumors with quiet genomes diagnosed mostly in children under 3 years of age and often cured by surgical resection and chemotherapy. However, a subset of HBs behave aggressively, displaying characteristic histologic features and higher genomic instability. Hepatocellular neoplasm-not otherwise specified (HCN-NOS) is a provisional diagnostic category for tumors exhibiting either intermediate or a combination of both HB and hepatocellular carcinoma (HCC) histological features. In this study, we characterized an HCN-NOS diagnosed in a 3-year-old patient presenting with a liver mass, in which both HB and HCC histological components were amendable to macro-dissection and molecular profiling. The spectrum of mutations, copy number changes, mRNA, and protein expression profiles within these 2 histologically distinct tumor areas demonstrate molecular heterogeneity and suggest intratumoral clonal evolution of this hepatocellular CTNNB1-mutant lesion.

PMID:37903123 | DOI:10.1177/10935266231204788

Permalink for 'Prognostic value of systemic inflammation response index in hepatoblastoma patients receiving preoperative neoadjuvant chemotherapy'

Prognostic value of systemic inflammation response index in hepatoblastoma patients receiving preoperative neoadjuvant chemotherapy

Fetched: October 31st, 2023, 5:02am GMT by Chen Zheng

Front Oncol. 2023 Oct 13;13:1276175. doi: 10.3389/fonc.2023.1276175. eCollection 2023.

ABSTRACT

INTRODUCTION: Inflammation is closely associated with tumor development and patient prognosis. The objective of this study is to assess the prognostic value of the preoperative inflammatory indexes in pediatric hepatoblastoma patients who receive neoadjuvant chemotherapy.

METHODS: A retrospective analysis was performed on clinical and pathological data of 199 hepatoblastoma patients who underwent hepatectomy with preoperative neoadjuvant chemotherapy from January 2015 to June 2020. The receiver operating characteristic curve was used to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI) in predicting OS and EFS. Patients were grouped based on optimal cutoff values of preoperative inflammatory indexes. Survival rates were calculated using the Kaplan-Meier method, and survival outcomes were compared between groups using the log-rank test. Univariate and multivariate Cox proportional hazards regression models were used to identify independent prognostic factors, and a nomogram was constructed using R software to predict the probability of OS.

RESULTS: The receiver operating characteristic curve showed prognostic value for OS, not EFS, in preoperative inflammatory indexes. Patients were categorized into low/high groups: SII ≤ 266.70/higher, NLR ≤ 1.24/higher, PLR ≤ 85.25/higher, and SIRI ≤ 0.72/higher. High NLR, PLR, SII, and SIRI groups had significantly lower 5-year OS than their low counterparts (all p-value < 0.05). The Cox analysis identified four independent prognostic factors: SIRI (HR=2.997, 95% CI: 1.119-8.031), microvascular invasion (HR=2.556, 95% CI: 1.14-5.73), the post-treatment extent of disease (POSTTEXT) staging (IV vs. I: HR=244.204, 95% CI:11.306-5274.556), and alpha-fetoprotein (>100 ng/ml: HR=0.11, 95% CI: 0.032-0.381) for hepatoblastoma patients with neoadjuvant chemotherapy. High SIRI group had more patients with adverse NLR, SII, and POSTTEXT III (all p-value < 0.05). Independent prognostic factors led to an OS nomogram with a concordance index of 0.85 (95% CI: 0.78-0.91, p-value = 1.43e-27) and the calibration curve showed a good fit between the prediction curve and the true curve.

CONCLUSIONS: SIRI is an independent prognostic factor of hepatoblastoma patients receiving neoadjuvant chemotherapy. The OS nomogram based on SIRI, POSTTEXT staging, MiVI, and AFP can be used to assess the prognosis of those patients.

PMID:37901310 | PMC:PMC10613067 | DOI:10.3389/fonc.2023.1276175

Permalink for 'Retracted: Exploration of Potential Biomarkers and Immune Landscape for Hepatoblastoma: Evidence from Machine Learning Algorithm'

Retracted: Exploration of Potential Biomarkers and Immune Landscape for Hepatoblastoma: Evidence from Machine Learning Algorithm

Fetched: October 28th, 2023, 5:02am GMT by Evidence-Based Complementary And Alternative Medicine

Evid Based Complement Alternat Med. 2023 Oct 18;2023:9893765. doi: 10.1155/2023/9893765. eCollection 2023.

ABSTRACT

[This retracts the article DOI: 10.1155/2022/2417134.].

PMID:37886423 | PMC:PMC10599939 | DOI:10.1155/2023/9893765

Combination of QSAR Modeling and Hybrid-Based Consensus Scoring to Identify Dual-Targeting Inhibitors of PLK1 and p38γ

Fetched: October 27th, 2023, 5:02am GMT by Zixuan Cheng

J Chem Inf Model. 2023 Nov 13;63(21):6912-6924. doi: 10.1021/acs.jcim.3c01252. Epub 2023 Oct 26.

ABSTRACT

Polo-like kinase 1 (PLK1) and p38γ mitogen-activated protein kinase (p38γ) play important roles in cancer pathogenesis by controlling cell cycle progression and are therefore attractive cancer targets. The design of multitarget inhibitors may offer synergistic inhibition of distinct targets and reduce the risk of drug-drug interactions to improve the balance between therapeutic efficacy and safety. We combined deep-learning-based quantitative structure-activity relationship (QSAR) modeling and hybrid-based consensus scoring to screen for inhibitors with potential activity against the targeted proteins. Using this combination strategy, we identified a potent PLK1 inhibitor (compound 4) that inhibited PLK1 activity and liver cancer cell growth in the nanomolar range. Next, we deployed both our QSAR models for PLK1 and p38γ on the Enamine compound library to identify dual-targeting inhibitors against PLK1 and p38γ. Likewise, the identified hits were subsequently subjected to hybrid-based consensus scoring. Using this method, we identified a promising compound (compound 14) that could inhibit both PLK1 and p38γ activities. At nanomolar concentrations, compound 14 inhibited the growth of human hepatocellular carcinoma and hepatoblastoma cells in vitro. This study demonstrates the combined screening strategy to identify novel potential inhibitors for existing targets.

PMID:37883148 | DOI:10.1021/acs.jcim.3c01252

Adaptation to volumetric compression drives hepatoblastoma cells to an apoptosis-resistant and invasive phenotype

Fetched: October 25th, 2023, 5:02am GMT by Xiangyu Gong

bioRxiv. 2023 Oct 10:2023.10.08.561453. doi: 10.1101/2023.10.08.561453. Preprint.

ABSTRACT

Liver cancer involves tumor cells rapidly growing within a packed tissue environment. Patient tumor tissues reveal densely packed and deformed cells, especially at tumor boundaries, indicative of physical crowding and compression. It is not well understood how these physical signals modulate tumor evolution and therapeutic susceptibility. Here we investigate the impact of volumetric compression on liver cancer (HepG2) behavior. We find that conditioning cells under a highly compressed state leads to major transcriptional reprogramming, notably the loss of hepatic markers, the epithelial-to-mesenchymal transition (EMT)-like changes, and altered calcium signaling-related gene expression, over the course of several days. Biophysically, compressed cells exhibit increased Rac1-mediated cell spreading and cell-extracellular matrix interactions, cytoskeletal reorganization, increased YAP and β-catenin nuclear translocation, and dysfunction in cytoplasmic and mitochondrial calcium signaling. Furthermore, compressed cells are resistant to chemotherapeutics and desensitized to apoptosis signaling. Apoptosis sensitivity can be rescued by stimulated calcium signaling. Our study demonstrates that volumetric compression is a key microenvironmental factor that drives tumor evolution in multiple pathological directions and highlights potential countermeasures to re-sensitize therapy-resistant cells.

SIGNIFICANCE STATEMENT: Compression can arise as cancer cells grow and navigate within the dense solid tumor microenvironment. It is unclear how compression mediates critical programs that drive tumor progression and therapeutic complications. Here, we take an integrative approach in investigating the impact of compression on liver cancer. We identify and characterize compressed subdomains within patient tumor tissues. Furthermore, using in vitro systems, we induce volumetric compression (primarily via osmotic pressure but also via mechanical force) on liver cancer cells and demonstrate significant molecular and biophysical changes in cell states, including in function, cytoskeletal signaling, proliferation, invasion, and chemoresistance. Importantly, our results show that compressed cells have impaired calcium signaling and acquire resistance to apoptosis, which can be countered via calcium mobilization.

PMID:37873476 | PMC:PMC10592664 | DOI:10.1101/2023.10.08.561453

Some novel bioactivities of Virgibacillus halodenitrificans carotenoids, isolated from Wadi El-Natrun lakes

Fetched: October 24th, 2023, 5:02am GMT by Doaa Fayez

Saudi J Biol Sci. 2023 Nov;30(11):103825. doi: 10.1016/j.sjbs.2023.103825. Epub 2023 Oct 5.

ABSTRACT

Carotenoids come in second among the most frequent natural pigments and are utilized in medications, nutraceuticals, cosmetics, food pigments, and feed supplements. Based on recent complementary work, Virgibacillus was announced for the first time as a member of Wadi El-Natrun salt and soda lakes microbiota, identified as Virgibacillus halodenitrificans, and named V. halodenitrificans DASH; hence, this work aimed to investigate several in vitro medicinal bioactivities of V. halodenitrificans DASH carotenoids. The carotenoid methanolic extract showed antioxidant activity based on diphenylpicrylhydrazyl (DPPH) scavenging capacity with a half-maximal concentration (IC50) of 1.6 mg/mL as well as nitric oxide (NO) scavenging action expressed by an IC50 of 46.4 µg/mL. The extract showed considerable inhibitory activity for alpha-amylase (α-amylase) and alpha-glucosidase (α-glucosidase) enzymes (IC50 of 100 and 173.4 μg/mL, respectively). Moreover, the extract displayed selective anticancer activity against Caco-2 (IC50 = 138.96 µg/mL) and HepG-2 cell lines (IC50 = 31.25 µg/mL), representing colorectal adenocarcinoma and hepatoblastoma. Likewise, the extract showed 98.9 % clearance for human hepatitis C virus (HCV) using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), HCV-NS5B polymerase activity inhibition (IC50 = 27.4 µg/mL), and selective inhibitory activity against human coronavirus (HCoV 229E) using the plaque reduction assay (IC50 = 53.5 µg/mL). As far as we can tell, the anticancer, antiviral, and antidiabetic attributes of Virgibacillus carotenoids are, de novo, reported in this work which accordingly invokes further exploration of the other medicinal, biotechnological, and industrial applications of Virgibacillus and haloalkaliphilic bacteria carotenoids.

PMID:37869364 | PMC:PMC10587757 | DOI:10.1016/j.sjbs.2023.103825

Circ-CCT2 activates Wnt/β-catenin signaling to facilitate hepatoblastoma development by stabilizing PTBP1 mRNA

Fetched: October 23rd, 2023, 5:02am GMT by Qin Zhu

Cell Mol Gastroenterol Hepatol. 2023 Oct 20:S2352-345X(23)00183-2. doi: 10.1016/j.jcmgh.2023.10.004. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Circ-CCT2 (hsa_circ_0000418) is a novel circular RNA that stems from the CCT2 gene. However, the expression of circ-CCT2 and its roles in hepatoblastoma are unknown. Our study aims to study the circ-CCT2 roles in hepatoblastoma development.

METHODS: Hepatoblastoma specimens were collected for examining the expression of circ-CCT2, TAF15, and PTBP1. CCK-8 and colony formation assays were applied for cell proliferation analysis. Migratory and invasive capacities were evaluated through wound healing and Transwell assays. The interaction between circ-CCT2, TAF15, and PTBP1 was validated by fluorescence in situ hybridization, RNA pull-down, and RNA immunoprecipitation. SKL2001 was used as an agonist of the Wnt/β-catenin pathway. A subcutaneous mouse model of hepatoblastoma was established for examining the function of circ-CCT2 in hepatoblastoma in vivo.

RESULTS: Circ-CCT2 was significantly up-regulated in hepatoblastoma. Overexpression of circ-CCT2 activated Wnt/β-catenin signaling and promoted hepatoblastoma progression, whereas knockdown of circ-CCT2 exerted opposite effects. Moreover, both TAF15 and PTBP1 were up-regulated in hepatoblastoma tissues and cells. TAF15 was positively correlated with the expression of circ-CCT2 and PTBP1 in hepatoblastoma. Furthermore, circ-CCT2 recruited and up-regulated TAF15 protein to stabilize PTBP1 mRNA and trigger Wnt/β-catenin signaling in hepatoblastoma. Overexpression of TAF15 or PTBP1 reversed knockdown of circ-CCT2-mediated suppression of hepatoblastoma progression. SKL2001-mediated activation of Wnt/β-catenin signaling reversed the anti-tumor effects of silencing of circ-CCT2, TAF15, or PTBP1.

CONCLUSIONS: Circ-CCT2 stabilizes PTBP1 mRNA and activates Wnt/β-catenin signaling through recruiting and up-regulating TAF15 protein, thus promoting hepatoblastoma progression. Our findings deepen the understanding of hepatoblastoma pathogenesis and suggest potential therapeutic targets.

PMID:37866478 | DOI:10.1016/j.jcmgh.2023.10.004

Protective efficacy of Toxoplasma gondii infected cells-derived exosomes against chronic murine toxoplasmosis

Fetched: October 22nd, 2023, 5:02am GMT by Gihan M Tawfeek

Acta Trop. 2023 Dec;248:107041. doi: 10.1016/j.actatropica.2023.107041. Epub 2023 Oct 17.

ABSTRACT

Exosomes were isolated from T. gondii infected human hepatoblastoma cells using the exosome isolation kit and characterized by electron microscopy and Western blotting. Exosomes adsorbed to alum adjuvant were evaluated as a potential immunizing agent against murine chronic toxoplasmosis compared to excretory secretory antigens (ESA)-alum. Mice were immunized at days 1, 15 and 29. The levels of IgG, IFN-γ, IL-4 and IL-10, CD4⁺ and CD8⁺ T cells were determined using sandwich enzyme-linked immunosorbent assay (sandwich ELISA) at days 14, 28 and 56 of the experiment. Then mice were infected orally with 10 cysts of T. gondii. The protective efficacy of the antigens were evaluated by counting the brain cysts and measuring the aforementioned humoral and cellular parameters 60 days post infection. The results showed that alum increased the protective efficacy of the exosomes. Immunization with exosome-alum induced both humoral and mixed Th1/Th2 cellular immune responses. Exosome-alum gave higher levels of the humoral and cellular parameters, compared to ESA-alum. After challenge infection, exosome-alum significantly reduced the brain cyst burden by 75 % while ESA-alum gave 42 % reduction and evoked higher humoral and cellular immune responses. Therefore, the possibility of using T. gondii infected cells-derived exosome-alum as a vaccine is a new perspective in toxoplasmosis.

PMID:37858877 | DOI:10.1016/j.actatropica.2023.107041

Identification of hepatoblastoma susceptibility loci in the TRMT6 gene from a seven-center case-control study

Fetched: October 19th, 2023, 5:02am GMT by Lin Ma

J Cell Mol Med. 2023 Oct 18. doi: 10.1111/jcmm.18006. Online ahead of print.

ABSTRACT

Hepatoblastoma, the most frequently diagnosed primary paediatric liver tumour, bears the lowest somatic mutation burden among paediatric neoplasms. Therefore, it is essential to identify pathogenic germline genetic variants, especially those in oncogenic genes, for this disease. The tRNA methyltransferase 6 noncatalytic subunit (TRMT6) forms a tRNA methyltransferase complex with TRMT61A to catalyse adenosine methylation at position N1 of RNAs. TRMT6 has displayed tumour-promoting functions in several cancer types. However, the contribution of its genetic variants to hepatoblastoma remains unclear. In this study, we investigated the association between four TRMT6 polymorphisms (rs236170 A > G, rs451571 T > C, rs236188 G > A and rs236110 C > A) and the risk of hepatoblastoma in a cohort of 313 cases and 1446 healthy controls. Germline DNA was subjected to polymorphism genotyping via the TaqMan qPCR method. Odds ratio (OR) and 95% confidence interval (CI) were used to determine hepatoblastoma susceptibility variants. The rs236170 A > G, rs236188 G > A and rs236110 C > A polymorphisms were significantly associated with hepatoblastoma risk. Combination analysis of the four polymorphisms revealed that children bearing 1-4 risk genotypes were at significantly enhanced hepatoblastoma risk compared to those without risk genotype (adjusted OR = 1.52, 95% CI = 1.19-1.95, p = 0.0008). We also conducted stratification analyses by age, sex and clinical stage. Ultimately, we found that the rs236110 C > A was significantly associated with the downregulation of MCM8, a neighbouring gene of TRMT6. In conclusion, we identified three susceptibility loci in the TRMT6 gene for hepatoblastoma. Our findings warrant further validation by extensive case-control studies across different ethnicities.

PMID:37850543 | DOI:10.1111/jcmm.18006

Permalink for 'Drug metabolism and inflammation related distinct miRNA signature of colchicine resistant familial Mediterranean fever patients'

Drug metabolism and inflammation related distinct miRNA signature of colchicine resistant familial Mediterranean fever patients

Fetched: October 17th, 2023, 5:02am GMT by Bilgesu Şafak Tümerdem

Int Immunopharmacol. 2023 Nov;124(Pt B):111011. doi: 10.1016/j.intimp.2023.111011. Epub 2023 Oct 14.

ABSTRACT

OBJECTIVE: Colchicine is the primary treatment for familial Mediterranean fever (FMF). Although colchicine is safe and effective in FMF patients, around 5-10% of patients show resistance to the drug. This study investigates the possibility of a link between colchicine resistance and the distinct miRNA profiles in colchicine resistant FMF patients.

METHODS: Differentially expressed miRNAs in colchicine resistant FMF patients were detected by Affymetrix 4.0 miRNA array analysis. These miRNAs were then categorized based on the role of their target genes in drug metabolism and inflammation related pathways. qRT-PCR was used to validate candidate miRNAs selected by Enrichr, a gene enrichment analysis system based on the relevance of possible target genes in drug metabolism pathways. Expression levels of these miRNAs' potential target genes were investigated by qRT-PCR. Then, a colchicine resistant hepatoblastoma cell line (HEPG2) was established, and the differentially expressed miRNAs and genes identified in patients were also analyzed in this colchicine-resistant cell line.

RESULTS: 25 differentially expressed miRNAs were detected in colchicine resistant FMF patients. miR-183-5p, miR-15b-5p, miR-505-5p, and miR-125a-5p were identified to be associated with drug resistance and inflammatory pathways and thus chosen for further validation. miR-183-5p, miR-15b-5p, miR-505-5p miRNAs showed significantly differential expression in qRT-PCR. NFKB1, NR3C1, PPARα - drug absorption, distribution, metabolism, and excretion (ADME) genes were predicted to be targeted by these miRNAs. Among these targets, NFKB1 and NR3C1 were differentially over expressed in colchicine resistant FMF patients. These findings were validated in the colchicine resistant hepatoblastoma cell line (HEPG2).

CONCLUSION: This is the first study evaluating the role of miRNAs in colchicine resistant patients with FMF. Their differential expression may result in resistance to standard colchicine treatment by affecting the expression of genes that take place in drug absorption, distribution, metabolism, and excretion (ADME) or nuclear receptors that regulate ADME genes, thus potentially playing a role in both drug metabolism and inflammation.

PMID:37844462 | DOI:10.1016/j.intimp.2023.111011

NTHL1 Gene Mutations in Polish Polyposis Patients-Weighty Player or Vague Background?

Fetched: October 15th, 2023, 5:02am GMT by Natalia Grot

Int J Mol Sci. 2023 Sep 26;24(19):14548. doi: 10.3390/ijms241914548.

ABSTRACT

Multiple polyposes are heterogeneous diseases with different underlying molecular backgrounds, sharing a common symptom: the presence of transforming into cancerous intestinal polyps. Recent reports have indicated biallelic mutations in the NTHL1 gene, which is involved in base excision repair (BER), as predisposing to an elevated risk of colorectal cancer (CRC). We aimed to evaluate the significance of the p.Q82* truncating variant in predisposition to intestinal polyposis by assessing its frequency in polyposis patients. We genotyped 644 Polish patients and 634 control DNA samples using high-resolution melting analysis (HRM) and Sanger sequencing. We found the p.Q82* variant in four polyposis patients; in three, it was homozygous (OR = 6.90, p value = 0.202). Moreover, the p.R92C mutation was detected in one patient. We also looked more closely at the disease course in patients carrying NTHL1 mutations. Two homozygous patients also presented other neoplasia. In the family case, we noticed the earlier presence of polyps in the proband and early hepatoblastoma in his brother. We cannot univocally confirm the relationship of p.Q82* with an increased risk of CRC. However, homozygous p.Q82* was more frequent by 10-fold in patients without other mutations identified, which makes NTHL1 gene screening in this group reasonable.

PMID:37834005 | PMC:PMC10572874 | DOI:10.3390/ijms241914548

Mesenchymal hamartoma versus hepatoblastoma: A diagnostic dilemma

Fetched: October 15th, 2023, 5:02am GMT by Arkadeep Dhali

Int J Surg Case Rep. 2023 Nov;112:108931. doi: 10.1016/j.ijscr.2023.108931. Epub 2023 Oct 10.

ABSTRACT

INTRODUCTION AND IMPORTANCE: Pediatric hepatic tumors present diagnostic challenges due to diverse clinical presentations and limited patient communication. Elevated serum alpha-fetoprotein (AFP) levels, often associated with hepatoblastoma, can occur in various hepatic conditions, adding complexity to diagnosis. This report emphasizes the importance of comprehensive assessment and integrated interpretation in such cases.

CASE PRESENTATION: We present a rare case of a 1-year-old female child with abdominal swelling and hepatomegaly. Imaging revealed a hypodense hepatic lesion with punctate calcifications. Initial biopsy suggested mesenchymal hamartoma, but subsequent biopsy confirmed hepatoblastoma, highlighting the diagnostic complexity.

CLINICAL DISCUSSION: Hepatoblastoma is the most common pediatric liver tumor, typically presenting with nonspecific symptoms. Serum AFP levels are elevated, aiding diagnosis. Imaging reveals heterogeneous, hypervascular masses. Treatment includes surgery and chemotherapy. Mesenchymal hamartoma is a rare benign tumor with variable symptoms and imaging features, emphasizing the need for histopathological confirmation. This case underscores the importance of a comprehensive diagnostic approach.

CONCLUSION: Diagnosing pediatric hepatic tumors requires an integrated assessment of clinical, laboratory, and imaging findings. Confirmatory biopsies are essential, as demonstrated by this case, where an initial diagnosis of mesenchymal hamartoma was revised to hepatoblastoma. Collaborative, multidisciplinary approaches are crucial for accurate diagnosis and effective therapeutic planning, offering hope for improved outcomes in these complex cases.

PMID:37832361 | PMC:PMC10667734 | DOI:10.1016/j.ijscr.2023.108931

Permalink for 'Ferroptosis regulator NOS2 is closely associated with the prognosis and cell malignant behaviors of hepatoblastoma: a bioinformatic and in vitro study'

Ferroptosis regulator NOS2 is closely associated with the prognosis and cell malignant behaviors of hepatoblastoma: a bioinformatic and in vitro study

Fetched: October 6th, 2023, 5:02am GMT by Lan Zhang

Front Oncol. 2023 Sep 19;13:1228199. doi: 10.3389/fonc.2023.1228199. eCollection 2023.

ABSTRACT

BACKGROUND: Hepatoblastoma (HB) is the most common liver tumor in children with easy metastasis. The emergence of ferroptosis as a novel form of cell death has gained increased attention in various human cancers. However, the roles of ferroptosis-related (FR) genes in HB remain elusive.

METHODS: The GSE133039, GSE131329, and GSE81928 datasets were utilized for screening core FR genes in HB. Through Lasso regression analysis and using the support vector machine recursive feature elimination (SVM-RFE) algorithm, three candidate FR genes were obtained for characterizing HB. Their expression patterns and their clinical associations were explored through the 'Limma' R package, and their diagnostic potential was evaluated using ROC curves. Nitric oxide synthase 2 (NOS2) emerged as a candidate for further analyses. The CIBERSORT algorithm and GSEA dataset were used to respectively investigate the immune and metabolism effects of NOS2; the former was validated through immunofluorescence. The GSDC database was employed to analyze the correlation between NOS2 expression and the therapeutic efficacy of multiple drugs. PCR, Western blotting, colony formation assays, and Transwell experiments, were used to determine biological functions of NOS2 in HB cells. Potential upstream transcription factors of NOS2 were predicted through the TRRUST, hTFtarget, GeneCards, and JASPAR databases.

RESULTS: NQO1, SLC1A4, and NOS2 were identified as potential genes in HB and found to be significantly upregulated in tumor samples. Nevertheless, only NOS2 was closely associated with HB clinicopathological characteristics; high NOS2 expression indicated poor prognosis, metastatic tendency, and late clinical stage. Immune analyses indicated that high NOS2 expression was concomitant with decreased infiltration levels of CD8+ T cells but increased infiltration levels of macrophages. GSEA revealed that NOS2 failed to affect the enrichments of glycolysis, fatty acid metabolism, and cholesterol biosynthesis in HB. Moreover, NOS2 was positively correlated with the IC50 values of trametinib, lapatinib, and cisplatin. NOS2 overexpression promoted the proliferation, migration and invasion of HepG2 and HuH-6 cells. JUND was identified as a potential transcriptional regulator of NOS2 by binding to its promoter (5'-TTCTGACTCTTTT-3').

CONCLUSION: NOS2 plays a significant role in HB clinical assessments and holds promise as a novel therapeutic target.

PMID:37795447 | PMC:PMC10546316 | DOI:10.3389/fonc.2023.1228199

Permalink for 'Maternal medically diagnosed infection and antibiotic prescription during pregnancy and risk of childhood cancer: A population-based cohort study in Taiwan, 2004 to 2015'

Maternal medically diagnosed infection and antibiotic prescription during pregnancy and risk of childhood cancer: A population-based cohort study in Taiwan, 2004 to 2015

Fetched: October 5th, 2023, 5:02am GMT by Anupong Sirirungreung

Int J Cancer. 2023 Oct 4. doi: 10.1002/ijc.34744. Online ahead of print.

ABSTRACT

While associations between maternal infections during pregnancy and childhood leukemia in offspring have been extensively studied, the evidence for other types of childhood cancers is limited. Additionally, antibiotic exposure during pregnancy could potentially increase the risk of childhood cancers. Our study investigates associations between maternal infections and antibiotic prescriptions during pregnancy and the risk of childhood cancer in Taiwan. We conducted a population-based cohort study using the Taiwan Maternal and Child Health Database (TMCHD), linked with national health and cancer registries. The study included 2 267 186 mother-child pairs, and the median follow-up time was 7.96 years. Cox proportional hazard models were utilized to estimate effects. Maternal infections during pregnancy were associated with a moderate increase in the risk of childhood hepatoblastoma (adjusted hazard ratio [HR] = 1.34; 95% confidence interval [CI]: 0.90-1.98) and a weaker increase in the risk of childhood acute lymphoblastic leukemia (ALL) (adjusted HR = 1.15; 95% CI: 0.99-1.35). Antibiotic prescriptions during pregnancy were also associated with an elevated risk of childhood ALL (adjusted HR = 1.30; 95% CI: 1.04-1.63), particularly with tetracyclines (adjusted HR = 2.15; 95% CI: 1.34-3.45). Several specific antibiotics were also associated with an increased risk of hepatoblastoma and medulloblastoma. Children exposed in utero to antibiotic prescription or both infections and antibiotics during pregnancy were at higher risk of developing ALL. Our findings suggest that there are associations between maternal infections, antibiotic use during pregnancy and the risk of several childhood cancers in addition to ALL and highlight the importance of further research in this area.

PMID:37792464 | DOI:10.1002/ijc.34744

Permalink for 'Pediatric cancer incidence among individuals with overgrowth syndromes and overgrowth features: A population-based assessment in seven million children'

Pediatric cancer incidence among individuals with overgrowth syndromes and overgrowth features: A population-based assessment in seven million children

Fetched: October 4th, 2023, 5:03am GMT by Gillean K Connolly

Cancer. 2023 Oct 3. doi: 10.1002/cncr.35041. Online ahead of print.

ABSTRACT

BACKGROUND: Overgrowth syndromes (e.g., Beckwith-Wiedemann) are associated with an increased risk of pediatric cancer, although there are few population-based estimates of risk. There are also limited studies describing associations between other overgrowth features (e.g., hepatosplenomegaly) and pediatric cancer. Therefore, cancer risk among children with these conditions was evaluated with data from a large, diverse population-based registry linkage study.

METHODS: This study includes all live births in Texas during the years 1999-2017. Children with overgrowth features and syndromes were identified from the Texas Birth Defects Registry; children with cancer were identified by linkage to the Texas Cancer Registry. Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between each overgrowth syndrome/feature and cancer, which were adjusted for infant sex and maternal age.

RESULTS: In the total birth cohort (n = 6,997,422), 21,207 children were identified as having an overgrowth syndrome or feature. Children with Beckwith-Wiedemann syndrome were 42 times more likely to develop pediatric cancer (95% CI, 24.20-71.83), with hepatoblastoma being the most common, followed by Wilms tumor. The presence of any isolated overgrowth feature was associated with increased cancer risk (HR, 4.70; 95% CI, 3.83-5.77); associations were strongest for hepatosplenomegaly (HR, 23.04; 95% CI, 13.37-39.69) and macroglossia (HR, 11.18; 95% CI, 6.35-19.70).

CONCLUSIONS: This population-based assessment confirmed prior findings that children with either overgrowth syndromes or features were significantly more likely to develop cancer. Overall, this study supports recommendations for cancer surveillance in children with these conditions and may also inform future research into cancer etiology.

PMID:37788149 | DOI:10.1002/cncr.35041

The Effects of Glypican-3 Deficiency on Radiosensitivity in Liver Cancer Cells

Fetched: October 4th, 2023, 5:03am GMT by J Y Chung

Int J Radiat Oncol Biol Phys. 2023 Oct 1;117(2S):e223-e224. doi: 10.1016/j.ijrobp.2023.06.1129.

ABSTRACT

PURPOSE/OBJECTIVE(S): Glypican-3 (GPC-3), a heparan sulfate proteoglycan involved in cellular proliferation, modulates signaling of FGF/FGFR, IGF/IGFR, HGF/Met, Wnt/Frizzled, among others and correlates with survival. GPC-3 is overexpressed in the majority of hepatocellular carcinoma and hepatoblastoma, but not in normal hepatocytes. Accordingly, it is being investigated as a liver cancer-selective target for radiopharmaceutical imaging and therapy. However, the potential linkage between GPC-3 expression and radiosensitivity has not yet been defined. In this study, we investigated the effects of GPC-3 deficiency on radiosensitivity in liver cancer cell lines.

MATERIALS/METHODS: CRISPR/Cas9 system was used to engineer GPC-3 knockout variants of liver cancer cell lines, HepG2 & Hep3B, both of which natively express GPC-3. Confirmation of knockout of GPC-3 was evaluated by RT-PCR, western blotting, flow cytometry, immunocytochemistry, and gDNA sequencing. Cell growth and migration were evaluated by BrdU insertion and wound-healing assays, respectively. In vitro radiosensitivity was examined by radiation-induced apoptosis/necrosis (Annexin V-APC and PI staining), cell cycle modification, γH2AX foci formation, and clonogenic assays (6 Gy). Wildtype and knockout lines were engrafted into athymic mice to assess tumor growth kinetics.

RESULTS: RT-PCR, western blotting, flow cytometry, and immunocytochemistry all confirmed GPC-3 knockout in both HepG2 and Hep3B cell lines. Nucleotide deletion at exon 3 of the GPC-3 gene was confirmed by gDNA sequencing in HepG2ΔGPC3 and Hep3BΔGPC3. GPC-3 deficiency reduced liver cancer cell proliferation (HepG2ΔGPC3, p = 0.027, and Hep3BΔGPC3, p = 0.031) and migration (HepG2ΔGPC3: 1.5-fold, p<0.001, and Hep3BΔGPC3: 2.3-fold, p<0.001) significantly when compared with wild type. GPC-3 deficiency reduced cell survival and clonogenicity (HepG2ΔGPC3: DEF = 1.23, Hep3BΔGPC3: DEF = 1.23) in liver cancer cells exposed to irradiation (6 Gy). The delayed repair of double-stranded DNA damage was observed in irradiated GPC-3 deficient liver cancer cells. Tumor growth was dramatically delayed by GPC-3 deficiency. Tumor weight measured at 50 (Hep3B) and 60 (HepG2) days after liver cancer cell inoculation corroborated these effects.

CONCLUSION: Knockout lines of HepG2 and Hep3B exhibited decreased cell proliferation, migration, and in vivo tumor growth compared to wildtype. GPC-3 deficiency was associated with increased sensitivity to radiation therapy. Studies identifying the pathways through which this radiosensitivity is mediated are ongoing.

PMID:37784908 | DOI:10.1016/j.ijrobp.2023.06.1129

Permalink for 'A multicenter prospective study on the management of hepatoblastoma in children: a report from the Chinese Children's Cancer Group'

A multicenter prospective study on the management of hepatoblastoma in children: a report from the Chinese Children's Cancer Group

Fetched: September 29th, 2023, 5:02am GMT by Meng-Jie Tang

World J Pediatr. 2023 Sep 28. doi: 10.1007/s12519-023-00750-6. Online ahead of print.

ABSTRACT

BACKGROUND: This study aimed to identify survival risk factors in Chinese children with hepatoblastoma (HB) and assess the effectiveness of the new treatment protocol proposed by the Chinese Children's Cancer Group (CCCG) in 2016.

METHODS: A multicenter, prospective study that included 399 patients with HB from January 2015 to June 2020 was conducted. Patient demographics, treatment protocols, and other related information were collected. Cox regression models and Kaplan-Meier curve methods were used.

RESULTS: The 4-year event-free survival (EFS) and overall survival (OS) were 76.9 and 93.5%, respectively. The 4-year EFS rates for the very-low-risk, low-risk, intermediate-risk, and high-risk groups were 100%, 91.6%, 81.7%, and 51.0%, respectively. The 4-year OS was 100%, 97.3%, 94.4%, and 86.8%, respectively. Cox regression analysis found that age, tumor rupture (R +), and extrahepatic tumor extension (E +) were independent prognostic factors. A total of 299 patients had complete remission, and 19 relapsed. Patients with declining alpha-fetoprotein (AFP) > 75% after the first two cycles of neoadjuvant chemotherapy had a better EFS and OS than those ≤ 75%.

CONCLUSIONS: The survival outcome of HB children has dramatically improved since the implementation of CCCG-HB-2016 therapy. Age ≥ 8 years, R + , and E + were independent risk factors for prognosis. Patients with a declining AFP > 75% after the first two cycles of neoadjuvant chemotherapy had better EFS and OS.

PMID:37770810 | DOI:10.1007/s12519-023-00750-6

Potential involvement of IL-32 in cell-to-cell communication between macrophages and hepatoblastoma

Fetched: September 27th, 2023, 5:02am GMT by Ahmad Adawy

Pediatr Surg Int. 2023 Sep 26;39(1):275. doi: 10.1007/s00383-023-05557-0.

ABSTRACT

PURPOSE: This study investigated the expression of interleukin 32 (IL-32) in hepatoblastoma, the most common primary pediatric liver tumor, and its possible roles in tumorigenesis.

METHODS: IL-32 expression was investigated in two hepatoblastoma cell lines (Hep G2 and HuH 6) in the steady state and after co-culture with macrophages by RNA-seq analysis and RT-qPCR, and after stimulation with chemotherapy. Cultured macrophages were stimulated by IL-32 isoforms followed by RT-qPCR and western blot analysis. IL-32 immunohistochemical staining (IHC) was performed using specimens from 21 hepatoblastoma patients. Clustering analysis was also performed using scRNA-seq data downloaded from Gene Expression Omnibus.

RESULTS: The IL-32 gene is expressed by hepatoblastoma cell lines; expression is upregulated by paracrine cell-cell communication with macrophages, also by carboplatin and etoposide. IL-32 causes protumor activation of macrophages with upregulation of PD-L1, IDO-1, IL-6, and IL-10. In the patient pool, IHC was positive only in 48% of cases. However, in the downloaded dataset, IL-32 gene expression was negative.

CONCLUSION: IL-32 was detected in hepatoblastoma cell lines, but not in all hepatoblastoma patients. We hypothesized that stimulation such as chemotherapy might induce expression of IL-32, which might be a critical mediator of chemoresistance in hepatoblastoma through inducing protumor activation in macrophages.

PMID:37751001 | DOI:10.1007/s00383-023-05557-0

Permalink for 'Elevated extracellular calcium ions accelerate the proliferation and migration of HepG2 cells and decrease cisplatin sensitivity'

Elevated extracellular calcium ions accelerate the proliferation and migration of HepG2 cells and decrease cisplatin sensitivity

Fetched: September 27th, 2023, 5:02am GMT by Haozhe Xu

J Biomed Res. 2023 Sep 10;37(5):340-354. doi: 10.7555/JBR.37.20230067.

ABSTRACT

Hepatoblastoma is the most frequent liver malignancy in children. HepG2 has been discovered as a hepatoblastoma-derived cell line and tends to form clumps in culture. Intriguingly, we observed that the addition of calcium ions reduced cell clumping and disassociated HepG2 cells. The calcium signal is in connection with a series of processes critical in the tumorigenesis. Here, we demonstrated that extracellular calcium ions induced morphological changes and enhanced the epithelial-mesenchymal transition in HepG2 cells. Mechanistically, calcium ions promoted HepG2 proliferation and migration by up-regulating the phosphorylation levels of focal adhesion kinase (FAK), protein kinase B, and p38 mitogen-activated protein kinase. The inhibitor of FAK or Ca ²⁺/calmodulin-dependent kinase Ⅱ (CaMKⅡ) reversed the Ca ²⁺-induced effects on HepG2 cells, including cell proliferation and migration, epithelial-mesenchymal transition protein expression levels, and phosphorylation levels of FAK and protein kinase B. Moreover, calcium ions decreased HepG2 cells' sensitivity to cisplatin. Furthermore, we found that the expression levels of FAK and CaMKⅡ were increased in hepatoblastoma. The group with high expression levels of FAK and CaMKⅡ exhibited significantly lower ImmunoScore as well as CD8 ⁺ T and NK cells. The expression of CaMKⅡ was positively correlated with that of PDCD1 and LAG3. Correspondingly, the expression of FAK was negatively correlated with that of TNFSF9, TNFRSF4, and TNFRSF18. Collectively, extracellular calcium accelerates HepG2 cell proliferation and migration via FAK and CaMKⅡ and enhances cisplatin resistance. FAK and CaMKⅡ shape immune cell infiltration and responses in tumor microenvironments, thereby serving as potential targets for hepatoblastoma.

PMID:37750331 | PMC:PMC10541776 | DOI:10.7555/JBR.37.20230067

Horseradish Peroxidase-Mediated Bioprinting via Bioink Gelation by Alternately Extruded Support Material

Fetched: September 23rd, 2023, 5:02am GMT by Takashi Kotani

ACS Biomater Sci Eng. 2023 Oct 9;9(10):5804-5812. doi: 10.1021/acsbiomaterials.3c00996. Epub 2023 Sep 22.

ABSTRACT

Horseradish peroxidase (HRP)-mediated extrusion bioprinting has a significant potential in tissue engineering and regenerative medicine. However, they often face challenges in terms of printing fidelity and structural integrity when using low-viscosity inks. To address this issue, a method that alternately extrudes bioinks and support material was developed in this study. The bioinks consisting of cells, HRP, and phenolated polymers, and the support material contained hydrogen peroxide (H2O2). The support material not only prevented the collapse of the constructs but also supplied H2O2 to facilitate the enzymatic reaction. 3D constructs with tall and complex shapes were successfully printed from a low-viscosity ink containing 10 U/mL HRP and 1.0% w/v phenolated hyaluronic acid (HA-Ph), with a support material containing 10 mM H2O2. Over 90% viability of mouse fibroblasts (10T1/2) was achieved following the printing process, along with a morphology and proliferation rate similar to that of nontreated cells. Furthermore, human hepatoblastoma (HepG2) cells showed an increased spheroid size over 14 days in the printed constructs. The 10T1/2 cells adhered and proliferated on the constructs printed from inks containing both phenolated gelatin and HA-Ph. These results demonstrate the great potential of this HRP-mediated extrusion bioprinting technique for tissue engineering applications.

PMID:37738620 | DOI:10.1021/acsbiomaterials.3c00996

Computational drug prediction in hepatoblastoma by integrating pan-cancer transcriptomics with pharmacological response

Fetched: September 21st, 2023, 5:02am GMT by Mario Failli

Hepatology. 2023 Sep 20. doi: 10.1097/HEP.0000000000000601. Online ahead of print.

ABSTRACT

Hepatoblastoma (HB) is the main paediatric liver cancer, but it is a very rare disease. Despite significant improvements in the treatment of children diagnosed with HB, limited treatment options exist for patients with advanced tumours. Besides, survivors generally have long-term adverse effects derived from treatment such as ototoxicity, cardiotoxicity, delayed growth, and secondary tumours. Accordingly, there is an urgent need to define new and efficient therapeutic strategies for patients with HB. Computational methods to predict drug sensitivity from a tumour's transcriptome have been successfully applied for some common adult malignancies, but specific efforts in paediatric cancers are lacking because of paucity of data. In this study, we computationally screened the efficacy of drugs in HB patients with the aggressive C2 subtype and poor clinical outcome starting from their transcriptome. Our method utilized publicly available collections of pan-cancer transcriptional profiles and drug responses across 36 tumour types and 495 compounds. The drugs predicted to be most effective were experimentally validated using patient-derived xenograft (PDX) models of HB grown in vitro and in vivo. We thus identified two CDK9 inhibitors, alvocidib and dinaciclib as potent HB growth inhibitors for the high-risk C2 molecular subtype. We also found that in a cohort of 46 patients with HB, high CDK9 tumour expression was significantly associated with poor prognosis. Our work proves the usefulness of computational methods trained on pan-cancer datasets to reposition drugs in rare paediatric cancers such as HB, and to help clinicians in choosing the best treatment options for their patients.

PMID:37729391 | DOI:10.1097/HEP.0000000000000601

Anti-ferroptotic PRKAA2 serves as a potential diagnostic and prognostic marker for hepatoblastoma

Fetched: September 19th, 2023, 5:02am GMT by Yi Xie

J Gastrointest Oncol. 2023 Aug 31;14(4):1788-1805. doi: 10.21037/jgo-23-110. Epub 2023 Aug 11.

ABSTRACT

BACKGROUND: The incidence rate of hepatoblastoma (HB), which is the most prevalent malignant tumour among children, rises each year. According to recent studies, a number of neoplastic disorders and ferroptosis are intimately connected. This study aims to identify key ferroptosis-related genes in HB and explore new directions for the diagnosis and treatment of HB.

METHODS: Differentially expressed ferroptosis-related genes were identified using the Gene Expression Omnibus datasets. The functional annotation of candidate genes was evaluated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Machine learning and receiver operating characteristic (ROC) curves revealed protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2), tribbles homolog 2 (TRIB2), and liver-type glutaminase (GLS2) as potential diagnostic genes of HB. By using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, relative expression of PRKAA2 was examined. The effect of PRKAA2 on proliferation, apoptosis, and ferroptosis of HB cells was verified in vitro and in vivo. Fisher's exact test was used to evaluate the clinical significance of PRKAA2 in HB.

RESULTS: The prognostic indicators had a substantial correlation with PRKAA2 expression, which rose dramatically in HB tissues. PRKAA2 promotes proliferation and inhibits ferroptosis in HB cells. PRKAA2 plays a role in ferroptosis by regulating hypoxia-inducible factor 1α (HIF-1α) and transferrin receptor 1 (TFR1).

CONCLUSIONS: PRKAA2 functions as a tumor-promoting factor in HB by promoting cell proliferation and prohibiting ferroptosis. Ferroptosis-related genes PRKAA2 is a potential diagnostic and prognostic marker for HB as well as a novel therapeutic target in the future.

PMID:37720445 | PMC:PMC10502548 | DOI:10.21037/jgo-23-110

BEX1 supports the stemness of hepatoblastoma by facilitating Warburg effect in a PPARγ/PDK1 dependent manner

Fetched: September 17th, 2023, 5:01am GMT by Qian Wang

Br J Cancer. 2023 Oct;129(9):1477-1489. doi: 10.1038/s41416-023-02418-4. Epub 2023 Sep 15.

ABSTRACT

BACKGROUND: Hepatoblastoma (HB) is a highly aggressive paediatric malignancy that exhibits a high presence of cancer stem cells (CSCs), which related to tumour recurrence and chemotherapy resistance. Brain expressed X-linked protein 1 (BEX1) plays a pivotal role in ciliogenesis, axon regeneration and differentiation of neural stem cells. However, the role of BEX1 in metabolic and stemness programs in HB remains unclear.

METHODS: BEX1 expression in human and mouse HB was analyzed using gene expression profile data from NCBI GEO and immunohistochemical validation. Seahorse extracellular flux analyzer, ultra-high-performance liquid-chromatography mass spectrometry (LC-MS), flow cytometry, qRT-PCR, Western Blot, sphere formation assay, and diluted xenograft tumour formation assay were used to analyze metabolic and stemness features.

RESULTS: Our results indicated that overexpression of BEX1 significantly enhanced the Warburg effect in HB cells. Furthermore, glycolysis inhibition largely attenuated the effects of BEX1 on HB cell growth and self-renewal, suggesting that BEX1 promotes stemness maintenance of HB cells by regulating the Warburg effect. Mechanistically, BEX1 enhances Warburg effect through the downregulation of peroxisome proliferator-activated receptor-gamma (PPARγ). Furthermore, pyruvate dehydrogenase kinase isozyme 1 (PDK1) is required for PPARγ-induced inhibition of Warburg effect in HB. In addition, BEX1 supports the stemness of HB by enhancing Warburg effect in a PPARγ/PDK1 dependent manner.

CONCLUSIONS: HB patients with high BEX1 and PDK1 expression had a poor prognosis. BEX1 promotes the stemness maintenance of HB cells via modulating the Warburg effect, which depends on PPARγ/PDK1 axis. Pioglitazone could be used to target BEX1-mediated stemness properties in HB by upregulating PPARγ.

PMID:37715024 | PMC:PMC10628275 | DOI:10.1038/s41416-023-02418-4

Permalink for 'Evaluating the clinical efficacy and limitations of indocyanine green fluorescence-guided surgery in childhood hepatoblastoma: a retrospective study'

Evaluating the clinical efficacy and limitations of indocyanine green fluorescence-guided surgery in childhood hepatoblastoma: a retrospective study

Fetched: September 12th, 2023, 5:02am GMT by Shan Liu

Photodiagnosis Photodyn Ther. 2023 Sep 9;44:103790. doi: 10.1016/j.pdpdt.2023.103790. Online ahead of print.

ABSTRACT

BACKGROUND: Indocyanine green (ICG) fluorescence guided surgery has been used to treat childhood hepatoblastoma (HB), but the advantages and disadvantages of this technique have not been fully discussed. The purpose of this study is to summarize the experience and to explore the clinical value of this technique for children with HB.

METHODS: 45 children with HB who underwent ICG fluorescence guided surgery (n = 22) and general surgery (n = 23) in our center from January 2020 to December 2022 were enrolled retrospectively.

RESULTS: All the liver tumors in the ICG group showed hyperfluorescence, including total and partial fluorescent types. With the help of ICG navigation, minimally invasive surgery was performed in 3 cases. 18.2 % of cases with tumors could not be accurately identified under white light, but could be identified by fluorescence imaging. The fluorescent cutting lines of 59.1 % of cases were consistent with the safe cutting lines. In 36.4 % of cases, the fluorescence boundary was not clear because of tumor necrosis. In 36.4 % of cases, the fluorescence could not be detected on the inner edge of the tumors because of the depth. A total of 29 ICG (+) suspicious lesions were found during the operations, of which 5 were true positive lesions.

CONCLUSION: ICG fluorescence guided surgery is safe and feasible in children with HB. This technique is helpful for locating tumors, determining margin and finding small lesions with negative imaging, especially in minimally invasive surgery. However, preoperative chemotherapy, tumor necrosis, tumor depth, and ICG administration impact the effect of fluorescence imaging.

PMID:37696318 | DOI:10.1016/j.pdpdt.2023.103790

11p15 Epimutations in Pediatric Embryonic Tumors: Insights from a Methylome Analysis

Fetched: September 10th, 2023, 5:02am GMT by Felipe Luz Torres Silva

Cancers (Basel). 2023 Aug 25;15(17):4256. doi: 10.3390/cancers15174256.

ABSTRACT

Embryonic tumors share few recurrent mutations, suggesting that other mechanisms, such as aberrant DNA methylation, play a prominent role in their development. The loss of imprinting (LOI) at the chromosome region 11p15 is the germline alteration behind Beckwith-Wiedemann syndrome that results in an increased risk of developing several embryonic tumors. This study analyzed the methylome, using EPIC Beadchip arrays from 99 sporadic embryonic tumors. Among these tumors, 46.5% and 14.6% presented alterations at imprinted control regions (ICRs) 1 and 2, respectively. Based on the methylation levels of ICR1 and ICR2, four clusters formed with distinct methylation patterns, mostly for medulloblastomas (ICR1 loss of methylation (LOM)), Wilms tumors, and hepatoblastomas (ICR1 gain of methylation (GOM), with or without ICR2 LOM). To validate the results, the methylation status of 29 cases was assessed with MS-MLPA, and a high level of agreement was found between both methodologies: 93% for ICR1 and 79% for ICR2. The MS-MLPA results indicate that 15 (51.7%) had ICR1 GOM and 11 (37.9%) had ICR2 LOM. To further validate our findings, the ICR1 methylation status was characterized via digital PCR (dPCR) in cell-free DNA (cfDNA) extracted from peripheral blood. At diagnosis, we detected alterations in the methylation levels of ICR1 in 62% of the cases, with an agreement of 76% between the tumor tissue (MS-MLPA) and cfDNA methods. Among the disagreements, the dPCR was able to detect ICR1 methylation level changes presented at heterogeneous levels in the tumor tissue, which were detected only in the methylome analysis. This study highlights the prevalence of 11p15 methylation status in sporadic embryonic tumors, with differences relating to methylation levels (gain or loss), location (ICR1 or ICR2), and tumor types (medulloblastomas, Wilms tumors, and hepatoblastomas).

PMID:37686532 | PMC:PMC10486592 | DOI:10.3390/cancers15174256

Permalink for 'Early steroids after paediatric liver transplantation protect against T-cell mediated rejection -results from the ChilSFree study'

Early steroids after paediatric liver transplantation protect against T-cell mediated rejection -results from the ChilSFree study

Fetched: September 8th, 2023, 5:02am GMT by Imeke Goldschmidt

Liver Transpl. 2023 Sep 5. doi: 10.1097/LVT.0000000000000255. Online ahead of print.

ABSTRACT

Steroid-free immunosuppression protocols gained popularity in pediatric liver transplantation (pLT) after the introduction of IL-2-receptor blockade for induction therapy. We analyzed the clinical and immunologic outcome data of the multicenter prospective observational ChilSFree study to compare the impact of steroid-free versus steroid-containing immunosuppressive therapy following pLT in a real-life scenario. Two hundred forty-six children [55.3% male, age at pLT median: 2.4 (range: 0.2-17.9) y] transplanted for biliary atresia (43%), metabolic liver disease (9%), acute liver failure (4%), hepatoblastoma (9%), and other chronic end-stage liver diseases (39%) underwent immune monitoring and clinical data documentation over the first year after pLT. Patient and graft survival at 1 year was 98.0% and 92.7%, respectively. Primary immunosuppression was basiliximab induction followed by tacrolimus (Tac) monotherapy (55%), Tac plus steroid tapering over 3 months (29%), or cyclosporine and steroid tapering (7%). One center used intraoperative steroids instead of basiliximab followed by Tac plus mycophenolate mofetil (7% of patients). N = 124 biopsy-proven T-cell-mediated rejections were documented in n = 82 (33.3%) patients. T-cell-mediated rejection occurred early (median: 41 d, range: 3-366 d) after pLT. Patients initially treated with Tac plus steroids experienced significantly fewer episodes of rejection than patients treated with Tac alone (chi-square p <0.01). The use of steroids was associated with earlier downregulation of proinflammatory cytokines interferon (IFN)-γ, Interleukin (IL)-6, CX motif chemokin ligand (CXCL)8, IL-7, and IL-12p70. Both primary immunosuppression with Tac plus steroids and living donor liver transplantation were independent predictors of rejection-free survival 1 year after pLT on logistic regression analysis. Adjunctive steroid therapy after pLT leads to earlier suppression of the post-pLT proinflammatory response and significantly reduced rejection rates during the first year after pLT (15.9%). Fifty-one percent of patients initially treated without steroids remain steroid-free over the first 12 months without rejection.

PMID:37678230 | DOI:10.1097/LVT.0000000000000255

GREB1 isoform 4 is specifically transcribed by MITF and required for melanoma proliferation

Fetched: September 3rd, 2023, 5:02am GMT by Koei Shinzawa

Oncogene. 2023 Oct;42(42):3142-3156. doi: 10.1038/s41388-023-02803-6. Epub 2023 Sep 1.

ABSTRACT

Growth regulation by estrogen in breast cancer 1 (GREB1) is involved in hormone-dependent and -independent tumor development (e.g., hepatoblastoma). In this study, we found that a GREB1 splicing variant, isoform 4 (Is4), which encodes C-terminal half of full-length GREB1, is specifically expressed via microphthalmia-associated transcription factor (MITF) in melanocytic melanoma, and that two MITF-binding E-box CANNTG motifs at the 5'-upstream region of GREB1 exon 19 are necessary for GREB1 Is4 transcription. MITF and GREB1 Is4 were strongly co-expressed in approximately 20% of the melanoma specimens evaluated (17/89 cases) and their expression was associated with tumor thickness. GREB1 Is4 silencing reduced melanoma cell proliferation in association with altered expression of cell proliferation-related genes in vitro. In addition, GREB1 Is4 targeting by antisense oligonucleotide (ASO) decreased melanoma xenograft tumor formation and GREB1 Is4 expression in a BRAF^V600E; PTEN^flox melanoma mouse model promoted melanoma formation, demonstrating the crucial role of GREB1 Is4 for melanoma proliferation in vivo. GREB1 Is4 bound to CAD, the rate-limiting enzyme of pyrimidine metabolism, and metabolic flux analysis revealed that GREBI Is4 is necessary for pyrimidine synthesis. These results suggest that MITF-dependent GREB1 Is4 expression leads to melanoma proliferation and GREB1 Is4 represents a new molecular target in melanoma.

PMID:37658191 | PMC:PMC10575781 | DOI:10.1038/s41388-023-02803-6

Permalink for 'Investigation of TGF-α-overexpressing mouse hepatocytes (TAMH) cultured as spheroids for use in hepatotoxicity screening of drug candidates'

Investigation of TGF-α-overexpressing mouse hepatocytes (TAMH) cultured as spheroids for use in hepatotoxicity screening of drug candidates

Fetched: September 2nd, 2023, 5:02am GMT by Kristin Beirow

J Appl Toxicol. 2023 Sep 1. doi: 10.1002/jat.4538. Online ahead of print.

ABSTRACT

The immortalized mouse liver cell line TAMH has been described as a valuable tool for studying hepatotoxic mechanisms, but until now, it has only been reported to grow as a monolayer in culture. However, culturing hepatocytes as three-dimensional (3D) spheroids has been shown to result in improved liver-specific functions (e.g., metabolic capacity) by better mimicking the in vivo environment. This approach may lead to more reliable detection of drug-induced liver injury (DILI) in the early phase of drug discovery, preventing post-marketing drug withdrawals. Here, we investigated the cultivation of TAMH as 3D spheroids, characterizing them with optical and transmission electron microscopy as well as analyzing their gene expression at mRNA level (especially drug-metabolizing enzymes) compared to TAMH monolayer. In addition, comparisons were made with spheroids grown from the human hepatoblastoma cell line HepG2, another current spheroid model. The results indicate that TAMH spheroids express hepatic structures and show elevated levels of some of the key phase I and II drug-metabolizing enzymes, in contrast to TAMH monolayer. The in vitro hepatotoxic potencies of the drugs acetaminophen and flupirtine maleate were found to be very similar between TAMH spheroidal and the monolayer cultures. Both the advantages and disadvantages of TAMH spheroids as an in vitro hepatotoxicity model compared to monolayer model are discussed.

PMID:37655636 | DOI:10.1002/jat.4538

Temporal changes in childhood cancer incidence and survival by stage at diagnosis in Australia, 2000-2017

Fetched: August 31st, 2023, 5:02am GMT by Danny R Youlden

Acta Oncol. 2023 Oct;62(10):1256-1264. doi: 10.1080/0284186X.2023.2251668. Epub 2023 Aug 30.

ABSTRACT

BACKGROUND: The Toronto Paediatric Cancer Stage Guidelines are a compendium of staging systems developed to facilitate collection of consistent and comparable data on stage at diagnosis for childhood cancers by cancer registries.

MATERIAL AND METHODS: This retrospective, observational cohort study investigated changes in stage-specific incidence and survival for children diagnosed between 2000-2008 compared to 2009-2017 using the population-based Australian Childhood Cancer Registry. Information on mortality for each patient was available to 31^st December 2020. Shifts in incidence by stage were evaluated using chi-square tests, and differences in stage-specific five-year observed survival for all causes of death over time were assessed using flexible parametric models.

RESULTS: Stage was assigned according to the Toronto Guidelines for 96% (n = 7944) of the total study cohort (n = 8292). Changes in the distribution of incidence by stage between the two diagnosis periods were observed for retinoblastoma, with stage 0 increasing from 26% to 37% of cases (p = 0.02), and hepatoblastoma, with metastatic disease increasing from 22% to 39% of cases (p = 0.04). There were large gains in stage-specific survival over time for stage IV rhabdomyosarcoma (five-year adjusted mortality hazard ratio for 2009-2017 compared to 2000-2008 of 0.38, 95% CI 0.19-0.77; p = 0.01), stage M3 for medulloblastoma (HR = 0.41, 95% CI 0.21-0.79; p = 0.01) and metastatic neuroblastoma excluding stage MS (HR = 0.61, 95% CI 0.44-0.84; p < 0.01).

CONCLUSION: These results indicate that improvements in childhood cancer survival in Australia are most likely due to refined management rather than changes in stage at diagnosis, particularly for metastatic solid tumours. Wide international uptake of the Toronto Guidelines will allow comprehensive evaluation of differences in survival between countries.

PMID:37647245 | DOI:10.1080/0284186X.2023.2251668

Permalink for 'Correction: Li et al. m6A mRNA Methylation Regulates LKB1 to Promote Autophagy of Hepatoblastoma Cells through Upregulated Phosphorylation of AMPK. Genes 2021, 12, 1747'

Correction: Li et al. m6A mRNA Methylation Regulates LKB1 to Promote Autophagy of Hepatoblastoma Cells through Upregulated Phosphorylation of AMPK. Genes 2021, 12, 1747

Fetched: August 27th, 2023, 5:02am GMT by Guohui Li

Genes (Basel). 2023 Aug 1;14(8):1575. doi: 10.3390/genes14081575.

ABSTRACT

In the original publication [...].

PMID:37628713 | PMC:PMC10395663 | DOI:10.3390/genes14081575

Advances in pediatric liver transplantation from the pediatric surgeon's perspective

Fetched: August 26th, 2023, 5:02am GMT by Hideaki Tanaka

Pediatr Surg Int. 2023 Aug 25;39(1):253. doi: 10.1007/s00383-023-05533-8.

ABSTRACT

Pediatric liver transplantation is a lifesaving state-of-the-art operation for children with various liver diseases, including cholestatic diseases, metabolic disorders, acute liver failure, and primary malignant liver tumors. Among these indications, transplantation for biliary atresia and hepatoblastoma is discussed in this review because pediatric surgeons are usually involved in their initial treatments. For biliary atresia, pediatric surgeons are advised to keep dissection of the hilar structures to a minimum during Kasai portoenterostomy in order to make total hepatectomy easier at transplantation. Early referral to a transplant team is recommended when worrisome signs of liver dysfunction, cirrhosis, portal hypertension and growth retardation are noted. Hepatoblastoma with multiplicity or located close to major vessels may indicate unresectability, and the transplant team needs to be consulted early after neoadjuvant chemotherapy is started. The graft size, including its thickness, needs to be evaluated before transplantation for small children, as tailoring the shape of the partial graft may be necessary during the transplant procedure.

PMID:37624479 | DOI:10.1007/s00383-023-05533-8

Mesenchymal Hamartoma With Elevated Alpha-Fetoprotein: A Diagnostic Pitfall

Fetched: August 22nd, 2023, 5:02am GMT by Amine Naggar

Glob Pediatr Health. 2023 Aug 18;10:2333794X231193560. doi: 10.1177/2333794X231193560. eCollection 2023.

ABSTRACT

Mesenchymal hamartoma (MH) is a benign liver tumor accounting for 3% to 8% of all liver tumors in children, commonly manifesting before 3 years of life. Distinguishing MH from hepatoblastoma and other liver tumors relies on imaging and alpha-fetoprotein (which is usually within normal range in MH), before histologic examination. We report a case of a hepatic MH associated with elevated alpha-fetoprotein, leading to a misdiagnosis of hepatoblastoma and the administration of chemotherapy. We draw the attention to the diagnostic difficulty and pitfalls related to alpha-fetoprotein elevation in the setting of a liver tumor, and we highlight the importance of imaging and histology in establishing the diagnosis.

PMID:37602142 | PMC:PMC10439734 | DOI:10.1177/2333794X231193560

Permalink for 'A Clinicopathological Study with Risk-Stratified Staging of Pediatric Hepatoblastoma: A 5-Year Experience from a Tertiary Cancer Center'

A Clinicopathological Study with Risk-Stratified Staging of Pediatric Hepatoblastoma: A 5-Year Experience from a Tertiary Cancer Center

Fetched: August 22nd, 2023, 5:02am GMT by Geeta V Patil Okaly

Iran J Pathol. 2023 Spring;18(2):165-172. doi: 10.30699/IJP.2023.1972340.3005. Epub 2023 Jun 20.

ABSTRACT

BACKGROUND & OBJECTIVE: Hepatoblastoma encompasses 1% of pediatric malignancies and is the most common liver malignancy in children. Ninety percent of cases are younger than 5 years of age. Clinical and pathological risk stratification forms a crucial role in determining the treatment strategy. This study aimed to assess the clinicopathological profile of hepatoblastoma with risk stratification and follow-up in children.

METHODS: A retrospective evaluation was performed on all pediatric patients diagnosed as hepatoblastoma between 2016 and 2020 in our institution. Clinical, radiological, biochemical, pathological, and treatment data were analyzed. Cases were stratified based on the SIOPEL protocol and compared with the outcome.

RESULTS: The median age of all children was 1 year, the male-to-female ratio was 2.3:1, and elevated α-fetoprotein (AFP) was observed in all cases. SIOPEL risk stratification showed that 50% of children were at high risk. The histopathological types were fetal (30%), embryonal (20%), and macrotrabecular (5%) patterns under epithelial type and mixed epithelial and mesenchymal type (45%) with 1 case showing teratoid features. During the follow-up period, 6 out of the 7 children who died, belonged to the high-risk SIOPEL category, and 5 presented a mixed epithelial and mesenchymal pattern.

CONCLUSION: Our study found a significant correlation between clinicopathological data, histopathological patterns, and outcomes. Accordingly, histopathological patterns could be considered one of the criteria for risk stratification. Histopathological risk stratification indicators (such as SIOPEL and PRETEXT) have strong prognostic and predictive outcomes; hence, our study emphasizes such parameters to aid oncologists.

PMID:37600579 | PMC:PMC10439754 | DOI:10.30699/IJP.2023.1972340.3005

A case series of appendicitis and pseudo-appendicitis in a paediatric intensive care unit

Fetched: August 19th, 2023, 5:01am GMT by Kam Lun Hon

Curr Pediatr Rev. 2023 Aug 11. doi: 10.2174/1573396320666230811092837. Online ahead of print.

ABSTRACT

INTRODUCTION: Appendicitis is a common childhood condition that can be diagnostically challenging. Severe cases may necessitate support in the critical or intensive care unit. These "critical appendicitis diagnoses" have rarely been described.

CASE DESCRIPTION: We retrospective reviewed the PICU database of the Hong Kong Children's Hospital and identified cases of suspected and confirmed appendicitis. Clinical features, radiologic findings and final diagnosis of each case were summarized and reported in this case series. We review six anonymized cases of appendicitis managed in a paediatric intensive care unit (PICU) to illustrate the different age spectrum and clinical manifestations of the condition. Rupture of the inflamed appendix, peritonitis and pancreatitis were some of the complications encountered. Crohn disease was found in one case as an underlying diagnosis. Also, one girl clinically diagnosed with appendicitis was found to be a case of ruptured hepatoblastoma with no appendicitis (i.e., pseudoappendicitis).

CONCLUSION: Prompt diagnosis, surgical removal of the inflamed appendix, and use of appropriate antimicrobials when indicated are essential in reducing mortality and morbidity associated with severe appendicitis. Significant premorbid conditions such as acute myeloid leukemia, mitochondrial encephalopathy lactic acidosis syndrome (MELAS), inflammatory bowel disease and complications may be present in patients needing intensive care as is illustrated in the present cases. Pseudoappendicitis is an important differential diagnosis. Imaging is crucial and useful in establishing and confirming the diagnosis of appendicitis and pseudo-appendicitis in these PICU cases.

PMID:37592922 | DOI:10.2174/1573396320666230811092837

Hepatoblastoma

Fetched: August 19th, 2023, 5:01am GMT by Sierra R. Musick

2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–.

ABSTRACT

Hepatoblastomas are the most common primary malignant liver tumor in pediatric patients, occurring mostly within the first 2 years of life. The histologic types are subdivided into 2 broad categories: epithelial type and mixed type. Over the last 3 decades, the treatment has advanced with neo-adjuvant chemotherapy now the standard of care for most cases. Neo-adjuvant chemotherapy and surgical resection produce a cure rate of approximately 70%, a vast improvement over the dismal 30% cure rate in the 1970s. Prognosis is based on many factors including alpha-fetoprotein levels, age at the time of diagnosis, completeness of resection, and clinical stage of the disease.

PMID:30521216 | Bookshelf:NBK534795

A spectrum of findings on computed tomography in paediatric abdominal and pelvic tumours in a Ghanaian teaching hospital

Fetched: August 15th, 2023, 5:01am GMT by Hafisatu Gbadamosi

Ghana Med J. 2022 Dec;56(4):295-302. doi: 10.4314/gmj.v56i4.8.

ABSTRACT

OBJECTIVES: To review the Computed Tomography( CT )features of pediatric oncological patients with abdominal and pelvic tumours and correlate these findings with their histopathological diagnosis.

DESIGN: This was a retrospective cross-sectional facility-based study.

SETTING: This study was conducted in the Pediatric Oncology Unit and Radiology Department of the Korle Bu Teaching Hospital.

PARTICIPANTS: Fifty-six pediatric oncology patients with contrast-enhanced abdominal and pelvic CT scans.

DATA COLLECTION: The abdominal and pelvic CT scans findings, patient biodata, and histopathology reports of oncology patients over four years were reviewed.

STATISTICAL ANALYSIS: Simple descriptive statistics using frequency distribution, percentages, means, and standard deviation were used to describe the various variables and presented tables.

RESULTS: The four commonest tumours were nephroblastoma, neuroblastoma, lymphoma, and hepatoblastoma. The mean age at diagnosis was 4.8 years, with a slightly higher male predominance. The majority of the tumours were extremely large at presentation. Overall, the CT - histopathology concordance was 79.2%.

CONCLUSION: Abdominal and pelvic CT scans play an important role in the diagnostic workup of pediatric malignancies by ensuring early and accurate diagnosis of these tumours.

FUNDING: None declared.

PMID:37575625 | PMC:PMC10416291 | DOI:10.4314/gmj.v56i4.8

$Permalink for 'Retreatment with Cisplatin May Provide a Survival Advantage for Children with Relapsed/Refractory Hepatoblastoma: An Institutional Experience'$

Retreatment with Cisplatin May Provide a Survival Advantage for Children with Relapsed/Refractory Hepatoblastoma: An Institutional Experience

Fetched: August 13th, 2023, 5:01am GMT by Katherine M Somers

Cancers (Basel). 2023 Aug 1;15(15):3921. doi: 10.3390/cancers15153921.

ABSTRACT

BACKGROUND: Hepatoblastoma (HB) is the most common liver malignancy in children. There is no standard of care for management of relapsed/refractory HB (rrHB) and reports in the literature are limited.

OBJECTIVE: To describe presenting features, biology, treatment strategies, and outcomes for pediatric patients with relapsed/refractory hepatoblastoma.

METHODS: An IRB-approved retrospective institutional review of patients with rrHB who presented for consultation and/or care from 2000-2019. Clinical, radiographic, and histologic data were collected from all patients.

RESULTS: Thirty subjects were identified with a median age of 19.5 months (range 3-169 months) at initial diagnosis and 32.5 months (range 12-194 months) at time of first relapse. 63% of subjects were male, 70% Caucasian, and 13% were born premature. Three subjects had a known cancer predisposition syndrome. Eight patients had refractory disease while 22 patients had relapsed disease. Average time from initial diagnosis to relapse or progression was 12.5 months. Average alpha-fetoprotein (AFP) at initial diagnosis was 601,203 ng/mL (range 121-2,287,251 ng/mL). Average AFP at relapse was 12,261 ng/mL (range 2.8-201,000 ng/mL). For patients with tumor sequencing (n = 17), the most common mutations were in CTNNB1 (13) and NRF2 (4). First relapse sites were lungs (n = 12), liver (n = 11) and both (n = 6). More than one relapse/progression occurred in 47% of subjects; 6 had ≥3 relapses. Pathology in patients with multiply relapsed disease was less differentiated including descriptions of small cell undifferentiated (n = 3), pleomorphic (n = 1), transitional liver cell tumor (n = 2) and HB with carcinoma features (n = 1). All subjects underwent surgical resection of site of relapsed disease with 7 subjects requiring liver transplantation. Overall survival was 50%. Survival was associated with use of cisplatin at relapse (78.6% with vs. 25% without, p = 0.012). The most common late effect was ototoxicity with at least mild sensorineural hearing loss found in 80% of subjects; 54% required hearing aids.

CONCLUSIONS: Retreatment with cisplatin at the time of relapse may provide an advantage for some patients with hepatoblastoma. Multiply relapsed disease was not uncommon and not associated with a worse prognosis. Careful attention should be paid to cumulative therapy-induced toxicity while concurrently aiming to improve cure.

PMID:37568737 | PMC:PMC10416880 | DOI:10.3390/cancers15153921

Permalink for 'Exploring thyroxine binding globulin structural changes and its release from human hepatoblastoma cells upon interaction with silica particles: A prelude to unrevealing the mechanism of thyroid hormone dysregulation'

Exploring thyroxine binding globulin structural changes and its release from human hepatoblastoma cells upon interaction with silica particles: A prelude to unrevealing the mechanism of thyroid hormone dysregulation

Fetched: August 13th, 2023, 5:01am GMT by Meiqi Wang

Int J Biol Macromol. 2023 Aug 9;251:126240. doi: 10.1016/j.ijbiomac.2023.126240. Online ahead of print.

ABSTRACT

Endocrine dysregulation in the presence of environmental chemical risk factors is a global adverse health concern. The aim of this investigation was to explore the structural changes and binding affinity of thyroxine (T4) binding protein (TBG) upon interaction with SiO2 particles as the second largest mineral in the Earth's crust and one of the most important constituents of rock, soil, and dust. Therefore, the interaction of TBG with SiO2 particles was assessed by fluorescence quenching, molecular docking, ANS and synchronous fluorescence, and far-UV CD analyses. Also, the release of TBG from human hepatoblastoma cell line, Hep G2, was assessed by ELISA assay. The results displayed that the value of stoichiometry of binding site (n) of TBG for T4 was approximately equal to one, which was reduced to 0.36 in the presence of SiO2 particles. Also, the binding affinity (Kb) values revealed that the binding affinity between T4 and TBG was strong (97.90 × 10⁵ L/mol), while the presence of SiO2 particles resulted in the calculation of a Kb around 0.00159 × 10⁵ L/mol, which was significantly lower than that of the absence of SiO2 particles. This data was also verified by molecular docking analyses which indicated that SiO2 particles interacted with the T4 binding pocket of TBG. Moreover, further studies exhibited that although the equimolar concentration of T4 to TBG resulted in the superior stability of TBG-T4 complex relative to free TBG, the presence of SiO2 particles with the same concentration led to denaturation of the secondary structure of TBG. Furthermore, it was seen that the amount of released TBG in the cell culture medium of Hep G2 was about 2.21 ng/mL protein, whereas this amount in SiO2 particles-treated cell group was significantly reduced to 1.71 ng/mL protein (*P < 0.05). In conclusion, this study implies that SiO2 particles show the potential to result in inhibition of TBG release, TBG denaturation, and interfere with TBG binding affinity which may lead to dysregulation of the thyroid hormone transport and associated signaling pathways.

PMID:37567530 | DOI:10.1016/j.ijbiomac.2023.126240

Anthropometric Outcomes in Survivors of Pediatric Solid Tumors

Fetched: August 8th, 2023, 5:02am GMT by Mehak Sehgal

Nutr Cancer. 2023;75(9):1795-1802. doi: 10.1080/01635581.2023.2242104. Epub 2023 Aug 6.

ABSTRACT

Nutritional status is an important aspect of childhood cancer, with a bearing on the disease and subsequent survivorship. We sought to evaluate the long-term anthropometric outcomes in a cohort of pediatric solid tumor survivors treated between 1994 and 2016. Anthropometry was noted at the time of presentation, after completion of therapy, and at the last follow-up. The z-scores for weight-for-age, height-for-age, and BMI-for-age were calculated using WHO growth charts for ages <5 years and the Indian Academy of Pediatrics growth charts for age >/= 5 years. BMI was calculated for adult survivors. We included 317 survivors, comprising 48, 81, and 188 survivors of Hepatoblastoma (HB), Malignant Germ cell Tumor (MGCT), and Wilms Tumor (WT) respectively. The median age at diagnosis was 24.5 (IQR 59-13.2) months, with a follow-up ranging from 5 to 19.54 years. The z-scores of the collective cohort and individual cohorts of HB, MGCT, and WT showed an improving trend from diagnosis to the last follow-up. The difference in the prevalence of malnutrition was found to be statistically significant when any two-time points were compared. Of the 28 adult survivors, 43% were noted to be underweight. Thus, anthropometric measures improve during follow-up, however, up to 15% of children persist in being malnourished.

PMID:37545131 | DOI:10.1080/01635581.2023.2242104

TRMT61B rs4563180 G>C variant reduces hepatoblastoma risk: a case-control study of seven medical centers

Fetched: August 3rd, 2023, 5:02am GMT by Dingyuan Zeng

Aging (Albany NY). 2023 Aug 1;15(15):7583-7592. doi: 10.18632/aging.204926. Epub 2023 Aug 1.

ABSTRACT

N¹-methyladenosine (m¹A) is an essential chemical modification of RNA. Dysregulation of RNA m¹A modification and m¹A-related regulators is detected in several adult tumors. Whether aberrant RNA m¹A modification is involved in hepatoblast carcinogenesis has not been reported. tRNA methyltransferase 61B (TRMT61B) is responsible for mitochondrial RNA m¹A modification. Some evidence has shown that genetic variants of TRMT61B might contribute to cancer susceptibility; however, its roles in hepatoblastoma are unknown. This study attempted to discover novel hepatoblastoma susceptibility loci. With the TaqMan method, we examined genotypes of the TRMT61B rs4563180 G>C polymorphism among germline DNA samples from 313 cases and 1446 controls. The association of the rs4563180 G>C polymorphism with hepatoblastoma risk was estimated based on odds ratios (ORs) and 95% confidence intervals (CIs). We found that the TRMT61B rs4563180 G>C polymorphism correlated significantly with a reduction in hepatoblastoma risk (GC vs. GG: adjusted OR=0.65, 95% CI=0.49-0.85, P=0.002; GC/CC vs. GG: adjusted OR=0.66, 95% CI=0.51-0.85, P=0.002). In stratified analysis, significant associations were detected in children younger than 17 months old, girls, and subgroups with stage I+II or III+IV tumors. False-positive report probability analysis validated that children with the GC or CC genotype, particularly in those <17 months of age, had a decreased risk of hepatoblastoma. The rs4563180 G>C polymorphism also correlated with expression of TRMT61B and the nearby gene PPP1CB. We identified a high-quality biomarker measuring hepatoblastoma susceptibility, which may contribute to future screening programs.

PMID:37531210 | PMC:PMC10457066 | DOI:10.18632/aging.204926

Permalink for 'Retraction statement: Ding, J., Wang, X., Gao, J. and Song, T. (2021), Silencing of cystatin SN abrogates cancer progression and stem cell properties in papillary thyroid carcinoma. FEBS Open Bio, 11: 2186-2197'

Retraction statement: Ding, J., Wang, X., Gao, J. and Song, T. (2021), Silencing of cystatin SN abrogates cancer progression and stem cell properties in papillary thyroid carcinoma. FEBS Open Bio, 11: 2186-2197

Fetched: August 2nd, 2023, 5:02am GMT

FEBS Open Bio. 2023 Aug;13(8):1540. doi: 10.1002/2211-5463.13664. Epub 2023 Jul 6.

ABSTRACT

[https:] The above article, published online on 08 June 2021 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the Editor-in-Chief Miguel De la Rosa, FEBS Press, and John Wiley and Sons Ltd. The retraction has been agreed following an investigation into concerns raised by a third party, which revealed inappropriate duplications between this and articles that were either previously published or published later in the same year [1-9]. Thus, the editors consider the conclusions of this manuscript substantially compromised. [1] Zheng, X., Huang, M., Xing, L. et al. The circRNA circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer. Mol Cancer 19, 73 (2020). [https:] [2] Li X, Wang H, Liu Z, Abudureyimu A. CircSETD3 (Hsa_circ_0000567) Suppresses Hepatoblastoma Pathogenesis via Targeting the miR-423-3p/Bcl-2-Interacting Mediator of Cell Death Axis. Front Genet. 2021 Sep 29;12:724197. doi: 10.3389/fgene.2021.724197. PMID: 34659347; PMCID: PMC8511783. [3] Du J, Zhong H, Ma B. Targeting a novel LncRNA SNHG15/miR-451/c-Myc signaling cascade is effective to hamper the pathogenesis of breast cancer (BC) in vitro and in vivo. Cancer Cell Int. 2021 Mar 31;21(1):186. doi: 10.1186/s12935-021-01885-0. PMID: 33952250; PMCID: PMC8097789. [4] Hong W, Xue M, Jiang J, Zhang Y, Gao X. Circular RNA circ-CPA4/ let-7 miRNA/PD-L1 axis regulates cell growth, stemness, drug resistance and immune evasion in non-small cell lung cancer (NSCLC). J Exp Clin Cancer Res. 2020 Aug 3;39(1):149. doi: 10.1186/s13046-020-01648-1. PMID: 32746878; PMCID: PMC7397626. [5] Ren N, Jiang T, Wang C, Xie S, Xing Y, Piao D, Zhang T, Zhu Y. LncRNA ADAMTS9-AS2 inhibits gastric cancer (GC) development and sensitizes chemoresistant GC cells to cisplatin by regulating miR-223-3p/NLRP3 axis. Aging (Albany NY). 2020 Jun 9;12(11):11025-11,041. doi: 10.18632/aging.103314. Epub 2020 Jun 9. PMID: 32516127; PMCID: PMC7346038. [6] Zheng Y, Liu L, Wang Y, Xiao S, Mai R, Zhu Z, Cao Y. Glioblastoma stem cell (GSC)-derived PD-L1-containing exosomes activates AMPK/ULK1 pathway mediated autophagy to increase temozolomide-resistance in glioblastoma. Cell Biosci. 2021 Mar 31;11(1):63. doi: 10.1186/s13578-021-00575-8. PMID: 33789726; PMCID: PMC8011168. [7] Lin H, Wang J, Wang T, Wu J, Wang P, Huo X, Zhang J, Pan H, Fan Y. The LncRNA MIR503HG/miR-224-5p/TUSC3 Signaling Cascade Suppresses Gastric Cancer Development via Modulating ATF6 Branch of Unfolded Protein Response. Front Oncol. 2021 Jul 26;11:708501. doi: 10.3389/fonc.2021.708501. PMID: 34381729; PMCID: PMC8352579. [8] Lu G, Li Y, Ma Y, Lu J, Chen Y, Jiang Q, Qin Q, Zhao L, Huang Q, Luo Z, Huang S, Wei Z. Long noncoding RNA LINC00511 contributes to breast cancer tumourigenesis and stemness by inducing the miR-185-3p/E2F1/Nanog axis. J Exp Clin Cancer Res. 2018 Nov 27;37(1):289. doi: 10.1186/s13046-018-0945-6. PMID: 30482236; PMCID: PMC6260744. [9] Zhao Y, Zheng R, Chen J, Ning D. CircRNA CDR1as/miR-641/HOXA9 pathway regulated stemness contributes to cisplatin resistance in non-small cell lung cancer (NSCLC). Cancer Cell Int. 2020 Jul 6;20:289. doi: 10.1186/s12935-020-01390-w. PMID: 32655321; PMCID: PMC7339514.

PMID:37410095 | PMC:PMC10392042 | DOI:10.1002/2211-5463.13664

Congenital hepatoblastoma presenting with hepatic arteriovenous fistulas: a case report

Fetched: August 1st, 2023, 5:02am GMT by Jiao Lin

Front Pediatr. 2023 Jul 13;11:1199224. doi: 10.3389/fped.2023.1199224. eCollection 2023.

ABSTRACT

AIM: Congenital hepatoblastoma, a rare malignant liver tumor in infancy, typically presents with abdominal distension or mass. Tumors detected antenatally or during the first three months of age are considered congenital hepatoblastoma. Hepatic arteriovenous fistulas (HAVF) are associated with high mortality in the neonatal period and can be caused by many secondary factors. This case report focuses on a patient with congenital hepatoblastoma accompanied by HAVF, highlighting the clinical and imaging characteristics and management strategies.

CASE PRESENTATION: A term infant presented with sudden tachypnea and heart failure on his first day of life. A cystic-solid mixed lesion in the fetus's liver was detected by an antenatal ultrasound scan. Postnatal digital subtraction angiography confirmed the presence of arteriovenous fistulas, which were treated with trans-arterial embolization. However, despite the intervention, the patient's heart failure did not improve. The patient underwent a left hepatectomy, and hepatoblastoma was discovered by histology of the resected hepatic lobe. Unfortunately, metastases were later discovered in the intracranial and ocular regions. Ultimately, the family decided to discontinue further treatment.

CONCLUSION: Congenital hepatoblastoma presenting with hepatic arteriovenous fistulas has not been previously described. Hepatoblastoma should be considered when alpha-fetoprotein levels show a significant elevation in newborns. Prenatal diagnosis may improve pre- and postnatal management.

PMID:37520052 | PMC:PMC10373925 | DOI:10.3389/fped.2023.1199224

Desmoplastic small round cell tumor of the liver: diagnosing a rare case on liver biopsy

Fetched: July 30th, 2023, 5:01am GMT by Xiao Feng

Diagn Pathol. 2023 Jul 29;18(1):84. doi: 10.1186/s13000-023-01373-1.

ABSTRACT

Desmoplastic small round-cell tumors (DSRCT) frequently develop in the retroperitoneum, pelvis, omentum, and mesentery. Here, we present an unusual case of primary DSRCT in the liver. The patient was an 11-year-old boy with multiple solid masses in the liver parenchyma. The tumor in the needle biopsy had a histology revealing a small round cell morphology and desmoplasia. It shows the immunohistochemical features of DSRCT and documentation of EWSR1-WT1 fusion.A potential diagnostic pitfall is exerted when evaluating liver biopsy, in which DSRCT is a great mimicker and may be easily confused with more common liver malignancies of childhood, such as hepatoblastoma, calcifying nested stromal-epithelial tumor, undifferentiated embryonal sarcoma, and other small round cell tumors, as well as the fibrolamellar variant of hepatocellular carcinoma. This distinction is critical because an accurate therapeutic approach requires a correct diagnosis.

PMID:37516860 | PMC:PMC10386280 | DOI:10.1186/s13000-023-01373-1

Permalink for 'Suppression of NASH-Related HCC by Farnesyltransferase Inhibitor through Inhibition of Inflammation and Hypoxia-Inducible Factor-1α Expression'

Suppression of NASH-Related HCC by Farnesyltransferase Inhibitor through Inhibition of Inflammation and Hypoxia-Inducible Factor-1α Expression

Fetched: July 30th, 2023, 5:01am GMT by Kohei Yamada

Int J Mol Sci. 2023 Jul 17;24(14):11546. doi: 10.3390/ijms241411546.

ABSTRACT

Inflammatory processes play major roles in carcinogenesis and the progression of hepatocellular carcinoma (HCC) derived from non-alcoholic steatohepatitis (NASH). But, there are no therapies for NASH-related HCC, especially focusing on these critical steps. Previous studies have reported that farnesyltransferase inhibitors (FTIs) have anti-inflammatory and anti-tumor effects. However, the influence of FTIs on NASH-related HCC has not been elucidated. In hepatoblastoma and HCC cell lines, HepG2, Hep3B, and Huh-7, we confirmed the expression of hypoxia-inducible factor (HIF)-1α, an accelerator of tumor aggressiveness and the inflammatory response. We established NASH-related HCC models under inflammation and free fatty acid burden and confirmed that HIF-1α expression was increased under both conditions. Tipifarnib, which is an FTI, strongly suppressed increased HIF-1α, inhibited cell proliferation, and induced apoptosis. Simultaneously, intracellular interleukin-6 as an inflammation marker was increased under both conditions and significantly suppressed by tipifarnib. Additionally, tipifarnib suppressed the expression of phosphorylated nuclear factor-κB and transforming growth factor-β. Finally, in a NASH-related HCC mouse model burdened with diethylnitrosamine and a high-fat diet, tipifarnib significantly reduced tumor nodule formation in association with decreased serum interleukin-6. In conclusion, tipifarnib has anti-tumor and anti-inflammatory effects in a NASH-related HCC model and may be a promising new agent to treat this disease.

PMID:37511305 | PMC:PMC10380354 | DOI:10.3390/ijms241411546

Children's Oncology Group's 2023 blueprint for research: Pediatric liver tumors

Fetched: July 27th, 2023, 5:02am GMT by Allison F O'Neill

Pediatr Blood Cancer. 2023 Sep;70 Suppl 6(Suppl 6):e30576. doi: 10.1002/pbc.30576. Epub 2023 Jul 26.

ABSTRACT

Liver tumors account for approximately 1%-2% of all pediatric malignancies, with the two most common tumors being hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Previous Children's Oncology Group studies have meaningfully contributed to the current understanding of disease pathophysiology and treatment, laying groundwork for the ongoing prospective international study of both HB and HCC. Future work is focused on elucidating the biologic underpinnings of disease to support an evolution in risk categorization, advancements in the multidimensional care required to treat these patients, and the discovery of novel therapies.

PMID:37495540 | PMC:PMC10529117 | DOI:10.1002/pbc.30576

Permalink for 'Serabelisib regulates GSDMD-mediated pyroptosis, apoptosis and migration of hepatoma cells via the PI3K/Akt/E-cadherin signaling pathway'

Serabelisib regulates GSDMD-mediated pyroptosis, apoptosis and migration of hepatoma cells via the PI3K/Akt/E-cadherin signaling pathway

Fetched: July 25th, 2023, 5:02am GMT by Ming Li

Adv Clin Exp Med. 2023 Jul 24. doi: 10.17219/acem/166511. Online ahead of print.

ABSTRACT

BACKGROUND: Liver cancer is a malignant tumor commonly seen in infants and young children. Serabelisib is a novel and effective phosphoinositide-3-kinase (PI3Kα) inhibitor, currently in trials for solid malignancy treatment, such as bladder cancer. However, it is unclear whether serabelisib affects liver cancer.

OBJECTIVES: To explore the effects of serabelisib on the proliferation, apoptosis, invasion, and metastasis of HepG2 and HuH-6 cells, and elucidate the relevant molecular mechanisms.

MATERIAL AND METHODS: The HepG2 cells were treated with 2 μM, 4 μM or 8 μM serabelisib, while the 0-μM group was used as a control. A plate clone formation assay was utilized to measure colony formation ability in each group, a 5-ethynyl-2'-deoxyuridine (EdU) assay examined cell proliferation, a Cell Counting Kit-8 (CCK-8) assay assessed cell viability, flow cytometry measured the cell cycle and apoptosis, JC-1 staining determined mitochondrial membrane potential, and transmission electron microscopy evaluated cell morphology. In addition, gene and protein expression levels of apoptosis markers, epithelial-mesenchymal transition (EMT), Gasdermin D (GSDMD), and the PI3K/protein kinase B (AKT) signaling pathway were measured.

RESULTS: After serabelisib intervention, HepG2 and HuH-6 cells formed fewer colonies, proliferated more slowly, and had reduced viability. The number of HepG2 and HuH-6 cells in the G2 and S phases decreased, apoptosis and the number of apoptotic bodies increased, and mitochondrial membrane potential decreased. Serabelisib treatment also reduced the migration and invasion capacity of the cells. Furthermore, genes and proteins of the PI3K/AKT signaling pathway were downregulated, while those that promote apoptosis and pyroptosis or inhibit EMT were upregulated.

CONCLUSIONS: Serabelisib inhibited the PI3K/AKT signaling pathway, thereby inhibiting EMT and promoting apoptosis and pyroptosis in HepG2 and HuH-6 cells.

PMID:37486695 | DOI:10.17219/acem/166511

Permalink for 'Case report: Minimal tissue damage and low coagulation liver resection for hepatoblastoma using indocyanine green fluorescence and water-jet dissector'

Case report: Minimal tissue damage and low coagulation liver resection for hepatoblastoma using indocyanine green fluorescence and water-jet dissector

Fetched: July 25th, 2023, 5:02am GMT by Shun Onishi

Front Pediatr. 2023 Jul 6;11:1221596. doi: 10.3389/fped.2023.1221596. eCollection 2023.

ABSTRACT

Near-infrared (NIR) fluorescence imaging with indocyanine green (ICG) has gained popularity in pediatric surgery as it has in general surgery. In addition, a water-jet dissector (WJD) has been successfully introduced in adult hepatic surgery. Tissue structures are dissected selectively and gently by the WJD. However, there have been no reports of hepatic resection for pediatric patients using a WJD. We applied NIR fluorescence imaging with ICG to visualize the resection line of the liver and used a WJD for liver parenchyma dissection in pediatric hepatoblastoma. The patient was a 3-year-old girl with a large liver tumor. Enhanced computed tomography revealed a liver tumor (maximum diameter: 120 mm) in the right lobe and three small lung metastases. The liver tumor was diagnosed as hepatoblastoma (PRETEXT 2) based on an open biopsy. We performed right hepatectomy after neoadjuvant chemotherapy. The right lobe was mobilized from the diaphragm, and then intraoperative ultrasound was performed to detect the localization of the tumor and its proximity to the vascular structures. We detected the right hepatic artery (RHA), right portal vein (RPV), and right hepatic vein (RHV). The middle hepatic vein was not involved. After ligation of the RHA and RPV to selectively control the right lobe inflow, ICG was administered intravenously and observed by an NIR endoscope. The resection line was clearly visualized by overlaying images in comparison to conventional demarcation line detection. Then, we used a WJD to dissect the parenchyma. Small vessels were divided from parenchymal tissue and were clearly visible. We resected them after clamping with metal clips. Finally, the RHV was transected by a linear stapler, and right hepatectomy was completed with 25 ml of blood loss. There was no postoperative hemorrhage. We performed hepaticojejunostomy because of stricture of the common bile duct on postoperative day 302. The patient was discharged after adjuvant chemotherapy. NIR imaging clearly showed the resection line. The WJD automatically separated, and thus made visible, the more resistant duct and vessel structures from the parenchyma. The combined use of NIR imaging and WJD was useful for pediatric hepatectomy.

PMID:37484776 | PMC:PMC10358326 | DOI:10.3389/fped.2023.1221596

Editorial: Recent advances in organ-sparing techniques in pediatric solid tumor surgery

Fetched: July 25th, 2023, 5:02am GMT by Chan Hon Chui

Front Pediatr. 2023 Jul 7;11:1247287. doi: 10.3389/fped.2023.1247287. eCollection 2023.

NO ABSTRACT

PMID:37484766 | PMC:PMC10361559 | DOI:10.3389/fped.2023.1247287

Alternative splicing of lncRNAs from SNHG family alters snoRNA expression and induces chemoresistance in hepatoblastoma

Fetched: July 23rd, 2023, 5:01am GMT by Ni Zhen

Cell Mol Gastroenterol Hepatol. 2023;16(5):735-755. doi: 10.1016/j.jcmgh.2023.07.007. Epub 2023 Jul 19.

ABSTRACT

BACKGROUND & AIMS: Hepatoblastoma (HB) is a common pediatric malignant liver tumor that is characterized by a low level of genetic mutations. Alternative splicing (AS) has been shown to be closely associated with cancer progression, especially in tumors with a low mutational burden. However, the role of AS in HB remains unknown.

METHODS: Transcriptome sequencing was performed on 5 pairs of HB tissues and matched non-tumor tissues to delineate the AS landscape in HB. AS events were validated in 92 samples from 46 patients. RNA pull-down and RNA immunoprecipitation assays were carried out to identify splicing factors that regulate the AS of small nucleolar RNA host genes (SNHG). Patient-derived organoids (PDOs) were established to investigate the role of the splicing factor polyadenylate-binding nuclear protein 1 (PABPN1).

RESULTS: This study uncovered aberrant alternative splicing in HB, including lncRNAs from SNHG family that undergo intron retention in HB. Further investigations revealed that PABPN1, a significantly upregulated RNA binding protein, interacts with splicing machinery in HB, inducing the intron retention of these SNHG RNAs and the downregulation of intronic small nucleolar RNAs (snoRNAs). Functionally, PABPN1 acts as an oncofetal splicing regulator in HB by promoting cell proliferation and DNA damage repair via inducing the intron retention of SNHG19. Knock-down of PABPN1 increases the cisplatin sensitivity of HB PDOs.

CONCLUSIONS: Our findings revealed the role of intron retention in regulating snoRNA expression in hepatoblastoma, explained detailed regulatory mechanism between PABPN1 and the intron retention of SNHG RNAs, and provided insight into the development of new HB treatment options.

PMID:37478905 | PMC:PMC10520360 | DOI:10.1016/j.jcmgh.2023.07.007

A 6-year-old boy with an atypical liver neoplasm harboring a novel RPS6KA3 variant

Fetched: July 22nd, 2023, 5:01am GMT by Daniel Bustamante

Lab Med. 2023 Jul 21:lmad061. doi: 10.1093/labmed/lmad061. Online ahead of print.

ABSTRACT

Pediatric hepatoblastoma (HBL) and hepatocellular carcinoma (HCC) are primary liver malignant neoplasms with 5-year event-free survival of >80% and <30%, respectively. In these patients, α-fetoprotein levels can guide surgical intervention and monitor disease progression. Although histology and immunohistochemical stains support diagnosis, genetic testing can elucidate mechanisms that drive pathogenesis. Pediatric HBL and HCC harbor well-characterized molecular signatures such as alterations in CTNNB1, TERT, and AXIN1 that alter the Wnt/β-catenin pathway. Approximately 8% of individuals with HCC harbor RPS6KA3 variants that appear with other gene mutations. Herein, we report a novel solitary pathogenic RPS6KA3 variant finding in a 6-year-old boy whose final diagnosis was hepatocellular malignant neoplasm, not otherwise specified.

PMID:37477894 | DOI:10.1093/labmed/lmad061

MRI-based deep learning model for differentiation of hepatic hemangioma and hepatoblastoma in early infancy

Fetched: July 19th, 2023, 5:01am GMT by Yuhan Yang

Eur J Pediatr. 2023 Oct;182(10):4365-4368. doi: 10.1007/s00431-023-05113-x. Epub 2023 Jul 18.

ABSTRACT

Hepatic hemangioma (HH) and hepatoblastoma (HBL) are common pediatric liver tumors and present with similar clinical manifestations with limited distinguishing value of serum AFP in early infancy. An accurate differentiation diagnostic tool is warranted for optimizing treatments and improving prognosis. The present study aimed to develop an innovative and cost-effective diagnostic tool to differentiate HH and HBL in early infancy using advanced deep learning (DL) techniques. One hundred forty patients ≤4 months old diagnosed as HH or HBL with histological specimens were recruited from two institutions assigned into a training set with cross-validation and a testing set for external validation, respectively. Based on MRI images, imaging diagnoses were interpreted by two radiologists, and imaging-derived radiomic features were extracted by pretrained convolutional neural networks (CNNs)-Xception extractor via DL analysis. A nomogram model was constructed integrating predictive clinical variables, radiologist-based interpretation, and DL features, evaluated comprehensively on diagnostic and calibration accuracy. The DL-based model performed an area under the receiver operating characteristic curve (AUC) of 0.966 for the training cohort and 0.864 for the testing cohort. The radiologist-interpreted differentiation model showed an AUC of 0.837 in the testing cohort. The integrated nomogram model represented an increasing performance with an AUC of 0.887, accuracy of 78.57%, sensitivity of 76.19%, and specificity of 80.95% in the testing cohort.

CONCLUSION: The MRI-based integrated model, a noninvasive preoperative diagnostic tool, yielded favorable efficacy for differentiating HH and HBL in early infancy, which might reduce the patients' costs of repetitive and unnecessary examinations or over-treatment.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05170282.

WHAT IS KNOWN: • Hepatic hemangioma (HH) and hepatoblastoma (HBL) are common pediatric liver tumors and present with similar clinical manifestations with limited distinguishing value of serum AFP in early infancy. • Considering the rare incidence of infantile hepatic tumors, the distinguishing accuracy between HBL and HH for cases in early infancy is unsatisfactory for radiologists' recognition solely.

WHAT IS NEW: • The MRI-based integrated model, a noninvasive preoperative diagnostic tool yielded favorable efficacy for differentiating HH and HBL in early infancy, which might reduce the patients' costs of repetitive and unnecessary examinations or over-treatment.

PMID:37462798 | DOI:10.1007/s00431-023-05113-x

An indocyanine green-based liquid biopsy test for circulating tumor cells for pediatric liver cancer

Fetched: July 19th, 2023, 5:01am GMT by Andres F Espinoza

bioRxiv. 2023 Jul 5:2023.07.03.547557. doi: 10.1101/2023.07.03.547557. Preprint.

ABSTRACT

BACKGROUND AND AIMS: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the most common malignant hepatocellular tumors seen in children. The aim of this work was to develop a liquid biopsy test for circulating tumor cells (CTCs) for these tumors that would be less invasive and provide information about the real-time state of tumors in response to therapies.

METHODS: For this test, we utilized indocyanine green (ICG), a far-red fluorescent dye that is used clinically to identify malignant liver cells in the body during surgery. We assessed ICG accumulation in cell lines with fluorescence microscopy and flow cytometry. For our CTC test, we developed a panel of liver tumor-specific markers, ICG, Glypican-3 (GPC3), and DAPI and tested this panel with cell lines and non-cancer control blood samples. We then used this panel to analyze whole blood samples for CTC burden with a cohort of 14 HB and HCC patients and correlated with patient characteristics and outcomes.

RESULTS: We showed that ICG accumulation is specific to liver cancer cells, compared to non-malignant liver cells, non-liver solid tumor cells, and non-malignant cells and can be used to identify liver tumor cells in a mixed population of cells. Experiments with the ICG/GPC3/DAPI panel showed that it specifically tagged malignant liver cells. With patient samples, we found that CTC burden from sequential blood samples from the same patients mirrored the patients' responses to therapy.

CONCLUSIONS: Our novel ICG-based liquid biopsy test for CTCs can be used to specifically count CTCs in the blood of pediatric liver cancer patients.

IMPACT AND IMPLICATIONS: This manuscript represents the first report of circulating tumor cells in the blood of pediatric liver cancer patients. The novel and innovative assay for CTCs shown in this paper will facilitate future work examining the relationship between CTC numbers and patient outcomes, forming the foundation for incorporation of liquid biopsy into routine clinical care for these patients.

GRAPHICAL ABSTRACT: Overview of novel liquid biopsy test for circulating tumor cells for pediatric liver cancer. Figure made with Biorender.

PMID:37461615 | PMC:PMC10349946 | DOI:10.1101/2023.07.03.547557

A TGF-β-dominant chemo-resistant phenotype of hepatoblastoma associated with aflatoxin exposure in children

Fetched: July 18th, 2023, 5:02am GMT by Xiao Xiang

Hepatology. 2023 Jul 17. doi: 10.1097/HEP.0000000000000534. Online ahead of print.

ABSTRACT

BACKGROUND AIMS: Hepatoblastoma (HB) is the most common liver cancer in children, posing a serious threat to children's health. Chemoresistance is the leading cause of mortality in HB patients. A more explicit definition of the features of chemotherapy resistance in HB represents a fundamental urgent need.

APPROACH RESULTS: We performed an integrative analysis including single-cell RNA sequencing, whole-exome sequencing, and bulk RNA sequencing in 180 HB samples, to reveal genomic features, transcriptomic profiles, and the immune microenvironment of HB. Multi-color immunohistochemistry staining and in vitro experiments were performed for validation. Here, we reported four HB transcriptional subtypes primarily defined by differential expression of transcription factors (TFs). Among them, the S2A subtype, characterized by strong expression of progenitor (MYCN, MIXL1) and mesenchymal TFs (TWIST1, TBX5), was defined as a new chemo-resistant subtype. The S2A subtype showed increased transforming growth factor beta (TGF-β) cancer-associated fibroblast and an immunosuppressive microenvironment induced by the upregulated TGF-β of HB. Interestingly, the S2A subtype enriched SBS24 signature and significantly higher serum aflatoxin B1-albumin (AFB1-ALB) level in comparison with other subtypes. Functional assays indicated that aflatoxin promotes hepatoblastoma to upregulate TGF-β. Furthermore, Clinical prognostic analysis showed that serum AFB1-ALB is a potential indicator of HB chemoresistance and prognosis.

CONCLUSIONS: Our studies offer new insights into the relationship between aflatoxin and HB chemoresistance and provide important implications for its diagnosis and treatment.

PMID:37459556 | DOI:10.1097/HEP.0000000000000534

Permalink for 'Protocol to dissociate and isolate wide-diversity single cells by density gradient centrifugation from human hepatoblastoma tissue'

Protocol to dissociate and isolate wide-diversity single cells by density gradient centrifugation from human hepatoblastoma tissue

Fetched: July 18th, 2023, 5:02am GMT by Xianchao Zhou

STAR Protoc. 2023 Jul 16;4(3):102449. doi: 10.1016/j.xpro.2023.102449. Online ahead of print.

ABSTRACT

Single-cell transcriptome sequencing can characterize various cell types in human liver tissue and facilitate understanding of hepatoblastoma heterogeneity. Here, we present a protocol for isolating hepatocytes and immune cells from human hepatoblastoma samples with high viability. We describe steps for tissue processing, enzymatic digestion, Percoll density gradient separation, cell lysis, cell suspension quality control, and scRNA library construction. We then detail sequencing and data analysis. This protocol is applicable to preparing single-cell suspensions from other human liver tissue samples.

PMID:37459235 | PMC:PMC10511933 | DOI:10.1016/j.xpro.2023.102449

Microcystins-Loaded Aged Nanoplastics Provoke a Metabolic Shift in Human Liver Cells

Fetched: July 15th, 2023, 5:02am GMT by Yixin He

Environ Sci Technol. 2023 Jul 25;57(29):10521-10531. doi: 10.1021/acs.est.3c00990. Epub 2023 Jul 14.

ABSTRACT

Studies concerning the toxicity of pollutant-loaded nanoplastics (NPs) toward humans are still in their infancy. Here, we evaluated the adsorption of microcystins (MCs) by pristine and aged polystyrene nanoplastics (PSNPs), prepared MCs-loaded aged PSNPS (1, 5, 10, 15, and 19 μg/mg), and systematically mapped the key molecular changes induced by aged and MCs-loaded PSNPs to human hepatoblastoma (HepG2) cells. According to the results, MC-LR adsorption is increased 2.64-fold by aging, and PSNP accumulation is detected in HepG2 cells. The cytotoxicity of the MC-LR-loaded aged PSNPs showed a positive relationship with the MC-LR amount, as the cell viability in the 19 μg/mg loading treatment (aPS-MC19) was 10.84% lower than aged PSNPs; meanwhile, more severe oxidative damage was observed. Primary approaches involved stressing the endoplasmic reticulum and reducing protein synthesis that the aged PSNPs posed for HepG2 cells, while the aggravated cytotoxicity in aPS-MC19 treatment was a combined result of the metabolic energy disorder, oxidative damage, endoplasmic reticulum stress, and downregulation of the MC-LR target protein. Our results confirm that the aged PSNPs could bring more MC-LR into the HepG2 cells, significantly interfere with biological processes, and provide new insight into deciphering the risk of NPs to humans.

PMID:37449315 | DOI:10.1021/acs.est.3c00990

Epidemiological Study of Malignant Paediatric Liver Tumours in Denmark 1985-2020

Fetched: July 15th, 2023, 5:02am GMT by Thomas N Nissen

Cancers (Basel). 2023 Jun 26;15(13):3355. doi: 10.3390/cancers15133355.

ABSTRACT

BACKGROUND: Malignant liver tumours in children are rare and national outcomes for this tumour entity are rarely published. This study mapped paediatric liver tumours in Denmark over 35 years and reported on the incidence, outcomes and long-term adverse events.

METHODS: We identified all liver tumours from the Danish Childhood Cancer Registry and reviewed the case records for patient and tumour characteristics, treatment and clinical outcome.

RESULTS: We included 79 patients in the analyses. Overall crude incidence was ~2.29 per 1 million children (<15 yr) per year, with 61 hepatoblastomas (HB), 9 hepatocellular carcinomas and 9 other hepatic tumours. Overall 5-year survival was 84%, 78% and 44%, respectively. Nine patients had underlying liver disease or predisposition syndrome. Seventeen children underwent liver transplantation, with two late complications, biliary stenosis and liver fibrosis. For HB, age ≥ 8 years and diagnosis prior to 2000 were significant predictors of a poorer outcome. Adverse events included reduced renal function in 10%, reduced cardiac function in 6% and impaired hearing function in 60% (19% needed hearing aids). Behavioural conditions requiring additional support in school were registered in 10 children.

CONCLUSIONS: In Denmark, incidences of malignant liver tumours during the last four decades have been increasing, as reported in the literature. HB survival has improved since the year 2000 and is comparable with international results. Reduced hearing is the major treatment-related side effect and affects approximately 60% of patients.

PMID:37444465 | PMC:PMC10341131 | DOI:10.3390/cancers15133355

Biliary complications post liver resection for pediatric liver tumors

Fetched: July 14th, 2023, 5:01am GMT by Mohd Yusran Othman

World J Pediatr Surg. 2023 Jul 4;6(3):e000589. doi: 10.1136/wjps-2023-000589. eCollection 2023.

ABSTRACT

OBJECTIVE: To review biliary complications following liver resection for liver tumors in children and their associated risk factors.

METHODS: Retrospectively, we reviewed children who underwent liver resection for liver tumors from 2010 to 2019. Demographic data, operative details, types of complications, interventions and outcomes were studied.

RESULTS: Eighty-six out of 108 liver resections were included in this study. The median age of patients was 1.8 years old, and 55% were male. The majority (95%) were malignant tumors, of which 87% were hepatoblastoma (n=71). The most common procedure performed was extended right hepatectomy (37%, n=32). Twelve (14%) patients had primary biliary complications: nine bile leakages and three biliary obstructions. Six cases of bile leakage were treated non-operatively with drainage only; however, one developed bilothorax. Three bile leakages underwent early operative intervention. Four patients underwent biliary reconstruction. Biliary complications were not significantly associated with age, sex, ethnicity or pathology of the tumor. Ten of them (83%) developed following extended hepatectomies (five right, five left), in which the left side had a higher rate of complications (63% vs 16%). None of the central hepatectomies had biliary complications. Biliary complication rates were significantly higher among those who had segmentectomy 1 (p=0.023).

CONCLUSIONS: Biliary complication is a significant morbidity following liver resection in children. Surgery is eventually required for complicated bile leakage and primary biliary strictures. Follow-up is mandatory since secondary biliary complications may occur after the initial resolution of bile leakage. The groups at high risk of developing biliary complications are extended left hepatectomies and segmentectomy 1.

PMID:37441088 | PMC:PMC10335567 | DOI:10.1136/wjps-2023-000589

Anabolic-androgenic anabolic steroids as a probable risk factor for hepatoblastoma in infants

Fetched: July 13th, 2023, 5:02am GMT by Armen Malekiantaghi

Clin Case Rep. 2023 Jul 10;11(7):e7676. doi: 10.1002/ccr3.7676. eCollection 2023 Jul.

ABSTRACT

KEY CLINICAL MESSAGE: The etiology of hepatoblastoma (HB) is still unknown; several risk factors have been identified. The only risk factor for the development of HB in presented case was the child's father using anabolic androgenic steroids. It may be a risk factor for developing HB in their children.

ABSTRACT: HB is the most common primary liver cancer in children. Its etiology is still unclear. The patient's father's use of androgenic anabolic steroids could be a risk factor for developing HB in his child. A 14-month-old girl was hospitalized with intermittent fever, severe abdominal distention, and anorexia. On initial examination, she was cachectic and pale. There were two hemangioma-like skin lesions in the back. Huge hepatomegaly was found and the ultrasound showed a hepatic hemangioma. The possibility of malignancy was considered due to the severe enlargement of the liver and the increased levels of the alpha-fetoprotein. An abdominopelvic CT scan was performed and finally, the diagnosis of HB was confirmed by pathology. There was no history of congenital anomalies or risk factors for HB.Also we did not find any risk factors in the mother's history either. The only positive finding in the father's history was the use of anabolic steroids for bodybuilding. Anabolic-androgenic anabolic steroids may be one of the possible causes of HB in children.

PMID:37434955 | PMC:PMC10332254 | DOI:10.1002/ccr3.7676

Associations between birth defects with neural crest cell origins and pediatric embryonal tumors

Fetched: July 12th, 2023, 5:02am GMT by Eugene C Wong

Cancer. 2023 Jul 11. doi: 10.1002/cncr.34952. Online ahead of print.

ABSTRACT

BACKGROUND: There are few assessments evaluating associations between birth defects with neural crest cell developmental origins (BDNCOs) and embryonal tumors, which are characterized by undifferentiated cells having a molecular profile similar to neural crest cells. The effect of BDNCOs on embryonal tumors was estimated to explore potential shared etiologic pathways and genetic origins.

METHODS: With the use of a multistate, registry-linkage cohort study, BDNCO-embryonal tumor associations were evaluated by generating hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox regression models. BDNCOs consisted of ear, face, and neck defects, Hirschsprung disease, and a selection of congenital heart defects. Embryonal tumors included neuroblastoma, nephroblastoma, and hepatoblastoma. Potential HR modification (HRM) was investigated by infant sex, maternal race/ethnicity, maternal age, and maternal education.

RESULTS: The risk of embryonal tumors among those with BDNCOs was 0.09% (co-occurring n = 105) compared to 0.03% (95% CI, 0.03%-0.04%) among those without a birth defect. Children with BDNCOs were 4.2 times (95% CI, 3.5-5.1 times) as likely to be diagnosed with an embryonal tumor compared to children born without a birth defect. BDNCOs were strongly associated with hepatoblastoma (HR, 16.1; 95% CI, 11.3-22.9), and the HRs for neuroblastoma (3.1; 95% CI, 2.3-4.2) and nephroblastoma (2.9; 95% CI, 1.9-4.4) were elevated. There was no notable HRM by the aforementioned factors.

CONCLUSIONS: Children with BDNCOs are more likely to develop embryonal tumors compared to children without a birth defect. Disruptions of shared developmental pathways may contribute to both phenotypes, which could inform future genomic assessments and cancer surveillance strategies of these conditions.

PMID:37432072 | DOI:10.1002/cncr.34952

Mechanism of preventive effects of exendin-4 and des-fluoro-sitagliptin in a murine model of fructose-induced prediabetes

Fetched: July 11th, 2023, 5:02am GMT by María Cecilia Castro

Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Sep;1868(9):159363. doi: 10.1016/j.bbalip.2023.159363. Epub 2023 Jul 8.

ABSTRACT

Protective effects of exendin-4 (glucagon-like peptide-1 -GLP-1- receptor agonist) and des-fluoro-sitagliptin (dipeptidyl peptidase-4 inhibitor) on fructose-induced hepatic disturbances were evaluated in prediabetic rats. Complementary, a possible direct effect of exendin-4 in human hepatoblastoma-derived cell line HepG2 incubated with fructose in presence/absence of exendin-9-39 (GLP-1 receptor antagonist) was investigated. In vivo, after 21 days of fructose rich diet, we determined: glycemia, insulinemia, and triglyceridemia; hepatic fructokinase, AMP-deaminase, and G-6-P dehydrogenase (G-6-P DH) activities; carbohydrate-responsive element-binding protein (ChREBP) expression; triglyceride content and lipogenic gene expression (glycerol-3-phosphate acyltransferase -GPAT-, fatty acid synthase -FAS-, sterol regulatory element-binding protein-1c -SREBP-1c); oxidative stress and inflammatory markers expression. In HepG2 cells we measured fructokinase activity and triglyceride content. Hypertriglyceridemia, hyperinsulinemia, enhanced liver fructokinase, AMP-deaminase, and G-6-P DH activities, increased ChREBP and lipogenic genes expression, enhanced triglyceride level, oxidative stress and inflammatory markers recorded in fructose fed animals, were prevented by co-administration of either exendin-4 or des-fluoro-sitagliptin. Exendin-4 prevented fructose-induced increase in fructokinase activity and triglyceride contain in HepG2 cells. These effects were blunted co-incubating with exendin-9-39. The results demonstrated for the first time that exendin-4/des-fluro-sitagliptin prevented fructose-induced endocrine-metabolic oxidative stress and inflammatory changes probably acting on the purine degradation pathway. Exendin 9-39 blunted in vitro protective exendin-4 effects, thereby suggesting a direct effect of this compound on hepatocytes through GLP-1 receptor. Direct effect on fructokinase and AMP-deaminase activities, with a key role in the pathogenesis of liver dysfunction induced by fructose, suggests purine degradation pathway constitute a potential therapeutic objective for GLP-1 receptor agonists.

PMID:37429413 | DOI:10.1016/j.bbalip.2023.159363

Permalink for 'Facile and green fabrication of tumor- and mitochondria-targeted AIEgen-protein nanoparticles for imaging-guided photodynamic cancer therapy'

Facile and green fabrication of tumor- and mitochondria-targeted AIEgen-protein nanoparticles for imaging-guided photodynamic cancer therapy

Fetched: July 7th, 2023, 5:02am GMT by De-Ping Wang

Acta Biomater. 2023 Sep 15;168:551-564. doi: 10.1016/j.actbio.2023.06.048. Epub 2023 Jul 5.

ABSTRACT

In recent years, aggregation-induced emission (AIE)-active materials have been emerging as a promising means for bioimaging and phototherapy. However, the majority of AIE luminogens (AIEgens) need to be encapsulated into versatile nanocomposites to improve their biocompatibility and tumor targeting. Herein, we prepared a tumor- and mitochondria-targeted protein nanocage by the fusion of human H-chain ferritin (HFtn) with a tumor homing and penetrating peptide LinTT1 using genetic engineering technology. The LinTT1-HFtn could serve as a nanocarrier to encapsulate AIEgens via a simple pH-driven disassembly/reassembly process, thereby fabricating the dual-targeting AIEgen-protein nanoparticles (NPs). The as designed NPs exhibited an improved hepatoblastoma-homing property and tumor penetrating ability, which is favorable for tumor-targeted fluorescence imaging. The NPs also presented a mitochondria-targeting ability, and efficiently generated reactive oxygen species (ROS) upon visible light irradiation, making them valuable for inducing efficient mitochondrial dysfunction and intrinsic apoptosis in cancer cells. In vivo experiments demonstrated that the NPs could provide the accurate tumor imaging and dramatic tumor growth inhibition with minimal side effects. Taken together, this study presents a facile and green approach for fabrication of tumor- and mitochondria-targeted AIEgen-protein NPs, which can serve as a promising strategy for imaging-guided photodynamic cancer therapy. STATEMENT OF SIGNIFICANCE: AIE luminogens (AIEgens) show strong fluorescence and enhanced ROS generation in the aggregate state, which would facilitate the image-guided photodynamic therapy [12-14]. However, the major obstacles that hinder biological applications are their lack of hydrophilicity and selective targeting [15]. To address this issue, this study presents a facile and green approach for the fabrication of tumor‑ and mitochondria‑targeted AIEgen-protein nanoparticles via a simple disassembly/reassembly of the LinTT1 peptide-functionalized ferritin nanocage without any harmful chemicals or chemical modification. The targeting peptide-functionalized nanocage not only restricts the intramolecular motion of AIEgens leading to enhanced fluorescence and ROS production, but also confers good targeting to AIEgens.

PMID:37414113 | DOI:10.1016/j.actbio.2023.06.048

Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma

Fetched: July 7th, 2023, 5:02am GMT by Jie Fang

Nat Commun. 2023 Jul 6;14(1):4003. doi: 10.1038/s41467-023-39717-6.

ABSTRACT

A lack of relevant genetic models and cell lines hampers our understanding of hepatoblastoma pathogenesis and the development of new therapies for this neoplasm. Here, we report an improved MYC-driven hepatoblastoma-like murine model that recapitulates the pathological features of embryonal type of hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of the human disease. Single-cell RNA-sequencing and spatial transcriptomics identify distinct subpopulations of hepatoblastoma cells. After deriving cell lines from the mouse model, we map cancer dependency genes using CRISPR-Cas9 screening and identify druggable targets shared with human hepatoblastoma (e.g., CDK7, CDK9, PRMT1, PRMT5). Our screen also reveals oncogenes and tumor suppressor genes in hepatoblastoma that engage multiple, druggable cancer signaling pathways. Chemotherapy is critical for human hepatoblastoma treatment. A genetic mapping of doxorubicin response by CRISPR-Cas9 screening identifies modifiers whose loss-of-function synergizes with (e.g., PRKDC) or antagonizes (e.g., apoptosis genes) the effect of chemotherapy. The combination of PRKDC inhibition and doxorubicin-based chemotherapy greatly enhances therapeutic efficacy. These studies provide a set of resources including disease models suitable for identifying and validating potential therapeutic targets in human high-risk hepatoblastoma.

PMID:37414763 | PMC:PMC10326052 | DOI:10.1038/s41467-023-39717-6

Permalink for 'Case report: Portal vein ligation: lessons from patients with PRETEXT III hepatoblastoma in restoring future liver remnant before major hepatectomy and literature review'

Case report: Portal vein ligation: lessons from patients with PRETEXT III hepatoblastoma in restoring future liver remnant before major hepatectomy and literature review

Fetched: July 6th, 2023, 5:02am GMT by Suiin Gang

Front Surg. 2023 Jun 19;10:1152901. doi: 10.3389/fsurg.2023.1152901. eCollection 2023.

ABSTRACT

BACKGROUND: We describe three cases involving three patients with PRETEXT III hepatoblastoma invading the hepatic hilum. After portal vein embolization, the patients underwent uncomplicated trisectionectomy.

METHODS: Medical records between March 2016 and March 2021 were reviewed, and three patients were selected. A literature review of techniques for increasing future liver remnant in children diagnosed with hepatoblastoma was also conducted.

RESULTS: All tumors involved the right lobe and hepatic hilum (PRETEXT III). After neoadjuvant chemotherapy, the tumor size decreased, but hilar involvement was unimproved. Right portal vein ligation (RPVL) was performed to increase the left lobe volume. Post-ligation, the remnant liver increased. Liver function was restored to normal levels within 5 days after the hepatectomy. All patients underwent two cycles of adjuvant chemotherapy without tumor recurrence.

CONCLUSIONS: RPVL can be safely performed before extended hepatic resection in children with a giant hepatoblastoma invading the hepatic hilum. The tumor was completely resected by securing a sufficient margin and increasing the residual liver volume with portal vein embolization. The patients recovered and underwent adjuvant chemotherapy without the deterioration of liver function.

PMID:37405062 | PMC:PMC10315569 | DOI:10.3389/fsurg.2023.1152901

Permalink for 'Preoperative Triple-Phase Three-Dimensional-Multi-Detector Computed Tomography Imaging of the Hepatic Vascular Tree: An Accurate Road Map Prior to Tumor Resection in Hepatoblastoma'

Preoperative Triple-Phase Three-Dimensional-Multi-Detector Computed Tomography Imaging of the Hepatic Vascular Tree: An Accurate Road Map Prior to Tumor Resection in Hepatoblastoma

Fetched: July 1st, 2023, 5:02am GMT by Aparajita Mitra

J Indian Assoc Pediatr Surg. 2023 May-Jun;28(3):233-241. doi: 10.4103/jiaps.jiaps_113_22. Epub 2023 May 2.

ABSTRACT

OBJECTIVE: To evaluate the hepatic vasculature/tumor relations in hepatoblastoma patients with three-dimensional (3D) reformatted images after triple-phase multi-detector computed tomography (MDCT) and to compare these with the surgical findings to judge the accuracy of this investigation.

MATERIALS AND METHODS: The study was carried out in hepatoblastoma patients after appropriate neo-adjuvant chemotherapy, prior to resection. Images were postprocessed at a dedicated workstation for multi-planar reformations, maximum intensity projection, curved planar reformations, and volume-rendered technique reconstructions. The reporting was done as per a specific protocol by both the radiologist and surgeon (per-operative findings) and the accuracy of MDCT ascertained as per concordance between the surgical and imaging findings.

RESULTS: Fourteen children (13 boys, 1 girl) underwent surgery. Clinically, relevant information regarding vascular, tumor involvement, and interface with vessels was provided by the study in all cases. Although all tumors were deemed resectable on preoperative imaging, one procedure was abandoned due to an unanticipated portal cavernoma. While a few anatomical variations were unexpectedly encountered during surgery, there was good concordance overall between findings on imaging and surgical exploration.

CONCLUSIONS: MDCT with 3D reformatting provides accurate virtual representations of the hepatic tumor. This allows simulation of surgical resection with decreased risk of vascular injury and postoperative liver failure.

PMID:37389399 | PMC:PMC10305947 | DOI:10.4103/jiaps.jiaps_113_22

Permalink for 'New Anthranilic Acid Hydrazones as Fenamate Isosteres: Synthesis, Characterization, Molecular Docking, Dynamics & in silico ADME, in vitro Anti-inflammatory and Anti-cancer Activity Studies'

New Anthranilic Acid Hydrazones as Fenamate Isosteres: Synthesis, Characterization, Molecular Docking, Dynamics & in silico ADME, in vitro Anti-inflammatory and Anti-cancer Activity Studies

Fetched: June 30th, 2023, 5:02am GMT by Halil Şenol

Chem Biodivers. 2023 Aug;20(8):e202300773. doi: 10.1002/cbdv.202300773. Epub 2023 Jul 17.

ABSTRACT

In this study, twenty new anthranilic acid hydrazones 6-9 (a-e) were synthesized and their structures were characterized by Fourier-transform Infrared (FT-IR), Nuclear Magnetic Resonance (¹ H-NMR - ¹³ C-NMR), and High-resolution Mass Spectroscopy (HR-MS). The inhibitory effects of the compounds against COX-II were evaluated. IC50 values of the compounds were found in the range of >200-0.32 μM and compounds 6e, 8d, 8e, 9b, 9c, and 9e were determined to be the most effective inhibitors. Cytotoxic effects of the most potent compounds were investigated against human hepatoblastoma (Hep-G2) and human healthy embryonic kidney (Hek-293) cell lines. Doxorubicin (IC50 : 8.68±0.16 μM for Hep-G2, 55.29±0.56 μM for Hek-293) was used as standard. 8e is the most active compound, with low IC50 against Hep-G2 (4.80±0.04 μM), high against Hek-293 (159.30±3.12), and high selectivity (33.15). Finally, molecular docking and dynamics studies were performed to understand ligand-protein interactions between the most potent compounds and COX II, Epidermal Growth Factor Receptor (EGFR), and Transforming Growth Factor beta II (TGF-βII). The docking scores were calculated in the range of -10.609--6.705 kcal/mol for COX-II, -8.652--7.743 kcal/mol for EGFR, and -10.708--8.596 kcal/mol for TGF-βII.

PMID:37384873 | DOI:10.1002/cbdv.202300773

Permalink for 'Consensus classification of pediatric hepatocellular tumors: A report from the Children's Hepatic tumors International Collaboration (CHIC)'

Consensus classification of pediatric hepatocellular tumors: A report from the Children's Hepatic tumors International Collaboration (CHIC)

Fetched: June 30th, 2023, 5:02am GMT by Soo-Jin Cho

Pediatr Blood Cancer. 2023 Jun 29:e30505. doi: 10.1002/pbc.30505. Online ahead of print.

ABSTRACT

BACKGROUND: Liver tumors are rare in children with histologic heterogeneity that makes diagnosis challenging. Systematic histopathological review, performed as part of collaborative therapeutic protocols, identified relevant histologic subtypes that are important to distinguish. The Children's Hepatic tumors International Collaboration (CHIC) was established to study pediatric liver tumors on a global scale and led to establishment of a provisional consensus classification for use in international clinical trials. The current study is the validation of this initial classification and first large-scale application by international expert reviewers.

PROCEDURE: The CHIC initiative includes data from 1605 children treated on eight multicenter hepatoblastoma (HB) trials. Review of 605 available tumors was performed by seven expert pathologists from three consortia (US, EU, Japan). Cases with discordant diagnoses were collectively reviewed to reach a final consensus diagnosis.

RESULTS: Of 599 cases with sufficient material for review, 570 (95.2%) were classified as HB by all consortia, and 29 (4.8%) as non-HB, which included "hepatocellular neoplasm, NOS" and malignant rhabdoid tumors. 453 of 570 HBs were classified as epithelial by final consensus. Some patterns (i.e., small cell undifferentiated, macrotrabecular, cholangioblastic) were selectively identified by reviewers from different consortia. All consortia identified a similar number of mixed epithelial-mesenchymal HB.

CONCLUSIONS: This study represents the first large-scale application and validation of the pediatric malignant hepatocellular tumors consensus classification. It is a valuable resource to train future generations of investigators on accurate diagnosis of these rare tumors and provides a framework for further international collaborative studies and refinement of the current classification of pediatric liver tumors.

PMID:37384428 | DOI:10.1002/pbc.30505

Adult hepatoblastoma: making the challenging distinction from hepatocellular carcinoma

Fetched: June 30th, 2023, 5:02am GMT by Allison Kaye L Pagarigan

J Liver Cancer. 2023 Mar;23(1):219-224. doi: 10.17998/jlc.2023.02.24. Epub 2023 Mar 13.

ABSTRACT

Hepatoblastoma is an exceptionally rare malignancy in adults with just over 70 non-pediatric cases reported in literature. Recounted is a case of a 49-year-old female who presented with acute right upper quadrant abdominal pain, elevated serum alpha fetoprotein and a large liver mass on imaging. Hepatectomy was performed under clinical suspicion of hepatocellular carcinoma. Immunomorphologic characteristics of the tumor proved consistent with hepatoblastoma of mixed epithelial and mesenchymal type. Hepatocellular carcinoma remains to be the primary differential diagnosis for adult hepatoblastoma, however, distinguishing between these two neoplasms requires close histomorphologic assessment and immunohistochemical profiling as clinical, radiologic and gross pathologic findings typically overlap. Making this distinction is highly crucial in the timely initiation of surgical and chemotherapeutic interventions for this inherently aggressive and rapidly fatal disease.

PMID:37384033 | PMC:PMC10202245 | DOI:10.17998/jlc.2023.02.24

UBE2C expression is elevated in hepatoblastoma and correlates with inferior patient survival

Fetched: June 29th, 2023, 5:01am GMT by Ruth Nousiainen

Front Genet. 2023 Jun 12;14:1170940. doi: 10.3389/fgene.2023.1170940. eCollection 2023.

ABSTRACT

Hepatoblastoma (HB) is the most common malignant liver tumor among children. To gain insight into the pathobiology of HB, we performed RNA sequence analysis on 5 patient-derived xenograft lines (HB-243, HB-279, HB-282, HB-284, HB-295) and 1 immortalized cell line (HUH6). Using cultured hepatocytes as a control, we found 2,868 genes that were differentially expressed in all of the HB lines on mRNA level. The most upregulated genes were ODAM, TRIM71, and IGDCC3, and the most downregulated were SAA1, SAA2, and NNMT. Protein-protein interaction analysis identified ubiquitination as a key pathway dysregulated in HB. UBE2C, encoding an E2 ubiquitin ligase often overexpressed in cancer cells, was markedly upregulated in 5 of the 6 HB cell lines. Validation studies confirmed UBE2C immunostaining in 20 of 25 HB tumor specimens versus 1 of 6 normal liver samples. The silencing of UBE2C in two HB cell models resulted in decreased cell viability. RNA sequencing analysis showed alterations in cell cycle regulation after UBE2C knockdown. UBE2C expression in HB correlated with inferior patient survival. We conclude that UBE2C may hold prognostic utility in HB and that the ubiquitin pathway is a potential therapeutic target in this tumor.

PMID:37377594 | PMC:PMC10291054 | DOI:10.3389/fgene.2023.1170940

Cytomorphology of paediatric hepatocellular carcinoma: A useful diagnostic adjunct

Fetched: June 27th, 2023, 5:02am GMT by Aasma Nalwa

Cytopathology. 2023 Sep;34(5):479-488. doi: 10.1111/cyt.13266. Epub 2023 Jun 26.

ABSTRACT

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common primary malignancy of the liver but is rare in the paediatric age group; thus, it may be misdiagnosed as the more common tumour, hepatoblastoma. Management varies in both these tumours, and pathological diagnosis thus plays an important role for definitive therapy. Only a few case reports available in the literature have described the cytological characteristics of paediatric HCC. The present study was thus planned to evaluate the cytomorphological features of paediatric HCC.

METHODS: Cases diagnosed with HCC on ultrasound-guided fine needle aspiration cytology over a period of 14 years were retrieved. The cases were evaluated for detailed cytological features including cellularity, architecture, sinusoidal wrapping, trabecular thickness, necrosis, anisonucleosis, chromatin, nucleoli, nuclear contours, bi- or multinucleation, intranuclear and intracytoplasmic inclusions, naked nuclei, extra-medullary haematopoiesis, monomorphism, and nuclear overlapping.

RESULTS: Twelve cases of HCC were included in the study. The median age at diagnosis was 10 years. Serum alpha-fetoprotein level was raised in most of them. Five of the 12 cases were characterised as moderately differentiated, three as poorly differentiated, two as well differentiated, and two as the fibrolamellar type of HCC. Cytohistological correlation was performed in seven cases.

CONCLUSIONS: Ultrasound-guided fine needle aspiration serves as a useful tool to diagnose paediatric HCC and differentiate it from other primary hepatic malignancies, especially hepatoblastoma which closely mimics HCC in this age group, as serum alpha protein levels and imaging findings are unable to distinguish these two tumours.

PMID:37357840 | DOI:10.1111/cyt.13266

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