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Endocrine/Neuroendocrine (30 unread)

PubMed - Merkel Cell Cancer

CD200 Expression in Neuroendocrine Neoplasms.

Fetched: August 21st, 2017, 5:00am GMT

CD200 Expression in Neuroendocrine Neoplasms.

Am J Clin Pathol. 2017 Sep 01;148(3):236-242

Authors: Love JE, Thompson K, Kilgore MR, Westerhoff M, Murphy CE, Papanicolau-Sengos A, McCormick KA, Shankaran V, Vandeven N, Miller F, Blom A, Nghiem PT, Kussick SJ

Abstract
Objectives: CD200 expression has been well studied in hematopoietic malignancies; however, CD200 expression has not been well-characterized in neuroendocrine neoplasms. We examined CD200 expression in 391 neuroendocrine neoplasms from various anatomic sites.
Methods: Tissue blocks containing pulmonary small cell carcinoma, pulmonary carcinoid, large cell neuroendocrine carcinoma, pancreatic neuroendocrine tumor, gastrointestinal carcinoid, and Merkel cell carcinoma were evaluated for CD200 expression by immunohistochemistry. A set of nonneuroendocrine carcinomas was stained for comparison.
Results: CD200 was expressed in 87% of the neuroendocrine neoplasms studied, including 60 of 72 (83%) pulmonary small cell carcinomas, 15 of 22 (68%) pulmonary carcinoids, three of four (75%) pulmonary large cell neuroendocrine carcinomas, 125 of 146 (86%) Merkel cell carcinomas, 79 of 83 (95%) gastrointestinal luminal carcinoids, and 56 of 60 (93%) pancreatic neuroendocrine tumors. Thirty-two of 157 (20%) nonneuroendocrine carcinomas expressed CD200. In gastrointestinal carcinoid and pancreatic neuroendocrine neoplasms, CD200 negativity correlated with higher grade.
Conclusions: CD200 is a relatively sensitive marker of neuroendocrine neoplasms and represents a potential therapeutic target in these difficult-to-treat malignancies.

PMID: 28821198 [PubMed - in process]
Cutaneous Merkel cell carcinoma: multiple asynchronous primary lesions in a patient on immunosuppressive therapy.

Fetched: August 18th, 2017, 5:00am GMT

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Cutaneous Merkel cell carcinoma: multiple asynchronous primary lesions in a patient on immunosuppressive therapy.

J Cutan Pathol. 2017 Mar;44(3):309-312

Authors: Sparks J, Sparks M, Malone JC

PMID: 27990669 [PubMed - indexed for MEDLINE]
A morphological and immunophenotypic map of the immune response in Merkel cell carcinoma.

Fetched: August 18th, 2017, 5:00am GMT

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A morphological and immunophenotypic map of the immune response in Merkel cell carcinoma.

Hum Pathol. 2016 Jun;52:190-6

Authors: Walsh NM, Fleming KE, Hanly JG, Dakin Hache K, Doucette S, Ferrara G, Cerroni L

Abstract
The susceptibility of Merkel cell carcinoma to the host immune response has prompted a search for effective immunotherapy. CD8-positive T lymphocytes are considered key effectors of this response, but the cellular infiltrates also harbor tumor-protective agents. By developing a comprehensive morphological and immunophenotypic map of tumor-infiltrating lymphocytes (TILS) in Merkel cell carcinoma, we aimed to establish a useful template for future studies. Twenty-two cases (mean age, 79years [range, 52-95]; male-female ratio, 10:12) were studied. TILS were categorized as brisk (7), nonbrisk (9), and absent(6). Merkel cell polyomavirus (MCPyV)-positive (16) and -negative (6) cases were included, as were those with pure (18) and combined (4) morphologies. One MCPyV+ case had undergone spontaneous regression. Immunohistochemical markers included CD3, CD4, CD8, CD20, CD68, FoxP3, PD-1, and CD123. Statistical analysis used Fisher exact tests and Spearman correlations. There was a significant correlation between brisk TILs and MCPyV+ status (P=.025). CD8+ T lymphocytes predominated, were present in significantly higher proportions in brisk infiltrates (P=.003), and showed a significant predilection for the intratumoral environment (P=.003). Immune inhibitors including T regulatory cells (FOXP3+) and PD-1+ "exhausted" immunocytes were present in lower proportions. Our findings support (1) the link between a brisk immune response and MCPyV positivity, (2) the supremacy of CD8+ cells in effecting immunity, and (3) the incorporation of immune inhibitors within the global infiltrate. Efforts to therapeutically arm the "effectors" and disarm the "detractors" are well focused. These will likely have the greatest impact on MCPyV-positive cases.

PMID: 26980039 [PubMed - indexed for MEDLINE]
Merkel cell carcinoma: Do Australians have a more aggressive variant and a worse outcome?

Fetched: August 16th, 2017, 5:00am GMT

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Merkel cell carcinoma: Do Australians have a more aggressive variant and a worse outcome?

Australas J Dermatol. 2017 Aug 13;:

Authors: Veness M

PMID: 28804895 [PubMed - as supplied by publisher]
Efficacy of isolated limb perfusion (ILP) in patients with Merkel cell carcinoma (MCC): A multicenter experience.

Fetched: August 16th, 2017, 5:00am GMT

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Efficacy of isolated limb perfusion (ILP) in patients with Merkel cell carcinoma (MCC): A multicenter experience.

Eur J Surg Oncol. 2017 Aug 03;:

Authors: van Veenendaal LM, Madu MF, Tesselaar MET, Verhoef C, Grünhagen DJ, van Akkooi ACJ

Abstract
BACKGROUND: Merkel cell carcinoma (MCC) is a rare and potentially aggressive neuroendocrine tumor of the skin, with a propensity for locoregional metastases. In two expert referral centers, isolated limb perfusion (ILP) is used to obtain locoregional control in selected locoregionally advanced MCC patients. This study describes our experience.
METHOD: Patients who underwent ILP for MCC were analyzed. ILP was performed with melphalan and tumor necrosis factor (TNF) combination therapy. Depending on the institution, either a normothermic or a hyperthermic temperature regimen was used. Baseline characteristics, toxicity data, locoregional progression-free survival (LPFS) and overall survival (OS) were assessed.
RESULTS: Four males and 6 females with a median age of 78 years (IQR 61-84 years) were included. Four patients underwent ILP for upper extremity disease and 6 for lower extremity disease. All patients received combination therapy with Melphalan and TNF, one patient with the addition of interferon-gamma. No signs of systemic toxicity were present post-ILP. Severe locoregional toxicity (compartment syndrome) occurred in 1 patient and 1 elderly patient with extensive atherosclerosis had to undergo transfemoral amputation due to critical ischemia. Eight patients could be included for response evaluation. The overall response rate (ORR) was 87.5% with a complete response (CR) rate of 62.5%. Two long-term responses of 53 months and 71 months were observed. Median LPFS was 5 months and median OS was 54 months.
CONCLUSION: ILP shows a high CR rate that can be durable. Therefore, ILP should be considered an effective treatment modality for locally advanced MCC.

PMID: 28802661 [PubMed - as supplied by publisher]
Merkel Cell Carcinoma Therapeutic Update.

Fetched: August 12th, 2017, 5:00am GMT

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Merkel Cell Carcinoma Therapeutic Update.

Curr Treat Options Oncol. 2016 Jul;17(7):36

Authors: Cassler NM, Merrill D, Bichakjian CK, Brownell I

Abstract
OPINION STATEMENT: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

PMID: 27262710 [PubMed - indexed for MEDLINE]
Drainage Patterns to Nontraditional Nodal Regions and Level IIB in Cutaneous Head and Neck Malignancy.

Fetched: August 11th, 2017, 5:00am GMT

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Drainage Patterns to Nontraditional Nodal Regions and Level IIB in Cutaneous Head and Neck Malignancy.

Otolaryngol Head Neck Surg. 2016 Dec;155(6):1005-1011

Authors: Creighton F, Bergmark R, Emerick K

Abstract
OBJECTIVES: (1) Determine the frequency of nontraditional sentinel lymph node (SLN) locations in cutaneous head and neck malignancy and (2) determine the frequency of level IIB SLNs in cutaneous head and neck malignancy.
DESIGN: Case series with chart review.
SETTING: Tertiary academic hospital.
SUBJECTS AND METHODS: In total, 145 consecutive sentinel lymph node biopsy (SLNB) specimens for cutaneous head and neck malignancies were reviewed from 2007 to 2015. Nodal regions were categorized into levels I to V, parotid, external jugular (EJ), perifacial, suboccipital, and postauricular regions. Primary locations were divided into scalp, forehead, cheek, ear, neck, nose, periocular, and lip. Frequencies of sentinel lymph node (SLN) locations for each primary location were determined.
RESULTS: Parotid, EJ, perifacial, suboccipital, postauricular, and level IIB lymph SLNs were identified as nontraditional lymph node regions at risk in head and neck cutaneous malignancy. EJ SLNs were present in over 15% of all cases and over 25% of periocular and cheek lesions. Perifacial SLNs were frequently present in nose and lip lesions. Suboccipital and postauricular nodes were only present in scalp lesions. Level II was the most common location for a SLN. In total, 15.9% of all cases involved level IIB. Scalp and ear primary lesions were most likely to drain to level IIB.
CONCLUSIONS: Nontraditional SLN locations, such as EJ, perifacial, suboccipital, postauricular, and parotid, as well as level IIB, are important sites of drainage for head and neck cutaneous malignancy. Prediction of at-risk lymph node regions is important to help guide SLNBs, elective and completion neck lymphadenectomy and radiation, and long-term observation.

PMID: 27554510 [PubMed - indexed for MEDLINE]

Causes of Carcinoid Tumors
News-Medical.net
MEN-1 is the abbreviation for multiple endocrine neoplasia type 1 and it is a group of disorders that give rise to neuroendocrine tumors in the parathyroid, pituitary and pancreas. Many carcinoid tumors occur together with MEN 1. Despite the fact that ...

Neuroendocrine Tumors - Pipeline Review, H1 2017; New Report Launched - Digital Journal

Posted: August 14th, 2017, 8:53pm GMT

Neuroendocrine Tumors - Pipeline Review, H1 2017; New Report ...
Digital Journal
Publisher's Pharmaceutical and Healthcare latest pipeline guide Neuroendocrine Tumors - Pipeline Review, H1 2017, provides comprehensive information on ...

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In-Depth Study on Global and Chinese Pancreatic Endocrine Tumor Drug Forecasts Market Growth Prospects Till 2022 - Digital Journal

Posted: August 10th, 2017, 4:29pm GMT

In-Depth Study on Global and Chinese Pancreatic Endocrine Tumor Drug Forecasts Market Growth Prospects Till 2022
Digital Journal
Albany, NY -- (SBWIRE) -- 08/10/2017 -- According to recent report findings, the number of pancreatic and gastrointestinal neuroendocrine tumors of the small intestine cases in patients has increased, which provides plentiful opportunity for the ...

Trial - Neuroendocrine Cancers

An Exploratory Tumor Biopsy-driven Study to Understand the Relationship Between Biomarkers and Clinical Response in Melanoma Patients Receiving REGN2810 (Anti-PD-1)

Posted: December 20th, 2016, 3:00pm GMT

Condition: Melanoma
Intervention: Drug: REGN2810
Sponsors: Regeneron Pharmaceuticals; Sanofi
Recruiting - verified August 2017
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A Study of Anti-PD-L1 Checkpoint Antibody (LY3300054) Alone and in Combination in Participants With Advanced Refractory Solid Tumors

Posted: June 1st, 2016, 2:00pm GMT

Conditions: Solid Tumor; Microsatellite Instability-High (MSI-H) Solid Tumors; Cutaneous Melanoma
Interventions: Drug: LY3300054; Drug: Ramucirumab; Drug: Abemaciclib; Drug: Merestinib
Sponsor: Eli Lilly and Company
Recruiting - verified August 2017

PubMed - Neuroendocrine Tumor

Effect of AP102, a subtype 2 and 5 specific somatostatin analog, on glucose metabolism in rats.

Fetched: August 21st, 2017, 5:00am GMT

Effect of AP102, a subtype 2 and 5 specific somatostatin analog, on glucose metabolism in rats.

Endocrine. 2017 Aug 18;:

Authors: Tarasco E, Seebeck P, Pfundstein S, Daly AF, Eugster PJ, Harris AG, Grouzmann E, Lutz TA, Boyle CN

Abstract
PURPOSE: Somatostatin analogs are widely used to treat conditions associated with hormonal hypersecretion such as acromegaly and metastatic neuroendocrine tumors. First generation somatostatin analogs, such as octreotide and lanreotide, have high affinity for somatostatin receptor subtype 2 (SSTR2), but have incomplete efficacy in many patients. Pasireotide targets multiple SSTRs, having the highest affinity for SSTR5, but causes hyperglycemia and diabetes mellitus in preclinical and clinical studies. AP102 is a new somatostatin analogs with high affinity at both SSTR2 and SSTR5. We aimed to characterize the effects of AP102 vs. pasireotide on random and dynamic glucose levels, glucoregulatory hormone concentrations and growth axis measures in healthy Sprague-Dawley rats.
METHODS: Three doses of each compound were evaluated under acute conditions (1, 10, and 30 µg/kg s.c.), and two doses during a chronic (4-week) infusion (3 and 10 µg/kg/h s.c.).
RESULTS: Neither acute nor chronic AP102 administration altered blood glucose concentrations or dynamic responses following an intraperitoneal glucose tolerance test. In contrast, acute and chronic pasireotide dosing increased random and post-intraperitoneal glucose tolerance test blood glucose measures, compared to vehicle-treated controls. Both AP102 and pasireotide acutely suppressed growth hormone levels, although insulin-like growth factor-1 and somatic growth was suppressed to a greater extent with pasireotide.
CONCLUSIONS: AP102 is a new dual SSTR2/SSTR5-specific somatostatin analog that acutely reduces growth hormone but does not cause hyperglycemia during acute or chronic administration in a healthy rat model. Further studies in diabetic animals and in humans are necessary to determine the potential utility of AP102 in the clinical setting.

PMID: 28822091 [PubMed - as supplied by publisher]
The 2017 World Health Organization classification of tumors of the pituitary gland: a summary.

Fetched: August 21st, 2017, 5:00am GMT

The 2017 World Health Organization classification of tumors of the pituitary gland: a summary.

Acta Neuropathol. 2017 Aug 18;:

Authors: Lopes MBS

Abstract
The 4th edition of the World Health Organization (WHO) classification of endocrine tumors has been recently released. In this new edition, major changes are recommended in several areas of the classification of tumors of the anterior pituitary gland (adenophypophysis). The scope of the present manuscript is to summarize these recommended changes, emphasizing a few significant topics. These changes include the following: (1) a novel approach for classifying pituitary neuroendocrine tumors according to pituitary adenohypophyseal cell lineages; (2) changes to the histological grading of pituitary neuroendocrine tumors with the elimination of the term "atypical adenoma;" and (3) introduction of new entities like the pituitary blastoma and re-definition of old entities like the null-cell adenoma. This new classification is very practical and mostly based on immunohistochemistry for pituitary hormones, pituitary-specific transcription factors, and other immunohistochemical markers commonly used in pathology practice, not requiring routine ultrastructural analysis of the tumors. Evaluation of tumor proliferation potential, by mitotic count and Ki-67 labeling index, and tumor invasion is strongly recommended on individual case basis to identify clinically aggressive adenomas. In addition, the classification offers the treating clinical team information on tumor prognosis by identifying specific variants of adenomas associated with an elevated risk for recurrence. Changes in the classification of non-neuroendocrine tumors are also proposed, in particular those tumors arising in the posterior pituitary including pituicytoma, granular cell tumor of the posterior pituitary, and spindle cell oncocytoma. These changes endorse those previously published in the 2016 WHO classification of CNS tumors. Other tumors arising in the sellar region are also reviewed in detail including craniopharyngiomas, mesenchymal and stromal tumors, germ cell tumors, and hematopoietic tumors. It is hoped that the 2017 WHO classification of pituitary tumors will establish more biologically and clinically uniform groups of tumors, make it possible for practicing pathologists to better diagnose these tumors, and contribute to our understanding of clinical outcomes for patients harboring pituitary tumors.

PMID: 28821944 [PubMed - as supplied by publisher]
Major postoperative complications after pancreatic resection for P-NETS are not associated to earlier recurrence.

Fetched: August 21st, 2017, 5:00am GMT

Major postoperative complications after pancreatic resection for P-NETS are not associated to earlier recurrence.

Eur J Surg Oncol. 2017 Aug 02;:

Authors: Valente R, Lykoudis P, Tamburrino D, Inama M, Passas I, Toumpanakis C, Luong TV, Davidson B, Imber C, Malagò M, Rahman SH, Shankar A, Sharma D, Caplin M, Fusai G

Abstract
BACKGROUND: The oncological impact of surgical complications has been studied in visceral and pancreatic cancer.
AIM: To investigate the impact of complications on tumour recurrence after resections for pancreatic neuroendocrine tumours.
METHODS: We have retrospectively analysed 105 consecutive resections performed at the Royal Free London Hospital from 1998 to 2014, and studied the long-term outcome of nil-minor (<3) versus major (≥3) Clavien-Dindo complications (CD) on disease-free (DFS) and overall survival (OS).
RESULTS: The series accounted for 41 (39%) pancreaticoduodenectomies, two (1.9%) central, 48 (45.7%) distal pancreatectomies, eight (7.6%) enucleations, four (3.8%) total pancreatectomies. Sixteen (15.2%) were extended to adjacent organs, 13 (12.3%) to minor liver resections. Postoperative complications presented in 43 (40.1%) patients; CD grade 1 or 2 in 23 (21.9%), grades ≥3 in 20 (19%). Among 25 (23.8%) pancreatic fistulas, 14 (13.3%) were grades B or C. Thirty-four (32.4%) patients developed exocrine, and 31 (29.5%) endocrine insufficiency. Seven patients died during a median 27 (0-175) months follow up. Thirty-day mortality was 0.9%. OS was 94.1% at 5 years. Thirty tumours recurred within 11.7 (0.8-141.5) months. DFS was 44% at 5 years. At univariate analysis, high-grade complications were not associated with shorter DFS (p = 0.744). At multivariate analysis, no parameter was independent predictor for DFS or OS. The comparison of nil-minor versus major complications showed no DFS difference (p = 0.253).
CONCLUSION: From our series, major complications after P-NETs resection are not associated to different disease recurrence; hence do not require different follow up or adjuvant regimens.

PMID: 28821361 [PubMed - as supplied by publisher]
External Validation of a Prognostic Model of Survival for Resected Typical Bronchial Carcinoids.

Fetched: August 21st, 2017, 5:00am GMT

External Validation of a Prognostic Model of Survival for Resected Typical Bronchial Carcinoids.

Ann Thorac Surg. 2017 Aug 16;:

Authors: Cattoni M, Vallières E, Brown LM, Sarkeshik AA, Margaritora S, Siciliani A, Imperatori A, Rotolo N, Farjah F, Wandell G, Costas K, Mann C, Hubka M, Kaplan S, Farivar AS, Aye RW, Louie BE

Abstract
BACKGROUND: This study aimed to assess the reliability and the validity of a prognostic model of survival recently developed by the European Society of Thoracic Surgery Neuroendocrine Tumor Working Group to predict 5-year overall survival after surgical resection of pulmonary typical carcinoid.
METHODS: We retrospectively collected data on 240 consecutive patients (164 men, 76 women; median age, 58 years [interquartile range, 47 to 68]) who underwent curative lung resection for pulmonary typical carcinoid in seven centers between 2000 and 2015. For each patient, we calculated the corresponding risk class (A, B, C, D) using the following variables: male, age, previous malignancy, Eastern Cooperative Oncology Group performance status, peripheral tumor, TNM stage. Kaplan-Meier method, and Cox proportional hazards model were used for the statistical analysis.
RESULTS: During a median follow-up of 42 months (interquartile range, 11 to 84), the 5-year overall survival was 94.2% (95% confidence interval [CI]: 90.2% to 98.2%); 15 of 240 patients died. A significantly decreasing rate of survival was observed from class A to class D (p = 0.004) with rates of 100% (95% CI: 100% to 100%), 96.3% (95% CI: 88.6% to 98.8%), 86.7% (95% CI: 63.0% to 95.7%), and 33.3% (95% CI: 0.9% to 77.4%), respectively, for class A, B, C, and D. This difference persisted also using clinical stage as a variable in the risk class calculation (p = 0.006). No differences were observed in term of overall survival among TNM stage I, II, and III patients (p = 0.94).
CONCLUSIONS: This prognostic model of survival is easily applicable, it is validated by our independent cohort, and it appears to stratify better than the traditional TNM staging. Therefore, it may be useful in counseling patients about their outcomes from surgical treatment and in tailoring treatment for high-risk patients.

PMID: 28821334 [PubMed - as supplied by publisher]
CD200 Expression in Neuroendocrine Neoplasms.

Fetched: August 21st, 2017, 5:00am GMT

CD200 Expression in Neuroendocrine Neoplasms.

Am J Clin Pathol. 2017 Sep 01;148(3):236-242

Authors: Love JE, Thompson K, Kilgore MR, Westerhoff M, Murphy CE, Papanicolau-Sengos A, McCormick KA, Shankaran V, Vandeven N, Miller F, Blom A, Nghiem PT, Kussick SJ

Abstract
Objectives: CD200 expression has been well studied in hematopoietic malignancies; however, CD200 expression has not been well-characterized in neuroendocrine neoplasms. We examined CD200 expression in 391 neuroendocrine neoplasms from various anatomic sites.
Methods: Tissue blocks containing pulmonary small cell carcinoma, pulmonary carcinoid, large cell neuroendocrine carcinoma, pancreatic neuroendocrine tumor, gastrointestinal carcinoid, and Merkel cell carcinoma were evaluated for CD200 expression by immunohistochemistry. A set of nonneuroendocrine carcinomas was stained for comparison.
Results: CD200 was expressed in 87% of the neuroendocrine neoplasms studied, including 60 of 72 (83%) pulmonary small cell carcinomas, 15 of 22 (68%) pulmonary carcinoids, three of four (75%) pulmonary large cell neuroendocrine carcinomas, 125 of 146 (86%) Merkel cell carcinomas, 79 of 83 (95%) gastrointestinal luminal carcinoids, and 56 of 60 (93%) pancreatic neuroendocrine tumors. Thirty-two of 157 (20%) nonneuroendocrine carcinomas expressed CD200. In gastrointestinal carcinoid and pancreatic neuroendocrine neoplasms, CD200 negativity correlated with higher grade.
Conclusions: CD200 is a relatively sensitive marker of neuroendocrine neoplasms and represents a potential therapeutic target in these difficult-to-treat malignancies.

PMID: 28821198 [PubMed - in process]
The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models.

Fetched: August 13th, 2017, 5:00am GMT

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The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models.

PLoS One. 2017;12(8):e0182852

Authors: Nölting S, Rentsch J, Freitag H, Detjen K, Briest F, Möbs M, Weissmann V, Siegmund B, Auernhammer CJ, Aristizabal Prada ET, Lauseker M, Grossman A, Exner S, Fischer C, Grötzinger C, Schrader J, Grabowski P, GERMAN NET-Z study group

Abstract
BACKGROUND/AIMS: The therapeutic options for metastatic neuroendocrine tumors (NETs) are limited. As PI3K signaling is often activated in NETs, we have assessed the effects of selective PI3Kp110α inhibition by the novel agent BYL719 on cell viability, colony formation, apoptosis, cell cycle, signaling pathways, differentiation and secretion in pancreatic (BON-1, QGP-1) and pulmonary (H727) NET cell lines.
METHODS: Cell viability was investigated by WST-1 assay, colony formation by clonogenic assay, apoptosis by caspase3/7 assay, the cell cycle by FACS, cell signaling by Western blot analysis, expression of chromogranin A and somatostatin receptors 1/2/5 by RT-qPCR, and chromogranin A secretion by ELISA.
RESULTS: BYL719 dose-dependently decreased cell viability and colony formation with the highest sensitivity in BON-1, followed by H727, and lowest sensitivity in QGP-1 cells. BYL719 induced apoptosis and G0/G1 cell cycle arrest associated with increased p27 expression. Western blots showed inhibition of PI3K downstream targets to a varying degree in the different cell lines, but IGF1R activation. The most sensitive BON-1 cells displayed a significant, and H727 cells a non-significant, GSK3 inhibition after BYL719 treatment, but these effects do not appear to be mediated through the IGF1R. In contrast, the most resistant QGP-1 cells showed no GSK3 inhibition, but a modest activation, which would partially counteract the other anti-proliferative effects. Accordingly, BYL719 enhanced neuroendocrine differentiation with the strongest effect in BON-1, followed by H727 cells indicated by induction of chromogranin A and somatostatin receptor 1/2 mRNA-synthesis, but not in QGP-1 cells. In BON-1 and QGP-1 cells, the BYL719/everolimus combination was synergistic through simultaneous AKT/mTORC1 inhibition, and significantly increased somatostatin receptor 2 transcription compared to each drug separately.
CONCLUSION: Our results suggest that the agent BYL719 could be a novel therapeutic approach to the treatment of NETs that may sensitize NET cells to somatostatin analogs, and that if there is resistance to its action this may be overcome by combination with everolimus.

PMID: 28800359 [PubMed - in process]
Novel PET tracer (68)Ga-DOTATATE PET/CT can be alternative imaging method in patients with insulinomas.

Fetched: August 13th, 2017, 5:00am GMT

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Novel PET tracer (68)Ga-DOTATATE PET/CT can be alternative imaging method in patients with insulinomas.

J Nucl Med Technol. 2017 Aug 10;:

Authors: Tuzcu ŞA, Pekkolay Z, Kılınç F, Tuzcu AK

Abstract
Insulinomas are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism. The diagnosis of insulinoma is established by demonstrating inappropriately high serum insulin concentrations during a spontaneous or induced episode of hypoglycaemia. Most of the insulinomas are islet-cell tumors. They are often small (less than 2 cm), benign, and difficult to localize with current imaging techniques. The non-invasive procedures such as transabdominal ultrasonography, spiral computed tomography (CT), magnetic resonance imaging (MRI), 111-In-pentetreotide imaging, fluorine-18-L-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA PET) and invasive procedures such as endoscopic ultrasonography or a selective arterial calcium stimulation test (SACST) with hepatic venous sampling can be used to show insulinomas. In this case report we used novel PET tracer (68)Ga-DOTATATE PET/CT for three patients with insulinoma. All patients' insulinomas were shown clearly with (68)Ga-DOTATATE PET/CT. (68)Gallium-DOTATATE PET/CT imaging may be a useful and non-invasive imaging technique to localized insulinomas preoperatively.

PMID: 28798227 [PubMed - as supplied by publisher]
Neuroendocrine Carcinoma of Gall Bladder: A Rare Presentation with Review of Literature.

Fetched: August 13th, 2017, 5:00am GMT

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Neuroendocrine Carcinoma of Gall Bladder: A Rare Presentation with Review of Literature.

Gulf J Oncolog. 2017 May;1(24):51-54

Authors: Gupta A, Ahmed P, Durgapal P, Kala P, Rao S, Pasricha R, Misra S

Abstract
Neuroendocrine tumors are the rarest tumors of gallbladder. The most aggressive variant is neuroendocrine carcinoma which presents in about 0.5% of all gallbladder carcinomas and 0.2% of all neuroendocrine tumors. It seems possible that survival rates can be improved by utilizing wide surgical resection combined with chemotherapy. We report a case of neuroendocrine carcinoma of gall bladder in a 20-year old female patient. In present case, the etiology was not known as patient did not have cholelithiasis or any symptoms related to chronic inflammation. Our extensive search of indexed literature shows that our patient was the youngest patient with this disease so far.

PMID: 28798003 [PubMed - in process]
Evaluation of the Upper Limb Lymphatic System: A Prospective Lymphoscintigraphic Study in Melanoma Patients and Healthy Controls.

Fetched: August 13th, 2017, 5:00am GMT

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Evaluation of the Upper Limb Lymphatic System: A Prospective Lymphoscintigraphic Study in Melanoma Patients and Healthy Controls.

Plast Reconstr Surg. 2017 04;139(4):1028e-1029e

Authors: Yamamoto T, Yamamoto N, Ishiura R

PMID: 28350688 [PubMed - indexed for MEDLINE]
A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector.

Fetched: August 13th, 2017, 5:00am GMT

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A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector.

Oncotarget. 2017 Feb 14;8(7):12272-12289

Authors: Lu ZH, Kaliberov S, Sohn RE, Kaliberova L, Du Y, Prior JL, Leib DJ, Chauchereau A, Sehn JK, Curiel DT, Arbeit JM

Abstract
While modern therapies for metastatic prostate cancer (PCa) have improved survival they are associated with an increasingly prevalent entity, aggressive variant PCa (AVPCa), lacking androgen receptor (AR) expression, enriched for cancer stem cells (CSCs), and evidencing epithelial-mesenchymal plasticity with a varying extent of neuroendocrine transdifferentiation. Parallel work revealed that endothelial cells (ECs) create a perivascular CSC niche mediated by juxtacrine and membrane tethered signaling. There is increasing interest in pharmacological metastatic niche targeting, however, targeted access has been impossible. Here, we discovered that the Gleason 7 derived, androgen receptor negative, IGR-CaP1 cell line possessed some but not all of the molecular features of AVPCa. Intracardiac injection into NOD/SCID/IL2Rg -/- (NSG) mice produced a completely penetrant bone, liver, adrenal, and brain metastatic phenotype; noninvasively and histologically detectable at 2 weeks, and necessitating sacrifice 4-5 weeks post injection. Bone metastases were osteoblastic, and osteolytic. IGR-CaP1 cells expressed the neuroendocrine marker synaptophysin, near equivalent levels of vimentin and e-cadherin, all of the EMT transcription factors, and activation of NOTCH and WNT pathways. In parallel, we created a new triple-targeted adenoviral vector containing a fiber knob RGD peptide, a hexon mutation, and an EC specific ROBO4 promoter (Ad.RGD.H5/3.ROBO4). This vector was expressed in metastatic microvessels tightly juxtaposed to IGR-CaP1 cells in bone and visceral niches. Thus, the combination of IGR-CaP1 cells and NSG mice produces a completely penetrant metastatic PCa model emulating end-stage human disease. In addition, the metastatic niche access provided by our novel Ad vector could be therapeutically leveraged for future disease control or cure.

PMID: 28103576 [PubMed - indexed for MEDLINE]
Clinicopathologic Characteristics and Mutational Status of Succinate Dehydrogenase Genes in Paraganglioma of the Urinary Bladder: A Multi-Institutional Korean Study.

Fetched: August 13th, 2017, 5:00am GMT

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Clinicopathologic Characteristics and Mutational Status of Succinate Dehydrogenase Genes in Paraganglioma of the Urinary Bladder: A Multi-Institutional Korean Study.

Arch Pathol Lab Med. 2017 May;141(5):671-677

Authors: Park S, Kang SY, Kwon GY, Kwon JE, Kim SK, Kim JY, Kim CH, Kim HJ, Moon KC, Pyo JY, Park WY, Park ES, Sung JY, Sung SH, Oh YH, Lee SE, Lee W, Lee JI, Cho NH, Jung SJ, Cho MS, Cho YM, Cho HY, Cha EJ, Chae YS, Choe G, Choi YJ, Huh J, Ro JY

Abstract
CONTEXT: - Because of the limited number of available primary bladder paraganglioma (PBPG) cases, the rates of succinate dehydrogenase (SDH) mutations and the clinicopathologic characteristics of SDH-deficient tumors have not been fully studied.
OBJECTIVE: - To define the clinicopathologic and molecular characteristics of PBPGs.
DESIGN: - A total of 52 PBPGs were collected retrospectively. SDHA and SDHB immunohistochemical stains were performed. In cases of SDHB expression loss, mutation analyses of SDHB, SDHC, and SDHD were performed.
RESULTS: - The clinicopathologic features were analyzed for 52 cases (M:F = 27:25), with a mean age of 56 years (range, 22-79 years). Tumor sizes were 0.5 to 8 cm (mean, 2.4 cm). Tumor necrosis was present in 5 of 52 cases (10%), involvement of muscularis propria in 41 (79%), and lymphovascular tumor invasion in 6 (12%). During a mean follow-up period of 41 months (range, 1-161 months), 3 of 52 patients (6%) developed metastases, but no one died from the disease. Immunohistochemistry for SDHA and SDHB showed that all cases were SDHA intact. Among them, 43 cases had intact SDHB, whereas 9 cases were SDHB deficient. Compared with the SDHB-intact cases, the SDHB-deficient cases were characterized by large tumor sizes (4.5 versus 1.9 cm; P < .001), a higher number of mitoses per 10 high-powered fields (2.6 versus 0.1; P = .002), and frequent lymphovascular tumor invasion (33% versus 7%; P = .02) and metastases (22% versus 2%; P = .02). Mutational analyses for SDHB, SDHC, and SDHD were performed in 9 SDHB-deficient cases. Among them, 6 cases were successfully sequenced and revealed SDHB mutations only.
CONCLUSIONS: - Large tumor size, a higher number of mitoses, and the presence of lymphovascular tumor invasion and SDHB mutations suggest malignant paraganglioma.

PMID: 27819762 [PubMed - indexed for MEDLINE]
Ccl22 Diverts T Regulatory Cells and Controls the Growth of Melanoma.

Fetched: August 13th, 2017, 5:00am GMT

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Ccl22 Diverts T Regulatory Cells and Controls the Growth of Melanoma.

Cancer Res. 2016 Nov 01;76(21):6230-6240

Authors: Klarquist J, Tobin K, Farhangi Oskuei P, Henning SW, Fernandez MF, Dellacecca ER, Navarro FC, Eby JM, Chatterjee S, Mehrotra S, Clark JI, Le Poole IC

Abstract
T regulatory cells (Treg) avert autoimmunity, but their increased levels in melanoma confer a poor prognosis. To explore the basis for Treg accumulation in melanoma, we evaluated chemokine expression in patients. A 5-fold increase was documented in the Treg chemoattractants CCL22 and CCL1 in melanoma-affected skin versus unaffected skin, as accompanied by infiltrating FoxP3(+) T cells. In parallel, there was an approximately two-fold enhancement in expression of CCR4 in circulating Treg but not T effector cells. We hypothesized that redirecting Treg away from tumors might suppress autoimmune side effects caused by immune checkpoint therapeutics now used widely in the clinic. In assessing this hypothesis, we observed a marked increase in skin Treg in mice vaccinated with Ccl22, with repetitive vaccination sufficient to limit Treg accumulation and melanoma growth in the lungs of animals challenged by tumor cell injection, whether using a prevention or treatment protocol design. The observed change in Treg accumulation in this setting could not be explained by Treg conversion. Overall, our findings offered a preclinical proof of concept for the potential use of CCL22 delivered by local injection as a strategy to enhance the efficacious response to immune checkpoint therapy while suppressing its autoimmune side effects. Cancer Res; 76(21); 6230-40. ©2016 AACR.

PMID: 27634754 [PubMed - indexed for MEDLINE]
Up-Regulated Expression of LAMP2 and Autophagy Activity during Neuroendocrine Differentiation of Prostate Cancer LNCaP Cells.

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Up-Regulated Expression of LAMP2 and Autophagy Activity during Neuroendocrine Differentiation of Prostate Cancer LNCaP Cells.

PLoS One. 2016;11(9):e0162977

Authors: Morell C, Bort A, Vara-Ciruelos D, Ramos-Torres Á, Altamirano-Dimas M, Díaz-Laviada I, Rodríguez-Henche N

Abstract
Neuroendocrine (NE) prostate cancer (PCa) is a highly aggressive subtype of prostate cancer associated with resistance to androgen ablation therapy. In this study, we used LNCaP prostate cancer cells cultured in a serum-free medium for 6 days as a NE model of prostate cancer. Serum deprivation increased the expression of NE markers such as neuron-specific enolase (NSE) and βIII tubulin (βIII tub) and decreased the expression of the androgen receptor protein in LNCaP cells. Using cDNA microarrays, we compared gene expression profiles of NE cells and non-differentiated LNCaP cells. We identified up-regulation of 155 genes, among them LAMP2, a lysosomal membrane protein involved in lysosomal stability and autophagy. We then confirmed up-regulation of LAMP2 in NE cells by qRT-PCR, Western blot and confocal microscopy assays, showing that mRNA up-regulation correlated with increased levels of LAMP2 protein. Subsequently, we determined autophagy activity in NE cells by assessing the protein levels of SQSTM/p62 and LC3 by Western blot and LC3 and Atg5 mRNAs content by qRT-PCR. The decreased levels of SQSTM/p62 was accompanied by an enhanced expression of LC3 and ATG5, suggesting activation of autophagy in NE cells. Blockage of autophagy with 1μM AKT inhibitor IV, or by silencing Beclin 1 and Atg5, prevented NE cell differentiation, as revealed by decreased levels of the NE markers. In addition, AKT inhibitor IV as well as Beclin1 and Atg5 kwockdown attenuated LAMP2 expression in NE cells. On the other hand, LAMP2 knockdown by siRNA led to a marked blockage of autophagy, prevention of NE differentiation and decrease of cell survival. Taken together, these results suggest that LAMP2 overexpression assists NE differentiation of LNCaP cells induced by serum deprivation and facilitates autophagy activity in order to attain the NE phenotype and cell survival. LAMP2 could thus be a potential biomarker and potential target for NE prostate cancer.

PMID: 27627761 [PubMed - indexed for MEDLINE]
Targeted Next-Generation Sequencing of Plasma DNA from Cancer Patients: Factors Influencing Consistency with Tumour DNA and Prospective Investigation of Its Utility for Diagnosis.

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Targeted Next-Generation Sequencing of Plasma DNA from Cancer Patients: Factors Influencing Consistency with Tumour DNA and Prospective Investigation of Its Utility for Diagnosis.

PLoS One. 2016;11(9):e0162809

Authors: Kaisaki PJ, Cutts A, Popitsch N, Camps C, Pentony MM, Wilson G, Page S, Kaur K, Vavoulis D, Henderson S, Gupta A, Middleton MR, Karydis I, Talbot DC, Schuh A, Taylor JC

Abstract
Use of circulating tumour DNA (ctDNA) as a liquid biopsy has been proposed for potential identification and monitoring of solid tumours. We investigate a next-generation sequencing approach for mutation detection in ctDNA in two related studies using a targeted panel. The first study was retrospective, using blood samples taken from melanoma patients at diverse timepoints before or after treatment, aiming to evaluate correlation between mutations identified in biopsy and ctDNA, and to acquire a first impression of influencing factors. We found good concordance between ctDNA and tumour mutations of melanoma patients when blood samples were collected within one year of biopsy or before treatment. In contrast, when ctDNA was sequenced after targeted treatment in melanoma, mutations were no longer found in 9 out of 10 patients, suggesting the method might be useful for detecting treatment response. Building on these findings, we focused the second study on ctDNA obtained before biopsy in lung patients, i.e. when a tentative diagnosis of lung cancer had been made, but no treatment had started. The main objective of this prospective study was to evaluate use of ctDNA in diagnosis, investigating the concordance of biopsy and ctDNA-derived mutation detection. Here we also found positive correlation between diagnostic lung biopsy results and pre-biopsy ctDNA sequencing, providing support for using ctDNA as a cost-effective, non-invasive solution when the tumour is inaccessible or when biopsy poses significant risk to the patient.

PMID: 27626278 [PubMed - indexed for MEDLINE]
YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2-EGFR Signaling Axis.

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YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2-EGFR Signaling Axis.

Cancer Res. 2016 Jun 15;76(12):3507-19

Authors: Guerrant W, Kota S, Troutman S, Mandati V, Fallahi M, Stemmer-Rachamimov A, Kissil JL

Abstract
The Hippo-YAP pathway has emerged as a major driver of tumorigenesis in many human cancers. YAP is a transcriptional coactivator and while details of YAP regulation are quickly emerging, it remains unknown what downstream targets are critical for the oncogenic functions of YAP. To determine the mechanisms involved and to identify disease-relevant targets, we examined the role of YAP in neurofibromatosis type 2 (NF2) using cell and animal models. We found that YAP function is required for NF2-null Schwann cell survival, proliferation, and tumor growth in vivo Moreover, YAP promotes transcription of several targets including PTGS2, which codes for COX-2, a key enzyme in prostaglandin biosynthesis, and AREG, which codes for the EGFR ligand, amphiregulin. Both AREG and prostaglandin E2 converge to activate signaling through EGFR. Importantly, treatment with the COX-2 inhibitor celecoxib significantly inhibited the growth of NF2-null Schwann cells and tumor growth in a mouse model of NF2. Cancer Res; 76(12); 3507-19. ©2016 AACR.

PMID: 27216189 [PubMed - indexed for MEDLINE]
miR-339-3p Is a Tumor Suppressor in Melanoma.

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miR-339-3p Is a Tumor Suppressor in Melanoma.

Cancer Res. 2016 Jun 15;76(12):3562-71

Authors: Weber CE, Luo C, Hotz-Wagenblatt A, Gardyan A, Kordaß T, Holland-Letz T, Osen W, Eichmüller SB

Abstract
Determinants of invasion and metastasis in cancer remain of great interest to define. Here, we report the definition of miR-339-3p as a novel tumor suppressive microRNA that blocks melanoma cell invasion without affecting cell survival. miR-339-3p was identified by a comprehensive functional screen of a human miRNA mimetic library in a cell-based assay for invasion by the melanoma cell line A375. miR-339-3p was determined as a strong inhibitor of invasion differentially expressed in melanoma cells and healthy melanocytes. MCL1 was defined as a target for downregulation by miR-339-3p, functioning through direct interaction with the 3' untranslated region of MCL1 mRNA. Blocking miR-339-3p by an antagomiR was sufficient to increase melanoma cell invasion, an effect that could be phenocopied by RNAi-mediated silencing of MCL1. In vivo studies established that miR-339-3p overexpression was sufficient to decrease lung colonization by A375 melanoma cells in NSG mice, relative to control cells. Overall, our results defined miR-339-3p as a melanoma tumor suppressor, the levels of which contributes to invasive aggressiveness. Cancer Res; 76(12); 3562-71. ©2016 AACR.

PMID: 27197185 [PubMed - indexed for MEDLINE]
T-cell Landscape in a Primary Melanoma Predicts the Survival of Patients with Metastatic Disease after Their Treatment with Dendritic Cell Vaccines.

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T-cell Landscape in a Primary Melanoma Predicts the Survival of Patients with Metastatic Disease after Their Treatment with Dendritic Cell Vaccines.

Cancer Res. 2016 Jun 15;76(12):3496-506

Authors: Vasaturo A, Halilovic A, Bol KF, Verweij DI, Blokx WA, Punt CJ, Groenen PJ, van Krieken JH, Textor J, de Vries IJ, Figdor CG

Abstract
Tumor-infiltrating lymphocytes appear to be a predictor of survival in many cancers, including cutaneous melanoma. We applied automated multispectral imaging to determine whether density and distribution of T cells within primary cutaneous melanoma tissue correlate with survival of metastatic melanoma patients after dendritic cell (DC) vaccination. CD3(+) T cell infiltration in primary tumors from 77 metastatic melanoma patients was quantified using the ratio of intratumoral versus peritumoral T-cell densities (I/P ratio). Patients with longer survival after DC vaccination had stronger T-cell infiltration than patients with shorter survival in a discovery cohort of 19 patients (P = 0.000026) and a validation cohort of 39 patients (P = 0.000016). I/P ratio was the strongest predictor of survival in a multivariate analysis including M substage and serum lactate dehydrogenase level. To evaluate I/P ratio as a predictive biomarker, we analyzed 19 chemotherapy-treated patients. Longer survival times of DC-vaccinated compared with chemotherapy-treated patients was observed for high (P = 0.000566), but not low (P = 0.154) I/P ratios. In conclusion, T-cell infiltration into primary melanoma is a strong predictor of survival after DC vaccination in metastatic melanoma patients who, on average, started this therapy several years after primary tumor resection. The infiltration remains predictive even after adjustment for late-stage prognostic markers. Our findings suggest that the I/P ratio is a potential predictive biomarker for treatment selection. Cancer Res; 76(12); 3496-506. ©2016 AACR.

PMID: 27197179 [PubMed - indexed for MEDLINE]
Complications following inguinal and ilioinguinal lymphadenectomies: a meta-analysis.

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Complications following inguinal and ilioinguinal lymphadenectomies: a meta-analysis.

J Plast Surg Hand Surg. 2016 Dec;50(6):315-320

Authors: Söderman M, Thomsen JB, Sørensen JA

Abstract
BACKGROUND: Inguinal lymphadenectomy is essential for regional staging of malignant melanoma in the lower part of the body. The procedure is associated with a wide range of complication rates. The objective of this study was to systematically review the literature for papers describing complication rates following inguinal (ID) and ilioinguinal (I-ID) lymphadenectomies, and estimate the actual complication rates in patients with malignant melanoma.
METHODS: The PubMed and EMBASE databases were searched for studies reporting complications following ID and I-ID for malignant melanomas.
RESULTS: A total of 416 records were identified, of which 20 were deemed eligible for this study. The complication rates (with 95% confidence intervals) were found to be as follows: overall complications = 52% (44-60%); lymphorrea = 29% (0-71%); seroma = 23% (18-29%); infection = 21% (15-27%); wound breakdown =14% (8-21%); skin edge necrosis = 10% (6-15%); haematoma = 3% (1-5%); and lymphoedema = 33% (25-42%).
CONCLUSION: Complication rates following ID and I-ID remain high, despite the many efforts to reduce these, with lymphorrea, seromas, and infections being the most prevalent complications.

PMID: 27146716 [PubMed - indexed for MEDLINE]