scholarly journals Evaluation of PARP and PDL-1 as potential therapeutic targets for women with high-grade neuroendocrine carcinomas of the cervix

2020 ◽  
Vol 30 (9) ◽  
pp. 1303-1307 ◽  
Author(s):  
Matthew Ryan Carroll ◽  
Preetha Ramalingam ◽  
Gloria Salvo ◽  
Junya Fujimoto ◽  
Luisa Maren Solis Soto ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Treatment Options ◽  
Therapeutic Targets ◽  
Large Cell ◽  
Small Cell ◽  
Cancer Center ◽  
High Grade ◽  
Mismatch Repair Proteins ◽  
Parp 1 ◽  
Neuroendocrine Carcinomas

ObjectivesWomen with recurrent high-grade neuroendocrine cervical cancer have few effective treatment options. The aim of this study was to identify potential therapeutic targets for women with this disease.MethodsSpecimens from patients with high-grade neuroendocrine carcinomas of the cervix were identified from pathology files at MD Anderson Cancer Center. Immunohistochemical stains for PD-L1 (DAKO, clone 22-C3), mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), somatostatin, and Poly (ADP-ribose) polymerase (PARP) were performed on sections from formalin-fixed paraffin-embedded tissue blocks. Nuclear PARP-1 staining was quantified using the H-score with a score of <40 considered low, 40–100 moderate, and ≥100 high.ResultsForty pathologic specimens from patients with high-grade neuroendocrine carcinomas of the cervix were examined (23 small cell, 5 large cell, 3 high-grade neuroendocrine, not otherwise specified, and 9 mixed). The mean age of the cohort was 43 years and the majority of patients (70%) were identified as white non-Hispanic. All 28 (100%) samples tested stained for mismatch repair proteins demonstrated intact expression, suggesting they were microsatellite stable tumors. Of the 31 samples tested for PD-L1 expression, only two (8%) of the 25 pure high-grade neuroendocrine carcinomas were positive whereas three (50%) of the six mixed carcinoma tumors tested positive. Of the 11 small cell specimens tested for PARP-1, 10 (91%) showed PARP expression with six (55%) demonstrating high expression and four (36%) showing moderate expression. Somatostatin staining was negative in 18 of 19 small cell cases (95%).ConclusionsPure high-grade neuroendocrine cervical carcinomas were microsatellite stable and overwhelmingly negative for PD-L1 expression. As the majority of tumors tested expressed PARP-1, inclusion of PARP inhibitors in future clinical trials may be considered.

Comparative Outcomes in Patients With Small- and Large-Cell Neuroendocrine Carcinoma (NEC) and Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MiNEN) of the Stomach

2020 ◽  
pp. 000313482095000
Author(s):  
Nam Young Choi ◽  
Byung-Sik Kim ◽  
Sung Tae Oh ◽  
Jeong Hwan Yook ◽  
Beom Su Kim
Keyword(s):  
Clinical Outcomes ◽  
Disease Free Survival ◽  
Large Cell ◽  
Small Cell ◽  
Neuroendocrine Neoplasm ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Intermediate Grade ◽  
Free Survival ◽  
Neuroendocrine Carcinomas

Background Gastric neuroendocrine carcinomas (NECs), consisting of both large- and small-cell NECs, and mixed adenoneuroendocrine carcinomas (MANECs), including mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs), are a group of high-grade malignancies. Few studies to date have reported clinical outcomes, including prognosis, in patients with these tumors. This study therefore evaluated the clinicopathologic outcomes and prognosis in patients with NECs and MANECs. Methods This study included 36 patients diagnosed with gastric NECs, including 23 with large-cell and 13 with small-cell NECs, and 85 with MiNENs, including 70 with high-grade and 15 with intermediate-grade MiNENs. Clinical outcomes, including overall survival (OS) and disease-free survival (DFS), were assessed. Results DFS was significantly poorer in patients with NEC than in patients with intermediate-grade MiNEN ( P < .05), whereas both OS and DFS were similar in patients with NEC and high-grade MiNEN ( P > .05). Patients with large-cell NEC were more likely to undergo aggressive surgery than patients with high-grade MiNEN ( P < .05). Lymphovascular invasion was more frequent and DFS poorer in patients with large-cell than small-cell NECs ( P < .05 each). Conclusion DFS is significantly poorer in patients with NEC than in patients with intermediate-grade MiNEN and significantly lower in patients with large-cell than small-cell NECs.

scholarly journals Updates and management algorithm for neuroendocrine tumors of the uterine cervix

2019 ◽  
Vol 29 (6) ◽  
pp. 986-995 ◽  
Author(s):  
Gloria Salvo ◽  
Antonio Gonzalez Martin ◽  
Naomi R Gonzales ◽  
Michael Frumovitz
Keyword(s):  
Neuroendocrine Tumors ◽  
Treatment Options ◽  
Distant Metastases ◽  
Large Cell ◽  
Initial Therapy ◽  
Small Cell ◽  
Oncologic Outcomes ◽  
Low Grade ◽  
High Tendency ◽  
Neuroendocrine Carcinomas

Neuroendocrine carcinomas of the cervix account for less than 2% of all invasive cervical cancers and are classified as low-grade (carcinoid, atypical carcinoid tumor) or high-grade (known as small- and large-cell) neuroendocrine carcinomas. There are increasing data showing that cervical neuroendocrine carcinomas may be associated with the human papillomavirus (HPV), especially HPV18, and most will stain positive for p16. Immunohistochemistry markers such as synaptophysin and CD56 are the most sensitive markers. Although there are no commonly associated mutations,PIK3CA,KRAS, andTP53are the most frequently found mutations in neuroendocrine tumors. Neuroendocrine cervical carcinomas are exceedingly aggressive tumors with a high tendency for nodal involvement and distant metastases. Age, lymph node metastases, smoking, pure small-cell histology, and tumor size are independent prognostic factors. Overall, the 5-year survival rate is 36% and the median overall survival ranges between 22 and 25 months. Treatment options are often extrapolated from small-cell lung cancer and limited retrospective studies. The preferred treatment is a multimodal approach of surgery, chemoradiation, and systemic chemotherapy. The most common chemotherapy regimen used as initial therapy is a combination of cisplatin and etoposide. In the setting of recurrent disease, a combination of topotecan, paclitaxel, and bevacizumab has demonstrated favorable outcomes. Multicenter tumor registries, such as the Neuroendocrine Cervical Tumor Registry (NeCTuR), are an opportunity to evaluate patterns of disease treatment and oncologic outcomes.

741 High-grade sinonasal carcinomas and surveillance of differential expression in immune related transcriptome

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A788-A788
Author(s):  
Diana Bell ◽  
Achim Bell ◽  
Renata Ferrarotto ◽  
Ehab Hanna
Keyword(s):  
Gene Expression ◽  
Malignant Tumors ◽  
Tumor Development ◽  
Large Cell ◽  
Cancer Center ◽  
High Grade ◽  
Sinonasal Carcinoma ◽  
Nut Carcinoma ◽  
Immune Oncology ◽  
Neuroendocrine Carcinomas

BackgroundThe skull base is the location of a wide variety of malignant tumors. Among them is sinonasal undifferentiated carcinoma (SNUC), a highly aggressive sinonasal neoplasm that was recently reclassified into subgroups of high-grade carcinomas with unique genomic events (e.g., SMARC-deficient carcinoma, nuclear protein in testis NUT carcinoma). Other high-grade carcinomas in this location are neuroendocrine carcinomas, sinonasal adenocarcinomas, and teratocarcinosarcomas. Given the rarity of these tumors, little transcriptomic data is available. The aim of this study was to characterize the immune-oncology gene expression profile in SNUC and other high-grade sinonasal carcinomas.MethodsNext-generation sequencing was performed in 30 high-grade sinonasal carcinoma samples using the HTG EdgeSeq Precision Immuno-Oncology Panel. Ingenuity pathway analysis was performed to understand the immunobiology, signaling, and functional perturbations during tumor development.ResultsThe samples were divided into 3 groups: 21 SNUCs and SMARC-deficient sinonasal carcinomas; 5 high-grade neuroendocrine carcinomas (HGNECs), with small cell and large cell variants; and 4 high-grade sinonasal carcinomas (HGSNCs) of mixed histology (1 NUT carcinoma, 1 teratocarcinosarcoma, and 2 sinonasal adenocarcinomas). PRAME and ASCL1 emerged as upregulated transcripts with strong protein validation for SNUC and HGNEC; other upregulated candidates EZH2 and BRCA1 offer consideration for alternative targeted therapy, and downregulation of major histocompatibility complex molecules and chemokines represent another hurdle in the development of effective immunotherapy.ConclusionsThis immune-oncology gene expression analysis of 3 groups of high-grade sinonasal carcinoma with emphasis on SNUC identified a number of differentially expressed transcripts reflecting effects on tumorigenesis. Identification of immune pathways should be further investigated for possible integration of immunotherapy into a multidisciplinary approach to these cancers and personalized treatment.Ethics ApprovalMD Anderson Cancer Center Institutional Review Board approval was obtained prior to the start of the study.

scholarly journals SOX11 is a sensitive and specific marker for pulmonary high-grade neuroendocrine tumors

2022 ◽  
Vol 17 (1) ◽  
Author(s):  
Lu Yu ◽  
Yuting Dong ◽  
Jin Xue ◽  
Sanpeng Xu ◽  
Guoping Wang ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Large Cell ◽  
Small Cell ◽  
Specific Marker ◽  
Tumor Type ◽  
High Grade ◽  
Immunohistochemical Expression ◽  
Small Cell Lung ◽  
Sox11 Expression ◽  
Neuroendocrine Carcinomas

Abstract Background Synaptophysin (SYN), chromogranin A (CGA), CD56 and insulinoma-associated protein 1 (INSM1) are proposed neuroendocrine (NE) markers used for diagnosis of pulmonary NE tumors. These NE markers have been identified in subsets of non-NE tumors requiring differential diagnosis, thus we sought to explore new NE markers. Methods We evaluated the immunohistochemical expression of SOX11, a transcription factor involved in neurogenesis, in pulmonary NE tumors and large cell carcinomas (LCCs). Results We found that SOX11 showed a sensitivity similar to INSM1 and CGA, and less than SYN and CD56 in small cell lung carcinomas (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). While SOX11 is more specific than the other four markers for diagnosis of high-grade neuroendocrine carcinomas (HG-NECs) because 1) None of LCCs (0/63), the most challenging non-NE tumor type for differential diagnosis due to overlapped morphology with LCNECs displayed SOX11 positivity. While expression of at least one of SYN, CGA, CD56 or INSM1 was identified in approximately 60% (18/30) of LCCs. 2) SOX11 was only expressed in 1 of 37 carcinoid tumors in contrast to diffuse expression of SYN, CGA, CD56 and INSM1. In HG-NECs, we noticed that SOX11 was a good complementary marker for SCLC diagnosis as it was positive in 7 of 18 SYN−/CGA−/CD56− SCLCs and 3 of 8 SYN−/CGA−/CD56−/INSM1− SCLCs, and SOX11 positivity in 4 of 6 SYN−/CGA−/CD56− cases previously diagnosed as LCCs with NE morphology provides additional evidence of NE differentiation for reclassification into LCNECs, which was further confirmed by electromicroscopical identification of neurosecretory granules. We also found SOX11 expression cannot predict the prognosis in patients with HG-NECs. Conclusions Therefore, SOX11 is a useful complementary transcriptional NE marker for diagnosis and differential diagnosis of SCLC and LCNEC.

CD117 immunoreactivity in high-grade neuroendocrine tumors of the lung: a comparative study of 39 large-cell neuroendocrine carcinomas and 27 surgically resected small-cell carcinomas

2004 ◽  
Vol 445 (5) ◽  
pp. 449-455 ◽  
Author(s):  
Giuseppe Pelosi ◽  
Michele Masullo ◽  
Maria Elena Leon ◽  
Giulia Veronesi ◽  
Lorenzo Spaggiari ◽  
...  
Keyword(s):  
Comparative Study ◽  
Neuroendocrine Tumors ◽  
Large Cell ◽  
Small Cell ◽  
High Grade ◽  
Neuroendocrine Carcinomas

scholarly journals Neuroendocrine Carcinomas of the Digestive Tract: What Is New?

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3766
Author(s):  
Anna Pellat ◽  
Anne Ségolène Cottereau ◽  
Benoit Terris ◽  
Romain Coriat
Keyword(s):  
Peptide Receptor Radionuclide Therapy ◽  
Large Cell ◽  
Current Data ◽  
World Health ◽  
High Grade ◽  
Ki 67 ◽  
Lung Cancers ◽  
Platinum Based Chemotherapy ◽  
Line Setting ◽  
Neuroendocrine Carcinomas

Neuroendocrine carcinomas (NEC) are rare tumors with a rising incidence. They show poorly differentiated morphology with a high proliferation rate (Ki-67 index). They frequently arise in the lung (small and large-cell lung cancer) but rarely from the gastrointestinal tract. Due to their rarity, very little is known about digestive NEC and few studies have been conducted. Therefore, most of therapeutic recommendations are issued from work on small-cell lung cancers (SCLC). Recent improvement in pathology and imaging has allowed for better detection and classification of high-grade NEN. The 2019 World Health Organization (WHO) classification has described a new entity of well-differentiated grade 3 neuroendocrine tumors (NET G-3), with better prognosis, that should be managed separately from NEC. NEC are aggressive neoplasms often diagnosed at a metastatic state. In the localized setting, surgery can be performed in selected patients followed by adjuvant platinum-based chemotherapy. Concurrent chemoradiotherapy is also an option for NEC of the lung, rectum, and esophagus. In metastatic NEC, chemotherapy is administered with a classic combination of platinum salts and etoposide in the first-line setting. Peptide receptor radionuclide therapy (PRRT) has shown positive results in high-grade NEN populations and immunotherapy trials are still ongoing. Available therapies have improved the overall survival of NEC but there is still an urgent need for improvement. This narrative review sums up the current data on digestive NEC while exploring future directions for their management.

Chromosomal aberrations in a series of large-cell neuroendocrine carcinomas: Unexpected divergence from small-cell carcinoma of the lung

2001 ◽  
Vol 32 (10) ◽  
pp. 1059-1063 ◽  
Author(s):  
Reinhard Ullmann ◽  
Susanna Petzmann ◽  
Anu Sharma ◽  
Philip Theo Cagle ◽  
Helmut Hans Popper
Keyword(s):  
Cell Carcinoma ◽  
Small Cell Carcinoma ◽  
Chromosomal Aberrations ◽  
Large Cell ◽  
Small Cell ◽  
Neuroendocrine Carcinomas

Phase II study of pembrolizumab-based therapy in previously treated extrapulmonary poorly differentiated neuroendocrine carcinomas: Results of Part B (pembrolizumab + chemotherapy).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4148-4148
Author(s):  
Jennifer A. Chan ◽  
Nitya Prabhakar Raj ◽  
Rahul Raj Aggarwal ◽  
Susan Calabrese ◽  
April DeMore ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Large Cell ◽  
Small Cell ◽  
Type I ◽  
First Line ◽  
Open Label ◽  
Total N ◽  
Poorly Differentiated ◽  
Neuroendocrine Carcinomas

4148 Background: The efficacy of immune checkpoint inhibitor (CPI) therapy has not been established in extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). In small cell lung cancer, CPI therapy is approved for use in the first-line and salvage settings. We investigated the efficacy and safety of pembrolizumab (PEM)-based therapy in biomarker-unselected patients (pts) with EP-PDNECs. PEM alone (Part A, N=14) was inactive (ASCO GI 2019; Abstr#363). We now report the results of Part B (PEM plus chemotherapy). Methods: We conducted an open label, multicenter, phase 2 study of PEM-based therapy in pts with EP-PDNECs, excluding Merkel cell carcinoma and well differentiated grade 3 neuroendocrine tumors (NET), with disease progression on first-line systemic therapy. In Part B of this trial, patients were treated with PEM 200 mg IV every 3 week cycle plus dealers’ choice chemotherapy (chemo): weekly irinotecan (IRI, 125 mg/m2 day 1,8 of every 21 day cycle) or weekly paclitaxel (PAC, 80 mg/m2). After PEM/IRI safety lead-in (N=6), 16 additional pts (total N=22) were enrolled. This was based on a primary endpoint of objective response rate (ORR) by RECIST 1.1 and a plan to test Ha ORR 31% vs H0 ORR 10% with 80% power at a type I error rate of 0.05. Secondary endpoints include safety, overall survival (OS), and progression-free survival (PFS). Serial blood samples and baseline tumor biopsies were required in all pts. Results: Preliminary data from Part B are available. Of 22 pts enrolled, male/female 15/7; median age 57 years (range 34-75); ECOG PS 0/1: 10/12; 6 large cell, 8 small cell, 8 NOS. Primary sites of disease: GI 73%, GYN 5%, unknown 23%. Ki67 index (available for 18 pts) median 68% (range 30 to >95%). Chemo choice: 17 IRI (77%) and 5 PAC (23%). PEM/IRI was safe based on lead-in. Median number of cycles of therapy administered was 3 (range 0-13). Treatment-related Gr 3 or 4 AE occurred in 7 (32%) of 22 pts overall: 4 (18%) had at least one Gr 3 AE attributed to PEM (1 pt each with pain, ALT increase, or nausea; 2 with fatigue); 7 (32%) had at least one Gr 3/4 AE attributed to chemo (2 with fatigue, 2 with neutropenia; 1 each with pain, ALT increase, hyponatremia, diarrhea, nausea, and/or acute kidney injury). No grade 5 AE. ORR was 9%: PR in 2 pts (9%), SD 3 pts (14%), PD 13 pts (60%); 4 pts (18%) unevaluable (off study before first scheduled scan). Median PFS 2 mo. At last follow-up, 5 pts (23%) were alive with 1 pt still on treatment. Median OS 4 mo. Of 21 pts off treatment, 76% off for PD, 10% off for AE, 14% off for withdrawal of consent/other therapy. Conclusions: PEM + chemotherapy was not effective in this pretreated, biomarker-unselected population of EP-PDNECs arising in different organs. Biomarker studies are planned (Parts A/B). Clinical trial information: NCT03136055.

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