Neuroendocrine Tumor Cells Research Articles

The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms.

Simple SummaryThe tumor microenvironment (TME) plays a role in promoting tumor progression. Elucidating the relationship between the TME and tumor cells will benefit current therapies. Therefore, this review summarizes the most recent relationship between the TME and tumor characteristics, discusses the differences in the TME at various sites along the digestive tract, and compares the TMEs of neuroendocrine tumors and neuroendocrine carcinomas. Microbial ecological changes in the TME were reviewed. The clinical application of the TME was summarized from bench to bedside. The TME can be used as a tumor drug target for diagnostic value, prognosis prediction, and efficacy evaluation, further revealing the potential of immune checkpoints combined with antiangiogenic drugs. The clinical application prospects of adoptive cell therapy and oncolytic viruses were described. The potential therapeutic approaches and strategies for gastrointestinal neuroendocrine neoplasms are considered.Gastroenteropancreatic neuroendocrine neoplasms feature high heterogeneity. Neuroendocrine tumor cells are closely associated with the tumor microenvironment. Tumor-infiltrating immune cells are mutually educated by each other and by tumor cells. Immune cells have dual protumorigenic and antitumorigenic effects. The immune environment is conducive to the invasion and metastasis of the tumor; in turn, tumor cells can change the immune environment. These cells also form cytokines, immune checkpoint systems, and tertiary lymphoid structures to participate in the process of mutual adaptation. Additionally, the fibroblasts, vascular structure, and microbiota exhibit interactions with tumor cells. From bench to bedside, clinical practice related to the tumor microenvironment is also regarded as promising. Targeting immune components and angiogenic regulatory molecules has been shown to be effective. The clinical efficacy of immune checkpoint inhibitors, adoptive cell therapy, and oncolytic viruses remains to be further discussed in clinical trials. Moreover, combination therapy is feasible for advanced high-grade tumors. The regulation of the tumor microenvironment based on multiple omics results can suggest innovative therapeutic strategies to prevent tumors from succeeding in immune escape and to support antitumoral effects.

DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor Everolimus in Tumoral Pituitary Cells.

The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors. In vitro studies demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolimus is reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in prolactin-secreting tumor cells (MMQ cells) through a β-arrestin 2-dependent mechanism. The aim of this study was to investigate the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of β-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%, p < 0.001 vs. basal) and reduced cyclin D3 expression. In the everolimus-unresponsive NF-PitNET group, everolimus determined a significant increase of p-AKT/total-AKT ratio (2.1-fold, p < 0.01, vs. basal) that was reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed everolimus did not affect MMQ cell proliferation and increased the p-AKT/total-AKT ratio (+1.53 ± 0.24-fold, p < 0.001 vs. basal), whereas cabergoline significantly reduced cell proliferation (-22.8 ± 6.8%, p < 0.001 vs. basal) and p-AKT. The combined treatment of everolimus and cabergoline induced a reduction of both cell proliferation (-34.8 ± 18%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone) and p-AKT/total-AKT ratio (-34.5 ± 14%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone). To test β-arrestin 2 involvement, silencing experiments were performed in MMQ cells. Our data showed that the lack of β-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory effects on both p-AKT and cell proliferation. In conclusion, this study revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way for a potential combined therapy in β-arrestin 2-expressing NF-PitNETs or other PitNETs resistant to conventional treatments.

HRAS expression predicts Lenvatinib responsiveness in human primary gastroenteropancreatic neuroendocrine tumor cells.

e16211 Background: Neuroendocrine neoplasms (NENs) are a rare group of heterogeneous tumors, with clinical presentation ranging from indolent and small lesions to very aggressive, metastatic and therapy refractory forms. Despite a high number of trials, few drugs have been introduced in the clinical practice and therapeutic options for systemic intervention are limited. The recent TALENT trial demonstrated the efficacy of Lenvatinib, a multi-tyrosine kinase inhibitor (MKI), in the treatment of patients with advanced well differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing from targeted therapies or somatostatin analogues with no other treatment indication. Lenvatinib might represent a novel therapeutic opportunity for these rare tumor patients. However, the treatment approach with MKI lacks clinically validated tissue or blood biomarkers to guide patient selection and improve efficacy. Methods: Here we established 11 human primary cultures from patients with GEP-NEN of different grades and sites of origin and assessed the antitumor activity of Lenvatinib compared with standard treatment agents. All primary cultures were molecularly characterized to identify possible predictors of response. Results: Lenvatinib exerted a significant inhibition of cell growth in primary GEP-NET cells, with median survival inhibitions similar or higher than those of standard treatments. Of the 11 primary cultures analyzed in our case series, 6 were classified as responder with survival inhibition higher than 15%, and 5 as non-responder with survival inhibition lower than 15%. A high expression of HRAS in the tumor tissues compared to the matched healthy tissues significantly correlated with responsiveness of primary cells to Lenvatinib. All 5 non-responder patients showed low expression of HRAS, while of the 6 responder patients, 5 showed a high HRAS expression and only 1 low. None of the other evaluated clinical variables (grade, Ki67, site of origin and syndromic disease) correlated with response. Conclusions: In conclusion, we believe that the evaluation of HRAS expression and mutation might be of great interest in GEP-NET patients receiving Lenvatinib to improve patient selection.

Perioperative chemotherapy with LP002, an anti-PD-L1 antibody, in patients with resectable gastric and gastroesophageal junction cancer: A prospective, open-label, phase Ib trial.

4041 Background: Immune checkpoint inhibitors were effective, either alone or in combination with chemotherapy, in pts with metastatic gastric or gastroesophageal junction (GEJ) cancers, but their role for resectable disease remained unknown. We report the safety and pathological response of gastric/GEJ cancer pts receiving LP002, an anti-PD-L1 antibody, plus chemotherapy as perioperative treatment in a phase Ib trial. Methods: We enrolled pts with previously untreated, PD-L1 positive, resectable (cT2-4a, any N, M0) gastric/GEJ cancer. Eligible pts received three preoperative and six postoperative 2-week cycles of intravenous LP002 900mg on day 1, intravenous cisplatin 50 mg/m2 on day 1, and 2000 mg/m2 5-fluorouracil as 48-h infusion starting on day 1. The standard surgery was scheduled 4-6 weeks after completion of 3 cycles of preoperative treatment. The primary endpoint was safety. Secondary endpoints included proportion of pts with R0 resection and pathological complete response (pCR), disease-free survival, and overall survival. With pre- and post-treatment samples, we also characterized genomic changes in tumor tissue with next generation sequencing (NGS), and alterations in the tumor immune microenvironment (TIME) using multiplex immunofluorescence staining. Results: From September 2020 to July 2021, 30 pts were enrolled into this study. The median age was 64.5 years (range, 50-74). Most primary tumors were in the GEJ (N=28, 93.3%). 29 pts (96.7%) had adenocarcinoma, and 1 had small cell neuroendocrine tumor. The median follow-up duration was 7.9 months (range: 5.1-10.6) as of data cut-off (November 1, 2021). All pts completed the planned preoperative treatment, and 27 pts (90.0%) proceeded to surgery. Reasons for surgery not being performed were metastatic disease in 1 patient, and patient request in 2 cases. 24 pts had R0 resection, while 3 underwent R1 resection. 1 patient achieved pCR (TRG 1 per the Mandard’s tumor regression grading system) and 5 pts (18.5%) reached TRG 2-3. Treatment-related adverse events (TRAEs) were observed in 27 pts during perioperative treatment. Most of the TRAEs were of grade 1 to 2. The most common grade 3 toxicities were nausea (23.3%), neutrophil count decreased (16.7%) and anorexia (6.7%). 11 pts had immune-related adverse events, mostly grade 1 hyperthyroidism (45.5%). There were no grade 4-5 TRAEs. NGS analysis revealed that the mutation frequencies of the 733 genes in the sequencing panel decreased after preoperative treatment in pts with TRG 2-3. The analysis of TIME is undergoing. Conclusions: LP002 plus cisplatin and 5-fluorouracil was safe in pts with resectable gastric or GEJ cancer, and could be a new perioperative treatment option for PD-L1 positive disease. Pts are followed-up for survival outcomes. Clinical trial information: NCT04755543.

Reciprocal interactions between fibroblast and pancreatic neuroendocrine tumor cells: putative impact of the tumor microenvironment

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

IGF2BP1 Promotes Proliferation of Neuroendocrine Neoplasms by Post-Transcriptional Enhancement of EZH2.

Simple SummaryNeuroendocrine neoplasms (NEN) are very heterogeneous malignancies arising at different sites of the body that show an increasing incidence in recent decades. Here, we show that IGF2 mRNA binding protein 1 (IGF2BP1) is highly expressed in NEN cell lines, leading to enhanced cell proliferation. This oncogenic function relies on post-transcriptional stimulation of EZH2 expression by IGF2BP1, resulting in epigenetic silencing of cell cycle inhibitors via tri-methylation of histone H3 at lysine 27 (H3K27me3). Combinatorial pharmacological targeting of IGF2BP1, EZH2, and the EZH2-activator Myc leads to synergistic antiproliferative and proapoptotic effects in NEN cells, representing a novel therapeutic strategy in neuroendocrine malignancies.Neuroendocrine neoplasms (NENs) represent a heterogenous class of highly vascularized neoplasms that are increasing in prevalence and are predominantly diagnosed at a metastatic state. The molecular mechanisms leading to tumor initiation, metastasis, and chemoresistance are still under investigation. Hence, identification of novel therapeutic targets is of great interest. Here, we demonstrate that the RNA-binding Protein IGF2BP1 is a post-transcriptional regulator of components of the Polycomb repressive complex 2 (PRC2), an epigenic modifier affecting transcriptional regulation and proliferation: Comprehensive in silico analyses along with in vitro experiments showed that IGF2BP1 promotes neuroendocrine tumor cell proliferation by stabilizing the mRNA of Enhancer of Zeste 2 (EZH2), the catalytic subunit of PRC2, which represses gene expression by tri-methylation of histone H3 at lysine 27 (H3K27me3). The IGF2BP1-driven stabilization and protection of EZH2 mRNA is m6A-dependent and enhances EZH2 protein levels which stimulates cell cycle progression by silencing cell cycle arrest genes through enhanced H3K27 tri-methylation. Therapeutic inhibition of IGF2BP1 destabilizes EZH2 mRNA and results in a reduced cell proliferation, paralleled by an increase in G1 and sub-G1 phases. Combined targeting of IGF2BP1, EZH2, and Myc, a transcriptional activator of EZH2 and well-known target of IGF2BP1 cooperatively induces tumor cell apoptosis. Our data identify IGF2BP1 as an important driver of tumor progression in NEN, and indicate that disruption of the IGF2BP1-Myc-EZH2 axis represents a promising approach for targeted therapy of neuroendocrine neoplasms.

Combined use of 177 Lu-DOTATATE peptide receptor radionuclide therapy and fluzoparib for treatment of well-differentiated neuroendocrine tumors: A preclinical study.

Peptide receptor radionuclide therapy (177 Lu-DOTATATE) causes DNA strand breaks and has been validated for well-differentiated neuroendocrine tumor treatment. Poly-(ADP-ribose)-polymerase inhibitors have also been used for malignant tumors with deficient DNA repair. We aimed to determine whether the poly-(ADP-ribose)-polymerase inhibitor fluzoparib could enhance the anti-tumor effects of 177 Lu-DOTATATE in neuroendocrine tumor cells and xenografts. The neuroendocrine characteristics of NCI-H727 bronchial carcinoid cells were evaluated by immunofluorescence staining. The synergistic effects of fluzoparib and 177 Lu-DOTATATE were evaluated by cell proliferation and flow cytometry assays. Tumor response and the side effects of combination therapy were also assessed in xenograft mice treated with 77 Lu-DOTATATE and fluzoparib alone or in combination. Somatostatin receptors were specifically expressed in NCI-H727 cells and tumor xenografts. 177 Lu-DOTATATE (22.20MBqmL-1 ) and fluzoparib (50µm) inhibited cell proliferation by 16.6% and 35.6%, respectively, compared to 73.2% in cells treated with their combination. Tumor cell proliferation was significantly suppressed by 177 Lu-DOTATATE (22.20MBqmL-1 , 4.4-fold) and fluzoparib (50µm, 2.1-fold). 177 Lu-DOTATATE caused cell cycle arrest mainly at G1 phase, whereas fluzoparib caused arrest at G2/M phase, and combined treatment with both agents caused cell cycle arrest at G1 phase, similar to 177 Lu-DOTATATE alone. The volume of tumor xenografts was reduced by 18.6% in mice receiving combined treatment, compared to 4.9% and 11.4% in mice treated with 177 Lu-DOTATATE or fluzoparib alone. Fluzoparib can potentiate the anti-tumor effect of 177 Lu-DOTATATE in NCI-H727 cells in a synergistic manner by arresting the cell cycle at G1 phase. Further preclinical and clinical studies are warranted to validate these findings.

Impact of Routine Surveillance Imaging on Detecting Recurrence in Sinonasal Malignancies

<h3>Purpose/Objective(s)</h3> Surveillance imaging guidelines for sinonasal malignancies are varied and lack scientific data supporting the basis of these recommendations. This study wishes to examine the utility of surveillance imaging in detecting local, regional, and distant failures as well as second primary tumors in patients with sinonasal malignancies treated with surgical resection followed by adjuvant radiation. <h3>Materials/Methods</h3> Using an IRB-approved institutional database of head and neck cancer patients, we performed a retrospective review of 41 patients with sinonasal malignancies treated at a single institution between the years 2005 to 2021. Patient information regarding tumor location, staging, pathology, smoking status, alcohol use, chemotherapy, radiation treatment plan, and data surrounding surveillance imaging including type, frequency, and concern for recurrence were collected. Patients were divided into two groups comparing the frequency and type of imaging ordered: patients with <4 scans/year Group 1 and ≥ 4 scans/year Group 2. We compared the time to recurrence between the two groups using log-rank test and Cox proportional hazard ratio. A p-value of < 0.05 was considered the threshold for significance. <h3>Results</h3> Median follow up was 37.5 months (14.4-68.9 months). Overall 80% (n=32) patients had primary nasal cavity malignancies and 20% (n=8) had paranasal sinus disease. Thirteen (32.5%) patients had a squamous cell carcinoma (32.5%), twelve (30.0%) patients had an esthesioneuroblastoma, 5 (12.5%) patients had an adenocarcinoma and 3 (7.5%) patients had sinonasal undifferentiated carcinomas. The remaining few patients had sarcomatoid squamous cell carcinoma, adenoid cystic carcinoma, large cell neuroendocrine, and small cell neuroendocrine tumors – with a majority of patients having advanced disease (AJCC 7^th edition). In 27.5% (n=11) patients there was a recurrence: 4 had local failures, 4 had regional failures, and 3 had distant failures. The type of imaging (CT vs. PET/CT vs. MRI) ordered had a non-significant association with recurrence (p=0.802). There was no association with the frequency (HR: 1.13, 95% CI: 0.73-1.74) and total number of scans (HR: 1.24 [0.93-1.66]) with time to recurrence. Rate of recurrence-free survival at 2-years was 86% and 80% in patients with <4 scans/year and ≥ 4 scans/year, respectively. <h3>Conclusion</h3> In our study, the recurrence rates were limited for patients with sinonasal malignancies treated with definitive intent. Increasing the total number or frequency of scans in the first year after treatment was not associated with time to recurrence. These findings suggest a judicious approach in using post-treatment surveillance imaging.

Primary Small Cell Neuroendocrine Carcinoma of the Larynx: A Case Report

1. Small cell neuroendocrine carcinoma of the larynx is a rare entity. The prognosis of this type of tumor is very poor, and the clinical course is rapidly fatal. We report a case of a 62-year-old patient who presented with a two years history of chronic dysphonia. Laryngoscopy revealed a bulging lesion in the glottic and supraglottic region. Morphological and immunohistochemical studies revealed a small cell neuroendocrine tumor. This patient received chemotherapy associated with concomitant radiotherapy with a good clinical and radiological evolution.

METASTATIC NEUROENDOCRINE TUMOR OF THE OVARY - AN UNUSUAL SITE

A 22 year old female with stage III small cell neuroendocrine carcinoma of the lung presented two years later with a large abdomino-pelvic mass. Core biopsy showed a metastatic high-grade neuroendocrine carcinoma. She responded poorly to chemotherapy. An exploratory laparotomy revealed bilateral large ovarian masses. Total hysterectomy with bilateral salpingo-oophorectomy was performed. Histopathology showed a metastatic high grade neuroendocrine carcinoma of both ovaries, consistent with metastasis from small cell neuroendocrine carcinoma of the lung. Post adjuvant chemotherapy she remained controlled over four years. We present a rare case of small cell neuroendocrine tumor of the lung with metastasis to the ovary.

Phase 1b study of tarlatamab, a half-life extended bispecific T-cell engager (HLE BiTEimmune therapy) targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer (NEPC).

TPS197 Background: NEPC is an aggressive cancer with no standard treatment approach and poor prognosis. It is usually treatment-emergent, occurring in 15%–20% of patients (pts) with metastatic castration-resistant prostate cancer following treatment with androgen signaling inhibitors (ASI) and is characterized by histological transformation from adenocarcinoma to a high-grade neuroendocrine tumor.1 The tumor associated antigen delta-like ligand 3 (DLL3) has been identified as a promising target in both NEPC and small cell lung cancer (SCLC), as it is highly expressed in these tumors and minimally expressed on normal tissue. Tarlatamab is a DLL3-targeting HLE BiTE® immune therapy designed to bind DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. In preclinical studies, tarlatamab induced T-cell dependent lysis of DLL3-expressing neuroendocrine tumor cell lines, including NEPC cells.2 Interim results of an ongoing first-in-human study in pts with SCLC (NCT03319940) show evidence for tarlatamab efficacy with an acceptable safety profile.3 Together, these findings support a clinical study of tarlatamab in NEPC. Methods: NCT04702737 is an open-label, phase 1b study evaluating tarlatamab infusion in pts with metastatic de novo or treatment-emergent NEPC, consisting of dose exploration and then dose expansion. Key eligibility criteria include adults (≥18 y) with metastatic NEPC whose disease progressed/recurred after ≥1 prior line of systemic therapy (platinum-based regimen for de novo NEPC or an ASI if treatment-emergent), measurable disease per RECIST 1.1 with Prostate Cancer Working Group 3 modifications, and ECOG performance status ≤2. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose or recommended phase 2 dose of tarlatamab. Secondary objectives are to evaluate antitumor activity (as assessed by objective response, duration of response, progression-free survival, overall survival, and disease control rate) and characterize pharmacokinetics. Four US and international study sites have been activated with two enrolled pts.

Abstract P3-12-26: Baseline characteristics and survival of neuroendocrine carcinoma of the breast- A SEER database analysis

Abstract Background: Neuroendocrine carcinoma of the breast (NECB) is a malignancy. The estimated incidence of this type of tumor ranges from less than 1% to 5%. The scarcity of data about these tumors creates a challenge for treatment. Prior studies have reported that clinically most NECB behave as other type of cancer, being more common in post-menopausal women. Using population-based cancer data, our study aims to describe the baseline characteristics, tumor biology, and prognosis of patients with NECB. Methods: Using the SEER database of the National Cancer Institute, we identified 433 cases of NECB diagnosed between 2000 and 2018. We assessed the patient age, sex, race, stage, grade of the tumor and histologic type. The additional information of estrogen receptor (ER), progesterone receptor (PR) and HER2 status were also included when available. Kaplan-Meir methods were used to estimate overall survival (OS). Cox proportional-hazard model was used to create multivariable analysis for OS. Results: We found that 427 (98.6%) of the patient were female, while only 6 (1.3%) patients were male. The mean age of diagnosis was 64 years[JA1] , (SD : 14.2 years). Most patients were White (n= 353, 82%), while 52 (12%) were black, and 27 (6.2%) were other race. About the tumor histology, 375 (86.6%) cases were neuroendocrine tumor not otherwise specified, 30 (6.9%) cases were large cell neuroendocrine tumors and 28 (6.4%) were carcinoid tumor of the breast. ER was positive in 70%, PR was positive in 57% of the patients in which these receptors were tested. 194 patients were assessed for Her 2, and only 6(3%) were her2 positive. 183 (42%) had any chemotherapy use, while 250 (58%) had no known use of chemotherapy. 326 patients had a documented stage, of those 77 (17%) were AJCC stage I, 140 (32%) stage II, 39 (9%) stage III and 70 (16%) stage IV. The[JA2] median OS for stage I, II, III, and IV were not-reached, 129, 45 and 13 months, respectively[JA3] . In the univariate analysis for OS, only for tumor grade 3 (HR = 2.2; 95% CI: 1.98,2.52; p= 0.002) , ER negative (HR = 2.0; 95% CI: 1.86,3.62; p= &amp;lt;0.001), PR (HR = 2.4; 95% CI: 2.1,2.63; p= &amp;lt;0.001), surgery (HR = 0.26; 95% CI: 0.11,0.40; p= &amp;lt;0.001), metastasis (HR = 0.19; 95% CI: 0.04,0.34; p= &amp;lt;0.001), stage IV cancer (HR = 2.3; 95% CI: 2.0,2.5; p= &amp;lt;0.001) were statistically significantly associated with OS. In a multivariate model, including age, histology, grade, ER, PR, stage group, metastasis, surgery and chemotherapy. We found that large cell histology (HR = 2.0; 95% CI: 1.0,4.3; p= 0.04), negative ER (HR = 2.0; 95% CI: 1.2,3.5; p= 0.01), negative PR (HR = 2.5; 95% CI: 1.4,4.4; p= 0.002), treatment with surgery (HR = 0.39; 95% CI: 0.22,0.69; p= 0.001), receiving chemotherapy (HR = 0.5; 95% CI: 0.31,0.79; p= 0.003), negative metastasis at diagnosis (HR = 0.05; 95% CI: 0.024,0.12; p= &amp;lt;0.001), cancer stage (HR = 2.3 for stage II and 7.2 for stage III, p&amp;lt;0.01. Stage I used as reference); were significantly associated with OS. Conclusion: Our study shows that NECB is a rare malignancy, and that the AJCC cancer staging can be used to adequately assess prognosis. Large cell histology, ER/PR negative, and advanced AJCC stage were inversely associated with survival, whereas chemotherapy use, surgery, and no metastasis at diagnosis, were positively associated with survival. As in other histologies of breast cancer, surgery and chemotherapy need to be strongly considered when treating NECB. Citation Format: Alvaro Alvarez Soto, Jesus Anampa. Baseline characteristics and survival of neuroendocrine carcinoma of the breast- A SEER database analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-26.

Poor outcome after systemic therapy in secondary high-grade pancreatic neuroendocrine tumors.

Longitudinal changes in pancreatic neuroendocrine tumor (panNET) cell proliferation correlate with fast disease progression and poor prognosis. The optimal treatment strategy for secondary panNET grade (G)3 that has progressed from a previous low- or intermediate-grade to high-grade panNET G3 is currently unknown. This was a single-center retrospective cohort study aimed to characterize treatment patterns and outcomes among patients with secondary panNET-G3. Radiological responses were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. A total of 22 patients were included and received a median of 2 (range, 1–4) treatment lines in 14 different combinations. Median overall survival (OS) was 9 months (interquartile range (IQR): 4.25–17.5). For the 15 patients who received platinum–etoposide chemotherapy, median OS was 7.5 months (IQR: 3.75–10) and median progression-free survival (PFS) was 4 months (IQR: 2.5–5.5). The 15 patients who received conventional panNET therapies achieved a median OS of 8 months (IQR: 5–16.75) and median PFS was 5.5 months (IQR: 2.75–8.25). We observed one partial response on 177Lu DOTA-TATE therapy. In conclusion, this hypothesis-generating study failed to identify any promising treatment alternatives for patients with secondary panNET-G3. This demonstrates the need for both improved biological understanding of this particular NET entity and for designing prospective studies to further assess its treatment in larger patient cohorts.

Anaesthetic Management of a Patient with Von-Hippel-Lindau Syndrome: A Conglomeration of Perplexities

Von-Hippel-Lindau (VHL) syndrome is an autosomal dominant disease with multisystem involvement. Tumours associated with VHL include, hemangioblastomas of the spine and brain, retinal capillary hemangioblastomas, renal cell carcinoma, pheochromocytoma, and neuroendocrine tumours of pancreas. We present a case of a 54 year old female second-degree uterovaginal prolapse scheduled for laparoscopic assisted vaginal hysterectomy. She was diagnosed with adult polycystic kidney disease, pheochromocytoma, parathyroid adenoma, vertebral hemangioma and multiple renal and hepatic cysts. Though genetic testing was not feasible, the co-existing systemic manifestations in this patient were strongly suggestive of Von Hippel Lindau syndrome. Owing to the multi-morbidities, central neuraxial block was deemed appropriate as opposed to general anaesthesia. In concert with the surgeons, it was decided to change the surgical plan to vaginal hysterectomy and avoid adrenaline infiltration at the surgical site, as it is known to precipitate arrythmias. We placed an intra-arterial catheter for continuous blood pressure monitoring before administration of the subarachnoid block and co-loaded the patient with fluids to avoid any drastic hypotension. The patient remained hemodynamically stable throughout the procedure, which could be attributed to extensive pre-operative work-up multi-disciplinary pre-operative optimization and synergistic management with surgical team. Providing anaesthesia to patients with multisystem involvement such as Von Hippel Lindau syndrome can be very challenging. Meticulous pre-anaesthetic evaluation and pre-operative optimization are often crucial. A multidisciplinary approach is often employed to achieve the best possible pre-operative functional status of these patients. Well-coordinated team with flexibility in management tailored to the patient helps achieve the best possible outcomes. Disclaimer: Informed consent was obtained from the patient prior to publication Main Points • Von-Hippel-Lindau (VHL) syndrome is an autosomal dominant disease with multisystem involvement; associated tumours include hemangioblastomas of the CNS, retinal capillary hemangioblastomas, renal cell carcinoma, pheochromocytoma, endolymphatic sac tumours of the middle ear, serous cystadenomas and neuroendocrine tumours of pancreas. • Providing anaesthesia to patients with multisystem involvement such as Von Hippel Lindau syndrome can be very challenging. Meticulous pre-anaesthetic evaluation and pre-operative optimization are often crucial. • A detailed anaesthetic plan, tailored to each patient, has to be formulated in elective cases, after an extensive work-up of the associated tumours. • Extensive pre-operative work-up, a multi-disciplinary approach towards pre-operative optimization and synergistic management with surgical team remains vital in minimizing peri-operative complications. • Anaesthetic implications are often at the nexus of surgical outcomes, hence, proper communication with the surgical team and arrival at a joint plan is crucial.

High-Throughput Analysis to Identify Activators of Notch Signaling.

The Notch pathway regulates many cellular functions in a context-dependent manner. Depending on the cell type, either the activation or inhibition of Notch signaling can influence many processes such as cellular proliferation, specification, differentiation, and survival. The activation of Notch signaling has been shown to have therapeutic advantages in some cancers, thus having a method to identify Notch-activating compounds is needed. In this chapter we outline a method for high-throughput analysis of potential Notch pathway activators in a pancreatic neuroendocrine tumor cell line as an example. We also include the steps for subsequent validation of results and preclinical testing.

Small cell neuroendocrine tumor of prostate presenting with sphenoidal metastasis: Case report

Small cell neuroendocrine tumor of prostate presenting with sphenoidal metastasis: Case report

Composite intestinal adenoma-microcarcinoid: An update and literature review.

Composite intestinal adenoma-microcarcinoid (CIAM) is a rare intestinal lesion consisting of conventional adenoma and small, well differentiated carcinoid [microcarcinoid (MC)] at its base. The incidence of CIAM is 3.8% in surgically resected colorectal polyps. While its pathogenesis is unknown, studies support the role of Wnt/β-catenin pathway in the tumorigenesis of CIAM. CIAMs have been primarily reported in the colon wherein they present as polyps with well-defined margins, similar to conventional adenomatous polyps. MC is usually found in adenomatous polyps with high-risk features such as large size, villous architecture, or high grade dysplasia. Histologically, the MC component is often multifocal and spans 3.9 to 5.8 millimeters in size. MC is usually confined within the mucosa but occasional CIAM cases with MC extending to the submucosa have been reported. MC of CIAM demonstrates bland cytology and inconspicuous proliferative activity. The lesional cells are positive for synaptophysin and 60% to 100% of cases show nuclear β-catenin positivity. MC poses a diagnostic challenge with its morphologic and immunohistochemical resemblance to both benign and malignant lesions, including squamous morules/metaplasia, adenocarcinoma, squamous cell carcinoma, sporadic neuroendocrine tumor and goblet cell adenocarcinoma. CIAM is an indolent lesion with a favorable outcome. Complete removal by polypectomy is considered curative. Awareness and recognition of this rare entity will help arrive at correct diagnosis and improve patient care. Currently, CIAM is not recognized as a subtype of mixed neuroendocrine-non-neuroendocrine neoplasm by WHO.

Abstract P024: Antitumoral effect of telotristat ethyl as a single agent in neuroendocrine tumor cell lines and potential synergies

Abstract Neuroendocrine tumors (NET) comprise a rare and heterogeneous family of tumors arising from cells throughout the diffuse endocrine system. Carcinoid syndrome, a common gastrointestinal and lung NET complication, is mainly caused by serotonin release into the bloodstream, promoting diarrhea, flushing and carcinoid heat disease. By inhibiting the tryptophan hydroxylase, telotristat ethyl diminishes the synthesis of serotonin and improves carcinoid-related bowel movements. However, to our knowledge, there is no data showing the potential activity of telotristat ethyl as anti-tumoral agent and not only as a symptom-reliever . The purpose of this study is to analyze possible anti-tumoral effects of telotristat ethyl in NETs. For this, we used the pancreatic NET cell lines BON-1 and QGP1, and the gastrointestinal cell line HROC57. We treated them with telotristat ethyl as a single agent or in combination with common NET therapies, such as somatostatin analogues, mTOR inhibitors, standard chemotherapy and tyrosine kinase inhibitors. We analyzed the effects of these treatments on cellular viability, apoptosis markers, cell cycle and signaling pathways. Telotristal ethyl as single agent induced apoptosis measured by MTT in all NET cell lines after 72 hours of treatment, with IC50 in the µM range. Telotristat ethyl maintained this apoptotic effect even after serotonin addition. Surprisingly, neither the somatostatin analog octreotide nor the standard NET chemotherapy capecitabin/temozolomide induced apoptosis in BON-1, QGP-1 nor HROC57, suggesting that these cell lines are somatostatin analog- and chemotherapy-resistant. mTOR inhibition by everolimus treatment in NET cell lines induced apoptosis as monotherapy with IC50 in the µM range. Telotristat ethyl combination with everolimus produced a strong synergetic effect, dramatically decreasing cell viability in all NET cell lines. Mechanistically, combination of telotristat ethyl with everolimus promoted increasing levels of the apoptosis marker Anexin V with no major effects on cell cycle. mTOR inhibition by everolimus, alone and in combination with telotristat ethyl, decreased phosphorylated levels of the mTOR pathway readout protein S6 and elevated phosphorylated p42/44 MAPK levels, with no clear effects of telotristat ethyl. Our results show that telotristat ethyl has the capacity to inhibit pancreatic and GI NET cells tumor growth as a single agent and seems synergistic when combined with mTOR inhibitors but not with antiangiogenics or chemotherapy. Citation Format: Arantzazu Sierra Ramirez, Marinela Méndez, Adrián Plaza, Andrés Pastor, Javier Molina Cerrillo, Pablo José Fernández Marcos, Teresa Alonso Gordoa, Enrique Grande Pulido. Antitumoral effect of telotristat ethyl as a single agent in neuroendocrine tumor cell lines and potential synergies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P024.

MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts

The MYCN oncoprotein drives the development of numerous neuroendocrine and pediatric tumors. Here we show that MYCN interacts with the nuclear RNA exosome, a 3'-5' exoribonuclease complex, and recruits the exosome to its target genes. In the absence of the exosome, MYCN-directed elongation by RNA polymerase II (RNAPII) is slow and non-productive on a large group of cell-cycle-regulated genes. During the S phase of MYCN-driven tumor cells, the exosome is required to prevent the accumulation of stalled replication forks and of double-strand breaks close to the transcription start sites. Upon depletion of the exosome, activation of ATM causes recruitment of BRCA1, which stabilizes nuclear mRNA decapping complexes, leading to MYCN-dependent transcription termination. Disruption of mRNA decapping in turn activates ATR, indicating transcription-replication conflicts. We propose that exosome recruitment by MYCN maintains productive transcription elongation during S phase and prevents transcription-replication conflicts to maintain the rapid proliferation of neuroendocrine tumor cells.

The Prognostic and Predictive Role of Chromogranin A in Gastroenteropancreatic Neuroendocrine Tumors - A Single-Center Experience.

Chromogranin A (CgA) is a non-specific biomarker excreted by neuroendocrine tumor (NET) cells. Elevation of circulating CgA level can be detected in gastroenteropancreatic (GEP)-NET patients and has been shown to correlate with tumor burden. The prognostic and predictive roles of CgA level and the change of CgA level are controversial. In this study, we retrospectively analyzed 102 grade 1/2 GEP-NET patients with available baseline or serial follow-up CgA levels from the National Cheng Kung University Hospital to evaluate the association between circulating CgA level and the tumor extent, overall survival (OS), and tumor response prediction. The baseline characteristics, baseline CgA level, and change of CgA level during follow-up and their association was analyzed. Sixty cases had baseline CgA levels available prior to any treatment and ninety-four cases had serial follow-up CgA levels available during treatment or surveillance. Baseline CgA levels were associated with stage and sex. Higher baseline CgA levels were associated with worse OS after adjusting for sex, stage, grade, primary site, and functionality (hazard ratio=13.52, 95% confidence interval (CI), 1.06-172.47, P=0.045). The cross-sectional analysis for the change of CgA level during follow-up showed that a ≥ 40% increase of CgA meant a higher probability of developing tumor progression or recurrence than those with a < 40% increase of CgA level (odds ratio=5.04, 95% CI, 1.31-19.4, P=0.019) after adjusting for sex, age, grade, stage, and functionality. Our study results suggest that CgA may be a predictive marker for tumor burden, OS, and tumor progression in GEP-NET patients.