Types Of Neuroendocrine Tumors Research Articles

Efficacy and Safety of [177Lu]Lu-DOTA-TATE in Adults with Inoperable or Metastatic Somatostatin Receptor-Positive Pheochromocytomas/Paragangliomas, Bronchial and Unknown Origin Neuroendocrine Tumors, and Medullary Thyroid Carcinoma: A Systematic Literature Review

We have performed a systematic review to evaluate the efficacy and safety of [177Lu]Lu-DOTA-TATE, a radioligand therapy, in advanced somatostatin receptor-positive pheochromocytoma/paraganglioma (PPGL), thymic neuroendocrine tumor (NET), bronchial NET, unknown primary NET, or medullary thyroid carcinoma (MTC). Studies identified in PubMed from inception to 13 May 2021 must have assessed [177Lu]Lu-DOTA-TATE as a single agent and reported outcome data for the specific NET types of interest. Two independent reviewers performed the screening and data extraction, resulting in 16 publications: PPGL (n = 7), bronchial NETs (n = 6; one also included NETs of unknown origin), and MTC (n = 3). Overall, [177Lu]Lu-DOTA-TATE offers encouraging antitumor activity (overall tumor response rates and disease control rates) across NET types. Safety was favorable with most adverse events mild to moderate in severity, transient, and consistent with those seen in patients with gastroenteropancreatic (GEP)-NETs. [177Lu]Lu-DOTA-TATE has been used effectively in clinical practice to treat NETs of non-GEP origin.

Gastric Neuroendocrine Tumor Type 1: A Case Report

33-year-old patient who is referred to Endocrinology Outpatient Consultation in March 2021 due to the finding in gastric polyp biopsy 9 mm sessile located in greater curvature, of low-grade neuroendocrine tumor (ki-67 < 3%) without infiltration of the muscularis layer own. It is followed jointly with the Digestive Service, performing mucosectomy in April 2021 on carcinoid in major curvature of the stomach, where there is no evidence of residual tumor in the anatomo-pathological study (A-P). After completing the study with other complementary tests, gastric neuroendocrine tumor type 1 is diagnosed against the background of chronic atrophic gastritis. At present, the patient continues with periodic gastroscopic check-ups scheduled by the Digestive Service.

An unusual association of folic acid deficiency with gastric neuroendocrine tumor type I

The association of gastric neuroendocrine tumour type I with macrocytic anaemia due to vitamin B12 deficiency is commonly encountered. The etiological cause of macrocytic anaemia must always be precisely established for the subsequent treatment guidance. We present the case of a 63-year-old patient admitted for marked physical asthenia, palpitations, abdominal pain, flatulence, paresthesia in the upper and lower limbs and concentration difficulties. Clinical examination revealed pale, dry skin, Hunter's glossitis, and tachycardic heart sounds. Bloodwork showed pancytopenia with macrocytic normochromic anaemia, vitamin B12 within normal limits, but with low folic acid levels. The reticulocyte crisis was documented on day three after initiating folic acid treatment. Exploration by upper digestive endoscopy and colonoscopy described multiple polypoid tumours in the greater curvature of the stomach. The histopathological and immunohistochemical examination lead to the diagnosis of gastric neuroendocrine tumours (NET) type G1. To our knowledge, there are no reports about an association of this type of tumour with folate deficiency-induced anaemia.

Spectral Computed Tomography-Derived Iodine Content and Tumor Response in the Follow-Up of Neuroendocrine Tumors-A Single-Center Experience.

Spectral computed tomography (SCT) allows iodine content (IC) calculation for characterization of hypervascularized neoplasms and thus might help in the staging of neuroendocrine tumors (NETs). This single-center prospective study analyzed the association between SCT-derived IC and tumor response in the follow-up of metastasized NETs. Twenty-six patients with a median age of 70 years (range 51-85) with histologically proven NETs and a total of 78 lesions underwent SCT for staging. Because NETS are rare, no primary NET types were excluded. Lesions and intralesional hotspots were measured in virtual images and iodine maps. Tumor response was classified as progressive or nonprogressive at study endpoint. Generalized estimating equations served to estimate associations between IC and tumor response, additionally stratified by lesion location. Most commonly affected sites were the lymph nodes, liver, pancreas, and bones. Median time between SCT and endpoint was 64 weeks (range 5-260). Despite statistical imprecision in the estimate, patients with higher IC in lymphonodular metastases had lower odds for disease progression (adjusted OR = 0.21, 95% CI: 0.02-2.02). Opposite tendencies were observed in hepatic and pancreatic metastases in unadjusted analyses, which vanished after adjusting for therapy and primary tumor grade.

Lateral transperitoneal laparoscopic management for paragangliomas in para-aortic position: Surgical experience from case reports of three patients

Paragangliomas are a type of neuroendocrine tumour with catecholamine secretion outside of the adrenal medulla. These tumours are frequently found in the para-aortic region, which makes them difficult to manage laparoscopically. We herein present a case report of three patients with paragangliomas in a difficult superior para-aortic position. All cases had symptoms of catecholamine release with uncontrolled episodic hypertension and had their tumours successfully removed by transperitoneal laparoscopic management. We have found this method to be a suitable approach because it reveals a wide surgical field and a view over all organs, especially blood vessels around the tumour. Although blood and urine dopamine and noradrenaline levels were not measured postoperatively, all three patients were discharged without complication and they did not display any more clinical symptoms. Lateral transperitoneal laparoscopic surgery provided a wide field of view, which clearly revealed the tumour and surrounding components indicating it is one of the safest and most effective approaches, especially for paragangliomas adjacent to large blood vessels.

Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists.

Peptide receptor radionuclide therapy (PRRT) has over the last two decades emerged as a very promising approach to treat neuroendocrine tumors (NETs) with rapidly expanding clinical applications. By chelating a radiometal to a somatostatin receptor (SSTR) ligand, radiation can be delivered to cancer cells with high precision. Unlike conventional external beam radiotherapy, PRRT utilizes primarily β or α radiation derived from nuclear decay, which causes damage to cancer cells in the immediate proximity by irreversible direct or indirect ionization of the cells' DNA, which induces apoptosis. In addition, to avoid damage to surrounding normal cells, PRRT privileges the use of radionuclides that have little penetrating and more energetic (and thus more ionizing) radiations. To date, the most frequently radioisotopes are β- emitters, particularly Yttrium-90 (90Y) and Lutetium-177 (177Lu), labeled SSTR agonists. Current development of SSTR-targeting is triggering the shift from using SSTR agonists to antagonists for PRRT. Furthermore, targeted α-particle therapy (TAT), has attracted special attention for the treatment of tumors and offers an improved therapeutic option for patients resistant to conventional treatments or even beta-irradiation treatment. Due to its short range and high linear energy transfer (LET), α-particles significantly damage the targeted cancer cells while causing minimal cytotoxicity toward surrounding normal tissue. Actinium-225 (225Ac) has been developed into potent targeting drug constructs including somatostatin-receptor-based radiopharmaceuticals and is in early clinical use against multiple neuroendocrine tumor types. In this article, we give a review of preclinical and clinical applications of 225Ac-PRRT in NETs, discuss the strengths and challenges of 225Ac complexes being used in PRRT; and envision the prospect of 225Ac-PRRT as a future alternative in the treatment of NETs.

Abstract B029: LSD1-HDAC6 dual inhibitor JBI-802 is an epigenetic modulating agent with a novel mechanism of action that target MYC amplification in multiple neuroendocrine tumor types

Abstract MYC is considered a master regulator of human cancers by modulating the transcription of numerous cancer-related genes. MYC amplification is reported in about 15% of all human cancers and is generally associated with poor prognosis and resistance to treatments. Focal amplification of MYC together with mutation in RB1 and p53 is an important event in the metastatic process of neuroendocrine tumor development. While limited options are available for direct targeting, transcriptional modulation via epigenetic modulating agent could be an attractive and viable option to target neuroendocrine cancers. JBI-802 inhibits the transcriptional regulator coREST via its component LSD1/HDAC6 therefore blocking neuroendocrine transdifferentiation and inducing cell death resulting in activity against neuroendocrine tumors. At the same time, this molecule has shown a good safety profile in toxicological studies. We have now identified a novel aspect of JBI-802 mechanism of action, the ability to induce downregulation of MYC RNA and degradation of MYC protein both in vitro and in animal models of two neuroendocrine tumors, small cell lung cancer and neuroendocrine prostate cancer JBI-802 showed significant anti-proliferative activity (0.2 to 1 µM) against several cancer cell lines as shown by Alamar blue or CTG assays. Sensitive ones included small cell lung cancer (SCLC), gastric cancer, breast cancer cell lines with RB1 mutation. Interestingly, dual inhibitor JBI-802 was also active in cell lines with MYC over-expression, while LSD1 selective inhibitors have been reported to be inactive in these cell lines. JBI-802 also inhibited MYC at RNA as well as protein level in hematological and solid tumors as assessed by RT-qPCR at RNA level and by Western blotting at protein level, while single agent LSD1 and HDAC6 inhibitors did not show significant modulation. JBI-802 also showed strong tumor growth inhibition of these tumors in mouse xenograft models. MYC levels showed a dose dependent inhibition in these tumors when tested at the end of the study. Only dual inhibition of both LSD1/HDAC6 with JBI-802 as opposed to single target inhibition is able to effectively downregulate MYC level and achieve efficacy in MYC amplified models in vivo and in vitro. This novel mechanism increases the potential population of neuroendocrine patients that could be sensitive to this compound, going beyond the proof of principle already established preclinically and clinically by single target LSD1 inhibitors. Therefore, by targeting 2 major pathways in neuroendocrine tumor development, JBI-802 novel mechanism of action is uniquely suited for the treatment of high unmet neuroendocrine tumors like small cell lung cancer, neuroendocrine prostate cancer and advanced, MYC amplified tumors. Based on this rationale, JBI-802 is being tested in phase 1/2 clinical trial focus on this type of tumors. Citation Format: Dhanalakshmi Sivanandhan, Sridharan Rajagopal, Chandru Gajendran, Naveen Sadhu, Mohd Zainuddin, Ramachandraiah Gosu, Luca Rastelli. LSD1-HDAC6 dual inhibitor JBI-802 is an epigenetic modulating agent with a novel mechanism of action that target MYC amplification in multiple neuroendocrine tumor types. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B029.

Co-Expression of Adaptor Protein FAM159B with Different Markers for Neuroendocrine Cells: An Immunocytochemical and Immunohistochemical Study.

Little is known about the adaptor protein FAM159B. Recently, FAM159B was shown to be particularly expressed in neuroendocrine cells and tissues, such as pancreatic islets and neuroendocrine cells of the bronchopulmonary and gastrointestinal tracts, as well as in different types of neuroendocrine tumours. To gain insights into possible interactions of FAM159B with other proteins and/or receptors, we analysed the co-expression of FAM159B and various neuroendocrine-specific markers in the cancer cell lines BON-1, PC-3, NCI-h82, OH-1, and A431 and also in human pancreatic tissues and pancreatic neuroendocrine tumours. The markers included prominent markers of neuroendocrine differentiation, such as chromogranin A (CgA), neuron-specific enolase (NSE), synaptophysin (SYP), insulinoma-associated protein 1 (INSM1), neural cell adhesion molecule 1 (NCAM1), serotonin (5-HT), somatostatin-14/28 (SST), and several receptors that are typically expressed by neuroendocrine cells, such as dopamine receptor 2 (D2R), somatostatin receptor (SSTR) 1, 2, 3, 4 and 5, and regulator of G-protein signalling 9 (RGS9). FAM159B was expressed evenly throughout the cytosol in all five cancer cell lines. Immunocytochemical and immunohistochemical analyses revealed co-expression of FAM159B with SYP, INSM1, RGS9, D2R, SSTR2, SSTR3, SSTR4, and SSTR5 and strong overlapping co-localisation with NSE. Double-labelling and co-immunoprecipitation Western blot analyses confirmed a direct association between FAM159B and NSE. These results suggest the involvement of FAM159B in several intracellular signalling pathways and a direct or indirect influence on diverse membrane proteins and receptors.

Epilepsy associated with pituitary neuroendocrine tumors: Current status of problem and interdisciplinary approach

This literature review is devoted to the problem of epilepsy caused by pituitary neuroendocrine tumors: their detailed classification with the latest recommendations of the World Health Organization 2022, clinical picture of each variant of pituitary neuroendocrine tumor in a complex multidisciplinary approach are considered. The main feature of the review is a detailed consideration of the epilepsy associated with this condition, which is considered to be a rather rare manifestation of the disease (incidence in patients is 0.5 %), due to which very few cases of epilepsy in patients with pituitary adenoma have been described in the literature. Our work has analyzed the fundamental works of domestic scientists in this field, as well as current information from foreign sources and most of the available clinical cases of epilepsy in this group of patients, revealing in detail the pathogenesis of epilepsy at all levels, including molecular changes. Modern techniques for the treatment approach in this group of patients are also described, the effectiveness of drug and surgical therapy is analyzed according to the criteria of the frequency of long-term persistent remission and recurrence, side effects of drugs and complications of transsphenoidal tumor resection are reviewed, including in terms of possible epilepsy; conclusions about the most rational and effective approach to treatment of various types of hypophysial neuroendocrine tumors are drawn.

Integrated proteogenomic characterization across major histological types of pituitary neuroendocrine tumors

Pituitary neuroendocrine tumor (PitNET) is one of the most common intracranial tumors. Due to its extensive tumor heterogeneity and the lack of high-quality tissues for biomarker discovery, the causative molecular mechanisms are far from being fully defined. Therefore, more studies are needed to improve the current clinicopathological classification system, and advanced treatment strategies such as targeted therapy and immunotherapy are yet to be explored. Here, we performed the largest integrative genomics, transcriptomics, proteomics, and phosphoproteomics analysis reported to date for a cohort of 200 PitNET patients. Genomics data indicate that GNAS copy number gain can serve as a reliable diagnostic marker for hyperproliferation of the PIT1 lineage. Proteomics-based classification of PitNETs identified 7 clusters, among which, tumors overexpressing epithelial-mesenchymal transition (EMT) markers clustered into a more invasive subgroup. Further analysis identified potential therapeutic targets, including CDK6, TWIST1, EGFR, and VEGFR2, for different clusters. Immune subtyping to explore the potential for application of immunotherapy in PitNET identified an association between alterations in the JAK1-STAT1-PDL1 axis and immune exhaustion, and between changes in the JAK3-STAT6-FOS/JUN axis and immune infiltration. These identified molecular markers and alternations in various clusters/subtypes were further confirmed in an independent cohort of 750 PitNET patients. This proteogenomic analysis across traditional histological boundaries improves our current understanding of PitNET pathophysiology and suggests novel therapeutic targets and strategies.

Hyperplasia of enterochromaffin-like (ECL) cells as a precursor of neuroendocrine gastric tumors in autoimmune gastritis

The purpose of this publication is to update knowledge about chronic autoimmune gastritis and about cases of hyperplasia of enterochromaffin-like (ECL) cells as precursors of the development of neuroendocrine gastric tumor type 1 due to clinical example’s demonstration. Discussion: the types and main characteristics of neuroendocrine tumors of the stomach were discussed, in particular tumors type 1 associated with autoimmune gastritis. The mechanisms of formation of neuroendocrine tumors in the stomach against the background of an autoimmune process were presented, two clinical examples presenting the algorithm of diagnosis of autoimmune gastritis and associated neuroendocrine tumors were presented. Both clinical examples demonstrated the presence of subepithelial formations of the stomach body according to FGDS, which have not been morphologically identified. Timely repeated FGDS with sampling of biopsies according to the OLGA standard made it possible to verify the formations, and the serological markers helped in clarifying the diagnosis and morphological nature of tumors. Conclusion: analysis of clinical data, anamnesis and esophagoduodenoscopy with morphological evaluation of the gastric mucosa biopsy may help to find out the cause and nature of chronic inflammation in the gastric mucosa. Atrophy of the glands in the stomach body, pseudopiloric metaplasia, hyperplasia of enterochromaffin (ECL) cells are sufficient morphological criteria for autoimmune gastritis. The study of the level of chromogranin A in blood serum can be considered as a marker of the development of type 1 neuroendocrine gastric tumor in patients with autoimmune gastritis and the presence of polyps in the stomach body.

S2824 Endoscopic Papillectomy for Gangliocytic Paraganglioma

Introduction: Neuroendocrine tumors (NET) most commonly occur in the small bowel; however, NETs at the ampulla of Vater are rare and more aggressive, irrespective of size. Gangliocytic paragangliomas (GP) are a more benign type of NET that must be properly differentiated from other similar appearing NETs, which may carry a worse prognosis. Case Description/Methods: A 77-year-old man presented with right flank pain and was incidentally found to have a duodenal mass in the periampullary region measuring 11 x 8 mm, with dilation of the common bile duct to 10 mm on computed tomography scan. Laboratory data showed normal liver function tests. Esophagogastroduodenoscopy revealed a subepithelial lesion at the ampulla, and endoscopic ultrasound (EUS) demonstrated a 15 x 12 mm hypoechoic subepithelial lesion arising from the submucosa. A fine needle biopsy was performed and immunohistochemical staining was positive for synaptophysin, chromogranin and pankeratin, consistent with neoplasm with neuroendocrine differentiation. Subsequent DOTATATE PET scan showed uptake in the ampullary region with no uptake anywhere else. The case was discussed in multidisciplinary conference, and the decision was made to proceed with endoscopic papillectomy given concerns for NET. An endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic papillectomy was performed. A biliary and pancreatic duct stent was placed. The pathology was consistent with gangliocytic paraganglioma, and the patient had no adverse events with removal of stents after four weeks. (Figure) Discussion: Gangliocytic paragangliomas typically arise in the second part of the duodenum, presenting as gastrointestinal bleeding and abdominal pain. Although its distribution varies significantly, GPs in particular embody epithelioid, spindle-shaped, and ganglion-like cell types. While GPs are predominantly benign, rare reports of spread to regional lymph nodes are present. Our report shows that endoscopic papillectomy is safe and effective for both diagnostic and therapeutic purposes in the management of ampullary gangliocytic paragangliomas.Figure 1.: Ampullary lesion prior to (A) and after endoscopic papillectomy (B), with histopathology consistent with ​gangliocytic paraganglioma (C).

Association between fibrosis markers and kidney function following peptide receptor radionuclide therapy in patients with neuroendocrine tumours

Peptide receptor radionuclide therapy (PRRT) is a treatment for neuroendocrine tumours (NET). Renal impairment is a known side effect due to kidney fibrosis. We investigated the association between novel specific fibrosis markers and kidney function following PRRT. We included 38 patients who had all finished PRRT. In serum and urine, we analysed levels of three different fibrosis markers, PRO-C6 (type VI collagen formation), PRO-C3 (type III collagen formation) and C3M (type III collagen degradation). We determined kidney function by the 51Cr-EDTA plasma clearance. We used Wilcoxon rank sum test and Spearman’s rank correlation to evaluate the association between the fibrosis markers and kidney function. We included 38 NET patients, 25 small-intestinal NET, 6 pancreatic NET, 2 pulmonary NET and 5 other types of NET. Median age was 69 years (IQR: 61–73). Median time from last PRRT to inclusion was 8 months (IQR: 3–20). We found significantly increased levels of serum PRO-C6 (p = .007) and urinary PRO-C6 (p = .033) and significantly decreased levels of urinary C3M (p = .035) in patients with impaired kidney function. Further, we observed a negative association between serum PRO-C6 and kidney function (rho = −0.33, p = .04) and a positive association between urinary C3M and kidney function (rho = 0.37, p = .02). We showed an association between the three fibrosis markers, serum PRO-C6, urinary PRO-C6 and urinary C3M and kidney function. These markers may help to improve the understanding of potential pathological tissue turnover and potentially improve monitoring of kidney function after PRRT in NET patients.

Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common type of neuroendocrine tumors and are being increasingly identified in clinical practice. The diagnosis, staging, management, and surveillance of GEP-NETs rely heavily on endoscopy, and consequently, it is important for gastroenterologists to have a solid understanding of these tumors. This article reviews the presentation, diagnosis, and management of both localized and advanced GEP-NETs, with increased emphasis on the role of endoscopy, to enable gastroenterologists and other practitioners to have the necessary tools for the care of patients with these tumors.

Molecular deciphering of primary liver neuroendocrine neoplasms confirms their distinct existence with foregut-like profile.

Isolated hepatic localizations of neuroendocrine tumors (NETs) are generally considered as metastatic NETs of unknown primary but could correspond to primary hepatic NETs (PHNETs), a poorly explored entity. We aimed to describe the clinicopathological and molecular features of PHNETs and compare them with other primary NETs. We assembled a retrospective cohort of patients managed for hepatic localization of NET without extra-hepatic primary tumor after exhaustive clinical, imaging, and immunohistochemical characterization. We performed whole-exome sequencing with mutational and copy number analysis. Transcriptomic profiles were compared with pancreatic (n = 31), small-bowel (n = 22), and lung (n = 15) NETs using principal component analysis, unsupervised clustering, and gene set enrichment analysis. Among 27 screened patients, 16 had PHNET (solitary tumor in 63%, median size 11 cm, G2 NETs in 81%) following clinical and pathological review. DNA analyses showed 'foregut-like' genomic profiles with frequent alterations in pathways of Fanconi DNA repair (75%), histone modifiers (58%), adherens junctions (58%), and cell cycle control (50%). The most frequently involved genes were KMT2A (58%), ATM (42%), CDH1, CDKN2C, FANCF, and MEN1 (33% each). Transcriptomic analyses showed that PHNETs clustered closer to foregut (pancreatic, lung) NETs than to midgut (small-bowel) NETs, while remaining a distinct entity with a specific profile. Assessment of potentially predictive biomarkers suggested efficacy of treatments usually active in foregut NETs. In conclusion, PHNETs display a foregut-like molecular profile distinct from other types of NETs, with recurrent molecular alterations. Upon exhaustive work-up to exclude an unrecognized primary tumor, PHNETs should not be considered metastatic NETs from an unknown primary. © 2022 The Pathological Society of Great Britain and Ireland.

Abstract 197: A systemic model derivation platform for generating 3D neuroendocrine tumor cell spheroids to accelerate cancer research

Abstract The Broad Cancer Cell Line Factory (CCLF) aims to increase the number and representation of in vitro/ex vivo cell models for common and rare cancer types. Neuroendocrine tumor (NET) cell model derivation is one of the CCLFs focus because it lacks well-characterized, publicly available models.Two major barriers existed in deriving NET cell models, including how to collect sufficient patient tumor tissue samples for the model derivation pilot and how to systematically iterate model derivation strategies since there is no prior knowledge for NET cell model generation success. Thus, we partnered with the MD Anderson Cancer Center, the Dana-Farber Cancer Institute, and the Rare Cancer Research Foundation to collect patient tissue samples. All patient’s NET tissues were sequenced with a targeted Pan-Cancer panel to ensure high tumor content. To reduce fibroblast outgrowth, we combined an empirical rich media matrix (HYBRID technology) with a 3D spheroid culture system to initiate one sample in 16-64 conditions. The growing cultures at passage 3-5 were genomically credentialed to ensure the driver events matched with the original patient tissue. So far, we have received more than 70 NET samples. While several derived models are still under culture, we successfully generated 5 genomically verified NET tumor models, including small intestinal, pancreas, and liver subtypes. To phenotypically characterize these NET models, neuroendocrine biomarkers such as chromogranin A, synaptophysin, SSTR2, and VMAT 1/2 were also evaluated using qRT-PCR and ELISA. We observed that these NET spheroid models display long doubling times (2-4 weeks) at later passages which limits their utility for large scale perturbation experiments and model sharing capability with the research community. While we are currently working on several strategies to improve the propagation ability in these models, 1 (out of 5) model has reached passage 15 with a 3 day doubling time. Genomic studies, such as RNAseq, will be performed to address the model transcriptome changes after overcoming growth plateaus. Here we showed that it is feasible to derive NET models from patient biospecimens using our HYBRID strategy. As we expand our NET cohort, we will further refine disease-specific model generation protocols for different NET types. Our goal is to share our model generation experience and make these tumor cell models publicly available to the research community in order to accelerate cancer research. Citation Format: Adel Attari, Madison Liistro, Barbara Van Hare, Jennifer Chan, Emma Coleman, Tim Heffernan, Bianca Amador, Matthew Meyerson, Jesse Boehm, William Sellers, Yuen-Yi (Moony) Tseng. A systemic model derivation platform for generating 3D neuroendocrine tumor cell spheroids to accelerate cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 197.

Malignant insulinoma: Can we predict the long-term outcomes?

Insulinomas are the most frequent type of functional pancreatic neuroendocrine tumors with a variety of neuroglycopenic and autonomic symptoms and well-defined diagnostic criteria; however, prediction of their clinical behavior and early differentiation between benign and malignant lesions remain a challenge. The comparative studies between benign and malignant cases are limited, suggesting that short clinical history, early hypoglycemia during fasting, high proinsulin, insulin, and C-peptide concentrations raise suspicion of malignancy. Indeed, malignant tumors are larger with higher mitotic count and Ki-67 proliferative activity, but there are no accurate histological criteria to distinguish benign from malignant forms. Several signaling pathways have been suggested to affect the pathophysiology and behavior of insulinomas; however, our knowledge is limited, urging a further understanding of molecular genetics. Therefore, there is a need for the identification of reliable markers of metastatic disease that could also serve as therapeutic targets in patients with malignant insulinoma. This opinion review reflects on current gaps in diagnostic and clinical aspects related to the malignant behavior of insulinoma.

Characteristics of patients with neuroendocrine tumors in the United States: A study of 392,412 patients.

10572 Background: To evaluate the characteristics and trends amongst patients with neuroendocrine tumors in the United States. Methods: Data was obtained from the United States Cancer Statistics database from 2001 to 2018. SEER*Stat 8.3.9.2 and Joinpoint regression program 4.9.0.0 were used to calculate characteristics and trends of these cancers per 100,000. The age-adjusted incidences were determined based on the standard population in the United States from 2000. Results: Of 392,412 patients with neuroendocrine tumors, 53.1% were identified in women and 46.9% in men. White, Black, Hispanic, Asian/Pacific Islander and unknown race comprised 73.6%, 14.1%, 7.8%, 2.7%, and 1.7% of the patient population respectively. The majority (64.7%) of tumors originated from the digestive system, followed by 24.5% from the respiratory system. In 2018, the incidence of all neuroendocrine tumors was higher in older (70-79 years) patients as compared to younger (< 50 years) ones at 30.17 vs. 2.79/100,000, in women as compared to men at 8.36 vs. 7.77/100,000, and in White patients as compared to Black, Hispanic, and Asian/Pacific Islander patients (10.82, 10.15, 5.08 and 4.80/100,000 respectively). Amongst different types of neuroendocrine tumors, those originating from the digestive system had the highest incidence at 6.72/100,000 in the year 2018 with colon tumors being the most common subtype. On trend analysis, the groups with the highest annual percent increase included: younger (< 50 years) patients increasing at 5.06%, Hispanic patients rising at 6.44%, and appendiceal tumors increasing at 12.89% per year. On intersection analysis, Black patients between the ages of 70-79 had the highest incidence at 33.39/100,000, while younger (< 50 years) Hispanic patients had the largest increase at 6.22% per year. Conclusions: The incidence of neuroendocrine tumors has increased over our study period. The highest incidence was found in older Non-Hispanic Black patients, with younger Hispanic patients having the highest annual percent increase. Further studies are warranted to better characterize the reasons for these trends and disparities amongst minority patients affected by these tumors.

Second primary malignancies (SPM) in patients with gastrointestinal stromal tumors (GIST): 10-year experience from the Ottawa Hospital (TOH).

11536 Background: The secondary malignancies in patients with GIST are relatively high. We present our 10-year experience of SPM in patients with GIST from a regional Cancer Centre in Canada. Methods: A retrospective cohort study was performed in all GIST patients treated at TOH between January 2011 and December 2021. Patients were identified using ICD-10 codes and electronic medical records reviewed. Clinicopathological data were analyzed. Logistic regression analysis was used to evaluate associated factors with SPM. Survival analysis was estimated with the use of the Kaplan-Meir method and compared by log-rank test. Results: In total, 248 patients with GIST were identified. Of these patients, 61 (25%) had SPM; synchronous (9, 15%) and metachronous (52, 85%). Nine patients had two additional primary cancers other than GIST, and four patients had three additional primary cancers. The median age at diagnosis was 70 (range 44 – 90) years, and males were (59%). The most common SPMs were skin cancer (14, 17%), melanoma (5), and non-melanoma (9), followed by prostate cancer (13, 16%) and breast cancer (12, 15%). Colorectal cancer and hematological malignancies were found in (5, 11%) patients each, while RCC was found in (4, 6%). Thyroid cancer, lung cancer, neuroendocrine tumor, bladder cancer, thymoma, and other types of cancers were collectively found in 15 patients (24%). The majority (57%) of SPM diagnosed before GIST, 30% after GIST. The most common primary GIST locations were in the stomach (62%), followed by the small bowel (30%), and the most common histology was spindle cell (69%), followed by mixed histology (13%). The majority of GIST were localized (46 patients, 75%). Based on Miettinen risk classes for non-metastatic GIST, 74% had zero to low-risk disease, while 26% had moderate or high-risk disease. There was no association between SPM and GIST primary site (p = 0.4), TNM stage (p = 0.8), histology (p = 0.2), Mitosis (p = 0.5), and Miettinen risk class (p = 0.6). The median follow-up time was 53 months (range 1 – 132), and four patients lost follow-ups. Five years overall survival of SPM group vs. non SPM, 79.8% vs. 94.1%, (p = 0.03). Cox regression did not reveal a significant association with the covariants Conclusions: We observed that one out of four GIST patients have SPM. Skin, prostate, breast cancers were the most common SPM associated with GIST. Molecular studies are needed to explore the association/underlying mechanisms of GIST with these malignancies.

Prognostic Value of the Largest Lesion Size for Progression-Free Survival in Patients with NET Undergoing Salvage PRRT with [177Lu]Lu-DOTATOC.

Simple SummaryPeptide receptor radionuclide therapy (PRRT) using radionuclide-labeled somatostatin analogues is based on the overexpression of somatostatin receptors on neuroendocrine tumors and is shown to have a good safety profile and efficacy in different types of metastatic neuroendocrine tumors. As this therapy is usually not curative, most patients experience disease progression after initial PRRT. In these cases, retreatment with PRRT, also called salvage PRRT, can be a treatment option, but little is known about the efficacy and possible risk factors. In this retrospective study that included 32 patients, we found that the size of the largest lesion is a significant predictor of disease progression after salvage PRRT. This risk factor is easy to obtain and can help identify patients who may benefit from intensified follow-up strategies.(1) Background: retreatment with radionuclide-labeled somatostatin analogues following disease progression after initial treatment cycles is often referred to as salvage peptide receptor radionuclide therapy (salvage PRRT). Salvage PRRT is shown to have a favorable safety profile in patients with metastatic neuroendocrine tumors (NETs), but numerous questions about the efficacy and prognostic or predictive factors remain to be answered. The purpose of this study was to evaluate two parameters that have shown prognostic significance in progression-free survival (PFS) in initial PRRT treatment, namely the size of the largest lesion (LLS) and the De Ritis ratio (aspartate aminotransferase (AST)/alanine aminotransferase (ALT)), as prognostic factors in the context of salvage PRRT. In addition, the PFS after initial PRRT was evaluated as a predictor of the PFS following salvage PRRT. (2) Methods: retrospective, monocentric analysis in 32 patients with NETs (gastroenteropancreatic, 23; unknown primary, 7; kidney, 1; lung, 1) and progression after initial PRRT undergoing retreatment with [177Lu]Lu-DOTATOC. The prognostic values of LLS, the De Ritis ratio, and PFS after initial treatment cycles regarding PFS following salvage PRRT were evaluated with univariable and multivariable Cox regression. PFS was defined as the time from treatment start until tumor progression according to RECIST 1.1 criteria, death from any cause or start of a new treatment due to progression of cancer-related symptoms (namely carcinoid syndrome). (3) Results: progression after salvage PRRT was observed in 29 of 32 patients with median PFS of 10.8 months (95% confidence interval (CI), 8.0–15.9 months). A higher LLS (hazard ratio (HR): 1.03; p = 0.002) and a higher De Ritis ratio (HR: 2.64; p = 0.047) were associated with shorter PFS after salvage PRRT in univariable Cox regression. PFS after initial PRRT was not associated with PFS following salvage PRRT. In multivariable Cox regression, only LLS remained a significant predictor. (4) Conclusions: the size of the largest lesion is easy to obtain and might help identify patients at risk of early disease progression after salvage PRRT. Validation is required.