Gastrointestinal Neuroendocrine Tumors Research Articles

Recent epidemiology of patients with gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NEN) in Japan: a population-based study

BackgroundThe worldwide prevalence and incidence of neuroendocrine neoplasms (NEN) have been increasing recently, although few studies have analyzed data on the current situation of NENs in Japan. Here, the Japan Neuroendocrine Tumor Society (JNETS) planned to investigate the recent incidence and distribution of these tumors using data from the national cancer registry started in 2016. This study examined the incidence and distribution of primary sites as well as rate of advanced disease from this population-based registry.MethodsA retrospective, population-based study using data from the national cancer registry in Japan (NCR) was conducted to evaluate patients with gastro-entero-pancreatic NEN (GEP-NEN) in 2016. Associated population data were used to determine annual age-adjusted incidences.ResultsA total of 6735 individuals were diagnosed with GEP-NEN in Japan in 2016. Annual onset incidence was 0.70/100,000 for pancreatic NEN and 2.84/100,000 for gastrointestinal NEN. NEN in the ileum accounted for only 1% of total GEP-NENs in Japan. Most NENs in the esophagus or lungs were neuroendocrine carcinomas (NECs), while the majority of those in the duodenum, ileum, appendix and rectum were grade 1 neuroendocrine tumors (NETs). Median age at initial diagnosis was in between 60 to 65. Tumors in the duodenum, appendix and rectum were mostly limited to local, while those in the esophagus, stomach and colon tended to show distant metastasis. In Japan, initial treatment for GEP-NENs was resection even if the tumor was NEC.ConclusionsThis is the first report of a national registry-based incidence and distribution of GEP-NEN in Japan. These data will serve as an important first step to determining the exact etiology and trends for this pathology in Japan.

Imaging of Gastrointestinal Neuroendocrine Tumors

Gastrointestinal neuroendocrine tumors (NETs) are a diverse group of neoplasms that arise from cells of the diffuse neuroendocrine system. Neuroendocrine tumors occur throughout the gastrointestinal tract. These tumors can produce a variety of hormones resulting in specific symptoms that may aid in their detection and classification. While all NETs have malignant potential, these tumors vary in their biologic characteristics and potential for metastatic disease. Although several classification schemes for neuroendocrine tumors have been proposed, the World Health Organization classification is currently the most widely accepted that will be reviewed in this paper. Various imaging modalities and techniques have evolved in recent years, including both morphologic and functional imaging techniques that will be explored in this paper. A thorough knowledge of the most recent classification schemes greatly aids radiologists in the assessment of gastrointestinal neuroendocrine tumors. Appropriate application of both morphologic and functional techniques is likewise essential for proper diagnosis and surveillance of gastrointestinal neuroendocrine tumors.

A single institution experience and review of the literature on the rare association between pancreatic neuroendocrine neoplasms and gastrointestinal stromal tumours

A single institution experience and review of the literature on the rare association between pancreatic neuroendocrine neoplasms and gastrointestinal stromal tumours

Patient reported experience of the burden of neuroendocrine tumors and impact of eSHINE Patient Support Program on patient quality of life.

Neuroendocrine tumors (NETs) are an uncommon cancer and difficult to diagnose and treat. Treatment is complicated by debilitating side effects, impacting quality of life. This Australia-wide survey aimed to increase our understanding of the impact and burden of NETs on patient quality of life (QoL) and to assess the benefit of a patient support program (eSHINE). Consented patients from the eSHINE mailing list (n=267) were invited to participate in an electronic self-reported survey comprising 29 questions on clinical characteristics, diagnosis, sociodemographics, impact of living with NETs and benefits of a patient support program. No formal sample size was calculated. All analyses were descriptive. A total of 144 participants (54%) responded. A total of 129 (48%) completed all questions. Approximately half of respondents were female, from metropolitan and rural areas, aged over 65 years and had a primary diagnosis of gastrointestinal NETs. Fifty-eight percent had been diagnosed over 5 years ago. Twenty-seven percent reported seeing four or more healthcare professionals prior to being diagnosed. Living with NETs had a large impact on patients' QoL. 83.5% reported fatigue, 76% felt their emotional health was impacted by NETs and 75% reported reduced ability to participate in leisure activities. Access to a supportive network to manage and treat NETs was extremely important to participants. Eighty-five percent of respondents reported the eSHINE program had a positive impact on their QoL. Patients value support from healthcare professionals and patient support programs such as eSHINE in managing NETs. The eSHINE Patient Support Program has a positive impact on patient QoL.

Racial/Ethnic Disparities and Survival Characteristics in Non-Pancreatic Gastrointestinal Tract Neuroendocrine Tumors

Background: We studied the effect of race and ethnicity on disease characteristics and survival in gastrointestinal neuroendocrine tumors. Methods: The Surveillance, Epidemiology, and End Results database was used to select patients with non-pancreatic gastrointestinal neuroendocrine tumors diagnosed between 2004 and 2015. Trends in survival were evaluated among three groups: Hispanic, non-Hispanic White, and non-Hispanic Black. Kaplan-Meier and Cox regression methods were performed to calculate overall survival and cause-specific survival after adjusting for patient and tumor characteristics. Results: A total of 26,399 patients were included in the study: 65.1% were non-Hispanic White, 19.9% were non-Hispanic Black, and 15% were Hispanic. Non-Hispanic White patients were more likely to be male (50.0%, p < 0.001), older than 60 years (48.0%, p < 0.001), and present with metastatic disease (17.7%, p < 0.001). Non-Hispanic White patients had small intestine neuroendocrine tumors, while Hispanic and non-Hispanic Black patients had rectum neuroendocrine tumors as the most common primary site. Hispanic patients had better overall survival, while non-Hispanic Black patients had better cause-specific survival versus non-Hispanic White patients. This finding was confirmed on multivariable analysis where Hispanic patients had improved overall survival compared to non-Hispanic White patients (Hazard ratio (HR): 0.89 (0.81-0.97)), whereas non-Hispanic Black patients had better cause-specific survival compared to non-Hispanic White patients (HR: 0.89 (0.80-0.98)). Conclusions: Race/ethnicity is an independent prognostic factor in patients with gastrointestinal neuroendocrine tumors.

LAT-1 and GLUT-1 Carrier Expression and Its Prognostic Value in Gastroenteropancreatic Neuroendocrine Tumors.

Simple SummaryGastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent about 70% of all NETs; however, improvement in their outcomes has yet to be achieved. Here, we aimed to analyze the role of metabolic players such as the amino acid transporter 1 (LAT-1) and glucose transporter 1 (GLUT-1), regulated by the oxygen-sensing mechanism Von Hippel Lindau-hypoxia-inducible factor (VHL-HIF), in gastroenteropancreatic neuroendocrine tumors (GEP-NET). We also aimed to correlate them with tumor malignancy and progression. We confirmed that specific mechanisms that increase nutrient uptake, such as LAT-1 and GLUT-1, are increased in GEP-NETs, whereas pVHL is decreased. Our results suggest that these biomarkers could have a potential role in NET pathophysiology which might be related to their proliferation and metastatic capacity.Cancer cells develop mechanisms that increase nutrient uptake, including key nutrient carriers, such as amino acid transporter 1 (LAT-1) and glucose transporter 1 (GLUT-1), regulated by the oxygen-sensing Von Hippel Lindau-hypoxia-inducible factor (VHL-HIF) transcriptional pathway. We aimed to analyze these metabolic players in gastroenteropancreatic neuroendocrine tumors (GEP-NET) and correlate them with tumor malignancy and progression. LAT-1, GLUT-1, and pVHL expression was analyzed in 116 GEP-NETs and 48 peritumoral tissue samples by immunohistochemistry. LAT-1 was stably silenced using specific shRNA in the human NET BON cell line. LAT-1 expression was significantly increased in tumor tissue compared to non-tumor tissue in both gastrointestinal (67% vs. 44%) and pancreatic NETs (54% vs. 31%). Similarly, GLUT-1 was substantially elevated in gastrointestinal (74% vs. 19%) and pancreatic (58% vs. 4%) NETs. In contrast, pVHL expression was decreased (85% vs. 58%) in pancreatic NETs. Tumors with metastases at diagnosis displayed increased LAT-1 and GLUT-1 and decreased pVHL expression (p < 0.001). In accordance with these data, silencing LAT-1 curtailed cell proliferation in BON cells. These findings suggest that specific mechanisms that increase nutrient uptake, such as LAT-1 and GLUT-1, are increased in GEP-NETs, whereas pVHL is decreased. These markers might be related to the proliferation and metastatic capacity of these tumors.

A rare case of metachronous neuroendocrine tumor after a colorectal adenocarcinoma: qualitative critical review of synchronous and metachronous gastrointestinal NET

Gastrointestinal neuroendocrine tumor (NET) associated with a metachronous intestinal adenocarcinoma is rare. We report the case of a 71-year-old man with an ileal NET. Patient has previously undergone a left colectomy for sigmoid cancer. We report a complete review both of the metachronous and synchronous NET. A comprehensive systematic literature search in PubMed, EMBASE, and MEDLINE identified a total of 35 relevant studies. This study includes an analysis of review articles, case reports, case series, retrospective studies and population-based studies. In the English literature to date, there are 21 case reports (19 synchronous cases and 2 metachronous cases), 3 case series and 3 review articles, and less than 10 retrospective studies or population-based studies. A total of 31 patients in 24 articles were included in the study: 28 patients with a synchronous gastrointestinal NET and colorectal adenocarcinoma and 3 patients with metachronous gastrointestinal NET and colorectal adenocarcinoma. The incidence of synchronous cancer (particularly for colorectal and gastric cancer) with a gastrointestinal NET ranges from 10 to 50%, while for the metachronous ones it is still unclear. This is the third metachronous case report and the first descriptive case of gastrointestinal NET diagnosed 2 years after a colorectal adenocarcinoma. An endoscopic follow-up program for gastrointestinal NET patients and/or for first-degree relatives of NET patients appears recommendable.

Updates in the advances of sporadic medullary thyroid carcinoma: from the molecules to the clinic.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy that originates in parafollicular cells. It is well-known that a quarter of MTC are involved in hereditary multiple endocrine neoplasia type 2 syndromes, whereas most MTC are sporadic. Unlike the commonly encountered gastrointestinal or pulmonary neuroendocrine tumors, most sporadic MTCs have distinct genetic alterations featured by somatic changes of either Rearranged during Transfection (RET) or RAS point mutation. The increasing application of next-generation sequencing, whole-exome sequencing, and other molecular detection techniques enables us to understand MTC comprehensively concerning its detailed molecular changes and their clinical correlations. This article reviews the advances in genetic alterations and their prognostic impact in sporadic MTC among different populations and discusses the associated tumor immune microenvironments and the potential role of immunotherapy targeting PD-L1/PD-1 in treating MTC. Furthermore, the current multikinase inhibitor targeting therapy for sporadic MTC has been summarized here and its efficacy and drug toxicity are discussed. Updates in advance of the role of calcitonin/procalcitonin/calcitonin-related polypeptide alpha (CALCA) gene transcripts in diagnosing and handling MTC are also mentioned. The treatment of advanced MTC is still challenging and might require a combination of several modalities.

S1958 Esophageal Neuroendocrine Tumor: A Rare Cause of Malignant Dysphagia

INTRODUCTION: The incidence of gastrointestinal (GI) neuroendocrine tumors (NETs) has risen in recent decades; however, esophageal NETs are exceedingly rare, with an estimated prevalence of 0.04% of all NETs. We present a patient with esophageal NET and highlight the unique features of this rare disease. CASE DESCRIPTION/METHODS: A 58-year-old previously health Caucasian man presented with shortness of breath, hypoxia, and 3-week history of progressive solid food dysphagia. The patient denied weight loss, anemia, or GI bleeding symptoms, and hemoglobin was 14. CT scan revealed 9 cm × 7.6 cm posterior mediastinal mass contiguous with a markedly thickened esophageal wall of 2.5 cm. The mass contacted the heart and the pericardium with a pericardial effusion. Additional findings included pleural effusions, bulky mediastinal lymphadenopathy, lower esophageal mass of 6.4 cm × 5.9 cm, and 9 cm conglomeration of gastrohepatic lymphadenopathy. Positive malignant cytology of suspected GI origin was obtained from the thoracentesis and the pericardiocentesis, both needed for hemodynamic improvement. EGD identified a 20 cm long malignant appearing esophageal stricture extending to the GE junction. Esophageal biopsy revealed high grade NET with positive CAM 5.2, pancytokeratin, synaptophysin, CD 56, CDX2 positive staining pattern consistent with NET of GI origin. The malignant dysphagia was palliated with a 23 mm × 155 cm esophageal stent. The patient is undergoing chemotherapy with carboplatin and etoposide. DISCUSSION: Esophageal NET is an exceedingly rare tumor, estimated prevalence of 1.4% of all GI-NETs, and hence there are few reports about clinical features. Reported findings suggest 80% male predominance, and a majority of patients are either asymptomatic (31%) or present with solid food dysphagia (26.9%). Weight loss (11.5%) and melena (7.7%) were less frequent symptoms in esophageal NETs. The mean tumor size ranged from 0.5 cm to 7 cm. This case illustrates: (1) Weight loss and anemia are not common findings with esophageal NET, when compared to more common esophageal malignancies, (2) A 20-cm long esophageal stricture is a length that has not previously been reported in the medical literature, (3) The extra-esophageal tumor burden without associated weight loss is not typical of common esophageal malignancies. These unusual features should prompt Gastroenterologists to consider rare causes of esophageal malignancies.

Immunophenotyping in incidental gastrointestinal neuroendocrine tumors: study at tertiary care centre

Background: Gastrointestinal neuroendocrine tumors are rare slow-growing tumors with distinct histological, biological, and clinical characteristics that have increased in incidence and prevalence in the last few decades. This study is aimed to find out the incidence of neuroendocrine tumors among the gastrointestinal tumors and to grade gastrointestinal neuroendocrine tumors.&#x0D; Materials and Methods: A total of 119 cases of gastrointestinal tumors of gastrointestinal neuroendocrine was included in the study. The paraffin blocks were retrieved and slides were stained with routine Hematoxylin and Eosin, synaptophysin, chromogranin, and Ki67. The histologic grading was done based on mitosis and Ki-67 index as per WHO 2017 classification.&#x0D; Results: Out of 119 cases of Gastrointestinal Tract tumor, 13 (10.92%) constituted neuroendocrine tumors. Duodenum was the most common site (38%) followed by the appendix (23%). The majority (1.9%) of the cases were categorized as of grade 1 followed by 2.3% of grade 2 and 1.19% of grade 3. Immunohistochemically, chromogranin, and synaptophysin were strongly expressed in all ten cases of neuroendocrine tumors. The Ki67 labeling index was &lt;3 % in 10 cases, while it was in the range of 3 – 20 % in 2 cases and &gt;20 % in one case.&#x0D; Conclusions: The incidence of gastrointestinal neuroendocrine tumors is on the rise. They should be considered in developing a differential diagnosis. Hence use of diagnostic modalities such as immunohistochemistry should be implemented for better treatment.

Clinical application of 18F-FDG PET/CT in&#x0D; oncology: Rare gastrointestinal malignant tumors&#x0D; (literature review)

Relevance: PET/CT is now becoming an integral part of cancer management protocols. 18F-fluorodeoxyglucose (18F-FDG)&#x0D; is the most common radiopharmaceutical for PET. However, the 18F-FDG PET/CT sensitivity and specificity vary widely in tumors of different histological structures and cell atypia degrees.&#x0D; The role of PET/CT in complex diagnostics of lymphomas is known. However, the specific use of this method in gastrointestinal neoplasms, especially at the initial stage of examination and in differential diagnostics, is not clearly defined since&#x0D; lymphomas account for only 1-5% of GI tumors.&#x0D; Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that arise from the diffuse neuroendocrine system&#x0D; enterochromaffin cells. NETs account for 0.5% of all neoplasms but become more common recently due to the advances in diagnostics. However, the significant achievements in the study of biological and molecular mechanisms of NETs’ behavior have&#x0D; not yet resulted in a common algorithm for their diagnostics and treatment.&#x0D; The purpose of this study was to review the experience of using 18F-FDG PET/CT in diagnostics of lymphomas and gastrointestinal neuroendocrine tumors as rare tumors to improve the criteria for the rational use of the 18F-FDG PET/CT method in&#x0D; their diagnostics and monitoring.&#x0D; Results: The use of 18F-FDG PET/CT is advisable at any stage of non-Hodgkin lymphomas, which are most common in the&#x0D; gastrointestinal tract, and for differential diagnostics, primary staging, and treatment efficiency monitoring in gastrointestinal&#x0D; lymphomas. 18F-FDG PET CT is also most valuable in aggressive non-Hodgkin lymphomas.&#x0D; Despite the importance of functional imaging in NETs, 18F-FDG PET/CT plays a supporting role in monitoring gastrointestinal NETs. 18F-FDG PET/CT is known to be efficient in prognosing the outcome of radionuclide therapy with peptide receptors&#x0D; in low-grade and progressive metastatic NETs.&#x0D; Conclusion: In lymphomas, 18F-FDG PET/CT is useful for primary staging, assessing early response to treatment, and&#x0D; re-staging. 18F-FDG PET/CT has a diagnostic value in undifferentiated gastrointestinal NETs, while its usefulness in well-differentiated gastrointestinal NETs is limited.

Surgical treatment for gastrointestinal neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare neoplasms, with an estimated annual incidence of 6.9/100 000. They arise from cells of the diffuse endocrine system, which are mainly dispersed throughout the gastrointestinal (GI), pancreatic, and respiratory tracts. The incidence of GI‐NETs has recently begun to show a steady increase. According to the Surveillance, Epidemiology, and End Results database, 53% of patients with NETs present with localized disease, 20% with locoregional disease, and 27% with distant metastases at the time of diagnosis. Surgery is the mainstay for the treatment of locoregional GI‐NETs. Endoscopic resection is an option for well‐differentiated early GI‐NETs, which are thought to very rarely metastasize to lymph nodes. A lesion that is technically difficult to resect via endoscopy is an indication for local resection (partial resection without lymph node dissection). GI‐NETs with possible lymph node metastasis is an indication for enterectomy with lymph node dissection. For NETs with metastatic lesions, cytoreduction surgery can control hormonal hypersecretion and alleviate symptoms; therefore, cytoreduction surgery is recommended. The indications for surgery vary and are based on the organ where the NET arose; therefore, an understanding of the patient's clinical state and individualized treatment that is based on the characteristics of the patient's GI‐NET is needed. This review summarizes surgical treatments of GI‐NETs in each organ.

Genetic Characteristics of Colorectal Neuroendocrine Carcinoma: More Similar to Colorectal Adenocarcinoma

BackgroundDespite the increasing incidence rate of colorectal neuroendocrine carcinoma (CR-NEC), there are still few sequencing data to depict the genomic characteristics of CR-NEC. Patients and MethodsNext-generation sequencing data of CR-NEC, colorectal adenocarcinoma (COREAD), lung neuroendocrine carcinoma (lung NEC), and gastrointestinal neuroendocrine tumor (GI-NET) were retrieved from the American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) database platform. Overall survival data of patients were obtained from cBioPortal. ResultsThe median tumor mutation burden (TMB) was 5.18 per megabase. TP53 (65.5%), APC (59.5%), KRAS (36.9%), BRAF (20.2%), and RB1 (16.7%) were the most common genes harboring somatic mutations. Nearly all of the BRAF mutations (88.2%) caused V600E. The most common copy number alterations were gain of MYC (12.3%), loss of RB1 (10.7%), and loss of PTEN (5.4%). Compared to lung NEC and GI-NET, the genetic characteristics of CR-NEC were more similar to that of COREAD. CR-NEC had a higher rate of potentially targetable gene alterations compared to lung NEC and GI-NET, and BRAFV600E might be a promising treatment target. Survival analysis indicated that patients with high TMB had significantly worse survival than patients with low TMB (P < .001). In addition, KRAS and RB1 alteration were found to be correlated with worse survival (both P = .023). ConclusionCR-NEC has genetic alterations that are more similar to COREAD than other entities. A substantial group of CR-NEC harboring potentially targetable alterations (BRAFV600E) deserves to be tested in clinical practice.

Characterization of a Novel Entity of G3 (High-grade Well-differentiated) Colorectal Neuroendocrine Tumors (NET) in the SEER Database.

Small studies suggest that a new entity of high-grade (HG) (G3, by Ki-67 or mitotic index) well-differentiated (histologically) gastrointestinal neuroendocrine tumors (NETs) exists, but prognosis and characteristics are unknown. We further characterized demographics and prognosis of patients with colorectal G3 NETs. We used the Surveillance Epidemiology and End Results (SEER) database to study colorectal NETs diagnosed from 2000 to 2015. We evaluated demographic, clinical, and tumor characteristics. We compared overall survival (OS) for G1-2 NET, G3 NET, and NEC (neuroendocrine carcinoma). We used logistic regression to detect grade associations and Cox proportional hazards models to examine predictors of survival. We identified 5894 cases with colorectal NET (5780 [98.1%] G1-2 and 114 [1.9%] G3); the cohort was 66% white, 47% male, and had a median age of 54. Patients with G3 NET were likely to be older (odds ratio [OR]: 2.23; 95% confidence interval [CI]: 1.19-4.19 for 60 to 69 vs. <50), unmarried (OR: 1.56; 95% CI: 1.02-2.38), and less likely to be diagnosed after 2010 (OR: 0.09; 95% CI: 0.06-0.15). OS for G3 NET (median, 36 mo; 95% CI: 13-92) fell between OS for NEC (median, 7 mo; 95% CI: 6-8), and G1-2 NET (median not reached, >120 mo). Among G1-3 NETs, black patients (hazard ratio [HR]: 1.30; 95% CI: 1.03-1.62), older patients (HR: 3.63; 95% CI: 2.63-5.01 for age 60 to 69 vs. <50), unmarried patients (HR: 1.40; 95% CI: 1.17-1.68), and those with HG features (HR: 3.97; 95% CI: 3.15-4.99) had worse survival. We defined a subset of G3 NETs that are HG and well differentiated, more common in older, unmarried patients, with a prognosis between that of NEC and G1-2 NETs. Our analysis adds the first national registry study in support of a new classification of nonpancreatic HG and well-differentiated NETs.

Somatostatin receptor scintigraphy in the follow up of neuroendocrine neoplasms of appendix.

BACKGROUNDNeuroendocrine tumors of appendix (ANETs) known as carcinoids, are rare endocrine neoplasms originated from enterochromaffin cells of gastrointestinal tract. ANETs are the third most frequent (16.7%) gastrointestinal neuroendocrine tumors, with the incidence of 0.08-0.2 cases/100000 during one year. Incidental ANETs occur in 0.2%-0.7% of emergency surgical resections because of suspected appendicitis which is usually the first manifestation of ANET. Although there are a lot of papers about application of somatostatin receptor scintigraphy in gastrointestinal neuroendocrine tumors, there are very rare sporadic cases described about ANETs particularly.AIMTo establish the role of somatostatin receptor scintigraphy (SRS) in the management of patients with neuroendocrine tumors of appendix (ANET).METHODSThe total of 35 patients was investigated, 23 females and 12 males, average age (43.7 ± 17.3 years). All patients had histological diagnosis of ANET (34 carcinoids of appendix and one tubular carcinoid). Majority of tumors have been found incidentally during surgery of: Acute appendicitis (n = 15), perforated appendicitis (n = 2), ileus (n = 3), hysterectomy (n = 3), ruptured ovarian cyst (n = 2), caecal volvulus (n = 1), while 9 patients had diagnosis of appendiceal tumor before the surgery. Seventeen patients had tumor grade (G) G1, 12 G2 and 6 G3. The right hemicolectomy was performed in 13, while the rest of the patients had appendectomy only. SRS was done early (2 h) and late (24 h) after i.v. application of 740 MBq technetium-99m ethylenediamine-N, N'-diacetic acid Hydrazinonicotinyl-Tyr3-Octreotide (technetium-99m-Tektrotyd, Polatom, Poland). SRS was performed for restaging in all the patients after surgery.RESULTSThere were 12 true positive (TP), 19 true negative, 3 false positive and 1 false negative SRS result. Sensitivity of the method was 92.31%, specificity was 86.36%, positive predictive value was 80.00%, negative predictive value was 95.00% and accuracy 88.57%. Receiver operating characteristics analysis showed that SRS scintigraphy is a good test for detection TP cases [area under the curve of 0.850, 95% confidence interval (CI): 0.710-0.990, P < 001]. Single photon emission computed tomography contributed diagnosis in 7 TP findings. In 10 patients Krenning score was 4 and in 2 was 3. In 8 patients SRS significantly changed the management of the patients (in two surgery was repeated, in 4 somatostatin analogues and in two peptide receptor radionuclide therapy). Median progression-free survival in SRS positive patients was 52 months (95%CI: 39.7-117.3 mo) while in SRS negative patients it was 60 months (95%CI: 42.8-77.1 mo), without statistically significant difference between the two groups (P = 0.434).CONCLUSIONIn conclusion, our results confirmed the value of SRS in the follow-up of the patients with ANET after surgery, if recurrences or metastases are suspected.

Overexpression of ODF1 in Gastrointestinal Tract Neuroendocrine Neoplasms: a Novel Potential Immunohistochemical Biomarker for Well-differentiated Neuroendocrine Tumors.

Gastrointestinal tract neuroendocrine neoplasms (NENs) are a group of rare heterogeneous tumors with different prognoses. The 2019 WHO classification of digestive system tumors defines the classification of NENs as neuroendocrine tumors (NETs G1-G3) and neuroendocrine carcinomas (NECs). We investigated outer dense fiber of sperm tails 1 (ODF1) expression in 137 gastrointestinal tract NENs including 53 NETs G1, 29 NETs G2, 3 NETs G3, and 52 NECs. Twenty adenocarcinomas and 6 squamous cell carcinomas also were included in the study. The results showed that ODF1 was positive in 83 of 85 (97.6%) primary gastrointestinal tract NETs, including 9 of 10 (90%) gastric, 19 of 19 (100%) small bowel, 10 of 11 (90.9%) colorectal, and 45 of 45 (100%) appendiceal neoplasms. There was a significantly statistical difference in the rates of ODF1 positivity in NETs (83/85, 97.6%) vs NECs (25/52, 48.1%, P < 0.001). ODF1 showed diffuse staining in NETs G1 (53/53, 100%) and NETs G2 (28/29, 96.6%), > 50% staining in NETs G3 (2/3, 66.7%), and focal staining (< 50%) in NECs (23/52, 44.2%) but 2 cases (2/52) showed > 50% staining. ODF1 showed no expression in all 20 adenocarcinomas and 6 squamous cell carcinomas. In conclusion, ODF1 was firstly identified as a novel marker for NENs, especially for NETs in the gastrointestinal tract. The expression mechanism and clinical significance of ODF1 in NENs needed further study.

Medullary Thyroid Cancer Patient’s Assessment of Quality of Life Tools: Results from the QaLM Study

Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumour and a rare variant of thyroid cancer with different aetiology, presentation and treatment to differentiated thyroid cancer. Currently available thyroid cancer-specific quality of life (QoL) tools focus on issues and treatments more relevant to patients with differentiated thyroid cancer and therefore may not address issues specific to a MTC diagnosis and cancer journey. Method: This prospective multicentre randomised study involved 204 MTC patients completing four quality of life questionnaires (QOLQ) and stating their most and least preferred. The questionnaires were a general instrument, the EORTC QLQ-C30, two disease-specific tools, the MD Anderson Symptom Inventory (MDASI) thyroid module and the City of Hope Quality of Life Scale/THYROID (amended) and the neuroendocrine questionnaire, EORTC QLQ-GINET21. Patients were randomised to complete the four questionnaires in one of 24 possible orders and then answered questions about which tool they preferred. The primary outcome measure was patients’ preferred QoL instrument for describing their concerns and for facilitating communication with their healthcare professional. Secondary analyses looked at differences between preferred QOLQs amongst patient subgroups (WHO performance status [0 and 1+], disease stage: early [T1–3, N0 or N1A], metastatic [T4, any T N1b] and advanced [any T any N M1], and type of MTC [sporadic and inherited]), identification of MTC patients’ least preferred questionnaire and clinicians’ views on the QoL tools in terms of their ability to highlight problems not otherwise ascertained by a standard clinical review. Results: No evidence of a difference was observed for most preferred QOLQ (p = 0.650). There was however evidence of a difference in least preferred questionnaire in the cohort of 128 patients who stated their least preferred questionnaire (p = 0.042), with 36% (46/128) of patients choosing the EORTC QLQ-GI.NET21 questionnaire. Subgroup analyses showed that there was no evidence of a difference in patients’ most preferred questionnaire in sporadic MTC patients (p = 0.637), patients with WHO PS 0 or 1+ (p = 0.844 and p = 0.423) nor when comparing patients with early, advanced local or metastatic disease (p = 0.132, p = 0.463 and p = 0.506, respectively). Similarly, subgroup analyses on patients’ least preferred questionnaires showed no evidence of differences in sporadic MTC patients (p = 0.092), patients with WHO PS 0 or 1+ (p = 0.423 and p = 0.276), nor in early or metastatic disease patients (p = 0.682 and p = 0.345, respectively). There was however some evidence to suggest a difference in least preferred questionnaire in patients with advanced local stage disease (p = 0.059), with 43% (16/37) of these patients choosing the EORTC QLQ-GI.NET21 questionnaire. Conclusions: MTC patients regardless of their performance status, disease aetiology and disease burden did not express a preference for any one particular questionnaire suggesting any of the tools studied could be utilized in this patient cohort. The least preferred questionnaire being a gastrointestinal NET specific tool suggests that diarrhoea was not a significant symptom and concern for the population studied.

Multiple metastatic NET of unknown primary site in a young patient with carcinoid syndrome: Can we treat it as a gastrointestinal NET?

Multiple metastatic NET of unknown primary site in a young patient with carcinoid syndrome: Can we treat it as a gastrointestinal NET?

Gastrointestinal neuroendocrine tumors in 2020.

Gastrointestinal neuroendocrine tumors are rare slow-growing tumors with distinct histological, biological, and clinical characteristics that have increased in incidence and prevalence within the last few decades. They contain chromogranin A, synaptophysin and neuron-specific enolase which are necessary for making a diagnosis of neuroendocrine tumor. Ki-67 index and mitotic index correlate with cellular proliferation. Serum chromogranin A is the most commonly used biomarker to assess the bulk of disease and monitor treatment and is raised in both functioning and non-functioning neuroendocrine tumors. Most of the gastrointestinal neuroendocrine tumors are non-functional. World Health Organization updated the classification of neuroendocrine tumors in 2017 and renamed mixed adenoneuroendocrine carcinoma into mixed neuroendocrine neoplasm. Gastric neuroendocrine tumors arise from enterochromaffin like cells. They are classified into 4 types. Only type I and type II are gastrin dependent. Small intestinal neuroendocrine tumor is the most common small bowel malignancy. More than two-third of them occur in the terminal ileum within 60 cm of ileocecal valve. Patients with small intestinal neuroendrocrine tumors frequently show clinical symptoms and develop distant metastases more often than those with neuroendocrine tumors of other organs. Duodenal and jejuno-ileal neuroendocrine tumors are distinct biologically and clinically. Carcinoid syndrome generally occurs when jejuno-ileal neuroendocrine tumors metastasize to the liver. Appendiceal neuroendocrine tumors are generally detected after appendectomy. Colonic neuroendocrine tumors generally present as a large tumor with local or distant metastasis at the time of diagnosis. Rectal neuroendocrine tumors are increasingly being diagnosed since the implementation of screening colonoscopy in 2000. Gastrointestinal neuroendocrine tumors are diagnosed and staged by endoscopy with biopsy, endoscopic ultrasound, serology of biomarkers, imaging studies and functional somatostatin scans. Various treatment options are available for curative and palliative treatment of gastrointestinal neuroendocrine tumors.

Abstract LB-330: Phase I study of procaspase activating compound-1 (PAC-1) for treatment of advanced malignancies

Abstract Background: PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells. This first-in-human, phase I, multicenter study for treatment of solid tumors or lymphoma evaluated safety, pharmacokinetics (PK), and preliminary clinical activity of single agent PAC-1 (NCT02355535). Methods: A modified- Fibonacci dose-escalation 3+3 design was used in both components. The primary objective was to assess maximum tolerated dose (MTD). PAC-1 was dosed from 75 to 750 mg daily orally (7 dose levels (DL)) on days 1-21 on 28 days cycle. Dose limiting toxicity (DLT) was assessed during first two cycles of therapy. For all dose cohorts, PK of PAC-1 was assessed following doses administered on days 1 and 21 of the first cycle. Disease response evaluation was done every two cycles. Neurologic and neurocognitive function (NNCF) tests were performed throughout the study due to concerns for potential neurotoxicity. Results: Forty-eight patients were enrolled with thirty-three completing two cycles of therapy and evaluable for DLT and response. DL 1-5 no DLTs were observed. DL 6 was expanded to 6 patients due to one episode of intracranial bleed that occurred during cycle 4 of treatment, assessed initially as possibly related to study drug, but later attributed to new brain metastasis and unrelated to PAC-1. Grade 1 and 2 neurological adverse events such as ataxia and hallucinations were noted in DL 7 and that DL was established as MTD and expanded to 9 patients to assure safety. This cohort was later expanded by additional 3 patients with diagnosis of gastrointestinal or pancreatic neuroendocrine tumors (NET), because of partial response was seen in one patient in first 9 patients at this DL. Review of NNCF testing showed a consistent pattern of stable neurologic and cognitive evaluations. Twenty patients had progressive disease, eleven stable disease (SD), and two patients had partial response (PR) (both with diagnosis of NET). The longest progression free survival was seen in patient with leiomyosarcoma (12 months). Three patients with NET had SD for 4, 6, and 8 months, two had PR with disease control for 4, and 6 months. The PK data demonstrated satisfactory systemic delivery of PAC-1 following oral administration and acceptable absorption and elimination profiles. The dose proportionality was shown for PAC-1 systemic exposure. The PAC-1 half-life was established at 31.1 hours. Conclusions: Single agent PAC-1 is well tolerated and 750 mg was determined to be safe and recommended for phase 2 studies. Intriguing activity of PAC-1 was seen in all patients with NET refractory to standard therapies that warrants further investigation in phase 2 clinical setting. Citation Format: Oana C. Danciu, Matthias Holdhoff, Richard A. Peterson, Paul J. Hergenrother, Theodore M. Tarasow, Arkadiusz Z. Dudek. Phase I study of procaspase activating compound-1 (PAC-1) for treatment of advanced malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-330.