Gastroenteropancreatic Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from the diffuse neuroendocrine system. They frequently originate in the gastroenteropancreatic (GEP) tract and the bronchopulmonary tree, and their incidence has steadily increased in the last 3 decades. Fundamental biologic and genomic differences underlie the clinical heterogeneity of NETs, and distinct molecular features characterize NETs of different grades and different primary sites. Although surgery remains the cornerstone of treatment for localized tumors, systemic treatment options for patients with metastatic NETs have expanded considerably. Somatostatin analogs have demonstrated both antisecretory and antitumor efficacy. Peptide receptor radionuclide therapy with lutetium-177 dotatate (177 Lu-DOTATATE) has been approved for advanced GEP-NETs. The antitumor activity of everolimus has been demonstrated across a wide spectrum of NETs, and the antiangiogenic agent sunitinib has been approved for pancreatic NETs (pNETs). Chemotherapy with temozolomide and capecitabine has recently demonstrated an unprecedented prolongation of progression-free survival in a randomized trial of pNETs. Multiple retrospective series have reported the efficacy of liver-directed therapies both for palliating symptoms of hormone excess and for controlling tumor growth. Telotristat, an oral inhibitor of tryptophan hydroxylase, has been shown to reduce diarrhea in patients with carcinoid syndrome. Defining the therapeutic algorithm and identifying biomarkers predictive of response to treatments are among the main priorities for the next decade of research in the NET field.

Association Between Female Sex and Better Survival in Gastroenteropancreatic Neuroendocrine Tumors.

INTRODUCTION: Studies conflict on whether sex influences survival in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). GEP-NETs express receptors and genes responsive to female hormones. We hypothesized that women would have improved survival and this difference would be greater in premenopausal age women compared to older women. MATERIALS AND METHODS: The National Cancer Database from 2004 to 2016 was queried for patients with GEP-NETs based on histologic code. Demographic, tumor, treatment, and socioeconomic characteristics were compared between men and women and age ≤45 or >65 y using Fisher's exact and Wilcoxon tests as appropriate. The primary endpoint was overall survival (OS), assessed by Kaplan-Meier survival analysis. RESULTS: Included in the study were 73,521 patients with small bowel neuroendocrine tumors (SBNETs), gastric neuroendocrine tumors (GNETs), or pancreas neuroendocrine tumors (36,197 female, 37,324 male). Women lived longer regardless of primary site, with the largest difference in GNETs (median OS 139 versus 85 mo) and smallest in SBNETs (121 versus 116, P < 0.001 for both). While male patients more often had high grade and metastatic disease, female sex remained independently associated with improved OS after adjusting for confounders (hazard ratio 0.84, P < 0.001). In GNETs and SBNETs, female sex had a larger beneficial effect on OS in premenopausal than postmenopausal patients. CONCLUSIONS: Women with GEP-NETs have improved survival over men, especially in the premenopausal age group. This may be due to a protective effect of female hormones; however, further studies are necessary to uncover the biologic basis of this difference.

Initial validation of the clinical significance of the NETest in Japanese gastroenteropancreatic neuroendocrine tumor patients.

As novel biomarkers for gastroenteropancreatic neuroendocrine tumors (GEPNET) are in demand, we aimed to validate the clinical value of the NETest in Japanese patients. Between 2021 and 2023, blood and clinical data were collected from patients with GEPNET. Among 35 patients (median age: 59 [49-66] years), 27 cases originated from the pancreas and eight from the gastrointestinal tract. Of 69 samples sent to the laboratory, 56 (81.2%) underwent NETest. The diagnostic sensitivity was 97.1%. Among three patients who underwent R0 resection and four treated with peptide receptor radionuclide therapy, the changes in NETest scores closely correlated with disease progression. The NETest demonstrated high diagnostic efficacy and accurate therapeutic monitoring capabilities in a Japanese population.

A Nomogram to Predict Individual Survival of Patients with Liver-Limited Metastases from Gastroenteropancreatic Neuroendocrine Neoplasms: A US Population-Based Cohort Analysis and Chinese Multicenter Cohort Validation Study.

INTRODUCTION: Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) with liver metastasis encompass a wide variety of clinical conditions with various prognosis, no statistical model for predicting the prognosis of these patients has been established. We sought to establish a more elaborative and individualized nomogram to predict survival of patients with liver-limited metastatic GEP-NENs. In addition, this nomogram was validated by both the Surveillance, Epidemiology, and End Results (SEER) database and a Chinese multicenter cohort. METHODS: Patients diagnosed with GEP-NENs with liver-limited metastasis between 2010 and 2016 were identified from the SEER database. Kaplan-Meier survival analysis was performed to analyze survival outcomes. A nomogram was established based on the independent prognostic variables identified from univariate and multivariate Cox regression analyses. The nomogram was evaluated in both an internal validation SEER dataset and an external validation dataset composed of patients from the Chinese multicenter cohort. RESULTS: A total of 1,474 patients from the SEER database and 192 patients from the multicenter cohort were included. Age, tumor size, differentiation, primary tumor resection, and liver metastasis resection were identified as independent prognostic factors by univariate and multivariate Cox analyses and were verified by Kaplan-Meier survival analysis (all p < 0.0001). A nomogram was developed and validated by calibration curves and areas under the curve of the external validation cohort, which showed good consistency and veracity in predicting overall survival. CONCLUSION: A nomogram was developed for the first time to predict the survival of patients with liver-limited metastases from GEP-NENs. Both internal and external validation demonstrated excellent discrimination and calibration of our nomogram. Based on this prognostic model, clinicians could develop more personalized treatment strategies and surveillance protocols.

Differential Effects of Somatostatin, Octreotide, and Lanreotide on Neuroendocrine Differentiation and Proliferation in Established and Primary NET Cell Lines: Possible Crosstalk with TGF-ß Signaling.

GEP-NETs are heterogeneous tumors originating from the pancreas (panNET) or the intestinal tract. Only a few patients with NETs are amenable to curative tumor resection, and for most patients, only palliative treatments to successfully control the disease or manage symptoms remain, such as with synthetic somatostatin (SST) analogs (SSAs), such as octreotide (OCT) or lanreotide (LAN). However, even cells expressing low levels of SST receptors (SSTRs) may exhibit significant responses to OCT, which suggests the possibility that SSAs signal through alternative mechanisms, e.g., transforming growth factor (TGF)-ß. This signaling mode has been demonstrated in the established panNET line BON but not yet in other permanent (i.e., QGP) or primary (i.e., NT-3) panNET-derived cells. Here, we performed qPCR, immunoblot analyses, and cell counting assays to assess the effects of SST, OCT, LAN, and TGF-ß1 on neuroendocrine marker expression and cell proliferation in NT-3, QGP, and BON cells. SST and SSAs were found to regulate a set of neuroendocrine genes in all three cell lines, with the effects of SST, mainly LAN, often differing from those of OCT. However, unlike NT-3 cells, BON cells failed to respond to OCT with growth arrest but paradoxically exhibited a growth-stimulatory effect after treatment with LAN. As previously shown for BON, NT-3 cells responded to TGF-ß1 treatment with induction of expression of SST and SSTR2/5. Of note, the ability of NT-3 cells to respond to TGF-ß1 with upregulation of the established TGF-ß target gene SERPINE1 depended on cellular adherence to a collagen-coated matrix. Moreover, when applied to NT-3 cells for an extended period, i.e., 14 days, TGF-ß1 induced growth suppression as shown earlier for BON cells. Finally, next-generation sequencing-based identification of microRNAs (miRNAs) in BON and NT-3 revealed that SST and OCT impact positively or negatively on the regulation of specific miRNAs. Our results suggest that primary panNET cells, such as NT-3, respond similarly as BON cells to SST, SSA, and TGF-ß treatment and thus provide circumstantial evidence that crosstalk of SST and TGF-ß signaling is not confined to BON cells but is a general feature of panNETs.

68 Ga-DOTATATE Positron Emission Tomography-Computed Tomography Quantification Predicts Response to Somatostatin Analog Therapy in Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: Somatostatin analogs (SSAs) are the frontline antitumor therapy in advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A subset of patients demonstrate early disease progression on SSA therapy, yet the currently known predictors for treatment failure lack specificity to affect therapeutic decision. SSAs target tumor somatostatin receptors, the level of which can be quantitatively assessed with 68 Ga-DOTATATE positron emission tomography-computed tomography (PET/CT). We investigated the ability of 68 Ga-DOTATATE PET/CT to predict response to SSA therapy. MATERIALS AND METHODS: The records of 108 consecutive patients with well-differentiated grade 1-2 GEP-NETs on SSA monotherapy who received 68 Ga-DOTATATE PET/CT scans were retrospectively reviewed to obtain baseline characteristics, 68 Ga-DOTATATE maximum standardized uptake value (SUVmax), and progression-free survival (PFS) data. The optimal SUVmax cutoff for patient stratification was obtained with receiver operating characteristic curve analysis. PFS in the high versus low SUVmax groups was compared with Kaplan-Meier survival analysis. The effects of baseline characteristics and SUVmax on PFS were examined with univariate and multivariate Cox regression. RESULTS: 68 Ga-DOTATATE SUVmax predicted therapeutic failure with sensitivity and specificity of 39% and 98%, respectively. SUVmax of <18.35 was associated with shorter PFS, which was reproduced in the subgroup analysis of SSA-naïve patients. Low SUVmax was the only predictor of early treatment failure (hazard ratio, 6.85) in multivariate analysis, as well as in the subgroup analysis of grade 2 GEP-NETs. CONCLUSION: Low SUVmax on 68 Ga-DOTATATE PET/CT independently predicts early failure on SSA monotherapy in patients with well-differentiated grade 1-2 GEP-NET. Patients with lack of expected benefit from SSA therapy can be readily identified using routine 68 Ga-DOTATATE PET/CT with very high specificity. IMPLICATIONS FOR PRACTICE: Based on 68 Ga-DOTATATE positron emission tomography-computed tomography imaging, clinicians can better inform patients on the expected benefit of somatostatin analog therapy for gastroenteropancreatic neuroendocrine tumors, especially when access to the therapy is difficult, and offer proactive discussion on alternative management options.

Models of Gastroenteropancreatic Neuroendocrine Neoplasms: Current Status and Future Directions.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare, heterogeneous group of tumors that originate from the endocrine system of the gastrointestinal tract and pancreas. GEP-NENs are subdivided according to their differentiation into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Since GEP-NENs represent rare diseases, only limited data from large prospective, randomized clinical trials are available, and recommendations for treatment of GEP-NEN are in part based on data from retrospective analyses or case series. In this context, tractable disease models that reflect the situation in humans and that allow to recapitulate the different clinical aspects and disease stages of GEP-NET or GEP-NEC are urgently needed. In this review, we highlight available data on mouse models for GEP-NEN. We discuss how these models reflect tumor biology of human disease and whether these models could serve as a tool for understanding the pathogenesis of GEP-NEN and for disease modeling and pharmacosensitivity assays, facilitating prediction of treatment response in patients. In addition, open issues applicable for future developments will be discussed.

The State of Peptide Receptor Radionuclide Therapy and Its Sequencing among Current Therapeutic Options for Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common form of neuroendocrine neoplasia, but there is no current consensus for the sequencing of approved therapies, particularly with respect to peptide receptor radionuclide therapy (PRRT). This comprehensive review evaluates the data supporting approved therapies for GEP-NETs and recommendations for therapeutic sequencing with a focus on how PRRT currently fits within sequencing algorithms. The current recommendations for PRRT sequencing restrict its use to metastatic, inoperable, progressive midgut NETs; however, this may change with emerging data to suggest that PRRT might be beneficial as neoadjuvant therapy for inoperable tumors, is more tolerable than other treatment modalities following first-line standard dose somatostatin analogs, and can be used as salvage therapy after disease relapse following prior successful cycles of PRRT. PRRT has also been shown to reduce tumor burden, improve quality of life, and prolong the time to disease progression in a broad spectrum of patients with GEP-NETs. As the various potential benefits of PRRT in GEP-NET therapy continues to expand, it is necessary to review and critically evaluate our treatment algorithms for GEP-NETs.

Duodenal, ampullary, and pancreatic neuroendocrine tumors: Oncologic outcomes are driven by tumor biology and tissue of origin.

BACKGROUND: Periampullary neuroendocrine tumors (NETs) arise from the duodenum, ampulla, and periampullary pancreas. Duodenal and ampullary NETs are rare and may have distinct biologic behavior from pancreatic NETs (P-NETs). We examined the outcomes of these entities. METHODS: An institutional database was queried for patients undergoing resection for pancreatic head, duodenal, or ampullary NETs from 2000 to 2018. Patients with MEN1 syndrome or follow up less than 12 months were excluded. RESULTS: Three hundred and ten patients were identified. Tumor locations were ampulla (n = 15), duodenum (n = 35) and pancreas (n = 260). Median follow-up and recurrence-free survival (RFS) were 60.9 (interquartile range [IQR]: 34.8-99.3) and 171.7 (IQR: 84.0-NR) months. Clinicopathologic data and survival outcomes were similar for duodenal and ampullary NETs (RFS: p = .347 and overall survival [OS]: p = .246) and were combined into an intestinal subtype (IS) group. There were no differences in OS or RFS when comparing IS-NET and P-NET. On multivariate analysis, tissue of origin was not associated with risk of recurrence. The current American Joint Committee on Cancer staging guidelines, which account for origin tissue, were predictive of outcomes for all subtypes. CONCLUSION: Tissue of origin does not appear to impact long-term outcomes when comparing IS-NETs and P-NETs. The AJCC staging system offers good discriminatory capacity in the context of the tissue type.

Risk factors affecting prognosis in metachronous liver metastases from WHO classification G1 and G2 gastroenteropancreatic neuroendocrine tumors after initial R0 surgical resection.

BACKGROUND: Here we describe the treatments and prognosis for metachronous metastases from gastroenteropancreatic neuroendocrine tumors (GEP-NETs) after initial R0 surgical resection at a large center in China. METHODS: The clinicopathological data and survival outcomes for 108 patients (median age, 54.0 years) with metachronous hepatic metastatic GEP-NETs disease who were initially treated using R0 surgical resection between August 2003 and July 2014 were analyzed using one-way comparisons, survival analysis, and a predictive nomogram. RESULTS: Fifty-five (50.9%) patients had pancreatic NETs and 92 (85.2%) had G2 primary tumors. For treatment of the hepatic metastases, 48 (44.4%) patients received liver-directed local treatment (metastasectomy, radiofrequency ablation, transcatheter arterial chemoembolization, etc.), 15 (13.9%) received systemic treatment (interferon, somatostatin analogs, etc.), and 45 (41.7%) received both treatments. Multivariable analyses revealed that OS was associated with hepatic tumor number (P < 0.001), treatment modality (P = 0.045), and elevated Ki-67 index between the metastatic and primary lesions (P = 0.027). The predictive nomogram C-index was 0.63. CONCLUSIONS: A higher Ki-67 index in metastases compared to primary tumor was an independent factor for poor prognosis. Local treatment was associated with prolonged survival of hepatic metastatic GEP-NET patients. Optimal treatment strategies based on clinicopathological characteristics should be developed.

Neuroendocrine carcinoma of the colon presenting as acute meningitis.

BACKGROUND: Neuroendocrine tumors represent an expansive group of neoplasms that share an etiology of epithelial origin with neuroendocrine differentiation. Poorly-differentiated neuroendocrine carcinomas behave similarly to their aggressive pulmonary counterpart, small cell lung carcinoma. Most patients with gastroenteropancreatic neuroendocrine tumors present with symptoms of metastasis, most commonly to the liver. There have been no case reports, to our knowledge, until now that demonstrate metastasis to the central nervous system. CASE PRESENTATION: A 72-year-old male with poorly-differentiated stage IIIB neuroendocrine carcinoma of the colon presented with acute altered mental status and right facial droop. Head CT was negative for an acute hemorrhagic process without evidence of suspicious lesions. Several days later, the patient developed fever and neck stiffness suspicious for bacterial meningitis. A lumbar puncture procedure was performed. Cytology of the CSF demonstrated metastatic disease to the central nervous system and the final diagnosis of carcinomatous meningitis secondary to metastatic neuroendocrine carcinoma of the colon was made. CONCLUSIONS: High-grade gastroenteropancreatic neuroendocrine carcinomas most commonly metastasize to the liver, which often corresponds with the patient's initial presentation. When neuroendocrine tumors do metastasize to the central nervous system, the primaries are most commonly of pulmonary origin. When meningeal metastasis does occur, it commonly presents as neurologic deficits or cerebrovascular events, rarely does meningeal metastasis mimic bacterial meningitis with symptoms of fever, photophobia and meningismus. As neuroendocrine carcinomas have been increasing in incidence over the past several decades, it is important to consider varying metastatic presentations when working up a patient with a diagnosis of neuroendocrine tumor.

Etiologies and management of cutaneous flushing: Malignant causes.

The second article in this 2-part continuing medical education series reviews the following malignant causes of flushing: mastocytosis, medullary thyroid carcinoma, pheochromocytoma, carcinoid tumors, gastroenteropancreatic neuroendocrine tumors, bronchogenic carcinoma, vasointestinal polypeptide secreting tumors, and renal cell carcinoma. The information provided will allow physicians to better distinguish patients who have worrisome presentations that require a more thorough investigation. Appropriate diagnostic workup and treatment options for these malignancies are reviewed.

Clinical Usefulness of Somatostatin Receptor Scintigraphy in Japanese Patients with Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND/AIMS: Somatostatin receptor (SSTR) scintigraphy (SRS) is the standard imaging modality for evaluation of gastroenteropancreatic neuroendocrine tumor (GEP-NET) in Western countries. However, this modality was not approved in Japan until recently. The purpose of this study was to evaluate the clinical efficacy of SRS for detecting GEP-NET in Japanese patients. METHODS: Japanese patients with advanced GEP-NET were enrolled and evaluated by the SRS and CT. We also compared SRS and immunohistochemical expression of SSTR type 2a (SSTR2a). RESULTS: We enrolled 16 patients and the primary sites were the pancreas in 9, the stomach in 1, the small intestine in 2, the colon in 3, and unknown in 1. SRS showed positive findings in 3 (100%) of grade 1 (G1) and in 12 (92.3%) of grade 2 (G2) lesions. In the liver, SRS and CT detected lesions in 13 and 14 cases, respectively. The concordance rate of SSTR2a expression with SRS findings was 93.8% in the whole body and 92.9% in the liver. CONCLUSIONS: SRS could detect almost all of G1 and G2. SRS could be useful to detect lesions, with a high concordance rate with CT and pathological findings. We confirmed that SRS is a useful and reliable modality for Japanese patients.

Pathology and Surgical Treatment of High-Grade Pancreatic Neuroendocrine Carcinoma: an Evolving Landscape.

Pancreatic neuroendocrine neoplasms (PNENs) are rare, accounting for less than 5% of all pancreatic tumors. High-grade pancreatic neuroendocrine carcinomas (hgPNECs) represent about 5% of all PNENs. They show highly aggressive behavior with dismal prognosis. Throughout the last two decades, there has been a notable progress in basic and clinical research of PNENs and a therapeutic trend towards both more aggressive and minimally invasive surgery. Despite these advances, hgPNECs as a distinct clinical entity remains largely unexplored among surgeons. This review of current development in pathology reporting and surgical treatment of hgPNECs aims at increasing the awareness of an evolving field in pancreatic surgery.

Analysis of 320 gastroenteropancreatic neuroendocrine tumors identifies TS expression as independent biomarker for survival.

Thymidylate synthase (TS), a critical enzyme for DNA synthesis and repair, is both a potential tumor prognostic biomarker as well as a tumorigenic oncogene in animal models. We have now studied the clinical implications of TS expression in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and compared these results to other cell cycle biomarker genes. Protein tissue arrays were used to study TS, Ki-67, Rb, pRb, E2F1, p18, p21, p27 and menin expression in 320 human GEP-NETs samples. Immunohistochemical expression was correlated with univariate and multivariate predictors of survival utilizing Kaplan Meier and Cox proportional hazards models. Real time RT-PCR was used to validate these findings. We found that 78 of 320 GEP-NETs (24.4%) expressed TS. NETs arising in the colon, stomach and pancreas showed the highest expression of TS (47.4%, 42.6% and 37.3%, respectively), whereas NETs of the appendix, rectum and duodenum displayed low TS expression (3.3%, 12.9% and 15.4%, respectively). TS expression in GEP-NETs was associated with poorly differentiated endocrine carcinoma, angiolymphatic invasion, lymph node metastasis and distant metastasis (p < 0.05). Patients with TS-positive NETs had markedly worse outcomes than TS-negative NETs as shown by univariate (p < 0.001) and multivariate (p = 0.01) survival analyses. Expression of p18 predicted survival in TS-positive patients that received chemotherapy (p = 0.015). In conclusion, TS protein expression was an independent prognostic biomarker for GEP-NETs. The strong association of increased TS expression with aggressive disease and early death supports the role of TS as a cancer promoting agent in these tumors.

Impact of primary tumor resection in the management of metastatic well-differentiated neuroendocrine tumors of the small bowel and pancreas.

Patients with gastroenteropancreatic (GEP) neuroendocrine tumors (NET) often present with advanced disease. Primary tumor resection (PTR) in the setting of unresectable metastatic disease is controversial. Most studies evaluating the impact of PTR on overall survival (OS) have been performed using large population-based databases, with limited treatment related data. This study aims to determine whether PTR improves OS and progression-free survival (PFS) in patients with metastatic well-differentiated GEP-NET. This is a retrospective single-institution study of patients with metastatic well-differentiated GEP-NET between 1978 and 2021. The primary outcome was OS. The secondary outcome was PFS. Chi-squared tests and Cox regression were used to perform univariate and multivariate analyses (MVA). OS and PFS were estimated using the Kaplan-Meier method and log-rank test. Between 1978 and 2021, 505 patients presented with metastatic NET, 151 of whom had well-differentiated GEP-NET. PTR was performed in 31 PNET and 77 SBNET patients. PTR was associated with improved median OS for PNET (136 vs. 61 months, p = .003) and SBNET (not reached vs. 79 months, p<.001). On MVA, only higher grade (HR 3.70, 95%CI 1.49-9.17) and PTR (HR 0.21, 95%CI 0.08-0.53) influenced OS. PTR resulted in longer median PFS for patients with SBNET (46 vs. 28 months, p = .03) and a trend toward longer median PFS for patients with PNET (20 vs. 13 months, p = .07). In patients with metastatic well-differentiated GEP-NET, PTR is associated with improved OS and may be associated with improved PFS and should be considered in a multidisciplinary setting. Future prospective studies are needed to validate these findings.

Improving Generalizability of PET DL Algorithms: List-Mode Reconstructions Improve DOTATATE PET Hepatic Lesion Detection Performance.

Deep learning (DL) algorithms used for DOTATATE PET lesion detection typically require large, well-annotated training datasets. These are difficult to obtain due to low incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and the high cost of manual annotation. Furthermore, networks trained and tested with data acquired from site specific PET/CT instrumentation, acquisition and processing protocols have reduced performance when tested with offsite data. This lack of generalizability requires even larger, more diverse training datasets. The objective of this study is to investigate the feasibility of improving DL algorithm performance by better matching the background noise in training datasets to higher noise, out-of-domain testing datasets. 68Ga-DOTATATE PET/CT datasets were obtained from two scanners: Scanner1, a state-of-the-art digital PET/CT (GE DMI PET/CT; n = 83 subjects), and Scanner2, an older-generation analog PET/CT (GE STE; n = 123 subjects). Set1, the data set from Scanner1, was reconstructed with standard clinical parameters (5 min; Q.Clear) and list-mode reconstructions (VPFXS 2, 3, 4, and 5-min). Set2, data from Scanner2 representing out-of-domain clinical scans, used standard iterative reconstruction (5 min; OSEM). A deep neural network was trained with each dataset: Network1 for Scanner1 and Network2 for Scanner2. DL performance (Network1) was tested with out-of-domain test data (Set2). To evaluate the effect of training sample size, we tested DL model performance using a fraction (25%, 50% and 75%) of Set1 for training. Scanner1, list-mode 2-min reconstructed data demonstrated the most similar noise level compared that of Set2, resulting in the best performance (F1 = 0.713). This was not significantly different compared to the highest performance, upper-bound limit using in-domain training for Network2 (F1 = 0.755; p-value = 0.103). Regarding sample size, the F1 score significantly increased from 25% training data (F1 = 0.478) to 100% training data (F1 = 0.713; p < 0.001). List-mode data from modern PET scanners can be reconstructed to better match the noise properties of older scanners. Using existing data and their associated annotations dramatically reduces the cost and effort in generating these datasets and significantly improves the performance of existing DL algorithms. List-mode reconstructions can provide an efficient, low-cost method to improve DL algorithm generalizability.

Correlation between clinicopathological characteristics and the clinical prognosis of patients with gastroenteropancreatic neuroendocrine tumors.

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are one of the most common types of NETs, accounting for 65-75% of all NETs. However, epidemiological characteristics of patients with GEP-NETs in China are still lacking. The present retrospective study aimed to investigate the local epidemiology of GEP-NETs and assess the prognostic factors in China. The data of 267 patients with GEP-NETs who were admitted to the First Affiliated Hospital of Bengbu Medical College (Bengbu, China) and the Affiliated Hospital of West Anhui Health Vocational College (Lu'an, China) were retrospectively reviewed. The clinical and pathological characteristics of the patients, as well as follow-up information, were collected, and the 5-year survival rate was calculated. Kaplan-Meier curves and log-rank analysis were used to analyze the prognostic factors. The stomach (100/267; 37.5%) was the most common site of GEP-NETs and the liver (25/39; 64.1%) was the most common metastatic site. A total of 166 (62.2%) and 219 (82.0%) patients had positive results for chromogranin A (CgA) and synaptophysin (Syn), respectively. The percentage of patients with tumor grade G1, G2 and G3 was 33.3, 21.0 and 45.7%, respectively. The 5-year overall survival rate was 79.7%, and the age, tumor site, distant metastasis and tumor grading upon diagnosis were all prognostic factors. In conclusion, the present case series investigated the epidemiology and prognostic factors of GEP-NETs in China. CgA and Syn could be used as diagnostic markers for NETs and the stomach was the most common primary tumor site. Lymph node metastasis, tumor site, distant metastasis and tumor grading were important prognostic factors.

Prevalence of Endocrine Manifestations and GIST in 108 Systematically Screened Patients With Neurofibromatosis Type 1.

Context: In patients with neurofibromatosis type 1 (NF1), guidelines suggest screening for pheochromocytoma by metanephrine measurement and abdominal imaging, which may lead to the discovery of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and their differential diagnosis, gastrointestinal stromal tumors (GISTs). Other endocrine manifestations such as follicular thyroid carcinoma and primary hyperparathyroidism have also been reported in a few cases. Objective: This study aimed to describe prevalence and clinical presentation of these manifestations through systematic screening in a large cohort of patients. Methods: In this monocentric retrospective study, 108 patients with NF1 were included and screened for endocrine manifestations and GISTs. Clinical, laboratory, molecular profile, pathology, and morphologic (abdominal computed tomography scan and/or magnetic resonance imaging) and functional imaging were collected. Results: Twenty-four patients (22.2% of the cohort, 16 female, mean age 42.6 years) presented with pheochromocytomas that were unilateral in 65.5%, benign in 89.7%, and with a ganglioneural component in 20.7%. Three female patients (2.8% of the cohort, aged 42-63 years) presented with well-differentiated GEP-NETs, and 4 (3.7%) with GISTs. One patient had primary hyperparathyroidism, 1 patient had medullary microcarcinoma, and 16 patients had goiter, multinodular in 10 cases. There was no correlation between pheochromocytoma and other NF1 tumoral manifestations, nor correlations between pheochromocytoma and NF1 genotype, despite a familial clustering in one-third of patients. Conclusion: The pheochromocytoma prevalence in this NF1 cohort was higher (>20%) than previously described, confirming the interest of systematic screening, especially in young women. The prevalence of GEP-NETs and GISTs was about 3%, respectively. No phenotype-genotype correlation was observed.

Site-specific trends in gastroenteropancreatic neuroendocrine neoplasms in Bavaria, Germany.

INTRODUCTION: Neuroendocrine neoplasms (NEN) are rare and heterogeneous epithelial tumors, occurring throughout the body. For gastroenteropancreatic (GEP)-NEN, rising incidence rates were reported for the last decades, with underlying causes remaining largely unexplained. We evaluated NEN trends stratifying by their histologic subtypes. METHODS: Incident cases of GEP-NEN diagnosed between 2005 and 2019 were retrieved from the prospective, population-based Bavarian Cancer Registry. GEP-NEN were divided in their histologic subtypes, that is, neuroendocrine tumors (NET) G1, NET G2/G3, other NET versus small-cell neuroendocrine carcinoma (NEC), large-cell NEC, and other NEC. We calculated annual age-standardized incidence rates (ASIRs) per 100,000 persons for the total of GEP-NEN, NEN histologic subtypes, and tumor sites. We used an annual percentage change (APC) approach including a joinpoint analysis to investigate NEN incidence trends. RESULTS: ASIR of GEP-NEN rose from 2.2 in 2005 to 4.8 in 2019, characterized by a significant increase until 2012 (APC 2005-2012: 10.1%), followed by modest rise (APC 2012-2019: 1.5%). In the last decade, this increase was mainly driven by the rise of NET G1 and G2/G3, while incidence for NEC declined. Over the study period, ASIR increased significantly for all GEP-sites except the colon. APCs were largest for the stomach, the appendix, the pancreas, and the rectum. CONCLUSIONS: This study found a significant increase in the incidence of GEP-NET. Though this development may partially be attributable to the increased use of advanced detection techniques and changes in NEN classification, further research should also focus on the identification of NEN risk factors.