The Safety and Efficacy of Peptide Receptor Radionuclide Therapy for Gastro-Entero-Pancreatic Neuroendocrine Tumors: A Single Center Experience.

The aim of the present study was to evaluate the safety and efficacy of radionuclide therapy with [177Lu]Lu-DOTA-TATE according to our single center experience at the University of Naples Federico II. For the present analysis, we considered 21 patients with progressive, advanced, well-differentiated G1 and G2 in patients with gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs) treated with [177Lu]Lu-DOTA-TATE according to the decisions of a multidisciplinary team. All patients underwent four cycles of 7-8 GBq of [177Lu]Lu-DOTA-TATE every 8 weeks. A whole-body scan (WBS) was performed 4, 48, and 168 h after each treatment. The dosimetry towards the organ at risk and target lesions was calculated. For each patient, renal and bone marrow parameters were evaluated before, during, and 3 months after the end of the treatment. Follow-up data were obtained and RECIST criteria were considered as the endpoint. Among 21 patients enrolled (mean age 65 ± 9 years); 17 (81%) were men and the small intestine was the most frequent location of disease (n = 12). A mild albeit significant variation (p < 0.05) in both platelets and white blood cell counts among all time points was observed, despite it disappearing 3 months after the end of the therapy. According to the RECIST criteria, 11 (55%) patients had a partial response to therapy and 8 (40%) had stable disease. Only one (5%) patient had disease progression 4 months after treatment. Our data confirm that [177Lu]Lu-DOTA is safe and effective in controlling the burden disease of G1/G2 GEP-NETs patients.

Dual Somatostatin Receptor/18F-FDG PET/CT Imaging in Patients with Well-Differentiated, Grade 2 and 3 Gastroenteropancreatic Neuroendocrine Tumors.

Our purpose was to prospectively assess the distribution of NETPET scores in well-differentiated (WD) grade 2 and 3 gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and to determine the impact of the NETPET score on clinical management. Methods: This single-arm, institutional ethics review board-approved prospective study included 40 patients with histologically proven WD GEP NETs. 68Ga-DOTATATE PET and 18F-FDG PET were performed within 21 d of each other. NETPET scores were evaluated qualitatively by 2 reviewers, with up to 10 marker lesions selected for each patient. The quantitative parameters that were evaluated included marker lesion SUVmax for each tracer; 18F-FDG/68Ga-DOTATATE SUVmax ratios; functional tumor volume (FTV) and metabolic tumor volume (MTV) on 68Ga-DOTATATE and 18F-FDG PET, respectively; and FTV/MTV ratios. The treatment plan before and after 18F-FDG PET was recorded. Results: There were 22 men and 18 women (mean age, 60.8 y) with grade 2 (n = 24) or grade 3 (n = 16) tumors and a mean Ki-67 index of 16.1%. NETPET scores of P0, P1, P2A, P2B, P3B, P4B, and P5 were documented in 2 (5%), 5 (12.5%), 5 (12.5%) 20 (50%), 2 (5%), 4 (10%), and 2 (5%) patients, respectively. No association was found between the SUVmax of target lesions on 68Ga-DOTATATE and the SUVmax of target lesions on 18F-FDG PET (P = 0.505). 18F-FDG/68Ga-DOTATATE SUVmax ratios were significantly lower for patients with low (P1-P2) primary NETPET scores than for those with high (P3-P5) primary NETPET scores (mean ± SD, 0.20 ± 0.13 and 1.68 ± 1.44, respectively; P < 0.001). MTV on 18F-FDG PET was significantly lower for low primary NETPET scores than for high ones (mean ± SD, 464 ± 601 cm3 and 66 ± 114 cm3, respectively; P = 0.005). A change in the type of management was observed in 42.5% of patients after 18F-FDG PET, with the most common being a change from systemic therapy to peptide receptor radionuclide therapy and from debulking surgery to systemic therapy. Conclusion: There was a heterogeneous distribution of NETPET scores in patients with WD grade 2 and 3 GEP NETs, with more than 1 in 5 patients having a high NETPET score and a frequent change in management after 18F-FDG PET. Quantitative parameters including 18F-FDG/68Ga-DOTATATE SUVmax ratios in target lesions and FTV/MTV ratios can discriminate between patients with high and low NETPET scores.

Investigating the causal relationship between gut microbiota and gastroenteropancreatic neuroendocrine neoplasms: a bidirectional Mendelian randomization study.

Background: The interaction between the intestinal flora and gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) remains poorly understood, despite the known effect of the gut microbiota on gastrointestinal adenocarcinomas. Hence, the present research aimed to determine the potential causal correlation between the intestinal flora and GEP-NENs by conducting a bidirectional Mendelian randomization (MR) analysis. Methods: Two-sample MR analysis was conducted using the summary statistics of the gut microbiota from the MiBioGen consortium and those of GEP-NENs from the FinnGen research project. The inverse-variance weighted approach was utilized as the primary analytical method. To enhance the robustness of our findings, multiple sensitivity tests were performed, including Cochran's Q test for evaluating heterogeneity, the MR-Egger intercept test to detect horizontal pleiotropy, and the MR-PRESSO test to identify outliers and assess pleiotropy bias. Additionally, a leave-one-out analysis was performed to validate the consistency of our findings. The MR-Steiger test was also utilized to determine the causal direction in the correlation between the gut microbiota and GEP-NENs. Finally, a reverse MR analysis was performed to assess reverse causality between the intestinal flora and GEP-NENs. Results: We identified 42 taxa of the gut microbiota that were potentially causally associated with GEP-NENs; of these taxa, 7, 8, 11, and 16 taxa were causally associated with pancreatic NENs, colorectal NENs, small intestinal NENs, and gastric NENs, respectively. After adjusting for false discovery rate (FDR) correction, we found significant causal links of Euryarchaeota with small intestinal NENs and Family XIII UCG-001 with gastric NENs. The sensitivity analyses confirmed the stability of these correlations. In the reverse MR analysis, colorectal NENs and small intestinal NENs were found to be associated with variations in 8 and 6 different taxa of the gut microbiota, respectively. After adjusting for FDR correction, no significant causal links were detected between GEP-NENs and the intestinal flora. Conclusion: The present study reveals a potential causal association between certain taxa of the intestinal flora and GEP-NENs, thus providing new perspectives regarding the role of the intestinal flora in the development of these tumors. These insights could provide innovative approaches to screen and prevent these diseases.

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) - Current literature review of diagnostics and therapy. What has changed in the management?

<b>Introduction:</b> Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are malignancies originating from cells of the diffuse endocrine system. They are rare and localize in the upper and lower parts of the gastrointestinal tract and in the pancreas. Despite such a varied location, GEP-NENs are considered a common group of neoplasms due to the fact of their similar morphology and ability to secrete peptide hormones and biologically active amines. They are associated with clinical manifestations specific to the substances produced by a particular neoplasm. The classification of GEP-NENs is constantly systematized and updated based on their differentiation and grading. The development of available diagnostic and treatment methods for these tumors has made significant progress over the past 10 years and is still ongoing.<b>Aim:</b> In the following paper, we review the diagnostics and treatment of GEP-NENs, taking into account the latest molecular, immunological, or gene-based methods. Imaging methods using markers for receptors allow for high diagnostic sensitivity<b>Methods:</b> Medical databases were searched for the latest information. The authors also sought confirmation of the content of a particular publication in another publications, so as to present the most reliable information possible.<b>Results:</b> Research results revealed that the diagnostics and treatment of GEP-NENs have significantly advanced in recent years. Surgical interventions, especially minimally invasive techniques, have shown efficacy in treating GEP-NENs, with specific therapies such as somatostatin analogs, chemotherapy, and peptide receptor radionuclide therapy demonstrating promising outcomes. The evolution of diagnostic methods, including imaging techniques and biomarker testing, has contributed to improved patient care and prognosis.<b>Conclusions:</b> The increasing incidence of GEP-NENs is attributed to enhanced diagnostic capabilities rather than a rise in population prevalence. The study emphasizes the importance of ongoing research to identify specific markers for early detection and targeted therapies to further enhance the effectiveness of treating these rare and heterogeneous malignancies. The findings suggest a positive trajectory in the management of GEP-NENs, with future prospects focused on personalized and targeted treatment approaches.

MEN1/DAXX/ATRX mutations enhance progression-free survival in gastroenteropancreatic neuroendocrine tumors treated with peptide receptor radionuclide therapy.

Pre-clinical data suggest that mutations in the MEN1, DAXX, and/or ATRX genes may potentially increase radiation efficacy in cancer cells. Herein, we explore the association between response to peptide receptor radionuclide therapy (PRRT) and those mutations in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We analyzed tissue-based next generation sequencing (NGS) assay results and clinicopathologic data from 28 patients with GEP-NETs treated with PRRT. Findings were correlated with progression-free survival (PFS) and objective response rate (ORR). Patients with mutations in MEN1, DAXX, and/or ATRX (n = 13) had a longer median PFS (26.47 vs 12.13 months; P = 0.014) than wild-type (n = 15) patients when adjusted for surgery prior to PRRT, tumor grade, and presence of TP53 mutation. Alterations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended toward longer PFS compared to patients without concurrent mutations (31.53 vs 17.97 months; P = 0.09). ORR was higher in patients with a mutation in MEN1, DAXX, or ATRX (41.67% vs 15.38%). In pancreatic NET patients, these target mutations also showed a longer PFS (28.43 vs 9.83 months; P = 0.04). TP53 alterations showed a shorter PFS than wild-type cases (11.17 vs 20.47 months; P = 0.009). Mutations in MEN1/DAXX/ATRX are associated with improved PFS in patients with GEP-NETs receiving PRRT and might be used as a biomarker for treatment response.

Real-World Study of Lanreotide Autogel in Routine Practice in Patients with Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) in Hong Kong and Taiwan.

INTRODUCTION: There is a lack of data on the efficacy, effectiveness, and safety of lanreotide autogel in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) of Chinese ethnicity. This noninterventional, retrospective study evaluated the effectiveness and safety of lanreotide autogel in patients of Chinese ethnicity with GEP-NETs in clinical practice. METHODS: Patients' charts were abstracted from five hospitals in Hong Kong and Taiwan (July-September 2021), where lanreotide autogel is approved for treating GEP-NETs. Included patients were adults with unresectable, metastatic, or locally advanced GEP-NETs who received a first injection (index) of lanreotide autogel 120 mg between 01 January 2017 and 30 June 2020 (planned sample size: N = 30). Follow-up ran from index to a maximum of 48 (± 4) weeks or until disease progression, start of new antitumor treatment, or death. The primary endpoint was progression-free survival (PFS) rate at week 48 (±4), and secondary endpoints included PFS rate at week 24 (±4), estimated using Kaplan-Meier analyses. All analyses were descriptive. RESULTS: Of 27 patients enrolled, 22 (81.5%) had 48 weeks of follow-up. Tumors of pancreatic origin were the most common (73.9%). PFS rate was 0.96 (95% confidence interval: 0.72 - 0.99) at 24 weeks and 0.82 (0.53-0.94) at 48 weeks. Overall, 74.1% patients experienced ≥ 1 treatment-emergent adverse event; none were serious. No deaths were reported. CONCLUSIONS: Lanreotide autogel was well tolerated and showed good tumor control rate in a real-world setting. These findings align with results from previous studies in Caucasian, Japanese, and Korean patients, thus supporting lanreotide autogel for treating patients with GEP-NETs of Chinese ethnicity.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare cancers that develop in the stomach, intestines, or pancreas. Lanreotide autogel is used to treat GEP-NETs in patients whose tumors cannot be removed by surgery or have spread to other body parts. At the time of the study, lanreotide autogel was not approved in mainland China for treating patients with GEP-NETs. Most clinical trials of lanreotide autogel were conducted in Caucasian patients, so more information is needed on whether lanreotide autogel is effective and well tolerated for treating GEP-NETs in patients of Chinese ethnicity. We performed this study to gain this information. In this study, we retrieved data from the medical records of patients of Chinese ethnicity with GEP-NETs who were treated with lanreotide autogel in Hong Kong and Taiwan. We examined the medical records to understand how these patients responded to lanreotide autogel. The results from this study showed that after 24 weeks of lanreotide autogel treatment, 22 of 23 patients had GEP-NETs that did not worsen. After 48 weeks of treatment, two of these patients had GEP-NETs that grew or spread, resulting in 20 patients with GEP-NETs that did not worsen at the end of the study. No patients had serious side effects related to lanreotide autogel. In conclusion, this study showed that lanreotide autogel is well tolerated and effective for treating patients of Chinese ethnicity with GEP-NETs in the real world, which is consistent with results from earlier studies in Caucasian patients. These results support the use of lanreotide autogel in these patients.

Gastroenteropancreatic neuroendocrine tumors in children and adolescents.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare in children and adolescents. Standard management of these tumors has not been well established due to their rarity in this age group. We aimed to report the clinical and pathological characteristics of patients with this rare disease followed and treated between the years 1993-2022. MATERIALS AND METHODS: The medical records of patients with GEP-NETs were reviewed. RESULTS: Fourteen patients (11 girls, 3 boys) were diagnosed with GEP-NET. The median age was 13 (9-18) years. Tumor localization was the appendix in 12, stomach in one and pancreas in one patient. Mesoappendix invasion was detected in four patients two of whom underwent right hemicolectomy (RHC) and lymph node dissection (LND). Of those, one patient had lymph node involvement. The other two had not further operations. Somatostatin was used in one with pancreatic metastatic disease and the other with gastric disease after surgery. No additional treatment was given in other patients. All patients are under follow-up without evidence of disease at a median follow-up of 85 months (7-226 months). CONCLUSION: GEP-NETs should be considered in the differential diagnosis of acute appendicitis and in cases with persistent abdominal pain. In children, there is invariably a favorable prognosis, and additional surgical interventions other than simple appendectomies generally do not provide benefits. Mesoappendix invasion may not necessitate RHC and LND.

A pilot study of the immune microenvironment of GI neuroendocrine carcinoma.

Gastroenteropancreatic high-grade (HG) neuroendocrine carcinoma (GEP-NEC) is an aggressive malignancy with limited treatment options and increasing incidence in the United States. Due to the rarity of the cancer and heterogeneity of the primary tumor location, data on GEP-NEC oncogenesis and its interaction with the host immune system are limited. A greater understanding of GEP-NEC and its tumor microenvironment (TME) would benefit efforts to develop more effective targeted therapies and rationally adapt immunotherapy to this disease. In this study, we profiled the expression of 770 unique genes using 21 biopsy samples from patients with GEP-NEC using the NanoString nCounter PanCancer IO 360 platform. Our results show several trends evident within the GEP-NEC TME. Greater expression of genes indicative of immune cell infiltration was present within the TME of patients <60 years of age and in patients with greater overall survival (OS). Tumors from patients with non-pancreatic NEC had diminished MHCII expression compared to pancreatic NEC, suggesting more prominent adaptive immune responses in the pancreatic GEP-NEC subtype. Patients with a >6 months OS had tumors with elevated NK cell gene signatures compared to patients with poor survival. Further, the analysis revealed numerous differentially expressed genes based on patient age, tumor location, response to treatment, and OS, which warrant future validation for assessing the relationship with clinical outcomes in patients.

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.

NETest in advanced high-grade gastroenteropancreatic neuroendocrine neoplasms.

Molecular blood biomarkers are lacking for high-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). To histologically distinguish between neuroendocrine carcinoma (NEC), neuroendocrine tumors G3 (NET G3), adenocarcinoma and MINEN is often challenging. The mRNA-based NETest has diagnostic, prognostic and predictive value in neuroendocrine tumors G1-2 but has not been studied in HG GEP-NEN. Patients with advanced HG GEP-NEN were prospectively included in an observational study. A blood sample was collected before the start of chemotherapy and pseudonymised before NETest was performed. NETest results are expressed as an activity index (NETest score) from 0 to 100. The normal score cut-off is 20. Histological sections were pseudonymised before centralized pathological re-evaluation. Samples from 60 patients were evaluable with the NETest. Main primary tumor sites were colon (14), rectum (12), pancreas (11) and esophagus (7). Re-classification: 30 NEC, 12 NET G3, 3 HG-NEN ambiguous morphology, 8 MiNEN, 3 adenocarcinomas with neuroendocrine differentiation (ADNE), 3 adenocarcinomas and 1 NET G2. Elevated NETest (>20) was seen in 38/45 (84%) HG GEP-NEN, all 17 large-cell NEC (100%), 11/13 (85%) small-cell NEC, all ambiguous cases and 7/12 (64%) NET G3. NETest was elevated in 5/8 (63%) MiNEN, 2/3 ADNE, however not in 3 adenocarcinomas. Median survival was 10.2 months (9.6-10.8 95%CI) for evaluable HG GEP-NEN treated with palliative chemotherapy (n = 39), and survival was significantly shorter in patients with NETest >60 with an OS of only 6.5 months. This is the first study to evaluate use of the NETest in advanced HG GEP-NEN. The NETest was almost always elevated in GEP-NEC and in all large-cell NEC. The NETest was also frequently elevated in NET G3 and MiNEN, however cases were limited. Baseline NETest was not predictive for benefit of chemotherapy, however a NETest >60 was prognostic with a shorter survival for patients receiving chemotherapy.

Gastroenteropancreatic neuroendocrine neoplasms: current development, challenges, and clinical perspectives.

Neuroendocrine neoplasms (NENs) are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are the most common subtype of NENs. Historically, GEP-NENs have been regarded as infrequent and slow-growing malignancies; however, recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades. In addition, an increasing number of studies have proven that GEP-NENs result in a limited life expectancy. These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed. Therefore, there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs. In this review, we have summarized the limitations and recent advancements in our comprehension of the epidemiology, clinical presentations, pathology, molecular biology, diagnosis, and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients.

Lutetium [177Lu]-DOTA-TATE in gastroenteropancreatic-neuroendocrine tumours: rationale, design and baseline characteristics of the Italian prospective observational (REAL-LU) study.

PURPOSE: Gastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [177Lu]-DOTA-TATE was approved for the treatment of GEP-NETs after the phase III NETTER 1trial demonstrated improved progression free survival, objective response rates and health-related quality of life (HRQoL) compared to high-dose somatostatin analogues. No real-world data exist on prescribing habits and clinically significant endpoints for [177Lu]Lu-DOTA-TATE treatment in Italy. REAL-LU is a multicentre, long-term observational study in patients with unresectable/metastatic GEP-NETs progressing on standard therapies in Italian clinical practice. A pre-specified interim analysis was performed at the end of the enrolment period, data from which are described herein. METHODS: Overall duration of REAL-LU will be approximately 48 months, with 12- and 36-month recruitment and follow-up periods, respectively. The primary objective is to evaluate [177Lu]Lu-DOTA-TATE effectiveness in terms of progression-free survival. Secondary objectives include safety, impact on HRQoL, and identification of prognostic factors. This pre-specified interim analysis describes patient profiles, at the end of enrollment, of those prescribed [177Lu]Lu-DOTA-TATE for GEP-NETs in Italy. RESULTS: Among 161 evaluable patients, mean age was 64.7 ± 10.3 years at study entry, 83.8% presented with no clinical signs of disease at physical examination, and most had minor disease symptoms. All patients had metastatic disease, most commonly in the liver (83.9%) with a median of two metastatic sites. In 90.7% of patients, the disease was stage IV, and 68.3% had ≥ 1 target lesion. [177Lu]Lu-DOTA-TATE was prescribed mainly as second-line therapy (61.6%) and following surgery (58.4%). HRQoL assessments revealed high levels of functioning and low levels of symptoms at baseline; 50.0% of patients were symptom-free at study entry. CONCLUSION: The characteristics of patients who received [177Lu]Lu-DOTA-TATE in Italy are similar to those of the GEP-NET population of NETTER 1 with trial but with a higher proportion of patients with a grade 2 (71%). With regard to the tumor grade profile, our study cohort appears to be closer to that of NETTER-2 study population which included patients with G2 or G3 advanced GEP-NETs (i.e. Ki-67 ≥ 10% and ≤ 55%). Further analysis of effectiveness and safety can be anticipated as REAL-LU data mature. STUDY REGISTRATION: ClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1.

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.

Long-term clinical outcomes of [177Lu]Lu-DOTATATE in patients with metastatic neuroendocrine tumors.

The incidence of gastroenteropancreatic neuroendocrine tumors has been rising and these tumors are usually only diagnosed at a metastatic stage. Present first line treatments include somatostatin analogs, targeted therapies and peptide receptor radionuclide therapy. The Lutetium-177 [177Lu] based radiotracer [177Lu]Lu-DOTATATE has only been approved as first-line treatment of metastatic midgut NETs however its efficacy as a third line or above treatment in patients with non ileal primaries has not been tested. In our study, we identified 25 patients with histologically confirmed well-differentiated metastatic neuroendocrine tumors and administered [177Lu]Lu-DOTATATE as a second line, third line and fourth line treatment. Our study demonstrated a notable response in patients with non-ileal primaries and heavily pretreated disease, warranting further studies for additional cycles of treatment.

Optimal surgical management of unifocal vs. multifocal NF-PNETs: a respective cohort study.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) represent 1-2% of pancreatic tumors, with recent guidelines recommending active surveillance for non-functioning PNETs (NF-PNETs) smaller than 2 cm. However, the management of multiple NF-PNETs, as well as the influence of tumor number on prognosis, remains under-researched. METHODS: This retrospective study analyzed NF-PNET patients who underwent pancreatic resection at Severance Hospital between February 1993 and August 2023, comparing the characteristics of patients diagnosed with multifocal tumors and those with unifocal tumors. A subgroup analysis of overall survival (OS) and recurrence-free survival (RFS) was performed based on multifocality employing the Kaplan-Meier method and the log-rank test. RESULTS: Of 187 patients, 169 (90.4%) had unifocal and 18 (9.6%) had multifocal tumors. Multifocal tumors were more likely to be diffusely spread, necessitating more total pancreatectomies (diffuse tumor location: 4.7% in unifocal vs. 38.9% in multifocal cases, p < 0.001; total pancreatectomy: 4.1% in unifocal vs. 33.3% in multifocal cases, p < 0.001). In patients with NF-PNET who underwent the same extent of pancreatic resection, no significant difference in the incidence of complication was observed regardless of multifocality. Moreover, no significant difference in OS was seen between the unifocal and multifocal groups (log-rank test: p = 0.93). However, the multifocal group exhibited a poorer prognosis in terms of RFS compared to the unifocal group (log-rank test: p = 0.004) Hereditary syndrome, tumor grade, size, lymphovascular invasion, and lymph node metastasis were key factors in the recurrence. CONCLUSION: This study's findings suggest that the presence of multiple tumors was associated with poorer recurrence-free survival but did not affect long-term survival following surgery. Given the long-term oncologic outcome and quality of life following surgery, resection of tumors over 2 cm is advisable in patients with multifocal PNETs, while a cautious "wait-and-see" approach for smaller tumors (under 2 cm) can minimize the extent of resection and improve the quality of life. In cases with only small multifocal NF-PNETs (< 2 cm), immediate resection may not be crucial, but the higher recurrence rate than that in solitary NF-PNET necessitates intensified surveillance.

Mixed neuroendocrine non-neuroendocrine neoplasms in gastroenteropancreatic tract.

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) are a heterogeneous group of malignant neoplasms that can settle in the gastroenteropancreatic tract. They are composed of a neuroendocrine (NE) and a non-NE component in at least 30% of each tumour. The non-NE component can include different histological combinations of glandular, squamous, mucinous and sarcomatoid phenotypes, and one or both of the components can be low-or high grade malignant. Recent changes in the nomenclature of these neoplasms might lead to great deal of confusion, and the lack of specific clinical trials is the main reason why their management is difficult. The review aims to clarify the definition of MiNEN and analyze available evidence about their diagnosis and treatment options according to their location and extension through careful analysis of the available data. It would be important to reach a general consensus on their diagnosis in order to construct a classification that remains stable over time and facilitates the design of clinical trials that, due to their low incidence, will require long recruitment periods.

Critical updates in neuroendocrine tumors: Version 9 American Joint Committee on Cancer staging system for gastroenteropancreatic neuroendocrine tumors.

The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including gastroenteropancreatic neuroendocrine tumors (GEP-NETs), is meant to be dynamic, requiring periodic updates to optimize AJCC staging definitions. This entails the collaboration of experts charged with evaluating new evidence that supports changes to each staging system. GEP-NETs are the second most prevalent neoplasm of gastrointestinal origin after colorectal cancer. Since publication of the AJCC eighth edition, the World Health Organization has updated the classification and separates grade 3 GEP-NETs from poorly differentiated neuroendocrine carcinoma. In addition, because of major advancements in diagnostic and therapeutic technologies for GEP-NETs, AJCC version 9 advocates against the use of serum chromogranin A for the diagnosis and monitoring of GEP-NETs. Furthermore, AJCC version 9 recognizes the increasing role of endoscopy and endoscopic resection in the diagnosis and management of NETs, particularly in the stomach, duodenum, and colorectum. Finally, T1NXM0 has been added to stage I in these disease sites as well as in the appendix.

Managing end-stage carcinoid heart disease: A case report and literature review.

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors, often diagnosed in an advanced stage when curative treatment is impossible and grueling symptoms related to vasoactive substance release by tumor cells affect patients' quality of life. Cardiovascular complications of GEP-NENs, primarily tricuspid and pulmonary valve disease, and right-sided heart failure, are the leading cause of death, even compared to metastatic disease. CASE SUMMARY: We present a case of a 35-year-old patient with progressive dyspnea, back pain, polyneuropathic leg pain, and nocturnal diarrhea lasting for a decade before the diagnosis of neuroendocrine carcinoma of unknown primary with extensive liver metastases. During the initial presentation, serum biomarkers were not evaluated, and the patient received five cycles of doxorubicin, which he did not tolerate well, so he refused further therapy and was lost to follow-up. After 10 years, he presented to the emergency room with signs and symptoms of right-sided heart failure. Panneuroendocrine markers, serum chromogranin A, and urinary 5-hydroxyindoleacetic acid were extremely elevated (900 ng/mL and 2178 µmol/L), and transabdominal ultrasound confirmed hepatic metastases. Computed tomography (CT) showed liver metastases up to 6 cm in diameter and metastases in mesenteric lymph nodes and pelvis. Furthermore, an Octreoscan showed lesions in the heart, thoracic spine, duodenum, and ascendent colon. A standard transthoracic echocardiogram confirmed findings of carcinoid heart disease. The patient was not a candidate for valve replacement. He started octreotide acetate treatment, and the dose escalated to 80 mg IM monthly. Although biochemical response and symptomatic improvement were noted, the patient died. CONCLUSION: Carcinoid heart disease occurs with carcinoid syndrome related to advanced neuroendocrine tumors, usually with liver metastases, which manifests as right-sided heart valve dysfunction leading to right-sided heart failure. Carcinoid heart disease and tumor burden are major prognostic factors of poor survival. Therefore, they must be actively sought by available biochemical markers and imaging techniques. Moreover, imaging techniques aiding tumor detection and staging, somatostatin receptor positron emission tomography/CT, and CT or magnetic resonance imaging, should be performed at the time of diagnosis and in 3- to 6-mo intervals to determine tumor growth rate and assess the possibility of locoregional therapy and/or palliative surgery. Valve replacement at the onset of symptoms or right ventricular dysfunction may be considered, while any delay can worsen right-sided ventricular failure.

Prognostic value of inflammation-related biomarkers in patients with gastroenteropancreatic neuroendocrine neoplasms: A systematic review and meta-analysis.

Hematological indicators of chronic systemic inflammation are significant biomarkers for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). We performed a systematic review and meta-analysis to assess the impact of certain factors on the overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) of patients with GEP-NENs. These factors include the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and C-reactive protein (CRP) levels. After searching the Medline, Embase, and Cochrane Library databases from January 1, 2000 to October 20, 2022 and the American Society of Clinical Oncology conference proceedings from January 1, 2017, hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted. Subgroup analyses were conducted to identify the origins of heterogeneity and examine the impact of factor grouping. The effects of the cut-off values and sample size were assessed by meta-regression. The results revealed that higher NLRs, PLRs, and CRP levels were associated with shorter OS (HR = 2.09, 95% CI = 1.55-2.8; HR = 1.79, 95% CI = 1.40-2.28; and HR = 2.88, 95% CI = 2.09-3.95, respectively; all p < 0.001). Higher NLRs and lower LMRs were associated with shorter DFS (HR = 3.34, 95% CI = 2.11-5.29 and HR = 2.71, 95% CI = 2.27-3.24, respectively; both p < 0.001). Higher PLRs and CRP levels were correlated with shorter PFS (HR = 3.48, 95% CI = 1.34-9.03, p = 0.01 and HR = 3.14, 95% CI = 1.63-6.08, p = 0.001). As demonstrated in the research, hematological indicators of systemic inflammation are promising biomarkers for GEP-NEN assessment.