Neuroendocrine Tumor G1 Research Articles

Incidence and Management of Appendiceal Neuroendocrine Tumors in Pediatric Population: A Bicentric Experience with 6285 Appendectomies.

Neuroendocrine tumors (NETs) are rare tumors that arise from neuroendocrine cells and are the most common tumors of the appendix. NETs of the appendix usually cause no symptoms and often go unnoticed until they cause acute appendicitis or are discovered during an accidental appendectomy. As the trend towards the conservative treatment of acute appendicitis increases in the pediatric population, the question arises as to whether the majority of NETs go undetected and are only discovered at an advanced stage. The purpose of the proposed study is to review the incidence and outcomes of treatment for NETs of the appendix in children and include the data presented in the data pool for further review. From 1 January 2009 to 1 November 2023, a total of 6285 appendectomies were performed in two large pediatric centers in Croatia. After a retrospective review of the case records and histopathologic findings, a total of 31 children (0.49%) were diagnosed with NET of the appendix and included in the further analysis. The primary outcome of this study was the incidence and treatment outcome of pediatric patients diagnosed with NET of the appendix. Secondary outcomes included the patients' demographic, clinical, and laboratory data and the histopathologic characteristics of tumor species. The overall incidence of NETs of the appendix was stable over the study years, with minor fluctuations. The median age of patients was 14 (interquartile range-IQR: 12, 16) years, with a female predominance (64.5%). The majority of patients (96.8%) presented with acute abdominal pain and underwent appendectomy because acute appendicitis was suspected. Acute appendicitis was confirmed by histopathology in 18 (58%) cases. NETs of the appendix were not detected preoperatively in any of the patients. Among patients with confirmed acute appendicitis, most (n = 14; 77.8%) were found to have non-perforated acute appendicitis. In most children, the tumor was located at the tip of the appendix (n = 18; 58.1%), and the majority of tumors had a diameter of less than 1 cm (n = 21, 67.7%). The mitotic count (n = 25, 80.6%) and Ki-67 proliferation index (n = 23, 74.2%) were low in most patients, so most tumors were classified as NET G1 (n = 25, 80.6%), while NET G2 and NET G3 were found in four (12.9%) and two (6.5%) patients, respectively. All children were treated with appendectomy only. The median follow-up time was 54 (IQR: 24, 95) months. The incidence of appendiceal NET among pediatric patients is very low. NET occurs most frequently in adolescents, with a female predominance. Most tumors are less than 1 cm in diameter, located at the tip, and associated with non-perforated appendicitis. Appendectomy is the treatment of choice, and major surgery was not necessary in our cohort.

Aranose: Domestic original cytostatic agent for treatment of neuroendocrine tumors of all localizations

Aranose is an original cytostatic, synthesized in the Russian Cancer Research Center, belongs to the class of nitrosourea derivatives (this class of drugs also including streptozotocin). In preclinical trials, Aranose has shown its activity in neuroendocrine tumors (NETs). Prospective clinical studies have confirmed high efficacy and good tolerability of the drug in different lines of treatment of patients with NET G1 and G2. Median PFS while Aranose treatment in a single mode or in combination with capecitabine, doxorubicin and temozolomide did not differ significantly (15.3 vs 15.8, 15.3 and 17.9 months, respectively, p = 0.791). After updating the histological classification and highlighting the prognostically unfavorable subgroup of NET G3, a prospective single-center clinical study of Aranose in the first line of NET G3 therapy was conducted. The standard dosage regimen of the drug was used: 500 mg/m2 from the first to the third days, a cycle of 21 days. On average, patients received nine courses of Aranose chemotherapy, but in case of an increase in the radiological response treatment continued until disease progression or unacceptable toxicity. Median PFS in the Aranose group was 12 months, in the group of patients receiving capecitabine and oxaliplatin combination – 5 months, in capecitabine and temozolomide combination – 7 months, in the etoposide with cisplatin or carboplatin group only 4 months. The frequency of objective responses in the Aranose group was 37 % (10/27), no complete responses were recorded. Disease stabilization was achieved in 40.7 % (11/27), thus, the frequency of disease control was 77.7 % (21/27). Disease control was maintained after 6 months or more in 63 % of patients.

Multiple endocrine neoplasia type 1 with Zollinger-Ellison syndrome: clinicopathological analysis of a Japanese family with focus on menin immunohistochemistry.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of multiple epithelial neuroendocrine tumors (NETs) and non-NETs in various organs. MEN1 encodes a 610-amino acid-long tumor suppressor protein, menin. The optimal treatment for multiple tumors, identification of the most critical tumors for patient prognosis, and menin immunohistochemistry findings remain controversial. Therefore, we aimed to elucidate these issues through a histological analysis of tumors and tumor-like lesions in a Japanese family, comprising a father and his two sons, who had MEN1 with Zollinger-Ellison syndrome (ZES). All family members had a germline alteration in exon 10, c.1714-1715 del TC of MEN1, and exhibited multiple synchronous and metachronous tumors. The patients had pulmonary NETs, hyperparathyroidism, hypergastrinemia, pituitary adenomas, pancreaticoduodenal NETs, adrenocortical adenoma with myelolipoma, nodular goiter of the thyroid, lipomas, and angiofibroma. Most tumors were resected and histologically examined. We compared their clinical courses and tumor histology, and conducted menin immunohistochemistry (IHC). Two patients died of pulmonary NET G2. One patient who underwent pancreaticoduodenectomy was cured of ZES; however, the two other patients who did not undergo pancreaticoduodenectomy suffered persistent ZES despite treatment with octreotide. Menin IHC revealed varying NET intensities, ranging from positive to negative stains. Pancreaticoduodenectomy is the most effective treatment for ZES. Long-term follow-up is essential for pulmonary NET G2 owing to the risk of distant metastasis and/or multiplicity. Moreover, the variability of menin IHC in MEN1-related tumors may indicate the pattern of tumor formation rather than the diagnostic utility of menin in MEN1.

1184MO Safety and efficacy of everolimus (EVE) as second-line treatment in neuroendocrine neoplasms G3 (NEN G3): An AIO phase II study (EVINEC)

1184MO Safety and efficacy of everolimus (EVE) as second-line treatment in neuroendocrine neoplasms G3 (NEN G3): An AIO phase II study (EVINEC)

Diagnostic accuracy of SSR-PET/CT compared to histopathology in the identification of liver metastases from well-differentiated neuroendocrine tumors

BackgroundHistopathology is the reference standard for diagnosing liver metastases of neuroendocrine tumors (NETs). Somatostatin receptor-positron emission tomography / computed tomography (SSR-PET/CT) has emerged as a promising non-invasive imaging modality for staging NETs. We aimed to assess the diagnostic accuracy of SSR-PET/CT in the identification of liver metastases in patients with proven NETs compared to histopathology.MethodsHistopathologic reports of 139 resected or biopsied liver lesions of patients with known NET were correlated with matching SSR-PET/CTs and the positive/negative predictive value (PPV/NPV), sensitivity, specificity, and diagnostic accuracy of SSR-PET/CT were evaluated. PET/CT reading was performed by one expert reader blinded to histopathology and clinical data.Results133 of 139 (95.7%) liver lesions showed malignant SSR-uptake in PET/CT while initial histopathology reported on ‘liver metastases of NET´ in 127 (91.4%) cases, giving a PPV of 91.0%. Re-biopsy of the initially histopathologically negative lesions (reference standard) nevertheless diagnosed ‘liver metastases of NET’ in 6 cases, improving the PPV of PET/CT to 95.5%. Reasons for initial false-negative histopathology were inadequate sampling in the sense of non-target biopsies. The 6 (4.3%) SSR-negative lesions were all G2 NETs with a Ki-67 between 2–15%.ConclusionSSR-PET/CT is a highly accurate imaging modality for the diagnosis of liver metastases in patients with proven NETs. However, we found that due to the well-known tumor heterogeneity of NETs, specifically in G2 NETs approximately 4–5% are SSR-negative and may require additional imaging with [18F]FDG PET/CT.

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

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. 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. 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. 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.

Controversies and prospects for surgical treatment of pancreatic neuroendocrine neoplasms with liver metastases

The incidence of pancreatic neuroendocrine neoplasm(pNEN) increased over the past two decades. Liver metastasis, the most common type of distal metastasis, is also one of the most important prognostic factors. Although several medical treatments, including biotherapy, chemotherapy, targeted therapy, peptide receptor radionuclide therapy and locoregional therapy, are available for pNEN with liver metastases, surgery is still the only possible treatment for cure. Currently, there are several controversies as regards surgical treatment for pNEN with liver metastases. These controversies include, but are not limited to, whether surgical resection is appropriate for pancreatic neuroendocrine tumor G3 with liver metastases, how to classify primary lesion and hepatic metastases comprehensively and accurately, what is the optimal surgical strategy for type Ⅱ liver metastases, who can benefit greatly from cytoreduction, and how to refine the Milan criteria for liver transplantation. This article aims to discuss those main controversies and provide prospects for future clinical trials.

Radioligand Therapy with [177Lu]Lu-DOTA-TATE or [177Lu]Lu-DOTA-TATE and [90Y]Y-DOTA-TATE in Patients with Neuroendocrine Neoplasms of Unknown Locations, or Locations Other Than the Midgut and Pancreas as Primaries in a G1, G2 and G3 Grade.

Neuroendocrine neoplasms (NENs) are a rare group of tumors with a different clinical course, prognosis and location. Radioligand therapy (RLT) can be used as a first or second line of treatment. It is registered in gastroenteropancreatic NENs (GEP-NENs) as grades G1 and G2. Tumors with an unknown point of origin, diagnosed outside the gastrointestinal tract and pancreas (non-GEP) or at the G3 grade, remain in the "grey area" of treatment. Analysis of 51 patients with NENs who underwent RLT in a single highest reference center from 2018 to 2023 was performed. Treatment was administrated to the patients with neoplasms of unknown origin, non-GEP-NENs, and ones with G3 grade. In total, 35 patients received 177-Lutetium (7.4 GBq), while 16 received 177-Lutetium and 90-Yttrium with equal activities (1.85 + 1.85 GBq). The progression-free survival (PFS) before RLT qualification was 34.39 ± 35.88 months for the whole study group. In subgroups of patients with an unknown tumor location (n = 25), the median PFS was 19 months (IQR = 23), with "other" locations (n = 21) at 31 months (IQR = 28), and with NEN G3 (n = 7) at 18 months (IQR = 40). After RLT, disease stabilization or regression was observed in 42 (87.5% of) patients. RLT did not cause statistical changes in creatinine or GFR values. Hematological parameters (RBC, WBC, PLT, HGB) as well as chromogranin A concentration decreased significantly. There were no statistical differences between both subgroups regarding the type of radioisotope (177-Lutetium vs. 177-Lutetium and 90-Yttrium). After RLT in long-term observation, the median observation time (OT) was 14 months (IQR = 18 months). In patients with progression (n = 8), the median PFS was 20 months (IQR = 16 months), while in patients with confirmed death (n = 9), the median overall survival (OS) was 8 months (IQR = 14 months). Our study showed that 87.5% of NEN patients with unknown origin, non-GEP-NENs, and those with GEP-NEN G3 grade had benefited from the radioligand therapy. There were no significantly negative impacts on renal parameters. The decrease of bone marrow parameters was acceptable in relation to beneficial disease course. The decrease of chromogranin concentration was confirmed as a predictive factor for disease stabilization or regression.

NET G3 vs NEC: p53 and Rb1 Immunolabeling in High-grade Gastrointestinal Neuroendocrine Neoplasms - Is It Enough for the Differential Diagnosis?

High-grade gastrointestinal neuroendocrine neoplasms (GI-NENs) are divided into well-differentiated G3 neuroendocrine tumors (NETs G3) and neuroendocrine carcinomas (NECs), having identical cut-offs of proliferation, but different biomolecular origins. This translates in distinct treatment choices. Our aim was to establish if p53/Rb1 immunohistochemical status in GI-NENs with Ki67 index >20% can predict the histopathological diagnosis. p53/Rb1 immunolabelling was performed on 42 cases of high-grade GI-NENs, diagnosed as NET G3, NEC and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) with NEC component. Immunolabeled slides were digitally scanned, with automatic quantification of p53 and Rb1, blind to the diagnosis. The p53 positive percentage was stratified; two cut-offs were selected, naming the intervals as N (null, <1%), T (tumor, 1%-20%) and C (carcinoma, >20%). The Rb1 expression loss in >90% of neoplastic cells was considered mutational. NETs G3 mainly showed the T status (14/16, 87.5%), followed by N (1/16, 6.25%) and C (1/16, 6.25%); NECs and NEC components in MiNENs predominantly expressed the C status (19/26, 73.08%), followed by N (5/26, 19.23%) and T (2/26, 7.69%) (p<0.001, χ 2 =27.017). NET G3s showed positive expression for Rb1; 73.08% of NECs expressed negative Rb1 (p<0.001, χ 2 =21.351). NECs and NEC components in MiNENs showed Rb1 mutational status in 13 C cases (13/19, 68.42%), 4 N cases (4/5, 80%) and in both the T cases (p=0.002, χ 2 =11.187). Our results highlight the correlations between the p53/Rb1 immunostainings and the histopathological diagnosis of high-grade GI-NENs. NECs and NEC components in MiNENs showed a p53 mutational status (0% or 21-100%) and predominantly negative Rb1 expression. NETs G3 showed a p53 wild-type status (1-20%) and retained Rb1 expression. These findings suggest that the differential diagnosis of high-grade GI-NENs may benefit from p53/Rb1 immunohistochemical tests in everyday practice.

Precision medicine applied to rare malignancies: A single-center experience at University Hospital of Verona.

e16296 Background: Therapeutic resources are often limited in rare tumors. NGS (Next Generation Sequencing) represents a valuable tool that can provide biological and prognostic information and guide therapeutic options. Here we describe a case series of the University Hospital of Verona, a center of excellence for neuroendocrine and pancreatic neoplasms. Methods: Between October 2020 and December 2022, 75 patients (pts) with a neuroendocrine neoplasm (NEN) or mixed neuroendocrine non-neuroendocrine neoplasia (MiNEN) underwent NGS analysis with an in-house assay CORE panel (covering 174 genes; 42 pts) or FoundationOne CDx panel (33 pts). We reported ACMG/AMP class IV-V molecular alterations as single nucleotide variations (SNVs), copy number variations (CNVs) including amplifications, deletions, fusions and loss of heterozygosity (LOH). Results: We included 53 well-differentiated neuroendocrine tumors (NETs), 17 poorly differentiated neuroendocrine carcinomas (NECs) and 5 MiNENs. The majority originated from gastro-entero-pancreatic tract (n=67, 89%). The most frequent gene alterations were TP53 (n=30; 12%: 28 SNV and 2 LOH); MEN1 (n=14, 5%: all SNV), CDKN2A (n=12; 5%: 2 SNV, 4 CNV LOH and 5 CNV loss), DAXX (n=12, 5%: all SNV) and RB1 (n=11, 4%: 8 SNV, 4 CNV LOH and 5 CNV loss). In MiNEN pts 3 druggable alterations were found: 1 TRIM-BRAF fusion, 1 SCL4A4-ROS1 fusion and 1 ERBB2 amplification. All MiNENs were MSS; median TMB (mTMB) was 4.86 mut/Mb. Among NET pts the most often altered genes were MEN1 (n=14), DAXX (n=12), TP53 (n=10), PTEN (n=7), CDKN2A (n=5), NF1 (n=5), TSC2 (n=5). The most prevalent mutations in NEC pts involved TP53 (n=17), RB1 (n=9), KRAS (n=7), CDKN2A (n=6), CDKN2B (n=5), CCNE1 (n=5), APC (n=4), SMAD4 (n=3). The mutational rate in NETs was 2.7 with a mTMB of 6.5; the mutational rate in NECs was 5.3 with a mTMB of 7.3 mut/Mb. In NET and NEC 23 actionable mutations were reported. In pancreatic NENs, DAXX mutation was present in 29% of NET G3 and absent in NEC cases. Among G1-G2 NET pts treated with PRRT in 2nd or further lines with a follow-up longer than 60 months (n=17), 6 (35%) were DAXX mutated and all (100%) were still alive at 5 years, compared to 7/11 (64%) in the DAXX wild type (wt) group. Focusing on NET with Ki67% between 3% and 55% (n=45), TP53 wt pts (n=35, 78%) showed a better median overall survival (mOS) than TP53 mutated (n=10, 22%) pts (131.3 vs 56.7 months; p= 0.0433). Conclusions: Our data support the role of NGS in pancreatic rare histologies. This work highlighted the negative prognostic role of TP53 status in G2-G3 NETs, the potential predictive role of DAXX in G1-G2 NET treated with PRRT and its contribution to the differential diagnosis between NET and NEC. Our findings suggest that the pathogenesis in NET is mostly mediated by defects in tumor suppressor genes, while the role of oncogene alterations seem to acquire more importance with increasingly poor differentiation.

Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society for the management of high grade gastroenteropancreatic and gynecologic neuroendocrine neoplasms.

High-grade neuroendocrine neoplasms are a rare disease entity and account for approximately 10% of all neuroendocrine neoplasms. Because of their rarity, there is an overall lack of prospectively collected data available to advise practitioners as to how best to manage these patients. As a result, best practices are largely based on expert opinion. Recently, a distinction was made between well-differentiated high-grade (G3) neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas, and with this, pathologic details, appropriate imaging practices and treatment have become more complex. In an effort to provide practitioners with the best guidance for the management of patients with high-grade neuroendocrine neoplasms of the gastrointestinal tract, pancreas, and gynecologic system, the North American Neuroendocrine Tumor Society convened a panel of experts to develop a set of recommendations and a treatment algorithm that may be used by practitioners for the care of these patients. Here, we provide consensus recommendations from the panel on pathology, imaging practices, management of localized disease, management of metastatic disease and surveillance and draw key distinctions as to the approach that should be utilized in patients with well-differentiated G3 neuroendocrine tumors vs poorly differentiated neuroendocrine carcinomas.

Single-incision laparoscopic surgery for intestinal intussusception due to neuroendocrine tumor

BackgroundSmall intestinal neuroendocrine tumor (NET) is uncommon, but intestinal intussusception caused by NET is even rare. We report a rare case of single-incision laparoscopic surgery (SILS) for intestinal intussusception due to NET G1.Case presentationA 72-year-old woman presented with vomiting, diarrhea, and abdominal pain. Contrast-enhanced computed tomography (CT) revealed the target sign in the ascending colon. An enhanced nodule was detected at the lead point, leading us to suspect a tumor. Colonoscopy showed a tumor at the lead point of the intestinal intussusception. Histological findings led to a diagnosis of NET G1. Single-incision laparoscopic ileocecal resection with regional lymphadenectomy was then performed. The patient was discharged 10 days postoperatively with no complications.ConclusionWe achieved SILS with regional lymphadenectomy for preoperatively diagnosed intestinal intussusception due to NET G1. Although this condition is rare, surgeons should take this possibility into consideration in cases showing similar findings.

Can Ampullary G1 and G2 Neuroendocrine Tumors Be Cured by Endoscopic Papillectomy?

At present, pancreaticoduodenectomy or local excision are the main treatment options for ampullary neuroendocrine tumors of any size with no distant spread. Endoscopic papillectomy provided a super minimally invasive treatment method for ampullary lesions. However, the studies of endoscopic papillectomy for ampullary neuroendocrine tumors were very limited. This study aimed to assess the feasibility of endoscopic papillectomy for ampullary neuroendocrine tumors. Between August 2007 and June 2021, seven patients with ampullary neuroendocrine tumors with no advanced signs underwent endoscopic papillectomy in our center. We assessed and analyzed the related clinical outcomes. Moreover, a comprehensive literature review was conducted. All the seven cases underwent endoscopic papillectomy successfully; six (85.7%) of them achieved the complete resection. No recurrence occurred over a median follow-up of 48 months (range 6-172 months). Moreover, 22 cases from the comprehensive search were included, and showed a promising clinical outcome. Endoscopic papillectomy appeared to be a feasible way to treat ampullary neuroendocrine tumors without the advanced signs, although further prospectively multicenter studies are warranted.

Development of novel prediction models for nodal and distant metastasis in G1 and G2 colorectal neuroendocrine tumors

We aimed to construct novel nomograms for nodal and distant metastasis for patients with G1 and G2 colorectal neuroendocrine tumors (NETs). A training set and validation set were obtained by including G1 and G2 colorectal NET patients from the Surveillance, Epidemiology, and End Results database and the Cancer Hospital Chinese Academy of Medical Science, respectively. The area under curve (AUC) values under receiver operating characteristic (ROC) curves, calibration plots, and the Hosmer‒Lemeshow tests were used to evaluate the discriminability and calibration of nomograms. In total, 3690 and 172 patients were included in the training set and validation set, respectively. Tumor size, location, and T stage were included in the nomogram predicting nodal metastasis. The AUC values of the nomogram were 0.972 (95% confidence interval (CI): 0.964-0.980) and 0.897 (95% CI: 0.846-0.948) in the training set and validation set, respectively. The calibration plots and Hosmer‒Lemeshow test for the training set (P = 0.999) and validation set (P = 0.537) showed good model calibration. Tumor size, T stage, and N stage were incorporated into the nomogram predicting distant metastasis. The ROC curves demonstrated desirable discrimination both in the training set (AUC = 0.938 (95% CI: 0.921-0.954)) and validation set (AUC = 0.938 (95% CI: 0.890-0.988)). The calibration curves and Hosmer‒Lemeshow test indicated acceptable model calibration both in the training set (P = 0.908) and validation set (P = 0.722). The proposed nomograms may be used as a reliable tool to predict the nodal and distant metastasis in G1 and G2 colorectal NETs.

Clinicopathological Characteristics of Low to Intermediate Grade Neuroendocrine Tumors with Oncocytic Features

Neuroendocrine tumors (NETs) with oncocytic features are rare. To date, few studies have described the metastatic characteristics of these tumors, most of which were limited by the low number of cases. One article characterized intermediate to high grade (G2 and G3) oncocytic NETs of the pancreas as having an ominous outcome; however, metastatic features of low-grade oncocytic NETs have, to our knowledge, been hitherto unexplored. Our study characterized the clinicopathological and metastatic features of 32 low to intermediate-grade oncocytic NETs of various organs. The most frequent metastatic site was the liver (63%). The metastatic rate of our cases was compared with Riihimaki’s study (metastatic rate of G1/G2 NETs was reported), as well as Heetfeld’s study and Lithgow’s study (metastatic rate of G3 NETs was reported). The overall metastatic rate of our cases is 84.4%, which is significantly higher than that of the G1/2 NETs from Riihimaki’s study (84.4% vs. 25%, p &lt; 0.0001), while similar to that of the G3 NETs from Heetfeld’s study (84.4% vs. 86.5%, p &gt; 0.05) and Lithgow’s study (84.4% vs. 80.8%, p &gt; 0.05). These data indicate that oncocytic features could potentially be characterized as high-risk features in addition to high Ki-67 index, mitotic count, and necrosis. Thus, imaging studies such as liver magnetic resonance imaging (MRI) may be warranted to detect liver metastases in NETs with distinctive oncocytic cytologic features even in the absence of other high-risk features.

Analysis of Patients with NET G1/G2 Neuroendocrine Tumors of the Small Intestine in the Course of Carcinoid Heart Disease-A Retrospective Study.

Neuroendocrine neoplasms of the small intestine (SI-NENs) are one of the most commonly recognized gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Carcinoid heart disease (CHD) is the primary cause of death in patients with the carcinoid syndrome (CS). The aim of this retrospective study was to evaluate possible factors impacting upon overall survival (OS) in subjects with both neuroendocrine tumors (NETs) G1/G2 of the small intestine (SI-NET) and CHD. Enrolled in our study of 275 patients with confirmed G1/G2 SI-NET, were 28 (10%) individuals with CHD. Overall survival was assessed using the Kaplan-Meier method. The Cox-Mantel test was used to determine how OS varied between groups. A Cox proportional hazards model was used to conduct univariate analyses of predictive factors for OS and estimate hazard ratios (HRs). Of the 28 individuals with confirmed carcinoid heart disease, 12 (43%) were found to have NET G1 and 16 (57%) were found to have NET G2. Univariate analysis revealed that subjects with CHD and without resection of the primary tumor had a lower OS. Our retrospective study observed that patients who presented with CHD and without resection of primary tumor had worse prognosis of survival. These results suggest that primary tumors may need to be removed when feasible, but further research is needed. However, no solid recommendations can be issued on the basis of our single retrospective study.

Chemotherapy in Well Differentiated Neuroendocrine Tumors (NET) G1, G2, and G3: A Narrative Review.

Neuroendocrine tumors (NETs) are rare neoplasms with a wide spectrum of clinical behavior, from the long survival of well-differentiated NETs to the dismal prognosis of high-grade neuroendocrine carcinomas (NECs), being G3 NETs a recently recognized intermediate entity. While the role of chemotherapy is well established in NECs, data on NETs mostly derives from small studies, experts' opinions, and extrapolating results from small-cell lung cancer studies. This narrative review aims to summarize available evidence about the use of chemotherapy in the setting of G1-2 NETs and G3 NETs. We performed literature research in PubMed Library for all articles published up to September 2022 about the efficacy of chemotherapy in NETs. Treatment regimens with STZ-5FU, CAPTEM, and anti-metabolite-based treatment are the most active and tolerated in gastroenteropancreatic NETs (GEP-NETs) G1-G2, while platinum-based regimens (FOLFOX/XELOX) and TEM/CAPTEM showed the best activity in thoracic NETs. Solid evidence about chemotherapy efficacy in G3 NETs is still lacking. Literature data support the use of chemotherapy in low-intermediate grade NETs after the failure of other therapies or if tumor shrinkage is needed. Studies assessing G3 NETs independently from NECs are needed to better understand the role of chemotherapy in this setting.

FOLFOX-bevacizumab chemotherapy in patients with metastatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) are highly vascularized neoplasms. While FOLFOX chemotherapy has shown efficacy in patients with advanced NETs, its combination with antiangiogenics has been scarcely described. Here, we report the efficacy and tolerance of FOLFOX-bevacizumab in this setting. We retrospectively studied all consecutive patients with metastatic NET treated by FOLFOX-bevacizumab in two expert centers from 2013 to 2020. We assessed time to treatment failure (TTF), objective response rate (ORR) and toxicity. We explored factors associated with TTF and ORR using multivariate analyses. We included 57 patients (35.1% female, median age 61.7 years), with pancreatic (66.7%), small-intestine (14%) or lung (7%) NETs. Most patients (57.9%) had extra-hepatic metastases and G3 NETs accounted for 40.3% of cases. Patients received a median of 17 cycles of treatment, including a median of sevencycles of bevacizumab and/or 5-fluorouracile maintenance. Median TTF was 15.5months (95% CI: 9.8-21.2) and was shorter in patients age > 60 years (HR 2.56, 95% CI: 1.16-5.64), p= .020) and >1 previous systemic treatment line (HR 4.15, 95% CI: 1.96-8.78), p< .001). The ORR was 42.9% and was higher in cases of performance status at 0 (OR 5.25, 95% CI: 1.13-24.35), p= .034) and G3 NET (OR 5.39, 95% CI: 1.23-23.52), p= .025). The FOLFOX-bevacizumab combination has promising efficacy in patients with progressive metastatic NETs and notably for G3 NETs, for which optimal treatment as yet remains ill-defined. Hence, it could be a relevant alternative to alkylating-based chemotherapy in this setting and should be further explored prospectively.

HORMONET: a phase II trial of tamoxifen for estrogen/progesterone receptor-positive neuroendocrine tumors.

Nearly 30% of neuroendocrine tumors (NETs) have evidence of immunohistochemical (IHC) expression of estrogen (ER) and/or progesterone (PR) receptors. Therefore, targeting ER/PR may offer an effective NET-directed treatment to select patients. We conducted a multicenter Simon two-stage single-arm phase II trial of tamoxifen in patients with metastatic, progressive NETs. Eligible patients had positive IHC expression of ER and/or PR ⩾ 1%. Prior therapy with somatostatin analogs was required for progressing/functioning cases. Main exclusion criterion was aggressive disease requiring cytotoxic therapy. The primary end point was disease control rate (DCR) at week 24 by Response Evaluation Criteria in Solid Tumors version 1.1. We planned to enroll 23 patients in the first stage, to reach a DCR at week 24 of 70% (versus 50%); if ⩾12 patients reached the primary end point, a total of 37 would be included. From February 2019 to February 2022, 23 out of 59 patients were eligible and enrolled: 15 (65%) were females; the most common sites were pancreas (11; 48%) and small bowel (6; 26%). In all, 13 patients (56.5%) had G2 NETs. At a median follow-up of 27 months, 13 patients (56.5%) had stable disease at week 24 and median progression-free survival (PFS) was 7.9 months [interquartile range (IQR): 3.7-12.1]. The best response was stable disease in 13 patients, with most patients experiencing minor tumor growth. Median PFS times were not significantly different according to ER/PR < or ⩾30% (p = 0.49) or ER versus PR expression (p = 0.19). One patient experienced grade 2 constipation. Tamoxifen for ER-/PR-positive NETs patients is safe but offers modest antitumor effects. Study of Tamoxifen in Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression (HORMONET). https://clinicaltrials.gov/ct2/show/NCT03870399?term=03870399&draw=2&rank=1. NCT03870399.

Management and endoscopic treatment of rectal neuroendocrine tumors.

Fifteen of 20 patients with rectal neuroendocrine tumors G1, smaller than 20 mm underwent endoscopic treatment. Complete endoscopic resecctionwas 93%, with bleeding rate 6% and recurrence relapse rate of 13%.