Outcome and survival were similar with laparoscopic and open pancreatectomy in 102 solid pseudopapillary neoplasms.

BACKGROUND: Solid pseudopapillary neoplasms of the pancreas (SPNP) are rare tumors predominantly in young women. We report the largest single-center cohort study comparing resection of SPNP by laparoscopic approach (LA) and the open approach (OA). METHOD: Between 2001 and 2021, 102 patients (84% women, median age: 30) underwent pancreatectomy for SPNP and were retrospectively studied. Demographic, perioperative, pathological, early and the long-term results were evaluated between patients operated by LA and those by OA. RESULTS: Population included 40 LA and 62 OA. There were no significant differences in demographics data between the groups. A preoperative biopsy by endoscopic ultrasound was performed in 45 patients (44%) with no difference between the groups. Pancreatoduodenectomy (PD) was less frequently performed by LA (25 vs 53%, p = 0.004) and distal pancreatectomy (DP) was more frequently performed by LA (40 vs 16%, p = 0.003). In the subgroup analysis by surgical procedure, LA-PD was associated with one mortality, less median blood loss (180 vs 200 ml, p = 0.034) and fewer harvested lymph nodes (11 vs 15, p = 0.02). LA-DP was associated with smaller median tumor size on imaging (40 vs 80mm, p = 0.048), shorter surgery (135 vs 190 min, p = 0.028), and fewer complications according to the median comprehensive complication index score (0 vs 8.7, p = 0.048). LA-Central pancreatectomy was associated with shorter surgery (160 vs 240, p = 0.037), less median blood loss (60 vs 200, p = 0.043), and less harvested lymph nodes (5 vs 2, p = 0.025). After a median follow-up of 60 months, two recurrences (2%) were observed and were unrelated to the approach. CONCLUSIONS: The LA for SPNP appears to be safe, should be applied cautiously in case of PD for large lesion, and was not associated with recurrence.

Appropriate use of morphological imaging for assessing treatment response and disease progression of neuroendocrine tumors.

Neuroendocrine tumors (NETs) are relatively rare neoplasms displaying heterogeneous clinical behavior, ranging from indolent to aggressive forms. Patients diagnosed with NETs usually receive a varied array of treatments, including somatostatin analogs, locoregional treatments (ablation, intra-arterial therapy), cytotoxic chemotherapy, peptide receptor radionuclide therapy (PRRT), and targeted therapies. To maximize therapeutic efficacy while limiting toxicity (both physical and economic), there is a need for accurate and reliable tools to monitor disease evolution and progression and to assess the effectiveness of these treatments. Imaging morphological methods, primarily relying on computed tomography (CT) and magnetic resonance imaging (MRI), are indispensable modalities for the initial evaluation and continuous monitoring of patients with NETs, therefore playing a pivotal role in gauging the response to treatment. The primary goal of assessing tumor response is to anticipate and weigh the benefits of treatments, especially in terms of survival gain. The World Health Organization took the pioneering step of introducing assessment criteria based on cross-sectional imaging. This initial proposal standardized the measurement of lesion sizes, laying the groundwork for subsequent criteria. The Response Evaluation Criteria in Solid Tumors (RECIST) subsequently refined and enhanced these standards, swiftly gaining acceptance within the oncology community. New treatments were progressively introduced, targeting specific features of NETs (such as tumor vascularization or expression of specific receptors), and achieving significant qualitative changes within tumors, although associated with minimal or paradoxical effects on tumor size. Several alternative criteria, adapted from those used in other cancer types and focusing on tumor viability, the slow growth of NETs, or refining the existing size-based RECIST criteria, have been proposed in NETs. This review article aims to describe and discuss the optimal utilization of CT and MRI for assessing the response of NETs to treatment; it provides a comprehensive overview of established and emerging criteria for evaluating tumor response, along with comparative analyses. Molecular imaging will not be addressed here and is covered in a dedicated article within this special issue.

European Neuroendocrine Tumor Society 2023 guidance paper for functioning pancreatic neuroendocrine tumour syndromes.

This ENETS guidance paper aims to provide practical advice to clinicians for the diagnosis, treatment and follow-up of functioning syndromes in pancreatic neuroendocrine tumours (NET). A NET-associated functioning syndrome is defined by the presence of a clinical syndrome combined with biochemical evidence of inappropriately elevated hormonal levels. Different hormonal syndromes can be encountered in pancreatic NET patients, including insulinoma, gastrinoma as well as the rare glucagonoma, VIPoma, ACTHoma, PTHrPoma, carcinoid syndrome, calcitoninoma, GHRHoma and somatostatinoma. The recommendations provided in this paper focus on the biochemical, genetic and imaging work-up as well as therapeutic management of the individual hormonal syndromes in well-differentiated, grade 1-3, functioning NET with the primary tumour originating in the pancreas, and for specific subtypes also in the duodenum.

High Tumor Uptake on 18F-FDOPA PET/CT Indicates Poor Prognosis in Patients with Metastatic Midgut Neuroendocrine Tumors: A Study from the Groupe d'étude des Tumeurs Endocrines and ENDOCAN-RENATEN Network.

PET/CT with 6-18F-fluoro-l-dopa (18F-FDOPA) has high diagnostic performance for midgut neuroendocrine tumors (NETs). We explored the prognostic role of 18F-FDOPA PET/CT uptake in metastatic midgut NETs. Methods: We included, in a test cohort (n = 166) and a full external validation cohort (n = 86), all consecutive patients with metastatic midgut NETs who underwent 18F-FDOPA PET/CT in 5 expert centers from 2010 to 2021. We measured the maximal uptake (SUVmax and SUVpeak) of the tumor and nontumor liver on each 18F-FDOPA PET/CT scan. We measured overall survival (OS) from the time of PET/CT and assessed prognostic factors using Kaplan-Meier and multivariable Cox proportional-hazards analyses in the test cohort, with replication in the validation cohort. Results: Patients had similar characteristics in both cohorts. In the test cohort, median follow-up was 60.3 mo. Patients with an SUVpeak tumor-to-liver (T/L) ratio of more than 4.2 had significantly shorter survival than those with a ratio of 4.2 or less (P = 0.01), with a 5-y OS rate of 74.1% ± 4.5% versus 95% ± 3.4%, respectively. On multivariable analysis, an SUVpeak T/L ratio of more than 4.2 remained associated with shorter OS (hazard ratio, 2.30; 95% CI, 1.02-5.22; P = 0.046) after adjustment for age, grade, number of previous lines, number of metastatic sites, and presence of carcinoid syndrome. In the validation cohort, the 5-y OS rate was 100% versus 57.8% ± 12.5% in patients with an SUVpeak T/L ratio ≤ 4.2 or > 4.2, respectively (P = 0.075). An increasing SUVpeak T/L ratio over time tended to have a pejorative prognostic impact. Conclusion: Tumor uptake on 18F-FDOPA PET/CT is an independent prognostic factor in patients with metastatic midgut NETs.

Management and outcomes of carcinoid heart disease with liver metastases of midgut neuroendocrine tumours.

OBJECTIVE: Despite recent advances in surgical and interventional techniques, knowledge on the management of carcinoid heart disease (CHD) remains limited. In a cohort of patients with liver metastases of midgut neuroendocrine tumours (NETs), we aimed to describe the perioperative management and short-term outcomes of CHD. METHODS: From January 2003 to June 2022, consecutive patients with liver metastases of midgut NETs and severe CHD (severe valve disease with symptoms and/or right ventricular enlargement) were included at Beaujon and Bichat hospitals. All patients underwent clinical evaluation and echocardiography. RESULTS: Out of 43 (16%) consecutive patients with severe CHD and liver metastases of midgut NETs, 79% presented with right-sided heart failure. Tricuspid valve replacement was performed in 26 (53%) patients including 19 (73%) cases of combined pulmonary valve replacement. The 30-day postoperative mortality rate was high (19%), and preoperative heart failure was associated with worse survival (p=0.02). Epicardial pacemakers were systematically implanted in operated patients and 25% were permanently paced. A postoperative positive right ventricular remodelling was observed (p<0.001). A greater myofibroblastic infiltration was observed in pulmonary versus tricuspid valves (p<0.001), suggesting that they may have been explanted at an earlier stage of the disease than the tricuspid valve, with therefore potential for evolution. CONCLUSIONS: We observed a high postoperative mortality rate and baseline right-sided heart failure was associated with worse outcome. In surviving patients, a positive right ventricular remodelling was observed. Prospective, multicentre studies are warranted to better define the management strategy and to identify biomarkers associated with outcome in CHD.

Spatial and temporal heterogeneity of digestive neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) are initially monoclonal neoplasms that progressively become polyclonal, with very different genotypic and phenotypic characteristics leading to biological differences, including the Ki-67 proliferation index, morphology, or sensitivity to treatments. Whereas inter-patient heterogeneity has been well described, intra-tumor heterogeneity has been little studied. However, NENs present a high degree of heterogeneity, both spatially within the same location or between different lesions, and through time. This can be explained by the emergence of tumor subclones with different behaviors. These subpopulations can be distinguished by the Ki-67 index, but also by the expression of hormonal markers or by differences in the intensity of uptake on metabolic imaging, such as 68Ga-somatostatin receptor and Fluorine-18 fluorodeoxyglucose positron emission tomography. As these features are directly related to prognosis, it seems mandatory to move toward a standardized, improved selection of the tumor areas to be studied to be as predictive as possible. The temporal evolution of NENs frequently leads to changes in tumor grade over time, with impact on prognosis and therapeutic decision-making. However, there is no recommendation regarding systematic biopsy of NEN recurrence or progression, and which lesion to sample. This review aims to summarize the current state of knowledge, the main hypotheses, and the main implications regarding intra-tumor spatial and temporal heterogeneity in digestive NENs.

Proposal of early CT morphological criteria for response of liver metastases to systemic treatments in gastroenteropancreatic neuroendocrine tumors: Alternatives to RECIST.

RECIST 1.1 criteria are commonly used with computed tomography (CT) to evaluate the efficacy of systemic treatments in patients with neuroendocrine tumors (NETs) and liver metastases (LMs), but their relevance is questioned in this setting. We aimed to explore alternative criteria using different numbers of measured LMs and thresholds of size and density variation. We retrospectively studied patients with advanced pancreatic or small intestine NETs with LMs, treated with systemic treatment in the first-and/or second-line, without early progression, in 14 European expert centers. We compared time to treatment failure (TTF) between responders and non-responders according to various criteria defined by 0%, 10%, 20% or 30% decrease in the sum of LM size, and/or by 10%, 15% or 20% decrease in LM density, measured on two, three or five LMs, on baseline (≤1 month before treatment initiation) and first revaluation (≤6 months) contrast-enhanced CT scans. Multivariable Cox proportional hazard models were performed to adjust the association between response criteria and TTF on prognostic factors. We included 129 systemic treatments (long-acting somatostatin analogs 41.9%, chemotherapy 26.4%, targeted therapies 31.8%), administered as first-line (53.5%) or second-line therapies (46.5%) in 91 patients. A decrease ≥10% in the size of three LMs was the response criterion that best predicted prolonged TTF, with significance at multivariable analysis (HR 1.90; 95% CI: 1.06-3.40; p = .03). Conversely, response defined by RECIST 1.1 did not predict prolonged TTF (p = .91), and neither did criteria based on changes in LM density. A ≥10% decrease in size of three LMs could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in LM density were not predictive of treatment efficacy. CLINICAL TRIAL REGISTRATION: Registered at CNIL-CERB, Assistance publique hopitaux de Paris as "E-NETNET-L-E-CT" July 2018. No number was assigned. Approved by the Medical Ethics Review Board of University Medical Center Groningen.

Sex differences on multikinase inhibitors toxicity in patients with advanced gastroenteropancreatic neuroendocrine tumours.

PURPOSE: There is an increasing interest in the role of sex and gender in cancer patients. The impact of sex differences in oncological systemic therapies is still unknown, and there is a lack of evidence specially in uncommon neoplasms like neuroendocrine tumours (NET). In the present study, we combine the differential toxicities by sex in five published clinical trials with multikinase inhibitors (MKI) in gastroenteropancreatic (GEP) NET. METHODS: We performed a pooled univariate analysis of reported toxicity in patients treated in five phase 2 and phase 3 clinical trials with MKI in the GEP NET setting: sunitinib (SU11248, SUN1111), Pazopanib (PAZONET), sorafenib-bevacizumab (GETNE0801) and Lenvatinib (TALENT). Differential toxicities between male and female patients were evaluated considering relationship with study drug and different weights of each trial by random effect adjustment. RESULTS: We found nine toxicities which were more frequent in female patients (leukopenia, alopecia, vomiting, headache, bleeding, nausea, dysgeusia, neutrophil count decreased and dry mouth) and two toxicities being more frequent in male patients (Anal Symptoms and Insomnia). Asthenia and diarrhoea were the only severe (Grade 3-4) toxicities more frequent in female patients. CONCLUSIONS: Sex-related differences in toxicity with the MKI treatment require targeted information and individualised management of patients with NET. Differential reporting of toxicity should be promoted when clinical trials are published.

Carcinoid heart disease in patients with midgut neuroendocrine tumours.

Carcinoid heart disease (CHD) is the main complication of carcinoid syndrome (CS) associated with metastatic small intestine neuroendocrine tumours (NETs). The pathophysiology of CHD is partly understood but vasoactive hormones secreted by NETs, especially serotonin, play a major role, leading to the formation of fibrous plaques. These plaque-like deposits involve the right side of the heart in >90% of cases, particularly the tricuspid and pulmonary valves, which become thickened, retracted and immobile, resulting in regurgitation or stenosis. CHD represents a major diagnostic and therapeutic challenge for patients with NET and CS and is associated with increased risk of morbidity and mortality. CHD often occurs 2-5 years after the diagnosis of metastatic NET, but diagnosis of CHD can be delayed as patients are often asymptomatic for a long time despite severe heart valve involvement. Circulating biomarkers (5HIAA, NT-proBNP) are relevant tools but transthoracic echocardiography is the key examination for diagnosis and follow-up of CHD. However, there is no consensus on the optimal indications and frequency of TTE and biomarker dosing regarding screening and diagnosis. Treatment of CHD is complex and requires a multidisciplinary approach. It relies on antitumour treatment, control of CS and surgical valve replacement in cases of severe CHD. However, cardiac surgery is associated with a high risk of mortality, notably due to perioperative carcinoid crisis and right ventricular dysfunction. Timing of surgery is the most crucial point of CHD management and relies on the case-by-case determination of the optimal compromise between tumour progression, cardiac symptoms and CS control.

Prospective Multicentric Assessment of 68Ga-DOTANOC PET/CT in Grade 1-2 GEP-NET.

The aim of this multicentric study was to prospectively compare 68Ga-DOTANOC PET/CT versus somatostatin receptor scintigraphy (SRS) with SPECT/CT, combined with multiphasic CT scan and MRI in patients with grade 1 or 2 gastroenteropancreatic neuroendocrine tumors (GEP-NET). Patients with histologically proven grade 1 or 2 GEP-NET with suspicion of recurrence or progression, or with typical aspects of GEP-NET on morphological imaging, were explored with conventional imaging (CI): SRS with SPECT/CT, multiphasic CT scan and/or liver MRI followed by 68Ga-DOTANOC PET/CT. The gold standard was based on histology and imaging follow-up. The data of 105 patients (45 woman and 60 men; median age) were analyzed. 68Ga-DOTANOC PET/CT sensitivity was significantly higher than CI sensitivity in per-patient (98.9% vs. 88.6%, p = 0.016) and per-region (97.6% vs. 75.6%, p < 0.001) analyses, in the detection of the primary (97.9% vs. 78.7%; p = 0.016), peritoneal carcinomatosis (95% vs. 30%, p < 0.001), and bone metastases (100% vs. 33.3%, p = 0.041). 68Ga-DOTANOC PET/CT had an impact on the therapeutic management of 41.9% (44/105) patients compared to decisions based on CI explorations. Our data confirm the superiority of 68Ga-DOTANOC PET/CT over CI in the detection of peritoneal carcinomatosis and bone metastasis, as well as its strong therapeutic impact on the management of patients with grade 1-2 GEP-NETs.

Volumetric Enhancing Tumor Burden at CT to Predict Survival Outcomes in Patients with Neuroendocrine Liver Metastases after Intra-arterial Treatment.

Purpose To investigate whether liver enhancing tumor burden (LETB) assessed at contrast-enhanced CT indicates early response and helps predict survival outcomes in patients with multifocal neuroendocrine liver metastases (NELM) after intra-arterial treatment. Materials and Methods This retrospective study included patients with NELM who underwent intra-arterial treatment with transarterial embolization (TAE) or chemoembolization (TACE) between April 2006 and December 2018. Tumor response in treated NELM was evaluated by using the Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST). LETB was measured as attenuation 2 SDs greater than that of a region of interest in the nontumoral liver parenchyma. Overall survival (OS); time to unTA(C)Eable progression, defined as the time from the initial treatment until the time when intra-arterial treatments were considered technically unfeasible, either not recommended by the multidisciplinary tumor board or until death; and hepatic and whole-body progression-free survival (PFS) were evaluated using multivariable Cox proportional hazards analyses, the Kaplan-Meier method, and log-rank test. Results The study included 119 patients (mean age, 60 years ± 11 [SD]; 61 men) who underwent 161 treatments. A median LETB change of -25.8% best discriminated OS (83 months in responders vs 51 months in nonresponders; P = .02) and whole-body PFS (18 vs 8 months, respectively; P < .001). A -10% LETB change best discriminated time to unTA(C)Eable progression (32 months in responders vs 12 months in nonresponders; P < .001) and hepatic PFS (18 vs 8 months, respectively; P < .001). LETB change remained independently associated with improved OS (hazard ratio [HR], 0.56), time to unTA(C)Eable progression (HR, 0.44), hepatic PFS (HR, 0.42), and whole-body PFS (HR, 0.47) on multivariable analysis. Neither RECIST nor mRECIST helped predict patient outcome. Conclusion Response according to LETB change helped predict survival outcomes in patients with NELM after intra-arterial treatments, with better discrimination than RECIST and mRECIST. Keywords: CT, Chemoembolization, Embolization, Abdomen/GI, Liver Supplemental material is available for this article. © RSNA, 2023.

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 seven cycles of bevacizumab and/or 5-fluorouracile maintenance. Median TTF was 15.5 months (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.

Life expectancy and likelihood of surgery in multiple endocrine neoplasia type 1: AFCE and GTE cohort study.

BACKGROUND: The overall natural history, risk of death and surgical burden of patients with multiple endocrine neoplasia type 1 (MEN1) is not well known. METHODS: Patients with MEN1 from a nationwide cohort were included. The survival of patients with MEN1 was compared with that of the general population using simulated controls. The cumulative probabilities of MEN1-specific operations and postoperative mortality were assessed, and surgical sequences were analysed using sunburst charts and Venn diagrams. RESULTS: A total of 1386 patients with MEN1 were included. Life expectancy was significantly reduced in patients with MEN1 compared with simulated controls from the general population, with a lifetime difference of 15 years. Mutations affecting the JunD interaction domain had a significant negative impact on survival. Survival for patients with MEN1 compared with the general population improved over time. The probability of experiencing at least one specific MEN1 operation was above 95 per cent after 75 years, and most patients had surgery at least twice during their lifetime. Time to a 50 per cent risk of MEN1 surgery was 30.5 years for patients born after 1960, compared with 47.9 years for those born before 1960. Sex and mutations affecting the JunD interacting domain had no impact on time to first surgery. There was considerable heterogeneity in surgical sequences, with no specific clinical pathway. CONCLUSION: Life expectancy was significantly lower among patients with MEN1 compared with the general population, and further decreased in patients with mutations affecting the JunD interacting domain. Almost all patients underwent at least one MEN1-specific operation during their lifetime, but there was no standardized sequence of surgery.

Laparoscopic-assisted liver transplantation: A realistic perspective.

Laparoscopic approach was rarely described in recipients for liver transplantation (LT). We report the feasibility and safety of laparoscopic-assisted LT (LA-LT) in patients with unresectable liver metastases of neuroendocrine tumors. Total hepatectomy was performed laparoscopically with graft implantation through an upper midline incision. Liver grafts were retrieved from deceased donors. From July 2019 to July 2021, six patients (4 women, 2 men) underwent LA-LT. Median age and BMI were 46 (29-54) and 24 (19-35) kg/m2 , respectively. Implanted grafts were reduced (n = 3), full (n = 2), and a right split liver (n = 1). Median surgical time was 405 min (390-450) and median blood loss was 425 ml (250-600). Median cold and warm ischemia times were 438 min (360-575) and 35 min (30-40), respectively. Median anhepatic phase was 51 min (40-67) and midline incision was 14 cm (13-20) long. On postoperative day 5, median prothrombin index and serum bilirubin levels were 95% (70-117) and 11 (10-37) µmol/L, respectively. No Clavien-Dindo > III complications were encountered. Median hospital stay was 12 days (10-14). After a median follow-up of 8 (8-32) months, all patients were alive without tumor recurrence or adverse event. This preliminary series suggests that in selected patients, LA-LT is a safe and effective option.

Immunophenotypic and molecular characterization of pancreatic neuroendocrine tumors producing serotonin.

Serotonin producing pancreatic neuroendocrine tumors (SP-PanNET) account for 0.58-1.4% of all pancreatic neuroendocrine tumors (PanNET). They may present with atypical symptoms, such as acute pancreatitis and are often radiologically characterized by main pancreatic duct dilatation. SP-PanNET are well differentiated neuroendocrine tumors (NET) distinct from classical PanNET by atypical serotonin secretion and abundant dense stroma deposition, like serotonin producing ileal NET leading in some cases to difficulties to reliably distinguish SP-PanNET from ileal NET metastases. The biology and molecular profile of SP-PanNET remain poorly characterized and the cell of origin within the pancreas is unclear. To address these questions, we analyzed a large cohort of SP-PanNET by immunohistochemistry (n = 29; ATRX, DAXX, MENIN, Islet1, PAX6, PDX1, ARX, CDX2), whole genome copy number array (Oncoscan™) and a large NGS panel (NovoPM™) (n = 10), FISH (n = 13) and RNA sequencing (n = 24) together with 21 ileal NET and 29 nonfunctioning PanNET (NF-PanNET). These analyses revealed a unique genomic profile with frequent isolated loss of chromosome 1 (14 cases-61%) and few pathogenic mutations (KMT2C in 2 cases, ARID1A in 1 case). Unsupervised RNAseq-based clustering showed that SP-PanNET were closer to NF-PanNET than ileal NET with an exclusive beta cell-like signature. SP-PanNET showed TGF-ß pathway activation signatures associated with extracellular matrix remodeling and similar signature were reproduced in vitro when pancreatic stellate cells were exposed to serotonin. SP-PanNET immunohistochemical profile resemble that of ileal NET except for PDX1 and PAX6 expression to a lesser extend suggesting that these two markers may be useful to diagnose SP-PanNET. Taken together, this suggests that SP-PanNET are a very specific PanNET entity with a peculiar biology leading to the characteristic fibrotic aspect.

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

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

ENETS standardized (synoptic) reporting for endoscopy in neuroendocrine tumors.

Despite efforts from various endoscopy societies, reporting in the field of endoscopy remains extremely heterogeneous. Harmonisation of clinical practice in endoscopy has been highlighted by application of many clinical practice guidelines and standards pertaining to the endoscopic procedures and reporting are underlined. The aim of the proposed "standardised reporting" is to (1) facilitate recognition of gastrointestinal neuroendocrine neoplasms (NEN) on initial endoscopy, (2) to enable interdisciplinary decision making for treatment by a multidisciplinary team, (3) to provide a basis for a standardised endoscopic follow-up which allows detection of recurrence or progression reliably, (4) to make endoscopic reports on NEN comparable between different units, and (5) to allow research collaboration between NEN centres in terms of consistency of their endoscopic data. The ultimate goal is to improve disease management, patient outcome and reduce the diagnostic burden on the side of the patient by ensuring the highest possible diagnostic accuracy and validity of endoscopic exams and possibly interventions.

177Lu-Dotatate plus long-acting octreotide versus high­dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results. METHODS: This open-label, randomised, phase 3 trial enrolled patients from 41 sites in eight countries across Europe and the USA. Patients were 18 years and older with locally advanced or metastatic, well differentiated, somatostatin receptor-positive midgut neuroendocrine tumours (Karnofsky performance status score ≥60) and disease progression on fixed-dose long-acting octreotide. Patients were randomly assigned (1:1) via an interactive web-based response system to intravenous 177Lu-Dotatate 7·4 GBq (200 mCi) every 8 weeks (four cycles) plus intramuscular long-acting octreotide 30 mg (177Lu-Dotatate group) or high-dose long-acting octreotide 60 mg every 4 weeks (control group). The primary endpoint of progression-free survival has been previously reported; here, we report the key secondary endpoint of overall survival in the intention-to-treat population. Final overall survival analysis was prespecified to occur either after 158 deaths or 5 years after the last patient was randomised, whichever occurred first. During long-term follow-up, adverse events of special interest were reported in the 177Lu-Dotatate group only. This trial is registered with ClinicalTrials.gov, NCT01578239. FINDINGS: From Sept 6, 2012, to Jan 14, 2016, 231 patients were enrolled and randomly assigned for treatment. The prespecified final analysis occurred 5 years after the last patient was randomly assigned (when 142 deaths had occurred); median follow-up was 76·3 months (range 0·4-95·0) in the 177Lu-Dotatate group and 76·5 months (0·1-92·3) in the control group. The secondary endpoint of overall survival was not met: median overall survival was 48·0 months (95% CI 37·4-55·2) in the 177Lu-Dotatate group and 36·3 months (25·9-51·7) in the control group (HR 0·84 [95% CI 0·60-1·17]; two-sided p=0·30). During long-term follow-up, treatment-related serious adverse events of grade 3 or worse were recorded in three (3%) of 111 patients in the 177Lu-Dotatate group, but no new treatment-related serious adverse events were reported after the safety analysis cutoff. Two (2%) of 111 patients given 177Lu-Dotatate developed myelodysplastic syndrome, one of whom died 33 months after randomisation (this person was the only the only reported 177Lu-Dotatate treatment-related death). No new cases of myelodysplastic syndrome or acute myeloid leukaemia were reported during long-term follow-up. INTERPRETATION: 177Lu-Dotatate treatment did not significantly improve median overall survival versus high-dose long-acting octreotide. Despite final overall survival not reaching statistical significance, the 11·7 month difference in median overall survival with 177Lu-Dotatate treatment versus high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up. FUNDING: Advanced Accelerator Applications, a Novartis company.

Pituitary adenoma in patients with multiple endocrine neoplasia type 1: a cohort study.

OBJECTIVE: Pituitary adenoma (PA) is one of the three major components of multiple endocrine neoplasia type 1 (MEN1). Recent studies have suggested that MEN1-associated PAs are less aggressive than initially estimated. We propose an analysis of the outcome of PAs with a standard of care treatment in a nationwide cohort of MEN1 patients. DESIGN: Retrospective observational nationwide cohort study using the MEN1 patient registry from the French Group of Endocrine Tumours (GTE). METHODS: The GTE database population consists of 1435 patients with MEN1. This analysis focused on 551 patients recruited after 2000 with at least 3 years of follow-up. The study outcome was tumour progression of PA defined by an increase in Hardy classification (HC) during follow-up according to referring physician regular reports. RESULTS: Among 551 MEN1 patients (index and related), 202 (36.7%) had PA, with 114 (56.4%) diagnosed by MEN1-related screening. PAs were defined according to HC as microadenoma (grade I) in 117 cases (57.9%), macroadenoma in 59 (29.2%) with 20 HC grade II and 39 HC grades III-IV and unspecified in 26 (12.8%). They were prolactinomas in 92 cases (45.5%) and non-secreting in 73 (36.1%). After a median follow-up of 3 years among the 137 patients with HC grades I-II, 4 patients (2.9%) presented tumour progression. CONCLUSION: PAs in patients with MEN1 are less aggressive than previously thought. Tumour progression is rare with a standard of care monitoring and treatment, especially in related patients who mostly present non-secreting microadenoma. MRI monitoring for asymptomatic MEN1 patients should be reduced accordingly.