BACKGROUND:Patients with advanced malignant adrenal tumors face poor prognoses with limited treatment options. Emerging data suggest that these rare tumors exhibit immunogenicity, potentially benefiting from intensified immunotherapy. METHODS:The SPENCER trial (NCT04187404) evaluates EO2401, an off-the-shelf in vivo peptide immunotherapy containing three synthetic HLA-A*02 restricted-peptides called OncoMimic and derived from human gut commensals that exhibit molecular mimicry to tumor-associated antigens (BIRC5, FOXM1, IL13RA2) combined with nivolumab in patients with locally advanced or metastatic adrenocortical carcinoma (ACC) or malignant pheochromocytoma/ paraganglioma (PPGL). We performed T cell receptor (TCR) repertoire sequencing to profile the TCR architecture in ACC and characterize vaccination imprints. RESULTS:Here we show that ACC patients are characterized by a restricted peripheral T cell richness. EO2401 does not expand highly shared TCR clones across patients but diversifies pre-existing T cell clusters. These clusters are not converging on known neoantigen-specific TCRs but exhibit generation probabilities characteristic of public clones some of which being shared across patients. CONCLUSIONS:These findings suggest that EO2401-based peptide immunotherapy combined with checkpoint inhibition can broaden and activate public, pre-existing T cell clusters, potentially enhancing tumor-specific immune responses.

Everolimus is the only approved therapy for patients with advanced neuroendocrine tumors (NET) of lung and thymus and new treatment options are urgently needed. Expression of somatostatin receptor 2 (SSTR2) is frequently seen in functional imaging in lung-NETs opening the opportunity to treat SSTR2 positive patients with radioligand therapies (RLT). Retrospective data suggest a potential meaningful benefit of RLT directed to SSTR2 in lung-NET patients. The LEVEL trial is a randomized, open-label, phase III international trial of 177Lu-edotreotide versus everolimus in patients with progressive, locally advanced or metastatic, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin. Patients could be treatment-naïve or have progressed (PD) on somatostatin analogues or ≤ 2 additional systemic treatments. Prior RLT or mTOR inhibitors are not permitted. Eligible patients are randomly assigned 3:2 to 6 cycles of 177Lu-edotreotide (total administered activity 7.5 ± 0.7 GBq / cycle) or to oral everolimus 10 mg once daily until PD or unacceptable toxicity. Only patients with positivity in somatostatin receptor imaging will be included. CT or MRI scans are performed every 12 weeks until PD. Blood samples are analyzed at baseline, at 1st tumor assessment, and at PD for pharmacodynamic endpoints. Archival tumor tissue samples will be analyzed for ancillary studies. The primary endpoint is progression-free survival (PFS) according to RECIST v1.1 based on local investigator assessment. Secondary endpoints include overall survival, overall response rate, safety, and quality of life (EORTC QLQ-C30). The expected sample size is 120 patients to demonstrate statistical significant risk reduction of 46.4 www.clinicaltrials.gov : NCT05918302 (June 23rd, 2023).

BACKGROUND:Adrenocortical carcinoma (ACC) is a rare cancer. The French ENDOCAN-COMETE network was established in 2009 to coordinate care locally and nationally, and to promote research and education on malignant adrenal tumors. Evidence demonstrating the benefits of this organization is currently lacking. PATIENTS AND METHODS:Patients diagnosed with ACC between 2010 and 2017 were identified from the French Network of Cancer Registries (FRANCIM). Patients were categorized based on referral to the ENDOCAN-COMETE network as either referred at diagnosis (R-ACC) or not referred, or referred late (nR-ACC). Median overall survival (OS) and OS rates at 1, 5, and 10 years were compared between the R-ACC and nR-ACC groups after adjustment for prognostic parameters. RESULTS:A total of 134 patients with ACC were identified from the FRANCIM registries, corresponding to an incidence of 1.4 cases per million person-years. Ten patients were excluded because of insufficient information regarding their health care pathway. The final analysis included 124 patients (mean age, 53.6 years; female-to-male ratio, 2:1). At diagnosis, 45.2% had European Network for the Study of Adrenal Tumours (ENSAT) stage I-II disease, 48.4% had stage III-IV disease, and 6.4% had an unknown stage; endocrine and/or tumour-related symptoms were present in 62.9% of patients. Among the analyzed patients, 87 (70%) were R-ACC, whereas 37 (30%) were nR-ACC. In patients with localized stage I-II ACC, OS rates were significantly higher in the R-ACC group than in the nR-ACC group: 1-year OS was 92% versus 85%, 5-year OS was 81% versus 55%, and 10-year OS was 75% versus 35%, respectively. This survival advantage remained significant after adjustment for prognostic factors (hazard ratio, 3.9; P=.026). In contrast, among patients with advanced ACC, OS rates were similar between the 2 groups. CONCLUSIONS:Our study demonstrates an OS benefit for patients with stage I-II ACC who were referred early to specialized centers within the ENDOCAN-COMETE network. The combined use of the French cancer registries and dedicated national networks provides the strongest evidence to date demonstrating the impact of such a network.

OBJECTIVE:The rising incidence of neuroendocrine tumors (NETs) and delayed motherhood raise concerns about pregnancy outcomes and management, yet data remain scarce. METHODS:This national cohort study, conducted through the GTE and RENATEN-ENDOCAN networks, included 17 women with NETs who experienced 26 pregnancies, resulting in 27 births. Maternal and fetal outcomes were analyzed based on tumor status, presence of carcinoid syndrome, and treatments during pregnancy. Early postpartum tumor evolution was evaluated using mRECIST on CT scans at 1 and 6 months after delivery. RESULTS:Median maternal age at first pregnancy was 31. Among women with resected localized NETs, 71.4% remained in remission post-pregnancy, while 28.6% experienced recurrence. In metastatic NETs, disease remained stable in 50% of cases, with 21.4% showing progression. Most progression was observed on 1-month postpartum scans. No worsening of carcinoid syndrome symptoms occurred. The overall cesarean rate was 16.7%, increasing to 25% in those with carcinoid syndrome. Live birth rates were high: 94.4% under surveillance and 91% under somatostatin analog (SSA) therapy. Intrauterine growth restriction rate was higher in patients receiving SSA therapy, while birth weight and length were not affected. No developmental issues were observed by age 2. CONCLUSION:Pregnancy is generally safe and successful in women with NETs. No major safety concerns were observed with SSA; however, these findings should be interpreted cautiously given the small sample size. Their use should remain individualized within a multidisciplinary approach, with early postpartum tumor assessment to optimize fetal and maternal outcomes.

BACKGROUND:To our knowledge, no randomised trial with peptide receptor radionuclide therapy has been done in patients with metastatic pancreatic neuroendocrine tumours. We aimed to evaluate the antitumour activity and safety of [177Lu]Lu-dota-tate in this setting. METHODS:OCLURANDOM is a randomised, open-label, non-comparative, phase 2 trial conducted in ten academic centres in France. Patients aged 18 years and older with pretreated, progressive, somatostatin receptor-positive, metastatic pancreatic neuroendocrine tumours and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1) using web-based software to receive intravenous [177Lu]Lu-dota-tate (7·4 GBq every 8 weeks up to four cycles) with concomitant amino acid infusion or oral sunitinib (37·5 mg once daily). Amino acid infusion was for at least 4 h starting 30 min before [177Lu]Lu-dota-tate infusion and included 16·8 g of arginine and 22 g of lysine in 2 L until May, 2018, and, from that date, a solution of 25 g of arginine and 25 g of lysine in 2 L. Randomisation was stratified according to Ki-67, liver involvement, and previous therapies. The primary endpoint was progression-free survival at 12 months assessed by real-time central review using Response Evaluation Criteria in Solid Tumours version 1.1 in the intention-to-treat population. Cross-over was allowed. Adverse events in the as-treated population were assessed continuously during the active phase of treatment and then every 3 months. Patients and the public were not involved in the design, conduct, reporting, or dissemination plans of this research. This trial was registered with ClinicalTrials.gov, NCT02230176, and is closed to enrolment. FINDINGS:Between Feb 13, 2015, and July 16, 2020, 84 patients were enrolled and randomly assigned to the [177Lu]Lu-dota-tate group (n=41) or the sunitinib group (n=43). 44 (52%) patients were women and 40 (48%) were men. Median follow-up was 72·5 months (IQR 61·4-88·4). Progression-free survival rate at 12 months was 33 (80·5% [90% CI 67·5-89·9]) of 41 patients in the [177Lu]Lu-dota-tate group versus 18 (41·9% [29·1-55·5]) of 43 patients in the sunitinib group. Grade 3-4 adverse events occurred in 18 (44%) of 41 patients in the [177Lu]Lu-dota-tate group and 31 (72%) of 43 patients in the sunitinib group. The most common grade 3-4 adverse events for all treatment groups were neutropenia (two [5%] of 41 in the [177Lu]Lu-dota-tate group vs 13 [30%] of 43 in the sunitinib group) and hypertension (four [10%] in the [177Lu]Lu-dota-tate group vs eight [19%] in the sunitinib group). Drug-related serious adverse events occurred in six (15%) patients in the [177Lu]Lu-dota-tate group (transaminase increase, neutropenia, thrombosis, and fever) and ten (23%) in the sunitinib group (gastrointestinal, general disorders, and sepsis). There was a 10·3-point (95% CI 2·4-18·2) difference in the Global Health Status score between the two groups in favour of [177Lu]Lu-dota-tate. Late adverse events (grade 2 or worse) were reported in 24 (60%) patients in the [177Lu]Lu-dota-tate group and in three (43%) of seven patients in the sunitinib group. One treatment-related death (acute leukaemia) occurred in the [177Lu]Lu-dota-tate group. INTERPRETATION:Using sunitinib as an internal control, our results show clinically significant antitumour efficacy of [177Lu]Lu-dota-tate in pretreated, progressive, somatostatin receptor-positive, metastatic pancreatic neuroendocrine tumours, and a better quality of life during the treatment phase. Late adverse events were reported in the [177Lu]Lu-dota-tate group that might affect the tolerance of subsequent lines of treatment. FUNDING:French Ministry of Health, through the National Institute for Cancer.

Hepatic arterial embolization reduces liver tumor burden and hormonal secretion in neuroendocrine tumors, but its safety in patients with carcinoid heart disease is underexplored, and current guidelines suggest managing the cardiac disease first. We assessed the safety and efficacy of hepatic arterial embolization in patients with neuroendocrine tumors and concomitant carcinoid heart disease in a single-center retrospective study including patients with liver metastases and carcinoid heart disease confirmed on expert transthoracic echocardiography between 2001 and 2025. The primary endpoint was procedural safety; secondary endpoints were symptom control, biochemical response, and overall survival. Twenty-seven patients (median age 58.6 years) underwent 69 embolization procedures using bland, conventional, and drug-eluting bead techniques. Severe carcinoid heart disease was present in 52% of patients, and right-sided valvular disease was found in 96%, with tricuspid regurgitation predominating. No procedure-related or cardiovascular death occurred. Two cardiac complications (7%) arose, both in patients with severe pre-existing valvular disease, together with four extra-cardiac complications. Carcinoid syndrome symptoms and urinary 5-hydroxyindoleacetic acid levels decreased significantly after treatment, whereas cardiac symptoms remained stable. Median overall survival was 6.25 years, with a five-year survival of 60%. Hepatic arterial embolization appears feasible with an acceptable safety profile in patients with neuroendocrine tumors and concomitant carcinoid heart disease when performed in expert centers with multidisciplinary management, and may contribute to carcinoid syndrome control. Prospective multicenter studies are warranted to confirm these findings and to define the optimal sequencing of hepatic arterial embolization and cardiac valve surgery.

This ENETS guidance paper, developed by a multidisciplinary working group, provides up-to-date and practical advice on the diagnosis and management of lung and thymic carcinoids, based on recent developments and study results. These recommendations aim to provide practical recommendations for the diagnosis, treatment and follow-up of these tumours, and pave the road for more standardised care for our patients expecting improved outcomes. This paper is structured on a question-answer format in order to address common dilemmas encountered in clinical practice, including controversial issues and areas of uncertainty, based on the best available evidence and expert opinion when good quality evidence is not available. Each recommendation will provide a level of evidence and grade of recommendation as per the GRADE system (adapted from the Infectious Disease Society of United States Public Health Service grading system).

Background: The International Medullary Thyroid Carcinoma Grading System (IMTCGS) is a two-tier score that classifies high-grade medullary thyroid carcinoma (MTC) by the presence of at least one of the following features: mitotic index ≥5/2 mm2, Ki-67 proliferation index ≥5%, or tumor necrosis. Cases lacking all three features are classified as low-grade. This study aimed to validate the prognostic role of the IMTCGS in patients with metastatic MTC. The prognostic significance of a high proliferative index (Ki-67 index ≥20%) was also investigated. Methods: We conducted a monocentric retrospective study of 99 metastatic MTC patients treated at Gustave Roussy between 2000 and 2024, in whom the IMTCGS was assessed on the primary tumor. Results: IMTCGS high-grade tumors were found in 67 patients (67.7%), who were older (p = 0.009) and had larger primary tumors (p < 0.001) compared with 32 patients with low-grade tumors. Postoperative calcitonin levels, number of metastatic sites/patient, prevalence of synchronous metastases, and RET-M918T mutation were similar between groups. Median overall survival (OS) was shorter in patients with IMTCGS high-grade than low-grade (4.8 vs. 13.9 years; p = 0.01), as was time to systemic treatment initiation (TTI) (1.0 vs. 4.8 years; p < 0.001). However, among the 75 patients who received systemic therapy, OS from treatment initiation was similar between the two groups (2.8 vs. 3.89 years; p = 0.865). RET-M918T mutation was not associated with worse OS. On multivariable analysis, IMTCGS high-grade and bone metastases were independently associated with both shorter OS and TTI (p < 0.05 for both). Patients with Ki-67 index ≥20% had worse OS (2.6 years) compared with those with Ki-67 index <5% (10.5 years; hazard ratio [HR] = 6.11; p < 0.001) and 5-19% (6.5 years; HR = 3.29; p = 0.001). Conclusions: The IMTCGS is a strong independent prognostic factor in patients with metastatic MTC. Patients with IMTCGS high-grade tumors and Ki-67 index ≥20% represent a high-risk subgroup with the poorest prognosis.

We report an additional case of FUS::CREM-rearranged neoplasm, with a distinctive clinical presentation and phenotype, in order to expand the spectrum of these tumors and to underline the major issues they raise in diagnosis and classification. A 52-year male patient, with a remote history of seminoma, presented with multiple lung, pancreatic, and renal tumor nodules, containing large nests of medium-sized epithelioid, monomorphic, tumor cells, which did not express any epithelial marker, but expressed all neuroendocrine markers. S100 protein labeled sustentacular-like cells. GATA3 and Phox2B were undetectable; CD99 was strongly positive. ALK was heterogeneously expressed. Ki-67 index ranged from 5 to 15% according to the location. A FUS (exon 7)::CREM (exon 6) fusion was detected in two tumors and confirmed by FISH. This paraganglioma-like malignant neoplasm may belong to the group of FET::CREB-rearranged mesenchymal neoplasms, currently in the course of delineation, and points to its phenotypic diversity.

INTRODUCTION:Thymic neuroendocrine tumors (Thy-NETs) constitute a poorly characterized ultrarare subgroup of NET. To characterize locally advanced or metastatic Thy-NET, to evaluate prognostic factors for survival, and to provide an overview of their current therapeutic management in two dedicated French national networks. METHODS:Retrospective multicenter study of two French ENDOCAN-RENATEN and RYTHMIC networks. RESULTS:A total of 74 patients (median age, 46 y) followed in 20 French centers between 1988 and 2020 were included. Main characteristics were as follows: male over female ratio of 2.7, multiple endocrine neoplasia type 1 inherited syndrome in 25 patients (34%), NET G2 atypical carcinoids in 31 patients (48%), 20 patients (31%) with NET G3 highly proliferative atypical carcinoids, and 11 patients (15%) with ectopic Cushing syndrome. Metastatic sites were as follows: lymph nodes (54 patients, 73%), bone (42 patients, 65%), lung (31 patients, 42%), and pleura (31 patients, 42%). A total of 64 patients (87%) had locally advanced Thy-NET and eight (11%) had synchronous metastases, at diagnosis. Pleural metastases were almost exclusively metachronous. Positive results for 18F-FDG or somatostain receptor imaging was found in 88% or 74% of cases, respectively. The 5-year overall survival was 85%. Univariate analysis on overall survival reveals a trend toward worse prognosis in case of female gender and bone metastases and better prognosis for patients with multiple endocrine neoplasia type 1. Partial responses were more frequently observed in patients treated with cytotoxic chemotherapy. CONCLUSION:This large series identifies specific characteristics of patients with advanced Thy-NET. Prognosis was better than previously reported. Perioperative pleural dissemination is suspected. Partial responses were mainly observed with chemotherapy.

Introduction Les corticosurrénalomes métastatiques (CSM) sont des cancers agressifs avec peu de ressources thérapeutiques. La détermination de l’expression des protéines du système MMR (MLH1, MSH2, MSH6, PMS2) en immunohistochimie (IHC) est maintenant recommandée. L’objectif de ce travail est de décrire la présentation phénotypique des ACC métastatiques avec mutation des gènes MMR. Méthodes Étude rétrospective d’un centre expert incluant les patients porteurs d’un CSM avec mutation somatique ou constitutionnelle d’un des gènes MMR. Résultats 11 patients (54 % d’homme, âge médian de 45 ans) ont été inclus. Au diagnostic, les caractéristiques étaient les suivantes : stade I 9 %, II 64 %, III 18 %, IV 9 % ; taille 95mm (50–195), Ki67 30 % (5–70), Weiss 7 (4–9), R0 90 %, syndrome sécrétoire 55 %. Le délai d’apparition des métastases était de 15,3 mois (4,2–34). Deux patients présentaient un syndrome de Lynch et 9 patients une mutation somatique d’un des gènes MMR retrouvée soit sur biopsie liquide (4/6) ou NGS tumoral (6/8) puis confirmée en IHC (9/9) ; trois avaient une instabilité microsatellitaire. Au stade métastatique, cette population était caractérisée par une survie prolongée (médiane non atteinte) après un suivi de 49±38 mois avec 90 % des patients traités par gestes locaux régionaux (LR) et mitotane. 45 % des patients ont reçu une chimiothérapie dans un délai de 16 mois (médiane SSP 4 mois, taux de réponse objective de 20 %) et un patient une immunothérapie sans réponse. Conclusion Les patients CSM avec mutation MMR semblent bénéficier d’une survie prolongée avec une grande proportion de patients traités par gestes LR et mitotane.

Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical carcinoids and atypical carcinoids (TCs and ACs)). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) vs placebo plus BSC, with an optional open-label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression-free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n = 51 (TCs, n = 29; ACs, n = 22); placebo, n = 26 (TCs, n = 16; ACs, n = 10)). Median (95% CI) PFS during double-blind and open-label phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable (NC)) months in TCs, and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN vs 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients’ quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR-positive TCs and ACs and suggests clinical benefit in TCs.

We report a large series of 40 patients presenting EPAS1-mutated paraganglioma (PGL) in whom we investigated a cause underlying chronic hypoxia. Four patients suffered from hypoxaemic heart disease. In patients with available haemoglobin electrophoresis results, 59% presented with a haemoglobin disorder, including six with sickle cell disease, five with sickle cell trait and two with heterozygous haemoglobin C disease. Histological and transcriptomic characterization of EPAS1 tumours revealed increased angiogenesis and high similarities with pseudohypoxic PGLs caused by VHL gene mutations. Sickle haemoglobinopathy carriers could thus be at increased risk for developing EPAS1-PGLs, which should be taken into account in their management and surveillance.