Is Palliative Laparoscopic Hyperthermic Intraperitoneal Chemotherapy Effective in Patients with Malignant Hemorrhagic Ascites?

Malignant hemorrhagic ascites may complicate the terminal evolution of digestive cancers with peritoneal carcinomatosis. It has a bad influence on prognosis and may severely impair patients’ quality of life. Palliative laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed to treat debilitating malignant ascites. Two cases of peritoneal carcinomatosis causing hemorrhagic ascites and severe anemia that needed iterative blood transfusions are reported. These patients were treated by laparoscopic HIPEC (mitomycin C and cisplatin with an inflow temperature of 43°C), resulting in cessation of peritoneal bleeding. No postoperative complication or relapse of ascites occurred during the following months. No more blood transfusion was needed. Laparoscopic HIPEC might be an effective and safe therapeutic option to consider in patients with malignant hemorrhagic ascites

European Neuroendocrine Tumour Society (ENETS) 2023 guidance paper for nonfunctioning pancreatic neuroendocrine tumours.

This ENETS guidance paper for well-differentiated nonfunctioning pancreatic neuroendocrine tumours (NF-Pan-NET) has been developed by a multidisciplinary working group, and provides up-to-date and practical advice on the management of these tumours. Using the extensive experience of centres treating patients with NF-Pan-NEN, the authors of this guidance paper discuss 10 troublesome questions in everyday clinical practice. Our many years of experience in this field are still being verified in the light of the results of new clinical, which set new ways of proceeding in NEN. The treatment of NF-Pan-NEN still requires a decision of a multidisciplinary team of specialists in the field of neuroendocrine neoplasms

Prognostic Role of Examined and Positive Lymph Nodes after Distal Pancreatectomy for Non-Functioning Neuroendocrine Neoplasms

Background: The most appropriate nodal staging system for non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) remains unclear. Despite some evidence is available for pancreaticoduodenectomy, the adequate nodal staging is still unknown for distal pancreatectomy (DP). The aim of the present study was to evaluate the prognostic impact of the number of positive lymph nodes (PLNs) after DP for NF-PanNETs and to define the minimal number of lymph nodes to be harvested for an appropriate nodal staging. Methods: Data were retrospectively collected from patients who underwent DP with curative intent (R0-R1) for sporadic well-differentiated NF-PanNETs in 4 European high-volume centres. NF-PanNETs with nodal involvement (N+) were subclassified into N1 (1–3 PLNs) and N2 (4 or more PLNs). Univariate and multivariate analyses of disease-free survival (DFS) were performed. Results: Of 271 patients in the study, 62 (23%) had nodal involvement (N+). A higher probability of N+ was associated with the following factors: grading, resection margin status, perineural and microvascular invasion, and the number of examined lymph nodes. Three-year DFS rate for N0, N1, and N2 patients was 92, 72, and 50%, respectively (p < 0.001). At multivariate analysis, independent predictors of DFS were grading, T stage, presence of necrosis, and nodal status. For patients with ≥12 examined/resected lymph nodes, the N status remained a significant predictor of disease recurrence (p < 0.001), while it failed to predict recurrence in patients with <12 lymph nodes examined/resected (p = 0.116). Conclusions: A minimal number of 12 nodes should be harvested in case of DP for NF-PanNET for an appropriate nodal staging. The number of positive lymph nodes is an independent predictor of DFS after DP for NF-PanNET, and the N0/N1/N2 nodal classification seems to be more relevant than the current N0/N+ staging

Prolonged Survival in a Patient with Neuroendocrine Tumor of the Cecum and Diffuse Peritoneal Carcinomatosis

Peritoneal carcinomatosis is a well-known factor of poor prognosis in patients with digestive adenocarcinomas. Peritoneal dissemination may also occur in midgut well-differentiated neuroendocrine tumors, but its influence on survival is ill-defined. We report here the history of a 64-year-old woman who had a neuroendocrine tumor of the cecum with multiple synchronous metastases in the liver and diffuse peritoneal carcinomatosis. She underwent surgical resection of the primary tumor and cytoreduction of liver metastases, and received subsequently chemotherapy and somatostatin analogs. In spite of the widespread extension of the disease, she survived for 13 years and died from a carcinoid heart disease. We discuss the natural history and prognostic factors in patients with midgut well-differentiated neuroendocrine tumors, with a focus on the impact of the peritoneal carcinomatosis

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.</p

Clinico-pathological and molecular characterization of digestive neuroendocrine tumour heterogeneity : intertumour, intratumour and chemo-induced heterogeneity

Les tumeurs neuroendocrines (TNE) touchent de multiples organes, sont souvent associées à des métastases principalement hépatiques, et présentent plusieurs niveaux d’hétérogénéité moléculaire, dont la caractérisation clinico-pathologique et moléculaire était l’objectif de ce travail : 1) selon l’origine de la TNE avec des anomalies moléculaires spécifiques, posant le problème des TNE hépatiques sans primitif identifié ; 2) intratumorale avec la coexistence de contingents présentant des degrés variables d’agressivité biologique ; 3) chimioinduite avec une progression des altérations moléculaires dans le temps.Le premier travail a étudié 16 TNE hépatiques sans primitif extra-hépatique après relecture exhaustive des tests cliniques, morphologiques et immunohistochimiques. L’analyse de l’exome de 12 tumeurs montrait un profil de type « intestin antérieur » et des altérations redondantes de la réparation de l’ADN, des modificateurs d’histones, des jonctions adhérentes et du contrôle du cycle cellulaire. L’analyse du transcriptome de 10 tumeurs, comparée à 15 TNE pulmonaires, 22 TNE de l’intestin grêle et 31 TNE pancréatiques (TNEP), indiquait que les TNE hépatiques primitives représentaient bien une entité distincte et n’étaient pas des métastases de TNE de primitif occulte. Le second travail a consisté en la caractérisation de l’hétérogénéité intratumorale des TNEP. L’évaluation de l’agressivité biologique des TNEP repose sur l’index Ki-67, soumis à un biais de prélèvement. Nous avons exploré la capacité d’évaluation du Ki-67 par la tomographie par émission de positrons au18fluorodésoxyglucose (TEP-FDG). Parmi 36 localisations de TNEP réséquées après TEP-FDG, il existait une corrélation significative entre l’intensité de fixation et le Ki-67. Parmi les neufs patients ayant plusieurs lésions-cibles, quatre présentaient une hétérogénéité du Ki-67, corrélée à une hétérogénéité de fixation en TEP-FDG. La TEP-FDG peut donc évaluer l’agressivité biologique des TNEP tout en prenant en compte l’hétérogénéité intratumorale et spatiale. Dix-neuf TNEP non prétraitées présentant une différence de Ki-67 ≥12% entre différentes zones tumorales ont ensuite été sélectionnés. Dans onze de ces tumeurs, nous avons sélectionné 20 low-spots, 20 medium-spots, et 15 high-spots selon le Ki-67. Une analyse du séquençage d’un panel ADN et du transcriptome de ces spots est en cours afin d’explorer les anomalies moléculaires associées à l’hétérogénéité intratumorale des TNEP.Le troisième travail a consisté en l’étude de l’hétérogénéité chimioinduite des TNEP. L’utilisation des chimiothérapies alkylantes, comme le témozolomide (TMZ) semble favoriser une progression moléculaire. Dans notre série multicentrique de 62 patients traités par alkylants (ALK1), pause thérapeutique et rechallenge des alkylants (ALK2), la survie sans progression était de 23,7 mois sous ALK1 et 9,2 mois sousALK2, témoignant d’une diminution dans le temps de l’efficacité des alkylants. Cela pouvait s’expliquer par l’augmentation de l’expression de la MGMT, enzyme de réparation de l’ADN (article 3). Nous avons identifié57 patients ayant une TNEP de grade 1 ou 2 traités par TMZ et chez qui un prélèvement tumoral post-TMZ était disponible, dont 29 (50%) avec progression vers une TNE de grade 3. Nous avons réalisé le séquençage d’un panel ADN et du transcriptome sur les prélèvements pré- et post-TMZ de 12 et 8 patients ayant une TNEP dont le grade a respectivement progressé ou non après TMZ. Les résultats préliminaires indiquent une hétérogénéité moléculaire post-traitement majeure, une augmentation du tumor mutational burden et l’accumulation de mutations impliquées dans la régulation du cycle cellulaire et de la réparation de l’ADN,surtout dans les prélèvements post-TMZ présentant une augmentation de grade, ouvrant des perspectives d’utilisation de l’immunothérapie.Neuroendocrine tumors (NETs) affect multiple organs, are often associated with metastases, mainly hepatic, and present several levels of molecular heterogeneity, the clinical-pathological and molecular characterization of which was the objective of this work: 1) according to the origin of NET with specific molecular abnormalities, posing the problem of hepatic NETs without identified primary tumor; 2) intratumor with the coexistence of components with varying degrees of biological aggressiveness; 3) chemoinduced with progression of molecular alterations over time. The first objective consisted in the study of 16 hepatic NETs without extrahepatic primary tumor after exhaustive review of clinical, morphological and immunohistochemical tests. Exome analysis of 12 tumors showed a foregut-like profile and redundant alterations in DNA repair, histone modifiers, adherent junctions and cell cycle control. Transcriptome analysis of 10 tumors, compared to 15 pulmonary NETs, 22 small-bowel NETs and 31 pancreatic NETs (PanNETs), indicated that primary hepatic NETs should be recognized as a separate entity and not as metastases of NETs of unknown primary. The second work consisted in the characterization of the intratumor heterogeneity of PanNETs. The assessment of the biological aggressiveness of PanNETs is based on the Ki-67 index, which is subject to sampling bias. We explored the ability to assess Ki-67 by 18fluorodeoxyglucose positron emission tomography (FDG-PET). Among 36 locations of PanNETs resected after FDG-PET, there was a significant correlation between FDG uptake and Ki-67. Among the nine patients with multiple target lesions, four presented heterogeneity of Ki-67, correlated with heterogeneity of FDG-PET uptake. FDG-PET can therefore assess the biological aggressiveness of PanNETs while taking intratumor and spatial heterogeneity into account, to guide the biopsies for instance. Twenty non-pretreated PanNETs showing a difference in Ki-67 ≥12% between different tumor areas were then selected. In 10 of these tumors, we selected 18 low-spots, 16 medium-spots, and 12 high-spots according to Ki-67. A DNA panel sequencing and transcriptome analysis of these spots is ongoing to explore the molecular abnormalities associated with intratumor heterogeneity of PanNETs. The third work consisted in the study of the chemo-induced heterogeneity of PanNETs. The use of alkylating chemotherapies, such as temozolomide (TMZ), appears to promote molecular progression. In our multicenter series of 62 patients treated with alkylating agents (ALK1), treatment break and alkylating rechallenge (ALK2), progression-free survival was 23.7 months under ALK1 and 9.2 months under ALK2, indicating a decrease of the effectiveness of alkylating agents over time. This could be explained by an increase in the expression of MGMT, a DNA repair enzyme. We identified 57 patients with grade 1 or 2 PanNETs treated with TMZ and in whom a post-TMZ tumor sample was available, including 29 (50%) with progression to grade 3 NET. We performed the sequencing of a DNA panel and transcriptome on pre- and post-TMZ samples from 12 and 8 patients with PanNETs whose grade has progressed or not after TMZ, respectively. Preliminary results indicate major post-treatment molecular heterogeneity, an increase in the tumor mutational burden and the accumulation of mutations involved in cell cycle regulation and DNA repair, especially in post-TMZ samples showing a progression in grade, opening up perspectives for the use of immunotherapy

Natural history of SPINK1 germline mutation related-pancreatitis

Background The aim was to describe genetic, clinical and morphological features in a large, multicentre European cohort of patients with SPINK1 related pancreatitis, in comparison with patients with idiopathic pancreatitis (IP). Methods All SPINK1 mutation carriers with pancreatic symptoms from two French and one English centers were included. Patients with IP were included in a control group. Genetic, clinical, radiological and biochemical data were collected. Findings 209 and 302 patients were included in the SPINK1 and control groups (median follow-up: 8.3 years (3.7–17.4) vs 5.3 (2.5–8.8)). The median age at onset of symptoms was 20.1 years (17.5–22.8) in the SPINK1 group versus 41.2 (35.2–45.2). The age of exocrine pancreatic insufficiency (EPI) onset in the SPINK1 group was 49.5 (44.5–54.6) years vs. 65.2 (62.1–68.3), p < 0.001. SPINK1 patients with EPI were 5.3%, 14.7%, 28.3% and 52.4% at 20, 30, 40 and 50 years. Diabetes occurred 37.7 (33.3–42.1) years following the onset of symptoms in the SPINK1 group vs. 30.6 (17.3–43.8) (p = 0.002). SPINK1 patients with diabetes were 7.8%, 13.4%, 26.3% and 43.4% at 30, 40, 50 and 60 years. Seven patients (3.3%) developed pancreatic cancer in the SPINK1 group (versus 3 (0.99%), p = 0.1), at a median age of 60 vs 66 years. The cancer risk was 0.8% before 50 years, 11.9%, 27.7%, 51.8% at 60, 70 and 80 years and was 12 times higher than in controls (Cox HR 12.0 (3.0–47.8), p < 0.001). Interpretation SPINK1 related pancreatitis is associated with earlier onset and pancreatic insufficiencies. p.N34S SPINK1 may well be associated with cancer

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 68 Ga-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