Survival of patients managed in France for duodenal neuroendocrine tumors (D-NET): a 20-year multicenter cohort study from the GTE group: a cohort study.

INTRODUCTION: Duodenal neuroendocrine tumours (D-NETs) have a low incidence; however, their diagnosis has been increasing. Features such as tumour location, size, type, histological grade, and stage were used to adapt the treatment to either endoscopic (ER) or surgical (SR) resections. There is no consensus regarding the definitive treatment. The authors' study aimed to describe the management of non-metastatic, well-differentiated D-NETs in France and its impact on patient survival. METHODS: A registry-based multicenter study using prospectively collected data between 2000 and 2019, including all patients managed for non-metastatic G1 and G2 D-NETs, was conducted in the GTE group. RESULTS: A total of 153 patients were included. Fifty-eight benefited from an ER, and 95 had an SR. No difference in recurrence-free survival (RFS) was observed regardless of treatment type. There was no significant difference between the two groups (ER vs. SR) in terms of location, size, grade, or lymphadenopathy, regardless of the type of incomplete resection performed or regarding the pre-therapeutic assessment of lymph node invasion in imaging. The surgery allowed for significantly more complete resection (patients with R1 resection in the SR group: 9 vs. 14 in the ER group, P<0.001). Among the 51 patients with positive lymph node dissection after SR, tumour size was less than or equal to 1 cm in 25 cases. Surgical complications were more numerous (P=0.001). In the sub-group analysis of G1-G2 D-NETs between 11 and 19 mm, there was no significant difference in grade (P=0.977) and location (P=0.617) between the two groups (ER vs. SR). No significant difference was found in both morphological and functional imaging, focusing on the pre-therapeutic assessment of lymph node invasion (P=0.387). CONCLUSION: Regardless of the resection type (ER or SR) of G1-G2 non-metastatic D-NETs, as well as the type of management of incomplete resection, which was greater in the ER group, long-term survival results were similar between ER and SR. Organ preservation seems to be the best choice owing to the slow evolution of these tumours.

Mesenteric sparing approach for advanced nodal extent in small intestinal neuroendocrine tumors. Is there a limit to the vascular resection in order to avoid creating a short small bowel syndrome? An anatomic research study.

PURPOSE: By selectively perfusing the first three jejunal arteries (JA), we aim to assess the individual perfusion length of small bowel (SB) and its impact on nodal resection in stage III-up small-intestinal neuroendocrine tumors (SI-NET). METHODS: Our anatomical research protocol implies a midline laparotomy and three measures of the SB length. We then perform a classical anterior approach of the superior mesenteric vessels. We carry on with the complete dissection and checking of the superior mesenteric artery (SMA) in order to identify the first three JA. Then we selectively perfuse each artery with colored latex solutions and measure the length of small bowel perfused respectively. RESULTS: We conducted our protocol on six cadaveric subjects. Mean(SD) SB length was 413(5.7), 535(13.2), 485(15), 353(25.1), 730(17.3) and 525(16° cm respectively from subject one to six. Most JA originated from the left side of the SMA. The first JA originated from its posterior wall in two subjects. Mean(SD) distance of origin of the first three JA was 4.6(1.3)cm, 6(1.1)cm and 7.1(0.9)cm respectively. Mean(SD) diameter of SMA was 10.8(3.3)mm. Mean diameter of the three first JA was 4(1.4)mm, 4(1.5)mm and 5(1.2)mm respectively. Mean(SD) SB length perfused by first and second JA was 224(14.9)cm, 175(8.6)cm, 238.3(7.6)cm, 84.3(5.1)cm, 233.3(5.8)cm and 218.3(10.4)cm respectively from subject one to six. CONCLUSION: We observed a trend suggesting that the first and second JA may sustain a SB length beyond the viable 1.5 m limit, implying the feasibility of stage III-up SI-NET resection with just two JA.

Neuropilin-2 and soluble neuropilin-2 in neuroendocrine neoplasms.

Neuropilin-2 (NRP2), a transmembrane non-tyrosine kinase receptor, has been described as a potential critical player in the tumourigenesis of several solid cancers, and particularly in neuroendocrine neoplasms (NEN). A soluble form of NRP2 (sNRP2) has been previously described and corresponds to a truncated splice isoform. Its prognostic value has never been studied in NEN. NRP2 expression was studied by immunochemistry on tissue microarrays (n=437) and on circulating tumour cells (CTC, n=5 patients with neuroendocrine carcinoma, NEC). We described the levels of sNRP2 in 229 patients with NEN using the ELISA method to identify the factors associated with sNRP2 levels and to evaluate its prognostic role; 90 blood donors represented the healthy control group. NRP2 was found in 97% of neuroendocrine tumours (396/410) and in 74% of NEC (20/27). NRP2 was also expressed in CTC of all the studied patients. The receiver operating characteristic (ROC) analysis showed that sNRP2 had a weak capacity to discriminate between NEN patients and healthy controls [area under curve (AUC)=0.601, p=0.053]. Abnormal sNRP2 levels were associated with inflammatory syndrome, bone and peritoneal metastases, and abnormal chromogranin A levels. Patients with high sNRP2 levels (sNRP2Q3-Q4) had significantly poorer overall survival in multivariate analysis (HR 0.16, 95%CI [0.04-0.67], p=0.015). In conclusion, the present study found that sNRP2 and NRP2 could represent a new prognostic biomarker and a therapeutic target, respectively, particularly in aggressive NEN.

pyHiM: a new open-source, multi-platform software package for spatial genomics based on multiplexed DNA-FISH imaging.

Genome-wide ensemble sequencing methods improved our understanding of chromatin organization in eukaryotes but lack the ability to capture single-cell heterogeneity and spatial organization. To overcome these limitations, new imaging-based methods have emerged, giving rise to the field of spatial genomics. Here, we present pyHiM, a user-friendly python toolbox specifically designed for the analysis of multiplexed DNA-FISH data and the reconstruction of chromatin traces in individual cells. pyHiM employs a modular architecture, allowing independent execution of analysis steps and customization according to sample specificity and computing resources. pyHiM aims to facilitate the democratization and standardization of spatial genomics analysis.

Beyond MEN1, when to think about MEN4? Retrospective study on 5600 patients in the French population & literature review.

CONTEXT: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically-negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear. OBJECTIVE: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients. DESIGN: Retrospective observational nationwide study. Narrative review of literature and variant class reassessment. PATIENTS: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French TENGEN network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants, i.e. with genetically-confirmed MEN4 diagnosis, in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database. RESULTS: From 5600 MEN1-suspected patients analyzed, four patients with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, PHPT and adrenal nodule, isolated PHPT, PHPT and pNET. We listed 29 patients with CDKN1B class 4/5 variants from literature. Compared to matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis. CONCLUSION: The prevalence of MEN4 is low. PHPT and PA represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families.

Outcome on Mesenteric Mass Response of Small-Intestinal Neuroendocrine Tumors Treated by 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy: The MesenLuth Study, a National Study from the French Group of Endocrine Tumors and Endocan-RENATEN Network.

A mesenteric mass (MM), characterized by fibrotic reaction, is present in most small-intestinal neuroendocrine tumors (SI-NETs). 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) has shown its efficacy in patients with progressive SI-NETs. However, because of specific tissue characteristics of desmoplastic MMs, we hypothesize that these lesions may be refractory to 177Lu-DOTATATE PRRT. Methods: From the national French Groupe d'étude des Tumeurs Endocrines database, we identified patients with an advanced SI-NET and a MM (≥2 cm with a retractile aspect) of a SI-NET treated by at least 1 course of 177Lu-DOTATATE PRRT. The primary endpoint was a MM objective response rate (ORR) of less than 5%. Secondary endpoints were metabolic response, MM-related safety, and clinical response, as well as MM progression-free survival (PFS) and non-MM PFS. Results: In total, 52 patients were included. The MM ORR was 4% (n = 2), and the non-MM ORR was 8% (n = 4). No patient had a MM metabolic response, and the non-MM metabolic response rate was 12% (n = 6). Among the 26 patients with baseline MM-related symptoms, 46% had a clinical response. Four patients presented with gastrointestinal complications during PRRT. The median MM-related PFS was not reached, and the non-MM PFS was 50.3 mo (95% CI, 38.2-61.7 mo). Conclusion: This study confirms that 177Lu-DOTATATE PRRT does not lead to morphologic response on MMs (ORR < 5%). However, it allows MM stability, with few MM-related side effects, and has a relevant impact on MM-related symptoms.

Assessment of the reproducibility of a C18 bonded phase based on ethylene-bridged hybrid organic/inorganic particles.

The batch-to-batch reproducibility of an endcapped trifunctional C18 bonded phase based on ethylene-bridged hybrid particles was assessed using a modified version of a chromatographic test developed by Neue and coworkers. The test involves the isocratic separation of six compounds chosen to probe different characteristics of the stationary phase, including hydrophobicity, hydrogen bonding and cation-exchange. The assessment was based on results for a total of 471 batches manufactured and tested over a 19 year time span. The results were compared to those for an endcapped monofunctional C18 bonded phase on silica particles, based on results generated for 246 batches over 29 years. Overall, both stationary phases show similar reproducibility, with relative standard deviations for the relative retentions ranging from 0.1 to 3.2 %.

Histopronostic factors in superficial colorectal adenocarcinomas treated by endoscopy: reproducibility and impact of immunohistochemistry and digital pathology.

Endoscopic dissection is the first-choice treatment for superficial pT1 colorectal adenocarcinoma (sCRC). Complementary surgery decision is influenced by histopronostic factors. Prognostic significance and reproducibility of each factor are not well established. The role of immunohistochemistry (IHC) and digital pathology in this context is unknown. Our aims were (1) to evaluate each histopronostic factor reproducibility comparing HES and IHC ± digital pathology and (2) to evaluate how the different techniques would affect indications for additional surgery. We performed a single-centre retrospective study of 98 patients treated between 2010 and 2019 in Hospices Civils de Lyon, France. We analyzed physical or digital slides of HES and keratin/desmin immunostaining of 98 sCRC dissection specimens. Three pathologists evaluate the histopronostic factors including submucosal invasion depth (SMI) measured using different recommended methods. Assessment of SMI with Ueno or JSCCR methods showed good to excellent interobserver reproducibility (IOR) (ICCs of 0.858 to 0.925) using HES staining and IHC. Assessment of budding on HES sections was poorly reproducible compared to IHC which exhibit moderate IOR (κ = 0.714). IHC increased high-grade budding detection. For lymphovascular invasion and poor differentiation, the IOR was poor (κ = 0.141, 0.196 and 0.313 respectively). IHC gave a better reproducibility for further treatment indication according to JSCCR criteria (κ = 0.763) or forthcoming European guidelines (κ = 0.659). Digital pathology was equivalent to the microscope for all analyses. Histopronostic factor reproducibility in sCRC is moderate. Immunohistochemistry may facilitate the evaluation of certain criteria and improve the reproducibility of treatment decisions.

Diagnosis with confidence: deep learning for reliable classification of laryngeal dysplasia.

BACKGROUND: Diagnosis of head and neck (HN) squamous dysplasias and carcinomas is critical for patient care, cure, and follow-up. It can be challenging, especially for grading intraepithelial lesions. Despite recent simplification in the last WHO grading system, the inter- and intraobserver variability remains substantial, particularly for nonspecialized pathologists, exhibiting the need for new tools to support pathologists. METHODS: In this study we investigated the potential of deep learning to assist the pathologist with automatic and reliable classification of HN lesions following the 2022 WHO classification system. We created, for the first time, a large-scale database of histological samples (>2000 slides) intended for developing an automatic diagnostic tool. We developed and trained a weakly supervised model performing classification from whole-slide images (WSI). We evaluated our model on both internal and external test sets and we defined and validated a new confidence score to assess the predictions that can be used to identify difficult cases. RESULTS: Our model demonstrated high classification accuracy across all lesion types on both internal and external test sets (respectively average area under the curve [AUC]: 0.878 (95% confidence interval [CI]: [0.834-0.918]) and 0.886 (95% CI: [0.813-0.947])) and the confidence score allowed for accurate differentiation between reliable and uncertain predictions. CONCLUSION: Our results demonstrate that the model, associated with confidence measurements, can help in the difficult task of classifying HN squamous lesions by limiting variability and detecting ambiguous cases, taking us one step closer to a wider adoption of AI-based assistive tools.

Systematic Resection of the Visible Scar After Incomplete Endoscopic Resection of Rectal Neuroendocrine Tumors.

INTRODUCTION: When initial resection of rectal neuroendocrine tumors (r-NETs) is not R0, persistence of local residue could lead to disease recurrence. This study aimed to evaluate the interest of systematic resection of non-R0 r-NET scars. METHODS: Retrospective analysis of all the consecutive endoscopic revisions and resections of the scar after non-R0 resections of r-NETs. RESULTS: A total of 100 patients were included. Salvage endoscopic procedure using endoscopic submucosal dissection or endoscopic full-thickness resection showed an R0 rate of near 100%. Residual r-NET was found in 43% of cases. DISCUSSION: In case of non-R0 resected r-NET, systematic scar resection by endoscopic full-thickness resection or endoscopic submucosal dissection seems necessary.

Characteristics and treatment options of glucagonomas: a national study from the French Group of Endocrine Tumors and ENDOCAN-RENATEN network.

OBJECTIVE: Glucagonoma is a very rare functional pancreatic neuroendocrine tumor (PanNET). We aimed to provide data on the diagnosis, prognosis, and management of patients with glucagonoma. DESIGN AND METHODS: In this retrospective national cohort, we included all patients with glucagonoma, defined by at least 1 major criterion (necrolytic migratory erythema [NME] and/or recent-onset diabetes, and/or weight loss ≥ 5 kg) associated with either glucagonemia > 2 × upper limit of normal or positive glucagon immunostaining. Antisecretory efficacy was defined as partial/complete resolution of glucagonoma symptoms. Antitumor efficacy was assessed according to the time to next treatment (TTNT). RESULTS: Thirty-eight patients were included with median age 58.7 yo, primary PanNET located in the tail (68.4%), synchronous metastases (63.2%). Median Ki-67 index was 3%. Most frequent glucagonoma symptoms at diagnosis were NME (86.8%), weight loss (68.4%), and diabetes (50%). Surgery of the primary PanNET was performed in 76.3% of cases, mainly with curative intent (61.5%). After surgery, complete resolution of NME was seen in 93.8% (n = 15/16). The secretory response rates were 85.7%, 85.7%, 75%, and 60% with surgery of metastases (n = 6/7), chemotherapy (n = 6/7), liver-directed therapy (n = 6/8), and somatostatin analogs (n = 6/10), respectively. All lines combined, longer TTNT was reported with chemotherapy (20.2 months). Median overall survival (OS) was 17.3 years. The Ki-67 index > 3% was associated with shorter OS (hazard ratio 5.27, 95% CI [1.11-24.96], P = .036). CONCLUSION: Patients with glucagonoma had prolonged survival, even in the presence of metastases at diagnosis. Curative-intent surgery should always be considered. Chemotherapy, peptide receptor radionuclide therapy, or liver-directed therapy seems to provide both substantial antitumor and antisecretory efficacies.

Right Axillary Artery Cannulation for Veno-Arterial Extracorporeal Membrane Oxygenation in Postcardiotomy Patients: A Single-Center Experience.

Background and Objectives: To analyze the patient outcome and complication rate of axillary artery cannulation for veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients who could not be weaned from cardiopulmonary bypass after cardiothoracic surgery. Materials and Methods: We analyzed the data of 179 patients who were supported with VA-ECMO with femoral-axillary access (FA VA-ECMO) after cardiothoracic surgery between January 2014 and January 2019 in our department. Patients requiring central aortic cannulation and patients with respiratory failure requiring veno-venous ECMO were excluded. Primary outcomes were in-hospital mortality and 1-year survival rate of patients who were weaned from VA-ECMO support. Secondary outcomes were cannulation-related complications at the axillary site, VA-ECMO-related complications, and systemic complications. Results: In our cohort, 60 (33.5%) patients were female. Mean age was 67.0 ± 10.9 years. Overall, 78 (43.5%) patients were operated upon electively, 37 (20.7%) patients underwent urgent surgery, and 64 (35.8%) patients underwent emergency surgical treatment. Sixty-seven patients (37.4%) were resuscitated preoperatively. The mean duration of VA-ECMO support was 8.4 ± 5.1 days. Weaning from VA-ECMO was successful in 87 (48.6%) patients; 62 (34.6%) patients survived the hospital stay. The 1-year survival rate was 74%. Subclavian bleeding occurred in 24 (13.4%) patients, femoral bleeding in 4 (2.2%) patients, ischemia of the upper limb in 11 (6.1%) patients, intracerebral bleeding in 9 (5%) patients, and stroke in 19 (10.6%) patients. Conclusions: In patients with acute LV dysfunction after cardiothoracic surgery who cannot be weaned from cardiopulmonary bypass, right axillary artery cannulation is a safe and reliable method for VA-ECMO support with an acceptable complication rate.

Overall Survival Differences in Young Black Colorectal Cancer Patients: a Report from the National Cancer Database.

Objectives: Black patients have the highest overall incidence rate of early onset colorectal cancer, with many of these patients presenting with more aggressive disease at diagnosis, ultimately leading to decreased overall survival. We aimed to (1) evaluate how race and age affected overall survival in colorectal cancer patients, and (2) determine the different demographic and clinical covariables that may influence survival in younger individuals. Methods: The 2017 National Cancer Database (NCDB) was used to identify all patients that had colorectal cancer between 2004-2017. These patients were then divided into groups according to age (<45 and ≥45 years old) and race (white and black). Overall survival (OS) between white and black groups according to age was compared. Initial testing of survivor functions between groups revealed violations of the proportional hazards assumption. Accordingly, we used parametric maximum likelihood analyses fitting the survivor functions to Weibull distributions. Logistic regression analysis was used to determine univariate and multivariate relationships between the covariates and race for younger subjects. Propensity score matching analysis was also used to control for differences in the demographic or clinical variables between the young black versus white subgroups. Results: Out of 1.4 million potential cases initially identified, 207,823 unique cases were deemed eligible for evaluation based on study criteria. Black patients in the study population were more likely to be female, have medical comorbidities, and come from areas with lower average income and baseline education. OS was lower in older patients of both race categories when compared to the younger cohorts. Among patients older than 45 years, there were no significant differences in proportional hazard of death between black and white patients. However, among those younger than 45 years, younger black patients had significantly increased hazard of death. Regarding disease burden at diagnosis, pathologic characteristics and overall risk of death, there were no significant differences between black and white patients. Conclusions: Overall survival in young black patients with colorectal cancer is significantly reduced when compared to young white patients, even when controlling for demographic and pathologic factors. This suggests that the outcome disparities between black and white patients are complex, and the underlying factors are not well understood.

The Need for Centralization for Small Intestinal Neuroendocrine Tumor Surgery: A Cohort Study from the GTE-Endocan-RENATEN Network, the CentralChirSINET Study.

BACKGROUND: The concept of surgical centralization is becoming more and more accepted for specific surgical procedures. OBJECTIVE: The aim of this study was to evaluate the relationship between procedure volume and the outcomes of surgical small intestine (SI) neuroendocrine tumor (NET) resections. METHODS: We conducted a retrospective national study that included patients who underwent SI-NET resection between 2019 and 2021. A high-volume center (hvC) was defined as a center that performed more than five SI-NET resections per year. The quality of the surgical resections was evaluated between hvCs and low-volume centers (lvCs) by comparing the number of resected lymph nodes (LNs) as the primary endpoint. RESULTS: A total of 157 patients underwent surgery in 33 centers: 90 patients in four hvCs and 67 patients in 29 lvCs. Laparotomy was more often performed in hvCs (85.6% vs. 59.7%; p < 0.001), as was right hemicolectomy (64.4% vs. 38.8%; p < 0.001), whereas limited ileocolic resection was performed in 18% of patients in lvCs versus none in hvCs. A bi-digital palpation of the entire SI length (95.6% vs. 34.3%, p < 0.001), a cholecystectomy (93.3% vs. 14.9%; p < 0.001), and a mesenteric mass resection (70% vs. 35.8%; p < 0.001) were more often performed in hvCs. The proportion of patients with ≥8 LNs resected was significantly higher (96.3% vs. 65.1%; p < 0.001) in hvCs compared with lvCs, as was the proportion of patients with ≥12 LNs resected (87.8% vs. 52.4%). Furthermore, the number of patients with multiple SI-NETs was higher in the hvC group compared with the lvC group (43.3% vs. 25.4%), as were the number of tumors in those patients (median of 7 vs. 2; p < 0.001). CONCLUSIONS: Optimal SI-NET resection was significantly more often performed in hvCs. Centralization of surgical care of SI-NETs is recommended.

European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for appendiceal neuroendocrine tumours (aNET).

The aim of the present guidance paper is to update the previous ENETS guidelines on well differentiated appendiceal neuroendocrine tumours (NET), providing practical guidance for the diagnosis and management of appendiceal NET (aNET); poorly differentiated neoplasms are dealt with in a separate guidance paper. This paper is structured on a question-answer format in order to also address controversial issues and areas where uncertainty regarding the management and follow-up of aNET exists. All recommendations are offered on the basis of the best available evidence, along with the authors' experiences in managing these neoplasms. Each recommendation for treatment will provide a level of evidence and grade of recommendation as per the GRADE system (adapted in Infectious Disease Society of United States Public Health Service grading system).