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.

Prognostic score for synchronous metastatic rectal cancer: A real-world study.

BACKGROUND: Prognostic factors of metastatic rectal cancer are not well known. AIM: The objective of this study was to identify prognostic factors of overall survival (OS) in a cohort of patients with non-resectable synchronous metastatic rectal cancer. METHODS: Patients were retrospectively enrolled from 18 French centres. Univariate and multivariate analyses were performed to identify prognostic factors for OS. A simple score was derived from this a development cohort RESULTS: A total of 243 patients with metastatic rectal cancer were included in the study. Median OS was 24.4 months, 95% CI [19.4-27.2]. Among patients with non-resected metastases (n=141), six independent prognostic factors associated with better OS were identified in multivariate analysis: primary tumour surgery, WHO score 0-1, middle or upper rectal tumour, lung metastases only, systemic chemotherapy and targeted agent in first line. A prognostic score individualized three groups, each factor counting for one point in the score (<3, = 3 et > 3). Their median OS were respectively 27.9 months, 95% CI [21.7-35.1], 17.1 months [11.9-19.7] (HR2/1=2.08, 95%, CI [1.31-3.30], p2/1=0.002) and 9.1 months [4.9-11.7] (HR3/2=2.32, 95% CI [1.38-3.92], p3/2=0.001). CONCLUSION: A prognostic score for non-resectable synchronous metastatic rectal cancer can be proposed to classify patients in three prognostic groups.

PROPERTY: study protocol for a randomized, double-blind, multicenter placebo-controlled trial assessing neurotoxicity in patients with metastatic gastrointestinal cancer taking PHYCOCARE® during oxaliplatin-based chemotherapy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common adverse effects of antineoplastic agents, ranging in prevalence from 19% to over 85%. Clinically, CIPN is a predominantly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. The high prevalence of CIPN among cancer patients makes it a major problem for both patients and survivors, as well as for their health care providers, especially because there is currently no single effective method of preventing CIPN; moreover, the options for treating this syndrome are very limited. Phycocyanin, a biliprotein pigment and an important constituent of the blue-green algae Spirulina platensis, has been reported to possess significant antioxidant and radical-scavenging properties, offering protection against oxidative stress, which is one of the hypothetic mechanisms, between others, of CIPN occurrence. METHODS: Our hypothesis is that phycocyanin may give protection against oxaliplatin-induced neuropathy in the treatment of gastrointestinal cancers. Our trial will be a randomized double-blind placebo-controlled study with 110 randomized patients suffering from metastatic gastrointestinal adenocarcinoma including esogastric, colorectal, and pancreatic cancers. Patients are being followed up in the gastroenterology or oncology departments of seven French hospitals. DISCUSSION: Due to the neuropathy, patients need to avoid injury by paying careful attention to home safety; patients' physicians often prescribe over-the-counter pain medications. If validated, our hypothesis should help to limit neurotoxicity without the need to discontinue chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT05025826. First published on August 27, 2021.

Adhesion of Gastric Cancer Cells to the Enteric Nervous System: Comparison between the Intestinal Type and Diffuse Type of Gastric Cancer.

Background: Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. The enteric nervous system (ENS) has been suggested to be involved in cancer development and spread. Objective: To analyze the GC cell adhesion to the ENS in a model of co-culture of gastric ENS with GC cells. Methods: Primary culture of gastric ENS (pcgENS), derived from a rat embryo stomach, was developed. The adhesion of GC cells to pcgENS was studied using a co-culture model. The role of N-Cadherin, a cell-adhesion protein, was evaluated. Results: Compared to intestinal-type GC cells, the diffuse-type GC cancer cells showed higher adhesion to pcgENS (55.9% ± 1.075 vs. 38.9% ± 0.6611, respectively, p < 0.001). The number of diffuse-type GC cells adherent to pcgENS was significantly lower in neuron-free pcgENS compared to neuron-containing pcgENS (p = 0.0261 and 0.0329 for AGS and MKN45, respectively). Confocal microscopy showed that GC cells adhere preferentially to the neurons of the pcgENS. N-Cadherin blockage resulted in significantly decreased adhesion of the GC cells to the pcgENS (p < 0.01). Conclusion: These results suggest a potential role of enteric neurons in the dissemination of GC cells, especially of the diffuse-type, partly through N-Cadherin.

[Re-visiting the Pronopall score ten years later: A multicenter retrospective study]. / Réévaluation du score Pronopall : une étude rétrospective multicentrique.

INTRODUCTION: The Pronopall score, which distinguishes 3 prognostic groups in patients with advanced cancer, was initially proposed in 2008 and validated in a study published in 2018 but including patients between 2009 and 2010. Since the last decade, cancer management and therapeutic options have progressed. The objective of this study was to confirm the value of this score in patients with digestive and thoracic cancer. METHODS: From July 2019 to November 2020, this retrospective multi-center study included patients with digestive or thoracic cancers who fulfilled the same inclusion criteria as those used in the initial study, and in whom the Pronopall score could be calculated using its four variables (albumin serum level, LDH level, ECOG score, number of metastatic sites). Survival curves were analyzed using the Kaplan-Meier method. RESULTS: One hundred patients were included. According to the Pronopall score, patients were separated into group A (score 8-10, 7 patients), group B (score 4-7, 41 patients) and group C (score 0-3, 52 patients). Median overall survival was 73 days, CI [17-129], 228 days, CI [128-328] and 575 days, CI [432-718] for groups A, B and C, respectively. Survival at 2 months was 28 % for population A, 61 % for population B, and 94 % for population C. CONCLUSION: This study confirms that the Pronopall score still allows clinically relevant discrimination of patients, score C being associated with a good prognosis compared to scores A and B.

Oxaliplatin and 5-Fluorouracil in Advanced Well-Differentiated Digestive Neuroendocrine Tumors: A Multicenter National Retrospective Study from the French Group of Endocrine Tumors.

INTRODUCTION: Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs); however, the available data are limited. Our aim was to assess the efficacy of FOLFOX (association of 5-fluorouracil with oxaliplatin) in a large series of patients with advanced digestive NETs. METHODS: All patients with advanced digestive well-differentiated NETs treated with at least 3 cycles of FOLFOX between January 2004 and December 2018 in 12 centers from the French Group of Endocrine Tumors were included. Tumor response rate according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, progression free survival (PFS), and overall survival, as well as prognostic factors, were analyzed retrospectively. RESULTS: One hundred fifty-five patients were included. Primary tumor locations were pancreas (n = 89), small intestine (n = 40), unknown with no evidence for lung primary (n = 13), stomach (n = 7), and rectum (n = 6). Median Ki-67 was 10%, and 65% of the tumors were grade 2. The partial response rate was 30% for pancreatic NETs, 12.5% for small intestine NETs, 38.5% for unknown primary NETs, 14% for gastric NETs, and 17% for rectal NETs. Significant prognostic factors for poor PFS after FOLFOX were progressive disease at the beginning of treatment (hazard ratio [HR] = 1.83, p = 0.007), hepatic involvement superior to 50% (HR = 2.67, p = 0.0001), and rectal primary tumor location (HR = 2.6, p = 0.0036). Among pancreatic NETs, insulinomas had a better median PFS (22 months) than other pancreatic NETs (9 months, p = 0.026) and showed a high rate (8/9) of serum glucose normalization. CONCLUSIONS: FOLFOX shows a promising antitumor activity in advanced digestive NETs. Rapid symptomatic response is observed in metastatic insulinomas.

Post first-line dacarbazine or temozolomide in neuroendocrine carcinoma.

OBJECTIVE: First-line chemotherapy in metastatic neuroendocrine carcinomas (NECs) is based on etoposide and platinum. However, there is no standard concerning second-line treatment. The objective of this study was to evaluate efficacy and tolerance of dacarbazine or temozolomide in metastatic digestive NEC as post first-line treatment. MATERIAL AND METHODS: This study included patients with a metastatic NEC of digestive or unknown primary site. All patients received platinum-etoposide as first-line chemotherapy. Primary endpoint was progression-free survival (PFS). Secondary endpoints were clinical/morphological responses, toxicity, and overall survival (OS). RESULTS: Twenty-seven patients were included: 17 received dacarbazine and 10 temozolomide as post-first line treatments. Median PFS was 3.0 (95%CI (2.2;3.7)) months. There was no significant difference between dacarbazine and temozolomide on PFS. Clinical and morphological responses were found in 12 and 9 patients, respectively. Median OS was 7.2 (95%CI (2.2;12.2)) months. The toxicity profile was that expected with such treatments. CONCLUSION: LV5FU2-dacarbazine or temozolomide-capecitabine chemotherapies allow a temporary clinical response for almost half of patients and/or a morphological response for a third of patients.

Endoscopic management of 345 small rectal neuroendocrine tumours: A national study from the French group of endocrine tumours (GTE).

Introduction: Small rectal neuroendocrine tumours are good candidates for endoscopic resection provided that complete pathological resection (R0) is obtained and their risk of metastatic progression is low. We conducted a large multicentre nationwide study to evaluate the outcomes of the management of non-metastatic rectal neuroendocrine tumours ≤2 cm diagnosed endoscopically. Patients and methods: The medical records, the endoscopic and pathological findings of patients with non-metastatic rectal neuroendocrine tumours ≤2 cm managed from January 2000-June 2018 in 16 French hospitals, were retrospectively analysed. The primary objective was to describe the proportion of R0 endoscopic resections. Results: A total of 329 patients with 345 rectal neuroendocrine tumours were included, 330 (96%) tumours were managed by local treatments: 287 by endoscopy only and 43 by endoscopy followed by transanal endoscopic microsurgery. The final endoscopic R0 rate was 134/345 (39%), which improved from the first endoscopy (54/225, 24%), to the second (60/100, 60%) and the third endoscopy (20/26, 77%). R0 was associated with endoscopic technique (90% for advanced techniques, 40% for mucosectomy and 17% for polypectomy), but not with tumour or patient characteristics. Twenty patients had metastatic disease, which was associated with tumour size ≥10 mm (odds ratio: 9.1, 95% confidence interval (3.5-23.5)), tumour grade G2-G3 (odds ratio: 4.2, (1.5-11.7)), the presence of muscular (odds ratio: ∞, (11.9-∞)) and lymphovascular invasion (odds ratio: 57.2, (5.6-578.9)). Conclusions: The resection of small rectal neuroendocrine tumours often requires multiple procedures. Training of endoscopists is necessary in order to better recognise these tumours and to perform the appropriate resection technique.

Crohn's-like acute severe colitis associated with Hermansky-Pudlak syndrome: A case report.

BACKGROUND: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, platelet storage pool deficiency and systemic complications associated with ceroid deposition in the reticuloendothelial system. HPS types 1 and 4 are associated with Crohn's disease (CD)-like gastrointestinal disorders, such as granulomatous enterocolitis or perianal disease. Cases of colitis can be particularly severe and, before the use of anti-tumor necrosis factor alpha (TNFα) therapy had become common, were reported as showing poor responsiveness to medical treatment. CASE SUMMARY: We present the case of a 51-year-old albino woman who presented with acute severe colitis that led to the diagnosis of HPS. Histologic findings of biopsy samples showed chronic inflammation with deep ulcerations, and granulomas without caseous necrosis. Molecular genetic analysis confirmed HPS type 1, with a homozygous 27 base-pair deletion in exon 20 of the HPS1 gene. Once the patient's bleeding diathesis was corrected by platelet transfusion, the granulomatous colitis responded dramatically to a medical treatment regimen that included corticosteroids, azathioprine and infliximab; this regimen is similar to that used in CD treatment. Although it remains unclear if the granulomatous enterocolitis in HPS is due to ceroid deposition or reflects the co-existence of CD and HPS, the fact that this case of HPS-related granulomatous colitis responded to the same therapeutic approach used in CD suggests that this type of colitis may result from HPS patients' genetic susceptibility to CD. CONCLUSION: We report a case of severe colitis that led to the diagnosis of HPS, which was responsive to azathioprine and infliximab.

Survival and prognostic factors analysis of 151 intestinal and pancreatic neuroendocrine tumors: a single center experience.

BACKGROUND: Intestinal and pancreatic neuroendocrine tumors (IP-NETs) are rare tumors with heterogeneous outcomes. The aim of our study was to determine the clinical, therapeutic and pathological factors which impact the overall survival (OS) in IP-NETs. METHODS: All the patients diagnosed with IP-NETs at the Nantes University Hospital between October 1994 and October 2013 were retrospectively analysed. Patients with MEN-1 (Type 1 Multiple Endocrine Neoplasia) or Von Hippel-Lindau syndrome were excluded. Additionally, a prospective analysis of tumor grade (mitotic index and Ki67 index) was performed on tumor samples. OS was evaluated by Kaplan-Meier method and prognostic factors by log-rank test and Cox model. RESULTS: The study included 151 patients. Median age was 60 (range, 14-81). Primary tumor was pancreatic in 86 patients (56.95%) and intestinal in 65 patients (43.05%). Tumors were metastatic (synchronous or metachronous) in 72 patients (47.7%). The median OS was 157 months. For all IP-NETs, age >65 years (P<0.0001), Ki67 >5% (P=0.03), synchronous metastases (P=0.016), primary tumor size >25 mm (P=0.03) and emergency surgery (P=0.007) were independent poor prognostic factors. CONCLUSIONS: In this large series of patients with IP-NET, age >65 years, Ki67 >5%, primary tumor size >25 mm, synchronous metastases and emergency surgery for acute complications have been identified as independent poor prognostic factors.

Short article: Evaluation of O6-methylguanine-DNA methyltransferase as a predicting factor of response to temozolomide-based chemotherapy in well-differentiated metastatic pancreatic neuroendocrine tumors.

OBJECTIVE: Temozolomide (TMZ) is an alkylating agent frequently used in well-differentiated metastatic pancreatic neuroendocrine tumors (PNETs) with very variable responses. O-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme whose loss of expression has been suggested to be predictive of response to TMZ in various human tumors. We evaluated the predictive value of MGMT status, assessed by immunohistochemistry (IHC) and methylation-specific PCR (MS-PCR), in well-differentiated metastatic PNETs treated by a TMZ-based chemotherapy. PATIENTS AND METHODS: All patients with metastatic PNETs treated with TMZ-based chemotherapy between 2010 and 2016 in two academic centers, for whom the tumor samples were available, were included. Clinical data were collected and the MGMT status of the tumors was analyzed using MS-PCR and IHC. RESULTS: Twenty-two patients (nine men, median age 61 years) were included. The loss of MGMT protein expression detected by IHC was observed in 13 (59%) patients and MGMT promoter hypermethylation was detected by MS-PCR in three (15%) out of 20 interpretable cases. MGMT status did not correlate significantly with the best radiological response according to the Response Evaluation Criteria In Solid Tumors criteria or with progression-free survival. There was no correlation between MGMT protein expression and MGMT gene promoter methylation. CONCLUSION: These results indicate that a deficient MGMT status in PNETs, determined by loss of protein expression in IHC or by the presence of MGMT gene promoter methylation measured by MS-PCR, is not associated with a better response to TMZ-based chemotherapy and cannot be used as a predictive marker to lead treatment decisions.