[Prehabilitation in chronic inflammatory bowel disease: the Proactive care pathway]. / Préhabilitation dans les maladies inflammatoires chroniques de l'intestin : le parcours de soins Proactive.

Inflammatory Bowel Diseases (IBD) cause diarrhea and abdominal pain that impair quality of life. Digestive damage frequently leads to undernutrition and sarcopenia, which worsen the prognosis of the disease. This led to the development of PROACTIVE, a multimodal prehabilitation program designed to improve the functional capacities, nutritional status and quality of life of IBD patients. 19 patients have been included in our pilot program, with an initial personalized multimodal assessment, 10 group sessions with 4 patients, and a final multimodal assessment proposing personalized care for home. Initial data are positive, showing an improvement in patients' physical capacity and quality of life after 6 weeks.

Diagnostic yield of repeat genetic testing in idiopathic chronic pancreatitis.

Genetic testing is performed for unexplained pancreatitis. The aim of this study was to evaluate the diagnostic value of repeating genetic testing in idiopathic pancreatitis when new predisposing genes are identified. We investigated 330 patients who were initially screened for PRSS1, SPINK1 and CFTR genes. A new analysis was performed by Next-Generation Sequencing (NGS) for PRSS1, SPINK1, CFTR, CTRC, CASR, CPA1, TRPV6 genes and the CEL-HYB1 allele in clinical practice, and patients were included in our cohort study. Additional rare variants were identified in 7.3 % of the patients. Screening for new pancreatitis genes is recommended when initial screening is limited. Routine use of NGS is a useful diagnostic tool in these cases.

A preoperative computed tomography radiomics model to predict disease-free survival in patients with pancreatic neuroendocrine tumors.

IMPORTANCE: Imaging has demonstrated capabilities in the diagnosis of pancreatic neuroendocrine tumors (pNETs), but its utility for prognostic prediction has not been elucidated yet. OBJECTIVE: The aim of this study was to build a radiomics model using preoperative computed tomography (CT) data that may help predict recurrence-free survival (RFS) or OS in patients with pNET. DESIGN: We performed a retrospective observational study in a cohort of French patients with pNETs. PARTICIPANTS: Patients with surgically resected pNET and available CT examinations were included. INTERVENTIONS: Radiomics features of preoperative CT data were extracted using 3D-Slicer® software with manual segmentation. Discriminant features were selected with penalized regression using least absolute shrinkage and selection operator method with training on the tumor Ki67 rate (≤2 or >2). Selected features were used to build a radiomics index ranging from 0 to 1. OUTCOME AND MEASURE: A receiving operator curve was built to select an optimal cutoff value of the radiomics index to predict patient RFS and OS. Recurrence-free survival and OS were assessed using Kaplan-Meier analysis. RESULTS: Thirty-seven patients (median age, 61 years; 20 men) with 37 pNETs (grade 1, 21/37 [57%]; grade 2, 12/37 [32%]; grade 3, 4/37 [11%]) were included. Patients with a radiomics index >0.4 had a shorter median RFS (36 months; range: 1-133) than those with a radiomics index ≤0.4 (84 months; range: 9-148; P = .013). No associations were found between the radiomics index and OS (P = .86).

Unexpected upper gastrointestinal polyps in patients with short bowel syndrome treated with teduglutide: need for close monitoring.

BACKGROUND: Teduglutide is a GLP-2 analog indicated for the treatment of short bowel syndrome (SBS) since 2015. Its efficacy in reducing parenteral nutrition (PN) has been shown in patients with SBS. OBJECTIVES: Because teduglutide is a trophic factor, the aim of this study was to assess risk of developing polypoid intestinal lesions during treatment. METHODS: A retrospective study was conducted in 35 patients with SBS treated with teduglutide for ≥1 y in a home PN expert center. All patients underwent ≥1 follow-up intestinal endoscopy during treatment. RESULTS: In the 35 patients, the small bowel length was 74 cm (IQR: 25-100), and 23 patients (66%) had a colon in continuity. Upper and lower gastrointestinal endoscopy was performed after a mean treatment duration of 23 mo (IQR: 13-27), and polypoid lesions were found in 10 patients (6 with a colon in continuity, 4 with an end jejunostomy) and no lesion in 25 patients. In 8 out of the 10 patients, the lesion was found in the small bowel. Five of these lesions presented an aspect of hyperplastic polyp without dysplasia, and 3 of a traditional adenoma with low-grade dysplasia. CONCLUSIONS: Our study highlights the importance of performing follow-up upper and lower gastrointestinal endoscopy in SBS patients treated with teduglutide and the potential need to make changes to the recommendations with respect to treatment initiation and follow-up.

Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies.

The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in cancer progression and in host immunity. Idelalisib was the first of this class to be approved with the second-generation Pi3 kinase inhibitors copanlisib, duvelisib and umbralisib, subsequently being approved in the United States. Real-world data are lacking, however, in relation to the incidence and toxicity of Pi3 kinase inhibitor-induced colitis. We here review, in the first instance, the general landscape of the Pi3K inhibitors in the context of hematological malignancies, with a focus on the adverse gastrointestinal side effects reported by various clinical trials. We further review the available worldwide pharmacovigilance data in relation to these drugs. Finally, we describe our own real-world experience with idelalisib-induced colitis management in our center and in a national setting.

Malnutrition with Low Muscle Mass Is Common after Weaning off Home Parenteral Nutrition for Chronic Intestinal Failure.

The differences in outcomes after weaning off intravenous support (IVS) for chronic intestinal failure (IF) are unclear. Adult IF patients who are weaned off IVS at a tertiary care center (June 2019−2022) were included in this study, and nutritional and functional markers were assessed before, during, and after weaning. Short bowel syndrome (SBS) was present in 77/98 of the IF patients, with different outcomes according to the final anatomy. The body weight and the BMI increased during IVS in those with a jejunocolonic (JC) anastomosis (p < 0.001), but weight loss was significant during follow-up (p < 0.001). Malnutrition was present in >60%, with a reduced muscle mass, which was found using bioelectrical impedance analysis (BIA), in >50% of SBS-JC patients. Although reduced hand-grip strength and sarcopenia were less common, the muscle quality, or phase angle (BIA), decreased during follow-up, also correlating with serum albumin and muscle mass (p ≤ 0.01). The muscle quality and albumin were low in the patients restarting IVS, which was only the case with ≤60 cm of small bowel. Closer follow-up and earlier treatment with teduglutide (TED) should be considered in these patients, as none of the TED-treated patients were malnourished or sarcopenic. Studies on the potential benefits of nutritional and physical interventions for low muscle mass and associations with outcomes are needed in chronic IF patients.

The PRSS3P2 and TRY7 deletion copy number variant modifies risk for chronic pancreatitis.

BACKGROUND: PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition. METHODS: We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction. RESULTS: We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77-0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression. CONCLUSIONS: The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection.

Systemic therapy in metastatic pancreatic adenocarcinoma: current practice and perspectives.

Major breakthroughs have been achieved in the management of metastatic pancreatic ductal adenocarcinoma (PDAC) with FOLFIRINOX (5-fluorouracil + irinotecan + oxaliplatin) and gemcitabine plus nab-paclitaxel approved as a first-line therapy, although the prognosis is still poor. At progression, patients who maintain a good performance status (PS) can benefit from second-line chemotherapy. To address the concern of achieving tumor control while maintaining a good quality of life, maintenance therapy is a concept that has now emerged. After a FOLFIRINOX induction treatment, maintenance with 5-fluorouracil (5-FU) seems to offer a promising approach. Although not confirmed in large, prospective trials, gemcitabine alone as a maintenance therapy following induction treatment with gemcitabine plus nab-paclitaxel could be an option, while a small subset of patients with a germline mutation of breast cancer gene (BRCA) can benefit from the polyadenosine diphosphate-ribose polymerase (PARP) inhibitor olaparib. The rate of PDAC with molecular alterations that could lead to a specific therapy is up to 25%. The Food and Drug Administration (FDA) recently approved larotrectinib for patients with any tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, and pembrolizumab for patients with a mismatch repair deficiency in a second-line setting, including PDAC. Research focused on targeted therapy and immunotherapy is active and could improve patients' outcomes in the near future.

Prognostic transcriptome classes of duodenopancreatic neuroendocrine tumors.

Duodenopancreatic neuroendocrine tumors (DPNETs) aggressiveness is heterogeneous. Tumor grade and extension are commonly used for prognostic determination. Yet, grade classes are empirically defined, with regular updates changing the definition of classes. Genomic screening may provide more objective classes and reflect tumor biology. The aim of this study was to provide a transcriptome classification of DPNETs. We included 66 DPNETs, covering the entire clinical spectrum of the disease in terms of secretion, grade, and stage. Three distinct molecular groups were identified, associated with distinct outcomes (log-rank P < 0.01): (i) better-outcome DPNETs with pancreatic beta-cell signature. This group was mainly composed of well-differentiated, grade 1 insulinomas; (ii) poor-outcome DPNETs with pancreatic alpha-cell and hepatic signature. This group included all neuroendocrine carcinomas and grade 3 DPNETs, but also some grade 1 and grade 2 DPNETs and (iii) intermediate-outcome DPNETs with pancreatic exocrine and progenitor signature. This group included grade 1 and grade 2 DPNETs, with some insulinomas. Fibrinogen gene FGA expression was one of the topmost expressed liver genes. FGA expression was associated with disease-free survival (HR = 1.13, P = 0.005) and could be validated on two independent cohorts. This original pathophysiologic insight provides new prognostic classification perspectives.

Outcomes of endoscopic submucosal dissection for early esophageal and gastric cardia adenocarcinomas.

OBJECTIVES: Adenocarcinomas of the esophagus and of the gastric cardia are regarded as a same clinical entity in oncology. For endoscopic resection however, endoscopic mucosal resection is recommended for esophageal adenocarcinoma, while endoscopic submucosal dissection (ESD) is advocated for gastric adenocarcinomas. Our aim was to compare the outcomes of ESD in both types of esophagogastric junction adenocarcinomas. METHODS: Between March 2015 and December 2019, we included all patients who underwent an ESD for early adenocarcinoma of the esophagogastric junction at a French tertiary referral center. Esophageal and gastric cardia adenocarcinomas were compared in terms of clinical, procedural and histological outcomes. RESULTS: 57 esophageal and 19 gastric cardia adenocarcinomas were included in the analysis, for a total of 76 patients. The median (IQR) size of the resections was 40 (40-57.5) and 50 (35-55)mm, p=0.96, respectively. En bloc resection was achieved in 100% and 89% for adenocarcinomas of the esophagus and the gastric cardia, p=0.06. Late adverse events occurred in 14% and 5.3%, respectively, p=0.44, with no severe adverse event. Curative resection rates were 67% and 63% for adenocarcinomas of the esophagus and the gastric cardia, respectively, p=0.89. CONCLUSION: ESD is a safe treatment for T1 adenocarcinomas of the esophagogastric junction, curative in two thirds of the patients, in tumors arising from the esophagus or from the stomach. ESD should be considered for the routine resection of esophageal adenocarcinomas.

Indications of Peptide Receptor Radionuclide Therapy (PRRT) in Gastroenteropancreatic and Pulmonary Neuroendocrine Tumors: An Updated Review.

Radionuclide therapy for neuroendocrine tumors is a form of systemic radiotherapy that allows the administration of targeted radionuclides into tumor cells that express a large quantity of somatostatin receptors. The two most commonly used radio-peptides for radionuclide therapy in neuroendocrine tumors are 90Y-DOTATOC and 177Lu-DOTATATE. Radio-peptides have been used for several years in the treatment of advanced neuroendocrine tumors. Recently, the randomized Phase III study NETTER-1 compared177Lu-DOTATATE versus high-dose (double-dose) octreotide LAR in patients with metastatic midgut neuroendocrine tumors, and demonstrated its efficacy in this setting. Strong signals in favor of efficiency seem to exist for other tumors, in particular for pancreatic and pulmonary neuroendocrine tumors. This focus on radionuclide therapy in gastroenteropancreatic and pulmonary neuroendocrine tumors addresses the treatment modalities, the validated and potential indications, and the safety of the therapy.

Management of esophageal strictures after endoscopic resection for early neoplasia.

BACKGROUND: Endoscopic resection of extensive esophageal neoplastic lesions is associated with a high rate of esophageal stricture. Most studies have focused on the risk factors for post-endoscopic esophageal stricture, but data on the therapeutic management of these strictures are scarce. Our aim is to describe the management of esophageal strictures following endoscopic resection for early esophageal neoplasia. METHODS: We included all patients with an endoscopic resection for early esophageal neoplasia followed by endoscopic dilatation at a tertiary referral center. We recorded the demographic, endoscopic, and histological characteristics, and the outcomes of the treatment of the strictures. RESULTS: Between January 2010 and December 2019, we performed 166 endoscopic mucosal resections and 261 endoscopic submucosal dissections for early esophageal neoplasia, and 34 (8.0%) patients developed an esophageal stricture requiring endoscopic treatment. The indication for endoscopic resection was Barrett's neoplasia in 15/34 (44.1%) cases and squamous cell neoplasia (SCN) in 19/34 (55.9%) cases. The median [(interquartile range) (IQR)] number of endoscopic dilatations was 2.5 (2.0-4.0). Nine of 34 (26.5%) patients required only one dilatation, and 22/34 (65%) had complete dysphagia relief following three endoscopic treatment sessions. The median number of dilatations was significantly higher for SCN [3.0 (2-7); range 1-17; p = 0.02], and in the case of circumferential resection [4.0 (3.0-7.0); p = 0.03]. Endoscopic dilatation allowed a sustained dysphagia relief in 33/34 (97.0%) patients after a mean follow-up of 25.3 ± 22 months. CONCLUSION: Refractory post-endoscopic esophageal stricture is a rare event. After a median of 2.5 endoscopic dilatations, 97.0% of patients were permanently relieved of dysphagia. Circumferential endoscopic esophageal resections should be considered when indicated.

Organ Preservation after Endoscopic Resection of Early Esophageal Cancer with a High Risk of Lymph Node Involvement.

Background: Esophagectomy is recommended after endoscopic resection of an early esophageal cancer when pejorative histoprognostic criteria indicate a high risk of lymph node involvement. Our aim was to analyze the clinical outcomes of a non-surgical, organ preserving management in this clinical setting. Patients and Methods: This retrospective study was performed in two tertiary centers from 2015 to 2020. Patients were included if they had histologically complete resection of an early esophageal cancer, with poor differentiation, lymphovascular invasion or deep submucosal invasion. Endoscopic resection was followed by chemoradiotherapy or follow-up in case of surgical contraindications or patient refusal. Outcome measures were disease-free survival (DFS), overall survival (OS), cancer specific survival (CSS) and toxicity of chemoradiotherapy. Results: Forty-one patients (36 with squamous cell carcinoma and 5 with adenocarcinomas) were included. The estimated high risk of lymph node involvement was based on poor differentiation (10/41; 24%), lympho-vascular invasion (11/41; 27%), muscularis mucosa invasion or deep sub-mucosal invasion (38/41; 93%). Thirteen patients (13/41; 32%) were closely monitored, and 28 (28/41; 68%) were treated by chemoradiotherapy or radiotherapy alone. In the close follow-up group, DFS, OS and CSS were 92%, 92% and 100%, respectively vs. 75%, 79% and 96%, respectively in the chemoradiotherapy group at the end of the follow-up. Serious adverse events related to chemoradiotherapy occurred in 10% of the patients. There were no treatment-related deaths. Conclusions: Our study shows that close follow-up may be an alternative to systematic esophagectomy after endoscopic resection of early esophageal cancer with a predicted high risk of lymph node involvement.

The Role of Interventional Radiology for the Treatment of Hepatic Metastases from Neuroendocrine Tumor: An Updated Review.

Interventional radiology plays an important role in the management of patients with neuroendocrine tumor liver metastasis (NELM). Transarterial embolization (TAE), transarterial chemoembolization (TACE), and selective internal radiation therapy (SIRT) are intra-arterial therapies available for these patients in order to improve symptoms and overall survival. These treatment options are proposed in patients with NELM not responding to systemic therapies and without extrahepatic progression. Currently, available data suggest that TAE should be preferred to TACE in patients with NELM from extrapancreatic origin because of similar efficacy and better patient tolerance. TACE is more effective in patients with pancreatic NELM and SIRT has shown promising results along with good tolerance. However, large randomized controlled trials are still lacking in this setting. Available literature mainly consists in small sample size and retrospective studies with important technical heterogeneity. The purpose of this review is to provide an updated overview of the currently reported endovascular interventional radiology procedures that are used for the treatment of NELM.

Medical Treatment of Advanced Pancreatic Neuroendocrine Neoplasms.

Pancreatic neuroendocrine neoplasms (panNENs) are relatively rare but their incidence has increased almost sevenfold over the last four decades. Neuroendocrine neoplasms are classified according to their histologic differentiation and their grade. Their grade is based on their Ki-67 proliferation index and mitotic index. Their prognosis is highly variable according to these elements and treatments also vary according to their classification. Surgery is the only curative treatment for localized and advanced panNENs and offers a better prognosis than non-surgical treatments. In the case of an advanced panNEN without the possibility of resection and/or ablation, medical treatment remains the cornerstone for improving survival and preserving quality-of-life. PanNENs are considered as chemosensitive tumors, unlike midgut neuroendocrine tumors. Thus, panNENs can be treated with chemotherapy, but targeted therapies and somatostatin analogs are also treatment options. The scarcity and heterogeneity of NENs make their management difficult. The present review aims to clarify the medical treatments currently available for advanced panNENs, based on their characteristics, and to propose a treatment algorithm.

Oral therapies in digestive oncology (Review).

Targeted therapy and oral chemotherapy indications are increasing in the realm of digestive oncology. Oral intake of cancer agents is sometimes compulsory (no i.v. equivalent) or is preferred by the patient or the physician. Although oral chemotherapy facilitates the treatment of oncology patients, the treatment diversity, risk of pharmaceutical interactions and monitoring of side effects are potentially challenging and need to be fully acknowledged by the physician. We offer here a literature review of the indications, doses, side effects and monitoring of every oral therapy indicated in Digestive Oncology. We suggest a prescription algorithm including therapeutic education by the physician or a trained nurse, and pharmaceutical counseling.

Early esophageal signet ring cell carcinoma: A contraindication to endoscopic resection?

INTRODUCTION: Endoscopic resection is a standard-of-care for early esophageal neoplasia. Early gastric signet ring cell carcinoma (SRCC) can be safely managed by endoscopic resection, if the early SRCC is limited to the mucosa and less than 15mm, with a low lymph node metastasis rate. It is not known if esophageal signet ring cell carcinoma is amenable to endoscopic resection. METHODS: We retrospectively collected demographic, procedural, oncologic and follow-up data from all patients with esophageal SRCC resected endoscopically at our institution, and compared them to those of patients with endoscopically resected poorly differentiated esophageal adenocarcinomas. RESULTS: Between 2016 and 2018, 170 endoscopic resections were performed for esophageal neoplasms, among which 7 patients with SRCC and 6 patients with poorly differentiated early adenocarcinomas were identified. The histologically complete (R0) resection rate was 28.6% (2/7) for SRCC vs. 100% for poorly differentiated adenocarcinomas (P=0.04). The presence of lymphovascular invasion or deep submucosal invasion led to curative resection rates of 14.2% (1/7) and 66.6% (4/6) for SRCC and poorly differentiated adenocarcinomas, respectively (P=0.1). CONCLUSION: Endoscopic resection of early esophageal SRCC is neither histologically complete, nor curative in the majority of cases. These data argue against upfront endoscopic resection when SRCC is evidenced on esophageal biopsies.

Outcomes of esophagectomy after noncurative endoscopic resection of early esophageal cancer.

BACKGROUND: Current guidelines recommend performing esophagectomy after endoscopic resection for early esophageal cancer when the risk of lymph node metastasis or residual cancer is found to be significant and endoscopic treatment is therefore noncurative. Our aim was to assess the safety and oncological outcomes of esophagogastric resection in this specific clinical setting. PATIENTS AND METHODS: A retrospective review from 2012 to 2018 was performed at four tertiary referral centers. All patients had a noncurative endoscopic resection of a clinical T1 esophageal cancer, followed by esophagectomy. Outcome measures were the rates of T0N0 specimens, overall survival, disease-free and cancer-specific survival, postoperative morbidity and mortality. RESULTS: A total of 30 patients (13 with squamous cell carcinoma and 17 with adenocarcinoma) were included. The reasons for noncurative endoscopic resection were: positive vertical margins (n = 12), squamous cell carcinoma with muscularis mucosae or submucosal layer invasion (n = 3 and 9), adenocarcinoma with deep submucosal invasion (n = 11), poorly differentiated tumor (n = 6) and lymphovascular invasion (n = 6). Overall, 63% of the esophagi were T0N0: most residual lesions were T1a metachronous lesions, and four (13%) patients had advanced pT status (n = 3) or lymph node metastases (n = 2). Overall survival, disease-free survival and cancer-specific survival were 83%, 75%, and 90% respectively. A total of 43% of patients had severe postoperative complications, and postoperative mortality was 7%. CONCLUSION: In this cohort, esophagectomy allowed the resection of residual advanced cancer or lymph node metastases in 13% of cases, at the cost of 43% severe morbidity and 7% mortality. Therefore, the possibility of close follow up needs to be balanced with a highly morbid surgical management in these patients.

Non-Pharmacological Therapeutic Options for Liver Metastases in Advanced Neuroendocrine Tumors.

The incidence of liver metastasis in digestive neuroendocrine tumors is high. Their presence appears as an important prognostic factor in terms of quality of life and survival. These tumors may be symptomatic because of the tumor burden itself and/or the hormonal hyper-secretion induced by the tumor. Surgery is the treatment of choice for resectable tumors and metastasis. Nevertheless, surgery is only possible in a small number of cases. The management of non-resectable liver metastasis is a challenge. The literature is rich but consists predominantly in small retrospective series with a low level of proof. Thus, the choice of one technique over another could be difficult. Local ablative techniques (radiofrequency) or trans-catheter intra-arterial liver-directed treatments (hepatic artery embolization, chemo-embolization, and radio-embolization) are frequently considered for liver metastasis. In the present review, we focus on these different therapeutic approaches in advanced neuroendocrine tumors, results (clinical and radiological), and overall efficacy, and summarize recommendations to help physicians in their clinical practice.