Superficial cancer of the stomach

Le cancer superficiel de l’estomac est un cancer limité à la muqueuse ou à la sous-muqueuse (T1). L’absence d’invasion de la musculaire muqueuse diminue le risque d’envahissement ganglionnaire et permet d’envisager un traitement endoscopique. Le risque de métastases ganglionnaires est corrélé à la taille de la tumeur, à l’envahissement en profondeur de la lésion et à l’aspect endoscopique de la lésion. Le traitement endoscopique consiste à réaliser, après repérage de la lésion, une dissection sous-muqueuse de celle-ci, et cela afin de permettre une résection en monobloc. Cette technique, limitée à certains centres, permet d’envisager un traitement curatif endoscopique de ces tumeurs et doit être suivie d’une surveillance rapprochée endoscopique

Quality Indicators for Colonoscopy Procedures: A Prospective Multicentre Method for Endoscopy Units

BACKGROUND AND AIMS: Healthcare professionals are required to conduct quality control of endoscopy procedures, and yet there is no standardised method for assessing quality. The topic of the present study was to validate the applicability of the procedure in daily practice, giving physicians the ability to define areas for continuous quality improvement. METHODS: In ten endoscopy units in France, 200 patients per centre undergoing colonoscopy were enrolled in the study. An evaluation was carried out based on a prospectively developed checklist of 10 quality-control indicators including five dependent upon and five independent of the colonoscopy procedure. RESULTS: Of the 2000 procedures, 30% were done at general hospitals, 20% at university hospitals, and 50% in private practices. The colonoscopies were carried out for a valid indication for 95.9% (range 92.5-100). Colon preparation was insufficient in 3.7% (range 1-10.5). Colonoscopies were successful in 95.3% (range 81-99). Adenoma detection rate was 0.31 (range 0.17-0.45) in successful colonoscopies. CONCLUSION: This tool for evaluating the quality of colonoscopy procedures in healthcare units is based on standard endoscopy and patient criteria. It is an easy and feasible procedure giving the ability to detect suboptimal practice and differences between endoscopy-units. It will enable individual units to assess the quality of their colonoscopy techniques

Sarcopenia Predicts Early Dose-Limiting Toxicities and Pharmacokinetics of Sorafenib in Patients with Hepatocellular Carcinoma

BACKGROUND: Sorafenib induces frequent dose limiting toxicities (DLT) in patients with advanced hepatocellular carcinoma (HCC). Sarcopenia has been associated with poor performance status and shortened survival in cancer patients. PATIENTS AND METHODS: The characteristics of Child Pugh A cirrhotic patients with HCC receiving sorafenib in our institution were retrospectively analyzed. Sorafenib plasma concentrations were determined at each visit. Toxicities were recorded during the first month of treatment, and sarcopenia was determined from baseline CT-scans. RESULTS: Forty patients (30 males) were included. Eleven (27.5%) were sarcopenic. Eighteen patients (45%) experienced a DLT during the first month of treatment. Sarcopenic patients experienced significantly more DLTs than non-sarcopenic patients did (82% versus 31%, p = 0.005). Grade 3 diarrhea was significantly more frequent in sarcopenic patients than in non-sarcopenic patients (45.5% versus 6.9%, p = 0.01), but not grade 3 hand foot syndrome reaction (9% versus 17.2%, p = 1). On day 28, median sorafenib AUC (n = 17) was significantly higher in sarcopenic patients (102.4 mg/l.h versus 53.7 mg/l.h, p = 0.013). CONCLUSIONS: Among cirrhotic Child Pugh A patients with advanced HCC, sarcopenia predicts sorafenib exposure and the occurrence of DLT within the first month of treatment

Mangafodipir Protects against Hepatic Ischemia-Reperfusion Injury in Mice

Mangafodipir is a contrast agent used in magnetic resonance imaging that concentrates in the liver and displays pleiotropic antioxidant properties. Since reactive oxygen species are involved in ischemia-reperfusion damages, we hypothesized that the use of mangafodipir could prevent liver lesions in a mouse model of hepatic ischemia reperfusion injury. Mangafodipir (MnDPDP) was compared to ischemic preconditioning and intermittent inflow occlusion for the prevention of hepatic ischemia-reperfusion injury in the mouse.Mice were subjected to 70% hepatic ischemia (continuous ischemia) for 90 min. Thirty minutes before the ischemic period, either mangafodipir (10 mg/kg) or saline was injected intraperitoneally. Those experimental groups were compared with one group of mice preconditioned by 10 minutes' ischemia followed by 15 minutes' reperfusion, and one group with intermittent inflow occlusion. Hepatic ischemia-reperfusion injury was evaluated by measurement of serum levels of aspartate aminotransferase (ASAT) activity, histologic analysis of the livers, and determination of hepatocyte apoptosis (cytochrome c release, caspase 3 activity). The effect of mangafodipir on the survival rate of mice was studied in a model of total hepatic ischemia.<0.01), and by higher rates of survival in treated than in untreated animals (P<0.001). The level of protection by mangafodipir was similar to that observed following intermittent inflow occlusion and higher than after ischemic preconditioning.Mangafodipir is a potential new preventive treatment for hepatic ischemia-reperfusion injury

Surgical and Oncological Outcomes After Preoperative FOLFIRINOX Chemotherapy in Resected Pancreatic Cancer : An International Multicenter Cohort Study

Background. Preoperative FOLFIRINOX chemotherapy is increasingly administered to patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) to improve overall survival (OS). Multicenter studies reporting on the impact from the number of preoperative cycles and the use of adjuvant chemotherapy in relation to outcomes in this setting are lacking. This study aimed to assess the outcome of pancreatectomy after preoperative FOLFIRINOX, including predictors of OS.Methods. This international multicenter retrospective cohort study included patients from 31 centers in 19 European countries and the United States undergoing pancreatectomy after preoperative FOLFIRINOX chemotherapy (2012-2016). The primary end point was OS from diagnosis. Survival was assessed using Kaplan-Meier analysis and Cox regression.Results. The study included 423 patients who underwent pancreatectomy after a median of six (IQR 5-8) preoperative cycles of FOLFIRINOX. Postoperative major morbidity occurred for 88 (20.8%) patients and 90-day mortality for 12 (2.8%) patients. An R0 resection was achieved for 243 (57.4%) patients, and 259 (61.2%) patients received adjuvant chemotherapy. The median OS was 38 months (95% confidence interval [CI] 34-42 months) for BRPC and 33 months (95% CI 27-45 months) for LAPC. Overall survival was significantly associated with R0 resection (hazard ratio [HR] 1.63; 95% CI 1.20-2.20) and tumor differentiation (HR 1.43; 95% CI 1.08-1.91). Neither the number of preoperative chemotherapy cycles nor the use adjuvant chemotherapy was associated with OS.Conclusions. This international multicenter study found that pancreatectomy after FOLFIRINOX chemotherapy is associated with favorable outcomes for patients with BRPC and those with LAPC. Future studies should confirm that the number of neoadjuvant cycles and the use adjuvant chemotherapy have no relation to OS after resection.Peer reviewe

Reversible Decrease of Portal Venous Flow in Cirrhotic Patients: A Positive Side Effect of Sorafenib

Portal hypertension, the most important complication with cirrhosis of the liver, is a serious disease. Sorafenib, a tyrosine kinase inhibitor is validated in advanced hepatocellular carcinoma. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of our study was to determine the effect of sorafenib on portal venous flow and portosystemic collateral circulation in patients receiving sorafenib therapy for advanced hepatocellular carcinoma. Porto-collateral circulations were evaluated using a magnetic resonance technique prior sorafenib therapy, and at day 30. All patients under sorafenib therapy had a decrease in portal venous flow of at least 36%. In contrast, no specific change was observed in the azygos vein or the abdominal aorta. No portal venous flow modification was observed in the control group. Sorafenib is the first anti-angiogenic therapy to demonstrate a beneficial and reversible decrease of portal venous flow among cirrhotic patients

Applications of derivatives of pharmacological modulation of reactive oxygen species form for optimization of patients treated with chemotherapy

Les formes réactives de l’oxygène (FRO) ont un rôle bien établi dans l’oncogénèse et le fonctionnement des cellules tumorales en augmentant les capacités de prolifération et d’invasion cellulaire. Les FRO présentent une moindre toxicité dans les cellules normales où le niveau de stress oxydant est bas et les systèmes d’oxydoréduction opérationnels. Une modulation pharmacologique de l’équilibre d’oxydoréduction permet d’améliorer l’efficacité des molécules cytotoxiques qui agissent sur les FRO. L’activité anti tumorale de la chimiothérapie étant médiée en partie par le stress oxydant, nous nous sommes dans un premier temps intéressé aux variations du stress oxydant lors d’un traitement par le sorafenib (Nexavar©), un inhibiteur de tyrosine kinases. Nous avons mis en évidence une activité anti tumorale du sorafenib liée à l’augmentation de la production d’anion superoxyde par les cellules. Ce phénomène nous a permis d’identifier un marqueur prédictif d’efficacité du sorafenib, le dosage des Produits d’Oxydation Avancée des Protéines (AOPP), dans le sérum des patients cirrhotiques développant un carcinome hépatocellulaire. Sachant que l’efficacité anti tumorale des chimiothérapies conventionnelles passe en partie par l’induction de FRO, nous nous sommes intéressés dans un deuxième temps au mangafodipir, un modulateur du stress oxydant, qui est connu pour augmenter l’index thérapeutique des agents cytotoxiques in vivo. Le mangafodipir diminue les effets toxiques du stress oxydatif dans des cellules non tumorales et potentialise l’activité anti tumorale de l’oxaliplatine. Ces données nous ont conduits à explorer in vivo et in vitro le mécanisme de la neurotoxicité induite par l’oxaliplatine et le rôle protecteur du mangafodipir. Nous avons ainsi observé dans un modèle murin que le mangafodipir prévient la neurotoxicité induite par l’oxaliplatine au niveau de la gaine de myéline. Nous avons confirmé ces résultats chez l’homme lors d’une étude de phase II. Compte tenu des taux plus élevés de FRO dans les cellules tumorales par rapport aux cellules normales, plusieurs stratégies ont été proposées pour cibler sélectivement les tumeurs sans endommager les tissus sains avec des modulateurs du stress oxydant. Notre troisième axe de travail a eu pour objectif d’identifier et de valider de nouvelles molécules liées à la modulation des FRO. Cette étude a été réalisée dans le cadre d’un projet du programme Européen Pierre et Marie Curie (International Training Network 7-FP7-2007-1-1-ITN201114), au sein du réseau REDCAT. Cette collaboration a permis de concevoir et de synthétiser de nouveaux agents thérapeutiques, les organochalcogenes. Nous avons mis en évidence in vitro et in vivo le potentiel anti tumoral de cette nouvelle classe thérapeutique et principalement celui du composé LAB027. Le LAB027 présente une activité anti tumorale seul ou associé à l’oxaliplatine. L’ensemble de ces travaux nous a permis d’envisager l’évaluation précoce de l’efficacité du sorafenib par un marqueur du stress oxydant, les AOPP, de mettre en évidence l’effet anti-neurotoxique d’un mimétique de la superoxyde dismutase, le mangafodipir et d’identifier une nouvelle classe médicamenteuse en oncologie, les organochalcogènes. Ces optimisations thérapeutiques permettent d’envisager une meilleure prise en charge des malades traités par chimiothérapie afin d’optimiser l’efficacité des traitements utilisés en oncologie.Reactive oxygen species (ROS) forms have an established role in oncogenesis and tumor cell function by increasing the capacity of proliferation and cell invasion. ROS have a lower toxicity in normal cells where the level of oxidative stress is low and redox systems operational. Pharmacological modulation of redox balance enhances the effectiveness of cytotoxic molecules that act on the FRO. The anti-tumor activity of chemotherapy is mediated in part by oxidative stress, we initially interested in the changes of oxidative stress during treatment with sorafenib (Nexavar©), an inhibitor of tyrosine kinases. We have demonstrated anti-tumor activity of sorafenib due to increased production of superoxide anion by cells. This allowed us to identify a predictive marker of efficacy of sorafenib dosing Products Advanced Oxidation Protein (AOPP) in the serum of patients with cirrhosis develop hepatocellular carcinoma. Knowing that the antitumor efficacy of conventional chemotherapy is partly through the induction of ROS, we are interested in a second time mangafodipir, a modulator of oxidative stress, which is known to increase the therapeutic index of cytotoxic agents in vivo. Mangafodipir reduces the toxic effects of oxidative stress in non-tumor cells and potentiates the anti-tumor activity of oxaliplatin. These data led us to explore in vivo and in vitro the mechanism of neurotoxicity induced by oxaliplatin and the protective role of mangafodipir. We observed in a mouse model that mangafodipir prevents neurotoxicity induced by oxaliplatin in the myelin sheath. We confirmed these results in humans in a phase II study. Given the higher levels of ROS in tumor cells compared to normal cells, several strategies have been proposed to selectively target tumors without damaging healthy tissue with modulators of oxidative stress. Our third area of work has aimed to identify and validate novel molecules related to the modulation of ROS. This study was conducted as part of a project of the European Pierre et Marie Curie (International Training Network 7-FP7-2007-1-1-ITN201114) within the network REDCAT. This collaboration has led to the design and synthesis of new therapeutic agents, organochalcogenes. We have demonstrated in vitro and in vivo antitumor potential of this new therapeutic class and mainly composed of the LAB027. LAB027 the present anti-tumor activity alone or in combination with oxaliplatin. All of this work has allowed us to consider the early assessment of the effectiveness of sorafenib a marker of oxidative stress, the AOPP, highlight the anti-nerve of a superoxide dismutase mimetic, mangafodipir and identify a new class of drugs in oncology, organochalcogènes. These optimizations allow therapeutic consider better care of patients treated with chemotherapy to enhance the efficacy of treatments used in oncology

Updates on the Treatment of Pancreatic Diseases: Focus on Surgery, Electrochemotherapy and Rituximab

The pancreas plays an important role in the human body with its two main endocrine and exocrine functions [...