Innovative pathways of chemosensitization in pancreatic ductal adenocarcinoma : acoustic cavitation and NRF2 inhibition

L’adénocarcinome pancréatique (AP) connaît une forte augmentation d’incidence, qui en fait la quatrième cause de mortalité par cancer avec un pronostic extrêmement sombre, moins de 5% des patients étant en vie à 5 ans. De nombreuses avancées dans la compréhension de l’oncogénèse pancréatique notamment sur les aspects génétiques, immunitaires et sur les interactions cellulaires du stroma tumoral ont permis d’envisager le développement de nouvelles stratégies de traitement. Cependant malgré des résultats pré-cliniques très encourageants aucune de ces stratégies n’a encore permis l’émergence d’un traitement plus efficace que la chimiothérapie standard. Ce travail de thèse a abordé 2 approches thérapeutiques innovantes distinctes mais potentiellement complémentaires dans le traitement de l’adénocarcinome pancréatique en étudiant in vitro (cultures cellulaire 2D et 3D) et in vivo (modèles ectopiques et orthotopiques) les effets sur la croissance tumorale de l’inhibition d’un acteur important du stress oxydant (la voie Nrf2) d’une part, de la combinaison d’une chimiothérapie liposomale et d’un agent physique, la cavitation ultrasonore, d’autre part. La cavitation ultrasonore est un effet mécanique des ultrasons permettant d’augmenter l’internalisation de molécules ou de gènes dans les cellules. Dans cette thèse, la faisabilité et l'efficacité de la combinaison d’une chimiothérapie liposomale ciblée par la cavitation ultrasonore a été évaluée dans des modèles murins orthotopiques d’AP. Un système de délivrance d’ultrasons a été adapté afin d’appliquer une cavitation inertielle focalisée sur des xénogreffes d’AP créées après l'injection de doxorubicine liposomale (L-DOX) selon une étude pharmacocinétique préliminaire réalisée dans un modèle murin. La L-DOX, conçue à base de phospholipides non saturés de dioleoylphosphatidyléthanolamine, connue pour être stable dans la circulation sanguine, a été choisie afin de maximiser son accumulation et le relargage du principe actif lors de la délivrance des ultrasons. Nous montrons que l’association de la L-DOX à la cavitation inertielle permet de réduire in vivo le volume tumoral dans un modèle orthotopique d’AP chez la souris nude. La cavitation inertielle peut donc augmenter l'effet antitumoral des liposomes porteurs de chimiothérapie avec un effet mécanique minimal sur le tissu environnant la tumeur.Des études récentes suggèrent que Nrf2 est une cible de choix pour vaincre la chimiorésistance de l’AP. Des méthodes in vitro et in vivo ont été utilisées afin d’examiner l'effet du brusatol associé à des agents chimiothérapeutiques de référence sur la mort cellulaire et son impact sur le stress oxydant. Nous montrons que l’inhibition de la voie Nrf2 par le brusatol, un composé naturel issu de Fructus Bruceae, potentialise les effets de la chimiothérapie et permet l’inhibition de la croissance tumorale in vitro sur des lignées cellulaires d’AP cultivées en 2D et 3D. Cette inhibition s’accompagne d’une modulation du stress oxydant dont témoignent l’augmentation des espèces réactives de l’oxygène (ROS) et la diminution du glutathion (GSH). In vivo, la combinaison du brusatol et de l'oxaliplatine a réduit le volume tumoral dans deux modèles murins de xénogreffe d’AP. Ces résultats suggèrent l'efficacité du brusatol pour lutter contre la chimiorésistance et renforce l’hypothèse d’un rôle clinique potentiel de l’inhibition de Nrf2 comme adjuvant à la chimiothérapie dans l’AP. Un travail clinique a également été mené en parallèle sur une modalité de traitement physique innovante, la radiofréquence endobiliaire, dans la prise en charge endoscopique de l’ampullome vatérien, tumeur rare à la croisée entre le tube digestif et le système biliopancréatique. Les résultats de cette étude prospective multicentrique seront également présentés dans cette thèse.Pancreatic ductal adenocarcinoma (PDAC) has increased in incidence over the past decade, leading it to be the fourth lethal cause of cancer in the world with a very poor prognosis, since less than 5% of patients are alive at 5 years. Many advances in the understanding of pancreatic tumorigenesis, notably on the genetic, immune and cellular stroma interactions of the tumor, have led to the development of new treatment strategies in the last decade. However, despite very encouraging pre-clinical results, none of these strategies has yet led to the emergence of a truly effective treatment in comparison with standard chemotherapy. This thesis focused on two innovative therapeutic modalities in the treatment of PDAC at a preclinical stage by studying in vitro (2D and 3D cell cultures) and in vivo (ectopic, orthotopic xenografts) the effects on the tumor growth of an inhibitor of the Nrf2 pathway (involved in oxidative stress), on the first hand, and of a physical element, ultrasound cavitation associated with liposomal chemotherapy, on the second hand. Ultrasound cavitation is a mechanical effect of ultrasound to increase the uptake of molecules or genes in cells. The feasibility and effectiveness of the combination of liposomal chemotherapy targeted by ultrasonic cavitation was evaluated in murin orthotopic models of PDAC. An ultrasound delivery system has been adapted to apply focused inertial cavitation to PDAC xenografts created after the injection of liposomal doxorubicin (L-DOX) according to a preliminary pharmacokinetic study carried out in the murine model. L-DOX, designed on unsaturated phospholipids of dioleoylphosphatidylethanolamine, was known to be stable in the bloodstream and to maximize its accumulation and release of the active drug during ultrasound delivery. This thesis shows that this therapeutic combination (L DOX and inertial cavitation) makes it possible to reduce the tumor volume in vivo in a nude mouse orthotopic model of PDAC. Inertial cavitation may be generated to increase the therapeutic effect of chemotherapybearing liposomes accumulated in the tumor with minimal mechanical effect on the surrounding tissue. Recent studies strongly suggest that Nrf2 is an ideal target against chemoresistance of PDAC. In vitro and in vivo methods were combined to examine the effect of brusatol associated with chemotherapeutic agents on cell death in addition to its impact on oxidative stress (reactive oxygen species and gluthation levels). This thesis demonstrates that the inhibition of the Nrf2 pathway via brusatol, a natural compound derived from Fructus Bruceae, potentiates the effects of chemotherapy and allows the inhibition of tumor growth in vitro on PDAC cell lines. This inhibition is accompanied by a modulation of oxidative stress by brusatol, with increasing ROS and decreasing GSH. In vivo, the combination of brusatol and oxaliplatin reduced tumor volume in two mouse models of PDAC xenograft. These results suggest the efficacy of using brusatol to combat chemoresistance and reinforce the idea that brusatol could be developed as an adjuvant to chemotherapy in PA. Clinical work was also carried out in parallel on an innovative physical treatment modality, endobiliary radiofrequency, in the management of adenoma of the ampoule of Vater, a rare tumor located between the digestive and the bilio-pancreatic systems. The results of this work will also be presented in this thesis

Evolution à long terme des patients atteints de maladie de Crohn répondeurs à l azathioprine

PARIS7-Xavier Bichat (751182101) / SudocSudocFranceF

Endoscopic diagnosis and management of esophagogastric variceal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

Main Recommendations 1 ESGE recommends that patients with compensated advanced chronic liver disease (ACLD; due to viruses, alcohol, and/or nonobese [BMI 10 mmHg and/or liver stiffness by transient elastography > 25 kPa) should receive, if no contraindications, nonselective beta blocker (NSBB) therapy (preferably carvedilol) to prevent the development of variceal bleeding. Strong recommendation, moderate quality evidence. 2 ESGE recommends that in those patients unable to receive NSBB therapy with a screening upper gastrointestinal (GI) endoscopy that demonstrates high risk esophageal varices, endoscopic band ligation (EBL) is the endoscopic prophylactic treatment of choice. EBL should be repeated every 2-4 weeks until variceal eradication is achieved. Thereafter, surveillance EGD should be performed every 3-6 months in the first year following eradication. Strong recommendation, moderate quality evidence. 3 ESGE recommends, in hemodynamically stable patients with acute upper GI hemorrhage (UGIH) and no history of cardiovascular disease, a restrictive red blood cell (RBC) transfusion strategy, with a hemoglobin threshold of 7 with active EVH at the time of endoscopy despite vasoactive agents, or HVPG > 20 mmHg), pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) within 72 hours (preferably within 24 hours) must be considered. Strong recommendation, high quality evidence.11 ESGE recommends that, for persistent esophageal variceal bleeding despite vasoactive pharmacological and endoscopic hemostasis therapy, urgent rescue TIPS should be considered (where available). Strong recommendation, moderate quality evidence. 12 ESGE recommends endoscopic cyanoacrylate injection for acute gastric (cardiofundal) variceal (GOV2, IGV1) hemorrhage. Strong recommendation, high quality evidence. 13 ESGE recommends endoscopic cyanoacrylate injection or EBL in patients with GOV1-specific bleeding. Strong recommendations, moderate quality evidence. 14 ESGE suggests urgent rescue TIPS or balloon-occluded retrograde transvenous obliteration (BRTO) for gastric variceal bleeding when there is a failure of endoscopic hemostasis or early recurrent bleeding. Weak recommendation, low quality evidence. 15 ESGE recommends that patients who have undergone EBL for acute EVH should be scheduled for follow-up EBLs at 1- to 4-weekly intervals to eradicate esophageal varices (secondary prophylaxis). Strong recommendation, moderate quality evidence. 16 ESGE recommends the use of NSBBs (propranolol or carvedilol) in combination with endoscopic therapy for secondary prophylaxis in EVH in patients with ACLD. Strong recommendation, high quality evidence

Diagnosis and management of acute lower gastrointestinal bleeding: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

Main Recommendations 1 ESGE recommends that the initial assessment of patients presenting with acute lower gastrointestinal bleeding should include: a history of co-morbidities and medications that promote bleeding; hemodynamic parameters; physical examination (including digital rectal examination); and laboratory markers. A risk score can be used to aid, but should not replace, clinician judgment. Strong recommendation, low quality evidence. 2 ESGE recommends that, in patients presenting with a self-limited bleed and no adverse clinical features, an Oakland score of ≤?8 points can be used to guide the clinician decision to discharge the patient for outpatient investigation. Strong recommendation, moderate quality evidence. 3 ESGE recommends, in hemodynamically stable patients with acute lower gastrointestinal bleeding and no history of cardiovascular disease, a restrictive red blood cell transfusion strategy, with a hemoglobin threshold of ≤?7?g/dL prompting red blood cell transfusion. A post-transfusion target hemoglobin concentration of 7-9?g/dL is desirable. Strong recommendation, low quality evidence. 4 ESGE recommends, in hemodynamically stable patients with acute lower gastrointestinal bleeding and a history of acute or chronic cardiovascular disease, a more liberal red blood cell transfusion strategy, with a hemoglobin threshold of ≤?8?g/dL prompting red blood cell transfusion. A post-transfusion target hemoglobin concentration of ≥?10?g/dL is desirable. Strong recommendation, low quality evidence. 5 ESGE recommends that, in patients with major acute lower gastrointestinal bleeding, colonoscopy should be performed sometime during their hospital stay because there is no high quality evidence that early colonoscopy influences patient outcomes. Strong recommendation, low quality of evidence. 6 ESGE recommends that patients with hemodynamic instability and suspected ongoing bleeding undergo computed tomography angiography before endoscopic or radiologic treatment to locate the site of bleeding. Strong recommendation, low quality evidence. 7 ESGE recommends withholding vitamin K antagonists in patients with major lower gastrointestinal bleeding and correcting their coagulopathy according to the severity of bleeding and their thrombotic risk. In patients with hemodynamic instability, we recommend administering intravenous vitamin K and four-factor prothrombin complex concentrate (PCC), or fresh frozen plasma if PCC is not available. Strong recommendation, low quality evidence. 8 ESGE recommends temporarily withholding direct oral anticoagulants at presentation in patients with major lower gastrointestinal bleeding. Strong recommendation, low quality evidence. 9 ESGE does not recommend withholding aspirin in patients taking low dose aspirin for secondary cardiovascular prevention. If withheld, low dose aspirin should be resumed, preferably within 5 days or even earlier if hemostasis is achieved or there is no further evidence of bleeding. Strong recommendation, moderate quality evidence. 10 ESGE does not recommend routinely discontinuing dual antiplatelet therapy (low dose aspirin and a P2Y12 receptor antagonist) before cardiology consultation. Continuation of the aspirin is recommended, whereas the P2Y12 receptor antagonist can be continued or temporarily interrupted according to the severity of bleeding and the ischemic risk. If interrupted, the P2Y12 receptor antagonist should be restarted within 5 days, if still indicated. Strong recommendation, low quality evidence.SCOPUS: ar.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

Erratum: Diagnosis and management of acute lower gastrointestinal bleeding: European Society of Gastrointestinal Endoscopy (ESGE) Guideline (Journal of Physical Chemistry (2021) 53 DOI: 10.1055/a-1496-8969)

In the above-mentioned article, the name of Enrique Rodriguez de Santiago has been corrected. This was corrected in the online version on June 17, 2021.SCOPUS: er.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

Endoscopic resection of early esophageal tumors in patients with cirrhosis or portal hypertension: a multicenter observational study

Background: Liver cirrhosis and esophageal cancer share several risk factors, such as alcohol intake and excess weight. Endoscopic resection is the gold standard treatment for superficial tumors. Portal hypertension and coagulopathy may increase the bleeding risk in these patients. This study aimed to assess the safety and efficacy of endoscopic resection for early esophageal neoplasia in patients with cirrhosis or portal hypertension. Methods: This retrospective multicenter international study included consecutive patients with cirrhosis or portal hypertension who underwent endoscopic resection in the esophagus from January 2005 to March 2021. Results: 134 lesions in 112 patients were treated, including by endoscopic submucosal dissection in 101 cases (75 %). Most lesions (128/134, 96 %) were in patients with liver cirrhosis, with esophageal varices in 71 procedures. To prevent bleeding, 7 patients received a transjugular intrahepatic portosystemic shunt, 8 underwent endoscopic band ligation (EBL) before resection, 15 received vasoactive drugs, 8 received platelet transfusion, and 9 underwent EBL during the resection procedure. Rates of complete macroscopic resection, en bloc resection, and curative resection were 92 %, 86 %, and 63 %, respectively. Adverse events included 3 perforations, 8 delayed bleedings, 8 sepsis, 6 cirrhosis decompensations within 30 days, and 22 esophageal strictures; none required surgery. In univariate analysis, cap-assisted endoscopic mucosal resection was associated with delayed bleeding (P = 0.01). Conclusions: In patients with liver cirrhosis or portal hypertension, endoscopic resection of early esophageal neoplasia appeared to be effective and should be considered in expert centers with choice of resection technique, following European Society of Gastrointestinal Endoscopy guidelines to avoid undertreatment