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e14015 Background: D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin comprising an EGFR wild-type and mutant-specific (EGFRvIII) monoclonal antibody (Ab) fragment and a genetically engineered form of the Pseudomonas exotoxin. When injected directly into the tumor by convection enhanced delivery (CED), immunotoxins induce both direct tumor killing and secondary immune responses by activation of CD4+ and CD8+ T-cells. Tumor-associated macrophages (TAMs) are the most prominent glioma-infiltrating immune cells and constitute up to 40% of the tumor mass. Upon binding of D2C7-IT to EGFR and cellular internalization, the Pseudomonas exotoxin moiety of the D2C7-IT kills residual GBM cells, upregulates proinflammatory CD40, and induces pattern recognition receptor pathway transcriptome expression. This potentially creates a proinflammatory glioma microenvironment where TAM activation may be further stimulated by sequential CED of 2141-V11, an Fc engineered anti-human CD40 agonist antibody developed at Rockefeller University. We are conducting a first in human trial of the combination of D2C7-IT + 2141-V11 administered via CED in recurrent MG patients. Methods: Eligibility includes adult patients with recurrence of a solitary supratentorial WHO grade 3 or 4 MG; ≥ 4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS ≥ 70%. Cohorts of 3 patients are treated with increasing levels of 2141-V11 to determine the maximum tolerated dose (MTD) of the compound administered intratumorally in conjunction with D2C7-IT. Dose escalation and de-escalation are managed using a modified Bayesian optimal interval (BOIN) design to identify the MTD. Intratumoral administration of D2C7-IT via CED (4612 ng/mL over 72 hours) is followed by a 7-hour infusion of 2141-V11, both infused at 0.5 mL/hr. 2141-V11 is dose-escalated to determine the MTD when combined with D2C7-IT. Four dose levels (DL) are planned: #1: 0.70 mg; #2: 2.0 mg; #3: 7.0 mg; #4: 21.0 mg. Results: As of February 7, 2022, three patients were treated at DL1 and DL2, and two patients at DL3. No DLTs have been observed, and all eight patients remain alive and in observation on study after 7.0, 6.5, 6.0, 4.4, 2.8, 2.4, 0.9 and 0.5 months. Early signs of tumor response have been observed, with one patient at DL1 and 2 patients at DL2 without radiographic evidence of active tumor. Grade 2 or higher AEs due to D2C7-IT and/or 2141-V11 include: headache (grade 3, n = 1; grade 2, n = 2); paresthesia (grade 3, n = 1; grade 2, n = 1); dysphasia (grade 3, n = 1); pyramidal tract disorder (grade 3, n = 1; grade 2, n = 1); and depressed level of consciousness (grade 2, n = 1). Enrollment is ongoing. Conclusions: Intratumoral administration of D2C7-IT + 2141-V11 via CED is safe, and encouraging efficacy results have been observed. Clinical trial information: NCT04547777.

TPS10062 Background: RAF gene fusions ( BRAF and RAF1) and BRAF V600E mutations are oncogenic drivers found on a mutually exclusive basis in most pediatric low-grade gliomas (LGGs). In addition, RAF fusions ( BRAF and RAF1) have also been identified in other pediatric solid tumors. Tovorafenib (DAY101) is an investigational, oral, highly selective, CNS-penetrant, small molecule, type II pan-RAF inhibitor. In contrast to type I BRAF inhibitors, tovorafenib does not induce RAS-dependent paradoxical activation of the MAPK pathway. In the phase 1 PNOC014 study in pediatric patients with recurrent/progressive LGG, tovorafenib was well tolerated and 7/8 patients with tumor harboring RAF fusions had meaningful clinical benefit. Recently, a child with a novel SNX8-BRAF fusion spindle cell sarcoma demonstrated a rapid and deep response when treated with tovorafenib. Methods: FIREFLY-1 (NCT04775485) is an open-label, multicenter, phase 2 study evaluating the safety and efficacy of tovorafenib monotherapy in pediatric patients with RAF-altered recurrent or progressive LGG or advanced solid tumors. The initial design included only patients with LGG (arm 1). Two new arms have now been added; arm 2 will allow tovorafenib treatment for patients with LGG harboring an activating RAF alteration after completion of enrollment to arm 1 and prior to tovorafenib regulatory approval; arm 3 will enroll patients with advanced solid tumors harboring an activating RAF fusion. Eligible patients are 6 months to 25 years of age, who have received ≥1 prior line of systemic therapy with documented radiographic progression, have evaluable and/or measurable disease by appropriate criteria, a Karnofsky or Lansky performance score of at least 50, and adequate organ function. Patients are excluded if their tumor has other driver mutations, they have neurofibromatosis type 1, central serous retinopathy, retinal vein occlusion, clinically significant active cardiovascular disease, or are currently being treated with a strong CYP2C8 inhibitor or inducer other than those allowed per protocol. Approximately 140 patients in total will be enrolled including 60 in arm 1, 60 in arm 2 and 20 in arm 3. Tovorafenib will be administered at 420 mg/m2 (not to exceed 600 mg) weekly (days 1, 8, 15 and 22) for 26, 28-day cycles (in the absence of disease progression or unacceptable toxicity). They may then continue tovorafenib or enter a drug holiday period. The primary endpoint is overall response rate, as defined by the RANO criteria (arm 1) or RECIST v1.1 (arm 3) and as determined by an independent radiology review committee. Secondary endpoints (arms 1 and 3) include safety and tolerability, pharmacokinetics, duration of response, time to response and progression-free survival. Tovorafenib is available in tablet or liquid suspension formulations. Clinical trial information: NCT04775485.

Les tumeurs sous-muqueuses (TSM) de l’estomac sont des lesions frequentes de decouverte souvent fortuite. La plupart des TSM sont asymptomatiques et d’evolution benigne, telles que les lipomes, les leiomyomes, les schwannomes, les pancreas aberrants. Certaines TSM gastriques ont un potentiel de malignite, notamment celles developpees a partir de la musculeuse comme les gastrointestinal stromal tumor et les tumeurs neuroendocrines. Le diagnostic de certitude de ces lesions peut etre difficile, meme apres la realisation d’une echoendoscopique et/ou de biopsies. La resection chirurgicale des tumeurs de plus de 2 cm est justifiee car elle permet une analyse histologique et un traitement carcinologique. Concernant les TSM gastriques de petite taille (

IF 7.191 (2017); International audience; BACKGROUND:Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI.PATIENTS AND METHODS:A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI

The sequential FOLFOX7–FOLFIRI combination is not superior to FOLFOX4 in colorectal cancer patients with resectable metastases. Patients with synchronous metastases preferably received perioperative chemotherapy, while patients with metachronous metastases were given postoperative chemotherapy in preference. We observed the highest long-term survival rates ever reported in this setting. Background Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative. Patients and methods In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m2) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m2) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m2). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS). Results A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7–FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7–FOLFIRI. Conclusions FOLFOX7–FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing. Clinical trials number NCT00268398.

Los tumores benignos del esofago son tumores poco frecuentes, generalmente de origen subepitelial. Alrededor de dos tercios de los tumores benignos del esofago son leiomiomas. El resto de tumores son de naturaleza diversa, quistica o tisular. A menudo, los tumores benignos del esofago se descubren de forma casual en el adulto joven; en determinados casos, pueden ser voluminosos y/o sintomaticos. La ecoendoscopia tiene un papel fundamental en la exploracion de los tumores benignos del esofago de aspecto submucoso y suele permitir realizar un diagnostico de presuncion y orientar el tratamiento, el cual es muy variable: puede ir desde la abstencion terapeutica a la extirpacion endoscopica o quirurgica.

Les tumeurs stromales gastro-intestinales (GIST) representent une entite nosologique largement meconnue jusqu’en 1998, date a laquelle le role majeur de KIT a ete mis en evidence. Tres rapidement apres, une therapie ciblee, l’imatinib a permis de completement modifier le pronostic des formes avancees. Environ 25–30% des GIST sont localisees dans le grele. Le diagnostic de GIST repose sur l’examen histologique avec mise en evidence de l’expression de KIT. Des mutations de KIT ou PDGFRA sont presentes dans 85% des GIST. Elles ont une valeur theranostique. La chirurgie d’exerese R0 sans effraction de la tumeur est le seul traitement potentiellement curatif des formes localisees. Un traitement adjuvant par imatinib est indique en cas de risque significatif de rechute metastatique. D’autres inhibiteurs de tyrosine-kinase ont deja montre leur efficacite en cas d’echappement a l’imatinib dans les GIST metastatiques.

Introduction La resection muqueuse endoscopique (EMR) est un traitement curatif des cancers epidermoides (SCC) superficiels de l’œsophage. L’objectif de cette etude etait d’evaluer l’evolution a long terme et la survie des patients traites par EMR.

Le principal motif d’exploration morphologique de l’intestin grele est le saignement digestif inexplique (SDI) exteriorise ou non. La principale cause de saignement digestif inexplique est la malformation arterioveineuse ou angiodysplasie. La videocapsule (VCE) ingeree est l’examen de premiere intention de l’intestin grele en cas de SDI. Elle doit etre realisee le plus precocement possible en cas de SDI exteriorise (apres endoscopies hautes et basses), et presente la meilleure rentabilite diagnostique par rapport aux explorations radiologiques et endoscopiques alternes. L’enteroscopie a double ballon et les techniques derivees (simple ballon et enteroscopie spiralee) permettent la confirmation histologique et le traitement endoscopique (coagulation par plasma argon, polypectomie) des lesions de l’intestin grele detectees par VCE ou par un examen radiologique. Le scanner avec enteroclyse (entero-TDM) est l’examen radiologique de reference pour le bilan lesionnel des enteropathies (maladie de Crohn ou maladie coeliaque compliquee) ou le diagnostic des tumeurs de l’intestin grele et le suivi des polyposes. L’IRM de l’intestin grele, non irradiante, pourrait supplanter le scanner dans un futur proche.

International audience; BACKGROUND:Metastatic colorectal cancer (mCRC) frequently occurs in elderly patients. However, data from a geriatric tailored randomized trial about tolerance to and the efficacy of doublet chemotherapy (CT) with irinotecan in the elderly are lacking. The benefit of first-line CT intensification remains an issue in elderly patients.PATIENTS AND METHODS:Elderly patients (75+) with previously untreated mCRC were randomly assigned in a 2 × 2 factorial design (four arms) to receive 5-FU (5-fluorouracil)-based CT, either alone (FU: LV5FU2 or simplified LV5FU2) or in combination with irinotecan [IRI: LV5FU2-irinotecan or simplified LV5FU2-irinotecan (FOLFIRI)]. The CLASSIC arm was defined as LV5FU2 or LV5FU2-irinotecan and the SIMPLIFIED arm as simplified LV5FU2 or FOLFIRI. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), safety and objective response rate (ORR).RESULTS:From June 2003 to May 2010, 71 patients were randomly assigned to LV5FU2, 71 to simplified LV5FU2, 70 to LV5FU2-irinotecan and 70 to FOLFIRI. The median age was 80 years (range 75-92 years). No significant difference was observed for the median PFS: FU 5.2 months versus IRI 7.3 months, hazard ratio (HR) = 0.84 (0.66-1.07), P = 0.15 and CLASSIC 6.5 months versus SIMPLIFIED 6.0 months, HR = 0.85 (0.67-1.09), P = 0.19. The ORR was superior in IRI (P = 0.0003): FU 21.1% versus IRI 41.7% and in CLASSIC (P = 0.04): CLASSIC 37.1% versus SIMPLIFIED 25.6%. Median OS was 14.2 months in FU versus 13.3 months in IRI, HR = 0.96 (0.75-1.24) and 15.2 months in CLASSIC versus 11.4 months in SIMPLIFIED, HR = 0.71 (0.55-0.92). More patients presented grade 3-4 toxicities in IRI (52.2% versus 76.3%).CONCLUSION:In this elderly population, adding irinotecan to an infusional 5-FU-based CT did not significantly increase either PFS or OS. Classic LV5FU2 was associated with an improved OS compared with simplified LV5FU2.CLINICALTRIALSGOV:NCT00303771.

Objective: To evaluate the placental expression of transforming growth factor-β3 (TGF-β3) in patients with HELLP syndrome and pre-eclampsia compared to controls, and its correlation to Doppler velocimetry analysis of the utero-placental blood flow. Study Design: Real-time PCR analysis was performed, after cesarean section, in placental samples from 10 women affected by HELLP syndrome, 10 women with pre-eclampsia and 10 controls. Pulsatility indices on Doppler waveform analysis from uterine and umbilical arteries were measured. Results: The mean TGF-β3 expression was significantly higher in patients with HELLP syndrome compared with the control group (p < 0.001), and no difference was observed in the pre-eclampsia group. TGF-β3 expression correlated positively with umbilical PI (p < 0.001). Conclusions: TGF-β3 may play a key role as regulator of a variety of cellular events occurring during HELLP syndrome, high local expression of this growth factor may be responsible for remodeling of the placental structure, which results in the dysfunction of maternal-fetal circulation.

Background: The purpose of the study was to prospectively evaluate the efficacy and tolerability of the FOLFIRI.3 regimen in patients with unresectable pancreatic adenocarcinoma. Patients and methods: Chemotherapy-naive patients with histologically proven advanced pancreatic adenocarcinoma were treated with the FOLFIRI.3 regimen, consisting of irinotecan 90 mg/m2 as a 60-min infusion on day 1, leucovorin 400 mg/m2 as a 2-h infusion on day 1, followed by 5-fluorouracil (5-FU) 2000 mg/m2 as a 46-h infusion and irinotecan 90 mg/m2, repeated on day 3, at the end of the 5-FU infusion, every 2 weeks. Results: Forty patients were enrolled, of whom 29 (73%) had metastatic disease. A total of 441 cycles were delivered (1–53). Grade 3–4 neutropenia occurred in 35% of the patients, accompanied by fever in two cases. Other relevant grade 3–4 toxic effects were nausea-vomiting (27%) and diarrhea (25%). Grade 2 alopecia occurred in 48% of the patients. There were no treatment-related deaths. The confirmed response rate was 37.5%. Stable disease was observed in 27.5% of the patients. The median progression-free and overall survivals were 5.6 months and 12.1 months, respectively. The 1-year survival rate was 51%. Conclusion: The FOLFIRI.3 regimen seems to be active on advanced pancreatic cancer and to have a manageable toxicity profile. The lack of cross-resistance between FOLFIRI.3 and gemcitabine-based regimens allows efficient second-line therapies.

Dans le cadre d'un doctorat, nous avons effectue une recherche comparative portant sur differentes caracteristiques psychologiques et psychodynamiques pouvant influencer l'adaptation a une maladie chronique ou cancereuse. L'idee generale est de mieux predire quels patients ont plus de risques de presenter des difficultes d'adaptation et devraient beneficier au moins d'un soutien psychologique. Parmi les axes etudies, nous avons cherche a evaluer le role joue, d'une part, par le type de maladie, sa severite « reelle », son traitement specifique et, d'autre part, par les representations et/ou croyances subjectives que les sujets concernes en ont, enfin, par la personnalite sous-jacente. Un autre objectif de ce travail est de montrer la complementarite d'une approche psychanalytique et d'une approche experimentale a partir d'autoquestionnaires standardises. Nous presentons ici certains resultats issus de cette deuxieme approche.

Les tumeurs stromales digestives sont les tumeurs mesenchymateuses les plus frequentes du tube digestif, le plus souvent localisees a l’estomac (70%). Elles sont caracterisees par une expression de la proteine c-kit par les cellules tumorales. Leur potentiel de malignite est souvent difficile a determiner. L’echo-endoscopie reste le meilleur examen pour l’exploration des tumeurs sous muqueuses gastriques. L’aspect echo-endoscopique des tumeurs stromales digestives est souvent tres evocateur. Certaines caracteristiques echo-endoscopiques sont associees a un risque accru de malignite. Grâce a des ameliorations techniques, la ponction sous echo-endoscopie a desormais une rentabilite elevee pour le diagnostic de tumeur stromale gastrique. Elle doit etre discutee dans les cas ou il existe un doute diagnostique avec une autre lesion sous-muqueuse qui pourrait elle conduire a une abstention therapeutique. Cette ponction ne permet pas en revanche de predire avec precision le potentiel de malignite. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the GI tract. Most tumors (70%) occur in the stomach. They are characterized by the expression of the receptor tyrosine kinase KIT. These tumors have a wide clinical spectrum from benign to malignant. A diagnosis of gastric GIST can be made with confidence when typical endoscopic ultrasonographic (EUS) features are observed. Several EUS features are suggestive of increased risk of malignancy. EUS-guided fine needle aspiration is nowadays reliable for the diagnosis of GIST, but cytomorphology cannot be used to assess malignant potential. EUS-guided fine needle aspiration must be considered in clinical management, if the result may have an impact on therapeutic strategy.

The aim of this study was to determine the diagnostic value of push enteroscopy in patients with chronic diarrhea and malabsorption of unclear origin.From January, 1997, to September, 1999, 16 consecutive patients with chronic diarrhea and biological signs of intestinal malabsorption but no evidence of celiac disease were explored by push enteroscopy. Previous duodenal histological findings had been normal in seven patients and abnormal but inconclusive in nine patients. Endoscopic and histological findings in the duodenum and in the jejunum were compared.Push enteroscopy with jejunal biopsy yielded a diagnosis in comparison with duodenal biopsy in two of 16 (12%) patients, respectively, in two of the nine (22%) patients with abnormal but inconclusive findings on duodenal biopsy, and none of the seven patients with normal duodenal histology. In the two patients in whom jejunal biopsy had diagnostic value but duodenal biopsy did not, the final diagnoses were invasive intestinal lymphoma and microsporidiosis.Push enteroscopy had diagnostic value in only 12% of patients with malabsorption of unclear origin, all of whom had had abnormal but inconclusive duodenal histological findings. Push enteroscopy with jejunal biopsy appears to have limited diagnostic value in patients with chronic diarrhea and malabsorption, especially when duodenal biopsies are histologically normal.

Background—Push-type enteroscopy, a recent method for investigating the small intestine, is currently undergoing assessment. Its diagnostic yield varies in the studies reported to date.Aim—To assess the diagnostic value of push-type enteroscopy according to indication.Patients and methods—From January 1994 to September 1995, 152 consecutive patients (mean age 34 years) underwent push-type enteroscopy (jejunoscopy, n=93; retrograde ileoscopy, n=17; and double way enteroscopy, n=42). The indications were: unexplained iron deficiency anaemia or macroscopic gastrointestinal bleeding (n=76), radiological abnormalities of the small intestine (n=23), chronic diarrhoea and/or malabsorption syndrome (n=18), abdominal pain (n=12), and miscellaneous (n=23). All patients had undergone previous negative aetiological investigations.Results—The jejunum and ileum were explored through 120 cm (30–160 cm) and 60 cm (20–120 cm). Digestive bleeding: lesions of the small bowel were found in 6% of the patients with isolated iron deficiency anaemia and 20% of patients with patent digestive haemorrhage. Radiological abnormalities of the small intestine: push-type enteroscopy provided a diagnosis or modified the interpretation of radiological findings in 18/23 cases (78%). Chronic diarrhoea and/or malabsorption: push-type enteroscopy yielded explanatory findings in four cases (22%). Abdominal pain: push-type enteroscopy provided no diagnosis.Conclusion—In this series, push-type enteroscopy was of particular value in investigating patients with radiological abnormalities of the small intestine. It was of some value in the exploration of patent digestive haemorrhage or chronic diarrhoea, but not of abdominal pain. Its value was limited in the exploration of iron deficiency anaemia.

Background and study aims Granular cell tumors of the esophagus are rare tumors. A definite diagnosis is achieved by endoscopic biopsies in only 50% of cases. Endoscopic ultrasonography (EUS) is the best procedure in the evaluation of upper gastrointestinal tract submucosal tumors. The aim of this study was to describe the endosonographic findings of esophageal granular cell tumors. Methods From January 1989 to March 1994, 15 patients with 21 granular cell tumors which had negative biopsies were examined by EUS (Olympus GF UM3 or GF UM20,7,5 and 12 MHz). In five cases, the tumor was also studied with a 20 MHz Olympus miniprobe. The final histological diagnoses were obtained by subsequent endoscopic snare resection in 20 cases and surgically in one case. Results The endosonographic features (with the GF UM3 or GF UM20) of esophageal granular cell tumors were: a) a tumor size of less than 2 cm in 95% of cases; b) an hypoechoic solid pattern in 100% of cases; c) a tumor arising in the inner layers in 95% (second echo-poor layer n=15; third echo-rich layer n=5). In one case, the endosonographic finding was transmural malignant infiltration of the esophageal wall (histologically confirmed). Conclusion When a granular cell tumor of the esophagus is suspected, EUS can show the inner layer location of the tumor and thus contribute to planning the endoscopic resection or follow up. When the tumor also invades the outer layers, EUS can contribute to planning the surgical resection.

We report transplantation outcomes of 258 children with Hurler syndrome (HS) after a myeloablative conditioning regimen from 1995 to 2007. Median age at transplant was 16.7 months and median follow-up was 57 months. The cumulative incidence of neutrophil recovery at day 60 was 91%, acute graft-versus-host disease (GVHD) (grade II-IV) at day 100 was 25%, and chronic GVHD and 5 years was 16%. Overall survival and event-free survival (EFS) at 5 years were 74% and 63%, respectively. EFS after HLA-matched sibling donor (MSD) and 6/6 matched unrelated cord blood (CB) donor were similar at 81%, 66% after 10/10 HLA-matched unrelated donor (UD), and 68% after 5/6 matched CB donor. EFS was lower after transplantation in 4/6 matched unrelated CB (UCB) (57%; P = .031) and HLA-mismatched UD (41%; P = .007). Full-donor chimerism (P = .039) and normal enzyme levels (P = .007) were higher after CB transplantation (92% and 98%, respectively) compared with the other grafts sources (69% and 59%, respectively). In conclusion, results of allogeneic transplantation for HS are encouraging, with similar EFS rates after MSD, 6/6 matched UCB, 5/6 UCB, and 10/10 matched UD. The use of mismatched UD and 4/6 matched UCB was associated with lower EFS.

Les HDB sont moins frequentes et generalement moins graves que les hemorragies digestives hautes. Elles sont plus souvent d’origine colique, et s’arretent spontanement le plus souvent. Devant une HDB abondante et/ou persistante, il faut realiser en urgence une coloscopie sous anesthesie apres preparation colique. Cette approche permet d’une part d’avoir une rentabilite diagnostique optimale, d’autre part d’augmenter la frequence de realisation d’un traitement endoscopique adapte a la cause du saignement.

Les tumeurs stromales gastro-intestinales (GIST) sont les sarcomes les plus frequents, derivant des cellules interstitielles de Cajal ou de l’un de leurs precurseurs [1–3]. Une mutation sur l’exon 11 du gene KIT, codant pour le domaine cytoplasmique juxtamembranaire de la proteine, et ayant une fonction regulatrice, a ete decrite dans les GIST en 1998. Une mutation oncogenique des genes KIT ou platelet derived growth factor receptor alpha (PDGFRA) codant pour des recepteurs de type tyrosine kinase est retrouvee dans environ 85 % des GIST de l’adulte [1–3]. II s’agit d’un facteur pathogenique essentiel. Les mutations observees dans les GIST sont dites « gain de fonction », car elles induisent une activation constitutive des proteines KIT ou PDGFRA.

B. Landi Gastrointestinal stromal tumors (GISTs) are the most frequent intramural mesenchymal tumors of the GI tract, mainly developed in the stomach (65% of cases). Endoscopy is the main diagnostic tool for tumors of moderate diameter (5cm). Endoscopic ultrasonography (EUS) is the best procedure to differenciate GISTs from other submucosal tumors. Fine-needle aspiration biopsies (FNABs) allow to obtain an histological diagnosis if necessary. Surgery remain the gold standard of treatment for localized GISTs, whereas endoscopic resection is not recommended for these tumors.

Le terme de tumeur sous-muqueuse (TSM) regroupe des lesions du tube digestif de nature variee (tableau I). Les lesions sousmuqueuses peuvent se developper a partir des differentes couches du tube digestif, de la partie profonde de la muqueuse a la sereuse, et peuvent etre d’origine tumorale ou non. Le terme de lesions sous-epitheliales serait donc plus approprie que celui de TSM, mais ce dernier reste employe en pratique courante, en particulier en endoscopie. Il est essentiel de differencier ces lesions, car certaines peuvent avoir un potentiel de malignite.

A randomized clinical trial was conducted to determine whether colonoscopy is useful in deciding how long to maintain steroid treatment in attacks of Crohn's disease involving the colon. One hundred forty-seven patients with acute attacks of colonic or ileocolonic Crohn's disease were treated by oral prednisolone, 1 mg.kg-1.day-1; 136 achieved clinical remission, but 96 of them still had active endoscopic lesions and were randomized either to immediate start of steroid tapering (group A; n = 46) or to continued prednisolone treatment at the same dosage for 5 more weeks before steroid tapering was begun (group B; n = 50). In the remaining 40 patients (already in endoscopic remission, group C), steroid tapering was begun immediately. After prednisolone discontinuation, patients were followed up for 18 months or until clinical relapse. Prolongation of prednisolone therapy significantly improved the endoscopic scores in group B (30% of endoscopic remission). The frequency of successful steroid weaning was almost identical in groups A and B (82% and 80%, respectively), as was the actuarially calculated relapse clinical rate after steroid withdrawal (P = 0.22). No factor predictive of clinical relapse could be found. The clinical course of patients in group C was similar to that of those in groups A and B. Overall, only 22% of the 147 patients were still in clinical remission and off steroids 18 months after prednisolone discontinuation, outlining the need for maintenance therapy. In conclusion, for patients who have achieved clinical remission, adjustment of steroid treatment duration on the basis of endoscopy results is of no benefit, and the endoscopic aspect has no prognostic value; thus, it appears unnecessary to repeat colonoscopy in such patients before steroid tapering is begun.

Clinical recommendations for diagnosis, treatment and follow-up of GIST have been established. However, management of tumors limited in size, more often diagnosed by gastroenterologists, remains controversial. The aim of this work was in a first part to analyze the literature on GIST less than 5cm in size and in a second part to elaborate propositions for the clinical management based on an expert panel opinion.

Gastrointestinal stromal tumors (GISTs) are the most frequent intramural mesenchymal tumors of the GI tract, mainly developed in the stomach (65% of cases). Endoscopy is the main diagnostic tool for tumors of moderate diameter (5cm). Endoscopic ultrasonography (EUS) is the best procedure to differenciate GISTs from other submucosal tumors. Fine-needle aspiration biopsies (FNABs) allow to obtain an histological diagnosis if necessary. Surgery remain the gold standard of treatment for localized GISTs, whereas endoscopic resection is not recommended for these tumors.

HELLP syndrome, acronym for hemolysis (H), elevated liver enzymes (EL), and low platelet count (LP), is a multisystemic disease that complicates pregnancy and is considered a severe variant of hypertensive disorders in pregnancy, that causes maternal and perinatal mortality and morbidity. The pathogenesis of HELLP syndrome is not completely understood and the obstetric approach with the induction of delivery is still the only specific therapy in HELLP syndrome. It is well known that the placenta and the incomplete trophoblast invasion of spiral arteries have a central role, but especially in severe pre-eclampsia and in the HELLP syndrome there is a systemic endothelial activation and damage. In this review we emphasize the inflammatory hypothesis and the role of inflammatory cytokines deriving from placenta in pre-eclampsia and HELLP syndrome, also in the light of our recent studies on cytokines pattern.

Background Few data are available from clinical trials for elderly patients receiving cetuximab. Patients and methods The clinical data of consecutive patients aged ≥70 years given cetuximab for metastatic CRC were retrospectively captured from hospital pharmacy registries in seven centers. Results Fifty-six patients received cetuximab ± with irinotecan. Median age was 76 years (70–84), 86% of patients were pretreated with fluoropyrimidines, irinotecan and oxaliplatin and 69.6% had documented resistance to irinotecan. Objective response rate was 21% (95% CI: 11–32%). The median progression-free survival was 4.4 months (95% CI: 3.0–5.7 months) and the median overall survival was 16.0 months (95% CI: 13.5–18.5 months). Skin rash occurred in 75% of the patients (11% grade 3) and diarrhea in 80% (20% grades 3–4). Conclusion Tolerability of cetuximab was acceptable in elderly patients with pretreated metastatic CRC. Efficacy appeared similar to that observed in younger patients.

The role of angiogenesis in tumor development and the identification of VEGF as a key factor in this process have recently led to the development of anti-angiogenic agents in the treatment of cancer. Among them, the major are those targeting the VEGF pathway, including anti-VEGF antibodies (bevacizumab) and VEGF receptor tyrosine kinase inhibitors (vatalanib, sorafenib, sunitinib...). Other therapeutic strategies inhibiting angiogenesis are under investigation, targeting the VEGF pathway or other crucial steps of angiogenesis. In digestive oncology, bevacizumab was the first anti-angiogenic agent to be registered in the fist-line treatment of metastatic colorectal cancer in which it was proved to be efficient in combination with a 5-fluorouracile (5FU)/acide folinique (AF) with or without irinotecan-based chemotherapy. Sunitinib and sorafenib have more recently been shown to be active in gastrointestinal stromal tumors and advanced hepatocellular carcinoma, respectively. Side effects associated with these anti-angiogenic agents are not those usually observed with conventional anticancer drugs and require a specific management. Many anti-angiogenic agents are currently under investigation in digestive tumors, opening new prospects but also raising many questions.

Introduction L'enteroscopie a double ballon (EDB) a l'inverse de l'enteroscopie poussee, permet, en theorie, la realisation de polypectomie dans l'intestin grele. Si la rentabilite diagnostique de l'EDB est mieux connue, la faisabilite et les complications de la polypectomie du grele restent mal evaluees. Nous rapportons notre experience chez 10 patients pour qui un traitement endoscopique de polypes du grele a ete realise. Patients et Methodes De Janvier 2004 a Septembre 2006, 10 EDB hautes ont ete realisees pour traitement endoscopique de polypes du grele parmi 246 EDB (4%) respectivement pour syndrome de Peutz Jeghers (n=4), HNPCC (n=2), Adenomatose hepatique familiale (n=1), anemie ferriprive (n=2), et melena (n=1). Nous rapportons l'analyse retrospective de ces dossiers. Resultats Vingt-huit polypes etaient visualises chez 10 patients (1–10), sessiles dans 7 cas et pedicules dans 21 cas, de 27mm de diametre moyen (3–50), localises dans le duodenum (n=8), jejunum proximal (n=10), jejunum median (n=4), et jejunum distal (n=6). Chez 1 patient, le traitement endoscopique a ete recuse en raison du nombre important de polypes (n=10). Un traitement endoscopique a ete effectue pour 17/18 polypes. Une resection endoscopique a l'anse diathermique a ete realisee dans 13/18 cas (72,2%) dont 2 selon la technique de mucosectomie. Une destruction au plasma argon (APC) a ete effectuee dans 4 cas (22,2%). La resection etait complete dans 12/13 cas. Une analyse histologique etait disponible pour 21 des 28 polypes (75%) correspondant a 17 hamartomes dont 3 avec contingent adenomateux en dysplasie de bas grade, 3 adenomes (2 en dysplasie de bas grade et 1 en dysplasie de haut grade), et 1 lipome. Une histologie n'etait pas obtenue pour 7/28 polypes en raison d'un traitement par APC (n=4), de l'absence de recuperation du polype (n=2) et d'une procedure interrompue (n=1). Le traitement endoscopique etait considere comme satisfaisant chez 8 patients sur 10. Un traitement chirurgical complementaire etait propose chez 2 patients. Deux cas d'hemorragie post polypectomie d'evolution favorable et un cas de pancreatite aigue Balthazar D ont ete observees. Conclusion La resection endoscopique de polypes de l'intestin grele est possible avec l'EDB. Elle devrait permettre une prise en charge plus adaptee des patients a haut risque de cancer de l'intestin grele, comme les syndromes de Peutz-Jegher, HNPCC ou autres polyposes.

Les tumeurs stromales digestives sont les tumeurs mesenchymateuses les plus frequentes du tube digestif (1, 2). Elles ont ete recemment caracterisees grâce a l’immunohistochimie et a la biologie moleculaire. Les cellules tumorales de type fusiforme et/ou epithelioide expriment la proteine c-kit (CD 117), recepteur trans-membranaire ayant une activite tyrosine-kinase. Une mutation de type « gain de fonction » du gene c-kit entraine une activation constitutionnelle de cette proteine. La decouverte d’un traitement cible des formes avancees par un inhibiteur de tyrosine-kinase (Glivec) en fait un modele passionnant.

BACKGROUND AND STUDY AIMS: The aim of the study was to assess the feasibility, diagnostic yield, and interobserver agreement of capsule endoscopy in the investigation of patients with obscure or occult gastrointestinal bleeding. PATIENTS AND METHODS: A total of 64 consecutive patients with occult bleeding (31 %) or overt bleeding (69 %) were assessed using capsule endoscopy after negative upper and lower endoscopy and small-bowel radiology. The quality of visualization of the small-bowel mucosa was scored from 1 (poor) to 4 (excellent). Thirty video capsule recordings with normal or abnormal findings were blindly assessed by four independent endoscopists. Interobserver agreement was evaluated using the kappa index. RESULTS: The small bowel was completely visualized in 57/64 patients (89 %). Incomplete small-bowel transit was most commonly due to prolonged gastric retention (five patients). The mucosa visualization scores (means) for the proximal, middle, and distal thirds of the small bowel were 3.7, 3.3, and 2.2 respectively. Visualization of the distal ileum was good (> or = 3) in 38 % and a bleeding site was found in 45 % of patients. Push-enteroscopy was also performed in 56 patients. The results of the two techniques were similar in 37 patients, capsule endoscopy was superior in 12 patients, and push-enteroscopy was superior in seven patients. Interobserver agreement was good for bleeding and for angiodysplasia, but poor for ulcers and tumors. Mean interobserver agreement was better among experienced endoscopists than among junior endoscopists. CONCLUSIONS: Capsule endoscopy allowed the whole small intestine to be explored in 89 % of patients, with good visualization of the mucosa, except distally. Interobserver agreement was better among the experienced endoscopists and was better for red-colored abnormalities (bleeding and angiodysplasia) than for ulcers and tumors.