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Resume Objectif de l’etude Rapporter la survie a long terme et la toxicite dans une large cohorte homogene de patients atteints d’un cancer de l’œsophage ou du cardia localement evolue et mettre en evidence des facteurs predictifs du controle locoregional et de la survie. Patients et methodes Cent-deux patients ont recu au centre hospitalier universitaire de Tours entre 1990 et 2010 une chimioradiotherapie concomitante neoadjuvante de 40 Gy a 44 Gy avec deux cures de 5-fluoro-uracile et cisplatine. Une œsophagectomie et un curage ganglionnaire ont ete realisee environ dix semaines apres la fin de la chimioradiotherapie. Resultats Le suivi median etait de 22,4 mois [6–185]. Les probabilites de survie globale a 2 et 5 ans etaient respectivement de 53 % et 27 %. La duree mediane de survie globale a ete estimee a 67 % en cas de reponse, de 26 % sinon ( p p p p p p Conclusion Nos resultats en termes de survie, de tolerance et de morbidite et de mortalite sont comparables a ceux de la litterature. La reponse histologique complete a ete associee a une meilleure probabilite de controle local, de survie sans maladie et de survie globale, ce d’autant qu’il y avait une reponse histologique complete ganglionnaire, faisant de la reponse histologique ganglionnaire un facteur pronostique majeur. more...

Background: Studies have shown the negative prognostic impact of increased time between colectomy and postoperative adjuvant chemotherapy (AC) in colon cancer (CC). Our aim was to investigate the role of age and non-organizational factors on access and time to AC. Methods: All adult patients undergoing surgery for stage II or III CC in the “Region Centre-Val de Loire” in 2013, were selected. Time to AC and socio-demographic factors were collected. Logistic regression modeling was used to identify factors associated with access to AC, and a multivariate analysis performed to identify factors associated with time to AC. Results: Among 404 stage II or III patients who underwent colectomy, 182 (45%; sex ratio 1.5; mean age 67.6 years; range 32–90) received AC. AC patients were younger than those without AC (67.6 vs. 77.9 years) and the difference was even greater for stage III patients (69.0 vs. 82.4). The median time to AC was 48 days, exceeding 42 days in 60% of cases. Living alone, postoperative morbidities, and emergency colectomy were independently associated with increased time to AC. Age and other factors were not associated with delayed AC. Conclusions: Emergency colectomy, postoperative morbidities, and living alone are associated with increased time to AC. Organizational measures to reduce the time to AC are therefore unlikely to have an impact. In contrast, age is not associated with increased time to AC, but to access to AC. Reasons for omitting AC in older patients requires further study. more...

Background The aim of this study was to compare the performance of the guaiac-based faecal occult blood test (G-FOBT), with that of three immunochemical faecal occult blood tests (I-FOBT) which allow automatic interpretation. Patients and methods Under the French organised screening programme, 85,149 average-risk individuals aged 50–74 participating in the third screening round, performed both the G-FOBT (Hemoccult-II test) and one of the I-FOBTs: FOB-Gold, Magstream and OC-Sensor. Results Given the chosen threshold, the positivity ratio between the different I-FOBTs and the G-FOBT was 2.4 for FOB-Gold, 2.0 for Magstream and 2.2 for OC-Sensor (P = 0.17). The three I-FOBTs were superior to the G-FOBT for colorectal cancer (CRC) detection. The ratios for detection rates were 1.6 (FOB-Gold), 1.7 (Magstream) and 2.1 (OC-Sensor) (P = 0.74). For non-invasive CRC they were, respectively, 2.5, 3.0 and 4.0 (P = 0.83) and for advanced adenomas 3.6, 3.1 and 4.0 (P = 0.39). Conclusions This study provides further evidence that I-FOBT is superior to G-FOBT. None of the three I-FOBTs studied appeared to be significantly better than the others. more...

Background Immunochemical faecal occult blood tests have greater sensitivity for colorectal cancer screening than guaiac-based tests; however the number of positive tests required is still under discussion. Methods A direct comparison of Hemoccult II with two immunochemical quantitative tests (OC-Sensor and FOB-Gold) using a 2-sample strategy was performed in over 30,000 patients undergoing colorectal cancer screening in France. Results Positivity ratio between immunochemical tests and Hemoccult II varied between 2.2 (OC-Sensor) and 2.4 (FOB-Gold) for the lowest cut-off value and 1.5–1.4 for the highest cut-off value. The positive predictive value for colorectal cancer was similar for immunochemical tests and Hemoccult II, and significantly higher for immunochemical tests for advanced adenomas. The detection rate of both colorectal cancer and advanced adenomas was higher with immunochemical tests than with Hemoccult II. With the 2-sample strategy and the lowest cut-off value the detection rate of colorectal cancer almost doubled and for advanced adenomas quadrupled. Conclusion For colorectal cancer screening with immunochemical faecal occult blood tests, an acceptable strategy would be 2-day sampling with at least one positive test at a cut-off between 150 and 200 ng/mL (OC-Sensor) and 176 and 234 ng/mL (FOB-Gold). Data on the ease of test interpretation and cost-effectiveness now necessary to make definitive choices. more...

Resume Contexte Le colloque singulier entre le medecin referent et le patient en cancerologie integre, depuis leur mise en place par le Plan cancer, les elements decisionnels issus de la reunion de concertation pluridisciplinaire (RCP). Methodes Afin d’evaluer l’impact de la RCP sur la relation medecin-patient, une etude a ete menee au centre hospitalier universitaire (CHU) de Tours entre janvier 2005 et mai 2006. Trois outils methodologiques complementaires ont ete elabores : un questionnaire patients, une etude de dossiers portant sur la mise en application des decisions de la RCP et un questionnaire aux medecins referents participant aux RCP. Resultats Cent quarante-cinq questionnaires ont ete recueillis aupres de patients dont le dossier a ete discute en RCP, 40 questionnaires recueillis aupres des medecins participant aux reunions et une analyse de 324 dossiers a ete realisee. Quatre-vingt pour cent des patients reconnaissaient l’avis de la RCP comme rassurant, 73 % exprimaient que le plus important pour eux etait la relation avec le medecin referent et 96 % avaient une totale ou grande confiance dans le medecin referent. La confiance semblait liee a la qualite de la communication, a la liberte de dialogue et a la competence reconnue du medecin en particulier dans le choix du traitement. L’etude des dossiers a montre que dans 91 % des cas, l’avis de la RCP etait applique et que, dans 69 % des cas, c’est le medecin referent qui delivrait l’information au patient apres la RCP. Du point de vue des medecins, 33/40 disaient que la RCP ne modifiait pas leur relation avec le patient. On note que 35/40 exprimaient que la consultation apres RCP facilitait la presentation de la decision et 37/40 que la decision appliquee etait toujours ou souvent en accord avec l’avis de la RCP. Conclusion La RCP apparait le plus souvent ne pas modifier le colloque singulier. De par la confiance que le patient lui accorde, le role du medecin referent est essentiel dans l’integration de l’avis collegial de la RCP et il s’agit de veiller au risque d’un desengagement de celui-ci dans le choix decisionnel. more...

Summary Objectives The most commonly used schedules are 5-FU in combination with CDDP with or without epirubicin (ECF) or docetaxel (TCF) in treatment of MGA patients (pts), independently of HER status. We evaluated the efficacy of FOLFIRI regimen in a large retrospective series of MGA pts. Methods Two hundred and twelve pts from 13 French centers were treated with at least one cycle of FOLFIRI (irinotecan 180 mg/m 2 intravenous (i.v.) over 90 minutes on day 1 with folinic acid (FA) 400 mg/m 2 i.v. over two hours followed by 5-FU 400 mg/m 2 i.v. bolus then 5-FU 2400 mg/m 2 continuous infusion over 46 hours on day 1, repeated every 14 days). Primary tumour sites were 120 (58%) stomach and 92 (42%) gastroesophageal junction. FOLFIRI was administered as first-line in 137 (65%) pts and as later-line in 75 (35%) pts for MGA. Results There was no difference between chemonaive and not chemonaive pts treated as first-line in terms of response rate 37% (95% CI: 25–50) vs 44% (95% CI: 21–69), median PFS, 6.7 (95% CI: 5.5–9.9) vs 5.3 months (95% CI: 3.6–6.9) ( P = 0.25), and OS, 13.1 (95% CI: 11.7–18.7) vs 8.8 months (95% CI: 7.3–15.6) ( P = 0.19), respectively. There was no difference between pts treated as second or later-line in terms of response rate 20% (95% CI: 8–39) vs 22% (95% CI: 6–48), median PFS, four months (95% CI: 2.8–5.4) vs 3.5 months (95% CI: 2.3–4.5) ( P = 0.56), and OS, 10.4 months (95% CI: 5.4–14.4) vs 5.3 months (95% CI: 3.5–11.3) ( P = 0.58), respectively. The global grade 3–4 toxicities were: diarrhea 11%, vomiting 9%, neutropenia 18%, febril neutropenia 4% (one toxic death). Conclusions This retrospective study confirms the activity and good tolerance of FOLFIRI regimen in MGA as first-line as well as later-line. more...

International audience; Introduction: Bevacizumab is an antivascular endothelial growth factor humanized monoclonal antibody used to inhibit angiogenesis in cancer. It displays an important interindividual pharmacokinetic variability, which could explain part of the interindividual differences in clinical response. Therefore, an assay to measure bevacizumab serum concentrations is needed. Methods: An enzyme-linked immunosorbent assay was developed using microtiter plates sensitised with vascular endothelial growth factor(165), a recombinant form of vascular endothelial growth factor. Lower and upper limits of quantitation as well as limit of detection were determined. Eight calibrators and three quality controls, with concentrations of 5 mg/L, 30 mg/L, and 75 mg/L, were tested on five occasions initially and on five subsequent occasions. Trough and peak serum concentrations of bevacizumab were measured in patients with metastatic colorectal cancer. Bevacizumab concentrations were described using a two-compartment population pharmacokinetic model with first-order constants. Results: Imprecision and accuracy of calibrators and quality controls were 20% or less, except for the zero calibrator. The limit of detection was 0.033 mg/L. Lower and upper limits of quantitation were 5 and 75 mg/L, respectively. A total of 175 blood samples was available for analysis from 16 patients. Median (range) trough and peak concentrations during the treatment were 47.2 (9.6-106.9) mg/L and 159.3 (33.0-327.3) mg/L, respectively. Conclusion: This method is rapid, accurate, reproducible, and may be useful for pharmacokinetic and pharmacokinetic-pharmacodynamic studies as well as in therapeutic drug monitoring of bevacizumab. more...

Background & Aims Little is known about the magnitude of the risk of anal and rectal cancer in patients with anal and/or perineal Crohn's disease. We aimed to assess the risk of anal and rectal cancer in patients with Crohn's perianal disease followed up in the Cancers Et Surrisque Associe aux Maladies Inflammatoires Intestinales En France (CESAME) cohort. Methods We collected data from 19,486 patients with inflammatory bowel disease (IBD) enrolled in the observational CESAME study in France, from May 2004 through June 2005; 14.9% of participants had past or current anal and/or perianal Crohn's disease. Subjects were followed up for a median time of 35 months (interquartile range, 29–40 mo). To identify risk factors for anal cancer in the total CESAME population, we performed a case-control study in which participants were matched for age and sex. Results Among the total IBD population, 8 patients developed anal cancer and 14 patients developed rectal cancer. In the subgroup of 2911 patients with past or current anal and/or perianal Crohn's lesions at cohort entry, 2 developed anal squamous-cell carcinoma, 3 developed perianal fistula–related adenocarcinoma, and 6 developed rectal cancer. The corresponding incidence rates were 0.26 per 1000 patient-years for anal squamous-cell carcinoma, 0.38 per 1000 patient-years for perianal fistula–related adenocarcinoma, and 0.77 per 1000 patient-years for rectal cancer. Among the 16,575 patients with ulcerative colitis or Crohn's disease without anal or perianal lesions, the incidence rate of anal cancer was 0.08 per 1000 patient-years and of rectal cancer was 0.21 per 1000 patient-years. Among factors tested by univariate conditional regression (IBD subtype, disease duration, exposure to immune-suppressive therapy, presence of past or current anal and/or perianal lesions), the presence of past or current anal and/or perianal lesions at cohort entry was the only factor significantly associated with development of anal cancer (odds ratio, 11.2; 95% CI, 1.18-551.51; P = .03). Conclusions In an analysis of data from the CESAME cohort in France, patients with anal and/or perianal Crohn's disease have a high risk of anal cancer, including perianal fistula–related cancer, and a high risk of rectal cancer. more...

Multidisciplinary meeting (MDM) in oncology has been institutionalised in France by the Cancer Plan. This study aims to determine the place of MDM in the decision process. From November 2004 to July 2005, we observed 29 meetings at the Tours Hospital and 324 case presentations, 80 in orthopaedics, 151 in gastroenterology and 93 in chest medicine. Forty physicians attending the meetings answered a questionnaire exploring their opinions on MDM and the collegial decision. We found that MDM is mostly the place for technical discussions and that patients' wishes are rarely addressed. The different medical specialities are well represented but we observed that only physicians attend MDM. Decisions for straightforward cases are rapidly validated. For more complex clinical situations (25 to 40% of case presentations), the multidisciplinary approach allows to adapt guidelines or to choose alternative treatments. All the physicians interviewed express that MDM legitimates the medical decision. It occurs that they disagree with the RCP decision. We discuss how MDM impacts on the medical decision as well as the shift from the individual decision to the collective one, particularly in term of responsibility. more...

International audience; Cetuximab is anti-epidermal growth factor receptor monoclonal antibody used in the treatment of colorectal and head and neck cancers. Part of the interindividual differences in response may be explained by interindividual variability in pharmacokinetics. An assay measuring cetuximab serum concentrations is therefore needed. An enzyme-linked immunosorbent assay was developed using microtiter plates sensitized with a recombinant human epidermal growth factor receptor extracellular domain. Lower and upper limits of quantitation and limit of detection were determined. Eight standard calibrators (SCs) and 3 quality controls (QCs), that is, 0.75, 7.5, and 15 mg/L, were tested on 5 occasions on 1 day and on 5 occasions on different days. Trough and peak serum concentrations of cetuximab were measured in 15 patients with metastatic colorectal cancer and I patient with undetermined neoplasia undergoing cetuximab-based chemotherapy. Cetuximab concentrations were described using a 2-compartment population pharmacokinetic model. Imprecision and accuracy of SC and QC were more...

Purpose A phase III, multicenter, randomized study compared conventional dosing of fluorouracil (FU) plus folinic acid with pharmacokinetically guided FU dose adjustment in terms of response, tolerability, and survival. Patients and Methods Two hundred eight patients with measurable metastatic colorectal cancer were randomly assigned to one of two arms: arm A (104 patients; 96 assessable), in which the FU dose was calculated based on body-surface area; and arm B (104 patients; 90 assessable), in which the FU dose was individually determined using pharmacokinetically guided adjustments. The initial regimen was 1,500 mg/m2 FU plus 200 mg/m2 folinic acid infusion during a continuous 8-hour period administered once weekly. FU doses were adjusted weekly in arm B based on a single-point measurement of FU plasma concentrations at steady state until the therapeutic range (targeted area under the curve 20-25 mg·h·L−1) previously established in other studies was reached. Results An intent-to-treat analysis of the 208 patients showed the objective response rate was 18.3% in arm A and 33.7% in arm B (P = .004). Median overall survival was 16 months in arm A and 22 months in arm B (P = .08). The mean FU dose throughout treatment was 1,500 mg/m2/wk in arm A and 1,790 ± 386 mg/m2/wk (range, 900 to 3,300 mg/m2/wk) in arm B. Toxic adverse effects were significantly more frequent and severe in arm A compared with arm B (P = .003). Conclusion Individual FU dose adjustment based on pharmacokinetic monitoring resulted in significantly improved objective response rate, a trend to higher survival rate, and fewer grade 3/4 toxicities. These results support the value of pharmacokinetically guided management of FU dose in the treatment of metastatic colorectal patients. more...

Summary Purpose Self-expandable metallic stent (SEMS) placement is an accepted palliative therapy for management of acute malignant bowel obstruction in advanced colorectal cancer. Nevertheless, data are lacking on the effects of systemic chemotherapy combined with colorectal SEMS. The aim of this study was to investigate the safety and efficacy of palliative chemotherapy for advanced colorectal cancer combined with colorectal SEMS placement. Patients and methods This multicentre retrospective study included all consecutive advanced colorectal cancer patients who received first-line palliative chemotherapy combined with endoscopic stenting for colorectal cancer with obstruction. We analyzed the number of cycles and the type of combination used. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, response rate, grade 3–4 toxicity and the outcomes of SEMS for malignant colorectal obstruction. Results A total of 38 patients were included. Among them, 25 patients received oxaliplatin and 5-fluorouracil combination chemotherapy. Objective response and stabilization occurred in 38 and 24% of patients, respectively. The median overall survival and progression-free survival from the start of chemotherapy were 18 and 5 months, respectively. The objective response rate and overall disease control rate were 38 and 62%, respectively. Toxicity was generally acceptable. Major complications related to stenting included perforation (8%), stent migration (5%), and reobstruction secondary to tumor ingrowths (13%). Conclusions Chemotherapy combined with colonic stenting as a first-line treatment seems to be a valid option in advanced colorectal cancer patients with malignant colorectal obstruction. more...

La mutation du gene suppresseur de tumeur p53 est decrite dans l'adenocarcinome du pancreas et dans le syndrome de Li-Fraumeni, qui est une forme rare de cancers hereditaires. Nous rapportons l'observation d'une malade porteuse d'une neomutation et chez laquelle est survenu a l'âge de 32 ans un adenocarcinome du pancreas. more...

Resume But de l'etude Identification retrospective de facteurs predictifs de la classification postoperatoire et de la densite de cellules tumorales residuelles (CTR) apres radiotherapie preoperatoire pour cancer du rectum, et valeur pronostique de ces deux parametres. Patients et methodes De 1 977 a 1 994, 167 patients ont recu une irradiation preoperatoire (dose mediane, 44 Gy ; delai moyen avant chirurgie, 5 semaines) pour un adenocarcinome du rectum. La classification postoperatoire et la densite de CTR ont ete respectivement etablies et quantifiees pour toutes les pieces operatoires par le meme anatomopathologiste. Resultats Neuf tumeurs etaient de stade 0 (5 %), 10 de stade A (6 %), 103 de stade B1–B3 (62 %) et 45 de stade C1–C3 (27 %). Apres une dose ≥ 44 Cy, 17 et 56 % des tumeurs correspondaient respectivement a un stade 0-A et B1–B3 contre 4 et 69 % apres une dose Conclusion Ces resultats suggerent un effet-dose sur le stade postoperatoire qui, meme apres irradiation, a conserve sa valeur pronostique. Differenciation tumorale et delai avant chirurgie ont ete les autres facteurs pronostiques significatifs du stade postoperatoire. more...

Lymphopenia is a predictor of the efficacy and hematological toxicity of chemotherapy in various advanced cancers. There is little data about this relationship in colorectal cancer. In this retrospective study, the influence of pretreatment lymphopenia on hematological toxicity and the efficacy of chemotherapy was investigated in colorectal cancer patients. In total, 260 patients were included in the study. Correlations between pre-treatment lymphopenia (lymphocyte count more...

Summary Background and aim Dietary polyethylene glycol (PEG) is extraordinarily potent in the chemoprevention of experimental colon carcinogenesis. PEG is used to treat constipation in France and in the USA. French laxatives include Forlax® (PEG4000), Movicol® and Transipeg® (PEG3350), and Idrocol® (pluronic F68). This study tests the hypothesis that use of a PEG-based laxative might reduce the prevalence of colorectal tumors. Methods In this population-based study, consecutive patients attending for routine total colonoscopy were enrolled during four months by the gastroenterologists of Indre-et-Loire. They were asked if they had previously taken a laxative or a NSAID. Age, gender, previous polyps, family history of colorectal cancer, constipation, digestive symptoms were also recorded. Tumors found during colonoscopy were categorized histologically. Results Records from 1165 patients fulfilled the inclusion criteria, 607 women and 498 men, mean age 58.3. Among those, 813 had no tumor, 329 had adenomas, and 23 had carcinomas. In a univariate analysis, older age, male gender, lack of digestive symptom, and previous polyps were more common in patients with colorectal tumors. In contrast, previous Forlax® intake was more common in tumor-free patients (odds ratio (OR) any use/no use, 0.52; 95% confidence interval, 0.27–0.94). More people used Forlax®, which contains a higher dose of PEG than the other PEG-laxatives, whose ORs were smaller than one, but did not reach significance. In multivariate analysis, older age and male gender were associated with higher risk, and NSAIDs use with lower risk, of colorectal tumors. Conclusion Forlax® users had a halved risk of colorectal tumors in univariate analysis, which suggests that PEG may prevent carcinogenesis. more...

The aim of our study was to evaluate the feasibility of enteral jejunal nutrition for acute pancreatitis using a self-propelling spiral distal end jejunal tube.Sixteen consecutive patients with acute pancreatitis in whom Flocare tubes were placed for enteral nutrition were included in this open prospective study. All of them had pancreatic and/or peripancreatic necrosis (Balthazar=D). The median computed topography index was 5 (range 3-10) and the median Ranson score was 2 (range 0-5). The nasoenteric Flocare tube (spiral distal end) was inserted in the stomach at the bedside. Self progression into the jejunum was assessed by X-ray at 1, 7 and 12 hours and then every 24 hours for 4 days. The rate of successful tube self-placement in the jejunum and the time to successful placement were noted.Insertion was successful in 12 of 16 patients (75%). Treitz's ligament was reached in a median of 12 hours (range 1-96 hours). For the remaining patients, the tube was successfully repositioned under fluoroscopic guidance in 2 and withdrawn in 2, one for oral renutrition and one to change to a weighted jejunal tube. No tube dysfunction or recurrence of pancreatitis occurred during the entire period of enteral nutrition.This study suggests that the nasoenteric Flocare tube can be used effectively and safely in early enteral jejunal nutrition for severe acute pancreatitis, without endoscopic or radiological manipulation. more...

Irritable bowel syndrome (IBS) is a common functional gastro-intestinal disease. In the absence of specific markers, definition and hence diagnosis depend on clinical presentation. Of the various attempts to set criteria for IBS, the most recent are Rome I and Rome II classifications.To estimate in a general population the prevalence of IBS using the modified Rome I criteria, and to investigate socio-demographic criteria, symptoms and management.A total of 11,131 people aged 18 years and over, representative of the French population, were surveyed. A diagnostic questionnaire based on the modified Rome I criteria was used to identify IBS sufferers, who were then questioned further about the symptoms and medical management of their IBS.Of the 5,299 men and 5,832 women interviewed, 445 had IBS according to the Rome I criteria, a prevalence of 4% (95% CI: 3.6%-4.4%). IBS was more frequent in women (5.3%) than in men (2.5%), with a sex ratio (F/M) of 2.3. In 9.1% of sufferers, onset had occurred less than 12 months ago, a yearly incidence of 3.6 per 1,000 of the population. In 32.3% of IBS sufferers diarrhoea was predominant, and in 34.6% constipation was predominant. Of IBS sufferers 83.7% had consulted a physician for their condition, and 87.6% had taken medication for their IBS symptoms over the previous 12 months.The prevalence of IBS observed in this study in France was close to the lower limit in published data (3 to 20%). Our results suggest that the Rome I criteria are not sensitive enough to detect all IBS patients in a population not actively seeking health care intervention for the condition. In this regard, the refined classification (Rome II) which was established after our study was carried-out should be evaluated. more...

To evaluate the effect of eradication treatment of Helicobacter pylori and the influence of H. pylori status on the incidence of gastrointestinal (GI) events in rheumatic patients receiving longterm conventional nonsteroidal antiinflammatory drug (NSAID) therapy combined with omeprazole.Patients (n = 919) requiring longterm NSAID therapy entered this multicenter, open label, parallel group study. H. pylori positive patients were randomized to receive either eradication therapy (omeprazole 20 mg bid, amoxicillin 1 g bid, and clarithromycin 500 mg bid for 7 days) or no therapy. Both these groups and the H. pylori negative patients were given omeprazole, 20 mg once daily, along with NSAID for the study duration (5-8 weeks). Treatment failure (primary outcome variable) was defined as the occurrence of severe GI event (symptomatic ulcer, bleeding, perforation) or dyspepsia leading to discontinuation of NSAID therapy, unscheduled consultation, or upper GI tract endoscopy.Treatment failure was recorded in 9/294 (3.06%) infected patients receiving eradication therapy, 8/219 (3.65%) infected patients receiving omeprazole alone, and 5/391 (1.28%) H. pylori negative patients (p0.05). H. pylori eradication did not appear to influence the incidence and severity of dyspeptic symptoms in infected patients.Our results do not support the use of H. pylori eradication therapy in rheumatic patients receiving conventional NSAID along with omeprazole. more...

Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma.To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed.EVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent).Everolimus, 7.5 mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2:1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group.The primary end point was overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease).No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy.Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib.clinicaltrials.gov Identifier: NCT01035229. more...

The aim of this prospective study was to determine whether anti-carcinoembryonic antigen (anti-CEA) scintigraphy is a useful additional technique in the diagnosis recurrence of colorectal cancer. Forty patients with suspected recurrence of colorectal cancer, underwent immunoscintigraphy (IS) and helical computed tomography (CT) in the 2 weeks before surgery. Surgical findings were used to evaluate the performance of the imaging techniques. Suspected areas on IS and CT were systematically explored. Helical CT was found to be superior to IS for the liver, the sensitivity and specificity of CT being 100% and 90%, respectively, vs 53% and 100% for IS. However, IS was better than CT for the detection of extra-hepatic abdominal recurrence: sensitivity and specificity of IS were 100 and 82% respectively vs 33 and 82% for CT. Seven cases of peritoneal carcinomatosis were overlooked by helical CT. Our results indicate that IS improves detection of extra-hepatic abdominal recurrence of colorectal cancer. Immunoscintigraphy is valuable as a guide to the treatment strategy and operative procedures. more...

172 Background: No effective treatment options exist for advanced HCC following sorafenib failure. Preliminary data suggest everolimus may provide benefit after sorafenib. EVOLVE-1 (NCT01035229) assessed the efficacy and safety of everolimus for advanced HCC after sorafenib failure. Methods: Pts aged ≥18 y with BCLC stage B or C HCC and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were sorafenib intolerant were randomized 2:1 to everolimus 7.5 mg/d or placebo. All pts received best supportive care. Randomization was stratified by region (Asia v rest of world) and macrovascular invasion (yes v no). Study drug was given continuously until disease progression or intolerable toxicity. CT/MRI was performed every 6 wk. Primary endpoint was OS. Secondary endpoints were TTP, disease control rate (DCR; percentage of pts with best overall response of CR, PR, or SD per RECIST 1.0), and safety. Final analysis was performed when 454 deaths occurred. Results: 546 pts from 18 countries enrolled from Apr 2010 to Mar 2012 (everolimus = 362, placebo = 184). Baseline characteristics were balanced between arms; median age was 66.0 y, 84.8% of pts were male, 86.3% had BCLC stage C disease, 16.7% were from Asia, 32.8% had macrovascular invasion, and 74.0% had extrahepatic disease. Prior sorafenib was discontinued for disease progression in 80.8% of pts and intolerance in 19.0%. Median OS was 7.56 mo with everolimus and 7.33 mo with placebo (HR 1.05; 95% CI 0.86-1.27; P = .675). Median TTP was 2.96 mo and 2.60 mo, respectively (HR 0.93; 95% CI 0.75-1.15). DCR was 56.1% and 45.1%, respectively (P = .010). The most common grade 3/4 AEs with everolimus (v placebo) were anemia (7.8% v 3.3%), asthenia (7.8% v 5.5%), decreased appetite (6.1% v 0.5%), and hepatitis B viral load increase or reappearance (6.1% v 4.4%). No pts experienced HCV flare. HBV reactivation was experienced by 39 pts (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. Conclusions: Everolimus did not improve OS in pts with advanced HCC whose disease progressed on or after sorafenib or who were sorafenib intolerant. The safety profile was consistent with that previously observed with everolimus. Clinical trial information: NCT01035229. more...

Purpose: Radiotherapy (RT) and concomitant chemotherapy ( CT ) is the standard treatment for non resectable esophageal cancer. Usual total radiation dose is 50 Gy. In order to enhance local control rate a Phase II study was initiated to evaluate the feasibility of a combined treatment with an external radiation dose of 60 Gy and three cycles of concomitant CT, using the three main active drugs (CDDP, 5 FU and MMC), followed by a high dose rate (HDR) brachytherapy delivering 10 Gy. Methods and Materials: Fifty-three patients, 48 men and 5 women, were entered in this study. Stages were evaluated with CT scan and with endoscopic sonography. Fifteen were Stage IIB, 38 Stage III. Treatment consisted of conventional fractionated RT to a total dose of 60 Gy delivered with 2 Gy per fraction, one fraction per day and five fractions per week. The CT regimen was a combination of Cisplatinum (CDDP) 20 mg/m 2 and 5 Fluorouracil (5FU) 600 mg/m 2 continuous infusion, from days 1-4 Mitomycin C (MMC) was given at 6 mg/m 2 on day 1. Three cycles were administered on days 1, 22, and 43. Brachytherapy was delivered one week after the end of external radiation therapy. Results: Full radiation therapy dose was delivered for 94% of the patients. CT compliance, evaluated on tbe mean relative dose-intensity was 85% for CDDP, 81% for 5FU and 51% for MMC. Overall grade 3 and 4 WHO toxicity rates were 23% and 7%, respectively. Haematologic toxicity was the most limiting factor. One patient died from treatment toxicity. Local control rate at one year was 74%. Three-year actuarial survival rate was 27%. Distant metastasis was the main cause of treatment failure. Swallowing score was good for 75% of the patients. Stage, performance status and weight loss were prognostic factors. Conclusion: This regimen with high dose RT, HDR brachytherapy and concomitant CT is feasible; however, a high level of haematologic toxicity was observed with the CDDP, 5FU and MMC regimen. Despite a poor compliance with CT, treatment results are very encouraging for patients with locally advanced disease. more...

To determine predictive factors and prognostic value of tumor downstaging and tumor sterilization after preoperative RT for rectal cancer.Between 1977 and 1994, 167 patients with a histologically proven adenocarcinoma (70 T2, 65 T3, 29 T4, and 3 local recurrences) underwent preoperative RT. Median dose was 44 Gy (5-73 Gy). Surgery was performed in a mean time of 5 weeks after RT. Pathologic specimens have been reviewed by the same pathologist in order to specify the modified Astler Coller classification (MAC), and to quantify the residual tumor cell density (RTCD).According to the MAC, there was 9 stage 0 (5%), 10 stage A (6%), 103 stage B1-B3 (62%), and 45 stage C1-C3 (27%) tumors. Seventeen percent and 56% of the patients who received a doseor = 44 Gy had respectively a 0-A and a B tumor, compared to 4 and 69% in those who received a dose44 Gy (p = 0.04). Tumor differentiation and a longer interval before surgery were significantly associated with a more frequent downstaging, and preoperative staging correlated well to the postoperative pathological findings. According to the RTCD, 62 tumors (37%) showed no or only rare foci of residual tumor cells (Group 1); 62 (37%) showed an intermediate RTCD (Group 2); and 43 (26%) a high RTCD (Group 3). No predictive factor of RTCD was statistically significant. In univariate analysis, postoperative staging was a significant prognostic factor, with corresponding 5-year overall survival rates in 0-A, B, and C stages of 92, 67, and 26% (p0.01). RTCD was not a prognostic factor. However, overall and disease-free survival rates for patients with complete pathologic response of 83% at 2 and 5 years suggested a better outcome in this subgroup of patients.The favorable influence of higher doses of preoperative RT on pathologic stage has been observed. Tumor differentiation, preoperative classification and time before surgery were the other predictive factors of tumor downstaging. However, there was no predictive factor of complete pathologic response. Even after preoperative RT, postoperative staging remained a prognostic factor. more...

Introduction Le sorafenib est un inhibiteur oral de tyrosine kinase ayant une activite anti-angiogenique. Il a recemment demontre un allongement de la survie chez des patients atteints d’un Carcinome Hepato-Cellulaire (CHC) avance, avec un taux de reponse objective inferieur a 5 %. Compte tenu des limites des criteres RECIST pour l’evaluation du sorafenib dans cette indication, il est imperatif d’evaluer d’autres criteres objectifs pour juger de son efficacite. Les progres realises dans le domaine de l’imagerie ultrasonore avec agents de contraste (ECUS) permettent de realiser des etudes fonctionnelles de la vascularisation des tumeurs et de ses modifications sous l’effet des traitements anti-angiogeniques. L’objectif de ce travail prospectif etait d’evaluer l’effet pharmacodynamique anti-angiogenique du sorafenib chez des patients traites pour un CHC au moyen de l’etude par ECUS des modifications de la micro-vascularisation tumorale. Patients et Methodes 14 patients consecutifs traites par sorafenib dans le cadre de l’Autorisation de Mise sur le Marche (AMM) pour un CHC avance etaient inclus dans cette etude prospective. L’âge median etait de 62 ans (41-70), le sex ratio de 13. 11 des patients etait porteurs d’une cirrhose alcoolique, 2 d’une cirrhose virale C et 1 d’une cirrhose virale B. L’effet anti-tumoral du traitement etait etudie au moyen d’une evaluation fonctionnelle par ECUS de la vascularisation d’une lesion hepatique cible de CHC realisee a l’initiation du traitement, a un mois (M1) et a trois mois (M3). Parallelement un scanner ou une IRM etait realise pour une evaluation selon les criteres RECIST a l’initiation du traitement et a M3, en prenant en compte de l’evolution lesionnelle strictement hepatique. La vascularisation tumorale en ECUS a ete evaluee au moyen de trois parametres par deux echographistes : Aire Sous la Courbe (AUC), Index de Perfusion (PI), Rapport des Pentes de Rehaussement (WIR). L’analyse quantitative de permettait de determiner une diminution, une stabilite, une progression ou un echappement vasculaire. Les donnees RECIST ont ete decrites, pour chaque imagerie classique, par deux radiologues differents. Resultats L’evaluation morphologique a M3 retrouvait 10 maladies « stables » (SD) et 4 progressions (PD). Les patients presentant une diminution vasculaire a M1 (criteres ECUS), soit 5 patients sur 14, persistaient en diminution vasculaire a M3, et presentaient dans 100 % des cas une stabilite morphologique des lesions a M3. Neuf autres patients presentaient a M1 une stabilite vasculaire. A M3, 4 maintenaient une stabilite vasculaire (3 SD et 1PD), 3 presentaient une progression vasculaire (2 PD et 1 SD) et 2 un echappement (2 PD). L’ECUS montrait donc a M3 une efficacite sur le plan vasculaire chez 35 % des patients (5/14) et une stabilisation chez 28,5 % (4/14) tandis que l’imagerie classique ne retrouvait pas de variation morphologique detectable chez 71,4 % d’entre eux (10/14). En cas de diminution vasculaire a M1, L’ECUS avait ici une Valeur Predictive Positive (VPP) de 100 % quant a l’absence de progression a M3 sur le plan des imageries classique et fonctionnelle. Conclusion Par rapport a l’imagerie classique, L’ECUS semble permettre une meilleure discrimination des patients repondant au sorafenib, par le suivi evolutif de la micro-vascularisation tumorale. Elle pourrait egalement determiner precocement les patients qui adopteront le profil de reponse le plus favorable. Il s’agit de la premiere etude decrivant l’evolution des parametres de vascularisation tumorale des CHC traites par sorafenib. Elle devrait etre prolongee par une etude multicentrique, avec un plus grand nombre de patients et un suivi prolonge. more...

Introduction Le cancer colorectal (CCR) releve souvent d’un traitement par chimiotherapie (CT). Peu de facteurs predictifs de toxicite et d’efficacite de la CT ont ete rapportes. Il a ete montre pour certains cancers que la lymphopenie (LP) etait predictive de toxicite et de moindre reponse a la CT. Nous rapportons les resultats definitifs de l’etude de la valeur predictive de la LP sur les effets de la CT dans le CCR. L’objectif de cette etude etait d’etudier le caractere predictif de la LP sur la survenue de toxicites hematologiques severes (grade 3-4) de la CT du CCR et une diminution de l’efficacite de la CT dans le CCR. Patients et Methodes Dans cette etude retrospective monocentrique, les dossiers des patients ayant recu une CT adjuvante ou une CT palliative de 1 ere ligne pour le traitement d’un CCR entre le 01/10/1999 et le 01/10/2007 ont ete examines. Les patients etaient repartis en deux groupes (LP et non LP) en fonction de leur numeration lymphocytaire avant le debut de la CT. La lymphopenie etait definie par un nombre de lymphocytes inferieur a 1 000 par mm 3 . Les donnees de toxicite clinique et biologique, gradees selon la CTC-AE ( Common Terminology Criteria for Adverse Events ) et l’efficacite du traitement (reponse a la CT evaluee selon les criteres RECIST, et survies sans progression [SSP] et globale [SG]) ont ete recueillies. Les taux de toxicites hematologiques severes et les taux de reponse a la CT etaient compares entre les deux groupes. Les SSP et SG etaient comparees par le Log-Rank test. Resultats Deux cent soixante patients ont ete inclus (158 hommes, 102 femmes, âge moyen 64,8 ans [extremes : 30 - 85], traitement adjuvant : n = 121, palliatif n = 139, cancer colique n = 195, rectal n = 65). La LP pretherapeutique etait constatee chez 49 patients (18,8 %). Un total de 2 318 cycles de CT a ete administre (mediane par patient = 12 cycles, extremes : 1 - 24). Cent dix-huit patients (45 %) ont ete traites par une monotherapie, a base de 5- Fluorouracile (n = 117) ou de raltitrexed (n = 1) ; 130 ont ete traites par une bitherapie (FOLFOX n = 96 soit 36,9 %, FOLFIRI n = 30 soit 11,5 %, TOMOX n = 2, TEGAFOX n = 1) ; 12 (5 %) ont ete traites par l’association d’une bitherapie et de bevacizumab. Un total de 29 evenements de toxicite hematologique de grade 3-4, a ete enregistre chez 27 patients. Le taux de toxicite hematologique severe etait de 10,4 % chez l’ensemble des patients (29/260) et etait significativement plus eleve dans le groupe LP (20,4 % vs 8 %, p = 0,01). En cas de CT palliative, la LP etait significativement associee a une diminution du taux de reponse a la CT (12,5 % vs 40,2 %, p = 0,004), de la SSP (medianes : 4 vs 7,25 mois, p = 0,033) et de la SG (medianes : 16 vs 24,4, p = 0,024). Conclusion En cas de CCR, la LP pretherapeutique est un facteur predictif de l’augmentation du risque de survenue de toxicites hematologiques severes de la CT et d’une moindre efficacite de la CT palliative. more...

Le taux de succes de pose de sondes naso-jejunales en queue de cochon type Flo-care tube au cours des PA est inferieur a celui du sujet sain mais reste bon. La pose est simple et peut etre realisee au lit du patient avec un taux de succes immediat de 50%, et de 100% apres repositionnement sous controle radioscopique. Le long delai de mise en place spontanee suggere de discuter l'indication de sa pose des les premiers jours d'hospitalisation. more...

Between 07/1977 and 10/1993, 147 patients (pts) received preoperative radiotherapy (RT) for rectal adenocarcinoma. There was 64 T2, 56 T3, 25 T4 tumors and 2 relapses after prior surgery. Median total dose of RT was 44 Gy (5–73 Gy), median fractionation 5 fractions (1–5) of 2 Gy (1.5–5 Gy) per week, and median duration of RT 5 weeks (1 day–9 weeks). Seventy-nine pts were treated with a 2-field technique, 66 pts with a 4-field technique and 2 pts with a direct perineal field. Median treated volume was 4.4 liters (1.2–9.4). One hundred and twenty pts were treated with X25 MV, the other 27 pts with 1.25 Mev 60Co. All irradiated rectal tumors have been reanalyzed by the same pathologist in order to quantify tumor sterilization. Three groups were individualized according to the residual tumor cell density (RTCD): absence or low, intermediate and high. All pts underwent surgery in a median delay of 4 weeks. Fifty-five tumors (37%) showed no (9/147) or low (46/147) RTCD; 51 (35%) showed an intermediate RTCD and 39 (27%) a high RTCD. The distribution of the pts according to age, tumor stage, tumor location, delay before surgery and RT parameters (total dose, fractionation, duration of treatment, 2 or 4-field technique, treated volume, X25 MV or 1.25 Mev 60Co photons) was not statistically different in the 3 groups. Five-year actuarial survival rates were 100% in the group of pts with no RTCD, 54% in the group with low RTCD, 44% in the group with intermediate RTCD and 53% in the group with high RTCO. The difference did not reach significance, probably because of the small number of sterilized tumors. These results suggest however that tumor sterilization is a favorable prognostic factor after preoperative RT in rectal cancer. more...

RT and concomitant CT is the standard treatment for non resectable esophageal cancer. Usual total radiation dose is 50 Gy. In order to enhance local control rate a phase II study was initiated to evaluate the feasibility of a combined treatment with an external radiation dose of 60 Gy and 3 cycles of concomitant CT followed by a high dose rate brachytherapy delivering 10 Gy (2 applications with 7 days interval). 73 patients (pts), 28 men and 5 women were treated between 1989 and 1993. Stages were evaluated with CT scan and with endoscope sonography for 41 pts: 13 were Stage IIB, 50 Stage III and 10 Stage IV. Treatment consisted in a conventional fractionated RT to a total dose of 60 Gy delivered with 2 Gy per fraction, one fraction per day and 5 fractions a week. The CT regimen was a combination of Cisplatinum 25 mg/m2 dl to d4, 5 Fluorouracil 600 mg/m2 continuous infusion dl to d4. 3 cycles were administered on dl, d22 and d43. Brachytherapy was delivered one week after the end of external radiation therapy. Full radiation therapy dose was delivered for 96% of the patients. CT compliance, evaluated on the drug dose and the CT interval, was good for 77% of the patients. Overall grade 3 and 4 WHO toxicity rates were 23% and 7% respectively. One pt died from treatment toxicity. Local control rate at one year was 74%. Three-year actuarial survival rate was 27%. Distant metastase was the main cause of treatment failure. Predictive factors of late effects related to brachytherapy and evaluation of a swallowing score will be presented, In a multivariate analysis Stage was the only prognostic factor. In conclusion this regimen with high dose RT and 3 cycles of concomitant CT is feasible. Treatment results are very encouraging for pts with locally advanced disease. more...

The acute effects of γ-irradiation on the gastric mucosa have been studied in a primate model. Fiberoptic gastroscopies were performed in 6 rhesus monkeys in the basal state as well as 3 h and 3, 7, and 9 days after total body irradiation (800 rads). Gastric biopsy specimens (diameter 1 mm) obtained during each session were examined using light microscopy and scanning electron microscopy; in addition, subsequent healing of the biopsy sites was assessed visually. Gastric biopsy sites were completely healed in 3 days in the basal state; in contrast, ulcer craters (diameter 1 mm) were still present at the site of the biopsies 3, 7, and 9 days after the biopsies were performed in irradiated animals. Light microscopic examination of the biopsy specimens demonstrated only lymphocytic infiltration of the lamina propria. In contrast, scanning electron microscopic examination revealed that the size and number of microvilli of the gastric surface epithelial cells were increased on the day of irradiation compared to basal; 3–9 days later, numerous gastric surface epithelial cells were damaged or had dissappeared so that bare areas of the lamina propria were visible in the specimens taken outside of the ulcer craters. These changes may reflect inadequate protection or insufficient regeneration of gastric mucosal cells which, in turn, would explain the persistence of ulcers after gastric biopsies were performed in irradiated monkeys. more...

3614 Background: Gilbert’s disease patients (pts) (homozygotous for the UGT1A1*28 allele) have a major risk (>30%) of severe, life-threatening, neutropenia when treated with Irinotecan (IRI). The aim of this study was to demonstrate that, in these pts, treated with IRI 1st line for mCRC, primary prevention with GCSF (lenograstim) reduces under 10% the risk of grade 4 or febrile neutropenia. Methods: This is a prospective, multicenter, phase II study of FOLFIRI + bevacizumab 1st line (IRI 180 mg/m² every 2 weeks) and primary prophylactic GCSF (D5 to D11 each course) in mCRC pts with Gilbert’s disease. Pre-chemotherapy UGT1A1 genotyping was centralized and standardized using a biological molecular technique applied on DNA blood-extracted lymphocytes. Using a 2-step Fleming design, (α=5% and β=90%), 30 pts had to be included with an interim analysis (IA) planned after 20 pts and 4 months of follow-up. Results: Twenty pts from 7 centers were included between 10/2007 and 02/2012 and 19 analysed for the IA. Median pts age was 63 years (range: 45-73), 60% were females, 90% were PS 0 or 1, 80% had a colic primary site and 73% hepatic metastases. The primary site was non- resected in 1/3 of pts. The total number of administered courses of chemotherapy was 229 with a median of 12 per pt (range: 1-40). Among all these courses, 213 were administered with GCSF. IRI was administered as defined by the protocol with a nearly 100% rate of received /theoretical dose. Grade 3 neutropenia rate was 10.5%. No grade 3-4 diarrhea, no grade 4 or febrile neutropenia and no toxic death were observed. No declared SAEs were related to GCSF. In term of best response at 6 months, 7 pts were in complete or partial response and 9 had stable disease. Median progression free survival and overall survival were respectively 8.7 months (4.9; 13.4) and 24.4 months (12.6; ND). Conclusions: This study is the first to demonstrate that a pharmacogenetic approach based on a simple genetic test easy to perform can achieve a high rate of safe and performant administration of IRI in high risk mCRC pts. Clinical trial information: NCT00541125. more...

Early radiation toxicity is characterized by nausea and vomiting. The authors have previously shown that gastric emptying, gastric motility, and gastric secretion were suppressed after total-body exposure to irradiation. In this studies, the authors evaluated the relation between vomiting and gastric function in nine rhesus monkeys and explored the possible role of prostaglandins (PG) in these phenomena. The concentration of PG in plasma and gastric juice was determined using a standard radioimmunoassay, and gastric-acid output was measured concurrently using a marker dilution technique. The animals were studied in the basal state and after total-body exposure to 800 cGy /sup 60/Co delivered at a rate of 500 cGy/min. Acid output was abolished from 40 min to 2 h after irradiation but had returned to preirradiation levels 2 days later. Plasma PGE2 and PGI2 (as measured by 6-keto-PGE determination) were not significantly modified by irradiation. In contrast, irradiation produced an immediate significant increase (P more...