FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial.

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/m(2)) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m(2)) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m(2)). 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.

Conservative surgery vs. duodeneopancreatectomy in primary duodenal gastrointestinal stromal tumors (GIST): a retrospective review of 114 patients from the French sarcoma group (FSG).

BACKGROUND: Duodenal GISTs represent 3-5% of all GISTs with limited understanding of patient outcomes. We conducted a retrospective analysis of primary localized duodenal GISTs. METHODS: Patients were identified via a survey from 16 FSG centers (n = 105), and a group of 9 patients enrolled in the BFR14 trial. Data were collected from the original database and patient files, in agreement with French legislation. RESULTS: 114 patients were included, with a median age of 57. Tumors originated mainly in D2 (33%), or D3 (24%), with a median size of 5 cm. 109 patients had resection of the primary tumor; with a Local Resection (LR, n = 82), a pancreaticoduodenectomy (PD, n = 23), and data were missing for 4 patients. Resections were R0 (n = 87, 79%), R1 (n = 8, 7%), R2 (n = 6). Tumor characteristics were: KIT+ (n = 104), CD34+ (n = 58). Miettinen risk was low (n = 43), and high (n = 52). Imatinib was administered preoperatively (n = 11) and post-operatively (n = 20). With a median follow-up of 36 months (2-250), 98 patients are alive, and 33 relapsed. The 5-year OS and EFS rates are 86.5% and 54.5%. EFS was similar for patients in the LR and the PD groups (P > 0.05). In multivariate analysis, ECOG PS, and CD34 expression are independent prognostic factors on OS. Miettinen risk and spindle cell type are independent predictive factors for relapse. CONCLUSIONS: Patients with resected duodenal GIST have a reasonably favorable prognosis. This study favors a preservation of pancreas when there are no anatomical constraints. LR exhibit similar survival and smaller morbidity then PD.

PP047. Outpatient management of pregnancy complicated by mild hypertensive disorders.

INTRODUCTION: Antenatal day care units have been experienced as an alternative to inpatient care for women with pregnancy complications including hypertensive disorders. OBJECTIVES: To assess the outcomes of outpatient management in women with gestational hypertension and mild preeclampsia and compare them to inpatient management. METHODS: Perinatal records of 294 patients (OUT group) attending the obstetric outpatient clinic were reviewed and compared with records of 398 women (IN group) attending the obstetric unit of the same tertiary referral center. The patients were divided as: GH, gestational hypertension (OUT: 194; IN: 244), GH with Intrauterine Growth Restriction (OUT: 52; IN: 78) and PE, mild preeclampsia (OUT: 48; IN: 76). The groups were comparable for age, parity, body mass index and gestational age at enrollment. RESULTS: When compared with patients treated in hospital, GH OUT women showed a higher gestational age at delivery (38±1.7 vs 35.5±2.3 weeks; p<0.001), longer time to delivery (62.0±4.8 vs 31.3±5.4days; p<0.001), higher birthweight (3251±389 vs 2271±759.1g; p<0.001), and a lower admission to neonatal intensive care unit (21.3% vs 0%; p<0.001) (hospitalization rate: 25%). Similarly, Mild PE women treated as out patient showed later gestational age at delivery (37±1.2 vs 34.4±1.7weeks), longer time to delivery (55.4±6.9 vs 35.3±4.5days), higher birthweight (3168±363 vs 2196±685.17g), and a lower admission to NICU (15.6% vs 35.5%) (hospitalization rate: 55.6%), than the inpatient controls. In the gestational hypertension with IUGR no significant differences were observed between out- and in-patient management. CONCLUSION: Women attending day care units have better or comparable perinatal outcomes than inpatients. Ambulatory management at a day-care unit is an option for monitoring and following up women with mild gestational hypertension or preeclampsia remote from term. Hospitalization remains an absolute indication if worsening of preeclampsia is diagnosed.

Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population-based study differ from those of advanced GISTs.

Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma. Most of the data available on GISTs derive from retrospective studies of patients referred to oncology centers. The MolecGIST study sought to determine and correlate clinicopathological and molecular characteristics of GISTs. Tumor samples and clinical records were prospectively obtained and reviewed for patients diagnosed in France during a 24-month period. Five hundred and ninety-six patients were included, of whom 10% had synchronous metastases. GISTs originated from the stomach, small bowel or other site in 56.4, 30.2 and 13.4% of cases, respectively. The main prognostic markers, tumor localization, size and mitotic index were not independent variables (P < 0.0001). Mutational status was determined in 492 (83%) patients, and 138 different mutations were identified. KIT and PDGFRA mutations were detected in 348 (71%) and 74 (15%) patients, respectively, contrasting with 82.8 and 2.1% in patients with advanced GIST (MetaGIST) (P < 0.0001). Further comparison of localized GISTs in the MolecGIST cohort with advanced GISTs from previous clinical trials showed that the mutations of PDGFRA exon18 (D842V and others) as well as KIT exon11 substitutions (W557R and V559D) were more likely to be seen in patients with localized GISTs (odds ratio 7.9, 3.1, 2.7 and 2.5, respectively), while KIT exon 9 502_503dup and KIT exon 11 557_559del were more frequent in metastatic GISTs (odds ratio of 0.3 and 0.5, respectively). These data suggest that KIT and PDGFRA mutations and standardized mitotic count deserve to be investigated to evaluate the relapse risk of GISTs.

Long-term outcome of patients treated with double balloon enteroscopy for small bowel vascular lesions.

OBJECTIVES: Early rebleeding rate after endoscopic therapy with double balloon enteroscopy (DBE) of hemorrhagic small bowel vascular lesions (SBVL) varies between 10 and 50%. In recent reports, long-term follow-up of patients have been described but rebleeding risk factors are still not well established. The aim of the current study was to identify long-term treatment success rate and rebleeding risk factors after DBE therapy in a large cohort. METHODS: We conducted a single-center, retrospective cohort study in a large French tertiary-referral center between January 2004 and December 2007. RESULTS: Among 261 patients presenting with obscure gastrointestinal bleeding (OGIB), SBVL was present in 133 patients and was treated successfully in 129 (97%) using mainly argon plasma coagulation. Ninety-eight patients were followed up for a mean period of 22.6±13.9 months (range 1-52). Rebleeding rate was 46% (45/98 patients) at 36 months. On multivariate analysis, the total number of observed lesions (hazard ratio (HR): 1.15, 95% confidence interval (CI): 1.06-1.25, P=0.001) and the presence of a valvular and/or arrhythmic cardiac disease (HR: 2.50, 95% CI: 1.29-4.87, P=0.007) were significantly associated with the risk of rebleeding. Complication rate of therapeutic DBE was 2.3% with no mortality. CONCLUSIONS: Endoscopic therapy using DBE for SBVL in patients with recurrent OGIB allows a long-term remission in more than half of the patients. Independent rebleeding risk factors after a first endoscopic therapy are an increased number of SBVL and an associated valvular/arrhythmic heart disease.

[Gastrointestinal stromal tumors (GIST)<5 cm in size: review of the literature and expert propositions for clinical management]. / Tumeurs stromales gastro-intestinales (GIST) de taille limitée (inférieure à 5cm): revue de la littérature et propositions pour la prise en charge.

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.

[Endoscopic approach to GIST]. / Place de l'endoscopie dans les GIST.

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 and placental inflammatory pathology.

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.

[Antiangiogenic agents and gastrointestinal cancers]. / Les antiangiogéniques en oncologie digestive.

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.

Cetuximab efficacy and safety in a retrospective cohort of elderly patients with heavily pretreated metastatic colorectal cancer.

BACKGROUND: Few data are available from clinical trials for elderly patients receiving cetuximab. PATIENTS AND METHODS: The clinical data of consecutive patients aged > or =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.

Placental overexpression of transforming growth factor-beta3 in the HELLP syndrome.

OBJECTIVE: To evaluate the placental expression of transforming growth factor-beta3 (TGF-beta3) 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-beta3 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-beta3 expression correlated positively with umbilical PI (p < 0.001). CONCLUSIONS: TGF-beta3 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.

[Not Available]. / Place de l'endoscopie dans les GIST.

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.

Dielectric response of aligned semiconducting single-wall nanotubes.

We report measurements of the full intrinsic optical anisotropy of isolated single-wall carbon nanotubes (SWNTs). By combining absorption spectroscopy with transmission ellipsometry and polarization-dependent resonant Raman scattering, we obtain the real and imaginary parts of the SWNT permittivity from aligned semiconducting SWNTs dispersed in stretched polymer films. Our results are in agreement with theoretical predictions, highlighting the limited polarizability of excitons in a quasi-1D system.

FOLFIRI.3, a new regimen combining 5-fluorouracil, folinic acid and irinotecan, for advanced pancreatic cancer: results of an Association des Gastro-Enterologues Oncologues (Gastroenterologist Oncologist Association) multicenter phase II study.

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/m(2) as a 60-min infusion on day 1, leucovorin 400 mg/m(2) as a 2-h infusion on day 1, followed by 5-fluorouracil (5-FU) 2000 mg/m(2) as a 46-h infusion and irinotecan 90 mg/m(2), 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.

Comparative measures of single-wall carbon nanotube dispersion.

Model composites of DNA-wrapped single-wall carbon nanotubes in poly(acrylic acid) are used to evaluate metrics of nanotube dispersion. By varying the pH of the precursor solutions, we introduce a controlled deviation from ideal behavior. On the basis of small-angle neutron scattering, changes in near-infrared fluorescence intensity are strongly correlated with dispersion, while optical absorption spectroscopy and resonant Raman scattering are less definitive. Our results represent the first systematic comparison of currently accepted measures of nanotube dispersion.

A phase II study of FOLFIRI-3 (double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients.

In advanced colorectal cancer previously treated with oxaliplatin, efficacy of irinotecan-based chemotherapy is poor and the best regimen is not defined. We designed FOLFIRI-3 and conducted a phase II study to establish its efficacy and safety in advanced colorectal cancer patients previously treated with FOLFOX. FOLFIRI-3 consisted of irinotecan 100 mg m-2 as a 60-min infusion on day 1, running concurrently with leucovorin 200 mg m-2 as a 2-h infusion on day 1, followed by 46-h continuous infusion of 5-fluorouracil (5FU) 2000 mg m-2, and irinotecan 100 mg m-2 repeated on day 3, at the end of the 5FU infusion, every 2 weeks. Sixty-five patients entered the study. The intent-to-treat objective response rate was 23% (95% CI 13-33%). Disease was stable in 37% of patients, progressed in 26% and was not assessable in 14%. From the start of FOLFIRI-3, median progression-free survival was 4.7 months and median survival 10.5 months. Main toxicities (% of patients) were grade 3-4 diarrhoea 23% and grade 4 neutropenia 11%. FOLFIRI-3 is a promising regimen achieving high response rate and progression-free survival in patients previously treated with FOLFOX with a moderate toxicity.

Push-and-pull enteroscopy in the small bowel using the double-balloon technique: results of a prospective European multicenter study.

BACKGROUND AND STUDY AIMS: The aim of this study was to evaluate the feasibility, safety, and clinical impact of push-and-pull enteroscopy (PPE) in patients with suspected or documented small-bowel diseases, in a prospective multicenter trial in three European medical centers. PATIENTS AND METHODS: A total of 100 patients (mean age 56 +/- 16 years; range 13 - 90) were included at the three institutions between July and November 2004. The leading symptoms were: acute recurrent or chronic gastrointestinal bleeding (n = 64), polyposis syndrome (n = 8), chronic abdominal pain (n = 7), chronic diarrhea (n = 7), and others (n = 14). RESULTS: No major PPE-associated complications such as perforation, bleeding, or relevant injury to the small-bowel tissue or mesentery were encountered. Minor complications occurred in 12 %. The mean time required to carry out the procedure from the oral and anal approaches was 75 +/- 19 min (32 - 150 min). The average insertion depths into the small bowel were 200 +/- 70 cm per PPE session (220 +/- 90 cm with the oral approach and 130 +/- 80 cm with the anal approach). The average radiation exposure (including diagnostic and therapeutic interventions) was 2.1 +/- 2.4 min and 155 +/- 159 dGy/cm2. PPE was fully diagnostic in 72 % of cases. The majority of the patients (34 %) were suffering from angiodysplasias; ulcerations and erosions of various etiologies were seen in 16 %, and polyps and tumors in 13 %. The PPE findings played a role in the subsequent treatment in 62 % of the patients. Endoscopic treatments, including argon plasma coagulation, polypectomy, dilation, and foreign-body extraction, were carried out in 42 %. Medical treatment was given in 12 %, and patients were referred for surgery in 8 % of cases. CONCLUSIONS: This prospective analysis shows that PPE is safe and has a high diagnostic and therapeutic yield in patients with suspected or known small-bowel disease.

Video capsule endoscopy for investigation of obscure gastrointestinal bleeding: feasibility, results, and interobserver agreement.

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.