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.

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.

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.

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.

[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.

[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.

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.

Carcinoembryonic gene member 2 mRNA expression as a marker to detect circulating enterocytes in the blood of colorectal cancer patients.

BACKGROUND: The aim of this study was to report our experience with a new molecular tool to detect circulating enterocytes in the blood of patients with colorectal cancer. METHODS: The study included 193 individuals: 78 patients with colorectal cancer and 115 controls composed of patients with benign colorectal diseases (n = 16), patients with noncolorectal cancer (n = 31), healthy individuals (n = 62), and healthy bone marrow transplantation donors (n = 6). A nested reverse transcriptase-polymerase chain reaction with specific primers for the carcinoembryonic gene member 2 (CGM2) was used to detect circulating enterocytes in the peripheral blood of 78 patients with colorectal cancer. The blood (n = 109) or the bone marrow (n = 6) of the 115 controls was studied to test the absence of CGM2 illegitimate transcription in nucleated blood cells and nucleated blood cell progenitors. The assay sensitivity was effective in detecting 1 CGM2-positive cell per 10(6) nucleated blood cells. RESULTS: Fifty-nine percent (46/78) of patients with colorectal cancer were found positive whereas all negative controls remained negative. Positivity rates were 38% (3/8) in Dukes' A classification, 43% (9/21) in Dukes' B, 77% (23/30) in Dukes' C, and 58% (11/19) in Dukes' D. CONCLUSIONS: The clinical significance of enterocyte detection in the blood of colorectal cancer patients by means of this CGM2 messenger RNA assay needs further evaluation.

[Dieulafoy colonic ulcer. A rare cause of lower gastrointestinal hemorrhage]. / Ulcère de Dieulafoy colique. Une cause rare d'hémorragie digestive basse.

Dieulafoy's disease is an unusual cause of gastrointestinal hemorrhage, reported to account for less than 2% of acute gastrointestinal bleeding episodes. Bleeding occurs from a defect in an unusually large submucosal artery, through a minute mucosal erosion. Endoscopic diagnosis is sometimes difficult, but primary endoscopic therapy may be successful and should be attempted. In most cases the lesion is found in the proximal stomach. Sixteen cases of Dieulafoy's lesion located in the colon have been reported in the literature but only nine have been confirmed by histology. We present the case of a 63 year-old male with Dieulafoy's lesion of the transverse colon which was diagnosed by endoscopy and confirmed by histology.

[Ileocolic linitis in Crohn's disease]. / Linite iléo-colique au cours d'une maladie de Crohn.

Intestinal cancer is uncommon in Crohn's disease but the risk of developing such a tumor is increased. Linitis plastica of the small bowel or colon is very rare. We report a case of ileocolonic linitis plastica which occurred 21 years after an ileocecal resection for Crohn's disease. Partial small bowel obstruction in relation with stricture of the preanastomotic loop prompted us to suspect disease recurrence. The tumor was not diagnosed either on preoperative work-up, or during surgery but only on the histological examination of the resected specimen. Palliative chemotherapy with 5 FU and folinic acid was performed. The patient was asymptomatic after a 17-month follow-up. This observation focuses on the clinical signs and course of linitis plastica. It also illustrates the difficulty of tumor diagnosis in Crohn's disease. Malignant transformation must be suspected if signs of active disease re-occur after a lengthy quiescent period.

[Severe hemorrhagic gastritis of radiation origin]. / Gastrite hémorragique sévère d'origine radique.

Severe gastric complications due to radiotherapy are uncommon, in particular hemorrhagic gastritis. A high total dose and, above all, high daily fraction appear to be the main risk factors in gastric injuries. A case of hemorrhagic gastritis induced by radiotherapy requesting a total gastrectomy is reported. The patient was treated for a primary gastric non-Hodgkin's lymphoma. Hemorrhagic gastritis occurred despite a low total dose (40 Gy) and 2 Gy daily fractions. Upper gastrointestinal endoscopy and repeated biopsies are usually insufficient to exclude a tumor recurrence. Endoscopic ultrasonography may argue for a recurrence or for radiation lesions. As the conservative treatment is usually ineffective, these gastrointestinal radiation injuries ought to be treated surgically. Besides it allows to ascertain the benign nature of radiation lesions.

[Comparison of push-type endoscopy and barium transit study of the small intestine in digestive bleeding and unexplained iron-deficiency anemia]. / Comparaison de l'entéroscopie poussée et du transit baryté de l'intestin grêle dans les saignements digestifs et les anémies ferriprives inexpliqués.

OBJECTIVES: A radiological examination of the small bowel is often performed in case of gastrointestinal bleeding of obscure origin. More recently, push-type enteroscopy has been reported as a valuable tool in this indication. The purpose of this study was to compare the diagnosis efficiency of these two procedures. METHODS: From February 1994 to February 1996, 40 patients (mean age: 52 years) with obscure gastrointestinal bleeding (iron-deficiency anemia without obvious cause of blood loss or malabsorption: n = 17; macroscopic gastrointestinal bleeding: n = 23) were examined by small bowel follow-through and push-type enteroscopy (jejunoscopy n = 19; double way examination n = 21). Each patient had negative upper and lower gastrointestinal tract endoscopies prior to small bowel examinations. RESULTS: Small bowel follow-through revealed only one lesion potentially responsible for blood loss (2.5%), corresponding to a jejunal leiomyoma. Push-type enteroscopy detected small bowel lesions potentially responsible for blood loss in 6 patients (15%). The lesions were located in the jejunum in 5 cases (arteriovenous malformations: n = 3; metastasis: n = 1; leiomyoma: n = 1), in the ileum in 1 case (leiomyoma). The efficiency of push-type enteroscopy for the detection of a small bowel lesion was of 22% in case of macroscopic bleeding and of 6% in case of iron-deficiency anemia. Push-type enteroscopy also revealed lesions previously undetected by gastroscopy or colonoscopy in 8 patients (20%). CONCLUSION: Push-type enteroscopy was more effective than small bowel follow-through to detect the origin of obscure gastrointestinal bleeding. Push-type enteroscopy revealed a cause of bleeding in 35% of patients, located in the small bowel in only 15% of the patients.

[Intraductal papillary mucinous tumors of the pancreas: are there any preoperative clinical and laboratory factors predictive of degeneration. Results of a French-Belgium collective series]. / Tumeurs intracanalaires papillaires mucineuses du pancréas: existe-t-il des facteurs pré-opératoires cliniques et biologiques prédictifs de dégénérescence? Résultats d'une série collective franco-belge.

Intraductal papillary and mucinous tumors are rare. We retrospectively analysed clinical, surgical and histological features and outcome of 41 operated patients (29 males, 12 females, mean age = 63 years). The commonest presenting manifestation was acute pancreatitis (41%). Tumor was located in only one pancreatic segment in 45% cases. Forty one per cent of patients had invasive carcinoma, 20% had tumor with severe dysplasia and 39% with minimal or moderate dysplasia. Only elevated age was significantly associated with invasive carcinoma. Eleven out of 17 patients with invasive carcinoma (65%) had a recurrence after surgery and 6 (35%) died. Among 24 patients with noninvasive tumor, 2 (8%) recurred without tumor-related death in the follow-up (48 months). This study underlines the need for early surgical resection in patients with intraductal papillary and mucinous tumor because of the high frequency of invasive carcinoma and the poor outcome of patients with invasive carcinoma.

[Pretherapeutic endosonography in rectal adenocarcinoma]. / L'échographie endocavitaire dans le bilan pré-thérapeutique de l'adénocarcinome rectal.

The advent of transrectal ultrasonography has contributed to improving therapeutic management of cancer of the rectum. The 7.5 MHz transrectal probe evidences five tissue layers in the rectal wall. The 10-12.5 MHz probe can visualize seven layers. Transrectal ultrasonography can also be used to explore the perirectal environment and detect possible nodes. Echographically, the tumor is seen as an hypoechogenic mass invading the rectal wall outwardly, disorganizing the wall structures. Parietal recurrence is seen as a hypoechogenic heterogeneous thickening. Ultrasonographic surveillance can be proposed for operable patients with a high risk of recurrence. Cautious interpretation is required due to the known limitations of transrectal ultrasonography. Truly invaded nodes may not be seen due to their small size (less than 2-3 mm) or their localization far from the probe (false negatives). Transrectal ultrasonography provides important information for therapeutic decision making in terms of surgical access and/or indications for possible adjuvant therapy. Transanal resection may also be ruled out if there are perirectal nodes. Patients may also be selected for preoperative radiotherapy, possibly associated with chemotherapy.

[Evaluation and interest in new molecular markers in colon cancer]. / Evaluation et intérêt de nouveaux marqueurs moléculaires en cancérologie colique.

The presence of colonic tumor cells in the circulation may predict colorectal carcinoma recurrence and metastases. We have developed a highly sensitive nested RT-PCR assay, with primers derived from the cytokeratin 20 (CK20) and the carcinoembryonic gene CGM2, to detect occult microdisseminated enterocytes in blood of colorectal cancer patients. Among 82 healthy controls analyzed, 40.2% (33/82) have a positive expression of CK20 mRNA which is not statistically different from the 45.5% (15/33) of positive results found in colon cancer patients. This sensitive method may detect non-tissue specific constitutive low level (illegitimate) expression of CK20 mRNA in peripheral nucleated blood cells (PNBC) of a significant number of healthy control as well as in a number of normal bone marrow. The low specificity of this assay therefore hampers its value to detect blood colon cancer dissemination. In 47 patients with colorectal carcinoma, CGM2 primers detected circulating enterocytes in 25 of them (53%). In disseminated Dukes' stage C disease patients, 17 out of 29 (59%) were found positive whereas in localized adenocarcinoma (Dukes's stage A and B), CGM2 primers detected enterocytes in 44% suggesting that an hematogenous spillage of colonic cells may be a relatively early event in colon cancer. None of the patients suffering from benign colonic pathologies or from diverticulitis were found positive for this assay. The analysis of 56 healthy individuals without known colorectal cancer, of 20 non-colorectal cancer patients and of 6 normal bone marrows provide evidence that this assay is highly specific and may predict an hematogenous spread of colonic cells in patients with organ-confined disease. Nevertheless, the clinical significance of enterocyte detection and the potential applications of this molecular tool merit longer term follow-up.

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.