[show abstract][hide abstract] ABSTRACT: Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). In this study, real-time quantitative reverse transcription demonstrated a significant expression of AM mRNA in tumor samples from colorectal cancer (CRC) patients in clinical stage II, III, and IV when compared with normal colorectal tissue. AM, CLR, RAMP2, and RAMP3 proteins were immunohistochemically localized in the carcinomatous epithelial compartment of CRC tissue. Tissue microarray analysis revealed a clear increase of AM, CLR, RAMP2, and RAMP3 staining in lymph node and distant metastasis when compared with primary tumors. The human colon carcinoma cells HT-29 expressed and secreted AM into the culture medium with a significant increase under hypoxia. Treatment of HT-29 cells with synthetic AM stimulated cell proliferation and invasion in vitro. Incubation with anti-AM antibody (αAM), anti-AM receptors antibodies (αAMR), or AM antagonist AM22-52 inhibited significantly basal levels of proliferation of HT-29 cells, suggesting that AM may function as an autocrine growth factor for CRC cells. Treatment with αAM significantly suppressed the growth of HT-29 tumor xenografts in vivo. Histological examination of αAM-treated tumors showed evidence of disruption of tumor vascularity with decreased microvessel density, depletion of endothelial cells and pericytes, and increased tumor cell apoptosis. These findings highlight the potential importance of AM and its receptors in the progression of CRC and support the conclusion that αAM treatment inhibits tumor growth by suppression of angiogenesis and tumor growth, suggesting that AM may be a useful therapeutic target.
[show abstract][hide abstract] ABSTRACT: PURPOSEElderly patients form a heterogeneous population. Evaluation of geriatric factors may help evaluate a patient's health status to better adapt treatment. PATIENTS AND METHODS
Elderly patients with previously untreated metastatic colorectal cancer (mCRC) were randomly assigned to receive fluorouracil (FU) -based chemotherapy either alone or in combination with irinotecan (IRI) in the Fédération Francophone de Cancérologie Digestive (FFCD) 2001-02 study. Sites participating in the geriatric substudy completed geriatric screening tools to perform prognostic factor analyses for treatment safety during the first 4 months after treatment initiation.ResultsThe geriatric score was calculated in 123 patients (44%). Median age was 80 years (range, 75 to 91 years). The Charlson comorbidity index was ≤ 1 in 75%, Mini-Mental State Examination (MMSE) score was ≤ 27/30 in 31%, and Instrumental Activities of Daily Living (IADL) showed impairment in 34% of the patients. Seventy-one patients (58%) had grade 3 to 4 toxicity, 41 (33%) had a dose-intensity reduction of more than 33%, and 54 (44%) had at least one unexpected hospitalization during the first 4 months after starting treatment. In multivariate analysis, significant predictive factors for grade 3-4 toxicity were IRI arm (odds ratio [OR], 5.03), MMSE ≤ 27/30 (OR, 3.84), and impaired IADL (OR, 4.67); for dose-intensity reduction of > 33%, the significant predictive factors were alkaline phosphates > 2 × upper limit of normal (OR, 4.16) and IRI arm (OR, 6.85); and for unexpected hospitalization, significant predictive factors were MMSE ≤ 27/30 (OR, 4.56) and Geriatric Depression Scale ≤ 2 (OR, 5.52). CONCLUSION
Geriatric factors (MMSE and IADL) are predictive of severe toxicity or unexpected hospitalization (MMSE) in a randomized prospective phase III study in mCRC. These results suggest that cognitive function and autonomy impairment should be taken into account when choosing a regimen for chemotherapy.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 03/2013;
[show abstract][hide abstract] ABSTRACT: Background Sorafenib is an oral anticancer agent targeting Ras-dependent signaling and angiogenic pathways. A phase I trial demonstrated that the combination of gemcitabine and sorafenib was well tolerated and had activity in advanced pancreatic cancer (APC) patients. The BAYPAN study was a multicentric, placebo-controlled, double-blind, randomized phase III trial comparing gemcitabine/sorafenib and gemcitabine/placebo in the treatment of APC. Patients and methods The patient eligibility criteria were locally advanced or metastatic pancreatic adenocarcinoma, no prior therapy for advanced disease and a performance status of zero to two. The primary end point was progression-free survival (PFS). The patients received gemcitabine 1000 mg/m(2) i.v., weekly seven times followed by 1 rest week, then weekly three times every 4 weeks plus sorafenib 200 mg or placebo, two tablets p.o., twice daily continuously. Results Between December 2006 and September 2009, 104 patients were enrolled on the study (52 pts in each arm) and 102 patients were treated. The median and the 6-month PFS were 5.7 months and 48% for gemcitabine/placebo and 3.8 months and 33% for gemcitabine/sorafenib (P = 0.902, stratified log-rank test), respectively. The median overall survivals were 9.2 and 8 months, respectively (P = 0.231, log-rank test). The overall response rates were similar (19 and 23%, respectively). Conclusion The addition of sorafenib to gemcitabine does not improve PFS in APC patients.
Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 07/2012; 23(11):2799-805.
[show abstract][hide abstract] ABSTRACT: To report the results of a medical management of sphincter of oddi dysfunction (SOD) after an intermediate follow-up period.
A total of 59 patients with SOD (2 men and 57 women, mean age 51 years old) were included in this prospective study. After medical treatment for one year, the patients were clinically re-evaluated after an average period of 30 mo.
The distribution of the patients according to the Milwaukee's classification was the following: 11 patients were type 1, 34 were type 2 and 14 were type 3. Fourteen patients underwent an endoscopic sphincterotomy (ES) after one year of medical treatment. The median intermediate follow-up period was 29.8 ± 3 mo (3-72 mo). The initial effectiveness of the medical treatment was complete, partial and poor among 50.8%, 13.5% and 35%, respectively, of the patients. At the end of the follow-up period, 37 patients (62.7%) showed more than 50% improvement. The rate of improvement in patients who required ES was not significantly different compared with the patients treated conservatively (64.2% vs 62.2%, respectively).
Our study confirms that conservative medical treatment could be an alternative to endoscopic sphincterotomy because, after an intermediate follow-up period, the two treatments show the same success rates.
World journal of gastroenterology : WJG. 04/2012; 18(14):1610-5.
[show abstract][hide abstract] ABSTRACT: We aimed to analyze the feasibility and efficacy of a new transperineal access to treat anorectal sepsis (fistulae and abscesses) under endoanal ultrasonography guidance.
Twenty-five patients (80% Crohn disease) were included retrospectively. Twenty-one patients had fistulae (perianal, urethroanal, and anovaginal) treated by injection of heterologous fibrin glue and cyanoacrylate. Four patients with abscesses were treated by irrigation-injection of normal saline solution and an aminoglycoside antibiotic.
Twenty-five patients underwent 32 treatment sessions. At 4 weeks' evaluation, 19 patients (90.5%) with anal fistulae ultimately achieved a 4-week short-term success. Of these, 5 patients (26%) showed resolution of symptoms and persistent occlusion of the fistula track at long-term follow-up (>6 mo). At 4-week follow-up, the treatment of abscesses was successful in 3 of 4 cases. However, a relapse was observed in 2 cases after a mean period of 3 months. No serious adverse events were observed.
Endoanal ultrasonography-assisted percutaneous transperineal injection represents a sphincter-sparing alternative to the surgical route, with interesting outcomes and excellent tolerability for the treatment of anorectal sepsis.
[show abstract][hide abstract] ABSTRACT: We analyzed the influence of 8 germinal polymorphisms of candidate genes potentially related to EGFR signalling (EGFR, EGF, CCND1) or antibody-directed cell cytotoxicity (FCGR2A and FCGR3A) on outcome of colorectal cancer (CRC) patients receiving cetuximab-based therapy.
Fifty-eight advanced CRC patients treated with cetuximab-irinotecan salvage therapy between 2001 and 2007 were analyzed (mean age 60; 50 PS 0-1). The following polymorphisms were analyzed on blood DNA: EGFR (CA repeats in intron 1, -216 G > T, -191C > A, R497K), EGF (A61G), CCND1 (A870G), FCGR2A (R131H), FCGR3A (F158V). Statistical analyses were conducted on the total population and on patients with wt KRas tumors. All SNPs were considered as ternary variables (wt/wt vs wt/mut vs mut/mut), with the exception of -191C > A EGFR polymorphism (AA patient merged with CA patients).
Analysis of skin toxicity as a function of EGFR intron 1 polymorphism showed a tendency for higher toxicity in patients with a low number of CA-repeats (p = 0.058). CCND1 A870G polymorphism was significantly related to clinical response, both in the entire population and in KRas wt patients, with the G allele being associated with a lack of response. In wt KRas patients, time to progression (TTP) was significantly related to EGFR -191C > A polymorphism with a longer TTP in CC patients as compared to others, and to CCND1 A870G polymorphism with the G allele being associated with a shorter TTP; a multivariate analysis including these two polymorphisms only retained CCND1 polymorphism. Overall survival was significantly related to CCND1 polymorphism with a shorter survival in patients bearing the G allele, and to FCGR3A F158V polymorphism with a shorter survival in VV patients (in the entire population and in KRas wt patients). FCGR3A F158V and CCND1 A870G polymorphisms were significant independent predictors of overall survival.
Present original data obtained in wt KRas patients corresponding to the current cetuximab-treated population clearly suggest that CCND1 A870G polymorphism may be used as an additional marker for predicting cetuximab efficacy, TTP and overall survival. In addition, FCGR3A F158V polymorphism was a significant independent predictor of overall survival.
[show abstract][hide abstract] ABSTRACT: The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer.
In this open-label, randomised, phase 3 trial, we randomly assigned patients (1:1 ratio) with advanced, measurable, non-resectable colorectal cancer and WHO performance status 0-2 to receive either first-line treatment with bolus (400 mg/m(2)) and infusional (2400 mg/m(2)) fluorouracil plus leucovorin (400 mg/m(2)) (simplified LV5FU2 regimen), second-line LV5FU2 plus oxaliplatin (100 mg/m(2)) (FOLFOX6), and third-line LV5FU2 plus irinotecan (180 mg/m(2)) (FOLFIRI) or first-line FOLFOX6 and second-line FOLFIRI. Chemotherapy was administered every 2 weeks. Randomisation was done centrally using minimisation (minimisation factors were WHO performance status, previous adjuvant chemotherapy, number of disease sites, and centre). The primary endpoint was progression-free survival after two lines of treatment. Analyses were by intention-to-treat. This trial is registered at ClinicalTrials.gov, NCT00126256.
205 patients were randomly assigned to the sequential group and 205 to the combination group. 161 (79%) patients in the sequential group and 161 (79%) in the combination group died during the study. Median progression-free survival after two lines was 10·5 months (95% CI 9·6-11·5) in the sequential group and 10·3 months (9·0-11·9) in the combination group (hazard ratio 0·95, 95% CI 0·77-1·16; p=0·61). All six deaths caused by toxic effects of treatment occurred in the combination group. During first-line chemotherapy, significantly fewer severe (grade 3-4) haematological adverse events (12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group; p<0·0001) and non-haematological adverse events (26 events vs 186 events; p<0·0001) occurred in the sequential group than in the combination group.
Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced, non-resectable colorectal cancer.
[show abstract][hide abstract] ABSTRACT: Chemotherapy combinations and addition of cetuximab or bevacizumab to chemotherapy have been shown to improve overall survival of metastatic colorectal cancer (CRC) patients. However, the efficacy of cetuximab when administered after bevacizumab failure is still unknown.
Fifty-eight consecutive patients diagnosed with advanced colorectal cancer between treated with cetuximab following irinotecan failure were included in our analysis. A multivariate Cox model analysis was performed to estimate the effect of previous bevacizumab regimen on survival.
Thirteen (22.4%) were pre-treated with anti-VEGF agents. None of them responded to cetuximab, and this subgroup presented a significantly decreased disease-specific survival as compared to treatment-naïve patients (9.1 months vs. 4.9 months; p=0.026). This difference remained statistically significant in a multivariate Cox model after adjusting for age, sex, performance status (PS), and K-RAS status (RR=2.2; 95% CI: 1.1-4.5, p=0.03).
These study results suggest that a previous anti-VEGF therapy decrease cetuximab efficiency.
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 07/2011; 43(11):917-9.
[show abstract][hide abstract] ABSTRACT: Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma. Although the 5-fluorouracil (5FU), folinic acid and cisplatin combination (LV5FU2-CDDP) is an option, the optimal order of the regimens must be determined. The first strategic phase III trial comparing LV5FU2-CDDP followed by gemcitabine versus gemcitabine followed by LV5FU2-CDDP was conducted.
Patients with metastatic pancreatic adenocarcinoma, performance status (PS) 0-2, without prior chemotherapy were randomly assigned (1:1) to receive either LV5FU2-CDDP followed by gemcitabine at disease progression or toxicity (Arm A), or the opposite sequence (Arm B). 202 patients had to be included and 170 deaths had to be observed to detect an expected improvement in median overall survival (OS) from 6.5 to 10 months in Arm A (two-sided α = 5% and β = 20%).
202 patients were included (Arm A, 102; Arm B, 100). Median age, male/female ratio, PS 0-1 and previous surgery were similar in the two arms. After a median follow-up of 44 months, median OS in Arm A was 6.6 months versus 8.0 months in Arm B (p = 0.85). Median progression-free survival was similar between Arms A and B. More grade 3/4 toxicities were observed when LV5FU2-CDDP was administered as a first-line treatment compared with gemcitabine: 79% versus 64% (p = 0.018).
This trial did not show any strategic advantage to using LV5FU2-CDDP as a first-line treatment and suggests that gemcitabine remains the standard first-line treatment. Sixty-one per cent of patients were able to receive a second line of chemotherapy.
[show abstract][hide abstract] ABSTRACT: Introduction
Le cétuximab est un anticorps monoclonal anti- EGFR qui a prouvé son efficacité dans les CCRM en association à une chimiothérapie à base d’irinotecan ou en monothérapie . De nombreuses études ont montré que la mutation KRAS est associée à un échec du traitement par cétuximab mais une faible proportion de patients KRAS sauvage sont répondeurs (10 à 49 %) . Le but de ce travail rétrospectif multicentrique était d’évaluer la valeur prédictive des polymorphismes liés à l’EGFR sur la réponse au cétuximab sur une série de patients atteints d’un CCRM.
Patients et Méthodes
Les patients inclus rétrospectivement dans deux centres universitaires avaient un adénocarcinome colorectal métastatique traité par cétuximab. La mutation KRAS était analysée sur l’ADN tumoral des prélèvements inclus en paraffine et les polymorphismes EGFR R497K, intron 1 EGFR, EGFR - 216 G/T, EGFR -191 C/A, FCGR2A H131R, FCGR3 V158F, EGF G61A et Cycline D1 A870G étaient étudiés par PCR-RFLP sur ADN extrait de culots leucocytaires ou de prélèvement tissulaires inclus en paraffine.
De décembre 2001 à décembre 2007, 58 patients ont été inclus. Parmi eux 86,2 % étaient en échappement thérapeutique à l’irinotecan et à l’oxaliplatine, et 22,4 % étaient prétraités par un anti-VEGF. La mutation KRAS a été retrouvée chez 16 patients (27,6 %). L’influence des polymorphismes a été testée chez les 43 patients ayant reçu au moins 6 cycles de cétuximab. Le taux de réponse était significativement amélioré chez les patients homozygotes pour l’allèle A de la CCND1 (50 % νs 8,6 %, p = 0,031). La survie sans progression (SSP médiane 2,7 mois) et la survie globale (SG médiane 8,4 mois) étaient significativement corrélées au polymorphisme EGFR-191 C/A avec une meilleure survie chez les patients homozygotes CC par rapport aux autres (p = 0,012 et 0,015 ; RR = 2,63 et 2,78, IC 95 % : 1,2 - 5,6 et 1,2 - 6,4, respectivement pour la SSP et la SG). Les autres polymorphismes n’influençaient ni la réponse ni la survie. La toxicité cutanée était significativement corrélée au polymorphisme de l’intron 1, avec une toxicité cutanée grade 2 et 3 plus importante chez les patients ayant un faible nombre de répétition dinucléotidique CA (85,7 % chez les patients avec une somme de CA ≤ 35 νs 55 % chez les patients avec une somme de CA > 35, p = 0,043, Odds ratio 4,9, IC 95 % CI : 1,1 - 22,1). Par ailleurs, la survie spécifique était significativement abaissée chez les patients traités antérieurement par un anti-VEGF de 9,1 à 4,9 mois (p = 0,03 RR = 2,2 ; IC 95 % : 1,1 - 4,5 p = 0,03).
Nos résultats suggèrent que les polymorphismes cycline D1 A870G, et EGFR -191C/A influencent significativement la réponse au cétuximab, la survie sans progression et la survie spécifique et confirment l’impact de l’intron 1 sur l’intensité de la toxicité cutanée. Un traitement antérieur par une thérapie anti VEGF est associé à une diminution significative de la survie spécifique.
Gastroenterologie Clinique Et Biologique - GASTROEN CLIN BIOL. 01/2009; 33(3).
[show abstract][hide abstract] ABSTRACT: The aim of this study was to investigate the clinical progression of patients who had severe acute pancreatitis (AP) and a stay in hospital of more than a month.
A total of 24 patients (median age: 57 years) were included in this eight-year retrospective study. Cure was defined as the restoration of the pancreatic parenchyma, and the disappearance of all pseudocysts and pancreatic fistulae. Data including the duration of hospital stay, disease severity and pancreatic sequelae were also collected.
The median total duration of the hospital stay was 67 days. The overall mortality rate was 20.8%, whereas the mortality rate due to AP was 12.5%. The average healing period was 7.7 months. On univariate analysis, patients who also had respiratory diseases, chronic alcoholism, necrotizing superinfection, pseudocyst, food intolerance and/or hospital-acquired infection took significantly longer to heal. After cure, we observed pancreatic and/or hepatic duct stenoses in 50% of cases, and the onset or aggravation of diabetes in 25%.
In patients hospitalized for more than one month because of necrotizing AP, the rate of mortality is around 20%, with a final hospital stay of two months and a healing period of more than seven months. In addition, half of the patients presented with pancreatic or biliary sequelae.
Gastroentérologie clinique et biologique. 11/2008; 33(3):210-6.
[show abstract][hide abstract] ABSTRACT: Endoscopic procedures have become a first-line approach to the treatment of pancreatic pseudocysts.
Our purpose was to determine the results of a therapeutic algorithm including EUS-assisted drainage, transpapillary drainage, and conventional endoscopic drainage in terms of (1) feasibility and efficacy of the endoscopic procedure and (2) morbidity.
Prospective study with a treatment algorithm drawn up before the endoscopic procedure, including either conventional endoscopic transmural drainage (CTMD), conventional transpapillary drainage (CTPD), or EUS-guided transmural drainage (EUS-GTD).
A total of 50 patients, including 15 women and 35 men with a mean age of 51 years, were included in this prospective study.
The mean size of the pseudocysts was 8.2 cm (range 3-12 cm). A total of 29 pseudocysts did not bulge into the digestive wall (58%); 24 (48%) neither bulged nor communicated with the pancreatic duct. EUS-GTD was performed on 28 patients (56%), CTMD on 13 patients (26%), and CTPD on 8 patients (16%), and endoscopic procedures failed in 1 patient. Technical feasibility was 98% (49/50), and clinical success was achieved in 90% of the cases and disappearance of the pseudocysts in 96% of the cases without significant differences among the 3 groups. The morbidity rate was 18% (9 cases). Five superinfections occurred in the EUS-GTD group and 1 in the CTMD group. One death occurred from late bleeding in the CTMD group.
Randomization of patients in this prospective study was not possible because of the different characteristics of the pseudocysts.
With this algorithm, clinical success was achieved in 45 (90%) of the cases and disappearance of the pseudocysts in 48 (96%) of the cases with a reasonable morbidity rate. In half of the cases, EUS is required for treating pancreatic pseudocyst.