Biomedical subjects

Xavier Paoletti

Publications and source records attributed to Xavier Paoletti.

9 recordsLinked to original sources

PubMed2006

Breast cancer risk in relation to abortion: Results from the EPIC study.

The role of spontaneous and induced abortion on breast cancer risk is examined among 267,361 women recruited into the European Prospective Investigation into Cancer and nutrition between 1992 and 2000. The data were collected from 20 centers, across 9 countries, and included information on a total of 4,805 women with breast cancer, of whom 1,657 reported having ever had any type of abortion. Overall, the relative risk of breast cancer in women who reported ever having had a spontaneous abortion was not significantly elevated when compared with women who reported never having had such an abortion (RR = 1.07, 95% CI = 0.99-1.14). However, there was some evidence of a slight increase in the risk of breast cancer among women who reported having had 2 or more spontaneous abortions (1.20, 1.07-1.35). The relative risk of breast cancer among women who reported ever having had an induced abortion when compared to women who reported never having had an induced abortion was 0.95 (0.87-1.03). Overall, the findings provide further unbiased evidence of the lack of an adverse effect of induced abortion on breast cancer risk.

Abortion, Induced↗

PubMed2006

Using the continual reassessment method: lessons learned from an EORTC phase I dose finding study.

Many clinicians often do not feel comfortable with the Continual Reassessment Method (CRM). This article reviews its implementation, showing the characteristics, advantages and limitations of this method in Phase I studies as an alternative to the classical 'Fibonacci' escalation schema. A two center, dose escalation phase I study of rViscumin was carried out. Thirty-seven patients were included at 14 different dose-levels (10 to 6400 ng/kg). The complete clinical results are presented elsewhere. A 2-step CRM design enables one to speed-up the study and most importantly to obtain an accurate estimate of the maximum tolerated dose (MTD). Different management issues related to a multicenter study are illustrated and we show how the method can go wrong when severe toxicity, or dose limiting toxicity (DLT), is not considered by the clinician as being sufficient to limit dose escalation (here a grade 3 asthenia related to the drug). This would have affected any dose finding methods. We believe that CRM is a good alternative to the standard method from both a statistical and a practical point of view but further methodological research is necessary to address the issues related to the composite nature of the endpoint.

Adolescent↗

PubMed2005

Successful long-term program for controlling methicillin-resistant Staphylococcus aureus in intensive care units.

OBJECTIVE: To evaluate the effectiveness of screening strategy and contact precautions for patients with methicillin-resistant Staphylococcus aureus (MRSA). DESIGN AND SETTING: Prospective observational cohort from 1 February 1995 to 31 December 2001 in three intensive care units (45 beds) in a French teaching hospital. PATIENTS: 8,548 patients admitted to the three ICUs had nasal screening on ICU admission and weekly thereafter. Contact precautions were used in MRSA-positive patients. The following variables were collected: age, gender, severity score, length of stay, workload, and colonization pressure (percentage of patient-days with an MRSA to the number of patient-days in the unit). Alcohol-based handrub solution was introduced in July 2000. We compared the period before this (P1) with that thereafter (P2). RESULTS: Of the 8,548 admitted patients 554 (6.5%) had MRSA at ICU admission, and 456 of the 7,515 (6.1%) exposed patients acquired MRSA. Acquisition incidence decreased from 7.0% in P1 to 2.8% in P2. Independent variables associated with MRSA acquisition were: age (adjusted odds ratio 1.013), severity score (1.047), length of ICU stay (1.015), colonization pressure (1.019), medical ICU (1.58), and P2 (0.49). CONCLUSIONS: MRSA control in these ICUs characterized by a high prevalence of MRSA at admission was achieved via multiple factors, including screening, contact precautions, and use of alcoholic handrub solution. Our results after adjustment of risk factors for MRSA acquisition and the steady improvement in MRSA over several years strengthen these findings. MRSA spreading can be successfully controlled in ICUs with high colonization pressure.

Adult↗

PubMed2005

Regulation of peritoneal and systemic neutrophil-derived tumor necrosis factor-alpha release in patients with severe peritonitis: role of tumor necrosis factor-alpha converting enzyme cleavage.

OBJECTIVE: Polymorphonuclear neutrophil (PMN) influx and peritoneal tumor necrosis factor (TNF)-alpha production are key host defense mechanisms during peritonitis. The aim of this study was to explore the potential interactions between TNF-alpha production and TNF-alpha converting enzyme (TACE) expression by PMN in the blood and peritoneum of patients with severe peritonitis. DESIGN: A prospective study. SETTING: A surgical adult intensive care unit in a university hospital. PATIENTS: A total of 29 consecutive immunocompetent patients with severe sepsis within 48 hrs of onset were enrolled and underwent laparotomy for a diffuse secondary peritonitis. Thirteen volunteers served as controls. MEASUREMENTS: Blood and peritoneal fluid recovered during laparotomy were analyzed and compared for 1) soluble TNF-alpha, soluble L-selectin, and type I and II TNF-alpha receptor levels; 2) PMN membrane TNF-alpha, membrane L-selectin, and TACE expression (flow cytometry); and 3) TNF-alpha production by cultured PMN. Correlations between these forms of PMN-derived TNF-alpha and the severity of the peritonitis and patient's outcome were investigated. MAIN RESULTS: Elevated soluble TNF-alpha levels in both plasma and peritoneal fluid from the patients were found, together with decreased expression of membrane TNF-alpha and TACE up-regulation at the PMN surface. Soluble L-selectin and type I and II TNF receptors were highly released, suggesting also the role of TACE. In contrast, the capacity of both blood and peritoneal PMN to synthesize TNF-alpha in vitro, in optimal conditions of stimulation (lipopolysaccharide + interferon-gamma), was impaired as compared with controls' blood PMN. Regulation of PMN-derived TNF-alpha was similar in the two compartments, but responses were more pronounced in the peritoneum. TACE up-regulation at the surface of blood-derived PMN correlated with the Sequential Organ Failure Assessment score and vital outcome. CONCLUSION: These human data demonstrate that mTACE is up-regulated at the PMN surface during severe peritonitis. This finding could be related to a paracrine regulatory loop involving some TACE substrates such as TNF-alpha, L-selectin, and TNF receptors.

ADAM Proteins↗

PubMed2004

Tension-free vaginal tape and associated procedures: a case control study.

OBJECTIVES: We compare objective and subjective cure rates after tension-free vaginal tape procedures performed alone or in conjunction with vaginal procedures. METHODS: One hundred eighty-six women underwent a tension-free vaginal tape procedure for stress or mixed urinary incontinence. One hundred women treated with tension-free vaginal tape alone (group 1) were compared with 40 women treated with tension-free vaginal tape and concomitant vaginal hysterectomy (group 2), and 46 patients treated with tension-free vaginal tape and pelvic floor reconstruction (group 3). Patient outcomes, surgical difficulties and complications are reported. Postoperative voiding diaries, standing stress-test results, and patient satisfaction were compared. RESULTS: There were no significant differences among the three groups in terms of age, menopausal status, BMI, previous incontinence surgery, or the type and degree of incontinence. Parity was significantly higher in the group treated with tension-free vaginal tape and pelvic floor reconstruction ( p=0.04 ). The overall perioperative complication rate was 15.6%. Women treated with tension-free vaginal tape and hysterectomy (group 2), and those treated with tension-free vaginal tape and pelvic floor reconstruction (group 3) had a significantly higher incidence of bladder injury (17.9% and 13%, respectively, versus 5% in group 1; p=0.05 ). Estimated blood loss and the frequencies of postoperative urgency and voiding disorders did differ significantly between women treated with tension-free vaginal tape alone and those who underwent associated procedures. The mean follow-up time was 24.5+/-2.6 months. No difference in the objective cure rate was found between the tension-free vaginal tape group and the other two groups (93% versus 97.5% and 91.1%; p=0.3 ). No difference in the subjective cure rate was found between the tension-free vaginal tape group and the groups undergoing associated procedures (72% versus 72.5% and 68.8%; p=0.4). CONCLUSION: Pelvic floor defects, benign uterine disorders and stress urinary incontinence can be safely treated with tension-free vaginal tape and vaginal procedures during the same surgical procedure.

Case-Control Studies↗

PubMed2003

Induced and spontaneous abortion and breast cancer risk: results from the E3N cohort study.

Recent reviews reach conflicting conclusions on breast cancer risk after spontaneous or induced abortion. E3N is a large-scale cohort study collecting detailed information on environmental and reproductive factors. We investigated the relation between breast cancer and a history of induced and/or spontaneous abortion, using the data from the 100,000 women aged 40-65 at entrance in 1990. Among them, over 2,600 new invasive breast cancers had been diagnosed by June 2000. Multivariate analysis, adjusted for known potential confounders, showed no association between a history of induced abortion and breast cancer risk either in the whole population (relative risk [RR] = 0.91, 95% confidence interval [CI] 0.82-0.99) or in subgroups defined by parity or by menopausal status. Overall, the association between spontaneous abortion and breast cancer was not significant (RR = 1.05, 95% CI 0.95-1.15). However, there is a suggestion of increased risk with increased number of miscarriages (RR = 1.20, 95% CI 0.92-1.56 after 3 or more). Moreover, an interaction with menopausal status was observed. In premenopause, the risk decreased with increasing number of spontaneous abortions, whereas it increased in postmenopause. Among nulliparous and parous women, the relative risk estimates were respectively equal to 1.16 (95% CI 1.04-1.30, p trend < 0.0008) and 1.14 (95% CI 1.01-1.28, p trend = 0.005). Premenopausal breast cancer, on the other hand, appeared to be less frequent in women who had had repeated miscarriages. We conclude that there is no relationship between breast cancer and induced abortion but that an association with spontaneous abortion is possible and may depend on menopausal status.

Abortion, Induced↗

PubMed2003

Phase II study of XR5000 (DACA), an inhibitor of topoisomerase I and II, administered as a 120-h infusion in patients with advanced ovarian cancer.

BACKGROUND: XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II. The aim of the present study was to evaluate the antitumoral activity and safety profile of XR5000 given as second-line chemotherapy in patients with ovarian cancer who had relapsed within 1 year after first-line chemotherapy with taxanes and platinum for advanced disease. PATIENTS AND METHODS: Patients received XR5000 at the dose of 3010 mg/m(2) through a 120-h central venous infusion every 3 weeks. Toxicity was graded according to the Common Toxicity Criteria (CTC), version 2.0. An independent panel assessed response every two cycles according to the World Health Organization (WHO) criteria. Gehan's rule was used for sample size determination. RESULTS: Sixteen patients were enrolled; one patient was ineligible because of prior melphalan single agent treatment. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (eight patients), 1 (five patients), or 2 (two patients). The 15 eligible patients received 43 cycles of XR5000 (median 2, range 1-8). Hematological toxicity was mild with only one grade 3 anemia in one patient. Other drug-related toxicities never exceeded grade 3 and included fatigue (four patients), thrombosis (one patient), nausea (one patient), stomatitis (one patient) as well as dyspnea/cough (one patient). One patient who had refused further therapy and controls after the first cycle was not assessable for response evaluation. No objective responses were observed. Four patients experienced stable disease and 10 patients progressive disease. The median time to progression was 42 days (CI 95% 40; 54). CONCLUSIONS: The complete lack of any objective response does not justify further evaluation of XR5000 in patients with advanced ovarian cancer using this dose and schedule, although the therapy was generally well tolerated.

Acridines↗

PubMed2003

Continual reassessment method for ordered groups.

We investigate the two-group continual reassessment method for a dose-finding study in which we anticipate some ordering between the groups. This is a situation in which, for either group, we have little or almost no knowledge about which of the available dose levels will correspond to the maximum tolerated dose (MTD), but we may have quite strong knowledge concerning which of the two groups will have the higher level of MTD, if indeed they do not have the same MTD. The motivation for studying this problem came from an investigation into a new therapy for acute leukemia in children. The background to this study is discussed. There were two groups of patients: one group already received heavy prior therapy while the second group had received relatively much lighter prior therapy. It was therefore anticipated that the second group would have an MTD higher or at least as high as the first. Generally, likelihood methods or, equivalently, the use of noninformative Bayes priors, can be used to model the main aspects of the study, i.e., the MTD for one of the groups, reserving more informative Bayes modeling to be applied to the secondary features of the study. These secondary features may simply be the direction of the difference between the MTD levels for the two groups or, possibly, information on the potential gap between the two MTDs.

Antineoplastic Agents↗

PubMed2002

Non-parametric optimal design in dose finding studies.

We describe a non-parametric optimal design as a theoretical gold standard for dose finding studies. Its purpose is analogous to the Cramer-Rao bound for unbiased estimators, i.e. it provides a bound beyond which improvements are not generally possible. The bound applies to the class of non-parametric designs where the data are not assumed to be generated by any known parametric model. Whenever parametric assumptions really hold it may be possible to do better than the optimal non-parametric design. The goal is to be able to compare any potential dose finding scheme with the optimal non-parametric benchmark. This paper makes precise what is meant by optimal in this context and also why the procedure is described as non-parametric.

Journal Article↗