Benzodiazepines for pediatric epilepsies and their risks in a cohort within the French health care data.

OBJECTIVE: The management of antiseizure treatment in patients with epilepsy relies on the benefit-risk ratio. Data on antiseizure medication (ASM) use in children are limited. We described antiseizure medication use in children with epilepsy (CwE) in France, with a focus on the chronic use of benzodiazepines and related implications. METHODS: We conducted a 5-year cohort study from January 2012, using data from the French national health care data system (Système National des Données de Santé). We included CwE identified through International Classification of Diseases, 10th Revision codes and medications from January 2012 to December 2015 and followed them until December 2016. We described ASMs and assessed whether the risk of initiating a polytherapy after a bitherapy depends on whether benzodiazepine was included in the bitherapy. RESULTS: We identified 62 885 CwE. Valproate was the most reimbursed ASM (40%), followed by lamotrigine (17.6%), levetiracetam (9.3%), clobazam (6.1%), and carbamazepine (5.8%). Prescriptions were initiated at the hospital in 74.5% of CwE. We observed a decrease in the number of CwE with at least one benzodiazepine reimbursement from 15.3% in 2013 to 10.1% in 2016 (p < .0001). The prevalence of CwE with levetiracetam reimbursements increased, whereas that of CwE with valproate decreased. A switch from a bitherapy to a polytherapy was more likely when the bitherapy included a benzodiazepine (subdistribution hazard ratio [sHR] = 1.20 [1.03-1.39]). SIGNIFICANCE: The prevalence of CwE with at least one benzodiazepine reimbursement decreased during the study period. Benzodiazepines were associated with an increased use of subsequent ASM polytherapy.

Amantadine use in the French prospective NS-Park cohort.

OBJECTIVE: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). BACKGROUND: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. METHODS: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). RESULTS: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. CONCLUSIONS: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.

Levosimendan in patients undergoing extracorporeal membrane oxygenation after cardiac surgery: an emulated target trial using observational data.

BACKGROUND: Retrospective cohorts have suggested that levosimendan may facilitate the weaning of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). We therefore studied this clinical question by emulating a randomized trial with observational data. METHODS: All patients with refractory postcardiotomy cardiogenic shock and assisted with VA-ECMO, admitted to a surgical intensive care unit at La Pitié-Salpêtrière Hospital between 2016 and 2019, were eligible. To avoid immortal-time bias, we emulated a target trial sequentially comparing levosimendan administration versus no levosimendan administration in patients treated with VA-ECMO. The primary outcome was time to successful ECMO weaning. The secondary outcomes were 30-day and 1-year mortality. We performed a multivariable analysis to adjust for confounding at baseline. RESULTS: Two hundred and thirty-nine patients were included in the study allowing building a nested trials cohort of 1434 copies of patients. No association of levosimendan treatment and VA-ECMO weaning was found (HR = 0.91, [0.57; 1.45], p = 0.659 in multivariable analysis), or 30-day mortality (OR = 1.03, [0.52; 2.03], p = 0.940) and 1-year mortality (OR = 1.00, [0.53; 1.89], p = 0.999). CONCLUSIONS: Using the emulated target trial framework, this study did not find any association of levosimendan treatment and ECMO weaning success after postcardiotomy cardiogenic shock. However, the population of interest remains heterogeneous and subgroups might benefit from levosimendan.

Clinical features, therapeutic choice and response by phototype in psoriasis: analysis of the French PsoBioTeq cohort.

BACKGROUND: Little is known about phototype and the response to systemic treatment in psoriasis. OBJECTIVES: To assess the characteristics of psoriasis, the therapeutic choice and its efficacy according to phototype. METHODS: We included patients from the PsoBioTeq cohort initiating a first biologic. Patients were classified according to their phototype. The evaluation included disease characteristics, choice of the initial biologic and therapeutic response at 12 months based on 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) and Dermatology Life Quality Index (DLQI) 0/1. RESULTS: Of the 1400 patients included, 423 (30.2%), 904 (64.6%) and 73 (5.2%) were in the phototype I-II, III-IV and V-VI groups, respectively. The V-VI group had a higher initial DLQI, and more frequently initiated ustekinumab. Patients in the V-VI group maintained the initial biologic prescribed as did the other phototype groups, even though the proportion of patients reaching PASI 90 and DLQI 0/1 at 12 months was lower in this group than the other groups. CONCLUSIONS: Patient phototype seems associated with quality of life and choice of the initial biologic in psoriasis. The phototype V-VI group less frequently switched treatments than did the other groups when the response was not efficient.

Novel Composite Endpoint for Assessing Outcomes in Liver Transplantation: Arterial and Biliary Complication-Free Survival.

Transplant and patient survival are the validated endpoints to assess the success of liver transplantation (LT). This study evaluates arterial and biliary complication-free survival (ABCFS) as a new metric. ABC, considered as an event, was an arterial or biliary complication of Dindo-Clavien grade ≥III complication dated at the interventional, endoscopic, or surgical treatment required to correct it. ABCFS was defined as the time from the date of LT to the dates of first ABC, death, relisting, or last follow-up (transplant survival is time from LT to repeat LT or death). Following primary whole LT (n = 532), 106 ABCs occurred and 99 (93%) occurred during the first year after LT. An ABC occurring during the first year after LT (overall rate 19%) was an independent factor associated with transplant survival (hazard ratio [HR], 3.17; P < 0.001) and patient survival (HR, 2.7; P = 0.002) in univariate and multivariate analyses. This result was confirmed after extension of the cohort to split-liver graft, donation after circulatory death, or re-LT (n = 658). Data from 2 external cohorts of primary whole LTs (n = 249 and 229, respectively) confirmed that the first-year ABC was an independent prognostic factor for transplant survival but not for patient survival. ABCFS was correlated with transplant and patient survival (ρ = 0.85 [95% CI, 0.78-0.90] and 0.81 [95% CI, 0.71-0.88], respectively). Preoperative factors known to influence 5-year transplant survival influenced ABCFS after 1 year of follow-up. The 1-year ABCFS was indicative of 5-year transplant survival. ABCFS is a reproducible metric to evaluate the results of LT after 1 year of follow-up and could serve as a new endpoint in clinical trials.

Dynamic evaluation of MRI-targeted, systematic and combined biopsy for prostate cancer diagnosis through 10 years of practice in a single institution.

PURPOSE: To perform a dynamic evaluation of the prostate cancer (PCa) detection rate according to the biopsy strategy over 10 years of practice in a single institution that pioneered MRI-targeted fusion biopsy (MRI-TB). METHODS: This stage 4 IDEAL study prospectively included all consecutive patients who underwent transrectal prostate biopsy for clinically suspected PCa between January 2010 and November 2020. Patients with positive MRI (PIRADS score ≥ 3) underwent both MRI-TB and systematic biopsy (SB) while those with negative MRI (PIRADS score < 3) underwent SB only. The main outcome was the evolution of the detection rate of clinically relevant PCa (csPCa; grade ≥ 2). The secondary outcome was the change in PCa detection rate according to the biopsy method. RESULTS: A total of 2942 men underwent prostate MRI and a prostate biopsy: 2322 underwent MRI-TB and 620 had SB only. The detection rate of csPCa increased 2.5-fold from 23 to 58%. The detection rate of PCa and csPCa was significantly higher in patients who underwent MRI-TB compared to those who underwent SB only (67% vs. 52% and 40% vs. 32%, respectively (P < 0.001 for both comparisons)). The number of csPCa diagnosed by MRI-TB increased linearly over the study period and represented the majority of PCa diagnoses after 2016. CONCLUSION: Implementation of MRI-TB in patients with positive MRI led to improved detection of csPCa.

Progression-free survival as a surrogate for overall survival in oncology trials: a methodological systematic review.

BACKGROUND: Progression-free survival (PFS) is a surrogate endpoint widely used for overall survival (OS) in oncology. Validation of PFS as a surrogate must be done for each indication and each intervention. We aimed to identify all studies evaluating the validity of PFS as a surrogate for OS in oncology, and to describe their methodological characteristics. METHODS: We conducted a systematic review by searching MEDLINE via PubMed and the Cochrane Library with no limitation on time, selected relevant studies and extracted data in duplicate on how surrogacy was evaluated (meta-analytic approach, assessment of correlation and level of evaluation). RESULTS: We identified 91 studies evaluating the validity of PFS as a surrogate for OS in 24 cancer localisations. Although a meta-analytic approach was used in 83 (91%) studies, the methods used to validate PFS as a surrogate of OS were heterogeneous across studies. Of the 47 studies concluding that PFS is a good surrogate for OS, for 15 (32%), there was no quantitative argument for surrogacy. CONCLUSIONS: Although most studies used a meta-analytic approach as recommended, our methodological review highlights heterogeneity in methods and reporting, which stresses the importance of developing and applying clear recommendations in this area.

Impact of a population-based asthma management program in France (Sophia Asthme): A matched controlled before-and-after quasi-experimental study using the French health insurance database (SNDS).

PURPOSE: Sophia Asthme (SA) is a chronic disease management program of the French national health insurance for adult patients with asthma. We evaluated the early impact of this intervention. METHODS: We conducted a matched controlled, before-and-after quasi-experimental study within the French Health Insurance Database (Système National Des Données de Santé [SNDS]). The SA program was implemented in a set of 18 Départements in France and targeted 18- to 44-year-old subjects, with at least two reimbursement dates for asthma drug therapy during the 12-month period prior to program targeting. Change in outcomes was assessed from the "before program" period (January-December 2014) to the "after program implementation" period (March 2015-February 2016) in the program group (eligible to SA program in the 18 Départements) and in the matched controlled group. The main outcome measure was the before-after change in proportion of subjects with a controllers/(controllers+relievers) ratio greater than 50%. RESULTS: Of the 99 578 subjects of the program group, 9225 (9.3%) actually participated in SA program. The program had no significant impact on the proportion of subjects with a ratio greater than 50%. However, subjects exposed to SA program were significantly more likely to be dispensed controller medications (OR = 1.04; 95% CI, 1.01-1.07) and to sustain their use of these medications (OR = 1.08; 95% CI, 1.05-1.12). CONCLUSION: We did not demonstrate any significant impact of the program on the primary outcome. The modest yet encouraging findings of this early evaluation suggest the need for reformulation of the program and its evaluation.

Reduced risk of cancer among low-dose aspirin users: Data from French health care databases.

PURPOSE: The effect of chronic use of low-dose aspirin (LDA) on overall cancer is still unclear owing to many controversial results and methodological limitations of studies. This study aimed to assess the effect of LDA use on overall cancer incidence among the French population. METHODS: We conducted a 10-year historical cohort study using the permanent sample of the French national health care databases: the Système National des Données de Santé (SNDS). We used data for 111 025 individuals aged 50 to 80 years at study entry (January 1, 2006) without prevalent cancer or LDA use. Individuals were followed until the earliest of cancer incidence, death from any cause, exit from the database, or end of the study on December 31, 2015. We estimated the effect of LDA on cancer incidence by using a dynamic model to account for the competing risk of death in the presence of time-dependent exposure and risk factors. RESULTS: LDA use was associated with reduced 10-year risk of cancer (subdistribution hazard ratio [SHR] 0.81 [95% CI 0.77-0.86]). The SHRs were 0.88 [0.82-0.94] for men and 0.93 [0.85-1.02] for women. Moreover, each additional year of LDA use was associated with reduced 10-year risk of cancer (SHR 0.93 [0.92-0.95]). LDA use was also associated with reduced 10-year risk of death (SHR 0.86 [0.82-0.91]). CONCLUSIONS: This is the first population-based study to demonstrate a protective effect of LDA on overall cancer incidence and to account for the main methodological issues of previous observational studies.

Effect of cumulative exposure to corticosteroid and DMARD on radiographic progression in rheumatoid arthritis: results from the ESPOIR cohort.

Objectives: Several authors have tried to predict the risk of radiographic progression in RA according to baseline characteristics, considering exposure to treatment only as a binary variable (Treated: Yes/No). This study aims to model the risk of 5-year radiographic progression taking into account both baseline characteristics and the cumulative time-varying exposure to corticosteroids or DMARDs. Methods: The study population consisted of 403 patients of the Etude et Suivi des Polyarthrites Indifférenciées Récentes cohort meeting the 1987 ACR or 2010 ACR/EULAR criteria for RA at inclusion and having complete radiographic data at baseline and 5 years. Radiographic progression was defined at 5 years as a significant increase of the Sharp/van der Heidje score (smallest detectable difference ⩾5). The best logistic regression model was selected from the following: model including only clinico-biological baseline characteristics; model considering baseline characteristics and treatments as binary variables; and model considering baseline characteristics and treatments as weighted cumulative exposure variables. Results: Radiographic progression occurred in 143 (35.5%) patients. The best model combined anti-citrullinated peptide antibody positivity, ESR, swollen joint count >14 and erosion score at baseline, as well as corticosteroids, MTX/LEF (MTX or LEF) and biologic DMARDs (bDMARDs) as weighted cumulative exposure variables. Recent cumulative exposure to high doses of corticosteroids (⩽ 3months) was significantly associated with the risk of 5-year radiographic progression and a significant protective association was highlighted for a 36-month exposure to bDMARDs. Conclusion: Corticosteroids and bDMARDs play an important role in radiographic progression. Accounting for treatment class and intensity of exposure is a major concern in predictive models of radiographic progression in RA patients.

Closed-form variance estimator for weighted propensity score estimators with survival outcome.

Propensity score (PS) methods are widely used in observational studies for evaluating marginal treatment effects. PS-weighting is a popular PS-based method that allows for estimating both the average treatment effect on the overall population (ATE) and the average treatment effect on the treated population (ATT). Previous research has shown that the variance of the treatment effect is accurately estimated only if the variance estimator takes into account the fact that the propensity score is itself estimated from the available data in a first step of the analysis. In 2016, Austin showed that the bootstrap-based variance estimator was the only existing estimator resulting in approximately correct estimates of standard errors when evaluating a survival outcome and a Cox model was used to estimate a marginal hazard ratio (HR). This author stressed the need to develop a closed-form variance estimator of the marginal HR accounting for the estimation of the PS. In the present research, we developed such variance estimators both for the ATE and ATT. We evaluated their performance with an extensive simulation study and compared them to bootstrap-based variance estimators and to naive variance estimators that do not account for the estimation step. We found that the performance of the proposed variance estimators was similar to that of the bootstrap-based estimators. The proposed variance estimators provide an alternative to the bootstrap estimator, particularly interesting in situations in which time-consumption and/or reproducibility are an important issue. An implementation has been developed for the R software and is freely available (package hrIPW).

Estimation of conditional and marginal odds ratios using the prognostic score.

Introduced by Hansen in 2008, the prognostic score (PGS) has been presented as 'the prognostic analogue of the propensity score' (PPS). PPS-based methods are intended to estimate marginal effects. Most previous studies evaluated the performance of existing PGS-based methods (adjustment, stratification and matching using the PGS) in situations in which the theoretical conditional and marginal effects are equal (i.e., collapsible situations). To support the use of PGS framework as an alternative to the PPS framework, applied researchers must have reliable information about the type of treatment effect estimated by each method. We propose four new PGS-based methods, each developed to estimate a specific type of treatment effect. We evaluated the ability of existing and new PGS-based methods to estimate the conditional treatment effect (CTE), the (marginal) average treatment effect on the whole population (ATE), and the (marginal) average treatment effect on the treated population (ATT), when the odds ratio (a non-collapsible estimator) is the measure of interest. The performance of PGS-based methods was assessed by Monte Carlo simulations and compared with PPS-based methods and multivariate regression analysis. Existing PGS-based methods did not allow for estimating the ATE and showed unacceptable performance when the proportion of exposed subjects was large. When estimating marginal effects, PPS-based methods were too conservative, whereas the new PGS-based methods performed better with low prevalence of exposure, and had coverages closer to the nominal value. When estimating CTE, the new PGS-based methods performed as well as traditional multivariate regression. Copyright © 2016 John Wiley & Sons, Ltd.

Self-controlled designs in pharmacoepidemiology involving electronic healthcare databases: a systematic review.

BACKGROUND: Observational studies are widely used in pharmacoepidemiology. Several designs can be used, in particular self-controlled designs (case-crossover and self-controlled case series). These designs offer the advantage of controlling for time-invariant confounders, which may not be collected in electronic healthcare databases. They are particularly useful in pharmacoepidemiology involving healthcare database. To be valid, they require the presence of some characteristics (key validity assumptions), and in such situations, these designs should be preferred. We aimed at describing the appropriate use and reporting of the key validity assumptions in self-controlled design studies. METHODS: Articles published between January 2011 and December 2014, and describing a self-controlled study design involving electronic healthcare databases were retrieved. The appropriate use (fulfilment of key assumptions) was studied in terms of major (abrupt onset event, rare or recurrent event, and intermittent exposure) and minor assumptions (those for which the design can be adapted). RESULTS: Among the 107 articles describing a self-controlled design, 35/53 (66%) case-crossover studies, and 48/55 (87%) self-controlled case series fulfilled the major validity assumptions for use of the design; 4/35 and 14/48 respectively did not fulfill the minor assumptions. Overall, 31/53 (58%) case-crossover studies and 34/55 (62%) self-controlled case series fulfilled both major and minor assumptions. The reporting of the methodology or the results was appropriate, except for power calculation. CONCLUSIONS: Self-controlled designs were not appropriately used in34% and 13% of the articles we reviewed that described a case-crossover or a self-controlled case series design, respectively. We encourage better use of these designs in situations in which major validity assumptions are fulfilled (i.e., for which they are recommended), accounting for situations for which the design can be adapted.

Evaluation of algorithms to identify incident cancer cases by using French health administrative databases.

PURPOSE: Administrative databases are increasingly being used in cancer observational studies. Identifying incident cancer in these databases is crucial. This study aimed to develop algorithms to estimate cancer incidence by using health administrative databases and to examine the accuracy of the algorithms in terms of national cancer incidence rates estimated from registries. METHODS: We identified a cohort of 463 033 participants on 1 January 2012 in the Echantillon Généraliste des Bénéficiaires (EGB; a representative sample of the French healthcare insurance system). The EGB contains data on long-term chronic disease (LTD) status, reimbursed outpatient treatments and procedures, and hospitalizations (including discharge diagnoses, and costly medical procedures and drugs). After excluding cases of prevalent cancer, we applied 15 algorithms to estimate the cancer incidence rates separately for men and women in 2012 and compared them to the national cancer incidence rates estimated from French registries by indirect age and sex standardization. RESULTS: The most accurate algorithm for men combined information from LTD status, outpatient anticancer drugs, radiotherapy sessions and primary or related discharge diagnosis of cancer, although it underestimated the cancer incidence (standardized incidence ratio (SIR) 0.85 [0.80-0.90]). For women, the best algorithm used the same definition of the algorithm for men but restricted hospital discharge to only primary or related diagnosis with an additional inpatient procedure or drug reimbursement related to cancer and gave comparable estimates to those from registries (SIR 1.00 [0.94-1.06]). CONCLUSION: The algorithms proposed could be used for cancer incidence monitoring and for future etiological cancer studies involving French healthcare databases. Copyright © 2017 John Wiley & Sons, Ltd.

On the use of propensity scores in case of rare exposure.

BACKGROUND: Observational post-marketing assessment studies often involve evaluating the effect of a rare treatment on a time-to-event outcome, through the estimation of a marginal hazard ratio. Propensity score (PS) methods are the most used methods to estimate marginal effect of an exposure in observational studies. However there is paucity of data concerning their performance in a context of low prevalence of exposure. METHODS: We conducted an extensive series of Monte Carlo simulations to examine the performance of the two preferred PS methods, known as PS-matching and PS-weighting to estimate marginal hazard ratios, through various scenarios. RESULTS: We found that both PS-weighting and PS-matching could be biased when estimating the marginal effect of rare exposure. The less biased results were obtained with estimators of average treatment effect in the treated population (ATT), in comparison with estimators of average treatment effect in the overall population (ATE). Among ATT estimators, PS-weighting using ATT weights outperformed PS-matching. These results are illustrated using a real observational study. CONCLUSIONS: When clinical objectives are focused on the treated population, applied researchers are encouraged to estimate ATT with PS-weighting for studying the relative effect of a rare treatment on time-to-event outcomes.

Second-line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine-platinum combination: A large multicenter study by the Association des Gastro-Entérologues Oncologues.

BACKGROUND: Few data are available on second-line chemotherapy (CT2) for advanced biliary tract cancer (ABTC). The aim of this multicenter study was to describe the CT2 regimens used, the response rates, and the outcomes of patients treated with various CT2 regimens. METHODS: Patients who received CT2 for ABTC at 17 French institutions after the failure of the gemcitabine-platinum combination were retrospectively studied. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method. Cox models were used for multivariate analyses. RESULTS: Among 603 patients who received first-line chemotherapy (CT1) for ABTC, 196 received CT2: 5-fluorouracil (5-FU) and irinotecan (n = 64), 5-FU and oxaliplatin (n = 21), 5-FU and cisplatin (n = 38), 5-FU or capecitabine (n = 40), sunitinib (n = 10), or other various regimens (n = 23). Among the 186 assessable patients, there were 22 partial responses and 70 stabilizations. After a median follow-up of 26.4 months, the median PFS and OS were 3.2 and 6.7 months, respectively. There was no significant difference in PFS or OS between CT2 regimens. Fluoropyrimidine-based doublet chemotherapy was not superior to fluoropyrimidine alone in terms of OS and PFS. In a multivariate analysis, a performance status of 0 to 1, disease control with CT1, and a carbohydrate antigen 19-9 (CA 19-9) level ≤ 400 IU/mL were significantly associated with longer PFS and OS. Grade 3 to 4 toxicity occurred in 32% of the patients. CONCLUSIONS: CT2 might provide disease control for selected patients with ABTC after the failure of gemcitabine-platinum, but the prognosis remains poor. No particular regimen seems superior to others, and this calls for new treatments. A good performance status, disease control with CT1, and a low level of CA 19-9 were associated with longer survival.

Regional copy number-independent deregulation of transcription in cancer.

Genetic and epigenetic alterations have been identified that lead to transcriptional deregulation in cancers. Genetic mechanisms may affect single genes or regions containing several neighboring genes, as has been shown for DNA copy number changes. It was recently reported that epigenetic suppression of gene expression can also extend to a whole region; this is known as long-range epigenetic silencing. Various techniques are available for identifying regional genetic alterations, but no large-scale analysis has yet been carried out to obtain an overview of regional epigenetic alterations. We carried out an exhaustive search for regions susceptible to such mechanisms using a combination of transcriptome correlation map analysis and array CGH data for a series of bladder carcinomas. We validated one candidate region experimentally, demonstrating histone methylation leading to the loss of expression of neighboring genes without DNA methylation.

A model combining excess and relative mortality for population-based studies.

Considering expected mortality provides an attractive approach to analyse mortality of population-based cohorts of patients presenting with a chronic disease. Two classes of methods are available: either modelling the excess mortality using an additive hazard model or modelling the relative mortality using a multiplicative hazard model. Because these two models are informative to look for factors associated with mortality related to a chronic disease, we developed an alternative model modelling both the excess and the relative mortality. We generalised Andersen and Vaeth's model to fit covariates and obtain directly an estimation of the Excess Mortality Ratio and Relative Mortality Ratio for each covariate. We assessed the performances of the combined model by using simulations, and it appeared satisfactorily. We illustrate the combined model by data collected in patients presenting with end-stage renal disease and treated by dialysis. The combined model offers the possibility of performing pure additive and multiplicative models and thus to compare their log-likelihoods. The combined model appears useful to select one of these pure models or to conclude to the need of modelling both excess and relative mortality. In this latter case, our model enabled better describing the effect of covariates on the excess and relative mortality.

Synovial sarcoma relapses in children and adolescents: prognostic factors, treatment, and outcome.

INTRODUCTION: Twenty-five to 32% of patients with synovial sarcoma (SS) relapse after appropriate treatment, and experience a poor outcome. Patients who can be salvaged by second-line therapy need to be more clearly identified. PATIENTS AND METHODS: Data of patients treated in SFCE (Société Française des Cancers de l'Enfant) centers with an initial diagnosis of localized SS before the age of 18 years and treated from 1/1988 to 12/2008, and who experienced at least one relapse, were retrieved. After descriptive analysis, statistical analysis was performed to determine prognostic factors. RESULTS: Thirty-seven patients were identified. First relapse occurred after a median interval of 24 months and was localized in 73.0% of cases and metastatic in 24.3% of cases. Treatment of relapse consisted of new surgery in 75.7% of cases, second-line chemotherapy in 73.0% of cases and radiotherapy in 48.6% of cases. Response rate to ifosfamide-based regimens was 36.4%. Overall, 70.3% patients achieved a second complete remission. Median 5-year-event-free survival was 32.8% and 5-year overall survival was 42.1%. Factors significantly correlated with better survival were primary tumor involving the limbs, age less than 12 years at diagnosis, absence of chemotherapy or radiotherapy as initial treatment and local relapse. CONCLUSION: Despite its poor overall outcome, relapse of synovial sarcoma sometimes remains curable. Aggressive surgery, when possible, in combination with chemotherapy and radiotherapy is the recommended treatment. Ifosfamide-based regimens may remain effective in patients with relapsed SS. However, alternative therapies should be proposed in patients with poor prognostic factors.