Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study.

BACKGROUND: Sex steroids could explain the course of multiple sclerosis (MS) in pregnancy. OBJECTIVE: To compare the annualized relapse rate (ARR) 12 weeks post-partum in women treated with nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2) versus placebo. METHODS: POPARTMUS is a randomized, proof-of-concept trial in women with MS, receiving oral NOMAc 10 mg/day and transdermal estradiol 75 µg/week, or placebo. RESULTS: Recruitment was stopped prematurely due to slow inclusions (n = 202). No treatment effect was observed on ARR after 12 weeks (sex steroids = 0.90 (0.58-1.39), placebo = 0.97 (0.63-1.50) (p = 0.79)). CONCLUSION: POPARTMUS failed showing efficacy of a NOMAc-E2 combination in preventing post-partum relapses.

Modeling excess hazard with time-to-cure as a parameter.

Cure models have been widely developed to estimate the cure fraction when some subjects never experience the event of interest. However, these models were rarely focused on the estimation of the time-to-cure, that is, the delay elapsed between the diagnosis and "the time from which cure is reached," an important indicator, for instance, to address the question of access to insurance or loans for subjects with personal history of cancer. We propose a new excess hazard regression model that includes the time-to-cure as a covariate-dependent parameter to be estimated. The model is written similarly to a Beta probability distribution function and is shown to be a particular case of the non-mixture cure models. Parameters are estimated through a maximum likelihood approach and simulation studies demonstrate good performance of the model. Illustrative applications to three cancer data sets are provided and some limitations as well as possible extensions of the model are discussed. The proposed model offers a simple and comprehensive way to estimate more accurately the time-to-cure.

For a sound use of health care data in epidemiology: evaluation of a calibration model for count data with application to prediction of cancer incidence in areas without cancer registry.

There is a growing interest in using health care (HC) data to produce epidemiological surveillance indicators such as incidence. Typically, in the field of cancer, incidence is provided by local cancer registries which, in many countries, do not cover the whole territory; using proxy measures from available nationwide HC databases would appear to be a suitable approach to fill this gap. However, in most cases, direct counts from these databases do not provide reliable measures of incidence. To obtain accurate incidence estimations and prediction intervals, these databases need to be calibrated using a registry-based gold standard measure of incidence. This article presents a calibration model for count data developed to predict cancer incidence from HC data in geographical areas without cancer registries. First, the ratio between the proxy measure and incidence is modeled in areas with registries using a Poisson mixed model that allows for heterogeneity between areas (calibration stage). This ratio is then inverted to predict incidence from the proxy measure in areas without registries. Prediction error admits closed-form expression which accounts for heterogeneity in the ratio between areas. A simulation study shows the accuracy of our method in terms of prediction and coverage probability. The method is further applied to predict the incidence of two cancers in France using hospital data as the proxy measure. We hope this approach will encourage sound use of the usually imperfect information extracted from HC data.

Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study.

BACKGROUND: Whether multiparametric MRI improves the detection of clinically significant prostate cancer and avoids the need for systematic biopsy in biopsy-naive patients remains controversial. We aimed to investigate whether using this approach before biopsy would improve detection of clinically significant prostate cancer in biopsy-naive patients. METHODS: In this prospective, multicentre, paired diagnostic study, done at 16 centres in France, we enrolled patients aged 18-75 years with prostate-specific antigen concentrations of 20 ng/mL or less, and with stage T2c or lower prostate cancer. Eligible patients had been referred for prostate multiparametric MRI before a first set of prostate biopsies, with a planned interval of less than 3 months between MRI and biopsies. An operator masked to multiparametric MRI results did a systematic biopsy by obtaining 12 systematic cores and up to two cores targeting hypoechoic lesions. In the same patient, another operator targeted up to two lesions seen on MRI with a Likert score of 3 or higher (three cores per lesion) using targeted biopsy based on multiparametric MRI findings. Patients with negative multiparametric MRI (Likert score ≤2) had systematic biopsy only. The primary outcome was the detection of clinically significant prostate cancer of International Society of Urological Pathology grade group 2 or higher (csPCa-A), analysed in all patients who received both systematic and targeted biopsies and whose results from both were available for pathological central review, including patients who had protocol deviations. This study is registered with ClinicalTrials.gov, number NCT02485379, and is closed to new participants. FINDINGS: Between July 15, 2015, and Aug 11, 2016, we enrolled 275 patients. 24 (9%) were excluded from the analysis. 53 (21%) of 251 analysed patients had negative (Likert ≤2) multiparametric MRI. csPCa-A was detected in 94 (37%) of 251 patients. 13 (14%) of these 94 patients were diagnosed by systematic biopsy only, 19 (20%) by targeted biopsy only, and 62 (66%) by both techniques. Detection of csPCa-A by systematic biopsy (29·9%, 95% CI 24·3-36·0) and targeted biopsy (32·3%, 26·5-38·4) did not differ significantly (p=0·38). csPCa-A would have been missed in 5·2% (95% CI 2·8-8·7) of patients had systematic biopsy not been done, and in 7·6% (4·6-11·6) of patients had targeted biopsy not been done. Four grade 3 post-biopsy adverse events were reported (3 cases of prostatitis, and 1 case of urinary retention with haematuria). INTERPRETATION: There was no difference between systematic biopsy and targeted biopsy in the detection of ISUP grade group 2 or higher prostate cancer; however, this detection was improved by combining both techniques and both techniques showed substantial added value. Thus, obtaining a multiparametric MRI before biopsy in biopsy-naive patients can improve the detection of clinically significant prostate cancer but does not seem to avoid the need for systematic biopsy. FUNDING: French National Cancer Institute.

Socioeconomic environment and disparities in cancer survival for 19 solid tumor sites: An analysis of the French Network of Cancer Registries (FRANCIM) data.

Social inequalities are concerning along the cancer continuum. In France, social gradient in health is particularly marked but little is known about social gradient in cancer survival. We aimed to investigate the influence of socioeconomic environment on cancer survival, for all cancers reported in the French Network of Cancer Registries. We analyzed 189,657 solid tumors diagnosed between 2006 and 2009, recorded in 18 registries. The European Deprivation Index (EDI), an ecological index measuring relative poverty in small geographic areas, assessed social environment. The EDI was categorized into quintiles of the national distribution. One- and five-year age-standardized net survival (ASNS) were estimated for each solid tumor site and deprivation quintile, among men and among women. We found that 5-year ASNS was lower among patients living in the most deprived areas compared to those living in the least deprived ones for 14/16 cancers among men and 16/18 cancers among women. The extent of cancer survival disparities according to deprivation varied substantially across the cancer sites. The reduction in ASNS between the least and the most deprived quintile reached 34% for liver cancer among men and 59% for bile duct cancer among women. For pancreas, stomach and esophagus cancer (among men), and ovary and stomach cancer (among women), deprivation gaps were larger at 1-year than 5-year survival. In conclusion, survival was worse in the most deprived areas for almost all cancers. Our results from population-based cancer registries data highlight the need for implementing actions to reduce social inequalities in cancer survival in France.

Performance of two formal tests based on martingales residuals to check the proportional hazard assumption and the functional form of the prognostic factors in flexible parametric excess hazard models.

Net survival, the one that would be observed if the disease under study was the only cause of death, is an important, useful, and increasingly used indicator in public health, especially in population-based studies. Estimates of net survival and effects of prognostic factor can be obtained by excess hazard regression modeling. Whereas various diagnostic tools were developed for overall survival analysis, few methods are available to check the assumptions of excess hazard models. We propose here two formal tests to check the proportional hazard assumption and the validity of the functional form of the covariate effects in the context of flexible parametric excess hazard modeling. These tests were adapted from martingale residual-based tests for parametric modeling of overall survival to allow adding to the model a necessary element for net survival analysis: the population mortality hazard. We studied the size and the power of these tests through an extensive simulation study based on complex but realistic data. The new tests showed sizes close to the nominal values and satisfactory powers. The power of the proportionality test was similar or greater than that of other tests already available in the field of net survival. We illustrate the use of these tests with real data from French cancer registries.

A multilevel excess hazard model to estimate net survival on hierarchical data allowing for non-linear and non-proportional effects of covariates.

The excess hazard regression model is an approach developed for the analysis of cancer registry data to estimate net survival, that is, the survival of cancer patients that would be observed if cancer was the only cause of death. Cancer registry data typically possess a hierarchical structure: individuals from the same geographical unit share common characteristics such as proximity to a large hospital that may influence access to and quality of health care, so that their survival times might be correlated. As a consequence, correct statistical inference regarding the estimation of net survival and the effect of covariates should take this hierarchical structure into account. It becomes particularly important as many studies in cancer epidemiology aim at studying the effect on the excess mortality hazard of variables, such as deprivation indexes, often available only at the ecological level rather than at the individual level. We developed here an approach to fit a flexible excess hazard model including a random effect to describe the unobserved heterogeneity existing between different clusters of individuals, and with the possibility to estimate non-linear and time-dependent effects of covariates. We demonstrated the overall good performance of the proposed approach in a simulation study that assessed the impact on parameter estimates of the number of clusters, their size and their level of unbalance. We then used this multilevel model to describe the effect of a deprivation index defined at the geographical level on the excess mortality hazard of patients diagnosed with cancer of the oral cavity. Copyright © 2016 John Wiley & Sons, Ltd.

Trends in excess mortality in follicular lymphoma at a population level.

BACKGROUND: Since the 1990s and since the development of humanised monoclonal antibodies in 1998, the treatment of non-Hodgkin lymphoma has undergone profound changes. Follicular lymphoma (FL) was the first to benefit from this treatment, and several clinical trials have shown a significant improvement in overall survival, but little information is available at a population level. OBJECTIVE: Our objective was to estimate changes in FL-specific mortality at a population level, with an appropriate methodology. METHODS: Two French retrospective population-based studies on FL were conducted, one from 1995 to 2004, in 1477 patients, and one from 1995 to 2010, in 451 patients. Trends in excess mortality rates (EMRs) according to age, sex, Ann Arbor stage and year of diagnosis were evaluated using the flexible model of Remontet et al. RESULTS: Trends in the EMR differed according to age at diagnosis and was higher in advanced stage (III, IV) in patients older than 65 yr. The EMR decreased linearly from 1995 to 2010. This decrease was more marked for advanced stages. CONCLUSION: FL-specific mortality decreased over the years of diagnosis, and the difference according to the lymphoma stage diminished in more recent years. However, progress in the management of FL was not able to erase age-related differences.

A joint frailty model to estimate the recurrence process and the disease-specific mortality process without needing the cause of death.

In chronic diseases, such as cancer, recurrent events (such as relapses) are commonly observed; these could be interrupted by death. With such data, a joint analysis of recurrence and mortality processes is usually conducted with a frailty parameter shared by both processes. We examined a joint modeling of these processes considering death under two aspects: 'death due to the disease under study' and 'death due to other causes', which enables estimating the disease-specific mortality hazard. The excess hazard model was used to overcome the difficulties in determining the causes of deaths (unavailability or unreliability); this model allows estimating the disease-specific mortality hazard without needing the cause of death but using the mortality hazards observed in the general population. We propose an approach to model jointly recurrence and disease-specific mortality processes within a parametric framework. A correlation between the two processes is taken into account through a shared frailty parameter. This approach allows estimating unbiased covariate effects on the hazards of recurrence and disease-specific mortality. The performance of the approach was evaluated by simulations with different scenarios. The method is illustrated by an analysis of a population-based dataset on colon cancer with observations of colon cancer recurrences and deaths. The benefits of the new approach are highlighted by comparison with the 'classical' joint model of recurrence and overall mortality. Moreover, we assessed the goodness of fit of the proposed model. Comparisons between the conditional hazard and the marginal hazard of the disease-specific mortality are shown, and differences in interpretation are discussed.

Multidimensional penalized splines for survival models: illustration for net survival trend analyses.

BACKGROUND: In descriptive epidemiology, there are strong similarities between incidence and survival analyses. Because of the success of multidimensional penalized splines (MPSs) in incidence analysis, we propose in this pedagogical paper to show that MPSs are also very suitable for survival or net survival studies. METHODS: The use of MPSs is illustrated in cancer epidemiology in the context of survival trends studies that require specific statistical modelling. We focus on two examples (cervical and colon cancers) using survival data from the French cancer registries (cases 1990-2015). The dynamic of the excess mortality hazard according to time since diagnosis was modelled using an MPS of time since diagnosis, age at diagnosis and year of diagnosis. Multidimensional splines bring the flexibility necessary to capture any trend patterns while penalization ensures selecting only the complexities necessary to describe the data. RESULTS: For cervical cancer, the dynamic of the excess mortality hazard changed with the year of diagnosis in opposite ways according to age: this led to a net survival that improved in young women and worsened in older women. For colon cancer, regardless of age, excess mortality decreases with the year of diagnosis but this only concerns mortality at the start of follow-up. CONCLUSIONS: MPSs make it possible to describe the dynamic of the mortality hazard and how this dynamic changes with the year of diagnosis, or more generally with any covariates of interest: this gives essential epidemiological insights for interpreting results. We use the R package survPen to do this type of analysis.

Olaparib in recurrent isocitrate dehydrogenase mutant high-grade glioma: A phase 2 multicenter study of the POLA Network.

Background: Based on preclinical studies showing that IDH-mutant (IDHm) gliomas could be vulnerable to PARP inhibition we launched a multicenter phase 2 study to test the efficacy of olaparib monotherapy in this population. Methods: Adults with recurrent IDHm high-grade gliomas (HGGs) after radiotherapy and at least one line of alkylating chemotherapy were enrolled. The primary endpoint was a 6-month progression-free survival rate (PFS-6) according to response assessment in neuro-oncology criteria. Pre-defined threshold for study success was a PFS-6 of at least 50%. Results: Thirty-five patients with recurrent IDHm HGGs were enrolled, 77% at ≥ 2nd recurrence. Median time since diagnosis and radiotherapy were 7.5 years and 33 months, respectively. PFS-6 was 31.4% (95% CI [16.9; 49.3%]). Two patients (6%) had an objective response and 14 patients (40%) had a stable disease as their best response. Median PFS and median overall survival were 2.05 and 15.9 months, respectively. Oligodendrogliomas (1p/19q codeleted) had a higher PFS-6 (53.4% vs. 15.7%, P = .05) than astrocytomas while an initial diagnosis of grade 4 astrocytoma tended to be associated with a lower PFS-6 compared to grade 2/3 gliomas (0% vs 31.4%, P = .16). A grade 2 or 3 treatment-related adverse event was observed in 15 patients (43%) and 5 patients (14%), respectively. No patient definitively discontinued treatment due to side effects. Conclusions: Although it did not meet its primary endpoint, the present study shows that in this heavily pretreated population, olaparib monotherapy was well tolerated and resulted in some activity, supporting further PARP inhibitors evaluation in IDHm HGGs, especially in oligodendrogliomas.

Cancer net survival on registry data: use of the new unbiased Pohar-Perme estimator and magnitude of the bias with the classical methods.

Net survival, the survival which might occur if cancer was the only cause of death, is a major epidemiological indicator required for international or temporal comparisons. Recent findings have shown that all classical methods used for routine estimation of net survival from cancer-registry data, sometimes called "relative-survival methods," provide biased estimates. Meanwhile, an unbiased estimator, the Pohar-Perme estimator (PPE), was recently proposed. Using real data, we investigated the magnitude of the errors made by four "relative-survival" methods (Ederer I, Hakulinen, Ederer II and a univariable regression model) vs. PPE as reference and examined the influence of time of follow-up, cancer prognosis, and age on the errors made. The data concerned seven cancer sites (2,51,316 cases) collected by FRANCIM cancer registries. Net survivals were estimated at 5, 10 and 15 years postdiagnosis. At 5 years, the errors were generally small. At 10 years, in good-prognosis cancers, the errors made in nonstandardized estimates with all classical methods were generally great (+2.7 to +9% points in prostate cancer) and increased in age-class estimations (vs. 5-year ones). At 15 years, in bad- or average-prognosis cancers, the errors were often substantial whatever the nature of the estimation. In good-prognosis cancers, the errors in nonstandardized estimates of all classical methods were great and sometimes very important. With all classical methods, great errors occurred in age-class estimates resulting in errors in age-standardized estimates (+0.4 to +3.2% points in breast cancer). In estimating net survival, cancer registries should abandon all classical methods and adopt the new Pohar-Perme estimator.

Unbiased estimates of long-term net survival of solid cancers in France.

In cancer studies, net survival (observed if cancer was the only cause of death) is a useful indicator but survival estimation at 5 years is insufficient for planning healthcare needs. We estimated the net survivals at 5 and 10 years in a cohort of 387,961 patients who had solid tumors between 1989 and 2004 and were followed-up until January 1, 2008. The cases were actively followed-up. Net survival was estimated with the unbiased Pohar-Perme method. The standardized net survival used the international cancer survival standard weights. In men, the standardized net survivals ranged from 92% at 5 years and 89% at 10 years (testis) to 6% at 5 years and 5% at 10 years (pancreas). In women, it ranged from 91% at 5 years and 88% at 10 years (thyroid) to 10% at 5 years and 7% at 10 years (pancreas). The most frequent cancers had the highest net survivals: 84% at 5 years and 71% at 10 years for prostate and 84% at 5 years and 74% at 10 years for breast cancer. Advanced age was associated with poorer prognosis. In most cancers, the net survivals at 5 and 10 years increased over periods of diagnosis. Net cancer survival is unaffected by mortalities due to other causes. It is the only indicator suitable for comparisons between countries or periods of diagnosis within a given country. The 10-year net survival confirmed the persistent unfavorable role of age in prognosis and the general improvement of cancer management over the last decade.

Changes in the dynamics of the excess mortality rate in chronic phase-chronic myeloid leukemia over 1990-2007: a population study.

Imatinib has transformed the prognosis and the management of chronic myeloid leukemia (CML) and has probably changed the patterns of mortality rates. We explored this change at each disease severity level (Sokal score) through a flexible statistical modeling of the effect of the year of diagnosis on the excess mortality rate. The study included 691 chronic-phase patients from Nord-Pas-de-Calais French CML registry diagnosed from 1990 to 2007. Imatinib was given to 93% of the patients diagnosed after 2000. Comparing the 1990-1994, 1995-1999, and 2000-2007 periods of diagnosis, the 5-year relative survival improved from 64% to 66% and 88%. The year of diagnosis was associated with a significant reduction of the excess mortality, but only in patients with intermediate to high Sokal scores. In high-risk patients diagnosed in the early 1990s, a peak of excess mortality was observed during the second year of follow-up. That peak decreased progressively over the years of diagnosis until disappearing in patients diagnosed after 2000. This study showed different effects according to Sokal scores of the use of imatinib on mortality in patients with chronic-phase CML and showed that since 2000 the pattern of mortality of high-risk patients became similar to that of intermediate-risk ones.

Is the Social Gradient in Net Survival Observed in France the Result of Inequalities in Cancer-Specific Mortality or Inequalities in General Mortality?

BACKGROUND: In cancer net survival analyses, if life tables (LT) are not stratified based on socio-demographic characteristics, then the social gradient in mortality in the general population is ignored. Consequently, the social gradient estimated on cancer-related excess mortality might be inaccurate. We aimed to evaluate whether the social gradient in cancer net survival observed in France could be attributable to inaccurate LT. METHODS: Deprivation-specific LT were simulated, applying the social gradient in the background mortality due to external sources to the original French LT. Cancer registries' data from a previous French study were re-analyzed using the simulated LT. Deprivation was assessed according to the European Deprivation Index (EDI). Net survival was estimated by the Pohar-Perme method and flexible excess mortality hazard models by using multidimensional penalized splines. RESULTS: A reduction in net survival among patients living in the most-deprived areas was attenuated with simulated LT, but trends in the social gradient remained, except for prostate cancer, for which the social gradient reversed. Flexible modelling additionally showed a loss of effect of EDI upon the excess mortality hazard of esophagus, bladder and kidney cancers in men and bladder cancer in women using simulated LT. CONCLUSIONS: For most cancers the results were similar using simulated LT. However, inconsistent results, particularly for prostate cancer, highlight the need for deprivation-specific LT in order to produce accurate results.

Factors influencing access to specialised haematology units during acute myeloblastic leukaemia patient care: A population-based study in France.

BACKGROUND: The excess mortality observed in Acute Myeloblastic Leukaemia (AML) patients, partly attributed to unequal access to curative treatments, could be linked to care pathways. METHODS: We included 1039 AML incident cases diagnosed between 2012-2016 from the 3 French blood cancer registries (3,625,400 inhabitants). We describe patients according to age, the medical entry unit and access to the specialised haematology unit (SHU) during follow-up. Multivariate logistic regression model was done to determine the association between covariables and access to SHU. A total of 713 patients (69%) had access to SHU during care. RESULTS: The most common care pathway concerned referral from the general practitioner to SHU, n = 459(44%). The univariate analysis observed a downward trend for the most deprived patients. Patients who consulted in SHU were younger (66 years vs. 83, p < 0.001), and 92% had access to cytogenetic analysis (vs. 54%, p < 0.001). They also had less poor prognosis AML-subtypes (AML-MRC, t-AML/MDS and AML-NOS) (38% vs. 69%); 77% with de novo AML (vs. 67%, p < 0.003)], more favourable cytogenetic prognostic status (23% vs. 6%, p < 0.001), less comorbidities (no comorbidity = 55% vs. 34%, p < 0.001) and treatments proposed were curative 68% (vs. 5.3%, p < 0.001). Factors limiting access to SHU were age over 80 years (OR, 0.14; 95% CI, 0.04-0.38), severe comorbidities (OR, 0.39; 95% CI, 0.21-0.69), emergency unit referral (OR, 0.28; 95% CI, 0.18-0.44) and non-SHU referral (OR, 0.12; 95% CI, 0.07-0.18). Consultation in an academic hospital increased access to SHU by 8.87 times (95% CI, 5.64-14.2). CONCLUSION: The high proportion of access to cytogenetic testing and curative treatment among patients admitted to SHU, and the importance of early treatment in AML underlines the importance of access to SHU for both diagnosis and treatment.

Effects of socioeconomic status on excess mortality in patients with multiple sclerosis in France: A retrospective observational cohort study.

Background: The effects of socio-economic status on mortality in patients with multiple sclerosis is not well known. The objective was to examine mortality due to multiple sclerosis according to socio-economic status. Methods: A retrospective observational cohort design was used with recruitment from 18 French multiple sclerosis expert centers participating in the Observatoire Français de la Sclérose en Plaques. All patients lived in metropolitan France and had a definite or probable diagnosis of multiple sclerosis according to either Poser or McDonald criteria with an onset of disease between 1960 and 2015. Initial phenotype was either relapsing-onset or primary progressive onset. Vital status was updated on January 1st 2016. Socio-economic status was measured by an ecological index, the European Deprivation Index and was attributed to each patient according to their home address. Excess death rates were studied according to socio-economic status using additive excess hazard models with multidimensional penalised splines. The initial hypothesis was a potential socio-economic gradient in excess mortality. Findings: A total of 34,169 multiple sclerosis patients were included (88% relapsing onset (n = 30,083), 12% progressive onset (n = 4086)), female/male sex ratio 2.7 for relapsing-onset and 1.3 for progressive-onset). Mean age at disease onset was 31.6 (SD = 9.8) for relapsing-onset and 42.7 (SD = 10.8) for progressive-onset. At the end of follow-up, 1849 patients had died (4.4% for relapsing-onset (n = 1311) and 13.2% for progressive-onset (n = 538)). A socio-economic gradient was found for relapsing-onset patients; more deprived patients had a greater excess death rate. At thirty years of disease duration and a year of onset of symptoms of 1980, survival probability difference (or deprivation gap) between less deprived relapsing-onset patients (EDI = -6) and more deprived relapsing-onset patients (EDI = 12) was 16.6% (95% confidence interval (CI) [10.3%-22.9%]) for men and 12.3% (95%CI [7.6%-17.0%]) for women. No clear socio-economic mortality gradient was found in progressive-onset patients. Interpretation: Socio-economic status was associated with mortality due to multiple sclerosis in relapsing-onset patients. Improvements in overall care of more socio-economically deprived patients with multiple sclerosis could help reduce these socio-economic inequalities in multiple sclerosis-related mortality. Funding: This study was funded by the ARSEP foundation "Fondation pour l'aide à la recherche sur la Sclérose en Plaques" (Grant Reference Number 1122). Data collection has been supported by a grant provided by the French State and handled by the "Agence Nationale de la Recherche," within the framework of the "Investments for the Future" programme, under the reference ANR-10-COHO-002, Observatoire Français de la Sclérose en Plaques (OFSEP).

Comparison of 2 Methods for Estimating Multiple Sclerosis-Related Mortality.

BACKGROUND AND OBJECTIVES: Determining whether multiple sclerosis (MS) causes death is challenging. Our objective was to contrast 2 frameworks to estimate probabilities of death attributed to MS (PMS) and other causes (Pother): the cause-specific framework (CSF), which requires the causes of death, and the excess mortality framework (EMF), which does not. METHODS: We used data from the Observatoire Français de la Sclérose en Plaques (OFSEP, n = 37,524) and from a comparative subset where causes of death were available (4,004 women with relapsing-onset MS [R-MS]). In CSF, the probabilities were estimated using the Aalen-Johansen method. In EMF, they were estimated from the excess mortality hazard, which is the additional mortality among patients with MS as compared with the expected mortality in the matched general population. PMS values were estimated at 30 years of follow-up, (1) with both frameworks in the comparative subset, by age group at onset, and (2) with EMF only in the OFSEP population, by initial phenotype, sex, and age at onset. RESULTS: In the comparative subset, the estimated 30-year PMS values were greater using EMF than CSF: 10.9% (95% CI 8.3-13.6) vs 8.7% (6.4-11.8) among the youngest and 20.4% (11.3-29.5) vs 16.2% (8.7-30.2) for the oldest groups, respectively. In the CSF, probabilities of death from unknown causes ranged from 1.5% (0.7-3.0) to 6.4% (2.5-16.4), and even after their reallocation, PMS values remained lower with CSF than with EMF. The estimated probabilities of being alive were close using the 2 frameworks, and the estimated POther (EMF vs CSF) was 2.6% (2.5-2.6) vs 2.1% (1.2-3.9) and 18.1% (16.9-19.3) vs 26.4% (16.5-42.2), respectively, for the youngest and oldest groups. In the OFSEP population, the estimated 30-year PMS values ranged from 7.5% (6.4-8.7) to 24.0% (19.1-28.9) in patients with R-MS and from 25.4% (21.1-29.7) to 36.8% (28.3-45.3) in primary progressive patients, depending on sex and age. DISCUSSION: EMF has the great advantage of not requiring death certificates, their quality being less than optimal. Conceptually, it also seems more relevant because it avoids having to state, for each individual, whether death was directly or indirectly caused by MS or whether it would have occurred anyway, which is especially difficult in such chronic diseases.

Estimating net survival: the importance of allowing for informative censoring.

Net survival, the one that would be observed if cancer were the only cause of death, is the most appropriate indicator to compare cancer mortality between areas or countries. Several parametric and non-parametric methods have been developed to estimate net survival, particularly when the cause of death is unknown. These methods are based either on the relative survival ratio or on the additive excess hazard model, the latter using the general population mortality hazard to estimate the excess mortality hazard (the hazard related to net survival). The present work used simulations to compare estimator abilities to estimate net survival in different settings such as the presence/absence of an age effect on the excess mortality hazard or on the potential time of follow-up, knowing that this covariate has an effect on the general population mortality hazard too. It showed that when age affected the excess mortality hazard, most estimators, including specific survival, were biased. Only two estimators were appropriate to estimate net survival. The first is based on a multivariable excess hazard model that includes age as covariate. The second is non-parametric and is based on the inverse probability weighting. These estimators take differently into account the informative censoring induced by the expected mortality process. The former offers great flexibility whereas the latter requires neither the assumption of a specific distribution nor a model-building strategy. Because of its simplicity and availability in commonly used software, the nonparametric estimator should be considered by cancer registries for population-based studies.

Farnesoid X receptor targeting for hepatitis C: study protocol for a proof-of-concept trial.

OBJECTIVE: To test the modulation of farnesoid X receptor activity on the replication of hepatitis C virus in chronically infected patients. METHODS: This is a proof-of-concept trial that was approved by the ex-French Agency for the Safety of Health Products (ex-Afssaps [currently ANSM]) and an ethics committee. It has started in January 2010. This one-arm, open-label study examines the safety and efficacy of the oral administration of guggulsterone. The main outcome measure will be the assessment of blood viral loads. RESULTS: We planned to enrol 15 genotype 1-infected patients that failed a first-line therapy. CONCLUSION: We think guggulsterone might be an effective therapeutic option for HCV genotype 1 patients who do not respond well to first-line therapy.