Validation of an algorithm for identifying incident cancer cases based on long-term illness and diagnosis related group program data from the French National Health Insurance Information System (SNDS).

PURPOSE: Three generic claims-based algorithms based on the Illness Classification of Diseases (10th revision- ICD-10) codes, French Long-Term Illness (LTI) data, and the Diagnosis Related Group program (DRG) were developed to identify retirees with cancer using data from the French national health insurance information system (Système national des données de santé or SNDS) which covers the entire French population. The present study aimed to calculate the algorithms' performances and to describe false positives and negatives in detail. METHODS: Between 2011 and 2016, data from 7544 participants of the French retired self-employed craftsperson cohort (ESPrI) were first matched to the SNDS data, and then toFrench population-based cancer registries data, used as the gold standard. Performance indicators, such as sensitivity and positive predictive values, were estimated for the three algorithms in a subcohort of ESPrI. RESULTS: The third algorithm, which combined the LTI and DRG program data, presented the best sensitivities (90.9%-100%) and positive predictive values (58.1%-95.2%) according to cancer sites. The majority of false positives were in fact nearby organ sites (e.g., stomach for esophagus) and carcinoma in situ. Most false negatives were probably due to under declaration of LTI. CONCLUSION: Validated algorithms using data from the SNDS can be used for passive epidemiological follow-up for some cancer sites in the ESPrI cohort.

Trends in incidence of invasive vaginal cancer in France from 1990 to 2018 and survival of recently diagnosed women - A population-based study.

OBJECTIVE: The aim of this study was to analyze trends in the incidence of vaginal cancer in France over a 28-year period and to present survival for recently-diagnosed women. METHODS: French cancer registries provided data on invasive vaginal cancers diagnosed from 1990 to 2015 and followed up through June 2018. Trends in incidence were analyzed using a Poisson model with a bidimensional penalized spline of age and year at diagnosis. Net survival analysis was restricted to recently-diagnosed cases (2010-2015) and used a novel approach based on a bidimensional penalized spline of age and time-since-diagnosis to model excess mortality hazard. RESULTS: With 162 new cases estimated in France in 2018, vaginal cancer represented 0.9 % of genital cancers in French women. In 2018, the world population age-standardized incidence rate was 0.2 per 100,000 person-years, median age at diagnosis was 75 years. The standardized incidence rate decreased significantly by 3 % per year (95 % CI, -3.8; -2.2) between 1990 and 2018 (0.4 cases per 100,000 person-year in 1990, vs 0.2 in 2018). Age-standardized net survival at 1 and 5 years after diagnosis was respectively 74 % and 45 %. CONCLUSIONS: This study confirms that vaginal cancer is still a rare malignancy in France with 5-year net survival that remains low. We observed a consistent decrease in the incidence rate between 1990 and 2018. It may be too early to attribute these trends to a positive impact of vaccination campaigns against hrHPV infection, since vaginal cancer mainly affects older women and HPV vaccination has only been available since the early 2000s, and only targets young girls.

To what extent do age, stage and treatment influence survival after invasive cervical cancer: a French population-based study.

PURPOSE: In an attempt to understand why cervical cancer (CC) survival is decreasing with diagnosis period among older women in France, this study aimed to estimate the effects of main prognostic factors on net survival in CC according to age. METHODS: French cancer registries databases were used to retrospectively analyze women diagnosed with CC in 2011-2012. Net survival was estimated with the Pohar-Perme method and prognostic factors (socio-demographic, clinical variables, stage at diagnosis, therapeutic management) were analyzed with Lambert and Royston's flexible parametric model. RESULTS: One thousand one hundred fifty three women with CC were identified. 30.4% were < 45, 41.4% 45-64, and 28.3% ≥ 65 years. Older women were diagnosed at a more advanced stage than younger women: 54.8% regional (FIGO IB2-IVA), 33.0% distant (IVB) in women ≥ 65 years vs 33.7% and 8.0%, respectively in women < 45 years. Half of women with regional stage of CC received recommended treatment; this rate decreased with increasing age (< 45: 66.1%, 45-64: 62.7%, ≥ 65: 29.2%). Older age was significantly associated with increased risk of death: hazard ratio 1.89 for age ≥ 65, as were regional stage (2.81), distant stage (15.99), and not receiving recommended treatment (2.26). CONCLUSION: Older women with CC diagnosed at advanced stage who do not receive standard of care are at markedly increased risk of death. Special attention to the management of older women is warranted in France, not only to diagnose cancer at an earlier stage (via gynecological follow-up in these menopaused women who remain at risk of CC), but also to ensure they receive standard of care, taking into account their overall state of health.

Plasmodium falciparum VAR2CSA-Specific IgG Subclass Responses Reflect Protection Against Low Birth Weight and Pregnancy-Associated Malaria.

Sequestration of Plasmodium falciparum-infected erythrocytes expressing the VAR2CSA antigen in the placenta results in poor pregnancy outcomes, including low birth weight and maternal anemia. Antigen-specific antibody-mediated immunity is acquired during successive pregnancies. Thus, evaluating VAR2CSA-specific IgG profiles among pregnant women will increase knowledge on the immunological mechanisms associated with protection, and help in the development of VAR2CSA-based placental malaria vaccines. Using the PAMVAC candidate vaccine antigen, we assessed anti-VAR2CSA IgG subclass responses of a cohort of pregnant Beninese, and analyzed their relationships with pregnancy outcomes. Cytophilic IgG1 and IgG3 responses were the most frequent, with prevalences ranging from 28% (IgG3) up to 50% (IgG1). Elevated levels of VAR2CSA-specific total IgG and cytophilic IgG3 during pregnancy were consistently associated with higher birth weights, whilst high levels of IgG4 were associated with a reduced risk of placental infections. This suggests that protective anti-VAR2CSA IgG responses are coordinated between both cytophilic and non-cytophilic antibodies.

Modelling the number of avoidable new cancer cases in France attributable to alcohol consumption by following official recommendations: a simulation study.

AIMS: To predict the effects of perfect adherence to the French alcohol consumption guidelines, a maximum of 10 standard alcoholic drinks per week with no more than two standard alcoholic drinks per day, during a 36-year period (2014-50). DESIGN: This simulation study is an adaption of the Sheffield Alcohol Policy Model. The dose-response relationship between alcohol consumption and alcohol-attributable cancer risks was defined by cancer site-specific risk functions, each modelled as a continuous risk. These estimates were used to compute the potential impact fraction (PIF) associated with alcohol consumption by cancer site. SETTING: The French general adult population during a 36-year period (2014-50). PARTICIPANTS: For the baseline scenario, the current distribution of consumption levels, the counterfactual scenario and perfect adherence to the French alcohol consumption guidelines, we generated for each gender and age group 1000 randomly distributed alcohol consumption values from calibrated group-specific gamma distribution. MEASUREMENTS: The predicted number of new cancer cases among men and women in France between 2015 and 2050 that could have been prevented by following the French government's alcohol consumption guidelines. FINDINGS: The simulation predicted that perfect adherence to the French government's alcohol consumption guidelines would prevent, on average, an estimated 15 952 cancer cases per year after the PIF reached its full effect, which would have represented 4.5% of new cancer cases in 2015. The number of averted cancer cases over the study period were highest for oral cavity, oropharynx and hypopharynx cancer (respectively, 118 462, 95% CI = 113 803-123 022 and 11 167, 95% CI = 10 149-12 229] for men and women; liver and intrahepatic bile ducts cancer (123 447, 95% CI = 112 581-133 404 and 2825, 95% CI = 2208,4095); colorectal cancer (89 859, 95% CI = 84 651-95 355 and 12 847, 95% CI = 11 545-14 245); and female breast cancer (61 649, 95% CI = 56 330-67 452). CONCLUSION: This simulation study of the French general population predicted that perfect adherence to the French government's alcohol consumption guidelines (no more than 10 standard alcoholic drinks per week and two per day) would prevent almost 16 000 cancer cases per year.

Cancer Among Adolescents and Young Adults Between 2000 and 2016 in France: Incidence and Improved Survival.

Purpose: This study was undertaken to determine cancer survival and describe the spectrum of cancers diagnosed among French adolescent and young adult (AYA) population. Methods: All cases of cancer diagnosed in 15-24 years, recorded by all French population-based registries (18% of the French population), over the 2000-2016 period, were included. Age-standardized incidence rates, conventional annual percentage change (cAPC) of incidence over time, and 5-year overall survival (5yOS) were calculated. Results: We analyzed 2734 cancer diagnoses in adolescents and 4199 in young adults. Overall incidence rates were 231.9/106 in 15-19 year olds and 354.0/106 in 20-24 year olds. The most frequently diagnosed cancers in male AYA were malignant gonadal germ-cell tumors (GCT), Hodgkin lymphoma (HL), and malignant melanoma and were HL, thyroid carcinoma, and malignant melanoma in females. Cancer incidence was stable over time with a cAPC of 0.8% (p = 0.72). For all cancers combined, 5yOS was 86.6% (95% CI: 85.8-87.4), >85% for HL, non-Hodgkin lymphomas (NHL), GCT, thyroid carcinomas, and malignant melanomas, and around 60% and lower for osteosarcomas, Ewing tumors, hepatic carcinomas, and rhabdomyosarcomas. The 5yOS has significantly improved from 2000-2007 to 2008-2015 for all cancers pooled, with a substantial gain of 4% for 15-19 year olds and 3% for 20-24 year olds. Conclusion: Notwithstanding the encouraging results for some cancers, and overall, persistent poorer survivals in AYA were shown compared to children for acute lymphoblastic leukemia, osteosarcoma, Ewing tumor, rhabdomyosarcoma, and malignant hepatic tumors. These disparities require further investigation to identify and address the causes of these inferior outcomes.

Modelling the impact of different front-of-package nutrition labels on mortality from non-communicable chronic disease.

BACKGROUND: Front-of-Package nutrition labels (FoPLs) are intended to help reduce the incidence of nutrition-related non-communicable diseases through an improvement in diet quality. FoPLs have been shown to improve the nutritional quality of purchases and have been associated with improved diet quality, which is in turn associated with reduced risk of non-communicable diseases. However, the potential impact of FoPLs on reducing mortality from chronic diseases has never been estimated. METHODS: Data from a laboratory experimental economics test were used to investigate the effects of five different FoPLs (Nutri-Score, Health Star Rating system, Multiple Traffic lights, Reference intakes and SENS (Système d'Etiquetage Nutritionnel Simplifié)) on the nutritional quality of household purchases. The relative differences in nutrient content and composition of food purchases were then applied to dietary intakes using data from an observational study, thus yielding estimates for 'reference' and 'labelled' diets. A macro-simulation study using the PRIME model was then conducted to estimate the impact of the modification in dietary intake as a result of FoPL use on mortality from diet-related non-communicable diseases. RESULTS: The use of FoPLs led to a substantial reduction in mortality from chronic diseases. Approximately 3.4% of all deaths from diet-related non-communicable diseases was estimated to be avoidable when the Nutri-Score FoPL was used. The remaining FoPLs likewise resulted in mortality reduction, although to a lesser extent: Health Star Rating system (2.8%), Reference Intakes (1.9%), Multiple Traffic Lights (1.6%), and SENS (1.1%). CONCLUSIONS: FoPLs have the potential to help decrease mortality from diet-related non-communicable diseases, and the Nutri-Score appears to be the most efficient among the five formats tested.

Plasmodium falciparum merozoite surface antigen-specific cytophilic IgG and control of malaria infection in a Beninese birth cohort.

BACKGROUND: Substantial evidence indicates that cytophilic IgG responses to Plasmodium falciparum merozoite antigens play a role in protection from malaria. The specific targets mediating immunity remain unclear. Evaluating antibody responses in infants naturally-exposed to malaria will allow to better understand the establishment of anti-malarial immunity and to contribute to a vaccine development by identifying the most appropriate merozoite candidate antigens. METHODS: The study was based on parasitological and clinical active follow-up of infants from birth to 18 months of age conducted in the Tori Bossito area of southern Benin. For 399 infants, plasma levels of cytophilic IgG antibodies with specificity for five asexual stage malaria vaccine candidate antigens were determined by ELISA in infants' peripheral blood at 6, 9, 12 and 15 months of age. Multivariate mixed logistic model was used to investigate the association between antibody levels and anti-malarial protection in the trimester following the IgG quantification. Moreover, the concentrations of merozoite antigen-specific IgG were compared between a group of infants apparently able to control asymptomatic malaria infection (CAIG) and a group of infants with no control of malaria infection (Control group (NCIG)). Protective effect of antibodies was also assessed after 15 months of malaria exposure with a Cox regression model adjusted on environmental risk. RESULTS: Cytophilic IgG responses to AMA1, MSP1, MSP2-3D7, MSP2-FC27, MSP3 and GLURP R2 were associated with increasing malarial infection risk in univariate analysis. The multivariate mixed model showed that IgG1 and IgG3 to AMA1 were associated with an increased risk of malarial infection. However infants from CAIG (n = 53) had significantly higher AMA1-, MSP2-FC27-, MSP3-specific IgG1 and AMA1-, MSP1-, MSP2-FC27-, MSP3 and GLURP-R2-specific IgG3 than those from NCIG (n = 183). The latter IgG responses were not associated with protection against clinical malaria in the whole cohort when protective effect is assessed after 15 months of malaria exposition. CONCLUSION: In this cohort, merozoite antigen-specific cytophilic IgG levels represent a marker of malaria exposure in infants from 6 to 18 months of age. However, infants with resolution of asymptomatic infection (CAIG) seem to have acquired naturally immunity against P. falciparum. This observation is encouraging in the context of the development of multitarget P. falciparum vaccines.

High level of soluble human leukocyte antigen (HLA)-G at beginning of pregnancy as predictor of risk of malaria during infancy.

Placental malaria has been associated with an immune tolerance phenomenon and a higher susceptibility to malaria infection during infancy. HLA-G is involved in fetal maternal immune tolerance by inhibiting maternal immunity. During infections HLA-G can be involved in immune escape of pathogens by creating a tolerogenic environment. Recent studies have shown an association between the risk of malaria and HLA-G at both genetic and protein levels. Moreover, women with placental malaria have a higher probability of giving birth to children exhibiting high sHLA-G, independently of their own level during pregnancy. Our aim was to explore the association between the level of maternal soluble HLA-G and the risk of malaria infection in their newborns. Here, 400 pregnant women and their children were actively followed-up during 24 months. The results show a significant association between the level of sHLA-G at the first antenatal visit and the time to first malaria infection during infancy adjusted to the risk of exposure to vector bites (aHR = 1.02, 95%CI [1.01-1.03], p = 0.014). The level of sHLA-G is a significant predictor of the occurrence of malaria infection during infancy consistent with the hypothesis that mother sHLA-G could be a biomarker of malaria susceptibility in children.

HLA-G expression during hookworm infection in pregnant women.

INTRODUCTION: HLA-G plays a key role on immune tolerance. Pathogens can induce soluble HLA-G (sHLA-G) production to down-regulate the host immune response, creating a tolerogenic environment favorable for their dissemination. To our knowledge, no study has yet been conducted to assess the relationship between sHLA-G and geohelminth infections. METHODS: The study was conducted in Allada, Southeastern Benin, from 2011-2014. The study population encompassed 400 pregnant women, included before the end of the 28th week of gestation and followed-up until delivery. At two antenatal care visits and at delivery, stool and blood samples were collected. Helminths were diagnosed by means of the Kato-Katz concentration technique. We used quantile regression to analyze the association between helminth infections and sHLA-G levels during pregnancy. RESULTS: sHLA-G levels gradually increased during pregnancy and reached maximal levels at delivery. Prevalence of helminth infections was low, with a majority of hookworm infections. We found significantly more hookworm-infected women above the 80th quantile (Q80) of the distribution of the mean sHLA-G level (p < 0.03, multivariate quantile regression). Considering only women above the Q80 percentile, the mean sHLA-G level was significantly higher in hookworm-infected compared to uninfected women (p = 0.04). CONCLUSION: High levels of sHLA-G were associated with hookworm infection in pregnant women. This result is consistent with the potential involvement of sHLA-G in immune tolerance induced by helminths during pregnancy.

Adolescent and young adult oncology patients in France: Heterogeneity in pathways of care.

BACKGROUND: In order to evaluate at the population level the impact of the actions developed in France since 2004 to organize the care of adolescents and young adults (AYAs) with cancer, we conducted the present study to provide an unbiased view of the pathway of care of these patients. METHODS: Using a population-based registry, we conducted a review of all cases of cancer diagnosed during 2012 and 2013 in 15- to 24-year-old patients living in nineteen French administrative areas. RESULTS: The median times for diagnosis and treatment of the 993 included AYAs were 9 weeks (3-22) and 1 day (0-20), respectively. Delays in diagnosis were significantly longer in young adults than in adolescents, especially for soft-tissue sarcomas (48.7 weeks vs. 15.4 weeks, P = 0.04) and bone tumors (21.4 weeks vs. 10.1 weeks, P = 0.04). The first physicians seen by patients were mostly general practitioners (67.4%). Most patients (77.5%) were treated in adult units. Management decisions were taken within the context of a multidisciplinary team (MDT) in 85.3% of cases. MDT meetings that involved both pediatric and adult oncologists were uncommon (15.7% of patients). Twenty-six percent of patients were included in randomized or nonrandomized clinical studies. The proportion of inclusion was significantly higher in adolescents (39.5%) than in young adults (16.8%). CONCLUSION: In France, pathways of care for AYAs are heterogeneous. It is necessary to organize a national network of expert centers with adequate medical skills and specific psychosocial support and facilities to provide the best possible care for these patients.

Soluble human leukocyte antigen -G during pregnancy and infancy in Benin: Mother/child resemblance and association with the risk of malaria infection and low birth weight.

Human leukocyte antigen (HLA) G is a tolerogenic molecule involved in the maternal-fetal immune tolerance phenomenon. Its expression during some infectious diseases leading to immune evasion has been established. A first study conducted in Benin has shown that the production of soluble HLA-G (sHLA-G) during the first months of life is strongly correlated with the maternal level at delivery and associated with low birth weight and malaria. However sHLA-G measurements during pregnancy were not available for mothers and furthermore, to date the evolution of sHLA-G in pregnancy is not documented in African populations. To extend these previous findings, between January 2010 and June 2013, 400 pregnant women of a malaria preventive trial and their newborns were followed up in Benin until the age of 2 years. Soluble HLA-G was measured 3 times during pregnancy and repeatedly during the 2 years follow-up to explore how sHLA-G evolved and the factors associated. During pregnancy, plasma levels of sHLA-G remained stable and increased significantly at delivery (p<0.001). Multigravid women seemed to have the highest levels (p = 0.039). In infants, the level was highest in cord blood and decreased before stabilizing after 18 months (p<0.001). For children, a high level of sHLA-G was associated with malaria infection during the follow-up (p = 0.02) and low birth weight (p = 0.06). The mean level of sHLA-G during infancy was strongly correlated with the mother's level during pregnancy (<0.001), and not only at delivery. Moreover, mothers with placental malaria infection had a higher probability of giving birth to a child with a high level of sHLA-g (p = 0.006). High sHLA-G levels during pregnancy might be associated with immune tolerance related to placental malaria. Further studies are needed but this study provides a first insight concerning the potential role of sHLA-G as a biomarker of weakness for newborns and infants.

Evolution of the levels of human leukocyte antigen G (HLA-G) in Beninese infant during the first year of life in a malaria endemic area: using latent class analysis.

BACKGROUND: HLA-G, a non-classical HLA class I antigen, is of crucial interest during pregnancy by inhibiting maternal immune response. Its role during infections is discussed, and it has been described that high levels of soluble HLA-G during childhood increase the risk of malaria. To explore more precisely interactions between soluble HLA-G and malaria, latent class analysis was used to test whether distinct sub-populations of children, each with distinctive soluble HLA-G evolutions may suggest the existence of groups presenting variable malaria susceptibility. METHOD: A study was conducted in Benin from 2010 to 2013 and 165 children were followed from birth to 12 months. Evolution of soluble HLA-G was studied by the latent class method. RESULTS: Three groups of children were identified: one with consistently low levels of soluble HLA-G during follow-up, a second with very high levels and a last intermediate group. In all groups, low birth weight, high number of malaria infections and high exposure to malaria transmission were associated with high level of soluble HLA-G. Placental malaria was not. Presence of soluble HLA-G in cord blood increased the probability of belonging to the highest trajectory. CONCLUSION: These results, together with previous ones, confirm the important role of HLA-G in the individual susceptibility to malaria. Assaying soluble HLA-G at birth could be a good indicator of newborns more fragile and at risk of infections during childhood.

High plasma levels of HLA-G are associated with low birth weight and with an increased risk of malaria in infancy.

BACKGROUND: The immunosuppressive properties of HLA-G protein can create a tolerogenic environment that may allow Plasmodium falciparum to avoid host immune responses. There are known associations between high levels of circulating soluble HLA-G (sHLA-G) and either parasite or viral infections and it has been suggested that the induction of sHLA-G expression could be a mechanism via which infectious agents subvert host immune defence. The study presented here is the first to investigate the possible association between sHLA-G and malaria or malaria related risk factors in Benin. METHODS: A parasitological and clinical follow-up of 165 mothers and their newborns from delivery through to one year of age was conducted in the Tori Bossito area of southern Benin. Plasma levels of sHLA-G were determined by ELISA in maternal peripheral and cord blood and again in infants' peripheral blood at 3, 6, 9 and 12 months of age. The associations between the levels of sHLA-G and malaria risk factors were investigated through multivariate mixed models. RESULTS: Strong correlations were observed between the maternal and cord plasma concentrations of sHLA-G. In multivariate analyses, high cord plasma levels of sHLA-G were independently associated with (i) low birth weight and (ii) an increased risk of P. falciparum infection in infancy. CONCLUSION: These results show for the first time the possible involvement of sHLA-G in generating immune tolerance during pregnancy-associated malaria. Soluble HLA-G may represent a useful marker of susceptibility to malaria in infants and be associated with the higher susceptibility to infection observed for LBW children.

Field evaluation of the intermittent preventive treatment of malaria during pregnancy (IPTp) in Benin: evolution of the coverage rate since its implementation.

BACKGROUND: Malaria is an important public health problem in Africa. Pregnant women are a vulnerable population and this disease can underlie an increased risk of low-birth weight newborns (< 2500 g); these women therefore need management during pregnancy. This was previously provided by chloroquine treatment, which, because of compliance problems and drug resistance, was replaced by intermittent preventive treatment with sulfadoxine-pyrimethamine (ITPp-SP) with two single doses taken after 16 weeks of amenorrhea, at least 4 weeks apart. This protocol was recommended by the World Health Organization (WHO) in 1998 and was initiated in Benin in 2006 after its political adoption in 2004.A retrospective longitudinal study was conducted in eight maternity hospitals in two geographical areas in Benin (in the south and north). The study investigated 2420 women who gave birth from 2005 to 2009. The antenatal cards of those women were randomly selected over 5 years with the aim of analyzing the IPT coverage in the study's maternity hospitals. RESULTS: The rate of IPT-SP coverage evolved from 3.7% in 2005 to 87.8% in 2009 for women who had received at least one dose and from 2.7% to 68.4% from 2005 to 2009 for those who had received complete ITP (two doses). Variability in the results was observed depending on the geographical area (north/south) and the type of area (rural/urban). CONCLUSIONS: In total, application of IPT-SP 2-doses has rapidly evolved since 2005, but the objective of 80% IPT coverage has not yet been achieved throughout the country. Moreover, problems of drug shortage recurring in the field (reported by health staff) remain to be resolved.