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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., (© 2018 Wiley Periodicals, Inc.)

Background: Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine carcinoma. Owing to its low incidence, epidemiological data are scarce and have never been analysed in France to identify the main epidemiological trends., Methods: Data from MCC patients diagnosed between 1998 and 2010 were obtained from 11 French cancer registries in the FRANCIM network. The main epidemiological characteristics of MCC were investigated between 2006 and 2010 because comprehensive data were only available for this period. The main focus was tumour incidence and mortality over time., Results: Between 1998 and 2010, 562 cases of MCC were reported in the registries. From 2006 to 2010 (290 cases), European- and world-standardized incidence rates were 0.26 and 0.43 per 100,000 person-years in men and 0.24 and 0.38 per 100,000 person-years in women. MCC is more frequent in females in France (56.9%) with male/female ratio 1.1. Relative survival rates were 84%, 56% and 42% at one, three and 5 years, respectively., Conclusions: The incidence of MCC clearly increased over time in all areas under focus. The standardized incidence in France was comparable to the incidence observed in other countries for the same period, but French data are too recent to conclude on an increase in MCC incidence. Prognosis remains poor in all countries in which data are available., (© 2018 European Academy of Dermatology and Venereology.)

The L-arginine/NO pathway is an important regulator of pulmonary hypertension, the leading cause of mortality in patients with the chronic lung disease of prematurity, bronchopulmonary dysplasia. L-arginine can be metabolized by NO synthase (NOS) to form L-citrulline and NO, a potent vasodilator. Alternatively, L-arginine can be metabolized by arginase to form urea and L-ornithine, a precursor to collagen and proline formation important in vascular remodelling. In the current study, we hypothesized that C3H/HeN mice exposed to prolonged hyperoxia would have increased arginase expression and pulmonary vascular wall cell proliferation. C3H/HeN mice were exposed to 14 days of 85% O 2 or room air and lung homogenates analyzed by western blot for protein levels of arginase I, arginase II, endothelial NOS (eNOS), ornithine decarboxylase (ODC), ornithine aminotransferase (OAT), and α-smooth muscle actin (α-SMA). Hyperoxia did not change arginase I or eNOS protein levels. However, arginase II protein levels were 15-fold greater after hyperoxia exposure than in lungs exposed to room air. Greater protein levels of ODC and OAT were found in lungs following hyperoxic exposure than in room air animals. α-SMA protein levels were found to be 7-fold greater in the hyperoxia exposed lungs than in room air lungs. In the hyperoxia exposed lungs there was evidence of greater pulmonary vascular wall cell proliferation by α-SMA immunohistochemistry than in room air lungs. Taken together, these data are consistent with a more proliferative vascular phenotype, and may explain the propensity of patients with bronchopulmonary dysplasia to develop pulmonary hypertension., (© 2017 John Wiley & Sons Australia, Ltd.)

Purpose: To analyze trends in second primary cancer (SPC) incidence by using a case-mix approach to standardize on first cancer site distribution., Methods: Cases registered by 13 French cancer registries between 1989 and 2010 and followed-up until June 2013 were included. The person-year approach was used to compute standardized incidence ratios (SIRs) of metachronous SPC. Usual SIRs and cancer site-specific weighted SIRs called "case-mix SIRs" (cmSIRs) were estimated by sex and calendar period of first cancer diagnosis. Calendar trends in SIRs and cmSIRs were compared., Results: More than 2.9 million person-years at risk were included. Among males, SIRs dropped from 1.49 to 1.23 between 1989-1994 and 2005-2010, while cmSIRs decreased from 1.40 to 1.27. This difference seems mainly related to a stronger representation of prostate cancers (at lower risk of SPC) and a weaker contribution of bladder and head and neck cancers (at higher risk of SPC) in recent periods of diagnosis. Among females, both SIRs and cmSIRs have remained stable at around 1.22 and 1.21, respectively., Conclusions: The cmSIR is an indicator that is not influenced by changes in first cancer site distribution. Its use should be encouraged to assess second cancer incidence control., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study aims to estimate the pathologic complete response (pCR) rate after neo-adjuvant chemotherapy and to compare disease-free survival (DFS) and overall survival (OS) between pCR and non-pCR groups of patients with triple-negative breast cancer (TNBC) and deleterious BRCA1 or BRCA2 mutation. We carried out a retrospective analysis of 53 patients including 46 BRCA1, 6 BRCA2, and 1 combined BRCA1 and BRCA2 mutation. All patients had been diagnosed with triple-negative breast cancer (TNBC) between 1997 and 2014. Neo-adjuvant therapy consisted of regimens that were based on anthracycline or an anthracycline-taxane doublet. DFS included any relapse or second cancer. The Kaplan-Meier method and the log-rank test were used to compare pCR and non-pCR groups. A pCR was observed in 23 (42.6% [95% CI, 29.2%-56.8%]) of the TNBC included. The pCR rate was 38.3% [95% CI, 26%-55%] among BRCA1 mutation carriers, and 66% among the 6 BRCA2 mutation carriers. Median follow-up was 4.4 years (range 0.62-16.2 years) and did not differ between the groups (P = .25). Fifteen relapses and six second cancers were recorded during the follow-up period. Eleven deaths occurred, all of which were in the non-pCR group. DFS (P < .01) and OS (P < .01) were significantly better in the pCR group than the non-pCR group. This study shows a high pCR rate after neo-adjuvant therapy in BRCA-mutated triple-negative breast cancer, and the survival results confirm the prognostic value of pCR in this group. These outcomes should be considered as a basis of comparison to be used by future studies about new therapies in this domain., (© 2017 Wiley Periodicals, Inc.)

Objectives: Epidemiological studies on the risk factors for salivary gland cancers (SGC) are rare, concern a small sample size, and show inconsistent results. The aim of the present work was to analyze several risk factors for SGC, using the data from the ICARE study, a multicenter, population-based case-control study., Materials and Methods: Data from 73 SGC cases and 3555 controls were collected using a standardized questionnaire on lifestyle habits, personal and family medical history, and lifetime occupational history. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regressions., Results: Tobacco use and alcohol consumption were not associated with the risk of SGC. A history of head and neck cancer or that of cervicofacial radiotherapy was associated with a higher risk of SGC (OR = 17.06, 95% CI: 4.34-67.05, and OR = 31.74, 2.48-405.25, respectively). Significantly increased risks were observed for some occupations: waiter (OR = 2.94, 1.11-7.78), charworker (OR = 3.02, 1.38-6.60), electrical and electronic equipment assembler (OR = 7.16, 2.02-25.38), plumber (OR = 3.95, 1.33-11.67), electric arc welder (OR = 6.15, 1.76-21.48), sheet-metal worker (OR = 2.89, 1.01-8.32), building painter (OR = 3.42, 1.01-11.49), and material handling equipment operator (OR = 5.05, 1.71-14.84). Results for industries were consistent with those observed for occupations., Conclusion: Our results showed that a history of head and neck cancer, cervicofacial radiotherapy, and several occupations and industries, were associated with an increased risk of SGC. Further studies with larger sample sizes are indicated to confirm our results., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Sex-related differences in cardiovascular health and disease have been identified, with males having a higher incidence of cardiovascular events but females more likely to develop arrhythmias. Adverse fetal environments are now accepted as a cause for the development of cardiovascular diseases in adulthood, but sex-related differences in response to adverse fetal environments have not been extensively explored. The combination of both in utero and postnatal exposure to inflammation is highly relevant for the infant that is born preterm or has clinical complications at birth or in early postnatal life. We have previously observed cardiac contractile deficiencies and dysregulation of Ca 2+ -handling proteins in our model of maternal lipopolysaccharide (LPS) and neonatal hyperoxia exposures (LPS/O 2 ). This investigation tested the hypothesis that there are sex-related differences in the adult pathologies after exposure to perinatal inflammation. Using pressure-volume assessments, males exposed to LPS/O 2 had more pronounced contractile deficiencies than similarly exposed females, but females tended to have long PR intervals. While both sexes demonstrated decreases in α-myosin heavy chain and connexin 43 after LPS/O 2 exposure compared with saline/room air controls, females indicated aberrant increases in microRNA 208a, microRNA 208b, and desmin expression. Our study supports our hypothesis that early life exposure to inflammation results in sex-dependent deficits in cardiovascular function. NEW & NOTEWORTHY Sex-specific differences in cardiovascular disease are recognized, but the mechanisms and origins are not well understood. Adverse maternal environments can influence cardiac development and later cardiovascular disease. This study identifies sex-dependent differences in cardiac disease associated with perinatal inflammation.

Background: The Chernobyl nuclear power plant accident occurred in Ukraine on April 26th 1986. In France, the radioactive fallout and thyroid radiation doses were much lower than in highly contaminated areas. However, a number of risk projections have suggested that a small excess in differentiated thyroid cancer (DTC) might occur in eastern France due to this low-level fallout. In order to investigate this potential impact, a case-control study on DTC risk factors was started in 2005, focusing on cases who were less than 15 years old at the time of the Chernobyl accident. Here, we aim to evaluate the relationship between some specific reports of potentially contaminated food between April and June 1986 - in particular fresh dairy products and leafy vegetables - and DTC risk., Methods: After excluding subjects who were not born before the Chernobyl accident, the study included 747 cases of DTC matched with 815 controls. Odds ratios were calculated using conditional logistic regression models and were reported for all participants, for women only, for papillary cancer only, and excluding microcarcinomas., Results: The DTC risk was slightly higher for participants who had consumed locally produced leafy vegetables. However, this association was not stronger in the more contaminated areas than in the others. Conversely, the reported consumption of fresh dairy products was not statistically associated with DTC risk., Conclusion: Because the increase in DTC risk associated with a higher consumption of locally produced vegetables was not more important in the most contaminated areas, our study lacked power to provide evidence for a strong association between consumption of potentially contaminated food and DTC risk., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Skin biopsy is the most relevant tool to diagnose small-fiber neuropathy. A well-documented normal dataset for intraepidermal nerve fiber in the distal leg is required to improve its diagnostic value., Methods: Three hundred healthy subjects were enrolled in the study, after clinical and biological screening to exclude neurological and systemic pathologies. A distal leg biopsy was taken and intraepidermal nerve fiber density after protein gene product-9.5 immunocytochemistry with brightfield microscopy was determined. Morphological variations of intraepidermal nerve fibers, previously described in small-fiber neuropathies, were analyzed. One hundred biopsies were also analyzed at the ultrastructural level., Findings: The median number of fibers was lower in men compared to women and decreased with age. Using statistical modeling taking into account age and gender, we calculated the 5th percentile of intraepidermal nerve fiber density as follows: 7.6156-0.0769 x age (years) + 1.5506 x gender (woman = 1; man = 0). We observed a low frequency of large swellings or horizontal branchings but an increasing frequency of small swellings of intraepidermal nerve fibers and irregular distribution along the dermal-epidermal junction with age. Axonal diameter of unmyelinated fibers of the papillary dermis did not vary with age or gender. Ultrastructural analysis also showed that fiber endings in close apposition to Merkel cells should not be mistaken for small-fiber swellings., Conclusions: Our dataset allows accurate calculation of the normal density of intraepidermal nerve fibers for each year of age and provides original morphological observations that improve the diagnostic value of skin biopsy in the distal leg for small-fiber neuropathy.

Objective: To present methodological issues that can arise with the assessment of the risk of a second primary cancer (SPC) occurring in the same site as a first cancer using registry data., Material and Methods: Data from ten French cancer registries were used, including data for patients with a first prostate cancer (in males), breast cancer (in females), and colon, lung and kidney cancer (in both sexes) diagnosed between 1989 and 2004. Standardized incidence ratios (SIRs) of SPC were computed by excluding, or not, the risk of an SPC at the same site., Results: For prostate cancer, the SIR dropped from 1.11 to 0.72 when the risk of SPC of the prostate was included. SIRs increased from 1.36 to 1.45, from 1.14 to 1.21, from 1.57 to 2.01, and from 1.37 to 1.51 for breast, colon, lung, and kidney respectively., Conclusion: The inclusion, or not, of an SPC at the same site can impact on SPC risk estimates., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To identify whether women presenting with reactive cellular changes (RCC) on their cervical smear face an increased risk for developing high grade cervical intraepithelial neoplasia (CIN2-3) or cancer as compared with women with an entirely normal smear., Study Design: French data from the association in charge of organized cervical cancer screening in Bas-Rhin administrative region were used to establish a cohort of 96,215 women presenting with a smear classified as entirely normal or with RCC during the year 2001. The Kaplan-Meyer method was used to calculate the probabilities of CIN2-3 and cancer at seven years of follow-up. Univariate and multivariate survival analyses were performed using Cox proportional hazard models., Results: Among the 95,559 women included in the final analysis, 32.2% presented a smear with RCC. After seven years of follow-up, 441 women developed a CIN2-3 and 35 a cancer. Probability of CIN2-3 was increased in the RCC group as compared with the group of women with a normal smear (0.7% versus 0.5%, p=0.002). Multivariate analyses showed that, compared with a normal cervical smear, RCC were associated with a significant 37% increased risk of CIN2-3 (HR=1.37 CI95 [1.13-1.66]). However, the risk of cancer was not significantly increased (HR=1.11 CI95 [0.55-2.23])., Conclusion: This study showed that, at seven years, women with RCC on their cervical smear face an increased risk of CIN2-3 but no significant increased risk of cancer. The distinction between entirely normal and RCC cervical smears should therefore not lead to specific clinical management., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Epidemiologic studies have found lower risks of lung cancer in farmers. However, little is known about the types of agricultural activities concerned. In the Agriculture and Cancer cohort, we assessed the relationship between animal farming and lung cancer by investigating the types of animals, tasks, and timing of exposure. Analyses included 170,834 participants from the Agriculture and Cancer (AGRICAN) cohort in France. Incident lung cancers were identified through linkage with cancer registries from enrollment (2005-2007) to 2011. A Cox model, adjusting for pack-years of cigarette smoking, was used to calculate hazard ratios and 95% confidence intervals. Lung cancer risk was inversely related to duration of exposure to cattle (≥40 years: hazard ratio = 0.60, 95% confidence interval: 0.41, 0.89; P for trend < 0.01) and to horse farming (≥20 years: hazard ratio = 0.64, 95% confidence interval: 0.35, 1.17; P for trend = 0.09), especially for adenocarcinomas, but not with poultry or pig farming. More pronounced decreased risks were reported among individuals who had cared for animals, undertaken milking, and who had been exposed to cattle in infancy. Our study provides strong evidence of an inverse association between lung cancer and cattle and horse farming. Further research is warranted to identify the etiologic protective agents and biological mechanisms., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Incomplete evaluation of venous invasion has led to conflicting results regarding the prognosis of patients undergoing pancreatectomy with a synchronous venous resection. This study evaluates the prognostic value associated with the presence and the depth of venous invasion in T3 pancreatic adenocarcinoma., Methods: This study evaluated retrospectively 181 consecutive pancreatoduodenectomies performed for T3N0M0 and T3N1M0 pancreatic adenocarcinomas (stages IIA and IIB) from January 2006 to December 2014. Univariate and multivariate Cox analyses were performed to assess survival prognostic factors., Results: Pancreatoduodenectomies with a segmental venous resection was performed on 91 patients, while 90 other patients had a standard pancreatoduodenectomies without venous resection. Pathologic venous invasion was detected in 68 (74%) of the 91 venous resection patients. Depth of venous invasion was into the adventitia (n = 25), media (n = 28), and intima (n = 15). The overall survival rates at 1, 3, 5, and 10 years were 75%, 33%, 21%, and 6%, respectively. There were no differences in survival between patients undergoing standard pancreatoduodenectomies and pancreatoduodenectomies with venous resection (27 vs 22 months; P = .28) or between patients with and without venous invasion (20 vs 27 months; P = .08). In multivariate analysis, depth of venous invasion into the intima (hazard ratio, 2.25; 95% confidence interval, 1.16-4.34; P = .0001) and adjuvant chemotherapy (hazard ratio, 0.16; 95% confidence interval, 0.09-0.43; P ≤ .0001) were identified as independent prognostic factors of overall survival., Conclusion: Depth of venous invasion into the intima indicates poor survival in pancreatic T3 adenocarcinoma. Preoperative identification of this factor could be helpful for better selection of patients for curative operation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Numerous studies have been conducted among farmers, but very few of them have involved large prospective cohorts, and few have included a significant proportion of women and farm workers. Our aim was to compare cancer incidence in the cohort (overall, by sex, and by work on farm, occupational status and pesticide use) within the general population., Methods: More than 180,000 participants in the AGRICAN cohort were matched to cancer registries to identify cancer cases diagnosed from enrolment (2005-2007) to 31st December 2011. We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (95%CIs)., Results: Over the period, 11,067 incident cancer cases were identified (7304 men and 3763 women). Overall cancer incidence did not differ between the cohort and the general population. Moreover, SIRs were significantly higher for prostate cancer (SIR=1.07, 95%CI 1.03-1.11) and non-Hodgkin lymphoma (SIR=1.09, 95%CI 1.01-1.18) among men, skin melanoma among women (SIR=1.23, 95%CI 1.05-1.43) and multiple myeloma (men: SIR=1.38, 95%CI 1.18-1.62; women: SIR=1.26, 95%CI 1.02-1.54). In contrast, SIRs were lower for upper aerodigestive tract and respiratory cancers. Increase in risk was greater in male farm workers for prostate and lip cancer, in female farm workers for skin melanoma, and in male farm owners for multiple myeloma. Moreover, incidence of multiple myeloma and skin melanoma was higher among male and female pesticide users respectively., Conclusion: We found a decreased incidence for tobacco-related cancers and an increased incidence of prostate cancers, skin melanoma and multiple myeloma. Specific subgroups had a higher cancer incidence related to occupational status and pesticide use., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: In retrospective case-control studies performed following nuclear tests or nuclear accidents, individual thyroid radiation dose reconstructions are based on fallout and meteorological data from the residential area, demographic characteristics, and lifestyle as well as dietary information. Collecting the latter is a controversial step, as dietary declarations may be affected by the subjects' beliefs about their risk behavior. This report analyses the potential for such bias in a case-control study performed in eastern France., Methods: The study included 765 cases of differentiated thyroid carcinoma matched with 831 controls. Risk perceptions and beliefs of cases and controls were compared using Chi 2 tests and differences in dietary reports were analyzed using a two-way ANOVA., Results: In general, atmospheric pollution and living near a nuclear power plant were the two major risks that may influence thyroid cancer occurrence cited by cases and controls. When focusing in particular on the consequences of the Chernobyl accident, cases were more likely to think that the consequences were responsible for thyroid cancer occurrence than controls. Vegetable consumption during the two months after the Chernobyl accident was correlated with the status of subjects, but not to their beliefs. Conversely, consumption of fresh dairy products was not correlated with the status or beliefs of subjects., Conclusion: We found no evidence of systematic bias in dietary reports according to the status or beliefs held by subjects about the link between thyroid cancer occurrence and Chernobyl fallout. As such, these dietary reports may be used in further studies involving individual dosimetric reconstructions., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Particulate matter (PM; PM 2.5 [PM with diameters of <2.5 μm]) exposure during development is strongly associated with adverse cardiovascular outcomes at adulthood. In the present study, we tested the hypothesis that in utero PM 2.5 exposure alone could alter cardiac structure and function at adulthood., Methods and Results: Female FVB mice were exposed either to filtered air or PM 2.5 at an average concentration of 73.61 μg/m 3 for 6 h/day, 7 days/week throughout pregnancy. After birth, animals were analyzed at 12 weeks of age. Echocardiographic (n=9-10 mice/group) and pressure-volume loop analyses (n=5 mice/group) revealed reduced fractional shortening, increased left ventricular end-systolic and -diastolic diameters, reduced left ventricular posterior wall thickness, end-systolic elastance, contractile reserve (dP/dt max /end-systolic volume), frequency-dependent acceleration of relaxation), and blunted contractile response to β-adrenergic stimulation in PM 2.5 -exposed mice. Isolated cardiomyocyte (n=4-5 mice/group) function illustrated reduced peak shortening, ±dL/dT, and prolonged action potential duration at 90% repolarization. Histological left ventricular analyses (n=3 mice/group) showed increased collagen deposition in in utero PM 2.5 -exposed mice at adulthood. Cardiac interleukin (IL)-6, IL-1ß, collagen-1, matrix metalloproteinase (MMP) 9, and MMP13 gene expressions were increased at birth in in utero PM 2.5 -exposed mice (n=4 mice/group). In adult hearts (n=5 mice/group), gene expressions of sirtuin (Sirt) 1 and Sirt2 were decreased, DNA methyltransferase (Dnmt) 1, Dnmt3a, and Dnmt3b were increased, and protein expression (n=6 mice/group) of Ca 2+ -ATPase, phosphorylated phospholamban, and Na + /Ca 2+ exchanger were decreased., Conclusions: In utero PM 2.5 exposure triggers an acute inflammatory response, chronic matrix remodeling, and alterations in Ca 2+ handling proteins, resulting in global adult cardiac dysfunction. These results also highlight the potential involvement of epigenetics in priming of adult cardiac disease., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: To develop a prediction model to quantify the cumulative risk of Second Primary Cancer (SPC) among cancer patients given that they survive their disease., Methods: A cohort of 293,435 patients based on data from twelve French cancer registries was analyzed. For five first cancer sites, SPC incidence rates were estimated using Poisson regression models. The cumulative risks of SPC were computed for different follow-up times. For comparison purpose, the same method was used to estimate the probability of cancer in the general population., Results: In this population-based cohort, 27,320 patients presented with a SPC. The cumulative risk of SPC varied depending on first cancer site, with a 10-year cumulative probability of SPC ranging from 6.2% for women with breast cancer to 44.0% for men with head and neck cancer. Compared with the general population, the 10-year cumulative risk of SPC was dramatically elevated for tobacco-related first cancers, with an increase of +7.3% for men aged 55 to 64 with a first lung cancer and +35.6% for men aged 45 to 54 with a first head and neck cancer. Lower differences were observed among patients diagnosed with a first prostate cancer (+5.5% among men aged 55 to 64), colorectal (+4.1% for women aged 55 to 64 and +6.3% for men aged 55 to 64), and breast (+2.0% among females aged 75 and older) cancers., Conclusion: This study provides physicians with a practical estimate to assess the risk of SPC of their patients more accurately., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Despite the frequency and lethality of oral cancers in France, there are no detailed general population data regarding the characteristics of these patients to fuel the public health authorities' reflections about early detection policies. Thus, the objective of this study was to determine, in the general population, the characteristics of both patients and tumours at the time of the diagnosis. A high-resolution, population-based study using 13 French registries was conducted on 1089 tumours diagnosed in 2010. Men accounted for 75% of cases. The most frequent sites were tonsil (28.4%) and oral tongue (21.1%). The median age varied from 56.7 years for floor of mouth to 66.4 years for gum. The lesions were mainly diagnosed on pain and those diagnosed after routine clinical examination were scarce (2.6%). There were 65.5% stage III and IV at diagnosis. Oral tongue, floor of mouth and palate presented tumours less than 2cm only in 34 to 40% of cases. Advanced stage was associated with the presence of comorbidities, and tonsil or base of tongue topography. Stage was not associated with Département, deprivation index or gender. This study provided a picture of the characteristics of oral cancer patients and their tumours and showed that diagnoses are often made late, even for those tumours most easily accessible to direct visual and tactile examination. Nevertheless, it remains to define the target population of an early detection and to evaluate the benefit of such detection on the mortality rate., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Objectives: Biosimilar infliximab, the first similar biological medicinal product containing monoclonal antibodies to be commercialised, is likely to contribute to a significant reduction in healthcare costs. We aimed to assess the cost savings potential over 1 year of the use of biosimilar infliximab for the treatment of rheumatoid arthritis (RA) patients in Alsace and in France, in a real-life setting., Methods: The analysis was based on a previously conducted observational study which evaluated the annual cost of the care of patients with RA treated with biological therapies in 2012 in Alsace. Average annual costs to manage RA patients were calculated, taking into account the decrease in the retail price between 2012 and 2015 (as given in the official national price list) and the local negotiated price for biosimilar infliximab. Annual cost savings for different biosimilar prescription scenarios were calculated using 2015 prices., Results: Management of RA patients with biosimilar infliximab was significantly cheaper than with adalimumab or etanercept (€11 907 vs €12 981 and €13 551, respectively). The projected annual cost savings reached €13.6 million nationally, if all adult RA patients treated with the originator infliximab switched to the biosimilar drug. These savings, if fully reallocated for the treatment of RA, would enable the treatment of 1141 additional patients., Conclusions: The study showed a positive financial impact of introducing biosimilar infliximab for the treatment of RA patients in France. Such savings could contribute to improved patient care by allowing more patients to be treated without more money being spent., Competing Interests: Competing interests: CS reports personal fees from Abbvie, Lilly, MSD, Pfizer and Roche, outside the submitted work; JS reports consulting and speaking fees from Abbott, Abbvie, Actelion, Amgen, BMS, Chugai, GSK, Hospira, LFB, MSD, Novartis, Pfizer, Roche and UCB, outside the submitted work.

This study's aims were: 1) to extract a comprehensive overview of the knowledge, experience and opinions of both community pharmacists and hospital pharmacists regarding biosimilar medicines in France; and 2) to identify the perceived problems and solutions to promoting their prescription. A 2015 web-based survey was conducted by the Observatoire des Médicaments, des Dispositifs Médicaux et de l'Innovation Thérapeutique of Alsace. A total of 802 pharmacists responded to the survey. Many (536, 66.8%, [95% confidence interval (CI) 63.6-70.1]) indicated that they were not familiar with biosimilars. Half of community pharmacists (95% CI 42.7-57.3) stated that they were not at all informed about biosimilar drugs, compared with 15.7% (95% CI 12.9-18.6) of hospital pharmacists. Almost all respondents (781, 97.4%, [95% CI 96.3-98.5]) had at least one pending question on biosimilars. Most of the questions were related to the manufacturing process, safety, substitution rules and the international non-proprietary name prescription. At the time of the study, 467 pharmacists (58.2%, [95% CI 54.8-61.6]) had already validated a prescription for a biosimilar drug, mainly for filgrastim. These latter were more comfortable in explaining the benefit of biosimilar medicines to the patient. Pharmacists were rather favorable to biosimilar drugs, and about 9 of 10 quoted healthcare cost savings as incentives to their prescription. However, many did not agree with allowing biosimilar substitution. "Patients' wishes to be treated with the originator" and "indication extrapolation" were the two main constraints identified. The survey highlighted the need to provide French pharmacists with accurate and comprehensive information regarding biosimilar medicines.

Purpose: Literature on agricultural activities and bladder cancer risk is scarce. However, farmers can be subjected to carcinogenic exposure (e.g. arsenic, previously used as a pesticide in France). This study aimed at assessing the role of a large range of agricultural activities and tasks on bladder cancer risk., Methods: The study population was the AGRIculture and CANcer cohort, a large prospective cohort of individuals affiliated to the agricultural health insurance scheme (MSA) in France. Incident bladder cancers were identified by cancer registries from enrolment (2005-2007) to 2009. Data on agricultural exposure during professional lifetime (5 animals, 13 crops, specific tasks) were obtained from the enrolment questionnaire. Associations between bladder cancer and agricultural exposure were analysed using a Cox model, adjusted for gender and smoking history., Results: Among the 148,051 farm owners and workers included in this analysis, 179 incident bladder cancers were identified. We observed an elevated risk among field-grown vegetable workers [HR 1.89, 95% CI (1.20-2.99)], with an exposure-response relationship with duration of work [≥30 years: HR 2.54, 95% CI (1.11-5.83), p-trend = 0.02], and higher risk among women [HR 3.82, 95% CI (1.58-9.25), p-interaction = 0.05]. Non-significantly increased risks were also observed in greenhouse farmers (HR = 1.95), pea sowing (HR = 1.84), rape sowing (HR = 1.64); several tasks involving pesticide use, especially seed treatment (HR = 1.24); and in activities and tasks potentially exposing to arsenic compounds via pesticide use (HR = 1.49) or re-entry tasks (HR = 1.63)., Conclusions: Our analyses raise the question of a possible link between agricultural activity, especially field-grown vegetables, and greenhouse cultivation and bladder cancer.

Background: The discovery of a solitary pulmonary nodule (SPN) on a chest imaging exam is of major clinical concern. However, the incidence rates of SPNs in a general population have not been estimated. The objective of this study was to provide incidence estimates of SPNs in a general population in 5 northeastern regions of France., Methods: This population-based study was undertaken in 5 regions of northeastern France in May 2002-March 2003 and May 2004-June 2005. SPNs were identified by chest CT reports collected from all radiology centres in the study area by trained readers using a standardised procedure. All reports for patients at least 18 years old, without a previous history of cancer and showing an SPN between 1 and 3 cm, were included., Results: A total of 11,705 and 20,075 chest CT reports were collected for the 2002-2003 and 2004-2005 periods, respectively. Among them, 154 and 297 reports showing a SPN were included, respectively for each period. The age-standardised incidence rate (IR) was 10.2 per 100,000 person-years (95% confidence interval 8.5-11.9) for 2002-2003 and 12.6 (11.0-14.2) for 2004-2005. From 2002 to 2005, the age-standardised IR evolved for men from 16.4 (13.2-19.6) to 17.7 (15.0-20.4) and for women from 4.9 (3.2-6.6) to 8.2 (6.4-10.0). In multivariate Poisson regression analysis, gender, age, region and period were significantly associated with incidence variation., Conclusions: This study provides reference incidence rates of SPN in France. Incidence was higher for men than women, increased with age for both gender and with time for women. Trends in smoking prevalence and improvement in radiological equipment may be related to incidence variations.

Background: Health-related quality of life (HRQoL) has been positioned as one of the major endpoints in oncology. Thus, there is a need to validate cancer-site specific survey instruments. This study aimed to perform a transcultural adaptation of the 50-item Expanded Prostate cancer Index Composite (EPIC) questionnaire for HRQoL in prostate cancer patients and to validate the psychometric properties of the French-language version., Methods: The EPIC questionnaire measures urinary, bowel, sexual and hormonal domains. The first step, corresponding to transcultural adaptation of the original English version of the EPIC was performed according to the back translation technique. The second step, comprising the validation of the psychometric properties of the EPIC questionnaire, was performed in patients under treatment for localized prostate cancer (treatment group) and in patients cured of prostate cancer (cured group). The EORTC QLQ-C30 and QLQ-PR25 prostate cancer module were also completed by patients to assess criterion validity. Two assessments were performed, i.e., before and at the end of treatment for the Treatment group, to assess sensitivity to change; and at 2 weeks' interval in the Cured group to assess test-retest reliability. Psychometric properties were explored according to classical test theory., Results: The first step showed overall good acceptability and understanding of the questionnaire. In the second step, 215 patients were included from January 2012 to June 2014: 125 in the Treatment group, and 90 in the Cured group. All domains exhibited good internal consistency, except the bowel domain (Cronbach's α = 0.61). No floor effect was observed. Test-retest reliability assessed in the cured group was acceptable, expect for bowel function (intraclass coefficient = 0.68). Criterion validity was good for each domain and subscale. Construct validity was not demonstrated for the hormonal and bowel domains. Sensitivity to change was exhibited for 5/8 subscales and 2/4 summary scores for patients who experienced toxicities during treatment., Conclusions: The French EPIC questionnaire seems to have adequate psychometric properties, comparable to those exhibited by the original English-language version, except for the construct validity, which was not available in original version.

Background: An important challenge of the longitudinal analysis of health-related quality of life (HRQOL) is the potential occurrence of a Response Shift (RS) effect. While the impact of RS effect on the longitudinal analysis of HRQOL has already been studied, few studies have been conducted on its impact on the determination of the Minimal Important Difference (MID). This study aims to investigate the impact of the RS effect on the determination of the MID over time for each scale of both EORTC QLQ-C30 and QLQ-BR23 questionnaires in breast cancer patients., Methods: Patients with breast cancer completed the EORTC QLQ-C30 and the EORTC QLQ-BR23 questionnaires at baseline (time of diagnosis; T0), three months (T1) and six months after surgery (T2). Four hospitals and care centers participated in this study: cancer centers of Dijon and Nancy, the university hospitals of Reims and Strasbourg At T1 and T2, patients were asked to evaluate their HRQOL change during the last 3 months using the Jaeschke transition question. They were also asked to assess retrospectively their HRQOL level of three months ago. The occurrence of the RS effect was explored using the then-test method and its impact on the determination of the MID by using the Anchor-based method., Results: Between February 2006 and February 2008, 381 patients were included of mean age 58 years old (SD = 11). For patients who reported a deterioration of their HRQOL level at each follow-up, an increase of RS effect has been detected between T1 and T2 in 13/15 dimensions of QLQ-C30 questionnaire, and 4/7 dimensions of QLQ-BR23 questionnaire. In contrast, a decrease of the RS effect was observed in 8/15 dimensions of QLQ-C30 questionnaire and in 5/7 dimensions of QLQ-BR23 questionnaire in case of improvement. At T2, the MID became ≥ 5 points when taking into account the RS effect in 10/15 dimensions of QLQ-C30 questionnaire and in 5/7 dimensions of QLQ-BR23 questionnaire., Conclusions: This study highlights that the RS effect increases over time in case of deterioration and decreases in case of improvement. Moreover, taking the RS into account produces a reliable and significant MID.

Background: Healthcare cost savings are closely linked to prescribers' confidence in and acceptance of the prescription of biosimilar drugs., Objectives: The aim of this study was to assess the knowledge, experience and opinions of hospital-based and office-based French rheumatologists with regard to biosimilar medicines and to identify the barriers to and possible options to promote their prescription., Methods: A web-based, self-administered survey was conducted among French rheumatologists from June 8 to August 2, 2015., Results: A total of 116 rheumatologists responded to the survey. Many reported having little knowledge and a lack of available information about biosimilar drugs, especially office-based rheumatologists. 98.3% of the respondents had at least one question about biosimilars, and seven in ten raised issues regarding substitution, iatrogenic effects or cost savings that might be achievable. Only eight rheumatologists had already prescribed a biosimilar drug. The most common barriers reported were indication extrapolation and a lack of data about tolerability. Nine out of ten physicians thought that starting a treatment with a biosimilar drug in biologic treatment-naïve patients was possible. The rheumatologists' opinions were rather favorable towards the implementation of biosimilars, but a majority expressed a negative opinion about substitution by the pharmacist., Conclusions: Our survey gave a better appreciation of the concerns associated with biosimilar prescriptions. Targeted communication initiatives, deeper experience and availability of new clinical data may help to address the outstanding questions and should overcome the misunderstandings surrounding biosimilar drugs among rheumatologists.

Background: The impact of prosthesis-patient mismatch (PPM) after aortic valve replacement (AVR) for aortic stenosis on exercise capacity remains controversial. The aim of this study was to analyze the long-term impact of PPM after mechanical AVR on maximal oxygen uptake (VO 2max )., Methods: The study included 75 patients who had undergone isolated mechanical AVR for aortic stenosis with normal left ventricular (LV) function between 1994 and 2012. Their functional capacity was evaluated on average 4.6 years after AVR by exercise testing, including measurement of their VO 2max , and by determining their New York Heart Association functional class and Short Form-36 score. Two groups were defined by measuring the patients' indexed effective orifice area (iEOA) by transthoracic echocardiography: a PPM group (iEOA < 0.85 cm 2 /m 2 ) and a no-PPM group (iEOA ≥ 0.85 cm 2 /m 2 )., Results: PPM was present in 37.0% of the patients. The percentage of the predicted VO 2max achieved was significantly lower in the PPM group (86.7 ± 19.5% vs 97.5 ± 23.0% in the no-PPM group; P = 0.04). Compared with the no-PPM group, the PPM group contained fewer patients in New York Heart Association functional class I and their mean Short Form-36 physical component summary score was significantly lower. The mean transvalvular gradient was significantly higher in the PPM group than in the no-PPM group (P < 0.001). Systolic and diastolic function and LV mass had normalized in both groups., Conclusions: PPM is associated in the long term with moderate but significant impairment of functional capacity, despite optimal LV reverse remodelling and normalization of LV systolic and diastolic function., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Human papillomaviruses (HPV) are involved in the development of anogenital and head and neck cancers. The purpose of this study was to assess the risk of developing a second primary cancer (SPC) after a first potentially-HPV-related cancer, and to analyze the sites where SPCs most frequently occurred in these patients. All patients with a first cancer diagnosed between 1989 and 2004, as recorded by 10 French cancer registries, were followed up until December 31, 2007. Only invasive potentially-HPV-related cancers (namely, cervical, vagina, vulva, anal canal, penile, oropharynx, tongue and tonsil) were included. Standardized Incidence Ratios (SIRs) were calculated to assess the risk of SPC. A multivariate Poisson regression model was used to model SIRs separately by gender, adjusted for the characteristics of the first cancer. 10,127 patients presented a first potentially-HPV-related cancer. The overall SIR was 2.48 (95% CI, 2.34-2.63). The SIR was 3.59 (95% CI, 3.33-3.86) and 1.61 (95% CI, 1.46-1.78) in men and women respectively. The relative risk of potentially-HPV-related SPC was high among these patients (SIR=13.74; 95% CI, 8.80-20.45 and 6.78; 95% CI, 4.61-9.63 for men and women, respectively). Women diagnosed in the most recent period (2000-2004) showed a 40% increase of their relative risk of SPC as compared with women diagnosed between 1989 and 1994 (ratio of SIRs=1.40; 95% CI, 1.06-1.85). HPV cancer survivors face an increased risk of SPC, especially second cancer. Clinicians may consider this increased risk of developing HPV-related SPC during follow-up to improve subsequent cancer prevention in these patients., (Copyright © 2016. Published by Elsevier Inc.)

Oxygen toxicity and antioxidant deficiencies contribute to the development of bronchopulmonary dysplasia. Aurothioglucose (ATG) and auranofin potently inhibit thioredoxin reductase-1 (TrxR1), and TrxR1 disruption activates nuclear factor E2-related factor 2 (Nrf2), a regulator of endogenous antioxidant responses. We have shown previously that ATG safely and effectively prevents lung injury in adult murine models, likely via Nrf2-dependent mechanisms. The current studies tested the hypothesis that ATG would attenuate hyperoxia-induced lung developmental deficits in newborn mice. Newborn C3H/HeN mice were treated with a single dose of ATG or saline within 12 hours of birth and were exposed to either room air or hyperoxia (85% O2). In hyperoxia, ATG potently inhibited TrxR1 activity in newborn murine lungs, attenuated decreases in body weight, increased the transcription of Nrf2-regulated genes nicotinamide adenine dinucleotide phosphate reduced quinone oxidoreductase-1 (NQO1) and heme oxygenase 1, and attenuated alterations in alveolar development. To determine the impact of TrxR1 inhibition on Nrf2 activation in vitro, murine alveolar epithelial-12 cells were treated with auranofin, which inhibited TrxR1 activity, enhanced Nrf2 nuclear levels, and increased NQO1 and heme oxygenase 1 transcription. Our novel data indicate that a single injection of the TrxR1 inhibitor ATG attenuates hyperoxia-induced alterations in alveolar development in newborn mice. Furthermore, our data support a model in which the effects of ATG treatment likely involve Nrf2 activation, which is consistent with our findings in other lung injury models. We conclude that TrxR1 represents a novel therapeutic target to prevent oxygen-mediated neonatal lung injury.

Objectives: To determine whether the risk of second primary cancer (SPC) among patients with bladder cancer (BCa) has changed over past years., Materials and Methods: Data from 10 French population-based cancer registries were used to establish a cohort of 10 047 patients diagnosed with a first invasive (≥T1) BCa between 1989 and 2004 and followed up until 2007. An SPC was defined as the first subsequent primary cancer occurring at least 2 months after a BCa diagnosis. Standardized incidence ratios (SIRs) of metachronous SPC were calculated. Multivariate Poisson regression models were used to assess the direct effect of the year of BCa diagnosis on the risk of SPC., Results: The risk of new malignancy among BCa survivors was 60% higher than in the general population (SIR 1.60, 95% confidence interval [CI] 1.51-1.68). Male patients presented a high risk of SPC of the lung (SIR 3.12), head and neck (SIR 2.19) and prostate (SIR 1.54). In multivariate analyses adjusted for gender, age at diagnosis and follow-up, a significant increase in the risk of SPC of the lung was observed over the calendar year of BCa diagnosis (P for linear trend 0.010), with an SIR increasing by 3.7% for each year (95% CI 0.9-6.6%); however, no particular trend was observed regarding the risk of SPC of the head and neck (P = 0.596) or the prostate (P = 0.518)., Conclusions: As the risk of SPC of the lung increased between 1989 and 2004, this study contributes more evidence to support the promotion of tobacco smoking cessation interventions among patients with BCa., (© 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.)

Objective: Alsace is a region in eastern France with a population of ∼2 million. All residents have high access to health care and an accredited referral center for SSc. Seeking care outside of this region is difficult because of the peculiar geography. The aim of this study was to assess the prevalence and spatial variation of systemic sclerosis (SSc) in eastern France., Methods: Data for SSc patients were obtained from 3 sources (all general practitioners and community specialists, capillaroscopy centers, and all public and private hospital records) and were used to estimate the prevalence of SSc. Surviving patients who resided in Alsace on January 1, 2008 and fulfilled the American College of Rheumatology and/or the LeRoy and Medsger criteria were included in this study. The clinical characteristics of the patients were also assessed. Potentially incomplete case ascertainment was corrected by capture-recapture analyses. Geographic disparities were assessed by spatial cluster analysis and by comparing our results with those for other geographic areas in the world for which data derived using similar methodology were available., Results: The review of 499 potential cases identified a total of 244 SSc patients. A trend toward a west-to-east gradient was observed but did not reach statistical significance. According to log-linear modeling, an estimated 83.87 additional cases were missed. Thus, the SSc prevalence was 228.42 cases per million adult inhabitants of Alsace (95% confidence interval 203.70-253.14); this prevalence was significantly higher than that in 2 other regions of France and comparable with the reported prevalence in Detroit, Michigan., Conclusion: The stringent methodology used in the current study is very likely to provide an accurate estimation of the prevalence of SSc. Design similarity with 3 other surveys extends the scope of the results by identifying geographic disparities that were previously indistinguishable due to methodologic differences., (© 2016, American College of Rheumatology.)

Purpose: Physical activity has been hypothesized to influence cancer occurrence through several mechanisms. To date, its relation with thyroid cancer risk has been examined in relatively few studies. We pooled 2 case-control studies conducted in Cuba and Eastern France to assess the relationship between self-reported practice of recreational physical activity since childhood and thyroid cancer risk., Methods: This pooled study included 1,008 cases of differentiated thyroid cancer (DTC) matched with 1,088 controls (age range 9-35 and 17-60 years in the French and Cuban studies, respectively). Risk factors associated with the practice of recreational physical activity were estimated using OR and 95% CI. Logistic regressions were stratified by age class, country, and gender and were adjusted for ethnic group, level of education, number of pregnancies for women, height, BMI, and smoking status., Results: Overall, the risk of thyroid cancer was slightly reduced among subjects who reported recreational physical activity (OR = 0.8; 95% CI 0.5-1.0). The weekly frequency (i.e. h/week) seems to be more relevant than the duration (years)., Conclusion: Long-term recreational physical activity, practiced since childhood, may reduce the DTC risk. However, the mechanisms whereby the DTC risk decreases are not yet entirely clear.

Background: Sequelae resulting from breast cancer negatively impact patients' quality of life. Although the deep inferior epigastric perforator (DIEP) flap has become a standard for autologous breast reconstruction, there are limited data regarding long-term quality of life. The authors studied patients' quality of life more than 5 years after DIEP flap breast reconstruction and compare it with two French reference samples., Methods: A cross-sectional study of quality of life was performed in women who underwent DIEP flap breast reconstruction between 1995 and 2007 using the Medical Outcomes Study 36-Item Health Survey (Short Form-36). The first reference sample included subjects from the French general population (n = 3308), and the second included cancer survivors who underwent mastectomy with (n = 70) or without (n = 135) breast reconstruction., Results: One hundred eleven respondents were analyzed among 186 eligible women. The mean follow-up period after reconstruction was 8.6 years (range, 5 to 15 years). There were no statistically significant differences in the quality of life between women from 45 to 64 years old who underwent DIEP flap breast reconstruction and from the French general population. Five of the eight Short Form-36 dimensions were significantly better in the DIEP flap breast reconstruction group in the 65- to 74-year-old cohort. In addition, quality of life of our study population was significantly higher than that of women who underwent mastectomy with or without any type of breast reconstruction., Conclusion: These results indicate that DIEP flap breast reconstruction allows patients with breast cancer to maintain a good postoperative quality of life comparable to that of the general population., Clinical Question/level of Evidence: Therapeutic, III.

Background: Unresolved inflammation resulting in capillary leakage with endothelial barrier dysfunction is a major contributor to postoperative morbidity and mortality after coronary artery bypass graft (CABG). Angiopoietins (ANGs) are vascular growth factors, also mediating inflammation and disruption of the endothelium, thus inducing capillary leakage. We hypothesized that changes in the relative serum levels of ANG1 and ANG2 influence endothelial barrier function and perioperative morbidity after CABG., Methods: After approval and informed consent, serum samples (n = 28) were collected pre CABG surgery, 1, 6, and 24 h after aortic de-clamping. ANG1, ANG2, soluble ANG receptor TIE2 (sTIE2), and IL-6 serum concentrations were analyzed by ELISA. Human pulmonary microvascular endothelial cells (HPMECs) were incubated with patient serum and FITC-dextran permeability was assessed. Furthermore, ANG2 secretion of HPMECs was analyzed after incubation with IL-6-containing patient serum., Results: CABG induced an early and sustained increase of ANG2/ANG1 ratio (5-fold after 24 h compared to pre-surgery). These changes correlated with elevated serum lactate levels, fluid balance, as well as the duration of mechanical ventilation. Permeability of HPMECs significantly increased after incubation with post-surgery serum showing a marked shift of ANG2/ANG1 balance (18-fold) compared to serum with a less pronounced increase (6-fold). Furthermore, CABG resulted in increased IL-6 serum content. Pre-incubation with serum containing high levels of IL-6 amplified the ANG2 secretion by HPMECs; however, this was not influenced by blocking IL-6., Conclusions: CABG affects the balance between ANG1 and ANG2 towards a dominance of the barrier-disruptive ANG2. Our data suggest that this ANG2/ANG1 imbalance contributes to an increased postoperative endothelial permeability, likewise being reflected by the clinical course. The results strongly suggest a biological effect of altered angiopoietin balance during cardiac surgery on endothelial permeability.

Biobanking or collection and storage of specimens for future research purposes have become an essential tool in many fields of biomedical research and aims to provide a better understanding of disease mechanisms as well as the identification of disease-specific biomarkers that can navigate in complex diseases. In this study, we assessed the use of Flinders Technology Associates (FTA) cards as a long-term storage device for cervical specimens with suspected human papillomavirus (HPV) infections. HPV detection and genotyping results in liquid-based transport media were compared to HPV results from FTA cards. The overall agreement for the presence of any HPV infection between liquid-based medium and FTA cards stored for 1 year at ambient temperature was 100%. Reproducibility analysis of HPV detection and genotyping from FTA cards demonstrated that FTA cards are a reliable medium to store and preserve viral nucleic acids. Biobanking of cervical cells on FTA cards may provide a key resource for epidemiological and retrospective HPV studies., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: Prostate cancer is one of the most frequent cancers among men worldwide. Its etiology is largely unknown, but an increased risk has been repeatedly observed among farmers. Our aim was to identify occupational risk factors for prostate cancer among farmers in the prospective cohort study AGRICAN., Methods: Data on lifetime agricultural exposures (type of crops, livestock and tasks including pesticide use, re-entry and harvesting) were collected from the enrolment questionnaire. During the period from enrolment (2005-2007) to 31 December 2009, 1672 incident prostate cancers were identified. Hazard ratios (HR) were estimated using Cox regression analysis., Results: We found an increased risk for cattle breeders using insecticides [HR 1.20, 95% confidence interval (95% CI) 1.01-1.42] with a significant dose-response relationship with number of cattle treated (P for trend 0.01). A dose-response relationship was also observed with the number of hogs (P for trend 0.06). We found an excess of prostate cancer risk among people involved in grassland activities, mainly in haymaking (HR 1.18, 95% CI 1.02-1.36). Pesticide use and harvesting among fruit growers were associated with an elevated prostate cancer risk, with a two-fold increased risk for the largest area. For potato and tobacco producers, an elevated prostate cancer risk was observed for almost all tasks, suggesting a link with pesticide exposure since all of them potentially involved pesticide exposure., Conclusions: Our analysis suggests that the risk of prostate cancer is increased in several farming activities (cattle and hog breeding, grassland and fruit-growing) and for some tasks including pesticide use.

Unlabelled: Extrapolation of clinical trials results to the general population is always challenging. We analysed 1047 patients diagnosed with an advanced stage disease between 1998 and 2005 in a french administrative department and found a good spread of modern chemotherapy since 1998 and targeted therapy since 2002. Moreover, the outcomes in patients treated according to guidelines are very proximal from those obtained in clinical trials., Background: Management of metastatic non-small-cell lung cancer has considerably evolved during the past 2 decades. In this study we aimed to assess how treatments have spread at a population-based level and their effect on survival., Patients and Methods: Medical records of patients diagnosed from 1998 to 2005 in the French department of Bas-Rhin were checked to collect data on patient characteristics and treatments received. Multivariate analysis of survival was performed using pretherapeutic and therapeutic factors including targeted therapies received as third-line treatment., Results: We included 1047 patients with stage IIIB to IV non-small-cell lung cancer. The proportion of patients who underwent chemotherapy increased from 373/471 (79.2%) to 491/576 (85.2%) over the 1998 to 2001 and 2002 to 2005 periods, and there was an increased use of third-generation drugs associated with platin. Third-line treatment was gefitinib or erlotinib in 73/155 (47.1%) of the cases among patients diagnosed from 2002 to 2005. Compared with older agents, targeted therapy administered as third-line treatment was associated with a longer survival but there was no significant difference in survival with recent chemotherapy agents in multivariate analyses (hazard ratio, 0.773; 95% confidence interval, 0.445-1.343)., Conclusion: Results of our study showed a good spread of modern chemotherapy and targeted therapy use at a population-based level. However, even if the general outcomes were improved along the years, the results observed in real clinical practice were slightly different from those reported in clinical trials., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The aim of this epidemiological study was to describe the incidence, mortality and survival of ovarian cancer (OC) in France, according to age, period of diagnosis, and histological type., Methods: Incidence and mortality were estimated from 1980 to 2012 based on data in French cancer registries and from the Centre for Epidemiology of Causes of Death (CépiDc-Inserm) up to 2009. Net survival was estimated from registry data using the Pohar-Perme method, on cases diagnosed between 1989 and 2010, with date of last follow-up set at 30 June 2013., Results: In 2012, 4615 cases of OC were diagnosed in France, and 3140 women died from OC. World population age-standardized incidence and mortality rates declined by respectively 0.6% and 1.2% per year between 1980 and 2012. Net survival at 5years increased slightly, from 40% for the period 1989-1993 to 45% for the period 2005-2010. Net survival varied considerably according to histological type. Germ cell tumors had better net survival at 10years (81%) compared to epithelial tumors (32%), sex cord-stromal tumors (40%) and tumors without biopsy (8%)., Conclusions: Our study shows a decline in incidence and mortality rates from ovarian cancer in France between 1980 and 2012, but net survival remains poor overall, and improved only slightly over the whole study period., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: Reperfusion ofmyocardial infarction is associated with inflammatory reaction and subsequentmyocardial remodeling with a rapid scar formation in mice. The cannabinoid receptor CB2 has been associated with cardioprotection and regulation ofmacrophage function.Weinvestigated its role in remodeling of reperfused infarction., Main Methods: One hour LAD-occlusion was followed by reperfusion over 6 h and 1, 3 and 7 days in wild-type C57/BL6J (WT) and CB2 receptor-deficient (Cnr2−/−)mice (n=8/group). Hearts were processed for functional, morphological and mRNA/protein analysis, and tissue concentration of endocannabinoidswas determined using liquid chromatography-multiple reaction monitoring., Key Findings: In contrast to a rapid formation of granulation tissue and a compacted non-transmural scar inWT mice after 7 days of reperfusion, Cnr2−/− mice showed a non-compacted transmural scar. Millar® left ventricular catheter measurements revealed a significantly worse function in Cnr2−/− mice.We found no compensatory elevation of endocannabinoid concentration in Cnr2−/− hearts. Macrophage infiltration was significantly stronger in Cnr2−/− hearts and affected also the remote septum, when compared to WT hearts.We found a cytokine-driven inflammatory response in Cnr2−/− hearts with no significant induction of chemokines. Immunohistochemistry for thrombospondin-1 revealed a dysfunctional infarction border zone formation in Cnr2−/− hearts. Cnr2−/−hearts showed no significant induction of tenascin C, collagen-Iα or lysil oxidase, thereby indicating adversemyocardial remodeling., Significance: Endocannabinoids act via CB2 receptor in the modulation of inflammatory response and myocardial remodeling after infarction. CB2 receptor plays an important role in the formation of infarction border zone, collagen deposition and organization of stable scar during remodeling.

We have previously shown that an adverse perinatal environment significantly alters lung growth and development and results in persistently altered cardiopulmonary physiology in adulthood. Our model of maternal LPS treatment followed by 14 days of neonatal hyperoxia exposure causes severe pulmonary disease characterized by permanent decreases in alveolarization and diffuse interstitial fibrosis. The current investigations tested the hypothesis that dysregulation of Notch signaling pathways contributes to the permanently altered lung phenotype in our model and that the improvements we have observed previously with maternal docosahexaenoic acid (DHA) supplementation are mediated through normalization of Notch-related protein expression. Results indicated that inflammation (IL-6 levels) and oxidation (F2a-isoprostanes) persisted through 8 wk of life in mice exposed to LPS/O2 perinatally. These changes were attenuated by maternal DHA supplementation. Modest but inconsistent differences were observed in Notch-pathway proteins Jagged 1, DLL 1, PEN2, and presenilin-2. We detected substantial increases in markers of apoptosis including PARP-1, APAF-1, caspase-9, BCL2, and HMGB1, and these increases were attenuated in mice that were nursed by DHA-supplemented dams during the perinatal period. Although Notch signaling is not significantly altered at 8 wk of age in mice with perinatal exposure to LPS/O2, our findings indicate that persistent apoptosis continues to occur at 8 wk of age. We speculate that ongoing apoptosis may contribute to persistently altered lung development and may further enhance susceptibility to additional pulmonary disease. Finally, we found that maternal DHA supplementation prevented sustained inflammation, oxidation, and apoptosis in our model., (Copyright © 2015 the American Physiological Society.)

Background: The economic burden linked to rheumatoid arthritis (RA) has greatly increased since the inclusion of biotherapies in the therapeutic arsenal., Objectives: This study aimed first to look at the breakdown of the rheumatoid arthritis patients on biotherapy in Alsace, France, in 2012, then to evaluate the annual cost per treated patient for each management pathway: inpatient care with intravenous biotherapies and/or outpatient care through the use of subcutaneous drugs, and finally to conduct a cost comparison with a focus on infliximab, adalimumab and etanercept., Methods: This observational study was conducted in Alsace using 2012 health claims data from the DCIR (Données de Consommation Inter Régime) and PMSI (Programme de Médicalisation des Systèmes d'Information) databases, taking into account direct medical and non-medical costs in a real-life setting and from a National Health Insurance perspective., Results: There were 5702 RA patients, i.e. 0.31 % of the Alsace population in 2012, including 1075 subjects (18.85 %) receiving biotherapy treatment. The most frequently prescribed biotherapies were etanercept and adalimumab. The estimated overall cost of care of these 5702 patients was €30.3 million, with about 50 % for the care of the 18.85 % patients on biotherapy. Average costs for inpatient, outpatient and mixed care ranged from €14,197 to €16,873 per patient per year. Annual average cost for management of a single RA patient with infliximab was significantly higher than with adalimumab and etanercept: €16,480 versus €14,116 and €14,338, respectively., Conclusion: These findings confirm the trends of initial modelling approaches and quantify the cost difference between various biotherapy management pathways., Competing Interests: Compliance with Ethical Standards Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Conflict of interest Dr. Sordet received lecture/speaker fees, fees for expert opinion and travel expenses, and was involved in clinical trials with MSD, BMS, Roche, Abbvie, and Pfizer. The other authors have nothing to disclose. Ethical approval The authors state that no ethical approval was needed.

Cardiac and skeletal muscle dysfunction is a recognized effect of cancer-induced cachexia, with alterations in heart function leading to heart failure and negatively impacting patient morbidity. Cachexia is a complex and multifaceted disease state with several potential contributors to cardiac and skeletal muscle dysfunction. Matrix metalloproteinases (MMPs) are a family of enzymes capable of degrading components of the extracellular matrix (ECM). Changes to the ECM cause disruption both in the connections between cells at the basement membrane and in cell-to-cell interactions. In the present study, we used a murine model of C26 adenocarcinoma-induced cancer cachexia to determine changes in MMP gene and protein expression in cardiac and skeletal muscle. We analyzed MMP-2, MMP-3, MMP-9, and MMP-14 as they have been shown to contribute to both cardiac and skeletal muscle ECM changes and, thereby, to pathology in models of heart failure and muscular dystrophy. In our model, cardiac and skeletal muscles showed a significant increase in RNA and protein levels of several MMPs and tissue inhibitors of metalloproteinases. Cardiac muscle showed significant protein increases in MMP-2, MMP-3, MMP-9, and MMP-14, whereas skeletal muscles showed increases in MMP-2, MMP-3, and MMP-14. Furthermore, collagen deposition was increased after C26 adenocarcinoma-induced cancer cachexia as indicated by an increased left ventricular picrosirius red-positive-stained area. Increases in serum hydroxyproline suggest increased collagen turnover, implicating skeletal muscle remodeling. Our findings demonstrate that cancer cachexia-associated matrix remodeling results in cardiac fibrosis and possible skeletal muscle remodeling. With these findings, MMPs represent a possible therapeutic target for the treatment of cancer-induced cachexia., (Copyright © 2015 the American Physiological Society.)

Unlabelled: Fatigue and muscle wasting are common symptoms experienced by cancer patients. Data from animal models demonstrate that angiotensin is involved in tumor-induced muscle wasting, and that tumor growth can independently affect myocardial function, which could contribute to fatigue in cancer patients. In clinical studies, inhibitors of angiotensin converting enzyme (ACE) can prevent the development of chemotherapy-induced cardiovascular dysfunction, suggesting a mechanistic role for the renin-angiotensin-aldosterone system (RAAS). In the present study, we investigated whether an angiotensin (AT) 1-receptor antagonist could prevent the development of tumor-associated myocardial dysfunction., Methods and Results: Colon26 adenocarcinoma (c26) cells were implanted into female CD2F1 mice at 8weeks of age. Simultaneously, mice were administered Losartan (10mg/kg) daily via their drinking water. In vivo echocardiography, blood pressure, in vitro cardiomyocyte function, cell proliferation assays, and measures of systemic inflammation and myocardial protein degradation were performed 19days following tumor cell injection. Losartan treatment prevented tumor-induced loss of muscle mass and in vitro c26 cell proliferation, decreased tumor weight, and attenuated myocardial expression of interleukin-6. Furthermore, Losartan treatment mitigated tumor-associated alterations in calcium signaling in cardiomyocytes, which was associated with improved myocyte contraction velocity, systolic function, and blood pressures in the hearts of tumor-bearing mice., Conclusions: These data suggest that Losartan may mitigate tumor-induced myocardial dysfunction and inflammation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The incidence of thyroid cancer has risen over the past decade, along with a rise in obesity. We studied the role of anthropometric risk factors for differentiated thyroid cancer at the time of diagnosis and at age 20 years in a case-control study conducted in eastern France between 2005 and 2010. The study included 761 adults diagnosed with differentiated thyroid cancer before 35 years of age between 2002 and 2006. They were matched with 825 controls from the general population. Odds ratios were calculated using conditional logistic regression models and were reported for all participants, those with papillary cancer only, and women only. The risk of thyroid cancer was higher for participants with a high body surface area (BSA), great height, or excess weight and for women with a high body fat percentage. Conversely, no significant association was found between body mass index and the risk of thyroid cancer. In the present study, we provide further evidence of the role of BSA and excess weight in the risk of thyroid cancer. These epidemiologic observations should be confirmed by further exploration of the biological mechanisms responsible for the associations of obesity and BSA with thyroid cancer., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Unlabelled: The prostate cancer became for two decades the most frequent cancer in men. We describe the evolution of its incidence and mortality from 1980 to 2011 for France., Methods: Incidence data were collected from registries and national incidence estimates were based on the use of mortality as a correlate of incidence., Results: After a very strong increase of incidence between 1980 (24.8/100,000) and 2005 (124.5/100,000), we observe a net decline since (97.7/100,000, in 2011). The reduction began earlier for the old patients. The evolution of mortality is very different. We observe a regular reduction since the end of 1990s (from 18.0/100,000 in 1990 to 10.5/100,000 in 2011). The reduction began earlier for the young patients., Conclusion: This pattern of evolution is observed in all the countries where the use of the PSA had caused an important increase of the diagnosis of prostate cancer., Level of Evidence: 3., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Objective: To provide head and neck squamous cell carcinoma (HNSCC) survival estimates with respect to patient previous history of cancer., Materials and Methods: Data from ten French population-based cancer registries were used to establish a cohort of all male patients presenting with a HNSCC diagnosed between 1989 and 2004. Vital status was updated until December 31, 2007. The 5-year overall and net survival estimates were assessed using the Kaplan-Meier and Pohar-Perme estimators, respectively. Multivariate Cox regression models were used to assess the effect of cancer history adjusted for age and year of HNSCC diagnosis., Results: Among the cases of HNSCC, 5553 were localized in the oral cavity, 3646 in the oropharynx, 3793 in the hypopharynx and 4550 in the larynx. From 11.0% to 16.8% of patients presented with a previous history of cancer according to HNSCC. Overall and net survival were closely tied to the presence, or not, of a previous cancer. For example, for carcinoma of the oral cavity, the five-year overall survival was 14.0%, 5.9% and 36.7% in case of previous lung cancer, oesophagus cancer or no cancer history, respectively. Multivariate analyses showed that previous history of cancer was a prognosis factor independent of age and year of diagnosis (p<.001)., Conclusion: Previous history of cancer is strongly associated with survival among HNSCC patients. Survival estimates based on patients' previous history of cancer will enable clinicians to assess more precisely the prognosis of their patients with respect to this major comorbid condition., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background. In a French large population-based case-control study we investigated the dose-response relationship between lung cancer and occupational exposure to diesel motor exhaust (DME), taking into account asbestos exposure. Methods. Exposure to DME was assessed by questionnaire. Asbestos was taken into account through a global indicator of exposure to occupational carcinogens or by a specific JEM. Results. We found a crude dose response relationship with most of the indicators of DME exposure, including with the cumulative exposure index. All results were affected by adjustment for asbestos exposure. The dose response relationships between DME and lung cancer were observed among subjects never exposed to asbestos. Conclusions. Exposure to DME and to asbestos is frequently found among the same subjects, which may explain why dose-response relationships in previous studies that adjusted for asbestos exposure were inconsistent.

Non-Hodgkin lymphoma (NHL) represents a heterogeneous group of diseases that are known to carry a considerable risk of second primary cancer (SPC). However, little attention has been paid to SPC risk assessment according to NHL subtypes. Data from 10 French population-based cancer registries were used to establish a cohort of 7546 patients with a first diagnosis of NHL (eight subtypes) between 1989 and 2004. Standardized incidence ratios (SIRs) of metachronous SPC were estimated. Among the 7546 patients diagnosed with a NHL, the overall SPC risk was 25% higher than that in the reference population (SIR = 1.25, 95% confidence interval 1.15-1.36). In univariate analysis, the SPC risk differed by lymphoma subtype. Interestingly, multivariate analysis showed that SPC risk did not differ significantly across NHL subtypes after adjustment for the other covariates (p = 0.786). Patients with NHL have an increased risk of SPC that is not influenced by the histological NHL subtype.

The incidence of thyroid cancer has increased in eastern Europe since the Chernobyl nuclear power plant accident. Although the radioactive fallout was much less severe and the thyroid radiation dose was much lower in France, a case-control study was initiated in eastern France. The present study included 633 young women who were diagnosed with differentiated thyroid cancer before 35 years of age between 2002 and 2006 and matched with 677 controls. Face-to-face interviews were conducted from 2005 to 2010. Odds ratios were calculated using conditional logistic regressions and were reported in the total group and by histopathological type of cancer ("only papillary" and "excluding microcarcinomas"). The risk of thyroid cancer was higher in women who had a higher number of pregnancies, used a lactation suppressant, or had early menarche. Conversely, breastfeeding, oral contraceptive use, and late age at first pregnancy were associated with a lower risk of thyroid cancer. No association was observed between thyroid cancer and having irregular menstrual cycle, undergoing treatment for menstrual cycle regularity shortly after menarche, having a cessation of menstruation, use of another contraceptive, history of miscarriage or abortion for the first pregnancy, or having had gestational diabetes. This study confirms the role of hormonal and reproductive factors in thyroid cancer, and our results support the fact that exposure to estrogens increases thyroid cancer risk., (© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)