Controlled human infection trials: Legitimacy and conditions of implementation in France.

This round table is the result of an observation. The observation being that controlled human infection clinical trials (also called "infectious challenge" trials or "Controlled Human Infection Models", "CHIM") recommended or even encouraged in the context of vaccine developments in particular, are not carried out in France. However, there are no formal prohibitions within regulations or ethical principles, which point to the prior assessment of risks and benefits for individuals and for society. The participants in this Round Table thus wished to examine, through the prism of their respective disciplines, the scientific and medical relevance of conducting such trials in France and, if possible, to imagine the conditions under which they would be carried out, thus resulting in recommendations on (1) the advisability of their conduct in France (2), the conditions under which they would be implemented in terms of logistics and regulations, and (3) their social acceptability. The recommendations on which the participants of the Round Table came to an agreement are presented as the analysis progresses.

[Healthy volunteers' protection around the world]. / VolREthics - Une initiative internationale de l'Inserm pour définir la protection des volontaires sains.

Healthy volunteers participating in biomedical research benefit from varying levels of protection in different parts of the world since they are too rarely identified as a specific subset of study participants with specific vulnerabilities and risks. These differences in protection can lead to unfair and ethically unacceptable situations. Healthy volunteers are subject to a number of risks, not only regarding the respect of their rights and of their health but they are also at risk of being exploited because of their financial situation, educational level and motivations. In the end, the scientific validity of the studies may also be called into question. Through its work, the VolREthics (Volunteers in Research and Ethics) initiative, set up by the Inserm ethics committee, outlines the ethical issues raised by the involvement of healthy volunteers in biomedical research, and highlights the need to improve their protection worldwide. Healthy volunteers are essential to scientific progress and society, and their potential vulnerabilities must be recognized and taken into account.

Title: VolREthics - Une initiative internationale de l'Inserm pour définir la protection des volontaires sains. Abstract: Les volontaires sains qui participent aux recherches biomédicales sont très rarement identifiés comme un groupe spécifique. Pourtant, de par leur vulnérabilité et les risques potentiels auxquels ils sont exposés, ils ne bénéficient que d'un niveau de protection qui reste variable selon les régions du monde. Il en résulte différents risques, non seulement pour le respect de leurs droits, de leur santé, mais également pour la validité scientifique des recherches. L'initiative internationale VolREthics (pour volontaires sains en recherche et éthique, ou Volunteers in Research and Ethics), lancée par le comité d'éthique de l'Inserm, a mis en évidence les questions éthiques soulevées par la participation des volontaires sains dans la recherche biomédicale. Elle insiste également sur la nécessité d'améliorer la protection de ces volontaires lors des recherches menées à travers le monde.

Diagnostic chest X-rays and breast cancer risk among women with a hereditary predisposition to breast cancer unexplained by a BRCA1 or BRCA2 mutation.

BACKGROUND: Diagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation. METHODS: We evaluated the effect of chest X-rays from diagnostic medical procedures in a dataset composed of 1552 BC cases identified through French family cancer clinics and 1363 unrelated controls. Participants reported their history of X-ray exposures in a detailed questionnaire and were tested for 113 DNA repair genes. Logistic regression and multinomial logistic regression models were used to assess the association with BC. RESULTS: Chest X-ray exposure doubled BC risk. A 3% increased BC risk per additional exposure was observed. Being 20 years old or younger at first exposure or being exposed before first full-term pregnancy did not seem to modify this risk. Birth after 1960 or carrying a rare likely deleterious coding variant in a DNA repair gene other than BRCA1/2 modified the effect of chest X-ray exposure. CONCLUSION: Ever/never chest X-ray exposure increases BC risk 2-fold regardless of age at first exposure and, by up to 5-fold when carrying 3 or more rare variants in a DNA repair gene. Further studies are needed to evaluate other DNA repair genes or variants to identify those which could modify radiation sensitivity. Identification of subpopulations that are more or less susceptible to ionizing radiation is important and potentially clinically relevant.

Cancer survivors' efforts to facilitate return to work.

This study assesses individual factors that influence return to work (RTW) and in particular on the cancer survivors' ability to prepare his/her job resumption. A self-administered questionnaire was completed by 105 cancer survivors after at least 4 weeks after the time of their RTW. Various methods of returning to work were compared between occupational and medical characteristics with multivariate statistical tests. Regular contact by a cancer survivor with the company during sick leave is associated with RTW within 1 year of diagnosis (ORaj = 5.78). Optional pre-reinstatement visit with the occupational physician is associated with the absence of employee activity's change (ORaj = 2.30). The cancer survivors who during treatment period ask for an adaption of treatment are more likely to have a change in working conditions (ORaj = 14.5). The adaptation to recovery conditions appears to be associated with survivors' effort to RTW. It should be confirmed with new studies.

When to do surgical resection for atypical breast lesions: Results of a prospective cohort of 518 lesions.

AIM: There is no consensual indication for surgical resection after diagnosis on per-cutaneous biopsy of borderline breast lesions (B3). We evaluate under-evaluation rate of per-cutaneous biopsy and predictive factors of under-evaluation. We analyze accuracy of reported decision-making tools. METHODS: We conduct a prospective multicentric study including, atypic-ductal hyperplasia (ADH), atypic-lobular hyperplasia (ALH), atypic-cylindro-cubic metaplasia (FEA), papilloma, radial scars (RS) and phyllod tumors. When several B3 lesions were associated, the more severe lesion was used to classify the lesion. We determined breast cancers (BC) rate and histologic type. Among 478 patients, 518 B3 lesions were studied: 15.1% (78) FEA, 48.6% (252) ADH, 16.8% (n = 87) ALH, 5.4% (n = 28) RS, 12% (n = 62) papilloma, 0.8% (n = 4) phyllod tumors and 0,8% (n = 4) with a suspicious low grade DCIS. More than 1 lesion was identified in 31.9% (165) of cases. A surgical resection was performed for 86.3% (447/518) lesions. Significant factors of surgical resection were: residual micro-calcification after biopsy (OR: 2.7) and type of B3 lesion. RESULTS: Overall BC rate was 15.3% (68/445) with 79.4% (54) in-situ carcinomas. According to B3 lesions, BC rates were 12.9% for FEA, 20% for ADH, 11.6% for ALH, 3.7% for RS, 8.8% for papilloma and 25% for suspicious in-situ carcinoma. A score has been calculated and patients were distributed in 3 groups. Patient's rates without BC were respectively: 100%, 80.4% and 80.6% (p = 0.029). CONCLUSION: In conclusion, it could be suggested to avoided complementary surgical resection in case of good radio-pathologic concordance and low probability of BC.

How to manage BRCA mutation carriers?

Inherited mutations in BRCA1 and BRCA2 genes increase the risk of development of cancer in organs especially in breast and ovary. Prevention and screening in BRCA mutation carriers are of high importance. Prophylactic surgeries are possible but are still insufficiently performed because they require surgical procedures in healthy patients. Guidelines for the management of BRCA mutations carriers must absolutely be part of the standard practice of all those involved in the management of these patients to increase the impact of the implementation of these preventive measures. There is no screening recommended for ovarian cancer. A risk-reducing bilateral salpingo-oophorectomy should be performed from age 35 to 40 years for BRCA1 mutation carriers and 40 to 45 years for BRCA2 mutation carriers. A screening for breast cancer should be performed annually from 30 years old by breast MRI and mammography. A risk-reducing bilateral mastectomy is recommended with nipple sparing mastectomy and immediate breast reconstruction from 30 years and before 40 years. A multidisciplinary care must be implemented for these patients with an important psychological support.

Socioeconomic deprivation is associated with decreased survival in patients with acute myeloid leukemia.

BACKGROUND: Socioeconomic deprivation is associated with poor prognosis in patients with solid tumors. However, few studies have assessed the association between socioeconomic parameters and prognosis in Acute Myeloid Leukemia (AML), and these report conflicting results. Our monocentric study assessed the impact of socioeconomic deprivation using the validated EPICES (Evaluation of Deprivation and Inequalities in Health Examination Centers) score in a prospective cohort of intensively treated AML patients. METHODS: EPICES questionnaires were given to patients receiving intensive chemotherapy for newly diagnosed AML at the Paoli Calmettes Institute between July 2012 and December 2014. Study participants were categorized as non-deprived (score <30.17), deprived (score 30.17-48.51), or very-deprived (score ≥ 48.52). The primary endpoint was Overall Survival (OS). The independence of EPICES score effects was analyzed via Cox regression with adjustment for confounding factors. RESULTS: 209 AML patients received the questionnaire, 149 (71.3 %) patients responded. The median EPICES score was 23.6; 26.8 % and 10.1 % of patients were deprived and very deprived, respectively. OS was 23.16 months (95 %CI [17.15-33.31]). According to multivariate analysis, a very-deprived EPICES score, European Leukemia Net categories, age, smoking, and the absence of allogeneic stem cell transplantation were independent factors associated with decreased OS. CONCLUSION: Our results underscore the importance of integrating nonbiological factors in the prognostic stratification of AML patients. The very deprived population exhibited worse OS, confirming that socioeconomic parameters play a role in patient outcomes in AML. Very deprived patients with AML should receive specific attention and adapted clinical management.

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.

Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost-effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious-predicted variants in DNA repair genes in familial breast cancer (BC) in a well-characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC (N = 1,207), and general population controls (N = 1,199). Sequencing data were filtered for rare loss-of-function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2, ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI, MAST1, POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (ORLoF = 17.4 vs. ORMV = 1.6; p Het = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious-predicted variants in PALB2, ATM and CHEK2 and to add MAST1, POLH, RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates.

Current and Former Smokers: Who Wants To Be Screened?

BACKGROUND: Lung cancer (LC) screening (LCS) with annual low-dose computed tomography scans has been seen to reduce the specific and overall mortality in selected populations. However, participation is key to successful screening programs. The EDIFICE (etude sur le dépistage des cancers et ses facteurs de compliance [survey on cancer screening and compliance factors]) nationwide observational surveys are used to assess behavior related to cancer screening programs in France. MATERIALS AND METHODS: Using comprehensive multivariate stepwise logistic regression analyses of data from current and former cigarette smokers, we sought to identify the explanatory factors associated with the intention to participate in an LCS program. RESULTS: Of the 1463 respondents with no personal history of cancer, 263 (36.4%) of the current cigarette smokers and 170 (26.3%) of the former cigarette smokers stated their willingness to participate in an LCS program. The explanatory factors differed between current cigarette smokers (already screened for LC: odds ratio [OR], 2.81; < 30 pack-years: OR, 2.69; intention to quit smoking: OR, 1.96; no social vulnerability: OR, 2.15) and former cigarette smokers (comorbidities: OR, 0.31). The usual eligibility criteria were not significantly explanatory. CONCLUSION: Our findings highlight the discrepancy that exists between target populations and individuals who actually intend to participate in a screening program for LC, with subsequent potential effects on the participation rates and, thus, on the efficacy of screening.

Beliefs and behavior regarding e-cigarettes in a large cross-sectional survey.

Although e-cigarette use is increasing dramatically, numerous concerns persist regarding toxicity and their role in smoking cessation. We assessed beliefs and behavior regarding e-cigarettes in an adult French population. The 4th French nationwide observational survey, EDIFICE 4, was conducted among representative samples of 1602 laypersons (age, 40-75 years) from 12 June-10 July 2014, using the quota method. Profile, beliefs and behavior were assessed by phone interviews of the participating lay population with no history of cancer (N = 1463). Tobacco use, nicotine dependence (Fagerström test) and e-cigarette use were assessed. E-cigarette users represented 6% of the study lay population. E-cigarette users regarded e-cigarettes as helpful for quitting tobacco smoking and reducing the risk of lung cancer. Current dual users (e-cigarettes + cigarettes) were more likely to attempt to quit than current exclusively cigarette smokers (odds ratio, 3.15 [1.74-5.70]), and to consider themselves at higher risk for lung cancer (OR 3.85 [2.47-5.99]). They also considered e-cigarette vapor to be less toxic than tobacco smoke in terms of both active and passive exposure. Dual users typically consider themselves at higher risk for cancer and intend to quit smoking. Physicians should be made aware of this specific sub-population for whom e-cigarettes may be a useful trigger in the smoking cessation process.

Telehealth applied to physical activity during cancer treatment: a feasibility, acceptability, and randomized pilot study.

PURPOSE: Previous studies have underlined the benefits of exercise during cancer therapy. However, patients are insufficiently active during treatment. Telehealth is used to encourage people to be active, reducing difficulties and offsetting the lack of infrastructure often reported. We aimed to identify the effects of recommendations and telehealth on the level of physical activity, fatigue, and quality of life. METHODS: Sixty patients suffering from various cancers under treatment were randomized into two groups. Every Sunday, they had to complete online questionnaires: number of steps, MFI-20, and EORTC-QLQ-30. Group R (recommendations) was given encouragement to improve physical activity during 8 weeks, using a recommendation guide, and received a weekly SMS text message for exercise promotion. Group C, without recommendations, was the control group. RESULTS: Two-way ANOVAs for repeated measures did not reveal effect on the number of steps walked over time; however, the results indicated a beneficial effect for group R related to self-reported fatigue (F = 2.686, p = .01) and quality of life (F = 2.431, p = .02). CONCLUSION: Surprisingly, the level of exercise in group R did not significantly increase, but self-reported fatigue and quality of life were improved. This study underlines that inexpensive sharing of time, human, and financial means, through a protocol of physical activity, improves patient health.

Decline in Cancer Screening in Vulnerable Populations? Results of the EDIFICE Surveys.

BACKGROUND: We studied cancer screening over time and social vulnerability via surveys of representative populations. METHODS: Individuals aged 50-75 years with no personal history of cancer were questioned about lifetime participation in screening tests, compliance (adherence to recommended intervals [colorectal, breast and cervical cancer]) and opportunistic screening (prostate and lung cancer). RESULTS: The proportion of vulnerable/non-vulnerable individuals remained stable between 2011 and 2016. In 2011, social vulnerability had no impact on screening participation, nor on compliance. In 2014, however, vulnerability was correlated with less frequent uptake of colorectal screening (despite an organised programme) and prostate cancer screening (opportunistic), and also with reduced compliance with recommended intervals (breast and cervical cancer screening). In 2016, the trends observed in 2014 were substantiated and even extended to breast, colorectal and cervical cancer screening uptakes. Social vulnerability has an increasingly negative impact on cancer screening attendance. The phenomenon was identified in 2014 and had expanded by 2016. CONCLUSION: Although organised programmes have been shown to ensure equitable access to cancer screening, this remains a precarious achievement requiring regular monitoring. Further studies should focus on attitudes of vulnerable populations and on ways to improve cancer awareness campaigns.

Perception of Lung Cancer Risk: Impact of Smoking Status and Nicotine Dependence.

BACKGROUND: The general population is nowadays well aware that tobacco smoking dramatically increases the risk of developing lung cancer. We hypothesized that a personal history of smoking and the level of nicotine dependence in current smokers may affect the perception of this risk among healthy individuals. METHODS: The fourth French nationwide observational survey, EDIFICE 4, was conducted by telephone among a representative sample of individuals (N = 1602) aged between 40 and 75 years. Interviewees were asked about their smoking habits, perception of the risk of lung cancer, and nicotine dependence (Fagerström test). RESULTS: Regardless of their smoking status or level of nicotine dependence, the majority (96%) of our study population (N = 1463) acknowledged that tobacco smoking is a major risk factor for lung cancer. For 34% of all respondents, smoking ≤ 10 cigarettes per day does not carry any risk of lung cancer. Only half the current smokers considered themselves to be at higher risk of lung cancer than the average-risk population. The majority of current cigarette smokers with a nicotine dependence considered themselves to be at higher risk for lung cancer while only 37% of non-nicotine-dependent individuals had the same perception (P < 0.01). Current smokers were more likely to consider a screening examination than former smokers and never-smokers. However, the intention to undergo screening was not significantly affected by the level of nicotine dependence. CONCLUSIONS: Awareness campaigns may first have to overcome misconceptions about light smoking and, secondly, to target specific populations (heavy smokers, those with a long history, highly dependent smokers).

Fluctuating Behavior of the French Population in Cancer Screening: 5th Edition of the EDIFICE Survey.

BACKGROUND: The EDIFICE surveys have assessed cancer screening behavior in the French population since 2005. METHODS: The 2016 edition was conducted among a representative sample of 1501 individuals (age, 50-75 years). The current analysis focuses on breast, colorectal, prostate, lung, and cervical cancer screening. RESULTS: The rate of women (50 to 74 years) declaring having had at least one breast cancer screening test in their lifetime remained stable and high between 2005 and 2016. Compliance with recommended screening intervals improved between 2005 and 2011 from 75 to 83%, respectively, then decreased significantly to 75% in 2016 (P = 0.02). Uptake of at least one lifetime colorectal cancer screening test procedure declared (individuals aged 50-74 years) increase from 25% in 2005 to 59% in 2011, stabilized at 60% in 2014, then reached 64% in 2016. Opportunistic prostate cancer screening (men aged 50-75 years) rose between 2005 and 2008 from 36 to 49%, plateaued until 2014 then dropped to 42% in 2016. The proportion of women aged 50-65 declaring having undergone one cervical cancer screening test dropped significantly between 2014 and 2016 from 99 to 94% (P < 0.01). Lastly, 11% of our survey population in 2014 and 2016 (55-74 years) declared having already undergone lung cancer screening. CONCLUSION: Cancer screening behavior fluctuates in France, regardless of the context, i.e., organized programs or opportunistic screening. This observation highlights the need for constant analysis of population attitudes to optimize public awareness campaigns.

Awareness and Misconceptions of Breast Cancer Risk Factors Among Laypersons and Physicians.

BACKGROUND: Primary prevention of cancer relies on awareness of and consequent identification of risk factors. We investigated knowledge of breast cancer risk factors not only among laywomen but also among female physicians. METHODS: The EDIFICE 4 nationwide observational survey was conducted by phone interviews of a representative female population (737 laywomen and 105 female physicians) aged 40-75 years, using the quota method. This analysis focuses on spontaneous replies to the question "In your opinion, what are the five main risk factors that increase the risk of breast cancer?". RESULTS: Heredity/Family history of breast cancer was the most widely recognized risk factor in both study populations (98.1% physicians vs. 54.2% laywomen; P ≤ 0.01). Smoking (19.0 and 17.5%) and alcohol consumption (3.8 and 5.5%) were among the lifestyle risk factors that were cited by similar proportions of physicians and laywomen, respectively. Other established risk factors were however very rarely cited by either physicians or laywomen, e.g., Exposure to medical radiation (4.8 vs. 0.4%, respectively; P ≤ 0.05) or not cited at all, i.e., Benign mastopathy and Personal history of breast cancer. CONCLUSION: This survey highlights a number of misconceptions relating to behavioral risk factors for breast cancer, including the relative impact of alcohol and tobacco consumption and the importance of menopausal status. The limited awareness of the risk related to Exposure to medical radiation, Benign mastopathy, or Personal history raises concern regarding compliance with national screening recommendations.

Colon Cancer Screening Programs: Impact of an Organized Screening Strategy Assessed by the EDIFICE Surveys.

BACKGROUND: The aim of EDIFICE surveys is to improve insight into the behavior of the French population with regard to cancer prevention and participation in screening programs. Via the colorectal cancer screening program, all average-risk individuals in the 50-74-year age group are invited every 2 years to do a guaiac-based or, since April 2015, an immunochemical fecal occult blood test. METHODS: The fifth edition of the nationwide observational survey was conducted by phone interviews using the quota method. A representative sample of 1299 individuals with no history of cancer (age, 50-74 years) was interviewed between 22 November and 7 December 2016. The present analysis focuses on minimum lifetime uptake of screening tests, compliance to recommended repeat-screening intervals, and reasons for non-participation. RESULTS: In 2016, 64% survey participants had been screened at least once and 38% had been screened in the previous 2 years, suggesting a trend towards increasing participation rates, particularly in the younger age categories and among men. The 2016 data also suggest that the newly implemented FIT-based screening program has been well perceived by the population. Up to one in four individuals cited "no risk factors" as the reason for not undergoing screening. This reveals ignorance of the fact that the colorectal cancer screening program actually targets all average-risk individuals in a given age group, without individual risk factors. CONCLUSION: We suggest the next step should be dedicated to educational approaches to explain exactly what screening involves and to persuasive messages targeting those who to date have remained unreceptive to information campaigns.

GATA2 gene analysis in several forms of hematological malignancies including familial aggregations.

The genetic predisposition to familial hematological malignancies has been previously reported highlighting inherited gene mutations. Several genes have been reported but genetic basis remains not well defined. In this study, we extended our investigation to a potential candidate GATA2 gene which was analyzed by direct sequencing in 119 cases including familial aggregations with a variety of hematological malignancies and sporadic acute leukemia belonging to Tunisian and French populations. We reported a deleterious p.Arg396Gln GATA2 mutation in one patient diagnosed with both sporadic acute myeloid leukemia (AML) and breast cancer. We also reported several GATA2 variations in familial cases. The absence of deleterious mutations in this large cohort of familial aggregations of hematological malignancies may strengthen the hypothesis that GATA2 mutations are an important predisposing factor, although as a secondary genetic event, required for the development of overt malignant disease.