European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer.

BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. DESIGN: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. CONCLUSION: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer.

Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests.

Based on nationwide data from the French national cancer institute (INCa), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with BRCA1/2 or MMR genes mutation. Genetic testing and consultations for familial high-risk individuals are exclusively funded and monitored by the INCa in France. All nationwide cancer genetics centers reported annually standardized parameters of activity from 2003 to 2011. The analysis included a total of 240,134 consultations and 134,652 genetic tests enabling to identify 32,494 mutation carriers. Referral for hereditary breast and ovarian cancer (HBOC) or colorectal cancer predisposition syndromes represented 59 % (141,639) and 23.2 % (55,698) consultations, respectively. From 2003 to 2011, we found a dramatic and steady increase of tests performed for BRCA1/2 (from 2,095 to 7,393 tests/year, P < 0.0001) but not for MMR genes (from 1,144 to 1,635/year, P = NS). The overall percentage of deleterious mutations identified in the probands tested was 13.8 and 20.9 % in HBOC and Lynch syndromes, respectively. Pooled analysis for BRCA1/2 and Lynch syndrome tests showed an inverse relationship between the percentage of mutation detected and the absolute number of tests performed over the time (overall Cochran-Armitage test for trend: P < 0.001). In families with BRCA1/2 or MMR identified mutations, there was an average number of 2.94 and 3.28 relatives performing targeted tests, respectively. This nationwide study shows a lack of referral and genetic testing in Lynch as compared to HBOC syndromes. Only a third of relatives of a proband with a predisposing mutation performed a targeted test. Enhanced information about benefit of genetic testing should be given to clinicians and patients for Lynch syndrome and relatives of a proband carrying an identified predisposing mutation.

Statistical transmutation in doped quantum dimer models.

We prove a "statistical transmutation" symmetry of doped quantum dimer models on the square, triangular, and kagome lattices: the energy spectrum is invariant under a simultaneous change of statistics (i.e., bosonic into fermionic or vice versa) of the holes and of the signs of all the dimer resonance loops. This exact transformation enables us to define the duality equivalence between doped quantum dimer Hamiltonians and provides the analytic framework to analyze dynamical statistical transmutations. We investigate numerically the doping of the triangular quantum dimer model with special focus on the topological Z(2) dimer liquid. Doping leads to four (instead of two for the square lattice) inequivalent families of Hamiltonians. Competition between phase separation, superfluidity, supersolidity, and fermionic phases is investigated in the four families.

Evolution between 2008 and 2018 of mothers' perception regarding vaccination and infant vaccine coverage in France.

OBJECTIVE: Monitoring of vaccination coverage rates (VCRs) is essential to assess the implementation of a country's vaccine policy and its effectiveness. Through the French Vaccinoscopy study, we measured the evolution of VCRs as well as mothers' opinion towards vaccination between 2008 and 2018, before and after implementation of infant mandatory vaccination extension. METHODS: This is a study based on an internet-standardised questionnaire. In 2018, a representative sample of 3000 mothers of infants 0 to 35 months of age answered on their opinion on vaccination and reported all vaccinations recorded in their child's health record. RESULTS: On the period considered, infant VCRs were stable and high for diphtheria, tetanus, poliomyelitis, pertussis and pneumococcus components and progressed for measles, mumps rubella, 2 doses at 24 months of age from 45.3% in 2008 to 81.0% in 2018, hepatitis B (HepB) complete primovaccination at 6 months of age from 45.9% in 2008 to 86.3% in 2017 and 95.5% in 2018, and meningococcus C (MenC) 1 dose at 6 months of age from 43.0% in 2017 to 74.2% in 2018. In 2018, 69.0% of mothers were in favour of vaccination while this rate dropped from 80.2% in 2012 to 64.0% in 2017, and 80.8 to 89.6% perceived HepB, MenC measles and pertussis vaccinations as useful/essential, percentages in progress versus 2017. CONCLUSION: Following the implementation of infant mandatory vaccination in 2018, proportion of mothers in favour of vaccination increased significantly. HepB and MenC VCRs significantly progressed between 2017 and 2018.

Infant mandatory vaccinations: Confirmation of a positive impact.

OBJECTIVE: Infant vaccines protecting against 11 diseases have changed from recommended to mandatory status in France for all children born from first of January 2018. Through Vaccinoscopie survey, we measured for the second consecutive year the impact of this new policy on vaccine coverage rates (VCRs) and mothers' perception regarding vaccination. METHODS: Web-based survey on a representative sample of 1500 mothers of 0 to 17-month-old infants. RESULTS: Non-optimal VCRs continued to increase in 2019 versus 2017 (according to age, +7 to 8 points VCR for Hepatitis B and +36 to 68 points for Meningococcus C). After a progressive decrease between 2012 and 2017, the rate of favorable mothers' opinion towards vaccination continued to progress in 2018 and 2019. CONCLUSION: These results confirmed the positive impact of this new law on infant VCRs and mothers' favorable opinion regarding vaccination.

MTHFR promoter hypermethylation in testicular biopsies of patients with non-obstructive azoospermia: the role of epigenetics in male infertility.

BACKGROUND: The causative mechanisms of male infertility are still poorly understood. Mutations in the Methylenetetrahydrofolate reductase (MTHFR) gene have been shown to be involved in male infertility; however, other mechanisms of pathogenesis, like promoter hyper-methylation, could also play a role. Therefore, in this study we compared the methylation status of the promoter region of MTHFR in male patients with non-obstructive azoospermia (NOA) and obstructive azoospermia without anomalies of spermatogenesis. METHODS: DNA from peripheral blood (PB) samples of 50 patients with NOA and 50 fertile men (controls) as well as DNA from testicular biopsies of 32 patients with NOA and five patients with obstructive azoospemia, but normal spermatogenesis, were analyzed by Methylation Specific PCR amplification using primers that hybridize to the CpG island in the promoter region of MTHFR. RESULTS: In PB, no differences in the methylation profile of the promoter region of MTHFR were observed between patients and controls. In testis biopsies, hyper-methylation was detected in 53% of the patients with NOA compared with 0% of patients with obstructive azoospermia (P = 0.03). CONCLUSIONS: These results indicate that hyper-methylation in testis DNA from NOA patients is specific and not due a general methylation defect, and suggest that epigenetic silencing of MTHFR could play a role in azoospermic infertility.

Effects of exercise intensity on lymphocyte H2O2 production and antioxidant defences in soccer players.

OBJECTIVE: Physical exercise is capable of enhancing or suppressing the immune response depending on the intensity and duration of exercise. This study investigated how exercise intensity influences the lymphocyte antioxidant response and the induction of cellular oxidative damage. DESIGN: Eighteen voluntary male pre-professional soccer players participated in this study. Sportsmen played a 60 min training match, and were divided into three groups depending on the intensity degree during the match: low, medium and high intensities. MEASUREMENTS: Malondialdehyde (MDA), vitamins C and E and haem oxygenase-1 (HO-1) gene expression were measured in lymphocytes. Reactive oxygen species (ROS) production was determined in lymphocytes and neutrophils. RESULTS: Lymphocyte MDA levels and H(2)O(2) production were significantly increased in the group which performed the most intense exercise. Neutrophil counts and ROS production increased progressively with the exercise intensity. Vitamin C significantly decreased after exercise in the highest-intensity group in comparison with initial values, whereas vitamin E levels significantly increased in the medium and high-intensity groups. HO-1 gene expression significantly increased in the medium and high-intensity groups. CONCLUSIONS: Exercise intensity affects the lymphocyte and neutrophil oxidant/antioxidant balance, but only exercise of high intensity induces lymphocyte oxidative damage.

Meningococcal C vaccine coverage in France in infants, children, and adolescents.

OBJECTIVES: Meningococcal C (MenC) vaccination was introduced in the French vaccination calendar in 2010 to reduce the incidence of invasive meningococcal C disease (IMDC), mainly through herd immunity. The Vaccinoscopie survey helps follow vaccination coverage rates (VCRs) of children. METHODS: This annual survey is based on a self-administered online questionnaire. In 2017, 4500 mothers of children completed the questionnaire and reported all vaccinations recorded in their child's health record. RESULTS: MenC vaccination was deemed indispensable or useful by 77% to 84% of mothers. The main barrier mentioned by mothers considering the vaccination useless/not very useful, was fear of adverse effects. VCR was estimated at 77% among 24-35-month-old infants, 79% among 6-year-old children, and 50% among 14-15-year-old adolescents. VCR strongly varied depending on the physician's advice for vaccination and on the type of follow-up. Six months after publication of the new French vaccine calendar in April 2017, with a MenC vaccine recommendation for all 5-month-old infants, 43% of infants had received a dose at 6 months of age. CONCLUSIONS: VCRs are insufficient to reach herd immunity. Between 2011 and 2017 more than 100 deaths could have been avoided in France if optimal VCRs had been achieved. Faced with this vaccine strategy failure, the new vaccine recommendation at 5 months of age seems well-accepted. This recommendation and the implementation of infant mandatory vaccination in 2018 should have a major impact on IMD C incidence in this age group.

Impact of mandatory vaccination extension on infant vaccine coverages: Promising preliminary results.

OBJECTIVE: In France infant vaccines protecting against 11 diseases have changed from a recommended to a mandatory status for all children born on or after January 1, 2018. Using the Vaccinoscopie survey, we measured the impact of this new vaccination policy on vaccine coverage rates (VCRs) and on mothers' perception of vaccination. METHODS: Online survey with 1000 mothers of 0- to 11-month-old infants. RESULTS: VCRs for at least one dose at the age of 6 months strongly progressed for diseases that previously did not meet Public Health objectives (+8 points for Hepatitis B and +31 points for meningococcal C vaccines). Mothers were more favorable to mandatory vaccination and better informed in 2018 than in 2017. CONCLUSION: These first results showed a positive impact of the extension of mandatory vaccination on mothers' opinion regarding vaccination and on infant VCRs.

Secondary findings from whole-exome/genome sequencing evaluating stakeholder perspectives. A review of the literature.

With the development of next generation sequencing, beyond identifying the cause of manifestations that justified prescription of the test, other information with potential interest for patients and their families, defined as secondary findings (SF), can be provided once patients have given informed consent, in particular when therapeutic and preventive options are available. The disclosure of such findings has caused much debate. The aim of this work was to summarize all opinion-based studies focusing on SF, so as to shed light on the concerns that this question generate. A review of the literature was performed, focusing on all PubMed articles reporting qualitative, quantitative or mixed studies that interviewed healthcare providers, participants, or society regarding this subject. The methodology was carefully analysed, in particular whether or not studies made the distinction between actionable and non-actionable SF, in a clinical or research context. From 2010 to 2016, 39 articles were compiled. A total of 14,868 people were interviewed (1259 participants, 6104 healthcare providers, 7505 representatives of society). When actionable and non-actionable SF were distinguished (20 articles), 92% of respondents were keen to have results regarding actionable SF (participants: 88%, healthcare providers: 86%, society: 97%), against 70% (participants: 83%, healthcare providers: 62%, society: 73%) for non-actionable SF. These percentages were slightly lower in the specific situation of children probands. For respondents, the notion of the «patient's choice¼ is crucial. For healthcare providers, the importance of defining policies for SF among diagnostic lab, learning societies and/or countries is outlined, in particular regarding the content and extension of the list of actionable genes to propose, the modalities of information, and the access to information about adult-onset diseases in minors. However, the existing literature should be taken with caution, since most articles lack a clear definition of SF and actionability, and referred to hypothetical scenarios with limited information to respondents. Studies conducted by multidisciplinary teams involving patients with access to results are sadly lacking, in particular in the medium term after the results have been given. Such studies would feed the debate and make it possible to measure the impact of such findings and their benefit-risk ratio.

Chordin is underexpressed in ovarian tumors and reduces tumor cell motility.

Ovarian cancers mostly derive from the monolayer epithelium that covers the ovary. There are currently very few molecular clues to the etiology of this cancer. Bone morphogenetic proteins (BMPs) are required for follicular development and female fertility and are expressed in the ovarian surface epithelium (OSE). We previously reported the expression of human chordin (CHRD), a BMP extracellular regulator, in the ovary. Here we show that CHRD is underexpressed in epithelium ovary cancer and epithelial cancer cell lines as compared with normal tissues and OSE, respectively. Besides, we detected BMP expression in all ovarian cell lines analyzed. To determine the functional relevance of the absence of CHRD mRNA in tumors and cancer cell lines, we studied the effects of CHRD on two cancer cell lines, BG1 and PEO14. Migratory and invasive properties were greatly reduced, whereas cell adhesion to the support was enhanced. In addition, we detected chordin (Chrd) expression in OSE of rat ovaries in a pattern similar to that of BMP4. Altogether, these results suggest that CHRD could participate in regulating BMP activity in normal OSE physiology, and that its mis-expression in OSE may facilitate cancer incidence and/or progression.

Criticality of a classical dimer model on the triangular lattice.

We consider a classical interacting dimer model which interpolates between the square lattice case and the triangular lattice case by tuning a chemical potential in the diagonal bonds. The interaction energy simply corresponds to the number of plaquettes with parallel dimers. Using transfer matrix calculations, we find in the anisotropic triangular case a succession of different physical phases as the interaction strength is increased: a short-range disordered liquid dimer phase at low interactions, then a critical phase similar to the one found for the square lattice, and finally a transition to an ordered columnar phase for large interactions. Our results indicate that criticality and nonbipartiteness are compatible in a dimer model. For the isotropic triangular case, we have indications that the system undergoes a first-order phase transition to an ordered phase, without appearance of an intermediate critical phase.

From adjuvant to preventive breast cancer treatment: bridging the gap over troubled waters.

Recently, chemoprevention trials have demonstrated the efficacy of preventive medical treatment (PMT) in reducing breast cancer (BC) detection rates in at-risk affected and unaffected women selected according to clinical and/or familial risk criteria, particularly with the use of tamoxifen (TAM). Major concerns limiting the routine use of TAM are the questionable benefit/risk ratio and poor patient compliance, which justify the studies undertaken to determine the efficacy of aromatase inhibitors (AIs) with respect to TAM. Issues such as therapy duration, impact on survival, incidence of side-effects and which subsets benefit most from treatment, still remain unsolved. Therefore, only ER+ BC patients are routinely subjected to PMT, independently of their BRCA1/2 status, using adjuvant hormonal therapy. More attention must be focused towards BRCA1/2 carriers as they are probably the women at highest risk of developing BC, in which available data remain controversial and in which hormone-therapy might be important. Hence, at-risk women (affected patients or unaffected women) should be carefully evaluated for inclusion into highly selected preventive clinical trials aimed at evaluating PMT independently of, or according to, BC predisposition status (unknown, positive or negative BRCA1/BRCA2 status) and with respect to menopausal status. BC patients, harboring a BRCA1/2 predisposition, may represent the best subset for extended adjuvant treatment, useful as PMT, simultaneously. Only the evolving differentiation of categories of at-risk women will allow physicians to discriminate PMT in a highly selective manner.

Differential expression of estrogen receptor-alpha and -beta messenger RNAs as a potential marker of ovarian carcinogenesis.

Although estrogen receptor (ER)-alpha is expressed in both benign and malignant ovarian tumors, the role of ER in ovarian carcinogenesis of epithelial tumors is still unknown. In view of the recent characterization of ER-beta, a second form of ER that seems to be highly expressed in ovaries, we reexamined this issue by studying the relative expression of ER-alpha and -beta in human ovarian tumor progression. We developed a competitive PCR assay based on coamplification of the two ERs in target nucleotide sequences displaying a high homology (exons 3 and 4). Coamplification experiments with varying amounts of plasmids containing ER-alpha and -beta cDNAs showed that this assay was reliable for discriminating as little as a 2-fold difference in the initial ER-alpha:ER-beta cDNA ratio. The relative expression of ER-alpha compared with ER-beta mRNAs was studied in human ovarian cancer cell lines (n = 5) and in normal ovaries (n = 6), then in human benign and malignant tumor samples including ovarian cysts (n = 24), borderline tumors (n = 3), and cancers (n = 10). In normal ovaries, ER-beta mRNA was the predominant ER form, whereas in ovarian cancer cell lines ER-alpha mRNA was markedly increased as compared with ER-beta. In benign and borderline tumors, ER-beta mRNA was detected in 78% of tumors, whereas ER-alpha mRNA was detected in 29%. In ovarian carcinomas, both ER-alpha and -beta mRNAs were expressed in 80% of tumors. The ER-alpha:ER-beta mRNA ratio was >1 in only one cyst sample (4%). In contrast, the ER-alpha:ER-beta mRNA ratio was markedly increased in ovarian cancers because 60% showed an ER-alpha:ER-beta mRNA >1. In situ hybridization experiments showed overlapping tissular distribution of ER-beta and -alpha expression in cancers and cysts, with a main localization in the epithelium and only a low level of expression in stromal cells. In summary, we found an increase in the ER-alpha:ER-beta mRNA ratio in ovarian carcinomas as compared with normal ovaries and cysts. These data suggest that overexpression of ER-alpha relative to ER-beta mRNA may be a marker of ovarian carcinogenesis.

[Is the simplification of the immunization schedule applied? Review 2 years after its implementation]. / La simplification du calendrier vaccinal est-elle appliquée ? Bilan 2ans après sa mise en place.

Repeating evaluations of vaccine coverage (VC) is essential to measure the implementation and effectiveness of vaccination policy. We report the results of VC in infants from the Vaccinoscopie® study in 2014 to assess the changes secondary to the new 2013 immunization schedule. METHOD: Study conducted on Internet among a representative sample of mothers reporting their child's vaccination record. RESULTS: The removal of the dose of DTPa-Hib at the age of 3 months was quickly adopted since only 1 % of children aged 6 months had received three doses of DTPa in 2014 compared to 96 % in 2012. The booster dose is administered earlier for the DTPa and hepatitis B components. The shift of MMR vaccination from 9 months of age for children participating in community structures to 12 months for all children was closely followed since only 2 % of 9- to 11-month-old children received a MMR vaccine in 2014 compared to 33 % in 2012. The second dose of MMR recommended at 16-18 months of age rather than between 13 and 24 months was actually followed by an earlier administration of this dose. At 18-20 months of age, 60 % received two doses of MMR in 2014 versus 41 % in 2012. Finally, for meningitis C vaccination, a significant increase of VC was observed in children 15-23 months of age (66 % in 2014 versus 44 % in 2012). CONCLUSION: The simplification of the infant immunization schedule was quickly applied and received excellent support from healthcare professionals. However, this measure alone is still not sufficient to meet the CV objectives defined by the HCSP.

Pertussis vaccination coverage among French parents of infants after 10years of cocoon strategy.

OBJECTIVES: The cocoon strategy against pertussis has been recommended in France since 2004 to indirectly protect young infants who are not yet vaccinated. We aimed to measure vaccination coverage among French parents of infants. METHODS: A representative sample of 300 mothers and 200 fathers of infants aged <12 months completed a self-administered online questionnaire. They all provided their own vaccination records. RESULTS: Overall, 87% of mothers believed vaccination against pertussis to be important; 83% reported being immunized against pertussis but their vaccination records showed that a third of them was wrong (34%). On the basis of our sample, the 2009-2014 vaccination coverage against pertussis among mothers increased from 22 to 61% (P<0.005); over the same period of time, vaccination coverage against diphtheria, tetanus, and polio remained stable (80%). Vaccination coverage against pertussis among fathers increased from 21 to 42% between 2010 and 2013 (P=0.009). In 2013, one couple out of four (26%) was adequately immunized against pertussis. CONCLUSION: The cocoon strategy was implemented 10years ago in France but vaccination coverage remains suboptimal among parents of young infants. Healthcare professionals must recommend vaccination against pertussis to young adults and check that their vaccination status is up to date.

Vaccination of pregnant women in France.

OBJECTIVE: Vaccination of pregnant women against seasonal influenza is recommended in France since 2010. We currently do not have any vaccination coverage (VC) data to assess the implementation of this recommendation. METHODS: Vaccinoscopie® is an annual study conducted online using a self-administered questionnaire. A section dedicated to parents' vaccination was included in 2014 and aimed at interviewing 300 mothers of infants aged<12 months to assess their opinion of vaccination with regard to their last and future pregnancies. The study also aimed to measure the influenza VC of these mothers during their last pregnancy. RESULTS: While 56% of mothers reported to have been informed of the importance of vaccination by a healthcare professional (HCP) during their last pregnancy, only 11% reported having been informed of the importance of influenza vaccination. Overall, 49% of mothers reported willing to be vaccinated during their next pregnancy to protect their baby, if the vaccination were to be recommended by a HCP. However, this rate was only 32% for influenza vaccination. In contrast, 52% of mothers reported willing to be vaccinated against pertussis during pregnancy if the vaccination were to be recommended by a HCP. The influenza VC estimates in pregnant women was 7%. CONCLUSION: Although influenza vaccination has been recommended for all French pregnant women for the past five years, HCPs rarely recommend this vaccination - hence, the low VC. Informing and raising awareness among HCPs seems to be crucial to improve this coverage.

Overexpression of transfected cathepsin D in transformed cells increases their malignant phenotype and metastatic potency.

Cathepsin D, an aspartic lysosomal proteinase, is overexpressed by breast cancer cells and highly correlated with the occurrence of metastasis in patients. We used an adenovirus transformed rat cell line that does not secrete cathepsin D, to study the consequences of transfecting human cathepsin D cDNA. Overexpression of human cathepsin D in stable transfectant clones, results in higher initial growth rates in low serum conditions, overgrowth at high cell densities resulting in stellate aggregates, and greater anchorage-independent growth in soft agar. The metastatic activity (mostly in liver) of cathepsin D clones injected into athymic mice was significantly higher than that of control clones. These results show that overexpression of cathepsin D increases the transformed phenotype of malignant cells in vitro and their metastatic potency in vivo.