New perspective on maintenance therapies for platinum- sensitive recurrent ovarian cancer in women with germline and somatic mutations in BRCA1 and BRCA2 genes.

Ovarian cancer (OC) is the seventh most common cancer in women. Although women diagnosed with OC are usually treated frontline with platinum-based chemotherapy, most of them relapse once treatment is halted. Therefore, maintenance therapies have been developed to secure the response and delay further chemotherapy. There are two established maintenance therapies for women affected by platinum-sensitive recurrent OC: bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, and olaparib, an inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARPi). Loss-of-function mutations in genes in the homologous recombination pathway, especially BRCA1 and BRCA2, predict higher rates of platinum sensitivity, better overall survival (OS), and better response to PARPi in women with OC. Among patients with platinum-sensitive recurrent OC, a BRCA mutation is the first genetically defined predictive marker for targeted therapy, since these patients are most likely to benefit from treatment with a PARPi, such as olaparib. In patients with platinum-sensitive recurrent OC without a BRCA mutation, bevacizumab currently seems to be the best maintenance option. Women with OC are progressively more routinely screened for germline BRCA mutations, and the implication of somatic BRCA mutations is increasingly being recognized in OC. Therefore, the recommendations should be updated to reflect the importance of both types of mutations. Together, these data highlight the fact that treatment of recurrent OC can be optimized using genomic contributions to individualize therapy and to improve treatment response.

Disclosure pattern and follow-up after the molecular diagnosis of BRCA/CHEK2 mutations.

Five to 10% of all breast cancer cases are due to mutations of high penetrance susceptibility genes, especially BRCA1 and BRCA2. In families with known BRCA mutations, disclosure of genetic test results could induce relatives to undergo genetic testing themselves and adopt cancer risk management strategies, if necessary. This study examines disclosure patterns of individuals tested for mutations in the BRCA1, BRCA2 and CHEK2 genes to first-degree relatives with emphasis on a possible gender difference. It also assesses which management strategy is preferred by mutation-positive women in Belgium and the influence of psychological characteristics on communication and choice of management strategy. Ninety-nine adults from BRCA/CHEK2 families, selected from the Centre of Medical Genetics of Antwerp, were included in the study. They were provided with medical and psychological questionnaires, the latter being the Self-Assessment Questionnaire, which is the Dutch version of the Spielberger State-Trait Anxiety Inventory and the Dutch version of the Coping Inventory for Stressful Situations (CISS-NL). The survey focused on disclosure, coping and management strategies with special attention on possible gender differences. The influence of socio-demographic and medical data on disclosure and cancer risk management as well as the influence of psychological features were examined by means of various statistical analyses. Ninety-nine patients were included, of whom 25 (25 %) were male. Eighty-seven percent of the participants informed all of their adult first-degree relatives about their mutation status without any gender discrimination. Seventy-eight percent of highly-educated participants informed all of their adult first-degree relatives, compared to 98 % of less formally-educated participants (p = 0.006). The majority of mutation-positive women preferred prophylactic surgery to surveillance. Psychological differences appeared to have little influence on disclosure patterns and management strategies. The gender difference seems to be less pronounced than previously assumed. A striking observation, however, is the fact that significantly more participants who were less formally-educated informed all of their adult first-degree relatives, compared to participants who were highly-educated. In our study population, most female mutation carriers opted for prophylactic surgery. Since the study population is small, further studies are needed to enhance the generalizability of these results.

Preconceptional care: a systematic review of the current situation and recommendations for the future.

UNLABELLED:  OBJECTIVE: To review the current knowledge and implementation of preconceptional care (PCC) in the Western world, focusing both on health care workers and the general population, and to analyze pathways to disseminate the influence of preconceptional care on pregnancy outcome. METHODS: A systematic literature study was performed using OvidSP and Pubmed, searching for articles about PCC and its implementation, published between 1966 and October 2012. Only randomized controlled trials and systematic reviews dealing with PCC in the Western world were retained. RESULTS: Forty-six articles were identified for review. PCC might result in better pregnancy outcomes, including e.g. a reduction of congenital abnormalities. There are no proven disadvantages of PCC. Health care workers are in favor of the implementation of PCC, but claim that they don't have enough knowledge to do so. The general population shows interest in receiving PCC. The implementation of PCC should be improved by e.g. the development of guidelines and checklists. CONCLUSIONS: As PCC might improve pregnancy outcomes and is considered important by health care workers and the general population, its implementation should be improved, e.g. by the development of guidelines and checklists.

Investigation of selected cytokine genes suggests that IL2RA and the TNF/LTA locus are risk factors for severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is the second most common cause of hair loss in humans, and has a genetically complex inheritance. The hypothesis that AA is autoimmune in nature is supported by previous studies. These report an association with specific HLA alleles, as well as genetic variants of other genes implicated in autoimmunity, such as various cytokine genes. However, these cannot yet be considered proven susceptibility loci, as many of these association findings were derived from small patient samples. OBJECTIVES: To investigate the association between AA and selected cytokine genes using a sample of 768 patients with AA and 658 controls of Central European origin. METHODS: Eleven single-nucleotide polymorphisms (SNPs) from cytokine genes implicated in previous AA studies were genotyped. These genes were IL1B, IL1A, IL1RN, MIF, IFNG and the TNF/LTA gene region. We also genotyped 15 SNPs selected from cytokine genes that have shown significant association with other autoimmune diseases. These genes were IL10, IL36RN, IL12B, IL6, IL2, IL23, IL2RA and IL4R. RESULTS: Significant association was found for two variants within both IL2RA and TNF/LTA. In the overall sample, the most significant results were obtained for the IL2RA variant rs706778 (P = 0·00038) and the TNF/LTA locus variant rs1800629 (P = 0·0017). In subgroup analyses, according to severity, age at onset and family history these effects were stronger in the severely affected patients, with the lowest P-values being obtained for rs706778 (P = 3·8 × 10(-6) ). CONCLUSIONS: Our results point to the involvement of IL2RA and the TNF/LTA region in the aetiology of AA, in particular severe AA, and provide further support for the hypothesis that AA is autoimmune in nature.

Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing.

Despite extensive analysis of the BRCA1 and BRCA2 genes, germline mutations are detected in <20% of families with a presumed genetic predisposition for breast and ovarian cancer. Recent literature reported RAD51C as a new breast cancer susceptibility gene. In this study, we report the analysis of 410 patients from 351 unrelated pedigrees. All were referred for genetic testing and we selected families with at least one reported case of ovarian cancer in which BRCA1&2 mutations were previously ruled out. We analyzed the coding exons, intron-exons boundaries, and UTRs of RAD51C. Our mutation analysis did not reveal any unequivocal deleterious mutation. In total 12 unique sequence variations were identified of which two were novel. Our study and others suggest a low prevalence of RAD51C mutations with an exception for some founder populations. This observation is in favor of the rare allele hypothesis in the debate over the nature of the genetic contribution to individual susceptibility to breast and ovarian cancer and further genome-wide studies in high risk families are warranted.

The TRAF1/C5 locus confers risk for familial and severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is a common hair loss disorder with a complex mode of inheritance. Autoimmune mechanisms are presumed to be crucial aetiologically. It is plausible that a number of autoimmune disorders may share a common genetic background. This phenomenon has been demonstrated in previous studies, which have shown an overlap of susceptibility alleles between AA and other autoimmune disorders. Recent studies have shown that genetic variants on the TRAF1/C5 (tumor necrosis factor receptor-associated factor 1, complement component 5) locus confer susceptibility to rheumatoid arthritis (RA). OBJECTIVES: To examine the role of the TRAF1/C5 locus in the development of AA using a large sample of 1,195 patients with AA and 1280 controls. METHODS: We genotyped the two most significant single nucleotide polymorphisms (SNPs) (rs10818488, rs2416808) from a former RA candidate gene study. After having obtained evidence for association, we performed a fine-mapping study and genotyped the locus with an additional 27 SNPs. RESULTS: While no significant result was obtained for the overall sample, rs2416808 showed significant associations in the analysis of the subgroups with severe AA and with a positive family history. The most significant P-value for rs2416808 was in familial cases (P = 0.004, P(corr) = 0.026). The fine mapping revealed significant associations for four additional SNPs in the analysis of subgroups, with rs2416808 remaining the most significant marker. CONCLUSIONS: Our results point to the involvement of the TRAF1/C5 locus in the aetiology of familial and severe AA, and provide further support for a shared aetiology between AA and other autoimmune disorders.

The R620W polymorphism in PTPN22 confers general susceptibility for the development of alopecia areata.

BACKGROUND: The functional R620W (c.1858C>T) variant of the protein tyrosine phosphatase nonreceptor 22 gene (PTPN22) has been associated with a variety of autoimmune disorders. A recent study has suggested that R620W also contributes to the severe form of alopecia areata (AA). OBJECTIVES: We sought to replicate the finding of an association between PTPN22 and severe AA. In addition, we wanted to study the effect of PTPN22 on the general risk to develop AA and on other subtypes of AA (mild AA, early/late age at onset, positive/negative family history). METHODS: The R620W variant was genotyped in a large case-control sample of Belgian-German origin with 435 patients and 628 controls. RESULTS: Significant results were obtained for the overall collective of patients with AA (P=0.007). Subdividing the sample according to severity of AA, family history and age at onset, we detected lowest P-values for patients with the severe form of AA (Pcorr=0.036), with a positive family history (Pcorr=0.042) and with an age at onset

Investigation of the functional variant c.-169T > C of the Fc receptor-like 3 (FCRL3) gene in alopecia areata.

A functional variant in the Fc receptor-like 3 (FCRL3) gene has been implicated in susceptibility to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and autoimmune thyroid disease. Investigating a large case-control sample of patients with alopecia areata (AA), we found no evidence for the involvement of FCRL3 in susceptibility to AA.

Investigation of the p.Ser278Arg polymorphism of the autoimmune regulator (AIRE) gene in alopecia areata.

A recent study has suggested that the g.961C >G (p.Ser278Arg) variant of the autoimmune regulator (AIRE) gene contributes to susceptibility to alopecia areata (AA). We attempted to replicate this finding using a case-control sample of Belgian-German origin (273 patients and 283 controls). Despite adequate power, our study results do not support a significant association of the risk allele in our AA patient sample. This remained the case when we stratified our sample according to severity and family history of disease. Our study results do not support the hypothesis that the g.961C >G (p.Ser278Arg) polymorphism of the AIRE gene is associated with an increased risk for AA.

Adams-Oliver syndrome: clinical description of a four-generation family and exclusion of five candidate genes.

We present a Belgian Adams-Oliver syndrome (AOS) family with 10 affected individuals over four generations, of which six were available for this study. Clinical symptoms observed in these patients were very variable as previously reported in other families and included large areas of alopecia on the vertex of the skull and serious limb reduction defects with agenesis of all toes of one foot. To identify the disease-causing gene, we sequenced the MSX1, CART1, P63 (P73L), RUNX2, and HOXD13 genes in this family and nine previously reported families, but no disease-causing mutations were found. Further investigation is ongoing in these families in order to identify the genetic cause of AOS.

Prenatal diagnosis of pentalogy of Cantrell: a case report.

Pentalogy of Cantrell is a very rare congenital disorder characterized by ectopia cordis in combination with an abdominal wall defect. A case diagnosed prenatally at 25 weeks' gestational age is presented.

Invasive papillary carcinoma of the male breast.

Intracystic papillary carcinoma of the male breast is a very rare disease with only a few cases reported in the literature. A case is described and the additional value of MRI is discussed. To our knowledge, this is the first report regarding the MRI findings of an intracystic papillary carcinoma of the male breast.

[Primary malignant melanoma of the female urethra]. / Primäres malignes Melanom der weiblichen Urethra.

Primary malignant melanomas of the urethra are extremely rare. Clinically they are usually mistaken for other malignant diseases or even benign lesions. The case of a 66-year-old woman is reported, who presented with local bleeding of the urethra. Macroscopically a polypoid tumor was seen on the meatus externus of the urethra. A biopsy was taken and the histology report revealed a malignant melanoma. There were no signs of metastases and therefore the treatment consisted of a wide local excision only. A review of literature regarding therapy and prognosis is presented.