BRCA1 and BRCA2 mutations in a population-based study of male breast cancer

Background: The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear. Methods: We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk. Results: Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives. Conclusion: These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found

Ambient vibration tests of a cross-laminated timber building

Cross-laminated timber has, in the last 6 years, been used for the first time to form shear walls and cores in multi-storey buildings of seven storeys or more. Such buildings can have low mass in comparison to conventional structural forms. This low mass means that, as cross-laminated timber is used for taller buildings still, their dynamic movement under wind load is likely to be a key design parameter. An understanding of dynamic lateral stiffness and damping, which has so far been insufficiently researched, will be vital to the effective design for wind-induced vibration. In this study, an ambient vibration method is used to identify the dynamic properties of a seven-storey cross-laminated timber building in situ. The random decrement method is used, along with the Ibrahim time domain method, to extract the modal properties of the structure from the acceleration measured under ambient conditions. The results show that this output-only modal analysis method can be used to extract modal information from such a building, and that information is compared with a simple structural model. Measurements on two occasions during construction show the effect of non-structural elements on the modal properties of the structure

Age dissection of the Milky Way discs: Red giants in the Kepler field

Ensemble studies of red-giant stars with exquisite asteroseismic (Kepler), spectroscopic (APOGEE), and astrometric (Gaia) constraints offer a novel opportunity to recast and address long-standing questions concerning the evolution of stars and of the Galaxy. Here, we infer masses and ages for nearly 5400 giants with available Kepler light curves and APOGEE spectra using the code PARAM, and discuss some of the systematics that may affect the accuracy of the inferred stellar properties. We then present patterns in mass, evolutionary state, age, chemical abundance, and orbital parameters that we deem robust against the systematic uncertainties explored. First, we look at age-chemical-abundances ([Fe/H] and [α/Fe]) relations. We find a dearth of young, metal-rich ([Fe/H] > 0.2) stars, and the existence of a significant population of old (8−9 Gyr), low-[α/Fe], super-solar metallicity stars, reminiscent of the age and metallicity of the well-studied open cluster NGC 6791. The age-chemo-kinematic properties of these stars indicate that efficient radial migration happens in the thin disc. We find that ages and masses of the nearly 400 α-element-rich red-giant-branch (RGB) stars in our sample are compatible with those of an old (∼11 Gyr), nearly coeval, chemical-thick disc population. Using a statistical model, we show that the width of the observed age distribution is dominated by the random uncertainties on age, and that the spread of the inferred intrinsic age distribution is such that 95% of the population was born within ∼1.5 Gyr. Moreover, we find a difference in the vertical velocity dispersion between low- and high-[α/Fe] populations. This discontinuity, together with the chemical one in the [α/Fe] versus [Fe/H] diagram, and with the inferred age distributions, not only confirms the different chemo-dynamical histories of the chemical-thick and thin discs, but it is also suggestive of a halt in the star formation (quenching) after the formation of the chemical-thick disc. We then exploit the almost coeval α-rich population to gain insight into processes that may have altered the mass of a star along its evolution, which are key to improving the mapping of the current, observed, stellar mass to the initial mass and thus to the age. Comparing the mass distribution of stars on the lower RGB (R <  11 R⊙) with those in the red clump (RC), we find evidence for a mean integrated RGB mass loss ⟨ΔM⟩ = 0.10 ± 0.02 M⊙. Finally, we find that the occurrence of massive (M ≳ 1.1 M⊙) α-rich stars is of the order of 5% on the RGB, and significantly higher in the RC, supporting the scenario in which most of these stars had undergone an interaction with a companion

Male gynecomastia and risk for malignant tumours – a cohort study

BACKGROUND: Men with gynecomastia may suffer from absolute or relative estrogen excess and their risk of different malignancies may be increased. We tested whether men with gynecomastia were at greater risk of developing cancer. METHODS: A cohort was formed of all the men having a histopathological diagnosis of gynecomastia at the Department of Pathology, University of Lund, following an operation for either uni- or bilateral breast enlargement between 1970–1979. All possible causes of gynecomastia were accepted, such as endogenous or exogenous hormonal exposure as well as cases of unknown etiology. Prior to diagnosis of gynecomastia eight men had a diagnosis of prostate carcinoma, two men a diagnosis of unilateral breast cancer and one had Hodgkin's disease. These patients were included in the analyses. The final cohort of 446 men was matched to the Swedish Cancer Registry, Death Registry and General Population Registry. RESULTS: At the end of the follow up in December 1999, the cohort constituted 8375.2 person years of follow-up time. A total of 68 malignancies versus 66.07 expected were observed; SIR = 1.03 (95% CI 0.80–1.30). A significantly increased risk for testicular cancer; SIR = 5.82 (95% CI 1.20–17.00) and squamous cell carcinoma of the skin; SIR = 3.21 (95% CI 1.71–5.48) were noted. The increased risk appeared after 2 years of follow-up. A non-significantly increased risk for esophageal cancer was also seen while no new cases of male breast cancer were observed. However, in the prospective cohort, diagnostic operations for gynecomastia may substantially have reduced this risk CONCLUSIONS: There is a significant increased risk of testicular cancer and squamous cell carcinoma of the skin in men who have been operated on for gynecomastia

Risk of second primary cancer in men with breast cancer

INTRODUCTION: A retrospective registry-based cohort study was conducted to examine the risk of second primary cancer following the occurrence of breast cancer in males. METHODS: Data obtained from the California Cancer Registry in the period 1988 to 2003 included 1,926 men aged 85 years and younger diagnosed with a first primary breast cancer. Person-year analysis was applied to determine the risk of second primary cancers after the occurrence of a first primary breast cancer. The effects of age, race, and time since the first breast cancer diagnosis were assessed. RESULTS: Of the 1,926 male breast cancer cases, 221 (11.5%) developed a second primary cancer. Men with first incidence of breast cancer have a significantly higher risk of second cancer (standardized incidence ratio (SIR) = 1.16, 95% confidence interval (CI) = 1.01–1.32). The risk of a second site-specific cancer is elevated for breast cancer (SIR = 52.12, 95% CI = 31.83–80.49), cutaneous melanoma (SIR = 2.98, 95% CI = 1.63–5.00) and stomach cancer (SIR = 2.11, 95% CI = 1.01–3.88). There is a general tendency towards higher risks of second malignancies among younger men compared to older men and the risk increased with the passage of time. CONCLUSION: Male breast cancer patients should be monitored carefully for the occurrence of second primary cancers, especially a second primary breast cancer

Protocol for German trial of Acyclovir and corticosteroids in Herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial [ISRCTN45122933]

Background The treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major unsolved problem in Neurology. Current gold standard for therapy is acyclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains up to 15%, less than 20% of patients are able to go back to work, and the majority of patients suffer from severe disability. This is a discouraging, unsatisfactory situation for treating physicians, the disabled patients and their families, and constitutes an enormous burden to the public health services. The information obtained from experimental animal research and from recent retrospective clinical observations, indicates that a substantial benefit in outcome can be expected in patients with HSVE who are treated with adjuvant dexamethasone. But currently there is no available evidence to support the routine use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter trial is the only useful instrument to address this question. Design GACHE is a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with HSVE. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaptation in the last stage. Conclusion 372 patients with proven HSVE (positive HSV-DNA-PCR), aged 18 up to 85 years; with focal neurological signs no longer than 5 days prior to admission, and who give informed consent will be recruited from Departments of Neurology of academic medical centers in Germany, Austria and The Netherlands. Sample size will potentially be extended after the second interim analysis up to a maximum of 450 patients. Trial Registration Current Controlled Trials ISRCTN4512293

Serum amyloid A (SAA): a novel biomarker for uterine serous papillary cancer

BACKGROUND: Uterine serous papillary carcinoma (USPC) is a biologically aggressive variant of endometrial cancer. We investigated the expression of Serum Amyloid A (SAA) and evaluated its potential as a serum biomarker in USPC patients. METHODS: SAA gene and protein expression levels were evaluated in USPC and normal endometrial tissues (NEC) by real-time PCR, immunohistochemistry (IHC), flow cytometry and by a sensitive bead-based immunoassay. SAA concentration in 123 serum samples from 51 healthy women, 42 women with benign diseases, and 30 USPC patients were also studied. RESULTS: SAA gene expression levels were significantly higher in USPC when compared with NEC (mean copy number by RT\u2013PCR\ubc162 vs 2.21; P\ubc0.0002). IHC revealed diffuse cytoplasmic SAA protein staining in USPC tissues. High intracellular levels of SAA were identified in primary USPC cell lines evaluated by flow cytometry and SAA was found to be actively secreted in vitro. SAA concentrations (mgml 1) had a median (95% CIs) of 6.0 (4.0\u20138.9) in normal healthy females and 6.0 (4.2\u20138.1) in patients with benign disease (P\ubc0.92). In contrast, SAA values in the serum of USPC patients had a median (95% CI) of 15.6 (9.2\u201356.2), significantly higher than those in the healthy group (P\ubc0.0005) and benign group (P\ubc0.0006). Receiver operating characteristics (ROC) analysis of serum SAA to classify advanced- and early-stage USPC yielded an area under the ROC curve of 0.837 (P\ubc0.0024). CONCLUSION: SAA is not only a liver-secreted protein but is also a USPC cell product. SAA may represent a novel biomarker for USPC to assist in staging patients preoperatively, and to monitor early-disease recurrence and response to therapy

Weekly cisplatin, epirubicin, and paclitaxel with granulocyte colony-stimulating factor support vs triweekly epirubicin and paclitaxel in locally advanced breast cancer: final analysis of a sicog phase III study

The present study aimed at evaluating whether a weekly cisplatin, epirubicin, and paclitaxel (PET) regimen could increase the pathological complete response (pCR) rate in comparison with a tri-weekly epirubicin and paclitaxel administration in locally advanced breast cancer (LABC) patients. Patients with stage IIIB disease were randomised to receive either 12 weekly cycles of cisplatin 30 mg m−2, epirubicin 50 mg m−2, and paclitaxel 120 mg m−2 (PET) plus granulocyte-colony stimulating factor support, or four cycles of epirubicin 90 mg m−2+paclitaxel 175 mg m−2 (ET) every 3 weeks. Overall, 200 patients (PET/ET=100/100) were included in this study. A pCR in both breast and axilla occurred in 16 (16%) PET patients and in six (6%) ET patients (P=0.02). The higher activity of PET was evident only in ER negative (27.5 vs 5.4%; P=0.026), and in HER/neu positive (31 vs 5%; P=0.037) tumours. The two arms yielded similar pCR rate in ER positive (PET/ET=7.5/7.1%) and HER/neu negative (PET/ET=10/6%) patients. At a 39 months median follow-up, 70 patients showed a progression or relapses (PET, 32 vs ET, 38). Anaemia, mucositis, peripheral neuropathy, and gastrointestinal toxicity were substantially more frequent in the PET arm. The PET weekly regimen is superior to ET in terms of pCR rate in LABC patients with ER negative and/or HER2 positive tumours Mature data in terms of disease-free and overall survival are needed to ascertain whether this approach could improve the prognosis of these subsets of LABC patients