Common founder BRCA2 pathogenic variants and breast cancer characteristics in Ethiopian Jews.

PURPOSE: BRCA1/2 founder pathogenic variants (PVs) occur in various populations, but data on the mutational spectrum in Africans are limited. We examined BRCA1/2 PVs in breast cancer patients of Ethiopian Jewish (EJ) origin. METHODS: We retrospectively analyzed BRCA1/2 test results and clinical features of EJ breast cancer patients from seven medical institutions. We obtained heterozygote carrier rates in affected individuals from the laboratories of the largest Israeli HMO (Clalit). Population carrier frequency was determined in EJ controls. RESULTS: We identified three recurrent BRCA2 PVs in 11 EJ breast cancer patients (9 females, 2 males): c.7579delG, c.5159C > A, and c.9693delA. Only c.5159C > A was previously reported in Africans. In women, mean age at diagnosis was 35.7y; 8/9 were diagnosed with advanced disease. All tumors were invasive, 4/9 were triple negative. Only 3/11 carriers had relevant family history. Carrier rate in high-risk breast cancer patients was 11% (3/28; 95%CI [2.3%, 28.2%]). Combined carrier rate among controls was 1.8% (5/280; 95%CI [0.6%, 4.1%]). CONCLUSION: EJs harbor 3 recurrent BRCA2 PVs presenting with relatively severe breast cancer morbidity. Combined with the high BRCA2 carrier rate in the EJ population, these findings merit increasing awareness in this community and suggest that a culturally adapted population screening approach may be warranted.

Audit feedback on reading performance of screening mammograms: An international comparison.

OBJECTIVE: Providing feedback to mammography radiologists and facilities may improve interpretive performance. We conducted a web-based survey to investigate how and why such feedback is undertaken and used in mammographic screening programmes. METHODS: The survey was sent to representatives in 30 International Cancer Screening Network member countries where mammographic screening is offered. RESULTS: Seventeen programmes in 14 countries responded to the survey. Audit feedback was aimed at readers in 14 programmes, and facilities in 12 programmes. Monitoring quality assurance was the most common purpose of audit feedback. Screening volume, recall rate, and rate of screen-detected cancers were typically reported performance measures. Audit reports were commonly provided annually, but more frequently when target guidelines were not reached. CONCLUSION: The purpose, target audience, performance measures included, form and frequency of the audit feedback varied amongst mammographic screening programmes. These variations may provide a basis for those developing and improving such programmes.

European guidelines for quality assurance in colorectal cancer screening and diagnosis: overview and introduction to the full supplement publication.

Population-based screening for early detection and treatment of colorectal cancer (CRC) and precursor lesions, using evidence-based methods, can be effective in populations with a significant burden of the disease provided the services are of high quality. Multidisciplinary, evidence-based guidelines for quality assurance in CRC screening and diagnosis have been developed by experts in a project co-financed by the European Union. The 450-page guidelines were published in book format by the European Commission in 2010.  They include 10 chapters and over 250 recommendations, individually graded according to the strength of the recommendation and the supporting evidence. Adoption of the recommendations can improve and maintain the quality and effectiveness of an entire screening process, including identification and invitation of the target population, diagnosis and management of the disease and appropriate surveillance in people with detected lesions. To make the principles, recommendations and standards in the guidelines known to a wider professional and scientific community and to facilitate their use in the scientific literature, the original content is presented in journal format in an open-access Supplement of Endoscopy. The editors have prepared the present overview to inform readers of the comprehensive scope and content of the guidelines.

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Spermine-directed immunosuppression of cervical carcinoma cell sensitivity to a majority of lymphokine-activated killer lymphocyte cytotoxicity.

The polyamine spermine, naturally present at millimolar levels in seminal plasma, inhibits proliferation of natural killer cells and T lymphocytes, directly binds to DNA and alters cervical cell ploidy indicating its potential ++contribution to the etiology of cervical cancer and its possible role in suppression of the destruction of dysplastic and neoplastic cervical epithelial cells by cytotoxic lymphocytes. This study demonstrates that spermine suppresses sensitivity of cervical carcinoma cells to lymphokine-activated killer (LAK) lymphocytes from more than half of normal individuals. Direct treatment of 51Cr-labelled QGU cervical carcinoma cells with < or = 10-11 M spermine for 1 h reduces cytotoxic destruction of QGU cells by human LAK lymphocytes up to 60% (p < or = 0.05) as shown by decreased LAK lymphocyte lytic units 20%. Cervical carcinoma cells are inherently very sensitive to LAK lymphocytes and spermine may be an important immunosuppressive agent in natural immunity against cervical cancer.

Cytokine modulation of immune defenses in cervical cancer.

Human papilloma viruses (HPV) are major factors in the etiology of cervical cancer. Natural killer (NK) lymphocytes, an important defense against viral diseases, are present in most HPV-associated lesions and cervical intraepithelial neoplasia. HPV positive cervical cancer cells and HPV-immortalized human cervical epithelial cells which possess properties similar to cervical dysplasia, however, are resistant to NK but are sensitive to lymphokine-activated killer (LAK) lymphocyte lysis. Sensitivity can be enhanced by treatment of cervical cells with leukoregulin, a cytokine secreted by lymphocytes. Combination treatment with leukoregulin and a chemotherapeutic drug, e.g. cisplatin, further enhances sensitivity of HPV-infected cells to LAK lymphocyte lysis. In contrast, gamma-interferon treatment of cervical cells can result in decreased sensitivity to LAK lysis illustrating the potential balance cytokines can exert in the immunologic control of cervical cancer.

Prediction of atrial and ventricular fibrillation complicating myocardial infarction from admission data: a prospective study.

This study set out to examine prospectively two logistic formulae based on admission clinical data to predict ventricular or atrial fibrillation complicating acute myocardial infarction. A prospective study of 87 consecutive patients with acute transmural myocardial infarction was conducted. The formula for predicting ventricular fibrillation from the diastolic blood pressure, degree of ST-segment elevation, and QTc had a sensitivity of 93%, specificity of 83%, and a predictive value for an abnormal test of 62% (13 of 14 patients who developed ventricular fibrillation were identified). The formula for predicting atrial fibrillation from the age of the patient, a history of heart failure, systolic blood pressure, and four electrocardiographic parameters had a sensitivity of 78%, specificity of 85%, and a predictive value of 67% (14 of 18 patients identified). Our study shows that patients with myocardial infarction who are liable to develop ventricular or atrial fibrillation can be identified on admission from simple clinical data.