Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

Subclinical involvement of the liver is associated with prognosis in treatment naïve cancer patients.

BACKGROUND: Routinely tested liver biomarkers as alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), butyryl-cholinesterase (BChE), albumin and bilirubin are altered in distinct malignancies and hepatic metastases. This study aimed to investigate whether all liver parameters have the ability to predict long-term mortality in treatment naïve cancer patients but without a malignant hepatic involvement. METHODS: We prospectively enrolled 555 consecutive patients with primary diagnosis of cancer without prior anticancer therapy. BChE, albumin, AST, ALT, GGT and bilirubin as well as the inflammatory makers C-reactive protein (CRP), serum amyloid A (SAA) and interleukin-6 (IL-6) were determined. All-cause mortality was defined as primary endpoint. RESULTS: During a median follow-up of 25 (IQR16-31) months 186 (34%) patients died. All liver parameters were significantly associated with all-cause mortality (p < 0.001 for all). However, for patients without a malignant primary or secondary hepatic involvement (82%) only the functional parameters BChE and albumin remained significantly associated with the primary endpoint (crude HR per 1-IQR increase 0.61, 95%CI:0.49-0.77; p < 0.001 for BChE and 0.58, 95%CI:0.47-0.70; p < 0.001 for albumin). This e ect was persistent after multivariate adjustment (adj.HR per 1-IQR increase 0.65, 95%CI:0.50-0.86; p = 0.002 for BChE and 0.63, 95%CI:0.50-0.79; p < 0.001 for albumin). BChE and albumin correlated inversely with CRP (r = -0.21, p < 0.001 and r = -0.36, p < 0.001), SAA (r = -0.19, p < 0.001 and r = -0.33, p < 0.001) and IL-6 (r = -0.13, p = 0.009 and r = -0.17, p = 0.001). CONCLUSIONS: Decreased serum BChE and albumin levels are associated with increased all-cause mortality in treatment-naïve cancer patients without a manifest malignant hepatic involvement irrespective of tumor entity or stage. This association may reflect progressing systemic inflammation and metabolic derangement with subclinical involvement of the liver.

Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality.

OBJECTIVE: Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer. METHODS: We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint. RESULTS: During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP. CONCLUSIONS: Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

Influence of low-dose oral contraception on peripheral blood lymphocyte subsets at particular phases of the hormonal cycle.

OBJECTIVE: To investigate the effects of low-dose oral hormonal contraception on the immune system during certain phases of the hormonal cycle. DESIGN: Prospective, nonrandomized, controlled study. SETTING: Academic research setting. PATIENT(S): Women with regular menstrual cycle using hormonal oral contraception (OC; Cileste, 250 microg of norgestimat and 35 microg of ethinylestradiol, or Marvelon, 150 microg of desogestrel and 30 microg of ethinylestradiol) and women not using hormonal or other forms of contraception. INTERVENTION(S): Peripheral blood lymphocyte subsets were determined by flow cytometry on the first day of menstruation (day 1), in the follicular phase (day 8), midcycle (day 15), and in the luteal phase (day 22). MAIN OUTCOME MEASURE(S): Levels of lymphocyte subpopulations. RESULT(S): Women using OC had significantly higher levels of CD3+ CD8+ cells throughout their pill cycle compared to controls. Furthermore, women taking Cileste had lower levels of natural killer (NK) cells during their cycle and also women taking Marvelon but only from days 8-15. Within the pill cycle of Cileste we observed an increase in CD20+ and CD20+ CD5+ cells from days 1-8. CONCLUSION(S): Cytotoxic lymphocytes, which are responsible for first-line immune defense, and B cells, which are involved in autoimmune disorders, are affected by OC.

Axillary lymph node dissection in pT1 breast cancer: a retrospective analysis of 315 patients and review of the literature.

Axillary lymph node status and pathologic features of the primary tumor are used to predict the prognosis and select appropriate adjuvant therapy for individual patients with breast cancer. The goal of our study is to identify a group of breast cancer patients who would not benefit from axillary dissection. We researched medical literature and conducted retrospective analyses of 315 consecutive postmenopausal women with breast tumors under 2.0 cm in diameter (pT1) in relation to the extent of axillary lymph node involvement. None of the 39 patients with pT1a tumors had axillary lymph node metastases (ALNM). Of the remaining 276 patients, the ALNM rate in the subgroup pT1b and grading 1 was 5.9%. As expected, the frequency of positive lymph nodes increased the larger the tumor and the higher the grading. Our data corresponds with some of the literature reviewed, although the percentage of axillary involvement described, especially in the subgroup of pT1a tumors, varies within a wide range (0-28%). Our data indicates that it is unlikely that invasive breast cancer pT1a (< or = 0.5 cm) is associated with axillary lymph node metastases in women older than 50 years. The authors conclude that the parameter tumor size, combined with age, can help to assess the risk for axillary lymph node metastases.

Pomegranate seed oil in women with menopausal symptoms: a prospective randomized, placebo-controlled, double-blinded trial.

OBJECTIVE: The aim of this study was to investigate the potential effects of pomegranate seed oil (PGS) on menopausal symptoms. METHODS: The prospective randomized, placebo-controlled, double-blinded trial was completed by 81 postmenopausal women, who received two daily doses of either 30 mg PGS containing 127 µg of steroidal phytoestrogens per dose or a placebo for 12 weeks. The participants reported their number of hot flashes and completed the Menopause Rating Scale II at baseline and at weeks 4, 8, 12, and 24. At baseline and after 12 weeks, hormonal status was determined. RESULTS: After 12 weeks of treatment, PGS reduced the number of hot flashes per day by 4.3 (38.7%), whereas placebo reduced it by 2.5 (25.6%). Both groups were significant compared with baseline, but the treated group was not significant compared with the placebo group (P = 0.17). After 24 weeks, the treated group showed a mean of 7.1 (interquartile range, 4.0) hot flashes per day compared with the placebo group with a mean of 8.8 (interquartile range, 5.0; P = 0.02). Although the overall sum score of the Menopause Rating Scale II parameters at week 12 decreased in the treated group from 16.0 to 9.0 at week 12 and in the placebo group from 18.0 to 14.5 (P = 0.08), the sum score of the vegetative somatic symptoms subgroup decreased strongly versus placebo (P < 0.03), attributable mainly to an improvement in sleeping disorders. PGS did not affect the hormone status, and no adverse effects were reported. CONCLUSIONS: In postmenopausal women, PGS does not significantly reduce hot flashes within a 12-week observation period, but further studies are needed to investigate the long-term effect.

Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany.

AIM: The aim of the study was to evaluate under praxis conditions the safety and efficacy of intravenous (i.v.) vitamin C administration in the first postoperative year of women with breast cancer. PATIENTS AND METHODS: Epidemiological multicentre cohort study, including 15 gynaecologists and general practitioners representatively distributed in Germany. Data from 125 breast cancer patients in UICC stages IIa to IIIb were selected for the study. A total of 53 of these patients were treated with i.v. vitamin C (supplied as Pascorbin® 7.5 g) additional to standard tumour therapy for at least 4 weeks (study group) and 72 without this additional therapy (control group). Main outcome measures were efficacy in regard to outcome and severity of disease- or therapy-induced complaints during adjuvant chemo- and radiotherapy and aftercare. RESULTS: Comparison of control and study groups revealed that i.v. vitamin C administration resulted in a significant reduction of complaints induced by the disease and chemo-/radiotherapy, in particular of nausea, loss of appetite, fatigue, depression, sleep disorders, dizziness and haemorrhagic diathesis. After adjustment for age and baseline conditions (intensity score before adjuvant therapy, chemotherapy, radiotherapy), the overall intensity score of symptoms during adjuvant therapy and aftercare was nearly twice as high in the control group compared to the study group. No side-effects of the i.v. vitamin C administration were documented. DISCUSSION: Oxidative stress and vitamin C deficiency play an important role in the etiology of adverse effects of guideline-based adjuvant chemo-/radiotherapy. Restoring antioxidative capacity by complementary i.v. vitamin C administration helps to prevent or reduce disease-, or therapy-induced complaints in breast cancer patients. CONCLUSION: Complementary treatment of breast cancer patients with i.v. vitamin C was shown to be a well tolerated optimization of standard tumour-destructive therapies, reducing quality of life-related side-effects.

Neutropenic event risk and impaired chemotherapy delivery in six European audits of breast cancer treatment.

GOALS OF WORK: The aims of this study were to assess chemotherapy treatment characteristics, neutropenic event (NE) occurrence and related risk factors in breast cancer patients in Western Europe. MATERIALS AND METHODS: Six retrospective audits of breast cancer chemotherapy were combined into a dataset of 2,860 individuals. NEs were defined as neutropenia-related hospitalisation, dose reduction > or = 15% or dose delay > or = 7 days. Summation dose intensity (SDI) was calculated to compare different types of chemotherapy regimens on a single scale. Risk factors of NE occurrence and of low relative dose intensity (RDI) < or = 85% were identified by multiple logistic regression. MAIN RESULTS: Patient populations were comparable between audits. Until 1998, cyclophosphamide, methotrexate and fluorouracil regimens were most frequently used, but thereafter, anthracycline-based regimens were most common. NEs occurred in 20% of the patients and low RDI in 16%. NE occurrence predicted low RDI and was associated with higher age, bigger body surface area, lower body mass index, regimen type, more chemotherapy cycles planned, normal to high SDI, concomitant radiotherapy and year of treatment. First cycle NE occurrence predicted NEs from cycle 2 onwards. A risk score using age, SDI, number of planned chemotherapy cycles and concomitant radiotherapy differentiated patients with increasing NE risk (9-37%). An alternative score version not using concomitant radiotherapy performed moderately less well. CONCLUSIONS: NEs occurred frequently in this combined dataset and they affected treatment delivery. Identifying patients at high NE risk enables targeted prophylaxis and may avoid dose limitations.