Reproductive history and risk of second primary breast cancer: the WECARE study.

BACKGROUND: Women with an initial breast cancer diagnosis are at elevated risk of developing subsequent cancer in the contralateral breast. Studies of reproductive factors and contralateral breast cancer (CBC) have provided inconsistent results. METHODS: We employed a case-control study nested within five population-based cancer registries in the United States and Denmark to examine associations between reproductive history and CBC risk. Cases were women with asynchronous CBC who had their first primary invasive breast cancer before age 55 years. Two controls, who had only one primary breast cancer diagnosis, were individually matched to each case on age and year of diagnosis, race, and registry. A total of 694 case-control triplets and 11 case-control pairs were enrolled. Information regarding possible CBC risk factors was obtained via telephone interviews. Multivariable conditional logistic regression was used to estimate rate ratios (RR) and 95% confidence intervals (95% CI) associated with risk factors of interest. RESULTS: Increasing number of full-term pregnancies (FTP) was inversely associated with CBC risk (P trend, 0.001). Women who reported menarche before age 13 years had an increased risk of CBC (RR, 1.26; 95% CI, 1.01-1.58). Age at first FTP, breastfeeding history, and age at menopause were not significantly associated with CBC risk. CONCLUSIONS: These results suggest age at menarche and parity, which are established risk factors for first primary breast cancer, are associated with CBC, whereas other reproductive risk factors associated with first primary breast cancer, such as age at first FTP, are less important factors in the development of CBC.     

Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers: A WECARE Study Report

BackgroundWomen with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers.MethodsA population-based, nested case–control study was conducted within a cohort of 52,536 survivors of unilateral breast cancer (UBC). Cases were 603 women with CBC and controls were 1199 women with UBC individually matched on age at diagnosis, race, year of first diagnosis and cancer registry. All women were tested for BRCA1 and BRCA2 mutations. Radiation absorbed dose from the initial radiotherapy (RT) to the CBC location within the contralateral breast was reconstructed from measurements in a tissue-equivalent phantom and details available in the therapy records.FindingsAmong women treated with radiation, the mean radiation dose was 1.1 Gy (range = 0.02–6.2 Gy). Risk of developing CBC was elevated among women who carried a deleterious BRCA1/BRCA2 mutation (rate ratio, RR = 4.5, confidence interval, CI = 3.0–6.8), and also among those treated with RT (RR = 1.2, CI = 1.0–1.6). However, among mutation carriers, an incremental increase in risk associated with radiation dose was not statistically significant.InterpretationMultiplicative interaction of RT with mutation status would be reflected by a larger association of RT with CBC among carriers than among non-carriers, but this was not apparent. Accordingly, there was no clear indication that carriers of deleterious BRCA/BRCA2 mutations were more susceptible to the carcinogenic effects of radiation than non-carriers. These findings are reassuring and have important clinical implications for treatment decisions and the clinical management of patients harbouring deleterious BRCA1/BRCA2 mutations.FundingAll work associated with this study was supported by the U.S. National Cancer Institute [R01CA097397, U01CA083178].     

Reproductive factors and risk of contralateral breast cancer by BRCA1 and BRCA2 mutation status: results from the WECARE study

Objective

Reproductive factors, such as early age at menarche, late age at menopause, and nulliparity are known risk factors for breast cancer. Previously, we reported these factors to be associated with risk of developing contralateral breast cancer (CBC). In this study, we evaluated the association between these factors and CBC risk among BRCA1 and BRCA2 (BRCA1/2) mutation carriers and non-carriers.

Methods

The WECARE Study is a population-based multi-center case–control study of 705 women with CBC (cases) and 1,397 women with unilateral breast cancer (controls). All participants were screened for BRCA1/2 mutations and 181 carriers were identified. Conditional logistic regression models were used to evaluate associations between reproductive factors and CBC for mutation carriers and non-carriers.

Results

None of the associations between reproductive factors and CBC risk differed between mutation carriers and non-carriers. The increase in risk with younger age at menarche and decrease in risk in women with more than two full-term pregnancies seen in non-carriers were not significantly different in carriers (adjusted RRs = 1.31, 95% CI 0.65–2.65 and 0.53, 95% CI 0.19–1.51, respectively). No significant associations between the other reproductive factors and CBC risk were observed in mutation carriers or non-carriers.

Conclusion

For two reproductive factors previously shown to be associated with CBC risk, we observed similar associations for BRCA1/2 carriers. This suggests that reproductive variables that affect CBC risk may have similar effects in mutation carriers and non-carriers.     

Glucose and lipid fluxes in the adipose tissue after meal ingestion in hyperthyroidism

BACKGROUND: Although insulin resistance is well established in hyperthyroidism, information on the effects of insulin on adipose tissue (AD) is limited. METHODS: To investigate this, a meal was given to 12 hyperthyroid (HR) and 10 euthyroid (EU) subjects. Blood was withdrawn for 360 min from veins draining the anterior abdominal sc AD and from the radial artery. Blood flow was measured with 133Xe. Lipoprotein lipase (LPL) was calculated as triglyceride flux across AD, and AD-lipolysis was calculated as glycerol flux minus LPL. RESULTS: Both groups displayed comparable postprandial glucose levels, with the HR having higher insulin levels than the EU. In AD of HR vs. EU: 1) blood flow was increased [area under curve 0-360 min (milliliters per 100 milliliters of tissue); 1746 +/- 208 vs. 1344 +/- 102, P = 0.001], but glucose uptake was normal [area under curve 0-360 min (micromoles per 100 milliliters of tissue); 501 +/- 114 vs. 368 +/- 48]; 2) fasting rates of lipolysis (nanomoles per minute per 100 milliliters of tissue; 329 +/- 75 vs. 89 +/- 22, P = 0.02) and nonesterified fatty acid (NEFA) release (nanomoles per minute per 100 milliliters of tissue; 841 +/- 146 vs. 316 +/- 97, P = 0.01), and plasma NEFA levels (micromoles per liter; 623 +/- 50 vs. 454 +/- 57, P = 0.03) were increased, but were all rapidly suppressed to levels similar to those in EU after the increase in plasma insulin levels after the meal; and 3) LPL was not stimulated by insulin. CONCLUSIONS: In hyperthyroidism, AD lipolysis and glucose uptake are resistant to insulin. The defect in lipolysis is manifested in the fasting state, whereas postprandially this rate is rapidly suppressed to normal. This may relieve tissues from the burden of NEFAs after the meal, thus facilitating muscle glucose disposal by insulin.     

p38 mitogen-activated protein kinase inhibitors for the treatment of chronic cardiovascular disease

p38 Mitogen-activated protein kinase (MAPK) has been implicated in cardiovascular disease and is activated by various factors, including neurohormones (e.g., catecholamines, angiotensin II and endothelin), hypoxia and wall stress. Activation of p38 MAPK can cause cardiac hypertrophy, negative inotropy and endothelial dysfunction. All of these conditions lead to chronic cardiovascular disease, which is becoming an ever growing burden on society. p38 MAPK inhibition may therefore be an interesting therapeutic approach to the treatment of various cardiovascular diseases. However, in vitro and in vivo results are conflicting and caution must be applied in the translation of bench results to the clinic.     

Work environment and occupational risk assessment for small animal Portuguese veterinary activities

The professional work of small animal veterinary staff encompasses a wide diversity of demanding tasks. This has prompted a number of studies covering physical, chemical, biological, ergonomic, or psychological hazards, as well as their health effects upon veterinary workers. However, such results were obtained from self-reported surveys (via paper or online). This study reports the identification of potential hazards and provides a risk assessment of 15 veterinary clinics based on data from walk-through surveys, interviews with workers, and quantification of indoor air quality parameters including concentration of volatile organic compounds (total, isoflurane, and glutaraldehyde). The risk arising from X-ray exposure was unacceptable in seven clinics; X-ray examination should be discontinued in the absence of isolated radiation rooms, poor safety practices, and lack of personal protective equipment. Ergonomic-related hazards and work practices should be revised as soon as possible, considering that improper postures, as well as moving and lifting heavy animals are major causes of musculoskeletal disorders. The risk levels were, in general, small or medium (acceptable) with regard to exposure to physical hazards (such as bites, scratches, cuts, and burns) and biological hazards. It was observed that the indoor air quality parameters including temperature, respirable particulate matter and total volatile organic compounds do not indicate a comfortable workplace environment, requiring clinics' attention to keep the safe environment. The veterinarians and nurses were exposed to isoflurane (above 2 ppm) during surgery if an extractor system for waste gas was used instead of a scavenging system. Finally, veterinary workers did not possess any type of training on occupational safety and health issues, even though they recognized its importance.     

Phase II trial of sequential paclitaxel and 1 h infusion of bryostatin-1 in patients with advanced esophageal cancer

BACKGROUND: We sought to determine the response rate and toxicity profile of sequential paclitaxel and bryostatin-1, a novel, selective inhibitor of protein kinase C, in patients with advanced esophageal cancer. PATIENTS AND METHODS: Patients with advanced esophageal and gastroesophageal junction cancer were enrolled. All gave informed consent. They were initially treated with paclitaxel 90 mg/m(2) intravenously on Day 1 and bryostatin-1 50 mug/m(2) on Day 2 weekly for three consecutive weeks out of four. Because of severe myalgias, dosing was reduced to paclitaxel 80 mg/m(2) with bryostatin-1 40 mug/m(2) and then to paclitaxel 80 mg/m(2) with bryostatin-1 25 mug/m(2). RESULTS: Twenty-four patients were enrolled, with 22 assessable for response. The partial response rate was 27%. 10 patients treated with bryostatin-1 40-50 mug/m(2) had a response rate of 40 versus 17% at bryostatin-1 25 mug/m(2) (p-value = 0.3). Median time-to-progression was 3.7 months and median survival was 8.3 months. Grade 3/4 myalgias were seen in 50% of patients. Myalgias appeared to be related to bryostatin-1 dose. Because of toxicity, the trial was closed prior to full accrual. CONCLUSIONS: Despite potential anti-tumor activity of this combination in patients with advanced esophageal cancer, further development is not warranted, given the severe toxicity, especially myalgias, that were seen.