Citations

Abstract Background: MicroRNAs (miRNA) are small, noncoding RNAs with important regulatory roles in tissue development, differentiation, proliferation, and when deregulated tumor formation. The goal of this study was to characterize the miRNA profile of normal breast tissue from carriers of either BRCA1 or BRCA2 mutations, with and without a prior history of cancer, for biomarker discovery for future prevention studies in high risk patient populations. Methods: MicroRNA profiling was conducted using a panel of breast candidate miRNAs and normal ‘non-cancerous’ tissue biopsy from 15 BRCA1 mutation carriers, 15 BRCA2 mutation carriers and 15 BRCA screened mutation negative subjects from high risk families. Results: While small differences were observed for any individual miRNA between groups, the most striking observation was the presence of a clear BRCA1 miRNA signature that was distinct from that in BRCA2 subjects or in the high-risk, non-mutation carriers. The BRCA1 pattern was present in normal appearing tissue biopsy independent of previous history of cancer, treatment for cancer, age, menopausal status or oophorectomy. BRCA2 carriers and high risk, mutation negative subjects showed an overall shared miRNA expression pattern. MicroRNA species that distinguished the groups included differences in the expressed levels of let-7a, let-7b, miR-125b, miR-145, miR-15b and members of the miR-181 family. Ongoing efforts include pathway modeling to gain insight on novel targets for prevention along with RT-PCR confirmation of differentiating microRNA species as well the potential downstream targets for example of miR-181b target genes including HOXA7, HOXA9, HOXA11 and PBX3. Conclusion: The presence of a distinctive miRNA profile in normal appearing tissue of BRCA1 mutation carriers suggest a major role of BRCA1 mutation status on the normal tissue not previously reported. If corroborated, miRNA profiling studies of normal breast tissue may prove useful in both risk assessment as well as providing insight on deregulated pathways for pharmacologic intervention for risk reduction in the BRCA carrier population. Citation Format: Sandhya Pruthi, Julie Buckmeier, Christina Preese, Vera J. Suman, Rachel M. Hurley, Patricia Thompson. microRNA expression profiling in normal breast epithelium of BRCA1 and BRCA2 carriers as prevention targets. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C47.

Abstract Purpose: BRCA1 and BRCA2 mutation carriers develop breast cancers with a tumor phenotype unique from spontaneous tumors. We surveyed documented BRCA mutation carriers to determine willingness to be contacted about participation in future breast cancer prevention research studies directed to their unique phenotype that may or may not require breast biopsies. Methods: At each of the 3 participating institutions, women at least 20 years of age with a documented germline deleterious mutation in BRCA1 or BRCA2 and no prior history of breast cancer were contacted to participate in a survey to ascertain their willingness to be contacted to participate in future prevention trials. Survey results were summarized using descriptive statistics. Results: Among 56 BRCA1 and BRCA2 mutation carriers who responded, 55.4% of women reported high or very high interest in participating in randomized control study of chemoprevention agent vs. placebo. Within this population, post-menopausal women demonstrated a higher interested in study participation (64.5%) versus pre-menopausal women (38.9%). When examining willingness to undergo breast biopsy for a chemoprevention study, women expressed near equal willingness (42.9%) and unwillingness (44.6%) for biopsy. Conclusions: BRCA1 and BRCA2 mutation carriers demonstrated significant interest in breast cancer prevention study participation involving trial agent versus placebo, and an equal expression of willingness and unwillingness to undergo breast biopsy, establishing the feasibility for future research elucidating targeted chemoprevention agents. Citation Format: Rachel M. Hurley, Vera J. Suman, Mary Daly, Funmi Olopade, Paul J. Limburg, Sandhya Pruthi. Assessment of interest for breast cancer prevention trial participation among BRCA mutation carriers. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C01.

Introduction: Hospitalists have been shown to have shorter lengths of stays than physicians with concurrent outpatient practices. However, hospitalists at academic medical centers may be less aware of local resources that can support the hospital to home transition for local primary care patients. We hypothesized that local family medicine patients admitted to a family medicine inpatient service have shorter length of stay than those admitted to general hospitalist services which also care for tertiary patients at an academic medical center. Methods: A retrospective cohort study was conducted at an academic medical center with a department of family medicine providing primary care to over 80 000 local patients. A total of 3100 consecutive family medicine patients admitted to either the family medicine inpatient service or a general medicine inpatient service over 3 years were studied. The primary outcome was length of stay, which was adjusted using multivariate linear regression for demographics, prior utilization, diagnosis, and disease severity. Results: Adjusted length of stay was 33% longer (95% CI 24%-44%) for local family medicine patients admitted to general medicine inpatient services as compared with the family medicine inpatient service. Readmission rates within 30 days were not different (19% vs 16%, P = .14). Conclusions: Local primary care patients were safely discharged from the hospital sooner on the family medicine inpatient service than on general medicine inpatient services. This is likely because the family physicians staffing their inpatient service are more familiar with outpatient resources that can be effectively marshaled to help local patients with the transition from hospital to home.

Abstract Background: Pancreatic cancer is the fourth-leading cause of cancer death in both men and women in the United States. The currently identified common susceptibility loci account for a small fraction of estimated heritability. We sought to estimate overall heritability of pancreatic cancer and partition the heritability by variant frequencies and functional annotations. Methods: Analysis using the genome-based restricted maximum likelihood method (GREML) was conducted on Pancreatic Cancer Case-Control Consortium (PanC4) genome-wide association study (GWAS) data from 3,568 pancreatic cancer cases and 3,363 controls of European Ancestry. Results: Applying linkage disequilibrium- and minor allele frequency-stratified GREML (GREML-LDMS) method to imputed GWAS data, we estimated the overall heritability of pancreatic cancer to be 21.2% (SE = 4.8%). Across the functional groups (intronic, intergenic, coding, and regulatory variants), intronic variants account for most of the estimated heritability (12.4%). Previously identified GWAS loci explained 4.1% of the total phenotypic variation of pancreatic cancer. Mutations in hereditary pancreatic cancer susceptibility genes are present in 4% to 10% of patients with pancreatic cancer, yet our GREML-LDMS results suggested these regions explain only 0.4% of total phenotypic variance for pancreatic cancer. Conclusions: Although higher than previous studies, our estimated 21.2% overall heritability may still be downwardly biased due to the inherent limitation that the contribution of rare variants in genes with a substantive overall impact on disease are not captured when applying these commonly used methods to imputed GWAS data. Impact: Our work demonstrated the importance of rare and common variants in pancreatic cancer risk.

ABSTRACT Background Vaginal diazepam is frequently used to treat pelvic floor tension myalgia and pelvic pain despite limited knowledge of systemic absorption. Aim To determine the pharmacokinetic and adverse event profile of diazepam vaginal suppositories. Methods We used a prospective pharmacokinetic design with repeated assessments of diazepam levels. Eight healthy volunteers were administered a 10-mg compounded vaginal diazepam suppository in the outpatient gynecologic clinic. Serum samples were collected at 0, 45, 90, 120, and 180 minutes; 8, 24, and 72 hours; and 1 week following administration of a 10-mg vaginal suppository. The occurrence of adverse events was assessed using the alternate step and tandem walk tests, the Brief Confusion Assessment Method, and numerical ratings. Plasma concentrations of diazepam and active long-acting metabolites were measured. Pharmacokinetic parameters were calculated by standard noncompartmental methods. Results The mean peak diazepam concentration (Cmax) of 31.0 ng/mL was detected at a mean time (Tmax) of 3.1 hours after suppository placement. The bioavailability was found to be 70.5%, and the mean terminal elimination half-life was 82 hours. The plasma levels of temazepam and nordiazepam peaked at 0.8 ng/mL at 29 hours and 6.4 ng/mL at 132 hours, respectively. Fatigue was reported by 3 of 8 participants. Clinical Implications Serum plasma concentrations of vaginally administered diazepam are low; however the half-life is prolonged. Strengths & Limitations Strengths include use of inclusion and exclusion criteria aimed at mitigating clinical factors that could adversely impact diazepam absorption and metabolism, and the use of an ultrasensitive LC-MS/MS assay. Limitations included the lack of addressing the efficacy of vaginal diazepam in lieu of performing a pure pharmacokinetic study with healthy participants. Conclusion Vaginal administration of diazepam results in lower peak serum plasma concentration, longer time to peak concentration, and lower bioavailability than standard oral use. Providers should be aware that with diazepam’s long half-life, accumulating levels would occur with chronic daily doses, and steady-state levels would not be reached for up to 1 week. This profile would favor intermittent use to allow participation in physical therapy and intimacy.