Increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population.

BACKGROUND: Germline mutations in BRCA2 have been linked to a higher risk of prostate cancer (PCa), and high frequency of BRCA1 and BRCA2 (BRCA1/2) gene alterations was recently reported in metastatic castration-resistant PCa specimens. Mutations in BRCA2 vary in racial and ethnic groups including African-American (AA) and Caucasian-American (CA) populations. METHODS: BRCA1 and BRCA2 genes were sequenced (Ion AmpliSeq targeted sequencing) in archived blood DNA specimens in 1240 PCa patients, including 30% AA patients, in three different cohorts: localized early stage (T2) PCa (N = 935); advanced PCa (50% T3-4) (N = 189); and metastatic PCa (N = 116). The sequences were analyzed for known and novel mutations in BRCA1/2. Statistical analyses were performed to determine associations of the mutations with clinico-pathological parameters. RESULTS: BRCA2 mutations with known pathogenic annotation were significantly more prevalent in men with advanced and metastatic PCa (3.1%) compared to patients with an organ-confined disease (0.7%). AA patients carried more frequently BRCA1/2 variants of unknown significance (VUS) when compared to Caucasian Americans (4.6 vs. 1.6%, respectively). Significantly, pathogenic BRCA2 mutations in men with localized early stage PCa increased the risk of distant metastasis. CONCLUSIONS: Germline variants of unknown significance in BRCA1/2 are more frequent in AA than CA PCa patients; however, the prevalence of pathogenic mutations were similar across the races. Patients carrying BRCA2 pathogenic mutations are more likely to progress to metastasis.

Use of the external pectoralis myocutaneous major flap in anterior skull base reconstruction.

Despite the emergence of free tissue transfer, the pectoralis major myocutaneous flap (PMMF) still has a role in anterior base skull reconstruction (when free tissue transfer is not feasible). The aim of this study is to evaluate the results of external PMMF in anterior skull base reconstruction. A retrospective study from 1977 to 2006 was conducted at Yale New Haven Hospital. 16 patients (mean age 64 years), presenting with a malignant tumour of the anterior base skull, were included. The primary pathology was recurrent squamous carcinoma. Tumour resection resulted in orbital exenteration in 60%, and bone resection of the anterior skull base in 81% of patients. The initial skin defect was 49 cm(2) (range 16-100 cm(2)). The PMMF was the primary reconstructive choice in 87%, and utilized after free flap failure in two cases. Three minor complications were noted. Orbital exenteration and anterior base skull resection is a surgical procedure that leads to significant reconstructive challenges. The PMMF remains a safe and versatile reconstructive tool in anterior skull base tumour resection. The externalized pedicle allows this flap to reach periorbital and anterior skull base.

TLE3 expression is associated with sensitivity to taxane treatment in ovarian carcinoma.

BACKGROUND: We have previously shown that transducin-like enhancer of split 3 (TLE3) is associated with outcome specifically in patients with taxane-treated breast cancer and not in patients treated with anthracycline-based regimens without a taxane. The purpose of this study was to assess the association between TLE3 expression and recurrence in patients with ovarian carcinoma treated with a taxane containing regimen as opposed to those treated with a platinum-based agent alone. METHODS: We carried out immunohistochemical staining of TLE3 in two series of ovarian cancer specimens from the University of Alabama at Birmingham, Birmingham, AL and the Royal Hospital for Women, Sydney, Australia. Local and distant recurrences within the first five years of follow-up were analyzed using Kaplan-Meier, Cox proportional hazard, and multivariate analysis to assess an association between TLE3 expression and response to therapy. RESULTS: TLE3 was expressed in approximately 30% of tumors and expression was associated with a favorable outcome only in patients who had received taxane as part of their treatment regimen (n = 173, HR = 0.62, P = 0.012; P(interaction) = 0.024). Further analysis revealed that the predictive association between TLE3 expression and outcome was strongest in patients with nonserous histology. CONCLUSION: High TLE3 expression predicts a favorable response to taxane containing chemotherapy regimens in ovarian carcinoma. IMPACT: Our findings warrant an independent evaluation of TLE3 as a potential therapeutic response marker for taxane-based chemotherapy in ovarian cancer.

Characterization of a novel anti-fatty acid synthase (FASN) antiserum in breast tissue.

Fatty acid synthase (FASN) expression has been reported in many different tumors, including breast cancer. In gene microarray studies, the fatty acid synthase gene co-clustered with cytokeratins 5 and 17 and other genes that defined the basal-like subset of breast cancers. To define the use of this marker in breast pathology, a rabbit polyclonal antiserum (S143) to a peptide fragment of this gene was produced and compared with a commercially available monoclonal antibody by immunohistochemistry on various tissue microarrays and whole tissue sections. The tissue microarrays included 1090 breast cancers and 244 normal breast tissues. Whole tissue sections consisted of benign and malignant tissues from breast resection specimens. In contrast to other 'basal' markers identified by gene expression profiling data, the fatty acid synthase (FASN) expression pattern in normal breast was notable for its expression in only a small subset of basal and suprabasal cells. Dual staining experiments revealed that the subpopulation of cells labeling with FASN did not coexpress myoepithelial markers CK5/6 or p63, but did coexpress e-cadherin. In addition to staining a subset of basal and suprabasal cells, the antiserum highlighted apocrine differentiation, and stained 106/144 (74%) cases of columnar cell lesions and five of five cases of flat epithelial atypia. Despite its association with basal keratins in gene array studies, FASN expression did not correlate significantly with the outcome in breast cancer. We describe an expression pattern that highlights only a subset of basal and suprabasal cells in normal breast ducts and we show by dual expression studies that this subset of cells is different from myoepithelial and basal cytokeratin-positive cells. In addition, FASN expression is described in apocrine metaplasia, columnar cell lesions, and flat epithelial atypia.

Changes in bleeding patterns with depot medroxyprogesterone acetate subcutaneous injection 104 mg.

OBJECTIVE: This study aims to assess changes in bleeding patterns with the use of depot medroxyprogesterone acetate (DMPA) 104 mg/0.65 ml subcutaneous injection (DMPA-SC 104). STUDY DESIGN: An analysis was conducted using data from two 1-year, noncomparative clinical trials (N=1787) and a 2-year randomized study comparing DMPA-SC 104 (N=266) with DMPA intramuscular injection (DMPA-IM). Bleeding was analyzed per 30-day interval by category and number of days. Analyses also were performed for age and body mass index (BMI) subgroups and for the percentages of women shifting from bleeding/spotting to amenorrhea after each injection. RESULTS: Each study showed decreased incidence of irregular bleeding and increased amenorrhea with continued use of DMPA-SC 104. Rates of amenorrhea at Month 12 (52-64% across studies) and Month 24 (71% in the 2-year trial) were comparable with those originally reported for DMPA-IM. Changes in bleeding patterns showed no consistent differences according to age or BMI. The percentages of subjects shifting from bleeding and/or spotting to amenorrhea increased with each subsequent injection. CONCLUSION: Clinical data show that the incidence of amenorrhea increases over time with the use of DMPA-SC 104.

Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation.

INTRODUCTION: This 7-year, prospective, matched-cohort, clinical study evaluated the effects of intramuscular depot medroxyprogesterone acetate (DMPA) (150 mg/mL) on bone mineral density (BMD) in women aged 25-35 years. METHODS: Bone mineral density changes in new DMPA-IM users (n=248) were compared with those in women using nonhormonal contraception (n=360) for up to 240 weeks of treatment and 96 weeks of posttreatment follow-up (in subjects receiving >or=1 dose). RESULTS: At week 240 of treatment, mean percentage changes from baseline in DMPA-IM vs. nonhormonal subjects were: -5.16% (n=21) vs. +0.19% (n=65), total hip (p<.001); -5.38% (n=33) vs. +0.43% (n=105), lumbar spine (p<.001). At week 96 posttreatment, these values were: -0.20% (n=25) vs. +0.84% (n=43), total hip (p=.047); -1.19% (n=41) vs. +0.47% (n=66), lumbar spine (p=.017). CONCLUSIONS: These results show BMD declines during DMPA-IM use; following discontinuation, significant increases in BMD occur through 96 weeks posttreatment.

Subcutaneous injection of depot medroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosis-associated pain.

OBJECTIVE: To compare the efficacy and safety of SC depot medroxyprogesterone acetate (DMPA-SC 104) with that of leuprolide acetate in treatment of endometriosis. DESIGN: Phase 3, multicenter, randomized, evaluator-blinded, comparator-controlled trial. SETTING: Clinical trial sites in Canada and United States. PATIENT(S): Two hundred seventy-four women with surgically diagnosed endometriosis. INTERVENTION(S): Intramuscular injections of DMPA-SC (104 mg) or leuprolide acetate (11.25 mg), given every 3 months for 6 months, with 12 months of posttreatment follow-up. MAIN OUTCOME MEASURE(S): Reduction in five endometriosis symptoms or signs (dysmenorrhea, dyspareunia, pelvic pain, pelvic tenderness, pelvic induration); change in bone mineral density (BMD), hypoestrogenic symptoms, bleeding, and weight. RESULT(S): The depot medroxyprogesterone acetate given SC was statistically equivalent to leuprolide in reducing four of five endometriosis symptoms or signs at the end of treatment (month 6) and in reducing all five symptoms after 12 months' follow-up (month 18). Patients in the DMPA-SC 104 group showed significantly less BMD loss than did leuprolide patients at month 6, with scores returning to baseline at 12 months' follow-up. No statistically significant differences in median weight changes were observed between groups. Compared with leuprolide, DMPA-SC 104 was associated with fewer hypoestrogenic symptoms but more irregular bleeding. CONCLUSION(S): Efficacy of DMPA-SC 104 was equivalent to that of leuprolide for reducing endometriosis-associated pain, with less impact on BMD and fewer hypoestrogenic side effects but more bleeding.

Suppression of ovulation by a new subcutaneous depot medroxyprogesterone acetate (104 mg/0.65 mL) contraceptive formulation in Asian women.

BACKGROUND: A new progestin-only, nondaily depot medroxyprogesterone acetate (DMPA) SC injectable contraceptive suspension (104 mg/0.65 mL) has been developed. Clinical trials (including dose-ranging, pharmacokinetic/pharmacodynamic, and contraceptive efficacy studies) indicating the effectiveness of this new formulation were conducted primarily in white women. However, results of an early study by the World Health Organization suggested that in Thai women, medroxyprogesterone acetate (MPA) may be metabolized in <91 +/- 7 days (the range for effective suppression of ovulation established in clinical trials), resulting in a faster return to ovulation in this population. OBJECTIVES: This study was designed to determine the duration of ovulation suppression and investigate the pharmacokinetic profile of MPA after a single SC injection of DMPA 104 mg/0.65 mL in Asian women. It also assessed the effect of ethnicity and injection site on the duration of ovulation suppression. METHODS: : This was a single-center, single-dose, open-label outpatient trial conducted in Singapore in Asian women aged 18 to 40 years. After 1 control cycle, women with confirmed ovulation were randomized in a 1:1 ratio to receive an SC injection of DMPA 104 mg/0.65 mL in either the anterior thigh or the abdomen. Serum concentrations of MPA, progesterone, estradiol, luteinizing hormone, and follicle-stimulating hormone were measured during the 91-day dosing interval and for an additional 15 days thereafter. RESULTS: Twenty-four Asian women (mean [SD] age, 33.8 [43] years; range, 22.7-40.1 years; mean [SD] body mass index, 22.4 [3.0] kg/m(2)) belonging to 5 ethnic groups (Chinese, Filipino, Indian, Malaysian, and Thai) were included in the study Ovulation suppression was maintained throughout the 91-day dosing interval, regardless of ethnicity or injection site. Ovulation was suppressed for at least 112 days after injection in 23 (95.8%) women, as evidenced by maintenance of serum progesterone concentrations <4.7 ng/mL. The pharmacokinetic parameters for MPA in these Asian women were similar to those previously reported in white women. The most frequently reported adverse events were flulike symptoms and headache, all of mild to moderate intensity. No serious adverse events were reported. CONCLUSIONS: In this study, SC DMPA 104 mg/0.65 mL provided effective suppression of ovulation for at least 91 days in Asian women. Ethnicity and injection site had no effect on MPA profiles.

Endoscopic versus open carpal tunnel release: a randomized trial.

PURPOSE: This study compared the outcomes in patients assigned to either endoscopic carpal tunnel release (ECTR) or traditional open carpal tunnel release (OCTR). METHODS: An unbalanced randomized clinical trial (91 endoscopic, 32 open) was conducted. Short-term and long-term outcomes were evaluated by a blinded assessor. The primary outcome measures were symptom severity measured on a self-report scale and nerve/vascular complications. Secondary outcomes included the McGill pain questionnaire, grip strength, pinch strength, sensory threshold (NK PSSD device, NK Biotechnical Corp, Minneapolis, MN), and time to return to work. RESULTS: Both groups improved on all outcomes. No differences were observed in primary outcomes between the groups at either baseline or follow-up at 1 week, 6 weeks, or 12 weeks after surgery. No significant complications occurred in either group. Grip strength and pain were significantly better at 1 and 6 weeks in the endoscopic group although differences dissipated by 12 weeks. No significant differences occurred in other secondary outcomes. Long-term satisfaction was lower in the endoscopic group, attributable to a 5% rate of re-operation. Lower rates of endoscopic release have occurred at our center once these results were available to surgeons and patients. CONCLUSIONS: No substantive difference in benefit was shown for these 2 methods of carpal tunnel release.

Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome.

While several prognostic factors have been identified in breast carcinoma, the clinical outcome remains hard to predict for individual patients. Better predictive markers are needed to help guide difficult treatment decisions. In a previous study of 78 breast carcinoma specimens, we noted an association between poor clinical outcome and the expression of cytokeratin 17 and/or cytokeratin 5 mRNAs. Here we describe the results of immunohistochemistry studies using monoclonal antibodies against these markers to analyze more than 600 paraffin-embedded breast tumors in tissue microarrays. We found that expression of cytokeratin 17 and/or cytokeratin 5/6 in tumor cells was associated with a poor clinical outcome. Moreover, multivariate analysis showed that in node-negative breast carcinoma, expression of these cytokeratins was a prognostic factor independent of tumor size and tumor grade.

Synthesis of ketone analogues of prolyl and pipecolyl ester FKBP12 ligands.

The recently discovered small-molecule ligands for the peptidyl and prolyl isomerases (PPIase) of FKBP12 have been shown to possess powerful neuroprotective and neuroregenerative effects. Ketone analogues of the prolyl and pipecolyl esters, which mimic only the FKBP binding domain portion of FK506, are proposed and an efficient synthetic strategy is presented in this report, along with the preliminary results of in vitro and in vivo biological studies.