CDO1 promoter methylation is associated with gene silencing and is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients.

Molecular biomarkers may facilitate the distinction between aggressive and clinically insignificant prostate cancer (PCa), thereby potentially aiding individualized treatment. We analyzed cysteine dioxygenase 1 (CDO1) promoter methylation and mRNA expression in order to evaluate its potential as prognostic biomarker. CDO1 methylation and mRNA expression were determined in cell lines and formalin-fixed paraffin-embedded prostatectomy specimens from a first cohort of 300 PCa patients using methylation-specific qPCR and qRT-PCR. Univariate and multivariate Cox proportional hazards and Kaplan-Meier analyses were performed to evaluate biochemical recurrence (BCR)-free survival. Results were confirmed in an independent second cohort comprising 498 PCa cases. Methylation and mRNA expression data from the second cohort were generated by The Cancer Genome Atlas (TCGA) Research Network by means of Infinium HumanMethylation450 BeadChip and RNASeq. CDO1 was hypermethylated in PCa compared to normal adjacent tissues and benign prostatic hyperplasia (P < 0.001) and was associated with reduced gene expression (ρ = -0.91, P = 0.005). Using two different methodologies for methylation quantification, high CDO1 methylation as continuous variable was associated with BCR in univariate analysis (first cohort: HR = 1.02, P = 0.002, 95% CI [1.01-1.03]; second cohort: HR = 1.02, P = 0.032, 95% CI [1.00-1.03]) but failed to reach statistical significance in multivariate analysis. CDO1 promoter methylation is involved in gene regulation and is a potential prognostic biomarker for BCR-free survival in PCa patients following radical prostatectomy. Further studies are needed to validate CDO1 methylation assays and to evaluate the clinical utility of CDO1 methylation for the management of PCa.

Evaluation of stool collections to measure efficacy of PERT in subjects with exocrine pancreatic insufficiency.

OBJECTIVE: The standard measure of pancreatic enzyme replacement therapy (PERT) efficacy in treating exocrine pancreatic insufficiency (EPI) is the coefficient of fat absorption (CFA). CFA measurement involves 72-hour stool collection, which presents a logistical challenge because, although the test may be performed on an outpatient basis in clinical practice, hospitalization is needed if assurance of complete collection and 100% compliance is required, for example, in controlled situations such as clinical trials. Our aim was to investigate sparse stool sample collection as an alternative to complete 72-hour collection for measurement of stool fat in subjects with EPI. SUBJECTS AND METHODS: Prospective data analysis from a previously published, double-blind, randomized, placebo-controlled, 2-period crossover trial in subjects ages 7 to 11 years with EPI caused by cystic fibrosis. Percentage fat (PF) data from sparse stool samples were compared with 72-hour CFA values as a dichotomous variable (<80%, ≥80%), with evaluation of sensitivity, specificity, and positive predictive value. Area under the curve values were obtained from receiver operating characteristic plots of sensitivity versus 1-specificity. RESULTS: Twelve subjects provided samples for this analysis. Multiple-sample PF values ≤30% were greatly predictive for CFA values ≥80%, as shown by positive predictive value, sensitivity, and specificity values ≥0.89, with high accuracy (AUCs ≥0.93). CONCLUSIONS: Sparse stool sampling for PF analysis appears to be a valid, practical alternative to 72-hour CFA determination and has potential as a screening tool in clinical practice to identify both suboptimal dosing in subjects with EPI receiving PERT and substantial fat malabsorption in subjects not receiving PERT.

Safety and efficacy of low-dose esterified estrogens and methyltestosterone, alone or combined, for the treatment of hot flashes in menopausal women: a randomized, double-blind, placebo-controlled study.

This study evaluated safety and efficacy of esterified estrogens and methyltestosterone administered alone or in combination for the treatment of hot flashes in menopausal women. The 0.30-mg esterified estrogens and 0.30-mg methyltestosterone combination was the lowest effective dose, and our results are consistent with the known safety profile of estrogen and androgen combination products.

Validation of a Women's Sexual Interest Diagnostic Interview--Short Form (WSID-SF) and a Daily Log of Sexual Activities (DLSA) in postmenopausal women with hypoactive sexual desire disorder.

INTRODUCTION: Currently, there is no clear standard assessment tool for the diagnosis and daily monitoring of hypoactive sexual desire disorder (HSDD) in postmenopausal women. AIM: The aim of the study was to validate (i) the Women's Sexual Interest Diagnostic Interview-Short Form (WSID-SF) which is a structured tool to identify HSDD; and (ii) the Daily Log of Sexual Activities (DLSA) which is a diary to monitor daily HSDD status in postmenopausal women. Both assessments were collected as self-reports by an interactive voice response system (IVRS). METHODS: At the initial study visit, 629 postmenopausal women, age 39-66, were evaluated for HSDD by the WSID-SF. In addition, in a subgroup of 175 subjects at five study sites, HSDD was assessed by physicians who were blinded to the WSID-SF diagnosis. During the 58-day study period, patients completed the DLSA daily through self-reported IVRS. All women also completed the Female Sexual Function Index (FSFI), Menopause Sexual Interest Questionnaire (MSIQ), Female Sexual Distress Scale (FSDS), Dyadic Adjustment Scale (DAS), and Kellner Symptom Questionnaire (KSQ) at both the initial study visit and at the end of the study. The WSID-SF-based identifications were compared with clinical diagnoses made based on physicians' clinical experience. Construct validity of the WSID-SF and DLSA were assessed based on comparisons with questionnaire results. Internal consistency and test-retest reliability of the DLSA were also evaluated. MAIN OUTCOME MEASURES: Main outcome measures include the agreement between WSID-SF diagnosis and clinician diagnosis, convergent and divergent validity of the WSID-SF and DLSA, and reliability of the DLSA. Results. Enrolled subjects were classified into HSDD (N = 468) and non-HSDD (N = 161) groups by WSID-SF. When compared with physician's diagnosis, WSID-SF-based diagnosis had a specificity of 89% and a sensitivity of 70% (kappa = 0.46, P < 0.001). WSID-SF showed significant correlation with each domain of the FSFI, MSIQ, and FSDS (all P < 0.001). As anticipated, WSID-SF had low or nonsignificant correlations with all domains of the DAS and the KSQ. Four different algorithms were piloted to calculate DLSA scores. Data on the detailed analysis conducted to evaluate the four scoring strategies is on file (not presented in this article). Ultimately, the weekly DLSA total score calculated by algorithm #4 was selected to validate the DLSA. In the test-retest reliability evaluation, the intraclass correlation coefficient was 0.80 for women with HSDD and 0.84 for women without HSDD (P < 0.001 for all analysis). In the known-group validity comparison, the weekly DLSA total score was significantly different (P < 0.001) among the HSDD and the no HSDD groups, with an effect size of 0.89-0.92 based on Cohen's d. The DLSA also showed convergent validity with moderate to high correlations with each domain of the FSFI, MSIQ, and FSDS (P < 0.001 for all correlations). As anticipated, the DLSA had weak correlations with the DAS and KSQ demonstrating divergent validity. CONCLUSIONS: The WSID-SF had good specificity and sensitivity (i.e., discriminative validity) in identifying HSDD in postmenopausal women. In addition, the DLSA is a reliable and valid patient-reported outcomes tool that can be utilized to assess effectiveness of treatments in postmenopausal women with HSDD. Further, the WSID-SF and DLSA both demonstrated good convergent and divergent validity.

Development and evaluation of the Women's Sexual Interest Diagnostic Interview (WSID): a structured interview to diagnose hypoactive sexual desire disorder (HSDD) in standardized patients.

INTRODUCTION: Female sexual dysfunction (FSD) is a common disorder in postmenopausal women. Currently, there is no clear "gold standard" for the diagnosis of FSD. AIM: The aim of this study was to evaluate the interrater reliability of the Women's Sexual Interest Diagnostic Interview (WSID), a new structured clinical interview designed to diagnose hypoactive sexual desire disorder (HSDD). The reliability of additional interview questions focused on the diagnosis of other types of FSD was also evaluated. MAIN OUTCOME MEASURES: The main outcome measure was the level of agreement in the diagnosis of FSD among clinical experts, between clinical experts and study coordinators, and between clinical experts and patients' self-reported interactive voice response system (IVRS) version of the WSID. METHODS: Two versions of WSID were developed based on current diagnostic criteria: a clinician-administered version using a structured interview guide, and a patient self-report version using an IVRS. Three sexual medicine experts developed 20 clinical scenarios portraying cases and noncases of HSDD and other FSD diagnostic subtypes. Ten actresses with experience in standardized patient interviewing rehearsed these scenarios and performed the scripted patient roles in a standardized clinical interview with clinical experts (not the author of the script) and study coordinators, on a one-on-one basis, using the WSID interview format. In addition, all actresses completed the IVRS version of the WSID. Interviews were videotaped and viewed by the expert panel. In each instance, the diagnosis that the interview was scripted to portray was considered as the "gold standard." Kappa (kappa) coefficients were utilized to assess the level of agreement among experts, between study coordinators and the "gold standard", and between the IVRS version of the WSID and the "gold standard". RESULTS: All experts agreed with the gold standard diagnosis provided by the author of the script (kappa=1.0). Similarly, there was perfect agreement among the experts on the presence of depressive symptomatology (kappa=1.0). On the related diagnoses of arousal disorder, orgasmic disorder, and sexual pain disorder, kappas of 0.894, 0.966, and 0.946 were observed (P<0.0001 for all comparisons). When study coordinator's WSID diagnoses were compared with the "gold standard," kappa for HSDD was 0.851; sensitivity was 0.864, and specificity and positive predictive value (PPV) were 1.00 (P<0.001 for all comparisons). When diagnoses obtained via IVRS interviews were compared with the "gold standard", kappa for HSDD was 0.802, sensitivity was 0.818, and specificity and PPV were 1.00 (P<0.001 for all comparisons). CONCLUSION: Agreement as estimated by kappa coefficients was consistently high in both clinician-administered and patient self-reported IVRS versions in the diagnosis of HSDD.

Combined esterified estrogens and methyltestosterone versus esterified estrogens alone in the treatment of loss of sexual interest in surgically menopausal women.

OBJECTIVE: To compare the effect of esterified estrogens and methyltestosterone versus esterified estrogens alone on diminished sexual interest in surgically menopausal women. DESIGN: This randomized, double-blind study compared the effect of combined esterified estrogens (1.25 mg) and methyltestosterone (2.5 mg) (EE/MT) versus esterified estrogens (1.25 mg) alone (EE) for 8 weeks. Several different sexual function questionnaires were used to measure response to therapy. Changes from baseline in sexual interest/function and hormone levels were evaluated after 4 and 8 weeks of treatment. RESULTS: A total of 102 women were randomized into the study; 52 (age range, 32-61 years) to EE/MT and 50 (age range, 33-62 years) to EE. After 8 weeks, significant differences between treatments were not seen in the Changes in Sexual Functioning Questionnaire (CSFQ-F-C) sexual desire/interest subscale score, the primary efficacy variable. In contrast statistically significant between-treatment differences were found for several secondary efficacy variables including Menopausal Sexual Interest Questionnaire (MSIQ) sexual interest/desire score, CSFQ-F-C arousal/erection subscale score and Women's Health Questionnaire sexual functioning subscale score. The mean serum concentration of bioavailable and free testosterone significantly increased, approximately doubling between baseline and the end of the study in patients receiving EE/MT, with a significant (P < 0.001) between-treatment difference. The mean serum concentration of sex hormone-binding globulin significantly decreased to less than one third of the pretreatment levels in patients receiving EE/MT (P < 0.001). Both treatments were well tolerated. CONCLUSIONS: The mixed results seen with the different sexual function questionnaires may be due to the CSFQ-F-C's lack of specificity for this population. Increased levels of bioavailable and free testosterone paralleled the improved MSIQ item scores. Both the EE and EE/MT treatments were well tolerated.

Menopausal Sexual Interest Questionnaire (MSIQ): a unidimensional scale for the assessment of sexual interest in postmenopausal women.

A panel of experts formulated relevant domains of sexual function with a focus on sexual interest and desire. The resulting 10-item scale, the Menopausal Sexual Interest Questionnaire (MSIQ), was examined for reliability (internal consistency and test-retest repeatability), construct validity (concurrent, convergent, and discriminant), sensitivity, and specificity in a clinical trial. A principal components analysis identified three factors (desire, responsiveness, and satisfaction) with eigenvalues > 1. A high degree of internal consistency was observed for each of the three domains. Test-retest repeatability correlation coefficients for domain scores were all highly significant. The MSIQ demonstrated adequate construct validity, with all three domains showing a high degree of sensitivity and with two of the three exhibiting specificity to the effects of treatment.