Fluorine-18-labelled Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography or Magnetic Resonance Imaging to Diagnose and Localise Prostate Cancer. A Prospective Single-arm Paired Comparison (PEDAL).

BACKGROUND AND OBJECTIVE: Multiparametric magnetic resonance imaging (mpMRI) of the prostate is used for prostate cancer diagnosis. However, mpMRI has lower sensitivity for small tumours. Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) offers increased sensitivity over conventional imaging. This study aims to determine whether the diagnostic accuracy of 18F-DCFPyL PSMA-PET/CT was superior to that of mpMRI for detecting prostate cancer (PCa) at biopsy. METHODS: Between 2020 and 2021, a prospective multicentre single-arm phase 3 imaging trial enrolled patients with clinical suspicion for PCa to have both mpMRI and PSMA-PET/CT (thorax to thigh), with reviewers blinded to the results of other imaging. Multiparametric MRI was considered positive for Prostate Imaging Reporting and Data System (PIRADS) 3-5. PSMA-PET/CT was assessed quantitatively (positive maximum standardised uptake value [SUVmax] >7) and qualitatively (five-point lexicon of certainty). Patients underwent targeted and systematic biopsy, with the technique at the discretion of the treating urologist. Clinically significant PCa (csPCa) was defined as International Society of Urological Pathology grade group (GG) ≥2. The primary outcome was the diagnostic accuracy for detecting PCa, reported as sensitivity, specificity, negative predictive value (NPV), and area under the curve (AUC) of the receiver operating curve. The secondary endpoints included a comparison of the diagnostic accuracy for detecting csPCa, assessing gains in combining PMSA-PET/CT with mpMRI to mpMRI alone. KEY FINDINGS AND LIMITATIONS: Of the 236 patients completing both mpMRI and PSMA-PET/CT, 184 (76.7%) had biopsy. Biopsy histology was benign (n = 73), GG 1 (n = 27), and GG ≥2 (n = 84). The diagnostic accuracy of mpMRI for detecting PCa (AUC 0.76; 95% confidence interval [CI] 0.69, 0.82) was higher than that of PSMA-PET/CT (AUC 0.63; 95% CI 0.56, 0.70, p = 0.03). The diagnostic accuracy of mpMRI for detecting csPCa (AUC 0.72; 95% CI 0.67, 0.78) was higher than that of PSMA-PET/CT (AUC 0.62; 95% CI 0.55, 0.69) but not statistically significant (p = 0.27). A combination of PSMA-PET/CT and mpMRI showed excellent sensitivity (98.8%, 95% CI 93.5%, 100%) and NPV (96%, 95% CI 79.6%, 99.9%) over mpMRI alone (86.9% and 80.7%, respectively, p = 0.01). Thirty-two patients (13.6%) had metastatic disease. They tended to be older (68.4 vs 65.1 yr, p = 0.023), and have higher prostate-specific antigen (PSA; median PSA 9.6 vs 6.2ng/ml, p < 0.001) and abnormal prostate on digital rectal examination (78.2% vs 44.1%, p < 0.001). CONCLUSIONS AND CLINICAL IMPLICATIONS: Multiparametric MRI had superior diagnostic accuracy to PSMA-PET/CT for detecting PCa, though the difference is not significant in case of csPCa detection. A combination of mpMRI and PSMA-PET/CT showed improved sensitivity and NPV. PSMA-PET/CT could be considered for diagnostic use in patients unable to have mpMRI or those with concerning clinical features but negative mpMRI. PATIENT SUMMARY: In this trial, we compared the ability of 18F-labelled prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) with that of multiparametric magnetic resonance imaging (mpMRI) to diagnose prostate cancer by biopsy in a prostate-specific antigen screening population. We found that MRI was superior to PSMA to diagnose prostate cancer, though there was no difference in ability to diagnose clinically significant prostate cancer. PSMA-PET/CT could be considered for diagnostic use in patients unable to have mpMRI or those with concerning clinical features but negative mpMRI. Combining MRI with PSMA-PET increases the negative predictive value over MRI alone and may help men avoid invasive prostate biopsy.

Australian surgical revision rate for benign prostatic obstruction.

OBJECTIVE: To evaluate the rate of revision surgery following commonly performed procedures for benign prostatic hyperplasia (BPH) is hyperplasia of both glandular and stromal components of prostate especially in periurethral transitional gland, using real-world data from Medicare Australia. METHODS: Prospection is a Healthcare Data Analytics firm that has negotiated access with the Medicare Benefits Schedule (MBS) to provide longitudinal data on the use of specific procedural item codes. We identified patients over the age of 40 years who had undergone primary transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP) or photoselective vaporization of the prostate (PVP) between 2005 and 2010 using MBS item numbers 37203, 37207 and 36854, respectively. Using longitudinal MBS data, primary outcomes included need for revision surgery at 5-years follow-up (2015). The release of these data was approved by Medicare Australia upon application. Data analysis was conducted using chi-squared tests and statistical significance was defined at P < 0.05. RESULTS: The distribution of primary surgical procedures performed between 2005 and 2010 was: TURP 5579 (90%), TUIP 345 (6%) and PVP 258 (4%). TURP was also the most prevalent procedure for treatment of lower urinary tract symptoms in men with BPH requiring revision surgery (75%). At 5-year follow-up the rate of revision surgery for TURP (573/5579), TUIP (47/345) and PVP (30/258) was 10.3%, 13.6% and 11.6%, respectively. The difference was not statistically significant (P = 0.12). There was no significant change (P = 0.59) observed over the years in number of men requiring revision surgery. CONCLUSION: This study indicates that TURP and PVP have a similar durability after 5 years of follow-up.

Multiparametric Magnetic Resonance Imaging of the Prostate and Prostate-specific Membrane Positron Emission Tomography Prior to Prostate Biopsy (MP4 Study).

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computerised tomography (PET/CT) is increasingly being utilised in the diagnostic pathway for prostate cancer (PCa). Recent publications have suggested that this might help identify those who can avoid biopsy. Objective: The primary objective of this study was to determine whether PET magnetic resonance imaging (MRI) fusion could negate the need to biopsy prior to prostatectomy in a selected population of men. Design setting and participant: Multiparametric MRI (mpMRI) for PCa is our standard of care prior to prostate biopsy. Biopsy-naïve men with one or more Prostate Imaging Reporting and Data System (PI-RADS) 4 or 5 lesions ≥10 mm on mpMRI were invited to undergo PSMA PET/CT prior to biopsy. Following ethics approval, 60 men were recruited between September 2020 and March 2021. The key exclusion criteria included a previous history of PCa and previous prostate surgery or biopsy. Outcome measurements and statistical analysis: A positive PET MRI fusion scan was defined as "consistent with" as per the Memorial Sloan Kettering Cancer Center lexicon of certainty, and concordance with biopsy results was analysed. Clinically significant PCa (csPCa) was defined as grade group (GG) ≥2 on pathology. A chi-square analysis was performed with statistical significance defined at p < 0.05. Results and limitations: A total of 71 mpMRI lesions were positive on 61 (86%) PET MRI fusion scans. Fifty-nine of 61 lesions biopsied confirmed csPCa in 54 (92%). Of five of 59 lesions for which either biopsy was negative or low-grade cancer was found, three had rebiopsy of which two were confirmed to have csPCa corroborating with PET MRI fusion and one was reconfirmed to have GG1 only. For the remaining two, both had another lesion elsewhere in the gland confirming csPCa, and hence rebiopsy was not performed. Ultimately, 56 of 59 (95%) lesions with a positive PET MRI fusion scan were confirmed to have csPCa. All GG ≥3 cancers had a positive PET MRI fusion scan. Conclusions: This prospective study of PET MRI fusion assessment of men with PI-RADS 4 or 5 lesion ≥10 mm on mpMRI confirms that the majority of men (95%) with a positive PET MRI fusion scan will have csPCa. This supports recently published retrospective data suggesting that selected men might avoid prostate biopsy prior to radical prostatectomy. Patient summary: In this research, we have confirmed that prostate-specific membrane antigen positron emission tomography/computerised tomography in combination with magnetic resonance imaging could have an important role in enabling a diagnosis of prostate cancer. Using the combination of these scans, we could confidently predict the presence of aggressive prostate cancer in some men for which treatment is warranted. This means that there are some men who could possibility proceed directly to having prostate cancer surgery without the need for a confirmatory prostate biopsy.

Relative Risk of Bladder and Kidney Cancer in Lynch Syndrome: Systematic Review and Meta-Analysis.

Background: The association between Lynch syndrome (LS) and a higher risk of upper tract urothelial carcinoma is well established, but its effect on the risk of bladder and kidney cancers remains controversial. This review aimed to compare the relative risk (RR) of bladder and kidney cancer in confirmed LS germline mutation carriers compared to the general population. Methods: Medline, Embase, Cochrane Central, and Google Scholar were searched on 14 July 2022 for studies published in English that reported on the rates of urological cancer in adults with confirmed LS germline mutation. The quality of included studies was assessed using Cochrane's tool to evaluate risk of bias in cohort studies. Random effects meta-analysis estimated the pooled relative risk of bladder and kidney cancer in LS carriers compared to the general population. The quality of the overall evidence was evaluated using GRADE. Results: Of the 1839 records identified, 5 studies involving 7120 participants from 3 continents were included. Overall, LS carriers had a statistically significantly higher RR of developing bladder cancer (RR: 7.48, 95% CI: 3.70, 15.13) and kidney cancer (RR: 3.97, 95% CI: 1.23, 12.81) compared to unaffected participants (p < 0.01). The quality of the evidence was assessed as "low" due to the inclusion of cohort studies, the substantial heterogeneity, and moderate-to-high risk of bias. Conclusion: Lynch syndrome is associated with a significant increase in the relative risk of kidney and bladder cancer. Clinicians should adopt a lower threshold for germline mutation genetic testing in individuals who present with bladder cancer. Further studies evaluating the role and cost-effectiveness of novel urine-based laboratory tests are needed. High-quality studies in histologically proven renal cell carcinoma and their underlying germline mutations are necessary to strengthen the association with LS.

High-dose vitamin D supplementation to prevent prostate cancer progression in localised cases with low-to-intermediate risk of progression on active surveillance (ProsD): protocol of a phase II randomised controlled trial.

INTRODUCTION: Active surveillance (AS) for patients with prostate cancer (PC) with low risk of PC death is an alternative to radical treatment. A major drawback of AS is the uncertainty whether a patient truly has low risk PC based on biopsy alone. Multiparametric MRI scan together with biopsy, appears useful in separating patients who need curative therapy from those for whom AS may be safe. Two small clinical trials have shown short-term high-dose vitamin D supplementation may prevent PC progression. There is no substantial evidence for its long-term safety and efficacy, hence its use in the care of men with PC on AS needs assessment. This protocol describes the ProsD clinical trial which aims to determine if oral high-dose vitamin D supplementation taken monthly for 2 years can prevent PC progression in cases with low-to-intermediate risk of progression. METHOD AND ANALYSIS: This is an Australian national multicentre, 2:1 double-blinded placebo-controlled phase II randomised controlled trial of monthly oral high-dose vitamin D supplementation (50 000 IU cholecalciferol), in men diagnosed with localised PC who have low-to-intermediate risk of disease progression and are being managed by AS. This trial will assess the feasibility, efficacy and safety of supplementing men with an initial oral loading dose of 500 000 IU cholecalciferol, followed by a monthly oral dose of 50 000 IU during the 24 months of AS. The primary trial outcome is the commencement of active therapy for clinical or non-clinical reason, within 2 years of AS. ETHICS AND DISSEMINATION: This trial is approved by Bellberry Ethics Committee (2016-06-459). All results will be reported in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12616001707459.

Leiomyoma in a Renal Allograft.

Leiomyomas are smooth muscle tumours that are rarely found in the kidney. There is one report of a leiomyoma in a kidney transplant in a paediatric recipient. Here, we report an adult renal transplant recipient who developed an Epstein-Barr virus-positive leiomyoma in his allograft 15 years after transplantation. The patient was converted to everolimus for posttransplant immunosuppression management and there was no sign of progression over a year.

Isolated Grade 5 Renal Trauma in a Hemodynamically Stable Patient.

Isolated grade 5 renal trauma in a hemodynamically stable patient is rare. It is therefore unsurprising there are conflicting recommendations on management of these injuries from authorities including the AUA, EAU and SIU. We present a 26-year-old male with flank pain following a 3-m fall whilst bicycle riding off a ramp, who was found to have an isolated grade 5 renal injury (shattered kidney). He was managed with early angio-embolization and subsequent nephrectomy due to ongoing bleeding. Further reports of clinician experience with this type of renal injury are needed to clarify best practice in management.

Issues of methods and interpretation in the National Cancer Institute formaldehyde cohort study.

In 2004, the International Agency for Research on Cancer (IARC) reclassified formaldehyde (FA) from a probable (Group 2A) to a known human carcinogen (Group 1) citing results for nasopharyngeal cancer (NPC) mortality from the follow-up through 1994 of the National Cancer Institute formaldehyde cohort study. To the contrary, in 2012, the Committee for Risk Assessment of the European Chemicals Agency disagreed with the proposal to classify FA as a known human carcinogen (Carc. 1A), proposing a lower but still protective category, namely as a substance which is presumed to have carcinogenic potential for humans (Carc. 1B). Thus, U.S. and European regulatory agencies currently disagree about the potential human carcinogenicity of FA. In 2013, the National Cancer Institute reported results from their follow-up through 2004 of the formaldehyde cohort and concluded that the results continue to suggest a link between FA exposure and NPC. We discuss in this commentary why we believe that this interpretation is neither consistent with the available data from the most recent update of the National Cancer Institute cohort study nor with other research findings from that cohort, other large cohort studies and the series of publications by some of the current authors, including an independent study of one of the National Cancer Institute's study plants. Another serious concern relates to the incorrectness of the data from the follow-up through 1994 of the National Cancer Institute study stemming from incomplete mortality ascertainment. While these data were corrected by the National Cancer Institute in subsequent supplemental publications, incorrect data from the original publications have been cited extensively in recent causal evaluations of FA, including IARC. We conclude that the NCI publications that contain incorrect data from the incomplete 1994 mortality follow-up should be retracted entirely or corrected via published errata in the corresponding journals, and efforts should be made to re-analyze data from the 2004 follow-up of the NCI cohort study.

Outcomes of transperineal template-guided prostate biopsy in 409 patients.

OBJECTIVE: To present the template-guided transperineal prostate biopsy (TPB) outcomes for patients of two urologists from a single institution. PATIENTS AND METHODS: We conducted a prospective study of 409 consecutive men who underwent TPB between December 2006 and June 2008 in a tertiary referral centre using a standardized 14-region technique. The procedure was performed as day surgery under general anaesthesia with fluoroquinolone antibiotic cover. Follow-up took place within 2 weeks, during which time men were interviewed using a standardized template. Results were compared with those of the Australian national prostate biopsy audits performed by the Urological Society of Australia and New Zealand (USANZ). RESULTS: Indications for biopsy included elevated prostate-specific antigen (PSA) level (75%), with a median PSA level of 6.5 ng/mL, abnormal digital rectal examination (8%) and active surveillance (AS) re-staging (18%). The mean patient age was 63 years and two-thirds of patients were undergoing their first biopsy. A positive biopsy was found in 232 men, 74% of whom had a Gleason score of ≥7. The overall cancer detection rate was 56.7% (USANZ 2005 national audit = 56.5%). Stratified between those having their first TPB or a repeat procedure (after a previous negative biopsy), the detection rates were 64.4 and 35.6%, respectively. Significantly higher detection rates were found in prostates <50 mL in volume than in larger prostates (65.2 vs 38.3%, respectively, P < 0.001). Haematuria was the most common side effect (51.7%). Others included dysuria (16.4%), acute urinary retention (4.2%) and fever (3.2%). One patient (0.2%) had septicaemia requiring i.v. antibiotics. Repeat biopsy was not associated with increased complication rates. CONCLUSIONS: TPB is a safe and efficacious technique, with a cancer detection rate of 56.7% in the present series, and a low incidence of major side effects. Stratified by prostate volume, the detection rate of TPB was higher in smaller glands. Given the relatively low rate of serious complications, clinicians could consider increasing the number of TPB biopsy cores in larger prostates as a strategy to improve cancer detection within this group. Conversely, in patients on AS programmes, a staging TPB may be a superior approach for patients undergoing repeat biopsy so as to minimize their risk of serious infection.

High-dose rate brachytherapy compared with open radical prostatectomy for the treatment of high-risk prostate cancer: 10 year biochemical freedom from relapse.

OBJECTIVE: • To compare long-term biochemical control of high-risk prostate cancer in those men receiving high-dose rate brachytherapy (HDRB) and radical prostatectomy (RP). PATIENTS AND METHODS: • The 10-year biochemical freedom from relapse (BFR) was calculated for 243 patients who underwent either RP or combined therapy with HDRB + external beam radiotherapy + androgen deprivation between 1998 and 2000. • INCLUSION CRITERIA: clinical stage ≥ T2b, or Gleason sum ≥ 8, or PSA level of > 20 ng/mL. Groups were appraised using the Kattan nomogram for surgery to calculate progression-free probability (PFP). RESULTS: • For the RP group (153 patients) the median PSA level was 8.1 ng/mL and the median age was 62.2 years. The median 5- and 10-year predicted PFP for RP was 64% and 56 %, respectively. The 5- and 10-year BFR was 65.5% and 55.4%. There was no significant difference between the predicted and the actual PFP for the RP group (P= 0.525). • For HDRB group (90 patients). The median PSA level was 14.2 ng/mL and the median age was 67.6 years. The median 5- and 10-year predicted PFP for HDRB was 46% and 35%, respectively. The 5- and 10-year BFR was 79.6% and 53.6%. There was a significant improvement between the actual and the predicted PFP for the HDRB group (P= 0.002). CONCLUSIONS: • Amongst a high-risk cohort, patients undergoing RP performed as predicted by the pre-treatment surgical nomogram, whereas the patients undergoing HDRB performed significantly better than was predicted by the surgical nomogram at 10 years.

Accuracy of primary systematic template guided transperineal biopsy of the prostate for locating prostate cancer: a comparison with radical prostatectomy specimens.

PURPOSE: We determined whether systematic template guided transperineal biopsies can accurately locate and sensitively detect prostate cancer. In addition, we reported discrepancies between diagnostic and pathological Gleason scores, and investigated whether prostate size had an effect on the cancer detection rate. MATERIALS AND METHODS: This retrospective diagnostic accuracy study compares the results of primary transperineal biopsies with the radical prostatectomy pathology of 414 consecutive patients treated at a single institution between November 2002 and August 2010. RESULTS: The average sensitivity and specificity for the detection of cancer in all prostates across all biopsy zones was 48% (95% CI 42.6-53.4) and 84.1% (95% CI 80-88.2), respectively. There was a statistically significant decrease in the sensitivity of transperineal biopsy in larger prostates (t11=4.687, p=0.001). The overall Kappa value was 0.255 (95% CI 0.212-0.298). Grading concordance between biopsy and pathology specimens was achieved in 65.7% of patients. Upgrading of Gleason scores occurred in 25.6% of patients and downgrading occurred in 8.8%. CONCLUSIONS: Our current transperineal biopsy method has only demonstrated fair agreement with the histopathology findings of the corresponding radical prostatectomy specimens. This finding is most likely due to the small, multifocal nature of prostate cancer in the patient series. The cancer detection rate was lower in larger prostates. Thus, clinicians may consider increasing the number of cores in larger prostates as a strategy to improve cancer detection.

Parathyroid carcinoma encountered after minimally invasive focused parathyroidectomy may not require further radical surgery.

BACKGROUND: Parathyroid carcinoma accounts for <1% of tumors in primary hyperparathyroidism (PHPT). Distinguishing parathyroid malignancy from benign disease is difficult both before and after initial surgery. Despite the improved specificity of a malignant diagnosis with immunohistochemistry for parafibromin and PGP9.5, proven metastatic behavior remains the gold standard of diagnosis. Minimally invasive focused parathyroidectomy (MIP) is widely performed in patients with PHPT and positive localization studies; thus, it is inevitable that some parathyroid carcinomas will be encountered at MIP. We present our experience of this rare entity. METHODS: The present study represents a surgical case series of patients with parathyroid carcinoma encountered after MIP. The clinicopathological features of benign and malignant parathyroid tumors were compared. Multiple regression analysis was undertaken to compare indicators of malignancy. RESULTS: Between May 1999 and April 2010, a total of 1,292 patients underwent MIP at the University of Sydney Endocrine Surgical Unit, and a histopathological diagnosis of parathyroid carcinoma was made in seven patients (0.5%). Staining for parafibromin and/or PGP9.5 was abnormal in five carcinomas (71%). Despite subsequent unilateral thyroid lobectomy and lymphadenectomy in six patients, no further malignancy was identified in any specimens. Compared to controls, preoperative calcium (p = 0.04) and parathyroid hormone (p = 0.01) were significantly higher in patients with malignancy. The positive predictive value of these parameters for carcinoma was 56 and 75%, respectively. CONCLUSIONS: In patients diagnosed with parathyroid carcinoma after MIP where preoperative imaging had already demonstrated localized disease, revision en bloc surgery did not reveal any residual disease. The benefits of further radical surgery for parathyroid carcinoma after MIP remain controversial.

A randomized controlled trial of low-dose hormone therapy on myocardial ischemia in postmenopausal women with no obstructive coronary artery disease: results from the National Institutes of Health/National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Compared with men, women have more evidence of myocardial ischemia with no obstructive coronary artery disease. Although low endogenous estrogen levels are associated with endothelial dysfunction, the role of low-dose hormone therapy has not been fully evaluated. We postulate that a 12-week duration of low-dose hormone replacement therapy is associated with myocardial ischemia and endothelial dysfunction. METHODS AND RESULTS: Using a multicenter, randomized, placebo-controlled design, subjects were randomized to receive either 1 mg norethindrone/10 microg ethinyl estradiol or placebo for 12 weeks. Chest pain and menopausal symptoms, cardiac magnetic resonance spectroscopy, brachial artery reactivity, exercise stress testing, and psychosocial questionnaires were evaluated at baseline and exit. Recruitment was closed prematurely because of failure to recruit after publication of the Women's Health Initiative hormone trial. Of the 35 women who completed the study, there was less frequent chest pain in the treatment group compared with the placebo group (P = .02) at exit. Women taking 1 mg norethindrone/10 microg ethinyl estradiol also had significantly fewer hot flashes/night sweats (P = .003), less avoidance of intimacy (P = .05), and borderline differences in sexual desire and vaginal dryness (P = .06). There were no differences in magnetic resonance spectroscopy, brachial artery reactivity, compliance, or reported adverse events between the groups. CONCLUSIONS: These data suggest that low-dose hormone therapy improved chest pain symptoms, menopausal symptoms, and quality of life, but did not improve ischemia or endothelial dysfunction. Given that it was not possible to enroll the prespecified sample size, these results should not be considered definitive.

Does hormone therapy improve age-related skin changes in postmenopausal women? A randomized, double-blind, double-dummy, placebo-controlled multicenter study assessing the effects of norethindrone acetate and ethinyl estradiol in the improvement of mild to moderate age-related skin changes in postmenopausal women.

BACKGROUND: In postmenopausal women, declining estrogen levels are associated with a variety of skin changes, many of which are reportedly improved by estrogen supplementation. OBJECTIVE: A study was conducted to assess the effects of continuous combined norethindrone acetate (NA) and ethinyl estradiol (EE) in the control of mild to moderate age-related skin changes in postmenopausal women. METHODS: Four hundred eighty-five subjects were enrolled in this 48-week randomized, double-blind study. Subjects were randomized to one of three study arms: placebo group (165 subjects), 1 mg NA/5 microg EE group (162 subjects), or a 1 mg NA/10 microg EE group (158 subjects). The primary efficacy parameters of the study were investigator global assessment of coarse and fine facial wrinkling at week 48 and subjective self-assessment of changes in wrinkling from baseline at week 48. Secondary parameters included investigator global assessment of skin laxity/sagging at week 48, investigator global assessment of skin texture/dryness at week 48, patient self-assessment of laxity/sagging, texture/dryness, and wrinkle depth determined by image analysis of skin replicas of the periorbital (crow's feet) and jowl areas, and skin elasticity determined by timed deformation and recoil. RESULTS: There were similar scores in investigator global assessment in wrinkling and sagging modules at baseline across all three treatment groups. There were slight decreases in all parameters for all treatment groups for the primary subject end points, but there were no statistically significant differences between the NA/EE groups and placebo. For subject self-assessment of overall severity of skin wrinkling, there were no significant changes at weeks 24 and 48 compared to baseline. These data were unaffected by smoking status or alcohol consumption. LIMITATIONS: This study assessed the effects of 48 weeks of low-dose estrogen upon facial skin in women who were, on average, 5 years postmenopausal. The effects of higher estrogen doses, longer treatment duration, or effects upon perimenopausal women cannot be extrapolated from this study. CONCLUSION: Low-dose hormone therapy for 48 weeks in postmenopausal women did not significantly alter mild to moderate age-related facial skin changes.

An approach to checking case-crossover analyses based on equivalence with time-series methods.

The case-crossover design has been increasingly applied to epidemiologic investigations of acute adverse health effects associated with ambient air pollution. The correspondence of the design to that of matched case-control studies makes it inferentially appealing for epidemiologic studies. Case-crossover analyses generally use conditional logistic regression modeling. This technique is equivalent to time-series log-linear regression models when there is a common exposure across individuals, as in air pollution studies. Previous methods for obtaining unbiased estimates for case-crossover analyses have assumed that time-varying risk factors are constant within reference windows. In this paper, we rely on the connection between case-crossover and time-series methods to illustrate model-checking procedures from log-linear model diagnostics for time-stratified case-crossover analyses. Additionally, we compare the relative performance of the time-stratified case-crossover approach to time-series methods under 3 simulated scenarios representing different temporal patterns of daily mortality associated with air pollution in Chicago, Illinois, during 1995 and 1996. Whenever a model-be it time-series or case-crossover-fails to account appropriately for fluctuations in time that confound the exposure, the effect estimate will be biased. It is therefore important to perform model-checking in time-stratified case-crossover analyses rather than assume the estimator is unbiased.

Changes in body composition in women over six years at midlife: ovarian and chronological aging.

CONTEXT: Understanding the menopause association with body weight is important because excess weight increases risk for stroke, incident cardiovascular disease, cardiovascular mortality, and all-cause mortality among the middle-aged. OBJECTIVE: The objective of this study was to examine chronological age and ovarian age and consider how these could influence body size and composition in midlife women. DESIGN AND SETTING: The Study of Women's Health Across the Nation is a longitudinal, community-based study. This report uses data from the Michigan Study of Women's Health Across the Nation site. PARTICIPANTS: Participants were 543 premenopausal or early perimenopausal African-American and Caucasian women aged 42-52 yr at baseline examination. MAIN OUTCOME MEASURES: Waist circumference, fat mass and skeletal muscle mass, from bioelectrical impedance, were assessed in seven annual serial measures. Annual FSH values were assayed by ELISA. The final menstrual period was defined retrospectively after 12 months of amenorrhea. RESULTS: There was an absolute cumulative 6-yr increase in fat mass of 3.4 kg and a 6-yr decrease in skeletal muscle mass of approximately 0.23 kg. There was an absolute cumulative 6-yr increase of approximately 5.7 cm in waist circumference. The (log)FSH change was positively correlated with (log)(fat mass) change. Waist circumference increased over the time period, but 1 yr after final menstrual period, the rate of increase slowed. Fat mass continued to increase with no change in rate. CONCLUSIONS: Both time (chronological aging) and ovarian aging contributed to substantial changes in body composition (fat and skeletal muscle mass) and waist circumference. These changes have important ramifications for establishing a metabolic environment that can be healthy or unhealthy.

Sex steroid hormone polymorphisms, high-density lipoprotein cholesterol, and apolipoprotein A-1 from the Study of Women's Health Across the Nation (SWAN).

We evaluated potential associations between single nucleotide polymorphism (SNP) variants in estrogen receptor (ERalpha and ERbeta) genes, high-density lipoprotein (HDL) cholesterol, and apolipoprotein A-1 (apoA-1) concentrations in women of 4 races/ethnicities. Participants included 1,520 African American, Caucasian, Chinese, and Japanese women from the Study of Women's Health Across the Nation (SWAN) who were premenopausal or perimenopausal and who were also enrolled in the SWAN Genetics Study, which collected blood for lipid analyses and carried out lymphocyte transformation from which DNA was extracted and genotyped. We evaluated SNPs from ERalpha and ERbeta genes (ESR1 and ESR2, respectively), including ESR1 rs9340799, ESR1 rs2234693, ESR1 rs728524, ESR1 rs3798577, ESR2 rs1255998, ESR2 rs1256065, and ESR2 rs1256030. The mean HDL cholesterol and apoA-1 values for these women were 1.47 mmol/L and 1.51 g/L, respectively. Japanese women with the ESR1 rs3798577 TC genotype had significantly lower apoA-1 (P=0.02) and HDL cholesterol levels (P=0.03) than did those with the TT genotype. African American women with the ESR1 rs728524 GG genotype had higher HDL cholesterol levels than did women with the AA or AG genotypes (P=0.05). ESR2 rs1256030 and ESR2 rs1256065 genotypes were associated with HDL cholesterol concentrations in Chinese women (P=0.05). Although associations were identified between the ESR1 and ESR2 SNP variants and lipids in these women, these associations were not consistently observed across the 4 racial/ethnic groups, nor were the associations consistently inclusive of both HDL cholesterol and apoA-1. These genetic variants provide limited evidence of associations with lipids that may help explain the cardioprotective effect of premenopausal status in women.

A methodology study to validate a structured diagnostic method used to diagnose female sexual dysfunction and its subtypes in postmenopausal women.

The currently accepted gold standard for diagnosis of female sexual dysfunction (FSD) is a nonstandardized interview by a clinician whose field of expertise is FSD. However, the limited number of experts in the field has implications for running efficient large-scale clinical trials. Therefore, we developed a structured diagnostic method (SDM) to enable diagnosis of FSD in postmenopausal women by health care professionals who are not FSD experts. Our study objectives were to evaluate both convergent validity and intrarater reliability of the SDM. The results showed that the method had good convergent validity and excellent intrarater reliability. Thus, we conclude that the SDM can reliably diagnose FSD status and FSD subtypes in postmenopausal women.