Sequential and Comparative Evaluation of Pain Treatment Effectiveness Response (SCEPTER), a pragmatic trial for conservative chronic low back pain treatment.

BACKGROUND: Chronic low back pain (cLBP) is a common and highly disabling problem world-wide. Although many treatment options exist, it is unclear how to best sequence the multitude of care options to provide the greatest benefit to patients. METHODS: The Sequential and Comparative Evaluation of Pain Treatment Effectiveness Response (SCEPTER) trial uses a pragmatic, randomized, stepped design. Enrollment targets 2529 participants from 20 Veterans Affairs (VA) medical centers. Participants with chronic low back pain will first be randomized to one of three options: 1) an internet-based self-management program (Pain EASE); 2) a tailored physical therapy program (Enhanced PT); or 3) continued care with active monitoring (CCAM), a form of usual care. Participants not achieving a 30% or 2-point reduction on the study's primary outcome (Brief Pain Inventory Pain Interference (BPI-PI) subscale), 3 months after beginning treatment may undergo re-randomization in a second step to cognitive behavioral therapy for chronic pain, spinal manipulation therapy, or yoga. Secondary outcomes include pain intensity, back pain-related disability, depression, and others. Participants will be assessed every three months until 12 months after initiating their final trial therapy. Companion economic and implementation analyses are also planned. RESULTS: The SCEPTER trial is currently recruiting and enrolling participants. CONCLUSIONS: Trial results will inform treatment decisions for the stepped management of chronic low back pain - a common and disabling condition. Additional analyses will help tailor treatment selection to individual patient characteristics, promote efficient resource use, and identify implementation barriers of interventions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT04142177.

A Population-Level Analysis of the Protective Effects of Androgen Deprivation Therapy Against COVID-19 Disease Incidence and Severity.

Background: The incidence and severity of coronavirus disease 19 (COVID-19) is substantially higher in men. Sex hormones may be a potential mechanism for differences in COVID-19 outcome in men and women. We hypothesized that men treated with androgen deprivation therapy (ADT) have lower incidence and severity of COVID-19. Methods: We conducted an observational study of male Veterans treated in the Veterans Health Administration from February 15th to July 15th, 2020. We developed a propensity score model to predict the likelihood to undergo Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing. We performed multivariable logistic regression modeling adjusted with inverse probability weighting to examine the relationship between ADT and COVID-19 incidence. We conducted logistic regression analysis among COVID-19 patients to test the association between ADT and COVID-19 severity. Results: We identified a large cohort of 246,087 VA male patients who had been tested for SARS-CoV-2, of whom 3,057 men were exposed to ADT, and 36,096 men with cancer without ADT. Of these, 295 ADT patients and 2,427 cancer patients not on ADT had severe COVID-19 illness. In the primary, propensity-weighted comparison of ADT patients to cancer patients not on ADT, ADT was associated with decreased likelihood of testing positive for SARS-CoV-2 (adjusted OR, 0.88 [95% CI, 0.81-0.95]; p = 0.001). Furthermore, ADT was associated with fewer severe COVID-19 outcomes (OR 0.72 [95% CI 0.53-0.96]; p = 0.03). Conclusion: ADT is associated with reduced incidence and severity of COVID-19 amongst male Veterans. Testosterone and androgen receptor signaling may confer increased risk for SARS-CoV-2 infection and contribute to severe COVID-19 pathophysiology in men.

In-Stent Restenosis in Saphenous Vein Grafts (from the DIVA Trial).

Saphenous vein grafts (SVGs) have high rates of in-stent restenosis (ISR). We compared the baseline clinical and angiographic characteristics of patients and lesions that did develop ISR with those who did not develop ISR during a median follow-up of 2.7 years in the DIVA study (NCT01121224). We also examined the ISR types using the Mehran classification. ISR developed in 119 out of the 575 DIVA patients (21%), with similar incidence among patients with drug-eluting stents and bare-metal stents (BMS) (21% vs 21%, p = 0.957). Patients in the ISR group were younger (67 ± 7 vs 69 ± 8 years, p = 0.04) and less likely to have heart failure (27% vs 38%, p = 0.03) and SVG lesions with Thrombolysis In Myocardial Infarction 3 flow before the intervention (77% vs 83%, p <0.01), but had a higher number of target SVG lesions (1.33 ± 0.64 vs 1.16 ± 0.42, p <0.01), more stents implanted in the target SVG lesions (1.52 ± 0.80 vs 1.31 ± 0.66, p <0.01), and longer total stent length (31.37 ± 22.11 vs 25.64 ± 17.42 mm, p = 0.01). The incidence of diffuse ISR was similar in patients who received drug-eluting-stents and BMS (57% vs 54%, p = 0.94), but BMS patients were more likely to develop occlusive restenosis (17% vs 33%, p = 0.05).

Stent-Only Versus Adjunctive Balloon Angioplasty Approach for Saphenous Vein Graft Percutaneous Coronary Intervention: Insights From DIVA Trial.

BACKGROUND: Direct stenting without pre-dilation or post-dilation has been advocated for saphenous vein graft percutaneous coronary intervention to decrease the incidence of distal embolization, periprocedural myocardial infarction, and target lesion revascularization. METHODS: We performed a post hoc analysis of patients enrolled in the DIVA (Drug-Eluting Stents Versus Bare Metal Stents in Saphenous Vein Graft Angioplasty; NCT01121224) prospective, double-blind, randomized controlled trial. Patients were stratified into stent-only and balloon-stent groups. Primary end point was 12-month incidence of target vessel failure (defined as the composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization). Secondary end points included all-cause death, stent thrombosis, myocardial infarction, and target lesion revascularization during follow-up. RESULTS: Of the 575 patients included in this substudy, 185 (32%) patients underwent stent-only percutaneous coronary intervention. Patients in the stent-only versus balloon-stent group had similar baseline characteristics and similar incidence of target vessel failure at 12-months (15% versus 19%; hazard ratio, 1.34 [95% CI, 0.86-2.08]; P=0.19). During long-term follow-up (median of 2.7 years), the incidence of definite stent thrombosis (1% versus 5%; hazard ratio, 9.20 [95% CI, 1.23-68.92]; P=0.0085), the composite of definite or probable stent thrombosis (5% versus 11%; hazard ratio, 2.52 [95% CI, 1.23-5.18]; P=0.009), and target vessel myocardial infarction (8% versus 14%; hazard ratio, 1.92 [95% CI, 1.08-3.40]; P=0.023) was lower in the stent-only group. Multivariable analysis showed that a higher number of years since coronary artery bypass grafting and >1 target saphenous vein graft lesions were associated with increased target vessel failure during entire follow-up, while preintervention Thrombolysis in Myocardial Infarction-3 flow was protective. CONCLUSIONS: In patients undergoing percutaneous coronary intervention of de novo saphenous vein graft lesions, there was no difference in target vessel failure at 12 months and long-term follow-up in the stent-only versus the balloon-stent group; however, the incidence of stent thrombosis was lower in the stent-only group, as was target vessel myocardial infarction. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01121224.

Veterans Affairs Cooperative Studies Program Study #553: Chemotherapy After Prostatectomy for High-risk Prostate Carcinoma: A Phase III Randomized Study.

BACKGROUND: The Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy. OBJECTIVE: To test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS). DESIGN, SETTING, AND PARTICIPANTS: Eligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was PFS. Secondary endpoints included overall, prostate cancer-specific, and metastasis-free survival, and time to androgen deprivation therapy. RESULTS AND LIMITATIONS: A total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2-103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p=0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58-1.11; p=0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32-0.92; p=0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43-0.99; p=0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%. CONCLUSIONS: Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage≥pT3b (ClinicalTrials.gov number NCT00132301). PATIENT SUMMARY: In this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit.

Rationale and design of the Drug-Eluting Stents vs Bare-Metal Stents in Saphenous Vein Graft Angioplasty (DIVA) Trial.

VA Cooperative Studies Program #571 (DIVA) was designed to evaluate the efficacy of drug-eluting stents (DES) for reducing aortocoronary saphenous vein bypass graft (SVG) failure when compared with bare-metal stents (BMS) in participants undergoing stenting of de novo SVG lesions. Participants undergoing clinically indicated stenting of de novo SVG lesions were randomized in a 1:1 ratio to DES or BMS. Randomization was stratified by presence/absence of diabetes mellitus and the number of target SVG lesions (1 vs ≥2) within each participating site. At sites that did not routinely administer 12-months of dual antiplatelet therapy after SVG stenting participants without acute coronary syndromes received 1 month of open-label clopidogrel, followed by 11 months of clopidogrel for those assigned to DES and 11 months of placebo for those assigned to BMS. The primary endpoint was the 12-month incidence of target-vessel failure (defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization). Secondary endpoints included the incidence of other clinical endpoints and the incremental cost-effectiveness of DES relative to BMS. Due to lower-than-anticipated target-vessel failure rates, target enrollment was increased from 519 to 762. The study had randomized 599 participants when recruitment ended in December 2015. The DIVA trial will provide clarity on the appropriate stent type for de novo SVG lesions.

Clinical trial designs for testing biomarker-based personalized therapies.

BACKGROUND: Advances in molecular therapeutics in the past decade have opened up new possibilities for treating cancer patients with personalized therapies, using biomarkers to determine which treatments are most likely to benefit them, but there are difficulties and unresolved issues in the development and validation of biomarker-based personalized therapies. We develop a new clinical trial design to address some of these issues. The goal is to capture the strengths of the frequentist and Bayesian approaches to address this problem in the recent literature and to circumvent their limitations. METHODS: We use generalized likelihood ratio tests of the intersection null and enriched strategy null hypotheses to derive a novel clinical trial design for the problem of advancing promising biomarker-guided strategies toward eventual validation. We also investigate the usefulness of adaptive randomization (AR) and futility stopping proposed in the recent literature. RESULTS: Simulation studies demonstrate the advantages of testing both the narrowly focused enriched strategy null hypothesis related to validating a proposed strategy and the intersection null hypothesis that can accommodate to a potentially successful strategy. AR and early termination of ineffective treatments offer increased probability of receiving the preferred treatment and better response rates for patients in the trial, at the expense of more complicated inference under small-to-moderate total sample sizes and some reduction in power. LIMITATIONS: The binary response used in the development phase may not be a reliable indicator of treatment benefit on long-term clinical outcomes. In the proposed design, the biomarker-guided strategy (BGS) is not compared to 'standard of care', such as physician's choice that may be informed by patient characteristics. Therefore, a positive result does not imply superiority of the BGS to 'standard of care'. The proposed design and tests are valid asymptotically. Simulations are used to examine small-to-moderate sample properties. CONCLUSION: Innovative clinical trial designs are needed to address the difficulties and issues in the development and validation of biomarker-based personalized therapies. The article shows the advantages of using likelihood inference and interim analysis to meet the challenges in the sample size needed and in the constantly evolving biomarker landscape and genomic and proteomic technologies.

Sequential design of phase II-III cancer trials.

Although traditional phase II cancer trials are usually single arm, with tumor response as endpoint, and phase III trials are randomized and incorporate interim analyses with progression-free survival or other failure time as endpoint, this paper proposes a new approach that seamlessly expands a randomized phase II study of response rate into a randomized phase III study of time to failure. This approach is based on advances in group sequential designs and joint modeling of the response rate and time to event. The joint modeling is reflected in the primary and secondary objectives of the trial, and the sequential design allows the trial to adapt to increase in information on response and survival patterns during the course of the trial and to stop early either for conclusive evidence on efficacy of the experimental treatment or for the futility in continuing the trial to demonstrate it, on the basis of the data collected so far.

Radial artery grafts vs saphenous vein grafts in coronary artery bypass surgery: a randomized trial.

CONTEXT: Arterial grafts are thought to be better conduits than saphenous vein grafts for coronary artery bypass grafting (CABG) based on experience with using the left internal mammary artery to bypass the left anterior descending coronary artery. The efficacy of the radial artery graft is less clear. OBJECTIVE: To compare 1-year angiographic patency of radial artery grafts vs saphenous vein grafts in patients undergoing elective CABG. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized controlled trial conducted from February 2003 to February 2009 at 11 Veterans Affairs medical centers among 757 participants (99% men) undergoing first-time elective CABG. INTERVENTIONS: The left internal mammary artery was used to preferentially graft the left anterior descending coronary artery whenever possible; the best remaining recipient vessel was randomized to radial artery vs saphenous vein graft. MAIN OUTCOME MEASURES: The primary end point was angiographic graft patency at 1 year after CABG. Secondary end points included angiographic graft patency at 1 week after CABG, myocardial infarction, stroke, repeat revascularization, and death. RESULTS: Analysis included 733 patients (366 in the radial artery group, 367 in the saphenous vein group). There was no significant difference in study graft patency at 1 year after CABG (radial artery, 238/266; 89%; 95% confidence interval [CI], 86%-93%; saphenous vein, 239/269; 89%; 95% CI, 85%-93%; adjusted OR, 0.99; 95% CI, 0.56-1.74; P = .98). There were no significant differences in the secondary end points. CONCLUSION: Among Veterans Affairs patients undergoing first-time elective CABG, the use of a radial artery graft compared with saphenous vein graft did not result in greater 1-year patency. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00054847.

Integrating tobacco cessation into mental health care for posttraumatic stress disorder: a randomized controlled trial.

CONTEXT: Most smokers with mental illness do not receive tobacco cessation treatment. OBJECTIVE: To determine whether integrating smoking cessation treatment into mental health care for veterans with posttraumatic stress disorder (PTSD) improves long-term smoking abstinence rates. DESIGN, SETTING, AND PATIENTS: A randomized controlled trial of 943 smokers with military-related PTSD who were recruited from outpatient PTSD clinics at 10 Veterans Affairs medical centers and followed up for 18 to 48 months between November 2004 and July 2009. INTERVENTION: Smoking cessation treatment integrated within mental health care for PTSD delivered by mental health clinicians (integrated care [IC]) vs referral to Veterans Affairs smoking cessation clinics (SCC). Patients received smoking cessation treatment within 3 months of study enrollment. MAIN OUTCOME MEASURES: Smoking outcomes included 12-month bioverified prolonged abstinence (primary outcome) and 7- and 30-day point prevalence abstinence assessed at 3-month intervals. Amount of smoking cessation medications and counseling sessions delivered were tested as mediators of outcome. Posttraumatic stress disorder and depression were repeatedly assessed using the PTSD Checklist and Patient Health Questionnaire 9, respectively, to determine if IC participation or quitting smoking worsened psychiatric status. RESULTS: Integrated care was better than SCC on prolonged abstinence (8.9% vs 4.5%; adjusted odds ratio, 2.26; 95% confidence interval [CI], 1.30-3.91; P = .004). Differences between IC vs SCC were largest at 6 months for 7-day point prevalence abstinence (78/472 [16.5%] vs 34/471 [7.2%], P < .001) and remained significant at 18 months (86/472 [18.2%] vs 51/471 [10.8%], P < .001). Number of counseling sessions received and days of cessation medication used explained 39.1% of the treatment effect. Between baseline and 18 months, psychiatric status did not differ between treatment conditions. Posttraumatic stress disorder symptoms for quitters and nonquitters improved. Nonquitters worsened slightly on the Patient Health Questionnaire 9 relative to quitters (differences ranged between 0.4 and 2.1, P = .03), whose scores did not change over time. CONCLUSION: Among smokers with military-related PTSD, integrating smoking cessation treatment into mental health care compared with referral to specialized cessation treatment resulted in greater prolonged abstinence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00118534.

Vitamin D status in children and young adults with inflammatory bowel disease.

OBJECTIVES: Previous studies of vitamin D status in pediatric patients with inflammatory bowel disease have revealed conflicting results. We sought to report (1) the prevalence of vitamin D deficiency (serum 25-hydroxy-vitamin D concentration < or = 15 ng/mL) in a large population with inflammatory bowel disease, (2) factors predisposing to this problem, and (3) its relationship to bone health and serum parathyroid hormone concentration. PATIENTS AND METHODS: A total of 130 patients (8-22 years of age) with inflammatory bowel disease, 94 with Crohn disease and 36 with ulcerative colitis, had serum 25-hydroxy-vitamin D, intact parathyroid hormone, and lumbar spine bone mineral density (using dual-energy x-ray absorptiometry) measured at Children's Hospital Boston. RESULTS: The prevalence of vitamin D deficiency was 34.6%. Mean serum 25-hydroxy-vitamin D concentration was similar in patients with Crohn disease and ulcerative colitis, 52.6% lower among patients with dark skin complexion, 33.4% lower during the winter months (December 22 to March 21), and 31.5% higher among patients who were taking vitamin D supplements. Serum 25-hydroxy-vitamin D concentration was positively correlated with weight and BMI z score, disease duration, and serum albumin concentration and negatively correlated with erythrocyte sedimentation rate. Patients with Crohn disease and upper gastrointestinal tract involvement were more likely to be vitamin D deficient than those without it. Serum 25-hydroxy-vitamin concentration was not associated with lumbar spine bone mineral density z score or serum parathyroid hormone concentration. CONCLUSIONS: Vitamin D deficiency is highly prevalent among pediatric patients with inflammatory bowel disease. Factors predisposing to the problem include having a dark-skin complexion, winter season, lack of vitamin D supplementation, early stage of disease, more severe disease, and upper gastrointestinal tract involvement in patients with Crohn disease. The long-term significance of hypovitaminosis D for this population is unknown at present and merits additional study.

Factor structure of the brief symptom inventory--18 in adult survivors of childhood cancer: results from the childhood cancer survivor study.

The factor structure of the Brief Symptom Inventory--18 (BSI-18; L. R. Derogatis, 2000) was investigated in a sample of adult survivors of childhood cancer enrolled in the Childhood Cancer Survivor Study (CCSS; N = 8,945). An exploratory factor analysis with a randomly chosen subsample supported a 3-factor structure closely corresponding to the 3 BSI-18 subscales: Depression, Anxiety, and Somatization. Confirmatory factor analysis with structural equation modeling validated this 3-dimensional structure in a separate subsample, though an alternative 4-factor model also fit the data. Analysis of the 3-factor model showed consistent fit in male and female participants. Compared with available community-based norms, survivors reported fewer symptoms of psychological distress. Together, results support the hypothesized 3-dimensional structure of the BSI-18 and indicate the measure may be useful in assessing psychological distress in this growing population of cancer survivors.

A new approach to modeling covariate effects and individualization in population pharmacokinetics-pharmacodynamics.

By combining Laplace's approximation and Monte Carlo methods to evaluate multiple integrals, this paper develops a new approach to estimation in nonlinear mixed effects models that are widely used in population pharmacokinetics and pharmacodynamics. Estimation here involves not only estimating the model parameters from Phase I and II studies but also using the fitted model to estimate the concentration versus time curve or the drug effects of a subject who has covariate information but sparse measurements. Because of its computational tractability, the proposed approach can model the covariate effects nonparametrically by using (i) regression splines or neural networks as basis functions and (ii) AIC or BIC for model selection. Its computational and statistical advantages are illustrated in simulation studies and in Phase I trials.

Maternal perspectives on children's health-related quality of life during the first year after pediatric hematopoietic stem cell transplant.

OBJECTIVE: To assess the longitudinal health-related quality of life (HRQL) of children receiving hematopoietic stem cell transplantation (HSCT). METHODS: Mothers (N = 160) of HSCT recipients aged 5-20 at six US transplant centers completed the Child Health Ratings Inventories (CHRIs), the Disease Impairment Inventory (DSII)-HSCT module, and the Short Form (SF)-36 at baseline, 3, 6, and 12 months. RESULTS: HRQL domain scores at baseline varied by recipient age and program site. Longitudinal data over the first year post-HSCT revealed lowest functioning at baseline and 3 months, with largest improvement in functioning between the 3 and 6-months assessments and continued improvement from 6 to 12 months. Recipients of unrelated donor transplants had steepest declines in functioning at 3 months and great HSCT-specific issues at 3 and 6 months. Among children who survived the first year, functioning at 12 months was similar across transplant types and surpassed baseline scores. Children who did not survive the first year exhibited deterioration in HRQL in the months before death and trajectories were strikingly different than for survivors. CONCLUSIONS: This study offers the first glimpse of the 12-month trajectory of HRQL following pediatric HSCT from mothers' perspectives. This study also highlights the importance of and approaches to addressing missing data in longitudinal research.

A randomized, controlled trial of a multifaceted intervention including alcohol-based hand sanitizer and hand-hygiene education to reduce illness transmission in the home.

OBJECTIVE: Good hand hygiene may reduce the spread of infections in families with children who are in out-of-home child care. Alcohol-based hand sanitizers rapidly kill viruses that are commonly associated with respiratory and gastrointestinal (GI) infections. The objective of this study was to determine whether a multifactorial campaign centered on increasing alcohol-based hand sanitizer use and hand-hygiene education reduces illness transmission in the home. METHODS: A cluster randomized, controlled trial was conducted of homes of 292 families with children who were enrolled in out-of-home child care in 26 child care centers. Eligible families had > or =1 child who was 6 months to 5 years of age and in child care for > or =10 hours/week. Intervention families received a supply of hand sanitizer and biweekly hand-hygiene educational materials for 5 months; control families received only materials promoting good nutrition. Primary caregivers were phoned biweekly and reported respiratory and GI illnesses in family members. Respiratory and GI-illness-transmission rates (measured as secondary illnesses per susceptible person-month) were compared between groups, adjusting for demographic variables, hand-hygiene practices, and previous experience using hand sanitizers. RESULTS: Baseline demographics were similar in the 2 groups. A total of 1802 respiratory illnesses occurred during the study; 443 (25%) were secondary illnesses. A total of 252 GI illnesses occurred during the study; 28 (11%) were secondary illnesses. The secondary GI-illness rate was significantly lower in intervention families compared with control families (incidence rate ratio [IRR]: 0.41; 95% confidence interval [CI]: 0.19-0.90). The overall rate of secondary respiratory illness was not significantly different between groups (IRR: 0.97; 95% CI: 0.72-1.30). However, families with higher sanitizer usage had a marginally lower secondary respiratory illness rate than those with less usage (IRR: 0.81; 95% CI: 0.65-1.09). CONCLUSIONS: A multifactorial intervention emphasizing alcohol-based hand sanitizer use in the home reduced transmission of GI illnesses within families with children in child care. Hand sanitizers and multifaceted educational messages may have a role in improving hand-hygiene practices within the home setting.

Androgen receptor cytosine, adenine, guanine repeats, and haplotypes in relation to ovarian cancer risk.

Biological and epidemiologic evidence suggest that androgen or its receptor may play a role in ovarian cancer pathogenesis. The most notable genetic factor influencing androgen receptor (AR) activity is the functional cytosine, adenine, guanine (CAG) repeat in which length is inversely proportional to its transactivational activity. Additional genetic variation due to single nucleotide polymorphisms in the AR gene may be captured through haplotypes. We genotyped the CAG microsatellite and six haplotype-tagging single nucleotide polymorphisms (rs962458, rs6152, rs1204038, rs2361634, rs1337080, rs1337082) of the androgen receptor gene in 987 ovarian cancer cases and 1,034 controls from a study conducted in New Hampshire and eastern Massachusetts between May 1992 and July 2003. We estimated haplotype frequencies and calculated odds ratios with 95% confidence intervals to evaluate the association between the haplotypes and the AR CAG microsatellite with ovarian cancer risk. We observed that carriage of two alleles with > or = 22 CAG repeats was associated with an increased risk of ovarian cancer compared with carriage of two alleles with <22 CAG repeats (covariate-adjusted odds ratios, 1.31; 95% confidence intervals, 1.01-1.69). Five common haplotypes in the AR gene were identified, but no association between these and ovarian cancer risk was observed. Our results suggest that possession of two long AR alleles (> or = 22 CAG repeats) may be associated with increased risk of ovarian cancer compared with women with two short AR alleles (<22 CAG repeats).

Development of a sensitive and specific enzyme-linked immunosorbent assay for thymosin beta15, a urinary biomarker of human prostate cancer.

OBJECTIVES: In tissue-based assays, thymosin beta15 (Tbeta15) has been shown to correlate with prostate cancer (CaP) malignancy and with future recurrence. To be clinically effective, it must be shown that Tbeta15 is released by the tumor into body fluids in detectable concentrations. Toward this end, we have worked to develop a quantitative high-throughput assay that can accurately measure clinically relevant concentrations of Tbeta15 in human urine. DESIGN AND METHODS: Sixteen antibodies were raised against recombinant Tbeta15 and/or peptide conjugates. One antibody, having stable characteristics over the wide range of pH and salt concentrations found in urine and minimal cross-reactivity with other beta thymosins, was used to develop a competitive enzyme-linked immunosorbent assay (ELISA). Urinary Tbeta15 concentration was determined for control groups; normal (N = 52), prostate intraepithelial neoplasia (PIN, N = 36), and CaP patients; untreated (N = 7) with subsequent biochemical failure, radiation therapy (N = 17) at risk of biochemical recurrence. RESULTS: The operating range of the competition ELISA fell between 2.5 and 625 ng/mL. Recoveries exceeded 75%, and the intra- and inter-assay coefficients of variability were 3.3% and 12.9%, respectively. No cross-reactivity with other urine proteins was observed. A stable Tbeta15 signal was recovered from urine specimens stored at -20 degrees C for up to 1 year. At a threshold of 40 (ng/dL)/mug protein/mg creatinine), the assay had a sensitivity of 58% and a specificity of 94%. Relative to the control groups, Tbeta15 levels were greater than this threshold in a significant fraction of the CaP patients (P < 0.001), including 5 of the 7 patients who later experienced PSA recurrence. CONCLUSIONS: We have established an ELISA that is able to detect Tbeta15 at clinically relevant concentrations in urine from patients with CaP. The assay will provide a tool for future clinical trials to validate urinary Tbeta15 as a predictive marker for recurrent CaP.

Use of thymosin beta15 as a urinary biomarker in human prostate cancer.

BACKGROUND: Additional prostate cancer (CaP) biomarkers are needed to increase the accuracy of diagnosis and to identify patients at risk of recurrence. In tissue-based assays, thymosin beta15 (Tbeta15) has been linked to an aggressive CaP phenotype and correlated with future tumor recurrence. We hypothesized that Tbeta15 may have clinical utility in biological fluids. METHODS: Tbeta15 was measured in urine from CaP patients; untreated (N = 61), prostatectomy (RP, N = 46), androgen deprivation therapy (ADT, N = 14) and control groups; normal (N = 52), genitourinary carcinoma (N = 15), non-malignant prostate disease (N = 81), and other urology (N = 73). We evaluated the utility of urinary Tbeta15 for CaP diagnosis, alone or in combination with prostate-specific antigen (PSA), and the relationship to CaP progression. RESULTS: A normal threshold of 40 (ng/dl)/(mug_protein/mg_creatinine) was defined using receiver operating characteristic analysis and marked the 19th centile for age-matched controls. The proportion of untreated CaP patients with urinary Tbeta15 above the threshold was significantly higher than normal and genitourinary disease controls (P < 0.001). RP caused urinary Tbeta15 to drop significantly (P = 0.005). Pre-surgery Tbeta15 concentrations greater than the normal threshold may confer greater risk of CaP recurrence. Relative to normal controls, patients receiving ADT for aggressive CaP were 12 times more likely to have elevated urinary Tbeta15 (P = 0.001, 95% CI = 2.8, 51.8). Combining PSA and Tbeta15 (PSA > 4, or PSA > 2.5, Tbeta15 > 40, or PSA = 2.5, Tbeta15 > 90) provided the same sensitivity as a 2.5 ng/ml PSA cutoff, but markedly improved diagnostic specificity. CONCLUSIONS: We report that Tbeta15 is a urinary biomarker for CaP and suggest that Tbeta15, in combination with PSA, can be used to improve both the sensitivity and specificity of CaP diagnosis.

Effect of environmental intervention on mouse allergen levels in homes of inner-city Boston children with asthma.

BACKGROUND: Recent studies have suggested that mouse allergen exposure and sensitization are common in urban children with asthma. The effectiveness of environmental intervention in reducing mouse allergen exposure has not been established. OBJECTIVE: To evaluate whether environmental intervention of mouse extermination and cleaning results in a reduction in mouse allergen levels. METHODS: Eighteen homes of children with positive mouse allergen skin test results and at least mild persistent asthma in urban Boston, MA, with evidence of mouse infestation or exposure were randomized in a 2:1 ratio (12 intervention and 6 control homes). The intervention homes received an integrated pest management intervention, which consisted of filling holes with copper mesh, vacuuming and cleaning, and using low-toxicity pesticides and traps. Dust samples were collected and analyzed for major mouse allergen (Mus m 1) and cockroach allergen (Bla g 1) at baseline and 1, 3, and 5 months after the intervention was started and compared with control homes. RESULTS: Mouse allergen levels were significantly decreased compared with control homes by the end of the intervention period at month 5 in the kitchen and bedroom (kitchen intervention, 78.8% reduction; control, 319% increase; P = .02; bedroom intervention, 77.3% reduction; control, 358% increase; P < .01; and living room intervention, 67.6% reduction; control, 32% reduction; P = .07). CONCLUSIONS: Mouse allergen levels were significantly reduced during a 5-month period using an integrated pest management intervention.

Gene therapy of prostate cancer with the soluble vascular endothelial growth factor receptor Flk1.

A variety of novel therapeutic approaches have emerged recently for the treatment of human cancers. We have coupled two of these therapeutic approaches, gene therapy and antiangiogenic therapy and tested them in two murine prostate cancer models Recombinant adenovirus encoding the ligand-binding ectodomain of the VEGF receptor 2 (Flk1) fused to an Fc domain was administered to SCID mice carrying orthotopic human LNCaP tumors as well as to transgenic (TRAMP) mice with spontaneous prostate tumors. Ad Flk1-Fc injection reduced tumor growth by 66% for orthotopic LNCaP tumors and by 42% for spontaneous tumors in TRAMP mice. Microvessel density in the primary tumors was reduced by 68% and 40% in the two models respectively. A decrease in microvessel density was also observed in lymphatic metastases in Ad Flk1-Fc-treated TRAMP mice and was correlated with a decrease in the frequency of regional metastases in the treated animals. Survival time was also extended in the Ad Flk1-Fc-treated TRAMP mice relative to the control-treated animals. Our results suggest that adenoviral delivery of soluble Flk1 receptor can reduce vascular density and prostate tumor growth and prolong survival time in orthotopically implanted tumors as well as in spontaneous prostate tumors in transgenic animals.