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Background. Evaluation of diagnostic assays and predictive performance of biomarkers based on the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC) are vital in diagnostic and targeted medicine. The partial area under the curve (pAUC) is an alternative metric focusing on a range of practical and clinical relevance of the diagnostic assay. In this article, we adopt and extend the min-max method to the estimation of the pAUC when multiple continuous scaled biomarkers are available and compare the performances of our proposed approach with existing approaches via simulations. Methods. We conducted extensive simulation studies to investigate the performance of different methods for the combination of biomarkers based on their abilities to produce the largest pAUC estimates. Data were generated from different multivariate distributions with equal and unequal variance-covariance matrices. Different shapes of the ROC curves, false positive fraction ranges, and sample size configurations were considered. We obtained the mean and standard deviation of the pAUC estimates through re-substitution and leave-one-pair-out cross-validation. Results. Our results demonstrate that the proposed method provides the largest pAUC estimates under the following three important practical scenarios: (1) multivariate normally distributed data for nondiseased and diseased participants have unequal variance-covariance matrices; or (2) the ROC curves generated from individual biomarker are relative close regardless of the latent normality distributional assumption; or (3) the ROC curves generated from individual biomarker have straight-line shapes. Conclusions. The proposed method is robust and investigators are encouraged to use this approach in the estimation of the pAUC for many practical scenarios. [ABSTRACT FROM AUTHOR]

Background. The iterative sure independence screening (ISIS) is a popular method in selecting important variables while maintaining most of the informative variables relevant to the outcome in high throughput data. However, it not only is computationally intensive but also may cause high false discovery rate (FDR). We propose to use the FDR as a screening method to reduce the high dimension to a lower dimension as well as controlling the FDR with three popular variable selection methods: LASSO, SCAD, and MCP. Method. The three methods with the proposed screenings were applied to prostate cancer data with presence of metastasis as the outcome. Results. Simulations showed that the three variable selection methods with the proposed screenings controlled the predefined FDR and produced high area under the receiver operating characteristic curve (AUROC) scores. In applying these methods to the prostate cancer example, LASSO and MCP selected 12 and 8 genes and produced AUROC scores of 0.746 and 0.764, respectively. Conclusions. We demonstrated that the variable selection methods with the sequential use of FDR and ISIS not only controlled the predefined FDR in the final models but also had relatively high AUROC scores. [ABSTRACT FROM AUTHOR]

Background Several prognostic models for overall survival (OS) have been developed and validated in men with metastatic castration-resistant prostate cancer (mCRPC) who receive first-line chemotherapy. We sought to develop and validate a prognostic model to predict OS in men who had progressed after first-line chemotherapy and were selected to receive second-line chemotherapy. Methods Data from a phase III trial in men with mCRPC who had developed progressive disease after first-line chemotherapy (TROPIC trial) were used. The TROPIC was randomly split into training (n = 507) and testing (n = 248) sets. Another dataset consisting of 488 men previously treated with docetaxel (SPARC trial) was used for external validation. Adaptive least absolute shrinkage and selection operator selected nine prognostic factors of OS. A prognostic score was computed from the regression coefficients. The model was assessed on the testing and validation sets for its predictive accuracy using the time-dependent area under the curve (tAUC). Results The nine prognostic variables in the final model were Eastern Cooperative Oncology Group performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of hormonal use, hemoglobin, prostate specific antigen, and alkaline phosphatase,The tAUCs for this model were 0.73 (95% confidence interval [CI] = 0.72 to 0.74) and 0.70 (95% CI = 0.68 to 0.72) for the testing and validation sets, respectively. Conclusions A prognostic model of OS in the postdocetaxel, second-line chemotherapy, mCRPC setting was developed and externally validated. This model incorporates novel prognostic factors and can be used to provide predicted probabilities for individual patients and to select patients to participate in clinical trials on the basis of their prognosis. Prospective validation is needed. [ABSTRACT FROM AUTHOR]

Objective The Brief Pain Inventory ( BPI) was designed to yield separate scores for pain intensity and interference. It has been proposed that the pain interference factor can be further broken down into unique factors of affective (e.g., mood) and activity (e.g., work) interference. The purpose of this analysis was to confirm this affective/activity interference dichotomy. Patients and Methods A retrospective confirmatory factor analysis was completed for a sample of 184 individuals diagnosed with castrate-resistant prostate cancer (age 40-86, mean = 65.46, 77% White non- Hispanic) who had been administered the BPI as part of Cancer and Leukemia Group B trial 9480. A one-factor model was compared against two-factor and three-factor models that were developed based on the design of the instrument. Results Root mean squared error of approximation (0.075), comparative fit index (0.971), and change in chi-square, given the corresponding change in degrees of freedom (13.33, P < 0.05) values for the three-factor model (i.e., pain intensity, activity interference, and affective interference), were statistically superior in comparison with the one- and two-factor models. This three-factor structure was found to be invariant across age, mean prostate-specific antigen, and hemoglobin levels. Conclusions These results confirm that the BPI can be used to quantify the degree to which pain separately interferes with affective and activity aspects of a patient's everyday life. These findings will provide clinical trialists, pharmaceutical sponsors, and regulators with confidence in the flexibility of the BPI as they consider the use of this instrument to assist with understanding the patient experience as it relates to treatment. [ABSTRACT FROM AUTHOR]

Background: Tamoxifen use has been associated with increased risk of thromboembolic events (TEs) in women with breast cancer and women at high risk for the disease. Factor V Leiden (FVL) is the most common inherited clotting factor mutation and also confers increased thrombosis risk. We investigated whether FVL was associated with TE risk in women with early-stage breast cancer who took adjuvant tamoxifen. [ABSTRACT FROM PUBLISHER]

We propose two innovations in statistical sampling for controls to enable better design of population-based case-control studies. The main innovation leads to novel solutions, without using weights, of the difficult and long-standing problem of selecting a control from persons in a household. Another advance concerns the drawing (at the outset) of the households them- selves and involves random-digit dialing with atypical use of list-assisted sampling. A common element throughout is that one capitalizes on flexibility (not broadly available in usual survey settings) in choosing the frame, which specifies the population of persons from which both cases and controls come. [ABSTRACT FROM AUTHOR]

Abstract: A graft-versus-tumor effect through nonmyeloablative allogeneic stem cell transplantation (N-SCT) in metastatic renal cell carcinoma (RCC) has been reported. An Intergroup phase II trial was undertaken to define further the feasibility, toxicity and efficacy of this approach in a multi-institutional setting, Patients with cytokine-refractory, metastatic RCC were treated with N-SCT. The conditioning regimen was fludarabine 30 mg·m−2 ·d−1 on day (d) −7 through d −3 and cyclophosphamide 60 mg·kg−1 ·d−1 on d −4 and d −3. Patients received 2-8 × 106 CD34+ cells/kg of granulocyte colony-stimulating factor mobilized stem cells from a 6/6 HLA-matched sibling donor. Immunosuppression after transplantation included tacrolimus and methotrexate. Twenty-two patients were enrolled at 14 institutions. Greater than 90% donor T-cell chimerism was observed in 17 of 19 evaluable patients (89%) by d +120. No objective response was observed. Acute graft-versus-host disease (GVHD) was observed in 11 patients (50%). Chronic GVHD was reported in 5 patients (23%). There was 1 patient death from liver failure secondary to chronic GVHD. Regimen-related mortality was 2 of 22 (9%; liver failure, sepsis). Median survival time was 5.5 months (95% confidence interval, 3.9-12.0 months) and the median time to progression was 3.0 months (95% confidence interval, 2.3-4.2 months). N-SCT for metastatic RCC is feasible in a multi-institutional setting. Adequate donor T-cell engraftment was achieved in most patients before disease progression. A graft-versus-tumor effect was not observed in this study despite acute and chronic GVHD, thus highlighting the need for further understanding of this approach. Allogeneic SCT remains investigational in RCC. [Copyright &y& Elsevier]

▪ BACKGROUND Even organizations with differing mammography recommendations agree that regular repeat screening is required for mortality reduction. However, most studies have focused on one-time screening rather than repeat adherence. We compare trends in beliefs and health-related behaviors among women screened and adherent to the National Cancer Institute's screening mammography recommendations (on schedule), those screened at least once and nonadherent (off schedule), and those never screened. METHODS Our data are from a baseline telephone interview conducted among 1287 female members of Blue Cross Blue Shield of North Carolina who were aged either 40 to 44 years or 50 to 54 years. ▪ RESULTS The 3 groups differed significantly on beliefs and health-related behaviors, with the off-schedule group almost consistently falling between the on-schedule and never screened groups. Off-schedule women were more likely than on-schedule women, but less likely than those never screened, to not have a clinical breast examination within 12 months, to be ambivalent about screening mammography, to be confused about screening guidelines, and to not be advised by a physician to get a mammogram in the past 2 years. Off-schedule women perceived their breast cancer risk as lower and were less likely to be up to date with other cancer screening. tests. ▪ CONCLUSIONS Our findings suggest that women who are off schedule are in need of mammography-promoting interventions, including recommendations from and discussion with their health care providers. Because they are more positive and knowledgeable about mammography than women who have never been screened, they may benefit from brief interventions from health care providers that highlight the importance of repeat screening. [ABSTRACT FROM AUTHOR]

Background: Herein, we report results from a genome-wide study conducted to identify protein quantitative trait loci (pQTL) for circulating angiogenic and inflammatory protein markers in patients with metastatic colorectal cancer (mCRC). The study was conducted using genotype, protein marker, and baseline clinical and demographic data from CALGB/SWOG 80405 (Alliance), a randomized phase III study designed to assess outcomes of adding VEGF or EGFR inhibitors to systemic chemotherapy in mCRC patients. Germline DNA derived from blood was genotyped on whole-genome array platforms. The abundance of protein markers was quantified using a multiplex enzyme-linked immunosorbent assay from plasma derived from peripheral venous blood collected at baseline. A robust rank-based method was used to assess the statistical significance of each variant and protein pair against a strict genome-wide level. A given pQTL was tested for validation in two external datasets of prostate (CALGB 90401) and pancreatic cancer (CALGB 80303) patients. Bioinformatics analyses were conducted to further establish biological bases for these findings. Results: The final analysis was carried out based on data from 540,021 common typed genetic variants and 23 protein markers from 869 genetically estimated European patients with mCRC. Correcting for multiple testing, the analysis discovered a novel cis-pQTL in LINC02869, a long non-coding RNA gene, for circulating TGF-β2 levels (rs11118119; AAF = 0.11; P-value < 1.4e-14). This finding was validated in a cohort of 538 prostate cancer patients from CALGB 90401 (AAF = 0.10, P-value < 3.3e-25). The analysis also validated a cis-pQTL we had previously reported for VEGF-A in advanced pancreatic cancer, and additionally identified trans-pQTLs for VEGF-R3, and cis-pQTLs for CD73. Conclusions: This study has provided evidence of a novel cis germline genetic variant that regulates circulating TGF-β2 levels in plasma of patients with advanced mCRC and prostate cancer. Moreover, the validation of previously identified pQTLs for VEGF-A, CD73, and VEGF-R3, potentiates the validity of these associations. [ABSTRACT FROM AUTHOR]

A prognostic model that predicts overall survival (OS) for metastatic urothelial cancer (MetUC) patients treated with cisplatin-based chemotherapy was developed, validated, and compared with a commonly used Memorial Sloan-Kettering Cancer Center (MSKCC) risk-score model. Data from 7 protocols that enrolled 308 patients with MetUC were pooled. An external multi-institutional dataset was used to validate the model. The primary measurement of predictive discrimination was Harrell’s c-index, computed with 95% confidence interval (CI). The final model included four pretreatment variables to predict OS: visceral metastases, albumin, performance status, and hemoglobin. The Harrell’s c-index was 0.67 for the four-variable model and 0.64 for the MSKCC risk-score model, with a prediction improvement for OS (the U statistic and its standard deviation were used to calculate the two-sided P = .002). In the validation cohort, the c-indices for the four-variable and the MSKCC risk-score models were 0.63 (95% CI = 0.56 to 0.69) and 0.58 (95% CI = 0.52 to 0.65), respectively, with superiority of the four-variable model compared with the MSKCC risk-score model for OS (the U statistic and its standard deviation were used to calculate the two-sided P = .02). [ABSTRACT FROM AUTHOR]

Background Multiple lines of evidence indicate that aspirin has an antineoplastic effect in the large bowel. Randomized clinical trials have been conducted to evaluate the effectiveness of aspirin for reducing the risk of colorectal adenomas. A meta-analysis of these trials will provide more precise estimates of the aspirin effect, both overall and in subgroups. Methods We combined data from all randomized double-blind placebo-controlled trials that evaluated aspirin for the prevention of colorectal adenomas. We used random-effects meta-analysis to estimate risk ratios and 95% confidence intervals (Cls) for the effect of aspirin on the occurrence of adenomas and of advanced lesions (ie, tubulovillous adenomas, villous adenomas, adenomas ⩾1 cm in diameter, adenomas with high-grade dysplasia, or invasive cancer). All statistical tests were two-sided. Results We identified four clinical trials with 2967 randomly assigned participants. Each trial evaluated aspirin for the secondary prevention of colorectal adenomas. Doses of aspirin tested ranged from 81 to 325 mg/d. The average age of participants at baseline was 58 years, and 60% were male. Median follow-up was 33 months. A total of 2698 participants underwent colonoscopic follow-up and were included in the analysis of adenoma occurrence and advanced-lesion occurrence after randomization. Among these participants, adenomas were found in 424 (37%) of the 1156 participants allocated to placebo and in 507 (33%) of the 1542 participants allocated to any dose of aspirin. Advanced lesions were found in 12% of participants in the placebo group and in 9% of participants allocated to any dose of aspirin. The pooled risk ratio of any adenoma for any dose of aspirin vs placebo was 0.83 (95% Cl = 0.72 to 0.96). This corresponded to an absolute risk reduction of 6.7% (95% Cl = 3.2% to 10.2%). For any advanced lesion, the pooled risk ratio was 0.72 (95% Cl = 0.57 to 0.90). We found no statistically significant effect modification for any of the baseline factors studied. Conclusion Aspirin is effective for the prevention of colorectal adenomas in individuals with a history of these lesions. [ABSTRACT FROM AUTHOR]

The article discusses a tailored intervention used to aid decision-making about hormone replacement therapy. Individually customized decision aids that include only the most important information could make it easier for women to consider the risks and benefits of hormone replacement therapy. The article describes the effect of customized decision aid on women's accuracy of perceived risk for breast cancer, confidence to decide about hormone therapy, and satisfaction with the decision. As a result, customized decision aid improved the accuracy of women's perceived breast cancer risk confidence to decide about hormone therapy, and satisfaction with the decision.

Background: Radium-223 is a targeted alpha-particle therapy that improves survival in men with metastatic castration resistant prostate cancer (mCRPC), particularly in men with elevated serum levels of bone alkaline phosphatase (B-ALP). We hypothesized that osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment. Methods: We conducted a pharmacodynamic study (NCT02204943) of radium-223 in men with bone mCRPC. Prior to and three and six months after radium-223 treatment initiation, we collected CTCs and metastatic biopsies for phenotypic characterization and CTC genomic analysis. The primary objective was to describe the impact of radium-223 on the prevalence of CTC B-ALP over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. We validated genomic findings in a separate independent study of men with bone metastatic mCRPC (n = 45) and publicly accessible data of metastatic CRPC tissues. Results: We enrolled 20 men with symptomatic bone predominant mCRPC and treated with radium-223. We observed greater radium-223 radioactivity levels in metastatic bone tumor containing biopsies compared with adjacent normal bone. We found evidence of persistent Cellsearch CTCs and B-ALP (+) CTCs in the majority of men over time during radium-223 therapy despite serum B-ALP normalization. We identified genomic gains in osteoblast mimicry genes including gains of ALPL, osteopontin, SPARC, OB-cadherin and loss of RUNX2, and validated genomic alterations or increased expression at the DNA and RNA level in an independent cohort of 45 men with bone-metastatic CRPC and in 150 metastatic biopsies from men with mCRPC. Conclusions: Osteomimicry may contribute in part to the uptake of radium-223 within bone metastases and may thereby enhance the therapeutic benefit of this bone targeting radiotherapy. [ABSTRACT FROM AUTHOR]

New systemic therapies have prolonged the lives of men with metastatic castration-resistant prostate cancer (mCRPC). Use of these therapies in the adjuvant setting when the disease may be micrometastatic and potentially more sensitive to therapies may decrease mortality from prostate cancer. However, the conduct of adjuvant prostate cancer clinical trials is hampered by taking longer than a decade to reach the meaningful endpoint of overall survival (OS) and the fact that many men never die from prostate cancer, even if they relapse. A validated intermediate clinical endpoint (ICE) in prostate cancer that is a robust surrogate for OS has yet to be defined. This paper details the plans, process, and progress of the international Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group to pool individual patient data from all available clinical trials of radiation or prostatectomy for localized disease and conduct the requisite analyses to determine whether an ICE can be identified. This paper further details the challenges and the a priori statistical analytical plans and strategies to define an ICE for adjuvant prostate cancer clinical trials. In addition, a brief review of the health economic analyses to model the benefits to patients, society and manufacturers is detailed. If successful, the results from this work will provide a robust surrogate for OS that will expedite the design and conduct of future adjuvant therapy trials using new agents that have proven activity in mCRPC. Moreover, it will also define the health economic benefits to patients and societies. [ABSTRACT FROM AUTHOR]

Abstract: Detailed Spanish records of mercury use and silver production during the colonial period in Potosí, Bolivia were evaluated to estimate atmospheric emissions of mercury from silver smelting. Mercury was used in the silver production process in Potosí and nearly 32,000 metric tons of mercury were released to the environment. AERMOD was used in combination with the estimated emissions to approximate historical air concentrations of mercury from colonial mining operations during 1715, a year of relatively low silver production. Source characteristics were selected from archival documents, colonial maps and images of silver smelters in Potosí and a base case of input parameters was selected. Input parameters were varied to understand the sensitivity of the model to each parameter. Modeled maximum 1-h concentrations were most sensitive to stack height and diameter, whereas an index of community exposure was relatively insensitive to uncertainty in input parameters. Modeled 1-h and long-term concentrations were compared to inhalation reference values for elemental mercury vapor. Estimated 1-h maximum concentrations within 500 m of the silver smelters consistently exceeded present-day occupational inhalation reference values. Additionally, the entire community was estimated to have been exposed to levels of mercury vapor that exceed present-day acute inhalation reference values for the general public. Estimated long-term maximum concentrations of mercury were predicted to substantially exceed the EPA Reference Concentration for areas within 600 m of the silver smelters. A concentration gradient predicted by AERMOD was used to select soil sampling locations along transects in Potosí. Total mercury in soils ranged from 0.105 to 155 mg kg−1, among the highest levels reported for surface soils in the scientific literature. The correlation between estimated air concentrations and measured soil concentrations will guide future research to determine the extent to which the current community of Potosí and vicinity is at risk of adverse health effects from historical mercury contamination. [Copyright &y& Elsevier]

This is the first study of adobe brick contamination anywhere in the world. Huancavelica, Peru is the site of historic cinnabar refining and one of the most mercury (Hg) contaminated urban areas in the world. Over 80% of homes in Huancavelica are constructed with adobe bricks made from Hg contaminated soil. In this study we measured total Hg concentrations in adobe brick, dirt floor, surface dust, and air samples from the interior of 60 adobe brick houses located in four neighborhoods. Concentrations of total Hg in adobe bricks, dirt floors, and surface dust ranged from 8.00 to 1070 µg/g, 3.06 to 926 µg/g, and 0.02 to 9.69 µg/wipe, respectively, with statistically significant differences between the four neighborhoods. Concentrations of Hg in adobe brick and dirt floor samples in Huancavelica were orders of magnitude higher than in Ayacucho, a non-mining town in Peru. A strong correlation exists between total Hg concentrations in adobe bricks and dirt floors which confirms that adobe bricks were being made on-site and not purchased from an off-site source. A strong correlation between surface dust and adobe bricks and dirt floors indicates that walls and floors serve as indoor sources of Hg contamination. Elemental Hg vapor concentrations were below detection (<0.5 µg/m3) in most homes; however in homes with detectable levels, concentrations up to 5.1 µg/m3 were observed. No statistically significant differences in Hg vapor measurements were observed between neighborhoods. This study demonstrates that building materials used widely in developing communities, such as adobe bricks, may be a substantial source of residential Hg exposure in silver or gold refining communities where Hg is produced or used for amalgamation in artisanal gold production. [ABSTRACT FROM AUTHOR]

A concurrent multicenter, randomized Phase II trial employing a recombinant poxviral vaccine provided evidence of enhanced median overall survival (OS) (p = 0.0061) in patients with metastatic castrate-resistant prostate cancer (mCRPC). The study reported here employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. Thirty-two patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three costimulatory molecules. Patients received boosters with recombinant fowlpox containing the same four transgenes. Twelve of 32 patients showed declines in serum PSA post-vaccination and 2/12 showed decreases in index lesions. Median OS was 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). Patients with greater PSA-specific T-cell responses showed a trend (p = 0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF versus no GM-CSF. Patients with a Halabi predicted survival of <18 months (median predicted 12.3 months) had an actual median OS of 14.6 months, while those with a Halabi predicted survival of ≥18 months (median predicted survival 20.9 months) will meet or exceed 37.3 months, with 12/15 patients living longer than predicted (p = 0.035). Treg suppressive function was shown to decrease following vaccine in patients surviving longer than predicted, and increase in patients surviving less than predicted. This hypothesis-generating study provides evidence that patients with more indolent mCRPC (Halabi predicted survival ≥18 months) may best benefit from vaccine therapy. [ABSTRACT FROM AUTHOR]