Joint confidence region estimation on predictive values.

For evaluating diagnostic accuracy of inherently continuous diagnostic tests/biomarkers, sensitivity and specificity are well-known measures both of which depend on a diagnostic cut-off, which is usually estimated. Sensitivity (specificity) is the conditional probability of testing positive (negative) given the true disease status. However, a more relevant question is "what is the probability of having (not having) a disease if a test is positive (negative)?". Such post-test probabilities are denoted as positive predictive value (PPV) and negative predictive value (NPV). The PPV and NPV at the same estimated cut-off are correlated, hence it is desirable to make the joint inference on PPV and NPV to account for such correlation. Existing inference methods for PPV and NPV focus on the individual confidence intervals and they were developed under binomial distribution assuming binary instead of continuous test results. Several approaches are proposed to estimate the joint confidence region as well as the individual confidence intervals of PPV and NPV. Simulation results indicate the proposed approaches perform well with satisfactory coverage probabilities for normal and non-normal data and, additionally, outperform existing methods with improved coverage as well as narrower confidence intervals for PPV and NPV. The Alzheimer's Disease Neuroimaging Initiative (ADNI) data set is used to illustrate the proposed approaches and compare them with the existing methods.

Improved Outcomes of Enhanced Recovery After Surgery (ERAS) Protocol for Radical Cystectomy with Addition of a Multidisciplinary Care Process in a US Comprehensive Cancer Care Center.

INTRODUCTION: Although enhanced recovery after surgery (ERAS) components include both anesthesia and surgical care processes, it is unclear whether a multidisciplinary approach to implementing ERAS care processes improves clinical outcomes. The addition of multidisciplinary care with anesthesiology-related components to an existing ERAS protocol for radical cystectomy at a US comprehensive cancer center provided an opportunity to compare short- and long-term outcomes. METHODS: We retrospectively compared the outcomes of 116 consecutive patients who underwent cystectomy after implementation of a multidisciplinary ERAS protocol with those of a historical control group of 143 consecutive patients who had been treated with a surgical ERAS protocol. Length of stay, return of bowel function, rate of blood transfusion, nausea, pain, and readmission rates were examined. RESULTS: Implementation of a multidisciplinary ERAS protocol was associated with better postsurgical symptom control, as indicated by lower rates of patient-reported nausea (P < .05). Multivariate Poisson regression analysis showed a decrease in estimated intraoperative transfusions (P ≤ .001) after adjusting for the effects of potential confounding variables. There were no statistically significant differences noted in length of stay, return of bowel function, 30- and 90-day complications, or readmissions. CONCLUSION: This is the first study to investigate the effects of adding anesthesia ERAS components to an existing surgical ERAS protocol for radical cystectomy. We found that with the addition of anesthesia-related interventions, there was a decrease in transfusions and nausea.

Multi-Dimensional Flow Cytometry Analyses Reveal a Dichotomous Role for Nitric Oxide in Melanoma Patients Receiving Immunotherapy.

Phenotyping of immune cell subsets in clinical trials is limited to well-defined phenotypes, due to technological limitations of reporting flow cytometry multi-dimensional phenotyping data. We developed a multi-dimensional phenotyping analysis tool and applied it to detect nitric oxide (NO) levels in peripheral blood immune cells before and after adjuvant ipilimumab co-administration with a peptide vaccine in melanoma patients. We analyzed inhibitory and stimulatory markers for immune cell phenotypes that were felt to be important in the NO analysis. The pipeline allows visualization of immune cell phenotypes without knowledge of clustering techniques and to categorize cells by association with relapse-free survival (RFS). Using this analysis, we uncovered the potential for a dichotomous role of NO as a pro- and anti-melanoma factor. NO was found in subsets of immune-suppressor cells associated with shorter-term (≤ 1 year) RFS, whereas NO was also present in immune-stimulatory effector cells obtained from patients with significant longer-term (> 1 year) RFS. These studies provide insights into the cell-specific immunomodulatory role of NO. The methods presented herein can be applied to monitor the pro- and anti-tumor effects of a variety of immune-based therapeutics in cancer patients. Clinical Trial Registration Number: NCT00084656 (https://clinicaltrials.gov/ct2/show/NCT00084656).

Impact of PI3K-AKT-mTOR Signaling Pathway Up-regulation on Prognosis of Penile Squamous-Cell Carcinoma: Results From a Tissue Microarray Study and Review of the Literature.

PURPOSE: To assess the prognostic value of PI3K-AKT-mTOR signaling pathway up-regulation in a contemporary cohort of penile squamous-cell carcinoma (PSCC) patients. PATIENTS AND METHODS: Tissue microarrays were constructed for 57 patients with invasive PSCC treated at our institution between 2000 and 2013. Immunohistochemical staining was performed for PTEN, AKT, and S6. Human papillomavirus (HPV) in-situ hybridization for high-risk subtypes was also performed. Biomarker expression was evaluated by a semiquantitative H score. Overall survival, disease-specific survival and recurrence-free survival stratified by biomarker expression (low vs. high) were estimated by the Kaplan-Meier method. Multivariable Cox regression models were used to determine predictors of mortality and recurrence. RESULTS: HPV in-situ hybridization was positive in 23 patients (40%). PTEN was down-regulated in 43 patients (75%), while phosphorylated-AKT (p-AKT) and phosphorylated-S6 (p-S6) were up-regulated in 27 (47%) and 12 patients (21%), respectively. In multivariable Cox regression models, patients with low expression of p-AKT had an increased risk of recurrence (hazard ratio [HR] = 3.95; 95% confidence interval [CI], 1.47-10.59; P = .02), while those with low expression of p-S6 had an increased risk of overall mortality (HR = 6.15; 95% CI, 1.55-24.36; P = .01). HPV status was an independent predictor of overall survival (HR = 6.99; 95% CI, 2.42-20.16; P < .001) and disease-specific survival (HR = 6.74; 95% CI, 2.02-22.48; P = .002). CONCLUSION: PI3K-AKT-mTOR signaling pathway up-regulation and HPV coinfection in PSCC are associated with favorable disease. mTOR pathway biomarkers along with HPV status may represent novel prognosticators for risk stratification of PSCC patients and may help guide treatment decisions and follow-up strategies. These findings require further investigation.

Twitter Conversations and English News Media Reports on Poliomyelitis in Five Different Countries, January 2014 to April 2015.

INTRODUCTION: Twitter and media coverage on poliomyelitis help maintain global support for its eradication. OBJECTIVE: To test our hypothesis that themes of polio-related tweets and media articles would differ by location of interest (hashtag of country name mentioned in the tweet; country name mentioned in media articles) but would be similar to each other (tweets and media articles) for each location of interest. METHODS: We retrospectively examined a 40% random sample of Twitter data containing the hashtag #polio from January 1, 2014, to April 30, 2015 (N = 79,333), from which we extracted 5 subcorpora each with a co-occurring hashtag #India (n = 5027), #Iraq (n = 1238), #Nigeria (n = 1364), #Pakistan (n = 11,427), and #Syria (n = 2952). We also retrieved and categorized 73 polio-related English-language news stories from within the same timeframe. We assessed the association between polio-related English news themes and the Twitter content. Descriptive analyses and unsupervised machine learning (latent Dirichlet allocation modeling) were conducted on the 5 Twitter subcorpora. RESULTS: The results of the latent Dirichlet allocation modeling on the specific subcorpora with country co-occurring hashtags showed significant differences between the 5 countries in terms of content. English mass media content focused largely on violence/conflicts and cases of polio, whereas social media focused on eradication and vaccination efforts along with celebrations. DISCUSSION: Contrary to our hypothesis, our evidence suggests Twitter content differs significantly from English mass media content. Evidence from our study helps inform media monitoring and communications surveillance during global public health crises, such as infectious disease outbreaks, as well as reactions to health promotion campaigns.

Dabrafenib inhibits the growth of BRAF-WT cancers through CDK16 and NEK9 inhibition.

Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF-mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS-mutant and KRAS-mutant cancer cell lines than vemurafenib. Using mass spectrometry-based chemical proteomics, we identified NEK9 and CDK16 as unique targets of dabrafenib. Both NEK9 and CDK16 were highly expressed in specimens of advanced melanoma, with high expression of both proteins correlating with a worse overall survival. A role for NEK9 in the growth of NRAS- and KRAS-mutant cell lines was suggested by siRNA studies in which silencing was associated with decreased proliferation, cell cycle arrest associated with increased p21 expression, inhibition of phospho-CHK1, decreased CDK4 expression, and the initiation of a senescence response. Inhibition of CDK4 but not CHK1 recapitulated the effects of NEK9 silencing, indicating this to be the likely mechanism of growth inhibition. We next turned our attention to CDK16 and found that its knockdown inhibited the phosphorylation of the Rb protein at S780 and increased expression of p27. Both of these effects were phenocopied in NRAS- and KRAS-mutant cancer cells by dabrafenib, but not vemurafenib. Combined silencing of NEK9 and CDK16 was associated with enhanced inhibition of melanoma cell proliferation. In summary, we have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations.

Adjuvant pelvic radiation is associated with improved survival and decreased disease recurrence in pelvic node-positive penile cancer after lymph node dissection: A multi-institutional study.

PURPOSE: Few studies have examined the role of radiation therapy in advanced penile squamous cell carcinoma. We sought to evaluate the association of adjuvant pelvic radiation with survival and recurrence for patients with penile cancer and positive pelvic lymph nodes (PLNs) after lymph node dissection. MATERIALS AND METHODS: Data were collected retrospectively across 4 international centers of patients with penile squamous cell carcinoma undergoing lymph node dissections from 1980 to 2013. Further, 92 patients with available adjuvant pelvic radiation status and positive PLNs were analyzed. Disease-specific survival (DSS) and recurrence were analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards model. RESULTS: 43% (n = 40) of patients received adjuvant pelvic radiation after a positive PLN dissection. Median follow-up was 9.3 months (interquartile range: 5.2-19.8). Patients receiving adjuvant pelvic radiation had a median DSS of 14.4 months vs. 8 months in the nonradiation group, respectively (P = 0.023). Patients without adjuvant pelvic radiation were associated with worse overall survival (hazard ratio [HR] = 1.7; 95% CI: 1.01-2.92; P = 0.04) and DSS (HR = 1.9; 95% CI: 1.09-3.36; P = 0.02) on multivariable analysis. Median time to recurrence was 7.7 months vs. 5.3 months in the radiation and nonradiation arm, respectively (P = 0.042). Patients without adjuvant pelvic radiation was also independently associated with higher overall recurrence on multivariable analysis (HR = 1.8; 95% CI: 1.06-3.12; P = 0.03). CONCLUSIONS: Adjuvant pelvic radiation is associated with improved survival and decreased recurrence in this population of patients with penile cancer with positive PLNs.