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The Pneumonia Score Index (PSI) was developed to estimate the risk of dying within 30 days of presentation for community-acquired pneumonia patients and is a strong predictor of 30-day mortality after COVID-19. However, three of its required 20 variables (skilled nursing home, altered mental status and pleural effusion) are not discreetly available in the electronic medical record (EMR), resulting in manual chart review for these 3 factors. The goal of this study is to compare a simplified 17-factor version (PSI-17) to the original (denoted PSI-20) in terms of prediction of 30-day mortality in COVID-19. In this retrospective cohort study, the hospitalized patients with confirmed SARS-CoV-2 infection between 2/28/20-5/28/20 were identified to compare the predictive performance between PSI-17 and PSI-20. Correlation was assessed between PSI-17 and PSI-20, and logistic regressions were performed for 30-day mortality. The predictive abilities were compared by discrimination, calibration, and overall performance. Based on 1,138 COVID-19 patients, the correlation between PSI-17 and PSI-20 was 0.95. Univariate logistic regression showed that PSI-17 had performance similar to PSI-20, based on AUC, ICI and Brier Score. After adjusting for confounding variables by multivariable logistic regression, PSI-17 and PSI-20 had AUCs (95% CI) of 0.85 (0.83-0.88) and 0.86 (0.84-0.89), respectively, indicating no significant difference in AUC at significance level of 0.05. PSI-17 and PSI-20 are equally effective predictors of 30-day mortality in terms of several performance metrics. PSI-17 can be obtained without the manual chart review, which allows for automated risk calculations within an EMR. PSI-17 can be easily obtained and may be a comparable alternative to PSI-20.

Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103 + CD39 + tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103 + CD39 + CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103 + CD39 + CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103 + CD39 + CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that will help define mechanisms of existing immunotherapy treatments, and may lead to future adoptive T-cell cancer therapies. Identifying and enumerating tumor-specific CD8 T cells are important for assessing cancer prognosis and therapy efficacy. Here the authors show that CD39 and CD103 mark a subset of tumor-infiltrating CD8 T cells that are tumor-reactive and exhibit characteristics of exhausted or tissue-resident memory T cells.

BackgroundHigh-volume centers (HVC), academic centers (AC), and longer travel distances (TD) have been associated with improved outcomes for patients undergoing surgery for pancreatic adenocarcinoma (PAC). Effects of mediating variables on these associations remain undefined. The purpose of this study is to examine the direct effects of hospital volume, facility type, and travel distance on overall survival (OS) in patients undergoing surgery for PAC and characterize the indirect effects of patient-, disease-, and treatment-related mediating variables. Patients and MethodsUsing the National Cancer Database, patients with non-metastatic PAC who underwent resection were stratified by annual hospital volume (< 11, 11–19, and ≥ 20 cases/year), facility type (AC versus non-AC), and TD (≥ 40 versus < 40 miles). Associations with survival were evaluated using multiple regression models. Effects of mediating variables were assessed using mediation analysis. ResultsIn total, 19,636 patients were included. Treatment at HVC or AC was associated with lower risk of death [hazard ratio (HR) 0.90, confidence interval (CI) 0.88–0.92; HR 0.89, CI 0.86–0.91, respectively]. TD did not impact OS. Patient-, disease-, and treatment-related variables explained 25.5% and 41.8% of the survival benefit attained from treatment at HVC and AC, reducing the survival benefit directly attributable to each variable to 4.9% and 6.4%, respectively.ConclusionsTreatment of PAC at HVC and AC was associated with improved OS, but the magnitude of this benefit was less when mediating variables were considered. From a healthcare utilization and cost–resource perspective, further research is needed to identify patients who would benefit most from selective referral to HVC or AC.

Background In 2016, the National Comprehensive Cancer Network included neoadjuvant chemotherapy as a treatment option for patients with clinical T4b colon cancer. However, there is little published data on the survival impact of neoadjuvant chemotherapy for locally advanced colon cancer. Methods Adult patients with non-metastatic clinically staged T3 or T4 colon cancer who underwent surgical resection were identified from the National Cancer Data Base between 2006 and 2014. Treatment was categorized as neoadjuvant chemotherapy followed by surgery and surgery followed by adjuvant chemotherapy. Overall survival was compared between the two groups using propensity score matching. Results Of 27,575 patients that met inclusion criteria, 26,654 (97%) were treated with surgery followed by adjuvant chemotherapy and 921 (3%) received neoadjuvant chemotherapy followed by surgery. After propensity score matching, patients with T4b colon cancer treated with neoadjuvant chemotherapy had a 23% lower risk of death at 3 years compared to patients that had adjuvant chemotherapy (HR 0.77, 95% CI 0.60–0.98; p  = 0.04). However, neoadjuvant chemotherapy did not demonstrate a similar significant benefit for patients with T3 and T4a disease. Conclusions Patients with clinical T4b colon cancer treated with neoadjuvant chemotherapy may have an improved survival compared to those who receive adjuvant chemotherapy. Further prospective investigation is warranted.

Background The H&E stromal tumor-infiltrating lymphocyte (sTIL) score and programmed death ligand 1 (PD-L1) SP142 immunohistochemistry assay are prognostic and predictive in early-stage breast cancer, but are operator-dependent and may have insufficient precision to characterize dynamic changes in sTILs/PD-L1 in the context of clinical research. We illustrate how multiplex immunofluorescence (mIF) combined with statistical modeling can be used to precisely estimate dynamic changes in sTIL score, PD-L1 expression, and other immune variables from a single paraffin-embedded slide, thus enabling comprehensive characterization of activity of novel immunotherapy agents. Methods Serial tissue was obtained from a recent clinical trial evaluating loco-regional cytokine delivery as a strategy to promote immune cell infiltration and activation in breast tumors. Pre-treatment biopsies and post-treatment tumor resections were analyzed by mIF (PerkinElmer Vectra) using an antibody panel that characterized tumor cells (cytokeratin-positive), immune cells (CD3, CD8, CD163, FoxP3), and PD-L1 expression. mIF estimates of sTIL score and PD-L1 expression were compared to the H&E/SP142 clinical assays. Hierarchical linear modeling was utilized to compare pre- and post-treatment immune cell expression, account for correlation of time-dependent measurement, variation across high-powered magnification views within each subject, and variation between subjects. Simulation methods (Monte Carlo, bootstrapping) were used to evaluate the impact of model and tissue sample size on statistical power. Results mIF estimates of sTIL and PD-L1 expression were strongly correlated with their respective clinical assays ( p  < .001). Hierarchical linear modeling resulted in more precise estimates of treatment-related increases in sTIL, PD-L1, and other metrics such as CD8+ tumor nest infiltration. Statistical precision was dependent on adequate tissue sampling, with at least 15 high-powered fields recommended per specimen. Compared to conventional t-testing of means, hierarchical linear modeling was associated with substantial reductions in enrollment size required ( n  = 25➔ n  = 13) to detect the observed increases in sTIL/PD-L1. Conclusion mIF is useful for quantifying treatment-related dynamic changes in sTILs/PD-L1 and is concordant with clinical assays, but with greater precision. Hierarchical linear modeling can mitigate the effects of intratumoral heterogeneity on immune cell count estimations, allowing for more efficient detection of treatment-related pharmocodynamic effects in the context of clinical trials. Trial registration NCT02950259 .

ABSTRACT Background Despite the favorable prognosis of AJCC stage I/II melanoma patients, up to 20%–30% will develop metastases. Our objective is to predict long‐term risk (probability) of recurrence in early‐stage melanoma patients. Methods A Risk Score to predict long‐term recurrence was developed using Cox regression based on 2668 patients. Five clinicopathological risk factors were included. The association of the Risk Score with the risk of recurrence was evaluated using parametric models (exponential, Weibull, and Gompertz models) and compared to the Cox model using the Akaike information criterion. The discrimination of the model was measured by time‐dependent ROC analyses. A calibration curve was used to evaluate the agreement between predicted and observed recurrence probabilities. Results The bootstrap adjusted C‐index was 0.76 (95% CI, 0.74–0.79) overall and 0.87 (0.83–0.90) and 0.82 (0.78–0.85) at one and two years, respectively, and then remained above 0.70 up to 20 years. The Gompertz model for prediction of survival from the Risk Score showed the best performance and displayed good agreement with the Kaplan–Meier curves. The calibration curve of the Gompertz model showed a good agreement between predicted and observed 2‐, 5‐, and 10‐year risk of recurrence. Population‐level analysis demonstrated a significant association of Risk Score with risk of recurrence, with 10‐year risks of recurrence of 4.5%, 13.0%, and 33.7% in the first, second, and third tertiles, respectively. Conclusion We developed a Risk Score to predict long‐term risk of recurrence for early‐stage melanoma patients. A Gompertz survival model fit to the Risk Score allows for individualized prediction of time‐dependent recurrence risk. Up to 20%–30% of stage I/II melanoma patients will ultimately develop metastases. In this study, we developed a clinical Risk Score model to predict long‐term risk of recurrence.

BackgroundMolecular testing on surgical specimens predicts disease recurrence and benefit of adjuvant chemotherapy in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) early-stage breast cancer (EBC). Testing on core biopsies has become common practice despite limited evidence of concordance between core/surgical samples. In this study, we compared the gene expression of the 21 genes and the recurrence score (RS) between paired core/surgical specimens.MethodsEighty patients with HR+/HER2− EBC were evaluated from two publicly available gene expression datasets (GSE73235, GSE76728) with paired core/surgical specimens without neoadjuvant systemic therapy. The expression of the 21 genes was compared in paired samples. A microarray-based RS was calculated and a value ≥ 26 was defined as high-RS. The concordance rate and kappa statistic were used to evaluate the agreement between the RS of paired samples.ResultsOverall, there was no significant difference and a high correlation in the gene expression levels of the 21 genes between paired samples. However, CD68 and RPLP0 in GSE73235, AURKA, BAG1, and TFRC in GSE76728, and MYLBL2 and ACTB in both datasets exhibited weak to moderate correlation (r < 0.5). There was a high correlation of the microarray-based RS between paired samples in GSE76728 (r = 0.91, 95% confidence interval [CI] 0.81–0.96) and GSE73235 (r = 0.82, 95% CI 0.71–0.89). There were no changes in RS category in GSE76728, whereas 82% of patients remained in the same RS category in GSE73235 (κ = 0.64).ConclusionsGene expression levels of the 21-gene RS showed a high correlation between paired specimens. Potential sampling and biological variability on a set of genes need to be considered to better estimate the RS from core needle biopsy.

Practice recommendations for mammography screening were issued by the U.S. Preventive Services Task Force in 2009 and expansion of insurance coverage was provided under the Patient Protection and Affordable Care Act soon thereafter, yet the influence of these changes on screening practices in the United States is not known. To determine changes in mammography screening and their associations with new practice recommendations and the Affordable Care Act, we examined patient-level data from 249,803 screening mammograms from January 1, 2008 through December 31, 2012 in a large community-based health system in the northwestern United States. Associations were determined by an intervention analysis of time-series data method. Among women screened, 64% were age 50-74 years; 84% self-identified as white race; 62% had commercial insurance; and 70% were seen in facilities located in metropolitan areas. Practice recommendations were associated with decreased screening volumes among women age <40 (-37.4 mammograms/month; -39.4% change; P<0.001), 40-49 (-106.0 mammograms/month; -11.2% change; P<0.001), and ≥75 (-54.7 mammograms/month; -10.0% change; P<0.001), but not women age 50-74. Implementation of the Affordable Care Act was associated with increased screening among women age 50-74 (+184.3 mammograms/month; +7.2% change; P=0.001), but not women <40 or ≥75; increases for age 40-49 were of borderline statistical significance (+56.9 mammograms/month; +6% change; P=0.06). Practice recommendations were also associated with decreased screening for women with commercial insurance, while the Affordable Care Act was associated with increased screening for women with Medicare, Medicaid, or other noncommercial sources of payment. Mammography screening volumes in a large community health system decreased among women age <50 and ≥75 in association with new U.S. Preventive Services Task Force practice recommendations, while insurance coverage changes under the Affordable Care Act were associated with increased screening volumes among women age 50-74.

BackgroundNeoadjuvant chemotherapy (NAC) is increasingly utilized to optimize survival in proximal pancreatic adenocarcinoma. However, few studies have explored the impact of NAC in distal pancreas cancer.MethodsPatients with resectable pancreatic adenocarcinoma of the body or tail treated with either upfront pancreatectomy or NAC followed by surgery were identified in the 2006–2014 National Cancer Database. Trends in utilization, predictors of use, and impact of NAC on overall survival were determined.ResultsOf 1485 patients, 176 (11.9%) received NAC. Use of NAC increased from 9.3% in 2006 to 16.9% in 2013 [odds ratio 1.14; 95% confidence interval (CI) 1.05–1.24; p = 0.001]. NAC patients were younger, had higher clinical stage, and preoperative CA 19-9 levels (all p < 0.05). After adjustment for patient-, tumor-, and treatment-related factors, increased clinical stage was the greatest independent predictor of neoadjuvant approach (p < 0.001). On multivariable analysis, survival benefit from NAC did not reach threshold of significance (95% CI 0.66–1.04; p = 0.10) for the entire cohort. However, NAC was associated with a significant survival advantage in clinical stage III with a 51% decreased yearly risk of death (adjusted hazard ratio 0.49; 95% CI 0.25–0.98; p = 0.04). A trend towards improved survival with NAC was observed among stage IIA (p = 0.09) and IIB (p = 0.07) patients.ConclusionsNeoadjuvant chemotherapy is associated with improved overall survival in Stage III distal pancreatic adenocarcinoma and shows promise in earlier stage disease. However, only a small percentage of patients receive NAC. Prospective evaluation of NAC in distal pancreatic adenocarcinoma is warranted based on these findings.