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Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence.Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated.Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 naïve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome.Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies. Clin Cancer Res; 24(18); 4416–28. ©2018 AACR.

PDF file - 77K, Long term changes in the persistence of TCR Vβ clonotypes in the blood following TIL adoptive transfer in representative responding patients

PDF file - 58K, Demographics and clinical characteristics of enrolled patients

PDF file - 1856K, Fig. S1. Schema of TIL adoptive cell therapy clinical trial; Fig. S2. Recovery of total white blood cell counts (WBC), absolute lymphocyte counts (ALC), and absolute neutrophil counts (ANC) during adoptive transfer TIL therapy in 31 treated patients; Fig. S3. Durable partial response of an intrathoracic melanoma mass near the aorta and heart in one patient at 6 weeks and 18 months after TIL infusion; Figure S4. Kaplan-Meier curves of overall survival and progression-free survival for all 31 treated patients; Figure S5. Kaplan-Meier curves of landmark-based overall survival and progression-free survival for irRC responding and non-responding TIL-treated patients; Fig. S6. Change in tumor burden over the first 20-22 months following TIL transfer therapy in responders and non-responders; Fig. S7. Box and whisker plot showing that telomere length of infused TIL was not significantly different between responders and non-responders

Supplementary figures and tables

PDF file - 69K, Derivation of the irRC best overall score

PDF file - 115K

PDF file - 76k, Table S3. Associations between categorical patient variables and clinical response; Table S4. Associations between continuous variables and clinical response

Water resources on the Canadian Prairies are at risk due to human settlement, agricultural intensification, and climatic change. The Red River Valley (RRV), Manitoba, Canada, represents a nexus of these cumulative stressors. Here land use change, combined with a recent increase in precipitation and runoff, imperils the protective function of tributaries draining to Lake Winnipeg. A concerted research effort over the past decade has greatly improved availability of data and knowledge about the RRV. However, a full synthesis of these data and information remain lacking. We undertook a review to identify and compare contemporary and historical land use, climatic, hydrologic, and water quality condition within the RRV. Then, using current knowledge of the ecological condition of streams in the RRV and elsewhere, we completed an ecological causal assessment of RRV tributaries to identify linkages and knowledge gaps between anthropogenic drivers and ecological endpoints. We found wastewater to be the candidate cause of ecological effects in RRV streams best supported by empirical evidence. A lack of complete lines of evidence linking agriculture, the greatest diffuse source of nutrient inputs, and ecological effects in RRV tributaries underscored a need for stressor-specific indicators and improved biomonitoring strategies to better detect likely impacts of land use. We also identified a need for research to connect well-known causal elements in the RRV, such as climatic variables and hydrological alteration, to ecological effects. Our findings provide direction for future research and can aid in development of an adaptive management strategy for tributaries of the RRV.

Introduction Short-term outcomes after distal pancreatectomy (DP) for retroperitoneal (RP) tumors are unknown. We sought to identify rates of postoperative pancreatic fistula (POPF) and morbidity after en bloc DP with RP tumor resection. Methods A retrospective review of 43 patients who underwent DP with RP tumor resection (1/2011–12/2017) was performed. Results Seventeen patients had RP sarcoma, 12 renal cell carcinoma, 11 gastrointestinal stromal tumor, and 3 adrenocortical carcinoma. Grade III-IV complications occurred in 7 patients. Grade B POPF occurred in 14 patients, grade C POPF in none, and biochemical leak in 6. Of 22 patients who developed radiographically evident peri-pancreatic fluid collections, 7 required percutaneous drainage. The 90-day readmission rate was 33%. Conclusions DP with RP tumor resection is associated with high rates of clinically relevant POPF compared to historical results for DP for primary pancreatic tumors. Multi-center studies to identify targetable predictors and risk mitigation strategies for POPF in this rare high-risk population are needed.

PURPOSE Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for patients with melanoma. PATIENTS AND METHODS Clinical data were extracted from the databases of 2 major melanoma centers in the United States and Australia for 1,918 patients with American Joint Committee on Cancer (AJCC) 8th edition stage III melanoma, diagnosed from 1998-2014, who had (negative) baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death, from stage III presentation and at benchmark time points 1, 2, and 5 years postdiagnosis. RESULTS At a median follow-up of 70.2 months, distant recurrence occurred in 711 patients (37.1%). The first site of distant metastasis was CNS only for 3.9% of patients, CNS and extracranial (EC) for 1.8%, and EC only for 31.4%. Overall, 16.7% of patients were diagnosed with CNS metastasis during follow-up. The cumulative incidence of CNS metastasis was 3.6% (95% CI, 2.9% to 4.6%) at 1 year, 9.6% (95% CI, 8.3% to 11.0%) at 2 years, and 15.8% (95% CI, 14.1% to 17.6%) at 5 years. The risk of CNS metastasis was significantly influenced by patient sex, age, AJCC stage, primary tumor site, and primary tumor mitotic rate in multivariable and conditional analyses. High primary tumor mitotic rate was significantly associated with increased risk of CNS metastasis at diagnosis and all subsequent time points examined. CONCLUSION Similar rates of CNS metastasis were observed in 2 large, geographically distinct cohorts of patients with stage III melanoma. The results highlight the importance of primary tumor mitotic rate. Furthermore, they provide a framework for developing evidence-based surveillance strategies and evaluating the impact of contemporary adjuvant therapies on the risk of CNS metastasis development.

OBJECTIVES: Retroperitoneal sarcomas (RPS) are often large at diagnosis calling into question the 7(th) edition AJCC size classification of 15cm). We evaluated the prognostic ability of the 8(th) edition using the National Cancer Database (NCDB). METHODS: Patients with RPS treated between 1998–2011 were identified from the NCDB; overall survival (OS) was compared. RESULTS: Of the 6,427 patients identified, 9% had tumors ≤5 cm (n=580), 19.4% 515cm (n=3,045). With the 8(th) edition, stage II patients (G2/3 ≤5cm) have a similar OS to stage IIIA patients (G2/3 5cm10cm) show a decrease in OS. Tumor size as a continuous variable had a modest effect on survival (HR 1.004, p=0.04). On multivariate analysis, higher T-stage was associated with decreased OS (T4 HR 1.3, p

Patients with well-differentiated liposarcomas (WDLPS) of the extremity and trunk are treated primarily with surgical resection, with radiation used for a number of anecdotal reasons, including large size and positive margins. In this study, we evaluate the appropriate role for radiation in these tumors. A retrospective chart review of patients with extremity and trunk soft tissue liposarcomas referred to a free-standing cancer center from January 1995 to December 2011 was performed. One hundred eighty-three patients with extremity and trunk soft tissue WDLPS were identified: 61 per cent were female, median age was 60 years (range, 19–84 years) and 2 per cent had a focal area of dedifferentiation, margin status was positive in 57 per cent. Fourteen per cent of patients received radiation. Fifty patients developed recurrent disease; 28 per cent of these received radiation. Median time to recurrence was 18 years (range, 0.7–22 years). Of the 50 patients who recurred, 14 (28%) received radiation. Radiation was associated with decreased second recurrence when administered for recurrent disease (P = 0.03). On multivariable analysis, tumor size ≤ 10 cm (P = 0.014) and anatomically difficult area of resection (P = 0.008) were predictive of increased risk of recurrence. Older age (P = 0.02), dedifferentiated liposarcomas (P < 0.001), and difficult area of resection (P = 0.02) were associated with the administration of radiotherapy. Administration of radiation therapy was not associated with decreased time to recurrence in WDLPS overall; however, it should be considered in patients with recurrent disease.

BACKGROUND Retroperitoneal sarcomas (RPS) are rare tumors for which complete surgical resection remains the mainstay of treatment. The objective of the current study was to determine the impact of hospital case volume on outcomes in patients with RPS. METHODS A total of 6950 patients with primary RPS who underwent surgical resection were identified from the National Cancer Data Base (1998-2011). Treating hospitals were classified by annual case volume; low-volume hospitals (LVHs) and high-volume hospitals (HVHs) were defined as those with ≤10 cases per year and >10 cases per year, respectively. Overall survival (OS) was compared using Kaplan-Meier curves. Cox proportional hazard models were created to compare risks. RESULTS Of the 1131 reporting hospitals, the majority (1127 hospitals; 99.6%) were LVHs treating the majority of patients (6270 patients; 90.2%). Patients treated at LVHs were more likely to have lower grade and smaller tumors, receive radiotherapy, and undergo incomplete macroscopic (R2) resection. Patients treated at HVHs had lower 30-day readmission rates (1.8% vs 3.4%; P

Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses over adjuvant treatment1; however, optimal regimens have not been defined. Herein, we report results from a randomized phase II study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma (NCT02519322). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs), and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results are the first to describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.

BACKGROUND: The benefit of preoperative chemoradiation (CXRT) over preoperative chemotherapy alone (“chemotherapy” hereafter) is unknown. By analyzing the National Cancer Database (NCDB), we investigated whether preoperative CXRT improves the incidence of primary tumor pathologic complete response (ypT0) and overall survival (OS) compared with preoperative chemotherapy in patients with gastric cancer. METHODS: Patients with non-metastatic gastric adenocarcinoma who underwent CXRT or chemotherapy followed by gastrectomy were included. Propensity score matching with a ratio of 1:1 was implemented to reduce selection bias. A conditional logistic regression model was used to compare incidences of ypT0 between groups, and Cox proportional hazards model was used to compare OS. RESULTS: We identified 8,464 patients. Median patient age was 63 years; 76% were male and 79% were white. ypT0 was observed in 16.1% of patients in the CXRT group and 6.6% in the chemotherapy group (p < 0.001). After propensity score matching, a total of 2,408 patients were matched. CXRT was associated with a higher incidence of ypT0 (OR 2.28, 95% CI 1.76–2.95; p < 0.0001) and higher frequency of R0 resection (92% vs. 86%; p < 0.001). However, CXRT was not associated with longer OS (HR 1.03, 95% CI 0.92–1.15; p = 0.63). Safety profiles (30-day mortality, 30-day readmission, and length of hospital stay) were equivalent between groups. CONCLUSIONS: In this study of gastric cancer patients from the NCDB, CXRT was associated with a higher incidence of ypT0 and R0 resection compared with chemotherapy, although it was not associated with a longer OS.

Current evidence regarding salvage resection for recurrent retroperitoneal (RP) sarcomas generally lacks detailed histology-specific analyses, but the aggressiveness of these tumors varies widely by histology. We investigated associations between timing and extent of salvage surgery and survival outcomes in patients with recurrent RP well-differentiated liposarcoma (WDLPS). The University of Texas MD Anderson Cancer Center Surgical Oncology sarcoma database was reviewed to identify patients with RP WDLPS who underwent surgical resection for first recurrent disease (salvage surgery) in 1995–2015. Medical records were retrospectively reviewed to identify factors associated with overall survival and disease-free survival. We identified 52 patients who underwent salvage surgery for RP WDLPS for first local recurrence; 28 (54%) underwent salvage surgery within 6 months after recurrence. Concomitant organ resections were performed in 32 (62%) patients, 4 (13%) of whom had pathologic invasion of resected organs. After R0/R1 resections (n = 45), 38 (84%) experienced a second local recurrence. Multivariable analyses revealed that organ invasion at the primary surgery [hazard ratio (HR) 13.08; p = 0.005] and disease-free interval

The 8th edition American Joint Committee on Cancer (AJCC) staging for soft tissue sarcomas of the trunk/extremities divides T stage into four categories and upstages nodal disease to stage IV. We used the National Cancer Database (NCDB) to evaluate the prognostic power of the new system. A total of 26,144 patients were identified from the NCDB from 2004 to 2013. Overall survival (OS) was compared using Kaplan–Meier and Cox proportional hazard models. Including T3 (10 cm > × >15 cm) and T4 (> 15 cm) categories resulted in an increased number of patients classified as stage III (5120 as IIIA [19.6%] and 4280 as IIIB [16.4%], vs. 7882 [30.1%] previously), and there was a small increase in the number of patients classified as stage IV (2776 [10.6%], vs. 2565 [9.8%] previously). In the 7th edition, the hazard ratio (HR) for death increases with stage, with large incremental increases between stages II–III and III–IV. In the 8th edition, the HR for death demonstrates smaller incremental increases between each stage. Five-year OS for 7th edition T1 and T2 patients was 78.8 and 58.8% (p

BACKGROUND The role of surgical resection in the treatment of patients with metastatic/recurrent gastrointestinal stromal tumors (GIST) is unclear. The aim of this study was to identify preoperative factors associated with oncologic outcomes for recurrent/metastatic GIST after tyrosine kinase inhibitor (TKI) therapy. METHODS We identified 107 patients with metastatic or recurrent GIST treated with TKIs and surgical resection (2002-2012). Patients that underwent palliative or incomplete resection were excluded. Complete resection was achieved in 87 patients which comprise the analytic cohort. Univariate and multivariate analyses were conducted to identify risk factors for GIST-specific survival (DSS) and time-to-recurrence (TTR). RESULTS At a median follow-up of 51 months (91 months for survivors), median DSS was 74 months and TTR was 21 months. By univariate analysis, unifocal disease, duration of TKI

Background No studies have investigated whether race/ethnicity is associated with the recommended use of preoperative chemotherapy or subsequent outcomes in gastric cancer. To determine whether there is such an association, analyses of patients with gastric cancer in the National Cancer Data Base (NCDB) were performed. Methods Patients with clinical T2-4bN0-1M0 gastric adenocarcinoma, as defined by the eighth edition of the American Joint Committee on Cancer staging manual, who underwent gastrectomy from 2006 to 2014 were identified from the NCDB. Multiple logistic regression was conducted to examine factors associated with preoperative chemotherapy use. Results This study identified 16,945 patients who met the criteria, and 8286 of these patients (49%) underwent preoperative chemotherapy. The use of preoperative chemotherapy remarkably increased over the study period, from 34% in 2006 to 65% in 2014. Preoperative chemotherapy was more commonly used for cardia tumors than noncardia tumors (83% vs 44% in 2014). In a multivariable analysis, races and ethnicities other than non-Hispanic (NH) white race were associated with less frequent use of preoperative chemotherapy in comparison with NH whites after adjustments for social, tumor, and hospital factors. The insurance status and the education level mediated an enhanced effect of racial/ethnic disparities in preoperative chemotherapy use. The use of preoperative chemotherapy and radiation therapy was associated with reduced racial/ethnic disparities in overall survival. Conclusions Racial/ethnic disparities in the use of preoperative chemotherapy and in outcomes exist among patients with gastric cancer in the United States. Efforts to improve the access to high-quality cancer care in minority groups may reduce racial disparities in gastric cancer in the United States. Cancer 2018;124:998-1007. © 2018 American Cancer Society.

Genome-wide association study (GWAS)-identified single-nucleotide polymorphisms (SNPs) are tag SNPs located in both transcribed and non-coding regulatory DNA regions, rather than representing causal or functional variants for disease. To identify functional variants or genes for melanoma susceptibility, we used functional mapping and annotation (FUMA) to perform functional annotation of the summary statistics of 2541 significant melanoma risk SNPs (P < 5 × 10−8) identified by GWAS. The original GWAS melanoma study included 15 990 cases and 26 409 controls, representing the largest international meta-analysis of melanoma susceptibility. We prioritized 330 unique genes, including those in immune cytokine signaling pathways, from 19 loci through positional, expression quantitative trait locus, and chromatin interaction mapping. In comparison, only 38 melanoma-related genes were identified in the original meta-analysis. In addition to the well-known melanoma susceptibility genes confirmed in the meta-analysis (MC1R, CDKN2A, TERT, OCA2 and ARNT/SETDB1), we also identified additional novel genes using FUMA to map SNPs to genes. Through chromatin interaction mapping, we prioritized IFNA7, IFNA10, IFNA16, IFNA17, IFNA14, IFNA6, IFNA21, IFNA4, IFNE and IFNA5; these 10 most significant genes are all involved in immune system and cytokine signaling pathways. In the gene analysis, we identified 72 genes with a P < 2.5 × 10−6. The genes associated with melanoma risk were DEF8 (P = 1.09 × 10−57), DBNDD1 (P = 2.19 × 10−42), SPATA33 (P = 3.54 × 10−38) and MC1R (P = 1.04 × 10−36). In summary, this study identifies novel putative melanoma susceptibility genes and provides a guide for further experimental validation of functional variants and disease-related genes.

Objective To identify health disparities in pediatric patients with melanoma that affect disease presentation and outcome. Study design This was a retrospective cohort study of all persons aged ≤18 years diagnosed with melanoma and enrolled in the Texas Cancer Registry between 1995 and 2009. Socioeconomic status (SES) and driving distance to the nearest pediatric cancer treatment center were calculated for each patient. Logistic regression was used to determine factors associated with advanced-stage disease. Life table methods and Cox regression were used to estimate survival probability and hazard ratios. Results A total of 185 adolescents (age >10 years) and 50 young children (age ≤10 years) were identified. Hispanics (n = 27; 12%) were 3 times more likely than non-Hispanic whites (n = 177; 75%) to present with advanced disease (OR, 3.8; 95% CI, 1.7-8.8). Young children were twice as likely as adolescents to present with advanced disease (OR, 2.2; 95% CI, 1.1-4.3). Distance to treatment center and SES did not affect stage of disease at presentation. Hispanics and those in the lowest SES quartile had a significantly higher mortality risk (hazard ratios, 3.0 [95% CI, 1.2-7.8] and 4.3 [95% CI, 1.4-13.9], respectively). In the adjusted survival model, only advanced disease was predictive of mortality ( P Conclusion Hispanics and young children with melanoma are more likely to present with advanced disease, and advanced disease is the single most important predictor of survival. Heightened awareness among physicians is needed to facilitate early detection of melanoma within these groups.

Motivated by a study for soft tissue sarcoma, this article considers the analysis of diseases recurrence and survival. A multivariate frailty hazard model is established for joint modeling of three correlated time-to-event outcomes: local disease recurrence, distant disease recurrence (metastasis), and death. The goals are to find out (i) the effects of treatments on local and distant disease recurrences, and death, (ii) the effects of local and distant disease recurrences on death, and (iii) the correlation between local and distant recurrences. By our approach, all these three important questions, which are commonly asked in similar medical research studies, can be answered by a single model. We put the proposed joint frailty model in a Bayesian framework and use a hybrid Monte Carlo algorithm for the computation of posterior distributions. This hybrid algorithm relies on the evaluation of the gradient of target log density and a guided walk progress, and it combines these two strategies to suppress random walk behavior. A further distinction is that the hybrid algorithm can update all the components of a multivariate state vector simultaneously. Simulation studies are conducted to assess the proposed joint frailty model and the computation algorithm. The motivating soft tissue sarcoma data set is analyzed for illustration purpose. Copyright © 2016 John Wiley & Sons, Ltd.

PurposeTo evaluate for an association between 25-hydroxyvitamin D levels (vitamin D) and outcome measures in patients with melanoma after evaluation is controlled for systemic inflammatory response (SIR) on the basis of simultaneous C-reactive protein (CRP) measurement.Materials and MethodsPlasma samples from 1,042 prospectively observed patients with melanoma were assayed for vitamin D and CRP. The associations of demographics and CRP with vitamin D were determined, followed by a determination of the association between vitamin D and stage and outcome measures from the date of blood draw. The vitamin D level was considered sufficient if it was 30 to 100 ng/mL. Kaplan-Meier and Cox regression analyses were performed.ResultsThe median vitamin D level was 25.0 ng/mL. The median follow-up time was 7.1 years. A lower vitamin D was associated with the blood draw during fall/winter months (P < .001), older age (P = .001), increased CRP (P < .001), increased tumor thickness (P < .001), ulcerated tumor (P = .0105), and advanced melanoma stage (P = .0024). On univariate analysis, lower vitamin D was associated with poorer overall (OS; P < .001), melanoma-specific survival (MSS; P = .0025), and disease-free survival (DFS; P = .0466). The effect of vitamin D on these outcome measures persisted after adjustment for CRP and other covariates. Multivariable hazards ratios per unit decrease of vitamin D were 1.02 for OS (95% CI, 1.01 to 1.04; P = .0051), 1.02 for MSS (95% CI, 1.00 to 1.04; P = .048), and 1.02 for DFS (95% CI, 1.00 to 1.04; P = .0427).ConclusionLower vitamin D levels in patients with melanoma were associated with poorer outcomes. Although lower vitamin D was strongly associated with higher CRP, the associations of lower vitamin D with poorer OS, MSS, and DFS were independent of this association. Investigation of mechanisms responsible for these associations may be of value to patients with melanoma.

Undifferentiated pleomorphic sarcomas (UPS) present a diagnostic and therapeutic challenge. Identification of prognostic molecular markers is required for the discovery of novel treatment approaches. The purpose of this study was to correlate clinicopathologic variables, expression of tyrosine kinase receptors, and markers of cell cycle progression and survival with oncologic outcomes. A tissue microarray containing 208 primary UPS samples was analyzed by immunohistochemistry for protein markers and in situ hybridization for microRNA. Staining results were correlated with clinicopathologic features and oncologic outcomes. Univariate and multivariate analyses were conducted to assess associations between expression of protein markers, mi-RNA, and outcome. At a median follow-up of 3.9 years (9 years for survivors), 5-year disease-specific survival (DSS) was 63 %. Clinical variables associated with improved DSS included age

Background Previous economic evaluations compared specific chemotherapy agents using input parameters from clinical trials and resource utilization costs. Cost-effectiveness of treatment groups (drug classes) using community-level effectiveness and cost data, however, has not been assessed for elderly patients with breast cancer. Objective To assess the cost-effectiveness of chemotherapy regimens by age and disease stage under "real-world" conditions for patients with breast cancer. Methods The Surveillance Epidemiology and End Results-Medicare data were used to identify patients with breast cancer with American Joint Committee on Cancer stage I/II/IIIa, hormone receptor–negative (estrogen receptor–negative and progesterone receptor–negative) patients from 1992 to 2009. Patients were categorized into three adjuvant treatment groups: 1) no chemotherapy, 2) anthracycline, and 3) non–anthracycline-based chemotherapy. Median life-years and quality-adjusted life-years (QALYs) were measured using Kaplan-Meier analysis and were evaluated against average total health care costs (2013 US dollars). Results A total of 4575 patients (propensity score–matched) were included for the primary analysis. The anthracycline group experienced 12.05 QALYs and mean total health care costs of $119,055, resulting in an incremental cost-effectiveness ratio of $7,688 per QALY gained as compared with the no chemotherapy group (QALYs 7.81; average health care cost $86,383). The non–anthracycline-based group was dominated by the anthracycline group with lower QALYs (9.56) and higher health care costs ($122,791). Base-case results were found to be consistent with the best-case and worst-case scenarios for utility assignments. Incremental cost-effectiveness ratios varied by age group (range $3,790–$90,405 per QALY gained). Conclusions Anthracycline-based chemotherapy was found cost-effective for elderly patients with early stage (stage I, II, IIIa) breast cancer considering the US threshold of $100,000 per QALY. Further research may be needed to characterize differential effects across age groups.

Soft tissue sarcomas are a heterogeneous and rare group of solid tumors of mesenchymal origin that can arise anywhere in the body. Although surgical resection is the mainstay of treatment for patients with localized disease, disease recurrence is common and 5-year overall survival is poor (~ 65%). Both radiation therapy and conventional chemotherapy are used to reduce local and distant recurrence. However, the utility of radiation therapy is often limited by disease location (in the case of retroperitoneal sarcomas, for instance) while systemic therapy with conventional lines of chemotherapy offer limited efficacy and are often poorly tolerated and associated with significant toxicity. Within the past decade, major advances have been made in the treatment of other malignancies including melanoma, renal cell carcinoma, and non-small cell lung carcinoma with the advent of immune-checkpoint inhibitors such as ipilimumab (anti-CTLA4), pembrolizumab (anti-PD1), and nivolumab (anti-PD1). The recently published SARC028 (NCT02301039), an open label, phase II, multicenter trial of pembrolizumab in patients with advanced bone and soft tissue sarcomas reported promising activity in select histologic subtypes of advanced STS, including undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. There is a clear need for novel and effective adjuncts in the treatment of STS. We hypothesize that immune checkpoint blockade will be effective in patients with surgically resectable primary or locally recurrent dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma when administered in the neoadjuvant setting. The primary aim of this phase II, single-center, open label, randomized non-comparative trial is to determine the pathologic response to neoadjuvant nivolumab monotherapy and combination nivolumab/ipilimumab in patients with resectable dedifferentiated liposarcoma of the retroperitoneum or undifferentiated pleomorphic sarcoma of the trunk or extremity treated with concurrent standard of care neoadjuvant radiation therapy. This study will help define the role of single agent anti-PD1 and combination anti-CTLA4 and anti-PD1 therapy in patients with surgically resectable dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma. ClinicalTrials.gov NCT03307616 , registered October 12, 2017.

To investigate the role of tumor cytokines/chemokines in melanoma immune response, we estimated proportions of immune cell subsets in melanoma tumors from TCGA, followed by evaluation of association between cytokine/chemokine expression and these subsets. We then investigated association of immune cell subsets, chemokines, and cytokines with patient survival. Finally, we evaluated immune cell TIL score for correlation with melanoma patient outcome in a separate cohort. There was good agreement between RNA-seq estimation of T-cell subset with pathologist-determined TIL score. Expression levels of cytokines IL-12A, IFNG, IL-10, and chemokines CXCL9 and CXCL10 were positively correlated with PDCD1, CTLA-4, and CD8+ T cell subset, but negatively correlated with tumor purity (Bonferroni-corrected P

Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated. Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 naïve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome. Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies. Clin Cancer Res; 24(18); 4416–28. ©2018 AACR.

Background The good preparation practices recommend a control of chemotherapy compound to minimise the risk of mistakes before patient’s administration. We tried to put in place an automated analytic method taking into account financial and technical criteria to control IV chemotherapy preparations. Purpose The purpose was to evaluate the identification and qualification performances of a new quality control system: the spectrophotometer (Druglog, pharmacolog, Uppsala). Material and methods The system is based on absorption spectroscopy in the ultraviolet and visual spectral range calculated according to the Beer-lambert law. Eight cytotoxic drugs were initially chosen based on level of clinical use. The statistical approach used for validation referred to the International Conference Harmonisation.1 Each drug calibration was made in triplicate the same day. These operations were repeated for three different sets and three different days. A mathematical model of linear regression representing the relationship between absorbance and concentration of the molecule has been applied. We were able to determine statistically the best calibration curve for each drug through the correlation coefficient’s (R²). Each validation standard was then analysed by the spectrophotometer to determine the relative error of the concentrations measured. Finally, a number of tests were performed on cytotoxic infusion kits. Results All calibration curves present a linear profile: R² average and maximal are higher than 0.98 except irinotecan with R²=0.96. The system has specifically identified each validation standard. The results show that the system can measure all compounds with a relative error less than 12%. The tests in production are presented in the following table. All drugs were correctly identified. Conclusion We can doubt the linearity of the irinotecan calibration and enquire about any matrix effect, or even a stability problem with NaCl diluent. During production tests, no kits were found with erroneous drugs. The dosing error rates were higher than those of the validation standards. We have considered a problem with the homogenisation kits. These first results are promising but we will therefore continue the collaboration with Pharmacolog and Uppsala to perform our analytical method of control. Reference and/or Acknowledgements ICH harmonised tripartite guideline validation of analytical procedures No conflict of interest

Introduction The incidence and clinical significance of lymph node metastasis (LNM, N1) in soft tissue sarcoma (STS) is unclear. Recent studies have focused on extremity/trunk STS (ETSTS). We sought to define the subgroup of patients with LNM at sarcoma diagnosis across all disease sites and histologies. Methods We identified and categorized 89,870 STS patients from the National Cancer Data Base (1998–2012) by nodal stage. Pathologically confirmed LNM (pN1) were identified in 1404 patients; 1750 had clinically suspicious but not pathologically confirmed LNM (cN1). Survival analyses were performed by Kaplan-Meier method. Results Of 3154 patients (3.5%) with pN1 or cN1 LNM at presentation, 1310 had synchronous distant metastasis (M1). LNM affected a small proportion of patients (5.8% head/neck, 5.3% intrathoracic, 5.1% intra-abdominal, 2.0% ETSTS). Angiosarcoma (6%), epithelioid (13%), clear cell (16%), and small cell sarcoma (19%) had the highest incidence of LNM, although liposarcoma, fibrous histiocytoma, and leiomyosarcoma accounted for the greatest number of LNM patients. For pN1M0 disease, median overall survival (OS) was 28.2 months, varying by histology. Among patients with pN1M0 STS, angiosarcoma, clear cell sarcoma, leiomyosarcoma, and fibrous histiocytoma were associated with worse median OS (19.4, 23.8, 27.1, and 29.3 months) compared to epithelioid sarcoma and liposarcoma (49.6 and 56.0 months, p Conclusion Despite clinical suspicion, pathologic LN evaluation in STS is inconsistently performed. LNM occurs across anatomic disease sites and is unevenly distributed across histologies. Although M1 disease portends poor prognosis regardless of LN status, LNM predicts worse OS in a histology-dependent manner in M0 disease.

Recent investigation has identified association of IL-12p40 blood levels with melanoma recurrence and patient survival. No studies have investigated associations of single-nucleotide polymorphisms (SNPs) with melanoma patient IL-12p40 blood levels or their potential contributions to melanoma susceptibility or patient outcome. In the current study, 818,237 SNPs were available for 1,804 melanoma cases and 1,026 controls. IL-12p40 blood levels were assessed among 573 cases (discovery), 249 cases (case validation), and 299 controls (control validation). SNPs were evaluated for association with log[IL-12p40] levels in the discovery data set and replicated in two validation data sets, and significant SNPs were assessed for association with melanoma susceptibility and patient outcomes. The most significant SNP associated with log[IL-12p40] was in the IL-12B gene region (rs6897260, combined P=9.26 × 10(-38)); this single variant explained 13.1% of variability in log[IL-12p40]. The most significant SNP in EBF1 was rs6895454 (combined P=2.24 × 10(-9)). A marker in IL12B was associated with melanoma susceptibility (rs3213119, multivariate P=0.0499; OR=1.50, 95% CI 1.00-2.24), whereas a marker in EBF1 was associated with melanoma-specific survival in advanced-stage patients (rs10515789, multivariate P=0.02; HR=1.93, 95% CI 1.11-3.35). Both EBF1 and IL12B strongly regulate IL-12p40 blood levels, and IL-12p40 polymorphisms may contribute to melanoma susceptibility and influence patient outcome.

BACKGROUND This study was performed to determine the maximum tolerated dose (MTD) of gemcitabine given concurrently with preoperative, fixed-dose external-beam radiation therapy (EBRT) for patients with resectable, high-risk extremity and trunk soft tissue sarcoma (STS). METHODS Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 with EBRT (50 Gy in 25 fractions over 5 weeks). The gemcitabine MTD was determined with a toxicity severity weight method (TSWM) incorporating 6 toxicity types. The TSWM is a Bayesian procedure that choses each cohort's dose to have a posterior mean total toxicity burden closest to a predetermined clinician-defined target. Clinicopathologic and outcome data were also collected. RESULTS Thirty-six patients completed the study. According to the TSWM, the gemcitabine MTD was 700 mg/m2. At this dose level, 4 patients (24%) experienced grade 4 toxicity; no toxicity-related deaths occurred. All tumors were resected with microscopically negative margins. Pathologic responses of >90% tumor necrosis were achieved in 17 patients (47%); 14 (39%) had complete responses. With a median follow-up of 6.2 years, the 5-year locoregional recurrence–free survival, distant metastasis–free survival, and overall survival rates were 85%, 80%, and 86%, respectively. CONCLUSIONS The TSWM combines data from qualitatively different toxicities and can be used to determine the MTD for a drug given as part of a multimodality treatment. Neoadjuvant gemcitabine plus radiation therapy is feasible and safe in patients with high-risk extremity and trunk STS. Major pathologic responses can be achieved, and after complete resection, long-term clinical outcomes are encouraging. Cancer 2015 © 2015 American Cancer Society.

Purpose To investigate the association between blood levels of C-reactive protein (CRP) in patients with melanoma and overall survival (OS), melanoma-specific survival (MSS), and disease-free survival. Patients and Methods Two independent sets of plasma samples from a total of 1,144 patients with melanoma (587 initial and 557 confirmatory) were available for CRP determination. Kaplan-Meier method and Cox regression were used to evaluate the relationship between CRP and clinical outcome. Among 115 patients who underwent sequential blood draws, we evaluated the relationship between change in disease status and change in CRP using nonparametric tests. Results Elevated CRP level was associated with poorer OS and MSS in the initial, confirmatory, and combined data sets (combined data set: OS hazard ratio, 1.44 per unit increase of logarithmic CRP; 95% CI, 1.30 to 1.59; P < .001; MSS hazard ratio, 1.51 per unit increase of logarithmic CRP; 95% CI, 1.36 to 1.68; P < .001). These findings persisted after multivariable adjustment. As compared with CRP < 10 mg/L, CRP ≥ 10 mg/L conferred poorer OS in patients with any-stage, stage I/II, or stage III/IV disease and poorer disease-free survival in those with stage I/II disease. In patients who underwent sequential evaluation of CRP, an association was identified between an increase in CRP and melanoma disease progression. Conclusion CRP is an independent prognostic marker in patients with melanoma. CRP measurement should be considered for incorporation into prospective studies of outcome in patients with melanoma and clinical trials of systemic therapies for those with melanoma.

Cumulative findings support the current National Comprehensive Cancer Network guidelines for surveillance in early-stage melanoma (stages IA–IIA), which recommend lifelong dermatologic surveillance with regular comprehensive skin exams, adding imaging studies only if there is clinical suspicion of recurrence.1 Regular clinical examination offers the highest diagnostic yield in detecting melanoma recurrences, with additional diagnostic benefit seen when imaging is used for patients in whom clinical evaluation or symptomatic presentation suggests the presence of distant disease. However, for patients with locally or regionally advanced melanoma (stages IIB–IIIC), there is a paucity of data to support the use of rigorous, routine surveillance imaging studies following appropriate staging and surgical treatment of their disease. Contemporary guidelines recommend, on the basis of low-level evidence (category 2B), that clinicians consider the addition of CT and/or PET/CT every 3 to 12 months for these patients.1 However, current data indicate that such a regimen would result in an exceedingly large number of studies performed to detect a limited number of surgically treatable recurrences and would have little impact on patient survival. Although there likely is a subset of patients with high risk melanoma in whom routine oncologic imaging surveillance has the potential to offer survival benefit, a more judicious approach to the use of imaging studies may be equally effective with little detrimental impact on survival. Such considerations are of increasing interest in the modern era of rising health care costs and impending limitations on resource utilization.

Few studies have examined the cancer incidence trends in the state of Texas, and no study has ever been conducted to compare the temporal trends of breast and colorectal cancer incidence in Texas with those of the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) in the United States. This study aimed to conduct a parallel comparison between the Texas Cancer Registry and the National Cancer Institute’s SEER on cancer incidence from 1995 to 2011. A total of 951,899 breast and colorectal cancer patients were included. Age-adjusted breast cancer incidence was 134.74 per 100,000 in Texas and 131.78 per 100,000 in SEER in 1995–2011, whereas age-adjusted colorectal cancer incidence was 50.52 per 100,000 in Texas and 49.44 per 100,000 in SEER. Breast cancer incidence increased from 1995 to 2001, decreased from 2002 to 2006, and then remained relatively stable from 2007 to 2011. For colorectal cancer, the incidence increased in 1995–1997, and then decreased continuously from 1998 to 2011 in Texas and SEER areas. Incidence rates and relative risks by age, gender and ethnicity were identical between Texas and SEER.

Summary Systematic reviews of diagnostic tests often involve a mixture of case–control and cohort studies. The standard methods for evaluating diagnostic accuracy focus only on sensitivity and specificity and ignore the information on disease prevalence that is contained in cohort studies. Consequently, such methods cannot provide estimates of measures related to disease prevalence, such as population-averaged or overall positive and negative predictive values, which reflect the clinical utility of a diagnostic test. We propose a hybrid approach that jointly models the disease prevalence along with diagnostic test sensitivity and specificity in cohort studies, and sensitivity and specificity in case–control studies. To overcome the potential computational difficulties in the standard full likelihood inference of the hybrid model proposed, we propose an alternative inference procedure based on composite likelihood. Such composite-likelihood-based inference does not suffer computational problems and maintains high relative efficiency. In addition, it is more robust to model misspecifications compared with standard full likelihood inference. We apply our approach to a review of the performance of contemporary diagnostic imaging modalities for detecting metastases in patients with melanoma.

Background We investigated whether concomitant organ removal as part of the primary resection of RP WDLPS confers an outcome advantage in patients treated at a major sarcoma center. Methods The departmental sarcoma database was reviewed to identify patients with RP WDLPS who underwent initial surgical resection for primary disease at MD Anderson Cancer Center during the study period 1995-2011. We retrospectively reviewed medical records and examined associations between clinicopathologic variables and overall survival (OS) as well as disease-free survival (DFS). Results Among 83 patients included in this study, 76 patients (92%) underwent complete resection (R0/R1). Concomitant organ resections were performed in 38 patients (46%). Invasion of the resected organ/s was seen in six patients (7%). Estimated OS was 11.3 years (5-year OS, 86%), and DFS was 5.4 years (5-year DFS, 51%). By multivariate analysis, concomitant organ resection was not associated with improved OS (P = 0.428) or DFS (P = 0.946), and lack of organ resection was associated with a lower risk of postoperative complications (P = 0.01). Conclusions Concomitant organ resection was not associated with a survival benefit in RP WDLPS in this study. In patients with primary RP WDLPS, we recommend selective resection of contiguous organs only if there is clinical suspicion of invasion.

Background Many surgeons experience work-related pain and musculoskeletal symptoms; however, comprehensive reporting of surgeon ailments is lacking in the literature. We sought to evaluate surgeons' work-related symptoms, possible causes of these symptoms, and to report outcomes associated with those symptoms. Materials and methods Five major medical indices were queried for articles published between 1980 and 2014. Included articles evaluated musculoskeletal symptoms and ergonomic outcomes in surgeons. A meta-analysis using a fixed-effect model was used to report pooled results. Results Forty articles with 5152 surveyed surgeons were included. Sixty-eight percent of surgeons surveyed reported generalized pain. Site-specific pain included pain in the back (50%), neck (48%), and arm or shoulder (43%). Fatigue was reported by 71% of surgeons, numbness by 37%, and stiffness by 45%. Compared with surgeons performing open surgery, surgeons performing minimally invasive surgery (MIS) were significantly more likely to experience pain in the neck (OR 2.77 [95% CI 1.30–5.93]), arm or shoulder (OR 4.59 [2.19–9.61]), hands (OR 2.99 [1.33–6.71], and legs (OR 12.34 [5.43–28.06]) and experience higher odds of fatigue (8.09 [5.60–11.70]) and numbness (6.82 [1.75–26.65]). Operating exacerbated pain in 61% of surgeons, but only 29% sought treatment for their symptoms. We found no direct association between muscles strained and symptoms. Conclusions Most surgeons report work-related symptoms but are unlikely to seek medical attention. MIS surgeons are significantly more likely to experience musculoskeletal symptoms than surgeons performing open surgery. Symptoms experienced do not necessarily correlate with strain., Highlights • 68% of surveyed surgeons reported experiencing generalized pain from operating. • Minimally-invasive surgeons were more likely to report pain, fatigue, and numbness. • Only 29% of surgeons reported seeking treatment for symptoms. • No association between objective strain on muscles and reported symptoms was found.

No studies have investigated whether race/ethnicity is associated with the recommended use of preoperative chemotherapy or subsequent outcomes in gastric cancer. To determine whether there is such an association, analyses of patients with gastric cancer in the National Cancer Data Base (NCDB) were performed.Patients with clinical T2-4bN0-1M0 gastric adenocarcinoma, as defined by the eighth edition of the American Joint Committee on Cancer staging manual, who underwent gastrectomy from 2006 to 2014 were identified from the NCDB. Multiple logistic regression was conducted to examine factors associated with preoperative chemotherapy use.This study identified 16,945 patients who met the criteria, and 8286 of these patients (49%) underwent preoperative chemotherapy. The use of preoperative chemotherapy remarkably increased over the study period, from 34% in 2006 to 65% in 2014. Preoperative chemotherapy was more commonly used for cardia tumors than noncardia tumors (83% vs 44% in 2014). In a multivariable analysis, races and ethnicities other than non-Hispanic (NH) white race were associated with less frequent use of preoperative chemotherapy in comparison with NH whites after adjustments for social, tumor, and hospital factors. The insurance status and the education level mediated an enhanced effect of racial/ethnic disparities in preoperative chemotherapy use. The use of preoperative chemotherapy and radiation therapy was associated with reduced racial/ethnic disparities in overall survival.Racial/ethnic disparities in the use of preoperative chemotherapy and in outcomes exist among patients with gastric cancer in the United States. Efforts to improve the access to high-quality cancer care in minority groups may reduce racial disparities in gastric cancer in the United States. Cancer 2018;124:998-1007. © 2018 American Cancer Society.

Background Optimal treatment strategies for retroperitoneal leiomyosarcoma (RPLMS), particularly recurrent disease, are unknown. Methods We searched the tumor registry at The University of Texas MD Anderson Cancer Center (MDACC) to identify patients with RPLMS treated between 1994 and 2013. Results We identified 172 patients with a diagnosis of a RPLMS. Among the 85 patients who underwent complete resection included in the survival analysis, the median overall survival (OS) was 8.3 years (95% confidence interval [CI], 5.7-12.3), 5-year local recurrence rate was 21%, and 5-year distant metastasis rate was 47%. Among 114 patients who experienced recurrence, patients who underwent salvage surgery for recurrent disease had longer OS after recurrence than patients who did not undergo salvage surgery (median survival after recurrence 5.6 vs 3.3 years, 3-year OS rates after recurrence 72.6% vs 58.1%, HR 0.402 [95%CI, 0.243-0.666]; P = 0.0004). Whether salvage surgery was performed for local or distant recurrence was not associated with OS. Patients who had a longer disease-free interval (≥12 months) had better progression-free survival after salvage surgery than those who had a shorter interval (HR, 0.437 [95%CI, 0.244-0.783]; P = 0.0055). Conclusions We recommend that salvage surgery be considered for selected patients with local or distant recurrence of RP LMS.

Surgery is the primary treatment for all subtypes of retroperitoneal liposarcoma, but neoadjuvant therapy may be warranted in cases of dedifferentiated liposarcoma (DDLS), which has an increased risk of recurrence and metastasis. Therefore, an accurate subtype-specific diagnosis is vital for appropriate consideration of neoadjuvant therapy. Previous studies assessing the subtype-specific accuracy of percutaneous biopsy are limited. We aimed to analyze the accuracy of preoperative percutaneous biopsy in the subtype-specific diagnosis of retroperitoneal liposarcoma and thus the reliability of percutaneous biopsy in guiding decisions about neoadjuvant treatment.We retrospectively reviewed the medical records, including the pathologic reports, interventional radiology reports, and operative reports, of patients registered in the retroperitoneal/well-differentiated liposarcoma (WDLS/DDLS) database at The University of Texas MD Anderson Cancer Center between 1993 and 2013.We identified 120 patients who underwent 137 preoperative percutaneous biopsies followed by surgical resections. Pathologic examination following resection indicated that 74 of the patients had WDLS and 63 had DDLS. The overall diagnostic accuracy of percutaneous biopsy for identifying the subtype of liposarcoma was 62.8 % (86/137); the accuracy for identifying WDLS was significantly higher (85.1 %; 63/74) than that for identifying DDLS (36.5 %; 23/63) (p0.01).Percutaneous biopsy has low accuracy in the diagnosis of retroperitoneal DDLS. This can potentially mislead physicians in the decision to implement neoadjuvant treatment. When developing treatment strategies, including clinical trials for patients with retroperitoneal liposarcoma, physicians should carefully consider the low accuracy of percutaneous biopsy in detecting DDLS.

Purpose Margin positivity after rectal cancer resection is associated with poorer outcomes. We previously developed an instrument for calculating hospital risk-adjusted margin positivity rate (RAMP) that allows identification of performance-based outliers and may represent a rectal cancer surgery quality metric. Methods This was an observational cohort study of patients with rectal cancer within the National Cancer Data Base (2003 to 2005). Hospital performance was categorized as low outlier (better than expected), high outlier (worse than expected), or non-RAMP outlier using standard observed-to-expected methodology. The association between outlier status and overall risk of death at 5 years was evaluated using Cox shared frailty modeling. Results Among 32,354 patients with cancer (mean age, 63.8 ± 13.2 years; 56.7% male; 87.3% white) treated at 1,349 hospitals (4.9% high outlier, 0.7% low outlier), 5.6% of patients were treated at high outliers and 3.0% were treated at low outliers. Various structural (academic status and volume), process (pathologic nodal evaluation and neoadjuvant radiation therapy use), and outcome (sphincter preservation, readmission, and 30-day postoperative mortality) measures were significantly associated with outlier status. Five-year overall survival was better at low outliers (79.9%) compared with high outliers (64.9%) and nonoutliers (68.9%; log-rank test, P < .001). Risk of death was lower at low outliers compared with high outliers (hazard ratio [HR], 0.61; 95% CI, 0.50 to 0.75) and nonoutliers (HR, 0.69; 95% CI, 0.57 to 0.83). Risk of death was higher at high outliers compared with nonoutliers (HR, 1.12; 95% CI, 1.03 to 1.23). Conclusion Hospital RAMP outlier status is a rectal cancer surgery composite metric that reliably captures hospital quality across all levels of care and could be integrated into existing quality improvement initiatives for hospital performance.

Cytokines such as Interleukin (IL)-12p70 ("IL-12") and IL-23 can influence tumor progression. We tested the hypothesis that blood levels of IL-12p40, the common subunit of both cytokines, are associated with melanoma progression. Blood from 2,048 white melanoma patients were collected at a single institution between March 1998 and March 2011. Plasma levels of IL-12p40 were determined for 573 patients (discovery), 249 patients (Validation 1) and 244 patients (Validation 2). Per 10-unit change of IL-12p40 level was used to investigate associations with melanoma patient outcome among all patients or among patients with early or advanced stage. Among stage I/II melanoma patients in the pooled data set, after adjustment for sex, age, stage and blood draw time from diagnosis, elevated IL-12p40 was associated with melanoma recurrence [hazard ratio (HR) = 1.04 per 10-unit increase in IL-12p40, 95% CI 1.02-1.06, p = 8.48 × 10(-5) ]; Elevated IL-12p40 was also associated with a poorer melanoma specific survival (HR = 1.06, 95% CI 1.03-1.09, p = 3.35 × 10(-5) ) and overall survival (HR = 1.05, 95% CI 1.03-1.08, p = 8.78×10(-7) ) in multivariate analysis. Among stage III/IV melanoma patients in the pooled data set, no significant association was detected between elevated IL-12p40 and overall survival, or with melanoma specific survival, with or without adjustment for the above covariates. Early stage melanoma patients with elevated IL-12p40 levels are more likely to develop disease recurrence and have a poorer survival. Further investigation with a larger sample size will be needed to determine the role of IL-12p40 in advanced stage melanoma patients.