Construction of residential histories to estimate long-term environmental exposures in the California Teachers Study cohort.

Environmental epidemiologic studies using geospatial data often estimate exposure at a participant's residence upon enrollment, but mobility during the exposure period can lead to misclassification. We aimed to mitigate this issue by constructing residential histories for participants in the California Teachers Study through follow-up (1995-2018). Address records have been collected from the US Postal Service, LexisNexis, Experian, and California Cancer Registry. We identified records of the same address based on geo-coordinate distance (≤250 m) and street name similarity. We consolidated addresses, prioritizing those confirmed by participants during follow-up questionnaires, and estimating the duration lived at each address using dates associated with records (e.g., date-first-seen). During 23 years of follow-up, about half of participants moved (48%, including 14% out-of-state). We observed greater mobility among younger women, Hispanic/Latino women, and those in metropolitan and lower socioeconomic status areas. The cumulative proportion of in-state movers remaining eligible for analysis was 21%, 32%, and 41% at 5, 10, and 20 years post enrollment, respectively. Using self-reported information collected 10 years after enrollment, we correctly identified 94% of movers and 95% of non-movers as having moved or not moved from their enrollment address. This dataset provides a foundation for estimating long-term environmental exposures in diverse epidemiologic studies in this cohort. IMPACT: Our efforts in constructing residential histories for California Teachers Study participants through follow-up (1995-2018) benefit future environmental epidemiologic studies. Address availability during the exposure period can mitigate misclassification due to residential changes, especially when evaluating long-term exposures and chronic health outcomes. This can reduce differential misclassification among more mobile subgroups, including younger women and those from lower socioeconomic and urban areas. Our approach to consolidating addresses from multiple sources showed high accuracy in comparison to self-reported residential information. The residential dataset produced from this analysis provides a valuable tool for future studies, ultimately enhancing our understanding of environmental health impacts.

Assessing trends in breast care surveillance metrics after implementing surgeon-specific tracking and performance reporting in a large, integrated cancer network.

BACKGROUND: There are few quality metrics and benchmarks specific to surgical oncology. Development of a surgeon-level performance metrics system based on peer comparisons is hypothesized to positively influence surgical decision-making. This study established a tracking and reporting system comprised of evidence and consensus-based metrics to assess breast care delivered by individual surgeons. METHODS: Surgeons' performance is assessed by a surveillance tracking system of metrics pertaining to referrals and surgical elements. This retrospective analysis of prospectively collected breast care data reports on recurring 6-month and cumulative data from nine care locations from 2015 to 2021. RESULTS: Breast care was provided to 6659 patients by 41 surgeons. A total of 27 breast care metrics were evaluated over 7 years. Metrics with consistent, proficient results were retired after 18 months, including the rate of core biopsy, specimen orientation, and referrals to medical oncology, genetics, and fertility, among others. In clinically node-negative, hormone receptor-positive patients 70 years of age or older, the cumulative rate of sentinel lymph node (SLN) biopsy significantly decreased by 40% over 5.5 years (p < .001). The overall breast conservation rate for T0-T2 cancer increased 10% over 7 years. At the surgeon level, improvements were made in the median number of SLNs removed and in operative note documentation. CONCLUSIONS: Implementation of a surgeon-specific, peer comparison-based metric and tracking system has yielded substantive changes in breast care management. This process and governance structure can serve as a model for quantification of breast care at other institutions and for other disease sites.

Genomic alterations and clinical outcomes in patients with dedifferentiated liposarcoma.

PURPOSE: Patients with unresectable dedifferentiated liposarcoma (DDLPS) have poor overall outcomes. Few genomic alterations have been identified with limited therapeutic options. EXPERIMENTAL DESIGN: Patients treated at Levine Cancer Institute with DDLPS were identified. Next generation sequencing (NGS), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) testing were performed on tumor tissue collected at diagnosis or recurrence/progression. Confirmation of genomic alterations was performed by orthologous methods and correlated with clinical outcomes. Univariate Cox regression was used to identify genomic alterations associated with clinical outcomes. RESULTS: Thirty-eight DDLPS patients with adequate tissue for genomic profiling and clinical data were identified. Patient characteristics included: median age at diagnosis (66 years), race (84.2% Caucasian), and median follow-up time for the entire cohort was 12.1 years with a range from approximately 3.5 months to 14.1 years. Genes involved in cell cycle regulation, including MDM2 (74%) CDK4 (65%), and CDKN2A (23%), were amplified along with WNT/Notch pathway markers: HMGA2, LGR5, MCL1, and CALR (19%-29%). While common gene mutations were identified, PDE4DIP and FOXO3 were also mutated in 47% and 34% of patients, respectively, neither of which have been previously reported. FOXO3 was associated with improved overall survival (OS) (HR 0.37; p = 0.043) along with MAML2 (HR 0.30; p = 0.040). Mutations that portended worse prognosis included RECQL4 (disease-specific survival HR 4.67; p = 0.007), MN1 (OS HR = 3.38; p = 0.013), NOTCH1 (OS HR 2.28, p = 0.086), and CNTRL (OS HR 2.42; p = 0.090). CONCLUSIONS: This is one of the largest retrospective reports analyzing genomic aberrations in relation to clinical outcomes for patients with DDLPS. Our results suggest therapies targeting abnormalities should be explored and confirmation of prognostic markers is needed. Dedifferentiated liposarcoma is one of the most common subtypes of soft tissue sarcoma yet little is known of its molecular aberrations and possible impact on outcomes. The work presented here is an evaluation of genetic abnormalities among a population of patients with dedifferentiated liposarcoma and how they corresponded with survival and risk of metastases. There were notable gene mutations and amplifications commonly found, some of which had interesting prognostic implications.

Survivorship Care Plans Improve the Identification of Post-radiation Hypothyroidism After Head and Neck Cancer Treatment.

BACKGROUND/AIM: Survivorship care programs (SCPs) educate patients on post-treatment side-effects, which may lead to earlier identification and mitigation of their impact. This study assessed the impact of SCP on identification and management of post-treatment hypothyroidism in a head and neck cancer population and evaluated socio-demographic factors in the effectiveness of SCPs. PATIENTS AND METHODS: A retrospective analysis was performed of sociodemographic and clinical characteristics of patients with head and neck cancer treated with radiation therapy between January 2011 and January 2019 at a large community cancer institution. Development of hypothyroidism was defined as elevated thyroid-stimulating hormone (TSH) or initiation of supplementation post-treatment. Cumulative incidence of hypothyroidism was analyzed with Gray's method. RESULTS: Of 608 patients, 483 (79%) had post-treatment TSH surveillance. A total of 203 (42%) of those patients developed hypothyroidism; 53 (11%) patients completed SCPs. The median follow-up was 1.4 (interquartile range=0.7-2.6) years with a median time until diagnosis of hypothyroidism of 1.2 (interquartile range=0.7-2.1) years. The median time to diagnosis was 12.0 months with SCP versus 14.2 months without. Race and insurance status were not associated with differences in thyroid surveillance. Patients with laryngeal cancer were at greatest risk of developing hypothyroidism (hazard ratio=1.92, confidence interval=1.44-2.56; p<0.077). Cumulative incidence of post-treatment hypothyroidism was higher in patients managed with SCP, 65.4% at 4 years, compared to those without (49.0%). Receipt of SCP was independently associated with an increased incidence of hypothyroidism detection (hazard ratio=1.51, confidence interval=1.04-2.20; p=0.030). CONCLUSION: In our experience, SCP utilization was independently associated with a diagnosis of hypothyroidism. This study supports implementation of a survivorship program for identification and management of post-treatment sequelae.

Ectodysplasin-A mRNA in exosomes released from activated hepatic stellate cells stimulates macrophage response.

INTRODUCTION: The interaction between activated hepatic stellate cells (aHSCs) and macrophages is central to liver fibrosis development. The cargo contained within aHSC exosomes (aHSC-EXOs) and how aHSC-EXOs affect macrophage function is poorly understood. METHODS: RNA from aHSC-EXOs was separated into small (<200-basepairs) and large (≥200-basepairs) RNA species, transfected into macrophages, and macrophage IL-6 and TNFα mRNA expression and protein secretion measured. Next generation sequencing was performed on EXOs from rat quiescent and aHSCs and human aHSCs. aHSCs were transfected with siRNA against ectodysplasin-A (EDA), EXOs collected, and their effect on macrophage function analyzed. Human cirrhotic liver was analyzed for EDA mRNA expression and compared to non-tumor liver (NTL). RESULTS: Transfection with large RNA from aHSC-EXOs stimulated macrophage IL-6 and TNFα mRNA expression and protein secretion. EDA mRNA was highly expressed in aHSCs and transfection of aHSCs with EDA-siRNA decreased aHSC-EXO EDA mRNA and blunted the effect of aHSC-EXOs on macrophage function (IL-6/TNFα expression and macrophage migration). Human cirrhotic liver exhibited high EDA mRNA compared to NTL. CONCLUSIONS: HSC activation leads to altered EXO mRNA/miRNA profiles with aHSC-EXOs mRNAs exerting a dominant role in altering macrophage function. Ectodysplasin-A mRNA is an important component in aHSC-EXOs in regulating macrophage function.

Increasing Inclusiveness of Patient-Centric Clinical Evidence Generation in Oncology: Real-World Data and Clinical Trials.

Rapid advancements in cancer discovery, diagnosis, and treatment options available to patients with cancer have highlighted the need for enhancements in clinical trial design. The drug development process is costly, with more than 80% of trials failing to reach recruitment targets. Historical approaches to trial design are increasingly burdensome and lack real-world application in the intent-to-treat patient population. Equitable access to clinical trials combined with increased availability of real-world data are creating new opportunities for inclusiveness, improved outcomes, and evidence-based advances in therapies that will generate more generalizable data to better inform clinical decision-making. Clinical trials need to be inclusive if lifesaving data are not to be missed and investigational therapies are to be more accessible to a broader patient base. Real-world data can facilitate the conduct of studies that are identifying and understanding where disparities exist and developing new interventions to improve patient care. The clinical trial design process should be a multistakeholder and consensus- and evidence-driven process in which stakeholders are working together across the health care industry to close the care gap and ensure elimination of barriers that prevent equal access to specialized cancer care and advanced therapies available in clinical trials. The patient voice is essential throughout the trial process; however, it is often excluded from the design process. Integrating real-world data as well as ensuring patient involvement in early trial design during drug development can enhance enrollment and retention, leading to greater diversity.

Extremity Soft Tissue Sarcoma: A Multi-Institutional Validation of Prognostic Nomograms.

BACKGROUND: Prognostic nomograms for patients with resected extremity soft tissue sarcoma (STS) include the Sarculator and Memorial Sloan Kettering (MSKCC) nomograms. We sought to validate these two nomograms within a large, modern, multi-institutional cohort of resected primary extremity STS patients. METHODS: Resected primary extremity STS patients from 2000 to 2017 were identified across nine high-volume U.S. institutions. Predicted 5- and 10-year overall survival (OS) and distant metastases cumulative incidence (DMCI), and 4-, 8-, and 12-year disease-specific survival (DSS) were calculated with Sarculator and MSKCC nomograms, respectively. Predicted survival probabilities stratified in quintiles were compared in calibration plots to observed survival assessed by Kaplan-Meier estimates. Cumulative incidence was estimated for DMCI. Harrell's concordance index (C-index) assessed discriminative ability of nomograms. RESULTS: A total of 1326 patients underwent resection of primary extremity STS. Common histologies included: undifferentiated pleomorphic sarcoma (35%), fibrosarcoma (13%), and leiomyosarcoma (9%). Median tumor size was 8.0 cm (IQR 4.5-13.0). Tumor grade distribution was: Grade 1 (13%), Grade 2 (9%), Grade 3 (78%). Median OS was 172 months, with estimated 5- and 10-year OS of 70% and 58%. C-indices for 5- and 10-year OS (Sarculator) were 0.72 (95% CI 0.70-0.75) and 0.73 (95% CI 0.70-0.75), and 0.72 (95% CI 0.69-0.75) for 5- and 10-year DMCI. C-indices for 4-, 8-, and 12-year DSS (MSKCC) were 0.71 (95% CI 0.68-0.75). Calibration plots showed good prognostication across all outcomes. CONCLUSIONS: Sarculator and MSKCC nomograms demonstrated good prognostic ability for survival and recurrence outcomes in a modern, multi-institutional validation cohort of resected primary extremity STS patients. External validation of these nomograms supports their ongoing incorporation into clinical practice.

Swallowing dysfunction after minimally invasive oesophagectomy.

OBJECTIVES: Patients undergoing oesophagectomy frequently experience malnutrition, which in combination with the catabolic effects of surgery can result in loss of muscle mass and function. Safe swallowing requires preservation of muscle mass. Swallowing dysfunction puts postoperative patients at risk for aspiration and pneumonia. Modified Barium Swallow Study (MBSS) enables assessment of postoperative swallowing impairments. The current study assessed incidence and risk factors associated with swallowing dysfunction and restricted diet at discharge in patients after oesophagectomy in a high-volume surgical centre. METHODS: Patients with an MBSS after oesophagectomy were identified between March 2015 to April 2020 at a high-volume surgical centre. Swallowing was quantitatively evaluated on MBSS with the Rosenbek Penetration-Aspiration Scale (PAS). Muscle loss was evaluated clinically with preoperative hand grip strength (HGS). Univariable and multivariable logistic and linear regression analyses were performed. RESULTS: 129 patients (87% male; median age 66 years) underwent oesophagectomy with postoperative MBSS. Univariate analysis revealed older age, preoperative feeding tube, lower preoperative HGS and discharge to non-home were associated with aspiration or penetration on MBSS. Age and preoperative feeding tube remained as independent predictors in the multivariable analysis. Both univariate and multivariable analyses revealed increased age and preoperative feeding tube were associated with diet restrictions at discharge. CONCLUSIONS: Swallowing dysfunction after oesophagectomy is correlated with increased age and need for preoperative enteral feeding tube placement. Further research is needed to understand the relationship between muscle loss and aspiration with the goal of enabling preoperative physiological optimisation and patient selection.

PET Imaging and Rate of Pathologic Complete Response in Esophageal Squamous Cell Carcinoma.

BACKGROUND: For locally advanced esophageal squamous cell carcinoma (ESCC), chemoradiation (ChemoRT) followed by surgery offers the best chance of cure, with a 35-50% pathologic complete response (pCR) rate. Given the morbidity of esophagectomy and the possibility of pCR with ChemoRT, a 'watch and wait' strategy has been proposed, particularly for squamous cell carcinoma. The ability to accurately predict which patients will have pCR from ChemoRT is critical in treatment decision making. This study assessed positron emission tomography (PET) in predicting pCR after neoadjuvant ChemoRT for ESCC. METHODS: ESCC patients treated with ChemoRT followed by surgery were identified. Maximum standard uptake value (SUV), metabolic tumor volume, total lesion glycolysis, and first-order textual features of standard deviation, kurtosis and skewness were measured from PET. Univariable and multivariable generalized linear method analyses were performed. A metabolic complete response (mCR) was defined as a post-therapy PET scan with maximum SUV < 4.0. RESULTS: Twenty-seven patients underwent ChemoRT followed by surgery, with overall pCR seen in 11 (41%) patients and radiographic mCR seen in 12 (44%) patients. Final pathology for these 12 patients revealed pCR (ypT0N0M0) in 5 (42%) patients and persistent disease in 7 (58%) patients. Univariate analysis did not reveal PET parameters predictive of pCR. CONCLUSION: Treatment of ESCC with ChemoRT often results in a robust clinical response. Among patients with an mCR after ChemoRT, disease persistence was found in 58%. The inability of PET to predict pCR is important in the context of a 'watch and wait' strategy for ESCC treated with ChemoRT.

Invited Commentary: Standards, Inputs, and Outputs-Strategies for Improving Data-Sharing and Consortia-Based Epidemiologic Research.

Data-sharing improves epidemiologic research, but the sharing of data frustrates epidemiologic researchers. The inefficiencies of current methods and options for data-sharing are increasingly documented and easily understood by any study group that has shared its data and any researcher who has received shared data. In this issue of the Journal, Temprosa et al. (Am J Epidemiol. 2021;191(1):147-158) describe how the Consortium of Metabolomics Studies (COMETS) developed and deployed a flexible analytical platform to eliminate key pain points in large-scale metabolomics research. COMETS Analytics includes an online tool, but its cloud computing and technology are the supporting rather than the leading actors in this script. The COMETS team identified the need to standardize diverse and inconsistent metabolomics and covariate data and models across its many participating cohort studies, and then developed a flexible tool that gave its member studies choices about how they wanted to meet the consortium's analytical requirements. Different specialties will have different specific research needs and will probably continue to use and develop an array of diverse analytical and technical solutions for their projects. COMETS Analytics shows how important-and enabling-the upstream attention to data standards and data consistency is to producing high-quality metabolomics, consortia-based, and large-scale epidemiology research.

Environmental Influences on Sleep in the California Teachers Study Cohort.

Only two-thirds of Americans meet the recommended 7 hours of sleep nightly. Insufficient sleep and circadian disruption have been associated with adverse health outcomes, including diabetes and cardiovascular disease. Several environmental disruptors of sleep have been reported, such as artificial light at night (ALAN) and noise. These studies tended to evaluate exposures individually. We evaluated several spatially derived environmental exposures (ALAN, noise, green space, and air pollution) and self-reported sleep outcomes obtained in 2012-2015 in a large cohort of 51,562 women in the California Teachers Study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for sleep duration and latency. After adjusting for age, race/ethnicity, chronotype, use of sleep medication, and self-reported trouble sleeping, ALAN (per 5 millicandela (mcd)/m2 luminance, OR = 1.13, 95% CI: 1.07, 1.20) and air pollution (per 5 µg/m3 PM2.5, OR = 1.06, 95% CI: 1.04, 1.09) were associated with shorter sleep duration (<7 hours), and noise was associated with longer latency (>15 minutes) (per 10 decibels, OR = 1.05, 95% CI: 1.01, 1.10). Green space was associated with increased duration (per 0.1 units, OR = 0.41, 95% CI: 0.28, 0.60) and decreased latency (per 0.1 units, OR = 0.55, 95% CI: 0.39, 0.78). Further research is necessary to understand how these and other exposures (e.g., diet) perturb an individuals' inherited sleep patterns and contribute to downstream health outcomes.

Preoperative Muscle Strength Is a Predictor of Outcomes After Esophagectomy.

BACKGROUND: Sarcopenia, loss of muscle mass and strength, has been associated with more frequent complications after esophagectomy. This study compared hand-grip strength, muscle mass, and intramuscular adipose tissue as predictors of postoperative outcomes and mortality after esophagectomy. METHODS: Minimally invasive esophagectomy was performed on 175 patients with esophageal cancer. Skeletal muscle index and skeletal muscle density were derived from preoperative CTs. Hand-grip strength was measured using dynamometer. Univariate and multivariable analyses were performed. RESULTS: Preoperative hand-grip strength was normal in 91 (52%), intermediate in 43 (25%), and weak in 41 (23%) patients. Hand-grip strength was significantly correlated with both skeletal muscle index and skeletal muscle density. Postoperative pneumonia occurred in 8/41 (20%) patients with weak strength compared to 4/91 (4%) with normal strength (p = 0.006; Cochran-Armitage Test). Prolonged postoperative ventilation occurred in 11/41 (27%) patients with weak strength compared to 11/91 (12%) with normal strength (p = 0.036). Median length of stay was 9 days in patients with weak strength compared to 7 days for those with normal strength (p = 0.005; Kruskal-Wallis Test). Discharge to non-home location occurred in 15/41 (37%) with weak strength compared to 8/91 (9%) with normal strength (p < 0.001). Postoperative mortality at 90 days was 4/41 (10%) with weak strength compared with no mortalities (0/91) in the normal strength group (p = 0.004). Mortality at 1 year was 18/39 (46%) in patients with weak strength compared to 6/81 (7%) with normal strength, among 158 patients with 1-year follow-up (p < 0.001). CONCLUSIONS: Preoperative hand-grip strength was found to be a powerful predictor of postoperative pneumonia, length of stay, discharge to non-home location, and mortality after esophagectomy.

Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma.

PURPOSE: Doxorubicin is standard therapy for advanced soft-tissue sarcoma (STS) with minimal improvement in efficacy and increased toxicity with addition of other cytotoxic agents. Pembrolizumab monotherapy has demonstrated modest activity and tolerability in previous advanced STS studies. This study combined pembrolizumab with doxorubicin to assess safety and efficacy in frontline and relapsed settings of advanced STS. PATIENTS AND METHODS: This single-center, single-arm, phase II trial enrolled patients with unresectable or metastatic STS with no prior anthracycline therapy. Patients received pembrolizumab 200 mg i.v. and doxorubicin (60 mg/m2 cycle 1 with subsequent escalation to 75 mg/m2 as tolerated). The primary endpoint was safety. Secondary endpoints included overall survival (OS), objective response rate (ORR), and progression-free survival (PFS) based on RECIST v1.1 guidelines. RESULTS: Thirty patients were enrolled (53.3% female; median age 61.5 years; 87% previously untreated) with 4 (13.3%) patients continuing treatment. The study met its primary safety endpoint by prespecified Bayesian stopping rules. The majority of grade 3+ treatment-emergent adverse events were hematologic (36.7% 3+ neutropenia). ORR was 36.7% [95% confidence interval (CI), 19.9-56.1%], with documented disease control in 80.0% (95% CI, 61.4-92.3%) of patients. Ten (33.3%) patients achieved partial response, 1 (3.3%) patient achieved complete response, and 13 (43.3%) patients had stable disease. Median PFS and OS were 5.7 months (6-month PFS rate: 44%) and 17 months (12-month OS rate: 62%), respectively. Programmed cell death ligand-1 (PD-L1) expression was associated with improved ORR, but not OS or PFS. CONCLUSIONS: Combination pembrolizumab and doxorubicin has manageable toxicity and preliminary promising activity in treatment of patients with anthracycline-naive advanced STS.

A multi-institutional validation study of prognostic nomograms for retroperitoneal sarcoma.

BACKGROUND AND OBJECTIVES: Prognostic nomograms for patients undergoing resection of retroperitoneal sarcoma (RPS) include the Sarculator and Memorial Sloan Kettering (MSK) sarcoma nomograms. We sought to validate the Sarculator and MSK nomograms within a large, modern multi-institutional cohort of patients with primary RPS undergoing resection. METHODS: Patients who underwent resection of primary RPS between 2000 and 2017 across nine high-volume US institutions were identified. Predicted 7-year disease-free (DFS) and overall survival (OS) and 4-, 8-, and 12-year disease-specific survival (DSS) were calculated from the Sarculator and MSK nomograms, respectively. Nomogram-predicted survival probabilities were stratified in quintiles and compared in calibration plots to observed survival outcomes assessed by Kaplan-Meier estimates. Discriminative ability of nomograms was quantified by Harrell's concordance index (C-index). RESULTS: Five hundred and two patients underwent resection of primary RPS. Histologies included leiomyosarcoma (30%), dedifferentiated liposarcoma (23%), and well-differentiated liposarcoma (15%). Median tumor size was 14.0 cm (interquartile range [IQR], 8.5-21.0 cm). Tumor grade distribution was: Grade 1 (27%), Grade 2 (17%), and Grade 3 (56%). Median DFS was 31.5 months; 7-year DFS was 29%. Median OS was 93.8 months; 7-year OS was 51%. C-indices for 7-year DFS, and OS by the Sarculator nomogram were 0.65 (95% confidence interval [CI]: 0.62-0.69) and 0.69 (95%CI: 0.65-0.73); plots demonstrated good calibration for predicting 7-year outcomes. The C-index for 4-, 8-, and 12-year DSS by the MSK nomogram was 0.71 (95%CI: 0.67-0.75); plots demonstrated similarly good calibration ability. CONCLUSIONS: In a diverse, modern validation cohort of patients with resected primary RPS, both Sarculator and MSK nomograms demonstrated good prognostic ability, supporting their ongoing adoption into clinical practice.

Hepatic stellate cell-derived exosomes modulate macrophage inflammatory response.

BACKGROUND: Hepatic stellate cell (HSC) differentiation/activation is central to liver fibrosis and is innately linked to the immune response to liver injury. Exosomes (EXOs) are important means of communication between cell populations. This study sought to characterize EXO release from HSCs and the effect of HSC-EXOs on macrophage cytokine release/function. METHODS: Liver from a rat fibrosis model was analyzed for EXO expression and localization. Quiescent and culture-activated rat and mouse HSCs and activated human HSCs were analyzed for microRNA expression. Mouse, rat, and human HSCs were culture-activated and EXOs purified from culture medium prior to addition to macrophages, and interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) mRNA and protein measured. The effect of activated HSC-EXOs on macrophage migration was assayed. RESULTS: Activation of rat HSCs led to increased EXO production in vivo, an effect mirrored by in vitro rat HSC culture-activation. Culture activation of mouse and rat HSCs led to altered EXO microRNA profiles, with a similar microRNA profile detected in activated human HSCs. Addition of activated HSC-EXOs to macrophages stimulated IL-6 and TNFα mRNA expression and protein secretion in mouse and human macrophages, but not for rat HSC-EXO-macrophages. Addition of human EXOs to macrophages stimulated migration, effects mirrored by the direct addition of rhIL-6 and rhTNFα. CONCLUSIONS: HSC-EXOs associate with macrophages and stimulate cytokine synthesis-release and macrophage migration. Constructing a comprehensive understanding of EXO interactions between liver cell populations in the setting of inflammation/fibrosis increases the potential for developing new diagnostic/therapeutic approaches.

Outdoor artificial light at night and risk of non-Hodgkin lymphoma among women in the California Teachers Study cohort.

BACKGROUND: Outdoor artificial light at night (ALAN) has been implicated in a growing number of adverse health outcomes. ALAN is believed to disrupt circadian rhythms and has been associated with increased inflammation, one of the hallmarks of cancer. We examined the association between outdoor ALAN and a cancer strongly associated with autoimmune and inflammatory conditions, non-Hodgkin lymphoma (NHL), in the prospective California Teachers Study cohort. METHODS: Outdoor ALAN was assigned to participant addresses at study baseline (1995-96) through use of the New World Atlas of Artificial Night Sky Brightness. Among 105,937 women followed from 1995 to 2015, linkage to the California Cancer Registry identified 873 incident cases of NHL. Age-stratified Cox proportional hazards models were used to calculate hazard ratios (HR) and 95 % confidence intervals (95 %CI) for overall NHL and the most common NHL subtypes; diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Multivariate analyses adjusted for previously reported subtype specific covariates (e.g. body mass index (BMI) for DLBCL). RESULTS: Compared to the lowest quintile, participants residing in the highest quintile of outdoor ALAN at baseline were more likely to develop NHL (HR = 1.32, 95 %CI = 1.07-1.63), and, in particular, DLBCL (HR = 1.87, 95 %CI = 1.16-3.02). The elevated risk for DLBCL remained statistically significant after adjusting for age, race/ethnicity, BMI, and socioeconomic status (DLBCL:HR = 1.87, 95 %CI = 1.16-3.02, NHL:HR = 1.32, 95 %CI = 1.07-1.63). There was no association between ALAN and FL or CLL/SLL. CONCLUSION: DLBCL risk was elevated among women residing in neighborhoods with greater outdoor ALAN. Future research in circadian disruption and DLBCL may clarify potential biological processes implicated in this association.

Effect of Surgical Approach on Node Harvest in Gastrectomy: Analysis of the National Cancer Database.

BACKGROUND: Gastrectomy is the cornerstone of treatment for gastric cancer. Recent studies demonstrated significant surgical outcome advantages for patients undergoing minimally invasive versus open gastrectomy. Lymph node harvest is an indicator of adequate surgical resection, and greater harvest is associated with improved staging and patient outcomes. This study evaluated lymph node harvest based on surgical approach. METHODS: Gastric adenocarcinoma patients were identified from NCDB who underwent gastrectomy between 2010 and 2016. Patients were classified by surgical approach into three cohorts: robotic, laparoscopic, or open gastrectomy. Clinical and demographic data were collected. Lymph node harvest was compared with univariate analysis and multivariable generalized linear mixed model. Univariate analysis with propensity matching was also performed to control for differences in patient population across cohorts. RESULTS: We identified 10,690 patients that underwent gastrectomy for gastric adenocarcinoma, with 68% males and median age of 66 (IQR 5774) years. 7161 (67%) underwent open, 2841 (26.6%) laparoscopic, and 688 (6.4%) robotic gastrectomy. Multivariable analysis revealed robotic was associated with a significantly higher median node harvest (18, IQR 1326) compared to laparoscopic (17, IQR 1125) and open gastrectomy (16, IQR 1023). Laparoscopic was also associated with significantly higher node harvest then open gastrectomy. Propensity-matched analysis (6950 patients) showed robotic gastrectomy was still associated with significantly higher node harvest (18, IQR 1226) compared to laparoscopic (17, IQR 1125) and open (17, IQR 1124); however, laparoscopic and open were not significantly different. CONCLUSION: Robotic approach is associated with increased node harvest compared to laparoscopic and open approach in gastrectomy patients.

Jejunostomy at the time of esophagectomy is associated with improved short-term perioperative outcomes: analysis of the NSQIP database.

Adequate preoperative and perioperative nutrition has been shown to improve outcomes for patients undergoing esophagectomy. The most effective way to provide enteral nutrition for patients after esophagectomy is via jejunostomy tube. There is an open debate whether a feeding jejunostomy tube is necessary at the time of esophagectomy. This study evaluated short term surgical outcomes for patients undergoing esophagectomy with and without concurrent jejunostomy tube placement. Esophageal cancer patients were identified from the NSQIP database who underwent esophagectomy between 2005 through 2016. Patients were classified into 2 cohorts: patients with concurrent jejunostomy tube placement and those without jejunostomy placement at the time of esophagectomy. Clinical and demographic data was collected. Differences in short term outcomes were assessed by univariate and multivariable analysis, including prolonged hospital stay (>30 days), in-hospital mortality, and 30-day mortality for both cohorts. We identified 8,632 patients that underwent esophagectomy for esophageal cancer with 80% males and mean age of 63.2±10.6 years. Twenty percent (n=1,723) had preoperative weight loss in the 6-month period preceding surgery. Forty-five percent (n=3,900) patients had jejunostomy placement at the time of esophagectomy. Overall, the rate of prolonged hospital stay (P=0.006), in-hospital mortality (P<0.001) and 30-day mortality (P<0.001) were significantly higher in patients without concurrent jejunostomy in both univariable and multivariable models. This study demonstrates that patients with jejunostomy placement at the time of esophagectomy have improved short term perioperative outcomes.

Using Marketing Automation to Modernize Data Collection in the California Teachers Study Cohort.

BACKGROUND: Like other cancer epidemiologic cohorts, the California Teachers Study (CTS) has experienced declining participation to follow-up questionnaires; neither the reasons for these declines nor the steps that could be taken to mitigate these trends are fully understood. METHODS: The CTS offered their 6th study questionnaire (Q6) in the fall of 2017 using an integrated, online system. The team delivered a Web and mobile-adaptive questionnaire to 45,239 participants via e-mail using marketing automation technology. The study's integrated platform captured data on recruitment activities that may influence overall response, including the date and time invitations and reminders were e-mailed and the date and time questionnaires were started and submitted. RESULTS: The overall response rate was 43%. Participants ages 65 to 69 were 25% more likely to participate than their younger counterparts (OR = 1.25; 95% CI, 1.18-1.32) and nonwhite participants were 28% less likely to participate than non-Hispanic white cohort members (OR = 0.72; 95% CI, 0.68-0.76). Previous questionnaire participation was strongly associated with response (OR = 6.07; 95% CI, 5.50-6.70). Invitations sent after 2 pm had the highest response (OR = 1.75; 95% CI, 1.65-1.84), as did invitations sent on Saturdays (OR = 1.48; 95% CI, 1.36-1.60). CONCLUSIONS: An integrated system that captures paradata about questionnaire recruitment and response can enable studies to quantify the engagement patterns and communication desires of cohort members. IMPACT: As cohorts continue to collect scientific data, it is imperative to collect and analyze information on how participants engage with the study.See all articles in this CEBP Focus section, "Modernizing Population Science."

Insights from Adopting a Data Commons Approach for Large-scale Observational Cohort Studies: The California Teachers Study.

BACKGROUND: Large-scale cancer epidemiology cohorts (CEC) have successfully collected, analyzed, and shared patient-reported data for years. CECs increasingly need to make their data more findable, accessible, interoperable, and reusable, or FAIR. How CECs should approach this transformation is unclear. METHODS: The California Teachers Study (CTS) is an observational CEC of 133,477 participants followed since 1995-1996. In 2014, we began updating our data storage, management, analysis, and sharing strategy. With the San Diego Supercomputer Center, we deployed a new infrastructure based on a data warehouse to integrate and manage data and a secure and shared workspace with documentation, software, and analytic tools that facilitate collaboration and accelerate analyses. RESULTS: Our new CTS infrastructure includes a data warehouse and data marts, which are focused subsets from the data warehouse designed for efficiency. The secure CTS workspace utilizes a remote desktop service that operates within a Health Insurance Portability and Accountability Act (HIPAA)- and Federal Information Security Management Act (FISMA)-compliant platform. Our infrastructure offers broad access to CTS data, includes statistical analysis and data visualization software and tools, flexibly manages other key data activities (e.g., cleaning, updates, and data sharing), and will continue to evolve to advance FAIR principles. CONCLUSIONS: Our scalable infrastructure provides the security, authorization, data model, metadata, and analytic tools needed to manage, share, and analyze CTS data in ways that are consistent with the NCI's Cancer Research Data Commons Framework. IMPACT: The CTS's implementation of new infrastructure in an ongoing CEC demonstrates how population sciences can explore and embrace new cloud-based and analytics infrastructure to accelerate cancer research and translation.See all articles in this CEBP Focus section, "Modernizing Population Science."