Local Pentraxin-2 Deficit Is a Feature of Intestinal Fibrosis in Crohn's Disease.

BACKGROUND: Pentraxin-2 (PTX-2) is a homo-pentameric plasma protein showing evidence of antifibrotic activity in Phase 2 clinical trials in idiopathic pulmonary fibrosis (IPF). Whether PTX-2 plays a role in other fibrotic diseases, including intestinal fibrosis which commonly occurs in inflammatory bowel disease (IBD), remains unknown. AIMS: This study aimed to qualitatively and quantitatively assess PTX-2 expression in fibrostenotic Crohn's disease (FCD) and determine whether expression is correlated with postsurgical restenosis. METHODS: Immunohistochemistry was performed in histologic sections of small bowel resected from patients with fibrostenotic Crohn's disease (FCD), comparing strictured segments with adjacent surgical margins from the same patient. Ileal resections from patients without inflammatory bowel disease were examined as controls. RESULTS: PTX-2 signal was analyzed in 18 patients with FCD and 15 patients without IBD and localized predominantly to submucosal vasculature, including arterial subendothelium and internal elastic lamina, and perivascular connective tissue. PTX-2 signal in the surgical margins from patients with FCD strictures (where tissue architecture was normal) was consistently lower than non-IBD samples. Fibrostenotic regions showed increased PTX-2 signal relative to surgical margins from the same patient in 14/15 paired samples. Submucosal/mural PTX-2 signal in fibrostenotic tissue was lower in patients who subsequently experienced re-stenosis (P = 0.015). CONCLUSIONS: This exploratory study is the first analysis of PTX-2 within the intestine, and demonstrates that PTX-2 signal is reduced in the architecturally normal bowel of patients with FCD. Lower submucosal PTX-2 levels in patients with re-stenosis raises the possibility of a protective role of PTX-2 in intestinal fibrosis.

Rapid Deployment of Whole Slide Imaging for Primary Diagnosis in Surgical Pathology at Stanford Medicine: Responding to Challenges of the COVID-19 Pandemic.

CONTEXT.­: Stanford Pathology began stepwise subspecialty implementation of whole slide imaging (WSI) in 2018 soon after the first US Food and Drug Administration approval. In 2020, during the COVID-19 pandemic, the Centers for Medicare & Medicaid Services waived the requirement for pathologists to perform diagnostic tests in Clinical Laboratory Improvement Amendments (CLIA)-licensed facilities. This encouraged rapid implementation of WSI across all surgical pathology subspecialties. OBJECTIVE.­: To present our experience with validation and implementation of WSI at a large academic medical center encompassing a caseload of more than 50 000 cases per year. DESIGN.­: Validation was performed independently for 3 subspecialty services with a diagnostic concordance threshold above 95%. Analysis of user experience, staffing, infrastructure, and information technology was performed after department-wide expansion. RESULTS.­: Diagnostic concordance was achieved in 96% of neuropathology cases, 100% of gynecologic pathology cases, and 98% of immunohistochemistry cases. After full implementation, 8 high-capacity scanners were operational, with whole slide images generated on greater than 2000 slides per weekday, accounting for approximately 80% of histologic slides at Stanford Medicine. Multiple modifications in workflow and information technology were needed to improve performance. Within months of full implementation, most attending pathologists and trainees had adopted WSI for primary diagnosis. CONCLUSIONS.­: WSI across all surgical subspecialities is achievable at scale at an academic medical center; however, adoption required flexibility to adjust workflows and develop tailored solutions. WSI at scale supported the health and safety of medical staff while facilitating high-quality patient care and education during COVID-19 restrictions.

Outcomes after liver transplantation in MPV17 deficiency (Navajo neurohepatopathy): A single-center case series.

BACKGROUND: MPV17-related mitochondrial DNA maintenance defect (MPV17 deficiency) is a rare, autosomal recessive mitochondrial DNA depletion syndrome with a high mortality rate in infancy and early childhood due to progression to liver failure. Liver transplantation for children with MPV17 deficiency has been considered controversial due to uncertainty about the potential progression of extrahepatic manifestations following liver transplantation. METHODS: We describe our institution's experience for two infants diagnosed with infantile MPV17 deficiency who presented in acute on chronic liver failure, but with normal development and normal neurological status who successfully underwent liver transplantation. RESULTS: Both patients underwent successful liver transplantation with normal development and neurological status at 3 years and 16 months post-transplant, respectively. CONCLUSIONS: In this rare disease population, we describe two infants with MPV17 deficiency who underwent liver transplantation for acute on chronic liver failure who continue to have normal development, without progression of neurological disease. MPV17 deficiency should not be considered a contraindication to liver transplantation.

The Role of Temperature in Modifying the Risk of Ozone-Attributable Mortality under Future Changes in Climate: A Proof-of-Concept Analysis.

Air pollution risk assessments typically estimate ozone-attributable mortality counts using concentration-response (C-R) parameters from epidemiologic studies that treat temperature as a potential confounder. However, some recent epidemiologic studies have indicated that temperature can modify the relationship between short-term ozone exposure and mortality, which has potentially important implications when considering the impacts of climate change on public health. This proof-of-concept analysis quantifies counts of temperature-modified ozone-attributable mortality using temperature-stratified C-R parameters from a multicity study in which the pooled ozone-mortality effect coefficients change in concert with daily temperature. Meteorology downscaled from two global climate models is used with a photochemical transport model to simulate ozone concentrations over the 21st century using two emission inventories: one holding air pollutant emissions constant at 2011 levels and another accounting for reduced emissions through the year 2040. The late century climate models project increased summer season temperatures, which in turn yields larger total counts of ozone-attributable deaths in analyses using temperature-stratified C-R parameters compared to the traditional temperature confounder approach. This analysis reveals substantial heterogeneity in the magnitude and distribution of the temperature-stratified ozone-attributable mortality results, which is a function of regional variability in both the C-R relationship and the model-predicted temperature and ozone.

Vascular remodeling of the small pulmonary arteries and measures of vascular pruning on computed tomography.

Pulmonary hypertension is characterized histologically by intimal and medial thickening in the small pulmonary arteries, eventually resulting in vascular "pruning." Computed tomography (CT)-based quantification of pruning is associated with clinical measures of pulmonary hypertension, but it is not established whether CT-based pruning correlates with histologic arterial remodeling. Our sample consisted of 138 patients who underwent resection for early-stage lung adenocarcinoma. From histologic sections, we identified small pulmonary arteries and measured the relative area comprising the intima and media (VWA%), with higher VWA% representing greater histologic remodeling. From pre-operative CTs, we used image analysis algorithms to calculate the small vessel volume fraction (BV5/TBV) as a CT-based indicator of pruning (lower BV5/TBV represents greater pruning). We investigated relationships of CT pruning and histologic remodeling using Pearson correlation, simple linear regression, and multivariable regression with adjustment for age, sex, height, weight, smoking status, and total pack-years. We also tested for effect modification by sex and smoking status. In primary models, more severe CT pruning was associated with greater histologic remodeling. The Pearson correlation coefficient between BV5/TBV and VWA% was -0.41, and in linear regression models, VWA% was 3.13% higher (95% CI: 1.95-4.31%, p < 0.0001) per standard deviation lower BV5/TBV. This association persisted after multivariable adjustment. We found no evidence that these relationships differed by sex or smoking status. Among individuals who underwent resection for lung adenocarcinoma, more severe CT-based vascular pruning was associated with greater histologic arterial remodeling. These findings suggest CT imaging may be a non-invasive indicator of pulmonary vascular pathology.

Biological data annotation via a human-augmenting AI-based labeling system.

Biology has become a prime area for the deployment of deep learning and artificial intelligence (AI), enabled largely by the massive data sets that the field can generate. Key to most AI tasks is the availability of a sufficiently large, labeled data set with which to train AI models. In the context of microscopy, it is easy to generate image data sets containing millions of cells and structures. However, it is challenging to obtain large-scale high-quality annotations for AI models. Here, we present HALS (Human-Augmenting Labeling System), a human-in-the-loop data labeling AI, which begins uninitialized and learns annotations from a human, in real-time. Using a multi-part AI composed of three deep learning models, HALS learns from just a few examples and immediately decreases the workload of the annotator, while increasing the quality of their annotations. Using a highly repetitive use-case-annotating cell types-and running experiments with seven pathologists-experts at the microscopic analysis of biological specimens-we demonstrate a manual work reduction of 90.60%, and an average data-quality boost of 4.34%, measured across four use-cases and two tissue stain types.

Digital Image Analysis for Estimating Stromal CD8+ Tumor-Infiltrating Lymphocytes in Lung Adenocarcinoma.

BACKGROUND: Stromal CD8+ tumor-infiltrating lymphocytes (TILs) are an important prognostic and predictive indicator in non-small cell lung cancer (NSCLC). In this study, we aimed to develop and test the feasibility of a digital image analysis (DIA) workflow for estimating stromal CD8+ TIL density. METHODS: A DIA workflow developed in a software platform (QuPath) was applied to a specified region of interest (ROI) within the stromal compartment of dual PD-L1/CD8 immunostained slides from 50 lung adenocarcinoma patients. A random tree classifier was trained from 25 training cases and applied to 25 test cases. The DIA-estimated CD8+ TIL densities were compared to manual estimates of three pathologists, who independently quantitated the percentage of CD8+ TILs from predefined ROIs in QuPath. RESULTS: The average estimated total stromal cell count per case was 520 (range: 282-816) by QuPath and 551 (range: 265-744) by pathologists. The DIA-estimated CD8+ TIL density (mean = 16.9%) was comparable to pathologists' manual estimates (mean = 15.9%). A paired t-test showed no statistically significant difference between DIA and pathologist estimates of CD8+ TIL density among both training (n = 25, P = 0.55) and test (n = 25, P = 0.34) cases. There was an almost perfect agreement between QuPath and each pathologist's estimates of CD8+ TIL density (κ = 0.85-0.86). CONCLUSIONS: These findings demonstrate the feasibility of applying a DIA workflow for estimating stromal CD8+ TIL density in NSCLC. DIA has the potential to provide an efficient and standardized approach for estimating stromal CD8+ TIL density.

Implementation of Collodion Bag Protocol to Improve Whole-slide Imaging of Scant Gynecologic Curettage Specimens.

BACKGROUND: Digital pathology has been increasingly implemented for primary surgical pathology diagnosis. In our institution, digital pathology was recently deployed in the gynecologic (GYN) pathology practice. A notable challenge encountered in the digital evaluation of GYN specimens was high rates of scanning failure of specimens with fragmented as well as scant tissue. To improve tissue detection failure rates, we implemented a novel use of the collodion bag cell block preparation method. MATERIALS AND METHODS: In this study, we reviewed 108 endocervical curettage (ECC) specimens, representing specimens processed with and without the collodion bag cell block method (n = 56 without collodion bag, n = 52 with collodion bag). RESULTS: Tissue detection failure rates were reduced from 77% (43/56) in noncollodion bag cases to 23/52 (44%) of collodion bag cases, representing a 42% reduction. The median total area of tissue detection failure per level was 0.35 mm2 (interquartile range [IQR]: 0.14, 0.70 mm2) for noncollodion bag cases and 0.08 mm2 (IQR: 0.03, 0.20 mm2) for collodion bag cases. This represents a greater than fourfold reduction in the total area of tissue detection failure per level (P < 0.001). In addition, there were no out-of-focus levels among collodion bag cases, compared to 6/56 (11%) of noncollodion bag cases (median total area = 4.9 mm2). CONCLUSIONS: The collodion bag method significantly improved the digital image quality of fragmented/scant GYN curettage specimens, increased efficiency and accuracy of diagnostic evaluation, and enhanced identification of tissue contamination during processing. The logistical challenges and labor cost of deploying the collodion bag protocol are important considerations for feasibility assessment at an institutional level.

Marked Decrease in CA 19-9 Level Belies Rapidly Progressive Lymphangitic Carcinomatosis in a Case of Metastatic Pancreatic Cancer.

Background: The CA 19-9 tumor marker is commonly used alongside imaging to trend chemotherapy response in patients with pancreatic ductal adenocarcinoma. Presentation: We describe an unusual clinical case of metastatic pancreatic cancer who achieved a marked decline in CA 19-9 but paradoxically developed widespread pulmonary lymphangitic carcinomatosis leading to rapid clinical decline and death. Conclusions: This case highlights the limitations of using the CA 19-9 tumor marker in isolation.

Impact of weather changes on air quality and related mortality in Spain over a 25 year period [1993-2017].

Climate change is a major public health concern. In addition to its direct impacts on temperature patterns and extreme weather events, climate change affects public health indirectly through its influence on air quality. Pollution trends are not only affected by emissions changes but also by weather changes. In this paper we analyze air quality trends in Spain of important air pollutants (C6H6, CO, NO2, NOx, O3, PM10, PM2.5, and SO2) recorded during the last 25 years, from 1993 to 2017. We found substantial reductions in ambient concentration levels for all the pollutants studied except for O3. To assess the influence of recent weather changes on air quality trends we applied generalized additive models (GAMs) using nonparametric smoothing; with and without adjusting for weather parameters including temperature, wind speed, humidity and precipitation frequency. The difference of annual slopes estimated by the models without and with adjusting for these meteorological variables represents the impact of weather changes on pollutant trends, i.e. the 'weather penalty'. The analyses were seasonally and geographically stratified to account for temporal and regional differences across Spain. The results were meta-analyzed to estimate weather penalties on ambient concentration trends at a national level as well as the impact on mortality for the most relevant pollutants. We found significant penalties for most pollutants, implying that air quality would have improved even more during our study period if weather conditions had remained constant. The largest weather influences were found for PM10, with seasonal penalties up to 22 µg⋅m-3 accumulated over the 25-year period in some regions. The national meta-analysis shows penalties of 0.060 µg⋅m-3 per year (95% Confidence Interval, CI: 0.004, 0.116) in cold months and 0.127 µg⋅m-3 per year (95% CI: 0.089, 0.164) in warm months. Penalties of this magnitude would correspond to 129 annual deaths (95% CI: 25, 233), i.e. approximately 3200 deaths over the 25-year period in Spain. According to our results, the health benefits of recent emission abatements for this pollutant in Spain would have been up to 10% greater if weather conditions had remained constant during the last 25 years.

Climate impact on ambient PM2.5 elemental concentration in the United States: A trend analysis over the last 30 years.

Weather impacts on the chemical composition of PM2.5 varies significantly over space and time given the diversity of particle components and the complex mechanisms governing particle formation and removal. In this study, we employed generalized additive models (GAMs) to estimate weather-associated changes in PM2.5 composition in the US during 1988-2017. We considered seven components of ambient PM2.5, which included elemental carbon (EC), organic carbon (OC), nitrate, sulfate, sodium, ammonium, and silicon. The impact of long-term weather changes on each PM2.5 component was defined in our study as "weather penalty". During our study period, temperature increased in four regions, including the Industrial Midwest and Northeast during the warm and cold season; and Upper Midwest and West in the cold season. Wind speed decreased in the both seasons. Relative humidity increased in the warm season and decreased in the cold season. The weather changes between 1988 and 2017 were associated with most PM2.5 components during both warm and cold seasons. The direction and the magnitude of the weather penalty varied considerably over the space and season. In the warm season, our findings suggest a nationwide weather penalty for EC, OC, nitrate, sulfate, sodium, ammonium, and silicon of 0.04, 0.21, 0.04, 0.35, -0.01, 0.05, and 0.01 µg/m3, respectively. In the cold season, the estimated total penalty was 0.04, 0.21, 0.06, 0.04, -0.01, -0.02, and 0.02 µg/m3, respectively.

Synthesis of Harvard Environmental Protection Agency (EPA) Center studies on traffic-related particulate pollution and cardiovascular outcomes in the Greater Boston Area.

The association between particulate pollution and cardiovascular morbidity and mortality is well established. While the cardiovascular effects of nationally regulated criteria pollutants (e.g., fine particulate matter [PM2.5] and nitrogen dioxide) have been well documented, there are fewer studies on particulate pollutants that are more specific for traffic, such as black carbon (BC) and particle number (PN). In this paper, we synthesized studies conducted in the Greater Boston Area on cardiovascular health effects of traffic exposure, specifically defined by BC or PN exposure or proximity to major roadways. Large cohort studies demonstrate that exposure to traffic-related particles adversely affect cardiac autonomic function, increase systemic cytokine-mediated inflammation and pro-thrombotic activity, and elevate the risk of hypertension and ischemic stroke. Key patterns emerged when directly comparing studies with overlapping exposure metrics and population cohorts. Most notably, cardiovascular risk estimates of PN and BC exposures were larger in magnitude or more often statistically significant compared to those of PM2.5 exposures. Across multiple exposure metrics (e.g., short-term vs. long-term; observed vs. modeled) and different population cohorts (e.g., elderly, individuals with co-morbidities, young healthy individuals), there is compelling evidence that BC and PN represent traffic-related particles that are especially harmful to cardiovascular health. Further research is needed to validate these findings in other geographic locations, characterize exposure errors associated with using monitored and modeled traffic pollutant levels, and elucidate pathophysiological mechanisms underlying the cardiovascular effects of traffic-related particulate pollutants. Implications: Traffic emissions are an important source of particles harmful to cardiovascular health. Traffic-related particles, specifically BC and PN, adversely affect cardiac autonomic function, increase systemic inflammation and thrombotic activity, elevate BP, and increase the risk of ischemic stroke. There is evidence that BC and PN are associated with greater cardiovascular risk compared to PM2.5. Further research is needed to elucidate other health effects of traffic-related particles and assess the feasibility of regulating BC and PN or their regional and local sources.

Effect modification of ambient particle mortality by radon: A time series analysis in 108 U.S. cities.

Numerous studies have reported a positive association between ambient fine particles and daily mortality, but little is known about the particle properties or environmental factors that may contribute to these effects. This study assessed potential modification of radon on PM2.5 (particulate matter with an aerodynamic diameter <2.5 µm)-associated daily mortality in 108 U.S. cities using a two-stage statistical approach. First, city- and season-specific PM2.5 mortality risks were estimated using over-dispersed Poisson regression models. These PM2.5 effect estimates were then regressed against mean city-level residential radon concentrations to estimate overall PM2.5 effects and potential modification by radon. Radon exposure estimates based on measured short-term basement concentrations and modeled long-term living-area concentrations were both assessed. Exposure to PM2.5 was associated with total, cardiovascular, and respiratory mortality in both the spring and the fall. In addition, higher mean city-level radon concentrations increased PM2.5-associated mortality in the spring and fall. For example, a 10 µg/m3 increase in PM2.5 in the spring at the 10th percentile of city-averaged short-term radon concentrations (21.1 Bq/m3) was associated with a 1.92% increase in total mortality (95% CI: 1.29, 2.55), whereas the same PM2.5 exposure at the 90th radon percentile (234.2 Bq/m3) was associated with a 3.73% increase in total mortality (95% CI: 2.87, 4.59). Results were robust to adjustment for spatial confounders, including average planetary boundary height, population age, percent poverty and tobacco use. While additional research is necessary, this study suggests that radon enhances PM2.5 mortality. This is of significant regulatory importance, as effective regulation should consider the increased risk for particle mortality in cities with higher radon levels. Implications: In this large national study, city-averaged indoor radon concentration was a significant effect modifier of PM2.5-associated total, cardiovascular, and respiratory mortality risk in the spring and fall. These results suggest that radon may enhance PM2.5-associated mortality. In addition, local radon concentrations partially explain the significant variability in PM2.5 effect estimates across U.S. cities, noted in this and previous studies. Although the concept of PM as a vector for radon progeny is feasible, additional research is needed on the noncancer health effects of radon and its potential interaction with PM. Future air quality regulations may need to consider the increased risk for particle mortality in cities with higher radon levels.

Ambient Temperature and Sudden Infant Death Syndrome in the United States.

BACKGROUND: Sudden infant death syndrome (SIDS) is a leading cause of infant mortality in the United States. While thermal stress is implicated in many risk factors for SIDS, the association between ambient temperature and SIDS remains unclear. METHODS: We obtained daily individual-level infant mortality data and outdoor temperature data from 1972 to 2006 for 210 US cities. We applied a time-stratified case-crossover analysis to determine the effect of ambient temperature on the risk of SIDS by season. We stratified the analysis by race, infant age, and climate. RESULTS: There were a total of 60,364 SIDS cases during our study period. A 5.6°C (10°F) higher daily temperature on the same day was associated with an increased SIDS risk of 8.6% (95% confidence interval [CI] = 3.6%, 13.8%) in the summer, compared with a 3.1% decrease (95% CI = -5.0%, -1.3%) in the winter. Summer risks were greater among black infants (18.5%; 95% CI = 9.3%, 28.5%) than white infants (3.6%; 95% CI = -2.3%, 9.9%), and among infants 3-11 months old (16.9%; 95% CI = 8.9%, 25.5%) than infants 0-2 months old (2.7%; 95% CI = -3.5%, 9.2%). The temperature-SIDS association was stronger in climate clusters in the Midwest and surrounding northern regions. CONCLUSIONS: Temperature increases were associated with an elevated risk of SIDS in the summer, particularly among infants who were black, 3 months old and older, and living in the Midwest and surrounding northern regions.

Body mass index and risk of colorectal carcinoma subtypes classified by tumor differentiation status.

Previous studies suggest that abnormal energy balance status may dysregulate intestinal epithelial homeostasis and promote colorectal carcinogenesis, yet little is known about how host energy balance and obesity influence enterocyte differentiation during carcinogenesis. We hypothesized that the association between high body mass index (BMI) and colorectal carcinoma incidence might differ according to tumor histopathologic differentiation status. Using databases of the Nurses' Health Study and Health Professionals Follow-up Study, and duplication-method Cox proportional hazards models, we prospectively examined an association between BMI and the incidence of colorectal carcinoma subtypes classified by differentiation features. 120,813 participants were followed for 26 or 32 years and 1528 rectal and colon cancer cases with available tumor pathological data were documented. The association between BMI and colorectal cancer risk significantly differed depending on the presence or absence of poorly-differentiated foci (Pheterogeneity = 0.006). Higher BMI was associated with a higher risk of colorectal carcinoma without poorly-differentiated foci (≥30.0 vs. 18.5-22.4 kg/m2: multivariable-adjusted hazard ratio, 1.87; 95% confidence interval, 1.49-2.34; Ptrend < 0.001), but not with risk of carcinoma with poorly-differentiated foci (Ptrend = 0.56). This differential association appeared to be consistent in strata of tumor microsatellite instability or FASN expression status, although the statistical power was limited. The association between BMI and colorectal carcinoma risk did not significantly differ by overall tumor differentiation, mucinous differentiation, or signet ring cell component (Pheterogeneity > 0.03, with the adjusted α of 0.01). High BMI was associated with risk of colorectal cancer subtype containing no poorly-differentiated focus. Our findings suggest that carcinogenic influence of excess energy balance might be stronger for tumors that retain better intestinal differentiation throughout the tumor areas.

Dietary glycemic and insulin scores and colorectal cancer survival by tumor molecular biomarkers.

Accumulating evidence suggests that post-diagnostic insulin levels may influence colorectal cancer (CRC) survival. Yet, no previous study has examined CRC survival in relation to a post-diagnostic diet rich in foods that increase post-prandial insulin levels. We hypothesized that glycemic and insulin scores (index or load; derived from food frequency questionnaire data) may be associated with survival from specific CRC subtypes sensitive to the insulin signaling pathway. We prospectively followed 1,160 CRC patients from the Nurses' Health Study (1980-2012) and Health Professionals Follow-Up Study (1986-2012), resulting in 266 CRC deaths in 10,235 person-years. CRC subtypes were defined by seven tumor biomarkers (KRAS, BRAF, PIK3CA mutations, and IRS1, IRS2, FASN and CTNNB1 expression) implicated in the insulin signaling pathway. For overall CRC and each subtype, hazard ratio (HR) and 95% confidence interval (95% CI) for an increase of one standard deviation in each of glycemic and insulin scores were estimated using time-dependent Cox proportional hazards model. We found that insulin scores, but not glycemic scores, were positively associated with CRC mortality (HR = 1.19, 95% CI = 1.02-1.38 for index; HR = 1.23, 95% CI = 1.04-1.47 for load). The significant positive associations appeared more pronounced among PIK3CA wild-type cases and FASN-negative cases, with HR ranging from 1.36 to 1.60 across insulin scores. However, we did not observe statistically significant interactions of insulin scores with PIK3CA, FASN, or any other tumor marker (p interaction > 0.12). While additional studies are needed for definitive evidence, a high-insulinogenic diet after CRC diagnosis may contribute to worse CRC survival.

Utility of Clinical Risk Stratification in the Selection of Muscle-Invasive Bladder Cancer Patients for Neoadjuvant Chemotherapy: A Retrospective Cohort Study.

Introduction: Level I evidence supports the use of cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer prior to radical cystectomy (RC). On average, 30-40% of patients achieve a complete pathologic response (i.e., stage pT0) after receiving NAC. Some centers risk-stratify patients, suggesting that there may be a higher-risk population that would derive the most benefit from NAC. Recently, a risk-stratification model developed at M.D. Anderson Cancer Center (MDACC) specified criteria for clinical staging and patient selection for NAC. We applied this model to our own RC patient cohort and evaluated our own experience with clinical risk stratification and the effect of NAC on post treatment risk categories. Methods: We retrospectively reviewed the charts of consecutive patients who underwent RC at two institutions between 2004 and 2014 and noted whether or not they received NAC. We determined the clinical stage by reviewing the exam under anesthesia, transurethral resection biopsy (TURBT) pathology, and preoperative imaging. Patients with cT2-T4a node-negative disease were included. Those with sarcomatoid features or adenocarcinoma were excluded. Patients were classified as high risk if they had tumor-associated hydronephrosis, clinical stage≥T3b-T4a disease, variant histology (i.e., micropapillary or small cell), or lymphovascular invasion (LVI), as specified by the MDACC model. Variables were examined for associations with cancer-specific survival (CSS), overall survival (OS), and risk-category reclassification. Results: We identified 166 patients with a median follow-up time of 22.2 months. In all, 117 patients (70.5%) did not receive NAC, 68 (58.1%) of whom we classified as high risk. Among patients not receiving NAC, CSS and OS were significantly decreased in high-risk patients (log-rank test p = 0.01 for both comparisons). The estimated age-adjusted hazard ratios of high-risk classification for cancer-specific and overall death were 3.2 (95% CI: 1.2 to 8.6) and 2.2 (95% CI: 1.1 to 4.4), respectively. On post-RC final pathology, 23 (46.9%) low-risk patients were up-classified to high risk and 17 (25.0%) high-risk patients were down-classified. Complete pathologic responses (pT0) were achieved in 7 (6.0%) patients and partial responses (pT1, pTa, pTis) were achieved in 28 (23.9%) patients. Of the 49 patients who did receive NAC, 43 (87.8%) received cisplatin-based and six (12.2%) received carboplatin-based regimens. Applying the MDACC model, we categorized 41 (83.7%) patients as high risk prior to NAC treatment. On final pathology, 3 (37.5%) low-risk patients were up-classified and 17 (41.5%) high-risk patients were down-classified. Complete pathologic responses (pT0) were seen in 13 (26.5%) patients and partial responses were seen in 10 (20.4%) patients. Although the utilization of NAC was not statistically significantly associated with CSS or OS (log-rank test p > 0.05 for both comparisons), it was associated with a 1.2 times increased odds (95% CI: 0.4 to 2.1) of post-RC reclassification from high to low risk on age-adjusted logistic regression. Conclusions: We found similar results using the clinical risk-stratification model in our cohort and showed that the high-risk category was associated with lower CSS and OS. NAC was associated with a higher probability of risk reclassification from high to low risk.

School Environmental Intervention to Reduce Particulate Pollutant Exposures for Children with Asthma.

BACKGROUND: Home-based interventions to improve indoor air quality have demonstrated benefits for asthma morbidity, yet little is known about the effect of environmental interventions in the school setting. OBJECTIVE: We piloted the feasibility and effectiveness of a classroom-based air cleaner intervention to reduce particulate pollutants in classrooms of children with asthma. METHODS: In this pilot randomized controlled trial, we assessed the effect of air cleaners on indoor air particulate pollutant concentrations in 18 classrooms (9 control, 9 intervention) in 3 urban elementary schools. We enrolled 25 children with asthma (13 control, 12 intervention) aged 6 to 10 years. Classroom air pollutant measurements and spirometry were completed once before and twice after randomization. Asthma symptoms were surveyed every 3 months. RESULTS: Baseline classroom levels of fine particulate matter (particulate matter with diameter of <2.5 µm [PM2.5]) and black carbon (BC) were 6.3 and 0.41 µg/m3, respectively. When comparing the intervention to the control group, classroom PM2.5 levels were reduced by 49% and 42% and BC levels were reduced by 58% and 55% in the first and second follow-up periods, respectively (P < .05 for all comparisons). When comparing the children randomized to intervention and control classrooms, there was a modest improvement in peak flow, but no significant changes in forced expiratory volume in 1 second (FEV1) and asthma symptoms. CONCLUSIONS: In this pilot study, a classroom-based air cleaner intervention led to significant reductions in PM2.5 and BC. Future large-scale studies should comprehensively evaluate the effect of school-based environmental interventions on pediatric asthma morbidity.

Integration of pharmacology, molecular pathology, and population data science to support precision gastrointestinal oncology.

Precision medicine has a goal of customizing disease prevention and treatment strategies. Under the precision medicine paradigm, each patient has unique pathologic processes resulting from cellular genomic, epigenomic, proteomic, and metabolomic alterations, which are influenced by pharmacological, environmental, microbial, dietary, and lifestyle factors. Hence, to realize the promise of precision medicine, multi-level research methods that can comprehensively analyze many of these variables are needed. In order to address this gap, the integrative field of molecular pathology and population data science (i.e., molecular pathological epidemiology) has been developed to enable such multi-level analyses, especially in gastrointestinal cancer research. Further integration of pharmacology can improve our understanding of drug effects, and inform decision-making of drug use at both the individual and population levels. Such integrative research demonstrated potential benefits of aspirin in colorectal carcinoma with PIK3CA mutations, providing the basis for new clinical trials. Evidence also suggests that HPGD (15-PDGH) expression levels in normal colon and the germline rs6983267 polymorphism that relates to tumor CTNNB1 (ß-catenin)/WNT signaling status may predict the efficacy of aspirin for cancer chemoprevention. As immune checkpoint blockade targeting the CD274 (PD-L1)/PDCD1 (PD-1) pathway for microsatellite instability-high (or mismatch repair-deficient) metastatic gastrointestinal or other tumors has become standard of care, potential modifying effects of dietary, lifestyle, microbial, and environmental factors on immunotherapy need to be studied to further optimize treatment strategies. With its broad applicability, our integrative approach can provide insights into the interactive role of medications, exposures, and molecular pathology, and guide the development of precision medicine.