Survival analysis under imperfect record linkage using historic census data.

BACKGROUND: Advancements in linking publicly available census records with vital and administrative records have enabled novel investigations in epidemiology and social history. However, in the absence of unique identifiers, the linkage of the records may be uncertain or only be successful for a subset of the census cohort, resulting in missing data. For survival analysis, differential ascertainment of event times can impact inference on risk associations and median survival. METHODS: We modify some existing approaches that are commonly used to handle missing survival times to accommodate this imperfect linkage situation including complete case analysis, censoring, weighting, and several multiple imputation methods. We then conduct simulation studies to compare the performance of the proposed approaches in estimating the associations of a risk factor or exposure in terms of hazard ratio (HR) and median survival times in the presence of missing survival times. The effects of different missing data mechanisms and exposure-survival associations on their performance are also explored. The approaches are applied to a historic cohort of residents in Ambler, PA, established using the 1930 US census, from which only 2,440 out of 4,514 individuals (54%) had death records retrievable from publicly available data sources and death certificates. Using this cohort, we examine the effects of occupational and paraoccupational asbestos exposure on survival and disparities in mortality by race and gender. RESULTS: We show that imputation based on conditional survival results in less bias and greater efficiency relative to a complete case analysis when estimating log-hazard ratios and median survival times. When the approaches are applied to the Ambler cohort, we find a significant association between occupational exposure and mortality, particularly among black individuals and males, but not between paraoccupational exposure and mortality. DISCUSSION: This investigation illustrates the strengths and weaknesses of different imputation methods for missing survival times due to imperfect linkage of the administrative or registry data. The performance of the methods may depend on the missingness process as well as the parameter being estimated and models of interest, and such factors should be considered when choosing the methods to address the missing event times.

Exogenous Insulin Therapy Is Associated with the Risk of Advanced Colorectal Adenoma in Patients with Diabetes Mellitus.

BACKGROUND/AIMS: Exogenous insulin therapy increases systemic exposure to insulin which may promote the development of colorectal neoplasia. We sought to evaluate the association between exogenous insulin therapy and the incidence of advanced adenoma in type 2 diabetes mellitus. METHODS: A retrospective cohort study was conducted from January 1, 2007, to January 1, 2018, in a regional health system serving the United States Philadelphia metropolitan area, Central New Jersey, and South Central Pennsylvania. Study patients consisted of a random sample of patients with type 2 diabetes mellitus aged 40-80 years who had undergone two rounds of colonoscopy examinations. The exposure was cumulative duration of insulin therapy (i.e., no use, 1-365 days and > 365 days). The outcome was time to incident advanced adenoma. RESULTS: Of the 975 eligible patients, 184 patients accumulated > 365 days of insulin therapy before the follow-up colonoscopy. The mean (standard deviation) duration between the two rounds of colonoscopy examination was 5.1 (2.9) years among the insulin users and 5.3 (3.9) years among non-users. Compared to no insulin exposure, receiving > 365 days of insulin therapy was associated with an increased incidence of advanced adenoma (adjusted hazard ratio [aHR] 4.84, 95% confidence interval [CI] 2.82-8.30), right-sided advanced adenoma (aHR 5.48, 95% CI 2.90-10.35), and 3 or more adenomas (aHR 2.61, 95% CI 1.46-4.69) at the follow-up colonoscopy examination. CONCLUSION: Insulin therapy is associated with an increased risk of advanced adenoma and may serve as a novel risk-stratification factor to enhance the efficiency of existing colorectal cancer screening and surveillance programs.

Liquid Chromatography-Mass Spectrometry Analysis of Frataxin Proteoforms in Whole Blood as Biomarkers of the Genetic Disease Friedreich's Ataxia.

Friedreich's ataxia (FRDA) is caused primarily by expanded GAA repeats in intron 1 of both alleles of the FXN gene, which causes transcriptional silencing and reduced expression of frataxin mRNA and protein. FRDA is characterized by slowly progressive ataxia and cardiomyopathy. Symptoms generally appear during adolescence, and patients slowly progress to wheelchair dependency usually in the late teens or early twenties with death on average in the 4th decade. There are two known mature proteoforms of frataxin. Mitochondrial frataxin (frataxin-M) is a 130-amino acid protein with a molecular weight of 14,268 Da, and there is an alternatively spliced N-terminally acetylated 135-amino acid form (frataxin-E) with a molecular weight of 14,953 Da found in erythrocytes. There is reduced expression of frataxin in the heart and brain, but frataxin is not secreted into the systemic circulation, so it cannot be analyzed in serum or plasma. Blood is a readily accessible biofluid that contains numerous different cell types that express frataxin. We have found that pig blood can serve as an excellent surrogate matrix to validate an assay for frataxin proteoforms because pig frataxin is lost during the immunoprecipitation step used to isolate human frataxin. Frataxin-M is expressed in blood cells that contain mitochondria, whereas extra-mitochondrial frataxin-E is found in erythrocytes. This means that the analysis of frataxin in whole blood provides information on the concentration of both proteoforms without having to isolate the individual cell types. In the current study, we observed that the distributions of frataxin levels for a sample of 25 healthy controls and 50 FRDA patients were completely separated from each other, suggesting 100% specificity and 100% sensitivity for distinguishing healthy controls from FRDA cases, a very unusual finding for a biomarker assay. Additionally, frataxin levels were significantly correlated with the GAA repeat length and age of onset with higher correlations for extra-mitochondrial frataxin-E than those for mitochondrial frataxin-M. These findings auger well for using frataxin levels measured by the validated stable isotope dilution ultrahigh-performance liquid chromatography-multiple reaction monitoring/mass spectrometry assay to monitor therapeutic interventions and the natural history of FRDA. Our study also illustrates the utility of using whole blood for protein disease biomarker discovery and validation.

Estimating the effect size of a hidden causal factor between SNPs and a continuous trait: a mediation model approach.

BACKGROUND: Observational studies and Mendelian randomization experiments have been used to identify many causal factors for complex traits in humans. Given a set of causal factors, it is important to understand the extent to which these causal factors explain some, all, or none of the genetic heritability, as measured by single-nucleotide polymorphisms (SNPs) that are associated with the trait. Using the mediation model framework with SNPs as the exposure, a trait of interest as the outcome, and the known causal factors as the mediators, we hypothesize that any unexplained association between the SNPs and the outcome trait is mediated by an additional unobserved, hidden causal factor. RESULTS: We propose a method to infer the effect size of this hidden mediating causal factor on the outcome trait by utilizing the estimated associations between a continuous outcome trait, the known causal factors, and the SNPs. The proposed method consists of three steps and, in the end, implements Markov chain Monte Carlo to obtain a posterior distribution for the effect size of the hidden mediator. We evaluate our proposed method via extensive simulations and show that when model assumptions hold, our method estimates the effect size of the hidden mediator well and controls type I error rate if the hidden mediator does not exist. In addition, we apply the method to the UK Biobank data and estimate parameters for a potential hidden mediator for waist-hip ratio beyond body mass index (BMI), and find that the hidden mediator has a large effect size relatively to the effect size of the known mediator BMI. CONCLUSIONS: We develop a framework to infer the effect of potential, hidden mediators influencing complex traits. This framework can be used to place boundaries on unexplained risk factors contributing to complex traits.

Identification of spatio-temporal clusters of lung cancer cases in Pennsylvania, USA: 2010-2017.

BACKGROUND: It is known that geographic location plays a role in developing lung cancer. The objectives of this study were to examine spatio-temporal patterns of lung cancer incidence in Pennsylvania, to identify geographic clusters of high incidence, and to compare demographic characteristics and general physical and mental health characteristics in those areas. METHOD: We geocoded the residential addresses at the time of diagnosis for lung cancer cases in the Pennsylvania Cancer Registry diagnosed between 2010 and 2017. Relative risks over the expected case counts at the census tract level were estimated using a log-linear Poisson model that allowed for spatial and temporal effects. Spatio-temporal clusters with high incidence were identified using scan statistics. Demographics obtained from the 2011-2015 American Community Survey and health variables obtained from 2020 CDC PLACES database were compared between census tracts that were part of clusters versus those that were not. RESULTS: Overall, the age-adjusted incidence rates and the relative risk of lung cancer decreased from 2010 to 2017 with no statistically significant space and time interaction. The analyses detected 5 statistically significant clusters over the 8-year study period. Cluster 1, the most likely cluster, was in southeastern PA including Delaware, Montgomery, and Philadelphia Counties from 2010 to 2013 (log likelihood ratio = 136.6); Cluster 2, the cluster with the largest area was in southwestern PA in the same period including Allegheny, Fayette, Greene, Washington, and Westmoreland Counties (log likelihood ratio = 78.6). Cluster 3 was in Mifflin County from 2014 to 2016 (log likelihood ratio = 25.3), Cluster 4 was in Luzerne County from 2013 to 2016 (log likelihood ratio = 18.1), and Cluster 5 was in Dauphin, Cumberland, and York Counties limited to 2010 to 2012 (log likelihood ratio = 17.9). Census tracts that were part of the high incidence clusters tended to be densely populated, had higher percentages of African American and residents that live below poverty line, and had poorer mental health and physical health when compared to the non-clusters (all p < 0.001). CONCLUSIONS: These high incidence areas for lung cancer warrant further monitoring for other individual and environmental risk factors and screening efforts so lung cancer cases can be identified early and more efficiently.

Validating the Factor Structure of the Psychosocial Assessment Tool Using Internet-Based Data.

OBJECTIVE: The Psychosocial Assessment Tool (PAT) is a well-validated, brief screener of family psychosocial risk. Since 2014 a web-based version of the PAT (WebPAT) has been available for use by clinicians and researchers, but the psychometric properties have not been examined. The objective of this article was to examine the factor structure and internal consistency of the WebPAT, which was administered to caregivers of youth with cancer. METHODS: The WebPAT was administered to 1,252 caregivers of youth with cancer across 29 institutions. Confirmatory factor analysis (CFA) was used to examine the factor structure of the WebPAT. Internal consistencies of the total and subscale scores were examined via the Kuder-Richardson 20 coefficient. The distribution of total PAT score across the three risk categories of the Pediatric Psychosocial Preventative Health Model (PPPHM) was also examined. RESULTS: The CFA supported the original seven-factor structure of the PAT (Family Structure, Social Support, Child Problems, Sibling Problems, Family Problems, Stress Reactions, and Family Beliefs). Internal consistencies were strong for the total PAT score and four subscales (Social Support, Child Problems, Sibling Problems, and Family Problems). The distribution of total PAT scores across PPPHM risk categories was consistent with prior research. CONCLUSIONS: The WebPAT is a psychometrically sound screener of psychosocial risk in families of youth with cancer. Healthcare providers can use the WebPAT to assess families' psychosocial risk and guide the provision of psychosocial care. Future research should evaluate the implementation of the PAT and identify barriers and facilitators to implementation.

Autologous CD4 T Lymphocytes Modified with a Tat-Dependent, Virus-Specific Endoribonuclease Gene in HIV-Infected Individuals.

MazF is an Escherichia coli-derived endoribonuclease that selectively cleaves ACA sequences of mRNA prevalent in HIV. We administered a single infusion of autologous CD4 T lymphocytes modified to express a Tat-dependent MazF transgene to 10 HIV-infected individuals (six remaining on antiretroviral therapy [ART]; four undergoing treatment interruption post-infusion) in order to provide a population of HIV-resistant immune cells. In participants who remained on ART, increases in CD4 and CD8 T cell counts of ~200 cells/mm3 each occurred within 2 weeks of infusion and persisted for at least 6 months. Modified cells were detectable for several months in the blood and trafficked to gastrointestinal lymph tissue. HIV-1 Tat introduced ex vivo to the modified CD4+ T cells induced MazF expression in both pre- and post-infusion samples, and MazF expression was detected in vivo post-viral-rebound during ATI. One participant experienced mild cytokine release syndrome. In sum, this study of a single infusion of MazF-modified CD4 T lymphocytes demonstrated safety of these cells, distribution to lymph tissue and maintenance of Tat-inducible MazF endoribonuclease activity, as well as sustained elevation of blood CD4 and CD8 T cell counts. Future studies to assess effects on viremia and latent proviral reservoir are warranted.

Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer.

OBJECTIVE: Platinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Preclinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) are synergistic. CAPRI (NCT03462342) is an investigator-initiated study of olaparib plus ceralasertib in recurrent HGSOC. Herein, we present results from the platinum-resistant cohort. METHODS: A Simon 2-stage design was utilized. Platinum-resistant HGSOC patients received ceralasertib 160 mg orally daily, days 1-7 and olaparib 300 mg orally twice daily, days 1-28 of a 28-day cycle until toxicity or progression. Primary endpoints were toxicity and efficacy including objective response rate (ORR) by RECIST. Secondary endpoint was progression-free survival (PFS). The null hypothesis (≤5% ORR) would be rejected if there were ≥ 1 responses in 12 patients. RESULTS: Fourteen PARPi-naïve patients were evaluable for toxicity; 12 were evaluable for response. Three had BRCA1 mutations (1 germline, 2 somatic). Adverse events possibly related to treatment were primarily grade (G) 1/2. G3 toxicities included nausea (14.3%), fatigue (7.1%), anorexia (7.1%), and anemia (7.1%). No objective responses occurred. Best response was stable disease in 9 patients and progressive disease in three. Five patients had a ≥ 20% to <30% reduction in disease burden, including 3 with BRCA1 mutations. Three of 11 patients (27%; 2 with BRCA1 mutations) evaluable by Gynecologic Cancer Intergroup criteria had >50% CA-125 decline, including 2 with CA-125 normalization. Median PFS was 4.2 months overall (90% CI:3.5-8.2) and 8.2 months (3.6 months-not determined) for patients with BRCA1 mutations. CONCLUSIONS: Olaparib plus ceralasertib is well-tolerated. No objective responses occurred, though a signal of activity was seen particularly in disease associated with BRCA1. Further evaluation of this combination should include alternate dosing strategies in genomically-selected populations.

Copper Oxide Nanoparticle-Induced Acute Inflammatory Response and Injury in Murine Lung Is Ameliorated by Synthetic Secoisolariciresinol Diglucoside (LGM2605).

Metal-oxide nanoparticles (MO-NPs), such as the highly bioreactive copper-based nanoparticles (CuO-NPs), are widely used in manufacturing of hundreds of commercial products. Epidemiological studies correlated levels of nanoparticles in ambient air with a significant increase in lung disease. CuO-NPs, specifically, were among the most potent in a set of metal-oxides and carbons studied in parallel regarding DNA damage and cytotoxicity. Despite advances in nanotoxicology research and the characterization of their toxicity, the exact mechanism(s) of toxicity are yet to be defined. We identified chlorination toxicity as a damaging consequence of inflammation and myeloperoxidase (MPO) activation, resulting in macromolecular damage and cell damage/death. We hypothesized that the inhalation of CuO-NPs elicits an inflammatory response resulting in chlorination damage in cells and lung tissues. We further tested the protective action of LGM2605, a synthetic small molecule with known scavenging properties for reactive oxygen species (ROS), but most importantly, for active chlorine species (ACS) and an inhibitor of MPO. CuO-NPs (15 µg/bolus) were instilled intranasally in mice and the kinetics of the inflammatory response in lungs was evaluated 1, 3, and 7 days later. Evaluation of the protective action of LGM2605 was performed at 24 h post-challenge, which was selected as the peak acute inflammatory response to CuO-NP. LGM2605 was given daily via gavage to mice starting 2 days prior to the time of the insult (100 mg/kg). CuO-NPs induced a significant inflammatory influx, inflammasome-relevant cytokine release, and chlorination damage in mouse lungs, which was mitigated by the action of LGM2605. Preventive action of LGM2605 ameliorated the adverse effects of CuO-NP in lung.

Association of Age with Efficacy of Immunotherapy in Metastatic Melanoma.

Management of melanoma has been revolutionized by the use of immune checkpoint inhibitors. Immune system changes associated with aging may affect the efficacy of immune-based therapies. Using the National Cancer Database, we evaluated the impact of age on the receipt and efficacy of modern immunotherapies in patients with metastatic melanoma. We identified 11,944 patients from 2011-2015, of whom 25% received immunotherapy. Older (≥60 years), compared with younger, patients were less likely to receive immunotherapy (odds ratio, 0.69; 95% confidence interval [CI], 0.61-0.78; p < .001). Immunotherapy was associated with a survival benefit in both younger and older patients (<60 years: hazard ratio [HR], 0.64; 95% CI, 0.57-0.72; p < .001; ≥60 years: HR, 0.55; 95% CI, 0.50-0.60; p < .001). Importantly, there was a statistically significant interaction between age and survival with immunotherapy, where a greater benefit was observed for older patients (pinteraction = 0.013). Further work studying the age-related response to immunotherapy is warranted.

Stability and change in family psychosocial risk over 6 months in pediatric cancer and its association with medical and psychosocial healthcare utilization.

PURPOSE: Family psychosocial risk in pediatric oncology can be assessed using the Psychosocial Assessment Tool (PAT), a brief parent report screener based on the Pediatric Psychosocial Preventative Health Model (PPPHM; universal, targeted, and clinical). However, little is known about risk over the course of treatment and its association with medical and psychosocial healthcare utilization. METHODS: Primary caregivers of children with cancer participated in this prospective multisite investigation, completing the PAT at diagnosis (T1; n = 396) and 6 months later (T2; n = 304). Healthcare utilization data were extracted from electronic health records. RESULTS: The distribution of PPPHM risk levels at T1 and T2 was highly consistent for the samples. Two-thirds of families remained at the same level of risk, 18% decreased and 16% increased risk level. Risk was not related to sociodemographic or treatment variables. The PAT risk score correlated with psychosocial contacts over the 6-month period. CONCLUSIONS: Although the majority of families reported universal (low) risk on the PAT and were stable in their risk level over 6 months, reassessing risk is helpful in identifying those families who report higher level of risk during treatment than at diagnosis. PAT scores were related to psychosocial services that are provided to most but not all families and could be tailored more specifically to match risk and delivery of evidence-based care.

Diversity by Race, Ethnicity, and Sex within the US Psychiatry Physician Workforce.

OBJECTIVE: This study assessed the distribution of race, ethnicity, and sex within the US psychiatry physician workforce and trends from 1987 to 2016. METHODS: The authors used physician workforce data to assess differences in race, ethnicity, and sex among psychiatric practicing physicians, faculty, fellows, residents, residency applicants, and medical graduate cohorts. Binomial tests were used for comparison between individual cohorts and to US population statistics. A simple linear regression model was used to assess trends among psychiatric residents and faculty over years 1987-2016. RESULTS: Within psychiatry, historically underrepresented minorities in medicine (URMs) had less representation as residents (16.2%), faculty (8.7%), and practicing physicians (10.4%) compared with the US population (32.6%), Ps < 0.0001. Females were underrepresented as psychiatric practicing physicians (38.5%, P < .0001). There was greater URM representation among residents (16.2%) compared with that of Psychiatry faculty and practicing physicians (Ps < .0001). Racial/ethnic representation did not differ significantly compared with subspecialty fellows; however, the addiction subspecialty contained the least URM and female diversity. Historical trends indicated the proportion of female faculty (0.9%/yr) increased nearly 1.5 times faster than that of female trainees (0.6%/year). Conversely, the proportion of URM residents (0.26%/year) increased over 4 times faster than that of URM faculty (0.06%/year), with black faculty actually decreasing in proportion. CONCLUSIONS: Female and URM representation within the psychiatry physician workforce is significantly lower than US population demographics; however, trends indicate diminishing underrepresentation. While psychiatry residency remains more diverse than other specialties, specific trends identify poor minority representation among psychiatry faculty and fellows as areas needing attention.

Screening for Family Psychosocial Risk in Pediatric Hematopoietic Stem Cell Transplantation with the Psychosocial Assessment Tool.

Family psychosocial risk screening is an important initial step in delivering evidence-based care in hematopoietic stem cell transplantation (HCT). Establishing an evidence-based screening approach that is acceptable, reliable, and valid is an essential step in psychosocial care delivery. This is a 3-institution multimethod study. In part 1, caregivers of children about to undergo HCT (n = 140) completed the Psychosocial Assessment Tool-Hematopoietic Cell Transplantation (PAT-HCT), a brief parent report screener adapted for HCT, and validating questionnaires. Families received feedback on their risks identified on the PAT-HCT. In part 2, 12 caregivers completed a semistructured interview about their perceptions of the PAT and the feedback process. The reliability and validity of the PAT-HCT total and subscale scores were tested using Kuder-Richardson-20 (KR-20) and Pearson correlations. Thematic content analysis was used to analyze the qualitative interview data. Internal consistency for the total score (KR-20 = .88) and the Child Problems, Sibling Problems, Family Problems, and Stress Reactions subscales were strong (KR-20 >.70). Family Structure, Social Support, and Family Beliefs subscales were adequate (KR-20 = .55 to .63). Moderate to strong correlations with the criteria measures provided validation for the total and subscale scores. Feedback was provided to 97.14% of the families who completed the PAT-HCT, and the mean rating of acceptability was >4.00 (on a 5-point scale). The qualitative data indicate that families appreciate the effort to provide screening and feedback. The PAT-HCT is a psychometrically sound screener for use in HCT. Feedback can be given to families. Both the screener and the feedback process are acceptable to caregivers.

Comparative toxicity outcomes of proton-beam therapy versus intensity-modulated radiotherapy for prostate cancer in the postoperative setting.

BACKGROUND: Despite increasing utilization of proton-beam therapy (PBT) in the postprostatectomy setting, no data exist regarding toxicity outcomes relative to intensity-modulated radiotherapy (IMRT). The authors compared acute and late genitourinary (GU) and gastrointestinal (GI) toxicity outcomes in patients with prostate cancer (PC) who received treatment with postprostatectomy IMRT versus PBT. METHODS: With institutional review board approval, patients with PC who received adjuvant or salvage IMRT or PBT (70.2 gray with an endorectal balloon) after prostatectomy from 2009 through 2017 were reviewed. Factors including combined IMRT and PBT and/or concurrent malignancies prompted exclusion. A case-matched cohort analysis was performed using nearest-neighbor 3-to-1 matching by age and GU/GI disorder history. Logistic and Cox regressions were used to identify univariate and multivariate associations between toxicities and cohort/dosimetric characteristics. Toxicity-free survival (TFS) was assessed using the Kaplan-Meier method. RESULTS: Three hundred seven men (mean ± SD age, 59.7 ± 6.3 years; IMRT, n = 237; PBT, n = 70) were identified, generating 70 matched pairs. The median follow-up was 48.6 and 46.1 months for the IMRT and PBT groups, respectively. Although PBT was superior at reducing low-range (volumes receiving 10% to 40% of the dose, respectively) bladder and rectal doses (all P ≤ .01), treatment modality was not associated with differences in clinician-reported acute or late GU/GI toxicities (all P ≥ .05). Five-year grade ≥2 GU and grade ≥1 GI TFS was 61.1% and 73.7% for IMRT, respectively, and 70.7% and 75.3% for PBT, respectively; and 5-year grade ≥3 GU and GI TFS was >95% for both groups (all P ≥ .05). CONCLUSIONS: Postprostatectomy PBT minimized low-range bladder and rectal doses relative to IMRT; however, treatment modality was not associated with clinician-reported GU/GI toxicities. Future prospective investigation and ongoing follow-up will determine whether dosimetric differences between IMRT and PBT confer clinically meaningful differences in long-term outcomes.

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma.

INTRODUCTION: We sought to determine which therapeutically targetable immune checkpoints, costimulatory signals, and other tumor microenvironment (TME) factors are independently associated with immune cytolytic activity (CYT), a gene expression signature of activated effector T cells, in human glioblastoma (GBM). METHODS: GlioVis was accessed for RNA-seq data from The Cancer Genome Atlas (TCGA). For subjects with treatment-naïve, primary GBM, we quantified mRNA expression of 28 therapeutically targetable TME factors. CYT (geometric mean of GZMA and PRF1 expression) was calculated for each tumor. Multiple linear regression was performed to determine the relationship between the dependent variable (CYT) and mRNA expression of each of the 28 factors. Variables associated with CYT in multivariate analysis were subsequently evaluated for this association in an independent cohort of newly diagnosed GBMs from the Chinese Glioma Cooperative Group (CGCG). RESULTS: 109 TCGA tumors were analyzed. The final multiple linear regression model included the following variables, each positively associated with CYT except VEGF-A (negative association): CSF-1 (p = 0.003), CD137 (p = 0.042), VEGF-A (p < 0.001), CTLA4 (p = 0.028), CD40 (p = 0.023), GITR (p = 0.020), IL6 (p = 0.02), and OX40 (p < 0.001). In CGCG (n = 52), each of these variables remained significantly associated with CYT in univariate analysis except for VEGF-A. In multivariate analysis, only CTLA4 and CD40 remained statistically significant. CONCLUSIONS: Using multivariate modeling of RNA-seq gene expression data, we identified therapeutically targetable TME factors that are independently associated with intratumoral cytolytic T-cell activity in human GBM. As a myriad of systemic immunotherapies are now available for investigation, our results could inform rational combinations for evaluation in GBM.

Understanding the predictive value of continuous markers for censored survival data using a likelihood ratio approach.

BACKGROUND: The likelihood ratio function (LR), the ratio of conditional probabilities of obtaining a specific marker value among those with the event of interest over those without, provides an easily interpretable way to quantify the update of the risk prediction due to the knowledge of the marker value. The LR has been explored for both binary and continuous markers for binary events (e.g., diseased or not), however the use of the LR in censored data has not been fully explored. METHODS: We extend the concept of LR to a time-dependent LR (TD-LR) for survival outcomes that are subject to censoring. Estimation for the TD-LR is done using Kaplan-Meier estimation and a univariate Cox proportional hazards (PH) model. A "scale invariant" approach based on marker quantiles is provided to allow comparison of predictive values between markers with different scales. Relationships to time-dependent receiver-operator characteristic (ROC) curves, area under the curve (AUC), and optimal cut-off values are considered. RESULTS: The proposed methods were applied to data from a bladder cancer clinical trial to determine whether the neutrophil-to-lymphocyte ratio (NLR) is a valuable biomarker for predicting overall survival following surgery or combined chemotherapy and surgery. The TD-LR method yielded results consistent with the original findings while providing an easily interpretable three-dimensional surface display of how NLR related to the likelihood of event in the trial data. CONCLUSIONS: The TD-LR provides a more nuanced understanding of the relationship between continuous markers and the likelihood of events in censored survival data. This method also allows more straightforward communication with a clinical audience through graphical presentation.

Retroviral and Lentiviral Safety Analysis of Gene-Modified T Cell Products and Infused HIV and Oncology Patients.

Replication-competent retrovirus/lentivirus (RCR/L) and insertional oncogenesis are potential safety risks with integrating viruses in gene-modified cell therapies. As such, the Food and Drug Administration guidances outline RCR/L-monitoring methods throughout the entire gene therapy treatment cycle. We present data for 17 vector lots, 375 manufactured T cell products, and 308 patients post-infusion across both HIV and oncology indications, showing no evidence of RCR/L. Given our data, a Poisson probability model estimates that a single patient, or a group of patients, would need to be followed for at least 52.8 years to observe one positive RCR/L event, highlighting the unlikelihood of RCR/L development. Additionally, we estimate the median time for lentivirus-modified T cell products to fall below the 1% vector sequence threshold in peripheral or whole blood that would trigger vector integration site analysis. These estimated times are 1.4 months in hematologic malignancies, 0.66 month in solid tumors, and 0.92 month in HIV. Based on these considerable safety data in HIV and oncology and recent Biologics License Applications filed for lentiviral-modified T cell products for hematologic malignancies, this may be an opportune time to re-evaluate the current guidelines for T cell gene therapy product testing and long-term patient monitoring.

Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma.

A patient with refractory multiple myeloma received an infusion of CTL019 cells, a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, after myeloablative chemotherapy (melphalan, 140 mg per square meter of body-surface area) and autologous stem-cell transplantation. Four years earlier, autologous transplantation with a higher melphalan dose (200 mg per square meter) had induced only a partial, transient response. Autologous transplantation followed by treatment with CTL019 cells led to a complete response with no evidence of progression and no measurable serum or urine monoclonal protein at the most recent evaluation, 12 months after treatment. This response was achieved despite the absence of CD19 expression in 99.95% of the patient's neoplastic plasma cells. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02135406.).

Long-term risk of second malignancies in women after breast conservation therapy for ductal carcinoma in situ or early-stage breast cancer.

PURPOSE: Women with ductal carcinoma in situ (DCIS) or early-stage breast cancer have an excellent prognosis, but their risk of developing second malignant neoplasms (SMNs) is not well established. We analyzed SMNs in a large cohort with long follow-up after breast conservation therapy. METHODS: The study population comprised 755 women with DCIS (n = 135) or stage I-II breast carcinoma (n = 620). Subjects were aged 25-89 (median 55) years when they underwent breast-conserving surgery followed by radiotherapy to the entire breast (60-68Gray) between 1992 and 2001. Additional treatment included hormonal therapy and/or chemotherapy based on clinical characteristics. SMNs were grouped by site. The rate of SMNs over time was determined using the Kaplan-Meier method. To compare the probability of developing SMNs overall and for specific organs or sites, probability estimates were obtained for a 55-year-old female from the Surveillance, Epidemiology, and End Results Program (SEER). RESULTS: Median follow-up from radiotherapy was 13.8 years. The 15-year age-adjusted probability of developing any SMN was 12.0%, close to the SEER rate of 12.1% for a non-breast malignancy. Systemic therapy and higher-dose radiotherapy (> 63 Gray) were not associated with significantly increased risks of SMNs. Compared to SEER, significantly increased risk was noted for gynecologic cancers and melanoma. CONCLUSIONS: Most SMNs were unrelated to treatment, and the 15-year incidence was similar to that of cancer in the SEER control group-findings that should be reassuring to patients. Further risk reduction is expected from prophylactic gynecologic surgery. Continued investigations into genetic links with melanoma are warranted.

Sustained Virological Response Is Associated with a Decreased Risk of Posttransplant Diabetes Mellitus in Liver Transplant Recipients with Hepatitis C-Related Liver Disease.

Posttransplant diabetes mellitus (PTDM), an increasingly recognized complication of solid organ transplantation, is associated with increased morbidity and mortality following liver transplantation (LT). Hepatitis C virus (HCV) infection is a consistent and modifiable risk factor for PTDM. Prior studies have demonstrated improvement in glucose metabolism following sustained virological response (SVR). However, the effect of SVR on the incidence of PTDM has not been previously investigated in a large cohort of LT recipients. We performed a single-center retrospective cohort study of LT recipients with HCV from January 1, 2010 to June 30, 2015 to compare the risk of sustained posttransplant diabetes mellitus (s-PTDM) prior to and following SVR. SVR was treated as a discrete time varying exposure. The s-PTDM was defined as de novo diabetes mellitus following LT of a >6-month duration. Univariate and multivariate Cox proportional hazards models were used to compare crude and adjusted time to s-PTDM prior to and following SVR. There were 256 eligible LT recipients analyzed. Median follow-up was 41.2 months. Overall, 31 (12.1%) and 178 (69.5%) patients achieved SVR prior to LT and following LT, respectively. During follow-up, 71 (27.7%) patients developed s-PTDM. The incidence of s-PTDM was greatest in the first year after LT. After adjustment for potential confounders, SVR was associated with a significantly reduced risk of s-PTDM (HR, 0.40; P = 0.048). In conclusion, eradication of HCV is independently associated with a reduced incidence of s-PTDM. This benefit appears to be most influenced by pre-LT SVR and persists throughout the post-LT period. Given the association between PTDM and posttransplant morbidity and mortality, these data provide another motivator for pre-LT or early post-LT treatment of HCV.