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Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in vivo that contribute to cancer relapse. Patients with chronic lymphocytic leukemia (CLL) have terminally differentiated T cells with an exhausted phenotype and experience low complete response rates after autologous CART therapy. Because PI3K inhibitor therapy is associated with the development of T-cell-mediated autoimmunity, we studied the effects of inhibiting the PI3Kδ and PI3Kγ isoforms during the manufacture of CART cells prepared from patients with CLL. Dual PI3Kδ/γ inhibition normalized CD4/CD8 ratios and maximized the number of CD8+ T-stem cell memory, naive, and central memory T-cells with dose-dependent decreases in expression of the TIM-3 exhaustion marker. CART cells manufactured with duvelisib (Duv-CART cells) showed significantly increased in vitro cytotoxicity against CD19+ CLL targets caused by increased frequencies of CD8+ CART cells. Duv-CART cells had increased expression of the mitochondrial fusion protein MFN2, with an associated increase in the relative content of mitochondria. Duv-CART cells exhibited increased SIRT1 and TCF1/7 expression, which correlated with epigenetic reprograming of Duv-CART cells toward stem-like properties. After transfer to NOG mice engrafted with a human CLL cell line, Duv-CART cells expressing either a CD28 or 41BB costimulatory domain demonstrated significantly increased in vivo expansion of CD8+ CART cells, faster elimination of CLL, and longer persistence. Duv-CART cells significantly enhanced survival of CLL-bearing mice compared with conventionally manufactured CART cells. In summary, exposure of CART to a PI3Kδ/γ inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in vivo., (© 2022 by The American Society of Hematology.)

Introduction: Diffuse large B-cell lymphoma (DLBCL) is genetically and clinically heterogeneous. Despite advances in genomic subtyping, standard frontline chemoimmunotherapy has remained unchanged for years. As high-throughput analysis becomes more accessible, characterizing drug-gene interactions in DLBCL could support patient-specific treatment strategies., Materials and Methods: From our systematic literature review, we compiled a comprehensive list of somatic mutations implicated in DLBCL. We extracted reported and primary sequencing data for these mutations and assessed their association with signaling pathways, cell-of-origin subtypes, and clinical outcomes., Results: Twenty-two targetable mutations present in ≥ 5% of patients with DLBCL were associated with unfavorable outcomes, yielding a predicted population of 31.7% of DLBCL cases with poor-risk disease and candidacy for targeted therapy. A second review identified 256 studies that had characterized the drug-gene interactions for these mutations via in vitro studies, mouse models, and/or clinical trials., Conclusions: Our novel approach linking the data from our systematic reviews with informatics tools identified high-risk DLBCL subgroups, DLBCL-specific drug-gene interactions, and potential populations for precision medicine trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Racial disparities in non-Hodgkin lymphoma (NHL) are not well-elucidated for specific catchment areas, which can influence outcomes. Leveraging regional data from a population-based cancer registry may provide unique opportunities to quantify NHL disparities., Materials and Methods: Using Surveillance, Epidemiology, and End Results (SEER) data for NHL cases diagnosed in Georgia from 2001 to 2015, we examined NHL incidence rates by lymphoma subtype and racial differences in baseline characteristics and outcomes for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Cox regression models identified predictors of overall survival (OS)., Results: SEER documented 38,504 NHL cases in Georgia from 2001 to 2015. The age-adjusted incidence rate for NHL in Georgia increased 1.03% per year, and the annual percentage change was 1.72 in blacks compared with 0.84 in whites. Compared with whites, blacks with DLBCL and FL were more likely to be diagnosed at a younger age (DLBCL, 54.1 vs. 65.5 years; P < .0001; FL, 58.4 vs. 64.0 years; P < .0001) and with B symptoms (DLBCL, 44.4% vs. 33.4%; P < .0001; FL, 28.5% vs. 21.4%; P = .004). Across racial categories, age at diagnosis > 60 years, advanced stage, and B symptoms predicted worse OS in DLBCL and FL. Blacks with DLBCL more commonly were diagnosed with stage III/IV disease (55.5% vs. 48.1%; P < .0001) and had worse 5-year relative survival (58.8% vs. 62.3%; P = .01)., Conclusions: Regional cancer registry data can be used to define incidence patterns and disparities in outcomes across NHL subtypes to help define key targets for interventions in a catchment area., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Although race and socioeconomic factors are associated with outcome in many malignancies, few studies have examined the effect of race and socioeconomic status on patients with mantle cell lymphoma (MCL)., Patients and Methods: We used the National Cancer Database to identify patients with MCL diagnosed between 2004 and 2013. We used χ 2 and analysis of variance to assess associations of covariates with race/ethnicity. For univariate and multivariable analyses of overall survival (OS) we used Cox proportional hazards models. OS from the time of diagnosis was the primary end point., Results: Of 18,120 MCL patients, 14,984 (83%) were white non-Hispanic (NH), 709 (4%) black NH, and 1096 (6%) Hispanic. Of these patients, 6798 (39%) had private insurance, 9520 (55%) Medicare, and 635 (4%) Medicaid. Compared with white NH race, black race was associated with treatment at an academic/research program (347 of 681 patients [51%] vs. 5577 of 14,851 [38%]), B symptoms (196 patients [28%] vs. 3 [25%]), Medicaid/uninsured status (101 patients [15%] vs. 642 [5%]), and residence in regions with lower average education and income (all P < .001). Compared with NH black and Hispanic patients, more white NH patients received stem cell transplantation (73 patients [10%] vs. 114 [10%] vs. 1891 [13%]; P < .001). In multivariable analysis, Hispanic ethnicity, private insurance, and treatment at an academic center were associated with better OS (5-year OS 55.8%, 66.2%, and 56.6%, respectively), whereas black race was associated with inferior OS (5-year OS 46.8%)., Conclusion: We identified disparities according to race and ethnicity in OS, independent of insurance and socioeconomic status. Further assessment of treatment patterns might elucidate new targets for improving access to care and health outcomes for rare cancers., (Copyright © 2019. Published by Elsevier Inc.)

Introduction: Influenza infection causes significant morbidity and mortality in patients with cancer, and annual influenza vaccination for individuals with cancer is recommended. We sought to examine the documentation rate of influenza vaccine administration, refusal, or counseling in the first year after diagnosis of diffuse large B cell lymphoma (DLBCL) for patients across 3 hospitals in 2 health care systems., Patients and Methods: Documentation of vaccine administration, refusal, or counseling by physicians, advanced practice providers, or nursing staff during the first period of influenza vaccine availability after diagnosis (August to April) was assessed in medical records of patients diagnosed with DLBCL between February 2015 and October 2017 who presented to Emory St. Joseph Hospital (community hospital), Winship Cancer Institute of Emory University (academic medical center), or Grady Memorial Hospital (county hospital)., Results: Of the 57% (61/107) of newly diagnosed patients with DLBCL who had vaccine-related documentation, 43% refused vaccination. Counseling was not documented for any patient. Inpatient nursing performed 75% of all documentation. Primary oncologists documented vaccination in 4% of all cases., Conclusion: Despite the limited immunization documentation and high refusal rates observed in this study, the influenza vaccine refusal rate was lower than the average for the United States, the state of Georgia, and the previous studies of patients with cancer. Although routine outpatient vaccination occurs, improvements in screening, strategies for sharing patient vaccine-related information, and counseling of patients who refuse the vaccine are needed. Further work is also needed to determine the effectiveness of influenza vaccination in patients receiving anti-cancer therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Respiratory syncytial virus (RSV) persists as a significant human pathogen that continues to contribute to morbidity and mortality. In children, RSV is the leading cause of lower respiratory tract infections, and in adults RSV causes pneumonia and contributes to exacerbations of chronic lung diseases. RSV induces airway epithelial inflammation by activation of the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor. Recently, EGFR inhibition was shown to decrease RSV infection, but the mechanism(s) for this effect are not known. Interferon (IFN) signaling is critical for innate antiviral responses, and recent experiments have implicated IFN-λ (lambda), a type III IFN, as the most significant IFN for mucosal antiviral immune responses to RSV infection. However, a role for RSV-induced EGFR activation to suppress airway epithelial antiviral immunity has not been explored. Here, we show that RSV-induced EGFR activation suppresses IFN regulatory factor (IRF) 1-induced IFN-λ production and increased viral infection, and we implicate RSV F protein to mediate this effect. EGFR inhibition, during viral infection, augmented IRF1, IFN-λ, and decreased RSV titers. These results suggest a mechanism for EGFR inhibition to suppress RSV by activation of endogenous epithelial antiviral defenses, which may be a potential target for novel therapeutics.

Background: Severe immune dysregulation such as seen in autoimmune (AI) disease is known to act as a significant risk factor for diffuse large B-cell lymphoma (DLBCL). However, little is known about the demographics or clinical outcomes of DLBCL that arises in the setting of AI disease., Patients and Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database for patients with a diagnosis from 1999 to 2009 linked to their Medicare claims data through 2011 to characterize the presentation, treatment, and survival patterns in DLBCL patients, including those with rheumatoid arthritis, systemic lupus erythematosus (SLE), Sjögren syndrome, and other B-cell-mediated AI diseases. We examined the baseline clinical characteristics for patients with B-cell-mediated AI disease, plotted the overall survival and lymphoma-related survival (LRS) for these groups, and compared the median survival times., Results: Patients with DLBCL and AI disease were more commonly female. However, patients with DLBCL and rheumatoid arthritis, SLE, Sjögren syndrome, or other B-cell AI diseases did not differ from other DLBCL patients in any other baseline presenting features and received similar first-line treatment. A trend toward decreased LRS was seen in patients with SLE and DLBCL compared with all other groups, but this difference was not statistically significant in this cohort., Conclusion: In the present retrospective claims-based cohort of older patients with DLBCL, concomitant AI disease was uncommon and was more likely to occur in female DLBCL patients, which likely reflects the greater incidence of AI disease in women. The possibility of lower LRS for SLE patients should be explored in future studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Individuals with cystic fibrosis (CF) are at high risk for depression and anxiety, which are associated with worse medical outcomes. Novel therapies for CF hold great promise for improving physical health, but the effects of these therapies on mental health remain poorly understood., Objective: This review aims to familiarize psychiatrists with the potential effect of novel CF therapies on depression and anxiety., Methods: We discuss novel therapies that directly target the mutant CF protein, the CF transmembrane regulator (CFTR), which are called CFTR modulators. We summarize depression and anxiety screening and treatment guidelines under implementation in accredited CF centers. Case vignettes highlight the complexities of caring for individuals with CF with comorbid depression and anxiety, including patients experiencing worsening depression and anxiety proximate to initiation of CFTR modulator therapy, and management of drug-drug interactions., Conclusions: Although CFTR modulator therapies provide hope for improving clinical outcomes, worsening depression and anxiety occurs in some patients when starting these novel agents. This phenomenon may be multifactorial, with hypothesized contributions from CFTR modulator-psychotropic medication interactions, direct effects of CFTR modulators on central nervous system function, the psychologic effect of starting a potentially life-altering drug, and typical triggers of depression and anxiety such as stress, pain, and inflammation. The medical and psychiatric complexity of many individuals with CF warrants more direct involvement of mental health specialists on the multidisciplinary CF team. Inclusion of mental health variables in patients with CF registries will facilitate further examination at an epidemiologic level., (Copyright © 2017 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Benzene is a known occupational carcinogen associated with increased risk of hematologic cancers, but the relationships between quantity of passive benzene exposure through residential proximity to toxic release sites, duration of exposure, lag time from exposure to cancer development, and lymphoma risk remain unclear., Methods: We collected release data through the Environmental Protection Agency's Toxics Release Inventory (TRI) from 1989 to 2003, which included location of benzene release sites, years when release occurred, and amount of release. We also collected data on incident cases of non-Hodgkin lymphoma (NHL) from the Georgia Comprehensive Cancer Registry (GCCR) for the years 1999-2008. We constructed distance-decay surrogate exposure metrics and Poisson and negative binomial regression models of NHL incidence to quantify associations between passive exposure to benzene and NHL risk and examined the impact of amount, duration of exposure, and lag time on cancer development. Akaike's information criteria (AIC) were used to determine the scaling factors for benzene dispersion and exposure periods that best predicted NHL risk., Results: Using a range of scaling factors and exposure periods, we found that increased levels of passive benzene exposure were associated with higher risk of NHL. The best fitting model, with a scaling factor of 4 kilometers (km) and exposure period of 1989-1993, showed that higher exposure levels were associated with increased NHL risk (Level 4 (1.1-160kilograms (kg)) vs. Level 1: risk ratio 1.56 [1.44-1.68], Level 5 (>160kg) vs. Level 1: 1.60 [1.48-1.74])., Conclusions: Higher levels of passive benzene exposure are associated with increased NHL risk across various lag periods. Additional epidemiological studies are needed to refine these models and better quantify the expected total passive benzene exposure in areas surrounding release sites., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with DLBCL exhibit widely divergent outcomes despite harboring histologically identical tumors. Currently, GEP and IHC algorithms assign patients to 1 of 2 main subtypes: germinal center B cell-like (GCB), or activated B cell-like (ABC), the latter of which historically carries a less favorable prognosis. However, it remains controversial as to whether these prognostic groupings remain valid in the era of rituximab therapy., Materials and Methods: A systematic literature review identified 24 articles from which meta-analyses were conducted, comparing survival outcomes for patients assigned to either GCB or ABC/non-GCB subtype using GEP and/or Hans, Choi, or Muris IHC algorithms., Results: Patients designated as GCB DLBCL using GEP fared significantly better in terms of overall survival than those with ABC DLBCL (hazard ratio, 1.85; P < .0001). In contrast, the Hans and Choi algorithms failed to identify significant differences in overall survival (P = .07 and P = .76, respectively) between GCB and non-GCB groups., Conclusions: Our study illustrates a lack of evidence supporting the use of the Hans and Choi algorithms for stratifying patients into distinct prognostic groups. Rather, GEP remains the preferred method for predicting the course of a patient's disease and informing decisions regarding treatment options., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Lung transplantation in mechanically ventilated (MV) patients has been associated with decreased posttransplant survival. Under the Lung Allocation Score (LAS) system, patients at greatest risk of death on the waiting list, particularly those requiring MV, are prioritized for lung allocation. We evaluated whether pretransplant MV is associated with poorer posttransplant survival in the LAS era. Using a national registry, we analyzed all adults undergoing lung transplantation in the United States from 2005 to 2010. Propensity scoring identified nonventilated matched referents for 419 subjects requiring MV at the time of transplantation. Survival was evaluated using Kaplan-Meier methods. Risk of death was estimated by hazard ratios employing time-dependent covariates. We found that pretransplant MV was associated with decreased overall survival after lung transplantation. In the first 6 months posttransplant, ventilated subjects had a twofold higher risk of death compared to nonventilated subjects. However, after 6 months posttransplant, survival did not differ by MV status. We also found that pretransplant MV was not associated with decreased survival in noncystic fibrosis obstructive lung diseases. These results suggest that under the LAS, pretransplant MV is associated with poorer short-term survival posttransplant. Notably, the increased risk of death appears to be strongest the early posttransplant period and limited to certain pretransplant diagnoses., (©Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)