Clinical and Radiographic Predictors of Progression and Survival in Relapsed/Refractory Lymphoma Patients Receiving Anti-CD19 CAR T-cell Therapy.

INTRODUCTION: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of relapsed/refractory (R/R) B-cell lymphomas, though certain patients do not respond to treatment or relapse afterwards. The purpose of this study is to determine patient variables that are predictive of response to CAR-T therapy. METHODS: We conducted a retrospective review of 59 R/R B-cell non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy. Risk factors for progression free survival (PFS) and overall survival (OS) were identified and multivariate logistic regression models for PFS and OS at 1 year were created using stepwise selection. The final multivariate logistic regression models were used to estimate the area under the receiver operating curve (AUROC). RESULTS: At median follow up of 25.6 months, median overall survival was not reached, and median progression free survival was 5.7 months. Stage IV disease (odds ratio (OR) 9.335, P = .025) was identified as a predictive variable for progression at day 365 with an AUC of 0.7922 (P < .001). IPI (OR 2.828, P = .014), ALC ≥ 0.50 at collection (OR 0.183, P = .043), CRP ≥ 11 (OR 6.177, P = .019), and tocilizumab administration (OR 0.062, P = .005) as predictors for death at day 365 with an AUC 0.8626 (P < .001). CONCLUSION: Clinical variables identify R/R lymphoma patients who are at risk for progression and poor overall survival after CAR T-cell therapy. IPI, CRP, ALC, and tocilizumab administration may be predictors of survival.

Innate Immune Checkpoint Inhibitors: The Next Breakthrough in Medical Oncology?

While immunotherapy has revolutionized the treatment of many types of advanced cancer, most patients still do not derive benefit. The currently available immune checkpoint inhibitors target the adaptive immune system, generating a T-cell antitumor response. However, an antitumor immune response depends on a complex interplay of both innate and adaptive immune cells. The innate immune system is a promising new target, and innate immune checkpoint inhibitors can disrupt inhibitory interactions ("don't eat me" signals) between tumor and both phagocytes and natural killer cells. The checkpoint inhibitor may also provide a stimulatory interaction ("eat me" signal), or this can be achieved through use of combination therapy. This generates antitumor effector functions including phagocytosis, natural cytotoxicity, antibody-dependent effects, and synergistic activation of the adaptive immune system via antigen presentation. This is a rapidly expanding area of drug development, either alone or in combination (with anticancer antibodies or adaptive immune checkpoint inhibitors). Here, we comprehensively review the mechanism of action and up-to-date solid tumor clinical trial data of the drugs targeting phagocytosis checkpoints (SIRPα/CD47, LILRB1/MHC-I, and LILRB2/MHC-I) and natural killer-cell checkpoints (TIGIT/CD112 + CD155, PVRIG/CD112, KIRs/MHC-I, and NKG2A-CD94/HLA-E). Innate immune checkpoint inhibitors could once again revolutionize immune-based cancer therapies.

A U.S. population-based study of insurance disparities in cancer survival among adolescents and young adults.

BACKGROUND: Adolescents and young adults (AYA), patients age 15-39, may experience worse outcomes than pediatric and adult patients. The aim of this paper was to document survival disparities associated with insurance status across the AYA age continuum in the United States. METHODS: We utilized the Surveillance, Epidemiologic, and End Results database to identify 66 556 AYA patients between 2007 and 2014 with 10 International Classification of Childhood Cancer diagnoses and calculated the Cox proportional hazard ratios of death for those with public or no insurance status compared to private insurance. The odds ratios of having a late stage of diagnosis by insurance status were also calculated. RESULTS: Insurance status was a statistically significant predictor of death for lymphoid leukemia (age 15-19, 30-34, and 35-39), acute myeloid leukemia (age 15-19 and 25-29), Hodgkin lymphoma (all ages), non-Hodgkin lymphoma (age 20-24, 25-29, 30-34, and 35-39), astrocytomas (age 30-34), other gliomas (age 25-29, 30-34, and 35-39), hepatic carcinomas (age 25-29), fibrosarcomas, peripheral nerve and other fibrous tumors (age 30-34), malignant gonadal germ cell tumors (age 20-24, 25-29, 30-34, and 35-39), and other and unspecified carcinomas (age 20-24, 25-29, 30-34, and 35-39), independent of stage at diagnosis. This hazard increased with age for most cancer types. Insurance status strongly predicted the odds of a metastatic cancer diagnosis for lymphoma, fibrosarcomas (age 15-19), germ cell tumors, and other carcinomas. CONCLUSIONS: AYA in the US experience disparities in cancer survival based on insurance status, independent of late stage of presentation. Patients age 26-39 may be especially vulnerable to health outcomes associated with poor socioeconomic status, treatment disparities, and poor access to care.

Chemical exposures in recently renovated low-income housing: Influence of building materials and occupant activities.

Health disparities in low-income communities may be linked to residential exposures to chemicals infiltrating from the outdoors and characteristics of and sources in the home. Indoor sources comprise those introduced by the occupant as well as releases from building materials. To examine the impact of renovation on indoor pollutants levels and to classify chemicals by predominant indoor sources, we collected indoor air and surface wipes from newly renovated "green" low-income housing units in Boston before and after occupancy. We targeted nearly 100 semivolatile organic compounds (SVOCs) and volatile organic compounds (VOCs), including phthalates, flame retardants, fragrance chemicals, pesticides, antimicrobials, petroleum chemicals, chlorinated solvents, and formaldehyde, as well as particulate matter. All homes had indoor air concentrations that exceeded available risk-based screening levels for at least one chemical. We categorized chemicals as primarily influenced by the occupant or as having building-related sources. While building-related chemicals observed in this study may be specific to the particular housing development, occupant-related findings might be generalizable to similar communities. Among 58 detected chemicals, we distinguished 25 as primarily occupant-related, including fragrance chemicals 6-acetyl-1,1,2,4,4,7-hexamethyltetralin (AHTN) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[g]-2-benzopyran (HHCB). The pre- to post-occupancy patterns of the remaining chemicals suggested important contributions from building materials for some, including dibutyl phthalate and xylene, whereas others, such as diethyl phthalate and formaldehyde, appeared to have both building and occupant sources. Chemical classification by source informs multi-level exposure reduction strategies in low-income housing.

Health Benefits of Green Public Housing: Associations With Asthma Morbidity and Building-Related Symptoms.

OBJECTIVES: We examined associations of several health outcomes with green and conventional low-income housing, where the prevalence of morbidities and environmental pollutants is elevated. METHODS: We used questionnaires and a visual inspection to compare sick building syndrome (SBS) symptoms and asthma-related morbidity among residents in multifamily units in Boston, Massachusetts, between March 2012 and May 2013. Follow-up was approximately 1 year later. RESULTS: Adults living in green units reported 1.35 (95% confidence interval [CI] = 0.66, 2.05) fewer SBS symptoms than those living in conventional (control) homes (P < .001). Furthermore, asthmatic children living in green homes experienced substantially lower risk of asthma symptoms (odds ratio [OR] = 0.34; 95% CI = 0.12, 1.00), asthma attacks (OR = 0.31; 95% CI = 0.11, 0.88), hospital visits (OR = 0.24; 95% CI = 0.06, 0.88), and asthma-related school absences (OR = 0.21; 95% CI = 0.06, 0.74) than children living in conventional public housing. CONCLUSIONS: Participants living in green homes had improved health outcomes, which remained consistent over the study period. Green housing may provide a significant value in resource-poor settings where green construction or renovation could simultaneously reduce harmful indoor exposures, promote resident health, and reduce operational costs.

PCR based determination of mitochondrial DNA copy number in multiple species.

Mitochondrial DNA (mtDNA) copy number is a critical component of overall mitochondrial health. In this chapter, we describe methods for isolation of both mtDNA and nuclear DNA (nucDNA) and measurement of their respective copy numbers using quantitative PCR. Methods differ depending on the species and cell type of the starting material and availability of specific PCR reagents.

Indoor air quality in green vs conventional multifamily low-income housing.

Indoor air quality is an important predictor of health, especially in low-income populations. It is unclear how recent trends in "green" building affect the indoor exposure profile. In two successive years, we conducted environmental sampling, home inspections, and health questionnaires with families in green and conventional (control) apartments in two public housing developments. A subset of participants was followed as they moved from conventional to green or conventional to conventional housing. We measured particulate matter less than 2.5 µm aerodynamic diameter (PM2.5), formaldehyde, nitrogen dioxide (NO2), nicotine, carbon dioxide (CO2), and air exchange rate (AER) over a seven-day sampling period coincident with survey administration. In multivariate models, we observed 57%, 65%, and 93% lower concentrations of PM2.5, NO2, and nicotine (respectively) in green vs control homes (p=0.032, p<0.001, p=0.003, respectively), as well as fewer reports of mold, pests, inadequate ventilation, and stuffiness. Differences in formaldehyde and CO2 were not statistically significant. AER was marginally lower in green buildings (p=0.109). Participants in green homes experienced 47% fewer sick building syndrome symptoms (p<0.010). We observed significant decreases in multiple indoor exposures and improved health outcomes among participants who moved into green housing, suggesting multilevel housing interventions have the potential to improve long-term resident health.

Developmental toxicity and DNA damage from exposure to parking lot runoff retention pond samples in the Japanese medaka (Oryzias latipes).

Parking lot runoff retention ponds (PLRRP) receive significant chemical input, but the biological effects of parking lot runoff are not well understood. We used the Japanese medaka (Oryzias latipes) as a model to study the toxicity of water and sediment samples from a PLRRP in Morehead City, NC. Medaka exposed in ovo to a dilution series of PLRRP water had increased odds of death before hatching, but not teratogenesis or delayed hatching. Next, we adapted a long-amplicon quantitative PCR (LA-QPCR) assay for DNA damage for use with the Japanese medaka. We employed LA-QPCR to test the hypotheses that PLRRP water and sediments would cause nuclear and mitochondrial DNA damage with and without full-spectrum, natural solar radiation. Fluoranthene with and without natural sunlight was a positive control for phototoxic polycyclic aromatic hydrocarbon-induced DNA damage. Fluoranthene exposure did not result in detectable DNA damage by itself, but in combination with sunlight caused significant DNA damage to both genomes. PLRRP samples caused DNA damage to both genomes, and this was not increased by sunlight exposure, suggesting the DNA damage was unlikely the result of PAH phototoxicity. We report for the first time that PLRRP-associated pollutants cause both nuclear and mitochondrial DNA damage, and that fluoranthene-mediated phototoxicity results in similar levels of damage to the nuclear and mitochondrial genomes. These effects may be especially significant in sensitive marine ecosystems.