Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia.

Background: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse.

Methods: A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel.

Tisagenlecleucel Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor-T Cells.

Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that facilitates the killing of CD19 B cells. A model was developed for the kinetics of tisagenlecleucel and the impact of therapies for treating cytokine release syndrome (tocilizumab and corticosteroids) on expansion. Data from two phase II studies in pediatric and young adult relapsed/refractory B cell acute lymphoblastic leukemia were pooled to evaluate this model and evaluate extrinsic and intrinsic factors that may impact the extent of tisagenlecleucel expansion.

Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia.

We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19 relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.

Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia.

Purpose: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).

Patients And Methods: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN).

Results: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders ( = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders ( = 8; 74% and 104% higher geometric mean Cmax and AUC0-28d, respectively) with persistence measurable beyond 2 years in responding patients.

Mental Health Service Use in Schools and Non-School-Based Outpatient Settings: Comparing Predictors of Service Use.

Researchers have consistently documented a gap between the large number of US youth meeting criteria for a mental health disorder with significant associated impairment, and the comparatively few youth receiving services. School-based mental health care may address the need-services gap by offering services more equitably to youth in need, irrespective of family economic resources, availability of transportation, and other factors that can impede access to community clinics. However, diagnoses alone do not fully capture the severity of an individual's mental health status and need for services.

School attendance problems and youth psychopathology: structural cross-lagged regression models in three longitudinal data sets.

This study tests a model of reciprocal influences between absenteeism and youth psychopathology using 3 longitudinal datasets (Ns = 20,745, 2,311, and 671). Participants in 1st through 12th grades were interviewed annually or biannually. Measures of psychopathology include self-, parent-, and teacher-report questionnaires.

The association of quality of life with potentially remediable disruptions of circadian sleep/activity rhythms in patients with advanced lung cancer.

Background: Cancer patients routinely develop symptoms consistent with profound circadian disruption, which causes circadian disruption diminished quality of life. This study was initiated to determine the relationship between the severity of potentially remediable cancer-associated circadian disruption and quality of life among patients with advanced lung cancer.

Methods: We concurrently investigated the relationship between the circadian rhythms of 84 advanced lung cancer patients and their quality of life outcomes as measured by the EORTC QLQ C30 and Ferrans and Powers QLI.

Validation of actigraphy to assess circadian organization and sleep quality in patients with advanced lung cancer.

Background: Many cancer patients report poor sleep quality, despite having adequate time and opportunity for sleep. Satisfying sleep is dependent on a healthy circadian time structure and the circadian patterns among cancer patients are quite abnormal. Wrist actigraphy has been validated with concurrent polysomnography as a reliable tool to objectively measure many standard sleep parameters, as well as daily activity.

A pilot study of male breast cancer in the Veterans Affairs healthcare system.

Background: We report our findings on a hospital-based retrospective pilot cohort with case-controls study, which we carried out to examine genetic, environmental, and occupational risk factors in men with breast cancer.

Methods: 86 men with breast cancer were diagnosed in eight VA medical centers that agreed to collaborate on this project. A case-control analysis was conducted on a subset of the male breast cancer cases (n = 44) and age- and ethnicity-matched controls (n = 77).

Circadian transcription profile of mouse breast cancer under light-dark and dark-dark conditions.

The circadian clock exists in virtually every cell and regulates key biological processes in cells and tissues. Even in cancer cells, DNA synthesis, cell division and tumor growth are gated by the circadian clock. This study examined the gene expression profiles of transplanted mouse breast tumor cells under normal light-dark (LD) as well as constant dark (DD) conditions.

Suppression of colitis-driven colon cancer in mice by a novel small molecule inhibitor of sphingosine kinase.

Sphingolipid metabolism is driven by inflammatory cytokines. These cascade of events include the activation of sphingosine kinase (SK), and subsequent production of the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). Overall, S1P is one of the crucial components in inflammation, making SK an excellent target for the development of new anti-inflammatory drugs.

Cleavage of the retinal pigment epithelium-specific protein RPE65 under oxidative stress.

The regeneration of the 11-cis-retinyl imine chromophore of rhodopsin during the visual cycle and mechanisms that control this process are central questions in the field of vision research. The retinal pigment epithelium (RPE)-specific protein RPE65 is centrally involved in the isomerization and hydrolysis of all-trans-retinyl esters. In this study, we investigated RPE65 cleavage and potential regulatory mechanisms under oxidative stress conditions.

Melatonin reprogrammes proteomic profile in light-exposed retina in vivo.

Melatonin, a small organic molecule synthesized by the pineal gland and the retina, has a variety of physiologic functions such as circadian clock pacemaker and antioxidant. Retinal melatonin is down-regulated by light and is barely detectable during the day. The absence of melatonin in the retina during prolonged light exposure may contribute to light-induced retinal degeneration.

Lessening Homelessness Among Persons with Mental Illness: A Comparison of Five Randomized Treatment Trials.

We evaluate the influence of housing, services, and individual characteristics on housing loss among formerly homeless mentally ill persons who participated in a five-site (4-city) study in the U.S. Housing and service availability were manipulated within randomized experimental designs and substance abuse and other covariates were measured with a common protocol.

Global breast cancer seasonality.

Human breast cancer incidence has seasonal patterns that seem to vary among global populations. The aggregate monthly frequency of breast cancer diagnosis was collected and examined for 2,921,714 breast cancer cases diagnosed across 64 global regions over spans from 2 to 53 years. Breast cancer is consistently diagnosed more often in spring and fall, both in the Northern and Southern Hemispheres, regardless of presumable menopausal status (50).

Clock genes and cancer.

Period genes ( Per2, Per1) are essential circadian clock genes. They also function as negative growth regulators. Per2 mutant mice show de novo and radiation-induced epithelial hyperplasia, tumors, and an abnormal DNA damage response.

Mammalian TIMELESS is required for ATM-dependent CHK2 activation and G2/M checkpoint control.

Timeless (Tim), a core circadian clock gene in Drosophila, is retained in mammals but has no apparent mammalian circadian clock function. Mammalian TIM is essential for ATR-dependent Chk1 activation and S-phase arrest. We report that TIM is likewise essential for ATM-dependent Chk2-mediated signaling of doxorubicin-induced DNA double strand breaks.

Circadian time-dependent tumor suppressor function of period genes.

The mammalian core clock genes, Periods (Per1 and Per2), have tumor suppressor properties. Decreased expression of Per1 and Per2 has been reported in several types of human cancers. On the other hand, overexpression of Per1 or Per2 inhibits cancer cell growth in culture.

The circadian clock gene Per1 suppresses cancer cell proliferation and tumor growth at specific times of day.

Cell cycle progression is tightly regulated. The expressions of cell cycle regulators, the products of which either promote or inhibit cell proliferation, oscillate during each cell cycle. Cellular proliferation and the expression of cell cycle regulators are also controlled by the circadian clock.

Imaging multidimensional therapeutically relevant circadian relationships.

Circadian clocks gate cellular proliferation and, thereby, therapeutically target availability within proliferative pathways. This temporal coordination occurs within both cancerous and noncancerous proliferating tissues. The timing within the circadian cycle of the administration of drugs targeting proliferative pathways necessarily impacts the amount of damage done to proliferating tissues and cancers.

Neuroprotective role of erythropoietin by antiapoptosis in the retina.

Erythropoietin (EPO) stimulates red blood cell production, in part by inhibiting apoptosis of the red blood cell precursors. The erythropoietic effects of EPO are circadian stage dependent. Retinal injury due to light occurs through oxidative mechanisms and is manifest by retinal and retinal pigment epithelium (RPE) cells apoptosis.

Actigraphic assessment of daily sleep-activity pattern abnormalities reflects self-assessed depression and anxiety in outpatients with advanced non-small cell lung cancer.

Objectives: We measured subjectively evaluated depression and anxiety, and objectively measured daily sleep-activity patterns in inpatients and outpatients with advanced non-small cell lung cancer (NSCLC) and determined whether cancer-associated depression and anxiety are accompanied by characteristic circadian rhythm abnormalities.

Methods: Equal numbers of inpatients (n=42) and outpatients (n=42) with advanced NSCLC were studied. Baseline depression and anxiety, assessed by the Hospital Anxiety and Depression Scale (HADS), and actigraphy were recorded before chemotherapy initiation.

Beta-catenin induces beta-TrCP-mediated PER2 degradation altering circadian clock gene expression in intestinal mucosa of ApcMin/+ mice.

Proliferation of intestinal epithelial cells is rhythmic throughout the day. This temporal organization occurs through the interaction between the endogenous peripheral circadian clock and pathways controlling cell cycle progression. Per2, a core clock gene with tumour suppresser function, is critical to clock function and to the regulation of cellular proliferation.