•Reinfusion extended CAR T-cell persistence in 52% of patients reinfused for relapse prevention, thereby potentially reducing relapse risk.•Reinfusion induced remissions in 50% of patients with CD19+ ...relapses after initial CART, but durability was limited without further therapy.
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Relapse after CD19-directed chimeric antigen receptor (CAR)–modified T cells remains a substantial challenge. Short CAR T-cell persistence contributes to relapse risk, necessitating novel approaches to prolong durability. CAR T-cell reinfusion (CARTr) represents a potential strategy to reduce the risk of or treat relapsed disease after initial CAR T-cell infusion (CARTi). We conducted a retrospective review of reinfusion of murine (CTL019) or humanized (huCART19) anti–CD19/4-1BB CAR T cells across 3 clinical trials or commercial tisagenlecleucel for relapse prevention (peripheral B-cell recovery BCR or marrow hematogones ≤6 months after CARTi), minimal residual disease (MRD) or relapse, or nonresponse to CARTi. The primary endpoint was complete response (CR) at day 28 after CARTr, defined as complete remission with B-cell aplasia. Of 262 primary treatments, 81 were followed by ≥1 reinfusion (investigational CTL019, n = 44; huCART19, n = 26; tisagenlecleucel, n = 11), representing 79 patients. Of 63 reinfusions for relapse prevention, 52% achieved CR (BCR, 15/40 38%; hematogones, 18/23 78%). Lymphodepletion was associated with response to CARTr for BCR (odds ratio OR, 33.57; P = .015) but not hematogones (OR, 0.30; P = .291). The cumulative incidence of relapse was 29% at 24 months for CR vs 61% for nonresponse to CARTr (P = .259). For MRD/relapse, CR rate to CARTr was 50% (5/10), but 0/8 for nonresponse to CARTi. Toxicity was generally mild, with the only grade ≥3 cytokine release syndrome (n = 6) or neurotoxicity (n = 1) observed in MRD/relapse treatment. Reinfusion of CTL019/tisagenlecleucel or huCART19 is safe, may reduce relapse risk in a subset of patients, and can reinduce remission in CD19+ relapse.
Black patients with breast cancer may be at greater risk for chemotherapy-related hematologic toxicity than white patients because of lower baseline blood cell counts. We hypothesize that these ...baseline differences could lead to excess hematologic toxicity and greater modification of chemotherapy dosing in black patients and that this may contribute to the poorer survival observed in black patients with breast cancer compared with white patients with breast cancer.
We performed a retrospective cohort study of black and white patients with breast cancer treated with adjuvant chemotherapy at an academic medical center over an 18-month period. Clinical chart review and pharmacy records were used to collect data on the following: modification of chemotherapy dose or administration; hematologic toxicity; blood cell counts before, during, and after therapy; occurrence of febrile neutropenia; use of prophylactic antibiotics; and use of granulocyte colony-stimulating factor in order to determine whether ethnicity was an independent predictor of these outcomes.
Among 23 black patients and 98 white patients with breast cancer treated with adjuvant chemotherapy, modification of chemotherapy administration occurred in 56 patients (46%). Modification was more common among black patients (65.2% vs. 41.8%; relative risk RR, 1.56;
P = 0.04). Black patients were more likely to receive reduced cumulative doses of adjuvant chemotherapy (RR, 2.49;
P = 0.03).
Our findings suggest that hematologic tolerability of adjuvant chemotherapy is similar in black and white patients. Strategies aimed at improving psychosocial barriers to adjuvant therapy and at reducing surgical complications in black patients may improve overall breast cancer outcomes in this group.
Low motivation levels experienced by students with exceptionalities in the area of mathematics are often cited as a major factor negatively affecting their potential for success (Baird & Scott, 2009; ...Reichrath, de Witte, & Winkens, 2010). In the wake of many ongoing experiments using new mobile technology and tablet devices in schools, this study examines the use of iPads from Apple in a secondary mathematics classroom and its potential effect on the motivation of students with exceptionalities. In addition, the study also takes an exploratory approach to documenting the factors impacting the planning, implementation and student use of mobile devices in the classroom. A total of 16 students, 1 teacher and 1 educational assistant participated in this study. A mixed methodology approach was taken which included collecting evidence from surveys and scales as well as from descriptive journals, interviews and observational field notes. In order to assess the students' level of motivation, the four attributes from Keller's 2006 ARCS Model were used as the basic analysis framework. These were: attention, relevance, confidence and satisfaction (Keller, ARCS Model, 2006). Preliminary analysis of the attributes indicates relative consistency over the course of the study, with some minor oddities explained further in the conclusions. An extensive list of exploratory findings regarding planning, implementation and student use of mobile devices in the mathematics classroom with students with exceptionalities indicated both positive and negative aspects regarding the integration of the devices. Some positive aspects include the ability to meet the needs of different levels, and types, of learners with a number of applications, as well as a noticed increase in the collaboration and healthy competition among students. Contrary to this, some negative aspects include the lack of availability of topic-specific applications and the level of frustration experienced by some student in the initial stages of learning a new application.
CART19-related toxicities may require treatment inpatient or in the ICU. We sought to describe inpatient/ICU resource utilization within 30 days of CART19 infusion and evaluate trends in resource ...utilization from 2012-2019.
We identified patients (pts) with ALL treated with CART19 on a clinical trial (NCT01626495, NCT02906371, and NCT02374333) or with the commercial product, tisagenlecleucel, at Children's Hospital of Philadelphia. Demographic, pharmacy, and inpatient data were extracted from the EHR from day of infusion (d0) to d+30 using a semi-automated EPIC data query tool. The Virtual Pediatric Systems database was queried for resource utilization data and PRISM 3 and PIM 2 severity of illness scores. Log-binomial and linear regression were used to estimate the association of patient characteristics with inpatient/ICU admission and inpatient/ICU length of stay (LOS). Similar models were used to estimate trends over time.
The analyses included 213 pts. Median age was 12y (range 1-29y); 60% were male. Prior to CART19, 42% had an alloHCT. Pre-infusion, 19% had high tumor burden (HTB), defined as bone marrow blasts ≥40%. From 2012-2019, the proportion of pts with prior alloHCT or HTB decreased (Table 1).
CART19 was infused in the outpatient setting in 198 (93%) pts. From d0 to d+30, 149 (70%) had ≥1 inpatient admission, starting at a median of d+2 (IQR +1 to +6). Among admitted pts, median cumulative inpatient LOS was 7d (IQR 4-13). From 2012-2019, there were linear trends toward decreases in proportion of pts admitted (p<.001) and in inpatient LOS (p<.001, Figure 1). These decreases persisted after adjustment for HTB (p=0.03 and p<.001).
ICU admission was required for 49 (23%) pts, starting at a median of day +5 (IQR +4 to +7). ICU admission was more frequent for pts with HTB HTB, 68% (95% CI, 52-81) vs. low burden, 11% (95% CI, 7-17), p<.001. Among ICU pts, resources utilized included tocilizumab (n=36, 75%), vasoactives (n=36, 75%), invasive mechanical ventilation (n=18, 8%), and dialysis (n=4, 8%). In the 30d follow-up period, median ICU LOS was 7d (IQR 3-12), but 6 (13%) pts remained in the ICU after d+30. Median duration of vasoactive, mechanical ventilation, and dialysis use was 5d, 7d and 2d, respectively. Predicted median risk of mortality was 6% (IQR 5-7) by PIM 2 and 11% (IQR 7-27) by PRISM 3 scores. However, observed 30d mortality was 1% (n=2) across the cohort, or 4% among ICU pts. From 2012-2019, there was a decrease in ICU admissions (p<.01), but no significant change in ICU LOS (Figure 1).
Other than HTB, baseline characteristics were not associated with inpatient/ICU admission or LOS.
In a cohort of 213 pediatric pts, over 90% were safely infused with CART19 in the outpatient setting. Though 70% required at least one admission, the proportion of pts admitted to the hospital or ICU and cumulative inpatient LOS decreased over the past 7 years.
Patients (pts) receiving CTL019 (tisagenlecleucel) for B-ALL with high tumor burden (HTB) are at high risk for developing severe CRS. Tocilizumab, an IL-6 receptor antibody, is a vital component of ...severe CRS management; however, its role in preventing severe CRS is not known. We sought to determine the effectiveness of preemptive tocilizumab (PT) administration in decreasing the rate of grade (gr) 4 CRS in HTB pts.
We conducted a pilot trial of risk-adapted PT after CTL019 (NCT02906371). HTB pts, defined as ≥40% bone marrow (BM) blasts immediately before infusion, received a single dose of PT for high persistent fever (2 temperatures ≥38.5C in 24hr). The primary endpoint was frequency of gr4 CRS (Penn scale), with an observed rate of ≤5/15 predefined as clinically meaningful. Secondary endpoints included complete remission (CR) rate and ICU length of stay (LOS). A comparator cohort with HTB who received standard CRS management (stdCRS) was identified from the initial CTL019 trial (NCT01626495).
Characteristics of the PT (n=15) and stdCRS (n=26) HTB cohorts are shown in Table 1. All pts developed gr≥2 CRS; median time to fever was longer in the PT cohort PT, 3d (IQR 2-9); stdCRS, 2d (IQR 1-7), p=0.03. Gr4 CRS was observed in 4/15 (27%) pts in the PT cohort vs. 13/26 (50%) in the prior stdCRS cohort RR 0.53 (95% CI, 0.21-1.34), p=0.18. In the stdCRS cohort, gr4 CRS was associated with earlier onset of fever (p=0.04). In patients with earlier CRS onset (fever by day +4), gr4 CRS was observed in 4/9 (44%) vs. 13/21 (62%) in the PT and stdCRS cohorts RR 0.72 (95% CI, 0.32-1.60), p=0.42. Except for a trend toward fewer vasoactive days in the PT cohort, ICU LOS and resource utilization were not significantly different (Table 2). The CR rate at day 28 was similar in the PT and stdCRS cohorts (87% vs. 85%, p=1.00).
Risk-adapted PT administration reduced gr4 CRS, meeting the predefined study endpoint, without impacting the CR rate. A secondary comparison to a prior trial showed a clinically meaningful decrease in the rate of gr4 CRS from 50% to 27%; however, the analysis was not powered to detect a statistically significant difference. Ongoing analyses will evaluate CAR T cell expansion, duration of remission, and additional safety endpoints, including rates of neurotoxicity.
Low motivation levels experienced by students with exceptionalities in the area of mathematics
are often cited as a major factor negatively affecting their potential for success (Baird & Scott,
2009; ...Reichrath, de Witte, & Winkens, 2010). In the wake of many ongoing experiments using
new mobile technology and tablet devices in schools, this study examines the use of iPads from
Apple in a secondary mathematics classroom and its potential effect on the motivation of
students with exceptionalities. In addition, the study also takes an exploratory approach to
documenting the factors impacting the planning, implementation and student use of mobile
devices in the classroom. A total of 16 students, 1 teacher and 1 educational assistant
participated in this study. A mixed methodology approach was taken which included collecting
evidence from surveys and scales as well as from descriptive journals, interviews and
observational field notes. In order to assess the students’ level of motivation, the four attributes
from Keller’s 2006 ARCS Model were used as the basic analysis framework. These were:
attention, relevance, confidence and satisfaction (Keller, ARCS Model, 2006). Preliminary
analysis of the attributes indicates relative consistency over the course of the study, with some
minor oddities explained further in the conclusions. An extensive list of exploratory findings
regarding planning, implementation and student use of mobile devices in the mathematics
classroom with students with exceptionalities indicated both positive and negative aspects
regarding the integration of the devices. Some positive aspects include the ability to meet the
needs of different levels, and types, of learners with a number of applications, as well as a
noticed increase in the collaboration and healthy competition among students. Contrary to this,
some negative aspects include the lack of availability of topic-specific applications and the level
of frustration experienced by some student in the initial stages of learning a new application.
UOIT
Bibliography: leaves 111-113.
An interferometric synthetic aperture radar (SAR) simulator was created for the purposes of experimenting with and demonstration of the interferometric process, mission ...planning and radar image interpretation. The simulation method employs image statistics and terrain geometry to form a synthetic image and requires inputs of a digital elevation model (DEM), flight path, description, radar parameters, a terrain classification map and temporal decorrelation factors. Output images include the following images: radar cross section, power, total coherence, temporal cohernece factor, geometrical coherence factor, absolute phase, interferograms and flattened interferograms.
DNA methylation plays an important role in the regulation of transcription. Genetic control of DNA methylation is a potential candidate for explaining the many identified SNP associations with ...disease that are not found in coding regions. We replicated 52,916 cis and 2,025 trans DNA methylation quantitative trait loci (mQTL) using methylation from whole blood measured on Illumina HumanMethylation450 arrays in the Brisbane Systems Genetics Study (n = 614 from 177 families) and the Lothian Birth Cohorts of 1921 and 1936 (combined n = 1366). The trans mQTL SNPs were found to be over-represented in 1 Mbp subtelomeric regions, and on chromosomes 16 and 19. There was a significant increase in trans mQTL DNA methylation sites in upstream and 5' UTR regions. The genetic heritability of a number of complex traits and diseases was partitioned into components due to mQTL and the remainder of the genome. Significant enrichment was observed for height (p = 2.1 × 10
), ulcerative colitis (p = 2 × 10
), Crohn's disease (p = 6 × 10
) and coronary artery disease (p = 5.5 × 10
) when compared to a random sample of SNPs with matched minor allele frequency, although this enrichment is explained by the genomic location of the mQTL SNPs.
Background
Anxiety and depression are commonly comorbid with each other, with anxiety often temporally preceding the development of depression. Although increasingly research has begun to investigate ...the role of sleep problems in depression, no study has examined insomnia as a mediator in the longitudinal relationship between anxiety and subsequent depression.
Methods
The current study utilizes data from Waves I, II, and IV of the National Longitudinal Study of Adolescent to Adult Health, a nationally representative prospective study conducted over a 14‐year period (n = 20,745, 50.5% female, M age at Wave I = 16.20). Participants completed portions of the Center for Epidemiologic Studies Depression Scale at Waves I and IV to assess depressive symptoms, a six‐item anxiety measure at Wave I, and three items assessing insomnia, sleep quality, and sleep duration at Wave II.
Results
Structural equation modeling indicated that insomnia and unrestful sleep significantly mediated the relationship between anxiety and subsequent depression. The relationship between anxiety and depression was not significantly mediated by sleep duration.
Conclusions
Findings suggest that anxiety may increase risk for the development of later depression through insomnia.
The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. ...Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.
Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement Kappa (κ) and reliability intra-class correlation coefficient (ICC) of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.
Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).
We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
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