Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease–negative (MRD-negative) complete remission (CR) rates in ...patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months; P < .0001; median OS, 20.0 vs 5.0 months; P = .014). In patients who achieved MRD-negative CR by flow cytometry, absence of the index malignant clone by IGH deep sequencing was associated with better EFS (P = .034). Stepwise multivariable modeling in patients achieving MRD-negative CR showed that lower prelymphodepletion lactate dehydrogenase concentration (hazard ratio HR, 1.38 per 100 U/L increment increase), higher prelymphodepletion platelet count (HR, 0.74 per 50 000/μL increment increase), incorporation of fludarabine into the lymphodepletion regimen (HR, 0.25), and allogeneic hematopoietic cell transplantation (HCT) after CAR T-cell therapy (HR, 0.39) were associated with better EFS. These data allow identification of patients at higher risk of relapse after CAR T-cell immunotherapy who might benefit from consolidation strategies such as allogeneic HCT. This trial was registered at www.clinicaltrials.gov as #NCT01865617.
•Baseline platelet count, lactate dehydrogenase, and lymphodepletion regimen impact EFS in patients in MRD-negative CR after CD19 CAR T-cell.•Allogeneic HCT after CD19 CAR T-cell therapy is well tolerated and may improve EFS.
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Background
Delays from the diagnosis of muscle‐invasive bladder cancer (MIBC) to radical cystectomy (RC) longer than 12 weeks result in higher mortality and shorter progression‐free survival. This ...study sought to identify factors associated with RC delays and to determine whether delays in care in the current treatment paradigm, which includes neoadjuvant chemotherapy (NAC), affect survival.
Methods
Subjects with American Joint Committee on Cancer stage II urothelial carcinoma of the bladder who underwent RC from 2004 to 2012 were identified from the linked Surveillance, Epidemiology, and End Results national cancer registry and the Medicare claims database and were stratified into RC groups with or without NAC. Cox multivariable proportional hazard models and multivariable logistic regression models assessed the significance of delays in RC for survival and identified independent characteristics associated with RC delays, respectively.
Results
This study identified 1509 patients with MIBC who underwent RC during the study period. In comparison with timely surgery, delays in RC increased overall mortality, regardless of the use of NAC (hazard ratio HR without NAC, 1.34; 95% confidence interval CI, 1.03‐1.76; HR after NAC, 1.63; 95% CI, 1.06‐2.52). Patients proceeding to RC without NAC had higher odds of delayed care if they lived in a high‐poverty neighborhood (odds ratio OR, 1.37; 95% CI, 1.01‐2.08) or nonmetropolitan area (OR, 1.61; 95% CI, 1.01‐2.55), were men (OR, 2.22; 95% CI, 1.25‐4.00), or required a provider transfer for bladder cancer care (OR, 1.82; 95% CI, 1.10‐3.03).
Conclusions
Delays in care from the time of either the initial diagnosis or the completion of NAC to RC are associated with worse overall survival among patients with MIBC. Timely surgery is fundamental in the treatment of MIBC, and this necessitates attention to disparities in access to complex surgical care and care coordination.
Delays from either the initial diagnosis or the completion of neoadjuvant chemotherapy to definitive local treatment with radical cystectomy are associated with decreased survival among patients with muscle‐invasive bladder cancer. Timely surgery is a fundamental part of treatment, and this necessitates attention to disparities in access to complex surgical care.
Introduction: Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated remarkable anti-tumor activity in B-cell malignancies and is under investigation in other hematologic malignancies ...and solid tumors. While highly efficacious, post-infusion T cell activity often results in massive cytokine release precipitating cytokine release syndrome (CRS), the signature toxicity of CAR T cells. This toxicity is characterized by systemic immune activation resulting in fever, hypotension, respiratory insufficiency and capillary leak. Either in conjunction with or in the absence of CRS, a subset of patients may also develop mild to severe neurotoxicity. Although the precise pathogenesis of CRS and neurotoxicity aren't fully elucidated, risk factors and mitigation strategies have been reported.
Areas covered: This manuscript provides an in-depth overview of the pathogenesis, clinical characteristics, current toxicity management strategies, and future perspectives pertaining to CRS and neurotoxicity.
Expert Opinion: As CAR T cell based therapies gain popularity in the management of various malignancies, the complimentary toxicities of CRS and neurotoxicity pose a clinical challenge in practice. Risk adaptive modeling incorporating disease profile, patient demographics, lymphodepletion, cell dosing, CAR T construct, and potentially cytokine gene polymorphisms may be instructive to assess individualized risk and optimal CRS/neurotoxicity management.
Peripheral blood eosinophilia (PBE) in inflammatory bowel disease (IBD) is associated with ulcerative colitis (UC) and active disease. Little data exist on the long-term impact of PBE on disease ...course. We aimed to investigate the multi-year patterns of PBE and its impact on disease severity in a large IBD cohort.
We performed a registry analysis of a consented, prospective, natural history IBD cohort at a tertiary center from 2009 to 2014. Demographics, comorbidities, disease activity, healthcare utilization, and time to hospitalization or surgical resection of patients who displayed PBE were compared to patients without PBE.
Of the 2,066 IBD patients, 19.2% developed PBE. PBE was significantly associated with UC (P<0.001), extensive colitis (P<0.001), and shorter disease duration (P=0.03). Over six years, PBE patients had more active disease (Harvey-Bradshaw Index P=0.001; ulcerative colitis activity index P<0.001), concurrent C-reactive protein elevation (P<0.001), healthcare utilization (hospitalization P<0.001, IBD surgery P<0.001), and more aggressive medical therapy (prednisone P<0.001, anti-TNF P<0.001). Patients with PBE had a significantly reduced time to hospitalization in both UC (P<0.001) and Crohn's disease (CD) (P<0.001) and reduced time to colectomy in UC (P=0.003). On multivariable modeling, PBE remained significantly associated with hospitalization and surgery in both CD and UC. New diagnosis of UC with PBE was associated with increased steroid (P=0.007) and anti-TNF (P=0.001) requirement.
This multi-year study of a large IBD cohort suggests that peripheral blood eosinophilia represents a biomarker of a distinct IBD subgroup, with a unique inflammatory signature, and at risk for worse clinical outcomes.
Background
The taxicab industry is a burgeoning occupation that predominantly employs immigrant males from low socioeconomic backgrounds. Factors such as sedentary nature, environmental factors, high ...stress coupled with socioeconomic factors may increase cardiovascular disease risk among taxicab drivers. Latinos, a growing immigrant population make up approximately 20% of this industry. However, few studies focus on their experiences as cab drivers or on the factors that may increase their cardiovascular risks.
Methods
This was an ethnographic qualitative study. Data was collected via individual interviews combined with Go‐Alongs. The Go‐Along is an observational qualitative method whereby researchers accompany participants during routine activities and make observations. Interviews and observations were transcribed and coded to identify emerging themes.
Results
Thirty‐two Latino male cab drivers participated; their mean age was 45 + 12 years; 47% did not finish high school; and 63% earned $30 000 or less. Time and stress emerged as dominant themes. Time constraints posed a barrier to healthy eating and physical activity. Drivers reported stress from constantly worrying about their finances and personal safety. Drivers also described stress from the physical toll of driving on the body. Go‐Alongs supported these themes and identified social interactions and environmental factors that could be leveraged for health promotion.
Conclusions
This study provided an opportunity for cab drivers to describe their perspectives on reasons why their occupation was associated with a high risk for cardiovascular disease. The Go‐Alongs contributed to the understanding of the social and environmental context that characterized cardiovascular risks in this occupation.
In the last decade, there has been an increasing interest in the role of space in the learning process. However, there is limited research about how different Learning Spaces (LS) can lead to ...Sustainable Development (SD). Therefore, this paper presents a systematic literature review aimed to identify how physical, virtual, and hybrid LS have been designed and used to support SD. From an initial sample of 204 articles between 2009 and 2021 found in the Scopus database, 33 were included after inclusion criteria were applied. Findings show a wide variety of focus in the uses of LS (e.g., promote education quality, accessibility, or environmental sustainability). In general, the design process of LS implies a top-bottom approach, where students remain as passive actors. Nevertheless, it has been identified a growing interest in codesign processes that promote broader participation and bottom-top perspectives. This study contributes to orientate the understanding of the concept of LS, and looks towards inspiring new teaching and learning practices.
Abstract
Background
Immunoglobulin G subclass 4 (IgG4) is hypothesized to play an immunomodulatory role, downregulating humoral immune responses. The role of this anti-inflammatory molecule in ...inflammatory bowel disease (IBD) has not been fully characterized. We sought to define alterations in serum IgG4 in patients with IBD and their association with multiyear disease severity.
Methods
We analyzed metadata derived from curated electronic health records from consented patients with IBD prospectively followed at a tertiary center over a 10-year time period. Patients with IBD with IgG4 serum levels available formed the study population. Demographics and multiyear clinical data were collected and analyzed. We stratified patients with IBD with low, normal, or high serum IgG4 levels.
Results
We found IgG4 characterized in 1193 patients with IBD and low IgG4 levels in 233 patients (20%) and elevated IgG4 levels in 61 patients (5%). An IgG4 deficiency did not significantly correlate with other antibody deficiencies. In a multiple Poisson regression analysis, low IgG4 was associated with more years on biologic agents (P = 0.002) and steroids (P = 0.049) and more hospital admissions (P < 0.001), clinic visits (P = 0.010), outpatient antibiotic prescriptions (P < 0.001), and CD-related surgeries (P = 0.011) during the study period after controlling for certain confounders. Elevated IgG4 was only associated with primary sclerosing cholangitis (P = 0.011). A cohort of patients with IgG4-deficient severe IBD received intravenous Ig replacement therapy, which benefited and was continued in 10 out of 11 individuals.
Conclusions
An IgG4 subclass deficiency, distinct from other antibody deficiencies, occurred commonly in a referral IBD population and was associated with multiple markers of disease severity. This is the first association of IgG4 subclass deficiency with an inflammatory disease process. Further work is needed to define the mechanistic role of IgG4 deficiency in this severe IBD subgroup.
Abstract The success of immune checkpoint inhibitors in advanced urothelial carcinoma provides patients with the prospect for durable objective responses. However, the majority of patients do not ...respond to immune checkpoint blockade. Several potential predictive biomarkers of response have been evaluated in hopes of better identifying likely responders, though each has been shown to have limitations. Going forward, development of reliable predictive biomarkers is imperative. Likewise, innovative treatment combination approaches to convert non-responders to responders are essential to continue making progress in the field.
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