Phase I/II Design for Selecting Subgroup-Specific Optimal Biological Doses for Prespecified Subgroups.

We propose a phase I/II trial design to support dose-finding when the optimal biological dose (OBD) may differ in two prespecified patient subgroups. The proposed design uses a utility function to quantify efficacy-toxicity trade-offs, and a Bayesian model with spike and slab prior distributions for the subgroup effect on toxicity and efficacy to guide dosing and to facilitate identifying either subgroup-specific OBDs or a common OBD depending on the resulting trial data. In a simulation study, we find the proposed design performs nearly as well as a design that ignores subgroups when the dose-toxicity and dose-efficacy relationships are the same in both subgroups, and nearly as well as a design with independent dose-finding within each subgroup when these relationships differ across subgroups. In other words, the proposed adaptive design performs similarly to the design that would be chosen if investigators possessed foreknowledge about whether the dose-toxicity and/or dose-efficacy relationship differs across two prespecified subgroups. Thus, the proposed design may be effective for OBD selection when uncertainty exists about whether the OBD differs in two prespecified subgroups.

Association of left atrial function with frailty: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Frailty is common in people with cardiovascular disease. Worse left atrial (LA) function is an independent risk factor for cardiovascular disease. However, whether worse LA function is associated with frailty is unclear. METHODS: We included 3292 older adults from the Atherosclerosis Risk in Communities study who were non-frail at baseline (visit 5, 2011-2013) and had LA function (reservoir, conduit, and contractile strain) measured from two-dimensional speckle-tracking echocardiography. LA stiffness index was calculated as a ratio of E/e' to LA reservoir strain. Frailty was defined using the validated Fried frailty phenotype. Incident frailty was assessed between 2016 and 2019 during two follow-up visits. LA function was analyzed as quintiles. Multivariable logistic regression examined odds of incident frailty. RESULTS: Median (interquartile range [IQR]) age was 74 (71-77) years, 58% were female, and 214 (7%) participants developed frailty during a median (IQR) follow-up of 6.3 (5.6-6.8) years. After adjusting for baseline confounders and incident cardiovascular events during follow-up, the odds of developing frailty was 2.42 (1.26-4.66) times greater among participants in the lowest (vs highest) quintile of LA reservoir strain and 2.41 (1.11-5.22) times greater among those in the highest (vs lowest) quintile of LA stiffness index. Worse LA function was significantly associated with the development of exhaustion, but not the other components of the Fried frailty phenotype. CONCLUSIONS: Worse LA function is associated with higher incidence of frailty and exhaustion component independent of LA size and left ventricular function. Future studies are needed to elucidate the underlying mechanisms that drive the observed association.

Association of central arterial stiffness with atrial myopathy: the Atherosclerosis Risk in Communities (ARIC) study.

Atrial myopathy-defined as abnormal left atrial (LA) size and function-is associated with an increased risk of atrial fibrillation, heart failure, and dementia. Central arterial stiffness is associated with increased atrial afterload and fibrosis and may be a risk factor for atrial myopathy. We examined the association of carotid-femoral pulse wave velocity (cfPWV) with LA function and assessed potential causal relationships. We included 2825 Atherosclerosis Risk in Communities (ARIC) study participants from Visit 5 (2011-2013). cfPWV was related to echocardiographic LA function continuously per 1-SD and categorically in quartiles. Mendelian randomization (MR) analysis was performed using U.K. Biobank-derived genetic variants associated with arterial stiffness index and cardiac magnetic resonance measures of LA function. When analyzed per SD increment (297.6 cm/s), higher cfPWV was significantly associated with lower LA reservoir and conduit strain (ß = -0.53%, 95% CI [-0.81, -0.25] and ß = -0.46%, 95% CI [-0.68, -0.25], respectively) after adjusting for demographics, clinical characteristics, systolic blood pressure, and left ventricular (LV) morphology and function. In MR analyses there was a non-significant inverse association of arterial stiffness index with LA total, passive, and active emptying fractions. Higher cfPWV is associated with lower LA reservoir and conduit strain, independent of systolic blood pressure and LV morphology and function. No evidence for a causal relationship between arterial stiffness index and alterations in LA function was found. Future studies should examine the prospective association of central arterial stiffness with LA function alterations.

Estimating the causal effect of filter ventilation levels in cigarettes on past 30-day smoking.

INTRODUCTION: Cigarettes with higher levels of filter ventilation are misperceived as less harmful and may be more appealing to consumers. Setting limits on filter ventilation has been considered as a policy, but a better understanding of any potential unintended consequences is needed. METHODS: Filter ventilation (0.2-61.1%) measured for 114 subbrands was merged with Wave 1 (2012-2013) of the Population Assessment of Tobacco Use and Health (PATH) data, restricted to adults 25+ years of age who smoked daily, and examined by quartiles. Inverse probability of exposure weights were used to estimate the causal effect of filter ventilation on past-30 day smoking at subsequent waves while accounting for potential confounders including demographics, menthol, heaviness of smoking and past quit attempts. RESULTS: Compared to those in the 1st (lowest) quartile of filter ventilation, those in the 2nd, 3rd and 4th quartiles had 1.02 (95% confidence interval: 0.57, 1.82), 0.86 (0.42, 1.73) and 1.52 (0.90, 2.56) times the odds of no past 30-day smoking at Wave 2 (approximately 1 year later, p=0.163), and 1.28 (0.80, 2.07), 1.11 (0.67, 1.83) and 1.65 (1.01, 1.24) times the odds of no past 30-day smoking at Wave 4 (3 years later, p = 0.238). CONCLUSIONS: This observational study found no strong evidence of a causal effect of filter ventilation on past 30-day smoking at approximately 1 and 3 years follow-up. However, our effect size estimates were not precise and thus an increase in the ability to quit smoking due to higher filter ventilation levels cannot be ruled out. IMPLICATIONS: Setting a maximum limit on filter ventilation (FV) in cigarettes could address the misperception that highly ventilated cigarettes are less harmful and the link between FV and lung adenocarcinoma. It is important to understand whether such a policy would have unintended consequences on longer-term smoking behavior. We found no strong evidence that FV affects past 30-day smoking 1-3 years later, but could not rule out the possibility that higher FV increases cessation rates. If future studies confirm these epidemiologic findings, this could mean that setting a limit on FV would not lead to reductions in the ability to quit smoking.

Statistical approaches for component-wise censored composite endpoints.

Composite endpoints defined as the time to the earliest of two or more events are often used as primary endpoints in clinical trials. Component-wise censoring arises when different components of the composite endpoint are censored differently. We focus on a composite of death and a non-fatal event where death time is right censored and the non-fatal event time is interval censored because the event can only be detected during study visits. Such data are most often analysed using methods for right censored data, treating the time the non-fatal event was first detected as the time it occurred. This can lead to bias, particularly when the time between assessments is long. We describe several approaches for estimating the event-free survival curve and the effect of treatment on event-free survival via the hazard ratio that are specifically designed to handle component-wise censoring. We apply the methods to a randomized study of breastfeeding versus formula feeding for infants of mothers infected with human immunodeficiency virus.

Islet Isolation Outcomes in Patients Undergoing Total Pancreatectomy With Islet Autotransplantation in the POST Consortium.

BACKGROUND: In total pancreatectomy with islet autotransplantation (TPIAT), a greater number of islets transplanted produces more favorable outcomes. We aimed to determine predictors of islet isolation outcomes. METHODS: We investigated factors associated with islet isolation outcomes expressed as islet number (IN), islet equivalents (IEQ; standardized to an islet with 150 µm diameter), IN/kg, or IEQ/kg using data from the multicenter Prospective Observational Study of TPIAT. Single-predictor linear regression was used to estimate the association of individual patient and disease characteristics with islet isolation outcomes, and augmented backward elimination was used to select variables to include in multivariable analyses. RESULTS: In multivariable analyses, only elevated hemoglobin A1c was associated with worse outcomes for all measures (P < 0.001 for all). Total IEQ obtained for transplant was higher for participants with Hispanic ethnicity (P = 0.002) or overweight status pre-TPIAT (P < 0.001) and lower with non-White race (P = 0.03), genetic pancreatitis (P = 0.02), history of lateral pancreaticojejunostomy (P = 0.03), and presence of atrophy (P = 0.006) or ductal changes (P = 0.014) on imaging. IEQ/kg was higher in females (P = 0.01) and Hispanic participants (P = 0.046) and generally lower with older age (nonlinear association, P < 0.001) and pancreatic atrophy (P < 0.001) on imaging. Total IN and IN/kg showed trends similar, but not identical, to IEQ and IEQ/kg, respectively. CONCLUSIONS: Patient demographics and certain pancreatic disease features were associated with outcomes from islet isolation. Hemoglobin A1c before TPIAT was the metabolic testing measure most strongly associated with islet isolation results.

Association of Left Atrial Function With Incident Chronic Kidney Disease in Older Adults.

Objective: To examine the association of left atrial (LA) function with incident chronic kidney disease (CKD) and assess the clinical utility of adding LA function to a CKD risk prediction equation. Patients and Methods: We included 4002 Atherosclerosis Risk in Communities study participants without prevalent CKD (mean ± SD age, 75±5 years; 58% female, 18% Black). Left atrial function (reservoir, conduit, and contractile strain) was evaluated by 2D-echocardiograms on 2011 to 2013. Chronic kidney disease was defined as greater than 25% decline in estimated glomerular filtration rate of less than 60 mL/min/1.73 m2, end-stage kidney disease, or hospital records. Cox proportional hazards models were used. Risk prediction and decision curve analyses evaluated 5-year CKD risk by diabetes status. Results: Median follow-up was 7.2 years, and 598 participants developed incident CKD. Incidence rate for CKD was 2.29 per 100 person-years. After multivariable adjustments, the lowest quintile of LA reservoir, conduit, and contractile strain (vs highest quintile) had a higher risk of CKD (hazard ratios [95% CIs]: 1.94 [1.42-2.64], 1.62 [1.19-2.20], and 1.49 [1.12-1.99]). Adding LA reservoir strain to the CKD risk prediction equation variables increased the C-index by 0.026 (95% CI: 0.005-0.051) and 0.031 (95% CI: 0.006-0.058) in participants without and with diabetes, respectively. Decision curve analysis found the model with LA reservoir strain had a higher net benefit than the model with CKD risk prediction equation variables alone. Conclusion: Lower LA function is independently associated with incident CKD. Adding LA function to the CKD risk prediction enhances prediction and yields a higher clinical net benefit. These findings suggest that impaired LA function may be a novel risk factor for CKD.

Addressing long-term mortality risk in patients undergoing total pancreatectomy with islet autotransplant (TPIAT): causes of death and risk factors.

BACKGROUND: Total pancreatectomy with islet autotransplant (TPIAT) can improve quality of life for individuals with pancreatitis but creates health risks including diabetes, exocrine insufficiency, altered intestinal anatomy and function, and asplenia. METHODS: We studied survival and causes of death for 693 patients who underwent TPIAT between 2001 and 2020, using the National Death Index with medical records to ascertain survival after TPIAT, causes of mortality, and risk factors for death. We used Kaplan Meier curves to examine overall survival, and Cox regression and competing-risks methods to determine pre-TPIAT factors associated with all-cause and cause-specific post-TPIAT mortality. RESULTS: Mean age at TPIAT was 33.6 years (SD = 15.1). Overall survival was 93.1% (95% CI 91.2, 95.1%) 5 years after surgery, 85.2% (95% CI 82.0, 88.6%) at 10 years, and 76.2% (95% CI 70.8, 82.3%) at 15 years. Fifty-three of 89 deaths were possibly related to TPIAT; causes included chronic gastrointestinal complications, malnutrition, diabetes, liver failure, and infection/sepsis. In multivariable models, younger age, longer disease duration, and more recent TPIAT were associated with lower mortality. CONCLUSIONS: For patients undergoing TPIAT to treat painful pancreatitis, careful long-term management of comorbidities introduced by TPIAT may reduce risk for common causes of mortality.

Association of Atrial Fibrillation With Stroke and Dementia Accounting for Left Atrial Function and Size.

BACKGROUND: Atrial fibrillation (AF) is associated with higher risks of ischemic stroke (IS) and dementia. Whether alterations in left atrial (LA) function or size-atrial myopathy-confound these associations remains unknown. OBJECTIVES: The purpose of this study was to examine the association of prevalent and incident AF with ischemic stroke and dementia in the ARIC (Atherosclerosis Risk In Communities) study, adjusting for LA function and size. METHODS: Participants at visit 5 (2011-2013) with echocardiographic LA function (reservoir, conduit, contractile strain, and emptying fraction) and size (maximal, minimal volume index) data, and without prevalent stroke or dementia were followed through 2019. For analysis, we used time-varying Cox regression. RESULTS: Among 5,458 participants (1,193 with AF, mean age of 76 years) in the stroke analysis and 5,461 participants (1,205 with AF, mean age of 75 years) in the dementia analysis, 209 participants developed ischemic stroke, and 773 developed dementia over 7.1 years (median). In a demographic and risk factor-adjusted model, AF was significantly associated with ischemic stroke (HR, 1.63; 95% CI: 1.11-2.37) and dementia (HR: 1.38, 95% CI: 1.13-1.70). After additionally adjusting for LA reservoir strain, these associations were attenuated and no longer statistically significant (stroke [HR: 1.33, 95% CI: 0.88-2.00], dementia [HR: 1.15, 95% CI: 0.92-1.43]). Associations with ischemic stroke and dementia were also attenuated and not statistically significant after adjustment for LA contractile strain, emptying fraction, and minimal volume index. CONCLUSIONS: AF-ischemic stroke and AF-dementia associations were not statistically significant after adjusting for measures of atrial myopathy. This proof-of-concept analysis does not support AF as an independent risk factor for ischemic stroke and dementia.

Nutritional Risks in Patients Undergoing Total Pancreatectomy Islet AutoTransplantation in the POST Consortium.

BACKGROUND AND AIMS: Total pancreatectomy with islet autotransplantation (TPIAT) can relieve pain for individuals with acute recurrent or chronic pancreatitis. However, TPIAT may increase the risk of poor nutritional status with complete exocrine pancreatic insufficiency, partial duodenectomy, and intestinal reconstruction. Our study's objective was to evaluate nutritional status, anthropometrics, and vitamin levels before and after TPIAT. METHODS: The multicenter Prospective Observational Study of TPIAT (POST) collects measures including vitamins A, D, and E levels, pancreatic enzyme dose, and multivitamin (MVI) administration before and 1-year after TPIAT. Using these data, we studied nutritional and vitamin status before and after TPIAT. RESULTS: 348 TPIAT recipients were included (68% adult, 37% male, 93% Caucasian). In paired analyses at 1-year follow-up, vitamin A was low in 23% (vs 9% pre-TPIAT, p < 0.001); vitamin E was low in 11% (vs 5% pre-TPIAT, p = 0.066), and 19% had vitamin D deficiency (vs 12% pre-TPIAT, p = 0.035). Taking a fat-soluble multivitamin (pancreatic MVI) was associated with lower risk for vitamin D deficiency (p = 0.002). Adults were less likely to be on a pancreatic MVI at follow-up (34% vs 66% respectively, p < 0.001). Enzyme dosing was adequate. More adults versus children were overweight or underweight pre- and post-TPIAT. Underweight status was associated with vitamin A (p = 0.014) and E (p = 0.02) deficiency at follow-up. CONCLUSIONS: Prevalence of fat-soluble vitamin deficiencies increased after TPIAT, especially if underweight. We strongly advocate that all TPIAT recipients have close post-operative nutritional monitoring, including vitamin levels. Pancreatic MVIs should be given to minimize risk of developing deficiencies.

Diagnosed Gonorrhea Among Privately Insured Women: Analysis of United States Claims Data.

Background: Gonorrhea incidence in the United States has risen by nearly 50% in the last decade, while screening rates have increased. Gonorrhea sequelae rates could indicate whether increased gonorrhea incidence is due to better screening. We estimated the association of gonorrhea diagnosis with pelvic inflammatory disease (PID), ectopic pregnancy (EP), and tubal factor infertility (TFI) in women and detected changes in associations over time. Materials and Methods: This retrospective cohort study included 5,553,506 women aged 18-49 tested for gonorrhea in the IBM MarketScan claims administrative database from 2013-2018 in the United States. We estimated incidence rates and hazard ratios (HRs) of gonorrhea diagnosis for each outcome, adjusting for potential confounders using Cox proportional hazards models. We tested the interaction between gonorrhea diagnosis and the initial gonorrhea test year to identify changes in associations over time. Results: We identified 32,729 women with a gonorrhea diagnosis (mean follow-up time in years: PID = 1.73, EP = 1.75, TFI = 1.76). A total of 131,500 women were diagnosed with PID, 64,225 had EP, and 41,507 had TFI. Women with gonorrhea diagnoses had greater incidence per 1000 person-years for all outcomes (PID = 33.5, EP = 9.4, TFI = 5.3) compared to women without gonorrhea diagnoses (PID = 13.9, EP = 6.7, TFI = 4.3). After adjustment, HRs were higher in women with a gonorrhea diagnosis vs. those without [PID = 2.29 (95% confidence interval, CI: 2.15-2.44), EP = 1.57, (95% CI: 1.41-1.76), TFI = 1.70 (95% CI: 1.47-1.97)]. The interaction of gonorrhea diagnosis and test year was not significant, indicating no change in relationship by initial test year. Conclusion: The relationship between gonorrhea and reproductive outcomes has persisted, suggesting a higher disease burden.

Human Effectors of Acute and Chronic GVHD Overexpress CD83 and Predict Mortality.

PURPOSE: Acute and chronic GVHD remain major causes of transplant-related morbidity and mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). We have shown CD83 chimeric antigen receptor (CAR) T cells prevent GVHD and kill myeloid leukemia cell lines. In this pilot study, we investigate CD83 expression on GVHD effector cells, correlate these discoveries with clinical outcomes, and evaluate critical therapeutic implications for transplant recipients. EXPERIMENTAL DESIGN: CD83 expression was evaluated among circulating CD4+ T cells, B-cell subsets, T follicular helper (Tfh) cells, and monocytes from patients with/without acute or chronic GVHD (n = 48 for each group), respectively. CD83 expression was correlated with survival, TRM, and relapse after alloHCT. Differential effects of GVHD therapies on CD83 expression was determined. RESULTS: CD83 overexpression on CD4+ T cells correlates with reduced survival and increased TRM. Increased CD83+ B cells and Tfh cells, but not monocytes, are associated with poor posttransplant survival. CD83 CAR T eliminate autoreactive CD83+ B cells isolated from patients with chronic GVHD, without B-cell aplasia as observed with CD19 CAR T. We demonstrate robust CD83 antigen density on human acute myeloid leukemia (AML), and confirm potent antileukemic activity of CD83 CAR T in vivo, without observed myeloablation. CONCLUSIONS: CD83 is a promising diagnostic marker of GVHD and warrants further investigation as a therapeutic target of both GVHD and AML relapse after alloHCT.

Higher doses of tisagenlecleucel are associated with improved outcomes: a report from the pediatric real-world CAR consortium.

Remarkable complete response rates have been shown with tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting CD19, in patients up to age 26 years with refractory/relapsed B-cell acute lymphoblastic leukemia; it is US Food and Drug Administration approved for this indication. Currently, patients receive a single dose of tisagenlecleucel across a wide dose range of 0.2 to 5.0 × 106 and 0.1 to 2.5 × 108 CAR T cells per kg for patients ≤50 and >50 kg, respectively. The effect of cell dose on survival and remission is not yet well established. Our primary goal was to determine if CAR T-cell dose affects overall survival (OS), event-free survival (EFS), or relapse-free-survival (RFS) in tisagenlecleucel recipients. Retrospective data were collected from Pediatric Real World CAR Consortium member institutions and included 185 patients infused with commercial tisagenlecleucel. The median dose of viable transduced CAR T cells was 1.7 × 106 CAR T cells per kg. To assess the impact of cell dose, we divided responders into dose quartiles: 0.134 to 1.300 × 106 (n = 48 [27%]), 1.301 to 1.700 × 106 (n = 46 [26%]), 1.701 to 2.400 × 106 (n = 43 [24%]), and 2.401 to 5.100 × 106 (n = 43 [24%]). OS, EFS, and RFS were improved in patients who received higher doses of tisagenlecleucel (P = .031, .0079, and .0045, respectively). Higher doses of tisagenlecleucel were not associated with increased toxicity. Because the current tisagenlecleucel package insert dose range remains broad, this work has implications in regard to targeting higher cell doses, within the approved dose range, to optimize patients' potential for long-standing remission.

Changes in patterns of traumatic brain injury in the Michigan Trauma Quality Improvement Program database early in the COVID-19 pandemic.

OBJECTIVE: The authors' objective was to investigate the impact of the global COVID-19 pandemic on hospital presentation and process of care for the treatment of traumatic brain injuries (TBIs). Improved understanding of these effects will inform sociopolitical and hospital policies in response to future pandemics. METHODS: The Michigan Trauma Quality Improvement Program (MTQIP) database, which contains data from 36 level I and II trauma centers in Michigan and Minnesota, was queried to identify patients who sustained TBI on the basis of head/neck Abbreviated Injury Scale (AIS) codes during the periods of March 13 through July 2 of 2017-2019 (pre-COVID-19 period) and March 13, 2020, through July 2, 2020 (COVID-19 period). Analyses were performed to detect differences in incidence, patient characteristics, injury severity, and outcomes. RESULTS: There was an 18% decrease in the rate of encounters with TBI in the first 8 weeks (March 13 through May 7), followed by a 16% increase during the last 8 weeks (May 8 through July 2), of our COVID-19 period compared with the pre-COVID-19 period. Cumulatively, there was no difference in the rates of encounters with TBI between the COVID-19 and pre-COVID-19 periods. Severity of TBI, as measured with maximum AIS score for the head/neck region and Glasgow Coma Scale score, was also similar between periods. During the COVID-19 period, a greater proportion of patients with TBI presented more than a day after sustaining their injuries (p = 0.046). COVID-19 was also associated with a doubling in the decubitus ulcer rate from 1.0% to 2.1% (p = 0.002) and change in the distribution of discharge status (p = 0.01). Multivariable analysis showed no differences in odds of death/hospice discharge, intensive care unit stay of at least a day, or need for a ventilator for at least a day between the COVID-19 and pre-COVID-19 periods. CONCLUSIONS: During the early months of the COVID-19 pandemic, the number of patients who presented with TBI was initially lower than in the years 2017-2019 prior to the pandemic. However, there was a subsequent increase in the rate of encounters with TBI, resulting in overall similar rates of TBI between March 13 through July 2 during the COVID-19 period and during the pre-COVID-19 period. The COVID-19 cohort was also associated with negative impacts on time to presentation, rate of decubitus ulcers, and discharge with supervision. Policies in response to future pandemics must consider the resources necessary to care for patients with TBI.

Outcomes After Nonresponse and Relapse Post-Tisagenlecleucel in Children, Adolescents, and Young Adults With B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Nonresponse and relapse after CD19-chimeric antigen receptor (CAR) T-cell therapy continue to challenge survival outcomes. Phase II landmark data from the ELIANA trial demonstrated nonresponse and relapse rates of 14.5% and 28%, respectively, whereas use in the real-world setting showed nonresponse and relapse rates of 15% and 37%. Outcome analyses describing fate after post-CAR nonresponse and relapse remain limited. Here, we aim to establish survival outcomes after nonresponse and both CD19+ and CD19- relapses and explore treatment variables associated with inferior survival. METHODS: We conducted a retrospective multi-institutional study of 80 children and young adults with B-cell acute lymphoblastic leukemia experiencing nonresponse (n = 23) or relapse (n = 57) after tisagenlecleucel. We analyze associations between baseline characteristics and these outcomes and establish survival rates and salvage approaches. RESULTS: The overall survival (OS) at 12 months was 19% across nonresponders (n = 23; 95% CI, 7 to 50). Ninety-five percent of patients with nonresponse had high preinfusion disease burden. Among 156 morphologic responders, the cumulative incidence of relapse was 37% (95% CI, 30 to 47) at 12 months (CD19+; 21% [15 to 29], CD19-; 16% [11 to 24], median follow-up; 380 days). Across 57 patients experiencing relapse, the OS was 52% (95% CI, 38 to 71) at 12 months after time of relapse. Notably, CD19- relapse was associated with significantly decreased OS as compared with patients who relapsed with conserved CD19 expression (CD19- 12-month OS; 30% [14 to 66], CD19+ 12-month OS; 68% [49 to 92], P = .0068). Inotuzumab, CAR reinfusion, and chemotherapy were used as postrelapse salvage therapy with greatest frequency, yet high variability in treatment sequencing and responses limits efficacy analysis across salvage approaches. CONCLUSION: We describe poor survival across patients experiencing nonresponse to tisagenlecleucel. In the post-tisagenlecleucel relapse setting, patients can be salvaged; however, CD19- relapse is distinctly associated with decreased survival outcomes.

Analysis of composite endpoints with component-wise censoring in the presence of differential visit schedules.

Composite endpoints are very common in clinical research, such as recurrence-free survival in oncology research, defined as the earliest of either death or disease recurrence. Because of the way data are collected in such studies, component-wise censoring is common, where, for example, recurrence is an interval-censored event and death is a right-censored event. However, a common way to analyze such component-wise censored composite endpoints is to treat them as right-censored, with the date at which the non-fatal event was detected serving as the date the event occurred. This approach is known to introduce upward bias when the Kaplan-Meier estimator is applied, but has more complex impact on semi-parametric regression approaches. In this article we compare the performance of the Cox model estimators for right-censored data and the Cox model estimators for interval-censored data in the context of component-wise censored data where the visit process differs across levels of a covariate of interest, a common scenario in observational data. We additionally examine estimators of the cause-specific hazard when applied to the individual components of such component-wise censored composite endpoints. We found that when visit schedules differed according to levels of a covariate of interest, the Cox model estimators for right-censored data and the estimators for cause-specific hazards were increasingly biased as the frequency of visits decreased. The Cox model estimator for interval-censored data with censoring at the last disease-free date is recommended for use in the presence of differential visit schedules.

Surgical approach and short-term outcomes in adults and children undergoing total pancreatectomy with islet autotransplantation: A report from the Prospective Observational Study of TPIAT.

BACKGROUND: Total pancreatectomy with islet autotransplantation (TPIAT) is a viable option for treating debilitating recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) in adults and children. No data is currently available regarding variation in approach to operation. METHODS: We evaluated surgical techniques, islet isolation and infusion approaches, and outcomes and complications, comparing children (n = 84) with adults (n = 195) enrolled between January 2017 and April 2020 by 11 centers in the United States in the Prospective Observational Study of TPIAT (POST), which was launched in 2017 to collect standard history and outcomes data from patients undergoing TPIAT for RAP or CP. RESULTS: Children more commonly underwent splenectomy (100% versus 91%, p = 0.002), pylorus preservation (93% versus 67%; p < 0.0001), Roux-en-Y duodenojejunostomy reconstruction (92% versus 35%; p < 0.0001), and enteral feeding tube placement (93% versus 63%; p < 0.0001). Median islet equivalents/kg transplanted was higher in children (4577; IQR 2816-6517) than adults (2909; IQR 1555-4479; p < 0.0001), with COBE purification less common in children (4% versus 15%; p = 0.0068). Median length of hospital stay was higher in children (15 days; IQR 14-22 versus 11 days; IQR 8-14; p < 0.0001), but 30-day readmissions were lower in children (13% versus 26%, p = 0.018). Rate of portal vein thrombosis was significantly lower in children than in adults (2% versus 10%, p = 0.028). There were no mortalities in the first 90 days post-TPIAT. CONCLUSIONS: Pancreatectomy techniques differ between children and adults, with islet yields higher in children. The rates of portal vein thrombosis and early readmission are lower in children.

Nonparametric estimation in an illness-death model with component-wise censoring.

In disease settings where study participants are at risk for death and a serious nonfatal event, composite endpoints defined as the time until the earliest of death or the nonfatal event are often used as the primary endpoint in clinical trials. In practice, if the nonfatal event can only be detected at clinic visits and the death time is known exactly, the resulting composite endpoint exhibits "component-wise censoring." The standard method used to estimate event-free survival in this setting fails to account for component-wise censoring. We apply a kernel smoothing method previously proposed for a marker process in a novel way to produce a nonparametric estimator for event-free survival that accounts for component-wise censoring. The key insight that allows us to apply this kernel method is thinking of nonfatal event status as an intermittently observed binary time-dependent variable rather than thinking of time to the nonfatal event as interval-censored. We also propose estimators for the probability in state and restricted mean time in state for reversible or irreversible illness-death models, under component-wise censoring, and derive their large-sample properties. We perform a simulation study to compare our method to existing multistate survival methods and apply the methods on data from a large randomized trial studying a multifactor intervention for reducing morbidity and mortality among men at above average risk of coronary heart disease.

Designing clinical trials with (restricted) mean survival time endpoint: Practical considerations.

BACKGROUND/AIMS: The difference in mean survival time, which quantifies the treatment effect in terms most meaningful to patients and retains its interpretability regardless of the shape of the survival distribution or the proportionality of the treatment effect, is an alternative endpoint that could be used more often as the primary endpoint to design clinical trials. The underuse of this endpoint is due to investigators' lack of familiarity with the test comparing the mean survival times and the lack of tools to facilitate trial design with this endpoint. The aim of this article is to provide investigators with insights and software to design trials with restricted mean survival time as the primary endpoint. METHODS: A closed-form formula for the asymptotic power of the test of restricted mean survival time difference is presented. The effects of design parameters on power were evaluated for the mean survival time test and log-rank test. An R package which calculates the power or the sample size for user-specified parameter values and provides power plots for each design parameter is provided. The R package also calculates the probability that the restricted mean survival time is estimable for user-defined trial designs. RESULTS: Under proportional hazards and late differences in survival, the power of the mean survival time test can approach that of the log-rank test if the restriction time is late. Under early differences, the power of the restricted mean survival time test is higher than that of the log-rank test. Duration of accrual and follow-up have little influence on the power of the restricted mean survival time test. The choice of restriction time, on the other hand, has a large impact on power. Because the power depends on the interplay among the design factors, plotting the relationship between each design parameter and power allows the users to select the designs most appropriate for their trial. When modification is necessary to ensure the difference in restricted mean survival time is estimable, the three available modifications all perform adequately in the scenarios studied. CONCLUSION: The restricted mean survival time is a survival endpoint that is meaningful to investigators and to patients and at the same time requires less restrictive assumptions. The biggest challenge with this endpoint is selection of the restriction time. We recommend selecting a restriction time that is clinically relevant to the disease and the clinical setting of the trial of interest. The practical considerations and the R package provided in this work are readily available tools that researchers can use to design trials with restricted mean survival time as the primary endpoint.