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Zhou, Qingning, Jianwen Cai, and Haibo Zhou. "Outcome-dependent sampling with interval-censored failure time data." Biometrics 74, no. 1 (August 3, 2017): 58–67. http://dx.doi.org/10.1111/biom.12744.
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Antolini, Laura, and Maria Grazia Valsecchi. "Performance of binary markers for censored failure time outcome: nonparametric approach based on proportions." Statistics in Medicine 31, no. 11-12 (December 12, 2011): 1113–28. http://dx.doi.org/10.1002/sim.4443.
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Issa, Naim, Camden L. Lopez, Aleksandar Denic, Sandra J. Taler, Joseph J. Larson, Walter K. Kremers, Luisa Ricaurte, et al. "Kidney Structural Features from Living Donors Predict Graft Failure in the Recipient." Journal of the American Society of Nephrology 31, no. 2 (January 23, 2020): 415–23. http://dx.doi.org/10.1681/asn.2019090964.
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BackgroundNephrosclerosis, nephron size, and nephron number vary among kidneys transplanted from living donors. However, whether these structural features predict kidney transplant recipient outcomes is unclear.MethodsOur study used computed tomography (CT) and implantation biopsy to investigate donated kidney features as predictors of death-censored graft failure at three transplant centers participating in the Aging Kidney Anatomy study. We used global glomerulosclerosis, interstitial fibrosis/tubular atrophy, artery luminal stenosis, and arteriolar hyalinosis to measure nephrosclerosis; mean glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area to measure nephron size; and calculations from CT cortical volume and glomerular density on biopsy to assess nephron number. We also determined the death-censored risk of graft failure with each structural feature after adjusting for the predictive clinical characteristics of donor and recipient.ResultsThe analysis involved 2293 donor-recipient pairs. Mean recipient follow-up was 6.3 years, during which 287 death-censored graft failures and 424 deaths occurred. Factors that predicted death-censored graft failure independent of both donor and recipient clinical characteristics included interstitial fibrosis/tubular atrophy, larger cortical nephron size (but not nephron number), and smaller medullary volume. In a subset with 12 biopsy section slides, arteriolar hyalinosis also predicted death-censored graft failure.ConclusionsSubclinical nephrosclerosis, larger cortical nephron size, and smaller medullary volume in healthy donors modestly predict death-censored graft failure in the recipient, independent of donor or recipient clinical characteristics. These findings provide insights into a graft’s “intrinsic quality” at the time of donation, and further support the use of intraoperative biopsies to identify kidney grafts that are at higher risk for failure.
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Thongprayoon, Charat, Caroline C. Jadlowiec, Shennen A. Mao, Michael A. Mao, Napat Leeaphorn, Wisit Kaewput, Pattharawin Pattharanitima, Pitchaphon Nissaisorakarn, Matthew Cooper, and Wisit Cheungpasitporn. "Distinct phenotypes of kidney transplant recipients aged 80 years or older in the USA by machine learning consensus clustering." BMJ Surgery, Interventions, & Health Technologies 5, no. 1 (February 2023): e000137. http://dx.doi.org/10.1136/bmjsit-2022-000137.
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ObjectivesThis study aimed to identify distinct clusters of very elderly kidney transplant recipients aged ≥80 and assess clinical outcomes among these unique clusters.DesignCohort study with machine learning (ML) consensus clustering approach.Setting and participantsAll very elderly (age ≥80 at time of transplant) kidney transplant recipients in the Organ Procurement and Transplantation Network/United Network for Organ Sharing database database from 2010 to 2019.Main outcome measuresDistinct clusters of very elderly kidney transplant recipients and their post-transplant outcomes including death-censored graft failure, overall mortality and acute allograft rejection among the assigned clusters.ResultsConsensus cluster analysis was performed in 419 very elderly kidney transplant and identified three distinct clusters that best represented the clinical characteristics of very elderly kidney transplant recipients. Recipients in cluster 1 received standard Kidney Donor Profile Index (KDPI) non-extended criteria donor (ECD) kidneys from deceased donors. Recipients in cluster 2 received kidneys from older, hypertensive ECD deceased donors with a KDPI score ≥85%. Kidneys for cluster 2 patients had longer cold ischaemia time and the highest use of machine perfusion. Recipients in clusters 1 and 2 were more likely to be on dialysis at the time of transplant (88.3%, 89.4%). Recipients in cluster 3 were more likely to be preemptive (39%) or had a dialysis duration less than 1 year (24%). These recipients received living donor kidney transplants. Cluster 3 had the most favourable post-transplant outcomes. Compared with cluster 3, cluster 1 had comparable survival but higher death-censored graft failure, while cluster 2 had lower patient survival, higher death-censored graft failure and more acute rejection.ConclusionsOur study used an unsupervised ML approach to cluster very elderly kidney transplant recipients into three clinically unique clusters with distinct post-transplant outcomes. These findings from an ML clustering approach provide additional understanding towards individualised medicine and opportunities to improve care for very elderly kidney transplant recipients.
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Mohsin Saeed, Noora, and Faiz Ahmed Mohamed Elfaki. "Parametric Weibull Model Based on Imputations Techniques for Partly Interval Censored Data." Austrian Journal of Statistics 49, no. 3 (February 20, 2020): 30–37. http://dx.doi.org/10.17713/ajs.v49i3.1027.
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The term survival analysis has been used in a broad sense to describe collection of statistical procedures for data analysis for which the outcome variable of interest is time until an event occurs, the time to failure of an experimental unit might be censored and this can be right, left, interval, and Partly Interval Censored data (PIC). In this paper, the analysis of this model is conducted based on parametric Weibull model via PIC data. Moreover, two imputation techniques are used, which are: left point and right point. The effectiveness of the proposed model is tested through numerical analysis on simulated and secondary data sets.
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Zhou, Qingning, Jianwen Cai, and Haibo Zhou. "Semiparametric inference for a two-stage outcome-dependent sampling design with interval-censored failure time data." Lifetime Data Analysis 26, no. 1 (January 7, 2019): 85–108. http://dx.doi.org/10.1007/s10985-019-09461-5.
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Guure, Chris B., and Samuel Bosomprah. "Bayesian Perspective on Random Censored Survival Data." International Scholarly Research Notices 2014 (October 29, 2014): 1–9. http://dx.doi.org/10.1155/2014/430357.
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A unit is said to be randomly censored when the information on time occurrence of an event is not available due to either loss to followup, withdrawal, or nonoccurrence of the outcome event before the end of the study. It is assumed in independent random/noninformative censoring that each individual has his/her own failure time T and censoring time C; however, one can only observe the random vector, say, (X;δ). The classical approach is considered for analysing the generalised exponential distribution with random or noninformative censored samples which occur most often in biological or medical studies. The Bayes methods are also considered via a numerical approximation suggested by Lindley in 1980 and that of the Laplace approximation procedure developed by Tierney and Kadane in 1986 with assumed informative priors alongside linear exponential loss function and squared error loss function. A simulation study is carried out to compare the estimators proposed in this paper. Two datasets have also been illustrated.
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Wang, Jian, and Sanjay Shete. "Estimation of indirect effect when the mediator is a censored variable." Statistical Methods in Medical Research 27, no. 10 (January 30, 2017): 3010–25. http://dx.doi.org/10.1177/0962280217690414.
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A mediation model explores the direct and indirect effects of an initial variable ( X) on an outcome variable ( Y) by including a mediator ( M). In many realistic scenarios, investigators observe censored data instead of the complete data. Current research in mediation analysis for censored data focuses mainly on censored outcomes, but not censored mediators. In this study, we proposed a strategy based on the accelerated failure time model and a multiple imputation approach. We adapted a measure of the indirect effect for the mediation model with a censored mediator, which can assess the indirect effect at both the group and individual levels. Based on simulation, we established the bias in the estimations of different paths (i.e. the effects of X on M [ a], of M on Y [ b] and of X on Y given mediator M [ c’]) and indirect effects when analyzing the data using the existing approaches, including a naïve approach implemented in software such as Mplus, complete-case analysis, and the Tobit mediation model. We conducted simulation studies to investigate the performance of the proposed strategy compared to that of the existing approaches. The proposed strategy accurately estimates the coefficients of different paths, indirect effects and percentages of the total effects mediated. We applied these mediation approaches to the study of SNPs, age at menopause and fasting glucose levels. Our results indicate that there is no indirect effect of association between SNPs and fasting glucose level that is mediated through the age at menopause.
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Wu, Xianfeng, Xiao Yang, Xinhui Liu, Chunyan Yi, Qunying Guo, Xiaoran Feng, Haiping Mao, Fengxian Huang, and Xueqing Yu. "Patient Survival and Technique Failure in Continuous Ambulatory Peritoneal Dialysis Patients with Prior Stroke." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 36, no. 3 (May 2016): 308–14. http://dx.doi.org/10.3747/pdi.2014.00030.
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Background To investigate patient survival and technical failure of patients with prior stroke receiving continuous ambulatory peritoneal dialysis (CAPD) in Southern China. Methods This was a retrospective study. All subjects were recruited from the peritoneal dialysis center in The First Affiliated Hospital of Sun Yat-sen University from 1 January 2006 to 31 December 2010. All eligible patients were assigned to stroke group and non-stroke group according to a history of stroke before receiving CAPD. The primary outcomes were all-cause mortality and death-censored technical failure. Cox regression was used to estimate risk factors of all-cause mortality and death-censored technique failure. Results Of the 1,068 recruited patients, 75 (7.0%) patients had a previous history of stroke. The all-cause mortality and death-censored technique failure were significantly higher in the stroke group compared with the non-stroke group, respectively (odds ratio [OR] 2.67, 95% confidence interval [CI] 1.59 – 4.46 and OR 2.52, 95% CI 1.19 – 5.34). Older age (changed by 10 years, hazard ratio [HR] 1.90, 95% CI 1.07 – 3.38), lower body mass index (BMI 18.5 – 23.9 vs < 18.5 kg/m2 reference, HR 0.17, 95% CI 0.05 – 0.55) and time to the first episode of peritonitis (HR 0.93, 95% CI 0.89 – 0.96) were independently associated with increased risk of all-cause mortality in patients with prior stroke. In addition, time to the first episode of peritonitis was associated with decreased risk of death-censored technique failure (HR 0.91, 95% CI 0.84 – 0.99) in those with prior stroke. Conclusions Continuous ambulatory peritoneal dialysis patients with prior stroke had high rates of all-cause mortality and technique failure compared with those without prior stroke. Older age, lower BMI, and time to the first episode of peritonitis were independent risk factors of all-cause mortality in patients with prior stroke.
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Stapleton, Caragh P., Graham M. Lord, Peter J. Conlon, and Gianpiero L. Cavalleri. "The relationship between donor-recipient genetic distance and long-term kidney transplant outcome." HRB Open Research 3 (July 29, 2020): 47. http://dx.doi.org/10.12688/hrbopenres.13021.1.
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Background: We set out to quantify shared genetic ancestry between unrelated kidney donor-recipient pairs and test it as a predictor of time to graft failure. Methods: In a homogenous, unrelated, European cohort of deceased-donor kidney transplant pairs (n pairs = 1,808), we calculated, using common genetic variation, shared ancestry at the genic (n loci=40,053) and genomic level. We conducted a sub-analysis focused on transmembrane protein coding genes (n transcripts=8,637) and attempted replication of a previously published nonsynonymous transmembrane mismatch score. Measures of shared genetic ancestry were tested in a survival model against time to death-censored graft failure. Results: Shared ancestry calculated across the human leukocyte antigen (HLA) significantly associated with graft survival in individuals who had a high serological mismatch (n pairs = 186) with those who did not have any HLA mismatches indicating that shared ancestry calculated specific loci can capture known associations with genes impacting graft outcome. None of the other measures of shared ancestry at a genic level, genome-wide scale, transmembrane subset or nonsynonymous transmembrane mismatch score analysis were significant predictors of time to graft failure. Conclusions: In a large unrelated, deceased-donor European ancestry renal transplant cohort, shared donor-recipient genetic ancestry, calculated using common genetic variation, has limited value in predicting transplant outcome both on a genomic scale and at a genic level (other than at the HLA loci).
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Henderson, Nicholas C., Thomas A. Louis, Gary L. Rosner, and Ravi Varadhan. "Individualized treatment effects with censored data via fully nonparametric Bayesian accelerated failure time models." Biostatistics 21, no. 1 (July 19, 2018): 50–68. http://dx.doi.org/10.1093/biostatistics/kxy028.
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Summary Individuals often respond differently to identical treatments, and characterizing such variability in treatment response is an important aim in the practice of personalized medicine. In this article, we describe a nonparametric accelerated failure time model that can be used to analyze heterogeneous treatment effects (HTE) when patient outcomes are time-to-event. By utilizing Bayesian additive regression trees and a mean-constrained Dirichlet process mixture model, our approach offers a flexible model for the regression function while placing few restrictions on the baseline hazard. Our nonparametric method leads to natural estimates of individual treatment effect and has the flexibility to address many major goals of HTE assessment. Moreover, our method requires little user input in terms of model specification for treatment covariate interactions or for tuning parameter selection. Our procedure shows strong predictive performance while also exhibiting good frequentist properties in terms of parameter coverage and mitigation of spurious findings of HTE. We illustrate the merits of our proposed approach with a detailed analysis of two large clinical trials (N = 6769) for the prevention and treatment of congestive heart failure using an angiotensin-converting enzyme inhibitor. The analysis revealed considerable evidence for the presence of HTE in both trials as demonstrated by substantial estimated variation in treatment effect and by high proportions of patients exhibiting strong evidence of having treatment effects which differ from the overall treatment effect.
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Yang, Aotian, David Miller, and Qing Pan. "Constrained maximum entropy models to select genotype interactions associated with censored failure times." Journal of Bioinformatics and Computational Biology 16, no. 06 (December 2018): 1840024. http://dx.doi.org/10.1142/s0219720018400243.
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We propose a novel screening method targeting genotype interactions associated with disease risks. The proposed method extends the maximum entropy conditional probability model to address disease occurrences over time. Continuous occurrence times are grouped into intervals. The model estimates the conditional distribution over the disease occurrence intervals given individual genotypes by maximizing the corresponding entropy subject to constraints linking genotype interactions to time intervals. The EM algorithm is employed to handle observations with uncertainty, for which the disease occurrence is censored. Stepwise greedy search is proposed to screen a large number of candidate constraints. The minimum description length is employed to select the optimal set of constraints. Extensive simulations show that five or so quantile-dependent intervals are sufficient to categorize disease outcomes into different risk groups. Performance depends on sample size, number of genotypes, and minor allele frequencies. The proposed method outperforms the likelihood ratio test, Lasso, and a previous maximum entropy method with only binary (disease occurrence, non-occurrence) outcomes. Finally, a GWAS study for type 1 diabetes patients is used to illustrate our method. Novel one-genotype and two-genotype interactions associated with neuropathy are identified.
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Bandyopadhyay, Uttam, and Rahul Bhattacharya. "A Randomized Two Stage Adaptively Censored Design With Application to Testing." Revista Colombiana de Estadística 42, no. 2 (July 1, 2019): 209–24. http://dx.doi.org/10.15446/rce.v42n2.65344.
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A two stage randomized design is developed for two treatment clinical trials in which response variables are exponential and the observations are censored by using failure censoring and time censoring in the first and second stages respectively. The censoring time for the second stage is determined from the outcomes of the first stage. An application to testing for the equality of treatment effects is given along with a comparative study with relevant properties.
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Abdel-Hamid, Alaa H., and Atef F. Hashem. "Inference for the Exponential Distribution under Generalized Progressively Hybrid Censored Data from Partially Accelerated Life Tests with a Time Transformation Function." Mathematics 9, no. 13 (June 28, 2021): 1510. http://dx.doi.org/10.3390/math9131510.
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In this article, the tampered failure rate model is used in partially accelerated life testing. A non-decreasing time function, often called a ‘‘time transformation function", is proposed to tamper the failure rate under design conditions. Different types of the proposed function, which have sufficient conditions in order to be accelerating functions, are investigated. A baseline failure rate of the exponential distribution is considered. Some point estimation methods, as well as approximate confidence intervals, for the parameters involved are discussed based on generalized progressively hybrid censored data. The determination of the optimal stress change time is discussed under two different criteria of optimality. A real dataset is employed to explain the theoretical outcomes discussed in this article. Finally, a Monte Carlo simulation study is carried out to examine the performance of the estimation methods and the optimality criteria.
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Chatzopoulos, Georgios S., and Larry F. Wolff. "Survival Rates and Factors Affecting the Outcome Following Immediate and Delayed Implant Placement: A Retrospective Study." Journal of Clinical Medicine 11, no. 15 (August 7, 2022): 4598. http://dx.doi.org/10.3390/jcm11154598.
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Background: Immediate implant placement into extraction sockets has become a widely acceptable treatment option to decrease treatment time and enhance esthetics. The objectives of this study were to assess and compare the survival rates of immediate and delayed implant treatment as well as to investigate the effect of patient- and site-related variables on the treatment outcome in a large-scale population-based study. Methods: Dental records of patients who received implant therapy were retrieved from the electronic records of the University of Minnesota School of Dentistry. Demographic characteristics, dental insurance status, socioeconomic status as well as medical history and tobacco use were recorded. The treatment outcome was included as a binary variable (survival/failure). Time to failure (date of procedure to date of visit with failure) was compared between immediate and delayed implant treatment in Cox regression models. Kaplan–Meier plots for the survival of both treatment modalities were created. Patient-sites without failure were censored at the last follow-up visit. Results: A total of 4519 records of implants were included. The sample mean age was 60.27 years and included 50.7% males and 12.9% tobacco users. High socioeconomic status was characterized for 82.3% of the included population and 63.0% of them were self-payers. Immediate implants were significantly more frequently placed in the maxillary arch (p < 0.001) than in the mandible. Tobacco users received more often a delayed rather than an immediate implant placement (p = 0.001). The survival rate analysis revealed there were no significant differences between immediate and delayed implant placements (p = 0.48). The mean follow-up time was 32.27 months during which 1.5% immediate and 1.1% delayed implants were removed. The estimated mean survival time for immediate implants was 68.90 months, while delayed implants placed in healed sockets showed a mean survival time of 75.11 months. A statistically significant association was found between gender (p = 0.03) and osteoporosis (p = 0.001) with treatment outcome. Conclusions: The placement of immediate implants achieved similarly high survival rates when compared to delayed implants placed in healed sites. Males and osteoporotic individuals showed significantly higher implant failure than females and non-osteoporotic patients. This study demonstrated that both immediate and delayed implant placements are sound options with predictable treatment outcome.
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Thongprayoon, Charat, Caroline C. Jadlowiec, Wisit Kaewput, Pradeep Vaitla, Shennen A. Mao, Michael A. Mao, Napat Leeaphorn, et al. "Distinct Phenotypes of Kidney Transplant Recipients in the United States with Limited Functional Status as Identified through Machine Learning Consensus Clustering." Journal of Personalized Medicine 12, no. 6 (May 25, 2022): 859. http://dx.doi.org/10.3390/jpm12060859.
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Background: There have been concerns regarding increased perioperative mortality, length of hospital stay, and rates of graft loss in kidney transplant recipients with functional limitations. The application of machine learning consensus clustering approach may provide a novel understanding of unique phenotypes of functionally limited kidney transplant recipients with distinct outcomes in order to identify strategies to improve outcomes. Methods: Consensus cluster analysis was performed based on recipient-, donor-, and transplant-related characteristics in 3205 functionally limited kidney transplant recipients (Karnofsky Performance Scale (KPS) < 40% at transplant) in the OPTN/UNOS database from 2010 to 2019. Each cluster’s key characteristics were identified using the standardized mean difference. Posttransplant outcomes, including death-censored graft failure, patient death, and acute allograft rejection were compared among the clusters Results: Consensus cluster analysis identified two distinct clusters that best represented the clinical characteristics of kidney transplant recipients with limited functional status prior to transplant. Cluster 1 patients were older in age and were more likely to receive deceased donor kidney transplant with a higher number of HLA mismatches. In contrast, cluster 2 patients were younger, had shorter dialysis duration, were more likely to be retransplants, and were more likely to receive living donor kidney transplants from HLA mismatched donors. As such, cluster 2 recipients had a higher PRA, less cold ischemia time, and lower proportion of machine-perfused kidneys. Despite having a low KPS, 5-year patient survival was 79.1 and 83.9% for clusters 1 and 2; 5-year death-censored graft survival was 86.9 and 91.9%. Cluster 1 had lower death-censored graft survival and patient survival but higher acute rejection, compared to cluster 2. Conclusion: Our study used an unsupervised machine learning approach to characterize kidney transplant recipients with limited functional status into two clinically distinct clusters with differing posttransplant outcomes.
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Lim, Wai H., Gursharan K. Dogra, Stephen P. McDonald, Fiona G. Brown, and David W. Johnson. "Compared with Younger Peritoneal Dialysis Patients, Elderly Patients have Similar Peritonitis-Free Survival and Lower Risk of Technique Failure, but Higher Risk of Peritonitis-Related Mortality." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 31, no. 6 (November 2011): 663–71. http://dx.doi.org/10.3747/pdi.2010.00209.
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BackgroundThe number of elderly patients with end-stage kidney disease (ESKD) is increasing worldwide, but the proportion of elderly patients commencing peritoneal dialysis (PD) is falling. The reluctance of elderly ESKD patients to consider PD may be related to a perception that PD is associated with greater rates of complications. In the present study, we compared outcomes between younger and older PD patients.MethodsUsing Australia and New Zealand Dialysis Registry data, all adult ESKD patients commencing PD between 1991 and 2007 were categorized into under 50, 50 – 64.9, and 65 years of age or older groups. Time to first peritonitis, death-censored technique failure, and peritonitis-associated and all-cause mortality were evaluated by multivariate Cox proportional hazards model analysis.ResultsOf the 12932 PD patients included in the study, 3370 (26%) were under 50 years of age, 4386 (34%) were 50 – 64.9 years of age, and 5176 (40%) were 65 years of age or older. Compared with younger patients (<50 years), elderly patients (≥65 years) had a similar peritonitis-free survival and a lower risk of death-censored technique failure [hazard ratio (HR): 0.85; 95% confidence interval (CI): 0.79 to 0.93], but they had higher peritonitis-related (HR: 2.31; 95% CI: 1.68 to 3.18) and all-cause mortality (HR: 2.90; 95% CI: 2.60 to 3.23).ConclusionsNot unexpectedly, elderly patients have higher peritonitis-related and all-cause mortality, which is likely a consequence of a greater prevalence of comorbid disease. However, compared with younger patients, elderly patients have superior technique survival and similar peritonitis-free survival, suggesting that PD is a viable renal replacement therapy in this group of patients.
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Gniewkiewicz, Michal, Katarzyna Czerwinska, Katarzyna Zielniok, and Magdalena Durlik. "Association of Circulating Anti-HLA Donor-Specific Antibodies and Their Characteristics, including C1q-Binding Capacity, in Kidney Transplant Recipients with Long-Term Renal Graft Outcomes." Journal of Clinical Medicine 12, no. 4 (February 7, 2023): 1312. http://dx.doi.org/10.3390/jcm12041312.
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Post-transplant antihuman leukocyte antigen donor-specific antibodies (anti-HLA DSAs) monitoring in kidney transplant recipients remains unclear and is currently under investigation. The pathogenicity of anti-HLA DSAs is determined by antibody classes, specificity, mean fluorescent intensity (MFI), C1q-binding capacity, and IgG subclasses. The aim of this study was to investigate the association of circulating DSAs and their characteristics with renal allograft long-term outcomes. The study included 108 consecutive patients from our transplant center who underwent kidney allograft biopsy between November 2018 and November 2020, 3 to 24 months after kidney transplantation. At the time of biopsy, patients’ sera were collected for analysis of anti-HLA DSAs. Patients were followed for a median time of 39.0 months (Q1–Q3, 29.8–45.0). Detection of anti-HLA DSAs at the time of biopsy (HR = 5.133, 95% CI 2.150–12.253, p = 0.0002) and their C1q-binding capacity (HR = 14.639, 95% CI 5.320–40.283, p ≤ 0.0001) were independent predictors of the composite of sustained 30% reduction from estimated glomerular filtration rate or death-censored graft failure. Identification of anti-HLA DSAs and their C1q-binding capacity could be useful in identifying kidney transplant recipients at risk for inferior renal allograft function and graft failure. Analysis of C1q is noninvasive, accessible, and should be considered in clinical practice in post-transplant monitoring.
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Dlouhy, Brian J., Ana W. Capuano, Karthik Madhavan, James C. Torner, and Jeremy D. W. Greenlee. "Preoperative third ventricular bowing as a predictor of endoscopic third ventriculostomy success." Journal of Neurosurgery: Pediatrics 9, no. 2 (February 2012): 182–90. http://dx.doi.org/10.3171/2011.11.peds11495.
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Object Patients with hydrocephalus often present with both intraventricular obstructive and communicating components, and determination of the predominant component is difficult. Other investigators have observed that third ventricular floor deformation, or “bowing” of the third ventricular floor, is a good indicator of intraventricular obstructive hydrocephalus, resulting in higher success rates with endoscopic third ventriculostomy (ETV). However, additional third ventricular bowing assessment and statistical evidence demonstrating a difference in ETV outcome with third ventricular bowing is needed. The authors hypothesized that patients with preoperative bowing of the third ventricle would exhibit greater long-term success rates after ETV and that lack of bowing would result in increased failure rates after ETV. Methods The authors determined success and failure for 59 ETVs performed in 56 patients, and recorded patient age, time to failure, and preoperative third ventricular anatomy, as well as history of infection, intraventricular hemorrhage, and previous shunt. Third ventricular anatomy was assessed on MR imaging for bowing, which was classified as any of the following: depression of the third ventricular floor, enlargement of the supraoptic recess, anterior curvature of the lamina terminalis, dilation of the proximal aqueduct to a greater extent than the distal aqueduct, and blunting or posterior bowing of the suprapineal recess. Univariate and multivariate analyses of ETV failure and the time to failure were performed using logistic regression and the Cox proportional hazards model, respectively. Results After adjusting for patient age and history of infection, there was a significant association between lack of anterior third ventricular preoperative bowing (either lamina terminalis, supraoptic recess, or third ventricular floor) and ETV failure (adjusted HR 2.79, 95% CI 1.08–7.20). Of the patients with bowing, 70.5% experienced success with ETV, as did 33.3% of the patients without bowing. Among the individual structures, absence of bowing in the anterior aspect of the third ventricular floor was significantly associated with censored time to ETV failure (multivariate HR 2.59, 95% CI 1.01–6.66; final model including age and history of infection). Conclusions The presence of preoperative third ventricular bowing is predictive of ETV success, with nearly a 3-fold likelihood of success compared with patients treated with ETV in the absence of such bowing. Although bowing is predictive, 33% of patients without bowing were also treated successfully with ETV.
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de Moraes, Thyago Proença, Ana Elizabeth Figueiredo, Ludimila Guedim de Campos, Marcia Olandoski, Pasqual Barretti, and Roberto Pecoits-Filho. "Characterization of the Brazpd ii Cohort and Description of Trends in Peritoneal Dialysis Outcome across Time Periods." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 34, no. 7 (November 2014): 714–23. http://dx.doi.org/10.3747/pdi.2013.00282.
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Observational studies from different regions of the world provide valuable information in patient selection, clinical practice, and their relationship to patient and technique outcome. The present study is the first large cohort providing patient characteristics, clinical practice, patterns and their relationship to outcomes in Latin America. The objective of the present study was to characterize the cohort and to describe the main determinants of patient and technique survival, including trends over time of peritoneal dialysis (PD) initiation and treatment. This was a nationwide cohort study in which all incident adult patients on PD from 122 centers were studied. Patient demographics, socioeconomic and laboratory values were followed from December 2004 to January 2011 and, for comparison purposes, divided into 3 groups according to the year of starting PD: 2005/06, 2007/08 and 2009/10. Patient survival and technique failure (TF) were analyzed using the competing risk model of Fine and Gray. All patients active at the end of follow-up were treated as censored. In contrast, all patients who dropped the study for any reason different from the primary event of interest were treated as competing risk. Significance was set to a p level of 0.05. A total of 9,905 patients comprised the adult database, 7,007 were incident and 5,707 remained at least 90 days in PD. The main cause of dropout was death (54%) and of TF was peritonitis (63%). Technique survival at 1, 2, 3, 4, and 5 years was 91%, 84%, 77%, 68%, and 58%, respectively. There was no change in TF during the study period but 3 independent risk factors were identified: lower center experience, lower age, and automated PD (APD) as initial therapy. Cardiovascular disease (36%) was the main cause of death and the overall patient survival was 85%, 74%, 64%, 54%, and 48% at 1, 2, 3, 4, and 5 years, respectively. Patient survival improved along all study periods: compared to 2005/2006, patients starting at 2007/2008 had a relative risk reduction (SHR) of 0.83 (95% confidence interval [CI] 0.72 – 0.95); and starting in 2009/2010 of 0.69 (95% CI 0.57 – 0.83). The independent risk factors for mortality were diabetes, age > 65 years, previous hemodialysis, starting PD modality, white race, low body mass index (BMI), low educational level, center experience, length of pre-dialysis care, and the year of starting PD. We observed an improvement in patient survival along the years. This finding was sustained even after correction for several confounders and using a competing risk approach. On the other hand, no changes in technique survival were found.
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Klotz, Laurence, Danny Vesprini, Perakaa Sethukavalan, Vibhuti Jethava, Liying Zhang, Suneil Jain, Toshihiro Yamamoto, Alexandre Mamedov, and Andrew Loblaw. "Long-Term Follow-Up of a Large Active Surveillance Cohort of Patients With Prostate Cancer." Journal of Clinical Oncology 33, no. 3 (January 20, 2015): 272–77. http://dx.doi.org/10.1200/jco.2014.55.1192.
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Purpose Active surveillance is increasingly accepted as a treatment option for favorable-risk prostate cancer. Long-term follow-up has been lacking. In this study, we report the long-term outcome of a large active surveillance protocol in men with favorable-risk prostate cancer. Patients and Methods In a prospective single-arm cohort study carried out at a single academic health sciences center, 993 men with favorable- or intermediate-risk prostate cancer were managed with an initial expectant approach. Intervention was offered for a prostate-specific antigen (PSA) doubling time of less than 3 years, Gleason score progression, or unequivocal clinical progression. Main outcome measures were overall and disease-specific survival, rate of treatment, and PSA failure rate in the treated patients. Results Among the 819 survivors, the median follow-up time from the first biopsy is 6.4 years (range, 0.2 to 19.8 years). One hundred forty-nine (15%) of 993 patients died, and 844 patients are alive (censored rate, 85.0%). There were 15 deaths (1.5%) from prostate cancer. The 10- and 15-year actuarial cause-specific survival rates were 98.1% and 94.3%, respectively. An additional 13 patients (1.3%) developed metastatic disease and are alive with confirmed metastases (n = 9) or have died of other causes (n = 4). At 5, 10, and 15 years, 75.7%, 63.5%, and 55.0% of patients remained untreated and on surveillance. The cumulative hazard ratio for nonprostate-to-prostate cancer mortality was 9.2:1. Conclusion Active surveillance for favorable-risk prostate cancer is feasible and seems safe in the 15-year time frame. In our cohort, 2.8% of patients have developed metastatic disease, and 1.5% have died of prostate cancer. This mortality rate is consistent with expected mortality in favorable-risk patients managed with initial definitive intervention.
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Cabrera, Cecilia, Alessandro Cozzi-Lepri, Andrew N. Phillips, Clive Loveday, Ole Kirk, Mounir Ait-Khaled, Peter Reiss, et al. "Baseline Resistance and Virological Outcome in Patients with Virological Failure who Start a Regimen Containing Abacavir: Eurosida Study." Antiviral Therapy 9, no. 5 (July 2004): 787–800. http://dx.doi.org/10.1177/135965350400900509.
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Objectives To investigate the ability of several HIV-1 drug-resistance interpretation systems, as well as the number of pre-specified combinations of abacavir-related mutations, to predict virological response to abacavir-containing regimens in antiretroviral therapy-experienced, abacavir-naive patients starting an abacavir-containing regimen in the EuroSIDA cohort. Patients and methods A total of 100 HIV-infected patients with viral load (VL) >500 copies/ml who had a plasma sample available at the time of starting abacavir (baseline) were included. Resistance to abacavir was interpreted by using eight different commonly used systems that consisted of rules-based algorithms or tables of mutations. Correlation between baseline abacavir-resistance mutations and month 6 virological response was performed on this population using a multivariable linear regression model accounting for censored data. Results The baseline VL was 4.36 log10 RNA copies/ml [interquartile range (IQR): 3.65–4.99 log10 RNA copies/ml] and the median CD4 cell count was 210 cells/μl (IQR: 67–305 cells/μl). Our patients were pre-exposed to a median of seven antiretrovirals (2–12) before starting abacavir therapy. The median (range) number of abacavir mutations (according to the International AIDS Society-USA) detected at baseline was 3.5 (0–8). Overall, the Kaplan–Meier estimate of the median month 6 VL decline was 0.86 log10 RNA copies/ml [95% confidence intervals (95% CI): 0.45–1.24]. The VL in those patients ( n=31) who intensified treatment by adding only abacavir decreased by a median 0.20 log10 RNA copies/ml (95% CI: -0.18; +0.94). The proportion of patients who harboured viruses fully resistant to abacavir among the eight genotypic resistance interpretation algorithms ranged from 12% [Agence Nationale de Recherches sur le SIDA (ANRS)] to 79% [Stanford HIV RT and PR Sequence Database (HIVdb)]. Some interpretation systems showed statistically significant associations between the predicted resistance status and the virological response while others showed no consistent association. The number of active drugs in the regimen was associated with greater virological suppression (additional month 6 VL reduction per additional sensitive drug=0.51, 95% CI: 0.15–0.88, P=0.006); baseline VL was also weakly associated (additional month 6 VL reduction per log10 higher=0.30, 95% CI: -0.02; +0.62, P=0.06). In contrast, the number of drugs previously received was associated with diminished viral reduction (additional month 6 VL reduction per additional drug=-0.14, 95% CI: -0.28; 0.00, P=0.05). Conclusions Our results revealed a high degree of variability among several genotypic resistance interpretation algorithms currently in use for abacavir. Therefore, the interpretation of genotypic resistance for predicting response to regimens containing abacavir remains a major challenge.
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Dantan, Etienne, Yohann Foucher, Marine Lorent, Magali Giral, and Philippe Tessier. "Optimal threshold estimator of a prognostic marker by maximizing a time-dependent expected utility function for a patient-centered stratified medicine." Statistical Methods in Medical Research 27, no. 6 (October 20, 2016): 1847–59. http://dx.doi.org/10.1177/0962280216671161.
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Defining thresholds of prognostic markers is essential for stratified medicine. Such thresholds are mostly estimated from purely statistical measures regardless of patient preferences potentially leading to unacceptable medical decisions. Quality-Adjusted Life-Years are a widely used preferences-based measure of health outcomes. We develop a time-dependent Quality-Adjusted Life-Years-based expected utility function for censored data that should be maximized to estimate an optimal threshold. We performed a simulation study to compare estimated thresholds when using the proposed expected utility approach and purely statistical estimators. Two applications illustrate the usefulness of the proposed methodology which was implemented in the R package ROCt ( www.divat.fr ). First, by reanalysing data of a randomized clinical trial comparing the efficacy of prednisone vs. placebo in patients with chronic liver cirrhosis, we demonstrate the utility of treating patients with a prothrombin level higher than 89%. Second, we reanalyze the data of an observational cohort of kidney transplant recipients: we conclude to the uselessness of the Kidney Transplant Failure Score to adapt the frequency of clinical visits. Applying such a patient-centered methodology may improve future transfer of novel prognostic scoring systems or markers in clinical practice.
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Thongprayoon, Charat, Shennen A. Mao, Caroline C. Jadlowiec, Michael A. Mao, Napat Leeaphorn, Wisit Kaewput, Pradeep Vaitla, et al. "Machine Learning Consensus Clustering of Morbidly Obese Kidney Transplant Recipients in the United States." Journal of Clinical Medicine 11, no. 12 (June 8, 2022): 3288. http://dx.doi.org/10.3390/jcm11123288.
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Background: This study aimed to better characterize morbidly obese kidney transplant recipients, their clinical characteristics, and outcomes by using an unsupervised machine learning approach. Methods: Consensus cluster analysis was applied to OPTN/UNOS data from 2010 to 2019 based on recipient, donor, and transplant characteristics in kidney transplant recipients with a pre-transplant BMI ≥ 40 kg/m2. Key cluster characteristics were identified using the standardized mean difference. Post-transplant outcomes, including death-censored graft failure, patient death, and acute allograft rejection, were compared among the clusters. Results: Consensus clustering analysis identified 3204 kidney transplant recipients with a BMI ≥ 40 kg/m2. In this cohort, five clinically distinct clusters were identified. Cluster 1 recipients were predominantly white and non-sensitized, had a short dialysis time or were preemptive, and were more likely to receive living donor kidney transplants. Cluster 2 recipients were older and diabetic. They were likely to have been on dialysis >3 years and receive a standard KDPI deceased donor kidney. Cluster 3 recipients were young, black, and had kidney disease secondary to hypertension or glomerular disease. Cluster 3 recipients had >3 years of dialysis and received non-ECD, young, deceased donor kidney transplants with a KDPI < 85%. Cluster 4 recipients were diabetic with variable dialysis duration who either received non-ECD standard KDPI kidneys or living donor kidney transplants. Cluster 5 recipients were young retransplants that were sensitized. One-year patient survival in clusters 1, 2, 3, 4, and 5 was 98.0%, 94.4%, 98.5%, 98.7%, and 97%, and one-year death-censored graft survival was 98.1%, 93.0%, 96.1%, 98.8%, and 93.0%, respectively. Cluster 2 had the worst one-year patient survival. Clusters 2 and 5 had the worst one-year death-censored graft survival. Conclusions: With the application of unsupervised machine learning, variable post-transplant outcomes are observed among morbidly obese kidney transplant recipients. Recipients with earlier access to transplant and living donation show superior outcomes. Unexpectedly, reduced graft survival in cluster 3 recipients perhaps underscores socioeconomic access to post-transplant support and minorities being disadvantaged in access to preemptive and living donor transplants. Despite obesity-related concerns, one-year patient and graft survival were favorable in all clusters, and obesity itself should be reconsidered as a hard barrier to kidney transplantation.
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Byrd, Kenneth, Panduka Nagahawatte, Michael Gary Martin, Matthew K. Stein, Kruti Patel, Lee Steven Schwartzberg, and Ari M. Vanderwalde. "Correlation between PD-L1 expression level and clinical benefit in 204 patients across malignancies at a single institution." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e14573-e14573. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e14573.
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e14573 Background: The utility of PD-L1 expression levels in predicting response to anti-PD-1 agents in many malignancies is uncertain. In this study, we describe outcomes of patients treated with anti-PD-1 agents by PD-L1 expression level. Methods: Molecular profiling of tumors in patients with newly diagnosed metastatic cancer was performed at West Cancer Center starting late 2014. Most profiling was performed by Caris, which in addition to NGS also reports PD-L1 expression (IHC, reported as percent expressed). Patients were included in this retrospective analysis if they were treated with an anti-PD-1 antibody and had available results from PD-L1 testing between 11/2014 and 11/2016. Time to treatment failure (TTF) was defined as time from first dose to documented progression, intolerance or death. Those without treatment failure were censored at the date of last contact. Pending formal retrospective RECIST review, clinical benefit rate (CBR) is reported. Results: 204 patients with reported PD-L1 expression started treatment with anti-PD-1 agents. Of these, 125 had non-small cell lung cancer, 31 had melanoma, 12 had renal cell carcinoma, and the remainder had other malignancies. 110 patients (54%) had PD-L1 expression level of 0%, 22 patients (11%) between 1-4%, 37 patients (18%) between 5-49%, and 35 patients (17%) >50%. Median TTF and CBR by PD-L1 overall and by malignancy are shown in the table below. Conclusions: Higher PD-L1 expression does appear to be associated with increased clinical benefit rate and time to treatment failure, though the highest levels of PD-L1 did not follow this pattern. Based on these surrogate endpoints, there appears to be substantial benefit with PD-1 inhibitor treatment even with 0% PD-L1 expression. Objective response rate will be presented. [Table: see text]
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Nassar, Mazen, and Farouq Mohammad A. Alam. "Analysis of Modified Kies Exponential Distribution with Constant Stress Partially Accelerated Life Tests under Type-II Censoring." Mathematics 10, no. 5 (March 4, 2022): 819. http://dx.doi.org/10.3390/math10050819.
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This study investigates, for the first time, the product of spacing estimation of the modified Kies exponential distribution parameters as well as the acceleration factor using constant-stress partially accelerated life tests under the Type-II censoring scheme. Besides this approach, the conventional maximum likelihood method is also considered. The point estimates and the approximate confidence intervals of the unknown parameters are obtained using the two methods. In addition, two parametric bootstrap confidence intervals are discussed based on both estimation methods. Extensive simulation studies are conducted by considering different censoring schemes to examine the efficiency of each estimation method. Finally, two real data sets for oil breakdown times of insulating fluid and minority electron mobility are analyzed to show the applicability of the different methods. Moreover, the reliability function and the mean time-to-failure under the normal use condition are estimated using both methods. Based on Monte Carlo simulation outcomes and real data analysis, we recommend using the maximum product of spacing to evaluate both the point and interval estimates for the modified Kies exponential distribution parameters in the presence of constant-stress partially accelerated Type-II censored data.
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Vanjire, Sachin, and Sanjay Patil. "Predictive Models for ABS and TPMS based on Gaussian Naïve Bays." International Journal on Recent and Innovation Trends in Computing and Communication 10, no. 9 (September 30, 2022): 125–32. http://dx.doi.org/10.17762/ijritcc.v10i9.5715.
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The car industry is currently preoccupied with the issue of safety. The increasing number of accidents occurring around the world as a result of automobile problems is a major contributing factor to these incidents. The amount of complicated electronics that is used in vehicles is becoming more prevalent every day. A great effort has been made in evaluating vehicle features in relation to vehicle components. Through such systems, a smart architecture and complex function designs are involved. During all of this vehicle transformation and evolution, the automotive industry recognises a high demand for vehicle safety. While designing and manufacturing this system, automotive experts understand a need for a strict monitoring and feedback system for complex vehicle architecture, which can notify the end user if there is any indication of a failure ahead of time.
In order to effectively participate in vehicle design activities, it is critical to grasp the significance of safety features. Tire system failures and braking system failures have played a large role in several recent traffic accidents. The failures of the tyre system and the braking system in the vehicle are addressed in this study. While investigating this system, it is discovered that it is supported by complex electrical systems, which include an ECU (electronic controller unit), sensors, and a wire system.
Through the use of these technologies, censored data can be processed in a timely manner and made available for diagnostic purposes. Nevertheless, car diagnostics is needed after any vehicle failure but that does not serve the aim of maintaining vehicle safety. As a result, predictive analysis or predictive diagnostics may be a viable option for informing the driver about the health of a particular vehicle component in advance. In this study, the author discusses the concepts of vehicle prognostics for the tyre pressure monitor system and the antilock braking system, which are accomplished using a statistical method of machine learning. In today's world, machine learning is expanding in breadth, and the world is becoming more aware of its enormous potential in the field of data analytics. It is the purpose of this study to introduce methodologies by which machine learning can assist vehicle predictive analytics to attain the intended goal of vehicle safety.The author of this article discusses how Bayesian statistics may be used to produce predictions in the form of probability estimation. The prediction's outcome is thoroughly analysed.
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McAtee, Casey L., Joseph Lubega, Michael E. Scheurer, and Rachel E. Rau. "Effects of Race and Ethnicity on Clinical Features, Tumor Genetics and Outcome in Children with KMT2A Rearranged Acute Myeloid Leukemia." Blood 136, Supplement 1 (November 5, 2020): 34. http://dx.doi.org/10.1182/blood-2020-136737.
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Black and Hispanic children with AML tend to have worse outcomes compared to White non-Hispanic children. Potential contributing factors include higher acuity at presentation, higher infection related mortality, and less availability of hematopoietic stem cell donors (Winestone. Amer J Hematol. 2017; Aplenc. Blood 2006; Gramatges. PBC 2017). We hypothesized that differences in disease biology contribute to inferior outcomes along racial/ethnic lines, and these differences may be apparent among specific cytogenetic subsets. To test this hypothesis, we mined the publicly available TARGET AML dataset which includes 956 newly diagnosed children with AML enrolled on Children's Cancer Group study CCG-2961 or Children's Oncology Group studies AAML03P1 or AAML0531. There were 557 White, non-Hispanic (WNH), 115 Black (including six Black Hispanic), 170 non-Black Hispanic, 45 Asian, and 69 patients of other races included in our analysis. Overall survival (OS) was defined as time from study entry until death; event free survival (EFS) was time from study entry to first event (induction failure, death, death without remission, or relapse). Patients were censored at the date of last contact. We used the Kaplan-Meier method to estimate OS and EFS; the log-rank statistic tested survival differences. Pearson's chi-squared or Fisher's exact test was used to test for differences between proportions. Welch's t-test, ANOVA, and Wilcoxon rank-sum tests were used for continuous variables. Comparing tumor cytogenetics by race/ethnicity: when compared to WNH children, t(8;21) was more common among Black (OR=2.03; 95% CI: 1.20-3.42) and Hispanic (OR=2.04; 95% CI: 1.29-3.24) children. Black children were also more likely to have either -5/-5q or -7/-7q compared to WNH (OR=2.60; 95% CI: 1.29-5.23). We then interrogated KMT2A rearrangements (KMT2Ar), finding that there was no difference in the percentage of patients with a KMT2Ar on the basis of race/ethnicity. The distribution of various KMT2A fusions in Hispanic patients was not significantly different than WNH, but Black children were more likely to have t(6;11)(q27;q23) both overall (OR=5.78; 95% CI: 1.73-19.28) and among patients with KMT2Ar (OR 7.29; 95% CI: 1.94-27.40). Black KMT2Ar children were older than WNH and Hispanic KMT2Ar children (11.2 vs. 6.5 years, p=0.002). Hispanic children with KMT2Ar had a higher presenting white blood cell count (WBC median 114,700/µL) compared to WNH (median WBC 49,600/µL; p=0.01) and Black (38,300/µL; p=0.006) children. We then investigated survival: similar to prior studies, Black children had inferior EFS and OS compared to WNH (both p<0.0001). Hispanic and Asian children had similar survival to WNH children. However, the EFS/OS of both Black and Hispanic children with KMT2Ar were worse than WNH with KMT2Ar (Fig1A,B), though the reasons for poor outcome were different for Black and Hispanic children. Eight of 21 Hispanic children had induction failure compared to 0/19 Black and 1/85 WNH children (p<0.001), whereas Black children tended to suffer death or relapse as first event. Higher WBC at presentation did not explain the difference in outcome for Hispanic children: when we restricted our analysis to those with a presenting WBC >100,000/µL, Hispanic children still had an inferior EFS compared to WNH with a trend towards inferior OS (Fig 1C, D). The poor outcome of Black children with KMT2Ar may be driven by the higher proportion with the known poor prognostic t(6;11) and older age; but even when restricted to age >10yrs, Black children tended to have worse outcomes compared to WNH patients. In conclusion, using the TARGET data set, we identified differences in tumor genetics, clinical features and outcome by race/ethnicity. Specifically, among KMT2Ar patients, we found that Black and Hispanic children had significantly worse outcomes than WNH - but for different reasons with potential biologic implications. The difference in age and distribution of KMT2A fusion among Black children suggest distinct AML pathogenesis, while higher presenting WBC and increased induction failure risk among Hispanic children suggest that genetic factors may contribute to disease phenotype and response to therapy. In ongoing work, we are investigating racial/ethnic differences in tumor biology and pharmacogenomics to better understand the causes of poor outcome with the ultimate aim of eliminating long-standing survival disparities. Disclosures Rau: Jazz Pharmaceuticals, Inc.: Consultancy, Other: Travel Fees.
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Bellini, Maria Irene, Aisling E. Courtney, and Jennifer A. McCaughan. "Living Donor Kidney Transplantation Improves Graft and Recipient Survival in Patients with Multiple Kidney Transplants." Journal of Clinical Medicine 9, no. 7 (July 5, 2020): 2118. http://dx.doi.org/10.3390/jcm9072118.
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Background: Failed kidney transplant recipients benefit from a new graft as the general incident dialysis population, although additional challenges in the management of these patients are often limiting the long-term outcomes. Previously failed grafts, a long history of comorbidities, side effects of long-term immunosuppression and previous surgical interventions are common characteristics in the repeated kidney transplantation population, leading to significant complex immunological and technical aspects and often compromising the short- and long-term results. Although recipients’ factors are acknowledged to represent one of the main determinants for graft and patient survival, there is increasing interest in expanding the donor’s pool safely, particularly for high-risk candidates. The role of living kidney donation in this peculiar context of repeated kidney transplantation has not been assessed thoroughly. The aim of the present study is to analyse the effects of a high-quality graft, such as the one retrieved from living kidney donors, in the repeated kidney transplant population context. Methods: Retrospective analysis of the outcomes of the repeated kidney transplant population at our institution from 1968 to 2019. Data were extracted from a prospectively maintained database and stratified according to the number of transplants: 1st, 2nd or 3rd+. The main outcomes were graft and patient survivals, recorded from time of transplant to graft failure (return to dialysis) and censored at patient death with a functioning graft. Duration of renal replacement therapy was expressed as cumulative time per month. A multivariate analysis considering death-censored graft survival, decade of transplantation, recipient age, donor age, living donor, transplant number, ischaemic time, time on renal replacement therapy prior to transplant and HLA mismatch at HLA-A, -B and -DR was conducted. In the multivariate analysis of recipient survival, diabetic nephropathy as primary renal disease was also included. Results: A total of 2395 kidney transplant recipients were analysed: 2062 (83.8%) with the 1st kidney transplant, 279 (11.3%) with the 2nd graft, 46 (2.2%) with the 3rd+. Mean age of 1st kidney transplant recipients was 43.6 ± 16.3 years, versus 39.9 ± 14.4 for 2nd and 41.4 ± 11.5 for 3rd+ (p < 0.001). Aside from being younger, repeated kidney transplant patients were also more often males (p = 0.006), with a longer time spent on renal replacement therapy (p < 0.0001) and a higher degree of sensitisation, expressed as calculated reaction frequency (p < 0.001). There was also an association between multiple kidney transplants and better HLA match at transplantation (p < 0.0001). A difference in death-censored graft survival by number of transplants was seen, with a median graft survival of 328 months for recipients of the 1st transplant, 209 months for the 2nd and 150 months for the 3rd+ (p = 0.038). The same difference was seen in deceased donor kidneys (p = 0.048), but not in grafts from living donors (p = 0.2). Patient survival was comparable between the three groups (p = 0.59). Conclusions: In the attempt to expand the organ donor pool, particular attention should be reserved to high complex recipients, such as the repeated kidney transplant population. In this peculiar context, the quality of the donor has been shown to represent a main determinant for graft survival—in fact, kidney retrieved from living donors provide comparable outcomes to those from single-graft recipients.
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Al-Jaishi, Ahmed A., Christopher W. McIntyre, Jessica M. Sontrop, Stephanie N. Dixon, Sierra Anderson, Amit Bagga, Derek Benjamin, et al. "Major Outcomes With Personalized Dialysate TEMPerature (MyTEMP): Rationale and Design of a Pragmatic, Registry-Based, Cluster Randomized Controlled Trial." Canadian Journal of Kidney Health and Disease 7 (January 2020): 205435811988798. http://dx.doi.org/10.1177/2054358119887988.
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Background: Small randomized trials demonstrated that a lower compared with higher dialysate temperature reduced the average drop in intradialytic blood pressure. Some observational studies demonstrated that a lower compared with higher dialysate temperature was associated with a lower risk of all-cause mortality and cardiovascular mortality. There is now the need for a large randomized trial that compares the effect of a low vs high dialysate temperature on major cardiovascular outcomes. Objective: The purpose of this study is to test the effect of outpatient hemodialysis centers randomized to (1) a personalized temperature-reduced dialysate protocol or (2) a standard-temperature dialysate protocol for 4 years on cardiovascular-related death and hospitalizations. Design: The design of the study is a pragmatic, registry-based, open-label, cluster randomized controlled trial. Setting: Hemodialysis centers in Ontario, Canada, were randomized on February 1, 2017, for a trial start date of April 3, 2017, and end date of March 31, 2021. Participants: In total, 84 hemodialysis centers will care for approximately 15 500 patients and provide over 4 million dialysis sessions over a 4-year follow-up. Intervention: Hemodialysis centers were randomized (1:1) to provide (1) a personalized temperature-reduced dialysate protocol or (2) a standard-temperature dialysate protocol of 36.5°C. For the personalized protocol, nurses set the dialysate temperature between 0.5°C and 0.9°C below the patient’s predialysis body temperature for each dialysis session, to a minimum dialysate temperature of 35.5°C. Primary outcome: A composite of cardiovascular-related death or major cardiovascular-related hospitalization (a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke) captured in Ontario health care administrative databases. Planned primary analysis: The primary analysis will follow an intent-to-treat approach. The hazard ratio of time-to-first event will be estimated from a Cox model. Within-center correlation will be considered using a robust sandwich estimator. Observation time will be censored on the trial end date or when patients die from a noncardiovascular event. Trial Registration: www.clinicaltrials.gov ; identifier: NCT02628366.
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Mendel, Jameson, Ankur Patel, Toral Patel, Robert Timmerman, Tu Dan, Lucien Nedzi, and Zabi Wardak. "RADI-05. FRACTIONATED TREATMENT OF BRAIN METASTASES WITH GAMMA KNIFE ICON." Neuro-Oncology Advances 1, Supplement_1 (August 2019): i22. http://dx.doi.org/10.1093/noajnl/vdz014.098.
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Abstract PURPOSE/OBJECTIVE(S): Stereotactic radiosurgery with Gamma Knife is a common treatment modality for patients with brain metastasis. The Gamma Knife ICON allows for immobilization with an aquaplast mask, permitting fractionated treatments. We describe one of the first experiences utilizing this technique with brain metastasis and evaluate outcomes. MATERIALS/METHODS: From June 2017 to November 2018, 29 patients with 43 separate intracranial lesions were treated with fractionated stereotactic radiotherapy using the gamma knife ICON at a single institution. Patients received between 20–30 Gy in 3–5 fractions with no margin over the course of 5 to 23 days. Local control was physician assessed. Local failure over time was modeled using cumulative incidence; lesions were censored at last radiographic follow up. RESULTS: Median tumor volume and prescription isodose was 7.7 cm3 (range 0.3–43.9) and 50% (range 40–65), respectively. Median radiographic follow-up was 7 months and median survival was 9 months. Radiation necrosis occurred in 3/3 patients treated with 27 Gy in 3 fractions, one requiring therapeutic resection. Incidence of local failure for all treated lesions was 9% at 1 year. Tumor volume >7 cm3 was associated with local failure on univariate analysis (p=0.025). 100% (2/2) lesions treated with 20 Gy in 5 fractions developed local recurrence. CONCLUSION: Fractionated stereotactic radiotherapy with the Gamma Knife ICON provides excellent local control for small and large brain metastases with minimal toxicity. Tumors >7 cm3 should receive at least 30 Gy in 5 fractions for optimal control. Treatment with 27 Gy in 3 fractions appears to have high rates of treatment related toxicity and should be avoided.
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Tang, Yongmin, Xiaojun Xu, Hua Song, Shilong Yang, Shuwen Shi, Jian Wei, Weiqun Xu, Binhua Pan, and Fenying Zhao. "Long-Term Outcome of Childhood Acute Myeloid Leukemia Treated in China." Blood 112, no. 11 (November 16, 2008): 4023. http://dx.doi.org/10.1182/blood.v112.11.4023.4023.
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Abstract Intensive chemotherapy has greatly improved the long-term treatment outcome in children with acute lymphoblastic leukemia (ALL), however, children with de novo acute myelogenous leukemia (AML) remain much less favorable prognosis. Most reports were from western countries while data from Chinese children with AML have been very limited. In this study, we reported the long-term outcome and the prognostic factors of childhood AML treated with modified National Protocol of Childhood Leukemia in China 1997 (NPCLC-AML97) during the past 8 years in our institution. From January1997 to December 2005, 185 children younger than 16 years old with de novo AML were enrolled into our hospital. The NPCLC-AML97 protocol included induction therapy either of DA (daunorubicin + cytarabine), HA (homoharringtonine + cytarabine), DAE (daunorubicin + cytarabine + etoposide) or CAG (Clarithromycin + cytarabine + G-CSF). When CR achieved, the same cycle was repeated as consolidation therapy. Intensification therapy consisted of 3 cycles of intermediate or high dose of cytarabin (I/HDAC) every other month. During the intermission, DA, HA, EA (etoposide + cytarabine) were given. Maintenance therapy was given monthly by sequential HA, EA, AT (cytarabine + 6-mercaptopurine) cycles and I/HDAC was administered every 6 months. The total course was about 2.0~2.5 years from CR. Of the 185 patients, 49 were M3 and 136 were other subtypes. Sixty patients abandoned within the first two weeks after diagnosis, 2 died before chemotherapy, and 123 were eligible for protocol evaluation. The 7-year OS and EFS rates for the whole cohort were 33.1±4.1% and 31.2±3.7%, respectively. For eligible patients, 111 patients (90.2%) achieved CR (95.1% for M3 and 87.8% for non-M3, P = 0.334). With a median follow-up time of 69 months, 70 patients (56.9%) developed significant infection during chemotherapy, 31 patients relapsed and the 5-year cumulative relapse rate was 48.2±5.6% with a median relapse time of 12 (range from 3 to 56) months. No CNS relapse was found. Forty-one patients (33.3%) died in this cohort until data censored. Survival curve showed that the 3-year, 5-year and 7-year estimates of OS were 61.0±4.9%, 55.7±5.1% and 50.2±5.5%, whereas the EFS rates were 50.9±4.9%, 46.9±5.1% and 46.9±5.1%, respectively. M3 was more curable than non-M3 (7-year OS: 66.9±8.8% vs. 38.7±6.8%, P = 0.003; 7-year EFS: 63.5±7.9% vs. 35.9±6.3%, P = 0.005). Univariate analysis showed that superior outcome were favored by initial WBC count less than 100×109/L, M3 subtype, good response to therapy (attaining CR after one cycle of induction for non-M3 or within 30 days for M3), high expression of CD13 and CD33, negative expressions of CD14, CD34 and HLA-DR. And multivariate analysis showed that treatment response, initial WBC count and expression status of CD14 on the surface of leukemic cells were independent prognostic factors for long term survival. We conclude that high incidence of APL, high abandonment rate and low incidence of CNS relapse are the features in this cohort. Abandonment, relapse and infection are the main causes of treatment failure. For patients who adhere to the protocol, a relatively good outcome can be achieved.
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Rumpsfeld, Markus, Stephen P. McDonald, and David W. Johnson. "Peritoneal Small Solute Clearance is Nonlinearly Related to Patient Survival in the Australian and New Zealand Peritoneal Dialysis Patient Populations." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 29, no. 6 (November 2009): 637–46. http://dx.doi.org/10.1177/089686080902900609.
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Background The contribution of peritoneal small solute clearance per se to peritoneal dialysis (PD) patient outcomes remains uncertain. The aim of the present study was to determine whether baseline peritoneal small solute clearance predicted subsequent survival in Australian and New Zealand PD patients. Methods The study included all adult patients in Australia and New Zealand that commenced PD between 1 April 2002 and 31 December 2005 and had a peritoneal Kt/V (pKt/V) measurement performed within 6 months of PD commencement. Time to death and death-censored technique failure were examined by Kaplan–Meier analyses and both univariate and multivariate Cox proportional hazards models. Results pKt/V measurements were available in 2434 (63%) of the 3841 individuals that began PD treatment in Australia and New Zealand during the study period. These patients were divided into 4 groups according to their baseline pKt/V values: <1.45 ( n = 599), 1.45 – 1.69 ( n = 550), 1.70 – 2.00 ( n = 607), and >2.00 ( n = 678). Compared with the reference group (pKt/V 1.70 – 2.00), patient mortality was significantly increased in individuals with pKt/V <1.45 [adjusted hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.24 – 2.84; p = 0.003] and tended to be increased in those with pKt/V 1.45 – 1.69 (adjusted HR 1.46, 95% CI 0.96 – 2.21; p = 0.074). Importantly, higher pKt/V values (>2.00) also tended to be associated with higher mortality (adjusted HR 1.42, 95% CI 0.96 – 2.11; p = 0.079). The other independent predictors of death were lower residual renal function (RRF), older age, peripheral vascular disease, diabetes mellitus, late referral, higher peritoneal permeability, and untreated hypertension. No interaction was observed between pKt/V, RRF, and survival. Death-censored technique failure was demonstrated to be significantly worse in the pKt/V 1.45 – 1.69 group (adjusted HR 1.36, 95% CI 1.03 – 1.79; p = 0.028), older individuals, and individuals with Asian racial origin. Conclusions Initial peritoneal Kt/V significantly and independently influences patient survival in Australian and New Zealand PD patients. Overall survival appears to be optimal in the pKt/V range 1.70 – 2.00, with poorer outcomes observed above and below these values. In particular, survival is significantly worse when the achieved pKt/V is <1.45. In addition, RRF is an important independent predictor of patient survival in the Australian and New Zealand incident PD patient populations. The results of this study should therefore draw attention to the possible danger of not delivering adequate PD dose to patients with considerable RRF.
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Aziz, Fahad, Anand Ramadorai, Sandesh Parajuli, Neetika Garg, Maha Mohamed, Didier A. Mandelbrot, David P. Foley, Michael Garren, and Arjang Djamali. "Obesity: An Independent Predictor of Morbidity and Graft Loss after Kidney Transplantation." American Journal of Nephrology 51, no. 8 (2020): 615–23. http://dx.doi.org/10.1159/000509105.
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Background: There is conflicting information on current medical and surgical complications associated with high body mass index (BMI) after kidney transplantation. Methods: In a single-center observational study, we analyzed the 5-year outcomes of all consecutive primary kidney transplant recipients between 2010 and 2015 based on BMI at the time of transplant. Results: There were 1,467 patients included in this study, distributed in the following groups based on BMI: underweight (n = 32, 2.2%), normal (n = 407, 27.7%), overweight (n = 477, 32.5%), grade I obesity (n = 387, 26.4%), grade II obesity (n = 155, 10.6%), and grade III obesity (n = 9, 0.6%). Obesity was associated with an increased incidence of delayed graft function (p = 0.008), length of stay (LOS, p = 0.03), 30-day surgical re-exploration (p = 0.02), and hospital readmission (p < 0.0001). Obesity was also associated with higher 1-year serum creatinine (p = 0.03) and increased 5-year incidence of cardiac events (p < 0.0001) and congestive heart failure (p < 0.0001). Multivariable Cox regression analyses determined grade III obesity (HR = 5.84, 95% CI: 1.40–24.36, p = 0.01), LOS >4 days (HR = 1.94, 95% CI: 1.19–3.18, p = 0.008), hospital readmission (HR = 2.25, 95% CI: 1.20–4.22, p = 0.01), 1-year serum creatinine >1.5 (HR = 1.95, 95% CI: 1.20–3.18, p = 0.007), and proteinuria (UPC) >1 g/g (HR = 1.85, 95% CI: 1.06–3.24, p = 0.03) as independent predictors of death-censored graft failure. Conclusion: In the current era of renal transplant care, obesity is common, and high BMI remains associated with significant medical and surgical complications after transplant.
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Azarnoush, Saba, Raphael Porcher, Regis Peffault de la Tour, Karima Yakouben, Benedicte Bruno, Marie Ouachee Chardin, Marie Robin, Andre Baruchel, Gerard Socie, and Jean-Hugues Dalle. "Outcome of Busulfan and Fludarabine-Based Reduced Intensity Conditioning Regimen for Related and Unrelated HSCT in Fanconi Anemia Patients." Blood 118, no. 21 (November 18, 2011): 1964. http://dx.doi.org/10.1182/blood.v118.21.1964.1964.
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Abstract Abstract 1964 Rationale: HSCT is the only curative treatment for Fanconi Anemia (FA) pts with either bone marrow failure or MDS/Leukemia. Due to characteristic chromosomal instability, the poor outcome of FA pts transplanted after so-called conventional myelo-ablative conditioning regimen has been proved. Then, reduced-intensity conditionning regimen (RIC) has been considered for years as a model for allogeneic HSCT in FA pts. The use of fludarabine-based cond' regimen from about 2000 increased dramatically the overall survival of FA pts. Different Flu-based RIC were developed. Patients and method: Between Feb'02 and Dec'10, 17 FA pts from 3 academic French centers were included: 11 from R. Debre hospital, 5 from St Louis hospital and 1 from J. de Flandre hospital. All pts underwent HSCT because of bone marrow failure. They presented no MDS or leukemia. All time-to-event outcomes were counted from the date of HSCT to the date of event or date of last follow-up, except acute GVHD that was arbitrarily censored at 200 days. Death was considered as a competing risk in analyses of neutrophil and platelet recovery and chronic and acute GVHD. Overall survival was estimated using Kaplan-Meier product-limit estimator. For competing risks analyses, cumulative incidences were estimated using usual methodology. Results: Median age at diagnosis and at HSCT were 4.7 years (range 1,8-9,3) and 7,4 years (range 4,4-15,2), respectively. 12 pts presented with less than 3 FA-related malformations and 5 with more than 3 malformations. 2 patients received more than 20 transfusions before HSCT, whereas 8 pts received less than 20 transfusions and 7 patients did not received any. 2 patients received androgen therapy before HSCT. All patients received the same RIC i.e. fludarabine 30mg/m2/d × 3d, cyclophosphamide 10mg/kg/d × 4d and IV busulfan (Bu) 0.75 of body weight- adjusted recommended dose (equivalent to 6.4mg/kg total dose of oral Bu). This RIC did not contain any irradiation. Graft versus-host disease (GvHD) prophylaxis consisted of CSA associated with MMF or corticosteroids. Donors were either matched related (sibling, n= 6; other, n=2) or unrelated (10/10, n= 6; 9/10, n= 3). Stem cell sources were BM (n=10), UCB (n=4) and PBSC (n=2). 9 out of 17 pts had a donor from the same gender whereas 4 male recipients received transplant from female donor. CMV status were −/−, −/+, +/− and +/+ for 8, 4, 1 and 4 D/R pairs, respectively. Median follow-up was 32 months (range 3–102). Successful engraftment was obtained in all patients with a median time for neutrophil recovery of 17 days (range 10–42). All patients presented with 100% donor chimerism. One patient experimented secondary graft failure and died at D291 from infection and renal failure. During transplant procedure, 13 pts experimented at least one severe infectious complication (staphylococcus n=2; pseudomonas n=1; aspergillus n= 2; candida n=2; viral reactivation n= 13). 1 pt presented with moderate hepatic veno-occlusive disease. Five pts died from TRM and 12 pts remained alive in a good health condition. 36 month OS was 69% (95%CI 50 to 96). Cumulative incidence of grade 2 to 4 acute GVHD was 71% (95%CI: 41–87). 5 pts presented with either limited (n=4) or extensive (n=1) chronic GvHD and 36 month cumulative incidence of chronic GVHD was 33% (95%CI 11 to 58). To date, no pt had secondary malignancy. Discussion: Our study confirms the good results obtained by other groups when using flu-based RIC in FA pts. Indeed, satisfying engraftment and long-time survival rates were obtained without any TBI, irrespective of the stem cell source and the donor type. However, we have a concern regarding the cGVHD rate we obtained. As demonstrated by an on-going study of EBMT registry, the risk of secondary malignancy in these pts is statistically correlated to cGvHD. Then, this rate still remains probably too high in our study, even though only one pt presented with extensive cGvHD and no pts developed any secondary malignancy. But this could be explained by the short follow-up. Suppression of one alkalyting agent may reduce both cGVHD incidence and other tissue injuries leading to secondary malignancies. Then, we claim for suppression of Bu for related donor HSCT. In FA pts receiving transplant from unrelated donor, the relative impact of either low-dose IV-Bu – as we used here - or low-dose irradiation on toxicity and especially development of secondary malignancies remains to be evaluated. Disclosures: No relevant conflicts of interest to declare.
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Vela, Carla, Thomas Jouve, Eloi Chevallier, Farida Imerzoukene, Raphaële Germi, Marion Le Marechal, Aurélie Truffot, et al. "Conversion to mTOR-Inhibitors Plus IV Immunoglobulins in Kidney-Transplant Recipients with BKV Infection: A Retrospective Comparative Study." Journal of Clinical Medicine 11, no. 24 (December 8, 2022): 7292. http://dx.doi.org/10.3390/jcm11247292.
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BK virus-associated nephropathy (PvAN) increases the risk of graft failure justifying treatment. Conversion to mammalian target of rapamycin inhibitors (mTORi) and Human polyclonal immunoglobulins (IVIg) could prevent the risk of PvAN. Our retrospective study assessed the efficacy of mTORi associated with IVIg therapy (mTORi±IVIg group) versus standard immunosuppression reduction to clear BKV DNAemia. Among forty-three kidney-transplanted patients with positive BKV DNAemia, we included twenty-six patients in the mTORi±IVIg group and reduced immunosuppression therapy for seventeen patients. We focused on BKV DNAemia clearance on the first-year. Renal function, rejection rate, evolution to PvAN, and complications of immunosuppression were assessed. BKV DNAemia decreased faster and significantly in the control group as compared to the mTORi±IVIg group (p < 0.001). Viral clearance was significantly higher in the control group compared to the mTORi±IVIg group (88% vs. 58%; p = 0.033). Death-censored graft loss, rejection rates and kidney-graft function at 12 months did not significantly differ. Multivariate analyses significantly associated BKV DNAemia clearance with reducing immunosuppression (OR = 0.11 (0.06–0.9), p = 0.045), female kidney donor (OR = 0.10 (0.01–0.59/)], p = 0.018) and time to first DNAemia, (OR = 0.88 (0.76–0.96), p = 0.019). In our study, the standard treatment for BKV DNAemia had better outcomes than an mTORi±IVIg conversion.
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European Pregnancy and Paediatric Infections Cohort Collabor, Alex Lyons, Lindsay Thompson, Elizabeth Chappell, Luminita Ene, Luisa Galli, Tessa Goetghebuer, et al. "Outcomes of etravirine-based antiretroviral treatment in treatment-experienced children and adolescents living with HIV in Europe and Thailand." Antiviral Therapy 27, no. 3 (June 2022): 135965352210921. http://dx.doi.org/10.1177/13596535221092182.
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Background Etravirine (ETR) is approved as a component of second or third-line antiretroviral treatment (ART) for children living with HIV. We assessed the outcomes of ETR-based ART in children in routine care in Europe and Thailand. Methods Data on children aged <18 years at ETR start were pooled from 17 observational cohorts. Characteristics at ETR start, immunological and virological outcomes at 12 months, discontinuations, adverse events (AEs) and serious adverse events (SAEs) were described. Follow-up was censored at ETR discontinuation, death or last visit. Results 177 children ever received ETR. At ETR start, median [IQR] age was 15 [12,16] years, CD4 count 480 [287, 713] cells/mm3, 70% had exposure to ≥3 ART classes and 20% had viral load (VL) <50 copies/mL. 95% received ETR in combination with ≥1 potent drug class, mostly protease inhibitor-based regimens. Median time on ETR was 24 [7, 48] months. Amongst those on ETR at 12 months ( n=141), 69% had VL<50 copies/mL. Median CD4 increase since ETR start ( n=83) was 147 [16, 267] cells/mm3. Overall, 81 (46%) discontinued ETR by last follow-up. Median time to discontinuation was 23 [8, 47] months. Common reasons for discontinuation were treatment simplification (19%), treatment failure (16%) and toxicity (12%). Eight children (5%) had AEs causally associated with ETR, all dermatological/hypersensitivity reactions. Two were SAEs, both Stevens–Johnson Syndrome in children on regimens containing ETR and darunavir and were causally related to either drugs; both resolved following ART discontinuation. Conclusion Children receiving ETR were predominantly highly treatment-experienced, over two-thirds were virally suppressed at 12 months.
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Vokes, E. E., K. M. Stenson, E. Kistner, B. Mittal, E. E. Cohen, M. A. List, B. E. Brockstein, F. R. Rosen, M. Witt, and D. J. Haraf. "Sequential evaluation of reduced radiotherapy doses in a phase II trial of induction chemotherapy (IndCT) followed by concomitant chemoradiotherapy (CTX) for advanced head and neck cancer (HNC)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 5528. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.5528.
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5528 Background: CTX constitutes a standard for locoregionally advanced HNC. IndCT may decrease distant failure rates (Brockstein Ann Oncol, 2003). The combination of these approaches has resulted in favorable early survival outcomes. CTX is limited by acute mucositis and long-term functional impairment. We examined the feasibility of lowering radiotherapy doses in sequential groups of patients (pts) to maintain high antitumor activity while decreasing toxicities. Methods: This was a 3-part, nonrandomized, phase II trial. Pts with stage IV (M0) HNC received 8 weeks of IndCT with carboplatin and paclitaxel (groups A & B ); carboplatin, AUC 2, and paclitaxel 135 mg/m2 weekly x 6; group C carboplatin AUC 6 day 1, and paclitaxel 100 mg/m2 days 1, 8, and 15 with cycle 2 beginning day 28. All pts received alternating week CTX with paclitaxel, infusional fluorouracil, oral hydroxyurea, and twice daily radiotherapy (T-FHX) (Kies JCO 2001). Radiotherapy to gross disease, high risk, and low risk microscopic disease consisted of group A (n = 68): 75, 60, 45 Gy; group B (n = 64): 75, 54, 39 Gy; group C (n = 90): 72, 51, 36 Gy. We have previously reported outcome data on groups A & B (Vokes JCO 2002 & Haraf CCR 2003). Results: A total of 222 pts were treated between 11/1998 and 2/2001. 74% were male, median age was 57. Best overall response (groups A/B/C): CR: 83/93/68%. With median follow-up time of 64/53/39 months; 3-year overall survival is 72%/67%/67% (logrank p = 0.76), progression-free survival 72%/65%/59% (logrank p = 0.44), time to progression (TTP, in which deaths prior to progression are censored unless due to treatment-related toxicity) 82%/86%/67% (logrank p = 0.019), and local control92%/97%/86% (logrank p = 0.10). Acute toxicities during concurrent chemoradiotherapy included grade 3/4 mucositis 72/2%; 65/11%; 57/8%; and dermatitis 47/15%; 19/26%; 28/2%. Conclusions: This 3-stage study suggests that acute toxicity can be reduced and high overall survival rates maintained while reducing doses of radiotherapy. The lower 3 year TTP rate in cohort C suggests a dose-response curve in the CTX setting. Schedule B may represent the best therapeutic index. Functional outcomes data are presented separately. [Table: see text]
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Leeaphorn, Napat, Jeremy Ryan A. Pena, Natanong Thamcharoen, Eliyahu V. Khankin, Martha Pavlakis, and Francesca Cardarelli. "HLA-DQ Mismatching and Kidney Transplant Outcomes." Clinical Journal of the American Society of Nephrology 13, no. 5 (April 23, 2018): 763–71. http://dx.doi.org/10.2215/cjn.10860917.
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Background and objectivesRecent evidence suggests that HLA epitope-mismatching at HLA-DQ loci is associated with the development of anti-DQ donor-specific antibodies and adverse graft outcomes. However, the clinical significance of broad antigen HLA-DQ mismatching for graft outcomes is not well examined.Design, setting, participants, & measurementsUsing the United Network Organ Sharing/the Organ Procurement and Transplantation Network (UNOS/OPTN) data, patients with primary kidney transplants performed between 2005 and 2014 were included. Patients were classified as having either zero HLA-DQ mismatches, or one or two HLA-DQ mismatches. Primary outcomes were death-censored graft survival and incidence of acute rejection.ResultsA total of 93,782 patients were included. Of these, 22,730 (24%) and 71,052 (76%) received zero and one or two HLA-DQ mismatched kidneys, respectively. After adjusting for variables including HLA-ABDR, HLA-DQ mismatching was associated with a higher risk of graft loss in living kidney donor recipients with an adjusted hazard ratio (HR) of 1.18 (95% confidence interval [95% CI], 1.07 to 1.30; P<0.01), but not in deceased kidney donor recipients (HR, 1.05; 95% CI, 0.98 to 1.12; P=0.18) (P value for interaction <0.01). When taking cold ischemic time into account, HLA-DQ mismatching was associated with a higher risk of graft loss in deceased kidney donor recipients with cold ischemic time ≤17 hours (HR, 1.12; 95% CI, 1.02 to 1.27; P=0.002), but not in deceased kidney donor recipients with cold ischemic time >17 hours (HR, 0.97; 95% CI, 0.88 to 1.06; P=0.49) (P value for interaction <0.01). Recipients with one or two HLA-DQ mismatched kidneys had a higher incidence of acute rejection at 1 year, with adjusted odds ratios of 1.13 (95% CI, 1.03 to 1.23; P<0.01) in deceased donor and 1.14 (95% CI, 1.03 to 1.27; P=0.02) in living donor kidney transplant recipients. Specific donor-DQ mismatches seemed to be associated with the risk of acute rejection and graft failure, whereas others did not.ConclusionsHLA-DQ mismatching is associated with lower graft survival independent of HLA-ABDR in living donor kidney transplants and deceased donor kidney transplants with cold ischemia time ≤17 hours, and a higher 1-year risk of acute rejection in living and deceased donor kidney transplants.
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Carpenter, Dustin, S. Ali Husain, Corey Brennan, Ibrahim Batal, Isaac E. Hall, Dominick Santoriello, Raphael Rosen, et al. "Procurement Biopsies in the Evaluation of Deceased Donor Kidneys." Clinical Journal of the American Society of Nephrology 13, no. 12 (October 25, 2018): 1876–85. http://dx.doi.org/10.2215/cjn.04150418.
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Background and objectivesBiopsies taken at deceased donor kidney procurement continue to be cited as a leading reason for discard; however, the reproducibility and prognostic capability of these biopsies are controversial.Design, setting, participants, & measurementsWe compiled a retrospective, single-institution, continuous cohort of deceased donor kidney transplants performed from 2006 to 2009. Procurement biopsy information—percentage of glomerulosclerosis, interstitial fibrosis/tubular atrophy, and vascular disease—was obtained from the national transplant database. Using univariable, multivariable, and time-to-event analyses for death-censored graft survival, we compared procurement frozen section biopsy reports with reperfusion paraffin-embedded biopsies read by trained kidney pathologists (n=270). We also examined agreement for sequential procurement biopsies performed on the same kidney (n=116 kidneys).ResultsFor kidneys on which more than one procurement biopsy was performed (n=116), category agreement was found in only 64% of cases (κ=0.14). For all kidneys (n=270), correlation between procurement and reperfusion biopsies was poor: overall, biopsies were classified into the same category (optimal versus suboptimal) in only 64% of cases (κ=0.25). This discrepancy was most pronounced when categorizing percentage of glomerulosclerosis, which had 63% agreement (κ=0.15). Interstitial fibrosis/tubular atrophy and vascular disease had agreement rates of 82% (κ=0.13) and 80% (κ=0.15), respectively. Ninety-eight (36%) recipients died, and 56 (21%) allografts failed by the end of follow-up. Reperfusion biopsies were more prognostic than procurement biopsies (hazard ratio for graft failure, 2.02; 95% confidence interval, 1.09 to 3.74 versus hazard ratio for graft failure, 1.30; 95% confidence interval, 0.61 to 2.76), with procurement biopsies not significantly associated with graft failure.ConclusionsWe found that procurement biopsies are poorly reproducible, do not correlate well with paraffin-embedded reperfusion biopsies, and are not significantly associated with transplant outcomes.
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LI, J., D. Yin, Z. Wang, M. Brigham, B. Lamoreaux, J. Kent, M. Francis-Sedlak, et al. "THU0408 EFFECT OF NEW-ONSET GOUT ON KIDNEY TRANSPLANT OUTCOMES: A RETROSPECTIVE COHORT ANALYSIS OF THE UNITED STATES RENAL DATA SYSTEM." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 441.2–442. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2060.
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Background:Gout is a frequent comorbidity in kidney transplant (KT) recipients. However, assessing the independent effect of gout on KT outcomes is difficult because of multiple confounders (e.g., temporal changes in estimated glomerular filtration rate [eGFR], cyclosporine or tacrolimus dose, urate-lowering medication use) that obscure a clear picture of gout’s potential impact.Objectives:This investigation assessed if the development of new-onset gout after KT was an independent risk factor for loss of graft function, as assessed by the need for maintenance hemodialysis following KT.Methods:This retrospective cohort study analyzed data on patients in the United States Renal Data System (USRDS) who received a primary KT between 1/1/2008 and 12/31/2015. The date of transplantation was the ‘index’ date. Eligible patients were required to have ≥24 months of Medicare coverage and no prior history of gout, defined as ≥1 claim with a gout diagnosis code in the 24 months prior to the index date. All patients were also required to have ≥12 months of coverage post index. Patients who died, experienced graft failure, or returned to dialysis <12 months post index were excluded. Because the first year following transplant is associated with the highest frequency of rejections, we evaluated subjects beginning 1 year after transplant. The exposure of interest was new-onset gout, defined as the presence of ≥2 claims for gout post index, and the primary endpoint was return to dialysis >12 months post index. Baseline time-invariant confounders included recipient and donor demographics and clinical characteristics at index. Time-varying confounders included body mass index (BMI) adjusted tacrolimus and cyclosporine dose, eGFR, and urate-lowering medication use post index. Patients who died or lost Medicare coverage >12 months post index were censored; all patients remaining at the end of the study period (12/31/2016) were also censored. A marginal structural model (MSM) was fitted to determine the relative risk of new-onset gout on return to dialysis, while controlling for both time-invariant and time-varying confounders.Results:18,525 of 466,589 KT recipients in the USRDS met study eligibility. Within the observation period, 1,399 (7.6%) developed new-onset gout and 1,420 (7.7%) returned to dialysis >12 months post index. Median time from index to new-onset gout and from index to return to dialysis was 16.2 months (IQR: 33.4) and 32.8 months (IQR: 28.4), respectively. Adjusting for baseline time-invariant and time-varying confounders via the MSM showed new-onset gout was associated with a 51% increased risk of return to dialysis >12 months post index (RR: 1.51, 95% CI: 1.03, 2.20).Conclusion:New-onset gout was independently associated with a 51% increased risk of return to dialysis >12 months after primary KT compared to a control cohort without gout. To our knowledge, this is the first observation of this outcome in an appropriately controlled cohort study of KT recipients with gout. Results from this analysis may have important implications for the monitoring and management of new-onset gout in the kidney transplant population.References:[1]Mandell BF.Cleve Clin J Med2008;75(Suppl 5):S5-8.[2]Forbess LJ, Fields TR.Sem Arthritis Rheum2012;42:146-54.[3]Gibson T.Curr Opin Rheumatol2012;24:127-31.[4]Zhang L, et al.Nephrol Dial Transplant2012;27:1836-9.[5]Clive DM.J Am Soc Nephrol2000;11:974-9.[6]Kalantar E, et al.Transplant Proc2011;43:584-5.[7]Lin HY, et al.N Engl J Med1989;321:287-92.[8]Ben Hmida M, et al.Transplant Proc1995;27:2722-4.[9]Kanbay M, et al.Transplant Proc2005;37:3119-20.[10]Baroletti S, Bencivenga GA.Prog Transplant2004;14:143-7.[11]Kim ED, et al.Am J Transplant2015;15:482-8.[12]Kim DG, et al.PloS One2018;13:e0209156.Disclosure of Interests: :Justin Li: None declared, David Yin: None declared, Zheng Wang: None declared, Mark Brigham: None declared, Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Jeffrey Kent Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Megan Francis-Sedlak Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Richard Johnson Shareholder of: Colorado Research Partners LLC, XORTX Therapeutics, Consultant of: Horizon Therapeutics, Eli Lilly, Speakers bureau: Horizon Therapeutics, Nandini Hadker: None declared, Kevin Francis: None declared, Herman Sanchez: None declared, Gavin Miyasato: None declared
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Zarzour, Ahmad, Aziz Nazha, Matt Kalaycio, Bhumika J. Patel, Aaron T. Gerds, Michael J. Clemente, Cassandra M. Hirsch, et al. "Outcome of Newly Diagnosed Acute Myeloid Leukemia (AML) Refractory to 1 or 2 Cycles of Induction Chemotherapy." Blood 126, no. 23 (December 3, 2015): 1319. http://dx.doi.org/10.1182/blood.v126.23.1319.1319.
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Abstract Background Achieving a complete remission (CR) in patients with newly diagnosed acute myeloid leukemia (AML) after induction chemotherapy with cytarabine and an anthracycline (7+3) remains an important treatment goal associated with better overall survival (OS). Approximately 25-30% of younger, and up to 50% of older patients (pts) fail to achieve CR. AML pts with residual leukemia at day 14 receive a second cycle of the same regimen; whether these pts have worse survival than pts not requiring re-induction is unclear. Information on pts with primary refractory AML and the best treatment strategy in this setting are limited. Methods Pts with newly diagnosed AML treated at our institution between 1/2000 and 1/2015 were included. Pts received standard induction chemotherapy with cytarabine for 7 days and an anthracycline for 3 days (7+3). Bone marrow biopsies were obtained at day 14 and a second cycle of the same regimen (7+3 for younger adults, 5+2 for older adults) was given to pts with residual leukemia (blasts > 5%). All responses were assessed at day 30 +/- 5 days post induction. Response was defined as CR and CR with incomplete hematologic recovery (CRi) or platelet recovery (CRp) per International Working Group (IWG) 2003 response criteria. Cytogenetic risk stratifications were based on CALGB/Alliance criteria. OS was calculated from the time of diagnosis to time of death or last follow up. A panel of 62 gene mutations that have been described as recurrent mutations in myeloid malignancies was used to evaluate whether genomic data can be used to predict response. Results: Among 227 pts with AML, 123 received 7+3 and had clinical and mutational data available. Median age was 60 years (range, 23-82). Median baseline WBC was 8.2 X 109/L (range, 0.3-227), hemoglobin 8.9 g/L (range, 4.7-13.8), platelets 47 X 109/L (range, 9-326), and BM blasts 46% (range, 20-95). Cytogenetic risk groups were: favorable in 12 (10%), intermediate in 68 (56%) [normal karyotype in 44 (36%)], and unfavorable in 42 (34%). A total of 93 pts (76%) responded, 69 (74%) received 1 cycle of induction and 24 (26%) required re-induction at day 14 due to residual leukemia. A total of 39 pts (32%) received allogeneic stem cell transplant (ASCT): 18 (46%) from a matched sibling donor, 16 (41%) from a matched unrelated donor and 5 (13%) had an umbilical cord transplant. With a median follow up of 13.5 months, the median OS for the entire group was 13 months (m, range, 0.1-120). The median OS for pts who failed 1-2 cycles of 7+3 was significantly worse than pts who responded (median 2.6 vs 16.9 m, p = 0.002). When pts undergoing ASCT were censored, the median OS was 2.3 vs 9.9 m, p= 0.003, respectively. Overall, 33 pts (27%) had residual leukemia at day 14 and received re-induction, 24 (72%) achieved a response at day 30+/- 5 days. The median OS for pts who received re-induction was inferior compared to pts who did not (10.1 vs. 16.1 months, p= 0.02). When pts who received ASCT were censored, the OS was similar (8.5 vs. 7.4 months, p = 0.49, respectively). Among the 30 pts with persistent disease following induction therapy at day 30, 11 (37%) died from induction complications, 6 (20%) received salvage therapy with mitoxantrone/etoposide/cytarabine, 3 (10%) received high dose cytarabine, 2 (7%) received azacitidine, and 8 (27%) received best supportive care. Among pts who received salvage chemotherapy 56% achieved CR and proceeded with ASCT. Two pts had ASCT with residual leukemia and relapsed within 3 m of ASCT. Pts who received ASCT after induction failure had a significantly better OS compared to non-transplant pts (median OS 22.0 vs. 1.4 months, p < 0.001, respectively); however, this benefit was only seen in pts who had ASCT in CR. We then investigated if genomic mutations can predict response or resistance to chemotherapy. Out of the 62 genes tested, only a TP53 mutation was associated with resistance, p = 0.02. Further, pts with TP53 mutations had significantly inferior OS compared to TP53 wild type regardless of ASCT status (1.4 vs 14.8 m, p< 0.001) Conclusion: Pts with newly diagnosed AML who fail induction chemotherapy with a 7+3 regimen have a poor outcome. Re-induction with the same regimen at day 14 for residual leukemia converted most non-responders to responders, but was associated with worse OS. ASCT improves outcome only in pts who achieve CR with salvage therapy. TP53 mutations predicted resistance to chemotherapy with 7+3. Disclosures Carew: Boehringer Ingelheim: Research Funding. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.
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Athale, Uma H., Maneka Puligandla, Kristen E. Stevenson, Barbara L. Asselin, Luis A. Clavell, Peter D. Cole, Kara M. Kelly, et al. "Excellent Outcome of Children with Down Syndrome (DS) and Acute Lymphoblastic Leukemia (ALL) Treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols 00-001 and 05-001." Blood 128, no. 22 (December 2, 2016): 761. http://dx.doi.org/10.1182/blood.v128.22.761.761.
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Abstract Background Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are shown to have increased therapy-related morbidity and mortality. Hence, therapy modifications and/or dose-reductions are common treatment strategies for this patient (pt) population. Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk-stratified treatment for children with and without DS and ALL. Aim: To define the toxicity profile and outcome of children with DS and de novo ALL treated on DFCI ALL Consortium therapy protocols 00-001 and 05-001 using therapy identical to non-DS patients. Methods: Demographic, clinical and outcome data of DS and non-DS patients enrolled on the DFCI ALL protocols 00-001 (2000-2004) and 05-001 (2005-2011) were analyzed. Risk categorization and protocol therapy have previously been described (J Clin Oncol 2013; 31:1202-10; Lancet Oncol 2015;16:1677-90). On both protocols, DS ALL pts were treated identically to non-DS pts without any dose reduction or modification, except for the option for DS ALL pts to receive 3 doses of leucovorin after IT methotrexate. Fisher's exact test was used to compare toxicities in the DS and non-DS pts and Gray test was used to compare the cumulative incidence of fracture and osteonecrosis. Overall survival (OS) was defined as time from registration to death. Event-free survival (EFS) was defined as time from registration to first event (defined as induction failure, relapse, second malignant neoplasm (SMN) or death due to any cause). Induction failure and induction death were included as events at time zero. Disease-free survival (DFS) was defined as time from complete remission (CR) to relapse, SMN or death. Pts without an event were censored at the last known follow-up. The Kaplan-Meier method was used for survival estimation and Greenwood's formula for calculation of 95% confidence interval (CI) of survival estimates. Outcome of DS patients was also examined using Ponte di Legno (PdL) risk group [Low risk (LR) was defined as age at diagnosis ≤ 6 yr. and white cell count < 10X109/L and, remainder as high risk (HR)].(Blood 2014;123:70-7). Two-sided p values <0.05 were considered significant. Results: Of 1286 eligible pts aged 1-18 yrs. with de novo ALL enrolled on protocols 00-001 and 05-001, 38 (3%) had DS. There was no difference in demographic or presenting clinical features between DS and non-DS ALL pts except immunophenotype (absence of T-ALL in DS vs 11.7% in non-DS, p=0.017) and presence of high hyperdiploidy (51-65 chromosomes) (8.8% in DS vs 25.1% in non-DS, p=0.027) (Table 1). Two DS-ALL pts withdrew from the study after achieving CR. There was no difference in the CR rates (DS: 100% vs non-DS: 95.2%, p=0.47) or proportion of pts with low end of induction minimal residual disease (MRD) between DS and non-DS groups (p=0.73). Toxicities were comparable except DS pts had significantly higher rates of ≥Grade 3 mucositis (data available for protocol 05-001 only) (DS: 52.0% vs. non-DS: 12.0%, p<0.001), non-CNS thrombosis/bleed (18.4% vs. 8.2%; p=0.036), and seizure (15.8% vs. 4.7%, p=0.010). DS pts also had marginally higher rate of bacterial and fungal infections (55.3% vs. 41.3%, p=0.096) (Table 2). All 38 DS pts achieved a CR and there were 4 relapses with 1 death due to disease. There were no treatment-related deaths in DS-ALL pts. With a median follow-up of 6.2 yrs. the 5-yr EFS, DFS, and OS of DS pts were similar to non-DS pts (90.7% [81.1-100.0] vs. 83.7% [81.7-85.9]; 90.7% [81.1-100.0] vs. 87.4% [85.5-89.3]; 97.1% [91.8-100.0] vs. 91.4% [89.8-93.0]), with the 95% CI overlapping for each comparison (Figures 1a and 1b). There was no difference in outcomes of DS-ALL PdL LR pts (n=13) compared to PdL HR pts (n=25) (5-yr EFS 90.0% [73.2-100.0]. vs. 91.0% [79.9-100.0]; 5-yr OS 100.0% [100.0-100.0] vs. 95.8% [88.2-100.0]). Conclusion: DS pts treated on DFCI ALL Consortium protocols without dose reduction or modifications achieved similar outcomes to non-DS pts. DS pts had a higher frequency of mucositis, infection, and seizures, but did not experience any treatment-related deaths. Other than a higher risk of thrombotic complications, they did not develop excessive toxicity to asparaginase. The low rates of relapse and toxicity-related mortality support the approach of unified therapy protocol for DS and non-DS ALL pts with emphasis on supportive care interventions to prevent toxicities. Overall and event free survival Overall and event free survival Disclosures Asselin: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy.
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Ayers, Emily C., Shaoying Li, Jeffrey Medeiros, David A. Bond, Kami J. Maddocks, Pallawi Torka, Angel Mier Hicks, et al. "Outcome of Patients with Aggressive B Cell Lymphomas Who Receive Second-Line Salvage Immunochemotherapy Following Treatment Failure of Intensive First-Line Immunochemotherapy." Blood 132, Supplement 1 (November 29, 2018): 453. http://dx.doi.org/10.1182/blood-2018-99-115527.
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Abstract Introduction: Salvage immunochemotherapy (IC), followed by high-dose chemotherapy with autologous stem cell transplantation if chemosensitive is standard-of-care second-line (2L) therapy (tx) for fit patients (pts) with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) when treated with first-line (1L) R-CHOP as shown in the CORAL study. Outcomes following receipt of salvage IC in the 2L setting for pts with DLBCL or high grade B cell lymphoma/B cell lymphoma unclassifiable (HGBL/BCLU) receiving intensive 1L tx remain unknown, and may be worse than those reported in CORAL given prior exposure to higher-dose IC in 1L setting. Here we report the results of a multicenter retrospective analysis of R/R DLBCL and HGBL/BCLU pts treated with intensive 1L tx who receive standard salvage 2L tx. Methods: Inclusion criteria were histologic diagnosis of DLBCL or HGBL/BCLU, R/R disease following 1L tx with R-EPOCH, R-HyperCVAD or R-CODOX-M/IVAC and receipt of 2L tx with R-ICE, R-DHAP, R-DHAC, R-ESHAP or R-GDP. Exclusion criteria were HIV positivity, post-transplant lymphoproliferative disorder, prior chronic lymphocytic leukemia and inadequate data. Therapy was given at the discretion of the treating physician. Progression free survival (PFS) was defined as the interval between time of first relapse or primary refractory disease and disease progression, change in therapy if no disease response or last follow-up in remission, and overall survival (OS) between time of first relapse or primary refractory disease and death or last follow-up while alive. Pts were treated from 2007-2017 and data were censored on 10/15/17. Results: A total of 195 pts treated at 20 US and Canadian academic medical centers were included. Clinicopathologic characteristics at time of R/R disease were 39% age >60 years, 62% male, 77% stage III-IV, 72% elevated LDH, 24% bone marrow (BM) involvement, 28% B symptoms present, 44% extranodal (EN) disease at >1 site, 19% ECOG performance status (PS) >1, 49% with International Prognostic Index score (IPI) ≥3, 46% HGBL/BCLU histology, 49% Ki67 ≥90%, and 61% germinal center (GCB) cell of origin (COO) by Hans algorithm. Of pts with available fluorescence in situ hybridization (FISH) data, 51%, 45% and 30% demonstrated MYC, BCL2 and BCL6 rearrangements (-R), respectively, and 37% were double hit lymphoma (DHL). Tx received in 1L were R-EPOCH in 82%, R-HyperCVAD in 16% and R-CODOX-M/IVAC in 2% of pts. R-ICE was received by 64% and other platinum-containing regimens by 36% as 2L tx. Most (86%) pts relapsed within 12 months (mo) of completion of 1L tx (early) and 58% of pts had primary refractory disease. For all pts, the median length of follow-up was 25.0 mo with a median PFS of 3.0 mo and median OS of 8.0 mo. Overall response rate to 2L tx among all pts was 44% (23% complete response [CR] and 21% partial response [PR]), and 48% with progressive disease. Pts achieving CR had significantly longer median PFS (32.0 vs 4.0 mo, p = 0.0001) and OS (not reached vs 13.0 mo, p = 0.0004) as compared to pts achieving PR. In pts who achieved CR or PR following 2L tx, 64% received consolidative transplant (42 autologous and 13 allogeneic) and achieved a median PFS and OS of 18.3 mo and 62.0 mo, respectively. As compared to pts relapsing ≥12 mo after completion of 1L tx (late), pts relapsing early were less likely to achieve CR (17% vs. 61%, p=0.0001) and experienced significantly shorter median PFS (2.8 vs. 23.0 mo, p<0.0001) and median OS (6.0 mo vs. not yet reached, p<0.0001). Univariate analysis incorporating clinicopathologic characteristics at the time of relapse demonstrated elevated LDH, stage III-IV disease, IPI ≥3, BM involvement, GCB COO, HGBL/BCLU histology, MYC-R, BCL2-R, DHL and early relapse to have a statistically significant increased hazard ratio (HR) for progression. All of these factors, as well as EN disease at >1 site, B symptoms, ECOG PS >1 and Ki67 ≥90%, but not BCL2-R, demonstrated a statistically significant increased HR for death. Multivariate analysis demonstrated only early relapse to have a statistically significant increased HR for progression (HR 2.47, p=0.024) and death (HR 5.90, p=0.001). Conclusion: Relapse <12 mo from completion of intensive 1L tx is associated with extremely poor outcomes in pts with DLBCL and HGBL/BCLU treated with standard salvage 2L tx. Novel therapeutics, including chimeric antigen receptor-modified T cell (CART) tx, should be investigated as 2L tx in this pt population. Figure. Figure. Disclosures Maddocks: Pharmacyclics: Research Funding; BMS: Research Funding; Teva: Honoraria; AstraZeneca: Honoraria; Novartis: Research Funding; Pharmacyclics/Janssen: Honoraria; Merck: Research Funding. Wagner-Johnston:Novartis: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTEX: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Merck: Research Funding; JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees. Karmali:Gilead: Speakers Bureau; AstraZeneca: Speakers Bureau. Kahl:Genentech: Consultancy; Juno: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Acerta: Consultancy; CTI: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy. Cohen:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Reddy:MEI Pharma: Research Funding. Ramchandren:Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding. Diefenbach:Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Research Funding; Trillium: Research Funding; Millenium/Takeda: Research Funding; Denovo: Research Funding; Acerta: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy. Olszewski:TG Therapeutics: Research Funding; Genentech: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Hill:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Assouline:Roche: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Landsburg:Curis: Consultancy, Research Funding; Takeda: Consultancy.
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Strambi, Angela, Maria Jakobsson, Fredrik Nilsson, Johannes Arpegard, and Johan Dalén. "Real-world experience of axitinib as second-line treatment in metastatic renal cell carcinoma: Analysis of the Swedish population." Journal of Clinical Oncology 40, no. 6_suppl (February 20, 2022): 315. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.315.
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315 Background: Axitinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, was approved in 2012 for the treatment of metastatic renal cell carcinoma (mRCC) after failure of prior treatment with sunitinib or a cytokine. Outside of randomized clinical trials, it is important to describe the clinical outcomes of more heterogeneous populations. This analysis aimed to describe time-to-treatment discontinuation (TTD) and overall survival (OS) for second-line (2L) axitinib in a real-world setting for a nationwide Swedish mRCC cohort. Methods: This retrospective analysis utilized the Swedish Health Data Registers, covering the entire Swedish population. Patients (aged ≥ 18 years) with mRCC had ≥ 1 filled prescription of axitinib in the 2L setting, after an anti-angiogenic targeted therapy, from marketing approval until December 2019. This analysis relied on data relating to dispensed pack size, strength and according to dosing as recommended by the product label. A grace period of 90 days was allowed between filled prescriptions including medication accumulated from overlapping prescriptions. Kaplan-Meier methods were used to describe TTD and OS. Results: In total, 110 patients received 2L axitinib. Patients were predominantly male (n = 84, 76.4%) with a mean (SD) age of 60.9 (9.6) years at diagnosis and 65.5 (9.9) years at 2L treatment initiation. Median (95% confidence interval [CI]) time to TTD was 5.2 (3.7, 6.1) months, with 6 (5.5%) patients still receiving treatment at the time of analysis. Median OS (95% CI) was 12.2 (7.7, 14.2) months; 25.5% (n = 28) of patient data remained censored at the time of analysis. Conclusions: OS in this analysis of a real-world Swedish population was generally consistent with that of the pivotal 2L axitinib clinical trial in patients with mRCC who previously received sunitinib (median [95% CI] 15.2 [12.8, 18.3] months; Motzer et al. Lancet Oncol 2013; 14: 552–62). TTD was consistent with the reported progression-free survival (median 6.5 months [95% CI] 5.7–7.9]). These results provide reassurance for the effectiveness of 2L axitinib in an unselected patient population in a real-world setting.
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Kang, Sangwook, and Kyu hyun Kim. "Accelerated failure time models for right censored failure time data." Journal of the Korean Data And Information Science Sociaty 29, no. 6 (November 30, 2018): 1365–79. http://dx.doi.org/10.7465/jkdi.2018.29.6.1365.
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Heldman, Madeleine R., Olivia S. Kates, Robert M. Rakita, Erika D. Lease, Ajit P. Limaye, and Cynthia E. Fisher. "468. Delayed Mortality Among Solid Organ Transplant Recipients Hospitalized for Covid-19: An International Multicenter Study." Open Forum Infectious Diseases 8, Supplement_1 (November 1, 2021): S336—S337. http://dx.doi.org/10.1093/ofid/ofab466.667.
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Abstract Background Studies of solid organ transplant recipients (SOTr) hospitalized for Covid-19 have focused on short-term outcomes with approximately 30 days of follow-up time. Intermediate-term mortality and associated risk factors for intermediate-term death have not previously been reported. Methods Using data from a multi-center registry, we assessed mortality by 90 days among SOTr hospitalized for Covid-19 between 3/1/2020 and 12/31/2020. Multivariable Cox-proportional hazard models were used to compare risk factors for mortality by 28 and 90 days. Covariates were selected a priori based on known predictors of death in SOTr hospitalized for Covid-19. All patients were followed for 90 days or were censored at the time of death or last clinical contact, if this occurred prior to day 90 after diagnosis. Results Among SOTr hospitalized for Covid-19, 198/979 (20%) died within 90 days of diagnosis and 37/198 (19%) of deaths occurred between days 29 and 90. Risk factors for mortality by day 90 days included age >65 years (1.8, 95% CI 1.3-2.4, P< 0.001), lung transplant (compared to non-lung) (1.6, 95% CI 1.1-2.4, P=0.02), chronic lung disease (2.2, 95% CI 1.5-3.4, P=0.002) and heart failure (1.9, 95% CI 1.2-2.9), which were similar to risk factors reported for 28-day mortality (Table 1). Diagnosis during the second half of 2020 (6/20-12/31/20) was associated with lower mortality by 28 days (aHR 0.7, 95% CI 0.5-1.0, P=0.03) compared to diagnosis during the early half of 2020 (3/1-6/19/20); however, mortality by 90 days was similar in the late and early time periods (aHR 0.9, 95% CI 0.7-1.2, P=0.54). Obesity and mTOR inhibitor use were also associated with death by 28 but not 90 days. Kaplan-Meier survival curves by time period of diagnosis are shown in Figure 1. Table 1. Multivariable Cox-Proportional Hazard Model for Mortality at 28 and 90-days Among Solid Organ Transplant Recipients Hospitalized for Covid-19 (N=979) Figure 1. Survival among SOT recipients hospitalized for Covid-19 by diagnosis time period Vertical tick marks represent censored cases. Early 2020 refers to cases diagnosed between March 1 and June 19, 2020 and late 2020 refers to cases diagnosed between June 20 and December 31, 2020. Conclusion Approximately 20% of deaths among SOTr hospitalized for Covid-19 occurred between days 29 and 90. Future investigations are required to discern the mechanism(s) for the improvement in early, but not late, mortality among SOTr with Covid-19 during the course of the pandemic. Disclosures Madeleine R. Heldman, MD, Cigna Lifesource (Other Financial or Material Support, Speaking honoraria)Thermo Fisher Scientific (Other Financial or Material Support, Speaking honoraria) Olivia S. Kates, MD, Merk (Scientific Research Study Investigator) Ajit P. Limaye, MD, astellas (Scientific Research Study Investigator)CTI (Scientific Research Study Investigator)GSK (Consultant)Johnson&Johnson (Other Financial or Material Support, Adjudication Committee)merck (Consultant, Grant/Research Support, Scientific Research Study Investigator)moderna (Scientific Research Study Investigator)Novartis (Other Financial or Material Support, DMC member)Novo Nordisk (Consultant)
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Keruakous, Amany R., Jennifer Holter Chakrabarty, Sarah Ann Schmidt, Mohamad O. Khawandanah, George Selby, and Carrie Yuen. "Hypomethylating Agent Maintenance Therapy after Allogeneic Stem Cell Transplant Improves Transplant Outcome in High Risk Acute Myelogenous Leukemia." Blood 134, Supplement_1 (November 13, 2019): 3297. http://dx.doi.org/10.1182/blood-2019-128316.
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Background: Allogeneic hematopoietic stem cell transplant (HSCT) is the only potential curative modality for high risk acute myelogenous leukemia (AML). However, relapse disease remains to be the main reason of failure of allogeneic HSCT. Salvage therapy for relapse AML after allogeneic HSCT is limited and rarely successful. Prognosis is poor with a 2-year survival rate of less than 20%. As majority of relapses occur within first 6 months after transplant, effective preventive intervention given early post allogeneic HSCT may be crucial. An ideal drug for pharmacologic maintenance is difficult to achieve as it should have activity against the disease without excessive myelosuppression or eradication of donor cells, and has minimal or low risk of exacerbation of graft-versus-host disease or additional toxicity. Azacitidine and decitabine are hypomethylating agents (HMAs), which work epigenetically to modulate various genes, including tumor suppressor genes. They have been shown to have benefits in improvement of event free survival and overall survival in relapse AML. Similar benefits have also been reported when low dose azacitadine was given after allogeneic stem cell transplant as a maintenance therapy. Method: This is a single institutional study carried out at the Bone Marrow Transplant Program at the University of Oklahoma Health Science Center. It was started as a case control study in June 2014 when post-transplant azacitadine protocol was initiated, and continues on as a prospective study. Subjects over 18 years old with high risk AML based on cytogenetic and molecular mutation undergoing allogeneic HSCT were enrolled from September 2013 to July 2018. The study is to compare outcome in patients received post-transplant low dose azacitidine at 32mg/m2 on days 1-5 every 28 days for 4 cycles initiating between 6-8 weeks post-transplant versus post-transplant observation. Multivariable cox proportional hazards model was derived to adjust for covariates that differ between the two treatment arms and was used to analyze time to relapse and overall survival in both arms; then our results were graphed using Kaplan Meier Plot. Results: This study included 49 patients undergoing allogeneic HSCT for high risk AML. They were divided into 2 groups with 31 patients received post-transplant azacitidine, and 18 patients did not (prior to initiation of post-transplant azacitadine protocol, control). Our Analysis concluded a greater proportion of deaths among the control group (88.89%) compared to the azacitidine group (25.81%). Majority of deaths in the control group was due to relapse (12 of 16 deaths). Relapse rate was higher in the control group (66.67%) as compared to azacitidine group (25.81%) with statistically significant improvement in time to relapse in the azacitidine group (not reach (NR)) versus 4.1 months in the control arm (log-rank p-value <0.0001) which was described in Figure (1). Median Overall survival was 7.6 months in control arm versus 27.4 months in the 8 patients who relapsed in azacitidine arm (log-rank p-value<0.0001). (Figure 2) Among the 29 subjects from both arms who were relapse-free, overall survival differed between the two treatment groups (log-rank p-value 0.003). Median survival time among those in the control group was 9.8 months. For the azacitidine arm, only 2 events occurred among the 23 relapse-free subjects while the remaining 21 subjects were censored (Figure 3). Among other transplant-related factors, disease status was not differed among the two groups (p=0.411), but conditioning regimen was (p=0.019) with a greater proportion of reduced intensity conditioning (RIC) in the control group (55.56%) than azacitadine group (22.58) (Table 1). After adjusting for conditioning regimen, hazard of relapse was 5.26 (1.99,13.93) times greater (p value<0.001) and death was 5.41 (1.99,13.93) times greater (p value<0.001) in the control group than azacitadine group. In our analysis, cause of death was not statistically significantly different among the two arms (p-value 0.325). Use of azacitidine post-HSCT did not increase the risk of GVHD or infections (table 2). Implications: Low dose azacitidine maintenance therapy after allogeneic stem cell transplant in high risk acute myelogenous leukemia decreases relapse rate, time to relapse and improved overall survival without increasing adverse events and no increased risk of graft-versus-host disease or infections. Disclosures No relevant conflicts of interest to declare.
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Riva-Cambrin, Jay, John R. W. Kestle, Curtis J. Rozzelle, Robert P. Naftel, Jessica S. Alvey, Ron W. Reeder, Richard Holubkov, et al. "Predictors of success for combined endoscopic third ventriculostomy and choroid plexus cauterization in a North American setting: a Hydrocephalus Clinical Research Network study." Journal of Neurosurgery: Pediatrics 24, no. 2 (August 2019): 128–38. http://dx.doi.org/10.3171/2019.3.peds18532.
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OBJECTIVEEndoscopic third ventriculostomy combined with choroid plexus cauterization (ETV+CPC) has been adopted by many pediatric neurosurgeons as an alternative to placing shunts in infants with hydrocephalus. However, reported success rates have been highly variable, which may be secondary to patient selection, operative technique, and/or surgeon training. The objective of this prospective multicenter cohort study was to identify independent patient selection, operative technique, or surgical training predictors of ETV+CPC success in infants.METHODSThis was a prospective cohort study nested within the Hydrocephalus Clinical Research Network’s (HCRN) Core Data Project (registry). All infants under the age of 2 years who underwent a first ETV+CPC between June 2006 and March 2015 from 8 HCRN centers were included. Each patient had a minimum of 6 months of follow-up unless censored by an ETV+CPC failure. Patient and operative risk factors of failure were examined, as well as formal ETV+CPC training, which was defined as traveling to and working with the experienced surgeons at CURE Children’s Hospital of Uganda. ETV+CPC failure was defined as the need for repeat ETV, shunting, or death.RESULTSThe study contained 191 patients with a primary ETV+CPC conducted by 17 pediatric neurosurgeons within the HCRN. Infants under 6 months corrected age at the time of ETV+CPC represented 79% of the cohort. Myelomeningocele (26%), intraventricular hemorrhage associated with prematurity (24%), and aqueductal stenosis (17%) were the most common etiologies. A total of 115 (60%) of the ETV+CPCs were conducted by surgeons after formal training. Overall, ETV+CPC was successful in 48%, 46%, and 45% of infants at 6 months, 1 year, and 18 months, respectively. Young age (< 1 month) (adjusted hazard ratio [aHR] 1.9, 95% CI 1.0–3.6) and an etiology of post–intraventricular hemorrhage secondary to prematurity (aHR 2.0, 95% CI 1.1–3.6) were the only two independent predictors of ETV+CPC failure. Specific subgroups of ages within etiology categories were identified as having higher ETV+CPC success rates. Although training led to more frequent use of the flexible scope (p < 0.001) and higher rates of complete (> 90%) CPC (p < 0.001), training itself was not independently associated (aHR 1.1, 95% CI 0.7–1.8; p = 0.63) with ETV+CPC success.CONCLUSIONSThis is the largest prospective multicenter North American study to date examining ETV+CPC. Formal ETV+CPC training was not found to be associated with improved procedure outcomes. Specific subgroups of ages within specific hydrocephalus etiologies were identified that may preferentially benefit from ETV+CPC.
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Zeidan, Amer M., Joshua F. Zeidner, Amy Duffield, Hanna A. Knaus, Anna Ferguson, Katherine Sheldon, Amy E. DeZern, et al. "Stabilization of Myelodysplastic Syndromes (MDS) Following Hypomethylating Agent (HMAs) Failure Using the Immune Checkpoint Inhibitor Ipilimumab: A Phase I Trial." Blood 126, no. 23 (December 3, 2015): 1666. http://dx.doi.org/10.1182/blood.v126.23.1666.1666.
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Abstract Background: Patients (pts) with higher-risk (HR)-MDS in whom HMAs fail have a dismal prognosis with a median overall survival (OS) of <6 months. Immune tolerance and evasion by malignant cells have been recognized as important mechanisms of progression in cancers including MDS. Immune checkpoint inhibition with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab improved outcomes in pts with solid tumors by overcoming this resistance mechanism. We hypothesized that CTLA-4 blockade in pts with HR-MDS post HMAs failure would be tolerable and lead to meaningful clinical responses. Methods: In an investigator-initiated, CTEP-sponsored phase 1b study, eligible pts with HR-MDS (defined by Intermediate-2 or high IPSS score, or intermediate-1 with ≥5% blasts in bone marrow [BM] or transfusion needs) who had primary or secondary failure of HMAs (≥4 cycles) received ipilimumab monotherapy at 2 dose levels (DL); DL1 used 3mg/kg and DL2 used 10mg/kg. In the induction phase [Figure 1], 4 doses were administered at 3-week intervals. Responding Pts and those with stable disease (SD) at end of induction received a maintenance phase with 4 more doses of ipilimumab administered at 3-month intervals (study total is 8 doses). BM biopsies were obtained at baseline, post cycles 2, 4, and before each maintenance dose. The primary objectives were to determine the tolerability of ipilimumab and identify the optimal dose for dose expansion. Toxicities were graded according to CTCAE 4.0 criteria. Responses were evaluated using International Working Group 2006 criteria at end of induction and before each maintenance dose. Overall survival (OS) was calculated from first dose of ipilimumab until death using Kaplan-Meier methods with censoring at time of allogeneic stem cell transplantation (alloSCT) or cutoff date for data collection on 6/30/2015. Results: Eleven pts were enrolled on the dose-escalation part of the study; 6 on DL1 and 5 on DL2. Median age was 63 years (range, 50-79). Five pts had received 2 prior lines of therapy (including HMAs) while 6 pts had received only HMAs; median number of HMAs cycles 5; range, 4-18. Five pts had a normal karyotype while each of the following categories were present in one pt: del5q, del7q, complex, trisomy 8 (2 pts unsuccessful karyotyping). At baseline, 4 pts were platelet transfusion-dependent and 5 were red blood cell transfusion-dependent. Median platelet count was 25×10⁹/L (range, 12-61×10⁹/L), median white blood cell count was 1.5×10⁹/L (range, 1.05-7.6×10⁹/L), median absolute neutrophil count was 0.28×10⁹/L (range, 0.06-4.7×10⁹/L), median hemoglobin was 9.4 gm/dL (range 7.6-10.8 gm/dL), and median BM blast percentage was 9% (range, 2-30%). All pts in DL1 received ≥2 ipilimumab doses; 2 received 6 or 8 doses. Three of 6 pts in DL1 developed grade 3 immune-related adverse events (IRAEs) while 4 of 5 pts at DL2 developed grade 3 IRAEs. Four pts (36%) experienced no IRAEs (3 at DL1 and 1 at DL2). All IRAEs were reversible with stopping ipilimumab +/- initiation of systemic steroids. No pt died due to an IRAE and all patients were successfully weaned from steroids. The spectrum of IRAEs was similar to that of ipilimumab use in pts with solid malignancies (rash, hepatitis, and diarrhea/colitis). Overall no pts had objective responses. Three pts (27.3%) had SD for >6 months; one had a prolonged SD after an IRAE, and one experienced an ongoing SD for >16 months. Three pts underwent alloSCT post ipilimumab without any additional toxicities and remain in complete remission at 2, 12 and 18 months post alloSCT, respectively. Median and mean OS for entire cohort (censoring at time of alloSCT) was 368 and 352 days, respectively (95%CI for mean OS, 264-440 days) [Figure 2]. Correlative studies evaluating dynamic changes in T-cell subsets, myeloid derived suppressor cells, cytokine levels, and T-cell receptor repertoire are in progress. Conclusions: Monotherapy withanti-CTLA-4 antibody ipilimumabat 3mg/kg is tolerable and can lead to prolonged disease stabilization. This dose is currently being evaluated further in a dose-expansion multi-center study. AlloSCT appears feasible post ipilimumab use but further data are needed. These results provide rationale for further exploration of immune checkpoint inhibition therapy in pts with MDS. Figure 1. Administration schedule Figure 1. Administration schedule Figure 2. Overall survival from first dose (censored at alloSCT or 6/30/2015). Figure 2. Overall survival from first dose (censored at alloSCT or 6/30/2015). Disclosures Off Label Use: Ipilimumab for MDS. Gore:Celgene: Consultancy, Honoraria, Research Funding.