Fine-Gray Competing Risk Regression Research Articles

A simple covert hepatic encephalopathy screening model based on blood biochemical parameters in patients with cirrhosis.

Covert hepatic encephalopathy (CHE) adversely affects clinical outcomes in patients with liver cirrhosis, although its diagnosis is difficult. This study aimed to establish a simple CHE screening model based on blood-related biochemical parameters. This retrospective study enrolled 439 patients who were assessed for CHE using a neuropsychiatric test between January 2011 and June 2019. A simple CHE (sCHE) score was calculated with hypoalbuminemia (≤ 3.5 g/dL) and hyperammonemia (≥ 80 μg/dL) as 1 point each. The association between sCHE score and CHE or overt hepatic encephalopathy (OHE) was assessed using logistic regression and Fine-Gray competing risk regression models. Of 381 eligible patients, 79 (21%) were diagnosed with CHE. The distribution of sCHE scores was 48% with 0 point, 33% with 1 point, and 19% with 2 points. Patients with sCHE score ≥ 1 point had a higher prevalence of CHE than those with sCHE score of 0 (27% vs. 14%, P = 0.002). A cut-off value of 1 point showed high discriminative ability for identifying CHE, with a sensitivity of 0.67, specificity of 0.56, positive predictive value of 0.27, and negative predictive value of 0.86. During the median follow-up period of 2.2 years, 58 (15%) patients developed OHE. Multivariate analysis showed that sCHE score ≥ 1 (sub-distribution hazard ratio [SHR], 2.69; 95% confidence interval [CI], 1.41-5.15) and CHE (SHR, 2.17; 95% CI, 1.26-3.73) independently predicted OHE. The sCHE score is a useful screening model for identifying patients with CHE and for predicting OHE occurrence.

Prognostic Implications of Left Ventricular Ejection Fraction and Left Ventricular End-Diastolic Diameter on Clinical Outcomes in Patients with ICD.

Background: Left ventricular ejection fraction (LVEF) is a suboptimal indicator of risk stratification for patients with an implantable cardioverter defibrillator (ICD). Studies have shown that left ventricular end-diastolic diameter (LVEDD) was associated with all-cause mortality and ventricular arrhythmias. We examined the quantified prognostic value of LVEF and LVEDD for clinical outcomes, respectively. Method: This study retrospectively enrolled patients with ICD implantation in a single center. The associations between LVEF or LVEDD and all-cause mortality and appropriate shocks were analyzed using Cox regression and Fine-gray competing risk regression, respectively. Result: During a median follow up of 59.6 months, 168/630 (26.7%) patients died. LVEF and LVEDD were strongly associated with all-cause mortality (LVEF per 10%: HR 0.77, 95%CI 0.64−0.93, p = 0.006; LVEDD per 10 mm: HR 1.54, 95%CI 1.27−1.85, p < 0.001). After a median interrogation time of 37.1 months, 156 (24.8%) patients received at least one shock. LVEF was not associated with appropriate shock, whereas larger LVEDD (per 10 mm) was significantly associated with a higher risk of shock (HR: 1.27, 95%CI 1.06−1.52, p = 0.008). The addition of LVEF or LVEDD to clinical factors provided incremental prognostic value and discrimination improvement for all-cause mortality, while only the addition of LVEDD to clinical factors improved prognostic value for shock intervention. Conclusions: Baseline LVEF and LVEDD show a linear relationship with all-cause mortality in patients with ICD. However, whereas LVEF is not associated with shock, a linear relationship exists between LVEDD and appropriate shock. LVEDD adds more predictive value in relation to all-cause mortality and appropriate shocks than LVEF.

Risk and prognosis of secondary malignant neoplasms after radiation therapy for bladder cancer: A large population-based cohort study.

To investigate the association between radiotherapy and the risk of second malignant neoplasm (SMN) development among patients with bladder cancer (BC). Overall survival (OS) is compared among patients developing SMN and without. We identified patients diagnosed with BC from the Surveillance, Epidemiology, and End Results (SEER) database. The development of an SMN is defined as any SMN occurring more than 5 years after the diagnosis of BC. The Fine-Gray competing risk regression is used to estimate the probability of SMN. The radiotherapy-associated risk (RR) for SMNs is assessed by Poisson regression. The Kaplan-Meier method was used to evaluate the OS of patients with SMNs. Propensity score matching (PSM) is performed. A total of 76575 BC patients are enrolled in our study. The probability of SMNs in the radiotherapy cohort is statistically higher than in the non-radiotherapy cohort. In competing risk regression analysis, radiotherapy is proven to be associated with a higher risk of SMN (Hazard ratio: 1.23; 95% CI: 1.102-1.368). The radiotherapy-associated risks significantly increase in the radiotherapy cohort (RR: 1.28; 95% CI: 1.14-1.43). In site-specific analysis, statistically significant results are observed in lung and bronchus (LAB) cancer and hematological malignancies. The OS rate in patients developing SMN is significantly lower than that among matched patients with primary BC. Radiotherapy for BC is associated with SMN. Radiotherapy increases the risk of secondary low-dose area cancer development, including LAB cancer or hematological malignancies. Notably, this effect is not observed in the high-dose area involving pelvic tumors. Patients developing SMN showed poorer OS.

Novel Prediction Models of Nonrelapse Mortality in Patients Specific to Each Reduced-Intensity Conditioning before Allogeneic Hematopoietic Stem Cell Transplantation: A Multicenter Analysis from the Kanto Study Group for Cell Therapy (KSGCT)

Introduction Despite recent developments on various transplantation procedures and supportive therapy, nonrelapse mortality (NRM) after allogeneic stem cell transplantation (allo-SCT) remains an essential issue. In choosing the appropriate regimen for allo-SCT, decision-making information that considers the complexity of different risk factors is vital. The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), which was initially derived and validated by investigators at the Fred Hutchinson Cancer Research Center to predict NRM, has become a widely validated tool for predicting outcomes in many transplant settings (Sorror et al. Blood. 2005). It can also stratify patients for the risk of other outcomes, including overall survival and graft versus host disease. Patients with a high HCT-CI score tend to prefer allo-SCT with reduced-intensity conditioning (RIC). Conversely, for those who has a low HCT-CI score but prefer allo-SCT with RIC, a prognostic indicator is unnecessary. Furthermore, the risk factors for NRM may differ among various conditioning regimens. Therefore, the current study aimed to establish a new prognostic model for patients specific to each RIC regimen before allo-SCT. Methods We performed a retrospective cohort study to develop prognostic models of NRM in patients conditioned with fludarabine/ busulfan (Flu/Bu) or fludarabine/melphalan (Flu/Mel). We selected patients who had leukemia and lymphoma in remission or had untreated or stable myelodysplastic syndrome and experienced initial allo-SCT relapse between 2007 and 2017 in the Kanto Study of Group for Cell Therapy. The primary outcome measure was 2-year NRM. Furthermore, we evaluated variables such as patient age, albumin value (Alb), liver function, renal function, respiratory function, ejection fraction (EF), C-reactive protein, stem cell source, donor type, usage of antithymocyte globulin, performance status (PS), recipient/donor sexes, time interval from diagnosis to transplant, usage of total body irradiation (TBI), and HCT-CI score. To identify a set of variables for Fine-Gray competing risk regression model, we used an Akaike Information Criterion (AIC)-based variable selection procedure. We assigned weights to individual parameters according to their prognostic significance in Fine-Gray models. The identified model's discriminative ability was assessed by Harrell's C-statistic. Results Among the 430 patients analyzed, 202 received Flu/Bu, and 228 received Flu/Mel. In Flu/Bu and Flu/Mel, the mean age was 60.6±6.2 and 57.8±8.5 years, the HCT-CI score ≤ 2 was observed in 77.2% and 78.1%, and 2-year NRM was found in 19.7% and 17.9% of the patients, respectively. Before transplantation, the most dominant parameters in Flu/Bu were Alb < 4.0 g/dL and EF < 55 %, whereas those in Flu/Mel were PS > 0, Alb < 4.0 g/dL, stem cell source, recipient/donor sexes and usage of TBI. Each of the abovementioned parameters, including PS > 0, was scored based on regression coefficients. To evaluate the 2-year NRM, we divided the total scores into several risk groups. In the Flu/Bu group, the NRM was 10.3 % in low (score 0, n = 69), 19.2 % in intermediate-1 (score 1, n =46), 25.4 % in intermediate-2 (score 2-3, n = 81) and 50.0 % in high (score 4-5, n = 6) scores. In the Flu/Mel group, the NRM was 8.6 % in low (score 0-2, n = 48), 15.2 % in intermediate (score 3-4, n = 139), and 37.4 % in high (score 5-8, n = 41) scores (Figure). Higher scores were strongly associated with worse NRM and survival. These models showed good discrimination, with C-statistic values of 0.64 in Flu/Bu and 0.67 in Flu/Mel. Conclusions Our prognostic models for NRM estimation can distinguish patients with a high NRM risk. To our knowledge, these models are the first prognostic models used to estimate NRM for standard-risk patients specific to each RIC regimen. This new simple index may help predict NRM and choose an appropriate conditioning regimen before allo-SCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of HLA-B Leader Mismatching on Outcomes after Haploidentical Transplantation with Antithymocyte Globulin

Objective Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is increasingly used to treat hematologic diseases in the last 10 years. Continuous effort has been made to identify a high-risk HLA mismatch pattern to avoid detrimental factors to HSCT outcomes. However, whether HLA-B leader could be used to optimize donor selection in haplo-HSCT with antithymocyte globulin (ATG) is unknown. We thus sought to evaluate the role of HLA-B leader in haplo-HSCT with ATG which may help to optimize donor selection. Method We conducted a single-center retrospective analysis of 570 patients who received haplo-HSCT for the treatment of hematological malignancies between Sep, 2012 and May, 2021 in our institution to test a series of hypotheses for a better understanding of the significance of HLA-B leader in haplo-HSCT with ATG. HLA-B leader genotype and shared HLA-B leader was determined using HLA-B Leader Assessment Tool. Probabilities of survival were estimated by the Kaplan-Meier method. Cumulative incidences of competing risk outcomes were estimated by competing risk model. The Cox proportional hazard regression and the Fine-Gray competing risks regression model was used to define hazard ratio (HR) and conduct multivariate analysis. All statistical analysis was performed with R version 4.0.5. Results All patients received myeloablative conditioning regimen with ATG for graft-versus-host-disease prevention. Median follow-up was 649 days (interquartile range [IQR] 398-965 days) for surviving patients.Relative to HLA-B leader matched transplantation, HLA-B leader mismatched transplantation had lower overall-survival (OS) (HR, 1.44; 95% CI, 1.02-2.01; P=0.04; Figure 1A) and higher non-relapse mortality (NRM) (HR, 1.56; 95% CI, 1.04-2.35, P=0.03; Figure 1B). These results were further demonstrated by multivariable analysis. With respect to specific causes of NRM, leader mismatch group had a higher risk of infection-related death (HR, 2.30; 95% CI, 1.25-4.23; P=0.01). Additionally, we found that relapse was adversely affected by a shared M relative to a shared T allotype in the leader matched subgroup (HR, 1.92; 95% CI, 1.07-3.47, P=0.03; Figure 1C). In terms of disease-free-survival (DFS) and OS, no significant differences were identified between shared M and shared T in both leader matched subgroup and leader mismatched subgroup (Figure 1D; Figure 1E). Notably, patients benefited from HLA-B leader match with a shared T, which was associated with superior OS (HR, 0.71; 95% CI, 0.51-0.98; P=0.035) and modestly increased DFS (HR, 0.74; 95% CI, 0.55-1.00; P=0.051) when compared with the other three groups. Additionally, in the subgroup with shared T, HLA-B leader mismatch had a non-statistically significant trend of higher NRM (HR, 1.50; 95% CI, 0.97-2.31, P=0.07; Figure 1F). Similar association was observed in multivariable models that relative to leader match with shared T, leader match with shared M was associated with higher relapse (HR, 1.85; 95% CI, 1.02-3.36; P=0.045) and leader mismatch with shared T was associated with inferior OS (HR, 1.57; 95% CI, 1.08-2.28; P=0.017). Conclusion Our findings suggested that mismatched HLA-B leader informed increased risk of NRM and lower OS. Furthermore, patients benefited from HLA-B leader matched donors with shared T. A paradigm inclusive of HLA-B leader might help to optimize donor selection and improve clinical outcomes of haplo-HSCT with ATG. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

External Beam Radiation Therapy With or Without Brachytherapy Boost in Men With Very-High-Risk Prostate Cancer: A Large Multicenter International Consortium Analysis

Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear. This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT+BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT+BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression. Among the entire cohort, 270 underwent EBRT and 101 EBRT+BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT+BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P=.42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P=.45) between EBRT+BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P=.42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P=.38). In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT+BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

Risk and prognosis of secondary bladder cancer after radiation therapy for pelvic cancer.

BackgroundRadiation therapy (RT) is a crucial modality for the local control of pelvic cancer (PC), but the effect of pelvic RT on the development of secondary malignancy is still unclear. This study aimed to identify the relationship between radiation therapy received for the treatment of primary PC and subsequent secondary bladder cancer (SBC).MethodsThe Surveillance, Epidemiology, and End Results (SEER) database (from 1975 to 2015) was queried for PC. Fine-gray competing risk regression and Cox regression analyses were employed to assess the cumulative incidence of SBC. Poisson regression and multiple primary standardized incidence ratios (SIR) were used to evaluate the radiotherapy-associated risk for patients receiving RT. Subgroup analyses of patients stratified by latency time since PC diagnosis, calendar year of PC diagnosis stage, and age at PC diagnosis were also performed. Overall survival (OS) was compared among different treatment groups with SBC by Kaplan–Meier analysis.ResultsA total of 318,165 observations showed that the primary cancers were located in pelvic cavity, 256,313 patients did not receive radiation therapy (NRT), 51,347 patients who underwent external beam radiation therapy (EBRT), and 10,505 patients receiving a combination of EBRT and brachytherapy (EBRT–BRT) who developed SBC. Receiving two types of radiotherapy was strongly consistent with a higher risk of developing SBC for PC patients in Fine-Gray competing risk regression (NRT vs. EBRT, adjusted HR= 1.71, 95% CI: 1.54-1.90, P<0.001; NRT vs. EBRT–BRT, adjusted HR= 2.16, 95% CI: 1.78-2.63, P<0.001). The results of the dynamic SIR and Poisson regression analysis for SBC revealed that a slightly increased risk of SBC was observed after RT in the early latency and was significantly related to the variations of age at PC diagnosis and decreased with time progress. For OS, the SBC after NRT, SBC after EBRT, and SBC after EBRT-BRT of 10-year survival rates were 37.9%, 29.2%, and 22.2%, respectively.ConclusionRadiotherapy for primary PC was associated with higher risks of developing SBC than patients unexposed to radiotherapy. Different pelvic RT treatment modalities had different effects on the risk of SBC.

Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia.

Predictors, genetic characteristics, and long-term outcomes of patients with SAA who clonally evolved after immunosuppressive therapy (IST) were assessed. SAA patients were treated with IST from 1989-2020. Clonal evolution was categorized as "high-risk" (overt myeloid neoplasm [meeting WHO criteria for dysplasia, MPN or acute leukemia] or isolated chromosome-7 abnormality/complex karyotype without dysplasia or overt myeloid neoplasia) or "low-risk" (non-7 or non-complex chromosome abnormalities without morphological evidence of dysplasia or myeloid neoplasia). Univariate and multivariate analysis using Fine-Gray competing risk regression model determined predictors. Long-term outcomes included relapse, overall survival (OS) and hematopoietic stem cell transplant (HSCT). Somatic mutations in myeloid cancer genes were assessed in evolvers and in 407 patients 6 months after IST. Of 663 SAA patients, 95 developed clonal evolution. Pre-treatment age >48 years and ANC > 0.87 × 109/L were strong predictors of high-risk evolution. OS was 37% in high-risk clonal evolution by 5 years compared to 94% in low-risk. High-risk patients who underwent HSCT had improved OS. Eltrombopag did not increase high-risk evolution. Splicing factors and RUNX1 somatic variants were detected exclusively at high-risk evolution; DNMT3A, BCOR/L1 and ASXL1 were present in both. RUNX1, splicing factors and ASXL1 somaticmutations detected at 6 months after IST predicted high-risk evolution.

Untreated Donor-Specific HLA Antibodies Are Associated With Graft Failure and Poor Survival After Haploidentical Transplantation With Post-Transplantation Cyclophosphamide in Pediatric Patients With Nonmalignant Disorders

Donor-specific HLA antibodies (DSAs) have been recognized as a major risk factor for graft failure (GF) in adult patients with malignancies undergoing haploidentical transplantation with post-transplantation cyclophosphamide (haplo-PTCy). However, the impact of DSAs after pediatric haplo-PTCy for nonmalignant disorders (NMDs) has been poorly reported. We sought to investigate whether preexisting DSAs adversely affect pediatric haplo-PTCy outcomes. We retrospectively analyzed 59 pediatric patients (≤21 years) who received their first haplo-PTCy for NMDs from January 2008 to December 2017. DSA testing was performed using single antigen beads, and mean fluorescence intensity (MFI) >1000 was considered positive, and MFI <1000 and >500 was considered potentially positive, based on HLA epitope reactivity patterns. Primary endpoints were neutrophil and platelet recovery and GF, whereas secondary endpoints included event-free and overall survival. Multivariable analyses were performed using Fine-Gray competing risk regression or Cox proportional hazards regression models. The median age was 10 years, and 66.1% were male. Main indications for haplo-PTCy were Fanconi anemia (n=33) and severe aplastic anemia (n=11). All patients received bone marrow as the graft source, and most patients (91.5%) received fludarabine-based conditioning. Overall, 15 patients (25.4%) had DSAs >500 MFI. Four patients had false-positive DSAs with median MFI of 1762. Of the 11 patients with true-positive DSA reactivity, 5 had 1 DSA, 5 had 2 DSAs, and 1 had 3 DSAs, with median MFI of 2372 (range 527-24,200). Four patients received desensitization therapy with rituximab and plasmapheresis, whereas 7 patients were untreated. All patients with treated DSAs achieved donor engraftment. In the multivariable analyses, untreated DSAs were associated with lower neutrophil recovery (subdistribution hazard ratio [SHR] = 0.15; 95% confidence interval [CI], 0.03-0.63; P=.001), increased GF (SHR=20.57; 95% CI, 6.57-64.43; P < .001), inferior event-free survival (hazard ratio [HR] = 10.09; 95% CI, 3.37-30.22; P < .001), and poor overall survival (HR 5.56; 95% CI, 1.92-16.12; P=.002). Both treated DSAs (SHR=0.26; 95% CI, 0.10-0.68; P=.006) and untreated DSAs (SHR=0.13; 95% CI, 0.04-0.37; P < .001) adversely affected platelet recovery. Our results indicate that the presence of DSAs is an independent predictor of poor outcomes after pediatric haplo-PTCy for NMDs. Therefore DSA-positive donors should be avoided whenever possible, and when a DSA-negative donor is unavailable, desensitization therapy must be performed to enhance the likelihood of donor engraftment and improve transplantation outcomes.

Long-term outcomes after discontinuing biological drugs and tofacitinib in patients with rheumatoid arthritis: A prospective cohort study.

This study examined long-term outcomes of biological disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib discontinuation in patients with rheumatoid arthritis (RA). Ninety-seven RA patients who desired drug discontinuation after sustained remission or low disease activity for at least 48 weeks due to stable treatment with biological drugs or tofacitinib were enrolled into this study. All patients were prospectively followed until disease flare or the end of the study. Discontinued drugs (previous drugs) were reintroduced to treat flares. Following bDMARD/tofacitinib discontinuation (mean follow-up, 2.1 years; standard deviation, 2.0), disease flare occurred at a crude incidence rate of 0.36 per person-year. The median time to flare was 1.6 years (95% confidence interval [CI] 0.9-2.6), and the cumulative flare probability was estimated to be 45% at 1 year, 64% at 3 years, and 80% at 5 years. No or little radiological progression was shown in 87.1% of patients who maintained remission for 3 years. A Fine‒Gray competing risk regression analysis showed that predictive factors for a flare were longer RA duration at the start of bDMARD/tofacitinib treatment, previous failure of treatment with bDMARDs, and a shorter period of remission or low disease activity before drug discontinuation. Type of discontinued drug was not identified as a predictive factor after adjusting for other predictor variables. Restarting previous treatment regimens led to rapidly regaining disease control in 89% of flare patients within 1 month. Discontinuation of bDMARD/tofacitinib may be a feasible strategy in RA patients, especially patients with early treated and longer-controlled RA. Flares are manageable in most RA patients and radiological progression is rare for at least 3 years in patients with sustained remission after bDMARD/tofacitinib discontinuation.

Relationships of leisure activities with physical and cognitive functions among Chinese older adults: A prospective community-based cohort study

Objectives Based on a prospective design, this study aimed to investigate the relationships of leisure activities with physical and cognitive functions among Chinese older adults. Methods The respondents aged 65 years or more were selected from the 2014-2018 of the Chinese Longitudinal Healthy Longevity Survey. Physical function measurement indicators were reflected by activities of daily living (ADL), instrumental activities of daily living (IADL), and physical performance (PP), while cognitive function was assessed by Mini-Mental State Examination. Fine-Gray competing risk regression models were used to analyze the data. Results Using the figures for 2014 as a baseline for the study, we included 6047, 6216, 5951, and 5916 respondents in the ADL, IADL, PP, and cognitive function analyses, respectively. The prospective results showed that keeping domestic animals or pets was related to a lower risk of ADL disability of respondents after adjustment (SHR: 0.619, 95% CI: 0.486, 0.788). Similarly, taking part in social activities (SHR: 0.781, 95%CI: 0.658, 0.929) and reading books or newspapers (SHR: 0.793, 95% CI: 0.656, 0.958) were associated with a lower risk of IADL disability. Playing cards or mahjong was correlated with a lower risk of cognitive impairment (SHR: 0.669, 95% CI: 0.507, 0.882), while keeping domestic animals or pets was related to a higher risk of cognitive impairment (SHR: 1.279, 95% CI: 1.047, 1.562). Conclusion Participation in leisure activities moderately may decrease the risk of a decline in physical and cognitive functions among Chinese older adults.

Single immediate instillation of chemotherapy is associated with decreased recurrence and progression in patients with high-risk non-muscle-invasive bladder cancer who receive adjuvant induction bacillus Calmette-Guérin therapy.

To investigate whether a single intravesical instillation of chemotherapy is associated with improved oncological outcomes in patients with high-risk non-muscle-invasive bladder cancer who receive adjuvant induction bacillus Calmette-Guérin therapy. This multi-institutional retrospective study included 205 patients with high-risk non-muscle-invasive bladder cancer who received adjuvant induction bacillus Calmette-Guérin therapy. Patients were divided into two groups: those who received the combined therapy of a single instillation of chemotherapy plus subsequent adjuvant induction bacillus Calmette-Guérin therapy (combined therapy group), and those who received adjuvant induction bacillus Calmette-Guérin therapy alone (bacillus Calmette-Guérin monotherapy group). Multivariable analyses using the inverse probability of treatment weighting method and Fine-Gray competing risk regression models were performed to evaluate the impact of a single instillation of chemotherapy on intravesical recurrence-free survival and muscle-invasive bladder cancer-free survival. Among the 205 patients, 130 (63%) and 75 (37%) were classified as the combined therapy and bacillus Calmette-Guérin monotherapy groups, respectively. Multivariable analyses using the inverse probability of treatment weighting method showed that a single instillation of chemotherapy was significantly associated with longer intravesical recurrence-free survival (hazard ratio 0.279; P < 0.001) and muscle-invasive bladder cancer-free survival (hazard ratio 0.078; P < 0.001). Fine-Gray competing risk regression model revealed that a single instillation of chemotherapy was associated with a significantly lower probability of intravesical recurrence and muscle-invasive bladder cancer progression, with an adjusted subdistribution hazard ratio of 0.477 (P = 0.008) and 0.261 (P = 0.043), respectively. A single intravesical instillation of chemotherapy may be a potential treatment option in patients with high-risk non-muscle-invasive bladder cancer who receive adjuvant induction bacillus Calmette-Guérin therapy.

MP56-12 UPPER TRACT RECURRENCE RISK BASED ON DRAINAGE METHOD FOR URETERAL OBSTRUCTION PRIOR TO RADICAL CYSTECTOMY

You have accessJournal of UrologyCME1 May 2022MP56-12 UPPER TRACT RECURRENCE RISK BASED ON DRAINAGE METHOD FOR URETERAL OBSTRUCTION PRIOR TO RADICAL CYSTECTOMY Wesley Yip, Daniel Sjoberg, Nathan Wong, Manuel de Jesus Escano, Song Jiang, Carissa Chu, Nicole Benfante, Sherri Donat, Harry Herr, Guido Dalbagni, Bernard Bochner, and Eugene Cha Wesley YipWesley Yip More articles by this author , Daniel SjobergDaniel Sjoberg More articles by this author , Nathan WongNathan Wong More articles by this author , Manuel de Jesus EscanoManuel de Jesus Escano More articles by this author , Song JiangSong Jiang More articles by this author , Carissa ChuCarissa Chu More articles by this author , Nicole BenfanteNicole Benfante More articles by this author , Sherri DonatSherri Donat More articles by this author , Harry HerrHarry Herr More articles by this author , Guido DalbagniGuido Dalbagni More articles by this author , Bernard BochnerBernard Bochner More articles by this author , and Eugene ChaEugene Cha More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002639.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Ureteral obstruction by bladder tumors can cause hydronephrosis with the potential for renal dysfunction. Renal drainage can be achieved by either ureteral stent placement or percutaneous nephrostomy tube, but there is a potential risk for upper tract seeding by retrograde manipulation during stent placement and reflux of urine. We aim to determine if retrograde ureteral stent placement prior to radical cystectomy (RC) increases the risk of upper tract recurrence. METHODS: 2475 patients who underwent RC at our institution from January 2000 to June 2016 were included in our analysis. Patients were categorized by: no drainage, nephrostomy tube only, or stent with or without nephrostomy tube. Fine-Gray competing risks regression analysis was used to assess whether ureteral stent placement increased the risk of upper tract recurrence, with recurrence to another region and death from other causes as the competing events. Univariable and multivariable models were then created, with the latter adjusted for pathologic T stage, carcinoma in situ (CIS) in the RC specimen, and prior intravesical therapy. RESULTS: Of 2475 patients who underwent RC, 111 upper tract recurrences were observed with a median follow-up of 6.0 years (IQR 2.5, 9.3) among those without an event. 2203 (89%) patients had no drainage, 88 (3.6%) had a nephrostomy tube only, and 184 (7.4%) had a ureteral stent with or without nephrostomy tube. There were 98 upper tract recurrences in the no drainage group, only 1 in the nephrostomy tube group, and 12 in the ureteral stent group. The probability of upper tract recurrence based on drainage method is displayed in Figure 1. On multivariable analysis, ureteral stent placement was associated with an increased risk of upper tract recurrence (HR 2.32; 95% CI 1.27, 4.22). CONCLUSIONS: Ureteral stent placement for ureteral obstruction prior to radical cystectomy is associated with an increased risk of upper tract recurrence compared to nephrostomy tube placement, although patient selection factors not accounted for in our analyses may be present. This should be considered when weighing the risks and benefits of ureteral stent versus nephrostomy tube placement in these patients. Source of Funding: Ruth L. Kirschstein National Research Service Award T32CA082088 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e977 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Wesley Yip More articles by this author Daniel Sjoberg More articles by this author Nathan Wong More articles by this author Manuel de Jesus Escano More articles by this author Song Jiang More articles by this author Carissa Chu More articles by this author Nicole Benfante More articles by this author Sherri Donat More articles by this author Harry Herr More articles by this author Guido Dalbagni More articles by this author Bernard Bochner More articles by this author Eugene Cha More articles by this author Expand All Advertisement PDF DownloadLoading ...

Association between social determinants of health and rates of liver transplantation in individuals with cirrhosis.

This study evaluated the association between neighborhood-level social determinants of health (SDOH) and liver transplantation (LT) among patients with cirrhosis who have universal access to health care. This was a retrospective population-based cohort study from 2000-2019 using administrative health care data from Ontario, Canada. Adults aged 18-70 years with newly decompensated cirrhosis and/or HCC were identified using validated coding. The associations between five neighborhood level SDOH quintiles and LT were assessed with multivariate Fine-Gray competing risks regression to generate subdistribution HRs (sHRs) where death competes with LT. Overall, n=38,719 individuals formed the cohort (median age 57 years, 67% male), and n=2788 (7%) received LT after a median of 23 months (interquartile range 3-68). Due to an interaction, results were stratified by sex. After multivariable regression and comparing those in the lowest versus highest quintiles, individuals living in the most materially resource-deprived areas (female sHR, 0.61; 95% CI, 0.49-0.76; male sHR, 0.55; 95% CI, 0.48-0.64), most residentially unstable neighborhoods (female sHR, 0.61; 95% CI, 0.49-0.75; male sHR, 0.56; 95% CI, 0.49-0.65), and lowest-income neighborhoods (female sHR, 0.57; 95% CI, 0.46-0.7; male sHR, 0.58; 95% CI, 0.50-0.67) had ~40% reduced subhazard for LT (p<0.01 for all). No associations were found between neighborhoods with the most diverse immigrant or racial minority populations or age and labor force quintiles and LT. This information highlights an urgent need to evaluate how SDOH influence rates of LT, with the overarching goal to develop strategies to overcome inequalities.

The association between social network index, atrial fibrillation, and mortality in the Framingham Heart Study

Social isolation might be considered as a marker of poor health and higher mortality. The aim of our analysis was to assess the association of social network index (SNI) with incident AF and death. We selected participants aged ≥ 55 years without prevalent AF from the Framingham Heart Study. We evaluated the association between social isolation measured by the Berkman-Syme Social Network Index (SNI), incident AF, and mortality without diagnosed AF. We assessed the risk factor-adjusted associations between SNI (the sum of 4 components: marriage status, close friends/relatives, religious service attendance, social group participation), incident AF, and mortality without AF by using Fine-Gray competing risk regression models. We secondarily examined the outcome of all-cause mortality. We included 3454 participants (mean age 67 ± 10 years, 58% female). During 11.8 ± 5.2 mean years of follow-up, there were 686 incident AF cases and 965 mortality without AF events. Individuals with fewer connections had lower rates of incident AF (P = 0.04) but higher rates of mortality without AF (P = 0.03). Among SNI components, only social group participation was associated with higher incident AF (subdistribution hazards ratio [sHR] 1.35, 95% CI 1.16–1.57, P = 0.0001). For mortality without AF, social group participation (sHR = 0.81, 95% CI 0.71–0.93, P = 0.002) and regular religious service attendance sHR = 0.76, 95% CI 0.67–0.87, P < 0.0001) were associated with lower risk of death. Social isolation was associated with a higher rate of mortality without diagnosed AF. In contrast to our hypothesis, we observed that poor social connectedness was associated with a lower rate of incident AF. This finding should be interpreted cautiously since there were very few participants in the lowest social connectedness group. Additionally, the seemingly protective effect of social isolation on AF incidence may be simply an artifact of the strong association between social isolation and increased mortality rate in combination with the large number of deaths as compared to AF events in our study. Further study is warranted.

Effect of age on the short- and long-term outcomes of patients undergoing curative liver resection for HCC

BackgroundFew studies have evaluated the outcomes of curative liver resection (LR) in octogenarian patients, analysed cancer-specific survival (CSS) with HCC-related death or explored the age-varying effect of HCC-related death in elderly patients undergoing LR. We aim to determine the effect of age on the short and long-term outcomes of LR for HCC. MethodologyBetween 2000 and 2018, 1,092 patients with primary HCC who underwent LR with curative intent were retrospectively reviewed. The log-rank test and Gray's test were used to assess the equality of survivor functions and competing risk-adjusted cumulative incidence functions between patients in the three age categories respectively. Regression adjustment was used to control for confounding bias via a Principal Component Analysis. Quantile, Firth logistic, Cox, and Fine-Gray competing risk regression were used to analyse continuous, binary, time-to-event, and cause-specific survival respectively. Restricted cubic splines were used to illustrate the dose-effect relationship between age and patient outcomes. ResultsThe study comprised of 764 young patients (<70 years), 278 septuagenarians (70–79 years old) and 50 octogenarians (≥80 years). Compared to young patients, octogenarians had significantly lower 5-year OS(62.1% vs 37.7%, p < 0.001). However, there was no significant difference in 1-year RFS(73.1% vs 67.0%, p = 0.774) or 5-year CSS (5.4% vs 15.2%, p = 0.674). Every 10-year increase in age was significantly associated with an increase length of stay (p < 0.001), postoperative complications (p = 0.004) and poorer OS(p = 0.018) but not significantly associated with major complications (p = 0.279), CSS(p = 0.338) or RFS(p = 0.941). ConclusionAge by itself was associated with OS after LR for HCC but was not a significant risk factor for HCC-related death.

Prostate weight and prostate cancer outcomes after radical prostatectomy: Results from the SEARCH cohort study.

Smaller prostates have been linked to unfavorable clinical characteristics and poor short-term outcomes following radical prostatectomy (RP). We examined the relation between prostate weight at RP and prostate cancer (PC) outcomes post-RP. Men in the SEARCH cohort undergoing RP between 1988 and 2017 (N = 6242) were studied for PC-specific mortality (PCSM) as the primary outcome, and for biochemical recurrence (BCR), castration-resistant PC (CRPC) and metastasis as secondary outcomes. Hazard ratios (HR) and 95% confidence intervals (CI) were determined for associations between prostate weight and outcomes using Fine-Gray competing risk regression multivariable analyses. Sensitivity analyses were also carried out following exclusion of: (i) men with extreme prostate weights (<20 g and ≥100 g); and (ii) men with elevated prostate specific antigen (PSA) levels. Median values for age, pre-RP PSA and prostate weight were 63 years, 6.6 ng/ml, and 42.0 g, respectively. During a median follow-up of 7.9 years, 153 (3%) died from PC, 2103 (34%) had BCR, 203 (3%) developed CRPC, and 289 (5%) developed metastases. Prostate weight was not associated with PCSM in the main analyses (multivariable HR = 1.43; 95% CI: 0.87-2.34) or in sensitivity analyses. Prostate weight was inversely associated with BCR in the main analyses (multivariable HR = 0.70; 95%CI: 0.61-0.79) which was unchanged in sensitivity analyses. HRs for prostate weight and CRPC and metastasis were elevated but statistical significance was not attained. Similar results were observed in sensitivity analyses. Inconsistent results for prostate weight and short-term vs longer-term outcomes highlight the need to better understand the complex biology leading to prostate size and the relevance of prostate size as a predictor of PC outcomes.

Association Between Antiseizure Drug Monotherapy and Mortality for Patients With Poststroke Epilepsy

There is little evidence to guide the choice of antiseizure medication (ASM) for patients with poststroke epilepsy. Theoretical concerns about detrimental effects of ASMs on survival exist. Enzyme-inducing drugs could interfere with secondary stroke prevention. The US Food and Drug Administration recently issued a safety announcement about the potential proarrhythmic properties of lamotrigine. To investigate whether mortality varies with specific ASMs among patients with poststroke epilepsy. A cohort study was conducted using individual-level data from linked registers on all adults in Sweden with acute stroke from July 1, 2005, to December 31, 2010, and subsequent onset of epilepsy before December 31, 2014. A total of 2577 patients receiving continuous ASM monotherapy were eligible for the study. Data were analyzed between May 27, 2019, and April 8, 2021. The dispensed ASM (Anatomical Therapeutic Chemical code N03A) determined exposure status, and the first dispensation date marked the start of treatment. The primary outcome, all-cause death, was analyzed using Cox proportional hazards regression with carbamazepine as the reference. Cardiovascular death (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes I0-I99 as the underlying cause) was assessed using Fine-Gray competing risk regression models. A total of 2577 patients (1400 men [54%]; median age, 78 years [IQR, 69-85 years]) were included. The adjusted hazard ratio of all-cause death compared with carbamazepine was 0.72 (95% CI, 0.60-0.86) for lamotrigine, 0.96 (95% CI, 0.80-1.15) for levetiracetam, 1.40 (95% CI, 1.23-1.59) for valproic acid, 1.16 (95% CI, 0.88-1.51) for phenytoin, and 1.16 (95% CI, 0.81-1.66) for oxcarbazepine. The adjusted hazard ratio of cardiovascular death compared with carbamazepine was 0.76 (95% CI, 0.61-0.95) for lamotrigine, 0.77 (95% CI, 0.60-0.99) for levetiracetam, 1.40 (95% CI, 1.19-1.64) for valproic acid, 1.02 (95% CI, 0.71-1.47) for phenytoin, and 0.71 (95% CI, 0.42-1.18) for oxcarbazepine. This cohort study's findings suggest differences in survival between patients treated with different ASMs for poststroke epilepsy. Patients receiving lamotrigine monotherapy had significantly lower mortality compared with those receiving carbamazepine. The opposite applied to patients prescribed valproic acid, who had a higher risk of cardiovascular and all-cause death. Levetiracetam was associated with a reduced risk of cardiovascular death compared with carbamazepine, but there was no significant difference in overall mortality.

Risk of Fracture Among Older Adults With Primary Hyperparathyroidism Receiving Parathyroidectomy vs Nonoperative Management

Primary hyperparathyroidism (PHPT) contributes to the development and progression of osteoporosis in older adults. The effectiveness of parathyroidectomy for reducing fracture risk in older adults is unknown. To compare the incidence of clinical fracture among older adults with PHPT treated with parathyroidectomy vs nonoperative management. This was a population-based, longitudinal cohort study of all Medicare beneficiaries with PHPT from 2006 to 2017. Multivariable, inverse probability weighted Cox proportional hazards and Fine-Gray competing risk regression models were constructed to determine the association of parathyroidectomy vs nonoperative management with incident fracture. Data analysis was conducted from February 17, 2021, to September 14, 2021. The primary outcome was clinical fracture at any anatomic site not associated with major trauma during the follow-up period. Among the 210 206 Medicare beneficiaries with PHPT (mean [SD] age, 75 [6.8] years; 165 637 [78.8%] women; 183 433 [87.3%] White individuals), 63 136 (30.0%) underwent parathyroidectomy within 1 year of diagnosis, and 147 070 (70.0%) were managed nonoperatively. During a mean (SD) follow-up period of 58.5 (35.5) months, the unadjusted incidence of fracture was 10.2% in patients treated with parathyroidectomy. During a mean (SD) follow-up of 52.5 (33.8) months, the unadjusted incidence of fracture was 13.7% in patients observed nonoperatively. On multivariable analysis, parathyroidectomy was associated with lower adjusted rates of any fracture (hazard ratio [HR], 0.78; 95% CI, 0.76-0.80]) and hip fracture (HR, 0.76; 95% CI, 0.72-0.79). At 2, 5, and 10 years, parathyroidectomy was associated with adjusted absolute fracture risk reduction of 1.2% (95% CI, 1.0-1.4), 2.8% (95% CI, 2.5-3.1), and 5.1% (95% CI, 4.6-5.5), respectively, compared with nonoperative management. On subgroup analysis, there were no significant differences in the association of parathyroidectomy with fracture risk by age group, sex, frailty, history of osteoporosis, or meeting operative guidelines. Fine-Gray competing risk regression confirmed parathyroidectomy was associated with a lower probability of any fracture and hip fracture when accounting for the competing risk of death (HR, 0.84; 95% CI, 0.82-0.85; and HR, 0.83; 95% CI, 0.80-0.85, respectively). This longitudinal cohort study found that parathyroidectomy was associated with a lower risk of any fracture and hip fracture among older adults with PHPT, suggesting a clinically meaningful benefit of operative management in this population.

Strong Predictors of Chromosomal Aberrations and Myeloid Neoplasia Following Immunosuppression Therapy for Severe Aplastic Anemia: A Retrospective Cohort Study

Introduction: Immune aplastic anemia (AA) is effectively treated with either immunosuppressive treatment (IST) or allogeneic hematopoietic stem cell transplant (HSCT). Clonal evolution remains the most feared long-term complication after IST. We investigated predictor factors, genetic characteristics, and long-term outcomes of patients who developed either secondary myeloid neoplasia or isolated chromosomal abnormalities without morphologic dysplasia after immunosuppression.Methods: All patients with severe AA treated at the NIH Clinical Center with IST from 1989-2020 who underwent clonal evolution were categorized as “high-risk” (overt myeloid neoplasia, or isolated chromosome 7 abnormality / complex cytogenetics) or “low-risk” (isolated chromosome abnormalities without overt myeloid neoplasia or dysplasia; isolated chromosome 7 abnormality or complex cytogenetics were characterized as high-risk). Univariable analysis was performed using the Fine-Gray competing risk regression model using death as a competing risk to determine predictors of clonal evolution. Classification and regression tree analysis of time to clonal evolution was performed on continuous baseline variables to partition the data based on the best categorical cutoff. Long term outcomes assessed included overall survival (OS) and HSCT. Error corrected next-generation sequencing (ECS) was used to assess for pathogenic somatic variants in known myeloid cancer genes in clonal evolvers both at time of evolution and in serial samples prior when available.Results: Of 659 patients with severe AA included in this study, 95 developed clonal evolution: 59 high-risk and 36 low-risk. Age >48 years at diagnosis and pre-treatment ANC >0.87x10 9/L were strong predictors of high-risk clonal evolution. High-risk clonal evolution was increased in patients aged >48 years, with cumulative incidence (CI) of 13.9% by 5 years compared to patients aged <48 years of 3.8% by 5 years (p<0.001). Baseline ANC >0.87 x10 9/L (independent of age) predicted an even higher risk of evolution; CI for high-risk evolution was 17% by 5 years (p<0.001). Combined high ANC and older age (>48 years) were prognostic of the greatest risk of high-risk evolution, with a hazard ratio (HR) of 5.51; conversely, ANC <0.87 x10 9/L and age <48 years was protective, with HR 0.32. High-risk clonal evolution was not significantly increased by use of eltrombopag with IST versus IST only (p=0.3), but there was an increase when all clonal evolution was considered (p=0.02). Overall survival in high-risk evolution was 35% at 5 years and in low-risk evolution was 84% (p<0.001). Patients with high-risk evolution who underwent HSCT (n=26) had better OS compared to those treated with chemotherapy or supportive care (p=0.005).RUNX1 (13 variants in 8 [35%] patients) and ASXL1 (13 variants in 10 [43%] patients) were the most frequent mutated genes at time of clonal evolution in high-risk patients, and BCOR/L1 (14 variants in 8 [32%] patients) was the most frequently mutated in the low-risk group. Longitudinal data were available in five high-risk and eight low-risk patients. Three of five high-risk patients had acquisition or expansion of RUNX1 clones at evolution. Small RUNX1 variants were present in two patients as early as three years prior to high-risk evolution. Splicing factor genes and RUNX1 somatic variants were detected exclusively in the high-risk group; DNMT3A, BCOR/L1 and ASXL1 gene mutations were present in both groups.Conclusion: Age and pre-treatment ANC strongly predict high-risk clonal evolution in AA patients after IST and may be used determine at-risk patients for long term follow-up. Outcomes in patients with low-risk evolution are favorable but poor in high-risk evolution without HSCT. The clonal landscape differs between high-risk and low-risk evolution; MDS-associated genetic mutations are enriched in high-risk evolution, in particular RUNX1. Further study of the role of RUNX1 in high-risk clonal evolvers may give insight into leukemogenesis in AA.Figure 1: Cumulative incidence (CI) of clonal evolution since immunosuppression with death treated as competing risk. (A) CI for development of all clonal evolution in patients >37 years (B) and high-risk clonal evolution in patients >48 years (C) CI for development of all clonal evolution when baseline ANC >0.87x10 9/L and (D) high-risk clonal evolution when baseline ANC >0.87x10 9/L. [Display omitted] DisclosuresYoung: Novartis: Research Funding.