Mortality In Long-term Survivors Research Articles

Abstract 6382: Risk prediction of dyslipidemia in long-term survivors of childhood cancer: A report from the St. Jude Lifetime Cohort

Abstract Background: Dyslipidemia is a significant contributor to the increased risk of cardiovascular morbidity and premature mortality in long-term survivors of childhood cancer. Identifying individuals at risk at an early stage provides an opportunity for tailored prevention approaches. Methods: Long-term childhood cancer survivors from the St. Jude Lifetime Cohort, (SJLIFE, n=2,559; median age 41 years, range 20-77 years) were directly assessed for dyslipidemia. Risk factors under consideration included demographic characteristics, cancer treatment exposures (cumulative doses of anthracyclines, platinum agents, glucocorticoids, and radiation therapy), comorbid conditions at the time of assessment (hypertension, diabetes mellitus, growth hormone deficiency, hypogonadism, hypothyroidism, cardiomyopathy, and chronic kidney disease), and externally validated multi-ancestry general-population polygenic risk scores (PRSs) for lipid values (total cholesterol, LDL-C, HDL-C, and triglycerides). Multivariable logistic regression predicted a 15-year risk of dyslipidemia (CTCAE grade ≥2 hypercholesterolemia and/or hypertriglyceridemia) including variables selected by the stepwise approach. Performance of the model was assessed by the area under the receiver operating characteristic curve (AUC). Results: Dyslipidemia was clinically identified in 543 (25.1%) SJLIFE survivors. AUC of a clinical model with sex, race, age at prediction, and comorbid conditions (diabetes, growth hormone deficiency, hypogonadism, hypothyroidism, and hypertension) was 0.80 (95% CI, 0.78-0.82). Inclusion of cancer treatment exposures (cumulative doses of anthracyclines, cisplatin, carboplatin, glucocorticoids, abdominal and cranial radiation therapy) significantly increased AUC to 0.82 (95% CI, 0.80-0.84; P=2.1×10-4). Addition of two PRSs for LDL-C (one included only genome-wide significant variants adjusted for statins and another consisted of all genome-wide variants) and the PRS for triglycerides provided further significant improvement in AUC to 0.86 (95% CI, 0.84-0.88; P=4.2×10-12). Conclusions: We developed a prediction model with good performance for identifying the risk of dyslipidemia in childhood cancer survivors. In addition to demographics and comorbidities, cancer treatments and inherited genetic factors contributed significantly to improving the risk prediction of dyslipidemia. Results may refine risk stratification for dyslipidemia in survivors and present opportunities for more precise and personalized preventive strategies to address cardiovascular health. Independent validation in survivors from the Childhood Cancer Survivor Study and the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER is currently underway. Citation Format: Kateryna Petrykey, Kendrick Li, Lu Xie, Achal Neupane, Angela Delaney, Christine Yu, Stephanie B. Dixon, Bonnie Ky, Cindy Im, Isaac B. Rhea, Jeffrey A. Towbin, Jason N. Johnson, Melissa Bolier, Vincent G. Pluimakers, Linda Broer, Sebastian J. Neggers, Marry M. van den Heuvel-Eibrink, Rebecca M. Howell, Kirsten K. Ness, Melissa M. Hudson, Gregory T. Armstrong, Yutaka Yasui, Yadav Sapkota. Risk prediction of dyslipidemia in long-term survivors of childhood cancer: A report from the St. Jude Lifetime Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6382.

Contemporary secondary prevention in survivors of ST-elevation myocardial infarction with and without chronic kidney disease: a retrospective analysis.

Survivors of myocardial infarction have an elevated risk of long-term mortality. We sought to evaluate guideline-directed medical treatment and its impact on long-term mortality in survivors of ST-elevation myocardial infarction (STEMI) according to their chronic kidney disease (CKD) stage. Using German health insurance claims data, 157663 hospitalized survivors of STEMI were identified. Regarding different CKD stages, we retrospectively analysed the filled prescriptions of platelet inhibitors (PAI)/oral anticoagulation, statins, beta-blocker and angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor antagonists (ACE-I/AT1-A) and their association with long-term mortality. Prescription rates for all four guideline-directed drugs were highest in patients without or with mild CKD and lowest in patients on dialysis. They dropped from 73.4% to 39.2% in patients without CKD and from 47.1% to 29% in patients on dialysis within the 5-year follow-up period. Mortality rates were dramatically increased in patients with CKD compared with patients without CKD (5-year mortality: no CKD, 16.7%; CKD stage 3, 47.1%; CKD stage 5d, 69.7%). Filled prescriptions of at least one drug class [one drug: hazard ratio (HR) 0.70, 95% confidence interval (95% CI) 0.66-0.74; four drugs: HR 0.28, 95% CI 0.27-0.30; P<.001 for both] as well as the distinct drug classes (statins: HR 0.55, 95% CI 0.54-0.56; ACE-I/AT1-A: HR 0.68, 95% CI 0.67-0.70; beta-blocker: HR 0.87, 95% CI 0.85-0.90; PAI/oral anticoagulation: HR 0.97, 95% CI 0.95-1.00; all P<.05) improved long-term mortality. An improved long-term guideline-recommended drug therapy after STEMI regardless of renal impairment might lead to beneficial effects on long-term mortality.

The economic burden and long-term mortality in survivors of extracorporeal membrane oxygenation in South Korea.

The economic burden for extracorporeal membrane oxygenation (ECMO) survivors is a critical issue. We investigated the total healthcare costs for one year following ECMO support and its association with three-year all-cause mortality. This population-based cohort study used data from the National Health Insurance Service (NHIS) in South Korea. Adult ECMO survivors (age ≥18 years who were alive ≥365 days following ECMO support) from January 1, 2005, to December 31, 2018, were included. The total healthcare costs for one year included all the expenses for hospital and outpatient clinic visits after discharge. In total, 6,044 patients were included in the final analysis comprising 3,566 (59.0%) in the cardiac indication group, 658 (10.9%) in the respiratory indication group, and 1,820 (30.1%) in the "other" group. The median total healthcare cost was United States Dollars (USD) 46,308.0 [interquartile range (IQR): 25,727.0-86,924.8]. The median ECMO support and hospital stay durations were three (IQR: 1-7) days and 25 (IQR: 15-31) days. In the multivariable Cox regression model, a USD 1,000 increase in the total healthcare cost was associated with an increase in the three-year all-cause mortality (hazard ratio, 1.01; 95% CI: 1.00-1.01; P=0.015). After one year, ECMO survivors accrued USD 46,308 in healthcare costs in South Korea. An increase in the total healthcare cost was associated with a higher risk of three-year all-cause mortality among ECMO survivors.

RDW Is an Independent Prognostic Biomarker in Patients with Chronic Graft-Versus-Host-Disease

Background Chronic graft-versus-host disease (cGVHD) is an important immunologic sequelae of allogeneic hematopoietic stem cell transplantation (HCT) that can lead to increased morbidity and mortality in long-term survivors. Red cell distribution width (RDW) is a measure of the variation of the mean corpuscular volume of red blood cells reflecting the degree of anisocytosis. Multiple epidemiological and longitudinal observational studies have shown that higher RDW values are associated with increased all-cause, cardiovascular and cancer-related mortality in different populations including patients as well as healthy participants but limited data exists in patients after HCT. Although RDW is affected to some degree by any type of anemia, the etiology of variation in RDW is considered to be multifactorial and overall incompletely understood. Whether RDW is affected by cGVHD activity or retains its prognostic significance for mortality is unknown. Patients and Methods The present study analyzed patients enrolled on the NIH cGVHD natural history study (NCT00092235) with existing measures of RDW (n=404). In addition to RDW, previously described laboratory markers of inflammation (Grkovic L. et al. Leukemia. 2012;26:633) significantly associated with cGVHD disease activity and other known prognostic factors associated with survival in cGVHD patients were considered. Results The median age of the cohort was 47.2 years (IQR 32-57) and male patients were slightly overrepresented (n=231, 57%). Information about the NIH global score was available in 98.5% of patients who had predominantly severe (72.4%) and moderate (25.6%) cGVHD (Table 1). The median potential follow-up of the total cohort was 11.9 years (IQR 8.4-14.5) and the 5-year overall survival (OS) 77.9% (95% CI, 68.3-77.0%), but the median OS was not reached. A clear split was identified between the first quartile and the remaining overlapping quartiles of RDW distinguishing two groups with statistically different OS: <13.4% vs ≥13.4% (p=0.0024, adjusted for 3 implicit cut-points). Five-year OS was 84.1% (95% CI, 75.3%-89.9%) and 69.1% (95% CI, 63.6%-74.0%) for patients with RDW <13.4% and ≥13.4%, respectively. In univariate analyses, RDW ≥13.4% was statistically associated with Karnofsky performance status (KPS) <80 (39% vs 19%; p=0.0003), cGVHD global score severe (77.6% vs 62%; p=0.0046), increasing involvement of skin (p=0.0023) and mouth (p=0.0043), steroid (70% vs 46%; p<0.0001) and mTOR inhibitor treatment (24% vs 7%; p=0.0002), extracorporeal photopheresis (22% vs 10%; p=0.0077), increased inflammatory markers CRP, C3 and C4 (all p≤0.0002, respectively) and lower IgG (p=0.0031) but not age, sex, kidney function (eGFR CKD-EPI 2021) or time from HCT to study consent. The multiple logistic model established oral cGVHD (OR 1.77; 95% CI, 1.2- 2.60), mTOR inhibitors (OR 3.49; 95% CI, 1.5- 8.30), LDH (OR 1.01; 95% CI, 1.01-1.02), Hb (OR 0.68; 95% CI, 0.57-0.80) and ANC (OR 1.21; 95% CI, 1.07-1.36) as independent factors associated with dichotomized RDW groups. The Cox proportional hazards model confirmed the independent association of RDW ≥13.4% with worse OS (HR 1.61; 95% CI, 1.05-2.47) and identified albumin <3.45 mg/dL (HR 1.78; 95% CI, 1.41-2.24) and IgG <6.3 g/L (HR 1.67; 95% CI, 1.20-2.31) as independent factors in addition to KPS <80 (HR 1.51; 95% CI, 1.06-2.14), eGFR <45 mL/min/1.73m2 (HR 2.27; 95% CI, 1.41-3.66) and lung cGVHD NIH grade 3 (HR 2.92; 95% CI, 1.86-4.57). Moreover, RDW ≥13.4% was associated with decreased relapse-free survival (5-year; 72.8% vs 87.8%; p=0.0062 for comparison of the full curves) and increased non-relapse mortality (5-year; 20.8% vs 7.6%; p=0.0082 for comparison of the full curves) but not with cumulative incidence of relapse (5-year; 6.5% vs 4.6%; p=0.45). Conclusion Patients with chronic GVHD and RDW ≥13.4% have a statistically worse overall survival due to higher risk of non-relapse mortality. Hypoalbuminemia and hypogammaglobulinemia — laboratory markers of increased inflammation and B-cell dysfunction — are additional independent poor prognostic factors identified by this study. It seems prudent that future therapeutic clinical trials should measure these laboratory markers to investigate whether they serve as surrogate biomarkers of chronic GVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Infectious complications and vaccines

Abstract Infections are a major cause of morbidity and can result in mortality in long-term survivors after allogeneic hematopoietic cell transplantation. Chronic graft-versus-host disease and delayed immune reconstitution are recognized risk factors. Different strategies must be utilized depending on the individual patient's situation but include prolonged antimicrobial prophylaxis and vaccination. Some important infections due to pathogens preventable by vaccination are pneumococci, influenza, varicella-zoster virus, and SARS-CoV-2. Despite the fact that such recommendations have been in place for decades, implementation of these recommendations has been reported to be poor.

Subsequent Cancers in Patients Affected with Moderate or Severe Chronic Graft-versus-Host Disease

Subsequent cancer (SC) is a significant cause of morbidity and mortality in long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic graft-versus-host disease (cGVHD) and treatment-related immunosuppression have been recognized as risk factors for SC. This study sought to investigate the incidence and risk factors for SC in patients with established cGVHD, assessed separately for onset of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)-categorized into nonmelanoma skin cancer (NMSC)-and all cancers other than NMSC. Two hundred and four patients were enrolled in the prospective cross-sectional cGVHD Natural History Study and underwent comprehensive clinical evaluation. Patients were followed-up with an annual survey. The cumulative incidences of NMSC and cancers other than NMSC with competing risks were estimated separately, and transplantation- and cGVHD-related factors were assessed for association with outcomes using Gray's test and multivariable Cox models. The time period for all analyses began at 2 years postevaluation to restrict analyses to patients presumed to not have had SC present at evaluation. Nineteen patients were diagnosed with NMSC and 19 were diagnosed with cancers other than NMSC, with 10-year cumulative incidences of 15.5% (95% confidence interval, 9.0% to 27.6%) and 13.8% (95% CI, 8.2% to 20.8%), respectively. Age at transplantation (hazard ratio [HR], 1.94; 95% CI, 1.23 to 3.06) and higher C-reactive protein level at evaluation (HR, 9.49; 95% CI, 1.26 to 71.58) were jointly associated with NMSC, and gastrointestinal cGVHD at evaluation (HR, 0.26; 95% CI, 0.09 to 0.78) was associated with reduced risk of NMSC. T cell depletion at transplantation (HR, 3.09; 95% CI, 1.17 to 8.20), lymphoma as an indication for transplantation (HR, 3.96; 95% CI, 1.56 to 10.05), and oral cGVHD severity at evaluation (HR, 4.36; 95% CI, 1.52 to 12.46) were jointly associated with cancers other than NMSC. This study estimates the incidence of SC in a population of allo-HSCT recipients with severe cGVHD and identifies correlations with the subsequent development of SC. These factors seem to differ between NMSC and cancers other than NMSC. Further longitudinal investigations accounting for dynamic and cumulative processes are needed to improve our understanding and management of SC.

Accelerated aging and mortality in long-term survivors of childhood cancer: A report from the St. Jude Lifetime Cohort (SJLIFE).

10045 Background: Survivors of childhood cancer have functional limitations and health-related morbidity consistent with an accelerated aging phenotype. We characterized aging using a Deficit Accumulation Index (DAI) which examines the accumulation of multiple aging-related deficits readily available from medical records and self-report. DAI’s are used as surrogates of biologic aging and are validated to predict mortality in adult cancer patients. Methods: We included childhood cancer survivors (N = 3,758, mean age 30 [SD 8], 22 [9] years post diagnosis, 52% male) and community controls (N = 575, mean age 34 [10] 44% male) who completed clinical assessments and questionnaires and who were followed for mortality through December 31st, 2018 (mean follow-up 6.1 [3.1] years). Using the initial SJLIFE clinical assessment, a DAI score was generated as the proportion of deficits out of 44 items related to aging, including chronic conditions (e.g. hearing loss, hypertension), psychosocial and physical function, and activities of daily living. The total score ranged 0 to 1; scores &gt; 0.20 are robust, while moderate and large clinically meaningful differences are 0.02 and 0.06, respectively. Linear regression compared the DAI in survivors and controls with an age*survivor/control interaction and examined treatment associations in survivors. Cox-proportional hazards models estimated risk of death associated with DAI. All models were adjusted for age, sex, and race. Results: Mean [SD] of DAI was 0.17 [0.11] for survivors and 0.10 [0.08] for controls. 32% of survivors had a DAI above the 90th percentile of the control distribution (p &lt; 0.001). After adjustment for covariates, survivors had a statistically and clinically meaningfully higher DAI score than controls (β = 0.072 95%CI 0.062, 0.081; p &lt; 0.001). When plotted against age, the adjusted DAI at the average age of survivors (30 years) was 0.166 (95% CI 0.160,0.171), which corresponded to 60 years of age in controls, suggesting premature aging of 30 years. The mean difference in DAI between survivors and controls increased with age from 0.06 (95% CI 0.04, 0.07) at age 20 to 0.11 (95% CI 0.08, 0.13) at age 60, consistent with an accelerated aging phenotype (p = 0.014). Cranial radiation, abdominal radiation, cyclophosphamide, platinum agents, neurosurgery, and amputation were each associated with a higher DAI (all p≤0.001). Among survivors, a 0.06 increase in DAI was associated with a 41% increased risk of all-cause mortality (HR 1.41 95%CI 1.32, 1.50; p &lt; 0.001). Conclusions: Survivors of childhood cancer experience significant age acceleration that is associated with an increased risk of mortality; longitudinal analyses are underway to validate these findings. Given the ease of estimating a DAI, this may be a feasible method to quickly identify survivors for novel and tailored interventions that can improve health and prevent premature mortality.

Trajectory Analysis for Long-Term Mortality in Survivors of Childhood Cancer: A Korean Nationwide Observational Study

Background Survival rates of childhood cancers have improved substantially over the past four decades. However, these improvements have been accompanied by substantial long-term morbidity and premature mortality. In this study, we analyzed trajectory groups that correlate with long-term mortality in childhood cancer survivors. M ethods The National Health Insurance Service (NHIS) database is a population-based cohort covering over 95% of the population across all regions of South Korea. We used the patient-level longitudinal NHIS database which included patients who first received a cancer code ([ICD 10: C]) under the age of 20 years from 2002-2017. The onset of cancer diagnosis was defined as the time of the earliest diagnosis in patients who were prescribed any treatment excluding surgery within one month after the initial diagnosis. Claims codes for chemotherapeutic agents, radiotherapy, and transplantation were designated and analyzed in the database. For trajectory analysis, the total numbers of claimed diagnostic codes per year were used as the input variable of the group-based trajectory method. The separate trajectories were identified using the Proc Traj procedure in SAS 9.4. Results A total of 71,323 people were extracted from the NHIS database. After washing out previously diagnosed patients in 2002, 58,964 people remained from 2003-2017. We included 14,101 patients without records of any treatment for 3 years after the first diagnosis in the final analysis. Trajectory groups were generated in 14,101 and 8,119 patients who have survived more than 5 years and more than 10 years, respectively. Among the ≥ 5 years survivors, three groups were classified: Group 1 (N=5,654; 40.1%), Group 2 (N=7,027; 49.8%), and Group 3 (N=1,420, 10.1%) (Figure 1(A)). Likewise, three trajectory groups were identified in ≥ 10 years survivors: Group 1 (N=3,104; 38.2%), Group 2 (N=4,148; 51.1%), and Group 3 (N=867; 10.7%) (Figure 1(B)). Notably, the risk of death was significantly different between each trajectory group according to Cox regression analysis after being corrected for age and sex (Table 1). In patients with a follow-up of 5 years or more, mortality risk was 4.84 times higher in Group 3 compared to Group 1 (P&amp;lt;0.001). Also, in patients with follow-up of 10 years or more, mortality risk was 11.55 times higher in Group 3 compared with Group 1 (P&amp;lt;0.001). In the survival graph from the timepoints of 5 or 10 years after diagnosis, there were significant differences in overall survival between each trajectory group of the two patient cohorts (P&amp;lt;0.001, Figure 2). To identify characteristics associated with survival differences between trajectory groups, baseline characteristics at diagnosis and treatments were analyzed (Table 2, 3). There were significant differences in age at time of diagnosis in three trajectory groups: in both cohorts, age at diagnosis was significantly younger in Group 3 of the lowest survival rates than other groups. For initial diagnosis, there were increasing trends of Lymphoid leukemia and brain tumors in Group 3 of both cohorts. For types of treatment, the proportions of patients who received only chemotherapy or radiotherapy decreased from Group 1 to Group 3. However, the proportions of patients who received combined treatment with any stem cell transplantation increased from Group 1 to Group 3. The follow-up periods were significantly lower in Group 3, which corresponded to the survival probabilities. Whereas the numbers of prescribed codes for any treatment were significantly higher in Group 3, indicating that patients in Group 3 received more frequent and condensed treatments within shorter periods than those in Group 2, and this relationship was also seen between Group 2 and Group 1. Conclusions This study is the first trajectory analysis conducted in childhood cancer survivors using population-based longitudinal data. In this study, unlike previous trajectory analyses based on characteristics at the time of diagnosis, trajectories were classified based on the burden of diagnosis during periods, which resulted in differences in long-term mortality, and then the differences in characteristics between each group were analyzed. Our findings indicate that that long-term mortality is related to age at diagnosis and concentration of treatment relative to total follow-up duration rather than the absolute duration or intensity of treatment. Disclosures No relevant conflicts of interest to declare.

Naïve Helper T-Cell and Regulatory T- and NK-Cell Subsets Are Associated with Pediatric Chronic Graft-Versus-Host Disease: Results of the ABLE / PBMTC 1202 Study

Pediatric chronic graft-versus-host disease (cGvHD) contributes to poor quality of life and increased morbidity and mortality in long term survivors of hematopoietic stem cell transplant (HSCT). Given the insidious nature of cGvHD, diagnosing cGvHD in children according to the National Institutes of Health Consensus Criteria (NIH-CC) can be challenging, particularly in the early phase of disease development. Diagnostic cGvHD biomarkers could aid in diagnosis. The Applied Biomarkers of Late Effects / Pediatric Blood and Marrow Transplant Consortium (ABLE / PBMTC 1202) study was a prospective, multi-institution study at 27 pediatric HSCT centers that evaluated biomarkers of cGvHD. Detailed clinical evaluation of cGvHD, including central adjudication when necessary, occurred as per the NIH-CC. Of the 302 enrolled children, 233 were included in this diagnostic cGvHD biomarker analysis, including 43 with cGvHD and 190 non-cGVHD controls. Peripheral blood was drawn into a STRECK tube at the onset of cGvHD and before escalation of immune suppression, sent overnight to a central laboratory, and evaluated by flow cytometry. Five flow cytometric antibody panels consisting of 76 combinations of cell surface markers were used to delineate subpopulations of T, Regulatory T (Tregs, CD4+CD127LowCD25+), B, NK, and myeloid cells. We analyzed each marker in two ways. First, to control for normal post-HSCT immune reconstitution, we divided cGvHD subjects into early- (day 0-120), mid- (day 121-240), and late-onset (&amp;gt;day 240) and compared their marker values against non-cGVHD controls at day 100, 6-months, and 12-months, respectively, using fixed effect linear regression models. Second, we compared the marker values of all cGvHD subjects at diagnosis against the marker values of non-cGvHD controls at all three time points and used mixed effect linear regression models to account for within-subject correlations. A cellular subpopulation was considered a clinically relevant and potential diagnostic cGvHD biomarker if all 4 criteria were met: a) the effect ratio (mean marker value of cGvHD subjects over non-cGvHD controls) was ≥1.3 or ≤0.75, b) the p-value was ≤.05, c) the receiver-operating characteristic area under the curve was ≥0.60, and d) the marker was detected by both the mixed effect model and in the same direction across all measurement time points in the fixed effect models. Using these criteria, 8 cellular subpopulations arose as potential diagnostic biomarkers of pediatric cGvHD (Table). Key subsets identified in cGvHD patients included decreased proportions of naïve helper T cells (CD4+CD45RA+, PD1-CD4+CD45RA+, CCR7+CD4+CD45RA+, CD27+CD4+CD45RA+), decreased naïve and recently emigrated Tregs (CD31+CD45RA+, PD1-CD45RA+), and decreased non-cytolytic regulatory NK cells (CD56BrightCD335High, CD56BrightPerforinLow). CD4+ recent thymic emigrants (CD4+CD31+CD45RA+), markers of thymopoeisis, were also significantly decreased in cGvHD (p=0.01) but did not meet all the required biomarker criteria. Evaluation of specific subsets of pediatric cGvHD showed that CD21LowCD19+ B cells were lower in patients with pulmonary (n=12) compared to a mucocutaneous predominant phenotype (n=31) (p=0.048). Cases of progressive cGvHD (n=18), characterized by concurrent acute GvHD features (overlap syndrome), had decreased proportions of CD19 B cells, T3 transitional B cells (CD38LowCD10-) and mature naïve B cells (IgD+CD27-), decreased naïve helper T cells (CCR7+CD4+CD45RA+) and increased activated NK cells (CD56dimCD69+) (all p&amp;lt;0.05). No cellular subsets were associated with the number of organ systems involved with cGvHD or global cGvHD severity according to the NIH-CC. Using a well characterized cohort of pediatric patients with cGvHD, the ABLE / PBTMC 1202 study showed that a variety of subpopulations of naïve helper T cells, Tregs, and regulatory NK cells were associated with cGvHD. Additional B-cell markers were associated with progressive cGvHD in children. These data support alterations in thymopoeisis and decreases in regulatory T- and NK-cell populations underlying pediatric cGvHD. Future work includes the addition of non-cellular plasma markers into a clinically applicable diagnostic biomarker algorithm to aid clinicians in the accurate diagnosis of pediatric cGvHD, as well as further validation in the ABLE 2.0 / Pediatric Transplant Cellular Therapy Consortium 1901 study. Disclosures Wahlstrom: Pharmacyclics: Current Employment. Pulsipher:Mesoblast: Honoraria; Adaptive: Research Funding; Miltenyi: Honoraria, Research Funding; Bellicum: Honoraria; Jasper: Honoraria; Novartis: Honoraria.

Thrombotic Microangiopathy Increases the Risk of Chronic Kidney Disease but Not Overall Mortality in Long-Term Survivors

Introduction: Thrombotic microangiopathy (TMA) is a known complication of allogeneic hematopoietic cell transplantation (HCT). Post-transplant TMA has been associated with acute kidney injury (AKI) and early mortality. However, the long-term kidney outcomes and survival in patients who recover from the disease have not been well characterized. Methods: We performed a retrospective cohort study of adult allogeneic HCT recipients transplanted during 2006-2015 who survived to one-year (index date) and had follow-up at the Long-Term Follow-Up (LTFU) clinic at the Fred Hutchinson Cancer Research Center (FHCRC). Patients were classified as TMA or non-TMA based on whether a diagnosis was made within one-year post-transplant (BBMT 2019;25:570). Outpatient creatinine values obtained during LTFU visits were assessed over time and averaged at the distinct years post-transplant. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula. Chronic kidney disease (CKD) was defined as eGFR &amp;lt;60 mL/min/1.73m2. Potential confounders included pre-HCT eGFR, prior autologous HCT, older age, female sex, black race, myeloablative conditioning (including high-dose total body irradiation), calcineurin/mTOR inhibitor exposure, development of AKI within 6 months, acute graft versus host disease (GVHD) within 6 months, and chronic GVHD within 12 months post-transplant. Pre-transplant hypertension and diabetes were not considered as confounders because they had no known association with TMA development. To assess the association between history of TMA and CKD over time among post-transplant survivors, generalized estimating equation (GEE) was used with exchangeable correlation, binomial family, and logit link, after adjustment for pre-index variables. GEE was chosen to model the longitudinal creatinine outcomes at discrete intervals and to help account for interval missingness. The adjusted odds ratio (OR), 95% confidence interval (CI), robust standard error (SE), and P-values were presented. Unadjusted Kaplan Meier (KM) analysis with landmark at 1 year was used to compare long-term overall survival. Results: Among 2091 patients that underwent first allogeneic HCT, we identified 1151 patients who had survived at least one-year and had available long-term follow-up data (Figure 1). Fifty-seven patients were survivors who had a history of TMA within one-year post-transplant and 1094 did not. Outpatient creatinine data were available in decreasing number of patients each year for the first 5 years post-transplant. The median eGFR over time for the two groups was shown in Figure 2. At one-year post-transplant, 52% of TMA survivors had CKD versus 27% of non-TMA survivors. After adjusting for other potential confounders, a history of TMA was associated with an odds ratio of 2.62 (95% CI 1.25-5.52) for CKD at one-year post-transplant (Table 1). There was no appreciable change in CKD status over time (non-significant interaction for TMA x year). The adjusted covariates had the expected magnitude and significance of association with CKD development, whereas age, pre-transplant eGFR, acute GVHD, and early AKI had the strongest association. While TMA was significantly associated with short-term mortality, there was no association between history of TMA and long-term overall survival in KM analysis landmarked beyond year one, where the conditional 5-year survival was 71% in the TMA survivors and 74% in the non-TMA survivors (log rank P= 0.113). Conclusions: In this study of 1151 post-transplant long-term survivors, we found that TMA survivors had higher risk of CKD post-transplant despite adjusting for key potential confounders. The overall eGFR had the largest decrease between pre-transplant and year-one post-transplant, with non-appreciable variation in subsequent years. While TMA patients were more likely to die early, in those who survived to one-year, their long-term mortality was similar to non-TMA patients. Limitations in the study include the lack of uniform follow-up for all transplant survivors and potentially unobserved confounders. Overall, our data suggest that TMA appears to be a time-limited systemic insult; although its damage to the kidney requires continued monitoring and management. Disclosures Lee: Amgen: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Kadmon: Research Funding; Incyte: Consultancy, Research Funding; Syndax: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Research Funding.

Long-term mortality in survivors of spontaneous intracerebral hemorrhage.

Factors associated with long-term mortality after spontaneous intracerebral hemorrhage (ICH) have been poorly investigated. Our objective was to identify variables associated with long-term mortality in a prospective cohort of 30-day ICH survivors. We prospectively included consecutive 30-day spontaneous ICH survivors. We evaluated baseline and follow-up clinical characteristics and magnetic resonance imaging (MRI) markers of chronic brain injury as variables associated with long-term mortality using univariate and multivariable Cox proportional hazard regression models. Of 560 patients with spontaneous ICH, 304 (54.2%) survived more than 30 days and consented for follow-up. During a median follow-up of 10 years (interquartile range: 8.0-10.5), 176 patients died. The cumulative survival rate at 10 years was 38%. In multivariable analysis, variables independently associated with long-term mortality were age (hazard ratio (HR) per 10-year increase: 1.68, 95% confidence interval (CI): 1.45-1.95), male gender (HR: 1.41, CI: 1.02-1.95), prestroke dependency (HR: 1.66, CI: 1.15-2.39), National Institutes of Health Stroke Scale score (HR per 1-point increase: 1.03, CI: 1.01-1.04), occurrence of any stroke (HR: 2.24, CI: 1.39-3.60), and dementia (HR: 1.51, CI: 1.06-2.16) during follow-up. Among MRI markers, only cerebral atrophy (HR per 1-point increase: 1.50, CI: 1.13-2.00) was independently associated with long-term mortality. Preexisting comorbidities, clinical severity at presentation, and significant clinical event during follow-up are associated with long-term mortality. Among MRI markers of chronic brain injury, only cerebral atrophy is associated with long-term mortality.

A case report and review of the literature: cardiotoxicities after radiotherapy for breast cancer patients with high-risk factors of cardiovascular disease.

Cardiovascular disease (CVD) is an important adverse effect of radiotherapy and is responsible for increased morbidity and mortality in long-term survivors with breast cancer. Patients may have pre-existing cardiovascular risk factors before treatment of breast cancer, and the effects of pre-existing cardiovascular risk factors can be compounded by radiotherapy. We report a case of left breast cancer in a 63-year-old female with a high risk of CVD who was suspected of having radiation-induced myocardium injury 1year after postoperative adjuvant therapy. Radiation oncologists should not only reduce the adverse effects by perfecting radiotherapy technology but also consider reducing other high-risk factors for CVD.

Association between the dietary inflammatory index and all-cause mortality in colorectal cancer long-term survivors.

Pro-inflammatory dietary factors have been shown to be associated with the incidence of a range of cancers. However, there are many fewer studies on the association between the inflammatory potential of diet and survival after cancer diagnosis. We examined the association between post-diagnosis dietary inflammatory index (DII®) scores and all-cause mortality in long-term survivors of colorectal cancer (CRC). DII scores were calculated from dietary data of 1,404 CRC survivors collected at a median of 6 years after CRC diagnosis. Using multivariable-adjusted Cox proportional hazards regression models, hazard ratios (HR) and 95% confidence intervals (CI) were estimated for the association of DII scores, modeled continuous and in quartiles, with all-cause mortality. After a median follow-up time of 7 years (after dietary assessment), 204 study participants had died. Overall, in the fully adjusted model there was a suggestion of a positive association between DII score and all-cause mortality (HRDIIquartile4vs1 : 1.36; 95% CI: 0.88-2.09 and HRDIIcontinuous : 1.08; 95% CI: 0.97-1.20). However, in subgroup analyses, we found significant differences in individuals with metastatic disease (HRDIIcontinuous : 1.34; 95% CI: 1.07-1.67) and the absence of stoma (HRDIIcontinuous : 1.15; 95% CI: 1.02-1.29). Overall, the post-diagnosis DII was not statistically significantly associated with all-cause mortality in CRC long-term survivors; however, there was suggestive evidence of an association in select subgroups.

Genetic Risk of Severe Chronic Graft-Versus-Host Disease Defined By Host-Derived CXCR3 Ligands

IntroductionSevere chronic graft-versus-host disease (cGVHD) is the leading cause of morbidity and mortality in long-term survivors after allogeneic stem cell transplantation (alloSCT). The CXCR3 signalling pathway may be implicated in cGVHD pathophysiology, since CXCR3 and its ligands (CXCL4, CXCL9, CXCL10 and CXCL11) are involved in attracting activated Th1 cells into inflamed tissues. To better understand the role of the CXCR3 axis in cGVHD, we measured serum levels of CXCR3 ligands in allograft recipients pre-transplant and on day 28 post-transplant, and correlated them to the single nucleotide polymorphisms (SNPs) in recipient CXCR3/CXCR3L genes in the context of severe cGVHD.Patients and methods:287 patients who were allografted at Heidelberg University Hospital, survived more than 6 months after alloSCT, and did not receive statin-based endothelial prophylaxis (SEP) constituted the no-SEP training cohort, whereas 401 patients who received SEP constituted the SEP cohort. DNA for genotyping was available for 545 patients (no-SEP 242, SEP 303) and sera for measuring CXCL9, CXCL10 and CXCL11 by ELISA were collected at pre-transplant for 405 patients (no-SEP 109, SEP 296) and at day +28 for 494 patients (no-SEP 152, SEP 342). The no-SEP validation cohort consisted of 202 patients who had been allografted at Berlin Charité and survived more than 6 months. CGVHD was diagnosed and graded using the National Institutes of Health's 2005 consensus criteria.Eighteen SNPs (7 in CXCL9-11, 7 in CXCL4 and 4 in CXCR3 loci) were selected and analyzed for association with severe cGVHD, treating non-relapse death and relapse without severe cGVHD as competing events. Associations of SNPs with serum chemokine levels were studied by Mann-Whitney U-test. Hazard ratios (HR) with 95% confidence interval (CI) were estimated using (cause-specific) Cox regression. Covariates considered in multivariate analysis were age, diagnosis, donor type, sex of donor and recipient and usage of ATG.Results:Overall, 50 of 287 patients (17.4%) in the no-SEP training cohort, 53 of 401 patients (13.2%) in the SEP cohort and 48 of 202 patients (23.8%) in the no-SEP validation cohort developed at least one episode of severe cGVHD. In the no-SEP training cohort, higher serum CXCL9 levels at day +28 were significantly associated with a higher risk of severe cGVHD in univariate analysis (HR 1.38 for every log2-fold change, 95% CI 1.10-1.75, P=0.01; Figure 1a). No significant association was found for serum CXCL10 and CXCL11 pre- or post-transplant with severe cGVHD.The rs884304 SNP in CXCL9-11 locus showed a significant association with severe cGVHD; patients with AA/AG genotypes carried a HR of 2.32 (95%CI 1.21-4.46, P=0.01) compared to patients with GG genotypes. In addition, 3 other SNPs (rs3733236 and rs4282209 in CXCL9-11, rs655328 in CXCL4 loci) were selected based on the effect on severe cGVHD (P <0.10) to calculate a combined genetic risk score. Patients with any low-risk genotypes (rs884304GG, rs3733236AA/AG, rs4282209AA/AG and rs655328TT) were classified as the low-risk. All others were considered as high-risk. Taken together, high-risk patients were found in 21.4% (52/242) of the no-SEP training cohort, 22.4% (68/303) of the SEP cohort and 19.8% (40/202) of the no-SEP validation cohort. Patients in the high-risk group had significantly higher serum CXCL9 levels at day +28 (Figure 1b) and a significantly higher risk of severe cGVHD (Figure 1c) on both univariate (HR 2.68, 95%CI 1.45-4.95, P=0.001) and multivariate analyses (HR 2.49, 95%CI 1.33-4.66, P=0.004). The effect of the combined score was confirmed in the no-SEP validation cohort (HR 3.02, 95%CI 1.60-5.72, P=0.001).In contrast, in the SEP cohort the adverse effect of high risk genotypes was not observed (HR 1.30, 95% CI 0.60-2.79, P=0.50). In addition, SEP reduced day +28 CXCL9 levels in patients with high-risk genotype but not in low-risk patients.Conclusion:In the absence of SEP, the risk of severe cGVHD could be predicted both by a genetic score of 4 SNPs in recipient CXCR3L genes and by serum CXCL9 levels at day +28. The genetic score influenced serum CXCL9 levels at day +28. Our results suggest that in high-risk patients, host-derived CXCR3 ligands are upregulated early after alloSCT and may promote the development of severe cGVHD. Endothelial prophylaxis may reduce the risk of severe cGVHD by regulating serum CXCL9 levels and, thus, warrants further study. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Topoisomerases and Anthracyclines: Recent Advances and Perspectives in Anticancer Therapy and Prevention of Cardiotoxicity.

Topoisomerases are ubiquitous enzymes involved in maintaining genomic stability of the cell by regulating the over- or underwinding of DNA strands. Besides their customary functions, topoisomerases are important cellular targets of widely used anticancer drugs. In particular, topoisomerase IIα (Top2α) has been postulated as the primary molecular target of anthracycline's anticancer activity, whereas topoisomerase IIβ (Top2β), the only Top2 present in heart tissue, seems to be involved in the development of anthracycline-induced cardiotoxicity. Noteworthy, cardiotoxicity is the most frequent adverse effect of both conventional and modern anticancer targeted therapy, representing the leading noncancer-related cause of morbidity and mortality in long-term survivors. The molecular mechanisms of anthracyclineinduced cardiotoxicity have been investigated for decades and, despite the numerous mechanistic hypotheses put forward, its aetiology and pathogenesis still remain controversial. This review is aimed at focusing on the double edge sword of topoisomerase-anthracycline interaction, and, in particular, on the potential role of topoisomerases in anthracyclines anticancer activity as well as in the pathogenesis of anthracycline-induced cardiotoxicity.

Sepsis: frontiers in diagnosis, resuscitation and antibiotic therapy.

Sepsis is a major growing global burden and a major challenge to intensive care clinicians, researchers, guideline committee members and policy makers, because of its high and increasing incidence and great pathophysiological, molecular, genetic and clinical complexity. In spite of recent progress, short-term mortality remains high and there is growing evidence of long-term morbidity and increased long-term mortality in survivors of sepsis both in developed and developing countries. Further improvement in the care of patients with sepsis will impact upon global health. In this narrative review, invited experts describe the expected challenges and progress to be made in the near future. We focus on diagnosis, resuscitation (fluids, vasopressors, inotropes, blood transfusion and hemodynamic targets) and infection (antibiotics and infection biomarkers), as these areas are key, if initial management and subsequent outcomes are to be improved in patients with sepsis.

Impact of a lifestyle modification program on the metabolic syndrome and associated risk factors in long-term survivors of stem cell transplantation.

Cardiovascular disease is a major cause of late morbidity and increased mortality in long-term survivors of haematological malignancy treated with stem cell transplantation (SCT).1, 2 The metabolic syndrome (MetS), a clustering of risk factors for cardiovascular disease, occurs frequently after SCT.3, 4 Lifestyle intervention is effective in reducing the occurrence of MetS and its components in both general population cohorts5 and survivors of non-haematological cancers,6 however, effectiveness following SCT is not established. This prospective pilot study aimed to assess the effectiveness of a 12-month lifestyle intervention program on reducing the number and/or severity of MetS risk factors in long-term survivors of SCT.

Risk of secondary solid malignancies after allogeneic hematopoietic stem cell transplantation and preventive strategies.

The risk of secondary solid malignancies is increased after allogeneic hematopoietic stem cell transplantation (HSCT). The risk starts at about 10 years after HSCT and continues even 20 years later. The most common secondary malignancies include squamous cell carcinoma of skin, genitourinary tract and oral cavity; lung and breast cancers. The use of total body irradiation or conditioning chemotherapy, chronic graft-versus-host disease and duration since HSCT can influence the risk of secondary solid malignancies. Secondary solid malignancies are common causes of nonrelapse mortality in long-term survivors and may account for up to 10% of late deaths. Avoiding smoking, alcohol use and excess sun exposure may reduce the risk. Cancer prevention guidelines are largely consensus-driven and follow the recommendations for general population.

Radiation-induced coronary artery disease: a second survivorship challenge?

10.2217/FON.15.121 © 2015 Future Medicine Ltd The role of adjuvant mediastinal radiation (RT) in improving disease-free survival in Hodgkin’s disease and breast cancer (BC) is well known. However, this survival advantage is accompanied by the late cardiac sequelae of radiation. Radiationinduced coronary artery disease (RICAD) is a challenging clinical entity and a major contributor to cardiovascular (CV) mortality in cancer survivors. In this review, we discuss the pathophysiology, surveillance and management challenges of RICAD.

Survival in South Asian and White European patients after acute myocardial infarction

ObjectiveTo examine the association between ethnicity and survival following acute myocardial infarction (AMI) in White European (WE) and South Asian (SA) patients from a multiethnic UK population.MethodsRetrospective, cohort study of...