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BACKGROUND/PURPOSE - Wilms tumor (WT) poses a cancer health disparity to black children globally, which has not been evaluated thoroughly for other pediatric renal cancers. We aimed to characterize health disparities among Tennessee children treated for any renal cancer.
METHODS - The Tennessee Cancer Registry (TCR) was queried for patients ≤18 years having any renal cancer (n = 160). To clarify treatment and outcomes, we performed a retrospective cohort study of pediatric renal cancer patients in our institutional cancer registry (ICR; n = 121). Diagnoses in both registries included WT, Sarcoma/Other, and Renal Cell Carcinoma. Wilcoxon/Pearson, Kaplan-Meier, and logistic regression were completed.
RESULTS - In both registries, WT comprised the most common renal cancer and youngest median age. Sarcoma was intermediate in frequency and age, and RCC was least common, having the oldest age (p < 0.001). In the TCR, black patients comprised 26% of all patients, presented more commonly with distant disease than white patients (37% v. 16%; p = 0.021), and showed worse overall survival (73% v. 89%; p = 0.018), while the ICR showed similar survival between race groups (92% v. 93%, p = 0.868). Sarcoma and metastases were independent predictors of death in both registries (p ≤ 0.002).
CONCLUSIONS - Black children in Tennessee presented with more advanced disease and experienced worse survival when combining all renal cancer types, particularly RCC and Sarcoma. When treated at a comprehensive pediatric cancer center, these survival disparities appear diminished.
TYPE OF STUDY - Prognostic study.
LEVEL OF EVIDENCE - Level II (retrospective cohort).
Copyright © 2020 Elsevier Inc. All rights reserved.
BACKGROUND - Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare variants implicated in LQT5 was sought through an international multicenter collaboration.
METHODS - Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death.
RESULTS - A total of 32 distinct rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, <0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], =0.590). The cumulative prevalence of the 32 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%).
CONCLUSIONS - The present study suggests that putative/confirmed loss-of-function variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.
OBJECTIVE - We describe the risk factors for peri-procedural and spontaneous arterial ischemic stroke (AIS) in children with cardiac disease.
METHODS - We identified children with cardiac causes of AIS enrolled in the International Pediatric Stroke Study registry from January 2003 to July 2014. Isolated patent foramen ovale was excluded. Peri-procedural AIS (those occurring during or within 72 hours of cardiac surgery, cardiac catheterization, or mechanical circulatory support) and spontaneous AIS that occurred outside of these time periods were compared.
RESULTS - We identified 672 patients with congenital or acquired cardiac disease as the primary risk factor for AIS. Among these, 177 patients (26%) had peri-procedural AIS and 495 patients (74%) had spontaneous AIS. Among non-neonates, spontaneous AIS occurred at older ages (median 4.2 years, interquartile range 0.97 to 12.4) compared with peri-procedural AIS (median 2.4 years, interquartile range 0.35 to 6.1, P < 0.001). About a third of patients in both groups had a systemic illness at the time of AIS. Patients who had spontaneous AIS were more likely to have a preceding thrombotic event (16 % versus 9 %, P = 0.02) and to have a moderate or severe neurological deficit at discharge (67% versus 33%, P = 0.01) compared to those with peri-procedural AIS.
CONCLUSIONS - Children with cardiac disease are at risk for AIS at the time of cardiac procedures but also outside of the immediate 72 hours after procedures. Many have acute systemic illness or thrombotic event preceding AIS, suggesting that inflammatory or prothrombotic conditions could act as a stroke trigger in this susceptible population.
Copyright © 2019 Elsevier Inc. All rights reserved.
BACKGROUND - Civilian penetrating traumatic brain injury (pTBI) is a serious public health problem in the United States, but predictors of outcome remain largely understudied. We previously developed the Survival After Acute Civilian Penetrating Brain Injuries (SPIN) score, a logistic, regression-based risk stratification scale for estimating in-hospital and 6-mo survival after civilian pTBI with excellent discrimination (area under the receiver operating curve [AUC-ROC = 0.96]) and calibration, but it has not been validated.
OBJECTIVE - To validate the SPIN score in a multicenter cohort.
METHODS - We identified pTBI patients from 3 United States level-1 trauma centers. The SPIN score variables (motor Glasgow Coma Scale [mGCS], sex, admission pupillary reactivity, self-inflicted pTBI, transfer status, injury severity score, and admission international normalized ratio [INR]) were retrospectively collected from local trauma registries and chart review. Using the original SPIN score multivariable logistic regression model, AUC-ROC analysis and Hosmer-Lemeshow goodness of fit testing were performed to determine discrimination and calibration.
RESULTS - Of 362 pTBI patients available for analysis, 105 patients were lacking INR, leaving 257 patients for the full SPIN model validation. Discrimination (AUC-ROC = 0.88) and calibration (Hosmer-Lemeshow goodness of fit, P value = .58) were excellent. In a post hoc sensitivity analysis, we removed INR from the SPIN model to include all 362 patients (SPINNo-INR), still resulting in very good discrimination (AUC-ROC = 0.82), but reduced calibration (Hosmer-Lemeshow goodness of fit, P value = .04).
CONCLUSION - This multicenter pTBI study confirmed that the full SPIN score predicts survival after civilian pTBI with excellent discrimination and calibration. Admission INR significantly adds to the prediction model discrimination and should be routinely measured in pTBI patients.
Copyright © 2019 by the Congress of Neurological Surgeons.
Background and Purpose- Sickle cell disease (SCD) and arteriopathy are pediatric stroke risk factors that are not mutually exclusive. The relative contributions of sickled red blood cells and arteriopathy to stroke risk are unknown, resulting in unclear guidelines for primary and secondary stroke prevention when both risk factors are present. We hypothesized that despite similarities in clinical presentation and radiographic appearance of arteriopathies, stroke evaluation and management differ in children with SCD compared with those without SCD. Methods- We compared presentation and management of children with and without SCD enrolled in the IPSS (International Pediatric Stroke Study) with acute arterial ischemic stroke, according to SCD and arteriopathy status. Regression modeling determined relative contribution of SCD and arteriopathy in variables with significant frequency differences. Results- Among 930 childhood arterial ischemic strokes, there were 98 children with SCD, 67 of whom had arteriopathy, and 466 without SCD, 392 of whom had arteriopathy. Arteriopathy, regardless of SCD status, increased likelihood of hemiparesis (odds ratio [OR], 1.94; 95% CI, 1.46-2.56) and speech abnormalities (OR, 1.67; 95% CI, 1.29-2.19). Arteriopathy also increased likelihood of headache but only among those without SCD (OR, 1.89; 95% CI, 1.40-2.55). Echocardiograms were less frequently obtained in children with SCD (OR, 0.58; 95% CI, 0.37-0.93), but the frequency of identified cardiac abnormalities was similar in both groups ( P=0.57). Children with SCD were less likely to receive antithrombotic therapy, even in the presence of arteriopathy (OR, 0.14; 95% CI, 0.08-0.22). Arteriopathy was associated with a significantly higher likelihood of antithrombotic therapy in children without SCD (OR, 5.36; 95% CI, 3.55-8.09). Conclusions- Arteriopathy, and not SCD status, was most influential of stroke presentation. However, SCD status influenced stroke management because children with SCD were less likely to have echocardiograms or receive antithrombotic therapy. Further work is needed to determine whether management differences are warranted.
BACKGROUND - Influenza vaccination (FV) is recommended for patients with cancer. Recent data suggested that the administration of the FV was associated with an increase in immune-related adverse events (irAEs) among patients on immune checkpoint inhibitors (ICIs). Myocarditis is an uncommon but serious complication of ICIs and may also result from infection with influenza. There are no data testing the relationship between FV and the development of myocarditis on ICIs.
METHODS - Patients on ICIs who developed myocarditis (n = 101) (cases) were compared to ICI-treated patients (n = 201) without myocarditis (controls). A patient was defined as having the FV if they were administered the FV from 6 months prior to start of ICI to anytime during ICI therapy. Alternate thresholds for FV status were also tested. The primary comparison of interest was the rate of FV between cases and controls. Patients with myocarditis were followed for major adverse cardiac events (MACE), defined as the composite of cardiogenic shock, cardiac arrest, hemodynamically significant complete heart block and cardiovascular death.
RESULTS - The FV was administered to 25% of the myocarditis cases compared to 40% of the non-myocarditis ICI-treated controls (p = 0.01). Similar findings of lower rates of FV administration were noted among myocarditis cases when alternate thresholds were tested. Among the myocarditis cases, those who were vaccinated had 3-fold lower troponin levels when compared to unvaccinated cases (FV vs. No FV: 0.12 [0.02, 0.47] vs. 0.40 [0.11, 1.26] ng/ml, p = 0.02). Within myocarditis cases, those administered the FV also had a lower rate of other irAEs when compared to unvaccinated cases (36 vs. 55% p = 0.10) including lower rates of pneumonitis (12 vs. 36%, p = 0.03). During follow-up (175 [IQR 89, 363] days), 47% of myocarditis cases experienced a MACE. Myocarditis cases who received the FV were at a lower risk of cumulative MACE when compared to unvaccinated cases (24 vs. 59%, p = 0.002).
CONCLUSION - The rate of FV among ICI-related myocarditis cases was lower than controls on ICIs who did not develop myocarditis. In those who developed myocarditis related to an ICI, there was less myocardial injury and a lower risk of MACE among those who were administered the FV.
BACKGROUND - Embryonal tumors arise typically in infants and young children and are often massive at presentation. Operative resection is a cornerstone in the multimodal treatment of embryonal tumors but potentially disrupts therapeutic timelines. When used appropriately, minimally invasive surgery can minimize treatment delays. The oncologic integrity and safety attainable with minimally invasive resection of embryonal tumors, however, remains controversial.
METHODS - Query of the Vanderbilt Cancer Registry identified all children treated for intracavitary, embryonal tumors during a 15-year period. Tumors were assessed radiographically to measure volume (mL) and image-defined risk factors (neuroblastic tumors only) at time of diagnosis, and at preresection and postresection. Patient and tumor characteristics, perioperative details, and oncologic outcomes were compared between minimally invasive surgery and open resection of tumors of comparable size.
RESULTS - A total of 202 patients were treated for 206 intracavitary embryonal tumors, of which 178 were resected either open (n = 152, 85%) or with minimally invasive surgery (n = 26, 15%). The 5-year, relapse-free, and overall survival were not significantly different after minimally invasive surgery or open resection of tumors having a volume less than 100 mL, corresponding to the largest resected with minimally invasive surgery (P = .249 and P = .124, respectively). No difference in margin status or lymph node sampling between the 2 operative approaches was detected (p = .333 and p = .070, respectively). Advantages associated with minimally invasive surgery were decreased blood loss (P < .001), decreased operating time (P = .002), and shorter hospital stay (P < .001). Characteristically, minimally invasive surgery was used for smaller volume and earlier stage neuroblastic tumors without image-defined risk factors.
CONCLUSION - When selected appropriately, minimally invasive resection of pediatric embryonal tumors, particularly neuroblastic tumors, provides acceptable oncologic integrity. Large tumor volume, small patient size, and image-defined risk factors may limit the broader applicability of minimally invasive surgery.
Copyright © 2018 Elsevier Inc. All rights reserved.
PURPOSE - The identification of biomarkers related to the prognosis of triple-negative breast cancer (TNBC) is critically important for improved understanding of the biology that drives TNBC progression.
METHODS - We evaluated gene expression in total RNA isolated from formalin-fixed paraffin-embedded tumor samples using the NanoString nCounter assay for 469 TNBC cases from the Shanghai Breast Cancer Survival Study. We used Cox regression to quantify Hazard Ratios (HR) and corresponding confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS) in models that included adjustment for breast cancer intrinsic subtype. Of 302 genes in our discovery analysis, 22 were further evaluated in relation to OS among 134 TNBC cases from the Nashville Breast Health Study and the Southern Community Cohort Study; 16 genes were further evaluated in relation to DFS in 335 TNBC cases from four gene expression omnibus datasets. Fixed-effect meta-analysis was used to combine results across data sources.
RESULTS - Twofold higher expression of EOMES (HR 0.90, 95% CI 0.83-0.97), RASGRP1 (HR 0.89, 95% CI 0.82-0.97), and SOD2 (HR 0.80, 95% CI 0.66-0.96) was associated with better OS. Twofold higher expression of EOMES (HR 0.89, 95% CI 0.81-0.97) and RASGRP1 (HR 0.87, 95% CI 0.81-0.95) was also associated with better DFS. On the contrary, a doubling of FA2H (HR 1.14, 95% CI 1.06-1.22) and GSPT1 (HR 1.33, 95% CI 1.14-1.55) expression was associated with shorter DFS.
CONCLUSIONS - We identified five genes (EOMES, FA2H, GSPT1, RASGRP1, and SOD2) that may serve as potential prognostic biomarkers and/or therapeutic targets for TNBC.
BACKGROUND - Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized.
OBJECTIVES - The authors sought to understand the presentation and clinical course of ICI-associated myocarditis.
METHODS - After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block.
RESULTS - The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates.
CONCLUSIONS - Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.
Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
OBJECTIVES - Sleep has physiological and behavioral impacts on diabetes outcomes, yet little is known about the impact of sleep disturbances in children with type 1 diabetes. The current study sought to characterize sleep in children with type 1 diabetes and in their parents and to examine the associations between child sleep, glycemic control and adherence, parent sleep and well-being, parental fear of hypoglycemia, and nocturnal caregiving behavior.
METHODS - Surveys were emailed to parents of 2- to 12-year-old participants in the Type 1 Diabetes (T1D) Exchange clinic registry. Clinical data were obtained from the registry for the 515 respondents.
RESULTS - In our sample, 67% of children met criteria for poor sleep quality. Child sleep quality was related to glycemic control (HbA1c of 7.9% [63 mmol/mol] in children with poor sleep quality vs 7.6% [60 mmol/mol] in children with non-poor sleep quality; P < 0.001) but not mean frequency of blood glucose monitoring (BGM) (7.6 times/day vs 7.4 in poor/non-poor quality; P = 0.56). Associations were similar for sleep duration. Children with poor sleep quality were more likely to experience severe hypoglycemia (4% in children with poor sleep quality vs 1% in children with non-poor sleep quality; P = 0.05) and more likely to experience DKA (7% vs 4%, respectively; P < 0.001). Poorer child sleep quality was associated with poorer parental sleep quality, parental well-being, and fear of hypoglycemia (P < 0.001 for all). Child sleep was not related to the use of diabetes-related technology (CGM, insulin pump).
CONCLUSIONS - Sleep may be a modifiable factor to improve glycemic control and reduce parental distress.
Copyright © 2017 Elsevier B.V. All rights reserved.