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Jinli Wang,1,2,* Min Jeong Seo,1,* Michael B Deci,1 Brian R Weil,3 John M Canty,3,4 Juliane Nguyen1,2 1Department of Pharmaceutical Sciences, School of Pharmacy, University at Buffalo, The State University of New York, Buffalo, NY, USA; 2Department of Biomedical Engineering, University at Buffalo, The State University of New York, Buffalo, NY, USA; 3Department of Medicine, Department of Physiology and Biophysics, Department of Biomedical Engineering, The Clinical and Translational Research Center, University at Buffalo, Buffalo, NY, USA; 4VA Western New York Healthcare System, Buffalo, NY, USA *These authors contributed equally to this work Background: After myocardial infarction (MI), inflammatory cells infiltrate the infarcted heart in response to secreted stimuli. Monocytes are recruited to the infarct via CCR2 chemokine receptors along a CCL2 concentration gradient. While infiltration of injured tissue with monocytes is an important component of the reparatory response, excessive or prolonged inflammation can adversely affect left ventricular remodeling and worsen clinical outcomes.Materials and methods: Here, we developed poly(ethylene glycol) (PEG)-distearoylphosphatidylethanolamine (PEG-DSPE) micelles loaded with a small molecule CCR2 antagonist to inhibit monocyte recruitment to the infarcted myocardium. To specifically target CCR2-expressing cells, PEG-DSPE micelles were further surface decorated with an anti-CCR2 antibody.Results: Targeted PEG-DSPE micelles showed eight-fold greater binding to CCR2-expressing RAW 264.7 monocytes than plain, non-targeted PEG-DSPE micelles. In a mouse model of MI, CCR2-targeting PEG-DSPE micelles loaded with a CCR2 small molecule antagonist significantly decreased the number of Ly6Chigh inflammatory cells to 3% of total compared with PBS-treated controls. Furthermore, CCR2-targeting PEG-DSPE micelles significantly reduced the infarct size based on epicardial and endocardial infarct arc lengths.Conclusion: Both non-targeted and CCR2-targeting PEG-DSPE micelles showed a trend toward improving cardiac function. As such, PEG-DSPE micelles represent a promising cardiac therapeutic platform. Keywords: CCR2, inflammatory monocytes, micelles, myocardial infarction

Deficits in endothelial cell repair mechanisms are thought to contribute to the aetiology of endothelial dysfunction and, subsequently, cardiovascular disease (CVD). CD31(+) T cells or so-called "angiogenic T cells" are a newly defined T cell subset that exhibit favourable vascular qualities and show a strong negative relation with atherosclerotic disease severity. Despite growing evidence that CD31(+) T cells are important for vascular homeostasis, it is currently unknown if CD31(+) T cell number and function are related to endothelial function and CVD risk in healthy adults. To address this question, we studied 24 healthy adult men (ages: 21-70). Endothelial function was assessed by the forearm blood flow (FBF) response to intra-arterial infusion of acetylcholine (ACh) and CVD risk was estimated by Framingham Risk Score (FRS). CD31(+) T cell number was determined by fluorescence-activated cell sorting. Magnetic-activated cell sorting was used to isolate CD31(+) T cells for Boyden chamber migration. No relation was observed between CD31(+) T cell number and FBF response to ACh or FRS. However, CD31(+) T cell migration to stromal cell-derived factor (SDF)-1α and vascular endothelial growth factor (VEGF) was positively correlated with FBF response to ACh (r = 0.43 for SDF-1α; r = 0.38 for VEGF; both P<0.05) and inversely related to FRS (r = -0.53 for SDF-1α; r = -0.48 for VEGF; both P<0.05). These findings demonstrate that CD31(+) T cell function, but not number, is associated with in vivo endothelial function and CVD risk in healthy adult men. [ABSTRACT FROM AUTHOR]

Background: Children living in poverty and those of marginalized race or ethnicity experience inferior disease outcomes across many cancers. Whether survival disparities exist in osteosarcoma is poorly defined. We investigated the association between race, ethnicity, and proxied poverty exposures and event-free and overall survival for children with nonmetastatic osteosarcoma receiving care on a cooperative group trial., Methods: We conducted a retrospective cohort study of US patients with nonmetastatic, osteosarcoma aged 5-21 years enrolled on the Children's Oncology Group trial AOST0331. Race and ethnicity were categorized to reflect historically marginalized populations, as Hispanic, non-Hispanic Black, non-Hispanic Other, and non-Hispanic White. Poverty was proxied at the household and neighborhood levels. Overall survival and event-free survival functions of time from trial enrollment were estimated using the Kaplan-Meier method. Hypotheses of associations between risks for event-free survival, death, and postrelapse death with race and ethnicity were assessed using log-rank tests., Results: Among 758 patients, 25.6% were household-poverty and 28.5% neighborhood-poverty exposed. Of the patients, 21% of children identified as Hispanic, 15.4% non-Hispanic Black, 5.3% non-Hispanic Other, and 54.0% non-Hispanic White. Neither household or neighborhood poverty nor race and ethnicity were statistically significantly associated with risks for event-free survival or death. Postrelapse risk for death differed statistically significantly across race and ethnicity with non-Hispanic Black patients at greatest risk (4-year postrelapse survival 35.7% Hispanic vs 13.0% non-Hispanic Black vs 43.8% non-Hispanic Other vs 38.9% non-Hispanic White; P = .0046)., Conclusions: Neither proxied poverty exposures or race and ethnicity were associated with event-free survival or overall survival, suggesting equitable outcomes following frontline osteosarcoma trial-delivered therapy. Non-Hispanic Black children experienced statistically significant inferior postrelapse survival. Investigation of mechanisms underlying postrelapse disparities are paramount., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Congenital proximal renal tubular acidosis (pRTA) is a rare systemic disease caused by mutations in the SLC4A4 gene that encodes the electrogenic sodium bicarbonate cotransporter, NBCe1. The major NBCe1 protein variants are designated NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A expression is kidney-specific, NBCe1-B is broadly expressed and is the only NBCe1 variant expressed in the heart, and NBCe1-C is a splice variant of NBCe1-B that is expressed in the brain. No cardiac manifestations have been reported from patients with pRTA, but studies in adult rats with virally induced reduction in cardiac NBCe1-B expression indicate that NBCe1-B loss leads to cardiac hypertrophy and prolonged QT intervals in rodents. NBCe1-null mice die shortly after weaning, so the consequence of congenital, global NBCe1 loss on the heart is unknown. To circumvent this issue, we characterized the cardiac function of NBCe1-B/C-null (KO b/c ) mice that survive up to 2 months of age and which, due to the uninterrupted expression of NBCe1-A, do not exhibit the confounding acidemia of the globally null mice. In contrast to the viral knockdown model, cardiac hypertrophy was not present in KO b/c mice as assessed by heart-weight-to-body-weight ratios and cardiomyocyte cross-sectional area. However, echocardiographic analysis revealed reduced left ventricular ejection fraction, and intraventricular pressure-volume measurements demonstrated reduced load-independent contractility. We also observed increased QT length variation in KO b/c mice. Finally, using the calcium indicator Fura-2 AM, we observed a significant reduction in the amplitude of Ca 2+ transients in paced KO b/c cardiomyocytes. These data indicate that congenital, global absence of NBCe1-B/C leads to impaired cardiac contractility and increased QT length variation in juvenile mice. It remains to be determined whether the cardiac phenotype in KO b/c mice is influenced by the absence of NBCe1-B/C from neuronal and endocrine tissues.

Germ cell tumors (GCT) are a complex, heterogeneous collection of tumors that may present in either gonadal or extragonadal sites. They consist of a variety of benign and malignant histologies that can occur at several locations throughout the body. An important component of treatment is surgical resection, and while the key components of resection are site specific, the universal goals of GCT resection include the complete resection of tumor without violating the tumor capsule, while preserving function of surrounding organs, minimizing morbidity, and assessing for regional spread., (© 2024 Wiley Periodicals LLC.)

Background: Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences has not been well described., Methods: Late mortality, subsequent malignant neoplasms (SMNs), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year Childhood Cancer Survivor Study (CCSS) survivors of neuroblastoma diagnosed 1987-1999. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n = 425]; intermediate [n = 252]; high [n = 245]). Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) of SMNs were compared with matched population controls. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals for CHC compared with 1029 CCSS siblings., Results: Among survivors (49.8% male; median age = 21 years, range = 7-42; median follow-up = 19.3 years, range = 5-29.9), 80% with low-risk disease were treated with surgery alone, whereas 79.1% with high-risk disease received surgery, radiation, chemotherapy ± autologous stem cell transplant (ASCT). All-cause mortality was elevated across risk groups (SMRhigh = 27.7 [21.4-35.8]; SMRintermediate = 3.3 [1.7-6.5]; SMRlow = 2.8 [1.7-4.8]). SMN risk was increased among high- and intermediate-risk survivors (SIRhigh = 28.0 [18.5-42.3]; SIRintermediate = 3.7 [1.2-11.3]) but did not differ from the US population for survivors of low-risk disease. Compared with siblings, survivors had an increased risk of grade 3-5 CHCs, particularly among those with high-risk disease (HRhigh = 16.1 [11.2-23.2]; HRintermediate = 6.3 [3.8-10.5]; HRlow = 1.8 [1.1-3.1])., Conclusion: Survivors of high-risk disease treated in the early days of risk stratification carry a markedly elevated burden of late recurrence, SMN, and organ-related multimorbidity, whereas survivors of low/intermediate-risk disease have a modest risk of late adverse outcomes., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss of MSH2. Through the use of patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation of colonic and brain organoids from reprogrammed EPCAM del iPSC derived from patient fibroblasts. Differentiation of iPSC to epithelial-colonic organoids exhibited continuous increased EPCAM expression and hypermethylation of the MSH2 promoter. This was associated with loss of MSH2 expression, increased mutational burden, MMRD signatures and MS-indel accumulation, the hallmarks of MMRD. In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients., (© 2024. The Author(s).)

Diastolic dysfunction arising from alterations in myocardial structure and/or function is a central component of several cardiovascular disorders, including heart failure with preserved ejection fraction (HFpEF). Basic research aimed at understanding underlying mechanisms contributing to the development of diastolic dysfunction has generally centered upon models of left ventricular (LV) hypertrophy arising from persistent and severe elevations in myocardial afterload (e.g., aortic banding). Mechanisms of hypertrophy-independent diastolic dysfunction, on the other hand, have received less attention, even though overt anatomic LV hypertrophy is absent in many HFpEF patients. Here, we describe the development of a novel porcine model of repetitive pressure overload (RPO) in which chronic, intermittent exposure to transient episodes of hypertension produces an increase in LV stiffness, interstitial fibrosis, cardiomyocyte hypertrophy, and capillary rarefaction without significant changes in LV mass. This model offers important insight into how diastolic dysfunction and HFpEF may develop in the absence of comorbidities, sustained hypertension, or LV hypertrophy, while also providing a useful translational research tool for investigation of novel therapeutic approaches to restore myocardial compliance and improve diastolic function., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Lymphovascular invasion (LVI) has been identified as a poor prognostic factor for a variety of tumors; however, its significance in malignant ovarian germ cell tumors (MOGCT) in pediatric and adolescent patients is not well described. We aim to clarify the significance of LVI in the subset of patients with nongerminomatous MOGCT., Methods: Records of patients 0-20 years of age with MOGCT enrolled on Children's Oncology Group study AGCT0132 were reviewed. Patients with documented presence or absence of LVI in either institutional or central review pathology reports were included., Results: Of 130 patients with MOGCTs, 83 patients had of the presence or absence of LVI documented in their pathology report. 42/83 patients (50.6%) were found to have LVI present. The estimated odds of having LVI was higher in patients with stage II and III disease, 11 years and older and with the presence of choriocarcinoma. Event-free survival (EFS) and overall survival (OS) remained high in patients with LVI. Approximately 50% of patients with a documented LVI status in either institutional pathology report or central review were found to have LVI., Conclusions: The presence of LVI was higher in tumors with adverse risk factors including higher stage and age greater than 11 years. While LVI was not associated with EFS or OS in the intermediate risk group, further work is necessary to determine the effect of LVI on long-term disease-free survival. We, therefore, recommend routinely incorporating LVI status into institutional pathology reports for pediatric and adolescent patients with MOGCT., Level of Evidence: III., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Chyle leaks are a common post-operative complication following solid-tumor resection in pediatric patients. Current treatments for persistent chyle leaks are limited, leading many patients to experience prolonged hospitalization, nutritional deficits and/or delays in cancer therapies. Lymphatic embolization is an emerging treatment option for chyle leaks, however, limited reports exist of its use in pediatric populations., Methods: We conducted a retrospective review of pediatric patients (<18) who underwent lymphangiogram with intent for lymphatic embolization for the management of chyle leaks following solid-tumor resection between 2017 and 2022., Results: Seven patients underwent a total of 11 attempted lymphatic embolization procedures after current standard of care treatments failed to resolve the leak. Lymphangiograms identified a chyle leak in 6 of 7 patients and embolization had a technical success rate of 73%. The complication rate was 9% and complications were limited to one episode of inadvertent gastric wall perforation that did not result in a gastric leak. Lymphatic embolization was ultimately associated with chyle leak resolution in 100% of patients within a median of 24 days, however, repeat embolization was required in 5 of 7 patients (83%)., Conclusion: Lymphatic embolization appears to be a safe and effective treatment for persistent chyle leaks in pediatric patients, leads to a direction reduction in chyle output, and has high rates of technical and clinical success. Complete resolution of the chyle leak may require multiple embolization procedures. Further work is needed to determine whether earlier intervention may offer benefit for the management of pediatric chyle leaks., Level of Evidence: IV., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Vascular dysfunction is a common cause of cardiovascular diseases characterized by the narrowing and stiffening of arteries, such as atherosclerosis, restenosis, and hypertension. Arterial narrowing results from the aberrant proliferation of vascular smooth muscle cells (VSMCs) and their increased synthesis and deposition of extracellular matrix (ECM) proteins. These, in turn, are modulated by arterial stiffness, but the mechanism for this is not fully understood. We found that survivin is an important regulator of stiffness-mediated ECM synthesis and intracellular stiffness in VSMCs. Whole-transcriptome analysis and cell culture experiments showed that survivin expression is upregulated in injured femoral arteries in mice and in human VSMCs cultured on stiff fibronectin-coated hydrogels. Suppressed expression of survivin in human VSMCs significantly decreased the stiffness-mediated expression of ECM components related to arterial stiffening, such as collagen-I, fibronectin, and lysyl oxidase. By contrast, expression of these ECM proteins was rescued by ectopic expression of survivin in human VSMCs cultured on soft hydrogels. Interestingly, atomic force microscopy analysis showed that suppressed or ectopic expression of survivin decreases or increases intracellular stiffness, respectively. Furthermore, we observed that inhibiting Rac and Rho reduces survivin expression, elucidating a mechanical pathway connecting intracellular tension, mediated by Rac and Rho, to survivin induction. Finally, we found that survivin inhibition decreases FAK phosphorylation, indicating that survivin-dependent intracellular tension feeds back to maintain signaling through FAK. These findings suggest a novel mechanism by which survivin potentially modulates arterial stiffness., Competing Interests: The authors have no conflicts to disclose., (© 2023 Author(s).)

Performance of the appropriate operation is highly important to ensure that any patient with a suspected ovarian germ cell tumor receives optimal therapy that prioritizes cure while simultaneoulsy minimizing risk of short and long-term toxicities of treatment. The following critical elements of any operative procedure performed for a suspected pediatric or adolescent ovarian germ cell tumor are reviewed: 1. Complete resection of the tumor via ipsilateral oophorectomy while avoiding tumor rupture and spillage, and 2. Performance of complete intraperitoneal staging at the time of initial tumor resection., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: One-third of children and young adults admitted for management of acute severe colitis (ASC) fail intravenous corticosteroids. Infliximab (IFX) or tacrolimus (TAC) is often used to prevent urgent colectomy in these patients. However, no prior studies have reviewed the outcome of pediatric patients with ASC who were treated with either IFX or TAC., Methods: We retrospectively identified 170 pediatric patients with ASC admitted to our institution who did not respond to intravenous corticosteroids and were subsequently treated with either IFX or TAC. We compared 6-month colectomy rates, time to colectomy, improvement in disease activity indices, and adverse effects., Results: The mean age of patients in the IFX (n = 84) and TAC (n = 86) groups were 14 and 13.8 years, respectively. The median study follow-up time was 23 months. The rate of colectomy 6 months from rescue therapy was similar whether patients received IFX or TAC (22.6% vs 26.7%, respectively, P = 0.53). The mean decline in Pediatric Ulcerative Colitis Activity Index scores from admission to discharge in those treated with IFX (31.9) or TAC (29.8) was similar (P = 0.63). Three patients treated with IFX experienced infusion reactions. Six patients treated with TAC experienced changes in renal function or electrolytes, and 4 patients reported neurologic symptoms., Conclusions: There were no significant differences in the likelihood of colectomy 6 months after initiating IFX or TAC rescue therapy. Efficacy of both agents was comparable. The types of adverse effects differed by therapy. These data support the use of either TAC or IFX in children with ASC refractory to intravenous corticosteroids., Competing Interests: J.M.Z. is a consultant for Takeda. Dr Bousvaros is a consultant for Arena, Takeda, Best Doctors, and Eli Lilly and receives research support from Prometheus, Janssen, Abbvie, Takeda, Buhlmann, Arena, and Eli Lilly. P.A.R. is a consultant for Abbvie, Daiichi Sankyo, and Very Well and receives research support from TechLab and IBD4Cure. The remaining authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Pediatric interventional oncology (PIO) is a growing field intended to provide additional or alternative treatment options for pediatric patients with benign or malignant tumors. Large series of patients treated uniformly and subjected to rigorous endpoints for efficacy are not available., Methods: We designed a collaborative initiative to capture data from pediatric patients with benign and malignant tumors who underwent a therapeutic interventional radiology procedure. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was utilized as a measure of radiologic response and data were collected regarding improvement in pain and functional endpoints. Cumulative incidence of progressive disease was calculated using both the treated site and the patient as the analytic unit., Findings: Forty patients, 16 with malignant tumors and 24 with benign tumors, underwent a total of 88 procedures. Cryo- and radiofrequency ablation were the most frequently utilized techniques for both cohorts of patients. A complete or partial response, or prolonged disease stability, were achieved in approximately 40% of patients with malignant tumors and 60% of patients with benign tumors. No patients had progressive disease as their best response. Resolution of pain and improved mobility with return-to-baseline activity were demonstrated across patients from both cohorts. Only minor complications were experienced., Interpretation: Interventional radiology-guided interventions can serve as an alternative or complementary approach to the treatment of benign and malignant tumors in pediatric patients. Prospective, multi-institutional trials are required to adequately study utility, treatment endpoints, and durability of response., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Multimodal cancer therapy places childhood cancer survivors at increased risk for chronic health conditions, subsequent malignancies, and premature mortality as they age. We aimed to estimate the cumulative burden of late (>5 years from cancer diagnosis), major surgical interventions among childhood cancer survivors, compared with their siblings, and to examine associations between specific childhood cancer treatments and the burden of late surgical interventions., Methods: We analysed data from the Childhood Cancer Survivor Study (CCSS), a retrospective cohort study with longitudinal prospective follow-up of 5-year survivors of childhood cancer (diagnosed before age 21 years) treated at 31 institutions in the USA, with a comparison group of nearest-age siblings of survivors selected by simple random sampling. The primary outcome was any self-reported late, major surgical intervention (defined as any anaesthesia-requiring operation) occurring 5 years or more after the primary cancer diagnosis. The cumulative burden was assessed with mean cumulative counts (MCC) of late, major surgical interventions. Piecewise exponential regression models with calculation of adjusted rate ratios (RRs) evaluated associations between treatment exposures and late, major surgical interventions., Findings: Between Jan 1, 1970, and Dec 31, 1999, 25 656 survivors were diagnosed (13 721 male, 11 935 female; median follow-up 21·8 years [IQR 16·5-28·4]; median age at diagnosis 6·1 years [3·0-12·4]); 5045 nearest-age siblings were also included as a comparison group. Survivors underwent 28 202 late, major surgical interventions and siblings underwent 4110 late, major surgical interventions. The 35-year MCC of a late, major surgical intervention was 206·7 per 100 survivors (95% CI 202·7-210·8) and 128·9 per 100 siblings (123·0-134·7). The likelihood of a late, major surgical intervention was higher in survivors versus siblings (adjusted RR 1·8, 95% CI 1·7-1·9) and in female versus male survivors (1·4; 1·4-1·5). Survivors diagnosed in the 1990s (adjusted RR 1·4, 95% CI 1·3-1·5) had an increased likelihood of late surgery compared with those diagnosed in the 1970s. Survivors received late interventions more frequently than siblings in most anatomical regions or organ systems, including CNS (adjusted RR 16·9, 95% CI 9·4-30·4), endocrine (6·7, 5·2-8·7), cardiovascular (6·6, 5·2-8·3), respiratory (5·3, 3·4-8·2), spine (2·4, 1·8-3·2), breast (2·1, 1·7-2·6), renal or urinary (2·0, 1·5-2·6), musculoskeletal (1·5, 1·4-1·7), gastrointestinal (1·4, 1·3-1·6), and head and neck (1·2, 1·1-1·4) interventions. Survivors of Hodgkin lymphoma (35-year MCC 333·3 [95% CI 320·1-346·6] per 100 survivors), Ewing sarcoma (322·9 [294·5-351·3] per 100 survivors), and osteosarcoma (269·6 [250·1-289·2] per 100 survivors) had the highest cumulative burdens of late, major surgical interventions. Locoregional surgery or radiotherapy cancer treatment were associated with undergoing late surgical intervention in the same body region or organ system., Interpretation: Childhood cancer survivors have a significant burden of late, major surgical interventions, a late effect that has previously been poorly quantified. Survivors would benefit from regular health-care evaluations aiming to anticipate impending surgical issues and to intervene early in the disease course when feasible., Funding: US National Institutes of Health, US National Cancer Institute, American Lebanese Syrian Associated Charities, and St Jude Children's Research Hospital., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens., Methods: Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents., Results: Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity., Conclusion: With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.

Background: Given emerging evidence of rapid non-genomic cytoprotective effects of triiodothyronine (T3), we evaluated the resuscitative efficacy of two nanoparticle formulations of T3 (T3np) designed to prolong cell membrane receptor-mediated signaling., Methods: Swine (n = 40) were randomized to intravenous vehicle (empty np), EPI (0.015 mg/kg), T3np (0.125 mg/kg), or T3np loaded with phosphocreatine (T3np + PCr; 0.125 mg/kg) during CPR following 7-min cardiac arrest (n = 10/group). Hemodynamics and biomarkers of heart (cardiac troponin I; cTnI) and brain (neuron-specific enolase; NSE) injury were assessed for up to 4-hours post-ROSC, at which time the heart and brain were collected for post-mortem analysis., Results: Compared with vehicle (4/10), the rate of ROSC was higher in swine receiving T3np (10/10; p < 0.01), T3np + PCr (8/10; p = 0.08) or EPI (10/10; p < 0.01) during CPR. Although time to ROSC and survival duration were comparable between groups, EPI was associated with a ∼2-fold higher post-ROSC concentration of cTnI vs T3np and T3np + PCr and the early post-ROSC rise in NSE and neuronal injury were attenuated in T3np-treated vs EPI-treated animals. Analysis of hippocampal ultrastructure revealed deterioration of mitochondrial integrity, reduced active zone length, and increased axonal vacuolization in EPI-treated animals vs controls. However, the frequency of these abnormalities was diminished in animals resuscitated with T3np., Conclusions: T3np achieved a ROSC rate and post-ROSC survival that was superior to vehicle and comparable to EPI. The attenuation of selected biomarkers of cardiac and neurologic injury at individual early post-ROSC timepoints in T3np-treated vs EPI-treated animals suggests that T3np administration during CPR may lead to more favorable outcomes in cardiac arrest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Myocardial fibrosis is a common postmortem finding among individuals with Sudden Cardiac Death (SCD). Numerous in vivo and in vitro studies have shown that increased galectin-3 (gal3) expression into the myocardium is associated with higher incidence of fibrosis. Although elevated gal3 expression is linked with myocardial fibrosis, its role in predicting the risk of SCD is unknown., Methods: We reviewed the clinical datasets and post-mortem examination of 221 subjects who had died suddenly. We examined myocardial pathology including the extent of cardiac hypertrophy, fibrosis, and the degree of coronary atherosclerosis in these subjects. In a select group of SCD subjects, we studied myocardial gal3 and periostin expression using immunohistochemistry. To further examine if a higher level of circulating gal3 can be detected preceding sudden death, we measured serum gal3 in a porcine model of subtotal coronary artery ligation which shows an increased tendency to develop lethal cardiac arrhythmias, including ventricular tachycardia or fibrillation., Results: Of the total 1314 human subjects screened, 12.7% had SCD. Comparison of age-matched SCD with non-SCD subjects showed that SCD groups had excessive myocardial fibrosis involving both the left ventricular free wall and interventricular septum. In pigs with subtotal coronary artery ligation and SCD, we detected significantly elevated circulating gal3 levels approximately 10 days preceding the SCD event. Immunohistochemistry showed increased myocardial gal3 and periostin expression in pigs that died suddenly, compared to the controls., Conclusion: Our study shows that increased gal3 is associated with a higher risk of myocardial fibrosis and the risk of SCD. This supports the importance of larger translational studies to target gal3 to prevent cardiac fibrosis and attenuate the risk of SCD.

Purpose: Kidney failure is a rare but serious late effect following treatment for childhood cancer. We developed a model using demographic and treatment characteristics to predict individual risk of kidney failure among 5-year survivors of childhood cancer., Methods: Five-year survivors from the Childhood Cancer Survivor Study (CCSS) without history of kidney failure (n = 25,483) were assessed for subsequent kidney failure (ie, dialysis, kidney transplantation, or kidney-related death) by age 40 years. Outcomes were identified by self-report and linkage with the Organ Procurement and Transplantation Network and the National Death Index. A sibling cohort (n = 5,045) served as a comparator. Piecewise exponential models accounting for race/ethnicity, age at diagnosis, nephrectomy, chemotherapy, radiotherapy, congenital genitourinary anomalies, and early-onset hypertension estimated the relationships between potential predictors and kidney failure, using area under the curve (AUC) and concordance (C) statistic to evaluate predictive power. Regression coefficient estimates were converted to integer risk scores. The St Jude Lifetime Cohort Study and the National Wilms Tumor Study served as validation cohorts., Results: Among CCSS survivors, 204 developed late kidney failure. Prediction models achieved an AUC of 0.65-0.67 and a C-statistic of 0.68-0.69 for kidney failure by age 40 years. Validation cohort AUC and C-statistics were 0.88/0.88 for the St Jude Lifetime Cohort Study (n = 8) and 0.67/0.64 for the National Wilms Tumor Study (n = 91). Risk scores were collapsed to form statistically distinct low- (n = 17,762), moderate- (n = 3,784), and high-risk (n = 716) groups, corresponding to cumulative incidences in CCSS of kidney failure by age 40 years of 0.6% (95% CI, 0.4 to 0.7), 2.1% (95% CI, 1.5 to 2.9), and 7.5% (95% CI, 4.3 to 11.6), respectively, compared with 0.2% (95% CI, 0.1 to 0.5) among siblings., Conclusion: Prediction models accurately identify childhood cancer survivors at low, moderate, and high risk for late kidney failure and may inform screening and interventional strategies.

Purpose: To describe the risk of late mortality, subsequent malignant neoplasms (SMNs), and chronic health conditions (CHCs) in survivors of neuroblastoma diagnosed in infancy by treatment era and exposures., Methods: Among 5-year survivors of neuroblastoma in the Childhood Cancer Survivor Study diagnosed age < 1 year between 1970 and 1999, we examined the cumulative incidence of late (> 5 years from diagnosis) mortality, SMN, and CHCs (grades 2-5 and 3-5). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs by decade and treatment (surgery-alone v chemotherapy with or without surgery [C ± S] v radiation with or without chemotherapy ± surgery [R ± C ± S]) among survivors and between survivors and 5,051 siblings., Results: Among 1,397 eligible survivors, the 25-year cumulative incidence of late mortality was 2.1% (95% CI, 1.3 to 3.9) with no difference by treatment era. Among 990 participants who completed a baseline survey, fewer survivors received radiation in more recent eras (51.2% 1970s, 20.4% 1980s, and 10.1% 1990s; P < .001). Risk of SMN was elevated only among individuals treated with radiation-containing regimens compared with surgery alone (HR [C ± S] , 3.2 [95% CI, 0.9 to 11.6]; HR [R ± C ± S] , 5.7 [95% CI, 1.2 to 28.1]). In adjusted models, there was a 50% reduction in risk of grade 3-5 CHCs in the 1990s versus 1970s (HR, 0.5 [95% CI, 0.3 to 0.9]; P = .01); individuals treated with radiation had a 3.6-fold risk for grade 3-5 CHCs (95% CI, 2.1 to 6.2) versus those treated with surgery alone. When compared with siblings, risk of grade 3-5 CHCs for survivors was lowest in the most recent era (HR [1970s] , 4.7 [95% CI, 3.4 to 6.5]; HR [1980s] , 4.6 [95% CI, 3.3 to 6.4]; HR [1990s] , 2.5 [95% CI, 1.7 to 3.9])., Conclusion: Neuroblastoma survivors treated during infancy have a relatively low absolute burden of late mortality and SMN. Encouragingly, risk of CHCs has declined in more recent eras with reduced exposure to radiation therapy.

Background: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas., Questions/purposes: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis?, Methods: The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys., Results: More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups., Conclusion: There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient., Level of Evidence: Level III, therapeutic study., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2022 by the Association of Bone and Joint Surgeons.)

Allogeneic cardiosphere-derived cell (CDC) therapy has been demonstrated to improve myocardial function when administered to reperfused myocardial infarcts. We previously pretreated animals with low-dose cyclosporine immunosuppression to limit allogeneic CDC rejection, but whether it is necessary and, if so, can be initiated at the time of reperfusion remains uncertain. Closed-chest swine ( n = 29 animals) were subjected to a 90-min left anterior descending (LAD) coronary artery occlusion. Using a three-way blinded design, we randomized two groups to receive global intracoronary infusions of 20 × 10 6 CDCs 30 min after reperfusion. A third control group was treated with saline. One CDC group received cyclosporine 10 min before reperfusion (2.5 mg/kg iv and 100 mg/day po), whereas the other groups received placebos. After 1 mo, neither chronic infarct size relative to area at risk (saline control, 46.2 ± 4.0%; CDCs, 46.4 ± 2.1%; and CDCs + cyclosporine, 49.2 ± 3.1%; P = 0.79) nor ejection fraction (saline control, 51 ± 2%; CDCs, 51 ± 2%; and CDC + cyclosporine, 48 ± 2%; P = 0.42) were different among treatment groups. Multiple histological measures of cellular remodeling, myocyte proliferation, and apoptosis were also not different among treatment groups. In contrast to previous studies, we were unable to reproduce the cardioprotective effects demonstrated by allogeneic CDCs without cyclosporine. Furthermore, initiation of intravenous cyclosporine at the time of reperfusion followed by oral therapy was not sufficient to elicit the functional improvement observed in studies where cyclosporine was started 72 h before CDC therapy. This suggests that oral cyclosporine pretreatment may be necessary to effect cardiac repair with allogeneic CDCs. NEW & NOTEWORTHY In a three-way blinded, randomized design, we determined whether allogeneic CDCs administered at reperfusion improved myocardial function and whether intravenous cyclosporine enhanced their efficacy. In contrast to prior studies using oral cyclosporine, CDCs with or without intravenous cyclosporine had no effect on function or infarct size. This indicates that CDCs may be most efficacious for treating chronic LV dysfunction where cyclosporine can be initiated at least 72 h before cell therapy.

Background: Long term central venous access is necessary for the treatment of several conditions affecting young children. Totally implantable access ports (ports) offer the advantage of containing no external components, thus simplifying their care and maintenance. However, there is no consensus on the safety of port placement in infants (birth to 1-year of age). The aim of this study was to describe complications associated with port placement in infants, including which specific factors may be associated with risk for developing complications among these patients, and thereby assess the safety of port placement in this young population., Methods: A two-institution, retrospective cohort study identified patients under 1-year old who underwent port placement. Intraoperative, early postoperative (within 30 days), and late postoperative (greater than 30 days) complications were recorded. Multivariate logistic regression models were employed to assess factors associated with port-related complications., Results: Among 121 patients who received a port, 36 (30%) experienced a complication with a median time to complication of 299.5 days [IQR 67.5-440.75]. Of those, 26 required unplanned port removal. Only 3 patients (2.5%) experienced an intraoperative complication, and 3 patients (2.5%) experienced a complication within 30 days of port placement. A diagnosis of cancer was found to be protective against early catheter malfunction (OR=0.31, p = 0.03). A non-statistically significant trend associated with increased complications for large caliber devices (>6.0Fr) and weight <7-kg (OR 2.20, p = 0.06 and OR=2.26, p = 0.11 respectively) was observed., Conclusions: Port placement appears to be safe for most infants with low or acceptable rates of intra- or post-operative complications. Smaller patient size (< 7 kg) and larger-sized catheters (> 6.0Fr) may be associated with an increased risk for complications among this population., Level of Evidence: III., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: We sought to analyze biologic, clinical, and prognostic differences according to pattern of failure at the time of first relapse in neuroblastoma., Patients and Methods: Children <21 years diagnosed with neuroblastoma between 1989 and 2017 with known site of first relapse (isolated local vs. distant only vs. combined local and distant sites) were identified from the International Neuroblastoma Risk Group (INRG) database. Data were compared between sites of relapse according to clinical features, biologic features, initial treatment, time to first relapse, and overall survival (OS) from time of first relapse., Results: Pattern of first relapse among 1833 children was 19% isolated local; 65% distant only; and 16% combined sites. All evaluated clinical and biologic variables with exception of tumor diagnosis differed statistically by relapse pattern, with patients with isolated local failure having more favorable prognostic features. Patients with stage 3 disease were more likely to have isolated local failure compared to all other stages (49% vs. 16%; p < .001). OS significantly differed by relapse pattern (5-year OS ± SE): isolated local: 64% ± 3%; distant only: 23% ± 2%; and combined: 26% ± 4% (p < .001). After controlling for age, stage, and MYCN status, patients with isolated local failure (adjusted hazard ratio [HR] = 0.46; 95% confidence interval [CI]: 0.33-0.62; p < .001) and distant-only failure (adjusted HR = 0.57; 95% CI: 0.45-0.71; p < .001) remained at decreased risk for death as compared to patients with combined failure., Conclusion: Patients with distant-only and combined failures have a higher proportion of unfavorable clinical and biological features, and a lower survival than those with isolated local relapse., (© 2022 Wiley Periodicals LLC.)

Malignant ovarian neoplasms are uncommon in the pediatric and adolescent population. Imaging and tumor markers help to guide the preoperative risk/benefit analysis for planned surgical management, which is the mainstay of therapy. An interdisciplinary approach should be taken in the management of this vulnerable population from diagnosis through post-treatment surveillance. In this review, the initial evaluation, risk stratification, and management of various types of malignant ovarian masses will be addressed, with a special focus on how to optimize an interdisciplinary approach to ovarian masses., (Copyright © 2021. Published by Elsevier Inc.)

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1 . Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: The incidence of and risk factors for late-onset kidney failure among survivors over the very long term remains understudied., Materials and Methods: A total of 25,530 childhood cancer survivors (median follow-up 22.3 years, interquartile range 17.4-28.8) diagnosed between 1970 and 1999, and 5045 siblings from the Childhood Cancer Survivor Study were assessed for self-reported late-onset kidney failure, defined as dialysis, renal transplantation, or death attributable to kidney disease. Piecewise exponential models evaluated associations between risk factors and the rate of late-onset kidney failure., Results: A total of 206 survivors and 10 siblings developed late-onset kidney failure, a 35-year cumulative incidence of 1.7% (95% confidence interval [CI] = 1.4-1.9) and 0.2% (95% confidence interval [CI] = 0.1-0.4), respectively, corresponding to an adjusted rate ratio (RR) of 4.9 (95% CI = 2.6-9.2). High kidney dose from radiotherapy (≥15Gy; RR = 4.0, 95% CI = 2.1-7.4), exposure to high-dose anthracycline (≥250 mg/m 2 ; RR = 1.6, 95% CI = 1.0-2.6) or any ifosfamide chemotherapy (RR = 2.6, 95% CI = 1.2-5.7), and nephrectomy (RR = 1.9, 95% CI = 1.0-3.4) were independently associated with elevated risk for late-onset kidney failure among survivors. Survivors who developed hypertension, particularly in the context of prior nephrectomy (RR = 14.4, 95% CI = 7.1-29.4 hypertension with prior nephrectomy; RR = 5.9, 95% CI = 3.3-10.5 hypertension without prior nephrectomy), or diabetes (RR = 2.2, 95%CI = 1.2-4.2) were also at elevated risk for late-onset kidney failure., Conclusions: Survivors of childhood cancer are at increased risk for late-onset kidney failure. Kidney dose from radiotherapy ≥15 Gy, high-dose anthracycline, any ifosfamide, and nephrectomy were associated with increased risk of late-onset kidney failure among survivors. Successful diagnosis and management of modifiable risk factors such as diabetes and hypertension may mitigate the risk for late-onset kidney failure. The association of late-onset kidney failure with anthracycline chemotherapy represents a novel finding that warrants further study., Competing Interests: Conflict of interest statement Authors have no competing financial or non-financial interests in relation to the present work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The efficacy of cell-based therapies relies on targeted payload delivery and enhanced cell retention. In vitro and in vivo studies suggest that the glycoengineering of mesenchymal and cardiosphere-derived cells (CDCs) may enhance such recruitment at sites of injury. We evaluated the role of blood cells in amplifying this recruitment. Thus, the human α(1,3)fucosyltransferase FUT7 was stably expressed in CDCs, sometimes with P-selectin glycoprotein ligand-1 (PSGL-1/CD162). Such FUT7 over-expression resulted in cell-surface sialyl Lewis-X (sLe X ) expression, at levels comparable to blood neutrophils. Whereas FUT7 was sufficient for CDC recruitment on substrates bearing E-selectin under flow, PSGL-1 co-expression was necessary for P-/L-selectin binding. In both cone-plate viscometer and flow chamber studies, chemokine driven neutrophil activation promoted the adhesion of glycoengineered-CDCs to blood cells. Here, blood neutrophils activated upon contact with IL-1β stimulated endothelial cells, amplified glycoengineered-CDC recruitment. In vivo, local inflammation in a mouse ear elicited both glycoengineered-CDC and peripheral blood neutrophil homing to the inflamed site. Glycoengineering CDCs also resulted in enhanced (~16%) cell retention at 24 h in a murine myocardial infarction model, with CDCs often co-localized with blood neutrophils. Overall, peripheral blood neutrophils, activated at sites of injury, may enhance recruitment of glycoengineered cellular therapeutics via secondary capture mechanisms., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Long-term survival following hematopoietic stem cell transplant (HSCT) in childhood continues to improve, and patients are thus increasingly faced with the late effects of treatment. Infertility is very common for both males and females following HSCT and is one of the most distressing sequelae. Adoption and surrogate egg or sperm donation are possibilities for some patients, but post-HSCT reversal of gonadal failure is not possible. We have recently initiated an oncofertility program with a dedicated practitioner with specific expertise in this area. Our practice is for her to meet with all families and age-appropriate patients during the pre-HSCT evaluation period. This allows patients and families to be accurately informed about the expected treatment-related infertility risk and the available options for fertility preservation. Sperm banking and egg or embryo cryopreservation are established approaches but are not achievable for many children and adolescents. Recently, the harvesting and cryopreservation of ovarian and testicular tissue represents a novel surgical option that allows for the possibility of fertility preservation to be extended to children of all ages. The purpose of this investigation is to evaluate the safety of these procedures proximal to conditioning therapy and HSCT. This is a retrospective report on a consecutive cohort of all patients aged 0 to 25 years who, after discussion with our oncofertility specialist, chose to undergo surgical fertility preservation (laparoscopic unilateral oophorectomy or testicular biopsy) at our institution between March 2018 and April 2020. These procedures occurred under general anesthesia at the time of central line placement prior to the initiation of HSCT conditioning. We assess the safety of the procedures in terms of postoperative complications and impact on HSCT course. Twenty-two patients underwent fertility preservation surgical procedures. Thirteen patients (59%) were female, median age 13 years (1 to 22 years), and 9 (41%) were male, median age 8 years (5 to 12 years). Fourteen (63%) were prepubertal and 8 (36%) pubertal. HSCT indications were hematologic malignancies/solid tumor (40%) and nonmalignant diseases (60%). Most received an allogenic graft (68%) and 81% had myeloablative conditioning. All patients became neutropenic at a median of 10 days (0 to 51 days) from the surgical procedure; 1 was neutropenic at the time of testicular tissue cryopreservation (TTC). The mean duration for the procedures performed, including ovarian tissue cryopreservation (OTC) or TTC, was 98 minutes (49 to 260 minutes) and 97 minutes (56 to 178 minutes), respectively. Estimated blood loss was minimal and no postoperative site infections occurred. One postprocedure, blood culture-negative fever was reported without an identifiable source; the patient completed 48 hours of antibiotics with resolution of fever. Sixty-two percent of females and 56% of males started conditioning within 24 hours of OTC/TTC (15 hours to 113 days; median, 1 day). The median time to engraftment was 22 days (9 to 33 days) in females and 17 days (11 to 67 days) in males, consistent with our institutional benchmarks. One patient with aplastic anemia had primary graft failure, attributed to low cell dose. This patient engrafted after a second transplant from an alternative donor but ultimately died of multiorgan failure. He was neutropenic for over 60 days and never experienced surgical site infection. There were no procedure-related delays to start of conditioning or to discharge. Children of all ages can now be offered the possibility of fertility preservation following HSCT for benign and malignant conditions. Our review suggests that these procedure for both females and males can be performed close to the start of conditioning, which allows for coupling with central access placement. These procedures appear to be safe and do not add to transplant-related morbidity., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: The purpose was to examine associations between treatment and chronic health conditions with neurocognitive impairment survivors of acute lymphoblastic leukemia (ALL) treated with chemotherapy only., Methods: This cross-sectional study included 1207 ALL survivors (54.0% female; mean age 30.6 years) and 2273 siblings (56.9% female; mean age 47.6 years), who completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire. Multivariable logistic regression compared prevalence of neurocognitive impairment between survivors and siblings by sex. Associations between neurocognitive impairment with treatment exposures and chronic conditions (graded according to Common Terminology Criteria for Adverse Events) were also examined. Statistical tests were 2-sided., Results: Relative to same-sex siblings, male and female ALL survivors reported increased prevalence of impaired task efficiency (males: 11.7% vs 16.9%; adjusted odds ratio [OR] = 1.89, 95% confidence interval [CI] = 1.31 to 2.74; females: 12.5% vs 17.6%; OR = 1.50, 95% CI = 1.07 to 2.14), as well as impaired memory (males: 11.6% vs 19.9%, OR = 1.89, CI = 1.31 to 2.74; females: 14.78% vs 25.4%, OR = 1.96, 95% CI = 1.43 to 2.70, respectively). Among male survivors, impaired task efficiency was associated with 2-4 neurologic conditions (OR = 4.33, 95% CI = 1.76 to 10.68) and with pulmonary conditions (OR = 4.99, 95% CI = 1.51 to 16.50), and impaired memory was associated with increased cumulative dose of intrathecal methotrexate (OR = 1.68, 95% CI = 1.16 to 2.46) and with exposure to dexamethasone (OR = 2.44, 95% CI = 1.19 to 5.01). In female survivors, grade 2-4 endocrine conditions were associated with higher risk of impaired task efficiency (OR = 2.19, 95% CI = 1.20 to 3.97) and memory (OR = 2.26, 95% CI = 1.31 to 3.92)., Conclusion: Neurocognitive impairment is associated with methotrexate, dexamethasone, and chronic health conditions in a sex-specific manner, highlighting the need to investigate physiological mechanisms and monitor impact through survivorship., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: We sought to estimate the prevalence, incidence, and timing of surgery for elective and non-elective hernia repairs., Methods: We performed a retrospective cohort study, abstracting data on children < 18 years from the 2005-2014 DoD Military Health System Data Repository, which includes > 3 million dependents of U.S. Armed Services members. Our primary outcome was initial hernia repair (inguinal, umbilical, ventral, or femoral), stratified by elective versus non-elective repair and by age. We calculated prevalence, incidence rate, and time from diagnosis to repair., Results: 19,398 children underwent hernia repair (12,220 inguinal, 5761 umbilical, 1373 ventral, 44 femoral). Prevalence of non-elective repairs ranged from 6% (umbilical) to 22% (ventral). Incidence rates of elective repairs ranged from 0.03 [95% CI: 0.02-0.04] (femoral) to 8.92 [95% CI: 8.76-9.09] (inguinal) per 10,000 person-years, while incidence rates of non-elective repairs ranged from 0.005 [95% CI: 0.002-0.01] (femoral) to 0.68 [95% CI: 0.64-0.73] (inguinal) per 10,000 person-years. Inguinal (median = 20, interquartile range [IQR] = 0-46 days), ventral (median = 23, IQR = 5-62 days), and femoral hernias (median = 0, IQR = 0-12 days) were repaired more promptly and with less variation than umbilical hernias (median = 66, IQR = 23-422 days)., Conclusions: These data describe the burden of hernia repair in the U.S. The large variation in time between diagnosis and repair by hernia type identifies an important area of research to understand mechanisms underlying such heterogeneity and determine the ideal timing for repair., Level of Evidence: Prognosis study II.

Germ cell tumors arise from primordial germ cells. Most develop in the gonads or along midline structures of the body. Genetic aberrations leading to disruption in the molecular signaling responsible for primordial germ cell migration early in development may provide rationale for why germ cell tumors originate in extragonadal locations. Establishing best practices for treating pediatric germ cell tumors remains an area of active investigation. Recent advances focused on limiting toxicities of therapy, identifying new therapies for relapsed and refractory tumors, defining best practices for surgical staging and resection, and developing novel methods to monitor for disease relapse., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Germ cell tumors (GCTs) comprise a wide spectrum of benign and malignant tumors. Neonatal GCTs are predominantly teratomas (mature or immature), which are typically cured with surgery alone. Relapses are infrequent even in the setting of microscopic residual disease; therefore, negative surgical margins at the cost of significant morbidity are not recommended. In neonates with metastatic malignant disease or malignant disease for which upfront surgical resection is not feasible without significant morbidity, an initial biopsy followed by neoadjuvant chemotherapy and delayed surgical resection is recommended. Carboplatin-based regimens should be considered when chemotherapy is indicated., Competing Interests: Disclosure R. Shah: The author has nothing to disclose. B.R. Weil: The author has nothing to disclose. C.B. Weldon: The author has nothing to disclose. J.F. Amatruda: The author has nothing to disclose. A.L. Frazier: Clinical advisory board, Decibel Therapeutics., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To describe variability in and consequences of opioid prescriptions following pediatric laparoscopic appendectomy., Summary Background Data: Postoperative opioid prescribing patterns may contribute to persistent opioid use in both adults and children., Methods: We included children <18 years enrolled as dependents in the Military Health System Data Repository who underwent uncomplicated laparoscopic appendectomy (2006-2014). For the primary outcome of days of opioids prescribed, we evaluated associations with discharging service, standardized to the distribution of baseline covariates. Secondary outcomes included refill, Emergency Department (ED) visit for constipation, and ED visit for pain., Results: Among 6732 children, 68% were prescribed opioids (range = 1-65 d, median = 4 d, IQR = 3-5 d). Patients discharged by general surgery services were prescribed 1.23 (95% CI = 1.06-1.42) excess days of opioids, compared with those discharged by pediatric surgery services. Risk of ED visit for constipation (n = 61, 1%) was increased with opioid prescription [1-3 d, risk ratio (RR) = 2.46, 95% CI = 1.31-5.78; 4-6 d, RR = 1.89, 95% CI = 0.83-4.67; 7-14 d, RR = 3.75, 95% CI = 1.38-9.44; >14 d, RR = 6.27, 95% CI = 1.23-19.68], compared with no opioid prescription. There was similar or increased risk of ED visit for pain (n = 319, 5%) with opioid prescription [1-3 d, RR = 1.00, 95% confidence interval (CI) = 0.74-1.32; 4-6 d, RR = 1.31, 95% CI = 0.99-1.73; 7-14 d, RR = 1.52, 95% CI = 1.00-2.18], compared with no opioid prescription. Likewise, need for refill (n = 157, 3%) was not associated with initial days of opioid prescribed (reference 1-3 d; 4-6 d, RR = 0.96, 95% CI = 0.68-1.35; 7-14 d, RR = 0.91, 95% CI = 0.49-1.46; and >14 d, RR = 1.22, 95% CI = 0.59-2.07)., Conclusions: There was substantial variation in opioid prescribing patterns. Opioid prescription duration increased risk of ED visits for constipation, but not for pain or refill.

Background: Desmoplastic small round cell tumor (DSRCT) is a rare aggressive sarcoma that affects children and young adults, and portends poor outcomes despite intensive multimodal treatment approaches. We report toxicity, response, and outcomes of patients with DSRCT treated with the addition of vincristine, irinotecan, and temozolomide (VIT) to interval-compressed chemotherapy as per Children's Oncology Group ARST08P1., Methods: All newly diagnosed pediatric patients with DSRCT treated at Dana-Farber Cancer Institute and Boston Children's Hospital between 2014 and 2019 as per ARST08P1, Arm P2 with replacement of VAC cycles with VIT, were identified. Medical records were reviewed for clinical and disease characteristics, and treatment response and outcomes., Results: Six patients were treated as per the above regimen. Median age at diagnosis was 15.1 years (range 3.2-16.4) and five patients were male. Five patients had abdominal primary tumors, of which one had exclusively intraabdominal and four had extraabdominal metastases. Two initial cycles of VIT were well tolerated with nausea, vomiting, diarrhea, and constipation as the most common adverse events. Overall response rate defined as partial or complete response after two initial cycles of VIT was 50%. For local control, all patients had surgical resection followed by radiotherapy, and two patients received hyperthermic intraperitoneal chemotherapy at the time of surgery. Of the four patients who have completed therapy to date, three remain disease-free with median follow-up time of 46.7 months., Conclusions: The addition of VIT to interval-compressed chemotherapy is tolerable and active in DSRCT, with activity warranting additional investigation., (© 2020 Wiley Periodicals LLC.)

Background: Gallbladder disease and need for cholecystectomy are common and significant contributors to patient morbidity and healthcare costs. Childhood cancer survivors are at elevated risk for developing cholelithiasis. However, their incidence of and risk factors for late (>5 years from diagnosis) cholecystectomy have not been studied., Methods: A total of 25,549 survivors (median age at diagnosis 6.9 years, range 0-21.0; current age 30.7 years, range 5.6-65.9) diagnosed between 1970 and 1999 and 5037 siblings were queried for self-reported cholecystectomy occurring five or more years from primary cancer diagnosis. Piecewise exponential models evaluated associations between cancer treatment exposures and late cholecystectomy., Results: Over a median follow-up period of 21.9 and 26.0 years, respectively, 789 survivors and 168 siblings underwent late cholecystectomy (cumulative incidence 7.2%, 95% confidence interval [CI] = 6.5-7.8% and 6.6%, 95% CI = 5.4-7.6%, respectively; rate ratio [RR] = 1.3, 95% CI = 1.1-1.5). Compared with siblings, survivors of acute lymphoblastic leukaemia (RR = 1.4, 95% CI = 1.2-1.8), soft tissue sarcoma (RR = 1.4, 95% CI = 1.0-1.8) and bone cancer (RR = 1.3, 95% CI = 1.0-1.8) were at the greatest risk. In addition to attained age, female sex and increasing body mass index, exposure to high-dose (≥750 mg/m 2 ) platinum chemotherapy (RR = 2.6, 95% CI = 1.5-4.5), vinca alkaloid chemotherapy (RR = 1.4, 95% CI = 1.1-1.8) or total body irradiation (TBI; RR = 2.2, 95% CI = 1.2-4.2) were each associated with late cholecystectomy., Conclusions: Independent of traditional risk factors for gallbladder disease, exposure to high-dose platinum chemotherapy, vinca alkaloid chemotherapy or TBI increased risk for late cholecystectomy. These findings should inform current long-term follow-up guidelines and education regarding risk for late cholecystectomy., Competing Interests: Conflict of interest statement None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Despite decades of research on the pathophysiology of myocardial stunning, protein changes and/or phosphorylation status underlying alterations in cardiac function/structure remain inadequately understood. Here, we utilized comprehensive and quantitative proteomic and phosphoproteomic approaches to explore molecular mechanisms of myocardial stunning in swine. The closed-chest swine ( n = 5 pigs) were subjected to a 10-min left anterior descending coronary artery (LAD) occlusion producing regional myocardial stunning. Tissues from the ischemic LAD region and a remote nonischemic area of the left ventricle were collected 1 h after reperfusion. Ion current-based proteomics (IonStar) and quantitative phosphoproteomics were employed in parallel to identify alterations in protein level and site-specific phosphorylation changes. A novel swine heart protein database exhibiting high accuracy and low redundancy was developed here to facilitate comprehensive study. Further informatic investigations identified potential protein-protein interactions in stunned myocardium. In total, we quantified 2,099 protein groups and 4,699 phosphorylation sites with only 0.4% missing values. Proteomic analyses revealed downregulation of contractile function and extracellular matrix remodeling. Meanwhile, alterations in phosphorylation linked with contractile dysfunction and apoptotic cell death were uncovered. NetworKIN/STRING analysis predicted regulatory kinases responsible for altered phosphosites, such as protein kinase C-mediated phosphorylation of cardiac troponin I-S199 and CaMKII-mediated phosphorylation of phospholamban-T17. In summary, the ion current-based proteomics and phosphoproteomics reliably identified novel alterations in protein content and phosphorylation contributing to contractile dysfunction, extracellular matrix (ECM) damage, and programmed cell death in stunned myocardium, which corroborate well with our physiological observations. Moreover, this work developed a comprehensive database of the swine heart proteome, a highly valuable resource for future translational research in porcine models with cardiovascular diseases. NEW & NOTEWORTHY We first used ion current-based proteomics and phosphoproteomics to reliably identify novel alterations in protein expression and phosphorylation contributing to contractile dysfunction, extracellular matrix (ECM) damage, and programmed cell death in stunned myocardium and developed a comprehensive swine heart-specific proteome database, which provides a valuable resource for future research in porcine models of cardiovascular diseases.

Remodeling of the coronary microcirculation is known to occur distal to a chronic coronary stenosis, but the reversibility of these changes and their functional significance on maximum myocardial perfusion before and after revascularization is unknown. Accordingly, swine instrumented with a chronic silastic stenosis on the left anterior descending coronary artery to produce hibernating myocardium underwent percutaneous coronary intervention (PCI; n = 8) and were compared with animals with a persistent stenosis ( n = 8), as well as sham controls ( n = 6). Stenotic animals demonstrated an increased subendocardial arteriolar wall thickness-to-lumen ratio (37.8 ± 3.3 vs. 28.3 ± 1.3% in sham, P = 0.04), reduced lumen area per arteriole (597 ± 88 vs. 927 ± 113 μm 2 , P = 0.04), and a compensatory increase in arteriolar density (9.4 ± 1.0 vs. 5.3 ± 0.4 arterioles/mm 2 , P < 0.01). As a result, vasodilated flow immediately after PCI was similar to normally perfused remote regions (5.1 ± 1.0 vs. 4.8 ± 0.9 ml·min -1 ·g -1 , P = 0.87). When assessed 1-mo after PCI, increases in wall thickness-to-lumen diameter (42.2 ± 3.3%) and reductions in lumen area per arteriole (638 ± 59 μm 2 ) remained unchanged, but arteriolar density returned to normal (5.2 ± 0.5 arterioles/mm 2 ). As a result, maximum subendocardial flow during adenosine declined and was lower than remote regions (2.6 ± 0.3 vs. 5.9 ± 1.1 ml·min -1 ·g -1 , P = 0.01). There was no microvascular remodeling in subepicardial arterioles, and maximum perfusion remained unchanged. These data demonstrate that subendocardial microvascular remodeling occurs distal to a chronic epicardial stenosis. The regression of arteriolar density without increases in luminal area may precipitate stress-induced subendocardial ischemia in the absence of a physiologically significant stenosis. NEW & NOTEWORTHY Swine with a chronic coronary stenosis exhibit subendocardial microvascular remodeling distal to a critical stenosis characterized by an increase in arteriolar wall thickness and reduction in lumen area with a compensatory increase in arteriolar density. The present study is the first to demonstrate that subendocardial arteriolar density normalizes 1-mo after revascularization, but the lumen area of individual arterioles remains reduced. This leads to a reduction in maximal subendocardial perfusion at this time point despite initial normalization of vasodilator reserve after revascularization. This pattern of chronic microvascular structural remodeling could contribute to recurrent subendocardial ischemia in the absence of coronary restenosis during tachycardia and increases in myocardial oxygen demand.

Background: Given the rarity of pediatric surgical disease, it is important to consider available large-scale data resources as a means to better study and understand relevant disease-processes and their treatments. The Military Health System Data Repository (MDR) includes claims-based information for > 3 million pediatric patients who are dependents of members and retirees of the United States Armed Services, but has not been externally validated. We hypothesized that demographics and selected outcome metrics would be similar between MDR and the previously validated American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-P) for several common pediatric surgical operations., Methods: We selected five commonly performed pediatric surgical operations: appendectomy, pyeloplasty, pyloromyotomy, spinal arthrodesis for scoliosis, and facial reconstruction for cleft palate. Among children who underwent these operations, we compared demographics (age, sex, and race) and clinical outcomes (length of hospital stay [LOS] and mortality) in the MDR and NSQIP-P, including all available overlapping years (2012-2014)., Results: Age, sex, and race were generally similar between the NSQIP-P and MDR. Specifically, these demographics were generally similar between the resources for appendectomy (NSQIP-P, n = 20,602 vs. MDR, n = 4363; median age 11 vs. 12 years; female 40% vs. 41%; white 75% vs. 84%), pyeloplasty (NSQIP-P, n = 786 vs. MDR, n = 112; median age 0.9 vs. 2 years; female 28% vs. 28%; white 71% vs. 80%), pyloromyotomy, (NSQIP-P, n = 3827 vs. MDR, n = 227; median age 34 vs. < 1 year, female 17% vs. 16%; white 76% vs. 89%), scoliosis surgery (NSQIP-P, n = 5743 vs. MDR, n = 95; median age 14.2 vs. 14 years; female 75% vs. 67%; white 72% vs. 75%), and cleft lip/palate repair (NSQIP-P, n = 6202 vs. MDR, n = 749; median age, 1 vs. 1 year; female 42% vs. 45%; white 69% vs. 84%). Length of stay and 30-day mortality were similar between resources. LOS and 30-day mortality were also similar between datasets., Conclusion: For the selected common pediatric surgical operations, patients included in the MDR were comparable to those included in the validated NSQIP-P. The MDR may comprise a valuable clinical outcomes research resource, especially for studying infrequent diseases with follow-up beyond the 30-day peri-operative period.

Background/purpose: The purpose of this systematic review by the American Pediatric Surgical Cancer Committee was to summarize evidence from the current medical literature regarding fertility restoration and hormone replacement for female children and adolescents treated with gonadotoxic treatments., Methods: Using PRISMA guidelines, questions were addressed by searching Medline, Cochrane, Embase Central and National clearing house databases using relevant search terms. Eligible studies included those that addressed ovarian tissue cryopreservation (OTC), oocyte harvest, ovarian transposition, and ovarian tissue auto-transplantation for females under the age of 20. Four reviewers independently screened studies for eligibility, extracted data and assessed the risk of bias. Study outcomes were summarized in a narrative synthesis., Results: Two thousand two hundred seventy-six studies were identified by database search and manual review and 2185 were eliminated based on defined exclusion criteria. Ninety-one studies served as the basis for the systematic review. There were 1019 patients who underwent OTC with ages ranging from 0.4 to 20.4 years old, with 298 under the age of 13. Twenty patients aged 13-20 years old underwent successful oocyte harvest. Thirty-seven children underwent ovarian transposition as a means of fertility preservation. Eighteen patients underwent auto-transplantation of thawed ovarian cortical tissue that was harvested before the age of 21 years resulting in 10 live births., Conclusions: Clinically accepted and experimental fertility preservation options such as OTC, oocyte cryopreservation, and ovarian transposition are available to females aged 20 years and younger who are at risk for premature ovarian insufficiency and infertility due to gonadotoxic treatments. There is a large cohort of pediatric-aged patients, with a wide variety of diagnoses and treatments, who have undergone fertility preservation. Currently, fertility and hormone restoration experience for patients who were 20- years of age or younger at the time of fertility preservation remains limited., Level of Evidence: IV., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Hematopoietic stem cell transplantation (HSCT) in the pediatric population is associated with pulmonary complications in 25% of recipients. The role of surgical lung biopsy (SLB) remains unclear because of concerns about both the therapeutic impact and morbidity associated with the procedure. A retrospective review of consecutive allogeneic HSCT recipients at Dana-Farber and Boston Children's Hospital Cancer and Blood Disorders Center between 2006 and 2016 was performed. All recipients who underwent SLB during the study period were identified and charts reviewed for perioperative complications, histopathologic findings, and changes in therapy delivered. Pearson's chi-square test and Student's t-test (or appropriate nonparametric test) were used to evaluate the associations between perioperative complication and categorical and continuous variables, respectively. Five hundred fifty-five HSCTs were included, among which 48 SLBs (8.6%) were identified. Median follow-up time was 24 months (range, 0 to 139). Thirty-day postoperative morbidity was 16.7% and 30-day postoperative mortality 10.4% (n = 5). The overall 30-day postoperative complication rate (including mortality) was 20.8% (n = 10). No mortalities were directly attributable to SLB. Definitive diagnoses were identified in 70.8% of SLBs (n = 34), and therapeutic changes occurred in 79.2% (n = 38). Overall, 83.3% of SLBs (n = 40) either provided a diagnosis or led to a change in therapy. SLB has an acceptable risk of perioperative complications in this medically complicated and often severely ill population. In most HSCT patients, SLB aids in defining the etiology of pulmonary infiltrates and can inform therapeutic decisions in patients where noninvasive diagnostic modalities have failed to provide a definitive diagnosis., (Copyright © 2019. Published by Elsevier Inc.)

Background: The prevalence and associated psychosocial morbidity of late-onset anorectal disease after surgery and radiotherapy for the treatment of childhood cancer are not known., Methods: A total of 25,530 survivors diagnosed between 1970 and 1999 (median age at cancer diagnosis, 6.1 years; age at survey, 30.2 years) and 5036 siblings were evaluated for late-onset anorectal disease, which was defined as a self-reported fistula-in-ano, self-reported anorectal stricture, or pathology- or medical record-confirmed anorectal subsequent malignant neoplasm (SMN) 5 or more years after the primary cancer diagnosis. Piecewise exponential models compared the survivors and siblings and examined associations between cancer treatments and late-onset anorectal disease. Multiple logistic regression with generalized estimating equations was used to evaluate associations between late-onset anorectal disease and emotional distress, as defined by the Brief Symptom Inventory 18 (BSI-18), and health-related quality of life, as defined by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36)., Results: By 45 years after the diagnosis, 394 survivors (fistula, n = 291; stricture, n = 116; anorectal SMN, n = 26) and 84 siblings (fistula, n = 73; stricture, n = 23; anorectal neoplasm, n = 1) had developed late-onset anorectal disease (adjusted rate ratio [RR] for survivors vs siblings, 1.2; 95% confidence interval [CI], 1.0-1.5). Among survivors, pelvic radiotherapy with ≥30 Gy within 5 years of the cancer diagnosis was associated with late-onset anorectal disease (adjusted RR for 30-49.9 Gy vs none, 1.6; 95% CI, 1.1-2.3; adjusted RR for ≥50 Gy vs none, 5.4; 95% CI, 3.1-9.2). Late-onset anorectal disease was associated with psychosocial impairment in all BSI-18 and SF-36 domains., Conclusions: Late-onset anorectal disease was more common among childhood cancer survivors who received higher doses of pelvic radiotherapy and was associated with substantial psychosocial morbidity., (© 2019 American Cancer Society.)

Purpose: The purpose of this study was to develop a pre-operative risk assessment tool for childhood and adolescent ovarian malignancy, in order to guide operative management of pediatric ovarian masses., Methods: We conducted a retrospective analysis of patients <18 years old who underwent ovarian surgery at two quaternary care pediatric centers over 4 years (1/1/13-12/31/16). Probability of malignancy was estimated based on imaging characteristics (simple cyst, heterogeneous, or solid), maximal diameter, and tumor markers (α-fetoprotein, β-human chorionic gonadotropin)., Results: Among 188 children with ovarian masses, 11% had malignancies. For simple cysts, there were no malignancies (0/24, 95% CI = 0-17%). Among solid lesions, 44% (15/34, 95% CI = 28-62%) were malignant. Among marker-elevated heterogeneous masses, 40% (2/5, 95% CI = 12-77%) were malignant. Conversely, small (≤10 cm) and large (>10 cm) marker-negative heterogeneous lesions had malignancy proportions of 0% (0/39, 95% CI = 0-11%) and 5% (2/40, 95% CI = 1-18%), respectively., Conclusions: Given the malignancy estimates identified from these multi-institutional data, we recommend an attempt at ovarian-sparing resection for simple cysts or tumor marker-negative heterogeneous lesions ≤10 cm. Oophorectomy is recommended for solid masses or heterogeneous lesions with elevated markers. Finally, large (>10 cm) heterogeneous masses with non-elevated markers warrant a careful discussion of ovarian-sparing techniques. Complete surgical staging is mandatory regardless of operative procedure., Type of Study: Study of Diagnostic Test., Level of Evidence: Level I., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Swine subjected to 2 weeks of repetitive pressure overload (RPO) exhibited significant myocyte loss, but left ventricular (LV) systolic function was preserved, and chamber dilatation did not occur. Instead, myocardial remodeling characterized by myocyte hypertrophy and interstitial fibrosis led to a marked reduction in LV diastolic compliance, which protected the heart from stretch-induced myocyte injury and preserved LV ejection fraction without anatomic LV hypertrophy. These results support a novel paradigm that links cardiac adaptations to RPO with the pathogenesis of reduced LV diastolic compliance and may explain how LV stiffening can occur in the absence of sustained hypertension or anatomic hypertrophy.

Intracoronary cardiosphere-derived cells (icCDCs) infused into the infarct-related artery reduce scar volume but do not improve left ventricular (LV) ejection fraction (LVEF). We tested the hypothesis that this reflects the inability of regional delivery to prevent myocyte death or promote myocyte proliferation in viable myocardium remote from the infarct. Swine ( n = 23) pretreated with oral cyclosporine (200 mg/day) underwent a 1-h left anterior descending coronary artery (LAD) occlusion, which reduced LVEF from 61.6 ± 1.0 to 45.3 ± 1.5% 30 min after reperfusion. At that time, animals received global infusion of allogeneic icCDCs ( n = 8), regional infusion of icCDCs restricted to the LAD using the stop-flow technique ( n = 8), or vehicle ( n = 7). After 1 mo, global icCDCs increased LVEF from 44.8 ± 1.9 to 60.8 ± 3.8% ( P < 0.05) with no significant change after LAD stop-flow icCDCs (44.8 ± 3.6 to 50.9 ± 3.1%) or vehicle (46.5 ± 2.5 to 47.7 ± 2.6%). In contrast, global icCDCs did not alter infarct volume (%LV mass) assessed at 2 days (11.2 ± 2.3 vs. 12.6 ± 2.3%), whereas it was reduced after LAD stop-flow icCDCs (7.1 ± 1.1%, P < 0.05). Histopathological analysis of remote myocardium after global icCDCs demonstrated a significant increase in myocyte proliferation (147 ± 32 vs. 14 ± 10 nuclei/10 6 myocytes, P < 0.05) and a reduction in myocyte apoptosis (15 ± 9 vs. 46 ± 10 nuclei/10 6 myocytes, P < 0.05) that increased myocyte nuclear density (1,264 ± 39 vs. 1,157 ± 33 nuclei/mm 2 , P < 0.05) and decreased myocyte diameter (13.2 ± 0.2 vs. 14.5 ± 0.3 μm, P < 0.05) compared with vehicle-treated controls. In contrast, remote zone changes after regional LAD icCDCs were no different from vehicle. These data indicate that changes in global LVEF after icCDCs are dependent upon preventing myocyte loss and hypertrophy in myocardium remote from the infarct. These arise from stimulating myocyte proliferation and reducing myocyte apoptosis indicating the importance of directing cell therapy to viable remote regions. NEW & NOTEWORTHY Administration of allogeneic cardiosphere-derived cells to the entire heart via global intracoronary infusion shortly after myocardial infarction favorably influenced left ventricular ejection fraction by preventing myocyte death and promoting myocyte proliferation in remote, noninfarcted myocardium in swine. In contrast, regional intracoronary cell infusion did not significantly affect remote zone myocyte remodeling. Global cell administration targeting viable myocardium remote from the infarct may be an effective approach to prevent adverse ventricular remodeling after myocardial infarction.

Background: Children who have undergone splenectomy may develop impaired immunologic function and heightened risk of overwhelming postsplenectomy infection. We sought to define the long-term rate of and risk factors for postsplenectomy sepsis., Methods: We leveraged the Military Health System Data Repository, a nationally representative claims database including >3 million children registered as dependents of members of the United States Armed Services (2005-2014). Inclusion criterion was splenectomy at age 18 years or prior. The primary outcome was hospitalization for sepsis., Results: Among 195 children who underwent splenectomy, 7% (n = 13) were hospitalized with sepsis, with an incidence of 1.8 (95% CI = 1.0-3.1) events per 100 person-years. The median time to sepsis was 224 days (IQR = 109-606) and 38% (5/13) of events occurred within the first postsplenectomy year. The postsplenectomy mortality rate was 1% (n = 3). After adjusting for underlying diagnosis, older age at splenectomy (HR = 0.90 per year, 95% CI = 0.81-0.99) was associated with decreased hazard of sepsis., Conclusions: In a contemporary national cohort, the prevalence of postsplenectomy sepsis was 7% (1.8 events per 100 person-years). Although most presented during the first year after splenectomy, many (62%) sepsis events occurred later, suggesting that postsplenectomy immunologic dysfunction persists beyond one year. The immunologic consequences of asplenia must continue to be acknowledged, as postsplenectomy sepsis remains a serious concern., Type of Study: Prognosis study., Level of Evidence: Level III., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Neuroblastoma is an embryonic cancer arising from neural crest stem cells. This cancer is the most common malignancy in infants and the most common extracranial solid tumor in children. The clinical course may be highly variable with the possibility of spontaneous regression in the youngest patients and increased risk of aggressive disease in older children. Clinical heterogeneity is a consequence of the diverse biologic characteristics that determine patient risk and survival. This review will focus on current progress in neuroblastoma staging, risk stratification, and treatment strategies based on advancing knowledge in tumor biology and genetic characterization. TYPE OF STUDY: Review article. LEVEL OF EVIDENCE: Level II., (Copyright © 2018 Elsevier Inc. All rights reserved.)