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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. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) may offer therapeutic benefit in the setting of sepsis and endotoxemia. Previous studies suggest that MSCs from female donors may possess better protective capabilities than their male counterparts. The present study examined whether female MSCs may offer a greater protective advantage in the setting of endotoxemic cardiac dysfunction compared with male MSCs. Adult male Sprague-Dawley rats were injected intraperitoneally with LPS and then treated with intraperitoneal injections of either saline, female MSCs, or male MSCs. Hearts and serum were then collected for analysis of myocardial function, myocardial protein, and myocardial and serum cytokines. Compared with male MSC or vehicle-treated animals, female MSC treatment resulted in greater preservation of myocardial function (P < 0.001). Serum and myocardial levels of all measured cytokines were comparable between rats given MSCs from male or female donors but substantially improved over rats given vehicle (P < 0.05). Reduced myocardial inflammation correlated with reduced levels of phosphorylated p38 MAPK expression in the myocardium of animals injected with MSCs of either sex (P < 0.05). The Bcl-xL/Bax ratio was increased to a greater extent following treatment with female MSCs vs. male MSCs (P < 0.05). Intraperitoneal administration of MSCs is effective in limiting myocardial inflammation and dysfunction in the rat endotoxemia model. Compared with treatment with their male counterparts, MSC treatment from female donors is associated with greater cardiac protection against acute endotoxemic injury. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have been used experimentally and clinically in the treatment of a wide variety of pathologies. It is now clear that a number of different mechanisms contribute to the therapeutic effects exerted by these cells. The ability of MSCs to interact with and modulate the functions of a wide variety of immune cells has been recognized as one such mechanism. The implications that the immunomodulatory properties of MSCs may have for the treatment of solid organ rejection, the Systemic Inflammatory Response Syndrome, cancer, and Crohn’s disease are reviewed herein. [ABSTRACT FROM AUTHOR]

Human bone marrow mesenchymal stem cells (MSCs) are a potent source of growth factors, which are partiy responsible for their beneficial paracrine effects. We reported previously that transforming growth factor-α (TGF-α), a putative mediator of wound healing and the injury response, increases the release of vascular endothelial growth factor (VEGF), augments tumor necrosis factor-α (TNF-α)-stimulated VEGF production, and activates mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI-3K) pathway in human MSCs. The experiments described in this report indicate that TGF-α increases MSC-derived hepatocyte growth factor (HGF) production. TGF-α-stimulated HGF production was abolished by inhibition of MEK, p38, PI-3K, or by small interfering RNA (siRNA) targeting TNF receptor 2 (TNFR2), but was not attenuated by siRNA targeting TNF receptor 1 (TNFR1). Ablation of TNFR1 significantly increased basal and stimulated HGF. A potent synergy between TGF-α and TNF-α was noted in MSC HGF production. This synergistic effect was abolished by MEK, P38, PI-3 K inhibition, or by ablation of both TNF receptors using siRNA. We conclude that 1) novel cross talk occurs between tumor necrosis factor receptor and TGF-α/epidermal growth factor receptor in stimulating MSC HGF production; 2) this cross talk is mediated, at least partially, via activation of MEK, p38, and PI-3K; 3) TGF-α stimulates MSCs to produce HGF by MEK, p38, PI-3K, and TNFR2-dependent mechanisms; and 4) TNFR1 acts to decrease basal TGF-α and TNF-α-stimulated HGF. [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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. US National Institutes of Health, US National Cancer Institute, American Lebanese Syrian Associated Charities, and St Jude Children's Research Hospital. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Stem cell-based therapies for myocardial ischemia have demonstrated promising early clinical results, but their benefits have been limited in duration due to impaired donor cell engraftment and function. Several strategies have emerged for enhancing stem cell function prior to their therapeutic use particularly with regard to stem cell homing, paracrine function, and survival. This review discusses current understandings of stem cell-mediated cardioprotection as well as methods of enhancing post-transplantation stem cell function and survival through hypoxic preconditioning, genetic manipulation, and pharmacologic pretreatment. Materials and Methods: A literature search was performed using the MEDLINE and PubMed databases using the keywords “stem cell therapy,” “myocardial ischemia,” “hypoxic preconditioning,” “paracrine function,” and “stem cell pretreatment.” Studies published in English since January 1990 were selected. In addition, studies were identified from references cited in publications found using the search terms. Results: All included studies utilized animal studies and/or in vitro techniques. Stem cell modifications generally targeted stem cell homing (SDF-1, CXCR4), paracrine function (VEGF, angiogenin, Ang-1, HGF, IL-18 binding protein, TNFR1/2), or survival (Akt, Bcl-2, Hsp20, HO-1, FGF-2). However, individual modifications commonly exhibited pleiotropic effects involving some or all of these general categories. Conclusion: These strategies for optimizing stem cell-mediated cardioprotection present unique potential sets of advantages and disadvantages for clinical application. Additional questions remain including those that are most efficacious in terms of magnitude and duration of benefit as well as whether combinations may yield greater benefits in both the preclinical and clinical settings. [ABSTRACT FROM AUTHOR]

Over the past century, numerous animal models have been developed in an attempt to understand myocardial and vascular injury. However, the successful translation of results observed in animals to human therapy remains low. To understand this problem, we present several animal models of cardiac and vascular injury that are of particular relevance to the cardiac or vascular surgeon. We also explore the potential clinical implications and limitations of each model with respect to the human disease state. Our results underscore the concept that animal research requires an in-depth understanding of the model, animal physiology, and the potential confounding factors. Future outcome analyses with standardized animal models may improve translation of animal research from the bench to the bedside. [Copyright &y& Elsevier]

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.). [ABSTRACT FROM AUTHOR]

The incidence of and risk factors for late-onset kidney failure among survivors over the very long term remains understudied. 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. 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/m2; 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. 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. • Overall, 1.7% of childhood cancer survivors develop late-onset kidney failure after 35 years. • Kidney dose ≥15 Gy of radiotherapy, ifosfamide, anthracycline and nephrectomy are risk factors. • Diabetes and hypertension are potentially modifiable factors to mitigate risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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/m2) 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. 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. • Cholecystectomy rates are 30% higher in childhood cancer survivors than in siblings. • High-dose platinum agents, vinca alkaloids and TBI increase risk for cholecystectomy. • These agents confer increased risk in survivors without classical risk factors. • These data will inform long-term follow-up guidelines for survivors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Surgical lung biopsy is common after pediatric hematopoietic stem cell transplant. • Risk for morbidity and mortality after lung biopsy is acceptable. • Most biopsy specimens yield a specific diagnosis. • Nearly 80% of lung biopsies result in a therapeutic change for the patient. 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. [ABSTRACT FROM AUTHOR]

Purpose: We sought to determine the incidence and timing of testicular atrophy following inguinal hernia repair in children.Methods: We used the TRICARE database, which tracks care delivered to active and retired members of the US Armed Forces and their dependents, including > 3 million children. We abstracted data on male children < 12 years who underwent inguinal hernia repair (2005-2014). We excluded patients with history of testicular atrophy, malignancy or prior related operation. Our primary outcome was the incidence of the diagnosis of testicular atrophy. Among children with atrophy, we calculated median time to diagnosis, stratified by age/undescended testis.Results: 8897 children met inclusion criteria. Median age at hernia repair was 2 years (IQR 1-5). Median follow-up was 3.57 years (IQR 1.69-6.19). Overall incidence of testicular atrophy was 5.1/10,000 person-years, with the highest incidence in those with an undescended testis (13.9/10,000 person-years). All cases occurred in children [Formula: see text] 5 years, with 72% in children < 2 years. Median time to atrophy was 2.4 years (IQR 0.64-3), with 30% occurring within 1 year and 75% within 3 years.Conclusion: Testicular atrophy is a rare complication following inguinal hernia repair, with children < 2 years and those with an undescended testis at highest risk. While 30% of cases were diagnosed within a year after repair, atrophy may be diagnosed substantially later.Level Of Evidence: Prognosis Study, Level II. [ABSTRACT FROM AUTHOR]

Background: The role of thymectomy in the treatment of juvenile myasthenia gravis (JMG) is poorly defined. The objective of this systematic review was to evaluate the effect of thymectomy on survival, disease severity, and peri-operative complications for patients with JMG.Methods: A search of MEDLINE, EMBASE, and the Cochrane Library (1/1/2000-3/1/2016) identified all English language, human studies of thymectomy for JMG. The population was patients with JMG age ≤18 years who underwent thymectomy (comparator group was unexposed to thymectomy). Outcomes included survival, disease severity, and post-operative complications. Data extraction was performed by independent reviewers.Results: Sixteen retrospective studies included 1131 participants with JMG and 488 (43%) underwent thymectomy. Post-operative improvement in JMG severity occurred for 77% (n = 376/488). Comparisons of thymectomy to non-operative management were mixed. Post-operative complications were poorly recorded. Power to compare surgical approaches was limited. Outcomes specific to antibodies, surgical pathology findings, severity of JMG, and timing of thymectomy were sparse.Conclusions: Existing data regarding thymectomy for JMG are limited and entirely retrospective. The majority of patients who underwent thymectomy had improvement in disease severity and post-operative complications were rare. Prospective, multicenter study of thymectomy for JMG is warranted. [ABSTRACT FROM AUTHOR]

Background: Neonatal mesenchymal stem cells exhibit less cardioprotective potential than their adult counterparts. Transforming growth factor-α (TGF-α) has been shown to stimulate adult stem cell VEGF production, however, it remains unknown whether it may augment neonatal stem cell paracrine function. We hypothesized that TGF-α would equalize adult and neonatal stem cell paracrine function and cardioprotection during acute ischemia/reperfusion. Materials and Methods: Bone marrow mesenchymal stem cells isolated from adult and 2.5 wk-old mice were treated with TGF-α (250 ng/mL) for 24 h. VEGF, HGF, IGF-1, IL-1β, and IL-6 production were measure in vitro, and cells were infused via an intracoronary route using a model of isolated heart perfusion. Results: TGF-α equalized adult and neonatal stem cell VEGF production but did not affect production of HGF, IGF-1, IL-1β, or IL-6. ERK, p38 MAPK, and JNK phosphorylation were greater in adult cells in response to TGF-α. Whereas infusion of adult but not neonatal stem cells was associated with improved myocardial functional recovery during reperfusion, infusions of either TGF-α-pretreated cell group were associated with the greatest functional recovery. TGF-α equalizes adult and neonatal mesenchymal stem cell VEGF production and cardioprotection in association with differential regulation of ERK, p38 MAPK, and JNK phosphorylation. [ABSTRACT FROM AUTHOR]

Background: Signal transducer and activator of transcription 3 (STAT3) regulates myocardial apoptosis, cellular proliferation, and the immune response after ischemia/reperfusion (I/R). STAT3 is also necessary for the production of vascular endothelial growth factor (VEGF) by mesenchymal stem cells (MSCs), which are known to reduce myocardial injury after I/R. However, it remains unknown whether STAT3 is an important mediator of MSC-based cardioprotection. We hypothesized that knockout of stem cell STAT3 would reduce MSC-derived myocardial functional recovery and increase myocardial inflammatory and apoptotic signaling. Study Design: With a Langendorff apparatus, male rat hearts were subjected to 15 minutes of equilibration and 25 minutes of ischemia, followed by 40 minutes of reperfusion. Immediately before ischemia, hearts received intracoronary infusions of vehicle, wild-type MSCs (WT MSCs) or STAT3 knockout MSCs (STAT3KO MSCs). Heart function was measured continuously. Myocardial homogenates were analyzed for production of interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α). Additionally, MSC production of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) were measured in vitro. Results: Hearts treated with WT MSCs exhibited the greatest functional recovery, and those treated with STAT3KO MSCs had equivalent recovery to vehicle. The highest proinflammatory cytokine levels were seen in vehicle-treated hearts, and the lowest in the WT MSC group. STAT3KO MSCs produced less IGF-1, but more HGF than WT MSCs. Finally, hearts treated with STAT3KO MSCs or vehicle had significantly higher caspase-3 levels than those treated with WT MSCs. Conclusions: Intracoronary infusions of MSCs improve postischemic left ventricular function and reduce proapoptotic and proinflammatory signaling via a STAT3-dependent mechanism. [Copyright &y& Elsevier]

Background: Bone marrow-derived mesenchymal stem cells (MSC) improve myocardial recovery after ischemia/reperfusion (I/R) injury. These effects are mediated in part by the paracrine secretion of angiogenic and tissue growth-promoting factors. Toll-like receptor 4 (TLR4) is expressed by MSC and induces apoptosis and inhibits proliferation in neuronal progenitors as well as many other cell types. It is unknown whether knock-out (KO) of TLR4 will change the paracrine properties of MSC and in turn improve MSC-associated myocardial protection. Methodology/Principal Findings: This study explored the effect of MSC TLR4 on the secretion of angiogenic factors and chemokines in vitro by using ELISA and cytokine array assays and investigated the role of TLR4 on MSC-mediated myocardial recovery after I/R injury in an isolated rat heart model. We observed that MSC isolated from TLR4 KO mice exhibited a greater degree of cardioprotection in a rat model of myocardial I/R injury. This enhanced protection was associated with increased angiogenic factor production, proliferation and differentiation. TLR4-dificiency was also associated with decreased phosphorylation of PI-3K and AKT, but increased activation of STAT3. siRNA targeting of STAT3 resulted in attenuation of the enhanced cardioprotection of TLR4-deficient MSC. Conclusions/Significance: This study indicates that TLR4 exerts deleterious effects on MSC-derived cardioprotection following I/R by a STAT3 inhibitory mechanism. [ABSTRACT FROM AUTHOR]

The article examines the effects of estrogen on pulmonary artery vasoreactivity and hypoxic pulmonary vasoconstriction. It shows that estrogen exerts a variety of nongenomic actions, which may allow for future therapeutic interventions in pulmonary vascular disease. The article discusses the mechanisms of action of estrogen.