Longitudinal assessment of Leydig cell function in male survivors of childhood cancer.

BACKGROUND: As the number and longevity of childhood cancer survivors increases, assessing treatment-associated late effects remains crucial. We longitudinally examined the incidence of and associated risk factors for Leydig cell dysfunction (LCD) and Leydig cell failure (LCF) in men treated for pediatric cancers at our institution. PROCEDURE: We performed a retrospective longitudinal cohort study of adult male survivors treated for various childhood cancers who are at risk for LCD. The outcomes of interest were serum testosterone and luteinizing hormone (LH) levels during childhood and adulthood. Risk factors assessed included treatment with stem cell transplant, total body irradiation (TBI), and exposure to alkylating agents. RESULTS: Out of 118 eligible subjects, 7.6% had LCF and 14.4% had LCD. Median age at last testosterone level was 20 years. Subjects with sufficient testosterone levels in adulthood (N = 105) remained sufficient for a mean of 11.1 years following completion of cancer treatment. We found significant associations between LCF and treatment with TBI (p < .003) and between LCF in adulthood and testosterone insufficiency in childhood (p < .001). No statistically significant association was found between LCF and cyclophosphamide equivalent dose greater than 20 g/m2 (p = .2). LCF/LCD occurred in a small number of nonirradiated patients treated with the highest doses of alkylators. CONCLUSIONS: Incidence of LCF and LCD are low in male survivors of childhood cancer. Longitudinally, there is an association between childhood testosterone insufficiency and LCF in adulthood. Alkylating agents and stem cell transplant without TBI were not associated with LCF in our study.

Is Multifocality a Predictor of Poor Outcome in Childhood and Adolescent Papillary Thyroid Carcinoma?

CONTEXT: Total thyroidectomy in pediatric papillary thyroid carcinoma (PTC) is recommended in national guidelines because of the high incidence of multifocal disease (MFD). OBJECTIVE: To determine the incidence of MFD in childhood and adolescent vs adult PTC and whether MFD is a predictor for poorer outcomes in childhood and adolescent PTC. METHODS: We conducted an institutional review board-approved review of patients with PTC undergoing surgery (1986-2021) at Memorial Sloan Kettering Cancer Center. Clinical and pathological characteristics in patients with unifocal disease (UFD) and MFD were compared using Pearson's χ2 test. Survival outcomes were analyzed using the Kaplan-Meier method and log-rank test. Multivariate analysis assessed the impact of MFD on outcome. RESULTS: MFD was less common in childhood and adolescent patients with PTC (45%; 127/283) than in adults (54%; 3023/5564; P = .002). Childhood and adolescent patients with UFD and MFD had similar tumor stage and PTC subtype at presentation, with no significant difference in histopathologic features. Median follow-up was 68 months. There was no significant difference in 5-year recurrence-free probability and overall survival was 100% in both groups. There was no significant difference in 5-year contralateral lobe PTC-free probability between patients with UFD and MFD treated with lobectomy. Multivariate analysis showed MFD was not a predictor for recurrence. CONCLUSION: MFD was less common in childhood and adolescent patients with PTC than adults and was not a predictor of poor outcome on multivariate analysis, with excellent long-term outcomes in all patients with PTC. MFD does not appear to warrant completion thyroidectomy in childhood and adolescent patients selected for lobectomy.

Slipped capital femoral epiphyses: A major on-target adverse event associated with FGFR tyrosine kinase inhibitors in pediatric patients.

Fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (TKIs) are increasingly being used off label in pediatrics. Long-term safety data are limited, and serious toxicities unique to pediatrics may emerge. In a retrospective analysis of patients less than 18 years of age with recurrent/refractory FGFR altered gliomas treated with FGFR TKIs at MSKCC (n = 7), we observed slipped capital femoral epiphyses in three of seven patients along with increased linear growth velocity. Clinicians should closely monitor bone health and have a low index of suspicion for serious orthopedic complications including slipped capital femoral epiphyses and inform patients of related risks as part of consent when treating with FGFR TKIs.

Body mass affects kinetic symmetry and inflammatory markers in adolescent knees during gait.

BACKGROUND: Early-onset osteoarthritis has been attributed to pro-inflammatory factors and biomechanical changes in obesity. However, research has yet to explore whether knee joint moments are asymmetrical in children with obesity and could precede the onset of knee osteoarthritis. The present study compares knee moment asymmetry between adolescents with and without obesity and examines the relationship between asymmetries and inflammatory biomarkers. METHODS: Twenty-eight adolescents (13-16 years) were classified as with (n = 12) or without (n = 16) obesity. Lower extremity kinetics were measured using three-dimensional motion analysis. Bilateral knee joint moments were analyzed in the sagittal, frontal, and transverse planes across stance phase. Kinetic asymmetry was calculated between the right and left sides and represented by the R2 value. Enzyme-linked immunosorbent assays analyzed serum 25-hydroxy vitamin D, interferon gamma, tumor nercrosis factor alpha, interleukin-6, and C-reactive protein levels. Parametric and non-parametric tests determined significant group differences in asymmetries and biomarkers, respectively. Spearman's correlations identified relationships between biomarkers and asymmetries with statistically significant group differences. FINDINGS: Adolescents with obesity had greater sagittal (loading, midstance) and frontal (midstance, pre-swing) plane kinetic knee asymmetry and higher concentrations of interleukin-6 and C-reactive protein. A moderately negative correlation existed between C-reactive protein and sagittal (loading, midstance) plane asymmetry, and also between interleukin-6 and frontal (pre-swing) plane asymmetry. INTERPRETATION: Inflammatory response increases with greater knee joint asymmetry, suggesting knee joint damage and altered joint loading co-exist in adolescents with obesity. Increased risk to joint health may exist in sub-phases where knee joints are improperly loaded.

Dysglycemia screening with oral glucose tolerance test in adolescents with polycystic ovary syndrome and relationship with obesity.

BACKGROUND: Adolescents with polycystic ovary syndrome (PCOS) are at increased risk of impaired glucose tolerance (IGT) and type 2 diabetes mellitus. The aim of this study is to evaluate dysglycemia and biochemical differences based on BMI status and assess the prognostic ability of elevated hemoglobin A1c (HbA1c) in predicting an abnormal 2 hour oral glucose tolerance test (OGTT). METHODS: Retrospective cohort of female patients aged 11-18 years who underwent 75-g OGTT and were evaluated for PCOS at an urban tertiary care hospital between January 2002 to December 2017. RESULTS: In 106 adolescents with PCOS who had OGTT results available, IGT was markedly pronounced in the ≥95th percentile BMI group (17 out of 72; 23.6%) compared with <95th percentile BMI group (4 out of 34; 11.7%). One patient with obesity met the criteria for type 2 diabetes. Patients with obesity had significantly higher homeostasis model assessment (HOMA-IR) and lower whole body insulin sensitivity index (WBISI) (p < 0.001) compared to patients without obesity. Free testosterone levels were also higher in patients with obesity (p< 0.03) and were significantly associated with HOMA-IR when controlling for body mass index (BMI). HbA1c did not demonstrate a strong ability to predict abnormal OGTT on receiver operating characteristic (ROC) curve analysis [Area under the curve (AUC) = 0.572, 95% CI: 0.428, 0.939]). CONCLUSIONS: In a study to assess glucose abnormalities in adolescents with PCOS, IGT was found to be markedly increased in patients with obesity, with abnormal glucose metabolism identified in over one-fifth of the patients. HbA1c alone may be a poor test to assess IGT and we recommend that adolescents diagnosed with PCOS and obesity undergo formal oral glucose tolerance testing.

Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement.

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Biochemical measures of ovarian function in female survivors of retinoblastoma treated with intra-arterial melphalan: an initial report.

Since 2006, ophthalmic artery chemosurgery (OAC) has been used for ocular-sparing treatment of retinoblastoma. Systemic exposure to melphalan is known to cause ovarian dysfunction, but the effect of melphalan-based OAC has not yet been determined. Here, we assess biochemical and symptomatic measures of ovarian function in a cohort of pubertal female survivors of retinoblastoma treated with melphalan-based OAC. These 13 patients all had normal gonadotropins at a median age of 11.1 years, 9.6 years from the completion of therapy. None had symptoms of ovarian dysfunction. This study provides initial evidence that ovarian function remains intact after melphalan-based OAC.

Possible Iodine-Induced Thyrotoxicosis in a Previously Healthy Adolescent following Administration of Iodinated Contrast Media.

Introduction. Jod-Basedow Syndrome refers to a paradoxical phenomenon in which large loads of iodine can cause hyperthyroidism. It is most commonly seen in populations already at risk for thyroid disease or those with underlying kidney disease. Case Presentation. We present a case of an acutely ill 17-year-old boy with symptomatic hyperthyroidism following an iodinated contrast CT scan to rule out appendicitis. Discussion/Conclusion. This case underscores the importance of recognizing this phenomenon even in the pediatric population and in those with no preexisting history of thyroid disease. Course complications including bronchospasm, hypertension, transaminitis, and bilateral palmar desquamating rash are rare and highlight the complexities involved in the disease state and in managing side effect profiles of treatment.

COVID-19 in pediatric survivors of childhood cancer and hematopoietic cell transplantation from a single center in New York City.

Childhood cancer survivors are at increased risk for treatment-related late effects; data are lacking on how coronavirus disease 2019 (COVID-19) infection impacts this cohort. We assessed COVID-19-related symptoms, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG seroprevalence, and rate of COVID-19-related hospitalization among 321 asymptomatic survivors of childhood cancer or transplantation seen for routine long-term follow-up between May and September 2020 in a New York City tertiary cancer center. While 10.9% (n = 35) reported possible COVID-19-related symptoms, 7.8% (n = 20) of those tested had positive SARS-CoV-2 IgG, and one patient (0.3%) required COVID-19-related hospitalization. This report suggests that childhood cancer survivors appear to be at relatively low risk for COVID-19 complications.

LONG-TERM FOLLOW UP AND TREATMENT OUTCOMES OF A 2 YEAR-OLD-BOY WITH METASTATIC TESTOSTERONE-SECRETING ADRENOCORTICAL CARCINOMA.

OBJECTIVE: Treatment of metastatic adrenocortical carcinoma (ACC) is challenging and long-term survival rates are exceedingly low. Long-term outcome data for pediatric patients who received mitotane is very limited. METHODS: We describe the case of a 2-year-old boy with ACC with a lung metastasis. He was treated with surgery, chemotherapy, and mitotane, and remains disease-free 13 years after diagnosis. RESULTS: The key endocrine issues learned from this case include: adrenal-derived sex-steroid and insulin-like growth factor-2 levels are correlated with disease status; very high doses of glucocorticoid and mineralocorticoid are required while on treatment of mitotane; and central precocious puberty needs to be detected and treated in a timely manner to preserve final adult height. CONCLUSION: We report a case of pediatric ACC with metastasis that was successfully treated with surgery, chemotherapy, and adjuvant therapy with mitotane. Appropriate endocrine testing and management are important for long-term survival and quality of life.

Utilization of clinical genetic counseling among childhood and young adult cancer survivors in a registry trial.

We describe utilization of clinical genetic services among survivors of childhood and young adult cancer after participation in a genetic registry. Clinical genetic counselors flagged 162 out of 1069 pedigrees (15.2%) as suggestive of inheritable cancer susceptibility, resulting in 126 (11.8%) referral letters. Following delivery of the referral letters, 19 (15.1%) participants completed clinical genetic counseling, 16 (12.7%) received testing, and four (3.2%) were found to have actionable results. Our results suggest a discordance between reported willingness to undergo genetic counseling and real-world utilization.

Anxiety and Type 1 Diabetes Management: Guardian and Child Report in a Pediatric Endocrinology Clinic.

BACKGROUND: Childhood anxiety prevents optimal diabetes management yet may be underrecognized by guardians. OBJECTIVE: We aimed to investigate associations among anxiety, diabetes treatment adherence, and diabetes symptom control through child and guardian report. METHODS: Cross-sectional pilot study surveying a convenience sample of children (ages 2-21) in a pediatric endocrinology clinic. Behavior Assessment System for Children, Second Edition 2, Self-Care Inventory Report, and Pediatric Quality of Life measured anxiety, diabetes treatment adherence, and diabetes symptom control. Analyses were performed with Spearman correlations. RESULTS: Prevalence of anxiety and related behaviors was higher when reported by children (13% and 24%) vs. guardians (5% and 13%). Child-reported anxiety was associated with worse symptom control in all ages (Pediatric Quality of Life [rs = -0.55, P < 0.01]) and worse treatment adherence in children aged ≤12 (Self-Care Inventory Report [rho = -0.601, P = 0.023]). Guardian-reported anxiety was associated with worse symptom control (Peds QL [rs = -0.38, P = 0.02]). Child- and guardian-reported anxiety were positively correlated (rho = 0.426, P = 0.017)-particularly for children aged >12 (rho = 0.686, P = 0.003)-although not significantly for children ≤ 12 (rho = 0.201, P = 0.473). CONCLUSION: Anxiety in children with type 1 diabetes varies with the domain of diabetes management (treatment adherence vs. symptom control) and reporting source (child vs. guardian). Children aged ≤12 exhibited a stronger relationship between higher anxiety and worse diabetes management with worse treatment adherence and symptom control in the presence of higher anxiety. Guardians of younger children were less effective at recognizing symptoms. Challenges identifying anxiety and its detrimental effects on diabetes management suggest routine screening of anxiety in pediatric endocrinology clinics is especially salient.

Care of Children and Adolescents with Diabetes Mellitus and Hyperglycemia in the Inpatient Setting.

PURPOSE OF REVIEW: Children and adolescents with acute hyperglycemia and diabetes mellitus frequently have acute, potentially life-threatening presentations which require high-acuity care in an inpatient and often intensive care setting. This review discusses the evaluation and care of hyperglycemia and diabetes mellitus in hospitalized children in both critical and non-critical care settings, highlighting important differences in their care relative to adults. RECENT FINDINGS: Diabetic ketoacidosis remains highly prevalent at diagnosis among children with type 1 diabetes, and hyperglycemic hyperosmolar state is increasingly prevalent among children with type 2 diabetes. Recent clinical trials have investigated the potential benefits of various types of intravenous fluids and their rates of administration as well as the risks and benefits of intensive glucose control in critically ill children. The Endocrine Society has developed guidelines focused on managing hyperglycemic hyperosmolar state, outlining important aspects of care shown to decrease morbidity and mortality. In the non-critical illness setting, intensive therapy on newly diagnosed diabetes is increasingly recommended at the outset. With the increasing incidence of diabetes mellitus in children and adolescents, recent studies addressing acute diabetes emergencies help inform best practices for care of hospitalized children with hyperglycemia and diabetes.

Growth Disturbances in Childhood Cancer Survivors.

Survival from childhood cancer has improved dramatically over the last few decades, resulting in an increased need to address the long-term follow-up and care of childhood cancer survivors. Appropriate linear growth is an important measure of health, with alterations of growth in children and short adult height in those who have completed growth serving as potential indicators of the sequelae of the underlying diagnosis or the cancer treatments. It is therefore critical that clinicians, particularly endocrinologists, be familiar with the patterns of altered growth which may be seen following diagnosis and treatment for childhood cancer. In this article, we will review the growth alterations seen in childhood cancer survivors, focusing on risk factors and considerations in evaluation and care.

Insulin and glucose homeostasis in childhood cancer survivors treated with abdominal radiation: A pilot study.

BACKGROUND: Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for both insulin-dependent and non-insulin-dependent diabetes. We sought to clarify the pathophysiology of diabetes after abdRT by performing dynamic studies of insulin and glucose and testing for type 1 diabetes-associated autoantibodies. PROCEDURE: Cross-sectional analysis of 2-year childhood cancer survivors treated with abdRT at age ≤21 years who underwent oral glucose tolerance testing and assessment of diabetes-related autoantibodies from December 2014 to September 2016. Prevalence of insulin/glucose derangements, indices of insulin sensitivity/secretion (homeostatic model assessment of insulin resistance [HOMA-IR], whole-body insulin sensitivity, insulinogenic index), autoantibody positivity, and treatment/demographic factors associated with adverse metabolic outcomes were assessed. RESULTS: Among 40 participants previously exposed to abdRT (57.5% male; median age at cancer diagnosis, 3.3 years [range, 0.5-20.1]; median age at study 14.3 years [range, 8.3-49.8]; none with obesity), 9 (22.5%) had glucose derangements (n = 4 with impaired fasting glucose [≥100 mg/dL]; n = 4 with impaired glucose tolerance [2-hour glucose 140-199 mg/dL]; n = 1 with previously unrecognized diabetes [2-hour glucose ≥200 mg/dL]). Three of the four individuals with impaired fasting glucose also had insulin resistance, as measured by HOMA-IR; an additional four subjects with normal glucose tolerance were insulin resistant. The subject with diabetes had normal HOMA-IR. No participant had absolute insulinopenia or >1 positive diabetes-related autoantibody. CONCLUSIONS: This study suggests that radiation-induced damage to the insulin-producing ß-cells is an unlikely explanation for the early derangements in glucose metabolism observed after abdRT. Research into alternative pathways leading to diabetes after abdRT is needed.

Hypothalamic-Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline.

Objective: To formulate clinical practice guidelines for the endocrine treatment of hypothalamic-pituitary and growth disorders in survivors of childhood cancer. Participants: An Endocrine Society-appointed guideline writing committee of six medical experts and a methodologist. Conclusions: Due to remarkable improvements in childhood cancer treatment and supportive care during the past several decades, 5-year survival rates for childhood cancer currently are >80%. However, by virtue of their disease and its treatments, childhood cancer survivors are at increased risk for a wide range of serious health conditions, including disorders of the endocrine system. Recent data indicate that 40% to 50% of survivors will develop an endocrine disorder during their lifetime. Risk factors for endocrine complications include both host (e.g., age, sex) and treatment factors (e.g., radiation). Radiation exposure to key endocrine organs (e.g., hypothalamus, pituitary, thyroid, and gonads) places cancer survivors at the highest risk of developing an endocrine abnormality over time; these endocrinopathies can develop decades following cancer treatment, underscoring the importance of lifelong surveillance. The following guideline addresses the diagnosis and treatment of hypothalamic-pituitary and growth disorders commonly encountered in childhood cancer survivors.

Improving Male Reproductive Health After Childhood, Adolescent, and Young Adult Cancer: Progress and Future Directions for Survivorship Research.

Reproductive health is a common concern and often a source of distress for male childhood, adolescent, and young adult cancer survivors. Clinical and epidemiologic research in survivor populations has identified alkylating agent chemotherapy, testicular radiation, and surgery or radiation to the genitourinary organs, lower spine, or the hypothalamic-pituitary region as risk factors for adverse reproductive outcomes, including impaired spermatogenesis, testosterone insufficiency, and sexual dysfunction. Much of the research on male survivors has focused on the outcome of fertility, using spermatogenesis, serum gonadotropins, and paternity as the measures. However, these studies often fail to account for the clinically relevant but difficult-to-quantify aspects of fertility such as sexual function, cancer-related delayed psychosocial development, medical comorbidities, and socioeconomic concerns. Clinical and basic science research has made significant contributions to improving reproductive outcomes for survivors, with recent advancements in the areas of fertility preservation, clinical assessment of reproductive function, and treatment of adverse reproductive outcomes. Furthermore, there is an emerging qualitative literature addressing the psychosexual aspects of male reproductive health, the clinical application of which will improve quality of life for survivors. This review summarizes the current survivorship literature on reproductive health outcomes for male survivors, including the epidemiology of impaired spermatogenesis, testosterone insufficiency, and sexual dysfunction; clinical and laboratory assessment of reproductive function; and established and investigational interventions to preserve reproductive function for patients newly diagnosed and survivors. Although survivorship research has made significant contributions to improving reproductive outcomes, additional scientific progress is needed in the areas of fertility preservation, risk assessment, and psychosexual support with the aim of optimizing reproductive health for current and future survivors.

New Agents, Emerging Late Effects, and the Development of Precision Survivorship.

Incremental improvements in the treatment of children and adolescents with cancer have led to 5-year survival rates reaching nearly 85%. In the past decade, impressive progress has been made in understanding the biology of many pediatric cancers. With that understanding, multiple new agents have become available that offer the promise of more-effective and less-toxic treatment. These include agents that target various cell surface antigens and engage the adaptive immune system, as well as those that interfere with key signaling pathways involved in tumor development and growth. For local control, surgery and radiation techniques also have evolved, becoming less invasive or featuring new techniques and particles that more precisely target the tumor and limit the dose to normal tissue. Nevertheless, targeted agents, like conventional chemotherapy, radiotherapy, and surgery, may have off-target effects and deserve long-term follow-up of their safety and efficacy. These include injury to the endocrine, cardiovascular, and immunologic systems. New radiation and surgical techniques that theoretically reduce morbidity and improve long-term quality of life must also be validated with actual patient outcomes. Finally, with advances in genomics, information on host susceptibility to late effects is beginning to emerge. Such knowledge, coupled with improved metrics that better describe the spectrum of potential late effects across the entire lifespan, can lead to the development of decision models that project the potential long-term health outcomes associated with various treatment and follow-up strategies. These developments will help extend the current focus on precision medicine to precision survivorship, where clinicians, patients, and families will have a better grasp of the potential risks, benefits, and tradeoffs associated with the growing number of cancer treatment options.

An alternative to the "Star Path" enhancement of the ADMA linear scaling method for protein modeling.

With the aim of improving the performance of macromolecular quantum chemistry conformation analysis and reaction path following methods, the Adjustable Density Matrix Assembler (ADMA) method has already been combined with some faster although less accurate density matrix extrapolation methods, such as the Löwdin-Inverse-Löwdin (LIL) extrapolation along a potential energy surface, and a strategically arranged back-and-forth switching between these methods has been proven to be advantageous. Here, an alternative approach is proposed and investigated, based on several actual test calculations, where the "inexpensive" LIL density matrix extrapolation steps are replaced by only somewhat more expensive, but still ADMA-based calculations, where in the "rough-search stage," only interactions of shorter distances within the macromolecule are considered. It is shown that this approach is viable, as an alternative to the "Star Path" method including both ADMA and LIL steps. © 2017 Wiley Periodicals, Inc.