Factors influencing risk-based care of the childhood cancer survivor in the 21st century.

The population of adult survivors of childhood cancer continues to grow as survival rates improve. Although it is well established that these survivors experience various complications and comorbidities related to their malignancy and treatment, this risk is modified by many factors that are not directly linked to their cancer history. Research evaluating the influence of patient-specific demographic and genetic factors, premorbid and comorbid conditions, health behaviors, and aging has identified additional risk factors that influence cancer treatment-related toxicity and possible targets for intervention in this population. Furthermore, although current long-term follow-up guidelines comprehensively address specific therapy-related risks and provide screening recommendations, the risk profile of the population continues to evolve with ongoing modification of treatment strategies and the emergence of novel therapeutics. To address the multifactorial modifiers of cancer treatment-related health risk and evolving treatment approaches, a patient-centered and risk-adapted approach to care that often requires a multidisciplinary team approach, including medical and behavioral providers, is necessary for this population. CA Cancer J Clin 2018;68:133-152. © 2018 American Cancer Society.

Assisted reproductive technology use and outcomes in childhood cancer survivors.

BACKGROUND: Treatment exposures for childhood cancer reduce ovarian reserve. However, the success of assisted reproductive technology (ART) among female survivors is not well established. METHODS: Five-year survivors of childhood cancer in the Childhood Cancer Survivor Study were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, which captures national ART outcomes. The authors assessed the live birth rate, the relative risk (RR) with 95% confidence intervals (95% CIs), and associations with treatment exposure using generalized estimating equations to account for multiple ovarian stimulations per individual. Siblings from a random sample of survivors were recruited to serve as a comparison group. RESULTS: Among 9885 female survivors, 137 (1.4%; median age at diagnosis, 10 years [range, 0-20 years]; median years of follow-up after age 18 years, 11 years [range, 2-11 years]) underwent 224 ovarian stimulations using autologous or donor eggs and/or gestational carriers (157 autologous ovarian stimulation cycles, 67 donor ovarian stimulation cycles). In siblings, 33 (1.4%) underwent 51 autologous or donor ovarian stimulations. Of those who used embryos from autologous eggs without using gestational carriers, 97 survivors underwent 155 stimulations, resulting in 49 live births, for a 31.6% chance of live birth per ovarian stimulation (vs. 38.3% for siblings; p = .39) and a 43.9% chance of live birth per transfer (vs. 50.0%; p = .33). Prior treatment with cranial radiation therapy (RR, 0.44; 95% CI, 0.20-0.97) and pelvic radiation therapy (RR, 0.33; 95% CI, 0.15-0.73) resulted in a reduced chance of live birth compared with siblings. The likelihood of live birth after ART treatment in survivors was not affected by alkylator exposure (cyclophosphamide-equivalent dose, ≥8000 mg/m2 vs. none; RR, 1.04; 95% CI, 0.52-2.05). CONCLUSIONS: Childhood cancer survivors are as likely to undergo treatment using ART as sibling controls. The success of ART treatment was not reduced after alkylator exposure. The results from the current study provide needed guidance on the use of ART in this population.

Concomitant Wilms tumor and autosomal dominant polycystic kidney disease.

BACKGROUND: Concomitant Wilms tumor (WT) and autosomal dominant polycystic kidney disease (ADPKD) is exceedingly rare, presenting a diagnostic and technical challenge to pediatric surgical oncologists. The simultaneous workup and management of these disease processes are incompletely described. PROCEDURE: We performed a retrospective analysis of patients treated at our institution with concomitant diagnoses of WT and ADPKD. We also review the literature on the underlying biology and management principles of these conditions. RESULTS: We present three diverse cases of concomitant unilateral WT and ADPKD who underwent nephrectomy. One patient had preoperative imaging consistent with ADPKD with confirmatory testing postoperatively, one was found to have contralateral renal cysts intraoperatively with confirmatory imaging post nephrectomy, and one was diagnosed in childhood post nephrectomy. All patients are alive at last follow-up, and the patient with longest follow-up has progressed to end-stage kidney failure requiring transplantation and dialysis in adulthood. All patients underwent germline testing and were found to have no cancer predisposition syndrome or pathogenic or likely pathogenic variants for WT. CONCLUSION: Concomitant inheritance of ADPKD and development of WT are extremely rare, and manifestations of ADPKD may not present until late childhood or adulthood. ADPKD is not a known predisposing condition for WT. When ADPKD diagnosis is made by family history, imaging, and/or genetic testing before WT diagnosis and treatment, the need for extensive preoperative characterization of cystic kidney lesions in children and increased risk of post-nephrectomy kidney failure warrant further discussion of surgical approach and perioperative management strategies.

Primary hypothyroidism in childhood cancer survivors: Prevalence, risk factors, and long-term consequences.

BACKGROUND: Data on primary hypothyroidism and its long-term impact on the health, cognition, and quality of life (QOL) of childhood cancer survivors are limited. This study examined the prevalence of and risk factors for primary hypothyroidism and its associations with physical, neurocognitive, and psychosocial outcomes. METHODS: This was a retrospective study with a cross-sectional health outcome analysis of an established cohort comprising 2965 survivors of childhood cancer (52.8% male; median current age, 30.9 years, median time since cancer diagnosis, 22.3 years). Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between primary hypothyroidism and cancer-related risk factors, cardiovascular disease risk factors, frailty, neurocognitive and QOL outcomes, social attainment, and subsequent thyroid carcinoma. Associations between serum free thyroxine and thyrotropin levels at assessment and health outcomes were explored. RESULTS: The prevalence of primary hypothyroidism was 14.7% (95% CI, 13.5%-16.0%). It was more likely in females (OR, 1.06; 95% CI, 1.03-1.08), was less likely in non-Whites (OR, 0.96; 95% CI, 0.93-0.99), was associated with thyroid radiotherapy (higher risk at higher doses), and was more common if cancer was diagnosed at an age ≥ 15.0 years versus an age < 5 years (OR, 1.05; 95% CI, 1.01-1.09). Primary hypothyroidism was associated with frailty (OR, 1.54; 95% CI, 1.05-2.26), dyslipidemia (OR, 1.52; 95% CI, 1.14-2.04), impaired physical QOL (OR, 1.66; 95% CI, 1.12-2.48), and having health care insurance (OR, 1.51; 95% CI, 1.07-2.12). CONCLUSIONS: Primary hypothyroidism is common in survivors and is associated with unfavorable physical health and QOL outcomes. The impact of thyroid hormone replacement practices on these outcomes should be investigated further.

Childhood Neurotoxicity and Brain Resilience to Adverse Events during Adulthood.

OBJECTIVE: This study used childhood cancer survivors as a novel model to study whether children who experience central nervous system (CNS) injury are at higher risk for neurocognitive impairment associated with subsequent late onset chronic health conditions (CHCs). METHODS: Adult survivors of childhood cancer (n = 2,859, ≥10 years from diagnosis, ≥18 years old) completed a comprehensive neurocognitive battery and clinical examination. Neurocognitive impairment was defined as age-adjusted z score < 10th percentile. Participants impaired on ≥3 tests had global impairment. CHCs were graded using the Common Terminology Criteria for Adverse Events v4.3 (grade 1, mild; 2, moderate; 3, severe/disabling; 4, life-threatening) and were combined into a severity/burden score by frequency and grade (none/low, medium, high, and very high). A total of 1,598 survivors received CNS-directed therapy including cranial radiation, intrathecal methotrexate, or neurosurgery. Logistic regression estimated the odds of neurocognitive impairment associated with severity/burden score and grade 2 to 4 conditions, stratified by CNS treatment. RESULTS: CNS-treated survivors performed worse than non-CNS-treated survivors on all neurocognitive tests and were more likely to have global neurocognitive impairment (46.9% vs 35.3%, p < 0.001). After adjusting for demographic and treatment factors, there was a dose-response association between severity/burden score and global neurocognitive impairment, but only among CNS-treated survivors (high odds ratio [OR] = 2.24, 95% confidence interval [CI] = 1.42-3.53; very high OR = 4.07, 95% CI = 2.30-7.17). Cardiovascular and pulmonary conditions were associated with processing speed, executive function, and memory impairments in CNS-treated but not non-CNS-treated survivors who were impacted by neurologic conditions. INTERPRETATION: Reduced cognitive/brain reserve associated with CNS-directed therapy during childhood may make survivors vulnerable to adverse cognitive effects of cardiopulmonary conditions during adulthood. ANN NEUROL 2021;89:534-545.

Kidney Function after Treatment for Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study.

BACKGROUND: Survivors of childhood cancer may be at increased risk for treatment-related kidney dysfunction. Although associations with acute kidney toxicity are well described, evidence informing late kidney sequelae is less robust. METHODS: To define the prevalence of and risk factors for impaired kidney function among adult survivors of childhood cancer who had been diagnosed ≥10 years earlier, we evaluated kidney function (eGFR and proteinuria). We abstracted information from medical records about exposure to chemotherapeutic agents, surgery, and radiation treatment and evaluated the latter as the percentage of the total kidney volume treated with ≥5 Gy (V5), ≥10 Gy (V10), ≥15 Gy (V15), and ≥20 Gy (V20). We also used multivariable logistic regression models to assess demographic and clinical factors associated with impaired kidney function and Elastic Net to perform model selection for outcomes of kidney function. RESULTS: Of the 2753 survivors, 51.3% were men, and 82.5% were non-Hispanic White. Median age at diagnosis was 7.3 years (interquartile range [IQR], 3.3-13.2), and mean age was 31.4 years (IQR, 25.8-37.8) at evaluation. Time from diagnosis was 23.2 years (IQR, 17.6-29.7). Approximately 2.1% had stages 3-5 CKD. Older age at evaluation; grade ≥2 hypertension; increasing cumulative dose of ifosfamide, cisplatin, or carboplatin; treatment ever with a calcineurin inhibitor; and volume of kidney irradiated to ≥5 or ≥10 Gy increased the odds for stages 3-5 CKD. Nephrectomy was significantly associated with stages 3-5 CKD in models for V15 or V20. CONCLUSIONS: We found that 2.1% of our cohort of childhood cancer survivors had stages 3-5 CKD. These data may inform screening guidelines and new protocol development.

Fertility preservation for male patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Male patients with childhood, adolescent, and young adult cancer are at an increased risk for infertility if their treatment adversely affects reproductive organ function. Future fertility is a primary concern of patients and their families. Variations in clinical practice are barriers to the timely implementation of interventions that preserve fertility. As part of the PanCareLIFE Consortium, in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in male patients who are diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. Recognising the need for global consensus, this clinical practice guideline used existing evidence and international expertise to rigorously develop transparent recommendations that are easy to use to facilitate the care of male patients with childhood, adolescent, and young adult cancer who are at high risk of fertility impairment and to enhance their quality of life.

Communication and ethical considerations for fertility preservation for patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.

Testicular involvement of acute lymphoblastic leukemia in children and adolescents: Diagnosis, biology, and management.

Acute lymphoblastic leukemia (ALL) in children and adolescents can involve the testes at diagnosis or upon relapse. The testes were long considered pharmacologic sanctuary sites, presumably because of the blood-testis barrier, which prevents the entry of large-molecular-weight compounds into the seminiferous tubule. Patients with testicular involvement were historically treated with testicular irradiation or orchiectomy. With the advent of contemporary intensive chemotherapy, including high-dose methotrexate, vincristine/glucocorticoid pulses, and cyclophosphamide, testicular leukemia present at diagnosis can be eradicated, with the risk of testicular relapse being 2% or lower. However, the management of testicular leukemia is not well described in the recent literature and remains relevant in low- and middle-income countries where testicular relapse is still experienced. Chemotherapy can effectively treat late, isolated testicular B-cell ALL relapses without the need for irradiation or orchiectomy in patients with an early response and thereby preserve testicular function. For refractory or early-relapse testicular leukemia, newer treatment approaches such as chimeric antigen receptor-modified T (CAR-T) cell therapy are under investigation. The control of testicular relapse with CAR-T cells and their penetration of the blood-testis barrier have been reported. The outcome of pediatric ALL has been improved remarkably by controlling the disease in the bone marrow, central nervous system, and testes, and such success should be extended globally. LAY SUMMARY: Acute lymphoblastic leukemia (ALL) in children and adolescents can involve the testes at diagnosis or upon relapse. Modern intensive chemotherapy has largely eradicated testicular relapse in high-income countries. Consequently, most current clinicians are not familiar with how to manage it if it does occur, and testicular relapse continues to be a significant problem in low- and middle-income countries that have not had access to modern intensive chemotherapy. The authors review the historical progress made in eradicating testicular ALL and use the lessons learned to make recommendations for treatment.

Cardiac remodeling after anthracycline and radiotherapy exposure in adult survivors of childhood cancer: A report from the St Jude Lifetime Cohort Study.

BACKGROUND: Limited data exist regarding left ventricular remodeling patterns observed in adult survivors of childhood cancer after therapy. METHODS: Among 1190 adult survivors diagnosed with childhood cancer (median age at diagnosis, 9 years [interquartile range (IQR), 3.8-14.4 years]; age at evaluation, 35.6 years [IQR, 29.5-42.8 years]), treatment exposures included anthracyclines (n = 346), chest radiotherapy (n = 174), both (n = 245), or neither (n = 425). Prospective echocardiographic assessment compared survivors with 449 noncancer controls classified according to left ventricle geometric patterns. Associations between left ventricle geometric patterns and decreased exercise tolerance were assessed. RESULTS: Overall, 28.2% of survivors (95% confidence interval [CI], 25.6%-30.8%) exhibited concentric remodeling, 2.4% (95% CI, 1.6%-3.5%) exhibited eccentric hypertrophy, and 1.1% (95% CI, 0.6%-1.9%) exhibited concentric hypertrophy. A greater proportion of survivors who received only chest radiotherapy (41%) had concentric remodeling compared with those who received only anthracyclines (24%), both (27%), or neither (27%; all P < .001), and all were greater than the proportions in noncancer controls (18%; all P < .05). Concentric remodeling was associated with radiation exposure, but not with anthracycline exposure, in multivariable models. Survivors who had concentric remodeling were more likely to have a maximal oxygen uptake peak <85% compared with those who had normal geometry (81.0% vs 66.3%; odds ratio, 1.75; 95% CI, 1.15-2.68). CONCLUSIONS: Chest radiation therapy, but not anthracycline therapy, increased the risk for concentric remodeling in survivors of childhood cancer. The presence of concentric remodeling was associated with increased exercise intolerance.

Cardiac biomarkers and association with subsequent cardiomyopathy and mortality among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort.

BACKGROUND: Survivors of childhood cancer exposed to cardiotoxic therapies are at significant cardiovascular risk. The utility of cardiac biomarkers for identifying the risk of future cardiomyopathy and mortality is unknown. METHODS: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) were assessed in 1213 adults 10 or more years from a childhood cancer diagnosis; 786 were exposed to anthracycline chemotherapy and/or chest-directed radiation therapy (RT). NT-proBNP values above age- and sex-specific 97.5th percentiles were considered abnormal. Generalized linear models estimated cross-sectional associations between abnormal NT-proBNP and anthracycline or chest RT doses as risk ratios with 95% confidence intervals (CIs). A Poisson distribution estimated rates and a Cox proportional hazards model estimated hazard ratios (HRs) for future cardiac events and death. RESULTS: At a median age of 35.5 years (interquartile range, 29.8-42.5 years), NT-proBNP and cTnT were abnormal in 22.5% and 0.4%, respectively. Exposure to chest RT and exposure to anthracycline chemotherapy were each associated with a dose-dependent increased risk for abnormal NT-proBNP (P for trend <.0001). Among exposed survivors with no history of Common Terminology Criteria for Adverse Events-graded cardiomyopathy and with normal systolic function, survivors with abnormal NT-proBNP had higher rates per 1000 person-years of cardiac mortality (2.93 vs 0.96; P < .0001) and future cardiomyopathy (32.10 vs 15.98; P < .0001) and an increased risk of future cardiomyopathy (HR, 2.28; 95% CI, 1.28-4.08) according to a multivariable assessment. CONCLUSIONS: Abnormal NT-proBNP values were prevalent and, among survivors who were exposed to cardiotoxic therapy but did not have a history of cardiomyopathy or current systolic dysfunction, identified those at increased risk for future cardiomyopathy. Further longitudinal studies are needed to confirm this novel finding.

Counseling and surveillance of obstetrical risks for female childhood, adolescent, and young adult cancer survivors: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Female childhood, adolescent, and young adult cancer survivors have an increased risk of adverse pregnancy outcomes related to their cancer- or treatment-associated sequelae. Optimal care for childhood, adolescent, and young adult cancer survivors can be facilitated by clinical practice guidelines that identify specific adverse pregnancy outcomes and the clinical characteristics of at-risk subgroups. However, national guidelines are scarce and vary in content. Here, the International Late Effects of Childhood Cancer Guideline Harmonization Group offers recommendations for the counseling and surveillance of obstetrical risks of childhood, adolescent, and young adult survivors. A systematic literature search in MEDLINE database (through PubMed) to identify all available evidence published between January 1990 and December 2018. Published articles on pregnancy and perinatal or congenital risks in female cancer survivors were screened for eligibility. Study designs with a sample size larger than 40 pregnancies in childhood, adolescent, and young adult cancer survivors (diagnosed before the age of 25 years, not pregnant at that time) were eligible. This guideline from the International Late Effects of Childhood Cancer Guideline Harmonization Group systematically appraised the quality of available evidence for adverse obstetrical outcomes in childhood, adolescent, and young adult cancer survivors using Grading of Recommendations Assessment, Development, and Evaluation methodology and formulated recommendations to enhance evidence-based obstetrical care and preconception counseling of female childhood, adolescent, and young adult cancer survivors. Healthcare providers should discuss the risk of adverse obstetrical outcomes based on cancer treatment exposures with all female childhood, adolescent, and young adult cancer survivors of reproductive age, before conception. Healthcare providers should be aware that there is no evidence to support an increased risk of giving birth to a child with congenital anomalies (high-quality evidence). Survivors treated with radiotherapy to volumes exposing the uterus and their healthcare providers should be aware of the risk of adverse obstetrical outcomes such as miscarriage (moderate-quality evidence), premature birth (high-quality evidence), and low birthweight (high-quality evidence); therefore, high-risk obstetrical surveillance is recommended. Cardiomyopathy surveillance is reasonable before pregnancy or in the first trimester for all female survivors treated with anthracyclines and chest radiation. Female cancer survivors have increased risks of premature delivery and low birthweight associated with radiotherapy targeting the lower body and thereby exposing the uterus, which warrant high-risk pregnancy surveillance.

Wilms Tumor (Nephroblastoma), Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Wilms Tumor focus on the screening, diagnosis, staging, treatment, and management of Wilms tumor (WT, also known as nephroblastoma). WT is the most common primary renal tumor in children. Five-year survival is more than 90% for children with all stages of favorable histology WT who receive appropriate treatment. All patients with WT should be managed by a multidisciplinary team with experience in managing renal tumors; consulting a pediatric oncologist is strongly encouraged. Treatment of WT includes surgery, neoadjuvant or adjuvant chemotherapy, and radiation therapy (RT) if needed. Careful use of available therapies is necessary to maximize cure and minimize long-term toxicities. This article discusses the NCCN Guidelines recommendations for favorable histology WT.

Psychological, educational, and social late effects in adolescent survivors of Wilms tumor: A report from the Childhood Cancer Survivor Study.

OBJECTIVE: To delineate the impact of treatment exposures and chronic health conditions on psychological, educational, and social outcomes in adolescent survivors of Wilms tumor. METHODS: Parent reports from the Childhood Cancer Survivor Study were analyzed for 666 adolescent survivors of Wilms tumor and 698 adolescent siblings. Adjusting for race and household income, survivors were compared to siblings on the Behavior Problems Index and educational outcomes. Multivariable modified Poisson regression estimated relative risks (RR) for therapeutic exposures and chronic health conditions (CTCAE 4.03 graded) among survivors, adjusting for sex, race, income, and age at diagnosis. RESULTS: Compared to siblings, adolescent survivors of Wilms tumor were more likely to take psychoactive medication (9.4% vs. 5.1%, p < 0.001) and utilize special education services (25.5% vs. 12.6%, p < 0.001) but did not differ significantly in emotional and behavioral problems. Survivors were less likely to be friendless (7.2% vs. 10.1%, p = 0.04) but were more likely to have difficulty getting along with friends (14.5% vs. 7.8%, p < 0.001). Among survivors, use of special education services was associated with abdomen plus chest radiation (RR = 1.98, CI:1.18-3.34). Those with grade 2-4 cardiovascular conditions had higher risk for anxiety/depression (RR = 1.95, CI:1.19-3.19), headstrong behaviors (RR = 1.91, CI:1.26-2.89), and inattention (RR = 1.56, CI:1.02-2.40). CONCLUSIONS: Adolescent survivors of Wilms tumor were similar to siblings with respect to mental health concerns overall but were more likely to require special education. Monitoring of psychosocial and academic problems through adolescence is warranted, especially among those treated with radiation to the abdomen plus chest or with cardiac conditions.

Extended field-of-view ultrasound imaging is reliable for measuring Transversus Abdominis muscle size at rest and during contraction.

BACKGROUND: The strength and size of core muscles, including the abdominal muscles, are crucial to proper function in most activities. Therefore, it is important to reliably assess these characteristics. Our primary objective was to determine if the length, thickness and cross-sectional area of the transversus abdominis (TrA) can be visualized independently from the internal and external abdominal oblique muscles using extended field of view ultrasound imaging at rest and with contraction and to establish its intra- and inter-tester reliability. METHODS: Twenty-six individuals were recruited to participate in the study (20 F, 6 M), average age 24.0 years (SD 9.4), height 170.7 cm (SD 8.6) and weight 63.9 kg (SD 9.0). From this total number of participants, two groups of 16 randomly selected participants were assessed to determine intra- and inter-tester reliability respectively. Extended field of view ultrasound images were obtained at three vertebral levels during rest and contraction in the side lying position for both the right and left sides of the trunk. RESULTS: Excellent intra-tester and inter-tester reliability was seen (ICC range of 0.972 to 0.984). The overall average percent standard error of the measurement for all measurements and locations was approximately 4%. The overall average minimal difference for the thickness measurement for the resting and contraction conditions combined were as follows: intratester 0.056 (0.014) cm and intertester 0.054 (0.017) cm, for area intratester 0.287 (0.086) cm2 and intertester 0.289 (0.101) cm2 and for length intratester 0.519 (0.097) cm and intertester 0.507 (0.085) cm. CONCLUSIONS: Extended field of view ultrasound imaging is an effective method of reliably capturing clear images of the TrA during rest and contraction. It provides an efficient mechanism for the analysis of muscle morphology by being able to measure the cross-sectional area, thickness, and length on one image. This methodology is recommended for studies investigating TrA function and training.

Diabetes mellitus among adult survivors of childhood acute lymphoblastic leukemia: A report from the St. Jude Lifetime Cohort Study.

BACKGROUND: Greater than one-half of children who are treated for acute lymphoblastic leukemia (ALL) develop ≥1 treatment-related medical conditions in their lifetime, many of which are known risk factors for diabetes mellitus. In the current study, the authors evaluated the prevalence and risk factors of diabetes mellitus among clinically assessed adult survivors of childhood ALL METHODS: The authors performed a retrospective evaluation of data from survivors of ALL and community controls who were enrolled in the St. Jude Lifetime Cohort Study between October 1, 2007, and June 30, 2016. Participants were adults with ≥10 years of survival of childhood ALL and community controls who completed clinical and laboratory evaluations. Data for the current analysis were abstracted from medical records. Exposures evaluated herein included chemotherapy and radiation exposures and medical history, including drug-induced diabetes mellitus. RESULTS: Of 1360 eligible adults who were ≥10-year survivors of childhood ALL, a total of 1044 completed the evaluations; these individuals had a mean age of 33.97±9.14 years and 50.86% were male. The 368 controls, 45.65% of whom were male, had a mean age of 35.33±10.21 years. Type 2 diabetes mellitus (T2DM) was found in approximately 7.47% of survivors and 3.80% of controls (odds ratio [OR], 2.07; 95% CI, 1.11-3.87). In adjusted models, among survivors, older age (OR, 1.05 for each additional year; 95% CI, 1.02-1.08), body mass index ≥30 kg/m2 (OR, 7.40; 95% CI, 2.61-20.97), and drug-induced diabetes mellitus occurring during ALL therapy (OR, 4.67; 95% CI, 2.53-8.61) were found to be associated with T2DM. CONCLUSIONS: Adult survivors of childhood ALL are at an increased risk of T2DM. Adult survivors of childhood ALL who are of older age, with an overweight or obese body mass index, and/or who developed drug-induced diabetes mellitus during treatment should be closely monitored for T2DM during long-term follow-up.

Clinically ascertained health outcomes, quality of life, and social attainment among adult survivors of neuroblastoma: A report from the St. Jude Lifetime Cohort.

BACKGROUND: The objective of this study was to characterize chronic disease, health-related quality of life (HRQOL), emotional distress, and social attainment among long-term survivors of neuroblastoma. METHODS: Chronic health conditions among 136 ≥10-year neuroblastoma survivors (median age, 31.9 years; range, 20.2-54.6 years) and 272 community controls (median age, 34.7 years; range, 18.3-59.6 years) were graded with a modified version of the Common Terminology Criteria for Adverse Events (version 4.03). HRQOL and emotional distress were assessed with the Medical Outcomes Study 36-Item Short Form Health Survey and the Brief Symptom Inventory-18. Log-binomial regression and logistic regression were used to compare the prevalence of chronic conditions and the frequency of reduced HRQOL, distress, and social attainment between survivors and controls. The cumulative burden approach was used to estimate multimorbidity. RESULTS: By the age of 35 years, survivors had experienced, on average, 8.5 grade 1 to 5 conditions (95% confidence interval [CI], 7.6-9.3), which was higher than the average for controls (3.3; 95% CI, 2.9-3.7). Compared with controls, survivors had a higher prevalence of any pulmonary (P = .003), auditory (P < .001), gastrointestinal (P < .001), neurological (P = .003), or renal condition (P < .001); were more likely to report poor physical HRQOL (P = .01) and symptoms of anxiety (P = .01) and somatization (P = .01); and were less likely to live independently (P = .01) or marry (P = .01). In analyses limited to survivors, those with 1 or more grade 3 to 5 conditions were more likely to report reduced general health (odds ratio [OR], 6.6; 95% CI, 1.6-26.9), greater bodily pain (OR, 4.2; 95% CI, 1.0-17.0), and unemployment (OR, 3.2; 95% CI, 1.2-8.5). CONCLUSIONS: Because of the high burden of chronic diseases and the associations of these morbidities with reduced HRQOL and social attainment, screening and interventions that provide opportunities to optimize health are important among neuroblastoma survivors.

Serum Alanine Aminotransferase Elevations in Survivors of Childhood Cancer: A Report From the St. Jude Lifetime Cohort Study.

The purpose of this study was to define the prevalence of and risk factors for elevated serum alanine aminotransferase (ALT) level among adult childhood cancer survivors (CCS). The study cohort comprised 2,751 CCS from the St. Jude Lifetime Cohort Study (>10 years postdiagnosis, age ≥18 years). Serum ALT level was graded using the Common Terminology Criteria for Adverse Events v. 4.03. Modified Poisson regression models were used to estimate relative risks and 95% confidence intervals for the association between demographic and clinical factors and grades 1-4 ALT on the selected models. A total of 1,339 (48.7%) CCS were female; 2,271 (82.6%) were non-Hispanic white. Median age at evaluation was 31.4 years (interquartile range [IQR] = 25.8-37.8); median elapsed time from diagnosis to evaluation was 23.2 years (IQR = 17.6-29.7). A total of 1,137 (41.3%) CSS had ALT > upper limit of normal (Common Terminology Criteria for Adverse Events v. 4.03 grade 1-1,058 (38.5%); grade 2-56 (2.0%); grade 3-23 (0.8%); grade 4-none). Multivariable models demonstrated non-Hispanic white race/ethnicity, age at evaluation in years, being overweight or obese, presence of the metabolic syndrome, current treatment with atorvastatin or rosuvastatin or simvastatin, hepatitis C virus infection, prior treatment with busulfan or thioguanine, history of hepatic surgery, and the percentage of liver treated with ≥10 Gray, ≥15 Gray, or ≥20 Gray were associated with elevated ALT. Conclusion: Grade 3 or 4 hepatic injury is infrequent in CCS. Mild hepatic injury in this group may be amenable to lifestyle modifications.

Psychosexual Functioning of Female Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort Study.

INTRODUCTION: There is a growing population of childhood cancer survivors at risk for adverse outcomes, including sexual dysfunction. AIM: To estimate the prevalence of and risk factors for sexual dysfunction among adult female survivors of childhood cancer and evaluate associations between dysfunction and psychological symptoms/quality of life (QOL). METHODS: Female survivors (N = 936, mean 7.8 ± 5.6 years at diagnosis; 31 ± 7.8 years at evaluation) and noncancer controls (N = 122) participating in the St. Jude Lifetime Cohort Study completed clinical evaluations, Sexual Functioning Questionnaires (SFQ), and Medical Outcomes Survey Short Forms 36 (SF-36). Linear models compared SFQ scores between sexually active survivors (N = 712) and controls; survivors with scores <10th percentile of controls were classified with sexual dysfunction. Logistic regression evaluated associations between survivor characteristics and sexual dysfunction, and between sexual dysfunction and QOL. OUTCOMES: Sexual dysfunction was defined by scores <10th percentile of noncancer controls on the SFQ overall, as well as the domains of arousal, interest, orgasm, and physical problems, while QOL was measured by scores on the SF-36 with both physical and mental summary scales. RESULTS: Sexual dysfunction was prevalent among 19.9% (95% CI 17.1, 23.1) of survivors. Those diagnosed with germ cell tumors (OR = 8.82, 95% CI 3.17, 24.50), renal tumors (OR = 4.49, 95% CI 1.89, 10.67), or leukemia (OR = 3.09, 95% CI 1.50, 6.38) were at greater risk compared to controls. Age at follow-up (45-54 vs 18-24 years; OR = 5.72, 95% CI 1.87, 17.49), pelvic surgery (OR = 2.03, 95% CI 1.18, 3.50), and depression (OR = 1.96, 95% CI 1.10, 3.51) were associated with sexual dysfunction. Hypogonadism receiving hormone replacement (vs nonmenopausal/nonhypogonadal; OR = 3.31, 95% CI 1.53, 7.15) represented an additional risk factor in the physical problems (eg, vaginal pain and dryness) subscale. Survivors with sexual dysfunction, compared to those without sexual dysfunction, were more likely to score <40 on the physical (21.1% vs 12.7%, P = .01) and mental health (36.5% vs 18.2%, P < .01) summary scales of the SF-36. Only 2.9% of survivors with sexual dysfunction reported receiving intervention. CLINICAL IMPLICATIONS: Health care providers should be aware of the increased risk of sexual dysfunction in this growing population, inquire about symptomology, and refer for appropriate intervention. STRENGTHS & LIMITATIONS: Strengths of this study include the use of a validated tool for evaluating sexual function in a large population of clinically assessed female childhood cancer survivors. Limitations include potential for selection bias, and lack of clinically confirmed dysfunction. CONCLUSION: Sexual dysfunction is prevalent among female childhood cancer survivors and few survivors receive intervention; further research is needed to determine if those with sexual dysfunction would benefit from targeted interventions. Bjornard KL, Howell CR, Klosky JL, et al. Psychosexual Functioning of Female Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort Study. J Sex Med 2020;17:1981-1994.

Cardiac autonomic dysfunction in survivors of childhood acute lymphoblastic leukemia: The St. Jude Lifetime Cohort Study.

BACKGROUND: Cardiac autonomic dysfunction (CAD) is possible following treatment for childhood cancer. The aims of our analyses were to compare the prevalence of CAD between adult survivors of childhood acute lymphoblastic leukemia and controls, compare exercise response among survivors with and without CAD, and identify treatment-related risk factors for CAD. PROCEDURE: Participants were treated for childhood acute lymphoblastic leukemia at St. Jude Children's Research Hospital between 1980 and 2003 (N = 338). A comparison group matched for race/ethnicity, age, and sex was also recruited (N = 325). Resting heart rate (HR) was assessed via electrocardiogram, and heart rate recovery (HRR) and exercise capacity were evaluated with submaximal cardiopulmonary exercise testing. RESULTS: CAD was present in 33.7% of survivors and 27.6% of controls (P = 0.09). Although mean resting HR did not differ between survivors and controls (74 ± 12 vs 72 ± 12 beats per minute (bpm), P = 0.07), survivors had lower mean HRR than controls (22 ± 9 vs 25 ± 10 bpm; P < 0.001). Survivors with CAD had lower peak exercise tolerance (25.7 ± 6.5 vs 21.2 ± 4.9 mL/kg/min, P < 0.001) than those without. Survivors treated with cyclophosphamide in combination with vincristine ≥38 mg/m2 and/or glucocorticoids ≥10 000 mg/m2 were 1.56 (95% CI 1.09-2.24) times more likely to have CAD than those without this treatment. Obese survivors were 1.78 (95% CI: 1.31-2.40) times more likely to have CAD than nonobese survivors (P < 0.001). CONCLUSION: CAD was present in over one third of survivors and was associated with lower exercise capacity. Obese survivors and those exposed to cyclophosphamide with high doses of vincristine and/or corticosteroids were at greatest risk.