Late Health Outcomes Among Survivors of Wilms Tumor Diagnosed Over Three Decades: A Report From the Childhood Cancer Survivor Study.

2023

2638-2650

05/2023

1527-7755

PURPOSE: To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens.

METHODS: Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents.

RESULTS: Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity.

CONCLUSION: With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.

10.1200/JCO.22.02111

J Clin Oncol

36693221

Health-Related Quality of Life at Diagnosis for Pediatric Thyroid Cancer Patients.

2023

e169-e177

04/2023

1945-7197

CONTEXT: Pediatric thyroid cancer (TC) incidence rates are increasing, yet TC has one of the highest survival rates. Despite increased prevalence, little is known about youth adjustment to TC, particularly compared to other pediatric cancers.

OBJECTIVE: The current study sought to describe health-related quality of life (HRQoL) in pediatric TC patients early after diagnosis compared to other pediatric cancer patients and healthy youth and examine predictors of HRQoL.

METHODS: Pediatric TC patients (ages 8.5-23.4 years) and their caregivers from a pediatric thyroid center completed psychosocial questionnaires as part of a clinic-based screening program around time of surgery. TC HRQoL was compared to other pediatric cancer and healthy youth reported norms. Clinical and demographic data extracted from the medical record were examined for predictors of HRQoL. The main outcome measures included the Pediatric Quality of Life Inventory (PedsQL) and Distress Thermometer.

RESULTS: Findings evidenced significantly higher HRQoL for TC patients than other pediatric cancers for all but emotional and school functioning. Compared to healthy youth, TC patients reported significantly lower functioning, except comparable social functioning. No significant differences in HRQoL were identified based on disease severity, thyroid disease history, or treatment. Patient distress was associated with HRQoL.

CONCLUSION: The findings suggest general resilience in TC patients compared to youth with other cancers, yet worse HRQoL than peers. Early universal screening is warranted due to a short TC treatment regimen. If administrative barriers preclude comprehensive screening, the single-item Distress Thermometer may identify patients for further comprehensive screening.

10.1210/clinem/dgac648

J Clin Endocrinol Metab

36330655

Late Health Outcomes Among Survivors of Wilms Tumor Diagnosed Over Three Decades: A Report From the Childhood Cancer Survivor Study.

2023

JCO2202111

01/2023

1527-7755

PURPOSE: To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens.

METHODS: Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents.

RESULTS: Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity.

CONCLUSION: With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.

10.1200/JCO.22.02111

J Clin Oncol

36693221

Clinicopathologic Characteristics of Pediatric Follicular Variant of Papillary Thyroid Carcinoma Subtypes: A Retrospective Cohort Study.

2022

1353-1361

11/2022

1557-9077

Follicular patterned thyroid nodules with nuclear features of papillary thyroid carcinoma (PTC) encompass a range of diagnostic categories with varying risks of metastatic behavior. Subtypes include the invasive encapsulated follicular variant of PTC (Ienc-fvPTC) and infiltrative fvPTC (inf-fvPTC), with tumors lacking invasive features classified as noninvasive follicular thyroid neoplasms with papillary-like features (NIFTPs). This study aimed to report the clinical and histological features of pediatric cases meeting criteria for these histological subtypes, with specific focus on Ienc-fvPTC and inf-fvPTC. In this retrospective cohort study, pediatric patients with thyroid neoplasms showing follicular patterned growth and nuclear features of PTC noted on surgical pathology between January 2010 and January 2021 were retrospectively reviewed and classified according to the recent 2022 World Health Organization (WHO) criteria. Clinical and histopathologic parameters were described for NIFTP, Ienc-fvPTC, and inf-fvPTC subtypes, with specific comparison of Ienc-fvPTC and inf-fvPTC cases. The case cohort included 42 pediatric patients, with 6 (14%), 25 (60%), and 11 (26%) patients meeting criteria for NIFTP, Ienc-fvPTC, and inf-fvPTC, respectively. All cases were rereviewed, and 5 patients originally diagnosed with Ienc-fvPTC before 2017 were reappraised as having NIFTPs. The NIFTP cases were encapsulated tumors without invasive features, lymph node or distant metastasis, or disease recurrence. Ienc-fvPTC tumors demonstrated clearly demarcated tumor capsules and capsular/vascular invasion, while inf-fvPTC tumors displayed infiltrative growth lacking a capsule. inf-fvPTC cases had increased prevalence of malignant preoperative cytology, lymph node metastasis, and distant metastasis ( < 0.01). These cases were treated with total thyroidectomy, lymph node dissection, and subsequent radioactive iodine therapy. Preliminary genetic findings suggest a predominance of fusions in inf-fvPTC cases versus point mutations in Ienc-fvPTC ( = 0.02). Pediatric NIFTP and fvPTC subtypes appear to demonstrate alignment between clinical and histological risk stratification, with indolent behavior in Ienc-fvPTC and invasive features in inf-fvPTC tumors.

10.1089/thy.2022.0239

Thyroid

36103376

Health-Related Quality of Life at Diagnosis for Pediatric Thyroid Cancer Patients.

2022

11/2022

1945-7197

CONTEXT: Pediatric thyroid cancer (TC) incidence rates are increasing, yet TC has one of the highest survival rates. Despite increased prevalence, little is known about youth adjustment to TC, particularly compared to other pediatric cancers.

OBJECTIVE: The current study sought to describe health-related quality of life (HRQoL) in pediatric TC patients early after diagnosis compared to other pediatric cancer patients and healthy youth and examine predictors of HRQoL.

DESIGN: Patients completed psychosocial questionnaires as part of a clinic-based screening program around time of surgery. TC HRQoL was compared to other pediatric cancer and healthy youth reported norms. Clinical and demographic data extracted from the medical record were examined for predictors of HRQoL.

SETTING: Pediatric Thyroid Center.

PATIENTS AND OTHER PARTICIPANTS: Pediatric TC patients (ages 8.5-23.4 years) and their caregivers.

MAIN OUTCOME MEASURES: Pediatric Quality of Life Inventory (HRQoL) and distress thermometer.

RESULTS: Findings evidenced significantly higher HRQoL for TC patients than other pediatric cancers for all but emotional and school functioning. Compared to healthy youth, TC patients reported significantly lower functioning, except comparable social functioning. No significant differences in HRQoL were identified based on disease severity, thyroid disease history, or treatment. Patient distress was associated with HRQoL.

CONCLUSIONS: The findings suggest general resilience in TC patients compared to youth with other cancers, yet worse HRQoL than peers. Early universal screening is warranted due to a short TC treatment regimen. If administrative barriers preclude comprehensive screening, the single-item distress thermometer may identify patients for further comprehensive screening.

10.1210/clinem/dgac648

J Clin Endocrinol Metab

36330655

Association Between Body Composition and Development of Glucose Intolerance after Allogeneic Hematopoietic Cell Transplantation.

2022

OF1-OF7

07/2022

1538-7755

BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) recipients have increased risk of developing glucose intolerance and diabetes mellitus (DM). The strongest risk factor for glucose intolerance is being overweight/obese, as determined by body mass index (BMI), which does not account for differences in body composition. We examined the association between body composition measures from pre-HCT CT and early-onset (≤30 days) de novo glucose intolerance after HCT, and determined its impact on nonrelapse mortality (NRM).

METHODS: This study included 749 patients without pre-HCT DM. Skeletal muscle loss [abnormal skeletal muscle gauge (SMG)] and abnormal visceral adiposity (VA) were defined by sex-specific tertiles. Fine-Gray proportional subdistribution HR estimates and 95% confidence intervals (CI) were obtained to determine the association between muscle loss and VA and development of glucose intolerance. 1 year NRM was calculated for patients alive at day 30.

RESULTS: Median age at HCT was 50.2 years. By day 30, 8.1% of patients developed glucose intolerance and 731 remained alive. In multivariable analysis, abnormal SMG was associated with increased risk of glucose intolerance in nonoverweight (BMI < 25 kg/m2) patients (HR = 3.00; 95% CI, 1.15-7.81; P = 0.024); abnormal VA was associated with increased risk of glucose intolerance in overweight/obese patients (HR = 2.26; 95% CI, 1.24-4.12; P = 0.008). Glucose intolerance was independently associated with NRM (HR = 1.88; 95% CI, 1.05-3.39; P = 0.035).

CONCLUSIONS: Abnormal SMG and VA were associated with glucose intolerance in nonoverweight and overweight/obese patients, respectively, which contributed to increased risk of 1 year NRM.

IMPACT: This information may guide personalized interventions to decrease the risk of adverse outcomes after HCT.

10.1158/1055-9965.EPI-21-1449

Cancer Epidemiol Biomarkers Prev

35797113

Indeterminate Thyroid Fine-Needle Aspirations in Pediatrics: Exploring the Clinicopathologic Features and Utility of Molecular Profiling.

2022

07/2022

1663-2826

INTRODUCTION: The diagnostic utility of molecular profiling for the evaluation of indeterminate pediatric thyroid nodules is unclear. We aimed to assess pediatric cases with indeterminate thyroid fine-needle aspiration (FNA) alongside clinicopathologic features and mutational analysis.

METHODS: A retrospective review of 126 patients with indeterminate cytology who underwent FNA between January 2010 and December 2021 at the Children's Hospital of Philadelphia was performed. Indeterminate cases defined by The Bethesda System for Reporting Thyroid Cytopathology (AUS/FLUS or TBSRTC III; FN/SFN or TBSRTC IV; SM or TBSRTC V) were correlated to clinicopathologic and genetic characteristics.

RESULTS: Of the 114 surgical cases, 48% were malignant, with the majority of malignant cases diagnosed as follicular variant of papillary thyroid carcinoma (28/55). Risk of malignancy increased with TBSRTC category: 23% for AUS/FLUS, 51% for FN/SFN, and 100% for SM nodules. There were significant differences in surgical approach (p < 0.01), performance of lymph node dissection (p < 0.01), histological diagnosis (p < 0.01), primary tumor focality/laterality (p = 0.04), and lymphatic invasion (p = 0.02) based on TBSRTC classification, with resultant differences in post-surgical risk stratification per American Thyroid Association (ATA) pediatric guidelines (p = 0.01). Approximately 89% (49/55) of cases were classified as ATA low-risk, and 5 of 6 patients with ATA intermediate- or high-risk disease had SM cytology. Somatic molecular testing was performed in 40% (51/126) of tumors; 77% (27/35) of malignant cases and 38% (6/16) of benign cases harbored driver alteration(s). Of the driver-positive malignant cases, 52% (14/27) were associated with low-risk (DICER1, PTEN, RAS, and TSHR mutations), 33% (9/27) were associated with high-risk (BRAF mutations and ALK, NTRK, and RET fusions), and 15% (4/27) had unreported risk for invasive disease (APC, BLM, and PPM1D mutations and TG-FGFR1 fusion). Incidence of high-risk drivers increased with TBSRTC category. Approximately 23% (8/35) of patients harboring thyroid malignancy did not have an identifiable driver alteration.

CONCLUSIONS: Molecular analysis is useful to discriminate benign and malignant thyroid nodules with indeterminate cytology. Patients with driver genetic alteration(s) and indeterminate cytology should consider surgical management secondary to the high incidence (82%; 27/33) of thyroid malignancy in these patients.

10.1159/000526116

Horm Res Paediatr

35871517

Exercise training and NR supplementation to improve muscle mass and fitness in adolescent and young adult hematopoietic cell transplant survivors: a randomized controlled trial {1}.

2022

795

07/2022

1471-2407

BACKGROUND: Advances in hematopoietic cell transplantation (HCT) have led to marked improvements in survival. However, adolescents and young adults (AYAs) who undergo HCT are at high risk of developing sarcopenia (loss of skeletal muscle mass) due to the impact of HCT-related exposures on the developing musculoskeletal system. HCT survivors who have sarcopenia also have excess lifetime risk of non-relapse mortality. Therefore, interventions that increase skeletal muscle mass, metabolism, strength, and function are needed to improve health in AYA HCT survivors. Skeletal muscle is highly reliant on mitochondrial energy production, as reflected by oxidative phosphorylation (OXPHOS) capacity. Exercise is one approach to target skeletal muscle mitochondrial OXPHOS, and in turn improve muscle function and strength. Another approach is to use "exercise enhancers", such as nicotinamide riboside (NR), a safe and well-tolerated precursor of nicotinamide adenine dinucleotide (NAD), a cofactor that in turn impacts muscle energy production. Interventions combining exercise with exercise enhancers like NR hold promise, but have not yet been rigorously tested in AYA HCT survivors.

METHODS/DESIGN: We will perform a randomized controlled trial testing 16 weeks of in-home aerobic and resistance exercise and NR in AYA HCT survivors, with a primary outcome of muscle strength via dynamometry and a key secondary outcome of cardiovascular fitness via cardiopulmonary exercise testing. We will also test the effects of these interventions on i) muscle mass via dual energy x-ray absorptiometry; ii) muscle mitochondrial OXPHOS via an innovative non-invasive MRI-based technique, and iii) circulating correlates of NAD metabolism via metabolomics. Eighty AYAs (ages 15-30y) will be recruited 6-24 months post-HCT and randomized to 1 of 4 arms: exercise + NR, exercise alone, NR alone, or control. Outcomes will be collected at baseline and after the 16-week intervention.

DISCUSSION: We expect that exercise with NR will produce larger changes than exercise alone in key outcomes, and that changes will be mediated by increases in muscle OXPHOS. We will apply the insights gained from this trial to develop individualized, evidence-supported precision initiatives that will reduce chronic disease burden in high-risk cancer survivors.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT05194397. Registered January 18, 2022, https://clinicaltrials.gov/ct2/show/NCT05194397 {2a}.

10.1186/s12885-022-09845-1

BMC Cancer

35854224

Clinicopathologic Characteristics of Pediatric Follicular Variant of Papillary Thyroid Carcinoma Subtypes: A Retrospective Cohort Study.

2022

09/2022

1557-9077

Follicular patterned thyroid nodules with nuclear features of papillary thyroid carcinoma encompass a range of diagnostic categories with varying risks of metastatic behavior. Subtypes include invasive encapsulated fvPTC (Ienc-fvPTC) and infiltrative fvPTC (inf-fvPTC) with tumors lacking invasive features classified as non-invasive follicular thyroid neoplasm with papillary-like features (NIFTP). This study aimed to report the clinical and histologic features of pediatric cases meeting criteria for these histological subtypes with specific focus on Ienc-fvPTC and inf-fvPTC. In this retrospective cohort study, pediatric patients with thyroid neoplasms showing follicular patterned growth and nuclear features of papillary thyroid carcinoma noted on surgical pathology between January 2010 and January 2021 were retrospectively reviewed and classified according to the recent 2022 World Health Organization (WHO) criteria. Clinical and histopathologic parameters were described for NIFTP, Ienc-fvPTC, and inf-fvPTC subtypes, with specific comparison of Ienc-fvPTC and inf-fvPTC cases. The case cohort included 42 pediatric patients, with 6 (14%), 25 (60%), and 11 (26%) patients meeting criteria for NIFTP, Ienc-fvPTC, and inf-fvPTC, respectively. All cases were re-reviewed, and 5 patients originally diagnosed with Ienc-fvPTC prior to 2017 were reappraised as NIFTP. The NIFTP cases were encapsulated tumors without invasive features, lymph node or distant metastasis, or disease recurrence. Ienc-fvPTC tumors demonstrated clearly demarcated tumor capsules and capsular/vascular invasion, while inf-fvPTC tumors displayed infiltrative growth lacking a capsule. Inf-fvPTC cases had increased prevalence of malignant pre-operative cytology, lymph node metastasis, and distant metastasis ( < 0.01). These cases were treated with total thyroidectomy, lymph node dissection, and subsequent radioactive iodine therapy. Preliminary genetic findings suggest a predominance of fusions in inf-fvPTC cases versus point mutations in Ienc-fvPTC ( < 0.01). Pediatric NIFTP and fvPTC subtypes appear to demonstrate alignment between clinical and histological risk stratification, with indolent behavior in Ienc-fvPTC and invasive features in inf-fvPTC tumors.

10.1089/thy.2022.0239

Thyroid

36103376

Diffusion Tensor Imaging of the Knee to Predict Childhood Growth.

2022

210484

2022 Mar 22

1527-1315

<p>Background Accurate and precise methods to predict growth remain lacking. Diffusion tensor imaging (DTI) depicts the columnar structure of the physis and metaphyseal spongiosa and provides measures of tract volume and length that may help predict growth. Purpose To validate physeal DTI metrics as predictors of height velocity (1-year height gain from time of MRI examination) and total height gain (height gain from time of MRI examination until growth stops) and compare the prediction accuracy with bone age-based models. Materials and Methods Femoral DTI studies ( values = 0 and 600 sec/mm; directions = 20) of healthy children who underwent MRI of the knee between February 2012 and December 2016 were retrospectively analyzed. Children with height measured at MRI and either 1 year later (height velocity) or after growth cessation (total height gain, mean = 34 months from MRI) were included. Physeal DTI tract volume and length were correlated with height velocity and total height gain. Multilinear regression was used to assess the potential of DTI metrics in the prediction of both parameters. Bland-Altman plots were used to compare root mean square error (RMSE) and bias in height prediction using DTI versus bone age methods. Results Eighty-nine children (mean age, 13 years ± 3 [SD]; 47 boys) had height velocity measured, and 70 (mean age, 14 years ± 1; 36 girls) had total height gain measured. Tract volumes correlated with height velocity ( = 0.49) and total height gain ( = 0.46) ( &lt; .001 for both) after controlling for age and sex. Tract volume was the strongest predictor for height velocity and total height gain. An optimal multilinear model including tract volume improved prediction of height velocity ( = 0.63, RMSE = 1.7 cm) and total height gain ( = 0.59, RMSE = 1.8 cm) compared with bone age-based methods (height velocity: = 0.32, RMSE = 2.9 cm; total height gain: = 0.42, RMSE = 5.0 cm). Conclusion Models using tract volume derived from diffusion tensor imaging may perform better than bone age-based models in children for the prediction of height velocity and total height gain. © RSNA, 2022.</p>

10.1148/radiol.210484

Radiology

35315716