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Objective: The American Thyroid Association (ATA) Pediatric Guidelines recommend selective, prophylactic central neck dissection (pCND) for patients with papillary thyroid carcinoma (PTC) based on tumor focality, tumor size, and the surgeon's experience. With the expansion of pre-surgical somatic oncogene testing and continued controversy over the benefits of pCND, oncogenic alteration data may provide an opportunity to stratify pCND. This study compared lymph node (LN) involvement in pediatric patients with PTC between tumors with low- and high-invasive-associated alterations to explore the potential utility of preoperative oncogenic alterations in the stratification of pCND. Methods: This is retrospective cohort study of pediatric patients who underwent somatic oncogene testing post thyroidectomy for PTC between July 2003 and July 2022. Results: Of 192 eligible PTC patients with postoperative somatic oncogene data, 19 tumors harbored somatic alterations associated with low-invasive disease (19/192, 10%), and 128 tumors harbored a BRAFV600E alteration (45/192, 23%) or an oncogenic fusion (83/192, 43%). Tumors with low-invasive alterations were less likely to present malignant preoperative cytology (2/18, 11%) than those with high-invasive alterations (97/124, 78%; P < 0.001). Twelve patients with low-invasive alterations had LNs dissected from the central neck (12/19, 63%) compared to 127 patients (127/128, 99%) with high-invasive alterations. LN metastasis was identified in two patients with low-invasive alterations (2/19, 11%) compared to 107 patients with high-invasive alterations (107/128, 84%; P < 0.001). Conclusion: Pediatric patients with low-invasive somatic oncogenic alterations are at low risk for metastasis to central neck LNs. Our findings suggest that preoperative knowledge of somatic oncogene alterations provides objective data to stratify pediatric patients who may not benefit from pCND.
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Metástasis Linfática , Disección del Cuello , Oncogenes , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/cirugía , Cáncer Papilar Tiroideo/patología , Masculino , Niño , Femenino , Estudios Retrospectivos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/cirugía , Adolescente , Metástasis Linfática/patología , Metástasis Linfática/genética , Oncogenes/genética , Tiroidectomía , Proteínas Proto-Oncogénicas B-raf/genética , PreescolarRESUMEN
Peutz-Jeghers syndrome (PJS) is a childhood-onset cancer predisposition syndrome that is associated with oral freckling and gastrointestinal polyposis. Male patients with PJS are at risk for large-cell calcifying Sertoli cell tumors in childhood. These tumors are estrogen-producing and can cause symptoms of precocious puberty, gynecomastia, and growth acceleration. Here we discuss our experience with spontaneous resolution or stabilization of breast enlargement without medical intervention in three patients with PJS and gynecomastia. These cases indicate that a watchful waiting approach can be considered in the management of gynecomastia in male children with PJS.
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BACKGROUND: Aromatase inhibitors (AI) may improve height in short stature conditions; however, the effect in childhood cancer survivors (CCS) is unknown. We assessed final adult height (FAH) in CCS treated with AI and GH compared with those treated with GH alone. METHODS: Retrospective cohort study of GH-deficient male CCS treated between 2007 and 2023. FAH was noted as the height at the fusion of growth plates or 18 years of age. Multivariable linear regression was used to examine treatment association with FAH, adjusting for other risk factors. RESULTS: Ninety-two patients were included; 70 were treated with GH and 22 with combination AI/GH. The mean age at GH initiation did not differ between groups. The mean age at AI initiation was 13.7 ± 1.9 years. A greater proportion of patients in the AI/GH group were treated with stem cell transplantation, abdominal radiation, total body irradiation, and cis-retinoic acid (p < .01). Multivariable linear regression demonstrated no significant treatment association with FAH Z-score (ß = 0.04, 95% CI: -0.9 to 0.9). History of spinal radiation (ß = -0.93, 95% CI: -1.7 to -0.2), lower starting height Z-score (ß = -0.8, 95% CI: -1.2 to -0.4), and greater difference between bone age and chronological age (ß = -0.3, 95% CI: -0.5 to -0.07) were associated with lower FAH Z-score. CONCLUSIONS: Adjuvant AI was not associated with increased FAH in male CCS compared with GH monotherapy. Future work is needed to determine the optimal adjunctive treatment to maximize FAH for this population.
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Inhibidores de la Aromatasa , Estatura , Supervivientes de Cáncer , Hormona de Crecimiento Humana , Neoplasias , Humanos , Masculino , Inhibidores de la Aromatasa/uso terapéutico , Estudios Retrospectivos , Estatura/efectos de los fármacos , Adolescente , Hormona de Crecimiento Humana/deficiencia , Niño , Neoplasias/tratamiento farmacológico , Estudios de Seguimiento , Trastornos del Crecimiento/tratamiento farmacológico , Trastornos del Crecimiento/etiología , Trastornos del Crecimiento/patología , Adulto , Pronóstico , Quimioterapia AdyuvanteRESUMEN
BACKGROUND: Current methods to predict height potential are inaccurate. Predicting height by using MRI of the physeal cartilage has shown promise but the applicability of this technique in different imaging setups has not been well-evaluated. PURPOSE: To assess variability in diffusion tensor imaging of the physis and metaphysis (DTI-P/M) of the distal femur between different scanners, imaging parameters, tractography software, and resolution. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Eleven healthy subjects (five males and six females ages 10-16.94). FIELD STRENGTH/SEQUENCE: 3 T; DTI single shot echo planar sequences. ASSESSMENT: Physeal DTI tract measurements of the distal femur were compared between different scanners, imaging parameters, tractography settings, interpolation correction, and tractography software. STATISTICAL TESTS: Bland-Altman, Spearman correlation, linear regression, and Shapiro-Wilk tests. Threshold for statistical significance was set at P = 0.05. RESULTS: DTI tract values consistently showed low variability with different imaging and analysis settings. Vendor to vendor comparison exhibited strong correlation (ρ = 0.93) and small but significant bias (bias -5.76, limits of agreement [LOA] -24.31 to 12.78). Strong correlation and no significant difference were seen between technical replicates of the General Electric MRI scanner (ρ = 1, bias 0.17 [LOA -1.5 to 1.2], P = 0.42) and the Siemens MRI scanner (ρ = 0.89, bias = 0.56, P = 0.71). Different voxel sizes (1 × 1 × 2 mm3 vs. 2 × 2 × 3 mm3) did not significantly affect DTI values (bias = 1.4 [LOA -5.7 to 8.4], P = 0.35) but maintained a strong correlation (ρ = 0.82). Gap size (0 mm vs. 0.6 mm) significantly affects tract volume (bias = 1.8 [LOA -5.4 to 1.8]) but maintains a strong correlation (ρ = 0.93). Comparison of tractography algorithms generated significant differences in tract number, length, and volume while maintaining correlation (ρ = 0.86, 0.99, 0.93, respectively). Comparison of interobserver variability between different tractography software also revealed significant differences while maintaining high correlation (ρ = 0.85-0.98). DATA CONCLUSION: DTI of the pediatric physis cartilage shows high reproducibility between different imaging and analytic parameters. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.
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PURPOSE: Type 2 diabetes mellitus (T2D) is a prevalent long-term complication of treatment in survivors of childhood cancer, with marked racial/ethnic differences in burden. In this study, we investigated trans-ancestral genetic risks for treatment-related T2D. PATIENTS AND METHODS: Leveraging whole-genome sequencing data from the St Jude Lifetime Cohort (N = 3,676, 304 clinically ascertained cases), we conducted ancestry-specific genome-wide association studies among survivors of African and European genetic ancestry (AFR and EUR, respectively) followed by trans-ancestry meta-analysis. Trans-/within-ancestry replication including data from the Childhood Cancer Survivor Study (N = 5,965) was required for prioritization. Three external general population T2D polygenic risk scores (PRSs) were assessed, including multiancestry PRSs. Treatment risk effect modification was evaluated for prioritized loci. RESULTS: Four novel T2D risk loci showing trans-/within-ancestry replication evidence were identified, with three loci achieving genome-wide significance (P < 5 × 10-8). Among these, common variants at 5p15.2 (LINC02112), 2p25.3 (MYT1L), and 19p12 (ZNF492) showed evidence of modifying alkylating agent-related T2D risk in both ancestral groups, but showed disproportionately greater risk in AFR survivors (AFR odds ratios [ORs], 3.95-17.81; EUR ORs, 2.37-3.32). In survivor-specific RNA-sequencing data (N = 207), the 19p12 locus variant was associated with greater ZNF492 expression dysregulation after exposures to alkylators. Elevated T2D risks across ancestry groups were only observed with increasing values for multiancestry T2D PRSs and were especially increased among survivors treated with alkylators (top v bottom quintiles: ORAFR, 20.18; P = .023; OREUR, 13.44; P = 1.3 × 10-9). CONCLUSION: Our findings suggest therapy-related genetic risks contribute to the increased T2D burden among non-Hispanic Black childhood cancer survivors. Additional study of how therapy-related genetic susceptibility contributes to this disparity is needed.
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Supervivientes de Cáncer , Diabetes Mellitus Tipo 2 , Estudio de Asociación del Genoma Completo , Neoplasias , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Factores de Riesgo , Masculino , Femenino , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Niño , Predisposición Genética a la Enfermedad , Adulto , Población Blanca/genética , AdolescenteRESUMEN
BACKGROUND: Sleep problems following childhood cancer treatment may persist into adulthood, exacerbating cancer-related late effects and putting survivors at risk for poor physical and psychosocial functioning. This study examines sleep in long-term survivors and their siblings to identify risk factors and disease correlates. METHODS: Childhood cancer survivors (≥5 years from diagnosis; n = 12â340; 51.5% female; mean [SD] age = 39.4 [9.6] years) and siblings (n = 2395; 57.1% female; age = 44.6 [10.5] years) participating in the Childhood Cancer Survivor Study completed the Pittsburgh Sleep Quality Index (PSQI). Multivariable Poisson-error generalized estimating equation compared prevalence of binary sleep outcomes between survivors and siblings and evaluated cancer history and chronic health conditions (CHC) for associations with sleep outcomes, adjusting for age (at diagnosis and current), sex, race/ethnicity, and body mass index. RESULTS: Survivors were more likely to report clinically elevated composite PSQI scores (>5; 45.1% vs 40.0%, adjusted prevalence ratio [PR] = 1.20, 95% CI = 1.13 to 1.27), symptoms of insomnia (38.8% vs 32.0%, PR = 1.26, 95% CI = 1.18 to 1.35), snoring (18.0% vs 17.4%, PR = 1.11, 95% CI = 1.01 to 1.23), and sleep medication use (13.2% vs 11.5%, PR = 1.28, 95% CI = 1.12 to 1.45) compared with siblings. Within cancer survivors, PSQI scores were similar across diagnoses. Anthracycline exposure (PR = 1.13, 95% CI = 1.03 to 1.25), abdominal radiation (PR = 1.16, 95% CI = 1.04 to 1.29), and increasing CHC burden were associated with elevated PSQI scores (PRs = 1.21-1.48). CONCLUSIONS: Among survivors, sleep problems were more closely related to CHC than diagnosis or treatment history, although longitudinal research is needed to determine the direction of this association. Frequent sleep-promoting medication use suggests interest in managing sleep problems; behavioral sleep intervention is advised for long-term management.
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Supervivientes de Cáncer , Neoplasias , Trastornos del Sueño-Vigilia , Humanos , Niño , Femenino , Adulto , Masculino , Neoplasias/terapia , Calidad de Vida/psicología , Trastornos del Sueño-Vigilia/complicaciones , Trastornos del Sueño-Vigilia/epidemiología , Trastornos del Sueño-Vigilia/psicología , Enfermedad Crónica , SueñoRESUMEN
BACKGROUND: Female survivors of childhood cancer are at risk for primary ovarian insufficiency (POI), defined as the cessation of gonadal function before the age of 40 years. We aimed to develop and validate models to predict age-specific POI risk among long-term survivors of childhood cancer. METHODS: To develop models to predict age-specific POI risk for the ages of 21-40 years, we used data from the Childhood Cancer Survivor Study (CCSS). Female survivors aged 18 years or older at their latest follow-up, with self-reported menstrual history information and free of subsequent malignant neoplasms within 5 years of diagnosis, were included. We evaluated models that used algorithms based on statistical or machine learning to consider all predictors, including cancer treatments. Cross-validated prediction performance metrics (eg, area under the receiver operating characteristic curve [AUROC]) were compared to select the best-performing models. For external validation of the models, we used data from 5-year survivors in the St Jude Lifetime Cohort (SJLIFE) with ovarian status clinically ascertained using hormone measurements (menopause defined by follicle stimulating hormone >30 mIU/mL and oestradiol <17 pg/mL) and medical chart or questionnaire review. We also evaluated an SJLIFE-based polygenic risk score for POI among 1985 CCSS survivors with genotype data available. FINDINGS: 7891 female CCSS survivors (922 with POI) were included in the development of the POI risk prediction model, and 1349 female SJLIFE survivors (101 with POI) were included in the validation study. Median follow-up from cancer diagnosis was 23·7 years (IQR 18·3-30·0) in CCSS and 15·1 years (10·4-22·9) in SJLIFE. Between the ages of 21 and 40 years, POI prevalence increased from 7·9% (95% CI 7·3-8·5) to 18·6% (17·3-20·0) in CCSS and 7·3% (5·8-8·9) to 14·9% (11·6-19·1) in SJLIFE. Age-specific logistic regression models considering ovarian radiation dosimetry or prescribed pelvic and abdominal radiation dose, along with individual chemotherapy predictors, performed well in CCSS. In the SJLIFE validation, the prescribed radiation dose model performed well (AUROC 0·88-0·95), as did a simpler model that considered any exposures to pelvic or abdominal radiotherapy or alkylators (0·82-0·90). Addition of the polygenic risk predictor significantly improved the average positive predictive value (from 0·76 [95% CI 0·63-0·89] to 0·87 [0·80-0·94]; p=0·029) among CCSS survivors treated with ovarian radiation and chemotherapy. INTERPRETATION: POI risk prediction models using treatment information showed robust prediction performance in adult survivors of childhood cancer. FUNDING: Canadian Institutes of Health Research, US National Cancer Institute.
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Supervivientes de Cáncer , Neoplasias , Insuficiencia Ovárica Primaria , Adulto , Humanos , Niño , Femenino , Adulto Joven , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Insuficiencia Ovárica Primaria/diagnóstico , Insuficiencia Ovárica Primaria/epidemiología , Insuficiencia Ovárica Primaria/etiología , Canadá , Sobrevivientes , Factores de Riesgo , Factores de EdadRESUMEN
Anticancer agents can impair ovarian function, resulting in premature menopause and associated long-term health effects. Ovarian toxicity is not usually adequately assessed in trials of anticancer agents, leaving an important information gap for patients facing therapy choices. This American Society of Clinical Oncology (ASCO) statement provides information about the incorporation of ovarian toxicity measures in trial design. ASCO recommends: (1) measurement of ovarian toxicity in relevant clinical trials of anticancer agents that enrol post-pubertal, pre-menopausal patients; (2) collection of ovarian function measures at baseline and at 12-24 months after anticancer agent cessation, as a minimum, and later in line with the trial schedule; and (3) assessment of both clinical measures and biomarkers of ovarian function. ASCO recognises that routine measurement of ovarian toxicity and function in cancer clinical trials will add additional complexity and burden to trial resources but asserts that this issue is of such importance to patients that it cannot continue to be overlooked.
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Antineoplásicos , Neoplasias , Femenino , Humanos , Estados Unidos , Neoplasias/terapia , Antineoplásicos/efectos adversos , Ovario , Oncología MédicaRESUMEN
With advancements in cancer treatment and supportive care, there is a growing population of childhood cancer survivors who experience a substantial burden of comorbidities related to having received cancer treatment at a young age. Despite an overall reduction in the incidence of most chronic health conditions in childhood cancer survivors over the past several decades, the cumulative incidence of certain late effects, in particular diabetes mellitus (DM), has increased. The implications are significant, because DM is a key risk factor for cardiovascular disease, a leading cause of premature death in childhood cancer survivors. The underlying pathophysiology of DM in cancer survivors is multifactorial. DM develops at younger ages in survivors compared to controls, which may reflect an "accelerated aging" phenotype in these individuals. The treatment-related exposures (i.e., chemotherapy, radiation) that increase risk for DM in childhood cancer survivors may be more than additive with established DM risk factors (e.g., older age, obesity, race, and ethnicity). Emerging research also points to parallels in cellular processes implicated in aging- and cancer treatment-related DM. Still, there remains marked inter-individual variability regarding risk of DM that is not explained by demographic and therapeutic risk factors alone. Recent studies have highlighted the role of germline genetic risk factors and epigenetic modifications that are associated with risk of DM in both the general and oncology populations. This review summarizes our current understanding of recognized risk factors for DM in childhood cancer survivors to help inform targeted approaches for disease screening, prevention, and treatment. Furthermore, it highlights the existing scientific gaps in understanding the relative contributions of individual therapeutic exposures and the mechanisms by which they exert their effects that uniquely predispose this population to DM following cancer treatment.
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INTRODUCTION: Childhood cancer survivors (CCS) are at risk for radiotherapy (RT) late effects, including second malignancies. Optimal screening for differentiated thyroid cancer (DTC) in CCS post-RT remains controversial. We assessed the outcome of thyroid ultrasound (US) surveillance in CCS exposed to RT. METHODS: 306 CCS were surveilled with thyroid US between 2002-2021. Surveillance was dependent on age at the time of primary diagnosis, interval from receipt of RT, and individual provider. Thyroid US, clinicopathologic features, and outcomes were described. Cutpoints of CCS RT age associated with varying risk of nodule presentation were explored. The selected cutpoints were used to define age categories, which were then used to compare thyroid nodule-related outcomes. Risk factors for thyroid nodule(s) were evaluated using multivariate logistic regression (odds ratio [OR] [95% confidence interval]). RESULTS: The most common CCS diagnoses were leukemia (32%), CNS tumor (26%), and neuroblastoma (18%). Patients received TBI (45%) and/or RT to craniospinal (44%), chest (11%), and neck regions (6%). About 49% (n = 150) of patients had thyroid nodule(s). Forty-four patients underwent surgery, and 28 had DTC: 19 with American Thyroid Association (ATA) low-risk classification, 2 with ATA intermediate-risk, and 7 with ATA high-risk disease. Age cutpoint analyses identified cutpoints 3 and 10; hence, ≤3, >3 to ≤10, and >10 years were used. Of the 9 patients with intermediate- or high-risk disease, 8 were ≤10 years and 1 was >10 years at the time of RT. Female sex (OR = 1.62 [1.13-2.12] p = 0.054) and greater interval between RT and first US (OR = 1.10 [1.04-1.16] p = 0.001) were independent risk factors for nodule presentation. CONCLUSIONS: Thyroid US surveillance may be beneficial for CCS exposed to RT at younger ages (≤10 years) for earlier detection of DTC, prior to developing advanced metastatic disease.
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The physis, or growth plate, is the primary structure responsible for longitudinal growth of the long bones. Diffusion tensor imaging (DTI) is a technique that depicts the anisotropic motion of water molecules, or diffusion. When diffusion is limited by cellular membranes, information on tissue microstructure can be acquired. Tractography, the visual display of the direction and magnitude of water diffusion, provides qualitative visualization of complex cellular architecture as well as quantitative diffusion metrics that appear to indirectly reflect physeal activity. In the growing bones, DTI depicts the columns of cartilage and new bone in the physeal-metaphyseal complex. In this "How I do It", we will highlight the value of DTI as a clinical tool by presenting DTI tractography of the physeal-metaphyseal complex of children and adolescents during normal growth, illustrating variation in qualitative and quantitative tractography metrics with age and skeletal location. In addition, we will present tractography from patients with physeal dysfunction caused by growth hormone deficiency and physeal injury due to trauma, chemotherapy, and radiation therapy. Furthermore, we will delineate our process, or "DTI pipeline," from image acquisition to data interpretation.
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Imagen de Difusión Tensora , Placa de Crecimiento , Niño , Adolescente , Humanos , Imagen de Difusión Tensora/métodos , Placa de Crecimiento/diagnóstico por imagen , Huesos , Anisotropía , AguaRESUMEN
CONTEXT: The American Thyroid Association (ATA) Pediatric Guidelines recommend patients not receive radioactive iodine therapy (RAIT) for differentiated thyroid cancer (DTC) confined to the thyroid. Since publication, there is ongoing concern whether withholding RAIT will result in a lower rate of remission. OBJECTIVE: This study explores whether ATA low-risk patients treated with and without RAIT achieved similar remission rates. METHODS: Medical records of patients <19 years old diagnosed with DTC and treated with total thyroidectomy between 2010 and 2020 were reviewed. Multivariate logistic regression was performed to evaluate factors influencing RAIT administration and remission rate. RESULTS: Ninety-five patients with ATA low-risk DTC were analyzed: 53% (50/95) and 47% (45/95) were treated with and without RAIT, respectively. RAIT was used to treat 82% of patients before 2015 compared with 33% of patients after 2015 (P < .01). No significant difference in 1-year remission rate was found between patients treated with and without RAIT, 70% (35/50) vs 69% (31/45), respectively. With longer surveillance, remission rates increased to 82% and 76% for patients treated with and without RAIT, respectively. Median follow-up was 5.8 years (IQR 4.3-7.9, range 0.9-10.9) and 3.6 years (IQR 2.7-6.6; range 0.9-9.3) for both cohorts. No risk factors for persistent or indeterminate disease status were found, including RAIT administration, N1a disease, and surgery after 2015. CONCLUSION: Withholding RAIT for pediatric patients with ATA low-risk DTC avoids exposure to radiation and does not have a negative impact on remission rates. Dynamic risk stratification at 1-year after initial treatment is a suitable time point to assess the impact of withholding RAIT for these patients.
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Adenocarcinoma , Neoplasias de la Tiroides , Humanos , Niño , Adulto Joven , Adulto , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/cirugía , Radioisótopos de Yodo/uso terapéutico , Tiroidectomía , Factores de Riesgo , Adenocarcinoma/cirugía , Estudios RetrospectivosRESUMEN
Type 2 diabetes mellitus (T2D) is an established late effect of treatment for childhood cancer. Leveraging detailed cancer treatment and whole-genome sequencing data among survivors of childhood cancer of European (EUR) and African (AFR) genetic ancestry in the St. Jude Lifetime Cohort (N=3,676; 304 cases), five novel diabetes mellitus (DM) risk loci were identified with independent trans-/within-ancestry replication, including in 5,965 survivors of the Childhood Cancer Survivor Study. Among these, common risk variants at 5p15.2 ( LINC02112 ), 2p25.3 ( MYT1L ), and 19p12 ( ZNF492 ) modified alkylating agent-related risks across ancestry groups, but AFR survivors with risk alleles experienced disproportionately greater risk of DM (AFR, variant ORs: 3.95-17.81; EUR, variant ORs: 2.37-3.32). Novel risk locus XNDC1N was identified in the first genome-wide DM rare variant burden association analysis in survivors (OR=8.65, 95% CI: 3.02-24.74, P=8.1×10 -6 ). Lastly, a general-population 338-variant multi-ancestry T2D polygenic risk score was informative for DM risk in AFR survivors, and showed elevated DM odds after alkylating agent exposures (quintiles: combined OR EUR =8.43, P=1.1×10 -8 ; OR AFR =13.85, P=0.033). This study supports future precision diabetes surveillance/survivorship care for all childhood cancer survivors, including those with AFR ancestry.
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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.
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Supervivientes de Cáncer , Obstrucción Intestinal , Neoplasias Renales , Neoplasias , Tumor de Wilms , Humanos , Niño , Neoplasias/terapia , Sobrevivientes , Tumor de Wilms/terapia , Evaluación de Resultado en la Atención de Salud , Enfermedad Crónica , Neoplasias Renales/terapiaRESUMEN
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.
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Calidad de Vida , Neoplasias de la Tiroides , Adolescente , Humanos , Niño , Adulto Joven , Adulto , Calidad de Vida/psicología , Estado de Salud , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/epidemiología , Encuestas y CuestionariosRESUMEN
PURPOSE: To characterize germline genetic risk factors of diabetes mellitus among long-term survivors of childhood cancer. METHODS: Adult survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS) Original Cohort (n = 5,083; 383 with diabetes) were used to conduct a discovery genome-wide association study. Replication was performed using the CCSS Expansion (n = 2,588; 40 with diabetes) and the St Jude Lifetime (SJLIFE; n = 3,351; 208 with diabetes) cohorts. Risk prediction models, stratified on exposure to abdominal radiation, were calculated using logistic regression including attained age, sex and body mass index, diagnosis, alkylating chemotherapy, age at cancer diagnosis, and a polygenic risk score (PRS) on the basis of 395 diabetes variants from the general population. Area under the receiver operating characteristic curve (AUC) was calculated for models on the basis of traditional risk factors, clinical risk factors, and PRS. RESULTS: There was a genome-wide significant association of rs55849673-A with diabetes among survivors (odds ratio, 2.9; 95% CI, 2.0 to 4.2; P = 3.7 × 10-8), which is related to expression of ERCC6L2 in the Genotype-Tissue Expression project. The association of rs55849673-A was observed largely among survivors not exposed to abdominal radiation (odds ratio = 3.5, P = 1.1 × 10-7) and the frequency of rs55849673-A was consistently higher among diabetic survivors in the CCSS Expansion and SJLIFE cohorts. Risk prediction models including traditional diabetes risk factors, clinical risk factors and PRS had an optimism-corrected AUC of 0.801, with an AUC of 0.751 in survivors treated with abdominal radiation versus 0.813 in survivors who did not receive abdominal radiation. CONCLUSION: There is evidence for a novel locus of diabetes among survivors not exposed to abdominal radiation. Further refinement and validation of clinic-based risk prediction models for diabetes among long-term survivors of childhood cancer is warranted.
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Supervivientes de Cáncer , Diabetes Mellitus , Neoplasias , Niño , Humanos , Neoplasias/epidemiología , Estudio de Asociación del Genoma Completo , Factores de Riesgo , ADN HelicasasRESUMEN
Introduction: 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. Methods: 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. Results: 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 (p < 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 (p = 0.02). Conclusions: 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.
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Adenocarcinoma Folicular , Carcinoma Papilar Folicular , Neoplasias de la Tiroides , Humanos , Niño , Cáncer Papilar Tiroideo , Adenocarcinoma Folicular/patología , Neoplasias de la Tiroides/patología , Estudios Retrospectivos , Radioisótopos de Yodo , Invasividad Neoplásica/patología , Recurrencia Local de Neoplasia , Estudios de Cohortes , Carcinoma Papilar Folicular/cirugía , Carcinoma Papilar Folicular/patologíaRESUMEN
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}.
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Ejercicio Físico , Trasplante de Células Madre Hematopoyéticas , Sarcopenia , Adolescente , Adulto , Suplementos Dietéticos , Ejercicio Físico/fisiología , Humanos , Músculo Esquelético , NAD/metabolismo , NAD/farmacología , Niacinamida/análogos & derivados , Compuestos de Piridinio , Calidad de Vida , Sobrevivientes , Adulto JovenRESUMEN
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.