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  • 1
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    Temporal trends in chronic disease among survivors of childhood cancer diagnosed across three decades: A report from the Childhood Cancer Survivor Study (CCSS).
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 18_suppl ( 2017-06-20), p. LBA10500-LBA10500
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 18_suppl ( 2017-06-20), p. LBA10500-LBA10500
    Abstract: LBA10500 Background: Modifications in childhood cancer treatments in recent decades have contributed to reductions in late mortality among 5-year survivors. We used the recently expanded CCSS cohort to investigate whether these changes have also reduced the incidence of chronic disease. Methods: We evaluated the incidence of severe, disabling/life-threatening, or fatal chronic health conditions (Common Terminology Criteria for Adverse Events, CTCAE grades 3-5) among 5-year survivors diagnosed prior to age 21 years from 1970 through 1999. We calculated the 15-year cumulative incidence of chronic health conditions by decade of cancer diagnosis and compared risk across decades using Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results: Among 23,601 survivors, median age 28 years (range 5-63), 21 years from diagnosis (5-43), the 15-year cumulative incidence of grade 3-5 conditions decreased from 12.7% in survivors diagnosed in the 1970s to 10.1% and 8.8% in those diagnosed in the 1980s and 1990s (per 10 years, HR 0.84 [95% CI = 0.80-0.89]). The association with diagnosis decade was attenuated (HR 0.92 [0.85-1.00] ) when detailed treatment data were included in the model, indicating that treatment reductions mediated risk. Adjusted for sex and attained age, significant reduction in risk over time was found among survivors of Wilms tumor (HR 0.57 [0.46-0.70]), Hodgkin lymphoma (HR 0.75 [0.65-0.85] ), astrocytoma (HR 0.77 [0.64-0.92]), non-Hodgkin lymphoma (HR 0.79 [0.63-0.99] ), and acute lymphoblastic leukemia (HR 0.86 [0.76-0.98]). Decreases were largely driven by a reduced incidence of endocrine conditions (1970s: 4.0% v. 1990s:1.6%; HR 0.66 [0.59-0.73] ) and subsequent malignant neoplasms (1970s: 2.4% v. 1990s: 1.6%; HR 0.85 [0.76-0.96]). Significant reductions were also found for gastrointestinal (HR 0.80 [0.66-0.97] ) and neurological conditions (HR 0.77 [0.65-0.91]), but not cardiac or pulmonary conditions. Conclusions: Changes in childhood cancer treatment protocols have not only extended lifespan for many survivors, but have also reduced the incidence of serious chronic morbidity in this population.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.18_suppl.LBA10500
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Genetic and treatment risks for diabetes mellitus (DM) in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS) and St. Jude Lifetime (SJLIFE) cohorts.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 10014-10014
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 10014-10014
    Abstract: 10014 Background: Childhood cancer survivors face increased risk for DM, a polygenic trait also attributable to cancer treatment exposures, particularly abdominal radiation. We aimed to characterize the role of genetic and treatment risk factors for DM among two large cohorts of childhood cancer survivors. Methods: We performed a nested case-control genome-wide association study for DM managed with oral medications in the original CCSS cohort (diagnosed 1970-1986). Logistic regression was conducted in the total sample (N = 5083) and stratified by 1) European ancestry (EA) and 2) abdominal radiation. Replication of suggestive variants (P 〈 1×10 -7 ) using Fisher’s exact test was performed in independent cohorts: i) CCSS expansion diagnosed 1987-1999 (N = 2588) and ii) SJLIFE diagnosed 1962-2012 (N = 2182). To evaluate the effect of cancer treatment on the background genetic predisposition to DM, we estimated standardized effect sizes (Z’) among EA survivors in each abdominal radiation group for 398 index variants from the largest population-based EA DM study. Radiation group Z’ estimates were compared using linear regression. Results: In the original CCSS cohort we identified nine variants associated with DM and provide further support for four linked variants in the ERCC6L2 locus. Among all survivors, the rs55849673-A allele was associated with increased odds for DM among survivors in the original CCSS cohort (minor allele frequency [MAF]-cases = 0.055; MAF-controls = 0.024; adjusted odds ratio [aOR] = 2.9, 95% CI: 2.0-4.2, P = 3.7×10 -8 ). Allele frequencies were consistent in the CCSS expansion (MAF-cases = 0.075; MAF-controls = 0.028; P = 0.07) and SJLIFE (MAF-cases = 0.036; MAF-controls = 0.027; P = 0.5). Additionally, rs55849673-A estimates were consistent among EA survivors and stronger among survivors not treated with abdominal radiation (MAF-cases = 0.052; MAF-controls = 0.021; aOR = 3.6, P = 1.6×10 -6 ). Notably, in the CCSS expansion all rs55849673-A EA carriers who developed DM did not receive abdominal radiation (MAF-cases = 0.1; MAF-controls = 0.026; P = 0.04). More broadly, the Z’ of population-based DM index variants were 78% lower in survivors treated with abdominal radiation than survivors not treated with abdominal radiation (beta = 0.22; P = 0.01), indicating the background genetic risk for DM may be altered by treatment. Conclusions: We provide evidence for a novel locus of DM in childhood cancer survivors. This locus is a regulatory region associated with expression of ERCC6L2, a gene implicated in an East Asian population-based DM study. Taken together, our findings support the overwhelming effect of abdominal radiation on DM risk in childhood cancer survivors, relative to other risk factors, and provide insight on a genetic locus that may be useful for DM risk prediction in the context of cancer treatment.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.10014
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 3
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    Treatment intensity and risk of chronic health conditions and late mortality among long-term survivors of Wilms tumor: A report from the Childhood Cancer Survivor Study.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 10553-10553
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 10553-10553
    Abstract: 10553 Background: Refinement in risk stratification has led to intensification of therapy for Wilms tumor (WT) patients with adverse prognostic factors. Chronic health conditions (CHCs) including cardiac conditions, subsequent malignant neoplasms (SMNs), and late mortality are known risks for WT survivors, however the impact of specific treatment regimens on these outcomes is largely unknown. Methods: Late mortality (all-cause and non-recurrence death 〉 5 years from diagnosis), SMNs, and severity-graded CHCs (2 = moderate, 3 = severe, 4 = life-threatening, 5 = fatal) were assessed in 5-year WT survivors in the Childhood Cancer Survivor Study diagnosed from 1970-99. Survivors were categorized according to therapy received (Table). Cumulative incidence of mortality and standard mortality ratios (SMR) were estimated. Piecewise exponential models estimated rate ratios (RR) with 95% confidence intervals (CI). Results: Among 1507 survivors (median age at follow-up 26 yrs; range 6-55), 35-year cumulative incidence of all-cause mortality was 7.9% (SMR 2.9, CI 2.3-3.6) and 5.1% (SMR 1.9, CI 1.4-2.4) for non-recurrence mortality. RRs for developing any grade 2-5 CHC, grade 3-5 SMN, and grade 2-5 cardiac CHCs were higher for survivors compared to sibling controls (2.0, CI 1.8-2.3; 7.4, CI 5.0-10.8; 2.6, CI 2.2-3.1, respectively). Compared with VA and no RT, RR for non-recurrence late mortality and CHCs among survivors were higher for VAD + any RT, and for ≥ 4 drugs + any RT (Table). Conclusions: Administering increased-intensity therapy for WT is associated with increased late health consequences and non-recurrence late mortality, necessitating strategies to monitor and improve long-term health among survivors. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.10553
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Congenital anomalies and health outcomes among survivors of childhood cancer: A report from the childhood cancer survivor study.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e22021-e22021
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e22021-e22021
    Abstract: e22021 Background: Although congenital anomalies are established risk factors for developing childhood cancer, less is known about health outcomes among survivors of childhood cancer with known congenital anomalies. Therefore, we estimated the risk of chronic health conditions (CHCs) and subsequent malignant neoplasms (SMNs) among survivors of childhood cancer by congenital anomaly status in the Childhood Cancer Survivor Study (CCSS). Methods: Overall, 22,247 five-year survivors self-reported congenital anomalies. We included 16 conditions present at birth, excluding self-reported genetic conditions. Patient-reported CHCs were graded using the Common Terminology Criteria for Adverse Events (CTCAE v. 4.03). Self-reported SMNs were confirmed through pathology report review. Hazard ratios (HR) of CHCs comparing survivors with vs. without congenital anomalies and their 95% confidence intervals (CI) were estimated using Cox regression with age as the time scale, adjusted for race/ethnicity, education, household income, health insurance, and original cancer treatment. Results: Among survivors (median age at cancer diagnosis 6 years (range 3-12), age at follow-up 31 years (range 25-39)), 16.9% (n = 3880) reported a congenital anomaly. The most common anomalies included: large/multiple birth marks (n = 1540, 40.4%); congenital heart defects (n = 693, 18.4%); and kidney, bladder, or genital abnormalities (n = 607, 14.6%). Relative to survivors without anomalies, those with anomalies more commonly had astrocytoma, Wilms tumor, and neuroblastoma primary cancers (p 〈 0.001), treated with radiation (p = 0.011), cyclophosphamide (p 〈 0.001), anthracyclines (p 〈 0.001), and epipodophyllotoxins (p = 0.044), and younger age at cancer diagnosis (11.3% vs. 5.7% diagnosed prior to one year of age, p 〈 0.001). Survivors with anomalies were more likely to develop any CHC (CTCAE grades 1-5 HR: 1.31, 95% CI: 1.23, 1.39); severe, disabling, life-threatening or fatal CHCs (grades 3-5 HR: 1.42 (95% CI: 1.28, 1.58); and multiple CHCs (≥2 conditions HR: 1.36, 95% CI: 1.27, 1.46; ≥3 conditions HR: 1.49, 95% CI: 1.37, 1.63). Survivors with anomalies had increased risk for adverse outcomes across multiple systems (all p 〈 0.001), including: hearing/vision/speech (HR: 1.37); urinary (HR: 1.42); hormonal/endocrine (HR: 1.24); heart/circulatory (HR: 1.35); digestive (HR: 1.49); and brain systems (HR: 1.42). We observed no differences in the risk of any SMN by congenital anomaly status (HR: 1.12, 95% CI: 0.90, 1.38). Conclusions: In our assessment, survivors of childhood cancer with self-reported congenital anomalies had an increased risk of developing CHCs compared to survivors without reported anomalies, but no increased risk of SMNs. Evaluating congenital anomalies allows identification of a population of childhood cancer survivors at high risk for poor long-term health outcomes.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e22021
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Effects of Sex, Race, and Puberty on Cortical Bone and the Functional Muscle Bone Unit in Children, Adolescents, and Young Adults
    The Endocrine Society ; 2010
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 95, No. 4 ( 2010-04-01), p. 1681-1689
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 95, No. 4 ( 2010-04-01), p. 1681-1689
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2009-1913
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2010
    detail.hit.zdb_id: 2026217-6
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  • 6
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    Disease Burden and Outcome in Children and Young Adults With Concurrent Graves Disease and Differentiated Thyroid Carcinoma
    The Endocrine Society ; 2018
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 103, No. 8 ( 2018-08-01), p. 2918-2925
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 103, No. 8 ( 2018-08-01), p. 2918-2925
    Abstract: Adults with differentiated thyroid cancer (DTC) and Graves disease (GD) demonstrate a greater reported disease burden and aggressive DTC behavior. To date, no studies have examined the impact and long-term outcome of concurrent GD and DTC (GD-DTC) in children and young adults. Design Single institution, retrospective longitudinal cohort study between 1997 and 2016. Participants One hundred thirty-nine children and young adults with DTC, diagnosed at median age 15 (range, 5 to 23) years, compared with 12 patients with GD-DTC, median age 18 (range, 12 to 20) years. Major Outcome Measures Patient demographics, preoperative imaging, fine needle aspiration (FNA) cytology, operative and pathological reports, laboratory studies, treatment, and subsequent 2-year outcomes. Results Compared with DTC, patients with GD-DTC were significantly older at the time of DTC diagnosis (P 〈 0.01). Patients with GD-DTC were more likely to exhibit microcarcinoma (P 〈 0.01), and 2 of 12 (17%) demonstrated tall cell variant papillary thyroid cancer (PTC) vs 2 of 139 (2%) in patients who had DTC alone (P = 0.03). Although patients with DTC showed greater lymphovascular invasion (60% vs 25%; P = 0.03), no group differences were noted in extrathyroidal extension, regional lymph node, and distant or lung metastasis. There were no group differences in the 2-year outcome for remission, persistent disease, or recurrence. Conclusions Concurrent DTC in pediatric patients with GD is not associated with a greater disease burden at presentation and shows no significant difference in 2-year outcomes compared with DTC alone. Similar to adults, microcarcinoma and tall cell variant PTC is prevalent in pediatric patients with GD-DTC. For patients who have GD-DTC with an identified nodule on ultrasound imaging prior to definitive therapy, FNA biopsy is recommended to guide definitive treatment.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2018-00026
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2018
    detail.hit.zdb_id: 2026217-6
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  • 7
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    Abnormal body composition is a predictor of adverse outcomes after autologous haematopoietic cell transplantation
    Wiley ; 2020
    In:  Journal of Cachexia, Sarcopenia and Muscle Vol. 11, No. 4 ( 2020-08), p. 962-972
    Details
    In: Journal of Cachexia, Sarcopenia and Muscle, Wiley, Vol. 11, No. 4 ( 2020-08), p. 962-972
    Abstract: The number of patients undergoing autologous haematopoietic cell transplant (HCT) is growing, but little is known about the factors that predict adverse outcomes. Low muscle mass and obesity are associated with disability and premature mortality in individuals with non‐malignant diseases and may predict outcomes after autologous HCT. Methods This was a retrospective cohort study of 320 patients who underwent autologous HCT for Hodgkin or non‐Hodgkin lymphoma between 2009 and 2014. Sarcopenia {skeletal muscle index male: 〈 43 cm/m 2 [body mass index (BMI) 〈 25 kg/m 2 ] or 〈 53 cm/m 2 [BMI ≥ 25 kg/m 2 ] and female: 〈 41 cm/m 2 [regardless of BMI]) and obesity [total abdominal adiposity ≥450.0 cm 2 (male), ≥396.4 cm 2 (female)] were assessed from single‐slice abdominal pre‐HCT computed tomography images. Length of hospital stay, first unplanned intensive care unit admission, and 30‐day unplanned readmission were evaluated based on body composition using multivariable regression analysis, and mortality was evaluated with Kaplan–Meier analysis and Gray's test. Results Median age at HCT was 53.3 years (range, 18.5 to 78.1 years); 26.3% were sarcopenic and an additional 7.8% were sarcopenic obese pre‐HCT. Sarcopenic obesity was associated with increased risk of prolonged hospitalization [odds ratio (OR) = 3.6, 95% confidence interval (CI) 1.3–9.8], intensive care unit admission (OR = 4.7, 95% CI 1.5–16.1), and unplanned readmission after HCT (OR = 13.6, 95% CI 2.5–62.8). Patients who were sarcopenic obese also had the highest mortality risk at 1 year [hazard ratio (HR): 3.9, 95% CI 1.1–11.0] and 5 years (HR: 2.5, 95% CI 1.1–5.5), compared with patients with normal body composition. Sarcopenia alone, but not obesity alone, was associated with an increased risk of these outcomes, albeit with a lower magnitude of risk than in patients who were sarcopenic obese. Conclusions Sarcopenic obesity was an important predictor of outcomes in patients undergoing autologous HCT. These findings could inform targeted prevention strategies in patients at highest risk of complications after HCT.
    Type of Medium: Online Resource
    ISSN: 2190-5991 , 2190-6009
    URL: Issue
    URL: Article
    DOI: 10.1002/jcsm.v11.4
    DOI: 10.1002/jcsm.12570
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2586864-0
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  • 8
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    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}
    Springer Science and Business Media LLC ; 2022
    In:  BMC Cancer Vol. 22, No. 1 ( 2022-12)
    Details
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2022-12)
    Abstract: 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}.
    Type of Medium: Online Resource
    ISSN: 1471-2407
    URL: Article
    DOI: 10.1186/s12885-022-09845-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 9
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    Fusion Oncogenes Are Associated With Increased Metastatic Capacity and Persistent Disease in Pediatric Thyroid Cancers
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 10 ( 2022-04-01), p. 1081-1090
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 10 ( 2022-04-01), p. 1081-1090
    Abstract: In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behavior than sole reliance on pathologic classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer (DTC) and investigate whether mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC. METHODS Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into RAS-mutant ( H-K-NRAS), BRAF-mutant ( BRAF p.V600E), and RET/ NTRK fusion ( RET, NTRK1, and NTRK3 fusions) to determine differences between subtype classification in regard to pathologic data (American Joint Committee on Cancer TNM) as well as response to therapy 1 year after initial treatment had been completed. RESULTS Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1 year. Patients with RET/ NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at 1 year than patients within RAS- or BRAF-mut subgroups. CONCLUSION Our data support that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathologic classification with patients with RET/ NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.21.01861
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 10
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    Germline Genetic and Treatment-Related Risk Factors for Diabetes Mellitus in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study and St Jude Lifetime Cohorts
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  JCO Precision Oncology , No. 6 ( 2022-12)
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 6 ( 2022-12)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.22.00239
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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