Survivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the heart was exposed, are at ...increased risk of cardiomyopathy. Symptomatic cardiomyopathy is typically preceded by a series of gradually progressive, asymptomatic changes in structure and function of the heart that can be ameliorated with treatment, prompting specialist organisations to endorse guidelines on cardiac surveillance in at-risk survivors of cancer. In 2015, the International Late Effects of Childhood Cancer Guideline Harmonization Group compiled these guidelines into a uniform set of recommendations applicable to a broad spectrum of clinical environments with varying resource availabilities. Since then, additional studies have provided insight into dose thresholds associated with a risk of asymptomatic and symptomatic cardiomyopathy, have characterised risk over time, and have established the cost-effectiveness of different surveillance strategies. This systematic Review and guideline provides updated recommendations based on the evidence published up to September, 2020.
Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early ...breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m−2: 1.24, 95% confidence interval (CI): 1.18–1.31), with more than twofold increased risk for survivors treated with ≥200 mg m−2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200–299 mg m−2, HR: 2.33 for 300–399 mg m−2 and HR: 2.78 for ≥400 mg m−2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59–6.63). For patients treated with or without chest irradiation, HRs per 100 mg m−2 of doxorubicin were 1.11 (95% CI: 1.02–1.21) and 1.26 (95% CI: 1.17–1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m−2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.
Survivors of childhood cancer may develop a second malignant neoplasm during adulthood and therefore require regular surveillance.
To examine adherence to population cancer screening guidelines by ...survivors at average risk for a second malignant neoplasm and adherence to cancer surveillance guidelines by survivors at high risk for a second malignant neoplasm.
Retrospective cohort study.
The Childhood Cancer Survivor Study (CCSS), a 26-center study of long-term survivors of childhood cancer that was diagnosed between 1970 and 1986.
4329 male and 4018 female survivors of childhood cancer who completed a CCSS questionnaire assessing screening and surveillance for new cases of cancer.
Patient-reported receipt and timing of mammography, Papanicolaou smear, colonoscopy, or skin examination was categorized as adherent to the U.S. Preventive Services Task Force guidelines for survivors at average risk for breast or cervical cancer or the Children's Oncology Group guidelines for survivors at high risk for breast, colorectal, or skin cancer as a result of cancer therapy.
In average-risk female survivors, 2743 of 3392 (80.9%) reported having a Papanicolaou smear within the recommended period, and 140 of 209 (67.0%) reported mammography within the recommended period. In high-risk survivors, rates of recommended mammography among women were only 241 of 522 (46.2%) and the rates of colonoscopy and complete skin examinations among both sexes were 91 of 794 (11.5%) and 1290 of 4850 (26.6%), respectively.
Data were self-reported. Participants in the CCSS are a selected group of survivors, and their adherence may not be representative of all survivors of childhood cancer.
Female survivors at average risk for a second malignant neoplasm show reasonable rates of screening for cervical and breast cancer. However, surveillance for new cases of cancer is very low in survivors at the highest risk for colon, breast, or skin cancer, suggesting that survivors and their physicians need education about their risks and recommended surveillance.
The National Cancer Institute, National Institutes of Health, and the American Lebanese Syrian Associated Charities.
Telomere length is associated with risk for thyroid subsequent malignant neoplasm in survivors of childhood cancer. Here, we investigated associations between thyroid subsequent malignant neoplasm ...and inherited variation in telomere maintenance genes.
We used RegulomeDB to annotate the functional impact of variants mapping to 14 telomere maintenance genes among 5,066 five-or-more year survivors who participate in the Childhood Cancer Survivor Study (CCSS) and who are longitudinally followed for incidence of subsequent cancers. Hazard ratios for thyroid subsequent malignant neoplasm were calculated for 60 putatively functional variants with minor allele frequency ≥1% in or near telomere maintenance genes. Functional impact was further assessed by measuring telomere length in leukocyte subsets.
The minor allele at Protection of Telomeres-1 (POT1) rs58722976 was associated with increased risk for thyroid subsequent malignant neoplasm (adjusted HR = 6.1, 95% CI: 2.4, 15.5, P = 0.0001; Fisher's exact P = 0.001). This imputed SNP was present in three out of 110 survivors who developed thyroid cancer vs. 14 out of 4,956 survivors who did not develop thyroid cancer. In a subset of 83 survivors with leukocyte telomere length data available, this variant was associated with longer telomeres in B lymphocytes (P = 0.004).
Using a functional variant approach, we identified and confirmed an association between a low frequency intronic regulatory POT1 variant and thyroid subsequent malignant neoplasm in survivors of childhood cancer. These results suggest that intronic variation in POT1 may affect key protein binding interactions that impact telomere maintenance and genomic integrity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Progress in therapy has made survival into adulthood a reality for most children, adolescents, and young adults with a cancer diagnosis today. Notably, this growing population remains vulnerable to a ...variety of long-term therapy-related sequelae. Systematic ongoing follow-up of these patients is, therefore, important to provide for early detection of and intervention for potentially serious late-onset complications. In addition, health counseling and promotion of healthy lifestyles are important aspects of long-term follow-up care to promote risk reduction for physical and emotional health problems that commonly present during adulthood. Both general and subspecialty health care providers are playing an increasingly important role in the ongoing care of childhood cancer survivors, beyond the routine preventive care, health supervision, and anticipatory guidance provided to all patients. This report is based on the guidelines that have been developed by the Children's Oncology Group to facilitate comprehensive long-term follow-up of childhood, adolescent, and young adult cancer survivors (www.survivorshipguidelines.org).
This study aimed to assess longitudinal associations between lifestyle and subsequent malignant neoplasms (SMNs) in young adult childhood cancer survivors.
Members of the St. Jude Lifetime Cohort ...(SJLIFE) aged ≥18 years and surviving ≥5 years after childhood cancer diagnosis were queried and evaluated for physical activity, cardiorespiratory fitness (CRF), muscle strength, body mass index (BMI), smoking, risky drinking, and a combined lifestyle score. Time to first SMN, excluding nonmalignant neoplasms and nonmelanoma skin cancer, was the outcome of longitudinal analysis.
Survivors (
= 4072, 47% female, 29% smokers, 37% risky drinkers, 34% obese, and 48% physically inactive) had a mean (SD) time between baseline evaluation and follow-up of 7.0 (3.3) years, an age of 8.7 (5.7) years at diagnosis, and an age of 30 (8.4) years at baseline lifestyle assessment. Neither individual lifestyle factors nor a healthy lifestyle score (RR 0.8, 0.4-1.3,
= 0.36) were associated with the risk of developing an SMN.
We did not identify any association between lifestyle factors and the risk of SMN in young adult childhood cancer survivors.
To estimate the prevalence of frailty among childhood cancer survivors and to determine the direct and indirect effects of treatment exposures, lifestyle factors, and severe, disabling, and ...life-threatening chronic condition on frailty.
Childhood cancer survivors (≥ 5 years since diagnosis), treated between 1970 and 1999 when < 21 years old (n = 10,899; mean age, 37.6 ± 9.4 years; 48% male, 86% white) and siblings were included (n = 2,097; mean age, 42.9 ± 9.4 years). Frailty was defined as ≥ 3 of the following: low lean mass, exhaustion, low energy expenditure, walking limitations, and weakness. Generalized linear models were used to evaluate direct and indirect associations between frailty and treatment exposures, sociodemographic characteristics, lifestyle factors, and chronic condition.
The overall prevalence of frailty among survivors was 3 times higher compared with siblings (6.4%; 95% CI, 4.1% to 8.7%;
2.2%; 95% CI, 1.2% to 3.2%). Survivors of CNS tumors (9.5%; 95% CI, 5.2% to 13.8%) and bone tumors (8.1%; 95% CI, 5.1% to 11.1%) had the highest prevalence of frailty. Survivors exposed to cranial radiation, pelvic radiation ≥ 34 Gy, abdominal radiation > 40 Gy, cisplatin ≥ 600 mg/m
, amputation, or lung surgery had increased risk for frailty. These associations were partially but not completely attenuated when sociodemographic characteristics, lifestyle factors, and chronic conditions were added to multivariable models. Cranial radiation (prevalence ratio PR, 1.47; 95% CI, 1.20 to 1.76), pelvic radiation ≥ 34 Gy (PR, 1.46; 95% CI, 1.01 to 2.11), and lung surgery (PR, 1.75; 95% CI, 1.28 to 2.38) remained significant after sociodemographic, lifestyle, and chronic conditions were accounted for.
Childhood cancer survivors reported a higher prevalence of frailty compared with siblings. Radiation and lung surgery exposures were associated with increased risk for frailty. Interventions to prevent, delay onset, or remediate chronic disease and/or promote healthy lifestyle are needed to decrease the prevalence of frailty and preserve function in this at-risk population.
Down syndrome is a chromosomal disorder with considerable neurodevelopmental impact and neurodegenerative morbidity. In a pilot trial in young adults with Down syndrome, memantine (a drug approved ...for Alzheimer's disease) showed a significant effect on a secondary measure of episodic memory. We aimed to test whether memantine would improve episodic memory in adolescents and young adults with Down syndrome.
We did a randomised, double-blind, placebo-controlled phase 2 trial with a parallel design, stratified by age and sex. Participants (aged 15–32 years) with either trisomy 21 or complete unbalanced translocation of chromosome 21 and in general good health were recruited from the community at one site in Brazil and another in the USA. Participants were randomly assigned (1:1) to receive either memantine (20 mg/day orally) or placebo for 16 weeks. Computer-generated randomisation tables for both sites (allocating a placebo or drug label to each member of a unique pair of participants) were centrally produced by an independent statistician and were shared only with investigational pharmacists at participating sites until unblinding of the study. Participants and investigators were masked to treatment assignments. Neuropsychological assessments were done at baseline (T1) and week 16 (T2). The primary outcome measure was change from baseline to week 16 in the California Verbal Learning Test–second edition short-form (CVLT-II-sf) total free recall score, assessed in the per-protocol population (ie, participants who completed 16 weeks of treatment and had neuropsychological assessments at T1 and T2). Linear mixed effect models were fit to data from the per-protocol population. Safety and tolerability were monitored and analysed in all participants who started treatment. Steady-state concentrations in plasma of memantine were measured at the end of the trial. This study is registered at ClinicalTrials.gov, number NCT02304302.
From May 13, 2015, to July 22, 2020, 185 participants with Down syndrome were assessed for eligibility and 160 (86%) were randomly assigned either memantine (n=81) or placebo (n=79). All participants received their allocated treatment. Linear mixed effect models were fit to data from 149 (81%) participants, 73 in the memantine group and 76 in the placebo group, after 11 people (eight in the memantine group and three in the placebo group) discontinued due to COVID-19 restrictions, illness of their caregiver, adverse events, or low compliance. The primary outcome measure did not differ between groups (CVLT-II-sf total free recall score, change from baseline 0·34 points 95% CI –0·98 to 1·67, p=0·61). Memantine was well tolerated, with infrequent mild-to-moderate adverse events, the most common being viral upper respiratory infection (nine 11% participants in the memantine group and 12 15% in the placebo group) and transient dizziness (eight 10% in the memantine group and six 8% in the placebo group). No serious adverse events were observed. Amounts of memantine in plasma were substantially lower than those considered therapeutic for Alzheimer's disease.
Memantine was well tolerated, but cognition-enhancing effects were not recorded with a 20 mg/day dose in adolescents and young adults with Down syndrome. Exploratory analyses point to a need for future work.
Alana Foundation.
For the Portuguese translation of the abstract see Supplementary Materials section.
Male patients with childhood, adolescent, and young adult cancer are at an increased risk for infertility if their treatment adversely affects reproductive organ function. Future fertility is a ...primary concern of patients and their families. Variations in clinical practice are barriers to the timely implementation of interventions that preserve fertility. As part of the PanCareLIFE Consortium, in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in male patients who are diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. Recognising the need for global consensus, this clinical practice guideline used existing evidence and international expertise to rigorously develop transparent recommendations that are easy to use to facilitate the care of male patients with childhood, adolescent, and young adult cancer who are at high risk of fertility impairment and to enhance their quality of life.
10029
Background: Type 2 diabetes (T2D) is an established late effect of cancer treatment among long-term survivors of childhood cancer. Genetic factors underpinning T2D in diverse populations of ...survivors have not been well studied. Methods: We conducted a multi-ancestry genome-wide association study (GWAS) for clinically ascertained T2D among survivors of European (EUR; N = 3,102 with 261 cases) and African (AFR; N = 574 with 43 cases) ancestry from SJLIFE. Replication analyses were performed between ancestries in SJLIFE and in EUR survivors in CCSS (N = 5,965; 270 self-reported cases). Two published T2D polygenic risk scores (PRSs) were assessed in survivors: a 338-variant multi-ancestry PRS (N~1.4 million; 49% non-EUR descent) and a ~6.9 million-variant EUR-only PRS (N~160K; DIAGRAM Consortium and UK Biobank Study). Treatment-related T2D risk effect modification was evaluated for abdominal irradiation and alkylating agents. Results: In SJLIFE AFR survivors, one novel locus with suggestive significance was identified (5p15.2: OR = 10.19, P = 5.1x10
-7
), replicating in both SJLIFE EUR (P = 0.011) and CCSS EUR survivors (P = 0.021). A EUR-specific genome-wide significant association at 8q11.21 ( SNTG1 intronic variant; OR = 1.99; P = 4.4x10
-8
) was replicated in CCSS (P = 8.1x10
-3
). Two other loci with suggestive associations (P < 5x10
-6
) in SJLIFE EUR survivors replicated in SJLIFE AFR survivors (P < 0.05), achieving genome-wide significance in multi-ancestry meta-analysis (2p25.3: OR = 2.05, P = 4.5x10
-8
; 19p12: OR = 2.43 P = 5.7x10
-9
). Each of the three novel trans-ancestral loci overlapped putative Polycomb-repressed regions, i.e., chromatin-based gene regulation elements, in pancreatic cells and displayed treatment-related effect heterogeneity across ancestry groups. Notably, AFR survivors with risk alleles experienced disproportionately greater T2D risk if treated with alkylating agents (2p25.3: OR = 3.95; 19p12: OR = 5.74; 5p15.2: OR = 17.81). Increases in the T2D odds per multi-ancestry PRS standard deviation were consistent in survivors across ancestries (SJLIFE EUR: OR = 1.84, P = 1.1x10
-16
; SJLIFE AFR: OR = 1.80, P = 2.8x10
-3
, CCSS EUR: OR = 1.60, P = 8.4x10
-13
). However, T2D risk association with the EUR-only PRS was absent in AFR survivors (OR = 0.97, P = 0.95). Conclusions: Multi-ancestry genetic analyses revealed three novel T2D risk alleles associated with disproportionately greater alkylating agent-related risk among African-ancestry survivors. Furthermore, an external multi-ancestry T2D PRS was associated with increased risk in diverse ancestry survivors, whereas a EUR-only PRS was not useful for African-ancestry survivors. This study supports precision diabetes surveillance and survivorship care for all childhood cancer survivors, including those in minority ancestry groups.
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