Yutaka Yasui

Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers

The diagnosis of Alzheimers disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimers disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimers disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.

Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma: an analysis from the St Jude Lifetime Cohort Study

Background The magnitude of cardiovascular morbidity among survivors of pediatric, adolescent, and young adult Hodgkin lymphoma is not known. Using medically ascertained data, we applied the cumulative burden metric to compare chronic cardiovascular health conditions among Hodgkin survivors and general population controls. Methods Among 670 survivors treated at St. Jude Children’s Research Hospital, who survived ≥10 years and became 18 years old, 348 were clinically assessed in the St. Jude Lifetime Cohort Study (SJLIFE). Age-sex-frequency-matched SJLIFE community-controls (n=272) were used for comparison. All SJLIFE participants underwent evaluation for 22 chronic cardiovascular health conditions. Direct assessments, combined with retrospective clinical reviews, were used to assign severity to conditions using a modified Common Terminology Criteria of Adverse Events (CTCAE) grading schema. Occurrences and CTCAE-grades of the conditions for 322 eligible non-SJLIFE participants were accounted for by multiple imputation. The mean cumulative count (treating death as a competing risk) was used to estimate cumulative burden. Findings At 50 years of age, the cumulative incidence of survivors experiencing at least one grade 3-5 cardiovascular condition was 45.5%. The survivor cohort experienced, on average, 430·6 (95% confidence interval, 380·7-480·6) grade 1-5 and 100·8 (77·3-124·3) grade 3-5 cardiovascular conditions per 100 survivors. At age 50, the grade 1-5 and 3-5 cumulative burdens of community-controls were appreciably lower at 227·4/100 (192·7-267·5) and 17·0/100 (8·4-27·5), respectively. Myocardial infarction and structural heart defects were the major contributors to the excess grade 3-5 cumulative burden among survivors. Higher cardiac radiation dose (≥35 Gy) was associated with an increased grade 3-5 cardiovascular burden. Interpretation The true impact of cardiovascular morbidity among pediatric Hodgkin lymphoma survivors is reflected in the cumulative burden. 50-year-old Hodgkin survivors will experience over two times the number of chronic cardiovascular health conditions compared community-controls and, on average, have one severe/life-threatening/fatal cardiovascular condition. The cumulative burden metric provides a more comprehensive approach to evaluating overall morbidity and will assist clinical researchers when designing future trials and refining general practice screening guidelines.

The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE).

Background Survivors of childhood cancer develop early and severe chronic health conditions (CHCs). A quantitative landscape of morbidity among survivors, however, has not been described. Methods Among 5,522 patients treated for childhood cancer at St. Jude Children’s Research Hospital who survived ≥10 years and were ≥18 years old, 3,010 underwent prospective clinical assessment and retrospective medical validation of health records as part of the St. Jude Lifetime Cohort Study. Age- and sex-frequency-matched community-controls (n=272) were used for comparison. 168 CHCs for all participants were graded for severity using a modified Common Terminology Criteria of Adverse Events. Multiple imputation with predictive mean matching was used for missing occurrences and grades of CHCs among the 2512 survivors not clinically evaluated. Mean cumulative count and marked-point-process regression were used for descriptive and inferential cumulative burden analyses, respectively. Findings The cumulative incidence of any grade CHC at age 50 was 99·9%; 96·0% (95·3%–96·8%) for severe/disabling, life-threatening or fatal CHCs. By age 50, a survivor experienced, on average, 17·1 (16·2–18·0) CHCs including 4·7 (4·6–4·9) graded as severe/disabling, life-threatening or fatal. The cumulative burden among survivors was nearly 2-fold greater than matched community-controls (p<0·001). Second neoplasms, spinal disorders and pulmonary disease were major contributors to the excess total cumulative burden. Significant heterogeneity in CHCs among survivors with differing primary cancer diagnoses was observed. Multivariable analyses demonstrated that age at diagnosis, treatment era and higher doses of brain and chest radiation are significantly associated with a greater cumulative burden and severity of CHCs. Interpretation The burden of surviving childhood cancer is substantial and highly variable. The total cumulative burden experienced by survivors of pediatric cancer, in conjunction with detailed characterization of long-term CHCs, provide data to better inform future clinical guidelines, research investigations and health services planning for this vulnerable, medically-complex population.

Approach for Classification and Severity-grading of Long-term and Late-onset Health Events among Childhood Cancer Survivors in the St. Jude Lifetime Cohort

Characterization of toxicity associated with cancer and its treatment is essential to quantify risk, inform optimization of therapeutic approaches for newly diagnosed patients, and guide health surveillance recommendations for long-term survivors. The NCI Common Terminology Criteria for Adverse Events (CTCAE) provides a common rubric for grading severity of adverse outcomes in cancer patients that is widely used in clinical trials. The CTCAE has also been used to assess late cancer treatment-related morbidity but is not fully representative of the spectrum of events experienced by pediatric and aging adult survivors of childhood cancer. Also, CTCAE characterization does not routinely integrate detailed patient-reported and medical outcomes data available from clinically assessed cohorts. To address these deficiencies, we standardized the severity grading of long-term and late-onset health events applicable to childhood cancer survivors across their lifespan by modifying the existing CTCAE v4.03 criteria and aligning grading rubrics from other sources for chronic conditions not included or optimally addressed in the CTCAE v4.03. This article describes the methods of late toxicity assessment used in the St. Jude Lifetime Cohort Study, a clinically assessed cohort in which data from multiple diagnostic modalities and patient-reported outcomes are ascertained. Cancer Epidemiol Biomarkers Prev; 26(5); 666–74. ©2016 AACR.

Premature Ovarian Insufficiency in Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort

ContextnLong-term follow-up data on premature ovarian insufficiency (POI) in childhood cancer survivors are limited.nnnObjectivenTo describe the prevalence of POI, its risk factors, and associated long-term adverse health outcomes.nnnDesignnCross-sectional.nnnSettingnThe St. Jude Lifetime Cohort Study, an established cohort in a tertiary care center.nnnPatientsnNine hundred twenty-one participants (median age, 31.7 years) were evaluated at a median of 24.0 years after cancer diagnosis.nnnMain Outcome MeasurenPOI was defined by persistent amenorrhea combined with a follicle-stimulating hormone level >30 IU/L before age 40. Multivariable Cox regression was used to study associations between demographic or treatment-related risk factors and POI. Multivariable logistic regression was used to study associations between POI and markers for cardiovascular disease, bone mineral density (BMD), and frailty. Exposure to alkylating agents was quantified using the validated cyclophosphamide equivalent dose (CED).nnnResultsnThe prevalence of POI was 10.9%. Independent risk factors for POI included ovarian radiotherapy at any dose and CED ≥8000 mg/m2. Patients with a body mass index ≥30 kg/m2 at the time of the St. Jude Lifetime Cohort assessment were less likely to have a diagnosis of POI. Low BMD and frailty were independently associated with POI.nnnConclusionnHigh-dose alkylating agents and ovarian radiotherapy at any dose are associated with POI. Patients at the highest risk should be offered fertility preservation whenever feasible. POI contributes to poor general health outcomes in childhood cancer survivors; further studies are needed to investigate the role of sex hormone replacement in improving such outcomes.

Risk and impact of pulmonary complications in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study

Pulmonary complications after cancer therapy are varied. This study describes pulmonary outcomes among childhood cancer survivors and evaluates their impact on daily activities.

Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer.

BackgroundnChildhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking.nnnMethodsnWe conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16u2009958u2009466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided.nnnResultsnAmong survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09u2009×u200910 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84u2009×u200910 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68u2009×u200910 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts.nnnConclusionsnOur study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer.

Childhood cancer survivorship research in minority populations: A position paper from the childhood cancer survivor study

By the middle of this century, racial/ethnic minority populations will collectively constitute 50% of the US population. This temporal shift in the racial/ethnic composition of the US population demands a close look at the race/ethnicity‐specific burden of morbidity and premature mortality among survivors of childhood cancer. To optimize targeted long‐term follow‐up care, it is essential to understand whether the burden of morbidity borne by survivors of childhood cancer differs by race/ethnicity. This is challenging because the number of minority participants is often limited in current childhood cancer survivorship research, resulting in a paucity of race/ethnicity‐specific recommendations and/or interventions. Although the overall childhood cancer incidence increased between 1973 and 2003, the mortality rate declined; however, these changes did not differ appreciably by race/ethnicity. The authors speculated that any racial/ethnic differences in outcome are likely to be multifactorial, and drew on data from the Childhood Cancer Survivor Study to illustrate the various contributors (socioeconomic characteristics, health behaviors, and comorbidities) that could explain any observed differences in key treatment‐related complications. Finally, the authors outlined challenges in conducting race/ethnicity‐specific childhood cancer survivorship research, demonstrating that there are limited absolute numbers of children who are diagnosed and survive cancer in any one racial/ethnic minority population, thereby precluding a rigorous evaluation of adverse events among specific primary cancer diagnoses and treatment exposure groups. Cancer 2016;122:2426–2439.

Longitudinal follow-up of adult survivors of Ewing sarcoma: A report from the Childhood Cancer Survivor Study

Ewing sarcoma survivors (ESSs) are at increased risk for treatment‐related complications. The incidence of treatment‐related morbidity and late mortality with aging is unknown.

A High-risk Haplotype for Premature Menopause in Childhood Cancer Survivors Exposed to Gonadotoxic Therapy

BackgroundnChildhood cancer survivors are at increased risk of therapy-related premature menopause (PM), with a cumulative incidence of 8.0%, but the contribution of genetic factors is unknown.nnnMethodsnGenome-wide association analyses were conducted to identify single nucleotide polymorphisms (SNPs) associated with clinically diagnosed PM (menopause < 40 years) among 799 female survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE). Analyses were adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian radiotherapy (RT) dose (all P values two-sided). Replication was performed using self-reported PM in 1624 survivors participating in the Childhood Cancer Survivor Study (CCSS).nnnResultsnPM was clinically diagnosed in 30 (3.8%) SJLIFE participants. Thirteen SNPs (70 kb region of chromosome 4q32.1) upstream of the Neuropeptide Receptor 2 gene (NPY2R) were associated with PM prevalence (minimum P = 3.3u2009×u200910-7 for rs9999820, all P < 10-5). Being a homozygous carrier of a haplotype formed by four of the 13 SNPs (seen in one in seven in the general population but more than 50% of SJLIFE clinically diagnosed PM) was associated with markedly elevated PM prevalence among survivors exposed to ovarian RT (odds ratio [OR] = 25.89, 95% confidence interval [CI] = 6.18 to 138.31, P = 8.2u2009×u200910-6); this finding was replicated in an independent second cohort of CCSS in spite of its use of self-reported PM (ORu2009=u20093.97, 95% CIu2009=u20091.67 to 9.41, P = .002). Evidence from bioinformatics data suggests that the haplotype alters the regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways.nnnConclusionsnThe haplotype captures the majority of clinically diagnosed PM cases and, with further validation, may have clinical application in identifying the highest-risk survivors for PM for possible intervention by cryopreservation.