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Background: Survivors of childhood central nervous system (CNS) tumors can develop motor and sensory impairment from their cancer and treatment history. We estimated the prevalence of motor and sensory impairment in survivors compared with controls through clinical assessment and identified associated treatment exposures and functional, quality of life (QOL), and social outcomes. Methods: Survivors of childhood CNS tumors from the St. Jude Lifetime Cohort (n = 378, median [range] age 24.0 [18.0–53.0] years, 43.4% female) ≥5 years from diagnosis and controls (n = 445, median [range] age 34.0 [18.0–70.0] years, 55.7% female) completed in‐person evaluation for motor and sensory impairment using the modified Total Neuropathy Score. Impairment was graded by modified Common Terminology Criteria for Adverse Events. Multivariable models estimated associations between grade ≥2 motor/sensory impairment, individual/treatment characteristics, and secondary outcomes (function by Physical Performance Test, fitness by physiologic cost index, QOL by Medical Outcomes Survey Short Form‐36 physical/mental summary scores, social attainment). Results: Grade ≥2 motor or sensory impairment was more prevalent in survivors (24.1%, 95% Confidence Interval [CI] 19.8%–29.4%) than controls (2.9%, CI 1.4–4.5%). Among survivors, in multivariable models, motor impairment was associated with vinca exposure <15 mg/m2 versus none (OR 4.38, CI 1.06–18.08) and etoposide exposure >2036 mg/m2 versus none (OR 12.61, CI 2.19–72.72). Sensory impairment was associated with older age at diagnosis (OR 1.09, CI 1.01–1.16) and craniospinal irradiation versus none (OR 4.39, CI 1.68–11.50). There were lower odds of motor/sensory impairment in survivors treated in the year 2000 or later versus before 1990 (Motor: OR 0.29, CI 0.10–0.84, Sensory: OR 0.35, CI 0.13–0.96). Motor impairment was associated with impaired physical QOL (OR 2.64, CI 1.22–5.72). Conclusions: In survivors of childhood CNS tumors, motor and sensory impairment is prevalent by clinical assessment, especially after exposure to etoposide, vinca, or craniospinal radiation. Treating motor impairment may improve survivors' QOL. [ABSTRACT FROM AUTHOR]

Objective: To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)‐directed therapies. Methods: A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS‐treated]; median age [range] = 25.5 years [18–48]; time since diagnosis = 17.7 years [6.8–30.2]) and 8039 without CNS‐directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal care needs, ability to work/attend school, attainment of driver's license, marital/partner status). Multivariable regression models, adjusted for age, sex, race/ethnicity, and chronic health conditions, estimated odds ratios (OR) or relative risks (RR) for associations between neurologic morbidity, functional independence, and emotional distress. Results: Among CNS‐treated survivors, three classes of independence were identified: (1) moderately independent, never married, and non‐independent living (78.7%); (2) moderately independent, unable to drive (15.6%); and (3) non‐independent (5.7%). In contrast to 50% of non‐CNS‐treated survivors and 60% of siblings, a fourth fully independent class of CNS‐treated survivors was not identified. History of stroke (OR = 2.50, 95% CI: 1.70–3.68), seizure (OR = 9.70, 95% CI: 7.37–12.8), neurosensory deficits (OR = 2.67, 95% CI: 2.16–3.31), and focal neurologic dysfunction (OR = 3.05, 95% CI: 2.40–3.88) were associated with non‐independence among CNS‐treated survivors. Non‐independence was associated with emotional distress symptoms. Interpretation: CNS‐treated survivors do not attain full independence comparable to non‐CNS‐treated survivors or siblings. Interventions to promote independence may be beneficial for survivors with treatment‐related neurological sequalae. [ABSTRACT FROM AUTHOR]

Background: Limited data exist regarding left ventricular remodeling patterns observed in adult survivors of childhood cancer after therapy. Methods: Among 1190 adult survivors diagnosed with childhood cancer (median age at diagnosis, 9 years [interquartile range (IQR), 3.8‐14.4 years]; age at evaluation, 35.6 years [IQR, 29.5‐42.8 years]), treatment exposures included anthracyclines (n = 346), chest radiotherapy (n = 174), both (n = 245), or neither (n = 425). Prospective echocardiographic assessment compared survivors with 449 noncancer controls classified according to left ventricle geometric patterns. Associations between left ventricle geometric patterns and decreased exercise tolerance were assessed. Results: Overall, 28.2% of survivors (95% confidence interval [CI], 25.6%‐30.8%) exhibited concentric remodeling, 2.4% (95% CI, 1.6%‐3.5%) exhibited eccentric hypertrophy, and 1.1% (95% CI, 0.6%‐1.9%) exhibited concentric hypertrophy. A greater proportion of survivors who received only chest radiotherapy (41%) had concentric remodeling compared with those who received only anthracyclines (24%), both (27%), or neither (27%; all P <.001), and all were greater than the proportions in noncancer controls (18%; all P <.05). Concentric remodeling was associated with radiation exposure, but not with anthracycline exposure, in multivariable models. Survivors who had concentric remodeling were more likely to have a maximal oxygen uptake peak <85% compared with those who had normal geometry (81.0% vs 66.3%; odds ratio, 1.75; 95% CI, 1.15‐2.68). Conclusions: Chest radiation therapy, but not anthracycline therapy, increased the risk for concentric remodeling in survivors of childhood cancer. The presence of concentric remodeling was associated with increased exercise intolerance. Chest radiation therapy increases the risk of concentric left ventricular remodeling as assessed by echocardiography, but anthracycline therapy does not increase the risk of concentric remodeling. Adult survivors of childhood cancer who have concentric remodeling are more likely to have a relative peak oxygen uptake <85% compared with survivors who have normal left ventricular geometry. [ABSTRACT FROM AUTHOR]

Background: Neurocognitive impairment and obesity are common adverse sequelae in survivors of childhood acute lymphoblastic leukemia (ALL); however, the association has not been investigated. Methods: Neurocognitive function was evaluated once in survivors of ALL who were at least 8 years old and 5 years from their diagnosis. In a cross‐sectional analysis, the associations with the body mass index (BMI) category and Z score were examined. A longitudinal analysis used the overweight/obesity area under the curve (AUC), which was determined via the trapezoidal rule by a sum of the integrals defined by the BMI Z score at each time point and the time intervals of the BMI measurement. Results: For 210 survivors, the median BMI Z score at diagnosis was 0.17, which increased to 0.54 at the end of induction and to 0.74 at the neurocognitive assessment. In the cross‐sectional analysis, overweight/obese survivors scored significantly lower than others on the measures of executive function (cognitive flexibility, planning, verbal fluency, working memory, and spatial construction; all P <.05), attention (attention span and risk taking; all P <.05), and processing speed (visual motor coordination, visual speed, and motor speed; all P <.05). In the longitudinal analysis, when the treatment period was subdivided into 4 time periods (induction, consolidation, early maintenance, and late maintenance), a greater overweight/obesity AUC during induction therapy was associated with worse cognitive flexibility (P =.01) and slower motor speed (P =.02), which persisted throughout the treatment. Conclusions: Overweight/obesity was significantly associated with neurocognitive impairment during long‐term follow‐up, and this association started early in treatment for ALL. Novel early interventions to provide cognitive training and prevent weight gain are required for patients at risk. In a cohort of 210 children with acute lymphoblastic leukemia (ALL) at a median follow‐up of 7.5 years from diagnosis, overweight/obese survivors score significantly worse than others on measures of neurocognitive performance. This association with overweight/obesity status is already seen during induction therapy, and this suggests that early multidisciplinary interventions should be implemented to prevent obesity and to alleviate adverse neurocognitive sequelae in survivors of ALL. [ABSTRACT FROM AUTHOR]

Background: Cancer‐related worry (CRW) is common among cancer survivors; however, little is known about factors associated with CRW or its impact on health behaviors in adult survivors of childhood cancer. Methods: Survivors in the St. Jude Lifetime Cohort Study (n = 3211; 51% male; mean age, 31.2 years [SD, 8.4 years]; mean time after diagnosis, 22.8 years [SD, 8.3 years]) underwent medical evaluations and completed ratings of CRW, psychological symptoms, and health behaviors. Multivariable modified Poisson regression models examined associations between CRW and treatment exposures, chronic health conditions, psychological symptoms, and health behaviors. Results: Sixty‐four percent of survivors (95% confidence interval [CI], 62.6‐65.9) reported worry about subsequent malignancy, 45% (95% CI, 43.5‐46.9) reported worry about physical problems related to cancer, and 33% (95% CI, 31.2‐34.4) reported worry about relapse. Multiple psychological symptoms, treatment exposures, and chronic conditions significantly increased the risk of CRW. Survivors reporting CRW were at increased risk for substance use, inadequate physical activity, and increased health care utilization after adjustments for chronic conditions. For example, with adjustments for chronic conditions, those who endorsed CRW were more likely to have ≥5 cancer‐related physician visits, ≥5 physician visits related to cancer, and ≥5 calls to a physician's office in the previous 2 years in comparison with survivors who were not worried. CRW was also associated with an increased risk of current tobacco use, past marijuana use, and current marijuana use. Conclusions: A substantial proportion of adult survivors of childhood cancer reported CRW associated with increased health care utilization. CRW may serve as an intervention target to promote well‐being and adaptive health behaviors. Cancer‐related worry is common among long‐term survivors of childhood cancer. It is associated with treatment exposures, chronic medical conditions, psychological and somatic symptoms, and maladaptive health behaviors. Cancer‐related worry is a modifiable construct that can be targeted via psychosocial interventions. [ABSTRACT FROM AUTHOR]

Background: Survivors of childhood cancer exposed to cardiotoxic therapies are at significant cardiovascular risk. The utility of cardiac biomarkers for identifying the risk of future cardiomyopathy and mortality is unknown. Methods: N‐terminal pro–B‐type natriuretic peptide (NT‐proBNP) and cardiac troponin T (cTnT) were assessed in 1213 adults 10 or more years from a childhood cancer diagnosis; 786 were exposed to anthracycline chemotherapy and/or chest‐directed radiation therapy (RT). NT‐proBNP values above age‐ and sex‐specific 97.5th percentiles were considered abnormal. Generalized linear models estimated cross‐sectional associations between abnormal NT‐proBNP and anthracycline or chest RT doses as risk ratios with 95% confidence intervals (CIs). A Poisson distribution estimated rates and a Cox proportional hazards model estimated hazard ratios (HRs) for future cardiac events and death. Results: At a median age of 35.5 years (interquartile range, 29.8‐42.5 years), NT‐proBNP and cTnT were abnormal in 22.5% and 0.4%, respectively. Exposure to chest RT and exposure to anthracycline chemotherapy were each associated with a dose‐dependent increased risk for abnormal NT‐proBNP (P for trend <.0001). Among exposed survivors with no history of Common Terminology Criteria for Adverse Events–graded cardiomyopathy and with normal systolic function, survivors with abnormal NT‐proBNP had higher rates per 1000 person‐years of cardiac mortality (2.93 vs 0.96; P <.0001) and future cardiomyopathy (32.10 vs 15.98; P <.0001) and an increased risk of future cardiomyopathy (HR, 2.28; 95% CI, 1.28‐4.08) according to a multivariable assessment. Conclusions: Abnormal NT‐proBNP values were prevalent and, among survivors who were exposed to cardiotoxic therapy but did not have a history of cardiomyopathy or current systolic dysfunction, identified those at increased risk for future cardiomyopathy. Further longitudinal studies are needed to confirm this novel finding. In this longitudinal cohort study including 1213 adult survivors of childhood cancer, nearly 25% have an abnormal N‐terminal pro–B‐type natriuretic peptide (NT‐proBNP) value for age and sex at the baseline. Among survivors exposed to cardiotoxic therapy who have a normal ejection fraction at the baseline, those with an abnormal NT‐proBNP value have more than twice the risk of future cardiomyopathy; this is a significant finding. [ABSTRACT FROM AUTHOR]

For the analysis of ultrahigh‐dimensional data, the first step is often to perform screening and feature selection to effectively reduce the dimensionality while retaining all the active or relevant variables with high probability. For this, many methods have been developed under various frameworks but most of them only apply to complete data. In this paper, we consider an incomplete data situation, case II interval‐censored failure time data, for which there seems to be no screening procedure. Basing on the idea of cumulative residual, a model‐free or nonparametric method is developed and shown to have the sure independent screening property. In particular, the approach is shown to tend to rank the active variables above the inactive ones in terms of their association with the failure time of interest. A simulation study is conducted to demonstrate the usefulness of the proposed method and, in particular, indicates that it works well with general survival models and is capable of capturing the nonlinear covariates with interactions. Also the approach is applied to a childhood cancer survivor study that motivated this investigation. [ABSTRACT FROM AUTHOR]

Objective: Sleep disorders are associated with psychological and physical health, although reports in long-term survivors of childhood cancer are limited. We characterized the prevalence and risk factors for behaviors consistent with sleep disorders in survivors and examined longitudinal associations with emotional distress and physical health outcomes.Methods: Survivors (n = 1933; median [IQR] age = 35 [30, 41]) and siblings (n = 380; age = 33 [27, 40]) from the Childhood Cancer Survivor Study completed measures of sleep quality, fatigue, and sleepiness. Emotional distress and physical health outcomes were assessed approximately 5 years before and after the sleep survey. Multivariable logistic or modified Poisson regression models examined associations with cancer diagnosis, treatment exposures, and emotional and physical health outcomes.Results: Survivors were more likely to report poor sleep efficiency (30.8% vs 24.7%; prevalence ratio [PR] = 1.26; 95% confidence interval, 1.04-1.53), daytime sleepiness (18.7% vs 14.2%; PR = 1.31 [1.01-1.71]), and sleep supplement use (13.5% vs 8.3%; PR = 1.56 [1.09-2.22]) than siblings. Survivors who developed emotional distress were more likely to report poor sleep efficiency (PR = 1.70 [1.40-2.07]), restricted sleep time (PR = 1.35 [1.12-1.62]), fatigue (PR = 2.11 [1.92-2.32]), daytime sleepiness (PR = 2.19 [1.71-2.82]), snoring (PR = 1.85 [1.08-3.16]), and more sleep medication (PR = 2.86 [2.00-4.09]) and supplement use (PR = 1.89[1.33-2.69]). Survivors reporting symptoms of insomnia (PR = 1.46 [1.02-2.08]), fatigue (PR = 1.31 [1.01-1.72]), and using sleep medications (PR = 2.16 [1.13-4.12]) were more likely to develop migraines/headaches.Conclusions: Survivors report more sleep difficulties and efforts to manage sleep than siblings. These sleep behaviors are related to worsening or persistently elevated emotional distress and may result in increased risk for migraines. Behavioral interventions targeting sleep may be important for improving health outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: The purpose of this study was to examine the prevalence and predictors of social difficulties in adolescent survivors of central nervous system (CNS) tumors. METHODS: Six hundred sixty‐five survivors of CNS tumors (53.8% male and 51.7% treated with cranial radiation therapy [CRT]), who had a current median age of 15.0 years (range, 2.0‐17.0 years) and were a median of 12.1 years (range, 8.0‐17.7 years) from their diagnosis, were compared with 1376 survivors of solid tumors (50.4% male), who had a median age of 15.0 years (range, 12.0‐17.0 years) and were a median of 13.2 years (range, 8.3‐17.9 years) from their diagnosis, and 726 siblings (52.2% male), who had a median age of 15.0 years (range, 12.0‐17.0 years). Social adjustment was measured with parent‐proxy responses to the Behavior Problems Index. Latent profile analysis defined social classes. Multinomial logistic regression, adjusted for age, sex, and age at diagnosis, identified predictors of class membership. Path analyses tested mediating effects of physical limitations, sensory loss, and cognitive impairment on social outcomes. RESULTS: Caregivers reported that survivors of CNS tumors were more likely to have 0 friends (15.3%) and to interact with friends less than once per week (41.0%) in comparison with survivors of solid tumors (2.9% and 13.6%, respectively) and siblings (2.3% and 8.7%, respectively). Latent profile analysis identified 3 social classes for survivors of CNS tumors: well‐adjusted (53.4%), social deficits (16.2%), and poor peer relationships (30.4%). However, 2 classes were identified for survivors of solid tumors and siblings: well‐adjusted (86.2% and 91.1%, respectively) and social deficits (13.8% and 8.9%, respectively). CRT predicted class membership for CNS survivors (odds ratio [OR] for poor peer relationships, 1.16/10 Gy; 95% confidence interval [CI], 1.08‐1.25; OR for social deficits 1.14/10 Gy; 95% CI, 1.04‐1.25; reference, well‐adjusted). Cognitive impairment mediated the association between all social outcomes and CRT (P values <.001). CONCLUSION: Almost 50% of survivors of CNS tumors experience social difficulties; the pattern is unique in comparison with solid tumor and sibling groups. Cognitive impairment is associated with increased risk, and this highlights the need for multitargeted interventions. Almost 50% of survivors of pediatric central nervous system tumors experience social difficulties; the pattern is unique in comparison with solid tumor and sibling groups. Cognitive impairment is associated with increased risk, and this highlights the need for multitargeted interventions. [ABSTRACT FROM AUTHOR]

Background: Survivors of childhood cancer are at significant risk for serious chronic health conditions and subsequent cancers because of their prior treatment exposures. However, little is known about survivors' perceptions of their future health risks.Methods: This study examined self-reported levels of concern about future health and subsequent cancer in 15,620 adult survivors of childhood cancer (median age, 26 years; median time since diagnosis, 17 years) and 3991 siblings in the Childhood Cancer Survivor Study. The prevalence of concerns was compared between survivors and siblings, and the impact of participant characteristics and treatment exposures on concerns was examined with multivariable modified Poisson regression to estimate relative risks (RRs) and 95% confidence intervals (CIs).Results: A substantial proportion of survivors were not concerned about their future health (31%) or developing cancer (40%). The prevalence of concern in survivors was modestly higher (RR for future health, 1.12; 95% CI, 1.09-1.15) or similar (RR for subsequent cancer, 1.02; 95% CI, 0.99-1.05) in comparison with siblings. Survivors exposed to high doses of radiation (≥20 Gy) were more likely to report concern (RR for future health, 1.13; 95% CI, 1.09-1.16; RR for subsequent cancer, 1.14; 95% CI, 1.10-1.18), but 35% of these high-risk survivors were not concerned about developing cancer, and 24% were not concerned about their future health.Conclusions: A substantial subgroup of survivors were unconcerned about their future health and subsequent cancer risks, even after exposure to treatments associated with increased risk. These survivors may be less likely to engage in beneficial screening and risk-reduction activities. Cancer 2018. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Objective: Disrupted sleep is common in pediatric cancer, which is associated with psychological distress and may impact neural recovery. Information regarding sleep during pediatric brain tumor treatment is limited. This study aimed to describe objective sleep-wake patterns and examine the sleep-mood relation in youth hospitalized for intensive chemotherapy and stem cell rescue.Methods: Participants included 37 patients (M age = 9.6 ± 4.2 years) enrolled on a medulloblastoma protocol (SJMB03) and their parents. Respondents completed a mood disturbance measure on 3 days, and patients wore an actigraph for 5 days as an objective estimate of sleep-wake patterns. General linear mixed models examined the relation between nocturnal sleep and next-day mood, as well as mood and that night's sleep.Results: Sleep duration was deficient, sleep efficiency was poor, and daytime napping was common, with large between-subjects variability. There were minimal mood concerns across all days. The sleep and next-day mood relationship was nonsignificant (P > .05). Greater parent-reported child mood disturbance on day 2 was associated with decreased same-night sleep (P < .001) and greater patient-reported mood disturbance was associated with greater same-night sleep latency (P = .036).Conclusions: Patients with medulloblastoma are vulnerable to disturbed sleep during hospitalization, and mood may be an important correlate to consider. Sleep and mood are modifiable factors that may be targeted to maximize daytime functioning. [ABSTRACT FROM AUTHOR]

Background: Children with non-Hodgkin lymphoma (NHL) undergo treatment with central nervous system-directed therapy, the potentially neurotoxic effects of which have not been reported in NHL survivors.Methods: NHL survivors (n = 187) participating in the St. Jude Lifetime Cohort who were 10 or more years from their diagnosis and were 18 years old or older underwent neurocognitive, emotional distress (Brief Symptom Inventory 18), and health-related quality of life (HRQOL) assessments (36-Item Short Form Health Survey). Age-adjusted z scores were compared with community controls (n = 181) and normative data. Treatment exposures were abstracted from medical records. Models adjusted for the age, sex, and time from diagnosis were used to calculate the risk of impairment.Results: The mean ages at evaluation were similar for the survivors and the controls (35.7 ± 8.9 vs 35.5 ± 11.0 years; P = .86). Survivors were 25.2 ± 8.8 years from their diagnosis: 43 (23%) received cranial radiation, 70 (37%) received high-dose methotrexate, 40 (21%) received high-dose cytarabine, and 151 (81%) received intrathecal chemotherapy. Survivors' intelligence and attention were within normal limits; however, their memory, executive function, processing speed, and academics were impaired in comparison with both population norms and community controls (P values < .05). Treatment-related exposures were not associated with neurocognitive function; however, neurocognitive impairment was associated with lower educational attainment, unemployment, and occupational status (P values < .03). Slower processing speed and worse self-reported executive function were associated with symptoms of depression (P values ≤ .003) and poorer HRQOL (P values < .05).Conclusions: Adult survivors of childhood NHL experience impaired neurocognitive function, which is associated with lower social attainment and poor HRQOL. Early-detection and intervention strategies are recommended. Cancer 2017. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Objective: To examine the potential mediating role of body image dissatisfaction on the association between treatment-related scarring/disfigurement and psychological distress in adult survivors of childhood cancer.Methods: Participants included 1714 adult survivors of childhood cancer (mean [SD] age at evaluation = 32.4 [8.0] years, time since diagnosis = 24.1 [8.1] years) enrolled in the St. Jude Lifetime Cohort Study. Survivors completed measures of body image, emotional distress, and posttraumatic stress symptoms (PTSS). Body image dissatisfaction (BID) was categorized into 2 groups (cancer-related and general) based on factor analysis. Using causal mediation analysis, we estimated the proportion of psychological distress associated with treatment-related scarring/disfigurement that could be eliminated by resolving BID through a hypothetical intervention.Results: Among survivors with scarring/disfigurement of the head, a sizable proportion of the relative excess of psychological distress could be eliminated if BID was successfully treated (males: [cancer-related BID: depression: 63%; anxiety: 100%; PTSS: 52%]; [general BID: depression: 70%; anxiety: 100%; PTSS: 42%]; females: [cancer-related BID: depression: 20%; anxiety; 36%; PTSS: 23%]; [general BID: depression: 32%; anxiety: 87%; PTSS: 38%]). The mediating effect of BID was less pronounced for the association between scarring/disfigurement of the body and psychological distress for both males and females.Conclusions: Body image dissatisfaction mediates the association treatment-related scarring/disfigurement and psychological distress among adult survivors of childhood cancer, particularly among survivors with scarring/disfigurement of the head and male survivors. Successful treatment of body image dissatisfaction has the potential to eliminate a substantial proportion of psychological distress related to scarring/disfigurement among adult survivors of childhood cancer. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to describe perceptions and associated risk factors of the impact of cancer on functional outcomes, including social relationships, exercise, finances, and religion, among adult survivors of childhood cancer.Methods: Evaluable participants included 3001 adult survivors (mean age, 32.5 years; range, 18.3-63.8 years; 24.1 years from diagnosis; 50.8% male; 84.9% Caucasian) who were enrolled in the St. Jude Lifetime Cohort study. Perceptions of the impact of cancer were assessed using the Brief Cancer Impact Assessment (BCIA). Regression models were used to evaluate risk factors for functional outcomes.Results: The median response on the BCIA was a perception that cancer had minimal impact on the domains assessed. Approximately 33.1% to 46.6% of survivors indicated this response across the 4 subscales, although responses ranged from very positive to very negative impact. Other than diagnosis (with survivors of brain tumors generally indicating a more negative impact of cancer, with subscale estimates of -1.25 for caregiving and finance and -1.01 for social and emotional and an odds ratio of 1.83 for exercise and diet), most variability was because of demographic factors, including sex, age, race, education, and employment.Conclusions: The current findings highlight that many long-term adult survivors perceive minimal impact of childhood cancer on functional aspects of adulthood, including caregiving, finances, exercise, social-emotional relationships, and religion. This suggests that survivors may not be focusing on the influence of likely physical and psychological late effects of their disease in their day-to-day lives. For those who do perceive a negative impact, variability in responses suggests that there are of survivors who may benefit from interventions focused on the achievement of functional goals. Cancer 2017;123:1625-1634. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Health complications related to childhood cancer may be influenced by risky health behaviors (RHBs), particularly when RHBs co-occur. To the authors' knowledge, only limited information is available describing how RHBs cluster among survivors of childhood cancer and their siblings and the risk factors for co-occurring RHBs.Methods: Latent class analysis was used to identify RHB clusters using longitudinal survey data regarding smoking, alcohol use, and physical activity from adult survivors (4184 survivors) and siblings (1598 siblings) in the Childhood Cancer Survivor Study. Generalized logistic regression was used to evaluate associations between demographic characteristics, treatment exposures, psychological distress, health conditions, and cluster membership.Results: Three RHB clusters were identified: a low-risk cluster, an insufficiently active cluster, and a high-risk cluster (tobacco and risky alcohol use and insufficient activity). Compared with siblings, survivors were more likely to be in the insufficiently active cluster (adjusted odds ratio [ORadj ], 1.17; 95% confidence interval [95% CI], 1.06-1.27) and were less likely to be in the high-risk cluster (ORadj , 0.79; 95% CI, 0.69-0.88). Risk factors for membership in the high-risk cluster included psychological distress (ORadj , 2.76; 95% CI, 1.98-3.86), low educational attainment (ORadj , 7.49; 95% CI, 5.15-10.88), income <$20,000 (ORadj , 2.62; 95% CI, 1.93-3.57), being divorced/separated or widowed (ORadj , 1.36; 95% CI, 1.03-1.79), and limb amputation (ORadj , 1.52; 95% CI, 1.03-2.24). Risk factors for the insufficiently active cluster included chronic health conditions, psychological distress, low education or income, being obese or overweight, female sex, nonwhite race/ethnicity, single marital status, cranial radiation, and cisplatin exposure.Conclusions: RHBs co-occur in survivors of childhood cancer and their siblings. Economic and educational disadvantages and psychological distress should be considered in screening and interventions to reduce RHBs. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2747-2756. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Survivors of childhood cancer who are treated with platinum-based chemotherapy and/or cranial radiation are at risk of treatment-induced hearing loss. However, the effects of such hearing loss on adult social attainment have not been well elucidated.Methods: Adult survivors of pediatric central nervous system (CNS) solid tumors (180 survivors) and non-CNS solid tumors (226 survivors) who were treated with potentially ototoxic cancer therapy completed audiologic evaluations and questionnaires assessing their perception of social functioning and social attainment (ie, independent living, marriage, and employment). Audiograms were graded with the Chang ototoxicity grading scale. Analyses were stratified by tumor type (ie, CNS vs non-CNS). Multivariable logistic regression models were conducted with adjustment for age; sex; chronic health conditions; and, for the CNS group, IQ. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported.Results: Serious hearing loss (that requiring a hearing aid or deafness) was detected in 36% of survivors of CNS tumors and 39% of survivors of non-CNS tumors. Serious hearing loss was associated with an increased risk of perceived negative impact in ≥1 areas of social functioning (survivors of non-CNS tumors: OR, 1.83 [95% CI, 1.00-3.34]). Among survivors of non-CNS tumors, serious hearing loss was associated with 2-fold increased risk of nonindependent living (OR, 2.19; 95% CI, 1.19-4.04) and unemployment or not graduating from high school (OR, 1.85; 95% CI, 1.00-3.34).Conclusions: A substantial proportion of adult survivors of childhood cancer treated with potentially ototoxic therapy have serious hearing loss. Treatment-induced hearing loss was found to be associated with reduced social attainment, both perceived and actual, in this study sample. [ABSTRACT FROM AUTHOR]

Background: Survivors of pediatric cancer have elevated risks of mortality and morbidity. Many late adverse effects associated with cancer treatment (eg, second cancers and cardiac and pulmonary disease) are also associated with cigarette smoking, and this suggests that survivors who smoke may be at high risk for these conditions.Methods: This study examined the self-reported smoking status for 9397 adult survivors of childhood cancer across 3 questionnaires (median time interval, 13 years). The smoking prevalence among survivors was compared with the smoking prevalence among siblings and the prevalence expected on the basis of age-, sex-, race-, and calendar time-specific rates in the US population. Multivariable regression models examined characteristics associated with longitudinal smoking patterns across all 3 questionnaires.Results: At the baseline, 19% of survivors were current smokers, whereas 24% of siblings were current smokers, and 29% were expected to be current smokers on the basis of US rates. Current smoking among survivors dropped to 16% and 14% on follow-up questionnaires, with similar decreases in the sibling prevalence and the expected prevalence. Characteristics associated with consistent never-smoking included a higher household income (relative risk [RR], 1.16; 95% confidence interval [CI], 1.08-1.25), higher education (RR, 1.32; 95% CI, 1.22-1.43), and receipt of cranial radiation therapy (RR, 1.08; 95% CI, 1.03-1.14). Psychological distress (RR, 0.86; 95% CI, 0.80-0.92) and heavy alcohol drinking (RR, 0.64; 95% CI, 0.58-0.71) were inversely associated. Among ever-smokers, a higher income (RR, 1.17; 95% CI, 1.04-1.32) and education (RR, 1.23; 95% CI, 1.10-1.38) were associated with quitting, whereas cranial radiation (RR, 0.86; 95% CI, 0.76-0.97) and psychological distress (RR, 0.80; 95% CI, 0.72-0.90) were associated with not having quit. The development of adverse health conditions was not associated with smoking patterns.Conclusions: Despite modest declines in smoking prevalence, the substantial number of consistent current smokers reinforces the need for continued development of effective smoking interventions for survivors. [ABSTRACT FROM AUTHOR]

BACKGROUND: Partial nephrectomy is considered by some for children with unilateral Wilms tumor (UWT) to avoid the theoretical complication of renal insufficiency. In the current study, the authors evaluated the prevalence of hypertension and impaired renal function in long-term survivors of nonsyndromic UWT who were treated without nephrotoxic chemotherapy or ionizing radiation. METHODS: Eligibility included age ≤15 years at the time of diagnosis of nonsyndromic UWT, treatment receipt before 2002, and maintenance of disease remission after unilateral nephrectomy without receipt of abdominal irradiation or nephrotoxic chemotherapy. Renal function was assessed by urinalysis and estimated glomerular filtration rate (eGFR). Patients receiving antihypertensive medication or those with blood pressure readings of >140/90 mm Hg were considered to be hypertensive. RESULTS: A total of 75 patients with a median age at diagnosis of 3.2 years (range, 0.2-12.1 years) met eligibility criteria. The median length of follow-up was 19.6 years (range, 10.0-32.8 years). All but 1 patient had stage I/II disease. Sixty-eight patients (90.7%) patients had WT with favorable histology and 7 patients had anaplastic histology. Sixteen patients (21.3%) had an eGFR <90 mL/minute/1.73m², 2 of whom also had proteinuria (12.5%). No patient had an eGFR <60 mL/minute/1.73m². Five patients (6.7%) had hypertension, 3 of whom were receiving antihypertensive medications. At the time of last follow-up, no patient had developed end-stage renal disease. CONCLUSIONS: Patients with UWT who were treated with unilateral radical nephrectomy without nephrotoxic chemotherapy or ionizing radiation appear to be at low risk of developing significant long-term renal dysfunction. For this patient population, the routine use of partial nephrectomy does not appear justified. However, monitoring and counseling are important for identifying the rare patient who develops subtle renal insufficiency and therefore might be at an increased risk of adverse cardiovascular sequelae. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to identify treatment and genetic factors associated with obesity among childhood cancer survivors.Methods: Participants included 1996 survivors who previously received treatment for cancer at St. Jude Children's Research Hospital and who survived ≥10 years from diagnosis (median age at diagnosis, 7.2 years; median age at follow-up, 32.4 years). Obesity was defined as a body mass index ≥30 kg/m(2) . The factors associated with adult obesity were identified by subgroup-specific (cranial radiation [CRT] exposure status) multivariable logistic regression. Single nucleotide polymorphisms (SNPs) associated with obesity were identified by subgroup-specific, exploratory, genome-wide association analyses using a 2-stage resampling approach with a type I error rate of 5 × 10(-6) .Results: Forty-seven percent of survivors who received CRT and 29.4% of those who did not receive CRT were obese at evaluation. In multivariable analyses, abdominal/pelvic radiation exposure was associated with decreased prevalence of obesity among survivors regardless of CRT status (P < .0001). The odds of obesity were increased among survivors who received CRT who had also received glucocorticoids (P = .014) or who were younger at diagnosis (P = .013). Among the survivors who had received CRT, 166 SNPs were associated with obesity. The strongest association was observed with reference SNP rs35669975 (P = 3.3 × 10(-8) ) on segment 33.3 of the long arm of chromosome 13 (13q33.3), approximately 30 kb downstream of FAM155A (family with sequence similarity 155, member A). SNPs within the glycine receptor α3 (GLRA3) gene and near the sex-determining region Y box 11 (SOX11) and cadherin 18 type 2 (CDH18) genes also were identified. These genes have been implicated in neural growth, repair, and connectivity.Conclusions: Obesity in childhood cancer survivors remains associated with previous exposure to CRT and glucocorticoids. Genetic variants related to neural connectivity may modify the risk of obesity among survivors who receive CRT. Validation of these findings in independent cohorts is required. [ABSTRACT FROM AUTHOR]

BACKGROUND Childhood cancer survivors (CCSs) are at risk for obesity. The purpose of this project was to determine which clinical measures of body composition are most accurate among CCSs in comparison with dual-energy x-ray absorptiometry (DXA). METHODS The agreement between the body mass index (BMI), skinfold percent body fat, and waist-to-height ratio (WHtR) and DXA was evaluated among 1361 CCSs (mean age, 32.4 ± 7.7 years) 10 or more years after the diagnosis. The sensitivity and specificity of BMI, skinfold, and WHtR obesity classifications were calculated with respect to DXA. Log-binomial regression, stratified by sex, was used to evaluate treatment-related factors for misclassification as nonobese by BMI, skinfolds, and WHtR. RESULTS The mean body fat values were 23.3% ± 7.7% (males) and 32.3% ± 8.1% (females) for skinfolds and 26.9% ± 7.4% (males) and 38.4% ± 7.7% (females) for DXA. Pearson correlations between skinfolds and DXA were high ( R = 0.83 for males, R = 0.84 for females). Skinfolds incorrectly classified 34.5% of obese males and 27.3% of obese females. BMI measures were the least sensitive with false-negative rates of 46.4% (males) and 53.1% (females). Males exposed to abdominal/pelvic radiation were at increased risk for misclassification as nonobese by BMI (relative risk, 1.57; 95% confidence interval, 1.25-1.95). The percentages classified as obese were highest with DXA (males, 63.1%; females, 84.8%) and lowest with BMI (males, 35.7%; females, 39.7%). Although skinfolds and WHtR underestimated the percentage classified as obese in comparison with DXA, the differences were not as large. CONCLUSIONS Findings suggest that skinfolds and WHtR are better than BMI for obesity classification in CCSs. Clinicians should be aware of the high risk of misclassifying obese CCSs as nonobese. Cancer 2015;121:2036-2043. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Survivors of childhood cancer treated with central nervous system (CNS)-directed therapy may be at risk for poor health care utilization because of neurocognitive deficits. This study examined associations between neurocognitive function and adherence to routine and risk-based medical evaluations in adult survivors exposed to CNS-directed therapy. METHODS Neurocognitive function and health care utilization were assessed in 1304 adult survivors of childhood cancer enrolled in the St. Jude Lifetime Cohort Study. Adherence to recommended care was defined as meeting guidelines published by the Children's Oncology Group. Multivariate models were used to evaluate associations between neurocognitive function and health screenings. Established predictors of health care utilization were included as covariates. Odds ratios (ORs) or prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated for variables maintained in the final models. RESULTS Adherence to recommended medical care was higher for routine care (general physician care, 57.6%; dental care, 49.1%) versus specialized care (survivor-focused care, 21.9%; echocardiogram, 19.9%). Higher intelligence was predictive of general physician care (OR, 1.74; 95% CI, 1.41-2.15) and survivor-focused care (OR, 1.44; 95% CI, 1.13-1.83) in comparison with no care, whereas better executive function skills were associated with reduced dental care (PR, 0.94; 95% CI, 0.91-0.98). Echocardiogram monitoring was not associated with neurocognition. Possible late effects of cancer treatment (pain and reduced cardiorespiratory fitness) were associated with an increased likelihood of receiving specialized medical care. CONCLUSIONS Survivors with reduced global cognition are at risk for poor health care utilization. Educational practices regarding recommended health care should be personalized to ensure comprehension by survivors with neurocognitive impairment. Cancer 2015;121:774-782. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Childhood cancer survivors (CCS) are at an increased risk of developing metabolic syndrome (MetSyn), which may be reduced with lifestyle modifications. The purpose of this investigation was to characterize lifestyle habits and associations with MetSyn among CCS. METHODS CCS who were ≥ 10 years from diagnosis, aged > 18 years, and participating in the St. Jude Lifetime Cohort Study completed medical and laboratory tests and a food frequency questionnaire. The Third Report of the National Cholesterol Education Program Adult Treatment Panel criteria were used to classify participants with MetSyn. Anthropometric, food frequency questionnaire, and self-reported physical activity data were used to characterize lifestyle habits according to World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations. Those who met ≥ 4 of 7 recommendations were classified as having followed guidelines. Sex-stratified log-binomial regression models were used to evaluate associations between dietary/lifestyle habits and MetSyn, adjusted for age, age at cancer diagnosis, receipt of cranial radiotherapy, education, and household income. RESULTS Among 1598 CCS (49.2% of whom were male, with a median age of 32.7 years [range, 18.9 years-60.0 years]), 31.8% met criteria for MetSyn and 27.0% followed WCRF/AICR guidelines. Females who did not follow WCRF/AICR guidelines were 2.4 times (95% confidence interval, 1.7-3.3) and males were 2.2 times (95% confidence interval, 1.6-3.0) more likely to have MetSyn than those who followed WCRF/AICR guidelines. CONCLUSIONS Adherence to a heart-healthy lifestyle is associated with a lower risk of MetSyn among CCS. There is a need to determine whether lifestyle interventions prevent or remediate MetSyn in CCS. Cancer 2014;120:2742-2750. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Adult survivors of childhood cancer are at risk for suicide ideation, although longitudinal patterns and rates of recurrent suicide ideation are unknown. This study investigated the prevalence of late report (ie, after initial assessment) and recurrent suicide ideation in adult survivors of childhood cancer, identified predictors of suicide ideation, and examined associations among suicide ideation and mortality. METHODS Participants included 9128 adult survivors of childhood cancer and 3082 sibling controls enrolled in the Childhood Cancer Survivor Study who completed a survey question assessing suicide ideation on one or more occasions between 1994 and 2010. Suicide ideation was assessed using the Brief Symptom Inventory-18 instrument. Mortality data was ascertained from the National Death Index. RESULTS Survivors were more likely to report late (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 1.5-2.5) and recurrent suicide ideation (OR = 2.6, 95% CI = 1.8-3.8) compared to siblings. Poor physical health status was associated with increased risk of suicide ideation in survivors (late report: OR = 1.9, 95% CI = 1.3-2.7; recurrent: OR = 1.9, 95% CI = 1.2-2.9). Suicide ideation was associated with increased risk for all-cause mortality (hazard ratio = 1.3, 95% CI = 1.03-1.6) and death by external causes (hazard ratio = 2.4, 95% CI = 1.4-4.1). CONCLUSIONS Adult survivors of childhood cancer are at risk for late-report and recurrent suicide ideation, which is associated with increased risk of mortality. Routine screening for psychological distress in adult survivors appears warranted, especially for survivors who develop chronic physical health conditions. Cancer 2014;120:271-277. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Event history studies occur in many fields including economics, medical studies, and social science. In such studies concerning some recurrent events, two types of data have been extensively discussed in the literature. One is recurrent event data that arise if study subjects are monitored or observed continuously. In this case, the observed information provides the times of all occurrences of the recurrent events of interest. The other is panel count data, which occur if the subjects are monitored or observed only periodically. This can happen if the continuous observation is too expensive or not practical, and in this case, only the numbers of occurrences of the events between subsequent observation times are available. In this paper, we discuss a third type of data, which is a mixture of recurrent event and panel count data and for which there exists little literature. For regression analysis of such data, we present a marginal mean model and propose an estimating equation-based approach for estimation of regression parameters. We conduct a simulation study to assess the finite sample performance of the proposed methodology, and the results indicate that it works well for practical situations. Finally, we apply it to a motivating study on childhood cancer survivors. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Recurrent event data occur in many clinical and observational studies, and in these situations, there may exist a terminal event such as death that is related to the recurrent event of interest. In addition, sometimes more than one type of recurrent events may occur, that is, one may encounter multivariate recurrent event data with some dependent terminal event. For the analysis of such data, one must take into account the dependence among different types of recurrent events and that between the recurrent events and the terminal event. In this paper, we extend a method for univariate recurrent and terminal events and propose a joint modeling approach for regression analysis of the data and establish the finite and asymptotic properties of the resulting estimates of unknown parameters. The method is applied to a set of bivariate recurrent event data arising from a long-term follow-up study of childhood cancer survivors. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Long-term survivors of childhood cancer are at risk for fatigue, sleep problems, and neurocognitive impairment, although the association between these outcomes has not been previously examined.Methods: Outcomes were evaluated in 1426 survivors from the Childhood Cancer Survivor Study using a validated Neurocognitive Questionnaire. Relative risks for neurocognitive impairment were calculated using demographic and treatment factors, and survivors' report on the Functional Assessment of Chronic Illness Therapy-Fatigue, the Short Form-36 Vitality Scale, the Pittsburgh Sleep Quality Index, and the Epworth Sleepiness Scale.Results: Neurocognitive impairment was identified in >20% of survivors, using sibling-based norms for comparison. Multivariate logistic regression models revealed that fatigue (risk ratio [RR], 1.34; 95% confidence interval [CI], 1.13-1.59), daytime sleepiness (RR, 1.68; 95% CI, 1.55-1.83), poor sleep quality (RR, 1.23; 95% CI, 1.01-1.49), and decreased vitality (RR, 1.75; 95% CI 1.33-2.30) were all associated with impaired task efficiency. Likewise, fatigue (RR, 1.77; 95% CI, 1.23-2.55), sleepiness (RR, 1.38; 95% CI, 1.14-1.67), and decreased vitality (RR, 3.08; 95% CI, 1.98-4.79) were predictive of emotional regulation problems. Diminished organization was associated with increased sleepiness (RR, 1.80; 95% CI, 1.31-2.48) and decreased vitality (RR, 1.90; 95% CI, 1.37-2.63). Impaired memory was associated with poor sleep quality (RR, 1.45; 95% CI, 1.19-1.76), increased sleepiness (RR, 2.05; 95% CI, 1.63-2.58), and decreased vitality (RR, 2.01; 95% CI, 1.42-2.86). The impact of fatigue, sleepiness, sleep quality, and vitality on neurocognitive outcomes was independent of the effects of cranial radiation therapy, steroids and antimetabolite chemotherapy, sex, and current age.Conclusions: Neurocognitive function in long-term survivors of childhood cancer appears particularly vulnerable to the effects of fatigue and sleep disruption. These findings suggest sleep hygiene should be emphasized among survivors, as it may provide an additional mechanism for intervention to improve neurocognitive outcomes. [ABSTRACT FROM AUTHOR]

Background: High-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) has been reported to be effective in treating children with recurrent central nervous system (CNS) malignancies.Methods: To evaluate the efficacy and toxicities of HDCT and ASCR, the medical records of 27 children with recurrent CNS malignancies who received such therapy at St. Jude Children's Research Hospital between 1989 and 2004 were reviewed.Results: The median age at diagnosis was 4.5 years (range, 0.4-16.6 years) and that at ASCR was 6.7 years (range, 1.1-18.5 years). Diagnoses included medulloblastoma (13 patients), primitive neuroectodermal tumor (3 patients), pineoblastoma (2 patients), atypical teratoid rhabdoid tumor (2 patients), ependymoma (3 patients), anaplastic astrocytoma (2 patients), and glioblastoma multiforme (2 patients). The 5-year overall and progression-free survival (PFS) rates were 28.2% and 18.5%, respectively. The 5-year PFS rate for patients aged<3 years at diagnosis (57.1%) was significantly better than older patients (5.0%) (P=.019). Among the 6 long-term survivors (5 with M0 disease and 1 with M3 disease at diagnosis), 5 received both radiotherapy and HDCT as part of their salvage regimen; 4 were aged<3 years at diagnosis and had received chemotherapy only as part of frontline therapy. Two patients died of transplant-related toxicities; 44% experienced grade 3 or 4 transplant-related toxicities (toxicities were graded according to the National Cancer Institute Common Toxicity Criteria).Conclusions: HDCT with ASCR is not an effective salvage strategy for older children with recurrent CNS malignancies. The significantly better outcome in the younger cohort was most likely related to the use of radiotherapy as part of the salvage strategy. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the effect of dexamethasone exposure on sleep and fatigue in pediatric patients with acute lymphoblastic leukemia (ALL). The authors claim that dexamethasone improves the cure rate of childhood ALL but causes physical and behavioral adverse events. They found that sleep and fatigue are behavioral responses to dexamethasone.

The main obstacles to successful haploidentical haematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections and severe graft- versus-host disease (GvHD). We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin in order to expedite immune reconstitution after a CD3-depleted haploidentical stem cell transplant. This protocol was used to treat 22 paediatric patients with refractory haematological malignancies. After transplantation, 91% of the patients achieved full donor chimaerism. They also showed rapid recovery of CD3+ T-cells, T-cell receptor (TCR) excision circle counts, TCR β repertoire diversity and natural killer (NK)-cells during the first 4 months post-transplantation, compared with those results from a group of patients treated with a myeloablative conditioning regimen. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft and induction of low grade GvHD may also enhance the potential anti-cancer immune effect. [ABSTRACT FROM AUTHOR]

Summary. Platelet refractoriness due to human leucocyte antigen (HLA) alloimmunization is a significant risk to allogeneic bone marrow transplant recipients. To identify factors contributing to this risk, we reviewed the records of 317 consecutive, paediatric, allogeneic bone marrow transplant recipients at a single institution. The 6-year estimated cumulative incidence of platelet refractoriness due to HLA alloimmunization was 2·6% ± 0·9%. The incidence among patients with chronic myelogenous leukaemia (CML) 12·5% ± 5·3% was significantly greater than that of other patients (1·1% ± 0·6%, P < 0·001). Graft rejection (P = 0·003) and the number of platelet transfusions during the first 90 d after bone marrow transplantation (BMT) (P = 0·0025) were also significantly associated with alloimmunization. The association with CML and with graft rejection was not seen among patients alloimmunized before transplantation. Eight patients developed alloimmunization, of whom three had mismatched grafts and four had unrelated grafts. Alloantibody specificities, identified in seven patients, were unrelated to host or graft major histocompatibility complex (MHC). Host recognition of alloantigens in transfused blood products, not graft–host recognition, therefore seems predominantly responsible for the alloimmunization. These results show that paediatric CML patients have a significantly increased risk of platelet refractoriness due to HLA alloimmunization after BMT. Identifying the mechanism for the increased alloimmunization risk may assist in the development of therapies to prevent platelet refractoriness. [ABSTRACT FROM AUTHOR]

The main obstacles to successful haploidentical haematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections and severe graft-versus-host disease (GvHD). We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin in order to expedite immune reconstitution after a CD3-depleted haploidentical stem cell transplant. This protocol was used to treat 22 paediatric patients with refractory haematological malignancies. After transplantation, 91% of the patients achieved full donor chimaerism. They also showed rapid recovery of CD3(+) T-cells, T-cell receptor (TCR) excision circle counts, TCRbeta repertoire diversity and natural killer (NK)-cells during the first 4 months post-transplantation, compared with those results from a group of patients treated with a myeloablative conditioning regimen. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.