Impairment In Long-term Survivors Research Articles

New Onset Neurocognitive Impairment in Long-Term Survivors of Early Adolescent and Young Adult Hematologic Malignancies: A Report from the Childhood Cancer Survivor Study

Background: Survivors of hematologic malignancies diagnosed during adolescence and early young adulthood (eAYA survivors) experience neurocognitive impairments as a result of intensive neurotoxic therapies, but the trajectory of these impairments as survivors age are not known. We examined longitudinal changes in neurocognitive outcomes in eAYA survivors compared to younger survivors and sibling controls. Methods: We identified 421 eAYA (diagnosed at 15-21 years) and 1758 pediatric (diagnosed at <15 years) survivors of ALL, AML, and Hodgkin lymphoma (HL), as well as 233 siblings from the Childhood Cancer Survivor Study (>5 year survivors diagnosed 1970-1999) who completed the Neurocognitive Questionnaire (NCQ) at two follow-up surveys (i.e. FU2, FU5) administered 11 years apart. Impairment was defined as a score in the worst 10% of the sibling cohort in task efficiency (TE), organization (Org), memory (Mem), and emotional regulation (ER) domains. Linear regression analysis was performed to estimate the change in neurocognitive T-scores and to identify factors associated with the changes, adjusting for age at initial (FU2) assessment and baseline T-score. The frequency of new onset impairments and associated risk factors were analyzed, specifically to identify survivors who had 1) neurocognitive improvement, ie. impaired at FU2 and became unimpaired vs. remained impaired on FU5, and 2) neurocognitive worsening, ie. unimpaired at FU2 and became impaired vs. remained unimpaired at FU5. Multivariable logistic analysis was performed to identify treatment exposures and chronic health conditions (CHCs) associated with the development or resolution of impairment. Smoking, physical activity, and healthcare utilization were examined as additional risk factors. Results: Compared to siblings, NCQ T-scores worsened over time for both survivors of eAYA (estimated mean score Δ1.9, range 0.5-3.4, p=0.01 in TE; Δ3.0, range 1.5-4.6, p<0.001 in Mem) and pediatric (estimated mean score Δ3.2, range 2.0-4.5, p<0.001 in TE; Δ1.3, range 0.1-2.5, p=0.03 in Org; Δ3.8, range 2.6-5.0, p<0.001 in Mem; Δ2.8, range 1.5-4.1, p<0.001 in ER) malignancies. Risk factors for worsening scores over time in eAYA survivors included having a neurologic CHC (TE: Δ4.9, 95% CI 1.7-8.1; ER: Δ4.2, 95% CI 0.9-7.4), receiving ≥35Gy chest radiation therapy (RT) (TE: Δ4.0, 95% CI 1.7-6.2; Mem: Δ3.3, 95% CI 1.2-5.4), receiving cranial RT (TE: Δ4.0, 95% CI 0.9-7.1; Mem: Δ5.7, 95% CI 2.7-8.7; ER: Δ3.4, 95% CI 0.5-6.4), and being female (Mem: Δ2.8, 95% CI 1.3-4.3). Being a never smoker was associated with improved scores over time in all domains (Δ range -3.2- -6.3). In the new onset impairment analysis, prevalence of TE and Mem impairments increased while Org and ER impairments decreased over time in eAYA and pediatric survivors ( Figure). Factors associated with new onset impairment in eAYA survivors included female sex (Mem: OR 3.2, 95% CI 1.6-6.5), cardiac CHC (ER: OR 3.0, 95% CI 1.03-8.8), respiratory CHC (TE: OR 3.0, 95% CI 1.1-8.0), endocrine CHC (Mem: OR 2.3, 95% CI 1.2-4.6), and neurologic CHC (TE: OR 3.1, 95% CI 1.2-8.2; Org: OR 4.2, 95% CI 1.3-13.7) ( Table). Corresponding CHC-associated impairments were not seen in pediatric survivors, except for neurologic CHC. In a separate model of treatment exposures, eAYA survivors who received salvage HL therapy (Mem: OR 4.8, 95% CI 1.5-15.3), ≥35Gy chest RT (Mem: OR 3.7, 95% CI 1.7-8.2; TE: OR 2.6, 95% CI 1.1-6.1), and cranial RT (Mem: OR 3.4, 95% CI 1.2-9.8; ER: OR 5.3, 95% CI 1.2-22.5) were more likely to experience new onset neurocognitive impairment. While being a never smoker was associated with a decreased odds of new onset impairment (ER: OR 0.1, 95% CI 0.0-0.5), no factors associated with resolution of impairment were found in eAYA survivors. Conclusions: Survivors of eAYA hematologic malignancies experience declining neurocognitive function as well as new onset impairments over time. Memory was the most affected domain. Risk factors for worsening impairment include being female, health comorbidities, and intensive treatment exposures, such as salvage therapy, high-dose chest RT, and cranial RT. Comorbidities may play a larger role in mediating new onset neurocognitive impairments in eAYAs than pediatric survivors. Future studies should focus on characterizing outcomes across the entire AYA age spectrum.

Right Ventricular Function in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia: From the CTOXALL Study

There are limited data regarding right ventricle (RV) impairment in long-term survivors of childhood acute lymphoblastic leukemia (CLS). The aim of this study was to assess RV function in these patients using echocardiographic conventional measurements and automated RV strain. Echocardiographic recordings of 90 CLS and 58 healthy siblings from the CTOXALL cohort were analyzed. For group comparisons, inverse probability weighting was used to reduce confounding. The CLS group (24.6 ± 9.7 years, 37.8% women) underwent an echocardiographic evaluation 18 (11–26) years after the diagnosis. RV systolic dysfunction was found in 16.7% of CLS individuals using RV free-wall strain (RVFWS) compared to 2.2 to 4.4% with conventional measurements. RV systolic function measurements were lower in the CLS than in the control group: TAPSE (23.3 ± 4.0 vs. 25.2 ± 3.4, p = 0.004) and RVFWS (24.9 ± 4.6 vs. 26.8 ± 4.7, p = 0.032). Modifiable cardiovascular risk factors such as obesity (p = 0.022) and smoking (p = 0.028) were independently associated with reduced RVFWS. In conclusion, RV systolic function impairment was frequent in long-term survivors of childhood leukemia, underscoring the importance of RV assessment, including RVFWS, in the cardiac surveillance of these patients.

Neuropathy and neurocognitive impairment in long-term survivors of pediatric cancer treated without central nervous system (CNS) directed therapy.

10020 Background: Survivors of pediatric cancer, including those without CNS-directed treatment, are at risk of neurocognitive impairment and peripheral or autonomic neuropathies; conditions that co-occur in non-cancer populations. Using the St. Jude Lifetime Cohort, we investigated associations between these sequelae to inform contributors to long-term cancer-related neurocognitive impairment. Methods: Clinically assessed survivors of pediatric cancer (N=2,138, mean age 31 [SD 13], 23[11] years from diagnosis, 51% male) not treated with CNS-directed therapy completed neurocognitive testing. Modified total neuropathy score peripheral sensory and motor subscales were combined with functional tasks and severity graded using a modified NCI CTCAE. Cardiac autonomic neuropathy was defined as impaired heart rate reserve (<80% age- sex-predicted or ≤62% with beta blocker). Separate log binomial regression models estimated risk of neurocognitive impairment (age adjusted z-score <10th percentile) associated with grade 2+ sensory, motor or autonomic neuropathy. Path analysis examined if pain with daily interference mediated associations between motor or sensory neuropathy and neurocognitive impairment. Results: 838 (39%) survivors had autonomic, 115 (5.4%) had motor and 162 (7.6%) had sensory neuropathy. Compared to those with no neuropathy, survivors with motor or sensory neuropathy had a higher risk of impairment in sustained attention, visual-motor processing speed, short- and long-term memory, and executive function (Table, p’s<0.01). Autonomic neuropathy was associated with a higher risk of impairment in visuo-motor processing speed (p=0.03). Pain partially mediated associations between sensory neuropathy and sustained attention (10% mediated, p=0.04), visual-motor processing speed (8% p=0.02), and executive function (14% p=0.02). Pain was not related to motor neuropathy. Conclusions: Peripheral and autonomic neuropathies are associated with significant risk of neurocognitive impairment in adult survivors of pediatric cancer. Research is needed to further understand shared mechanisms (e.g., pain, inflammation) to design targeted interventions to improve neuropathic symptoms and neurocognitive function. [Table: see text]

Lack of cognitive impairment in long-term survivors of colorectal cancer

BackgroundOur longitudinal study reported cognitive impairment in 43% of people following diagnosis of localised colorectal cancer (CRC) versus 15% in healthy controls (p < 0.001) and 50% versus 13% 1–2 years later (p < 0.001). Here we evaluate cognitive function and neuroimaging in a subgroup at long-term follow-up.Patients and methodsCancer-free Australian participants in the study, and controls, completed cognitive and functional assessments. Neuroimaging was optional. Blood tests included inflammatory markers, clotting factors, sex hormones and apolipoprotein E genotype. The primary endpoint was demographically and practice effect-corrected cognitive scores comparing CRC survivors with controls over time examined using a linear mixed model, adjusted for baseline performance. Secondary endpoints included cognitive impairment rate using the Global Deficit Score [GDS > 0.5], Functional Deficit Score, blood results and neuroimaging.ResultsThe study included 25 CRC survivors (60% men, median age 72) at mean 9 years after baseline (9 received adjuvant chemotherapy) and 25 controls (44% men, median age 68) at mean 6 years after baseline. There were no significant differences in cognitive scores or proportion with cognitive impairment (16 vs. 8%) between survivors and controls and no evidence of accelerated ageing in CRC survivors. Baseline cognitive performance predicted for subsequent cognitive function. There were no differences in functional tests or blood tests between groups. In 18 participants undergoing neuroimaging, 10 CRC survivors had higher myoinositol levels than 8 controls, and lower volume in the right amygdala and caudate and left hippocampal regions.ConclusionsThere was no difference in cognitive capacity and function between CRC survivors and controls 6–12 years after diagnosis. Differences in neuroimaging require confirmation in a larger sample.Highlights• No evidence of long term cognitive impairment in colorectal cancer survivors compared to controls 6–12 years after diagnosis• No evidence of accelerated cognitive ageing in colorectal cancer survivors• No evidence of long-term functional impairment in colorectal cancer survivors

Biomarkers of gut microbial transfer and their association with cognitive impairment in long-term survivors of testicular germ cell tumors.

426 Background: Survivors of testicular germ cell tumors (GCT) may suffer from long-term cognitive impairment. We hypothesized that disruption of intestinal barrier during chemotherapy and/or radiotherapy may be a contributing factor of cognitive dysfunction within the gut-blood-brain axis. Methods: GCT survivors (N = 142) from National Cancer Institute of Slovakia completed the Functional Assessment of Cancer Therapy Cognitive Function questionnaires during their annual follow-up visit at 9-year median (range 4-32). Biomarkers of gut microbial transfer and dysbiosis (GMT) high mobility group box-1 (HMGB-1), lipopolysaccharide (LPS), d-lactate and sCD14 were measured from peripheral blood obtained during the same visit. Each questionnaire score was correlated with biomarkers of GMT. Survivors were treated with orchiectomy only (N = 17), cisplatin-based chemotherapy (N = 108), radiotherapy to the retroperitoneum (N = 11) or both (N = 6). Results: GCT survivors with higher sCD14 had worse cognitive function perceived by others (CogOth domain) (mean ± SEM; 14.6 ± 0.25 vs 15.4 ± 0.25, p = 0.019), lower perceived cognitive abilities (CogPCA domain) (20.0 ± 0.74 vs 23.4 ± 0.73, p = 0.025) and lower overal cognitive function score (109.2 ± 0.74 vs 116.7 ± 1.90, p = 0.021). There were no significant cognitive declines associated with HMGB-1, d-lactate and LPS. Survivors treated with ≥ 400mg/m2 of cisplatin based chemotherapy had higher LPS (567.8 ± 42.7 vs 462.9 ± 51.9, P = 0.03). Survivors treated with chemotherapy + radiotherapy vs orchiectomy only had non-significantly higher sCD14 (7279.9 ± 810.1 vs 5851.0 ± 481.7, P = 0.09). Conclusions: sCD14 may serve as a promising biomarker of cognitive impairment in long-term cancer survivors. While chemotherapy and radiotherapy-induced intestinal injury may be the underlying mechanism, further research using animal models and larger patient cohorts are needed to explore the pathogenesis of cognitive impairment in GCT survivors.

Cognitive Impairment in Long-Term Survivors of Testicular Cancer More Than 20 Years after Treatment

Simple SummaryImpaired cognition can be a late effect after treatment in long-term testicular cancer survivors, negatively affecting their daily life. However, little data is available beyond 20 years post-treatment. We assessed cognitive impairment in very-long-term survivors after treatment. In this study, we enrolled testicular cancer survivors with a follow-up duration ≥ 20 years—and age-matched healthy controls. Cognitive testing included the Auditory Verbal Learning Test, Letter Fluency Test, and Trail Making Test. We used fasting blood samples to assess the presence of hypogonadism and measured cardiovascular damage and aging parameters. We included 184 testicular cancer survivors (66 chemotherapy patients, 53 radiotherapy patients, and 65 orchiectomy only patients) and 70 healthy controls. The median follow-up was 26 years. Testicular cancer survivors performed worse on cognitive tests compared to controls. In univariate analysis, the presence of hypogonadism was associated with lower cognitive scores. Physicians and patients should be informed about timely cardiovascular risk management and testosterone supplementation therapy during follow-up to reduce the risk of cognitive impairment.Background: Impaired cognition can be a late effect after treatment in long-term testicular cancer (TC) survivors, negatively affecting their daily life. However, little data is available beyond 20 years post-treatment. We assessed cognitive impairment in very long-term TC survivors after CT or RT and compared the results with stage I TC survivors and controls. Methods: In this cross-sectional multicenter cohort study, we enrolled TC survivors (treated with orchiectomy followed by CT or RT or orchiectomy only)—with a follow-up duration ≥ 20 years—and age-matched healthy controls. Cognitive testing included the Auditory Verbal Learning Test, Letter Fluency Test, Category Fluency Test, and Trail Making Test. We used fasting blood samples to assess the presence of hypogonadism and measured cardiovascular aging parameters, including carotid pulse wave velocity (c-PWV) and advanced glycation end products (AGEs). Results: We included 184 TC survivors (66 CT patients, 53 RT patients, and 65 orchiectomy-only patients) and 70 healthy controls. The median follow-up was 26 years (range: 20–42). TC survivors had a lower combined score of the cognitive tests (mean cumulative Z-score −0.85; 95% CI −1.39 to −0.33) compared to controls (mean 0.67; 95% CI −0.21 to 1.57, p < 0.01). In univariate analysis, the presence of hypogonadism (β −1.50, p < 0.01), high c-PWV (β −0.35, p = 0.09), and high AGEs (β −1.27, p = 0.02) were associated with lower cognitive scores, while only AGEs (β −1.17, p = 0.03) remained a significant predictor in multivariate analysis (Model R2 0.31, p < 0.01). Conclusions: Long-term TC survivors performed worse on cognitive tests compared to controls. Physicians and patients should be informed about timely cardiovascular risk management and testosterone supplementation therapy during follow-up to reduce the risk of cognitive impairment. Trial Registration: NCT02572934.

Medulloblastoma in adults: an analysis of clinico-pathological, molecular and treatment factors.

Medulloblastoma is a highly malignant, embryonal tumor, which is rare in adults, and shows distinct clinical, histopathological, molecular and treatment response features. We retrospectively investigated 44 adults (age 17-48 years) with a histological diagnosis of medulloblastoma, and in 23 immunohistochemistry was used to identify the molecular subgroups. We analyzed demographic, diagnostic, therapeutic and cognitive data, and correlated with PFS (progression-free-survival) and OS (overall survival). We observed a male prevalence and a median age of 31 years. Symptoms at onset were related to infratentorial location, while myeloradicular and/or cranial nerve involvement was rare. Histological examination showed the classic variant in 75% of patients, the desmoplastic/nodular in 23% and the anaplastic in one. As for molecular diagnosis, 17 patients were SHH and 6 non-WNT/non-SHH (5 group 4 and 1 group 3), while no WNT subgroup was found. The SHH subgroup had a prevalence of high-risk patients and leptomeningeal involvement. Patients underwent gross total or subtotal/partial resection, and craniospinal irradiation, followed in 20 cases by adjuvant chemotherapy. Median OS and PFS were 16.9 and 12 years, respectively. Metastatic disease at presentation and subtotal/partial resection were associated with worse prognosis, while the addition of chemotherapy did not yield a significant advantage over radiotherapy alone. Cognitive impairment in long-term survivors was limited and late relapses occurred in 15% of patients. Future studies with adequate sample size and long-term follow-up should prospectively investigate the role of surgery and adjuvant therapies across the different molecular subgroups to see whether a personalized approach is feasible.

Prevalence and Predictors of Neurocognitive Impairment in Long-Term Survivors of Childhood Hodgkin Lymphoma: A Report from the Childhood Cancer Survivor Study

Background: Long-term survivors of childhood Hodgkin lymphoma (HL) are at significant risk for cardiovascular, pulmonary, and endocrine morbidity in addition to subsequent cancers. Emerging evidence suggests that HL survivors may also experience persistent neurocognitive impairment, however the prevalence of neurocognitive impairment has not been well characterized. Further, little work has been done to examine how specific treatments or comorbidities are associated with these impairments. Methods: The current study included 1,760 survivors (52.0% female, mean[sd] 37.5 [6.0] years old, 23.6 [4.7] years from diagnosis) of childhood Hodgkin lymphoma and 3,180 sibling controls (54.5% female, 33.2 [8.5] years old) from the Childhood Cancer Survivor Study. Participants completed questionnaires assessing four domains of neurocognitive impairment (task efficiency, emotional regulation, organization, and memory). Impairment for each domain was defined as a score worse than the 90th percentile of community controls. Treatment exposures were abstracted from the medical record. Second malignancies (SMN) were self-reported and subsequently confirmed by pathology findings or medical record review. Chronic health conditions were self-reported and systematically graded according to the NCI CTCAE v4.3 (Grade 1 mild, Grade 2 moderate, Grade 3 severe/disabling, Grade 4 life-threatening). Generalized estimating equations were used to calculate risk of impairment in survivors compared with siblings adjusted for age, sex, and race. Among HL survivors, multivariable log-binomial regression was used to calculate risk of impairment associated with demographic, clinical, and treatment factors. Separate models examined risk associated with Grade 2+ chronic health conditions adjusted for age, sex, and race. Results: 10.8% of HL survivors reported impaired task efficiency (vs. 7.7% in siblings), 16.6% emotional regulation (vs. 11.5% in siblings), 12.1% organization (vs. 10.3% in siblings), and 8.1% memory (vs. 5.7% in siblings). Compared with siblings, survivors reported significantly higher risk of impairment in each of the four neurocognitive domains after adjusting for age, sex, and race (Table). Female survivors had elevated risk of impairment on emotional regulation (RR [95%CI] 1.4 [1.1,1.9)) and memory (2.0 [1.3,3.0]). Compared with white survivors (91.8% of the population), non-white survivors had higher risk of impairment in task efficiency (2.1 [1.2, 3.5]) and emotional regulation (1.7 [1.0,2.7]). Current smokers (12.3%) had higher risk of impairment in task efficiency (1.9 [1.2, 3.1]), emotional regulation (2.5 [1.7,3.7]), and memory (1.7 [1.0,3.0]). Having a late-relapse (&amp;gt;5 years from diagnosis) or a second malignancy (20.0%) was associated with elevated risk of impairment in task efficiency (1.6 [1.06,2.3]). While not statistically significant, anthracycline exposure (39.8%) was associated with higher risk of impairment in task efficiency (1.3 [0.7,2.2]) and memory (1.6 [0.9,3.0]). No statistically significant associations were noted for bleomycin, corticosteroids, or chest radiation. HL survivors with pulmonary morbidity (8.5%) had a higher risk of impairment on task efficiency (1.9 [1.2,3.0]) compared to those without. Cardiovascular conditions (32.9%) were associated with elevated risk of impairment in all domains (RR range from 1.5 to 2.1, all p&amp;lt;0.05, Table). Endocrine (54.3%) and neurologic conditions (6.6%) were associated with an increased risk of task efficiency, emotional regulation, and memory impairments (RR range from 1.4 to 5.5, all p&amp;lt;0.05, Table). Conclusions: Survivors experienced significantly more neurocognitive impairment compared to sibling controls. Among survivors, potentially modifiable risk factors such as smoking and chronic health conditions were associated with neurocognitive impairment while treatment exposures showed little association. Mitigation or prevention of smoking and chronic health conditions may improve neurocognitive functioning in HL survivors Table Disclosures No relevant conflicts of interest to declare.

Vincristine induced neuropathy and functional impairment in long-term survivors of childhood cancer

Vincristine induced neuropathy and functional impairment in long-term survivors of childhood cancer

Cognitive and Neurobehavioral Impairment in Long-Term Survivors Treated for Nasopharyngeal Cancer with Intensity-Modulated Radiation Therapy

Cognitive and Neurobehavioral Impairment in Long-Term Survivors Treated for Nasopharyngeal Cancer with Intensity-Modulated Radiation Therapy

Neurocognitive and Patient-Reported Outcomes in Adult Survivors of Childhood Osteosarcoma.

This study provides the first objective data documenting neurocognitive impairment in long-term survivors of childhood osteosarcoma. To examine neurocognitive, neurobehavioral, emotional, and quality-of-life outcomes in long-term survivors of childhood osteosarcoma. Cross-sectional cohort study at an academic research hospital, with prospective treatment and chronic health predictors. Outcome data were collected from June 2008 to August 2014. Data analysis was completed in April 2015. Survivors of osteosarcoma recruited from the St Jude Lifetime Cohort Study were compared with community controls. Neurocognitive function, neurobehavioral symptoms, emotional distress, and quality of life. Outcomes were examined in relation to pharmacokinetic indices of methotrexate exposure and current chronic health conditions, which were assessed through medical examination and coded according to Common Terminology Criteria for Adverse Events, Version 4.03. Eighty survivors of osteosarcoma (mean [SD] age, 38.9 [7.6] years; time since diagnosis, 24.7 [6.6] years; 42% female) were compared with 39 community controls (age, 39.0 [11.7] years; 56% female). Survivors demonstrated lower mean scores in reading skills (-0.21 [95% CI, -0.32 to -0.10] vs 0.05 [95% CI, -0.13 to 0.23]; P = .01), attention (-0.78 [95% CI, -1.32 to -0.24] vs 0.24 [95% CI, -0.07 to 0.55]; P = .002), memory (-0.24 [95% CI, -0.48 to 0] vs 0.27 [95% CI, -0.08 to 0.62]; P = .01), and processing speed (-0.15 [95% CI, -0.35 to 0.05] vs 0.74 [95% CI, 0.44 to 1.03]; P < .001). Results of pharmacokinetic analysis showed that high-dose methotrexate maximum plasma concentration (estimate = 0; P = .48), median clearance (estimate = -0.11; P = .76), and median/cumulative exposure (estimate = 0; P = .45) were not associated with neurocognitive outcomes. Any grade 3 or 4 Common Terminology Criteria for Adverse Events cardiac, pulmonary, or endocrine condition was associated with poorer memory (t = 2.93; P = .006) and slower processing speed (t = 3.03; P = .002). Survivor-reported poor general health was associated with decreased sustained attention (estimate = 0.24; P = .05) and processing speed (estimate = 0.34; P = .005). Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which is related to current chronic health conditions and not to original treatment with high-dose methotrexate. Prospective longitudinal studies are needed to identify onset and progression of impairment to inform optimal interventions.

Neurodevelopmental outcome at 2 years in twin-twin transfusion syndrome survivors randomized for the Solomon trial

The preferred treatment for twin-twin transfusion syndrome is fetoscopic laser coagulation of inter-twin vascular anastomoses on the monochorionic placenta. Severe postoperative complications can occur when inter-twin vascular anastomoses remain patent including twin-anemia polycythemia sequence or recurrent twin-twin transfusion syndrome. To minimize the occurrence of residual anastomoses, a modified laser surgery technique, the Solomon technique, was developed in which the entire vascular equator is coagulated. In the Solomon randomized controlled trial (NTR1245), the Solomon technique was associated with a significant reduction in twin-anemia polycythemia sequence and recurrence of twin-twin transfusion syndrome when compared with the standard laser surgery technique. Although a significant improvement in perinatal outcome was shown after the Solomon technique, the clinical importance should also be ascertained with long-term follow-up evaluation of the surviving children. The purpose of this study was to compare the long-term neurodevelopmental outcome in surviving children with twin-twin transfusion syndrome who were included in the Solomon randomized trial and treated with either the Solomon technique or standard laser surgery technique. Routine standardized follow-up evaluation in survivors, at least 2 years after the estimated date of delivery, was performed at 2 of the 5 centers that participated in the Solomon trial: Buzzi Hospital Milan (Italy) and Leiden University Medical Center (The Netherlands). The primary outcome of this follow-up study was survival without long-term neurodevelopmental impairment at age 2 years. Neurodevelopmental impairment was defined as cerebral palsy, cognitive and/or motor development score of <85, bilateral blindness, or deafness. Cognitive and motor development was evaluated with the use of Bayley-III. All analyses per fetus, neonate, or child were conducted with the generalized estimated equation module to account for the effect that observations between co-twins are not independent. The primary outcome (survival without neurodevelopmental impairment) was detected in 95 of 141 cases (67%) in the Solomon group and in 99 of 146 cases (68%) in the standard group (P= .92). Neurodevelopmental impairment in long-term survivors who were included for follow-up evaluation was detected in 12 of 107 cases (11%) in the Solomon and in 10 of 109 cases (9%) in the standard group (P= .61). Neurodevelopmental impairment was due to cerebral palsy in 1 case (1%; spastic unilateral) in the Solomon group and in 2 cases (2%; spastic unilateral and spastic bilateral) in the standard group (P= .58). Cognitive development <85 cases was detected in 2 of 105 children (2%) in the Solomon group and in 6 of 106 children (6%) in the standard group (P=.23). Motor development <85 occurred in 8 of 103 children (8%) inthe Solomon group and 3 of 104 children (3%) in the standard group (P= .23). We found no difference in survival without neurodevelopmental impairment between the Solomon and standard laser techniques. In view of the reduction of short-term complications and the absence of increased adverse long-term effects, these data support the use of the Solomon technique in the treatment of twin-twin transfusion syndrome.

The Childhood Cancer Survivor Study-Neurocognitive Questionnaire (CCSS-NCQ) revised: item response analysis and concurrent validity.

Childhood cancer survivors are at risk for neurocognitive impairment related to cancer diagnosis or treatment. This study refined and further validated the Childhood Cancer Survivor Study-Neurocognitive Questionnaire (CCSS-NCQ; Krull et al., 2008), a scale developed to screen for impairment in long-term survivors of childhood cancer. Items related to task efficiency, memory, organization, and emotional-regulation domains were examined using item response theory (IRT). Data were collected from 833 adult survivors of childhood cancer who completed self-report and direct neurocognitive testing for the St. Jude Lifetime Cohort Study. The revision process included: (a) content-validity mapping of items to domains, (b) constructing a revised CCSS-NCQ, (c) selecting items within specific domains using IRT, and (d) evaluating concordance between the revised CCSS-NCQ and direct neurocognitive assessment. Using content and measurement properties, 32 items were retained (8 items in 4 domains). Items captured low to middle levels of neurocognitive concerns. The latent domain scores demonstrated poor convergent/divergent validity with the direct assessments. Adjusted ESs (ES; Cohen's d) for agreement between self-reported memory and direct memory assessment were moderate for total recall (ES = 0.66), long-term memory (ES = 0.63), and short-term memory (STM; ES = 0.55). ESs between self-rated task efficiency and direct assessment of attention were moderate for focused attention (ES = 0.70) and attention span (ES = 0.50), but small for sustained attention (ES = 0.36). Cranial radiation therapy and female gender were associated with lower self-reported neurocognitive function. The revised CCSS-NCQ demonstrates adequate measurement properties for assessing day-to-day neurocognitive concerns in childhood cancer survivors, and adds useful information to direct assessment.

Regional brain glucose metabolism and neurocognitive function in adult survivors of childhood cancer treated with cranial radiation.

The objective of this study was to examine associations between regional brain metabolism, as measured by (18)F-FDG PET, and neurocognitive outcomes in adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation. Thirty-eight adult survivors of ALL were randomly selected from a large cohort treated with cranial radiation therapy (19 with 18 Gy and 19 with 24 Gy of exposure). At a mean age of 26.4 (range, 22.3-37.4) years, and 23.5 (range, 20.4-32.8) years since diagnosis, patients underwent comprehensive neurocognitive evaluations and brain (18)F-FDG PET imaging during a resting condition. (18)F-FDG PET images were analyzed stereotactically, and pixel values were normalized to global activity. Predefined region-of-interest and voxel-based correlation analyses were performed. Compared with national norms, survivors demonstrated lower vocabulary (P < 0.001), reading (P < 0.001), mathematics (P < 0.001), working memory (P < 0.001), oral naming speed (P < 0.001), and cognitive flexibility (P < 0.001). Metabolic activity was higher in basal gangliar structures for those treated with 24 Gy of cranial radiation therapy (P = 0.04). Metabolic activity was positively correlated with oral naming speed in both lateral frontal lobes (ρ = 0.48 and 0.47 for right and left frontal regions, respectively, P < 0.01) and negatively correlated with cognitive flexibility in the sections of the basal ganglia (P < 0.01 for both caudate and putamen). Neurocognitive impairment in long-term survivors of ALL treated with cranial radiation appears to be associated with increased metabolic activity in frontal cerebral cortical and subcortical regions in the basal ganglia, suggesting decreased efficiency of the frontostriatal brain circuit.

Functioning of long-term survivors of first-ever intracerebral hemorrhage

There are few data on long-term functional outcome after intracerebral hemorrhage (ICH). We aimed to assess functional dependency and cognitive impairment in long-term survivors of first-ever intracerebral hemorrhage. Between August and November 2011, we contacted all survivors from a cohort of 134 consecutive patients hospitalized with a first-ever ICH in the period 2005-2009 in a well-defined catchment area. We did an extensive face-to-face follow-up including the National Institute of Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), the Barthel Index (BI), and the Montreal Cognitive Assessment (MoCA). Fifty-one patients (38%) were alive. Fifty agreed to take part in the follow-up. The median follow-up time was 3.8 years. Thirty-four patients (68%) were independent (mRS 0-2) and 16 (32%) dependent (mRS 3-5). Factors independently associated with dependency were leukoaraiosis score (OR 2.3 per increasing point, P = 0.003) and female sex (OR 5.1, P = 0.038). Twenty-seven patients (61%) had cognitive impairment (MoCA ≤ 23). Factors independently associated with cognitive impairment were age (OR 2.4 per 10 years, P = 0.010) and lobar ICH location (OR 14.1, P = 0.016). A large proportion of long-term survivors of ICH in Southern Norway live functionally independent lives in their private homes. Dependency is linked to leukoaraiosis and female sex. Cognitive impairment is common and linked to lobar location of ICH.

Neuropsychological testing and biomarkers in the management of brain metastases

Prognosis for patients with brain metastasis remains poor. Whole brain radiation therapy is the conventional treatment option; it can improve neurological symptoms, prevent and improve tumor associated neurocognitive decline, and prevents death from neurologic causes. In addition to whole brain radiation therapy, stereotactic radiosurgery, neurosurgery and chemotherapy also are used in the management of brain metastases. Radiosensitizers are now currently being investigated as potential treatment options. All of these treatment modalities carry a risk of central nervous system (CNS) toxicity that can lead to neurocognitive impairment in long term survivors. Neuropsychological testing and biomarkers are potential ways of measuring and better understanding CNS toxicity. These tools may help optimize current therapies and develop new treatments for these patients. This article will review the current management of brain metastases, summarize the data on the CNS effects associated with brain metastases and whole brain radiation therapy in these patients, discuss the use of neuropsychological tests as outcome measures in clinical trials evaluating treatments for brain metastases, and give an overview of the potential of biomarker development in brain metastases research.

Physical performance in long-term survivors of acute leukaemia in childhood.

The aim of this study was to assess the physical performance in long-term survivors of acute leukaemia in childhood and to evaluate the effects of anthracycline therapy. Electrocardiography, echocardiography and spiroergometry were carried out on 56 patients aged 9-28 years, of whom 44 patients had been treated with 15-483 mg/m2 doxorubicin (or equivalent). Acute leukaemia had been diagnosed 1.5-16 years earlier. Of the patients 75% reached normal maximal oxygen uptake, 69% normal oxygen uptake at the anaerobic threshold and 95% normal maximal work rate. Of the patients 75% achieved adequate values for maximal heart rate and 78% normal blood lactate concentration. No difference was seen between patients treated with and without anthracyclines. The results of this study provide little evidence for cardiopulmonary impairment in long-term survivors of ALL. Both the cardiac function, as evaluated by ECG and echocardiography, and the physical performance in spiroergometry are normal in a large number of these patients. Anthracycline treatment does not appear to have a negative effect on these parameters.

Growth impairment in long-term survivors of childhood cancer

Growth impairment in long-term survivors of childhood cancer

Growth impairment in long-term survivors of childhood cancer

Growth impairment in long-term survivors of childhood cancer

Lung function impairment in long-term survivors of Hodgkin's disease

Treatment of Hodgkin's disease (HD) involves radiation and chemotherapy, modalities known to cause lung injury. In Norway, between 1980 and 1988, 129 patients aged less than 50 years at the time of diagnosis, had curative treatment with thoracic radiation alone or combined-modality therapy for supradiaphragmatic HD. We have examined 116 (90%) of these patients by interview, chest X-ray and lung function tests, 5-13 years after treatment. Nearly 30% of the patients had dyspnoea on exertion and associated reductions in total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and gas transfer (TLCO) (p < 0.05). Radiographic evidence of no, slight or moderate fibrosis occurred in 32%, 54% and 14% of the patients, respectively. Moderate fibrosis was associated with reductions in FVC, FEV1 and TLCO (p < 0.05). Radiation plus chemotherapy containing bleomycin-anthracyclines (median cumulative bleomycin dose 120 mg) was associated with decreases in FVC and TLCO (p < 0.05). In the multivariate analysis, chemotherapy with bleomycin-anthracyclines was the only significant predictor for lung function impairment. More than five years after therapy, respiratory symptoms and reduction in lung function were diagnosed in nearly one-third of otherwise healthy HD survivors.