Neurocognitive impairment, employment, and social status in radiotherapy-treated adult survivors of childhood brain tumors.

BACKGROUND: Little is known of the cognitive functions, employment, and social status in adult survivors of childhood brain tumor (BT). We aimed to determine the long-term neurocognitive profile of radiotherapy-treated adult survivors of childhood BT and the relationship between cognitive functions and employment and social status. METHODS: Neurocognitive profiles of survivors were assessed in a Finnish national cohort of 71 radiotherapy-treated survivors of childhood BT (median follow-up time: 21 years [range: 5-33 years]) using a cross-sectional design. Neurocognitive outcomes were compared to control (n = 45) and normative values. Tumor- and treatment-related data were collected from the patient files. Information on employment and social status was gathered. RESULTS: Survivors' (median age: 27 years [range: 16-43 years]) median verbal and performance intelligence quotient (IQ) was 90 (range: 49-121) and 87 (range: 43-119), respectively. The cognitive domains with the greatest impairment were executive functions (median z score, -3.5 SD [range: -25.0 to 1.3 SD]), and processing speed and attention (median z score, -2.5 SD [range: -24.9 to 0.5 SD]). Executive functions were associated with employment, educational level, living independently, having an intimate relationship, and having a driving license. Processing speed and attention were related to educational level, living independently, having an intimate relationship, and having a driving license. Performance IQ was associated with educational level and employment status. Working memory was associated with educational level and living independently. CONCLUSIONS: Radiotherapy-treated adult survivors of childhood BT experience significant neurocognitive impairment, which is associated with difficulties related to employment and social status.

Radiation-induced accelerated aging of the brain vasculature in young adult survivors of childhood brain tumors.

BACKGROUND: Cranial radiotherapy may damage the cerebral vasculature. The aim of this study was to understand the prevalence and risk factors of cerebrovascular disease (CVD) and white matter hyperintensities (WMHs) in childhood brain tumors (CBT) survivors treated with radiotherapy. METHODS: Seventy CBT survivors who received radiotherapy were enrolled in a cross-sectional study at a median 20 years after radiotherapy cessation. The prevalence of and risk factors for CVD were investigated using MRI, MRA, and laboratory testing. Tumors, their treatment, and stroke-related data were retrieved from patients' files. RESULTS: Forty-four individuals (63%) had CVD at a median age of 27 years (range, 16-43 years). The prevalence rates at 20 years for CVD, small-vessel disease, and large-vessel disease were 52%, 38%, and 16%, respectively. Ischemic infarcts were diagnosed in 6 survivors, and cerebral hemorrhage in 2. Lacunar infarcts were present in 7, periventricular or deep WMHs in 34 (49%), and mineralizing microangiopathy in 21 (30%) survivors. Multiple pathologies were detected in 44% of the participants, and most lesions were located in a high-dose radiation area. Higher blood pressure was associated with CVD and a presence of WMHs. Higher cholesterol levels increased the risk of ischemic infarcts and WMHs, and lower levels of high-density lipoprotein and higher waist circumference increased the risk of lacunar infarcts. CONCLUSIONS: Treating CBTs with radiotherapy increases the risk of early CVD and WMHs in young adult survivors. These results suggest an urgent need for investigating CVD prevention in CBT patients.

Radiation-Induced Meningiomas After Childhood Brain Tumor: A Magnetic Resonance Imaging Screening Study.

Purpose: Childhood brain tumors (CBTs) and their treatment increase the risk of secondary neoplasms (SNs). We studied the incidence of secondary craniospinal tumors with magnetic resonance imaging (MRI) screening in a national cohort of survivors of CBT treated with radiotherapy, and we analyzed the Finnish Cancer Registry (FCR) data on SNs in survivors of CBT with radiotherapy registered as a part of the primary tumor treatment. Methods: A total of 73 survivors of CBT participated in the MRI study (mean follow-up of 19 ± 6.2 years). The incidence of SNs in a cohort of CBT patients (N = 569) was retrieved from the FCR (mean follow-up of 11 ± 12.9 years). Brain tumors were diagnosed at age ≤16 years between the years 1970 and 2008 in the clinical study and the years 1963 and 2010 in the FCR population. Results: Secondary brain tumors, meningiomas in all and schwannoma in one, were found in 6 of the 73 (8.2%) survivors with a mean of 23 ± 4.3 years after the diagnosis of the primary tumor. The cumulative incidence was 10.2% (95% confidence interval [CI] 3.9-25.1) in 25 years of follow-up. In the FCR data, the 25-year cumulative incidence of SNs was 2.4% (95% CI 1.3-4.1); only two brain tumors, no meningiomas, were registered. Conclusion: Survivors of CBT treated with radiotherapy have a high incidence of meningiomas, which are rarely registered in the FCR.

Bone mineral density is compromised in very long-term survivors of irradiated childhood brain tumor.

INTRODUCTION: The increase in the number of childhood brain tumor survivors warrants detailed research to increase our knowledge regarding the possible physical and psychosocial adverse outcomes of tumor and tumor therapy. The aim of this study was to evaluate the current bone health by measuring the bone mineral density (BMD) in irradiated, adult long-term survivors of childhood brain tumors. MATERIAL AND METHODS: We studied a national cohort of 74 adult survivors of childhood brain tumors treated with irradiation in Finland between 1970 and 2008. Dual X-ray absorptiometry (DXA) was performed for the femoral necks, total hips, and lumbar spine. Laboratory tests were conducted for evaluating the pituitary, thyroid, and gonadal functions. The participants were interviewed, examined clinically, and the disease and treatment related data were retrieved from the patient files. RESULTS: One fourth of the patients (23.6%) had sex- and age-normalized z-scores below the expected range for age (z-score ≤ -2.0). Mean BMD scores were decreased in all the DXA measurement sites. Male sex was associated with low BMD (p < .05), while body mass index (BMI) had a significant positive association with BMD (p < .01). Mode of irradiation (with or without spinal irradiation) or inclusion of chemotherapy in the treatment did not affect BMD significantly. However, patients with a ventriculoperitoneal shunt had lower BMD than those without a shunt (p < .05). Follicle stimulating hormone (FSH) and luteinizing hormone (LH) were negatively associated with BMD in women (p < .05). However, a higher cumulative dose of glucocorticoids during treatment was not associated with lower BMD, while low BMD was significantly associated with previous fractures in long bones. DISCUSSION: Low BMD should be taken in consideration in treatment of irradiated childhood brain tumor survivors especially in those with previous fractures in long bones.

Posterior Reversible Encephalopathy Syndrome: Risk Factors and Impact on the Outcome in Children With Acute Lymphoblastic Leukemia Treated With Nordic Protocols.

Posterior reversible encephalopathy syndrome (PRES) in children with acute lymphoblastic leukemia has been increasingly recognized as a clinicoradiological entity. Our aim was to describe the incidence of PRES in pediatric patients with ALL, identify its risk factors, and examine its prognostic importance. For this research, we conducted a systematic, retrospective review of the patient records in a population-based series of children with acute lymphoblastic leukemia (n=643) treated in Finland from 1992 to 2008. Of the patients with ALL, 4.5% (n=29) developed radiologically confirmed PRES, of which 28 cases occurred during induction. Hypertension (P=0.006; odds ratio [OR], 4.10, confidence interval [CI], 1.50-11.25), constipation (P=0.001; OR, 5.60; CI, 2.02-15.52), and >14 days of alkalinization (P=0.017; OR, 3.27; CI, 1.23-8.68) were significant independent risk factors for PRES. One-third of the patients developed epilepsy. Relapses occurred significantly more often in those patients with PRES (P=0.001), which was associated with worse overall survival (P=0.040; 5-year survival=75.9% [60.3%-91.4%] vs. 88.4% [85.8%-90.9%]). Using NOPHO-ALL 92/2000 protocols, PRES is a significant early complication of therapy in ALL, and was associated with a poorer prognosis and significant neurological morbidity.

Young patients with hematologic and lymphatic malignancies have an increased risk of hip and knee arthroplasty.

Background Skeletal complications such as osteonecrosis (ON) are potential adverse events in patients treated for cancer, especially in those treated for hematologic and lymphatic malignancies (HLMs). ON may damage the hip or knee joints and may lead to arthrosis requiring total joint arthroplasty (TJA). The aim of this study was to address the risk of TJA in patients with cancer, especially those treated for HLM, in a nationwide population-based setting. Material and methods All patients who had undergone TJA after cancer diagnosis between the years 2000 and 2012 were identified by linking the Arthroplasty Register and the Cancer Registry. Standardized incidence ratios (SIRs) of TJAs were calculated to assess whether patients with any cancer, but especially HLM, have increased risk for TJA when compared with the general population. Results In patients with HLM or other cancer, the overall SIRs were similar compared with the general population. However, in HLM patients under 50 years of age, the SIR was 7.6, and in patients under 35 years of age, it was 45.5. The corresponding SIRs in patients with other cancers were 3.6 and 6.6, respectively. The highest SIRs, including all age groups, were among patients with acute lymphoblastic leukemia (SIR = 4.5) and acute myeloid leukemia (SIR = 1.9). Discussion HLMs imply an increased risk for TJA compared with the general population. The risk is especially high in patients younger than 50 years, regardless of the type of HLM. Young patients with HLM, as well as their healthcare providers, should be aware of the highly increased risk of skeletal complications requiring TJA.

Low depressive symptom and mental distress scores in adult long-term survivors of childhood acute lymphoblastic leukemia.

Childhood cancer survivors are thought to be at risk of psychological difficulties. We examined the prevalence of depressive symptoms and mental well-being in adult long-term survivors of childhood acute lymphoblastic leukemia (ALL) at a mean age of 20 years after the cessation of therapy. Depressive symptoms were assessed with Beck Depression Inventory (BDI-21) and mental distress with General Health Questionnaire (GHQ-12) among 73 ALL survivors and 146 healthy controls. The ALL survivors obtained significantly lower BDI scores (P=0.046) compared with the controls, indicating less depressive symptoms among the ALL survivors. BDI scores indicated a significantly less frequent moderate or severe depression in the ALL survivors compared with the controls (P=0.039). BDI scores indicated no depression in 80.8% of the ALL survivors and 73.3% of the control group. The female ALL survivors obtained lower BDI scores than did the female controls (P=0.005). No difference was found in GHQ-12 scores between the survivors and the controls. Survivors of ALL reported fewer depressive symptoms and equal mental well-being compared with healthy controls. Our findings support the idea that childhood leukemia survivors' subjective experience of well-being is possibly affected by repressive adaptive style.

High health-related quality of life among long-term survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Health-related quality of life (HRQoL) was assessed in a cohort of long-term childhood acute lymphoblastic leukemia (ALL) survivors. PROCEDURE: Rand-36-Item health Survey (RAND-36) was used to assess subjective HRQoL in 74 survivors of ALL an average of 20 years after the diagnosis. Cranial irradiation had been administered to 46 of the survivors, while 28 survivors had solely been treated with chemotherapy. The control group consisted of 146 healthy young adults selected from local population registry. Survivors were examined by a physician and late effects were graded using the Common Terminology Criteria for Adverse Events (CTCAEv3). RESULTS: ALL survivors achieved significantly higher scores than the controls on three of the eight HRQoL subscales; role limitations due to emotional problems (P = 0.030), mental health (P = 0.030) and vitality (P = 0.004). In comparison to controls, survivors with a follow-up of more than 20 years had significantly higher scores on vitality (P = 0.006) and mental health (P = 0.011). Survivors with severe (grade 3 and 4) late effects scored significantly better than controls on vitality (P = 0.043) and mental health (P = 0.040). Patients who had been treated for an ALL relapse and had received the most intensive chemo- and radiotherapy had significantly higher scores on mental health (P = 0.004) and vitality (P = 0.004) than the controls. CONCLUSIONS: Long-term survivors of childhood ALL reported equal or better HRQoL in RAND-36. Higher HRQoL scores were associated with more severe late effects and intensive therapy. Our findings support the idea of response bias.

Progressive neurocognitive impairment in young adult survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Despite the extensive literature on neuropsychological sequelae after treatment of childhood acute lymphoblastic leukemia (ALL), the very-long-term neurocognitive outcome of the survivors is poorly studied. We assessed neuropsychological functioning in a population-based cohort of young adult childhood ALL survivors. PROCEDURE: Neuropsychological testing was performed on 64 survivors an average of 20 years after the diagnosis. The test battery included verbal intelligence quotient (VIQ) and performance intelligence quotient (PIQ), memory function, orientation and attention as well as motor performance. Cranial irradiation had been administered to 44 survivors as part of ALL treatment, whereas 20 survivors had been treated solely with chemotherapy. A control group consisted of 45 healthy young adults. Earlier neuropsychological test results of 45 of the survivors were available for comparison. RESULTS: The ALL survivors attained significantly lower test scores than the controls in all the neuropsychological function areas. The mean VIQ test scores were 91, 100, and 109 (P < 0.001), and the mean PIQ test scores 100, 111, and 118 (P < 0.001) for the irradiated survivors, non-irradiated survivors and controls, respectively. Memory and motor functions were impaired among the irradiated survivor group compared with the controls. A significant decline in PIQ and VIQ test scores was observed in the irradiated survivor group during the follow-up period, but only in VIQ in the non-irradiated group. CONCLUSIONS: Survivors of childhood ALL suffer from long-lasting progressive neuropsychological impairment, especially when treatment includes cranial irradiation.

Osteonecrosis in children treated for lymphoma or solid tumors.

PURPOSE: The purpose of this study was to find out the incidence of and clinical risk factors for magnetic resonance imaging (MRI)-detected osteonecrosis (ON) in children treated for lymphoma or solid tumors. PATIENTS AND METHODS: The development of ON was studied in 32 childhood cancer patients who underwent MRI scanning of the lower extremities at the end of their treatment. The underlying malignancy was Wilms tumor in 8 patients, non-Hodgkin lymphoma (NHL) in 8, Hodgkin disease (HD) in 7, rhabdomyosarcoma in 6, and other occasional solid tumors in 3 patients. RESULTS: Six of the 32 patients (19%) had ON. The mean age of the patients with ON at diagnosis was 12.7 years compared with 5.8 years for the patients without ON (P<0.001). All the patients with ON had either HD (4 patients) or NHL (2 patients). Two (33%) of the patients with ON were symptomatic. CONCLUSIONS: ON in MRI was found to be a common complication in children after treatment for HD or NHL. The risk for ON seems to be very low in patients with other solid tumors even when they receive high cumulative doses of dexamethasone.

Scholastic achievements of childhood leukemia patients: a nationwide, register-based study.

PURPOSE: Studies concerning the scholastic achievement of survivors of childhood leukemia have yielded controversial results. We studied the school marks of childhood leukemia survivors in a register-based study. PATIENTS AND METHODS: Three hundred seventy-one patients with a diagnosis of leukemia before the age of 16 years who were born between 1974 and 1986 and alive on their 16th birthday were identified from the Finnish Cancer Registry. Five matched controls were sought for each patient from the Population Register Center of Finland. Information on the ninth-grade school report was obtained from Statistics Finland. The overall mark average and the marks (scale 4 to 10) for mother tongue, foreign language, mathematics, and physical education were compared between the patients and controls. RESULTS: The ninth-grade school report was obtained by 97.6% of the patients and 98.5% of the controls. The patients whose treatment included cranial irradiation had a lower overall mark average (mean difference, -0.24; 95% CI, -0.33 to -0.15) and lower marks for all assessed school subjects compared with their controls. Of the patients treated with chemotherapy alone, only the females with leukemia diagnosed before 7 years of age had lower school marks than their controls. The biggest difference was observed in the marks for foreign language among the irradiated females diagnosed at a young age (mean difference, -1.0; 95% CI, -1.25 to -0.74). CONCLUSION: Leukemia treatment that includes cranial irradiation impairs scholastic achievement. It is noteworthy that treatment of leukemia with chemotherapy alone impairs school performance only in females diagnosed before school age.

High body mass index increases the risk for osteonecrosis in children with acute lymphoblastic leukemia.

PURPOSE: The aim of the study was to determine the incidence of and clinical risk factors for radiographic osteonecrosis (ON) in children treated for acute lymphoblastic leukemia (ALL) using the Nordic ALL protocols. PATIENTS AND METHODS: Ninety-seven consecutive patients with childhood ALL were studied prospectively by magnetic resonance imaging (MRI) of the lower extremities at the end of the treatment. RESULTS: Twenty-three (24%) of the 97 patients had ON. Seven of the patients (30%) were symptomatic, and three patients (13%) required surgical interventions. Multiple logistic regression analysis showed that high body mass index (BMI; P = .04), female sex (P = .01), older age at diagnosis (P < .001), and higher cumulative dexamethasone dose (P = .03) were independent risk factors for radiographic ON. The cumulative prednisone dose did not differ significantly between the patients with and without ON. The incidence of radiographic ON decreased significantly, from 36% to 7%, when the duration of dexamethasone exposure during the delayed-intensification phase was shortened from 3 to 4 weeks to 2 weeks with a taper (P = .001). CONCLUSION: ON as determined by MRI was found to be a common complication in children and adolescents after treatment with the Nordic ALL protocols. Revision of the ALL protocols by shortening the single exposure to dexamethasone has diminished the risk for ON remarkably. High BMI was identified as a new significant risk factor for ON.

Motor nervous system impairment persists in long-term survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: The objective of the current study was to determine whether therapy for childhood acute lymphoblastic leukemia (ALL) results in long-lasting neurologic signs or electrophysiologic injuries within the motor tracts. METHODS: Twenty-seven children who were treated for ALL were studied clinically 5 years after the cessation of therapy by means of motor-evoked potentials (MEPs) elicited by magnetic stimulation transcranially and peripherally. An equal number of healthy children matched with regard to age, gender, and height served as the control group. RESULTS: The MEP latencies to the hands and legs elicited by stimulation at the cortex were prolonged significantly in the children treated for ALL compared with the control group, with the differences being 2.2 milliseconds [ms] (P < 0.001) from the cortex to the thenar on the right side and 2.0 ms (P < 0.001) on the left, and 1.4 ms (P = 0.004) from the cortex to the leg on the right side and 1.3 ms (P = 0.004) on the left. Correspondingly, the MEP latency from the fifth lumbar vertebrae (LV) level to the leg also was prolonged, by 1.0 ms (P = 0.005) on the right side and 0.8 ms (P = 0.005) on the left side. The calculated latency between the cortex and the LV level was not found to be significantly longer in those patients treated for ALL compared with the healthy controls. Neurologic signs, in the form of depressed deep tendon reflexes, were observed in 8% of the patients, whereas approximately 33% of the patients were found to have fine or gross motor difficulties and dysdiadochokinesia. CONCLUSIONS: Neurologic signs still persisted 5 years after therapy for ALL. Approximately 33% of the patients had fine or gross motor difficulties and dysdiadochokinesia, and demyelinative injuries to the peripheral nerve tracts were found proximally but not within the central nervous system.