Novel non-neutral mitochondrial DNA mutations found in childhood acute lymphoblastic leukemia.

Mitochondria produce adenosine triphosphate (ATP) for energy requirements via the mitochondrial oxidative phosphorylation (OXPHOS) system. One of the hallmarks of cancer is the energy shift toward glycolysis. Low OXPHOS activity and increased glycolysis are associated with aggressive types of cancer. Mitochondria have their own genome (mitochondrial DNA [mtDNA]) encoding for 13 essential subunits of the OXPHOS enzyme complexes. We studied mtDNA in childhood acute lymphoblastic leukemia (ALL) to detect potential pathogenic mutations in OXPHOS complexes. The whole mtDNA from blood and bone marrow samples at diagnosis and follow-up from 36 ALL patients were analyzed. Novel or previously described pathogenic mtDNA mutations were identified in 8 out of 36 patients. Six out of these 8 patients had died from ALL. Five out of 36 patients had an identified poor prognosis genetic marker, and 4 of these patients had mtDNA mutations. Missense or nonsense mtDNA mutations were detected in the genes encoding subunits of OXPHOS complexes, as follows: MT-ND1, MT-ND2, MT-ND4L and MT-ND6 of complex I; MT-CO3 of complex IV; and MT-ATP6 and MT-ATP8 of complex V. We discovered mtDNA mutations in childhood ALL supporting the hypothesis that non-neutral variants in mtDNA affecting the OXPHOS function may be related to leukemic clones.

Venous thrombosis in children and adolescents with Hodgkin lymphoma in Sweden.

INTRODUCTION: Pediatric patients with Hodgkin lymphoma (HL) have several risk factors for venous thromboembolism (VTE). Although these patients are occasionally treated with thromboprophylaxis, no guidelines are implemented in Sweden. Scarce data from adult patients indicate an increased risk of VTE, but pediatric data is largely missing. Given the favorable overall survival of HL, there should reasonably be more focus on preventing complications. MATERIALS AND METHODS: We conducted a retrospective cohort study, including all patients registered in the Childhood Cancer Registry under the age of 18years diagnosed with HL between January 2005 and December 2015 in Sweden. RESULTS: Data was retrieved from the medical records of all 163 patients (100%) at six Swedish pediatric cancer centers. The incidence of VTE was 7.7% (symptomatic VTE 3.9%). The median follow-up was 3.4years (range 0.3-10.5). Only five patients (3.1%) were treated with thromboprophylaxis. All VTE events occurred in the older age category (11-17years) and all but one (92.7%) had a mediastinal mass. While the VTE did not significantly affect the treatment of HL, it caused increased morbidity and 2/12 developed a post-thrombotic syndrome. No significant risk factors for VTE were identified. CONCLUSIONS: VTE is a relatively common complication of HL and its treatment, causing increased acute and long-term morbidity. However, due to limited number of events we could not demonstrate risk-factors for VTE that would identify patients who might benefit from thromboprophylaxis.

The classification of osteonecrosis in patients with cancer: validation of a new radiological classification system.

AIM: To validate a new, non-joint-specific radiological classification system that is suitable regardless of the site of the osteonecrosis (ON) in patients with cancer. MATERIAL AND METHODS: Critical deficiencies in the existing ON classification systems were identified and a new, non-joint-specific radiological classification system was developed. Seventy-two magnetic resonance imaging (MRI) images of patients with cancer and ON lesions were graded, and the validation of the new system was performed by assessing inter- and intra-observer reliability. RESULTS: Intra-observer reliability of ON grading was good or very good, with kappa values of 0.79-0.86. Interobserver agreement was lower but still good, with kappa values of 0.62-0.77. Ninety-eight percent of all intra- or interobserver differences were within one grade. Interobserver reliability of assessing the location of ON was very good, with kappa values of 0.93-0.98. CONCLUSION: All the available radiological ON classification systems are joint specific. This limitation has spurred the development of multiple systems, which has led to the insufficient use of classifications in ON studies among patients with cancer. The introduced radiological classification system overcomes the problem of joint-specificity, was found to be reliable, and can be used to classify all ON lesions regardless of the affected site.

Scholastic achievements of children with brain tumors at the end of comprehensive education: a nationwide, register-based study.

BACKGROUND: Cancer treatment may affect school performance. Scholastic achievements after childhood brain tumors have not been previously reported on the level of actual grades. PATIENTS AND METHODS: Patients with brain tumor (n = 300) were identified from the Finnish Cancer Registry. Population controls (n = 1,473) were matched for age, gender, and place of living. Their ninth grade school reports were obtained from Statistics Finland. Age at diagnosis and cranial irradiation (CRT) were considered in analyses, and the level of parental education was taken into model as a covariate. RESULTS: Six percent of patients did not finish their comprehensive school at the usual age. Patients had lower overall averages than their controls (95% CI for the difference -0.30, -0.16). Girls differed from their controls independently of the age at diagnosis or CRT. Boys treated with CRT at school age, but not before school age, had poorer results than their controls (95% CI -0.65, -0.18). The grades of patients were significantly lower in each school subject, and differed most in foreign language. Young girls with CRT had greatest differences from their controls (95% CI -1.73, -0.86) in this subject. In mathematics, patients diagnosed before school age had greatest difference from their controls. In their mother tongue, patients differed less from their controls. CONCLUSIONS: Few patients with brain tumor missed the ninth grade certificate at the age of 16. Grades in foreign language (representing verbal performance) were most affected. However, the patients fared poorer than controls in each subject. The difference was most pronounced among girls. Girls were more sensitive to the adverse effects of irradiation.

Motor nervous pathway function is impaired after treatment of childhood acute lymphoblastic leukemia: a study with motor evoked potentials.

BACKGROUND: The objective was to evaluate whether motor nervous pathways are affected when patients are treated for childhood acute lymphoblastic leukemia (ALL). PROCEDURE: Thirty-two children with ALL were studied at the end of treatment by means of motor evoked potentials (MEPs) elicited by magnetic stimulation (MS) transcranially and peripherally and underwent a detailed neurological examination. Thirty-two healthy children matched with them for age, sex, and height served as a control group. RESULTS: The latencies of the MEPs were significantly prolonged along the entire motor nervous pathway in the patients with ALL compared with the healthy controls, indicating demyelination in the thick motor fibres. The MEP amplitudes of the distal extremities elicited by stimulation at the brachial plexus and LV spinal level were significantly lowered in the patients treated for ALL, also indicating anatomical or functional loss of descending motor fibres and/or muscle fibres. The MEP amplitudes elicited by cortical MS showed wider variation and no clear abnormalities were found. Neurological signs and symptoms were common after treatment: 41% of the patients had depressed deep tendon reflexes, 31% had fine motor difficulties and 63% gross motor difficulties, and 34% had dysdiadochokinesia. The conduction delay within the peripheral nerve was related to the post-therapeutic interval after administration of vincristine and the lesions within the CNS to the number of injections of intrathecal methotrexate. CONCLUSIONS: The present results show adverse effects of the ALL treatment on the entire motor nervous pathways. In our experience, the measurement of MEPs by MS provides an objective, painless, and practical tool for assessing the treatment-related neurotoxicity in both the CNS and the peripheral nerves. These disturbances in the motor nervous pathways at the end of treatment raise the question of the long-term effects of ALL treatment on the motor nerve tracts, and have led us to employ MEPs to study these effects in long-term survivors of ALL.

White matter changes on MRI during treatment in children with acute lymphoblastic leukemia: correlation with neuropsychological findings.

BACKGROUND: Treatment of childhood acute lymphoblastic leukemia (ALL) may cause structural and functional brain damage. To find out the incidence of white matter changes during therapy, a prospective MRI study was designed, and the findings were correlated with neuropsychological evaluation. PROCEDURE: Thirty-three children with ALL underwent serial cranial MRI before, during, and after therapy. Twenty-eight of these children underwent also neuropsychological assessment at the end of treatment. They all received intravenous and intrathecal methotrexate for central nervous system (CNS) therapy, 15 patients received cranial irradiation in addition. RESULTS: Transient high-intensity white matter changes were observed by MRI in three children 9% (95% CI, 2-24%) who received chemotherapy only. The high-intensity changes were most prominent in the frontal lobes in two of these children. The children with white matter changes were significantly younger than those with normal MRI (2.8 vs. 7.4 years; mean). There was no correlation between neuropsychological tests and white matter changes, except in attention and in tests referring to the frontal areas in general. CONCLUSIONS: White matter changes are occasionally observed during therapy with the current Nordic protocols. Young children may be more susceptible to developing white matter changes after repeated intravenous methotrexate injections. There is no systematic correlation between neuropsychological deficits and MRI findings.

Cerebral glucose metabolism in survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Cranial radiation therapy (CRT) has been suggested to be a principal factor responsible for long term neurocognitive deficits in survivors of acute lymphoblastic leukemia (ALL). However, neither reduction of the irradiation dose nor the elimination of irradiation entirely appear to have abolished neurocognitive impairment in long term ALL survivors. Positron emission tomography (PET) and [(18)F]-fluorodeoxyglucose (FDG) can be used to quantitate cerebral glucose metabolism, a potential indicator of treatment-induced adverse central nervous system (CNS) effects. The purpose of this study was to assess whether CRT is associated with defects in cerebral glucose metabolism in long term ALL survivors. The authors also studied whether chemotherapy and/or the severity of disease have deleterious effects on glucose metabolism. METHODS: Forty long-term survivors of childhood ALL were studied using FDG PET. All subjects went through an elaborate neurocognitive assessment. In 20 of these children, the prophylactic treatment of the CNS had been CRT combined with methotrexate (MTX), and it was MTX only in the remaining 20 children. RESULTS: No major differences were found in the regional cerebral glucose utilization or in neurocognitive performance between the irradiated and nonirradiated groups. A high leukocyte count at the time of diagnosis was found to be associated inversely with cerebral glucose utilization. CONCLUSIONS: CRT does not appear to affect cerebral glucose metabolism in long term survivors of ALL. By contrast, the association between the leukocyte count and glucose utilization implies that disease severity may be partly responsible for adverse CNS effects in long term survivors of childhood ALL.

Cerebral blood flow and glucose metabolism in long-term survivors of childhood acute lymphoblastic leukaemia.

Central nervous system treatment for childhood acute lymphoblastic leukaemia (ALL) has been reported to cause changes in cerebral blood flow and glucose metabolism. Little is known about the association of these functional changes with neuropsychological defects and structural changes. The aim of the present study was to assess the relationship between changes in regional cerebral blood flow and glucose utilisation in long-term survivors of ALL, and the association of these functional abnormalities with neurocognitive and structural defects. 8 survivors of childhood ALL were studied with single photon emission tomography (SPECT) using Tc99m-ethyl cysteinate dimer (ECD) as tracer and with positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) as tracer. 8 healthy controls also underwent FDG-PET. All subjects also underwent magnetic resonance imaging and neuropsychological assessment 5 years after cessation of the therapy. Focal cerebral blood flow abnormalities were found in ECD-SPECT in 5 of the 8 survivors. Glucose utilisation appeared normal in the corresponding regions. However, glucose utilisation was decreased in thalamus and cerebellum in the survivors of ALL as compared with healthy controls. 3 patients had severe and 5 patients mild neurocognitive difficulties. The changes in cerebral blood flow and FDG uptake did not correspond neuroanatomically with the neurocognitive defects. Focal defects in cerebral blood flow in long-term survivors of ALL are not associated with changes in local cerebral glucose utilisation. Neurocognitive difficulties are not consistently associated with either changes in cerebral blood flow or with decreased glucose utilisation. Therefore, based on the present set of studies FDG-PET and ECD-SPECT cannot yet be recommended for the evaluation of long-term neurocognitive defects associated with treatment of ALL.

Bone marrow changes on MRI in children with acute lymphoblastic leukaemia 5 years after treatment.

T1-weighted magnetic resonance imaging (MRI) of the lower extremities was performed 5 years after the cessation of therapy on 25 children treated for acute lymphoblastic leukaemia (ALL). Signal intensity pathologies considered to be related with the leukaemia itself or the treatment of ALL were found in nine of 25 children (36%). Two of these children had findings of osteonecrosis, five had a patchy signal pattern, one had diffuse inhomogeneity of the bone marrow signal intensity in complete remission and one had diffusely decreased signal intensity preceding the diagnosis of relapse. MRI unexpectedly revealed many bone marrow pathologies in symptomless children successfully treated for ALL. Especially, osteonecrosis might cause significant disability, and the aetiology, clinical course and prognosis of this complication are not well known. The intensive dexamethasone medication included in the treatment protocols may be responsible for the development of osteonecrosis. However, the prognosis of osteonecrosis in the long run requires further studies.

Nerve lesions after therapy for childhood acute lymphoblastic leukemia.

BACKGROUND: The objective of the current study was to use somatosensory evoked potentials (SEP) to detect signs of nerve lesions in the peripheral nerve and in the central nervous system (CNS) after 3 years of treatment for childhood acute lymphoblastic leukemia (ALL). METHODS: The somatosensory potentials evoked by stimulation of the median nerve and posterior tibial nerve were recorded in 31 children with ALL after 3 years of therapy. All patients were examined clinically. The 14 standard risk patients had been treated with chemotherapy according to the Nordic regimen, and the 17 intermediate risk or high risk patients had been treated with chemotherapy and cranial irradiation according to the ALL BFM-83 protocol. RESULTS: A decrease in amplitudes was observed at the brachial plexus and spinal cord (C7) in the median SEP, and at the knee, spinal cord (Th12), and cortex in the tibial SEP, indicating axonal injury within the entire CNS in the patients with ALL compared with healthy age-, gender-, and height-matched controls. Prolongation of the SEP latencies was found within the spinal cord, indicating demyelination. These SEP changes had persisted for 2 years since the last injection/infusion of vincristine or methotrexate, which are the principal neurotoxic drugs used in chemotherapy for ALL. Clinical signs of nerve injury such as depressed deep tendon reflexes and gross or fine motor difficulties were found in approximately 33% of the patients and dysdiadochokinesia in 50%. CONCLUSIONS: Treatment of ALL in children principally with vincristine and methotrexate causes long-standing axonal injury throughout the nervous system and demyelination within the spinal cord. These changes are associated with clinical neurologic findings.

A longitudinal magnetic resonance imaging study of the brain in survivors in childhood acute lymphoblastic leukemia.

BACKGROUND: The objective of this study was to evaluate changes in magnetic resonance imaging (MRI) of the brain in children with acute lymphoblastic leukemia (ALL) during the first 5 years after the cessation of therapy and to correlate MRI abnormalities with neuropsychologic outcome. METHODS: Thirty-two children with ALL were studied at the end of treatment and 5 years later by brain MRI and the results were compared with the neuropsychologic findings. Fifteen patients had received chemotherapy alone and 17 had received chemotherapy plus cranial radiation. RESULTS: MRI of the brain was abnormal in 6 of 30 patients at the end of treatment and in 8 of 32 patients 5 years later. White matter changes (WMC) were found in 3 patients at the end of treatment and in 4 patients 5 years later. Two patients had developed new mild changes, whereas in one case WMC had normalized during the follow-up. Two patients had old hemorrhages or calcifications at each examination, with some improvement after follow-up, although one case revealed a new calcification or hemorrhage. Signs of cortical atrophy were observed in five patients at both evaluations. The patients with abnormal MRI findings did not differ significantly in their performance in the neuropsychologic tests from the patients with normal MRI findings, but the two patients with persistent WMC had a depression of verbal functions. CONCLUSIONS: Abnormalities in brain MRI were infrequent at the end of treatment for childhood ALL and 5 years later. They did not appear to correlate significantly with neuropsychologic outcome. Brain MRI is not very informative as a routine follow-up method during the first 5 years after treatment.

Brain perfusion after treatment of childhood acute lymphoblastic leukemia.

UNLABELLED: Children with acute lymphoblastic leukemia (ALL) have impairment in their neuropsychological functioning and morphological changes in their brain after cranial irradiation and chemotherapy. The aim of this study was to identify possible brain perfusion defects caused by different types of treatment and their association with abnormalities in cerebral MRI and neuropsychological and clinical neurological findings. METHODS: Twenty-five consecutive children with ALL at the cessation of chemotherapy or after 1 yr were included. All of the children were given intravenous and intrathecal methotrexate for central nervous system therapy, 13 of them received cranial radiation therapy. Brain SPECT, cerebral MRI, clinical neurological and neuropsychological evaluations were performed. RESULTS: Eleven of the 25 patients (44%) had brain perfusion defects in SPECT, eight of whom were treated with chemotherapy alone, and three received cranial irradiation. Two patients had small bilateral white matter changes on MRI; their brain SPECT scans were abnormal, although the findings were not related. Impairment of neuropsychological functioning was found in 86% of the patients tested. No significant difference between the patients with abnormal and normal SPECT were found. Those patients with abnormal SPECT were younger than those with normal SPECT and had received more frequent intravenous methotrexate infusions. CONCLUSION: Brain SPECT detected perfusion defects that had occurred after treatment for childhood ALL. These defects may be related to frequent administration of a combination of intravenous and intrathecal methotrexate and/or young age.