Hypothalamic-pituitary-adrenal axis function in survivors of childhood acute lymphoblastic leukemia and healthy controls

Of all malignancies in children, acute lymphoblastic leukemia (ALL) is the most common type. Since survival significantly improves over time, treatment-related side effects become increasingly important. Glucocorticoids play an important role in the treatment of ALL, but they may suppress the hypothalamic-pituitary-adrenal (HPA) axis. The duration of HPA axis suppression is not yet well defined. The present study aimed at assessing the function of the HPA axis by determining the cortisol awakening response (CAR) and the dexamethasone (DEX) suppression test in children that were treated for childhood ALL, compared to a healthy age and sex matched reference group. In addition, questionnaires regarding sleep, fatigue, depression and quality of life were completed by the children and their parents. Fourty-three survivors who finished their treatment for childhood ALL 37 (interquartile range 22-75) months before and 57 healthy controls were included. No differences in CAR were observed between ALL survivors and the reference group, but survivors of ALL had higher morning cortisol levels and an increased cortisol suppression in response to oral dexamethasone. Higher cortisol levels in childhood ALL survivors were associated with more fatigue and poorer quality of life. We conclude that the experience of a stressful life event in the past may have caused a long-term dysregulation of the HPA axis in childhood ALL survivors, as reflected in an increased cortisol production and an enhanced negative feedback mechanism.     

Peripheral neuropathy in survivors of childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children. Recent advances in treatment have led to dramatically improved survival rates. Standard ALL treatment includes multiple administrations of the chemotherapeutic drug vincristine, which is a known neurotoxic agent. Although peripheral neuropathy is a well-known toxicity among children receiving vincristine acutely, the long-term effects on the peripheral nervous system in these children are not clear. The objective of this study was to determine the prevalence of neuropathy and its impact on motor function and quality of life (QOL) among children who survived ALL. Thirty-seven survivors of childhood ALL aged 8–18 underwent evaluation for neuropathy through self-reported symptoms, standardized examinations, and nerve conduction studies (NCS). Functional impact of neuropathy was assessed using the Bruininks-Oseretsky test of Motor Proficiency (BOT-2). QOL was assessed using the PedsQL. Nerve conduction study abnormalities were seen in 29.7% of children who were longer than 2 years off therapy for ALL. Most children with an abnormal examination or NCS did not have subjective symptoms. Although overall motor function was below population norms on the BOT-2, presence of neuropathy did not significantly correlate with motor functional status or QOL.     

Utility of the N-back task in survivors of childhood acute lymphoblastic leukemia

The N-back task is often used in functional brain imaging studies to activate working memory networks; however, limited information is available on its association to clinical outcomes in children or cancer survivors. A total of 137 survivors of acute lymphoblastic leukemia (ALL; mean current age = 14.3 years, SD = 4.8; time since diagnosis = 7.6 years, SD = 1.6) completed the N-back task and comprehensive neurocognitive testing, including standardized measures of attention, processing speed, and working memory. Results indicated that females demonstrated significantly slower reaction times (0-back p = .02; 1-back p = .03) than males. Survivors <15 years old at the time of testing demonstrated a significant decrease in accuracy as working memory load increased compared to survivors ≥15 years old (p < .001). Performance on the N-back task was associated with nonverbal working memory (r_s = .56, p < .001) in survivors ≥15 years of age. For younger survivors, N-back performance was more strongly associated with attention skills. Results suggest the N-back assesses different cognitive constructs at younger compared to older childhood ages. These age differences should be considered in interpreting functional brain imaging results.     

Neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on contemporary treatment protocols: A systematic review

The intensified administration of chemotherapeutic drugs has gradually replaced cranial radiation therapy (CRT) for the treatment of childhood acute lymphoblastic leukemia (ALL). While CRT is often implicated in neurocognitive impairment in ALL survivors, there is a paucity of the literature that evaluates the persistence of neurocognitive deficits in long-term survivors of pediatric ALL who were treated with contemporary chemotherapy-only protocols. Results from this systematic review concurred to the probable cognitive-sparing effect of chemotherapy-based protocols over CRT in long-term survivors. However, coupled with multiple intrinsic and extrinsic factors, survivors who received chemotherapy treatment still suffered from apparent cognitive impairment, particularly in the attention and executive function domains. Notably, there is evidence to suggest that the late neurotoxic effect of methotrexate on survivors’ neurocognitive performance may be dose-related. This review also recommends future pharmacokinetic, neuroimaging and genetic studies to illuminate the multifactorial nature of this subject matter and discusses the potential value of neurochemical, physiological, inflammatory and genetic markers for the prediction of susceptibility to neurocognitive impairment in long-term survivors of childhood ALL.     

Quantitative EEG in long-term survivors of acute lymphoblastic leukemia

Conventional and quantitative aspects of electroencephalographic recordings obtained during a follow-up surveillance study in long-term survivors of acute lymphoblastic leukemia in childhood were investigated with respect to differences in central nervous system prophylaxis given during antileukemic therapy and compared with data derived from healthy controls. Central nervous system prophylaxis consisted either of cranial irradiation (18 Gray, group A, N = 8) or intermediate high-dose methotrexate (2000 mg/m²; group B, N = 5), each combined with intrathecal methotrexate. Conventional electroencephalographic analysis revealed comparable results in all three study groups. However, quantitative electroencephalography showed significantly increased absolute power scores for all frequency bands in both long-term survivor groups. Relative power estimates revealed a significant increase increase in δ/gt activities in both prophylaxis groups compared to healthy controls, which were countered by decreased percentage power scores in the -range. Quantitative electroencephalographic comparisons between both central nervous system prophylaxis groups revealed only small differences in quantity, not quality, of the observed power disturbances with slightly higher deviations in irradiated long-term survivors than in nonirradiated ones. Topographical distributions of spectral band power were comparable between all three study groups without evidence for therapy-related topographical differences.     

Executive function late effects in survivors of pediatric brain tumors and acute lymphoblastic leukemia

Background: Survivors of pediatric brain tumors (BT) and acute lymphoblastic leukemia (ALL) are at risk for neurocognitive late effects related to executive function. Procedure: Survivors of BT (48) and ALL (50) completed neurocognitive assessment. Executive function was compared to estimated IQ and population norms by diagnostic group. Results: Both BT and ALL demonstrated relative executive function weaknesses. As a group, BT survivors demonstrated weaker executive functioning than expected for age. Those BT survivors with deficits exhibited a profile suggestive of global executive dysfunction, while affected ALL survivors tended to demonstrate specific rapid naming deficits. Conclusion: Findings suggest that pediatric BT and ALL survivors may exhibit different profiles of executive function late effects, which may necessitate distinct intervention plans.     

Abnormal cerebral glucose metabolism in long-term survivors of childhood acute lymphocytic leukemia

Chemotherapy and radiation treatment of the central nervous system may cause delayed neurotoxicity in children with acute lymphocytic leukemia. We evaluated 12 long-term survivors of childhood leukemia using [18F]fluorodeoxyglucose positron emission tomography, computed tomography scans, clinical neurological examinations, and neuropsychological tests. Regional cerebral metabolic rate for glucose (rCMRGlc) values for white matter were lower in the older long-term survivors (greater than 18 years old) treated with cranial radiation and intrathecal chemotherapy than in normal control subjects or survivors who had been treated with intrathecal chemotherapy alone. The ratio of white matter: cortex rCMRGlc values was lower than control values in the long-term survivors treated with cranial radiation and intrathecal chemotherapy, regardless of age, but not in those treated with intrathecal chemotherapy alone. By contrast, thalamic rCMRGlc values were lower than control values in older survivors regardless of treatment, and the ratio for thalamus:cortex rCMRGlc values was lower in all the treatment groups than in the control subjects. The highest rCMRGlc values were found in the youngest children, indicating an important effect of age on cerebral glucose metabolism. No neuropsychological deficits were identified in patients treated only with intrathecal chemotherapy; however, lower IQ scores were found in the long-term survivors who had been treated with cranial radiation and intrathecal chemotherapy. Treatment of the central nervous system with cranial radiation and intrathecal chemotherapy may cause prolonged alterations in white-matter and thalamic rCMRGlc, which may permit the identification and assessment of neurotoxicity in long-term survivors of acute lymphocytic leukemia by [18F]fluorodeoxyglucose positron emission tomography.     

Visuomotor control in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only.

Treatment for childhood acute lymphoblastic leukemia (ALL), which includes CNS prophylaxis, is associated with central and peripheral neurotoxicity. The purpose of the present study was to analyze the effects of chemotherapy on various levels of visuomotor control in survivors of childhood ALL treated without cranial irradiation, and to identify risk factors for possible deficits. Visuomotor function was compared between children after treatment for ALL (n = 34), children after treatment for Wilms tumor, which consists of non-CNS directed chemotherapy (n = 38), and healthy controls (n = 151). Three tasks were administered: a simple visual reaction time task and two tasks measuring visuomotor control with one requiring a higher level of cognitive control than the other. Visuomotor deficits were detected only in the ALL group, with poorer performance restricted to the condition requiring the highest level of control. Significant risk factors for poorer performance were female gender and a short time since end of treatment, and a trend was found for a young age at diagnosis. A high cumulative methotrexate dose was an adverse predictive factor in girls. The results indicate that chemotherapy-induced central neurotoxicity in childhood ALL treatment is associated with higher order visuomotor control deficits. Girls appear to be particularly vulnerable.     

Unusual seizures with a benign course in a case of acute lymphoblastic leukemia of childhood

We report the unusual seizures in a patient with acute lymphoblastic leukemia. The convulsive disorder began acutely as partial somatomotor status epilepticus and with diffuse EEG slowing. The seizures then became myoclonic-atonic (drop attacks) and an EEG focus appeared on the left paramedian centro-parietal areas, activated by proprioceptive stimuli. Despite the severity of the clinical picture at onset, the seizures showed a benign course, and disappeared on carbamazepine therapy. We think that this epileptic syndrome may have been caused by diffuse iatrogenic encephalopathy, probably related to intrathecal methotrexate therapy. Dedicated to Prof. S. Auricchio for his 60th birthday.     

Thrombosis in children with acute lymphoblastic leukemia: part I. Epidemiology of thrombosis in children with acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. With the advent of aggressive multimodality therapy, ALL has become a curable disease for majority of pediatric patients. Thromboembolism (TE) is a well-recognized serious complication in association with ALL leading to significant morbidity. It can be potentially fatal in over 50% of the affected patients. Development of TE does interfere with the scheduled treatment plan for ALL and, thus, ultimate outcome from ALL. Recent evidence indicates that concomitant administration of asparaginase and steroids is likely to be associated with higher incidence of TE, especially in children with at least one prothrombotic risk factor. In addition, older children and patients with high risk ALL may be at higher risk for developing TE. However, the epidemiology and the exact pathogenesis of this entity have not yet been clearly defined. To reduce the incidence of TE and its impact on overall outcome as well as on the quality of life in children undergoing treatment for ALL, further studies to define the epidemiology of TE in relation to the biology of ALL and chemotherapy protocols are urgently needed. The purpose of this review is to evaluate the current knowledge of TE in association with ALL in children, especially in relation with the treatment protocols and genetic background. This review will be published in three parts. The first part will review the available information regarding epidemiology of TE in children with ALL.     

Value of EEG in childhood acute lymphoblastic leukemia

The EEG was recorded in 110 patients with acute lymphoblastic leukemia at the time of diagnosis, in 25 at the time of relapse and in 62 patients at discontinuation of treatment. At the time of diagnosis the EEG was abnormal in 60% of the patients. The abnormality showed no correlation with the prognosis. The EEG was correlated with the leukocytosis of the CSF and with the immunologic cell type of the leukemia. At the time of relapse the EEGs did not differ from those obtained at the time of diagnosis. No specific features distinguished the EEGs of the patients with CNS relapse. At discontinuation of treatment the EEG was abnormal in 31% of the patients. The EEG was not correlated with the method of CNS prophylaxis. Thus, it seems that the usefulness of electroencephalography in leukemic patients lies mainly in the diagnosis of neurologic complications.     

Intellectual function in muscular dystrophies

Summary Intellectual function was studied in 28 boys with Duchenne dystrophy, 12 patients with facioscapulohumeral-type and 10 patients with limb-girdle-type muscular dystrophy. A definite relationship between intelligence level and the type of muscle disease was found. The more severe the genetic damage manifested by the rapidity of progression of muscular dystrophy the more definite the affection of the CNS manifesting as mental deficit. The factors influencing the level and structure of intelligence seem to exert their effect before the manifestation of muscle lesions.     

Thrombosis in children with acute lymphoblastic leukemia Part III. Pathogenesis of thrombosis in children with acute lymphoblastic leukemia: effects of host environment

This concluding section of the series will evaluate the role of host environment in the development of thromboembolism (TE) in children with acute lymphoblastic leukemia (ALL). The available evidence suggests that TE in association with childhood ALL is a multifactorial entity resulting from the interaction of the disease, chemotherapy and its effects, and possible prothrombotic states inherent to the host. The few studies conducted so far in children with ALL have reported wide variability in the prevalence of prothrombotic defects and its impact on the risk of TE. The prevalence of prothrombotic defects varies in different ethnic population. Since different ALL therapy studies use different chemotherapeutic agents in various dosage and combination, it is important that every major study group assesses the risk of TE, including the prevalence of prothrombotic defects, within their therapy plan. This will help to identify the population at risk for TE and for thromboprophylaxis, if indicated.     

White versus gray matter function as seen on neuropsychological testing following bone marrow transplant for acute leukemia in childhood

Current theory suggests that neurocognitive late effects of treatments for childhood cancer such as difficulties with attention, processing speed and visual-motor ability are the result of white matter damage. Neuroimaging studies have produced a variety of white matter findings. However, although white matter is thought to be differentially affected, previous studies have not demonstrated a discrepancy between white and gray matter function. The present study included 36 children treated for childhood leukemia with hematopoietic stem cell transplant (HCT). Their performance on neurocognitive measures traditionally thought to measure white matter was compared to performance on measures thought to measure gray matter function. Composite white and gray matter standard scores were created based on neuropsychological measures that individuals with known white or gray matter damage perform poorly. As predicted, composite white matter scores (mean = 98.1) were significantly lower (t = 2.26, p = 0.03) than composite gray matter scores (mean = 102.5). Additionally, as gray matter performance increased, the difference between gray and white matter scores increased (R = 0.353, p = 0.035). Overall, the results of this study support the current theory that white matter damage is responsible for the more subtle neurocognitive late effects resulting from treatment for childhood leukemia.     

Physical function and fitness in long-term survivors of childhood leukaemia

Objective: To evaluate the physical function and fitness in survivors of childhood leukaemia 5–6 years after cessation of chemotherapy.

Materials and methods: Thirteen children (six boys and seven girls; mean age 15.5 years) who were treated for leukaemia were studied 5–6 years after cessation of therapy. Physical function and fitness were determined by anthropometry, motor performance, muscle strength, anaerobic and aerobic exercise capacity.

Results: On motor performance, seven of the 13 patients showed significant problems in the hand-eye co-ordination domain. Muscle strength only showed a significantly lower value in the mean strength of the knee extensors. The aerobic and the anaerobic capacity were both significantly reduced compared to reference values.

Conclusion: Even 5–6 years after cessation of childhood leukaemia treatment, there are still clear late effects on motor performance and physical fitness. Chemotherapy-induced neuropathy and muscle atrophies are probably the prominent cause for these reduced test results. Physical training might be indicated for patients surviving leukaemia to improve fitness levels and muscle strength.     

Neuroleukemiosis: case report of leukemic nerve infiltration in acute lymphoblastic leukemia

We describe a patient in remission from acute lymphoblastic leukemia who developed a painless common peroneal neuropathy. Magnetic resonance imaging (MRI) revealed nerve thickening and enhancement, while a positron emission tomography (PET) scan demonstrated increased fluorodeoxyglucose uptake in a large segment of the neurovascular bundle, suggesting peripheral nerve infiltration. Both findings resolved following treatment with chemotherapy that crossed the blood-nerve barrier. In selected patients presenting with peripheral neuropathy, MRI and PET scan can be helpful in the diagnosis of peripheral nerve infiltration.     

成人 Ph 染色体／BCR-ABL 融合基因阳性 ALL 临床分析

目的：总结Ph染色体／BCR‐ABL融合基因阳性急性淋巴细胞白血病（ALL）患者的临床特点。方法选取我院2009—2014年收治的37例Ph＋ ALL患者,均接受标准VDCP ±伊马替尼（IM ）诱导治疗,有合适供者的患者在第1次完全缓解（CR1）期行异基因造血干细胞移植（allo‐HSCT）。无合适供者的患者继续强化巩固治疗,获得分子生物学缓解（MCR）者可选择接受自体造血干细胞移植（ASCT）;其他患者继续完成再诱导、巩固、维持治疗。分析患者的无病生存（DFS）、总生存（OS）情况和复发率（RR）。结果34例（91.2％）患者获得CR ,其中1个疗程CR率为83.8％。随访至2014‐01‐10,共27例规范治疗的患者,中位随访时间28.8个月,DFS期和OS期分别为（21.5±3.4）、（28.8±3.6）个月。化疗组9例均复发;ASCT组4例中1例移植前后未使用IM者在移植后1 a内均复发,另3例应用IM 者持续MCR已达移植后13、17和27个月;allo‐HSCT组14例中2例死于移植并发症,3例死于复发,患者未达到中位生存时间,3 a OS率（57.1±13.7）％,3 a DFS率（35.7±13.3）％。结论在Ph＋ALL的治疗中,allo‐HSCT是年轻患者首选治疗手段,IM联合化疗可使患者及早获得并维持CR ,减少复发,为患者接受allo‐HSCT提供更多机会。对于无条件移植的患者,IM联合化疗能够获得较高CR ,但易复发,治疗仍值得进一步探讨。