Background

To extend investigation beyond global cognitive measures prevalent in the literature, this study examined attention and working memory (WM) abilities of survivors of childhood acute lymphoblastic leukemia (ALL), the separate contributions of attention and WM to IQ and their association with neuroimaging changes.

Methods

Ninety seven children with ALL received risk-directed therapy based on presenting clinical and biological factors. During consolidation therapy, low-risk patients received half the dose of intravenous methotrexate that standard-/high-risk patients received, and fewer doses of triple intrathecal therapy. Patients were classified according to end of consolidation MRIs (normal or leukoencephalopathy) and continuous measures of white matter structure were computed. As part of the protocol study, children completed cognitive assessment two years later (completion of therapy), utilizing Digit Span Forward (DSF) for attention and Digit Span Backward (DSB) for WM.

Results

For the total sample and standard/high risk group, Total Digit Span (TDS), DSF, and DSB were impaired relative to norms (p < .05). In the low risk group, only DSB was impaired (p <.0001). Across groups, a higher percentage of patients performed below the average range (scale score < 7) on DSB (66%) than DSF (14%) or TDS (18%). Regression analysis indicated that DSB predicted Estimated IQ (p <.05), after accounting for DSF. Leukoencephalopathy was predictive of lower TDS (p <.05).

Conclusions

WM appears especially sensitive to treatment-related changes in ALL survivors, detecting difficulties potentially missed by global intelligence measures. These findings ma y facilitate identification of vulnerable neural pathways and development of targeted cognitive interventions.

Posterior fossa syndrome is characterized by cerebellar dysfunction, oromotor/oculomotor apraxia, emotional lability and mutism in patients after infratentorial injury. The underlying neuroanatomical substrates of posterior fossa syndrome are unknown, but dentatothalamocortical tracts have been implicated. We used pre- and postoperative neuroimaging to investigate proximal dentatothalamocortical tract involvement in childhood embryonal brain tumour patients who developed posterior fossa syndrome following tumour resection. Diagnostic imaging from a cohort of 26 paediatric patients previously operated on for an embryonal brain tumour (13 patients prospectively diagnosed with posterior fossa syndrome, and 13 non-affected patients) were evaluated. Preoperative magnetic resonance imaging was used to define relevant tumour features, including two potentially predictive measures. Postoperative magnetic resonance and diffusion tensor imaging were used to characterize operative injury and tract-based differences in anisotropy of water diffusion. In patients who developed posterior fossa syndrome, initial tumour resided higher in the 4th ventricle (P = 0.035). Postoperative magnetic resonance signal abnormalities within the superior cerebellar peduncles and midbrain were observed more often in patients with posterior fossa syndrome (P = 0.030 and 0.003, respectively). The fractional anisotropy of water was lower in the bilateral superior cerebellar peduncles, in the bilateral fornices, white matter region proximate to the right angular gyrus (Tailerach coordinates 35, –71, 19) and white matter region proximate to the left superior frontal gyrus (Tailerach coordinates –24, 57, 20). Our findings suggest that multiple bilateral injuries to the proximal dentatothalamocortical pathways may predispose the development of posterior fossa syndrome, that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical underlying pathophysiological component of posterior fossa syndrome, and that decreased fractional anisotropy in the fornices and cerebral cortex may be related to the abnormal neurobehavioural symptoms of posterior fossa syndrome.

Background and Purpose

White matter (WM) hyperintensities on T2-weighted MRI are the most common imaging manifestation of neurotoxic effects of therapy for central nervous system prophylaxis in childhood acute lymphoblastic leukemia (ALL). This project uses voxel-based analyses of T2-weighted imaging of patients during treatment to identify which WM regions are preferentially damaged.

Material and Methods

Two sets of conventional T2-weighted axial images were acquired on a 1.5T MRI from 197 consecutive patients (85 female / 112 male; aged 1.0-18.9 years) enrolled on an institutional ALL treatment protocol. Images were acquired after completion of induction therapy and after the final of the four courses of intravenous high-dose methotrexate in consolidation therapy (3.9±0.8 months apart). Voxel-wise statistical testing of the incremental change between normalized longitudinal T2 images was performed with radiologist reading (normal or abnormal) and treatment risk-arm as covariates.

Results

Two highly significant bilateral clusters of T2 signal intensity change were identified in both one-group and two-group analyses. The regions were symmetrical in size, shape, and average signal intensity. Increased T2-weighted signal intensity from these regions both within and between examinations were nonlinear functions of age at examination and the difference between the examinations was greater for older subjects which received more intense therapy.

Conclusion

These analyses identified specific WM tracts involving predominantly the anterior, superior, and posterior corona radiata and superior longitudinal fasciculus, which were at increased risk of developing T2-weighted hyperintensities during therapy for childhood ALL. These vulnerable regions may be the etiology of subsequent cognitive difficulties consistently observed in survivors.

Background

The combination of a platinating agent and etoposide has induced responses in various pediatric tumors. This study estimates the maximum tolerated dose (MTD) of an oxaliplatin and etoposide regimen in children with recurrent solid tumors.

Methods

Oxaliplatin was administered on day 1 and etoposide on days 1-3 of each 21-day course. Cohorts of 3-6 patients were enrolled at 3 dose levels: 1) oxaliplatin 130 mg/m2 and etoposide 75 mg/m2; 2) oxaliplatin 130 mg/m2 and etoposide 100 mg/m2; and 3) oxaliplatin 145 mg/m2 and etoposide 100 mg/m2. Calcium and magnesium infusions were used at dose level 3 in an attempt to escalate the oxaliplatin dose past the single-agent MTD.

Results

The 16 patients received a total of 63 courses. At dose level 1, dose-limiting epistaxis, neuropathy, and neutropenia occurred in 1 of 6 patients. No dose-limiting toxicity (DLT) occurred at level 2 (n=6). At dose level 3, 2 of 4 patients experienced dose-limiting neutropenia; none experienced grade 3/4 acute neuropathy. Six patients required prolongation of the oxaliplatin infusion because of acute sensory neuropathy. Responses were observed in patients with medulloblastoma (1 CR) and pineoblastoma (1 PR); 3 others with atypical teratoid rhabdoid tumor, ependymoma, and soft tissue sarcoma had prolonged disease stabilization.

Conclusions

The MTD of this regimen is oxaliplatin 130 mg/m2 given on day 1 and etoposide 100 mg/m2 /day given on days 1-3. Neutropenia is the DLT. Calcium and magnesium infusions did not allow escalation of the oxaliplatin dose. The combination was well-tolerated and showed_antitumor activity.

Systemic and intrathecal methotrexate (MTX) are integral components of acute lymphoblastic leukemia (ALL) therapy, but can be associated with neurotoxicity. We describe here the case of an adolescent male with T-cell ALL who developed recurrent episodes of subacute neurotoxicity characterized by slurred speech, emotional lability, and hemiparesis after intrathecal MTX administration. Serial magnetic resonance imaging with diffusion-weighted imaging showed recurrent areas of restricted diffusion within cerebral hemispheric white matter, which correlated chronologically with the administration of intrathecal therapy and severity of clinical symptoms. Resolution of diffusion abnormalities did not preclude further toxicity and a large lesion could cause persisting symptoms.

STATEMENT OF TRANSLATIONAL RELEVANCE

Although chemotherapy has been used in most clinical trials for children with high-grade glioma, no drug regimen has so far stood out as particularly beneficial for these patients.

Based on pre-clinical and clinical experience in adults with similar tumors, we report for the first time the results of a Phase I study which used erlotinib during and after radiotherapy in children with high-grade glioma. We characterized the acute and chronic toxicities associated with erlotinib therapy. Within the context of a Phase I study, we also performed extensive pharmacokinetic and molecular studies.

We observed preliminary encouraging outcome in a subgroup of our patients, particularly those with anaplastic astrocytoma. Therefore, the current study established a platform for future clinical trials to incorporate erlotinib in the treatment of high-grade glioma in children.

Purpose

To estimate the maximum-tolerated dose (MTD) of erlotinib administered during and after radiotherapy (RT), and to describe the pharmacokinetics of erlotinib and its metabolite OSI-420 in patients between 3 and 25 years with newly diagnosed high-grade glioma who did not require enzyme-inducing anticonvulsants.

Experimental Design

Five dosage levels (70, 90, 120, 160, and 200mg/m2 per day) were planned in this Phase I study. Dose-limiting toxicities (DLTs) were evaluated during first 8 weeks of therapy. Local RT (dose between 54 and 59.4 Gy) and erlotinib started preferentially on the same day. Erlotinib was administered once daily for a maximum of 3 years. Pharmacokinetic studies were obtained after first dose and on day 8 of therapy. Mutational analysis of EGFR kinase domain, PIK3CA, and PTEN was performed in tumor tissue.

Results

Median age at diagnosis of 23 patients was 10.7 years (range, 3.7 to 22.5 years). MTD of erlotinib was 120mg/m2 per day. Skin rash and diarrhea were generally well controlled with supportive care. DLTs were diarrhea (n=1), increase in serum lipase (n=1), and rash with pruritus (n=1). The pharmacokinetic parameters of erlotinib and OSI-420 in children were similar to those described in adults. However, there was no relationship between erlotinib dosage and drug exposure. No EGFR kinase domain mutations were observed. Two patients with glioblastoma harbored mutations in PIK3CA (n=1) or PTEN (n=1).

Conclusions

Although the MTD of erlotinib in children with newly diagnosed high-grade glioma was 120mg/m2 per day, pharmacokinetic studies demonstrated wide inter-patient variability in drug exposure.

Voxel-based morphometry was used to compare brain structure morphology of survivors of posterior fossa brain tumor (PFBT) with that of normal sibling controls to investigate disease- or cancer treatment–induced changes. Two different spatial normalization approaches that are available in public domain software (free-form deformation (FFD) and discrete cosine transform (DCT)) were compared for accuracy of normalization in the PFBT patients. Anatomical landmark matching demonstrated that spatial normalization was more accurate with FFD than with DCT. Voxel-based morphometry of the FFD-normalized magnetic resonance images from PFBT survivors and sibling controls detected reduced gray matter density in the thalamus and entorhinal cortex and reduced white matter density in the internal capsule, hypothalamus, corpus callosum, and cuneus of the occipital lobe in the PFBT survivors. Identification of these morphologic lesions may help localize the neural substrates of disease- or therapy-induced cognitive deficits in survivors of childhood cancer.

The purpose of this study was to use objective quantitative magnetic resonance imaging (MRI) methods to develop a computer-aided detection (CAD) tool to differentiate white matter (WM) hyperintensities into either leukoencephalopathy (LE) induced by chemotherapy or normal maturational processes in children treated for acute lymphoblastic leukemia without irradiation. A combined MRI set consisting of T1-weighted, T2-weighted, proton-density-weighted and fluid-attenuated inversion recovery images and WM, gray matter and cerebrospinal fluid proportional volume maps from a spatially normalized atlas were analyzed with a neural network segmentation based on a Kohonen self-organizing map (SOM). Segmented maps were manually classified to identify the most hyperintense WM region and the normal-appearing genu region. Signal intensity differences normalized to the genu within each examination were generated for four time points in 228 children. A second Kohonen SOM was trained on the first examination data and divided the WM into normal-appearing or LE groups. Reviewing labels from the CAD tool revealed a consistency measure of 89.8% (167 of 186) within patients. The overall agreement between the CAD tool and the consensus reading of two trained observers was 84.1% (535 of 636), with 84.2% (170 of 202) agreement in the training set and 84.1% (365 of 434) agreement in the testing set. These results suggest that subtle therapy-induced LE can be objectively and reproducibly detected in children treated for cancer using this CAD approach based on relative differences in quantitative signal intensity measures normalized within each examination.

Introduction

During the past three decades, improvements in the treatment of childhood leukemia have resulted in high cure rates, particularly for acute lymphoblastic leukemia (ALL). Unfortunately, successful therapy has come with a price, as significant morbidity can result from neurological affects which harm the brain and spinal cord. The expectation and hope is that chemotherapy, as a primary means of CNS therapy, will result in acceptable disease control with less CNS morbidity than has been observed with combinations of chemotherapy and radiotherapy over the past several decades.

Methods and results

In this review we discuss the poignant, historical aspects of CNS leukemia therapy, outline current methods of systemic and CNS leukemia therapy, and present imaging findings we have encountered in childhood leukemia patients with a variety of acute neurological conditions. A major objective of our research is to understand the neuroimaging correlates of acute and chronic effects of cancer and therapy. Specific features related to CNS leukemia and associated short-term toxicities, both disease- and therapy-related, are emphasized in this review with the specific neuroimaging findings. Specific CNS findings are similarly important when treating acute myelogenous leukemia (AML), and details of leukemic involvement and toxicities are also presented in this entity.

Conclusion

Despite contemporary treatment approaches which favor the use of chemotherapy (including intrathecal therapy) over radiotherapy in the treatment of CNS leukemia, children still occasionally experience morbid neurotoxicity. Standard neuroimaging is sufficient to identify a variety of neurotoxic sequelae in children, and often suggest specific etiologies. Specific neuroimaging findings frequently indicate a need to alter antileukemia therapy. It is important to appreciate that intrathecal and high doses of systemic chemotherapy are not innocuous and are associated with acute, specific, recognizable, and often serious neurological consequences.

Introduction

Medical advances over the last several decades, including CNS prophylaxis, have greatly increased survival in children with leukemia. As survival rates have increased, clinicians and scientists have been afforded the opportunity to further develop treatments to improve the quality of life of survivors by minimizing the long-term adverse effects. When evaluating the effect of antileukemia therapy on the developing brain, magnetic resonance (MR) imaging has been the preferred modality because it quantifies morphologic changes objectively and noninvasively.

Method and results

Computer-aided detection of changes on neuroimages enables us to objectively differentiate leukoencephalopathy from normal maturation of the developing brain. Quantitative tissue segmentation algorithms and relaxometry measures have been used to determine the prevalence, extent, and intensity of white matter changes that occur during therapy. More recently, diffusion tensor imaging has been used to quantify microstructural changes in the integrity of the white matter fiber tracts. MR perfusion imaging can be used to noninvasively monitor vascular changes during therapy. Changes in quantitative MR measures have been associated, to some degree, with changes in neurocognitive function during and after treatment

Conclusion

In this review, we present recent advances in quantitative evaluation of MR imaging and discuss how these methods hold the promise to further elucidate the pathophysiologic effects of treatment for childhood leukemia.