Pretreatment Normal WM Magnetization Transfer Ratio Predicts Risk of Radiation Necrosis in Patients with Medulloblastoma.

BACKGROUND AND PURPOSE: Radiation necrosis, for which abnormal WM enhancement is a hallmark, is an uncommon complication of craniospinal irradiation in children with medulloblastoma. The magnetization transfer ratio measures macromolecular content, dominated by myelin in the WM. We investigated whether the pretreatment supratentorial (nonsurgical) WM magnetization transfer ratio could predict patients at risk for radiation necrosis after radiation therapy for medulloblastoma. MATERIALS AND METHODS: Ninety-five eligible patients with medulloblastoma (41% female; mean age, 11.0 [SD, 5.4] years) had baseline balanced steady-state free precession MR imaging before proton or photon radiation therapy. Associations among baseline supratentorial magnetization transfer ratio, radiation necrosis (spontaneously resolving/improving parenchymal enhancement within the radiation field)3, age, and the presence of visible brain metastases were explored by logistic regression and parametric/nonparametric techniques as appropriate. RESULTS: Twenty-three of 95 (24.2%) children (44% female; mean age, 10.7 [SD, 6.7] years) developed radiation necrosis after radiation therapy (19 infratentorial, 1 supratentorial, 3 both). The mean pretreatment supratentorial WM magnetization transfer ratio was significantly lower in these children (43.18 versus 43.50, P = .03). There was no association between the supratentorial WM magnetization transfer ratio and age, sex, risk/treatment stratum, or the presence of visible brain metastases. CONCLUSIONS: A lower baseline supratentorial WM magnetization transfer ratio may indicate underlying structural WM susceptibility to radiation necrosis and may identify children at risk for developing radiation necrosis after craniospinal irradiation for medulloblastoma.

Anatomic Neuroimaging Characteristics of Posterior Fossa Type A Ependymoma Subgroups.

BACKGROUND AND PURPOSE: Posterior fossa type A (PFA) ependymomas have 2 molecular subgroups (PFA-1 and PFA-2) and 9 subtypes. Gene expression profiling suggests that PFA-1 and PFA-2 tumors have distinct developmental origins at different rostrocaudal levels of the brainstem. We, therefore, tested the hypothesis that PFA-1 and PFA-2 ependymomas have different anatomic MR imaging characteristics at presentation. MATERIALS AND METHODS: Two neuroradiologists reviewed the preoperative MR imaging examinations of 122 patients with PFA ependymomas and identified several anatomic characteristics, including extension through the fourth ventricular foramina and encasement of major arteries and tumor type (midfloor, roof, or lateral). Deoxyribonucleic acid methylation profiling assigned ependymomas to PFA-1 or PFA-2. Information on PFA subtype from an earlier study was also available for a subset of tumors. Associations between imaging variables and subgroup or subtype were evaluated. RESULTS: No anatomic imaging variable was significantly associated with the PFA subgroup, but 5 PFA-2c subtype ependymomas in the cohort had a more circumscribed appearance and showed less tendency to extend through the fourth ventricular foramina or encase blood vessels, compared with other PFA subtypes. CONCLUSIONS: PFA-1 and PFA-2 ependymomas did not have different anatomic MR imaging characteristics, and these results do not support the hypothesis that they have distinct anatomic origins. PFA-2c ependymomas appear to have a more anatomically circumscribed MR imaging appearance than the other PFA subtypes; however, this needs to be confirmed in a larger study.

Longitudinal associations between exposure to anesthesia and neurocognitive functioning in pediatric medulloblastoma.

AIM: To examine whether anesthesia exposure is associated with neurocognitive decline in pediatric medulloblastoma. METHODS: Patients were treated at St. Jude Children's Research Hospital and completed ≥2 protocol-directed neurocognitive assessments (n = 107) as part of a multisite clinical trial for pediatric medulloblastoma (NCT00085202). Patients received risk-adapted craniospinal photon irradiation, followed by four cycles of high-dose chemotherapy and stem cell rescue. Neurocognitive testing was completed at study baseline (after surgery and <2 weeks of starting radiation therapy) and annually for 5 years. Data on anesthesia exposure during treatment was abstracted from medical records. RESULTS: Patients were 10.2 years at diagnosis on average (SD = 4.5; 37% female, 73% average-risk). Mean cumulative anesthesia duration was 20.4 h (SD = 15.2; range 0.7-55.6 h). In the overall group, longer anesthesia duration was associated with greater declines in IQ (Estimate = -0.08, P < 0.001), attention (Estimate = -0.10, P < .001) and processing speed (Estimate = -0.13, P < 0.001). Similar results were shown in subgroups of patients who were <7 years at diagnosis (IQ = -0.14, P = 0.027; Attention = -0.25: P = 0.011), ≥7 years at diagnosis (Attention = -0.07, P = 0.039; Processing Speed = -0.08, P = 0.022), treated for high-risk disease (IQ = -0.09, P = 0.024; Attention = -0.11, P = 0.034; Processing Speed = -0.13, P = 0.001), or treated for average-risk disease (IQ = -0.05, P = .022; Attention = -0.08, P = 0.011; Processing Speed = -0.10, P < 0.001). CONCLUSION: Greater anesthesia exposure is a risk factor for clinically significant neurocognitive decline, in addition to factors of age at diagnosis and treatment risk arm. This result is notable as there are evidence-based strategies that can limit the need for anesthesia. Limiting anesthesia exposure, as feasible, may mitigate neurocognitive late effects, and thus, improve quality of life for survivors.

Neuroimaging Findings in Children with Constitutional Mismatch Repair Deficiency Syndrome.

BACKGROUND AND PURPOSE: Constitutional mismatch repair deficiency is a hereditary childhood cancer predisposition syndrome characterized by brain tumors and colorectal and hematologic malignancies. Our objective was to describe the neuroimaging findings in patients with constitutional mismatch repair deficiency. MATERIALS AND METHODS: This retrospective study included 14 children with genetically confirmed constitutional mismatch repair deficiency who were referred to 2 tertiary pediatric oncology centers. RESULTS: Fourteen patients from 11 different families had diagnosed constitutional mismatch repair deficiency. The mean age at presentation was 9.3 years (range, 5-14 years). The most common clinical presentation was brain malignancy, diagnosed in 13 of the 14 patients. The most common brain tumors were glioblastoma (n = 7 patients), anaplastic astrocytoma (n = 3 patients), and diffuse astrocytoma (n = 3 patients). Nonspecific subcortical white matter T2 hyperintensities were noted in 10 patients (71%). Subcortical hyperintensities transformed into overt brain tumors on follow-up imaging in 3 patients. Additional non-neoplastic brain MR imaging findings included developmental venous anomalies in 12 patients (85%) and nontherapy-induced cavernous hemangiomas in 3 patients (21%). CONCLUSIONS: On brain MR imaging, these patients have both highly characteristic intra-axial tumors (typically multifocal high-grade gliomas) and nonspecific findings, some of which might represent early stages of neoplastic transformation. The incidence of developmental venous anomalies is high in these patients for unclear reasons. Awareness of these imaging findings, especially in combination, is important to raise the suspicion of constitutional mismatch repair deficiency in routine diagnostic imaging evaluation or surveillance imaging studies of asymptomatic carriers because early identification of the phenotypic "gestalt" might improve outcomes.

MRI Patterns of Extrapontine Lesion Extension in Diffuse Intrinsic Pontine Gliomas.

BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a devastating childhood cancer that despite being primarily diagnosed by MR imaging alone, lacks robust prognostic imaging features. This study investigated patterns and quantification of extrapontine lesion extensions as potential prognostic imaging biomarkers for survival in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: Volumetric analysis of baseline MR imaging studies was completed in 131 patients with radiographically defined typical diffuse intrinsic pontine gliomas. Extrapontine tumor extension was classified according to the direction of extension: midbrain, medulla oblongata, and right and left middle cerebellar peduncles; various extrapontine lesion extension patterns were evaluated. The Kaplan-Meier method was used to estimate survival differences; linear regression was used to evaluate clinical-radiographic variables prognostic of survival. RESULTS: At least 1 extrapontine lesion extension was observed in 125 patients (95.4%). Of the 11 different extrapontine lesion extension patterns encountered in our cohort, 2 were statistically significant predictors of survival. Any extension into the middle cerebellar peduncles was prognostic of shorter overall survival (P = .01), but extension into both the midbrain and medulla oblongata but without extension into either middle cerebellar peduncle was prognostic of longer overall survival compared with those having no extension (P = .04) or those having any other pattern of extension (P < .001). CONCLUSIONS: Within this large cohort of patients with typical diffuse intrinsic pontine gliomas, 2 specific extrapontine lesion extension patterns were associated with a significant overall survival advantage or disadvantage. Our findings may be valuable for risk stratification and radiation therapy planning in future clinical trials.

Novel MYC-driven medulloblastoma models from multiple embryonic cerebellar cells.

Group3 medulloblastoma (MBG3) that predominantly occur in young children are usually associated with MYC amplification and/or overexpression, frequent metastasis and a dismal prognosis. Physiologically relevant MBG3 models are currently lacking, making inferences related to their cellular origin thus far limited. Using in utero electroporation, we here report that MBG3 mouse models can be developed in situ from different multipotent embryonic cerebellar progenitor cells via conditional expression of Myc and loss of Trp53 function in several Cre driver mouse lines. The Blbp-Cre driver that targets embryonic neural progenitors induced tumors exhibiting a large-cell/anaplastic histopathology adjacent to the fourth ventricle, recapitulating human MBG3. Enforced co-expression of luciferase together with Myc and a dominant-negative form of Trp53 revealed that GABAergic neuronal progenitors as well as cerebellar granule cells give rise to MBG3 with their distinct growth kinetics. Cross-species gene expression analysis revealed that these novel MBG3 models shared molecular characteristics with human MBG3, irrespective of their cellular origin. We here developed MBG3 mouse models in their physiological environment and we show that oncogenic insults drive this MB subgroup in different cerebellar lineages rather than in a specific cell of origin.

Translational Pharmacokinetic-Pharmacodynamic Modeling and Simulation: Optimizing 5-Fluorouracil Dosing in Children With Pediatric Ependymoma.

We previously investigated novel therapies for pediatric ependymoma and found 5-fluorouracil (5-FU) i.v. bolus increased survival in a representative mouse model. However, without a quantitative framework to derive clinical dosing recommendations, we devised a translational pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation approach. Results from our preclinical PK-PD model suggested tumor concentrations exceeded the 1-hour target exposure (in vitro IC90), leading to tumor growth delay and increased survival. Using an adult population PK model, we scaled our preclinical PK-PD model to children. To select a 5-FU dosage for our clinical trial in children with ependymoma, we simulated various 5-FU dosages for tumor exposures and tumor growth inhibition, as well as considering tolerability to bolus 5-FU administration. We developed a pediatric population PK model of bolus 5-FU and simulated tumor exposures for our patients. Simulations for tumor concentrations indicated that all patients would be above the 1-hour target exposure for antitumor effect.

Elevated cerebral blood volume contributes to increased FLAIR signal in the cerebral sulci of propofol-sedated children.

BACKGROUND AND PURPOSE: Hyperintense FLAIR signal in the cerebral sulci of anesthetized children is attributed to supplemental oxygen (fraction of inspired oxygen) but resembles FLAIR hypersignal associated with perfusion abnormalities in Moyamoya disease and carotid stenosis. We investigated whether cerebral perfusion, known to be altered by anesthesia, contributes to diffuse signal intensity in sulci in children and explored the relative contributions of supplemental oxygen, cerebral perfusion, and anesthesia to signal intensity in sulci. MATERIALS AND METHODS: Supraventricular signal intensity in sulci on pre- and postcontrast T2 FLAIR images of 24 propofol-sedated children (6.20 ± 3.28 years) breathing supplemental oxygen and 18 nonsedated children (14.28 ± 2.08 years) breathing room air was graded from 0 to 3. The Spearman correlation of signal intensity in sulci with the fraction of inspired oxygen and age in 42 subjects, and with dynamic susceptibility contrast measures of cortical CBF, CBV, and MTT available in 25 subjects, were evaluated overall and compared between subgroups. Factors most influential on signal intensity in sulci were identified by stepwise logistic regression. RESULTS: CBV was more influential on noncontrast FLAIR signal intensity in sulci than the fraction of inspired oxygen or age in propofol-sedated children (CBV: r = 0.612, P = .026; fraction of inspired oxygen: r = -0.418, P = .042; age: r = 0.523, P = .009) and overall (CBV: r = 0.671, P = .0002; fraction of inspired oxygen: r = 0.442, P = .003; age: r = -0.374, P = .015). MTT (CBV/CBF) was influential in the overall cohort (r = 0.461, P = .020). Signal intensity in sulci increased with contrast in 45% of subjects, decreased in none, and was greater (P < .0001) in younger propofol-sedated subjects, in whom the signal intensity in sulci increased with age postcontrast (r = .600, P = .002). CONCLUSIONS: Elevated cortical CBV appears to contribute to increased signal intensity in sulci on noncontrast FLAIR in propofol-sedated children. The effects of propofol on age-related cerebral perfusion and vascular permeability may play a role.

Clinical, radiological, histological and molecular characteristics of paediatric epithelioid glioblastoma.

AIMS: A few case series in adults have described the characteristics of epithelioid glioblastoma (e-GB), one of the rarest variants of this cancer. We evaluated clinical, radiological, histological and molecular characteristics in the largest series to date of paediatric e-GB. METHODS: Review of clinical characteristics and therapy, imaging studies and histology was performed in patients younger than 22 years with e-GB seen at our institution over 15 years. Sequencing of hotspot mutations and fluorescence in situ hybridization of relevant genes were undertaken. RESULTS: Median age at diagnosis of six patients was 7.6 years. Tumours originated in the cerebral cortex (n = 2) or diencephalon (n = 4). Three patients presented with acute, massive haemorrhage and three had leptomeningeal dissemination at diagnosis. Paediatric e-GB had the typical histological characteristics seen in adult tumours. Universal immunoreactivity for INI1 and lack of diverse protein expression were seen in all cases. One tumour had a chromosome 22q loss. Three tumours (50%) harboured a BRAF: p.V600E. One thalamic tumour had an H3F3A p.K27M. All patients received radiation therapy with (n = 3) or without chemotherapy (n = 3). All patients experienced tumour progression with a median survival of 169 days. One patient with nonmetastatic disease had early leptomeningeal progression. Two patients had symptomatic tumour spread outside the central nervous system (CNS) through a ventriculoperitoneal shunt. One additional patient had widespread metastases outside the CNS identified at autopsy. CONCLUSIONS: Paediatric e-GBs are rare cancers with an aggressive behaviour that share histological and genetic characteristics with their adult counterparts. BRAF inhibition is a potential treatment for these tumours.

The role of inherited TPMT and COMT genetic variation in cisplatin-induced ototoxicity in children with cancer.

Ototoxicity is a debilitating side effect of platinating agents with substantial interpatient variability. We sought to evaluate the association of thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) genetic variations with cisplatin-related hearing damage in the context of frontline pediatric cancer treatment protocols. In 213 children from the St. Jude Medulloblastoma-96 and -03 protocols, hearing loss was related to younger age (P = 0.013) and craniospinal irradiation (P = 0.001), but did not differ by TPMT or COMT variants. Results were similar in an independent cohort of 41 children from solid-tumor frontline protocols. Functional hearing loss or hair cell damage was not different in TPMT knockout vs. wild-type mice following cisplatin treatment, and neither TPMT nor COMT variant was associated with cisplatin cytotoxicity in lymphoblastoid cell lines. In conclusion, our results indicated that TPMT or COMT genetic variation was not related to cisplatin ototoxicity in children with cancer and did not influence cisplatin-induced hearing damage in laboratory models.

Imaging changes in very young children with brain tumors treated with proton therapy and chemotherapy.

SUMMARY: PT promises to reduce side effects in children with brain tumors by sparing normal tissue compared with 3D conformal or intensity-modulated radiation therapy. Information is lacking about the combined effects of PT and chemotherapy in young children. We describe imaging changes in 8 very young children with localized brain tumors who received PT after chemotherapy. Mostly transient signal abnormalities and enhancement in brain parenchyma were observed by serial MR imaging, which were consistent with radiation-induced effects on normal-appearing tissue. Correlation with PT planning data revealed that the areas of imaging abnormality were located within or adjacent to the volume that received the highest radiation dose. Radiologists should be aware of these findings in children who receive PT after chemotherapy. In this report, we describe the time course of these PT-related imaging findings and correlate them with treatment and clinical outcomes.

Cerebellocerebral diaschisis is the likely mechanism of postsurgical posterior fossa syndrome in pediatric patients with midline cerebellar tumors.

BACKGROUND AND PURPOSE: PFS occurs in approximately 25% of pediatric patients receiving surgery for midline posterior fossa tumors. Increasing evidence suggests that PFS represents a complex supratentorial cortical dysfunction related to surgery-induced disruption of critical cerebellocerebral connections. The purpose of this study was to determine whether a consistent surgical damage pattern may be identified in patients with PFS by early postoperative anatomic imaging analysis of the pECP and to test whether DSC can detect corresponding changes in cerebral cortical perfusion to indicate a secondary, remote functional disturbance, which could suggest a diaschisis-like pathomechanism. MATERIALS AND METHODS: Eleven patients with postoperative PFS were evaluated retrospectively and were paired with age- and sex-matched control subjects in whom PFS did not develop. MR imaging work-up included DSC within 3 to 4 weeks after surgery as well as early postoperative anatomic imaging to evaluate components of the pECP. RESULTS: DSC showed significant decreases in CBF within frontal regions (P < .05) and a trend to global cerebral cortical hypoperfusion in patients with PFS. Logistic regression analysis suggested a strong (potentially predictive) relationship between bilateral damage to pECP and the development of PFS (P = .04). CONCLUSIONS: Our data suggest that the primary cause of PFS is the bilateral surgical damage to the pECP. This leads to a trans-synaptic cerebral cortical dysfunction (a form of bilateral crossed cerebellocerebral diaschisis), which manifests with DSC-detectable global, but dominantly frontal, cortical hypoperfusion in patients with patients with PFS compared with age- and sex-matched control subjects.

Comparison of native E. coli and PEG asparaginase pharmacokinetics and pharmacodynamics in pediatric acute lymphoblastic leukemia.

Asparaginase (ASP) is used routinely in frontline clinical trials for the treatment of childhood acute lymphoblastic leukemia (ALL). The goals of this study were to assess the pharmacokinetics and pharmacodynamics of ASP and to mathematically model the dynamics between ASP and asparagine (ASN) in relapsed ALL. Forty children were randomized to receive either native or polyethylene glycolated (PEG) Escherichia coli ASP during reinduction therapy. Serial plasma ASP and ASN, cerebrospinal fluid (CSF) ASN, and serum anti-ASP antibody samples were collected. The ASP clearance was higher (P = 0.001) for native vs. PEG ASP. Patients with antibodies to PEG ASP had faster PEG ASP clearance (P = 0.004) than did antibody-negative patients. Patients who were positive for antibodies had higher CSF ASN concentrations than did those who were negative (P = 0.04). The modeling suggests that by modifying dosages, comparable ASN depletion is achievable with both preparations. At relapse, there were significant pharmacokinetic and pharmacodynamic differences attributable to ASP preparation and antibody status.

Mechanisms of resistance: useful tool to design antibacterial agents for drug - resistant bacteria.

Drug-resistant bacteria are now a global health threat. In the last 5 years the WHO, The House of Lords (UK), the Centre for Disease Control (USA) and many more agencies have presented reports on the scale of this problem. Microorganisms multiply very rapidly and have adapted to fill almost every available environmental niche (Rapidly growing species of bacteria under ideal conditions of growth can multiply in about 20 minutes). All members of the chemically related beta-lactam class act at the same phase in cell wall synthesis; as a result, a bacterial cell resistant to one agent is often resistant to all other analogues. The beta-peptide has two promising characteristics that distinguish it from traditional antibiotics. Firstly, bacteria may have trouble developing resistance to the beta-peptide since bacterial defenses may not recognize its unnatural amino acids. Secondly, the magainins that the beta-peptides mimic have been around for millions of years, yet bacteria have not become resistant to them. All classes of antibiotics are subject to resistance by an efflux mechanism mediated by more than one type of pump within the same organism. The bacterial cell may have a membrane pump capable of pumping a class or several classes of antibacterial agents back out of the cell. Other mechanisms of drug resistance include destruction of beta-lactam ring by beta-lactamases, impermeability of the drug into the bacterial cell wall, alteration of targets within the bacterial cells and the by-pass mechanism (bacterial cell may have acquired an alternative mechanism for achieving the essential function).

Low-dose oral etoposide-based induction regimen for children with acute lymphoblastic leukemia in first bone marrow relapse.

We evaluated the clinical response to low-dose etoposide in relapsed acute lymphoblastic leukemia (ALL). Of the 45 patients with ALL in first bone marrow relapse enrolled on the ALL R15 protocol, 44 had received epipodophyllotoxins during frontline therapy. In the first week of remission induction therapy, patients received etoposide (50 mg/m(2) per day) administered orally as a single agent once or twice daily. On Day 8, patients started to receive dexamethasone, vincristine, and L-asparaginase. Etoposide was administered until Day 22. Two courses of consolidation therapy were followed by continuation therapy or hematopoietic stem cell transplantation. After 7 days of single-agent etoposide treatment, peripheral blast cell counts (P=0.013) and percentages of bone marrow blasts (P=0.016) were significantly reduced. In all, 38 (84.4%) attained second remission. Only time to relapse was significantly associated with outcome (P=0.025): the 5-year event-free survival estimates (+/-se) were 52.0+/-9.6% for those with late relapse and 20.0+/-8.0% for those with early relapse. We conclude that low-dose etoposide administered orally has a cytoreductive effect in relapsed ALL.

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse.

Using flow cytometric techniques capable of detecting 0.01% leukemic cells, we prospectively studied minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) after first relapse. At the end of remission reinduction, 41 patients had a bone marrow sample adequate for MRD studies; 35 of these were in morphologic remission. Of the 35 patients, 19 (54%) had MRD >/=0.01%, a finding that was associated with subsequent leukemia relapse. The 2-year cumulative incidence of second leukemia relapse was 70.2+/-12.3% for the 19 MRD-positive patients and 27.9+/-12.4% for the 16 MRD-negative patients (P=0.008). Among patients with a first relapse off therapy, 2-year second relapse rates were 49.1+/-17.8% in the 12 MRD-positive and 0% in the 11 MRD-negative patients (P=0.014); among those who received only chemotherapy after first relapse, the 2-year second relapse rates were 81.5+/-14.4% (n=12) and 25.0+/-13.1% (n=13), respectively (P=0.004). Time of first relapse and MRD were the only two significant predictors of outcome in a multivariate analysis. We conclude that MRD assays should be used to guide the selection of postremission therapy in patients with ALL in first relapse.

A mechanistic mathematical model of temozolomide myelosuppression in children with high-grade gliomas.

Temozolomide (TMZ) is currently being evaluated for the treatment of high-grade gliomas in children. Myelosuppression (the suppression of bone marrow activity) is the dose-limiting toxicity for TMZ in adults and children. Empirical methods (i.e. relations between the percent change in absolute neutrophil count (ANC) and the area under the plasma concentration curve (AUC) of TMZ or its active metabolite MTIC) showed poor results when attempting to describe myelosuppression from serial data derived during TMZ therapy in a Phase II study of children with high-grade glioma. Therefore, to improve our understanding of the myelosuppressive effects of TMZ and MTIC in children we developed a mechanistic mathematical model. The model describes the progression of neutrophils from their production in the bone marrow to their release in the plasma. Included in the model are the feedback effects of granulocyte colony stimulating factor (G-CSF), which stimulates neutrophil production when there is a decrease in circulating neutrophils. The model is fit to serial ANC measurements obtained after TMZ dosing and it is able to explain, among other things, the lag in ANC reduction following a dose of TMZ, the ANC nadir, and the 'rebound effect' observed where the ANC recovers to levels greater than that observed pre-TMZ dose. This model will be useful for the prospective design of clinical trials of TMZ in children with cancer.

Urolithiasis in pediatric patients with acute lymphoblastic leukemia.

We evaluated the incidence, timing, and consequences of urolithiasis in children with acute lymphoblastic leukemia (ALL). A total of 20 patients with urolithiasis were identified from 2095 patients with ALL treated at St Jude Children's Research Hospital on consecutive protocols between 1968 and 1998. For remission induction therapy, all patients received daily prednisone; continuation chemotherapy regimens differed by protocol with some including pulses of prednisone or dexamethasone and others no glucocorticoid. Patients with urolithiasis were older at diagnosis of ALL than those without urolithiasis (median age, 7.5 vs 5.0 years; P=0.03) and less likely to be black (P=0.03) than white or Hispanic, but sex and treatment era did not differ. Presenting symptoms included abdominal or flank pain, hematuria, and dysuria. All stones analyzed biochemically were calcium stones. The incidence of urolithiasis after completion of therapy was 1.8 per 10 000 person-years. Compared to this baseline rate, the relative risk of urolithiasis was 45 (P<0.01) during induction therapy, 22 (P<0.01) during continuation therapy with glucocorticoids, and 5.1 (P>0.05) during continuation therapy without glucocorticoids. Urolithiasis occurred 4.5 times more often during continuation treatment with glucocorticoids than without (P<0.05). Seven patients (35%) had recurrent urolithiasis. Patients with ALL are at risk of developing calcium renal stones during chemotherapy, especially when a glucocorticoid is included.