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Amar Gajjar

Publications and source records attributed to Amar Gajjar.

54 records · Page 3Linked to original sources
PubMed2004

Late neurocognitive sequelae in survivors of brain tumours in childhood.

As survival among children treated for cancer continues to improve, more attention is being focussed on the late effects of cancer treatment. In children treated for brain tumours, chronic neurocognitive effects are especially challenging. Deficits in cognitive development have been described most thoroughly among children treated for posterior-fossa tumours, specifically medulloblastomas and ependymomas, which account for about 30% of all newly diagnosed cases of brain tumours in children. Most children who have survived brain tumours have required surgical resection and focal or craniospinal radiotherapy (irradiation of the entire subarachnoid volume of the brain and spine), with or without systemic chemotherapy. Historically, intelligence quotient (IQ) scores have provided a benchmark against which to measure changes in cognitive development after treatment. Observed declines in IQ are most likely a result of failure to learn at a rate that is appropriate for the age of the child, rather than from a loss of previously acquired knowledge. The rate of IQ decline is associated with a several risk factors, including younger age at time of treatment, longer time since treatment, female sex, as well as clinical variables such as hydrocephalus, use of radiotherapy and radiotherapy dose, and the volume of the brain that received treatment. Loss of cerebral white matter and failure to develop white matter at a rate appropriate to the developmental stage of the child could partly account for changes in IQ score. Technical advances in radiotherapy hold promise for lowering the frequency of neurocognitive sequelae. Further efforts to limit neurocognitive sequelae have included design of clinical trials to test the effectiveness of cognitive, behavioural, and pharmacological interventions.

Antineoplastic Agents↗
PubMed2004

Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist.

Pediatric high-grade gliomas represent a heterogeneous group of tumors that accounts for 15%-20% of all pediatric central nervous system tumors. These neoplasms predominantly involve the supratentorial hemispheres or the pons, in which case the tumors are usually called diffuse brainstem gliomas. The diagnosis of supratentorial neoplasms is dependent on their histologic appearance. The maximum possible surgical resection is always attempted since the degree of surgical resection is the main prognostic factor for these patients. Older children (>3 years) with supratentorial neoplasms undergo a multimodality treatment comprised of surgical resection, radiation therapy, and chemotherapy. The addition of chemotherapy seems to improve the survival of a subset of these children, particularly those with glioblastoma multiforme. However, 2-year survival rates remain poor for children with supratentorial neoplasms, ranging from 10%-30%. The diagnosis of a diffuse brainstem glioma is based upon typical imaging, dispensing with the need for surgery in the majority of cases. Radiation therapy is the mainstay of treatment for children with diffuse brainstem gliomas. The role of chemotherapy for these children is not clear, and it is, in general, employed in the context of an investigational study. Less than 10% of children with diffuse brainstem gliomas survive 2 years. Because the outcome for patients with either type of tumor is poor when standard multimodality therapy is used, these children are ideal candidates for innovative treatment approaches.

Astrocytoma↗
PubMed2004

Abnormal hippocampal development in children with medulloblastoma treated with risk-adapted irradiation.

BACKGROUND AND PURPOSE: Children with medulloblastoma demonstrate post-treatment neurocognitive deficits in a number of areas, including memory performance. However, there is no definitive understanding of the neuropathology underlying these functional deficits. Previous literature has reported that hippocampal integrity is crucial to the acquisition of new episodic memories. Therefore, we hypothesized that longitudinal hippocampal volume measurements are abnormal in patients with medulloblastoma and thereby provide a possible substrate for explaining memory dysfunction. METHODS: Twenty-five pediatric patients underwent 159 serial MR imaging examinations (mean = six examinations per patient) for up to 5 years after irradiation and chemotherapy treatment for medulloblastoma. Right and left hippocampal volumes were obtained by manually tracing 1.5-mm contiguous coronal sections through the structure. Random coefficient models were used to examine longitudinal change in hippocampal volume as a function of time after diagnosis. RESULTS: Both right and left hippocampal volumes initially decreased after treatment. This abnormal volume pattern continued until approximately 2-3 years after diagnosis, when hippocampal volumes returned toward a normal positive growth pattern. Volume loss occurred predominately in the posterior regions. Female sex, low parental education, shunt placement, and positive seizure history all had a significant negative impact on hippocampal volume. CONCLUSION: Pediatric medulloblastoma survivors demonstrate an abnormal pattern of hippocampal volume development after treatment. Radiation dose mapping may expand our understanding of region-specific changes in hippocampal volume. Further exploration of the relationships between radiation therapy, memory dysfunction, and hippocampal pathology in this population is warranted.

Amnesia↗
PubMed2003

Clear cell ependymoma: a clinicopathologic and radiographic analysis of 10 patients.

BACKGROUND: Clear cell ependymoma (CCE) is an uncommon central nervous system tumor with a predilection for the supratentorial region in children. Histologically, it may mimic oligodendroglioma, central neurocytoma, hemangioblastoma, and renal cell carcinoma. METHODS: The authors reviewed the clinical, radiographic, and pathologic features, therapy, and outcome in 10 children with CCE who were treated at St. Jude Children's Research Hospital (1984-2003). Fluorescence in situ hybridization (FISH) was performed using 1p/1q, 19p/19q, CEP18/DAL1, and bcr/NF2 probe pairs. RESULTS: The median patient age at diagnosis was 7.5 years (range, 1-19 years). Tumors occurred supratentorially in 9 of 10 patients. All tumors had rounded nuclei with surrounding, clear halos and at least focal perivascular pseudorosettes. Seven tumors had anaplastic features. No deletions involving 1p, 19q, or NF2 were detected. The tumors from 5 of 7 patients, all with anaplasia, had losses of both CEP18 and DAL-1. Radiographically, all tumors were enhanced, and 9 tumors had associated cysts with enhancing walls. Seven patients underwent gross total resection, which was near total in one patient and subtotal in two patients. Five patients received immediate postoperative local radiotherapy. Three patients were diagnosed initially with pilocytic astrocytoma (one patient) and oligodendroglioma (two patients) and were observed. The progression-free survival and overall survival rates at 5 years were 34% +/- 20% and 75% +/- 19%, respectively. The median follow-up was 37 months (range, 5-239 months). Five patients developed local recurrence within a median of 9 months after diagnosis. Two patients developed extracranial soft tissue and lymph node metastases. CONCLUSIONS: CCEs were found to have a predilection for extraneural metastases and early recurrence and demonstrate characteristic radiographic features, anaplastic histologic features, and chromosome 18 losses. The authors recommend resection followed by local radiotherapy as the treatment of choice in children.

Adolescent↗
PubMed2003

Population pharmacokinetics of temozolomide and metabolites in infants and children with primary central nervous system tumors.

PURPOSE: To construct a population pharmacokinetic model for temozolomide (TMZ), a novel imidazo-tetrazine methylating agent and its metabolites MTIC and AIC in infants and children with primary central nervous system tumors. METHODS: We evaluated the pharmacokinetics of TMZ and MTIC in 39 children (20 boys and 19 girls) with 132 pharmacokinetic studies (109 in the training set and 23 in the validation set). The median age was 7.1 years (range 0.7 to 21.9 years). Children received oral TMZ dosages ranging from 145 to 200 mg/m(2) per day for 5 days in each course of therapy. Serial plasma samples were collected after the first and fifth doses of the first and third courses. Approximately eight plasma samples were collected up to 8 h after each dose, and assayed for TMZ, MTIC, and AIC by HPLC with UV detection. A one-compartment model was fitted to the TMZ and metabolite plasma concentrations using maximum likelihood estimation. Covariates, including demographics and biochemical data were tested for their effects on TMZ clearance (CL/F) and MTIC AUC utilizing a two-stage approach via linear mixed-effects modeling. RESULTS: The population mean (inter- and intrapatient variability expressed as %CV) for the pharmacokinetic parameters (based on the training set) were as follows: TMZ CL/F 5.4 l/h (53.4, 17.5), Vc/F 14.0 l (48.5, 39.2), C(max) 9.1 mg/l (20.8, 29.1), and MTIC AUC 1.0 microg/ml.h (13.9, 30.0). Covariate analysis showed that increasing age and body surface area (BSA) were associated with a significant increases in TMZ CL, Vc, and C(max) ( P<0.05), and that increasing age was associated with significant decreases in TMZ and MTIC AUC. Indicators of liver and renal function were not significantly associated with TMZ pharmacokinetics or MTIC AUC. The final model with the significant covariates was validated using the remaining 23 pharmacokinetic studies. CONCLUSIONS: This study extends previous work done in adults, and identified BSA and age as covariates that account for variability in TMZ disposition in infants and children with primary CNS malignancies.

Adolescent↗
PubMed2003

ERBB1 is amplified and overexpressed in high-grade diffusely infiltrative pediatric brain stem glioma.

PURPOSE: This study was conducted to investigate the incidence of ERBB1 amplification and overexpression in samples of diffusely infiltrative (WHO grades II-IV) pediatric brain stem glioma (BSG) and determine the relationship of these abnormalities to expression and mutation of TP53 and tumor grade. EXPERIMENTAL DESIGN: After central pathology review, the incidence of ERBB1 amplification and overexpression was determined in 28 samples (18 surgical biopsy and 10 postmortem specimens) of BSG using quantitative PCR and immunohistochemistry, respectively. Mutation and expression of TP53 were also determined in these same samples by direct sequence analysis of microdissected tumor material and immunohistochemistry, respectively. All experimental procedures were performed blind to tumor grade. RESULTS: Twelve, 9, and 7 tumors were classified as WHO grades II, III, and IV, respectively. A significant increase in ERBB1 expression was observed with increasing tumor grade (P < 0.001). Two grade IV tumors displayed intense membranous ERBB1 expression in 90% of tumor cells in association with high-level ERBB1 gene amplification. One grade III tumor also contained low-level amplification of ERBB1. Six tumors demonstrated TP53 nuclear immunoreactivity, and six contained a mutation in TP53. No correlation was observed between abnormalities in TP53 and either tumor grade or amplification and overexpression of ERBB1. CONCLUSIONS: These data suggest that ERBB1 signaling is important for the development of childhood BSG and is worthy of study as a therapeutic target in this disease. Our data also indicate that the genetics of childhood BSG are complex and include both grade-dependent amplification and overexpression of ERBB1 and grade-independent expression and mutation of TP53.

Adolescent↗
PubMed2003

Developmental model relating white matter volume to neurocognitive deficits in pediatric brain tumor survivors.

BACKGROUND: The primary objective of this study was to test the hypothesis that, among survivors of pediatric brain tumors, the association between reduced volumes of normal-appearing white matter (NAWM) and intellectual/academic achievement deficits can be explained by patient problems with memory and attention. METHODS: Quantitative tissue volumes from magnetic resonance imaging scans and neurocognitive assessments were obtained for 40 long-term survivors of pediatric brain tumors. They were treated with radiotherapy (RT) with or without chemotherapy 2.6-15.3 years earlier (median, 5.7 years) at an age of 1.7-14.8 years (median, 6.5 years). Neurocognitive assessments included standardized tests of intellect (intelligence quotient [IQ]), attention, memory, and academic achievement. RESULTS: Analyses revealed significant impairments in patients' neurocognitive test performance on all measures. After statistically controlling for age at RT and time from RT, significant associations were found between NAWM volumes and both attentional abilities and IQ, and between attentional abilities and IQ. Subsequent analyses supported the hypothesis that attentional abilities, but not memory, could explain a significant amount of the relationship between NAWM and IQ. The final developmental model predicting academic achievement based on NAWM, attentional abilities, and IQ explained approximately 60% of the variance in reading and spelling and almost 80% of the variance in math. CONCLUSIONS: The authors demonstrated that the primary consequence of reduced NAWM among pediatric patients treated for brain tumors was decreased attentional abilities, leading to declining IQ and academic achievement.

Adolescent↗
PubMed2003

Effect of intrapatient dosage escalation of irinotecan on its pharmacokinetics in pediatric patients who have high-grade gliomas and receive enzyme-inducing anticonvulsant therapy.

The authors set out to determine the effect of intrapatient dose escalation of irinotecan on its disposition in pediatric patients with high-grade glioma who received concomitant enzyme-inducing anticonvulsants (EIAs). During Course 1, a 60-minute intravenous infusion of irinotecan (20 mg/m(2) per day) was administered once daily for 5 days on each of 2 consecutive weeks. The authors measured the concentrations of the lactone forms of irinotecan and its metabolites 7-ethyl-10-hydroxycamptothecin (SN-38), SN-38 glucuronide, and 7-ethyl-10-[4-N-(5-aminopeptanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) in serial plasma samples collected on Days 1 and 12 of Course 1. For the 6 patients who received EIAs but whose SN-38 areas under the concentration-time curve (AUCs) on Day 1 were below clinically significant levels, irinotecan dosage was increased, and subsequent pharmacokinetic studies were performed. Thirty-five patients were enrolled. The rate of irinotecan clearance was greater for patients who received EIAs than for those who did not (P = 0.0008), whereas systemic exposure to irinotecan (P = 0.02) and SN-38 (P = 0.0001) was lower for those treated with EIAs than for those who were not. Of the 6 patients whose irinotecan dosages were increased, 3 experienced an increase in the SN-38 AUC between Days 1 and 12. For 1 patient, the SN-38 AUC on Day 12 was lower than on Day 1; this result likely was due to an increased dose of EIAs during the same period. Despite irinotecan dose escalation to 60 and 80 mg/m(2), the SN-38 AUCs for 2 patients did not increase to clinically significant levels. The type and grade of toxicity did not differ between the two patient groups. Increasing the dosage of irinotecan increased the SN-38 AUC in some patients who received concomitant EIA therapy.

Adolescent↗
PubMed2003

Pharmacokinetics and pharmacodynamics of oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia.

PURPOSE: To study the pharmacokinetics and pharmacodynamics of once- versus twice-daily oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Fifty-eight patients were randomly assigned to etoposide at 50 mg/m(2)/d with once- versus twice-daily doses for 22 days. On day 8, vincristine, asparaginase, and dexamethasone were started. Etoposide pharmacokinetics and pharmacodynamics were studied for 47, 28, and 26 patients on day 1, 8, and 22, respectively, of remission reinduction therapy. RESULTS: Of 48 patients with pharmacokinetic data, 42 (87.5%) achieved complete remission, three (6.3%) failed to achieve remission, and three (6.3%) died during induction. Median etoposide day 8 area under concentration-time curve (AUC) and cumulative AUC tended to be greater (P =.06 and P =.07, respectively) in patients (n = 23) who achieved complete remission (24 and 522 micro mol/L x h, respectively) than in patients (n = 3) who did not (14 and 303 micro mol/L x h, respectively). Three of eight patients with plasma concentrations exceeding 1.7 micro M (1 micro g/mL) for more than 8 hours daily, compared with one of 20 patients with concentrations exceeding 1.7 micro M for <or= 8 hours daily, were unable to receive all 22 days of etoposide because of toxicity. There was no difference in the AUC at day 1 or day 8 with once- versus twice-daily doses (P =.55 and P =.86, respectively). CONCLUSION: A pharmacodynamic relationship exists between systemic etoposide exposure and response to therapy when oral etoposide is used as part of remission induction regimens for relapsed or refractory childhood ALL.

Administration, Oral↗
PubMed2003

Survival and functional outcome of children with hypothalamic/chiasmatic tumors.

BACKGROUND: The management of children with hypothalamic (H) and/or chiasmatic (C) tumors remains controversial. We evaluated the impact of clinical and neuroimaging parameters and primary therapy on overall (OS) and progression-free (PFS) survival and on neuroendocrine and neurocognitive outcome in children with H and/or C tumors. METHODS: Records were reviewed for 73 children with H and/or C tumors treated at St. Jude Children's Research Hospital between October 1981 and December 1999. RESULTS: Thirty-six patients received irradiation or chemotherapy immediately postdiagnosis and 37 were observed. The 6-year OS and PFS rates were 86 +/- 5%; and 36 +/- 7%, respectively. The 6-year PFS rates for the irradiation, chemotherapy, and observation groups were 69 +/- 16%, 12 +/- 11%, and 37 +/- 9%, respectively. In multivariate analysis, intracranial NF1 lesions (P = 0.015) and initial irradiation (P = 0.056) led to better PFS rates. There was no difference in OS between those initially treated or observed. Mean serial intelligence quotient (IQ) scores were 86 and 86 at diagnosis and at 6 years later, respectively. Patients younger than 5 years old had a lower mean IQ score at diagnosis (79.1) than older patients (96.3; P = 0.003). Patients who were irradiated at diagnosis had a significantly higher cumulative incidence of endocrinopathy at 3 years (P = 0.008). CONCLUSIONS: Overall survival for children with H and/or C tumors is excellent. Initial treatment with radiation and the presence of intracranial NF1 lesions were positive predictors of PFS. Mean IQ is significantly compromised at diagnosis, but does not change over time or with irradiation. Overall survival is not affected by initial observation. We recommend observation in asymptomatic patients, platinum-based chemotherapy in younger patients, and irradiation in older symptomatic patients.

Adolescent↗
PubMed2003

Predicting intellectual outcome among children treated with 35-40 Gy craniospinal irradiation for medulloblastoma.

Fifty children diagnosed with medulloblastoma completed 188 psychological evaluations using the Wechsler Intelligence Scales for Children (D. Wechsler, 1974, 1991) over a 7-year study period following 35-40 Gy postoperative craniospinal irradiation. Random coefficient models were used to predict the trend in the children's intellectual performance as a function of time since diagnosis, with both patient and treatment variables as parameters of this function. A quadratic model demonstrated a delay prior to decline in performance for older patients, whereas the younger patients showed an immediate loss of performance with a plateau at approximately 6 years postdiagnosis. A steeper decline was found for those with higher baseline performance. Clinicians may use the proposed predictive model to identify those patients who are at risk of significant intellectual decline.

Adolescent↗
PubMed2003

A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors.

PURPOSE: To assess the use of a pharmacokinetically guided topotecan strategy and evaluate the toxicity of protracted i.v. topotecan in children with recurrent solid tumors. EXPERIMENTAL DESIGN: Fifteen children with measurable relapsed or refractory solid tumors received topotecan i.v. over 30 min 5 days a week for two consecutive weeks. Doses were individualized based on the patient's topotecan systemic clearance to attain a single day topotecan lactone area under the plasma concentration time curve (AUC) of 120-180 ng/ml x h (cohort 1) or 80-120 ng/ml x h (cohort 2). Clinical responses and toxicity were assessed by standard criteria. RESULTS: Twenty-nine courses of topotecan were administered, 11 in cohort 1 and 18 in cohort 2. The median topotecan dosages required to achieve the target AUCs for cohorts 1 and 2 were 4 mg/m(2) (range, 2.6-6) and 3 mg/m(2) (range, 2.6-4.2), respectively. The intersubject variance for topotecan clearance exceeded the intrasubject variance by 2-fold. With the pharmacokinetic targeting approach, we observed that 78% (46 of 59) of the measured AUC values were within the target range. The median number of days to an absolute neutrophil count >/=500/mm(3) was similar between the two cohorts; however, febrile neutropenia and serious infections limited our ability to deliver drug dosages needed to secure the higher systemic exposure (cohort 1). Five partial responses were observed. CONCLUSION: Protracted topotecan dosing using a pharmacokinetic strategy was possible in this heavily pretreated group of children.

Adolescent↗
PubMed2002

Persistence of lymphoblasts in bone marrow on day 15 and days 22 to 25 of remission induction predicts a dismal treatment outcome in children with acute lymphoblastic leukemia.

We determined the prognostic importance of morphologically identifiable persistent disease at day 15 and days 22 to 25 of remission induction in childhood acute lymphoblastic leukemia (ALL). Among 546 patients entered on 2 consecutive protocols, 397 patients had evaluable bone marrow (BM) examinations on day 15 (+/- 1 day) and 218 on days 22 to 25 (+/- 1 day). Fifty-seven patients (14%) had persistent lymphoblasts (> or = 1%) in the BM on day 15 and 27 patients (5.5%) had persistent lymphoblasts on days 22 to 25. The 5-year event-free survival (EFS) was significantly worse for patients with lymphoblasts on day 15 (40% +/- 6%) or on days 22 to 25 (4% +/- 3%) as compared to those without lymphoblasts on these dates (78% +/- 2% and 76% +/- 2%, respectively, P <.001 for both comparisons). A worse prognosis was observed even for patients with a low percentage of lymphoblasts (ie, 1%-4%) at either day 15 (5-year EFS = 56% +/- 8%) or days 22 to 25 (5-year EFS = 0%) compared to those without morphologically identifiable persistent lymphoblasts at these times (P <.001 for both comparisons). The prognostic impact of persistent lymphoblasts on both dates remained significant after adjusting for other known risk factors, including treatment protocol, age, white blood cell count, DNA index, cell lineage, and central nervous system status, and National Cancer Institute/Rome criteria simultaneously. Hence, persistence of lymphoblasts (even 1%-4%) on day 15 of remission induction was associated with a poor prognosis and on days 22 to 25 signified a particularly dismal outcome; these very high-risk patients require novel or more intensive therapy to improve outcome.

Blast Crisis↗
PubMed2002

Phase I study of combination topotecan and carboplatin in pediatric solid tumors.

PURPOSE: We conducted a phase I trial of escalating doses of topotecan (TOPO) in association with a fixed systemic exposure of carboplatin (CARBO) with or without granulocyte colony-stimulating factor (G-CSF) in children. PATIENTS AND METHODS: Two separate cohorts of patients (pts) with solid tumors were studied: (A) pts with refractory or recurrent disease and (B) pts with no prior myelosuppressive therapy or newly diagnosed tumors for which there was no standard chemotherapy. CARBO was given on day 1 at an area under the curve of 6.5, followed by TOPO as a continuous infusion for 3 days; the starting dose of TOPO was 0.50 mg/m(2)/d. Cycles were repeated every 21 days. G-CSF was given at a dose of 5 microg/kg/d starting on day 4. RESULTS: Forty-eight of 51 pts were assessable for toxicity. In group A, dose-limiting myelosuppression persisted despite de-escalation of TOPO to 0.3 mg/m(2)/d and use of G-CSF. In group B, the maximum-tolerated dose of TOPO was 0.5 mg/m(2)/d for 3 days, and 0.6 mg/m(2)/d for 3 days with G-CSF. No significant nonhematologic toxicities were observed. Among 46 pts assessable for response, one had complete response, five had partial response, and 18 had stable disease. CONCLUSION: Although this combination possesses antineoplastic activity in pediatric solid tumors, hematologic toxicity precluded any meaningful TOPO dose escalation. The addition of G-CSF did not alter this. The potential for preservation of activity and diminution of toxicity with alternative sequences and schedules of administration (topoisomerase followed by alkylating or platinating agents) should be evaluated.

Adolescent↗
PubMed2002

Medulloblastoma metastatic to the suprasellar region at diagnosis: a report of six cases with clinicopathologic correlation.

The presence of metastatic disease in patients newly diagnosed with medulloblastoma remains one of the most important prognostic factors that determines event-free survival. In the present study, anatomic distribution and the signal characteristics and enhancement patterns of subtle anterior third ventricular recess metastases were compared with those of the original tumor; medical records were reviewed for clinical presentation, surgical stage, treatment and long-term outcomes. All foci were clinically occult; 5 out of 6 had negative cerebrospinal fluid cytology, and in 4 out of 6, the only evidence of metastatic disease was documented suprasellar disease that resolved or significantly improved following irradiation and chemotherapy. Histologically, 3 of the 6 patients had tumors with large cell/anaplastic features, a significant increase compared to the expected incidence of 4-8.8%. Patients with tumors that show large cell/anaplastic features may be at higher risk for early metastatic involvement of this unusual site.

Brain Neoplasms↗
PubMed2002

Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy.

PURPOSE: The purpose of this study was to determine the effect of enzyme-inducing anticonvulsants (EIAs) on the disposition of irinotecan and metabolites in pediatric patients with high-grade glioma. EXPERIMENTAL DESIGN: Pediatric patients with newly diagnosed high-grade glioma were enrolled on this study between March 1999 and February 2001. During course 1, irinotecan was administered as a 60-min i.v. infusion at a dosage of 20 mg/m(2)/day for 5 days of 2 consecutive weeks. On days 1 and 12 of course 1, we collected serial plasma samples to measure the concentrations of the lactone and total forms of irinotecan and its metabolites SN-38 (7-ethyl-10-hydroxycamptothecin), SN-38 glucuronide (7-ethyl-10-[3,4,5-trihydroxy-pyran-2-carboxylic acid]camptothecin), and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin. RESULTS: Thirty-one patients were enrolled. In patients receiving EIAs, the area under the concentration versus time curve (AUC) of irinotecan lactone and SN-38 lactone was significantly lower (P = 0.01 and P = 0.002, respectively), and the irinotecan lactone clearance was significantly higher (P = 0.0003), as compared with those in patients who received no EIAs. The glucuronidation ratio was higher (P = 0.0009), and the ratio of SN-38 AUC to irinotecan AUC was lower (P = 0.02) in patients who received EIAs. Two patients receiving EIAs tolerated increased irinotecan dosages of 30 and 40 mg/m(2)/day without toxicity. One patient receiving EIAs experienced grade 3 diarrhea when the dosage of irinotecan was increased to 60 mg/m(2)/day. CONCLUSIONS: EIAs increase the clearance of irinotecan and cause a decrease in systemic exposure to the active metabolite SN-38. Patients who are receiving irinotecan and who require anticonvulsants should be placed on non-EIA therapy, when possible.

Adolescent↗
PubMed2002

Decline in corpus callosum volume among pediatric patients with medulloblastoma: longitudinal MR imaging study.

BACKGROUND AND PURPOSE: A decline in intrahemispheric cerebral white matter volume in children treated for brain tumors with cranial irradiation has been well documented. It was hypothesized that the development of the corpus callosum, the largest white matter commissure of the brain, would also be adversely affected after treatment with cranial irradiation in pediatric patients treated for medulloblastoma. METHODS: After diagnosis, 35 patients (22 male and 13 female patients) with histologically proved medulloblastoma were treated by maximal surgical resection, risk-adapted craniospinal irradiation, and chemotherapy. Using quantitative measurement techniques with MR imaging, corpus callosum volume was measured at multiple time points for each patient during a 4-year period. RESULTS: Quantitative MR imaging analyses of 239 examinations in 35 patients showed, in contrast to normal development, that the total midsagittal corpus callosum area decreased with time from craniospinal irradiation (-18.0 mm(2)/y; P <.0001). After examination of seven corpus callosum subregions, significant declines were also observed: genu (-2.2 mm(2)/y; P =.03), rostral body (-2.0 mm(2)/y; P =.04), anterior midbody (-1.4 mm(2)/y; P =.005), posterior midbody (-1.2 mm(2)/y; P =.004), isthmus (-2.4 mm(2)/y; P =.001), and splenium (-5.0 mm(2)/y; P =.007). CONCLUSION: The greatest deviation from normal development occurred in the most posterior subregions of the corpus callosum: the isthmus and the splenium. These corpus callosum subregions, associated with fibers traversing from the temporal, posterior parietal, and occipital lobes, are normally expected to have the highest rate of growth during childhood. However, these regions also received the highest total dose of irradiation, providing a possible explanation for atypical corpus callosum development observed in these 35 patients treated for medulloblastoma.

Adolescent↗