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PurposeMedulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. Prior to advances in molecular subgrouping, we sought to reduce the late effects of radiation in patients with average-risk medulloblastoma.MethodsWe performed a single-arm, multi-institution study, reducing the dose of craniospinal irradiation by 25% to 18 Gray (Gy) with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy.ResultsTwenty-eight (28) patients aged 3-30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 79% (95% confidence interval [CI] 58% to 90%) and 93% (95% CI 74% to 98%), respectively. The 5-year RFS and OS were 71% (95% CI 50% to 85%) and 86% (95% CI 66% to 94%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities.ConclusionsGiven the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from a reduced craniospinal radiation dose of 18 Gy without impacting relapse-free or overall survival.Clinical Trial RegistrationClinicalTrials.gov identifier: NCT00031590

The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations1. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation2. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patient's lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.

BACKGROUND Because few large studies of pediatric ependymoma treatment are available, the authors believed that a retrospective review of treatment outcomes from a single institution would yield potentially valuable information regarding potential prognostic factors. In this article, they report their 20-year institutional experience with this disease. METHODS Medical records were reviews of patients with intracranial ependymoma who received their initial treatment at the Children's Hospital of Philadelphia (CHOP)/Hospital of the University of Pennsylvania (HUP) between January 1980 and December 2000. Of the 61 patients who were identified, 49 patients underwent primary therapy at CHOP/HUP and formed the basis for the study. Actuarial overall survival (OS) and progression-free survival (PFS) were determined by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the log-rank test and Cox proportional-hazards models. RESULTS With median follow-up of 110.2 months, the 5-year OS and PFS rates were 66.2% and 40.7%, respectively. Older age and higher radiation dose significantly predicted for improved OS. Anaplastic histology predicted for decreased PFS. Cervical spinal cord extension resulted in decreased OS primarily caused by failures outside the primary site. Patients who had a favorable prognosis (aged ≥3 years, no dissemination or cord extension, complete resection, and radiation dose ≥54 grays [Gy]) had 5-year OS and PFS rates of 83.1% and 60.6%, respectively. CONCLUSIONS In this study of patients with pediatric intracranial ependymoma, OS and PFS rates were concordant with the rates published in other modern series. The finding of a dose response up to 54 Gy supported the current trend toward dose escalation. Tumor extension to the cervical spine was identified as a predictor for failure outside of the primary site. Although the survival rates were encouraging, there is still significant room for improvement in the management of this disease. Cancer 2007. © 2007 American Cancer Society.

BACKGROUND Because few reports on outcome in patients with pediatric malignant gliomas during the magnetic resonance imaging era were available, the authors studied the outcomes of children with these tumors at their institution. METHODS The medical records of 39 patients with nonbrainstem, malignant gliomas who were treated at the Hospital of the University of Pennsylvania/Children's Hospital of Philadelphia between February 1, 1989 and December 31, 2000 were reviewed retrospectively. Magnetic resonance imaging was used to assess tumors at presentation and at follow-up. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan–Meier method. Univariate and multivariate analyses were performed using a Cox proportional hazards model. RESULTS The median follow-up for the 14 surviving patients was 47.6 months. The median PFS for all patients was 12.2 months, and the median OS for all patients was 21.3 months. The extent of surgery was the strongest prognostic factor for predicting outcomes in these patients, with a median survival of 122.2 months in patients who underwent macroscopic total resection compared with 14.1 months in patients who had significant residual disease after surgery. In univariate analyses, other than the extent of surgery, only the absence of visual symptoms at diagnosis significantly predicted improved OS. Local control was improved for patients who underwent better resection and had smaller tumors. In multivariate analyses, although the extent of surgery continued to predict outcomes significantly, histologic grade, which was not significant in the univariate analysis, also was significant. CONCLUSIONS Children with malignant gliomas appeared to fare better than their adult counterparts. Because the extent of resection was one of the strongest predictors of outcome, the authors concluded that the optimal therapy for these patients would include the maximal possible resection. Cancer 2004. © 2004 American Cancer Society.

Purpose Clinically effective measurement of cognitive toxicity from photon radiation therapy (XRT) should be accurate, sensitive, and specific. This pilot study tested translational findings on phasic changes in children's memory systems that are sensitive and insensitive to toxic XRT effects to identify a possible neuroplastic effect. Methods and Materials Memory processes were prospectively tested before XRT and at 3 later time points up to 2 years in 35 children with mixed primary brain tumors who had not experienced recurrence. Memory processes were verbal-semantic, visual-semantic, and visual-perceptual, including accuracy, speed to recall, encoding, retrieval, and recognition. The mixed-effects model included time (to estimate slope), covariates (age, tumor locus, XRT field, and medications) as fixed effects, and individual random intercepts. A sensitivity analysis examined the influence of XRT dose to the hippocampi on memory. Results Retrieval from long-term verbal-semantic memory declined 2 months after completing XRT, as seen in adults, and was lowest at 1 year, which was delayed in comparison with adults. Double dissociation from visual-perceptual memory at baseline and 2 months was found, consistent with adults. Recovery was demonstrated 2 years after XRT. Patterns were unchanged when dose to hippocampus was included in the model. Conclusions Verbal and semantic long-term retrieval is specifically sensitive to XRT-related cognitive dysfunction, without effect on visual-perceptual memory. Children reached nadir in XRT-sensitive memory 1 year after XRT and recovered by 2 years, which is later than that observed in adults. The protracted period of post-XRT injury may represent the maturation of the human hippocampus and white matter into late adolescence.

Background Despite improvements in the treatment of pediatric acute lymphoblastic leukemia, approximately one in five patients will develop recurrent disease. The majority of these patients do not survive. This limited institution study sought to improve event-free survival (EFS) by intensification of chemotherapy. Procedure Twenty-one patients with either an isolated marrow (n = 16) or a combined marrow and central nervous system relapse (n = 5) received treatment according to Children's Hospital of Philadelphia protocol CHP-540. Six patients had an initial remission of

Background We assessed efficacy and morbidity of chemotherapy and 1,800 cGy of hypofractionated craniospinal irradiation (CSI) in children with central nervous system (CNS) relapse following first remisssion of acute lymphoblastic leukemia (ALL). Procedure Nineteen patients with isolated CNS relapse and 4 with combined CNS/marrow or CNS/testicular relapse received treatment according to Children's Hospital of Philadelphia (CHOP) protocols CHP-449 and CHP-497. CNS treatment included intrathecal methotrexate, cytarabine, and hydrocortisone and 1,800 cGy CSI in 16 fractions over 12 months. Systemic therapy consisted of reinductions with vincristine, prednisone, and daunorubicin and reconsolidations with cytarabine, etoposide, and L-asparaginase every 56 days for 2 years. Outcome measures were event-free survival (EFS), survival, growth, and neuropsychologic assessment or school performance. Results Follow-up of survivors from first relapse ranges from 52 to 133 months(median 91 months). Actuarial survival and EFSat 10 years are 58% (CI95 = 38–78%) and 54% (CI95 = 32–76%). Events include 2 second CNS, 4 marrow, 1 testicular, and 2 testicular/marrow relapses and 1 secondary leukemia. EFS is 100% (CI95 = 93–100%) in 9 patients with recurrence more than 26 months from diagnosis. Three patients have significant treatment-related reduction in stature. Median full-scale IQs of 6 patients tested were 112 pretreatment and 111 posttreatment among surviving patients. All 17 survivors attend regular school, but 2 receive supplementary special services. Conclusions Lower dose, hypofractionated CSI, intrathecal chemotherapy, and moderately intensive systemic chemotherapy provide excellent disease control for patients with late isolated CNS or combined marrow and CNS relapse. Children with brief first remissions remain at substantial risk of subsequent relapse with this therapy, especially in the marrow and testes. Med. Pediatr. Oncol. 34:125–131, 2000. © 2000 Wiley-Liss, Inc.

Purpose. We reviewed all pediatric cases referred for emergent/urgent therapy (requiring treatment within 48 hours) to identify frequency, patterns of presentation, and efficacy of therapy. We defined five categories of emergent/urgent therapy based on irradiated site and/or signs: Group I, spinal cord compression; Group II, respiratory compromise; Group III, infradiaphagmatic distress; Group IV, intracranial signs; Group V, pain. Materials and Methods. From 2/1/88-3/1/ 94, 104 children with 115 problems were referred by specialists at the Children's Hospital of Philadelphia. Diagnosis, nature of the emergency, and response were examined. Responses were categorized as complete resolution, improvement or stabilization, and progression. Results. The 104 children represented 12%, of referrals during the study period. The most common tumors were CNS PNET and gliomas (20%); and neuroblastoma (20%). Forty-five problems occurred with newly diagnosed tumors and 70 after progression. Ninety-one episodes were managed with radiation therapy and 24 with other modalities. Patients with spinal cord/cauda equina (n = 33) compression improved (55%) or stabilized (30%). Patients with respiratory compromise from thoracic (n = 14) or abdominal (n = 5) disease had a response rate of 72%. Eight patients in group III had a 66% response. In Group IV (n = 16), 63% had complete responses and 19% had stabilization. Group V (n = 15) patients had a complete or partial response of 93%. Conclusion. Approximately 10% of children referred for radiation therapy required emergent/urgent treatment. Eighty percent of patients achieved stabilization or showed improvement in signs and symptoms, indicating that radiotherapy is a valuable and reliable component of multimodal care in such situations.

Pre-clinical data and adult experience suggests that topoisomerase targeted anti-cancer agents may be highly schedule dependent, and efficacy may improve with prolonged exposure. To investigate this hypothesis, 28 children with recurrent brain and solid tumors were enrolled in a phase II study of oral etoposide (ETP). Patients were prescribed ETP at 50 mg/m2/ day for 21 consecutive days. Courses were repeated every 28 days pending bone marrow recovery. Evaluation of response was initially performed after 8 weeks and then every 12 weeks either by CT or MRI. Three of 4 patients with PNET (primitive neuroectodermal tumor)/medulloblastora achieved a partial response (PR). Two of 5 with ependymoma responded, one with a complete response and one with a PR. Toxicity was manageable with only 1 admission for fever and neutropenia in 120 cycles of therapy. Five patients had grade 3 or 4 neutropenia. One had grade 4 thrombocytopenia and one grade 2 mucositis and withdrew as a result. One patient had grade 2 diarrhea. Two patients who achieved a PR had received ETP as part of prior combination chemotherapy regimens. Daily oral etoposide is active in recurrent PNET/medulloblastoma and ependymoma. Toxicity is manageable and rarely requires intervention. Daily oral etoposide in combination with crosslinking agents should be considered in future phase III trials. Determination of activity in glioma and solid tumors is not complete.

RO-10. PROSPECTIVE SLOPES OVER EIGHT YEARS IN COGNITIVE MARKERS OF PHOTON RADIOTHERAPY FOR PEDIATRIC BRAIN TUMORS Carol L. Armstrong1,2, Julie Petersen1,3, Michael J. Fisher1,2, Robert A. Lustig1,2, Jane E. Minturn1,2, Jean B. Belasco1,2, Sarah Amedoro1, Cathy Bolton3, Peter C. Phillips1,2, and Christine E. Hill-Kayser1,2; The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Drexel University, Philadelphia, PA, USA PURPOSE: This prospective longitudinal study examined late-delayed effects (pre-treatment to 8y) of IMRT/conformal photon radiotherapy (RT) on cognition in children with brain tumors. We previously demonstrated that memory systems are affected differentially by RT, and investigated the pattern over eight years of these RT-specific cognitive markers. At the latedelayed phase, clinical information suggests a generalized decline in cognition, but no prospective studies report the late phase cognitive toxicity (.5 yr post treatment). METHODS: Participants were 28 patients with mixed primary brain tumors (18 males; age range: 4-17, M 1⁄4 9.04, SD 1⁄4 3.32; 61% had grosstotal resection)whocompletedbaseline andat leastone follow-upassessment frombaseline-8years (115 visits). Verbal-semantic memory wasassessed using a supraspan test of word memory (Rey Auditory Verbal Learning (RAVL, 4-forms)) for encoding, retrieval after interference, and retrieval after a delay. Complex Figure (CF, 2-forms) measured visuoperceptual memory immediately and after delay. Picture Recognition (PR) measured visual-semantic memory (accuracy, speed to recognize). Analyses used age-referenced Z scores in a mixed effects model; whole brain versus focal RT was a covariate. RESULTS: Verbal retrieval indices, but not encoding, were sensitive to the late-effects with progressive decline, and greater detriment in hippocampus-sensitive delayed retrieval. CF recall demonstrated continuous improvement to eight years. Bi-hemispherically processed PR demonstrated no decline over eight years. Dose burden significantly predicted retrieval but not encoding or recognition. CONCLUSIONS: Results evidence significant change over time, with differential changes in cognition, and no general decline. The sensitivity of retrieval infers multi-substrate injury not limited to hippocampus. Neuro-Oncology 18:iii159–iii164, 2016. doi:10.1093/neuonc/now082.10 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

PURPOSE In an effort to improve outcome in patients with metastatic or high-risk localized Ewing's sarcoma family of tumors (ESF) and rhabdomyosarcoma (RMS), we explored the role of consolidation therapy with total-body irradiation (TBI) plus autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS Ninety-one patients were entered onto one of three consecutive protocols from 1981 to 1986. Induction therapy consisted of four or five cycles of vincristine, doxorubicin, and cyclophosphamide (VAdriaC); in the earlier series, patients received one or two cycles with dactinomycin instead of doxorubicin. Irradiation of the primary site was used for local control. Patients who attained a complete response (CR) to induction therapy were eligible for consolidation with 8 Gy TBI plus VAdriaC and ABMT. RESULTS Nineteen patients were ineligible for consolidation after failing to achieve or maintain a CR following induction therapy; all 19 are dead of disease. Seven eligible patients elected to forgo consolidation; three of seven are long-term event-free survivors. Sixty-five patients received consolidation therapy; 20 of 65 are long-term event-free survivors. A local control rate of 83% was achieved using radiation therapy as the primary modality of local control. Patients with metastatic disease at diagnosis fared substantially worse than did patients with localized tumors (6-year event-free survival [EFS] rate, 14% v 38%; two-sided P [P2] = .008). CONCLUSIONS Consolidation of patients with metastatic or high-risk localized pediatric sarcomas with 8 Gy TBI plus ABMT has failed to improve the outcome of this group of patients. Metastatic disease at diagnosis continues to confer the poorest prognosis. New therapeutic strategies are needed to consolidate more effectively the remissions that can be achieved in the majority of these patients.

Purpose A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib ( SCH66336 ) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured. Patients and Methods Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m2/dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment. Results Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m2/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m2/dose levels resulted in a recommended phase II dose of 115 mg/m2/dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer. Conclusion Although the estimated MTD by the CRM model was 98.5 mg/m2/dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m2/dose administered twice daily by mouth with concurrent loperamide.

Purpose To examine US and United Kingdom (UK) parents’ approaches to care and treatment when standard therapy has failed and consider implications for clinical practice. Methods We conducted a prospective, ethnographic study of parents, patients, and staff, including participant-observation; open-ended, semistructured interviews; and review of medical records at a US and UK pediatric oncology center. Thirty-four children (n = 17 US, 17 UK), whose disease had recurred with less than 30% chance of cure, were enrolled between March 2001 and June 2002 and followed until death (n = 11 US, 14 UK) or close of study in December 2005 (n = 6 US, 3 UK). Results There were no major differences between parents’ approaches in the US and UK despite differences in health care systems, institutions, and parents’ religion or ethnicity. All parents continued to have or request meetings with the oncologist and investigative procedures. No parent initiated discontinuation of cancer- or symptom-directed interventions. In 28 of 34 cases (13 US, 15 UK), parents continued to pursue cancer-directed therapies; in 16 of 28 cases (seven US, nine UK), parents initiated inquires beyond what was offered. Conclusion Understanding parents’ behavior requires attention to the reason and emotion they bring to decision making and their children's care, their unique responsibilities as parents, and what they learn throughout the illness. Parents do not see cancer-directed therapy and symptom-directed care as mutually exclusive, alternative approaches. Parents will not be constrained by what the oncologist offers. Physicians and parents discuss and negotiate care and treatment throughout the illness. Our findings suggest developing integrative care models incorporating cancer-directed, symptom-directed, and supportive care throughout the illness; they are most consistent with parents’ approaches and advances in pediatric oncology.

Purpose The optimal treatment for intracranial germinomas remains controversial. We report on our 25-year experience using craniospinal irradiation (CSI) for this disease. Methods and materials Between September 1976 and May 2001, 39 patients with biopsy-proven intracranial germinomas seen at the Children's Hospital of Philadelphia/Hospital of the University of Pennsylvania received CSI. Thirteen of 36 patients (36%) had evidence of spinal dissemination. Median doses to the whole brain, primary site, and spine were 36 Gy (range, 18–44.2 Gy), 50.4 Gy (range, 44–55.8 Gy), and 30.6 Gy (range, 18–40 Gy), respectively. Results With a median follow-up of 7.1 years (range: 1.5–20.2 years), there have been no documented relapses. This includes 5 patients without spinal dissemination who received 18–19.8 Gy to the craniospinal axis; for these patients, the median length of follow-up was 5.5 years (range, 1.3–6.8 years). One patient, who had no evidence of disease 12.9 years after CSI, died of unknown causes 4 months later. Conclusions Our treatment of intracranial germinomas with CSI has yielded outstanding results with no known relapses during a long follow-up period. These results must be considered when evaluating other approaches, such as chemotherapy only or local field irradiation.

Purpose The optimal management of craniopharyngiomas remains controversial, especially in children and young adults. This study reports a single institution's experience with such patients. Methods and materials Between 1974 and 2001, 76 patients were treated for craniopharyngioma at the Children's Hospital of Philadelphia and the Hospital of University of Pennsylvania (HUP). Of these, 75 patients (97%) were evaluable with long-term follow-up. Although all patients underwent attempted gross total resection, 27 had documentation of less than total resection with 18 of these patients receiving immediate postoperative radiotherapy (RT). An additional 22 patients received RT at HUP after failing surgery alone. Results Median follow-up for all patients was 7.6 years. The 10-year actuarial overall survival, relapse-free survival, and local control (LC) rates for all patients were 85%, 48%, and 53%, respectively. When comparing the 57 patients treated with surgery alone to the 18 treated with subtotal resection (STR) followed by RT, a significant difference in LC rates at 10 years (42% vs. 84%, respectively; p = 0.004) was noted. However, no statistically significant difference in overall survival was found between the two groups, because RT was highly effective as salvage therapy. Twenty-two patients at HUP treated with RT after relapse had a 10-year ultimate LC rate comparable to that of patients who received RT immediately after STR. Conclusion RT given either immediately after STR or at relapse is effective in controlling craniopharyngiomas.

10077 Background: Radiotherapy (RT) results in excellent local control and outcomes for resected EP. Proton RT may reduce acute and late RT-related toxicity by reduced exposure of normal brain and ...

10076 Background: Radiation therapy (RT) has historically been delayed for infants with brain tumors due to data suggesting unacceptable toxicity after photon RT. Proton therapy allows definite spa...

Three children, two boys and one girl, with Down syndrome (DS) who presented with preleukemia and loss of all or part of chromosome 7 were studied. Initial presentation, with cytopenias and less than 25% blasts in the bone marrow, was between 13 and 30 months of age. Progression to acute nonlymphocytic leukemia occurred 1-8 months after initial presentation. The morphologic type was megakaryoblastic in two, and undifferentiated in one. Two children achieved remission with intensive therapy, and one continues in remission off therapy; the other child died in remission of accidental causes. The third child died of respiratory distress and leukemia after no intervention was chosen. These cases represent the first examples of chromosome 7 abnormalities associated with DS and leukemia, and suggest differences from the "monosomy 7" syndrome seen in children without DS.

2060 Background: The prognosis for most patients with recurrent malignant brain tumors is dismal. Treatment options are limited especially for patients who have already received irradiation. TMZ is an oral alkylating agent which is approved for use in patients with high grade glioma and has also been shown to have activity in patients with recurrent medulloblastoma. It’s primary dose-limiting toxicity is non- cumulative bone marrow suppression. In the present study, TMZ is given in a dose escalation fashion with fixed doses of high dose thiotepa and carboplatin with AHCR in the treatment of patients with recurrent or refractory malignant brain tumors. Methods: Treatment consisted of TMZ twice daily on days -10 to -6 followed by thiotepa 300 mg/m2/day and carboplatin AUC=7/day on days -5 to -3 with AHCR on day 0. Filgrastim was given day +1 and continued until engraftment. Results: 27 patients (18M; 9F) ages 3–46 years were treated from 11/00 until 10/04. Diagnoses included high grade glioma (n=12); medulloblastoma/PNET (n=9); CNS germ cell tumor (GCT) (n=4); and 1 each ependymoma and spinal cord PNET. TMZ doses ranged from 50 mg/m2 twice daily (100 mg/m2/day) to 200 mg/m2 twice daily (400 mg/m2/day) for 5 days. One patient had dose limiting toxicity consisting of reversible veno-occlusive disease at dose level 3 (TMZ 100 mg/m2 twice daily). Two patients had dose limiting toxicity at dose level 7 (TMZ 200 mg/m2 twice daily) consisting of transient encephalopathy (n=1) and severe mucositis (n=1). Additional toxicities included bacteremia (n=11), C. difficile enteritis (n=6) and grade 4 elevation of bilirubin and/or liver transaminases (n=2). There were no toxic deaths. Survival included 3 patients with glioma (38–48 months); two of whom had relapsed following standard dose TMZ; 3 patients with PNET/MB (48–72 months) and 3 patients with CNS GCT (26–71 months). Conclusions: Increased doses of TMZ are feasible when given with AHCR. There is presently a phase II study underway through the Pediatric Blood and Marrow Transplant Consortium evaluating the efficacy of TMZ at a dose of 175 mg/m2/day twice daily for 5 days with high dose thiotepa and carboplatin and AHCR. No significant financial relationships to disclose.

A large proportion of children with Wilms' tumor will become long-term disease-free survivors. A small number of these children are at risk of developing second malignant neoplasms. There have been no previous reports of osteogenic sarcoma of the chest wall following treatment of Wilms' tumor. Our patient was age seven years when he received surgery, radiation therapy and chemotherapy for Wilms' tumor, eight years when he received radiation and chemotherapy for pulmonary metastases of Wilms' tumor, and 13 years when he developed osteogenic sarcoma of the chest wall.

The case history of a child with acute promyelocytic leukemia (APL) is reported to illustrate both an unusual presentation of APL as a pelvic mass and to review the pathophysiology and treatment of the disease. Therapy of APL consists of chemotherapy, namely adriamycin/daunomycin for remission induction, and of control of disseminated intravascular coagulation. A chloroma, if present, may require local irradiation in addition to chemotherapy. With aggressive management, the number of prolonged remissions may be greater for APL than for any other form of acute myelogenous leukemia (AML), with significant numbers of patients achieving five-year survival.

Seventeen patients with peripheral neuroepithelioma were treated with an intensive chemotherapy regimen of vincristine, Adriamycin (Adria Laboratories, Columbus, OH), and cyclophosphamide (VADRIAC) in combination with radiation therapy. Fifteen patients with stage III (seven) or stage IV (eight) at presentation were treated on a more intensive regimen including total body irradiation (TBI) (8 Gy). Two patients with stage I (one) or II (one) disease received a less intensive chemotherapy regimen of VADRIAC. Therapy was completed within 6 to 7 months in all patients. The disease arose in the chest wall in 12 patients, pelvis in three patients, and extremity in two patients. Sixteen of the 17 (94%) patients achieved a complete remission. With a median follow-up of 18 months, ten patients remain in complete remission with an actuarial survival of 68% and an actuarial relapse-free survival of 56% at 12 months. On the basis of our initial experience with this tumor, we believe that peripheral neuroepithelioma is a chemoresponsive and radioresponsive tumor.

Melphalan is now being investigated as an intravenous (IV) bolus chemotherapeutic agent in children with resistant tumors involving the bone marrow. Two patients received 2 mg/kg melphalan, IV bolus; 10 patients received 1 mg/kg. Seven of the ten patients receiving 1 mg/kg had noticeable downward trends in the serum sodium concentrations, whereas both patients receiving 2 mg/kg developed hyponatremia (serum sodium concentration [SNa], mEq/l = 124-125) and inappropriate urinary sodium losses. Syndrome of inappropriate antidiuretic hormone (SiADH) is a previously unreported complication of high dose bolus melphalan therapy.

Nine evaluable patients with refractory solid tumors received mitomycin C as a single intravenous injection at a dose of 20 mg/m2 at 6- to 8-week intervals. Toxicity was tolerable. One patient with Wilms' tumor had a transient decrease in liver size. Pharmacokinetic data on three patients have suggested that the disposition of mitomycin C were comparable to those obtained in adults.

Two patients treated with high dose methotrexate otrexate with citrovorum rescue (HDMTX-CF) for osteogenic sarcoma developed the acute onset of neurologic deficits. Prior to the onset of symptoms, one child suffered brief episodes of altered consciousness. Both patients developed hemiparesis and then steadily improved over 72 hours. Laboratory evaluations disclosed normal coagulation parameters and nontoxic serum methotrexate levels at onset of symptoms. Computed tomography in one child disclosed a large low absorption abnormality. This patient represents the first reported case of positive radiologic findings associated with this syndrome. The two patients recovered completely and received further HDMTX-CF without sequelae. This condition may result from transient demyelination or embolic cerebrovascular disease.

Thirty-one previously untreated patients with Ewing's sarcoma were treated with an intensive chemotherapy program of vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cyclosphosphamide (VADRIAC) in combination with radiation therapy to the primary site (greater than 50 Gy) and bone metastases (45 to 50 Gy). An intensified regimen with one further cycle of chemotherapy (VADRIAC), total body irradiation (TBI), and autologous bone marrow transplantation was given to patients with primary tumors of the pelvis, humerus, femur, and chest wall without metastases and to all patients with metastases at diagnosis. Patients with primary tumors of the distal extremity and other sites without metastases at diagnosis were treated on a less intensive chemotherapy regimen of VADRIAC without the intensification. Therapy was completed within 6 to 7 months in all patients. Thirteen patients had metastatic disease at diagnosis; only two of these had the lung as the sole site of metastatic disease. Eighteen patients had no evidence of metastatic disease at diagnosis: ten of these patients had tumors that arose in central axis and proximal extremity sites, and eight had tumors that arose in distal extremity and other sites. Thirty of the 31 patients achieved a complete remission, although two patients underwent amputation: one before chemotherapy and radiation and one after chemotherapy and radiation because of persistent local disease. Seventeen remain in their first complete remission at a median time on study of 30 months and a median time after completion of therapy of 24 months. Fourteen patients have relapsed (13) or progressed (1): ten in metastatic sites and four in the primary site. One patient had persistent local disease after radiation requiring amputation. Nine of the 13 patients with metastatic disease at diagnosis have relapsed compared with five of the 18 patients without metastatic disease. For the entire group, the actuarial survival is 78% (65% to 87%) at 30 months, and the actuarial disease-free survival is 58% (46% to 69%) at 30 months.

With a constant region probe (c-lambda) from the immunoglobulin light chain gene cluster, we performed in situ hybridization to bone marrow chromosome preparations from a patient with a Ph-positive form of acute lymphocytic leukemia. Results in this patient indicate that the immunoglobulin chain genes were involved in the 9;22 chromosome rearrangement.

We report here the clinical and cytogenetic findings in a 3-year-old girl with pre-B-cell acute lymphoblastic leukemia presenting as a primary tumor of bone. A unique translocation t(7;15)(q22;q14-15) is described.