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Objective Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism‐based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test‐retest reliability of the measures and the application of data reduction techniques to improve reproducibility. Methods Data were analyzed from the STARS clinical trial (n = 146), a multi‐center double‐blind placebo‐controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra‐class correlation coefficients were generated between pre‐ and post‐performances (16‐week interval) on neuropsychological endpoints in the placebo group to determine test‐retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. Results Test‐retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test‐retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. Interpretation These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test‐retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of non-metastatic BGTGs, the 5- and 10-year event-free survival (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survival (OS) were 100%, and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980 to 2400 cGy/cGy[RBE]), WBI: 2340 (1800 to 3000 cGy/cGy[RBE]), WVI: 2340 cGy/cGy(RBE) (1800 to 2550 cGy/cGy[RBE]), focal: 3600 cGy (3060 to 5400 cGy). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p=0.84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p=0.0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

Data for visual acuity (VA) after treatment of neurofibromatosis type 1-associated optic pathway gliomas (NF1-OPGs) are limited. We retrospectively collected VA, converted to logMAR, before and after targeted therapy with everolimus for NF1-OPG, and compared to radiologic outcomes (14/18 with NF1-OPG, 25 eyes [three without quantifiable vision]). Upon completion of treatment, VA was stable in 19 eyes, improved in four eyes, and worsened in two eyes; visual and radiologic outcomes were discordant. In summary, the majority of children with NF1-OPG exhibited stabilization of their VA after everolimus treatment. A larger, prospective study will help delineate visual outcomes after targeted therapy.

Background High-dose chemotherapy (HDC) strategies were developed to avoid unacceptable neurotoxicity associated with craniospinal irradiation in infants with embryonal brain tumors. However, the impact of molecular and pathological characterizations in such approaches and long-term outcome have not been widely described in young children. Methods We retrospectively collected information from seven North American institutions, on young children with medulloblastoma (MB) treated with sequential HDC, as per the CCG 99703 protocol. Data collection included clinical presentation, histology, molecular subgroup, irradiation, ototoxicity, and neurocognitive evaluations. Results The cohort included 53 patients diagnosed at a median age of 24 months (2.9–63.2). Seventeen patients (32.1%) had nodular desmoplatic MB, all belonging to the sonic Hedgehog (SHH) subgroup, as did 30% of classic MB. The 5-year progression-free survival (PFS) and overall survival (OS) was 69.6% (±6·9%) and 76.1% (±6.5%), respectively. Seventeen (32.1%) patients received irradiation (nine adjuvant radiotherapy [RT]). Patients with SHH and group 3 MB had a 5-year PFS of 86·2% (±7.4%) and 49·1% (±14%), respectively (P = 0.03). The 5-year PFS radiation free for group 3 MB was 46.4%. Patients with macroscopic metastasis (M2 and M3) had a worst survival. Fifteen (45.5%) patients had significant ototoxicity. Mean Full Scale Intellectual Quotient (FSIQ) for 24 survivors was 91.6 (range 52–119). Conclusions This HDC strategy led to an encouraging OS while only 20% of the patients received adjuvant RT. SHH MB, irrespective of histological subgroup, had an excellent outcome. Such intensive therapy may not be needed for this subgroup. Patients with classic histology or group 3 had an encouraging PFS of 58% and 46.4%, respectively, in the absence of adjuvant RT. The neurocognitive profile of the survivors appears to be within the normal range.

BACKGROUND To evaluate tumor responses, event-free survival (EFS), overall survival (OS), and toxicity of chemotherapy, children with neurofibromatosis type 1 (NF1) and progressive low-grade glioma were enrolled into the Children's Oncology Group (COG) A9952 protocol and treated with carboplatin and vincristine (CV). METHODS Non-NF1 patients were randomized to CV or thioguanine, procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and vincristine in COG A9952. NF1 patients were assigned to CV only. NF1 patients and non-NF1 patients who were treated with CV were compared with respect to baseline characteristics, toxicity, tumor responses, EFS, and OS. RESULTS A total of 127 eligible patients with NF1 were nonrandomly assigned to CV: 42 NF1 patients (33%) had events, and 6 (4.7%) died. The 5-year EFS rate was 69% ± 4% for the CV-NF1 group and 39% ± 4% for the CV–non-NF1 group (P

A 3-year-old boy with sickle cell anemia (SCA) presented with progressive daily emesis and was found to have an anaplastic ependymoma. Radiation therapy and chemotherapy are usually employed after subtotal resections of anaplastic ependymomas, although the benefits from chemotherapy are unclear. To mitigate the risks of adjuvant treatment in this patient at risk for SCA-associated vasculopathy, renal impairment, and other end-organ damage, proton beam irradiation without chemotherapy was chosen. Scheduled packed red blood cell transfusions were instituted to maintain sickle hemoglobin levels less than 30%. This case highlights treatment complexities for malignant brain tumors in patients predisposed to treatment-related adverse effects.

Background Supratentorial PNETs (sPNET) are uncommon embryonal malignancies of the central nervous system whose prognosis has historically been poor. We evaluated the outcome and prognostic factors of children with sPNET treated prospectively on a Children’s Oncology Group trial.

Background Pirfenidone, an oral anti-inflammatory, antifibrotic agent with activity in idiopathic pulmonary fibrosis, may mediate anti-tumor activity in neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN) by inhibition of fibroblast proliferation and collagen synthesis. The primary objective of this open label, single arm phase II trial was to evaluate the activity of pirfenidone in children and young adults with inoperable PN. Procedure Patients (3–21 years) with NF1-related progressive PN received pirfenidone at the previously determined optimal dose (500 mg/m2 orally, q8h) on a continuous dosing schedule (one cycle = 28 days). Volumetric MRI analysis was used to assess response. Progression was defined as ≥20% PN volume increase compared to baseline. Pirfenidone would be considered active if it doubled the median time to progression (TTP) compared to the TTP on the placebo arm of a phase II trial with the farnesyltransferase inhibitor tipifarnib, which used near identical eligibility criteria. Toxicities, objective response rate, and quality of life (QOL) also were evaluated. Results Thirty-six patients were enrolled and tolerated pirfenidone well with intermittent nausea and vomiting as the most frequent toxicities. A dose reduction was required in only three patients. The median TTP for pirfenidone was 13.2 months compared to 10.6 months for the placebo control group from the tipifarnib trial (two-tailed P = 0.92; one-tailed P = 0.46). No objective responses were observed. Conclusions Pirfenidone was well tolerated, but did not demonstrate activity as defined in this trial and does not warrant further evaluation in children with NF1 and progressive PN. Pediatr Blood Cancer 2014;61:1598–1602. © 2014 Wiley Periodicals, Inc.

Background Patients with Neurofibromatosis Type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. There are no standard treatment options for PN other than surgery, which is often difficult due to the extensive growth and invasion of surrounding tissues. Mammalian Target of Rapamcyin (mTOR) acts as a master switch of cellular catabolism and anabolism and controls protein translation, angiogenesis, cell motility, and proliferation. The NF1 tumor suppressor, neurofibromin, regulates the mTOR pathway activity. Sirolimus is a macrolide antibiotic that inhibits mTOR activity. Procedure We conducted a 2-stratum phase II clinical trial. In stratum 2, we sought to determine whether the mTOR inhibitor sirolimus in subjects with NF1 results in objective radiographic responses in inoperable PNs in the absence of documented radiographic progression at trial entry. Results No subjects had better than stable disease by the end of six courses. However, the children's self-report responses on health-related quality of life questionnaires indicated a significant improvement in the mean scores of the Emotional and School domains from baseline to 6 months of sirolimus. Conclusions This study efficiently documented that sirolimus does not cause shrinkage of non-progressive PNs, and thus should not be considered as a treatment option for these tumors. This study also supports the inclusion of patient-reported outcome measures in clinical trials to assess areas of benefit that are not addressed by the medical outcomes. Pediatr Blood Cancer 2014;61:982–986. © 2013 Wiley Periodicals, Inc.

Criteria for new drug approval include demonstration of efficacy. In neuro-oncology, this is determined radiographically utilizing tumor measurements on MRI scans. Limitations of this method have been identified where drug activity is not reflected in decreased tumor size. The RANO (Response Assessment in Neuro-Oncology) working group was established to address limitations in defining endpoints for clinical trials in adult neuro-oncology and to develop standardized response criteria. RAPNO was subsequently established to address unique issues in pediatric neuro-oncology. The aim of this paper is to delineate response criteria issues in pediatric clinical trials as a basis for subsequent recommendations.

cerebral vasculature, disruption of the blood–brain barrier, and direct damage to cerebral white matter as well as damage to neural progenitor cells in neuronal niches [6,7] Purpose. Assess the intellectual and academic outcomes as well as risk factors associated with treatment for average-risk medulloblastoma in childhood using 23.4 Gy of craniospinal radiotherapy plus adjuvant chemotherapy. Methods. From an overall sample of 379 enrolled in the parent study (COG A9961), 110 patients received a total of 192 assessments over more than 5 years with standardized IQ and academic achievement tests. Random coefficient models of the various outcomes were developed that incorporated covariates including chemotherapy regimen, age at diagnosis, sex, initial Full Scale IQ, and mutism. Results. Participants in this study were found to be comparable to the overall sample in all demographic, disease, and treatment factors, except there were more gross total resections in the subsample undergoing intellectual and academic assessment. Major findings include significant decline in both intellectual and academic domains over time that were greater in children who were younger at diagnosis and had higher initial intelligence test scores. Children with mutism were at higher risk for initial effects on intelligence. No effects of sex were found. Conclusion. These results show progressive decline over several years post-treatment in standardized intellectual and academic scores. Despite recent improvements in therapies for these children, most notably a decrease dose of craniospinal radiation, they remain at risk. The pursuit of less toxic treatments, particularly for younger children, should continue. Neuropsychological surveillance should be routine at centers treating children with brain tumors. Pediatr Blood Cancer 2013;60:1350‐1357. 2013 Wiley Periodicals, Inc.

In the US, approximately 2,500 children are diagnosed annually with brain tumors. Their survival ranges from >90% to 80% (standard-risk) to 60% (high-risk). For those with high-grade gliomas (HGGs) including diffuse intrinsic pontine gliomas, 5-year survival remains

Aim Difficulties in neurocognition and social interaction are the most prominent causes of morbidity and long-term disability in children with neurofibromatosis type 1 (NF1). Symptoms of attention-deficit–hyperactivity disorder (ADHD) have also been extensively recognized in NF1. However, systematic evaluation of symptoms of autism spectrum disorder (ASD) in children with NF1 has been limited. Method We present a retrospective, cross-sectional study of the prevalence of symptoms of ASD and ADHD and their relationship in a consecutive series of 66 patients from our NF1 clinic. The Social Responsiveness Scale and the Vanderbilt ADHD Diagnostic Parent Rating Scale were used to assess symptoms of ASD and ADHD. Results Sixty-six participants (42 males, 24 females) were included in this study. Mean age at assessment was 10 years 11 months (SD 5y 4mo). Forty percent of our NF1 sample had raised symptom levels reaching clinical significance on the Social Responsiveness Scale (T ≥ 60), and 14% reached levels consistent with those seen in children with ASDs (T ≥ 75). These raised levels were not explained by NF1 disease severity or externalizing/internalizing behavioral disorders. There was a statistically significant relationship between symptoms of ADHD and ASD (χ2=9.11, df=1, p=0.003, φ=0.56). Particularly salient were the relationships between attention and hyperactivity deficits, with impairments in social awareness and social motivation. Interpretation We found that symptoms of ASD in our NF1 population were raised, consistent with previous reports. Further characterization of the specific ASD symptoms and their impact on daily function is fundamental to the development and implementation of effective interventions in this population, which will probably include a combination of medical and behavioral approaches.

Background Because definitive resection or radiotherapy for pediatric low-grade gliomas (LGGs) may be associated with severe and permanent adverse effects, medical management has taken a significant role. Bevacizumab-based therapy has demonstrated encouraging responses; however, longer-term toxicity, response durability and alternative dosing regimens have not been evaluated. Procedure This was a retrospective review of children with multiply recurrent, progressive LGGs treated with bevacizumab-based therapy and followed for at least 12 months after treatment completion. Toxicity was uniformly graded and imaging was centrally reviewed. Results All fourteen patients had failed at least two prior treatment regimens; six had dissemination. Patients received initial bevacizumab-based therapy at a median age of 5.3 years (range, 1–12 years). Median treatment duration was 12 months (range, 1–24 months). 12 patients had an objective response; 2 had stable disease. Median time to maximum response was 9 weeks (range, 7–17 weeks). No patients progressed on therapy, although 13/14 progressed after stopping bevacizumab at a median of 5 months. Four patients were re-treated with bevacizumab and all again responded or stabilized. Alternative dosing strategies were effective, including bevacizumab monotherapy and prolonging the dosing interval to 3 weeks. High-grade bevacizumab-related toxicities consisted of grade 3 proteinuria (n = 2), primary inflammatory arthritis (n = 1), and somnolence (n = 1). Toxicities resolved within 6 months of treatment cessation except one case of hypertension. Conclusions Bevacizumab-based therapy is successful at inducing rapid LGG response. Patients progressing off-therapy may be successfully re-treated with bevacizumab. Nearly all tumors progress once treatment is discontinued. Toxicities are not insignificant but usually reversible. Pediatr Blood Cancer 2013; 60: 776–782. © 2012 Wiley Periodicals, Inc.

Purpose Standard therapy for childhood intracranial ependymoma is maximal tumor resection followed by involved-field irradiation. Although not used routinely, chemotherapy has produced objective responses in ependymoma, both at recurrence and in infants. Because the presence of residual tumor following surgery is consistently associated with inferior outcome, the potential impact of pre-irradiation chemotherapy was investigated. Methods Between 1995 and 1999, the Children's Cancer Group undertook a Phase II trial of pre-irradiation chemotherapy in children 3–21 years of age with intracranial ependymoma and radiological evidence of post-operative residual tumor. Results Of 84 patients, 41 had residual tumor, and were given four cycles of cisplatin-based chemotherapy prior to irradiation. Of 35 patients fully evaluable for response to chemotherapy, 14 (40%) demonstrated complete response, 6 (17%) partial response, 10 (29%) minor response or stable disease, and 5 (14%) demonstrated progressive tumor growth. For the entire group, 5-year overall survival (OS) and event-free survival (EFS) was 71 ± 6%, and 57 ± 6%, respectively. The pre-irradiation chemotherapy group demonstrated EFS comparable to that of patients with no residual tumor who received irradiation alone (55 ± 8% vs. 58 ± 9%, P = 0.45). Any benefit of chemotherapy was restricted to patients with greater than 90% tumor resection. Conclusions Children with near total resection of ependymoma may benefit from pre-irradiation chemotherapy. Patients with subtotal resection have inferior outcome despite responses to chemotherapy, and should be considered for second-look surgery prior to irradiation. Pediatr Blood Cancer 2012; 59: 1183–1189. © 2012 Wiley Periodicals, Inc.

Background To determine the toxicity and efficacy of rapamycin and erlotinib for the treatment of recurrent pediatric low-grade gliomas (LGGs). Methods Patients 1 year disease control. Conclusions The combination of rapamycin and erlotinib is well tolerated in children with LGGs. Objective responses were infrequent, although there was prolonged disease stabilization in some patients with LGGs, especially in two children with NF1. Pediatr Blood Cancer 2013; 60: 71–76. © 2012 Wiley Periodicals, Inc.

BACKGROUND: Interferon-α is a cytokine that has demonstrated activity in patients with supratentorial gliomas, but its ideal dose and schedule of administration is unknown. Studies suggest that low-dose, continuous exposure is more efficacious than intermittent, high doses. The authors performed a phase 2 study of recombinant interferon α-2b with monomethoxy polyethylene glycol (PEG-Intron®) in children with diffuse intrinsic pontine glioma (DIPG), a population with dismal survival despite decades of clinical investigation. The primary objective was to compare 2-year survival with a historic cohort that received radiation therapy alone. METHODS: Patients received weekly subcutaneous PEG-Intron® at a dose of 0.3 μg/kg beginning 2 to 10 weeks after the completion of radiation therapy until they developed disease progression. Patients were evaluated clinically and radiographically at regular intervals. Serum and urine were assayed for biomarkers before each cycle. Quality-of-life (QOL) evaluations were administered at baseline and before every other cycle of therapy to the parents of patients ages 6 to 18 years. RESULTS: Thirty-two patients (median age, 5.3 years; range, 1.8-14.8 years) were enrolled and received a median of 7 cycles of therapy (range, from 1 cycle to ≥70 cycles). PEG-Intron® was well tolerated, and no decrease in QOL scores was noted in the subset of patients tested. The 2-year survival rate was 14%, which was not significantly improved compared with the historic cohort. However, the median time to progression was 7.8 months, which compared favorably with recent trials reporting a time to progression of 5 months in a similar population. CONCLUSIONS: Although low-dose PEG-Intron® therapy did not significantly improve 2-year survival in children with DIPG compared with an historic control population, it did delay the time to progression. Cancer 2012;3607–3613. © 2011 American Cancer Society.

Background Studies have found associations between cancer therapies and auditory complications, but data are limited on long-term outcomes and risks associated with multiple exposures. Procedure The Childhood Cancer Survivor Study is a retrospective cohort investigating health outcomes of long-term survivors (5+ years) diagnosed and treated between 1970 and 1986 compared to a randomly selected sibling cohort. Questionnaires were completed by 14,358 survivors of childhood cancer and 4,023 sibling controls. Analysis determined the first occurrence of four auditory conditions in two time periods: diagnosis to 5 years post-diagnosis, and ≥5 years post-diagnosis. Multivariable analyses determined the relative risks (RR) and 95% confidence interval (CI) of auditory conditions by treatment exposure. Results Five or more years from cancer diagnosis, survivors were at increased risk of problems hearing sounds (RR = 2.3; 95% CI: 1.8–2.8), tinnitus (RR = 1.7; 95% CI: 1.4–2.1), hearing loss requiring an aid (RR = 4.4; 95% CI: 2.8–6.9), and hearing loss in 1 or both ears not corrected by a hearing aid (RR = 5.2; 95% CI: 2.8–9.5), when compared to siblings. Temporal lobe and posterior fossa radiation was associated with these outcomes in a dose-dependent fashion. Exposure to platinum compounds was associated with an increased risk of problems hearing sounds (RR = 2.1; 95% CI: 1.3–3.2), tinnitus (RR = 2.8; 95% CI: 1.9–4.2), and hearing loss requiring an aid (RR = 4.1; 95% CI: 2.5–6.7). Conclusions Childhood cancer survivors are at risk of developing auditory complications. Radiation and platinum compounds are determinants of this risk. Follow-up is needed to evaluate the impact of auditory conditions on quality of life. Pediatr Blood Cancer 2011;57:126–134. © 2011 Wiley-Liss, Inc.

The neurofibromatoses (NF) encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect 100,000 Americans; over 2 million persons worldwide; and are caused by mutation of tumor suppressor genes. Individuals with NF1 in particular may develop tumors anywhere in the nervous system; additional manifestations can include learning disabilities, bone dysplasia, cardiovascular defects, unmanageable pain, and physical disfigurement. Ultimately, the NFs can cause blindness, deafness, severe morbidity, and increased mortality and NF1 includes a risk of malignant cancer. Today there is no treatment for the NFs (other than symptomatic); however, research efforts to understand these genetic conditions have made tremendous strides in the past few years. Progress is being made on all fronts, from discovery studies-understanding the molecular signaling deficits that cause the manifestations of NF-to the growth of preclinical drug screening initiatives and the emergence of a number of clinical trials. An important element in fuelling this progress is the sharing of knowledge, and to this end, for over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share ideas and build collaborations. The 2010 NF Conference held in Baltimore, MD June 5-8, 2010 hosted over 300 NF researchers and clinicians. This paper provides a synthesis of the highlights presented at the Conference and as such, is a "state-of-the-field" for NF research in 2010.

The NF Conference is the largest annual gathering of researchers and clinicians focused on neurofibromatosis and has been convened by the Children’s Tumor Foundation for over 20 years. The 2009 NF Conference was held in Portland, Oregon from June 13th – June 16th, 2009 and co-chaired by Kathryn North from the University of Sydney and The Children’s Hospital at Westmead, Sydney, Australia; and Joseph Kissil from the Wistar Institute, Philadelphia. The Conference included 80 platform presentations in 9 sessions over 4 days; over 100 abstracts presented as posters; and three Keynote presentations. To date, there have been tremendous advances in basic research in the pathogenesis of neurofibromatosis, and more recently in progress toward identifying effective drug therapies and the commencement of neurofibromatosis clinical trials. The NF Conference attendees have significantly increased (doubling from 140 in 2005 to 280 attending in 2009) with a significant increase in attendance of physicians and clinical researchers. Correspondingly the NF Conference scope has expanded to include translational research, clinical trials and clinical management issues while retaining a core of basic research. These themes are reflected in the highlights from the 2009 NF Conference presented here.

Young children with emaciation caused by a hypothalamic glioma are considered to have diencephalic syndrome (DS), which is often poorly controlled with conventional treatment. We describe an infant with DS whose tumor progressed following chemotherapy. Biopsy was performed for molecular testing and demonstrated a BRAF fusion. Treatment with the MEK inhibitor trametinib for 18 months resulted in reduction of tumor size, normalization of his weight curve, and marked neurodevelopmental improvement. Our results build on earlier reports of using targeted agents for low-grade glioma, and we review the evolving management strategy for such patients in the era of precision medicine.

The RASopathies are a group of genetic syndromes caused by germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Some of these syndromes are neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, LEOPARD syndrome and Legius syndrome. Their common underlying pathogenetic mechanism brings about significant overlap in phenotypic features and includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, GI and ocular abnormalities, and a predisposition to cancer. The proceedings from the symposium “Genetic Syndromes of the Ras/MAPK Pathway: From Bedside to Bench and Back” chronicle the timely and typical research symposium which brought together clinicians, basic scientists, physician-scientists, advocate leaders, trainees, students and individuals with Ras syndromes and their families. The goals, to discuss basic science and clinical issues, to set forth a solid framework for future research, to direct translational applications towards therapy and to set forth best practices for individuals with RASopathies was successfully meet with a commitment to begin to move towards clinical trials.

SU5416 is a novel small molecule tyrosine kinase inhibitor of the VEGF receptors 1 and 2. A phase I dose escalation study stratified by concurrent use (stratum II) or absence (stratum I) of enzyme-inducing anticonvulsant drugs was undertaken to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile of SU5416 in pediatric patients with refractory brain tumors. Dose escalations were conducted independently for stratum I starting at 110 mg/m(2) while stratum II started at 48 mg/m(2). Thirty-three eligible patients were treated on stratum I (n = 23) and stratum II (n = 10). Tumor types included 23 glial tumors, 4 neural tumors, 4 ependymomas, and 2 choroid plexus carcinomas. The MTD in stratum I was initially estimated to be 110 mg/m(2). The protocol was amended to determine the MTD after excluding transient AST elevation. Re-estimation of the MTD began at the 145 mg/m(2) dose level but due to development of SU5416 being stopped by the sponsor, the trial was closed before completion. The most serious drug-related toxicities were grade 3 liver enzyme abnormalities, arthralgia, and hallucinations. The plasma pharmacokinetics of SU5416 was not significantly affected by the concurrent administration of enzyme-inducing anticonvulsant drugs. Mean values of the total body clearance, apparent volume of distribution, and terminal phase half-life of SU5416 for the 19 patients in stratum I were 26.1 +/- 12.5 l/hr/m(2), 41.9 +/- 21.4 l/m(2), and 1.11 +/- 0.41 hr, respectively. The plasma pharmacokinetics of SU5416 in children was similar to previously reported findings in adult cancer patients. Prolonged disease stabilization was observed in 4 of 16 stratum I patients.

Purpose—Children and adolescents with malignant astrocytomas recurring after initial treatment have a dismal prognosis, with only rare patients surviving one year beyond recurrence. The purpose of this study was to attempt to improve their survival. Methods—Twenty-seven children and adolescents with malignant astrocytomas (17 glioblastoma multiforme and 10 anaplastic astrocytoma) following initial tumor progression, received myeloablative chemotherapy followed by autologous marrow rescue with one of three thiotepa and etoposide-based chemotherapy regimens, administered alone (n=11) or combined with carmustine (n=5) or carboplatin (n=11). Time to progression and death following myeloablative chemotherapy for these patients was compared non-randomly with outcome of a contemporaneously treated cohort of similar patients who received only conventional chemotherapy following initial tumor progression. The two cohorts were compared for age, histology, prior therapies, extent of surgical resection at progression and time from initial diagnosis to progression. Results—Five of 27 children (two with glioblastoma multiforme and three with anaplastic astrocytoma) survive event-free from 8.3 to 13.3 years (median of 11.1 years) following myeloablative chemotherapy. Of 56 children with recurrent malignant astrocytoma who received

BACKGROUND Limited data exist on the comprehensive assessment of late medical and social effects experienced by survivors of childhood and young adult acute myeloid leukemia (AML). METHODS This analysis included 272 5-year AML survivors who participated in the Childhood Cancer Survivor Study (CCSS). All patients were diagnosed at age ≤21 years between the years 1970 and 1986, and none underwent stem cell transplantation. Rates of survival, relapse, and late outcomes were analyzed. RESULTS The average follow-up was 20.5 years (range, 5–33 years). The overall survival rate was 97% at 10 years (95% confidence interval [95%CI], 94%–98%) and 94% at 20 years (95% CI, 90%–96%). Six survivors reported 8 recurrences. The cumulative incidence of recurrent AML was 6.6% at 10 years (95% CI, 3.7%–9.6%) and 8.6% at 20 years (95% CI, 5.1%–12.1%). Ten subsequent malignant neoplasms (SMN) were reported, including 4 with a history of radiation therapy, for a 20-year cumulative incidence of 1.7% (95% CI, 0.02%–3.4%). Six cardiac events were reported, for a 20-year cumulative incidence 4.7% (95% CI, 2.1%–7.3%). Half of the survivors reported a chronic medical condition and, compared with siblings, were at increased risk for severe or life-threatening chronic medical conditions (16% vs 5.8%; P < .001). Among those aged ≥25 years, the age-adjusted marriage rates were similar among survivors and the general United States population (57% for both) and lower compared with siblings (67%; P < .01). Survivors' college graduation rates were lower compared with siblings but higher than the general population (40% vs 52% vs 34%, respectively; P < .01). Employment rates were similar between survivors, siblings, and the general population (93%, 97.6%, and 95.8%, respectively). CONCLUSIONS Long-term survival from childhood AML ≥5-years after diagnosis was favorable. Late-occurring medical events remained a concern with socioeconomic achievement lower than expected within the individual family unit, although it was not different from the general United States population. Cancer 2008. © 2008 American Cancer Society.

BACKGROUND High-grade astrocytomas (HGA) carry a dismal prognosis and compose nearly 20% of all childhood brain tumors. The role of high-dose chemotherapy (HDCT) in the treatment of HGA remains unclear. METHODS In a nationwide study, The Children's Cancer Group (CCG) prospectively evaluated 102 children with HGA and postoperative residual disease for efficacy and toxicity of four courses of HDCT before radiotherapy (RT). Patients were randomly assigned to one of three couplets of drugs: carboplatin/etoposide (Regimen A), ifosfamide/etoposide (Regimen B), or cyclophosphamide/etoposide (Regimen C). After HDCT, all patients were to receive local RT followed by lomustine and vincristine. Twenty-six patients were excluded after central neuroradiographic review (n = 8) or pathology review (n = 18). RESULTS Of 76 evaluable patients (median age, 11.95 yrs; range, 3–20 yrs), 30 patients relapsed during HDCT, and 11 others did not complete HDCT because of toxicity. Nonhematologic serious toxicities were common (29%), and 21% of patients did not receive RT. Objective response rates were not associated with amount of residual disease and did not statistically differ between regimens: 27% (Regimen A), 8% (Regimen B), and 29% (Regimen C). Overall survival (OS) was 24% ± 5% at 5 years and did not differ between groups. Median time to an event was longest for Regimen A (283 days compared with 83 and 91 days for Regimens B and C, respectively). The five-year, event-free survival (EFS) rate for all patients was 8% ± 3% and 14% ± 7% for Regimen A (P = 0.07). CONCLUSIONS OS and EFS were not affected by histologic grade. Patients who responded to HDCT had a nominally higher survival rate (P = 0.03 for trend). The authors conclude that these commonly used HDCT regimens provide no additional clinical benefit to conventional treatment in HGA, regardless of the amount of measurable residual tumor. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND Ninety percent of children with diffuse, intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit to these children, and a potential way to improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing; however, its delivery to the primary tumor site is problematic. RMP-7 is a bradykinin analog that causes selective permeability of the blood-brain-tumor interface. The objective of this Phase I study was to determine the toxicity and feasibility of delivering RMP-7 and carboplatin for 5 successive days during radiotherapy to children with newly diagnosed, diffuse, intrinsic brainstem gliomas. METHODS RMP-7 was given prior to the end of carboplatin infusion. Local radiotherapy, in dose fractions of 180 centigrays (cGy) per day (to a total dose of 5940 cGy), was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion in cohorts of 3 patients, until there was treatment-limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, and their median age was 7 years (age range, 3–12 yrs). RESULTS One child died early during treatment of progressive disease and was not assessable for toxicity. Treatment for 3 weeks, 4 weeks, and 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. One of 3 children treated at the full duration of therapy (33 doses over 7 weeks) developed dose-limiting hepatotoxicity and neutropenia. The estimated median survival was 328 days, and 1 patient remained free of disease progression for > 400 days after the initiation of treatment. CONCLUSIONS The results of this study confirmed the feasibility of giving RMP-7 and carboplatin daily during radiotherapy to children with brainstem tumors. Cancer 2005. © 2005 American Cancer Society.

During the past 30 years, changes in the treatment of children and adolescents with cancer have led to substantial improvements in survival. Although treatment-related factors have been shown to impact subsequent health status and quality of life, there is limited information on survivors who are now two or more decades after treatment. The Childhood Cancer Survivor Study (CCSS) was established as a resource for investigating the long-term outcomes of a cohort of 5-year survivors of childhood and adolescent cancer, diagnosed between 1970-1986. The CCSS cohort has more than 14,000 active participants, including survivors of leukemia, brain tumors, Hodgkin disease, non-Hodgkin lymphoma, Wilms tumor, neuroblastoma, soft-tissue sarcoma, and bone tumors. Study participants, extensively characterized by their cancer therapy, have provided self-reported sociodemographic- and health-related information. Although the survivor population has been found to be at significantly increased risk of several adverse outcomes, such as late mortality, second cancers, pulmonary complications, pregnancy loss, low birth weight of offspring, and decreased education, the overall proportion of survivors affected is relatively small. Subgroups at high risk of adverse outcomes, defined by treatment-related, demographic, or medical factors, can be identified. The ongoing evaluation of large and diverse cohorts of cancer survivors will aid in further identifying individuals who should be the target of innovative intervention strategies.

Background Increased attention has been directed toward the long-term health outcomes of survivors of childhood cancer. To facilitate such research, a multi-institutional consortium established the Childhood Cancer Survivor Study (CCSS), a large, diverse, and well-characterized cohort of 5-year survivors of childhood and adolescent cancer. Procedure Eligibility for the CCSS cohort included a selected group of cancer diagnoses prior to age 21 years between 1970–1986 and survival for at least 5 years. Results A total of 20,276 eligible subjects were identified from the 25 contributing institutions, of whom 15% are considered lost to follow-up. Currently, 14,054 subjects (69.3% of the eligible cohort) have participated by completing a 24-page baseline questionnaire. The distribution of first diagnoses includes leukemia (33%), lymphoma (21%), neuroblastoma (7%), CNS tumor (13%), bone tumor (8%), kidney tumor (9%), and soft-tissue sarcoma (9%). Abstraction of medical records for chemotherapy, radiation therapy, and surgical procedures has been successfully completed for 98% of study participants. Overall, 78% received radiotherapy and 73% chemotherapy. Conclusion The CCSS represents the largest and most extensively characterized cohort of childhood and adolescent cancer survivors in North America. It serves as a resource for addressing important issues such as risk of second malignancies, endocrine and reproductive outcome, cardiopulmonary complications, and psychosocial implications, among this unique and ever-growing population. Med. Pediatr. Oncol. 2002;38:229–239. © 2002 Wiley-Liss, Inc.

Children with neurofibromatosis type 1 (NF1) are predisposed to develop central nervous system neoplasms, the most common of which are low-grade gliomas (LGGs). The absence of human NF1 associated LGG-derived cell lines, coupled with an inability to generate patient-derived xenograft models, represents barriers to profile molecularly targeted therapies for these tumors. Thus, genetically engineered mouse models have been identified to evaluate the interplay between Nf1-deficient tumor cells and nonneoplastic stromal cells to evaluate potential therapies for these neoplasms. Future treatments might also consider targeting the nonneoplastic cells in NF1-LGGs to reduce tumor growth and neurologic morbidity in affected children.

BACKGROUND The outcome of a child with a primitive neuroectodermal tumors arising supratentorially (SPNET) is not well characterized and may differ from the outcome of a patient with a histologically similar cerebellar tumor (medulloblastoma [MB]). Recently, 5-year progression free survival rates as high as 80% have been reported for children with MB treated with craniospinal radiation (CRT) and chemotherapy including cisplatin, lomustine (CCNU), and vincristine (VCR). METHODS The authors reviewed the outcome of 22 consecutive patients age 3 years and older (mean age, 10 years; range, 3-18 years) with SPNET who were treated at the study institutions between 1981 and 1996. Tumor location included was 13 pineal, 6 cortical, and 3 thalamic or suprasellar. Five patients had disease dissemination at diagnosis. All patients underwent surgery and staging, followed by CRT and chemotherapy with cisplatin, CCNU, and VCR. RESULTS Of the 22 patients, 13 had developed disease progression and 10 had died at the time of last follow-up. Overall progression free survival (PFS) was 47% ± 11% at 3 years and 37% ± 11% at 5 years. There was a significant difference in PFS between patients with localized disease versus those with disseminated disease (P = 0.04). There was no statistical association between tumor location and survival. Although not significant (P = 0.21), there was a trend toward better survival of those patients with complete or near-complete resection compared with those with partial resection or biopsy. CONCLUSIONS The results of the current study demonstrate that the outcome for children with SPNET treated with radiation and chemotherapy appears worse than for children with MB treated with identical therapy. This suggests that there may be biologic differences between supratentorial and infratentorial primitive neuroectodermal tumors, thus requiring refinements in treatment. Cancer 2000;88:2189–93. © 2000 American Cancer Society.

BACKGROUND The diencephalic syndrome (DS), which is manifested by progressive emaciation and failure to thrive in an apparently alert, cheerful infant, usually is due to a low grade hypothalamic glioma. Treatment with aggressive surgery and/or radiotherapy is variably successful in controlling disease and may result in severe neurologic sequelae. Chemotherapy recently has been shown to be effective in patients with low grade gliomas of childhood, but it is used infrequently in those with DS. METHODS The authors evaluated the efficacy of a regimen of carboplatin and vincristine on improving weight, causing tumor shrinkage, and delaying the need for alternative therapies in seven children (ages 9-20 months; median age, 11 months) with DS. Five patients weighed less than the 5th percentile for their age at the start of the study, one weighed within the 10th percentile, and one weighed within the 25th percentile. RESULTS At follow-up (range, 6-54 months; median, 28 months), the patients' weights had increased by 66-95% (median, 80%). On magnetic resonance imaging, four patients had a >50% reduction in tumor mass, one had a 25-50% reduction, and two had stable disease. In those patients with radiographic response to treatment, weight gain was accomplished with oral feedings in four of five patients, whereas those with stable disease required nasogastric, nasojejunal, or gastrostomy tube supplementation to maintain weight. Disease progression occurred at a median of 24 months after initiation of chemotherapy, and two patients remained free of progressive disease at last follow-up. Five patients were alive a median of 59 months from diagnosis. The need for radiation or other therapies was delayed in six of seven children. Therapy was tolerated without significant toxicities. CONCLUSION The authors conclude that treatment of DS with a carboplatin and vincristine regimen results in demonstrable weight gain, may result in tumor shrinkage, and in some cases, significantly delays the need for alternative therapies. Cancer 1998;83:166-172. © 1998 American Cancer Society.

BACKGROUND Topotecan is a topoisomerase I inhibitor that has good penetration across the blood-brain barrier and significant antitumor activity against human brain tumor xenografts. In a Phase I trial in children with refractory cancer, topotecan was well tolerated when administered as a 24-hour infusion. The maximum tolerated dose was 5.5 mg/m2 and the dose-limiting toxicity was myelosuppression. This Phase II study of topotecan was performed to assess the activity of topotecan against childhood brain tumors. METHODS Forty-five children with either a previously treated primary brain tumor that was refractory to standard therapy, or an untreated brain stem glioma or glioblastoma multiforme, received topotecan administered as a 24-hour intravenous infusion every 21 days. The initial dose was 5.5 mg/m2 with escalation to 7.5 mg/m2 on the second and subsequent doses in patients who did not experience dose-limiting toxicity. RESULTS There were no complete or partial responses in the patients with high grade glioma (n = 9), medulloblastoma (n = 9), or brain stem glioma (n = 14). One of 2 patients with a low grade glioma had a partial response lasting more than 17 months; 3 patients with a brain stem glioma had stable disease for 12 to 28 weeks; and 1 patient with a malignant neuroepithelial tumor and 1 patient with an optic glioma had stable disease for 41 weeks and 22 weeks, respectively. Dose esalation from 5.5 mg/m2 to 7.5 mg/m2 was well tolerated in the first 11 patients enrolled on this study who had not received prior craniospinal radiation therapy. The starting dose was subsequently increased to 7.5 mg/m2 for patients without prior craniospinal radiation. CONCLUSIONS Topotecan administered as a 24-hour infusion every 21 days is inactive in high grade gliomas, medulloblastomas, and brain stem tumors. Cancer 1996;78:527-31.

BACKGROUND Prognosis for the majority of children with brain stem gliomas is dismal. In previous studies, recombinant beta-interferon (rβIF) has been shown to be effective for children with recurrent brain stem gliomas and may also act synergistically with radiotherapy (RT). METHODS Thirty-two children with diffuse intrinsic brain stem gliomas were treated with (rβIF) and 7200 centigray (cGy) of hyperfractionated RT (100 cGy twice-daily fractions) to determine the toxicity of treatment and the tolerance of the brain stem to this regimen, as well as to assess survival. Patients were treated with rβIF 3 times per week during RT and then for 8 weeks following RT. Initially, a dose escalation trial was performed. RESULTS Interferon was initially begun at 12.5 × 106 IU/m2 and escalated up to 400 × 106 IU/m2. The safe starting dose was determined to be 100 × 106 IU/m2. Due to unacceptable toxicity, the maintenance dose was reduced to 200 × 106 IU/m2. Therapy was relatively well tolerated, although 13 of the patients required dose modifications due to hepatic or hematologic toxicity. Four of the patients had to discontinue treatment due to this toxicity. One patient died while receiving maintenance IF of encephalopathy, seizures, and brain stem dysfunction; believed possibly due to the rβIF. Thirty of the 32 patients have developed progressive disease. The median time to progression from study entry was five months and the median time to death was 9 months. CONCLUSIONS We conclude that rβIF plus hyperfractionated therapy can be tolerated by children with newly diagnosed brain stem gliomas, although there is occasional dose-limiting hepatic, blood, and central nervous system toxicity. This therapy did not result in a higher rate of disease control. Cancer 1996;77:2150-6.

Encephalopathy, leukoencephalopathy, and secondary parkinsonism occurred in 3 children with refractory leukemia undergoing allogenic bone marrow transplantation (BMT) who were treated with high-dose amphotericin B for pulmonary aspergillosis or sinus aspergillosis that did not involve the nervous system. Treatment included high-dose cytosine arabinoside, cyclophosphamide, and total body irradiation prior to the BMT. The children developed a progressively worsening encephalopathy and parkinsonian features, characterized by resting tremor, cogwheel rigidity, and masklike facies. Neuroimaging studies showed cerebellar, cerebral, and basal ganglia atrophy, as well as frontal and temporal lobe white matter involvement. Two of the 3 patients recovered, although 1 has residual intellectual impairment. The third succumbed to non-central nervous system Epstein-Barr virus-lymphoproliferative disease and had autopsy-confirmed leukoenephalopathy.

Background. Very young children with central nervous system malignant brain tumors have a poor prognosis. As compared with older children, survival is less likely, and those children who do survive frequently have severe impairment of growth and cognitive abilities, resulting partly from treatment with radiotherapy. Therefore, an intensive chemotherapeutic regimen was used to treat children younger than 2 years of age with a diagnosis of malignant astrocytomas. Patients and Methods. Thirty-nine children younger than 24 months of age who were diagnosed with malignant astrocytoma were treated on a Childrens Cancer Group protocol with an eight-drug chemotherapeutic regimen (vincristine, carmustine, procarbazine, bydroxyurea, cisplatin, cytosine arabinoside, prednisone, and dimethyl-triazenoimidazole-carboxamide) after surgery and postoperative staging. Radiation therapy was to be deferred until the completion of chemotherapy. Results. The objective response rate after two cycles of chemotherapy was 24%. Most patients did not receive radiotherapy. Progression-free survival (PFS) and survival at 3 years was 36% (standard error, 8%) and 51% (8%), respectively. The PFS of those children with anaplastic astrocytoma was 44% (11%), significantly better than that of glioblastoma multiforme (GBM) (0%). Extent of resection was not associated significantly with PFS, but tumors within the cerebral hemispheres were associated with a more favorable prognosis. Tumor progression occurred locally in almost all cases and early in treatment (median PFS, 8 months). Conclusion. Chemotherapy appears to be effective primary adjuvant treatment for some very young children with anaplastic astrocytomas. Overall, however, survival remains poor, especially for children with GBM. Strategies to improve outcome require early intervention, because tumor progression occurs soon after diagnosis in the majority of patients. Cancer 1995 ; 75 :1045-50.

Background. Gliomas of the hypothalamus and optic pathways (H/OPG) comprise 5% of pediatric intracranial tumors, present most frequently in patients younger than age 5 years, and may have a more aggressive course in younger children. This study examined clinical characteristics and consequences of treatment of young children diagnosed with H/OPG. Methods. The authors reviewed the course, treatment, and outcomes of 46 children diagnosed with H/OPG younger than age 5 years; the median follow-up was 72 months. The median age at diagnosis was 27 months. Results. Fifteen (33%) of 46 patients had neurofibromatosis-1 (NF-1).Forty children (87%) had tumor progression in the follow-up period, and tumor growth was less common in children with NF-1. Initial therapy was limited to surgical resection in three and radiation in five children. To postpone radiation until after the age of 5 years, initial therapy was limited to chemotherapy in 32 patients. Radiation was not required in 9 of these patients and was postponed for 40 months (mean) in 17. Of the 46 children, 5 died of tumor progression, 4 became blind, and 20 of 34 evaluable patients had endocrine abnormalities. Endocrinopathy did not correlate with therapy. Ten of 17 children evaluated by questionnaire required special education. There was a trend for educational problems to occur in children who were irradiated before the age of 5 years. Conclusions. Gliomas of the hypothalamus and optic pathways and their treatment cause long term morbidity in young children. Chemotherapy postpones radiation effectively, and this delay may reduce neurologic morbidity; however, 60% of children eventually relapse. By contrast, patients with NF-1 have indolent disease. Cancer 1995;75:1051-9.

Background. Brain stem gliomas remain the childhood brain tumors most resistant to treatment. Treatments with hyperfractionated radiotherapy at doses as high as 7560 cGy have been fairly well tolerated. This study was undertaken to determine the toxicity and possible efficacy of hyperfractionated radiotherapy in children with brain stem gliomas using 100 cGy of radiation twice daily, to a total dose of 7800 cGy. Methods. Sixty-six children (mean age at diagnosis, 7.5 years) with diffuse intrinsic brain stem gliomas were treated. Patients were evaluated for potential toxicity of treatment, progression-free survival, survival, and response to treatment. Results. Objective response to treatment was documented in 20 of 58 (34%) evaluable patients, with 8 (14%) patients having a greater than 50% reduction in tumor size. Overall survival was 35% plus or minus 6% at 1 year and 11% plus or minus 6% at 3 years. Intralesional cystic/necrotic radiographic changes developed in nine patients 6 weeks after radiation, and three of these patients subsequently improved without antitumor intervention. Six of 14 autopsied patients had evidence of probable radiation-induced intralesional necrotic damage, and in 1, necrosis may have played a role in death. Thirty-three of 66 patients were treated with steroids for prolonged periods. Conclusions. The results of this treatment regimen demonstrate that hyperfractionated radiotherapy, as delivered in this study to a total dose of 7800 cGy, is relatively well tolerated, but may result in prolonged steroiduse dependency and possible radiation-associated damage. Objective responses to treatment were seen in 34% of patients, but these results were not better than those seen at lower doses of hyperfractionated radiotherapy. There is no evidence that radiation to 7800 cGy results in improved survival for patients with diffuse intrinsic brain stem gliomas.

Background. Most children with brain stem gliomas (BSG) die within 18 months of diagnosis. Early experience suggested that hyperfractionated radiation therapy (RT) at a dose of 72 Gy, administered in 1-Gy fractions twice daily, possibly improved disease-free survival for children with BSG. Methods. To better characterize the toxicity and possible efficacy of this dose and fractionation of RT, 53 assessable children with diffuse intrinsic or malignant BSG were treated. Survival figures also were combined with outcome in 36 patients treated in a previous pilot study. Results. An objective response to treatment was observed in 28 of 53 (53%) patients; a partial response occurred in 7. No child died of treatment-related brain necrosis, although 7 of 53 did have intralesional cystic/necrotic changes within 6 weeks of completion of RT. The overall survival rate for patients in the study was 38% (± 6.5) at 1 year, 14% (± 5.4) at 2 years, and 8% (± 6.5) at 3 years. Leptomeningeal dissemination was observed in 4 of 48 (8%) children who had relapses. A greater than 2-month duration of symptoms before diagnosis was related to a better prognosis. There was no statistical association between any other clinical parameter, neuroradiographic finding, or pathologic finding and outcome. Combined with that in 35 patients treated in the pilot study, the survival rate in 88 children was 14% (k 5) at 3 years. Conclusions. The radiographic response rate is encouraging; however, it cannot be concluded that hyperfractionated RT, at this dose schedule and total dose, is superior to conventional RT. Cancer 1993; 72:1414-21.

Background. Both thiotepa and its active metabolite, tepa, efficiently cross the blood-brain barrier. After intravenous administration, the cerebrospinal fluid concentrations achieved are nearly identical to those in olasma. This provides a strong rationale for testing this agent against brain tumors. Methods. Sixty pediatric patients with recurrent primary brain tumors were treated on a multiinstitutional Phase II study of intravenous thiotepa at a dose of 5 mg/m2 administered every 3 weeks. This dose is the result of a prior pediatric Phase I trial and is significantly higher than those previously recommended. Results. Three of 13 assessable patients with medul-oblastoma had partial responses lasting 22, 25, and 54 weeks. Although no objective responses were observed in 6 assessable patients with malignant gliomas and 14 with brain stem gliomas, 5 of 16 and 4 of 14 patients in elese respective strata had prolonged periods of stable isease (SD) lasting from 12 to more than 33 weeks. Nine ssessable patients with ependymoma had no objective esponse, but two had SD, both for more than 33 weeks. Myelosuppression was the principle toxic effect encoun-ered and appeared to be more severe in patients who had received prior craniospinal radiation therapy or nitro-urea therapy. Conclusions. By conventional Phase II criteria, thiotepa appears to have activity in medulloblastoma. Based on several patients with prolonged SD, it also may possess some limited activity in brain stem and malignant gliomas. The steep in vitro dose-response curve of thiotepa and the long durations of response or SD observed with the dose reported here suggest that moderate-dose to high-dose thiotepa with cytokine support or autologous bone marrow rescue may be associated with an improved response rate to this agent. Cancer 1993; 72:271–5.

A 3-year-old girl received conventional-dose external beam posterior fossa irradiation (5400 cGy in 30 fractions over 40 days) for good-risk medulloblastoma. Soon thereafter, she experienced an extraneural (occipital scar, cervical lymph nodes) and central nervous system (CNS) recurrence. Intensive cisplatin and cyclophosphamide chemotherapy led to rapid disappearance of the extraneural disease. Methotrexate was administered via a ventricular reservoir. After 2 months of chemotherapy, CNS toxicity progressed rapidly from ataxia to paraplegia to quadriplegia to central respiratory failure. Radiographic scans and autopsy material revealed brain stem necrosis. This unusual toxicity raises concern about the safety of aggressive systemic chemotherapy and intrathecal therapy, when given after conventional radiotherapy.

Background. A higher total dose of radiation therapy administered in fractionated lower individual doses twice daily (hyperfractionated radiation therapy) has been reported to improve survival for children with brain stem gliomas. However, this higher dose of radiation therapy may cause more sequelae. Method. Eighty-eight children with brain stem gliomas were treated with 100 cGy twice daily to a total dose of 7200 cGy. Patients were carefully followed up for treatment-related clinical or radiographic worsening. Results. Thirteen (15%) had intralesional cystic/necrotic changes within 8 weeks of completion of treatment. Children with these changes had a variable clinical course, including steady deterioration in one child; initial improvement, followed by progressive deterioration in three; and initial improvement, followed by deterioration, with subsequent improvement or prolonged stabilization of condition without additional antineoplastic treatment in nine. Conclusion. This latter “triphasic” course suggests that “early” worsening after hyperfractionated radiation therapy at 7200 cGy may be a sequelae of therapy, rather than a symptom of progressive tumor growth. This has substantial implications for patient care and evaluation of the efficacy of treatment.