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Neurofibromatosis type 1 (NF1) is a common autosomal dominant condition caused by mutation in the NF1 tumor-suppressor gene which encodes neurofibrin, a regulator of cell proliferation through the RAS/MAPK pathway. NF1 patients frequently develop central nervous system low-grade gliomas (LGGs), but are also at increased risk for developing malignant tumors such as neuroblastoma which combined are associated with worse prognosis. The association between NF1 and neuroblastoma has been well established, though rarely reported, and its molecular basis still requires further investigation. Additionally, MEK inhibition via disruption of the RAS/MAPK pathway has been shown to be effective in neuroblastoma models in vitro, and is currently being tested in several LGG clinical trials. Co-occurrence of both tumors in a patient with NF1 is exceedingly rare and has been reported only once thus far. Here, we report on the first case in the literature for the use of a MEK inhibitor in a seven years old NF1 patient with high-risk metastatic neuroblastoma and optic pathway glioma without BRAF mutation or fusion. The patient is currently maintained on MEK inhibitor monotherapy for over a year with minimal dermatological side effects. Significant radiographic improvement in the optic pathway glioma as well as stability in the metastatic neuroblastoma has been demonstrated. Comprehensive clinical molecular testing of both tumors is currently pending.

BACKGROUND: The optimal management of young children with newly-diagnosed supratentorial ependymomas remains poorly-defined. We report outcomes of young children under 7 years old at diagnosis prospectively treated on three sequential multi-center trials of intensive chemotherapy with intent of avoiding irradiation. METHODS: Between 1991 and 2009, 14 children (median/mean ages of 34 months, range 3–74 months) were enrolled on “Head Start” (HS) trials (3 on HS-I, 3 on HS-II and 8 on HS-III). Induction chemotherapy was identical on HS-I and HS-II; on HS-III, this regimen was supplemented with high-dose systemic methotrexate in each cycle. Consolidation was uniform with a single cycle of marrow-ablative thiotepa/etoposide/carboplatin followed by autologous hematopoietic cell rescue. Irradiation was reserved for children >72 months old or with residual disease following Induction. Tumor pathology underwent central review. RESULTS: Ten children achieved initial gross total resections (GTRx) of tumor and 4 subtotal resections 2 of whom achieved GTRx following chemotherapy. Pathology revealed cellular ependymoma in 6 and anaplastic ependymoma in 8. There was 1 toxic death in Induction, on HS-I. Four children relapsed (3 on HS-II, 1 on HS-III), all locally, 3 expiring of disease despite focal irradiation, 20–72 months from initial diagnosis; the fourth continues recurrence-free after GTRx and focal irradiation. Seven patients survive without irradiation. CONCLUSIONS: Young children with supratentorial ependymomas have a good survival outcome when treated with irradiation-avoiding chemotherapy incorporating high-dose systemic methotrexate. However, it remains unclear if similar results could have been achieved with GTRx alone. The prognostic significance of molecular subtype is under evaluation.

Metabolism of drugs in infants and young children is significantly different from older individuals due to differences in distribution, protein-binding capacity, hepatic metabolism and renal excretion. Body surface area (BSA) is used to dose chemotherapeutics in older children; however, this is inappropriate for infants and young children since it does not take into account the differences in extracellular water distribution. We describe four cases of sinusoidal obstruction syndrome (SOS) that occurred in young children while receiving induction chemotherapy with cisplatin, etoposide, vincristine, cyclophosphamide and high-dose methotrexate on the “Head Start (HS)” 4 clinical trial using BSA for dosing (mg/m2). Patients #1 and #2 were both 2-years old at diagnosis, received and tolerated the first two cycles with mg/kg dosing uneventfully, then turned 3-years old and received cycle #3 with mg/m2 dosing as per protocol guidelines, and developed SOS. Patient #3 was 3-years old at diagnosis, received induction chemotherapy with mg/m2 dosing, and developed SOS during the very first cycle. Patient #4 was 4-years old at diagnosis and received all 3 induction cycles with mg/m2 dosing, developed serious nephrotoxicity during cycle #1 followed by SOS during cycle #3. In contrast, none of the 40 patients treated on HS II protocol with identical chemotherapy regimen, but with mg/kg dosing, developed SOS. Caution should be exercised when dosing young children between 3-6 years of age by BSA. The HS 4 trial was amended and reopened after external, independent DSMB review to dose all chemotherapy drugs in children

BACKGROUND: Primary CNS embryonal carcinoma confers a poor prognosis despite conventional chemotherapy and radiotherapy. We report upon a novel treatment approach to CNS embryonal carcinoma using intensive, including marrow-ablative, chemotherapy followed by maintenance therapy with brentuximab-vedotin without irradiation. Brentuximab-vedotin is an anti-CD30 antibody conjugated to an anti-tubulin synthetic analog. METHODS: Retrospective review of two patients’ medical records treated since 2015 at Nationwide Children’s Hospital. RESULTS: We report upon the management of two patients with suprasellar pure, CD30-positive embryonal carcinoma. A 17-years-old female with Down syndrome compounded by autism and a 9-years-old male with documented cognitive dysfunction received two cycles of carboplatin/etoposide interspersed with one cycle of cyclophosphamide/etoposide for induction, followed by three cycles of marrow-ablative thiotepa/carboplatin with autologous hematopoietic cell rescue. The first patient achieved complete radiographic and tumor marker response to induction and marrow-ablative chemotherapy, and has completed six cycles of intravenous brentuximab-vedotin, continuing now disease-free 28 months since diagnosis without adverse effects. The second patient had a complete serum and cerebrospinal fluid tumor marker response and a dramatic radiographic response with a small residual abnormality at the end of marrow-ablative chemotherapy that was found at surgery to be composed of predominately reactive changes. Currently, the patient has received the first of six proposed cycles of intravenous brentuximab-vedotin. CONCLUSION: Intensive, including marrow-ablative chemotherapy followed by maintenance with an anti-CD30 antibody-drug conjugate may provide selective and safe alternative to radiotherapy in the management of patients with CNS embryonal carcinoma especially for patients at high risk of developing irradiation-related complications.

BACKGROUND: Pediatric cancer cure rates differ among high-income countries (HIC) and low-to-middle income (LMIC) countries. The World Health Organization reports 20% of LMIC have the necessary data and resources to significantly decrease the rate of mortality in their patients. We compared individual capacities of two major pediatric institutions from a HIC and LMIC caring for children with CNS cancer, the second most common type of cancer of childhood. METHODS: A quantitative-needs assessment questionnaire and key informant interviews were used to evaluate the treatment of children with CNS cancer at IOP/GRAACC/UNIFESP children’s cancer center in São Paulo, Brazil and Nationwide Children’s Hospital/The Ohio State University (NCH/OSU) in Columbus, OH; United States. RESULTS: Both hospitals have 24-hour pediatric oncology, nursing and pediatric intensivist coverage. Supportive care including social workers, psychologists, child life specialists, and physical/occupational/speech therapists are available at both centers. Differences included 2 part-time neuro-radiologists and 2 pathologists at IOP/GRAACC/UNIFESP, whereas 8 full-time neuro-radiologists and 12 pathologists (with 2 specially trained in neuro-pathology) at NCH/OSU. There are 4 pediatric neurosurgeons on staff at each hospital, however, 2 surgical days at IOP/GRAACC/UNIFESP, compared to 7 days/week at NCH/OSU. Additionally, delays in initiation of radiation treatment at IOP/GRAACC/UNIFESP extended 2–4 weeks compared to less than 1 week at NCH/OSU. CONCLUSION: Center-specific differences in resources exist in highly-specialized hospitals caring for children with CNS cancer in LMIC and HIC. This quantitative-needs assessment can develop targeted strategies for effective interventions to improve on the management of children with CNS cancers.

INTRODUCTION: Pediatric low-grade gliomas (pLGG) represent the most common brain tumors in children. Though malignant transformation is rare, these tumors pose a formidable therapeutic challenge due to anatomy-limiting surgical options and local recurrence. The temporal and therapy-driven genomic evolution in pLGG is largely unknown. METHODS: To characterize the temporal genomic heterogeneity of pLGG, we performed fluorescence in situ hybridization, mutation-specific immunohistochemistry, and exome analyses on paired tumor samples from primary diagnostic and subsequent surgeries of 27 pLGG patients. RESULTS: 59 tumor samples were available for review and included pilocytic / pilomyxoid astrocytoma (PA) (67%), low grade astrocytoma (19%), ganglioglioma (11%), and pleomorphic xanthoastrocytoma (3%). BRAF duplication/rearrangement was detected in 56% of tested samples, limited to PA in all but one patient (ganglioglioma). 58% of samples harbored CDKN2A deletion, which was demonstrable across various histologies. BRAF duplication/rearrangement was found consistently conserved across primary and subsequent surgical samples, whereas CDKN2A status changed in 60% of tested temporal pairs, with deletion acquisition the most frequent finding (40%) at second surgery. Likewise, BRAF V600E mutation in one PA was lost at second surgery. Although CDKN2A status changes were seen following surgery alone, the addition of chemo-and/or radiation therapy was associated with a higher rate of temporal CDKN2A deletion acquisition (50%, versus 33% with surgery alone). CONCLUSION: Temporal genomic heterogeneity may be encountered in a significant proportion of pLGG, with some alterations potentially facilitated by therapy. Recurrence biopsy may provide improved guidance, particularly if targeted therapeutics are being considered.

PURPOSE: The LATB is a weekly teleconference operating over 3.5 years connecting pediatric neuro-oncologists from high-income countries with pediatric subspecialists from 20 Latin-American countries. This survey explored the participants’ experience utilizing this resource. METHODS: A web-based questionnaire was distributed to 159 participants through email and www.Cure4Kids.org. RESULTS: Ninety-five respondents (60%) from all the 20 participating countries completed the survey. Sixty-one reported frequent-attendance (≥ 1 per month), 23 reported infrequent-attendance (< 1 per month), and 11 never participated. The main barriers to attendance were the subspecialist’s respective workload (64%), the timing of the teleconference (38%), and internet connectivity problems (29%). Subspecialist’s workload amount was more commonly reported as a barrier compared with other barriers, in both the frequent and infrequent-attendance groups (p

Activation of the MAPK pathway represents a hallmark of pediatric low-grade glioma (pLGG) and is frequently caused by BRAF alterations. BRAF-V600E represent an aggressive type of pLGG with less than optimal response to conventional chemo-radiation approaches. While clinical trials using BRAF-V600E inhibitors are ongoing, these data are not yet available. We have assembled an international cohort of BRAF-V600E glioma patients treated off-label with BRAF inhibitors as a monotherapy. Complete molecular, clinical and imaging data is being collected and compared to previous chemo-radiation therapies. Ongoing data form the taskforce on 40 BRAF-V600E gliomas from 25 international institutions is summarized below. The most prevalent histologies were ganglioglioma, pilocytic astrocytoma and pleomorphic xanthoastrocytoma, located mainly in the chiasm, brainstem and temporal lobes. Strikingly, 66% of BRAF V600E pLGG patients achieved partial response (PR) to targeted inhibitors versus only 6.6% response to conventional chemotherapy (p

To evaluate the Quality of Life (QoL) and Social-Emotional/Behavioral functioning of survivors treated on the "Head Start I" protocol at participating medical centers across the United States between 1991 and 1997. Parents of 25 of 27 (92.5%) patients completed the Child Health Questionnaire PF-50 (CHQ), to assess their child's QoL, along with the Behavior Assessment System for Children (BASC), to assess their social-emotional/behavioral functioning, after a mean follow-up of 5.7 years (range 13-96 months). Nineteen (76%) of the 25 parents subsequently completed the same instruments after a mean of 11.6 years (range 90-181 months), three (12%) patients died of disease and three (12%) were lost to follow-up. Mean Physical and Psychosocial QoL Summary Scores on the CHQ at Time 1 (T1) and Time 2 (T2) were within the normal range. Of the ten individual means for CHQ subscales, nine were within normal limits with the exception of Parental Emotional Impact at T1 and General Health at T2. Additionally, mean scores on the BASC at T1 and T2 were within normal limits for Externalizing and Internalizing Behaviors as well as Adaptive Skills. Serial analyses between T1 and T2 revealed non-significant changes over time with the exception of decreased General Health on the CHQ. The lack of QoL and Social-Emotional/Behavioral deficits suggests that the Head Start I protocol, involving intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue in order to avoid or delay cranial irradiation, provides encouraging pilot data warranting continued monitoring.

Purpose Choroid plexus carcinomas are pediatric tumors with poor survival rates and a strong, but poorly understood, association with Li-Fraumeni syndrome (LFS). Currently, with lack of biologic predictors, most children are treated with aggressive chemoradiation protocols. Patients and Methods We established a multi-institutional tissue and clinical database, which enabled the analysis of specific alterations of the TP53 tumor suppressor and its modifiers in choroid plexus tumors (CPTs). We conducted high-resolution copy-number analysis to correlate these genetic parameters with family history and outcome. Results We studied 64 patients with CPTs. All individuals with germline TP53 mutations fulfilled LFS criteria, whereas all patients not meeting these criteria harbored wild-type TP53 (P < .001). TP53 mutations were found in 50% of choroid plexus carcinomas (CPCs). Additionally, two sequence variants known to confer TP53 dysfunction, TP53 codon72 and MDM2 SNP309, coexisted in the majority of TP53 wild-type CPCs (92%) and not in TP53 mutated CPC (P = .04), which suggests a complementary mechanism of TP53 dysfunction in the absence of a TP53 mutation. High-resolution single nucleotide polymorphism (SNP) array analysis revealed extremely high total structural variation (TSV) in TP53-mutated CPC tumor genomes compared with TP53 wild-type tumors and choroid plexus papillomas (CPPs; P = .006 and .004, respectively). Moreover, high TSV was associated with significant risk of progression (P < .001). Five-year survival rates for patients with TP53-immunopositive and -immunonegative CPCs were 0% and 82 (± 9%), respectively (P < .001). Furthermore, 14 of 16 patients with TP53 wild-type CPCs are alive without having received radiation therapy. Conclusion Patients with CPC who have low tumor TSV and absence of TP53 dysfunction have a favorable prognosis and can be successfully treated without radiation therapy.

Childhood central nervous system (CNS) germinoma are highly curable brain tumors characterized pathologically by varying degrees of lymphocytic infiltration. The authors present a case of a CNS germinoma with significant regression in size following surgery and administration of dexamethasone, prior to initiation of chemotherapy or irradiation. The authors speculate the possible mechanism involved in its occurrence. Perioperative corticosteroid administration in patients with CNS germinoma may obfuscate the increase in response demonstrated with various chemotherapy regimens or with irradiation in CNS germinomas.

The authors report the experience at the Children's Hospital Los Angeles with brain tumors diagnosed before 6 months of age, describing the characteristics of the patients, their tumors, treatment strategies, and prognostic factors.Thirty-three children who were identified between 1979 and 2005 were included. Twelve were female (36%). There were 11 gliomas, 9 choroid plexus tumors, 8 medulloblastomas and supratentorial primitive neuroectodermal tumors (PNET), 2 atypical teratoid/rhabdoid tumors (ATRT), and 1 each of ependymoma, craniopharyngioma, and immature teratoma. Locations of primary tumors included 21 supratentorial (64%) and 7 posterior fossa, and 5 tumors involved both compartments. The treatment strategies included 5 patients with biopsy only, 18 less than gross total resections (GTRx), and 9 GTRx. Fourteen children (42%) received chemotherapy. Three patients (9%) received irradiation, 1 at initial diagnosis and 2 at relapse. Nine patients (27%) demonstrated metastases, 6 at diagnosis and 3 at relapse.The Kaplan Meier analysis of event-free survival (EFS) and overall survival (OS) for all patients is 21 +/- 9% and 35 +/- 9% at 5 years. For the glioma patients, the 4-year OS is 48 +/- 17%, while the 5-year OS for the medulloblastoma/PNET/ATRT patients is 12 +/- 11% (p = .39). The 5-year OS for children achieving a GTRx is 64 +/- 21% and for those withGTRx is 27 +/- 10% (p = .08).

Background The treatment of central nervous system (CNS) germ cell tumors (GCT) remains controversial. The purpose of this study was to demonstrate efficacy of a chemotherapy only strategy, with less morbidity, when compared to regimens with irradiation. Methods Between January 2001 and December 2004 newly diagnosed patients with CNS GCT were treated with one of two risk-tailored chemotherapy regimens. Twenty-five patients aged 4 months to 24.5 years were stratified: Regimen A consisted of 4–6 cycles of carboplatin/etoposide alternating with cyclophosphamide/etoposide for low risk (LR) localized germinoma with normal cerebrospinal fluid (CSF) and serum tumor markers. Regimen B consisted of 4–6 cycles of carboplatin/cyclophosphamide/etoposide for intermediate-risk (IR) germinoma with positive human chorionic gonadotrophin-beta (HCGβ) and/or CSF HCGβ 50 mIU/ml. Results Eleven patients were classified as LR, 2 IR, and 12 HR. Seventeen (68%) patients achieved complete radiographic and marker responses after two courses and 19 (76%) after four courses of chemotherapy. Eleven patients relapsed at a mean of 30.8 months; eight of them subsequently received irradiation. The 6-year event free and overall survival for the 25 patients was 45.6% and 75.3%, respectively. Conclusion These intensive chemotherapy regimens proved less effective than irradiation containing regimens. Our results indicate that, at the present time, standard treatment for CNS GCT continues to include irradiation either alone or combined with chemotherapy for pure germinomas and with chemotherapy for those with MMGCT. Pediatr Blood Cancer 2010;54:377–383. © 2009 Wiley-Liss, Inc.

Background Trilateral retinoblastoma has been lethal in virtually all cases previously reported. We describe a series of 13 patients treated with intensive chemotherapy, defined as the intention to include high-dose chemotherapy with autologous hematopoietic stem cell rescue. Procedure Induction chemotherapy generally included vincristine, cisplatin or carboplatin, cyclophosphamide, and etoposide. Hematopoietic stem cells typically were harvested after the first or second cycle of induction chemotherapy, usually from peripheral blood. High-dose chemotherapy regimens were thiotepa-based (n = 7) or melphalan and cyclophosphamide (n = 3). Results Trilateral sites were pineal (n = 11) and suprasellar (n = 2); 7 patients had localized (M-0) disease and six had leptomeningeal dissemination (M-1+). Five patients had trilateral retinoblastoma at original diagnosis of intra-ocular retinoblastoma; eight later developed trilateral disease at a median of 35 months (range 3–60 months) following diagnosis of intra-ocular retinoblastoma. One patient died of toxicity (septicemia and multi-organ system failure) during induction and three developed disease progression prior to high-dose chemotherapy. Nine patients received high-dose chemotherapy at a median of 5 months (range 4–9) post-diagnosis of trilateral disease. Five patients survive event-free at a median of 77 months (range 36–104 months) and never received external beam radiation therapy. Four of seven patients with M-0 disease survive event-free versus only one of six patients with M-1+ disease. Conclusions Intensive chemotherapy is potentially curative for some patients with trilateral retinoblastoma, especially those with M-0 disease Pediatr Blood Cancer 2010;54:384–387. © 2009 Wiley-Liss, Inc.

BACKGROUND: The role of myeloablative chemotherapy in children with recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors (MB/ST-PNET) is controversial, in particular in patients who develop recurrent disease after craniospinal radiotherapy. METHODS: In this retrospective analysis, the authors investigated the outcome of children with recurrent MB/ST-PNET who were referred for myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue at Childrens Hospital Los Angeles. RESULTS: Thirty-three children were referred for myeloablative chemotherapy: Fourteen of those children were never transplanted because of pre-transplant adverse events, and 19, including 6 without and 13 with previous irradiation, underwent transplant. Conditioning regimens included a backbone of thiotepa, which was given either in a single cycle or in multiple sequential cycles. The 3-year post-transplant event-free survival rate in unirradiated versus previously irradiated children was 83% ± 15% versus 20% ± 12%, respectively (P = .04). One child who had never been exposed to radiotherapy died of toxicity; the other children received post-transplant radiotherapy and remained disease free. Nine previously irradiated children experienced 4 toxic deaths and 6 tumor recurrences (1 patient had both): An interval of

Background Anaplastic large cell lymphoma (ALCL) is characterized by advanced disease at presentation (70–80% of pediatric cases) and accounts for 10–15% of all childhood lymphomas. Treatment strategies for pediatric ALCL vary from short pulse B-NHL chemotherapy to prolonged leukemia like therapy. The optimal treatment strategy is unknown. Methods CCG-5941 used a compressed aggressive multiagent T-cell lineage chemotherapy regimen consisting of a 3-week induction therapy (vincristine, prednisone, cyclophosphamide, daunomycin, asparaginase) followed by a 3-week consolidation period (vincristine, prednisone, etoposide, 6-thioguanine, cytarabine, asparaginase, methotrexate) followed by six courses of maintenance chemotherapy at 7-week intervals (cyclophosphamide, 6-thioguanine, vincristine, prednisone, doxorubicin, asparaginase, methotrexate etoposide, cytarabine). Total therapy was 48 weeks. Results Eighty-six children (male 56%, female 44%) with non-localized ALCL (CD30+) were treated. The majority of tumors were positive for ALK (90%) and of T lineage (83%). Extranodal disease was common (mediastinum 35%, skin 15%, lung 14%, bone 12%, bone marrow 13%, liver 6%, and other viscera 17%). Grade 4 neutropenia occurred in 82% of patients. The 5-year EFS was 68% (95% CI of 57–78%) and the 5-year OS was 80% (95% CI of 69–87%). There were 21 relapses and 4 toxic deaths as first events. Relapse occurred early with 17 (81%) relapses occurring within 2 years of diagnosis and 12 (57%) while receiving therapy. Univariate analysis for risk factors only identified bone marrow involvement predicting lower EFS (P = 0.03). Conclusions CCG-5941 demonstrated efficacy similar to previously reported regimens but with significant hematologic toxicity. Pediatr Blood Cancer 2009;52:335–339. © 2008 Wiley-Liss, Inc.

Pediatric lymphoblastic lymphoma (LL) has utilized treatment strategies similar to childhood acute lymphoblastic leukaemia (ALL) with prolonged maintenance chemotherapy. We report the results of a pilot study to estimate the feasibility, toxicity and efficacy of a 12-month aggressive multi-agent chemotherapy regimen in children and adolescents with advanced LL. Between July 1994 and June 1997, 85 eligible children and adolescents with advanced LL (Stage III/IV) were enrolled on this pilot study. Patients achieving a complete response following induction and consolidation received six cycles of maintenance chemotherapy for a total duration of 12 months. Grade III/IV toxicities included: hematological (80%), infections (20%), stomatitis and elevated transaminases, (29%). There were a total of 19 events, 13 relapses, two secondary acute myeloid leukaemia and four toxic deaths (5%). The 5-year event-free survival (EFS) and overall survival (OS) was 78 +/- 4.5% and 85 +/- 3.9%, respectively. Relapsed patients had a 5-year OS of only 33 +/- 14%. Multivariate analysis failed to demonstrate age, gender, lactate dehydrogenase level, presence of marrow and/or central nervous system disease to have independent prognostic value. These results suggest that this experimental approach is safe and results in similar outcomes as more prolonged childhood ALL regimens.

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 To determine the impact of diagnostic serum and/or cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (b-HCG) elevations on survival in newly diagnosed patients with central nervous system germ cell tumors (CNS GCT) treated with chemotherapy with the intent to avoid irradiation. Procedure Seventy-five patients with newly diagnosed CNS GCT enrolled in two sequential internationally conducted clinical trials with serum and CSF AFP and b-HCG levels available from initial diagnosis were retrospectively analyzed. Subjects received platinum based chemotherapy and were followed with serial imaging and tumor marker evaluations. Results The 5-year overall survival (OS) and event free survival (EFS) for patients with normal tumor markers compared with those with elevated markers at diagnosis was 78% (95% CI 51–91%) versus 60% (95% CI 46–72%) (P = 0.08) and 22% (95% CI 7–43%) versus 28% (95% CI 16–40%) (P = 0.68). The hazard ratio of death for patients with elevated markers was 1.9 times as high as that for those with normal markers (95% CI 0.58–6.5) after adjusting for other baseline characteristics. There was no observed difference in survival among patients with histologically confirmed germinomas, irrespective of level of b-HCG. Conclusions Patients with elevated tumor markers appear to have poorer OS independent of tumor histology, although these differences do not reach statistical significance (P ≤ 0.05). No differences were observed in EFS between groups likely due to the poor response of chemotherapy only approach to patients with normal markers. b-HCG elevations in biopsy proven germinomas do not seem to alter a patient's prognosis. Pediatr Blood Cancer 2008;51:768–773. © 2008 Wiley-Liss, Inc.

BACKGROUND AND PURPOSE: In a subset of in vivo MR spectra acquired from pediatric brain tumors, we have observed an unassigned peak. The goal of this study was to determine the molecule of origin, and the prevalence and concentration of this chemical in various pediatric brain tumors. MATERIALS AND METHODS: Single-voxel point-resolved spectroscopy (PRESS) spectra from 85 patients with brain tumors and 469 control subjects were analyzed. Citrate seemed to be a likely candidate, and model spectra of citrate were added to the basis set of metabolites for automated processing with use of LCModel software. Absolute “apparent” concentrations of citrate and the Cramer-Rao lower bounds (CRLB), indicators for the reliability of detection, were determined. RESULTS: “Apparent” citrate was detected in 26 of 85 patients with CRLB of less than 25%. Diffuse intrinsic brain stem glioma (DIBSG) had the highest mean concentration (4.0 ± 1.1 mmol/kg in all subjects), and 8 of 12 patients had CRLB less than 25%. A significant reduction of citrate (P < .01) was observed in 6 DIBSGs that had follow-up MR spectroscopy studies after radiation therapy. “Apparent” citrate with CRLB less than 25% was detected in 5 of 22 medulloblastomas (mean citrate, 2.9 ± 2.2 mmol/kg), in 5 of 14 ependymomas (2.6 ± 1.8 mmol/kg), 5 of 14 astrocytomas (1.9 ± 1.2 mmol/kg), and 3 of 23 pilocytic astrocytomas (1.4 ± 1.1 mmol/kg). In control subjects older than 6 months, CRLB less than 25% was not observed, whereas CRLB less than 25% was observed in 39 of 194 subjects younger than 6 months,. CONCLUSION: MR signal consistent with citrate was observed in pediatric brain tumors and in the developing brain of infants younger than 6 months.

Background Children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNET) have poor outcomes compared to medulloblastoma patients, despite similar treatments. In an effort to improve overall survival (OS) and event-free survival (EFS) and to decrease radiation exposure, the Head Start (HS) protocols treated children with newly diagnosed sPNET utilizing intensified induction chemotherapy (ICHT) followed by consolidation with myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR). Procedures Between 1991 and 2002, 43 children with sPNET were prospectively treated on two serial studies (HS I and II). After maximal safe surgical resection, patients on HS I and patients with localized disease on HS II were treated with five cycles of ICHT (vincristine, cisplatin, cyclophosphamide, and etoposide). Patients on HS II with disseminated disease received high-dose methotrexate during ICHT. If the disease remained stable or in response, patients received a single cycle of high-dose myeloablative chemotherapy followed by AuHCR. Results Five-year EFS and OS were 39% (95%CI: 24%, 53%) and 49 (95%CI: 33%, 62%), respectively. Non-pineal sPNET patients faired significantly better than those patients with pineal sPNETs. Metastasis at diagnosis, age, and extent of resection were not significant prognostic factors. Sixty percent of survivors (12 of 20) are alive without exposure to radiation therapy. Conclusions ICHT followed by AuHCR in young patients with newly diagnosed sPNET appears to not only provide an improved EFS and OS for patients who typically have a poor prognosis, but also it successfully permitted deferral and elimination of radiation therapy in a significant proportion of patients. Pediatr Blood Cancer 2008;50:312–318. © 2007 Wiley-Liss, Inc.

Purpose To determine the survival of infants and young children with non-metastatic medulloblastoma using intensive myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR). Methods Twenty-one children less than 3 years old at diagnosis with non-metastatic medulloblastoma were enrolled on two identical serial studies, “Head Start” I and “Head Start” II. After surgery, patients received five cycles of induction chemotherapy consisting of vincristine, cisplatin, cyclophosphamide and etoposide. Following induction, all patients underwent myeloablative chemotherapy using carboplatin, thiotepa and etoposide with AuHCR. Irradiation was used only at relapse. Results The 5-year event-free (EFS) and overall survival (OS) rates (±SE) for all patients, patients with gross total resection, and patients with residual tumor were 52 ± 11% and 70 ± 10%, 64 ± 13% and 79 ± 11%, and 29 ± 17% and 57 ± 19%, respectively. The 5-year EFS and OS ( ± SE) for patients with desmoplastic and classical medulloblastoma were 67 ± 16% and 78 ± 14%, and 42 ± 14 and 67 ± 14%, respectively. There were four treatment related deaths. The majority of survivors (71%) avoided irradiation completely. Mean intellectual functioning and quality of life (QoL) for children surviving without irradiation was within average range for a majority of survivors tested. Conclusion This strategy of brief intensive chemotherapy for young children with non-metastatic medulloblastoma eliminated the need for craniospinal irradiation 52% of the patients, and may preserve QoL and intellectual functioning. The excellent survival rates are somewhat dampened by high toxic mortality. Pediatr Blood Cancer 2008;50:1169–1175. © 2008 Wiley-Liss, Inc.

Primary intraspinal peripheral primitive neuroectodermal tumors (pPNETs) are extremely rare tumors with only seven reported cases in the literature. The histopathologic diagnosis of this tumor is complex and has led to a variety of treatment approaches. The distinction between central and peripheral type primary spinal cord PNETs has not always been made in the literature, leading to a paucity of data in this disease. We present here two young patients with primary intraspinal pPNET, their treatment and outcome. The first patient, a 27 year old male, presented with an intradural mass extending from L2 through L5, after multiple relapses, he is currently alive with disease after 72 months, the longest survival yet reported. The second patient, a 16 year old female, presented with an intradural mass at the cauda equina from L2 through L5, and is currently alive with responsive disease at 5 months after initial diagnosis. Here, we discuss the clinical course, the pathology and treatment for this disease and review the literature.

Background Retinoblastoma patients with RB1 germline mutations are at risk of developing second malignancies and external beam radiation therapy increases the risk. Carboplatin-containing chemotherapy regimens in conjunction with local therapies have been investigated for intraocular retinoblastoma, but the lack of data regarding the efficacy of single agent intravenous carboplatin prompted this phase II study. Procedure Twenty-five patients (43 eyes) were treated with intravenous carboplatin (18.7 mg/kg for patients

Background: The purpose of this study is to investigate the efficacy of an intensive chemotherapy induction regimen followed by myeloablative chemotherapy and autologous hematopoietic stem cell rescue (AHSCR) in children with newly diagnosed ependymoma. Patients and Methods: Twenty-nine children less than 10 years of age at diagnosis of ependymoma were enrolled on the “Head Start” studies. Twenty-four patients with localized disease received an induction regimen including five cycles of chemotherapy (cisplatin, vincristine, etoposide cyclophosphamide, and high dose methotrexate for patients with metastatic disease). Following induction, individuals without evidence of disease proceeded to marrow-ablative chemotherapy (thiotepa, carboplatin, and etoposide) with AHSCR. Results: The estimated 5-year event free survival (EFS) and overall survival (OS) from diagnosis were 12% (±6%) and 38% (±10%), respectively. The toxic mortality amongst this group of 29 patients was 10.3%. Younger age (less than 18 months at diagnosis) was the only statistically significant prognostic factor. The estimated 5-year OS rate for the five patients with metastatic disease at presentation was 80% (±18%). Overall, radiation-free survival at 5 years from diagnosis was 8% (±5%). Conclusions: The use of an intensive induction chemotherapy regimen including myeloablative chemotherapy followed by AHSCR in newly diagnosed young children with ependymoma is not superior to other previously reported chemotherapeutic strategies. Pediatr Blood Cancer 2007;49:34–40. © 2006 Wiley-Liss, Inc.

Recent SEER data suggest that we have made modest improvements in the survival of children with brain cancer, from 58% 5-year survival in the period of diagnosis from 1975 to 1979 to 73% in the period from 1995 to 2000 [1]. These data must be viewed with both caution and discernment. First, even if accurate, they apply only to perhaps the 15% of the world’s children with brain tumors who happen to reside within the “developed” countries such as the United States. Second, it is important to remember that 5-year survival rates from the majority of childhood brain tumors (low-grade astrocytomas, craniopharyngiomas, children beyond infancy with medulloblastomas, and ependymomas) do not represent cures; late relapses, second malignancies, and late deaths from toxicities of the disease or from treatment are well recognized. Finally, of course, such survival statistics pay no attention to quality of survivorship; and a significant proportion of children who survive brain tumors carry a tremendous burden of physical, endocrinologic, neurocognitive, and psychological sequelae into their adult lives. Yet progress has been made, albeit frustratingly slowly, in treating some pediatric brain tumors. What has brought about those advances that have been accomplished in recent decades? The advent of advanced imaging—the CAT scan in the 1970s and the MRI in the 1980s—has facilitated earlier and more precise diagnosis and perhaps opportunities for more radical and less morbid tumor resections

BACKGROUND: Individuals with Trisomy 21 have a striking cancer distribution, with a 10- to 20- fold increased risk of acute leukemia compared to a markedly decreased incidence of solid tumors. Medulloblastoma, the most common malignant brain tumor of childhood, is particularly rare in the DS population, with only one published case. As demonstrated in a mouse model of DS, the supernumerary chromosome 21 is associated with cerebellar hypoplasia and a decreased number of external granule cell layer progenitor cells (EGLs). Treatment of these mice with sonic hedgehog (Shh) signaling pathway agonists promotes normalization of EGLs and improved cognitive functioning. PATIENT: We describe a 21 month-old male with DS with desmoplastic/nodular medulloblastoma (DNMB) - a tumor derived from Shh dysregulation and over-activation of EGLs. Immunohistochemistry revealed patchy cytoplasmic GAB-1 staining and patchy strong YAP-1 nuclear and cytoplasmic staining, further placing this DNMB into the new consensus molecular classification Shh subgroup. Additional testing revealed a de novo heterozygous germ line mutation in the PTCH1 gene encoding a tumor suppressor protein in the Shh pathway; both parents tested negative for this mutation. CONCLUSIONS: The reduced presence of EGLs in DS patients offers a plausible explanation for the disparity of medulloblastoma in this population. Conversely, patients with PTCH1 germ line mutations experience Shh pathway overstimulation resulting in Gorlin (Nevoid Basal Cell Carcinoma) Syndrome and an increased incidence of malignant transformation of EGLs leading to medulloblastoma formation. This represents the first documented report of an individual with DS (developmental failure of EGLs, decreased incidence of medulloblastoma) simultaneously carrying PTCH1 germ line mutation (overstimulated EGLs, increased incidence of medulloblastoma). Thus, we observe a highly unusual circumstance in which the PTCH1 mutation appears to ‘trump’ the effects of trisomy 21 in causation of Shh-activated medulloblastoma. Additional genomic studies are ongoing and will be presented.

PURPOSE: Bifocal presentation of central nervous system (CNS) germinomas, with synchronous pineal and suprasellar involvement, is common, and associated with favorable outcome. However, the incidence and outcome of bifocal presentation of non-germinomatous germ cell tumors (NGGCT) is less well described. METHODS: Medical records of patients with CNS NGGCT treated at Children's Hospital Los Angeles between 1993 and 2014 were reviewed for clinical characteristics, treatment and outcome. RESULTS: Seven (24.1%) of 29 patients diagnosed with CNS NGGCT between 1993 and 2014 had bifocal involvement. The mean age at diagnosis was 13.1 years (range: 8-22 years). Diagnosis was made on tumor marker elevation in seven patients, and confirmed on histopathology on one patient. Seven patients had elevated AFP and one patient had elevated βHCG in serum and/or CSF. Two patients are still undergoing therapy and have not been included in the survival analyses. Four of remaining five patients are long term survivors at 41, 56, 57, and 97 months. Patient #1 received initial chemotherapy without irradiation, relapsed in the 3rd ventricle at 10 months, and was successfully salvaged with high-dose chemotherapy (HDCx) with autologous hematopoietic stem cell rescue (AuHCR) and 3600cGy craniospinal irradiation (CSI) with local boost. Patient #2 had partial response to chemotherapy, underwent HDCx and AuHCR, followed by 3600cGy CSI with boost. Patients #3 and #4 received chemotherapy with a complete response, followed by whole ventricular irradiation with a local boost. Patient #5 received chemotherapy only, developed ventricular relapse at 75 months, was treated with cyclophosphamide and vinblastine followed by CSI with boost, but died at 87 months. CONCLUSIONS: Our experience suggests that bifocal NGGCT may be more common than previously thought, and may be more likely to have yolk-sac component given elevated AFP, and therefore have a better prognosis than other NGGCT.

Medulloblastoma, the most common malignant brain tumor in children, occurs with increased frequency in individuals with Fanconi anemia who have biallelic germline mutations in BRCA2. We describe an 8 year old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal irradiation. Despite this, the patient succumbed to a second recurrence of his medulloblastoma, which presented eight months after diagnosis as malignant pleural and peritoneal effusions. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization and next generation sequencing analysis. In addition to the BRCA2 6174delT, the medulloblastoma cells had amplification of MYC, deletion at Xp11.2 and isochromosome 17, but no structural variations or overexpression of GFI1 or GFI1B. To our knowledge, this is the first pair of diagnosis/recurrence medulloblastoma cell lines, the only medulloblastoma cell lines with BRCA2 6174delT described to date, and the first reported case of a child with medulloblastoma associated with a germline BRCA2 6174delT who did not also have Fanconi anemia.

BACKGROUND: Medulloblastomas in children can be categorized into four molecular subgroups with differing clinical characteristics such that subgroup determination aids in prognostication and risk-adaptive treatment strategies. Magnetic resonance spectroscopy (MRS) is a widely available, non-invasive tool used to determine metabolic characteristics of tumors providing diagnostic information without the need for tumor tissue. In this study we investigated the hypothesis that metabolite concentrations measured by MRS would differ between molecular subgroups of medulloblastoma allowing for accurate subgroup determination. METHODS: Magnetic resonance spectroscopy was used to measure metabolites in medulloblastomas across molecular subgroups (SHH = 12, Groups 3/4 = 17, WNT = 1). Levels of fourteen metabolites were analyzed to determine those which were most discriminant for medulloblastoma subgroups in order to construct a multivariable classifier to distinguish between combined Group 3/4 and SHH tumors. RESULTS: Medulloblastomas across molecular subgroups revealed distinct spectral features. A five metabolite subgroup classifier inclusive of creatine, myo-inositol, taurine, aspartate and lipid 13a was developed that could discriminate between Group 3/4 and SHH medulloblastomas with excellent accuracy (cross-validated Area Under the Curve AUC = 0.88). Group 3 and Group 4 tumors demonstrated metabolic profiles with readily detectable taurine, lower levels of lipids and high levels of creatine. SHH tumors showed prominent choline and lipid with low levels of creatine and little or no evidence of taurine. CONCLUSIONS: The data show that medulloblastomas of different molecular subgroups differ metabolically as measured using MRS. MRS is a potentially useful and accurate tool to determine medulloblastoma molecular subgroups.

Recurrence of malignant brain tumors results in a poor prognosis with limited treatment options. High-dose chemotherapy with autologous hematopoietic cell rescue (AHCR) has been used in patients with recurrent malignant brain tumors and has shown improved outcomes compared with standard chemotherapy. Temozolomide is standard therapy for glioblastoma and has also shown activity in patients with medulloblastoma/primitive neuro-ectodermal tumor (PNET), particularly those with recurrent disease. Temozolomide was administered twice daily on days -10 to -6, followed by thiotepa 300 mg/m(2) per day and carboplatin dosed using the Calvert formula or body surface area on days -5 to -3, with AHCR day 0. Twenty-seven patients aged 3-46 years were enrolled. Diagnoses included high-grade glioma (n=12); medulloblastoma/PNET (n=9); central nervous system (CNS) germ cell tumor (n=4); ependymoma (n=1) and spinal cord PNET (n=1). Temozolomide doses ranged from 100 mg/m(2) per day to 400 mg/m(2) per day. There were no toxic deaths. Prolonged survival was noted in several patients including those with recurrent high-grade glioma, medulloblastoma and CNS germ cell tumor. Increased doses of temozolomide are feasible with AHCR. A phase II study using temozolomide, carboplatin and thiotepa with AHCR for children with recurrent malignant brain tumors is being conducted through the Pediatric Blood and Marrow Transplant Consortium.

To evaluate patterns of relapse and outcome in patients newly diagnosed with CNS Mixed Malignant GCT (MMGCT) treated initially with chemotherapy alone.A retrospective chart review was conducted using all 25 patients enrolled on the International CNS GCT Study III, with at least 7 years follow-up for all surviving patients.Thirteen patients at diagnosis had CNS MMGCT by pathology and tumor markers (n = 11), or tumor markers alone (n = 2). Twelve received chemotherapy alone, one additionally receiving focal irradiation prior to relapse. Six patients (46%) relapsed (mean of 30.5 months; range 6-59 months), two beyond and four within the primary site alone. Three patients relapsed early (6-23 months from diagnosis), two with alpha-fetoprotein elevations and one without tumor markers assessed; all three expired of progressive disease at 2-10 months following initial relapse. Three patients relapsed late (37-59 months) without AFP elevations, one with pathologically pure germinoma, two with mild beta-human chorionic gonadotropin elevations; these patients survive disease-free at 86+, 94+, and 126+ months following additional treatment.Patients with CNS MMGCT relapsing following chemotherapy alone display two distinct patterns of recurrence and outcome; patients relapsing early possess MMGCT elements and have a dismal prognosis, while patients relapsing late do so with pure germinomatous elements and have an excellent outcome. Current cooperative group studies utilizing more localized fields of irradiation should monitor closely the patterns of relapse and outcome; late recurrences with germinomatous elements might be avoided by initial use of low-dose larger field irradiation in select patients.

Among pediatric non-Hodgkin lymphomas, one of the most distinctive types is anaplastic large cell lymphoma (ALCL). Specific chromosomal abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia, but chromosome abnormalities have not been evaluated for prognostic value in pediatric ALCL. For Children's Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, three patients were enrolled with cytogenetic analysis of ALCL and simultaneously enrolled on treatment protocol CCG-552. Pathology material and karyotypes at initial diagnosis underwent central review. Demographics included ages of 9, 12, and 14 years, and a male/female ratio of 1:2. All patients had advanced disease (stage III). Disease progressed or relapsed in two patients, and one died. Chromosomal abnormalities, including t(2;5)(p23;q35), the ALK/NPM fusion gene, and complex karyotypes with multiple additional abnormalities, were identified in all three patients. In two patients with progressive disease or relapse, additional chromosomal abnormalities at 1q21 and 10q24, possibly involving MCL1 and HOX11/TCL3, respectively, may have contributed to worse outcome. Pediatric ALCL cases frequently have complex karyotypes and usually involve ALK/NPM translocations in this limited study. Additional chromosome abnormalities may be involved in the pathogenesis of ALCL. Further studies are warranted in larger cohorts of children and adolescents with ALCL.

In reporting on molecular studies involving malignant gliomas in adults, authors have noted that deletions of PTEN and amplification of EGFR are common and may contribute to tumor development, providing a rationale for a number of therapies aimed at these molecular targets. The frequency of comparable abnormalities has not been defined in a sizable pediatric cohort. To address this issue, we examined tumor samples from the Children's Cancer Group 945 study, a large randomized trial of treatment for childhood malignant gliomas.Tissue sections in 62 evaluable cases were examined, and the tumors were isolated by microdissection. Polymerase chain reaction amplification was used to detect PTEN mutations. Deletions of PTEN were also assessed by fluorescence in situ hybridization (FISH) in 27 cases and loss of heterozygosity analysis in 54; EGFR was assessed using immunohistochemistry to identify areas with maximal EGFR expression, followed by FISH to determine EGFR amplification. Alteration of the PTEN sequence was detected in just one of 62 tumors, in conjunction with loss of chromosome 10; PTEN deletions without mutation were evident in seven additional tumors. The PTEN alterations were more common in glioblastoma multiforme (seven of 25 tumors) than other tumor subgroups (one of 37 tumors) (p = 0.0056). Although 14 of 38 evaluable tumors had increased EGFR expression compared to normal tissue, only one tumor exhibited amplification of EGFR.Alterations in PTEN and amplification of EGFR are uncommon in pediatric malignant gliomas, in contrast to adult malignant gliomas. From this one can infer that the pediatric and adult tumors involve distinct molecular causes. The results of this study have important implications for the adaptation of glioma therapies aimed at molecular targets in adults to the treatment of childhood gliomas, and highlight the need for investigations of therapies specifically directed toward childhood tumors.

Purpose O6-Methylguanine-DNA methyltransferase (MGMT) functions to counteract the cytotoxic effects of alkylating agents, such as nitrosoureas, which play a central role in the treatment of childhood malignant gliomas. Epigenetic silencing of MGMT has been associated with prolonged survival in adults with malignant gliomas, although the association between MGMT expression status and outcome in pediatric malignant gliomas has not been defined. Methods We examined the association between MGMT expression and survival duration using tumor samples from the Children's Cancer Group 945 study, the largest randomized trial for childhood malignant gliomas completed to date. All patients received alkylator-based chemotherapy as a component of adjuvant therapy. Archival histopathologic material yielded tissue of sufficient quality for immunohistochemical assessment of MGMT expression status in 109 specimens. Results Twelve of the 109 samples demonstrated overexpression of MGMT compared with normal brain. Five-year progression-free survival was 42.1% ± 5% in the 97 patients whose tumors had low levels of MGMT expression versus 8.3% ± 8% in the 12 patients whose tumors overexpressed MGMT (P = .017, exact log-rank test). The association between MGMT overexpression and adverse outcome remained significant after stratifying for institutional histologic diagnosis (eg, anaplastic astrocytoma or glioblastoma multiforme), as well as age, amount of residual tumor, and tumor location. Conclusion Overexpression of MGMT in childhood malignant gliomas is strongly associated with an adverse outcome in children treated with alkylator-based chemotherapy, independently of a variety of clinical prognostic factors.

We previously reported a phase 2 trial of 69 patients with newly diagnosed anaplastic or aggressive oligodendroglioma who were treated with intensive procarbazine, CCNU (lomustine), and vincristine (PCV) followed by high-dose thiotepa with autologous stem cell rescue. This report summarizes the long-term follow-up of the cohort of 39 patients who received high-dose thiotepa with autologous stem cell support. Thirty-nine patients with a median age of 43 (range, 18–67) and a median KPS of 100 (range, 70–100) were treated. Surviving patients now have a median follow-up of 80.5 months (range, 44–142). The median progression-free survival is 78 months, and median overall survival has not been reached. Eighteen patients (46%) have relapsed. Neither histology nor prior low-grade oligodendroglioma correlated with risk of relapse. Persistent nonenhancing tumor at transplant was identified in our initial report as a significant risk factor for relapse; however, long-term follow-up has not confirmed this finding. Long-term neurotoxicity has developed only in those patients whose disease relapsed and required additional therapy; no patient in continuous remission has developed a delayed neurologic injury. This treatment strategy affords long-term disease control to a subset of patients with newly diagnosed anaplastic oligodendroglioma without evidence of delayed neurotoxicity or myelodysplasia.

Pediatric high grade gliomas represent a heterogeneous group of tumors with poor prognoses despite the use of multimodal treatment. Very little progress has been made over the past decades in identifying efficacious therapeutic modalities against both high grade gliomas and diffuse brainstem gliomas in children. The degree of surgical resection is the most important clinical prognostic factor for children with high grade gliomas, and a complete resection should be attempted whenever feasible. The role of radiation therapy in the treatment of older children with high grade gliomas and diffuse brain stem gliomas is undisputed; however the benefit of using radiation for patients less than 6 years of age (with high grade gliomas) might be questionable. Despite the absence of solid evidence to support its use, chemotherapy is routinely used against these tumors. Currently temozolomide is being investigated due to its activity in adult trials and based on preliminary data regarding recurrent disease. A small subgroup of patients can be successfully treated with high dose chemotherapy followed by autologous stem cell rescue. Early trials using this modality in the past had been associated with high morbidity and mortality. High dose chemotherapy with autologous stem cell rescue in selected patients with minimal residual disease, angiogenesis inhibitors, radiosensitizers and other biological modifiers are being currently investigated in phase I/II trials.

Germinomas and embryonal carcinomas are central nervous system (CNS) germ cell tumors (GCT) that may overexpress the proto-oncogene c-KIT, a receptor tyrosine kinase, of which dasatinib is a potent inhibitor. This retrospective review presents the feasibility and tolerability of dasatinib administration in select patients with CNS germinoma. Between November 2008 and April 2010, six patients with newly diagnosed (n = 3) or recurrent (n = 3) CNS GCT were treated in an effort to avoid irradiation and/or delay recurrence. The daily doses administered were 100-170 mg/m(2) with mostly grade 1-2 toxicities. Dasatinib may play a role in future treatment strategies for CNS GCT.

Purpose To evaluate the efficacy and toxicity of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in patients with relapsed or progressive CNS germ cell tumors (GCTs). Patients and Methods Twenty-one patients with CNS GCTs who experienced relapse or progression despite having received initial chemotherapy and/or radiotherapy were treated with thiotepa-based HDC regimens followed by ASCR. Results Estimated overall survival (OS) and event-free survival (EFS) rates for the entire group 4 years after HDC were 57% ± 12% and 52% ± 14%, respectively. Seven of nine (78%) patients with germinoma survived disease-free after HDC with a median survival of 48 months. One patient died as a result of progressive disease (PD) 39 months after HDC, and another died as a result of pulmonary fibrosis unrelated to HDC 78 months after ASCR without assessable disease. However, only four of 12 patients (33%) with nongerminomatous germ cell tumors (NGGCTs) survived without evidence of disease, with a median survival of 35 months. Eight patients with NGGCTs died as a result of PD, with a median survival of 4 months after HDC (range, 2 to 17 months). Patients with germinoma fared better than those with NGGCTs (P = .016 and .014 for OS and EFS, respectively). Patients with complete response to HDC also had significantly better outcome (P < .001 for OS and EFS) compared with patients with only a partial response or stable disease. There were no toxic deaths because of HDC. Conclusion Dose escalation of chemotherapy followed by ASCR is effective therapy for patients with recurrent CNS germinomas and might be effective in patients with recurrent NGGCTs with a low tumor burden.

Central nervous system (CNS) germ cell tumors (GCT) account for less than 5% of primary brain tumors in children and young adults, but they continue to attract much attention. Over the past decade, two advances have led to re-evaluation of what constitutes conventional therapy for CNS GCT. For pure germinomas, the challenge remains the determination of the optimal field and dose of irradiation and whether or not the use of chemotherapy can lead to a reduced dose or elimination of irradiation altogether without compromising disease control or survival. For non-germinomatous germ cell tumors, an improvement in the current dismal prognosis is imperative.

Purpose. High rates of overall and event-free survival have been reported in patients with intracranial germinomas treated with craniospinal radiotherapy. More recently, similar results have been reported with chemotherapy combined with radiotherapy to more localized treatment volumes. Our interest in exploring chemotherapy without radiotherapy in patients with CNS germinomas was based on concerns about the late sequelae of radiotherapy to the brain or neuraxis and also the well documented success of chemotherapy alone in patients with disseminated extracranial germinomas. The primary objective of this study was to determine whether intensive cisplatin and cyclophosphamide-based combination chemotherapy, without radiotherapy, was effective in patients with CNS germinomas. Patients and Methods. Nineteen patients were enrolled, ranging in age from 1 to 24 years (median, 14 years). Thirteen were male. Nine had diabetes insipidus. Therapy comprised two courses of Regimen 'A' (cisplatin, etoposide, cyclophosphamide, and bleomycin) followed by MRI evaluation. Patients achieving a complete remission (CR) completed all planned therapy with two courses of regimen 'B' (carboplatin, etoposide, and bleomycin). Patients achieving less than a CR received two courses of Regimen 'B' followed by another evaluation. Those in CR after four courses of treatment received one additional course of Regimen 'A' and Regimen 'B', while those not in CR after four treatment courses underwent second look surgery and/or radiation therapy. Results. Eleven of 11 patients with residual postoperative disease assessable for response achieved a CR. With a median follow-up of 6.5 years, eight out of 19 (0.42) patients remain in CR 1 without radiotherapy and another three patients are in stable second or subsequent remissions. Three patients died from treatment-related toxicity and another died in CR 1 from an uncharacterized leukoencephalopathy. The 5-year event-free survival (EFS) was 0.47 ± 0.23 and 5-year overall survival (OS) was 0.68 ± 0.22. Conclusions. Intensive cisplatin and cyclophosphamide-based chemotherapy was effective in achieving remissions, however, the long-term outcome using this treatment program was unsatisfactory and associated with unacceptable morbidity and mortality, particularly in patients with diabetes insipidus.

BACKGROUND The objectives of the current study were to determine the outcome of children who were treated with chemotherapy and radiotherapy on the Children's Cancer Group (CCG) high-grade glioma protocol (CCG-945) who were diagnosed with low-grade gliomas on post hoc central pathologic review and to identify clinical and biologic features associated with prognosis. METHODS Between 1985 and 1991, 250 children with institutionally classified high-grade gliomas were enrolled on CCG-945. Patients older than 24 months with intracranial lesions were assigned randomly to receive either lomustine, vincristine, and prednisone (control regimen) or the 8-drugs-in-1-day regimen (experimental regimen); younger patients and those with primary spinal cord tumors were assigned nonrandomly to the experimental regimen. Central independent review by 5 neuropathologists led to a reclassification of low-grade glioma in 70 patients, who were the focus of the current study. RESULTS The study involved 42 males and 28 females (median age, 7.7 years) with a median follow-up of 10.4 years. At 5 years, the progression-free survival (PFS) rate was 63% ± 6%, and the overall survival (OS) rate was 79% ± 5%, compared with a PFS rate of 19% ± 3% (P < 0.0001) and an OS rate of 22% ± 3% (P < 0.0001) in the remainder of the cohort. Significantly poorer 5-year PFS was seen in children younger than 24 months, those with fibrillary astrocytoma, and those with posterior fossa tumors. Patients demonstrated a modest improvement in PFS but no improvement in OS compared with children with low-grade gliomas who were treated with contemporary chemotherapy-alone approaches. CONCLUSIONS The current report calls attention to the importance of central pathologic review in large multiinstitutional trials of children with gliomas and suggests that aggressive front-line combined chemoradiotherapy does not confer a survival advantage in this highly selected population of patients. Cancer 2003;98:1243–52. © 2003 American Cancer Society. DOI 10.1002/cncr.11637

To assess the activity and tolerability of temozolomide in children with progressive low-grade gliomas (LGGs).The authors reviewed the records of 13 children (6 months to 19 years old) with progressive LGGs and magnetic resonance imaging evidence of unresectable tumors who were treated with temozolomide at the authors' institution since 1999.Four patients received a 5-day regimen of temozolomide (150 mg/m2 per day) repeated every 28 days, and nine patients received a 42-day regimen (75 mg/m2 per day) repeated every 56 days. Three patients demonstrated partial responses to temozolomide, with a median time to maximal response of 5 months (range 4-12 months), and one had a minor response at 9 months. Four patients developed progression while on temozolomide, with a median time to progression of 7 months (range 1-12 months). Five patients had disease stabilization. Among the five patients with prior chemotherapy and/or radiation therapy, temozolomide was associated with disease stabilization in three and tumor response in one. In the three patients with neurofibromatosis type 1, two patients experienced tumor responses and one disease stabilization. Thrombocytopenia, nausea, emesis, and fatigue were the most common toxicities. Four patients discontinued therapy because of the side effects.Temozolomide is active in children with LGGs. It is effective in previously treated patients and in patients with neurofibromatosis type 1. The 42-day regimen appears less toxic than the 5-day regimen. Any impact on survival for these patients remains to be demonstrated.

Purpose: Temozolomide (Temodar; Schering-Plough Corp, Kenilworth, NJ) is an imidazole tetrazinone that undergoes chemical conversion to the active methylating agent 5-(3-methyltriazen-1yl)imidazole-4-carboximide under physiologic conditions. Previous studies have confirmed activity of Temodar in the treatment of progressive and newly diagnosed malignant gliomas. We have extended these results, and now we report results of a phase II trial of Temodar for patients with progressive, low-grade glioma. Patients and Methods: Temodar was administered orally once a day for five consecutive days (in a fasting state) at a starting dose of 200 mg/m2/d. Treatment cycles were repeated every 28 days following the first daily dose of Temodar. Response criteria used a combination of magnetic resonance imaging and physical examination to evaluate activity. Results: Forty-six patients with low-grade glioma have been treated to date. The objective response rate was 61% (24% complete response and 37% partial response), with an additional 35% of patients having stable disease. Median progression-free survival (PFS) was 22 months (95% confidence interval [CI], 15 to ∞ months) with a 6-month PFS of 98% (95% CI, 94% to 100%) and a 12-month PFS of 76% (95% CI, 63% to 92%). Toxicity observed during the study was limited to only six patients. Three patients experienced grade 3 neutropenia, with a duration greater than 3 weeks in one patient, and two patients experienced grade 3 thrombocytopenia. One patient experienced ≥ grade 4 toxicity, with intracerebral hemorrhage, neutropenia, thrombocytopenia, sepsis, and death. Conclusion:Initial results indicate that Temodar may be active in the treatment of low-grade glioma, and thus, further evaluation of this agent in the treatment of these tumors is warranted.

Historically, the survival of children and adolescents with Burkitt's and Burkitt-like lymphoma had been poor. Recently, short and intensive chemotherapy appears to have improved disease outcome. We therefore reviewed the results of four successive Children's Cancer Group trials conducted on 470 children with disseminated Burkitt's and Burkitt-like lymphoma. Of the patients studied, the median age was 8 years (0-21 years), the male:female ratio was 4:1, 58% had lactate dehydrogenase (LDH) > or = 500 IU/l, 23% had M2 or M3 bone marrow (BM), and 12% demonstrated central nervous system involvement. In a multivariate analysis, the 4-year event-free survival (EFS) in patients > or = 15-years-old compared with or = 500 IU/l compared with LDH < 500 IU/l was 49 +/- 3 versus 71 +/- 4% (P < 0.001). Furthermore, patients treated on the most recent protocol, which was short and more intensive, had a significantly improved survival compared with those on previous trials (4-year EFS 80 +/- 6 versus 54 +/- 2%, P < 0.001). In summary, the outcome for childhood Burkitt's and Burkitt-like lymphoma has recently improved with the use of short and intensive B-cell non-Hodgkin's lymphoma-directed therapy.

Purpose: To study the effectiveness of combined chemotherapy and radiotherapy for children with high-grade astrocytomas of the posterior fossa.

Childhood atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) is a recently described entity. Diagnosis is based on distinctive light microscopy and immuno-histochemical findings, coupled with molecular genetic analysis. Most AT/RTs demonstrate monosomy 22 or deletions of chromosome band 22q11 with alterations of the hSNFS/INII gene. The tumor's incidence is still undefined, but it may comprise as high as I in 4 primitive CNS tumors in infants. Treatment is far from optimal, but there are occasional long-term survivors, especially among older children. Therapeutic approached have included surgery, chemotherapy, and radiotherapy. Prospective clinical trials are needed for children with AT/RTs.

BACKGROUND: Wnt pathway medulloblastoma has high relapse-free survival following standard cranio-spinal irradiation with primary site boost and adjuvant chemotherapy. However, rare patients do develop recurrences. We report a case with comprehensive molecular characterization of both initial and recurrent tumor. CASE REPORT: A seven year old girl had local recurrence of a gross totally resected non-metastatic classic Wnt pathway medulloblastoma, 21 months after receiving 18Gy craniospinal irradiation with primary site boost to 54Gy, with weekly vincristine, followed by a modified maintenance chemotherapy regimen including 9 cycles of vincristine, temozolomide, oral etoposide, alternating with vincristine and carboplatin or cyclophosphamide. The original tumor was YAP-1 and nuclear beta-catenin positive, GAB1 and monosomy 6 negative, cmyc and nmyc non-amplified. Rare tumor cells were noted to be HMB45 or desmin and/or myogenin positive. The recurrent lesion demonstrated classic Wnt pathway medulloblastoma without HMB45 or desmin reactivity or monosomy 6. The child has since received marrow-ablative thiotepa and carboplatin with autologous stem cell rescue. Analysis of both initial and recurrent tumors was performed using Illumina Human Methylation 850K Array. Mutational analysis on tumor DNA was performed via NextGen sequencing on Illumina NextGen platform for 130 brain tumor-related genes. DNA methylation profile of the recurrent tumor demonstrated classic medulloblastoma, Wnt activated. A copy number profile demonstrated several chromosomal aberrations without amplifications. MGMT promoter was unmethylated, while the gene panel sequencing revealed a variant in CTNNB1 (same as the original tumor). Germ line analyses are pending. CONCLUSION: The absence of monosomy 6 in the face of CTNNB1 mutation may highlight a worse prognostic variant of Wnt pathway medulloblastoma. The presence of melanocytic and/or rhabdomyoblastic markers by IHC may also indicate a less optimal prognosis even amongst Wnt pathway activated medulloblastoma.

Background The adverse effects of irradiation on endocrine function among patients with pediatric brain tumor are well documented. Intensive induction chemotherapy followed by marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) without central nervous system (CNS) irradiation has demonstrated efficacy in a proportion of very young children with some malignant CNS tumors. This study assessed the long-term endocrine function of young children following chemotherapy-only treatment regimens. Procedures A retrospective chart review was performed on 99 patients under 6 years of age with malignant brain tumors newly diagnosed between May 1991 and October 2010 treated with irradiation-avoiding strategies. Thirty patients survived post-AuHCR without cranial irradiation for a mean of 8.1 years (range 3.0–22.25 years). The patient cohort included 18 males and 12 females (mean age at AuHCR of 2.5 years, range 0.8–5.1 years). Results All 30 surviving patients had documented normal age-related thyroid function, insulin-like growth factor binding protein 3 (IGF-BP3), prolactin, testosterone, and estradiol levels. Insulin-like growth factor 1 age-related levels were abnormal in one child with normal height. Ninety-seven percent of patients had normal cortisol levels, while follicle-stimulating hormone and LH levels among females were normal in 83% and 92%, respectively, and in 100% of males. Growth charts demonstrated age-associated growth within 2 standard deviations of the mean in 67% of patients. Of 10 patients (33%) with short stature, 6 had proportional diminutions in both height and weight. Conclusions These findings demonstrate that the use of relatively brief, intensive chemotherapy regimens including marrow-ablative chemotherapy with AuHCR results in fewer endocrine sequelae than treatment schemes utilizing CNS irradiation.