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PURPOSE To determine clinical characteristics and response to treatment for children with supratentorial primitive neuroectodermal tumors (S-PNETs). PATIENTS AND METHODS After surgery and staging, 55 patients aged 1.5 to 19.3 years with S-PNETs were randomized to receive craniospinal radiotherapy (RT) followed by eight cycles of 1-(2-chloro-ethyl)-3-cyclohexylnitrosourea (CCNU), vincristine (VCR), and prednisone (standard treatment) or two cycles of 8-in-1 chemotherapy followed by RT and then eight additional cycles of 8-in-1. RESULTS Three-year Kaplan-Meier estimates (estimate +/- SE) of survival and progression-free survival (PFS) rates for patients with confirmed diagnoses of S-PNET were 57% +/- 8% and 45% +/- 8%, respectively; survival and PFS rates for children with PNETs located in the pineal region were 73% +/- 12% and 61% +/- 13%, respectively, and were significantly different from the other S-PNETs (P < .03). The 8-in-1 arm had greater toxicity than the standard-treatment arm. Distributions of PFS between the two treatment groups were not significantly different (P > .5). Other univariate prognostic factors that influenced PFS included metastasis (M) stage (P < .03: M0 50% +/- 9% v M1-4 0%) and age (P < .02: 1.5 to 2 years 25% +/- 13% v > or = 3 years 53% +/- 9%). CONCLUSION In this first randomized treatment trial for S-PNETs in children, no significant differences were detected between the two treatment groups. M0 and pineal site of involvement were independent predictors of a better outcome. However, survival was better than previously reported.

PURPOSE In a previous randomized trial, the addition of adjuvant chemotherapy to postoperative radiotherapy proved beneficial in the treatment of childhood high-grade astrocytomas. The present study tests the hypothesis that an eight-drug adjuvant chemotherapy regimen would improve survival in such children compared with the three-drug regimen of the prior study. PATIENTS AND METHODS Between April 1985 and May 1990, patients between the ages of 18 months and 21 years with newly diagnosed high-grade astrocytomas were eligible for this study, as determined by the treating institution's histopathologic diagnosis. Treatment consisted of postoperative local-field radiotherapy and adjuvant chemotherapy, either lomustine (CCNU), vincristine, and prednisone (control regimen) or eight-drugs-in-1-day chemotherapy (experimental regimen). Two cycles of postoperative preirradiation chemotherapy were administered in the experimental regimen. Patients were evaluated radiographically every 3 months after irradiation. RESULTS Eighty-five eligible patients were randomized to the control regimen and 87 to the experimental regimen. The progression-free survival (PFS) and overall survival (OS) at 5 years were 33% (SE = 5%) and 36% (SE = 6%), respectively. There was no statistical difference in outcome between the two chemotherapy regimens. In patients with confirmed diagnoses of anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM), anaplastic astrocytoma, greater than 90% resection, and nonmidline tumor location were characteristics predictive of an improved PFS. There was a difference in toxicity between the two chemotherapeutic regimens, with greater myelosuppression and hearing loss in the experimental regimen. Tumor recurrence occurred primarily within the primary tumor site. CONCLUSIONS There is no benefit to the treatment of high-grade astrocytomas in children with eight-drugs-in-1-day chemotherapy compared with CCNU, vincristine, and prednisone. Extent of tumor resection and histopathologic diagnosis are significant prognostic variables. The overall outcome for children with high-grade astrocytomas remains poor.

Breastfed infants of women who have had gastric or intestinal bypass procedures may develop nutritional deficiencies. We describe a 10-month-old exclusively breastfed white male infant who presented with vomiting, failure to thrive, and megaloblastic anemia. He was found to have vitamin B12 deficiency. His mother had undergone a gastric bypass procedure for morbid obesity 2 years prior to her pregnancy with this child. She had subclinical vitamin B12 deficiency, with an abnormal Schilling test that corrected with the addition of intrinsic factor. Therefore, we believe that the mother's gastric bypass had caused a decrease in available intrinsic factor, resulting in subclinical vitamin B12 deficiency and decreased breast milk B12. Although she was asymptomatic, her breastfed infant developed symptomatic B12 deficiency. This is the first reported case of a maternal gastric bypass resulting in vitamin B12 deficiency in an infant. These mothers should receive vitamin supplements, including vitamin B12, during and after pregnancy, and may require parenterally administered vitamin B12.

This study was undertaken to evaluate the radiographic response to two cycles of chemotherapy prior to irradiation in newly diagnosed children with high-grade astrocytomas.One hundred and thirty children less than 21 years of age with newly-diagnosed high-grade astrocytoma were treated with the 'eight-drugs-in-one-day' chemotherapy regimen as part of a phase III multi-institutional Childrens Cancer Group (CCG) trial. Computerized Tomographic (CT) or Magnetic Resonance Image (MRI) scans, obtained after two cycles of chemotherapy had been administered, were compared with post-operative scans to determine treatment response. Scans were evaluated by institutional radiologists, and were reviewed centrally by a single neuroradiologist.Of 79 patients with evaluable post-operative residual tumor on CT or MRI scans, 26 (33%) were determined on institutional evaluation to have had an objective response. However, central review of scans documented responses on only 14/79 (18%). A significantly higher response rate on central review was observed for those children 36 months of age or less at study entry than for older children (33% v 11%; p0.001). However, a higher disease progression rate was also observed for those children 36 months of age or less than for older children (21% v 2.6%; p0.001).In this study, the largest yet reported in newly-diagnosed children with high-grade astrocytomas, the chemotherapy regimen has activity in younger children. The differences in response rates reported by institutional and central review highlight the difficulties inherent in assessing response to brain tumor therapy. However, the study does demonstrate the consistent ability of radiologists to identify disease progression within the institutional and central reviews.

2011 Background: The use of high dose chemotherapy with autologous hematopoietic cell rescue (AuHCR) is a potentially curative approach to the management of young children with medulloblastoma (MB), with the additional benefit of avoiding the late effects of irradiation. We report the outcome of young children with MB treated on “Head Start” III, a prospective, multi-national clinical trial. Methods: Between April 2003 and December 2009, 92 children with newly-diagnosed MB were enrolled amongst 29 participating institutions. All children were to receive 5 induction cycles (vincristine, cisplatin, cyclophosphamide, etoposide, high dose methotrexate - cycles 1, 3, 5), and vincristine, cyclophosphamide, oral VP-16 and temozolomide (cycles 2, 4), followed by 1 consolidation cycle of myeloablative chemotherapy (thiotepa, carboplatin, etoposide) and AuHCR. Only children between 6 -10 years old or with residual tumor pre-consolidation, were to receive irradiation after consolidation. Results: The 3-year event-fr...

9519 Background: Outcomes for children with newly diagnosed CNS PNET remain poor compared to medulloblastoma. Head Start I and II improved survival for these patients, demonstrating a role for intensified induction chemotherapy followed by autologous hematopoietic cell rescue (AuHCR). Head Start III was developed to further improve outcomes for these children. Methods: Between April 2003 and December 2009, 52 children with newly diagnosed CNS PNET were enrolled among 22 institutions. Patients were to receive 5 induction cycles (vincristine, cisplatin, cyclophosphamide, etoposide, and high dose methotrexate in cycles 1, 3, and 5; vincristine, cyclophosphamide, oral etoposide and temozolomide in cycles 2 and 4) followed by (in children without tumor progression) consolidation with myeloablative chemotherapy (thiotepa, carboplatin and etoposide) with AuHCR. Induction Regimen D was replaced midway through the study by D2, with reduced cyclophosphamide and methotrexate doses due to toxicities. Patients with re...

2081 Background: Newly-diagnosed adolescents and adults with medulloblastoma experience substantial toxicities with “standard” maintenance chemotherapy regimens including CCNU, cisplatin and vincri...

1509 Background: Li-Fraumeni syndrome (LFS) carries a staggering lifetime risk of developing cancer. However, to date, routine biochemical and radiographic surveillance has been discouraged due to the lack of evidence supporting its effectiveness. Methods: A clinical surveillance protocol for LFS has been implemented at The Hospital for Sick Children in Toronto and has been adopted by several institutions in the United States. TP53 mutation analysis and complete family histories, including site and age at diagnosis of neoplasms, were prospectively collected for 8 LFS families who have members participating in this protocol. Results: Among the eight families, 49 TP53 mutation carriers were identified. The surveillance protocol detected 9 tumors in 6 of 16 TP53 mutation carriers who were screened. All 16 are alive after a mean follow-up time of 38 months compared with 11/33 (33.3%) TP53 mutation carriers who did not undergo surveillance (p = 5.29 × 10-6). All 6 TP53 mutation carriers (100%) who developed ca...

Twenty patients, aged 6 months to 20 years, with low-grade astrocytoma (LGA) participated in a chemotherapy trial of vincristine (VCR) and etoposide (VP-16). Fourteen children had recurrent progressive disease at entry on study. Prior treatment consisted of surgical resection alone (6), surgical resection and irradiation (4), surgical resection, irradiation and chemotherapy (2), surgery and chemotherapy (1), and irradiation and chemotherapy (1). Six patients were treated at initial diagnosis of LGA because they were less than 5 years old (5) or for a second primary tumor (1). Four recurrent patients and 3 newly diagnosed patients underwent surgical debulking of their tumors immediately prior to study entry. Tumors were located in the optic nerve/chiasm/hypothalamus (8), brain stem/cerebellum (4), cerebral hemispheres (3), midline structures (3), and spinal cord (2). The treatment plan administered in an out-patient setting consisted of weekly VCR 1.5 mg/m2 for 7 to 8 weeks and VP-16100 mg/m2 for 5 days repeated every 6 weeks for a total of 18 months of therapy. Responses were evaluated by computerized tomography or magnetic resonance imaging. Of the 20 patients, l exhibited a partial response maintained for 12+ months, 3 exhibited minor responses maintained for a period of 10+ to 35 months, and 11 maintained stable disease for 10 to 42 months. Of the 11 patients with stable disease, 2 were withdrawn early from the study without further therapy. Five of the 20 patients developed progressive disease; for 4 of these 5, this occurred during the first course of therapy. Subsequently, these 5 died due to tumor. Vincristine and etoposide produced minimal hematological and neurological toxicity and appeared to offer some benefit in patients with LGA. The authors suggest the therapy potentially can produce prolonged disease stabilization, or perhaps help avoid irradiation in the young child with LGA.

The treatment of pediatric lymphoblastic lymphoma (LL) has developed in parallel with treatment strategies for childhood acute lymphoblastic leukemia using a BFM backbone. The excellent results of the NHL/BFM 90 trial prompted us to design this randomized factorial study to determine whether a regimen without high dose methotrexate (HDMTX) the CCG BFM will result in the same outcome as NHL/BFM-90 and whether intensification with anthracycline and cyclophosphamide would further improve disease free survival. From June 2000 to October 2005, 257 patients with Murphy’s Stage III and IV (excluding CNS disease) LL were randomized to one of the four regimens. All regimens used the BFM/NHL95 backbone. The CCG BFM regimen had intrathecal (IT) methotrexate throughout interim maintenance and maintenance without IV methotrexate. The NHL BFM utilized I.V. Methotrexate 5 Gms/m2 and intrathecal MTX every 2 weeks for four doses during interim maintenance without further intrathecal MTX during maintenance. One of each backbone regimens was further intensified with anthracycline and cyclophosphamide early in induction and delayed intensification. The median age was 10.3 years, 195 (76%) were males; 43 (17%) had >5% bone marrow involvement. Twelve patients with CNS disease were not randomized and received intensification and HD HDMTX with delayed CNS radiation (data not reported here). Major toxicities have been related to bone marrow suppression with 4 toxic deaths, 3 due to sepsis and 1 from cerebral hemorrhage. The frequency of grade III/IV neutropenia (alone, with fever or with infection), anemia, and thrombocytopenia were higher in the intensified arms during induction. Three of the four toxic deaths occurred on the intensified arms. The three years EFS of the HDMTX vs. none is 84.5% ± .3.5% vs. 82.7± 3.8 (ρ= 0.93) and the intensification vs. none is 83.4% ±3.7 vs 83.0% ± 3.6 (ρ= 0.66). Therefore, there was no significant difference between treatment arms. These results suggest that neither HDMTX nor early intensification improves EFS in LL. Future direction should focus on identifying biological factors early in therapy so alternative therapies may be investigated.

Between April 1986 and March 1989, ten patients under 21 years of age with histologically confirmed malignant astrocytoma, received marrow-ablative chemotherapy with either thiotepa and Etoposide (five patients) or thiotepa, Etoposide and BCNU (five patients), followed by bone marrow ‘rescue’. Nine patients had glioblastoma multiforme (GBM), and one patient had an intrinsic brain stem anaplastic astrocytoma (AA). Seven patients were treated for recurrent tumor. Two patients who developed GBM as second malignancies were treated directly following surgical resection. One patient had received irradiation only for recently diagnosed cervical spinal cord GBM. Thiotepa was administered at a total dose of 600–900 mg/M2 over three days, Etoposide was administered at a total dose of 1500 mg/M2 over three days, and BCNU was administered at a total dose of 600 mg/M2 over four days. Non-hematopoietic toxicities have been mainly transient, predictable and acceptable, consisting of oropharyngeal mucositis, cutaneous hyperpigmentation, erythema and desquamation. Four patients achieved complete responses (CR), as determined by radiographic evaluation (CT and/or MRI) on day 28 post-marrow infusion. The mean remission duration of those with CR is 290 + days; two patients presently remain in remission. Two patients achieved partial responses (PR, greater than 50% tumor shrinkage) by day 28 post-marrow infusion; both developed disease progression, at day 61 and 94 post-marrow infusion, respectively. One patient, with a brain stem AA, had stable disease maintained for 13 months post-marrow infusion. With a total (CR + PR) response rate of 60%, these regimens merit evaluation in broader categories of recurrent brain tumor patients, as well as in patients with newly-diagnosed GBM.

Numerous laboratory and clinical investigations have suggested that immunological mechanisms may be responsible for the hemopoietic suppression in a large number of patients with aplastic anemia. Bone marrow culture studies incubating T-lymphocytes from these patients with normal allogeneic bone marrow have resulted in a decrease in the number of erythroids and myeloid colony formation in cultures.1–3 Conversely, bone marrow T cell depletion has resulted in an increase in the number of colonies.4 More recently, it has been demonstrated that the majority of patients with aplastic anemia exhibit a large number of circulating activated T-lymphocytes, producing γ interferon.5–7 Since various studies have shown an inhibitory effect of this lymphokine on hematopoiesis in vitro 8–10 and in vivo,11 it has been postulated that γ interferon may play an important role in the pathogenesis of acquired aplastic anemia.12 On clinical grounds, it has been found that prior immunosuppressive conditioning is necessary for successful bone marrow transplantation in identical twins in approximately half of the cases.13,14 In addition, some patients conditioned by immunosuppressive agents including antilymphocyte globulin (ALG) for bone marrow transplantation have achieved autologous bone marrow regeneration.15–18 The above observations have led to several therapeutic trials with antilymphocyte globulin (ALG) and antithymocyte globulin (ATG) in patients with acquired aplastic anemia with variable rates of response ranging from 17 to 85%.19,20 Most studies, including a recent multicenter trial, however, have reported a hematologic response in 40–60% of the patients.21

9507 Background: The use of dose-intensive chemotherapy with autologous hematopoietic cell rescue (AuHCR) is a potentially curative approach to the management of infants and young children with non-metastatic (M-0) medulloblastoma, with the additional benefit of avoiding the late effects of irradiation. We report the results of the “Head Start” I (1991 to 1997) and “Head Start” II (1997 to 2002) clinical trials, using this approach, to treat children with M-0 medulloblastoma, who were less than three years of age at diagnosis. Methods: Twenty one children were enrolled on these two serial studies. After surgery, patients received a uniform induction chemotherapy regimen consisting of five cycles of vincristine, cisplatin, cyclophosphamide and etoposide. Following completion of induction, all patients underwent myeloablative consolidation chemotherapy using carboplatin, thiotepa and etoposide followed by AuHCR, and did not receive irradiation. Irradiation was used only at relapse. Quality of life (QoL) and social and emotional behavior were evaluated on “Head Start” I, and cognitive functioning was evaluated on “Head Start” II survivors. Results: The five-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 ± 17%, and 29 ± 17% and 57 ± 19%, respectively. The five-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. Young age ( No significant financial relationships to disclose.

9552 Background: The prognosis for young children with newly diagnosed malignant brain tumors with leptomeningeal dissemination remains poor. From Jan 1997 to Mar 2003, “Head Start II” Regimen A2, intensified with high-dose methotrexate, was offered to this high-risk population. Methods: Eligibility: patients < 10 yrs of age; confirmed diagnosis of medulloblastoma (MB), primitive neuroectodermal tumor (PNET), ependymoma and choroid plexus carcinoma (CPC); and high-risk status as determined by neuroaxis dissemination. Patients with atypical teratoid/rhabdoid tumor (ATRT), regardless of stage, were also eligible. Treatment: 5 cycles of vincristine (0.05 mg/kg/week × 3 doses), cisplatin (3.5 mg/kg), etoposide (4 mg/kg/day × 2 days), cyclophosphamide (65 mg/kg/day × 2 days), and methotrexate (400 mg/kg) with leucovorin. Children without progressive disease (PD) by the end of induction underwent a single consolidation cycle (carboplatin, etoposide, thiotepa) with autologous stem cell rescue. Reduced dose RT (2340cGy CSI and focal boost) was reserved for any with residual disease at the end of induction or for the older patient (>6 yrs of age). Results: 40 patients were enrolled (MB, 22; PNET, 6; ependymoma, 5; AT/RT, 6; CPC, 1), med age at diagnosis 38 mos (range 5 to 119 mos). Significant toxicities of this intensified regimen included GI toxicities and infections. Among the entire cohort, there were 26 CR, 6 PR, 2 with stable disease and 4 with PD (and 2 toxic deaths), for a CR +PR response rate of 82%. For disseminated MB (4 M1; 2 M2; 16 M3), the CR rate alone is 77% (17/22). The 5-year EFS and OS for disseminated MB are 45% (95% CI, 24 % to 64%) and 54% (95% CI, 31% to 72%), respectively. Of note, 6/12 MB survivors (all M3) did not receive RT and all are NED >5 years from diagnosis. In addition, there are 3 AT/RT survivors, 12, 54 and 66 mos post-diagnosis who did not receive RT. Conclusions: This intensified regimen is feasible and tolerable. For patients with disseminated MB, the majority of whom had M3 disease at diagnosis, the impressive response rate and outcomes suggest that the addition of methotrexate is justified for future studies. Long- term neuropsychological outcomes are being studied at this time. No significant financial relationships to disclose.

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

The treatment of advanced (Stage III/IV) pediatric lymphoblastic lymphoma (LL) has recently utilized treatment strategies similar to childhood acute lymphoblastic leukemia (ALL) with prolonged maintenance chemotherapy for up to two years (Burkhardt et al JCO, 2006) compared to older treatment strategies of less intense lymphoma type therapy (Anderson et al NEJM, 1983). The CCG previously piloted a “NY regimen” for “lymphomatous” ALL with a new intensive induction/intensive conditioning and alternating non-cross resistant combination maintenance therapy (Steinherz et al JCO, 1986). We modified the NY regimen for lymphomatous ALL in children with advanced (Stage III/IV) lymphoblastic lymphoma with ≤25% BM lymphoblasts. Between July 1994 and June 1997, 85 eligible LL patients with advanced disease (Stage III/IV) were enrolled in a pilot study CCG-5941 to estimate toxicity, feasibility and efficacy of a short (12 month) aggressive multiagent chemotherapy regimen. Patients were staged according to the St. Jude staging system. Induction (3wks) consisted of VCR, Pred, Daunomycin, Cyclophosphamide, L-ASP and IT MTX/ARA-C. Consolidation (3wks) consisted of VCR, ARA-C, VP-16, HD MTX and IT MTX. There were six maintenance courses each consisting of 4 pulses: A (Cylcophosphamide, 6TG), B (VCR, Pred, Dauno), C (VCR, HD MTX, L-ASP) and D (ARA-C, VP-16). CNS positive pts received 1800 cGy-cranial and 600 cGy spinal at completion of chemotherapy (approximately 1 yr). Central pathology review (84%) and immunophenotyping were preformed with CD3, CD5, CD45RO, TDT, CD 79 and CD20. Neupogen (G-CSF) was given after each cycle to maintain dose intensity. Median age 10 yrs (1–18 yrs), 64% male, median f/u 7.2 yrs, 91% T-cell, 7% B-cell, 2% mixed lineage, 27% LDH ≥2nL, 12 % M2 BM, 5% CNS positive. Among the 85 patients there were four deaths unrelated to disease progression (4.7%), three due to infectious complications and one due to venoclusive disease of the liver. Two second malignant neoplasms (AML) have occurred. Hematopoietic (grade III/IV) toxicity occurred in approximately 80% of patients, resulting in delays in chemotherapy. The 5yr event free survival (EFS) is 78±4.5% and 3 yr overall survival (OS) is 85±3.9%. Analysis of EFS by age, sex, induction responses, marrow status at diagnosis (M2 vs M1), presence of CNS disease, LDH ≥2nL and presence of mediastinal mass was not significant. The prognosis in patients with progressive/relapsed disease was dismal with a 2 yr OS of 33±14%. These pilot results suggest that this experimental approach in children and adolescents with advanced LL is safe and feasible and results in similar long term efficacy as compared to more prolonged maintenance ALL type chemotherapy regimens.

9057 Background: HDC/SCR is a novel approach for treatment of children with brain tumors. Despite several studies suggesting results are better in children with primitive neural ectodermal tumors (PNET) or medulloblastoma (MB), it is controversial whether other factors can predict outcome. Methods: We retrospectively analyzed data from 53 patients who underwent HDC/SCR for brain tumors at Children Hospital Los Angeles between June 1992 and June 2005. Patients were aged 4 months to 15.8 years at diagnosis and 9 months to 18.1 years at transplant. In all cases the conditioning regimen included thiotepa and/or etoposide and/or carboplatin. The variables considered were age at diagnosis, histology, extent of disease, conditioning regimen, radiation therapy, stem cell type and timing of transplant. Results: Diagnoses included 33 PNET/MB, 8 high-grade gliomas, 5 ependymomas, 3 germinomas, 2 choroid plexus carcinomas and 2 rhabdoid tumors. Overall event free survival at 36 months was 53±9.1% in PNET/MB and 40±15.5% in tumors with other histology. Variables associated with better EFS in PNET/MB were no prior progression (p=0.00094), no spread into bone marrow (p=1.2 E-10) and age less than 3 years at diagnosis (p=0.046). There was a trend toward improved outcome if there was gross total resection of the tumor (p=0.11). Patients with PNET transplanted before progression had better EFS if they had localized disease at diagnosis (p=0.00024), and if gross total surgical resection was accomplished (p=0.11). Patients with PNET/MB transplanted after progression had better EFS if there was no spread of disease into blood or bone marrow (p=0.00023), if they were male (p=0.053), had localized disease at relapse (p=0.12) and if radiotherapy was given after transplant (p=0.053). In patients with tumors of other histology, the only variable associated with prolonged EFS was gross total resection (p=0.026). Conclusions: Children most likely to benefit from HDC/SCR for brain tumors are those less than 3 years old who are newly diagnosed with PNET that is locally confined, and those with a non-PNET diagnosis who have gross total resection of tumor. No significant financial relationships to disclose.

Stephen A. Sands, PsyD,’ Stewart Kellie, MD,2 Howard Weiner, MD,I Amy Davidow, PhD,3 Cathy Pietanq4 Blunca Die? MD,5 Judith Villablanca, MD,6 Casilda Balmaceda, MD, and Jonathan Firy New York, New York

PURPOSE: From 1986 to 1992, “eight-drugs-in-one-day” (8-in-1) chemotherapy both before and after radiation therapy (XRT) (54 Gy tumor/36 Gy neuraxis) was compared with vincristine, lomustine (CCNU), and prednisone (VCP) after XRT in children with untreated, high-stage medulloblastoma (MB).PATIENTS AND METHODS: Two hundred three eligible patients with an institutional diagnosis of MB were stratified by local invasion and metastatic stage (Chang T/M) and randomized to therapy. Median time at risk from study entry was 7.0 years.RESULTS: Survival and progression-free survival (PFS) ± SE at 7 years were 55% ± 5% and 54% ± 5%, respectively. VCP was superior to 8-in-1 chemotherapy, with 5-year PFS rates of 63% ± 5% versus 45% ± 5%, respectively (P = .006). Upon central neuropathology review, 188 patients were confirmed as having MB and were the subjects for analyses of prognostic factors. Children aged 1.5 to younger than 3 years had inferior 5-year estimates of PFS, compared with children 3 years old or older (P = .0014; 32% ± 10% v 58% ± 4%, respectively). For MB patients 3 years of age or older, the prognostic effect of tumor spread (M0 v M1 v M2+) on PFS was powerful (P = .0006); 5-year PFS rates were 70% ± 5%, 57% ± 10%, and 40% ± 8%, respectively. PFS distributions at 5 years for patients with M0 tumors with less than 1.5 cm2of residual tumor, versus ≥ 1.5 cm2of residual tumor by scan, were significantly different (P = .023; 78% ± 6% v 54% ± 11%, respectively).CONCLUSION: VCP plus XRT is a superior adjuvant combination compared with 8-in-1 chemotherapy plus XRT. For patients with M0 tumors, residual tumor bulk (not extent of resection) is a predictor for PFS. Patients with M0 tumors, ≥ 3 years with ≤ 1.5 cm2residual tumor, had a 78% ± 6% 5-year PFS rate. Children younger than 3 years old who received a reduced XRT dosage had the lowest survival rate.

The authors have attempted to summarize the contributions that have been made towards improvements in the management of children with brain tumors by the development of sophisticated imaging tools for diagnosis, by the development of more sophisticated and versatile neurosurgical tools, by refinements in radiation therapy delivery equipment and techniques, and by the introduction of chemotherapy into therapy regimens. Overall, the interaction of all of these modalities is stressed, culminating in a comprehensive multidisciplinary approach to the management of children with brain tumors.

Immunophenotyping studies with monoclonal antibodies have revealed the heterogeneity of childhood acute lymphoblastic leukemia (ALL) and non- Hodgkin's lymphoma (NHL). The lymphoid malignancies of T-cell lineage are particularly heterogeneous and, until now, no single monoclonal antibody has been found to identify all cases of T-ALL and T-NHL. A monoclonal antibody, 4H9, recognizes an antigen of 40,000 molecular weight on normal and malignant T cells. Thirty-six cases of childhood T- ALL and T-NHL were tested, and in all cases, the malignant blast cells were reactive with 4H9, whereas malignant cells from 61 cases of non-T ALL and NHL were not reactive with 4H9. Monoclonal antibody 4H9 is a sensitive and specific reagent for the identification of childhood T- cell ALL and NHL and should be extremely useful in immunophenotyping studies of lymphoid malignancies.

"Primary" pulmonary histiocytosis X, a well-described entity in young adult males in which pulmonary disease is the overriding site of involvement, is exceedingly rare in children younger than 15 years old. We report a new case in a 2-year-old male and review other reported prepubertal cases. The diagnosis of pulmonary histiocytosis X is based on examination of lung tissue. Langerhans cells containing Birbeck granules, seen by electron microscopy, are virtually pathognomonic of histiocytosis X. These Langerhans cells also react with a monoclonal antibody (OKT6) as well as with antibody to S-100 protein. Based on the lack of consensus for the appropriate treatment of pulmonary histiocytosis X and on our patient's favorable response, we recommend initial therapy with corticosteroids alone, reserving more toxic agents for patients who fail to respond to this initial therapy.

Allogeneic bone marrow transplantation (BMT) has been applied with increasing frequency and success to the treatment of children with severe immune deficiency disease,1,2 aplastic anemia,3,4 and the acute leukemias.5,8 Patients with these otherwise rapidly fatal diseases receive an intravenous infusion of marrow from a healthy donor. The healthy marrow either "replaces" the deficient marrow of children with immune deficiency or aplastic anemia, or "rescues" the marrow of children who have received ablative antileukemic therapy. The resultant engraftment makes the patient a chimera, with reconstitution of mature hematopoietic and immunologic cells of donor origin. When successful, this results in long-term survival with normal marrow function, no recurrence of the original disease, and a return to normal childhood activity and function with only a few irreversible but major side effects (such as infertility following total body irradiation).9

A case of acute lymphoblastic leukemia with morphological characteristics of Burkitt's leukemia (L3 morphology) is presented. This patient's lymphoblasts were lacking in surface immunoglobulin, but were found to contain cytoplasmic IgM. This is the first report of a morphologically B-cell leukemia showing pre-B-cell characteristics immunologically.

A case of clear cell sarcoma of tendons and aponeuroses and a co-existent IgM deficiency is reported. The tumor arose in the Achilles tendon with metastases to the skin, bone, and lymph nodes. The tumor, examined by light and electron microscopy, consisted of glycogen-containing clear cells with melanotic and amelanotic features. There was no detectable serum IgM. The IgA levels were normal and IgG levels were elevated. Peripheral blood lymphocytes contained a normal amount (4.5%) of IgM-bearing cells. Cultured mononuclear cells from the patient suppressed production of IgM by normal lymphocytes, suggesting a role of suppressor cells in the IgM deficiency. The co-existence of soft tissue sarcomas and immunoglobulin deficiency states is reviewed.

Thirty-one adult patients with malignant glioma (23 with glioblastoma multiforme, six with anaplastic astrocytoma, and two with brainstem glioma) were treated with up to ten cycles of “eight-drugs-in-oneday” chemotherapy (methylprednisolone 300 mg/m2, vincristine 1.5 mg/m2 [maximum of 2 mg/cycle], CCNU 75 mg/m2, procarbazine 75 mg/m2, hydroxyurea 3000 mg/m2, cisplatin 90 mg/m2, cytosine arabinoside 300 mg/m2, and imidazole carboxamide 150 mg/m2). Chemotherapy was planned as two cycles before and eight cycles after 60 Gy of involved brain irradiation. A total of 117 cycles of chemotherapy was administered. There was one treatment-related death. Myelosuppression was the most frequent toxic effect (leucopenia was

To determine the current neurosurgical treatment of children with medulloblastomas, we reviewed the operative reports and neurosurgical report forms from 141 children with posterior fossa medulloblastomas treated on two current Children’s Cancer Study Group (CCSG) protocols, CCG-921 for high-stage and CCG-923 for low-stage medulloblastoma. Most medulloblastoma operations were performed in major medical centers: 61% of the operations were performed in CCSG member institutions, 23% in CCSG affiliates and 16% in other institutions. The tumor T stage distribution was as follows: T1 – 4%, T2 – 15%, T3A – 35%, T3B – 36%, and T4 – 10%. Tumors infiltrated the brainstem in 38% of cases and were associated with hydrocephalus in 91% of cases. Hydrocephalus was managed by external ventricular drains in 50% and by shunts in 60%. Adjunctive instruments (e.g., microscope, ultrasonic aspirator) were used in 93% of the operations. Tumor removals were as follows: biopsy only 3%, partial removals 13%, subtotal removals 13%, near total removals 41% and gross total removals in 40%; 90% or more of the tumor was removed in 81% of the operations. Forty-seven percent of the operations were performed by pediatric neurosurgeons. Near total and gross total removals were performed significantly more often (p < 0.05) by pediatric neurosurgeons than by general neurosurgeons. Postoperative morbidity was reported in 46% of cases, including neurologic morbidity in 26% of cases. There was no significant difference in patient morbidity between pediatric and general neurosurgeons.

This case report describes a 16-year-old girl with pure red cell aplasia of 7 months duration. The erythrocyte characteristics and in vitro culture of erythroid progenitors was similar to that found in transient erythroblastopenia of childhood (TEC), a disorder most commonly seen in children 2 to 6 years of age. This case may represent the adolescent equivalent of TEC.

The Drash syndrome of Wilms tumor, glomerulonephritis and male pseudohermaph-roditism (XY gonadal dysgenesis), was first reported in 1967 (Drash et al, 1970; Denys et al, 1967). Since then reports have pointed to the delayed appearance of some manifestations of the syndrome with specific attention paid to the late development of renal failure, or Wilms tumor, in patients with XY gonadal dysgenesis. Therefore, early accurate diagnosis of this syndrome is important. We report on a phenotypically and genotypically normal girl with Wilms tumor and glomerulonephritis. This report and others, which indicate that the syndrome may be present in patients without ambiguous genitalia, lead us to suggest that all girls with Wilms tumor should be considered at risk for the Drash syndrome. If possible, a careful evaluation of the ovaries at surgery is advisable. Furthermore, vigilant follow-up of renal function in Wilms tumor patients is warranted.

Mature polymorphonuclear neutrophilic leukocytes (PMNL) from a 2.5-year-old female with infantile chronic myelogenous leukemia (CML) were stimulated with phorbol myristate acetate or opsonized zymosan. The resulting enzymatic NADPH oxidation and the cellular O2- release and luminol-enhanced chemiluminescence were measured. The patient's PMNL responded normally in all respects. Thus, mature infantile CML PMNL undergo a normal respiratory burst following either soluble or particulate stimulation. Our review of the literature emphasizes the importance of studying a well-defined population of PMNL in patients with myelodysplasia.

HLA-matched bone marrow transplantation is an effective form of treatment for some patients with malignant osteopetrosis, a defect of osteoclast function. Following transplant, normal osteoclasts differentiate from donor-derived marrow stem cells and can function normally in some of these patients. For patients without an HLA-matched marrow donor, pharmacologic treatments have not yet proved effective. This article demonstrates that normal osteoclast function can be obtained following the transplantation of HLA-nonidentical marrow that has been purged of T lymphocytes in vitro.

✓ The common soil fungus, Fusarium, is rarely pathogenic in man but occasionally causes serious disease, particularly in immunocompromised hosts. A case is reported of Fusarium brain abscess and meningitis occurring in a patient with chronic infectious mononucleosis syndrome and immunodeficiency. The patient died despite aspiration of the abscess and treatment with amphotericin B. This case demonstrates the importance of identifying the offending pathological organism through abscess aspiration in immunocompromised patients.