Purpose To assess an intensified treatment in the context of clinical and biologic risk factors in metastatic medulloblastoma. Patients and Methods Patients (4 to 21 years old, diagnosed between 2001 and 2007) received induction chemotherapy, dose-escalated hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy. Subgroup status and other biologic parameters were assessed. Results In 123 eligible patients (median age, 8.2 years old; median follow-up, 5.38 years), 5-year event-free survival (EFS) and overall survival (OS) were 62% (95% CI, 52 to 72) and 74% (95% CI, 66 to 82), respectively. OS was superior compared with the precedent HIT ’91 trial. The 5-year EFS and OS were both 89% (95% CI, 67 to 100) for desmoplastic/nodular (n = 11), 61% (95% CI, 51 to 71) and 75% (95% CI, 65 to 85) for classic (n = 107), and 20% (95% CI, 0 to 55) and 40% (95% CI, 0 to 83) for large-cell/anaplastic (n = 5) medulloblastoma ( P < .001 for EFS; P = .001 for OS). Histology (hazard ratio, 0.19 for desmoplastic/nodular and 45.97 for large-cell/anaplastic medulloblastoma) and nonresponse to the first chemotherapy cycle (hazard ratio, 1.97) were independent risk factors (EFS). Among 81 (66%) patients with tumor material, 5-year EFS and OS differed between low-risk (wingless [WNT], n = 4; both 100%), high-risk ( MYCC/ MYCN amplification; n = 5, both 20%), and intermediate-risk patients (neither; n = 72, 63% and 73%, respectively). Survival rates were different between molecular subgroups (WNT, n = 4; sonic hedgehog [SHH; n = 4]; group 4 [n = 41]; group 3 with [n = 3] or without [n = 17] MYCC/MYCN amplification; P < .001). All cases showed p53 immuno-negativity. There was no association between patients with nonresponding tumors to induction chemotherapy and WNT ( P = .143) or MYCC/MYCN status ( P = .075), histologic subtype ( P = .814), or molecular subtype ( P = .383), as assessed by Fisher’s exact test. Conclusion This regimen was feasible and conferred overall favorable survival. Our data confirm the relevance of subgroup status and biologic parameters (WNT/ MYCC/ MYCN status) in a homogeneous prospective trial population, and show that metastatic group 3 patients do not uniformly have poor outcomes. Biologic subgroup, MYCC/ MYCN status, response to induction chemotherapy, and histologic subtype may serve for improved treatment stratification.

The Hirntumorstudien (HIT)-LGG-1996 protocol offered a comprehensive treatment strategy for pediatric patients with low-grade glioma (LGG), ie, observation, surgery, adjuvant radiotherapy, and chemotherapy to defer the start of irradiation in young children. In this current study, we sought to determine clinical factors for progression and survival. Between October 1, 1996 and March 31, 2004, 1031 patients were prospectively recruited into an observation arm (n = 668) and a nonsurgical arm stratifying 12 months of vincristine-carboplatin chemotherapy (n = 216) and conventional radiotherapy/brachytherapy (n = 147) in an age-dependent manner. Median patient age was 6.9 years; 28 patients had diencephalic syndrome, 44 had dissemination, and 108 had neurofibromatosis type 1(NF-1). Main tumor location was the supratentorial midline (40.4%), and the main histology was pilocytic astrocytoma (67.9%). Following a median observation of 9.3 years, 10-year overall survival (OS) was 0.94 and 10-year event-free survival (EFS) was 0.47. Ten-year progression-free survival was 0.62 following radiotherapy and 0.44 following chemotherapy. Sixty-one of 216 chemotherapy patients received radiotherapy 0.3-8.7 years after initial diagnosis. By multivariate analysis, diencephalic syndrome and incomplete resection were found to be unfavorable factors for OS and EFS, age ≥11 years for OS, and supratentorial midline location for EFS. Dissemination, age <1 year, and nonpilocytic histology were unfavorable factors for progression following radiotherapy (138 patients); and diencephalic syndrome, dissemination, and age ≥11 years were unfavorable factors following chemotherapy (210 patients). NF-1 patients and boys experienced prolonged tumor stabilization with chemotherapy. A nationwide multimodal treatment strategy is feasible for pediatric LGG. Extended follow-up yielded results comparable to single-institution series for the treatment groups. Three-quarters of surviving chemotherapy patients have not yet received radiation therapy. Infants with or without diencephalic syndrome and dissemination bear the highest risk for death and progression following diagnosis or treatment.

INTRODUCTION: Craniopharyngioma is histologically benign but associated with poor quality of life outcomes. The US NCI’s Surveillance, Epidemiology and End Results (SEER) Program began collecting data regarding craniopharyngioma in 2004. METHODS: Using SEER-STAT, we identified all patients with ICD-O-3 codes for craniopharyngioma. Age was divided into 3 groups. Surgical intervention was divided into 3 groups: none, subtotal, and gross total/radical resection. Demographic, follow-up and treatment data were collected. RESULTS: Among 662 patients: 30.7% were ,19 years of age; 13.6% were 20-34 years and 55.7% were .35 years. Age-adjusted incidence per 1,000,000 population was 1.7, 1.1, and 1.9, respectively. Ages with highest incidence were 65-69 and 70-74 years (2.6/million) followed by 5-9 and 60-64 years (2.5/ million). Radiation data was documented in 649 (98.0%) patients. Of these, 22.0% were treated. Radiation rates were 25.6%, 14.6%, and 21.9% in the three age groups. Surgery was documented in 579 (87.5%) patients. Of these, 81.2% underwent surgery. Among patients ,19 years: 17.3% had no surgery, 27.7% had STR and 54.9% had Radical/GTR. Among those 20-34 years, 11.3% had no surgery, 35.0% had STR and 53.8% had Radical/GTR. Among those .35 years, 21.5% had no surgery, 23.0% had STR and 55.5% had Radical/GTR. Radiation rates were 21.1%, 17.8% and 22.9% in the three surgical groups. Follow-up was available for 6/662 patients (0.91%). CONCLUSIONS: Craniopharyngioma is rare. The bimodal incidence shows a larger peak during the 7-8 decades of life than during the 2 decade. 18.8% of patients underwent no surgical intervention, conflicting with most reports. Radiation treatment correlated with neither extent of resection nor age. Possible explanations include variability in treatment strategies, incomplete data, and the inclusion of patients with non-surgical lesions other than craniopharyngioma. Regarding craniopharyngioma, data regarding morbidity, longer follow-up, and comparative analyses with patient level datasets will maximize SEERs value in this population.

PURPOSE:To analyze the frequency, prognostic factors, and outcome of children with atypical teratoid/rhabdoid tumors (AT/RT), a rare and highly malignant embryonal brain tumor.MATERIALS AND METHODS:Clinical data of patients diagnosed between 1988 and 2004 with AT/RT who were registered to the German HIT trial center, were correlated with outcome. Patient numbers for AT/RT were compared to numbers for primitive neuroectodermal tumors and medulloblastomas (PNET/MB) registered to the population-based HIT trials.RESULTS:We identified 56 patients with the centrally confirmed histopathological diagnosis of AT/RT with a median age of 1.2 years (range, 0.1-14.0 years). The AT/RT:PNET/MB ratio was 1:12.2 for all children, and 1:1.5 for children younger than 1 year at diagnosis. Three-year overall survival (OS) and event-free survival (EFS) for all patients were 22% and 13%, respectively. Eight patients (14%) are considered long-term event-free survivors (follow-up 1.4-10.6 years). By univariable analyses, younger age, metastatic disease, infratentorial location, and less than complete remission at the end of chemotherapy were identified as negative influencing factors for OS. By multivariable analyses, younger age (OS, EFS) and metastatic disease (OS) were identified as independent risk factors.CONCLUSION:The incidence of AT/RT in children below 1 year is higher than previously reported. A subset of patients with favorable clinical risk factors profits from intensive multimodal treatment. Prospective clinical and biological studies are needed to further define prognostic factors and optimize therapy.

BACKGROUND:We describe demographic data of disseminated childhood low-grade glioma (DLGG) prospectively recruited in the HIT-LGG 1996 study and evaluate the impact of primary chemotherapy (CT) on the outcome of these tumors, which have previously only been described in small and retrospective series. PATIENTS AND METHODS:The multicenter study HIT-LGG 1996 accrued 1181 children and adolescents with low-grade glioma. 61 patients (5.2%) had tumor dissemination, with 2.8% being present at diagnosis. Frequencies of dissemination for different subgroups were calculated. Efficiency of first-line CT with vincristine/carboplatin was defined in 24 children with dissemination prior to first-line non-surgical-treatment. RESULTS:Incidence of dissemination was high among infants (16%) with hypothalamic-chiasmatic-glioma (HCG) and diencephalic syndrome. A relevant percentage of HCG showed isolated spinal dissemination. CT achieved objective and overall response rates of 25% and 79% of the primary tumor and a similar response of disseminated lesions. Clinical stabilization or improvement could be achieved in the majority of patients during treatment. However, 20 of 24 patients experienced further progression and 5-year PFS was 6%. Dissemination prior to CT was a negative prognostic factor for PFS within the study (P = 0.005). Overall-survival of primary DLGG was inferior compared to LGG without dissemination at diagnosis (P < 0.001). CONCLUSION:Complete MRI scan should be a standard diagnostic procedure in young children with hypothalamic-chiasmatic tumors especially if presenting with diencephalic syndrome. Dissemination in childhood LGG relates to impaired PFS. CT delays progression for responders. Multicenter studies have to evaluate the efficacy of extended treatment strategies in DLGG to improve outcome.

BACKGROUND:Due to the lacking specificity of symptoms making a correct diagnosis can be a challenge in children with medulloblastoma. This can lead to prediagnostic symptomatic intervals (PSIs) of several weeks to months. It is unknown whether the length of the PSI is associated with an inferior survival outcome in this population.METHODS:To study the association of PSI with disease stage at diagnosis, tumour control and survival in children with medulloblastoma, prospectively collected data on PSI, clinical, and biological features were analysed in 224 patients diagnosed at the age of 3-18 years and treated within the prospective randomised multicentre trial HIT'91.RESULTS:Patients with lower-stage disease tended towards a longer median PSI than those with higher-stage disease (M0 stage, 2.0 months; M1 stage, 2.0 months; M2/M3 stage, 1 month; p = 0.094. M0/1 stage versus M2/3 stage; p = 0.025). The patient group with the longest PSI had the best survival outcome (PSI ≥ 4.0 months: 10-year overall survival rate (OS), 71%; PSI < 4.0 months, 10-year OS, 61%; p = 0.056). Age at diagnosis was positively correlated with PSI (p = 0.027). No associations were found between PSI and sex histological subtype, presence of postoperative residual tumour, or c-myc and TrkC mRNA expression.CONCLUSION:Contrary to a common belief that a longer PSI may adversely affect prognosis, a longer PSI was associated with a trend towards lower metastatic stage and better survival probabilities. Nevertheless these findings do not obviate the importance of a timely diagnosis in paediatric patients with medulloblastoma.

BackgroundHypothalamic obesity has major impact on prognosis and quality of life (QoL) in childhood craniopharyngioma.Patients and methodsFor this study, 120 patients were prospectively recruited during 2001 and 2007 and evaluated after 3 years of follow-up (KRANIOPHARYNGEOM 2000). Body mass index (BMI) and QoL at diagnosis and 36 months after diagnosis were analysed based on the reference assessment of tumour localisation and post-surgical hypothalamic lesions. Treatment was analysed based on the neurosurgical strategy of 50 participating neurosurgical centres, the centre size based on the patient load.ResultsBMI SDS at diagnosis was similar in patients with or without hypothalamic involvement. Surgical lesions of anterior and posterior hypothalamic areas were associated with higher increase in BMI SDS during 36 months post-diagnosis compared with patients without or only anterior lesion (+1.8 BMISD, P=0.033, +2.1 BMISD; P=0.011), negative impact on QoL in patients with posterior hypothalamic lesions. Surgical strategies varied among the 50 neurosurgical centres (three large-sized, 24 middle-sized and 23 small-sized centres). Patients treated in small-sized centres presented with a higher rate of hypothalamic involvement compared with those treated in the middle- and large-sized centres. Treatment in large-sized centres was less radical, and the rates of complete resection and hypothalamic surgical lesions were lower in large-sized centres than those of the middle- and small-sized centres. However, a multivariable analysis showed that pre-operative hypothalamic involvement was the only independent risk factor for severe obesity (P=0.002).ConclusionsRadical neurosurgical strategies leading to posterior hypothalamic lesions are not recommended due to the potential to exacerbate hypothalamic obesity and impaired QoL. Treatment should be confined to experienced multidisciplinary teams.

Abstract Background: High grade gliomas (HGG) are highly invasive tumors and respond poorly to conventional treatments. Although significant progress has been made in understanding the molecular pathways that lead to the development of HGG in adults, comparatively few data is available for gliomas of childhood. The death-associated protein 3 (DAP3) is localized on the chromosomal region 1q21-22 that has been previously described as a region of frequent chromosomal gain associated with poor outcome in HGG. Moreover, DAP3 has been reported to be overexpressed and to play anti-apoptotic role in invasive glioblastoma cells. Methods: In the current study to investigate the functional role of DAP3 in pediatric versus adult HGG, we suppressed the endogenous DAP3 protein using DAP3-specific short hairpin RNA (shRNA) or chemical inhibitors of protein kinase C, and analyzed the phenotypic effect on glioma cell proliferation, migration, mitochondrial morphology and apoptosis. Results: We found that knockdown of DAP3 by shRNA induced mitochondrial fragmentation and apoptosis in pediatric glioma cell lines while in adult glioma cell lines it suppressed cell proliferation and reduced mitochondrial potential without inducing mitochondrial fragmentation. Specific chemical inhibition of the two classical PKC isoforms (PKCα and PKCβ) significantly reduced the expression of DAP3 protein in both pediatric and adult glioma cell lines. The inhibition of PKCα changed cell morphology, mitochondrial status and significantly suppressed proliferation and migration of both pediatric and adult glioma cell lines without associated caspase activation indicating that DAP3 may mediate nonapoptotic form of cell death in HGG. The suppression of PKCβ rendered pediatric glioma cells more sensitive to the apoptotic effect of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) through a caspase-dependent process as compared with adult glioma cells suggesting a possible implication of DAP3 in intrinsic and extrinsic pathways for apoptosis in pediatric HGG. Conclusion: Our findings confirmed the anti-apoptotic role of DAP3 in glioma cell biology suggesting that specific PKC isoforms mediated the DAP3 suppression of apoptosis in HGG and pointed out the specific functional role of this protein in mitochondrial maintenance. DAP3 may represent a novel target for the treatment of gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 196. doi:10.1158/1538-7445.AM2011-196

Ependymoblastoma is a rare malignant brain tumor of early childhood. Data on clinical behavior and optimal treatment strategies are scarce. We report on 11 consecutively treated children with centrally confirmed diagnosis of CNS ependymoblastoma, registered between February 1994 and October 2006 to the prospective GPOH-HIT multicenter brain tumor trials, and treated by multimodal regimens. Median age at diagnosis was 3.5 years (range, 1.8–5.6 years), and the median follow-up of survivors was 5.9 years (range, 2.2–12.7 years). Initial stage was M0 in 9, and M0/1 (no cerebrospinal fluid examination done) in 2 patients. Gross-total tumor resection was achieved in 7 patients, incomplete resection in 4 patients. Further primary therapy included chemotherapy in all patients, craniospinal radiotherapy in 5 patients and high-dose chemotherapy in 2 patients. Tumor response to chemotherapy was observed in 1 of 4 evaluable patients. Tumor progression occurred in 7 patients after a median time of 5.0 months (range, 2.5–19.2 months). Five-year progression-free survival was 36.4% (±14.5%), 5-year overall survival 30.3% (±15.9%). Of 4 survivors, 3 had gross-total tumor resection, and all were treated by either craniospinal radiotherapy and/or high-dose chemotherapy with autologous blood stem cell rescue. Prognosis of children with ependymoblastoma is poor, but sustained remissions have been achieved after multimodal treatment. Considerable diagnostic discrepancies between local and central pathologists underscore the importance of central review. Further studies are needed to improve survival of children with this rare malignant central nervous system tumor.

Pediatric Blood & CancerVolume 56, Issue 3 p. 503-505 Letter to the Editor Late complete remission of supratentorial primitive neuroectodermal tumor (CNS-PNET) after multiple relapses André O. von Bueren MD, PhD, Corresponding Author André O. von Bueren MD, PhD [email protected] Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Department of Paediatric Haematology/Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg, GermanyUniversity Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.===Search for more papers by this authorMonika Warmuth-Metz MD, Monika Warmuth-Metz MD Department of Neuroradiology, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorPaul G. Schlegel MD, Paul G. Schlegel MD Department of Paediatric Haematology/Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorNiels Soerensen MD, Niels Soerensen MD Pediatric Neurosurgery, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorJuergen Krauss MD, Juergen Krauss MD Pediatric Neurosurgery, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorWolfgang Roggendorf MD, Wolfgang Roggendorf MD Department of Neuropathology, Institute of Pathology, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorTorsten Pietsch MD, Torsten Pietsch MD Department of Neuropathology, University of Bonn, Bonn, GermanySearch for more papers by this authorWolfgang Feiden MD, Wolfgang Feiden MD Department of Neuropathology, Saarland University, Homburg, GermanySearch for more papers by this authorNorbert Graf MD, Norbert Graf MD Department of Pediatric Hematology and Oncology, Saarland University, Homburg, GermanySearch for more papers by this authorFabian Pohl MD, Fabian Pohl MD Department of Radiotherapy and Radiooncology, University of Regensburg, Regensburg, GermanySearch for more papers by this authorMichael Flentje MD, Michael Flentje MD Department of Radiation Oncology, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorJoachim Kuehl MD, Joachim Kuehl MD Department of Paediatric Haematology/Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorStefan Rutkowski MD, Stefan Rutkowski MD Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Department of Paediatric Haematology/Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this author André O. von Bueren MD, PhD, Corresponding Author André O. von Bueren MD, PhD [email protected] Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Department of Paediatric Haematology/Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg, GermanyUniversity Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.===Search for more papers by this authorMonika Warmuth-Metz MD, Monika Warmuth-Metz MD Department of Neuroradiology, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorPaul G. Schlegel MD, Paul G. Schlegel MD Department of Paediatric Haematology/Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorNiels Soerensen MD, Niels Soerensen MD Pediatric Neurosurgery, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorJuergen Krauss MD, Juergen Krauss MD Pediatric Neurosurgery, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorWolfgang Roggendorf MD, Wolfgang Roggendorf MD Department of Neuropathology, Institute of Pathology, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorTorsten Pietsch MD, Torsten Pietsch MD Department of Neuropathology, University of Bonn, Bonn, GermanySearch for more papers by this authorWolfgang Feiden MD, Wolfgang Feiden MD Department of Neuropathology, Saarland University, Homburg, GermanySearch for more papers by this authorNorbert Graf MD, Norbert Graf MD Department of Pediatric Hematology and Oncology, Saarland University, Homburg, GermanySearch for more papers by this authorFabian Pohl MD, Fabian Pohl MD Department of Radiotherapy and Radiooncology, University of Regensburg, Regensburg, GermanySearch for more papers by this authorMichael Flentje MD, Michael Flentje MD Department of Radiation Oncology, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorJoachim Kuehl MD, Joachim Kuehl MD Department of Paediatric Haematology/Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorStefan Rutkowski MD, Stefan Rutkowski MD Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Department of Paediatric Haematology/Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this author First published: 28 November 2010 https://doi.org/10.1002/pbc.22914Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL REFERENCES 1 Fangusaro J, Massimino M, Rutkowski S, et al. Non-cerebellar primitive neuroectodermal tumors (PNET): Summary of the Milan consensus and state of the art workshop on marrow ablative chemotherapy with hematopoietic cell rescue for malignant brain tumors of childhood and adolescents. Pediatr Blood Cancer 2010; 54: 638– 640. 2 Kortmann RD, Kuhl J, Timmermann B, et al. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: Results of the German prospective randomized trial HIT'91. Int J Radiat Oncol Biol Phys 2000; 46: 269– 279. 3 Rutkowski S, De Vleeschouwer S, Kaempgen E, et al. Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study. Br J Cancer 2004; 91: 1656– 1662. Volume56, Issue3March 2011Pages 503-505 ReferencesRelatedInformation

Background: High grade gliomas (HGG) of childhood represent approximately 7% of pediatric brain tumors. They are highly invasive tumors and respond poorly to conventional treatments. Although significant progress has been made in understanding the molecular pathways that lead to the development of HGG in adults, comparatively few data is available for gliomas of childhood. The death-associated protein 3 (DAP3) is localized on the chromosomal region 1q21-22 that has been previously described as a region of frequent chromosomal gain in pediatric HGG. It encodes a 46 kDa mitochondrial ribosomal GTP-binding pro-apoptotic protein. DAP3 has been reported to be overexpressed in glioblastomas and to protect glioblastoma cells from camptothecin-induced apoptosis. Methods: In the current study, to investigate the functional role of DAP3 in pediatric HGG we suppressed the endogenous DAP3 using DAP3-specific short hairpin RNA (shRNA) and analyzed the mitochondrial morphology by immunofluorescence in vitro. Results: We found that repression of DAP3 by shRNA induced mitochondrial fragmentation and apoptosis in pediatric glioma cell lines while in adult glioma cell lines it reduced proliferation. Protein kinase C (PKC) has been implicated in the proliferation and apoptosis of glial tumors and has been suggested to phosphorylate DAP3 in mitochondria. Western blot analysis showed that adult glioma cells expressed higher levels of PKCα and lower levels of PKCβ as compared with pediatric glioma cell lines. Specific inhibition of the two PKC isoforms (PKCα and PKCβ) reduced the expression of DAP3 protein in both pediatric and adult glioma cell lines without affecting the mitochondrial morphology. The inhibition of PKCα in adult glioma cells significantly suppressed proliferation as compared with pediatric glioma cell lines. The suppression of PKCβ rendered pediatric glioma cells more sensitive to the apoptotic effect of TRAIL through a caspase-dependent process as compared with adult glioma cells suggesting a possible implication of DAP3 in intrinsic and extrinsic pathways for apoptosis in pediatric HGG. Our findings confirmed the anti-apoptotic role of DAP3 in glioma cell biology and pointed out the specific functional role of this protein in mitochondrial maintenance. Conclusion: The results suggest that the phosphorylation of DAP3 which may result from differential activation of specific PKC isoforms in glioma cells is required for functional suppression of apoptosis by DAP3 in HGG. DAP3 may represent a novel target for the treatment of gliomas. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4351.

BACKGROUND:Controversies surround various treatment variables for patients with childhood craniopharyngioma such as growth hormone (GH) replacement, which some believe can exacerbate recurrence/progression. We prospectively assessed the risk of tumor recurrence/progression in survivors of childhood craniopharyngioma. METHODS:Multivariable analyses of risk factors (age at diagnosis, degree of resection, irradiation, GH treatment and gender) and descriptive analyses of overall survival (OS) and event-free survival (EFS) rates were performed in 117 patients, recruited prospectively and evaluated after 3 years of follow-up in the German, Austrian and Swiss multicenter trial KRANIOPHARYNGEOM 2000. RESULTS:We observed a 3-year OS of 0.97 and a 3-year EFS of 0.46, indicating high recurrence rates after complete resection (CR) (n = 47; 3-year-EFS: 0.64) and high progression rates after incomplete resection (IR) (n = 64; 3-year EFS: 0.31). The risk of an event decreased by 80% after CR compared to IR (hazard ratio = 0.20; p < 0.001). Irradiation had protective effects on EFS: irradiated patients had an 88% lower risk of recurrence/progression compared to patients without/before irradiation (hazard ratio = 0.12; p < 0.001). GH treatment had no impact on 3-year EFS rates. CONCLUSIONS:Tumor recurrences/progressions are frequent and occur early after initial treatment of childhood craniopharyngioma. A radical resection preserving the integrity of hypothalamic structures appears optimal at original diagnosis. Irradiation was efficient in preventing recurrences/progressions. GH treatment had no impact on the low 3-year EFS observed in our study. However, further conclusions on the influence of GH on recurrence rates have to be refined to long-term follow-up studies of patients with childhood craniopharyngioma.