Desmoplastic Medulloblastoma Research Articles

Central Nervous System-type Neuroepithelial Tumors and Tumor-like Proliferations Developing in the Gynecologic Tract and Pelvis: Clinicopathologic Analysis of 23 Cases.

Central nervous system (CNS)-type tumors and tumor-like proliferations arising in the gynecologic tract and pelvis are rare. Clinicopathologic features of 23 cases are reported using the current WHO classification system for CNS tumors, with selected relevant immunohistochemical and molecular genetic analyses when possible. There were 12 embryonal tumors, including 7 medulloepitheliomas, 2 embryonal tumors (not otherwise specified), 1 embryonal tumor with multilayered rosettes, 1 embryonal tumor with features of nodular desmoplastic medulloblastoma, and 1 medulloblastoma with extensive nodularity, with primary sites including ovary (7), uterus/endometrium (3), and pelvis (2). Six ovarian tumors had associated germ cell tumors (3 immature teratomas [1 also with yolk sac tumor], 2 mature cystic teratomas, and 1 yolk sac tumor). These tumors typically had some expression of synaptophysin (10/10), GFAP (5/9), S100 (3/6), and NeuN (3/3) and were negative for C19MC amplicon by fluorescence in situ hybridization (0/5). There were 6 glial tumors, including 3 ependymomas (1 anaplastic), 1 oligodendroglioma, not otherwise specified, 1 pilocytic astrocytoma, and 1 atypical glial proliferation after therapy of a high-grade high-stage immature teratoma, with primary sites including ovary (4), fallopian tube (1), and pelvic sidewall (1). Four ovarian tumors had associated teratomas (2 immature and 2 mature). These tumors expressed GFAP (5/6), OLIG2 (2/3), and S100 (1/1), and the pilocytic astrocytoma was negative for BRAF (V600E) mutant protein. There were 4 neuronal or mixed glioneuronal tumors, including 3 neurocytomas and 1 malignant (high-grade) glioneuronal neoplasm, all primary ovarian and associated with teratomas (3 mature, 1 immature). These tumors expressed synaptophysin (4/4), GFAP (1/3), NeuN (1/2), and OLIG2 (1/2). Single-nucleotide polymorphism microarray analysis of the malignant glioneuronal neoplasm demonstrated a partial deletion at location (1)(p36.23p35.2) on chromosome 1p, and 2 regions of deletion at locations (19)(q11q13.12) and (19)(q13.41qter) on 19q. One neurocytoma had no 1p and 19q co-deletions. There was 1 meningioma in the pelvis. For 10 patients with embryonal tumors and follow-up, 5 were alive with no evidence of disease (mean/median: 60/52 mo), 4 were alive with recurrent disease (mean/median: 32/31 mo), and 1 died of disease (13 mo). For 5 patients with other tumor types and follow-up, all were alive without evidence of disease (mean/median: 33/30 mo). Diagnostic evaluation and classification per systems used for primary CNS tumors are recommended for the wide spectrum of CNS-type neuroepithelial tumors that can occur in the female genital tract and pelvis.

Desmoplastic medulloblastoma in an adult patient

Though medulloblastoma is considered as a childhood brain tumor, it may occur less frequently in adolescents and rarely in adults. While desmoplastic medulloblastoma histologic variant is observed in approximately 15% of childhood cases, it constitutes more than 50% of adult cases. In this article, we discuss a desmoplastic medulloblastoma case in view of the current literature.

Desmoplastic Medulloblastoma: A literature review and case report investigating most common clinical presentations in the adult (P6.117)

Desmoplastic Medulloblastoma: A literature review and case report investigating most common clinical presentations in the adult (P6.117)

Extraneuraxial metastases from medulloblastoma: Single-institution outcome analyses

Introduction: Novel biological insights have led to consensus classification of medulloblastoma into four distinct molecular subgroups. It is widely accepted that medulloblastomas have a higher propensity for extraneuraxial metastases (ENM) compared to other primary brain tumors. We sought to review our own institutional experience of ENM from medulloblastoma. Materials and Methods: Patients with a histological diagnosis of medulloblastoma and ENM were identified from institutional neuro-oncology database. Patient-, disease-, and treatment-related details were retrieved by retrospective review of medical case records. Results: A total of 573 patients with medulloblastoma were registered from 2005 to 2016, of which 13 patients were detected with ENM. Median age of our study cohort was 17 years (range: 3–25 years) at index diagnosis. Ten (77%) patients had desmoplastic medulloblastoma, while 3 (23%) patients had large-cell/anaplastic histology. Five of 7 (71%) patients with known molecular subgroup affiliation belonged to sonic hedgehog subgroup, while the remaining two (29%) were subgroup 3 medulloblastoma. The median time to development of ENM was 13 months (range: 2–72 months) with common sites being bone (77%), bone marrow (62%), and lymph nodes (46%). Median overall survival after diagnosis of ENM was 2 months (range: 1–25 months) with 1-year survival probability of 23%. Patients with desmoplastic medulloblastoma had longer median overall survival compared to anaplastic histology (4.5 months vs. 1 month; P = 0.07). None of the other putative prognostic factors such as age at ENM, concurrent central nervous system involvement, visceral metastases, or time to relapse impacted overall survival. Conclusions: ENM from medulloblastoma, although rare, is frequently associated with desmoplastic histology. Bone, bone marrow, and lymph nodes are the most common sites of extraneuraxial involvement. Survival outcomes remain universally poor mandating the testing of newer agents and/or novel molecularly targeted therapies.

Desmoplastic Medulloblastoma with Atypical Presentation in an Adult Patient: A Case Report

Desmoplastic Medulloblastoma with Atypical Presentation in an Adult Patient: A Case Report

ACNS1221: A phase II study for the treatment of non metastatic desmoplastic medulloblastoma in children less than 4 years of age—A report from the Children Oncology Group.

10505 Background: Nodular desmoplastic medulloblastoma and medulloblastoma with extensive nodularity (ND/MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients. Methods: We prospectively conducted a single-arm multicenter trial of conventional chemotherapy for non-metastatic ND/MBEN, based on a modified HIT SKK2000 regimen excluding the use of intraventricular methotrexate (MTX) injection, with the aim to achieve a similar outcome with reduced treatment related neurotoxicity. The design required 37 patients and targeted a 2-year PFS of ≥ 90%. Secondary objectives included evaluation of feasibility of timely central pathology review, prospective evaluation of the cohort’s molecular profile and neurocognitive outcomes. Results: Between 12/2013 and 07/2016, 26 patients were enrolled, including 16 males and 10 females, diagnosed at a median age of 19.7 months (7.1-42.9 months). Four patients had residual disease at baseline. There were 19 ND and 7 MBEN medulloblastoma, confirmed by central pathology review. All cases were reviewed within 10 days by at least 2 of the 3 neuropathologists. The study was closed early following interim analysis due to a higher than expected relapse rate. At last follow-up, 7 patients had relapsed (3 local, 2 distant and 2 combined) at a median time of 9.7 months from diagnosis (range, 9.5-13.7 months). One patient subsequently died of disease. The current median follow-up for the 25 survivors is 1 year (range, 0.2-1.9 years) and the 1 year PFS rate is 66.2% (SE 12.2%). Based on the currently available information, older age (p = 0.07) and ND histology (p = 0.009) appear to be associated with worse PFS. To date none of the patients with MBEN histology have relapsed. Conclusions: The proposed modified regimen of chemotherapy without intraventricular MTX failed to achieve the desirable 2 y PFS of 90%, leading to premature closure of the study. Ongoing molecular characterization of the cohort may help uncover patients who may still benefit from this regimen. Clinical trial information: NCT02017964.

OS02.4 Long-term Outcome of Infants and Young Children with Newly Diagnosed Nodular Desmoplastic Medulloblastoma Treated on “Head Start” III Protocol

Background: High-dose chemotherapy with autologous hematopoietic cell rescue (AuHCR) is a potentially curative approach used in the management young children with medulloblastoma), with the additional benefit of avoiding the late-effects of craniospinal irradiation (CSI). Nodular desmoplastic medulloblastoma (NDMB) patients have been shown to have a favorable outcome in most contemporary infant clinical trials. We report the outcome of young children with NDMB treated on “Head Start” III, a ­prospective, multi-national clinical trial. Methods: Between April 2003 and December 2009, 92 children with newly-diagnosed medulloblastoma were enrolled amongst 29 participating institutions, of whom 27 patients had NDMB. 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 2-year event-free (EFS) and overall survival (OS) rates (+/- SE) for patients with ND medulloblastoma enrolled on HS III (primary objective of the study) were 89 ± 6% and 93 ± 5%, respectively. The 5-year EFS and OS rates were 89 ± 6% and 89 ± 6%, respectively. For 15 patients with localized NDMB (M0), the 5-year EFS and OS rates were 93 ± 6% and 93 ± 6%, respectively. Only one patient died, from CNS hemorrhage related to an accidental fall while undergoing induction. The remaining 14 patients are surviving without having received any irradiation. For 11 patients with disseminated NDMB (M+), the 5-year EFS and OS rates were 82 ± 12% and 81 ± 12%, respectively. One patient died from progressive disease post-transplant and one patient died of toxicity (6 months of age at diagnosis) from veno-occlussive disease and multi-organ failure post-transplant. Only 3 of remaining 9 surviving patients with M+ disease received CSI (2340cGy, 2160cGy, and 2700cGy, respectively, along with posterior fossa boost to a total dose of 5400cGy) according to protocol guidelines. One patient did not have staging work-up performed. Multi-variate Cox regression analyses of the entire cohort revealed ND medulloblastoma histology to be the only significant independent predictor of EFS after adjusting for metastatic status, initial extent of resection of the primary tumor, regimen, age and sex (p<0.001). The 5-year irradiation-free EFS rate for Desmoplastic patients was 88+/-6%. Conclusion: These are among the best survival data published so far on young children with ND medulloblastoma, while avoiding CSI in most patients, including 6 of 9 patients with disseminated disease.

EZH2 and Sonic Hedgehog Inhibition Reduce Proliferation, Migration, In Vitro Tumorigenesis, and CD133 Expression in Desmoplastic Medulloblastoma Cells

Medulloblastoma is the malignant brain tumor that most affects children and young people. Its treatment is very aggressive and can leave important neurocognitive sequelae in patients. Medulloblastoma can be classified histologically and molecularly in different subtypes. Our work focuses on the specific subtype in which the sonic hedgehog pathway is altered. DAOY cells, which correspond to desmoplastic Shh medulloblastoma, were independently treated with two pharmacological inhibitors: cyclopamine and DZNep. Cyclopamine directly inhibits Smo, thus inhibiting the sonic hedgehog pathway; while DZNep acts at the epigenetic level by inhibiting EZH2 function, a histone-lysine N-methyltransferase. The two inhibitions were compared cellularly and molecularly, demonstrating that both drugs reduced cell viability, colony formation, cell migration and the expression of cancer stem cells related genes, like CD133. In addition, the expression of different genes of the sonic hedgehog, EZH2, and other genes regulated by EZH2 and GLI1 were evaluated. The initial hypothesis, according to which the expression of EZH2 would regulate the sonic hedgehog pathway was not demonstrated. Quite the opposite, we observed that the sonic hedgehog pathway could positively regulate EZH2 expression. Our results, however, should be subjected to further experiments in order to elucidate the relationship between the epigenetic regulation exerted by EZH2 and the regulation of the sonic hedgehog pathway in medulloblastoma.

Dynamic susceptibility contrast perfusion imaging in biopsy-proved adult medulloblastoma

Medulloblastoma (MB) is a high-grade rare brain tumor in adults, with heterogeneous imaging features and variable enhancing patterns. Diffusion and spectroscopy multimodal imaging have already been described in adult MB, yet perfusion has not been explored. This study aimed to evaluate vascularity in adult classic and desmoplastic MB, using perfusion-weighted dynamic susceptibility contrast (DSC) MRI and histopathology. Six histologically proved MB patients were classified as classic (n=3) and desmoplastic (n=3). DSC perfusion MRI was performed in three centers and retrospectively evaluated. Postprocessing included automatic arterial input function, motion and contrast leakage correction. Region of interest (ROI) delineation was performed on three perfusion slices to obtain a total of three cerebral blood volume ratios (rCBV) that were averaged to serve as the main rCBV. Permeability was evaluated on K2 maps. Low rCBVs were observed in all cases (mean rCBV=1.19±0.39). rCBV values were lower than 2 for classic MB and lower than 1 for desmoplastic MB. All cases showed an increase of permeability on K2 maps. Our preliminary results suggest that MB exhibits rCBV values close to 1 and increased permeability on DSC perfusion imaging, especially in desmoplastic cases, which could be explained by fibrous matrix. This type of perfusion pattern contrasts with those given by other enhancing subtentorial tumors such as metastasis, high-grade gliomas or hemangioblastomas.

A case of multifocal medulloblastoma in an adult patient

Only five cases of multifocal medulloblastoma in the adult have been reported to date.We present a case in a male patient in his 50th decade of life who presented with three extra-axial lesions associated with a parenchymatous lesion of the right middle cerebellar peduncle.Sputum sample examination revealed larvae compatible with strongyloides stercoralis, which was our main differential diagnosis. Histological and immunohistochemical studies revealed the existence of a desmoplastic medulloblastoma.

Abstract A45: Novel SUFU splice mutation in a child with multiple tumors

Abstract The heritable basis of medulloblastoma is largely unknown. Genes in DNA stability (BRCA1/2), DNA damage (TP53), Sonic Hedgehog-Patched-Gli signaling (PTCH1, SUFU) and WNT signaling pathways (APC) when mutated predispose to brain tumor development. Identification of syndromic stigmata identified before the evolution of malignancy provides an opportunity for screening and family planning. However, given the rarity of these syndromes, incomplete genotype/phenotype description and variable penetrance, outcome data and recommendations founded on expansive evidence are lacking. Gorlin syndrome (OMIM: 109400) is a phakomatosis distinguished by multiple jaw keratinocytes, basal cell carcinomas, macrocephaly, bossing of the forehead, coarse facial features, and milia. Other features described include skeletal anomalies, ectopic calcification in the falx, cardiac and ovarian fibromas, and primitive neuroectodermal tumors. Moreover, patients are exquisitely sensitive to radiation and sun exposure. Mutations in PTCH1 and SUFU underpin Gorlin syndrome or Nevoid Basal Cell Carcinoma Syndrome. Here we describe a 9 year-old female with a history of desmoplastic medulloblastoma, ovarian fibrothecoma and meningioma. The child's treatment to date has included chemotherapy, autologous stem cell transplantation, and intrathecal chemotherapy for her brain tumor and surgical resection of her ovarian tumors. The patient's family history was salient for a paternal aunt diagnosed with a meningioma at 18 years of age and paternal grandfather diagnosed with leukemia in his late 50s. Diagnosis of desmoplastic medulloblastoma at age 3 years and having a family history young onset meningioma, Gorlin syndrome was queried and prompted PTCH1 and SUFU molecular genetic testing. Testing revealed a novel heterozygous germline SUFU mutation, c.1023-2A&amp;gt;T mutation predicted to lead to aberrant splicing and a heterozygous germline PTCH1, c_6_-4delGGC, pre-coding variant of uncertain significance. The SUFU mutation segregated on the paternal side consistent with the family history. A familial exome analysis is underway in efforts to understand disease penetrance in this family. At present, in the absence of guidelines differentiating screening for individuals with SUFU vs. PTCH1 mutations, family members harboring the SUFU mutation are being surveyed with Gorlin syndrome recommendations and increased neuroimaging. Given limited remaining therapeutic options, if the proband is judged to require adjuvant treatment in the future, targeted molecular agents against smoothened (SMO) with vismodegib which has been shown to be an effective therapeutic intervention for patients with PTCH1 mutations are potential considerations. In conclusion, utilizing genomic sequencing we have detected a novel SUFU mutation in a child with multiple cancers and family history consistent with mutations in the Sonic Hedgehog-Patched-Gli pathway. In the absence of genotype/phenotype specific guidelines, Gorlin syndrome recommendations including intensive brain MRI are being followed and given the paucity of data related to outcome for targeted therapies in children with pathogenic SUFU mutations further investigations are warranted. Citation Format: Michael F. Walsh, Megan Harlan, Jennifer Kennedy, Jacob Musinsky, Michael LaQuaglia, Zsofia Stadler, Stephan Gilheeney, Kenneth Offit. Novel SUFU splice mutation in a child with multiple tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A45.

The Antiproliferative and Pro-apoptotic Effects of Methoxyamine on Pediatric Medulloblastoma Cell Lines Exposed to Ionizing Radiation and Chemotherapy.

Medulloblastoma (MB) treatment is continuously evolving. Better treatment approaches, focused on particular molecular pathways involved in MB development and progression support new treatment strategies. This article explores the antiproliferative, proapoptotic and radiosensitizing effects of Methoxyamine (MX), a base excision repair (BER) inhibitor that has shown anticancer potential by sensitizing tumor cells to ionizing radiation and chemotherapy. The DAOY (a desmoplastic cerebellar-derived MB) and ONS-76 (classical MB) cell lines were treated with MX at different concentrations, either alone or combined with various chemotherapeutic compounds: cisplatin (CDDP), temozolomide (TMZ) and thiotepa (THIO). Additionally, cell lines were exposed to MX and treated at different ionizing radiation fractions. Measurement of cell growth by XTT assay, clonogenic assay and detection of apoptotic cell death through caspase activity was obtained. Exposure to MX significantly decreased cell proliferation (p<0.05) while increasing cell apoptosis (p<0.05). Growth reduction was concentration-dependent for both DAOY and ONS-76 cells lines. Conversely, MX failed to enhance the cytotoxicity of CDDP, TMZ, and THIO. Moreover, MX treatment radiosensitized both cell lines, with ONS-76 cells being more prone to radiation effects at higher doses of exposure. These data support the role of MX as a direct cytotoxic compound for pediatric MB cells by inhibiting the BER pathway. Nevertheless, an antagonism, rather than a synergic or additive effect of MX with different concentrations of CDDP, TMZ and THIO was observed. Likewise, the radiosensitizing effect on MB cell lines seems to depend on radiation doses and MB subtype. This information may be relevant for clinical study designs employing BER inhibitors for MB.

Ventilation with facial mask in the prone position for radiotherapy procedures in children

ObjectivesVentilation of patients undergoing procedures in the prone position represents a challenge for the anesthesiologist, especially when trying to avoid tracheal intubation. This study aimed to test the effectiveness and safety of a prototype designed for pediatric facial mask ventilation in the prone position. Materials and methodsA prospective descriptive study was conducted on 105 sedations performed in 3 children scheduled for radiotherapy treatment of posterior fossa desmoplastic medulloblastoma (6 and 4 y.o. males), and neuroblastoma in temporal area (4 y.o. male). Induction and maintenance of sedation were conducted with sevoflurane in oxygen, maintaining spontaneous ventilation. After achieving loss of consciousness and immobility, the patients were placed in the prone position. Their heads were fixed with the forehead and face supported by a prototype made with a cast of expanded polystyrene (EPS), which held the facial mask (connected to a Mapleson D circuit), and the back of the head immobilized with a layer of thermoplastic material. Time variables and complications were recorded. ResultsAll sedations were performed according to the planned protocol. All patients maintained oxygen saturation levels above 95%, and no complications were reported. Daily hospital length of stay including the procedure and post anesthetic recovery was 54.4±7.9min (mean±SD). ConclusionsThe prototype and the sedation technique with face mask in the prone position employed were effective and safe, allowing the completion of the radiotherapy sessions and securing the airway in a minimally invasive way, maintaining adequate ventilation, light sedation and enabling early hospital discharge.

Metastatic medulloblastoma in adults: Outcome of patients treated according to the HIT2000 protocol

BackgroundDue to the rarity of metastatic medulloblastoma in adults, knowledge about the efficacy and toxicity of intensified chemotherapy and radiotherapy is limited. Patients and methodsAdults with disseminated medulloblastoma registered in the HIT2000 trial as observational patients and treated according to one of two different treatment regimens were analysed. The sandwich strategy MET-HIT2000AB4 consists of postoperative chemotherapy, hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy; while the HIT′91 maintenance strategy consists of postoperative craniospinal radiotherapy, and maintenance chemotherapy. ResultsTwenty-three patients (median age: 30.7years), diagnosed from November 2001 to July 2009, and treated in 18 institutions in Germany and Austria, were eligible. The median follow-up of surviving patients was 3.99years. The 4-year event-free survival (EFS) and overall survival (OS)±standard error (SE) were 52%±12% and 91%±6%, respectively. The survival was similar in both treatment groups (HIT′91 maintenance strategy, n=9; MET-HIT2000AB4 sandwich strategy, n=14). Patients with large cell/anaplastic medulloblastoma relapsed and died (n=2; 4-year EFS/OS: 0%) and OS differed compared to patients with classic (n=11; 4-year EFS/OS: 71%/91%) and desmoplastic medulloblastoma (n=10; 4-year EFS/OS: 48%/100%), respectively (p=0.161 for EFS and p=0.033 for OS).Treatment-induced toxicities consisted mainly of neurotoxicity (50% of patients, ⩾ °II), followed by haematotoxicity and nephrotoxicity/ototoxicity. The professional outcome appeared to be negatively affected in the majority of evaluable patients (9/10). ConclusionsTreatment of adults with metastatic medulloblastoma according to the intensified paediatric HIT2000 protocol was feasible with acceptable toxicities. EFS rates achieved by both chemotherapeutic protocols were favourable and appear to be inferior to those obtained in older children/adolescents with metastatic disease.

Ventilación con mascarilla facial en decúbito prono para tratamiento radioterápico en niños

ObjectivesVentilation of patients undergoing procedures in the prone position represents a challenge for the anesthesiologist, especially when trying to avoid tracheal intubation. This study aimed to test the effectiveness and safety of a prototype designed for pediatric facial mask ventilation in the prone position. Material and methodsA prospective descriptive study was conducted on 105 sedations performed in 3 children scheduled for radiotherapy treatment of posterior fossa desmoplastic medulloblastoma (6 and 4 y.o. males), and neuroblastoma in temporal area (4 y.o. male). Induction and maintenance of sedation were conducted with sevoflurane in oxygen, maintaining spontaneous ventilation. After achieving loss of consciousness and immobility, the patients were placed in the prone position. Their heads were fixed with the forehead and face supported by a prototype made with a cast of expanded polystyrene (EPS), which held the facial mask (connected to a Mapleson D circuit), and the back of the head immobilized with a layer of thermoplastic material. Time variables and complications were recorded. ResultsAll sedations were performed according to the planned protocol. All patients maintained oxygen saturation levels above 95%, and no complications were reported. Daily hospital length of stay including the procedure and post anesthetic recovery was 54.4±7.9min (mean±SD). ConclusionsThe prototype and the sedation technique with face mask in the prone position employed were effective and safe, allowing the completion of the radiotherapy sessions and securing the airway in a minimally invasive way, maintaining adequate ventilation, light sedation and enabling early hospital discharge.

MB-28 * GENOME-WIDE COPY NUMBER ANALYSIS, NEUROPATHOLOGICAL CLASSIFICATION AND ANALYSIS OF HEDGEHOG ACTIVATION: HISTOLOGY REFLECTS GENETICS AND BIOLOGY IN MEDULLOBLASTOMAS OF YOUNG CHILDREN

The identification of desmoplastic/nodular histology as an independent favourable prognostic marker in medulloblastoma (MB) of infancy has allowed the reduction of therapy in these patients to decrease longterm side-effects. Although we were able to demonstrate different origins and pathway activation of desmoplastic versus non-desmoplastic MB, the genomics and pathway activation has not been exactly related to the different histological MB subtypes. 168 MBs of children under 5 years of age were diagnosed according to the WHO 2007 classification, and FFPE material was analysed in detail by immunohistochemical techniques (including staining of hedgehog targets YAP-1 and p75-NGFR) as well as by molecular inversion profiling (MIP) to assess the genomic landscape of infant MB. GISTIC analysis was performed to identify significant copy number alterations in MB subtypes. MB with extensive nodularity (MBEN, n = 22) and desmoplastic MB (DMB, n = 42) were both characterized by LOH of chromosomal arms 9q or 10q (MBEN, 77% of cases; DMB, 76%), whereas classic MB (CMB, n = 90) and large cell or anaplastic MBs (LCA-MB, n = 14) frequently showed specific gains of chromosomal arm 17q (CMB, 67%; LCA-MB, 79%),partially occurring as isochromosome 17q (CMB, 30%; LCA-MB, 57%), and gains of OTX2 (CMB, 73%; LCA-MB, 79%). Moreover 10/14 (71%) of LCA-MB carried MYCC (n = 9) or MYCN (n = 1) amplifications. The overall frequency of chromosomal copy number aberrations was significantly lower in the desmoplastic/nodular subtypes compared to non-desmoplastic subtypes. Importantly, there was a high correlation between desmoplastic/nodular histology (MBEN and DMB) versus non-desmoplastic subtypes with hedgehog pathway activation shown by the expression of Yap-1 and p75-NGFR (concordance rate, >98%). In summary, histology of infant MB is associated with specific recurrent chromosomal alterations and reflects their biology determined by their cellular origin and developmental pathway activation. Immunohistological assessment of pathway markers and genomic profiling by MIP can help to classify infant MBs.

MB-32 * FEASIBILITY OF VORINOSTAT COMBINED WITH ISOTRETINOIN AND CHEMOTHERAPY FOR YOUNG CHILDREN WITH NEWLY DIAGNOSED EMBRYONAL BRAIN TUMORS: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY

BACKGROUND: Pre-clinical evaluation of vorinostat and isotretinoin demonstrated cytotoxicity in medulloblastoma (MB) and synergistic activity when combined with cisplatin. This study sought to evaluate the feasibility of combining vorinostat and isotretinoin with cytotoxic chemotherapy in young children with newly diagnosed brain tumors. METHODS: Eligible patients were less than 4 years of age with newly diagnosed medulloblastoma (MB) or supratentorial primitive neuroectodermal tumor (CNS-PNET). Localized desmoplastic MB was excluded. Treatment consisted of 3 induction cycles given every 21 days with vorinostat and isotretinoin(days 1-4), cisplatin(day 4), vincristine(days 4,11,18), cyclophosphamide(days 5-6), and etoposide(days 4-6); 3 consolidation cycles with carboplatin and thiotepa(days 1-2) with stem cell rescue(day 4); and 12 cycles of monthly maintenance therapy with vorinostat and isotretinoin. Patients with M0 MB received focal radiation therapy following consolidation therapy; others received radiation at the discretion of the treating physician. Craniospinal radiation was not allowed on protocol. RESULTS: 31 patients received treatment on study; 19 (61.3%) were male; 7 (22.6%) had spinal cord or cerebrospinal fluid metastasis at diagnosis. Diagnosis was MB for 20, other CNS-PNET for 11. 24/31 patients completed 3 cycles of induction therapy within the pre-specified feasibility endpoint of 98 days. Eight experienced disease progression on therapy. Twelve completed therapy, five continue on therapy, five discontinued study treatment without progression, and one died of pulmonary toxicity following second cycle of consolidation. Two-year Progression Free Survival and Overall Survival for the entire cohort were 64.4% (SE ±11.1%) and 75.6% (SE ±10.0%), respectively; 68.2% (SE ±12.8%) and 77.0% (SE ±11.1%) for MB. Frozen tumor was collected from 30/31 tumors. CONCLUSION: It is feasible to administer vorinostat with isotretinoin and chemotherapy to young children with newly diagnosed MB or CNS-PNET. This multimodality therapy regimen resulted in encouraging progression-free survival without craniospinal radiation in a high-risk group of young children. Genomic studies are planned.

Pilot Study of Intensive Chemotherapy With Peripheral Hematopoietic Cell Support for Children Less Than 3 Years of Age With Malignant Brain Tumors, the CCG-99703 Phase I/II Study. A Report From the Children's Oncology Group

BackgroundThe primary goals of the Children's Cancer Group 99703 study were to assess the feasibility and tolerability of—as well as the response rate to—a novel dose-intensive chemotherapy regimen. MethodsBetween March 1998 and October 2004, 92 eligible patients were enrolled. Following biopsy/resection, patients received three identical cycles of Induction chemotherapy (vincristine, cyclophosphamide, etoposide, and cisplatin) administered every 21-28 days. Patients without tumor progression then received three consolidation cycles of marrow-ablative chemotherapy (thiotepa and carboplatin) followed by autologous hematopoietic cell rescue. ResultsThe maximum tolerated dose of thiotepa was 10 mg/kg/day × 2 days per cycle. The toxic mortality rate was zero during induction and 2.6% during consolidation. Centrally evaluated response rates to induction and consolidation in evaluable patients with residual tumor were 73.3% and 66.7%, respectively. Disease progression rates on induction and consolidation were 4%. Five-year event-free survival and overall survival were 43.9 ± 5.2% and 63.6 ± 5% respectively. Gross total resection versus less than gross total resection were the only significant outcome comparisons: 5-year maximum tolerated dose and overall survival of 54.4 ± 7% versus 28.9 ± 7% (P = 0.0065) and 75.9 ± 8% versus 48.7 ± 8% (P = 0.0034), respectively. The 5-year maximum tolerated dose for localized (M0) versus metastatic (M1+) medulloblastoma was 67.5 ± 9.5% versus 30 ± 14.5% (P = 0.007). The 5-year maximum tolerated dose and overall survival for desmoplastic medulloblastoma patients versus other medulloblastoma were 78.6 ± 11% versus 50.5 ± 12% (P = 0.038) and 85.7 ± 9.4% versus 60.6 ± 11.6% (P = 0.046), respectively. ConclusionsThis phase I dose-escalation study of marrow-ablative thiotepa regimen determined a maximum tolerated dose that had acceptable toxicity. Overall survival data justify this strategy for current Children's Oncology Group studies.

Paired box gene 8 (PAX8) expression is associated with sonic hedgehog (SHH)/wingless int (WNT) subtypes, desmoplastic histology and patient survival in human medulloblastomas.

The paired box gene 8 (PAX8) plays crucial roles in organ patterning and cellular differentiation during development and tumorigenesis. Although its function is partly understood in vertebrate development, there is poor data concerning human central nervous system (CNS) development and brain tumours. We investigated developing human (n = 19) and mouse (n = 3) brains as well as medulloblastomas (MBs) (n = 113) for PAX8 expression by immunohistochemistry. Human MB cell lines were assessed for PAX8 expression using polymerase chain reaction and immunoblotting and analysed for growth and migration following PAX8 knock-down by small interfering ribonucleic acid (siRNA). PAX8 protein expression was associated with germinal layers in human and murine forebrain and hindbrain development. PAX8 expression significantly decreased over time in the external granule cell layer but increased in the internal granule cell layer. In MB subtypes, we observed an association of PAX8 expression with sonic hedgehog (SHH) and wingless int subtypes but not with group 3 and 4 MBs. Beyond that, we detected high PAX8 levels in desmoplastic MB subtypes. Univariate analyses revealed high PAX8 levels as a prognostic factor associated with a significantly better patient prognosis in human MB (overall survival: Log-Rank P = 0.0404, Wilcoxon P = 0.0280; progression-free survival: Log-Rank P = 0.0225; Wilcoxon P = 0.0136). In vitro assays revealed increased proliferation and migration of MB cell lines after PAX8 siRNA knock-down. In summary, high PAX8 expression is linked to better prognosis in MBs potentially by suppressing both proliferative and migratory properties of MB cells. The distinct spatio-temporal expression pattern of PAX8 during brain development might contribute to the understanding of distinct MB subtype histogenesis.

Neurofibromatosis type 2 patient presenting with medulloblastoma

Background:Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome with a frequency of 1 in 25,000 live births and a penetrance of almost 100% by the sixth decade of life. The main tumors occurring in NF2 patients are bilateral vestibular schwannomas, other peripheral, cranial and spinal nerve schwannomas, intracranial and intraspinal meningiomas, ependymomas, and gliomas.Case Description:We report the case of a 6-year-old boy who presented with a 1-month history of nausea and recurrent vomiting. Physical examination was positive for ataxic gait and left-sided facial nerve palsy. Family history was positive for NF2 in the patient's father and paternal uncle. Magnetic resonance imaging brain revealed a solid enhancing lesion arising from the right cerebellar cortex, which was effacing the fourth ventricles and causing hydrocephalus. Craniotomy and excision of the lesion were performed. Histopathology report confirmed the diagnosis to be desmoplastic medulloblastoma. Based on the patients’ subsequent history and family history, he was diagnosed to be a case of NF2.Conclusion:This is the first case of medulloblastoma occurring in a patient with NF2 and raises the possibility of an association between medulloblastoma and NF2.