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|Year : 2006 | Volume
| Issue : 1 | Page : 16-23
Medulloblastomas: New directions in risk stratification
Chitra Sarkar, Prabal Deb, Mehar Chand Sharma
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
Medulloblastomas (MBs) are the most common malignant brain tumors in children. Current therapeutic approaches combine surgery, radiotherapy, and chemotherapy. Although, there has been significant improvement in long-term survival rates, the tumor remains incurable in about a third of patients while cognitive deficits and other sequelae of therapy are common among long-term survivors. Hence a major challenge remains to differentiate high-from low-risk patients and to tailor therapy based on the degree of biological aggressiveness. A clinical risk-stratification system has been widely used in MBs based on age, extent of resection and the Chang staging system. However, recent reports indicate that these clinical variables are inadequate methods of defining disease risk. This has prompted search for new markers for MB stratification. Recent studies indicate that the classification of MBs according to profiles of histopathology and molecular abnormalities possibly help better risk-stratification of patients, thereby rationalizing approaches to therapy, increasing cure rate, reducing long-term side effects and developing novel therapeutic strategies. The most accurate outcome prediction till date has been obtained through microarray gene expression profiling. In this article, the current histopathological classification and the recent advances in molecular genetics of MBs are reviewed. Global efforts to translate this knowledge of disease biology into clinical practice especially as outcome predictors are highlighted.
Keywords: Histopathology, medulloblastoma, molecular genetics, prognostic factors, risk-stratification.
|How to cite this article:|
Sarkar C, Deb P, Sharma MC. Medulloblastomas: New directions in risk stratification. Neurol India 2006;54:16-23
Medulloblastoma (MB) is one of the five embryonal tumors of the central nervous system (CNS) included in the current WHO classification (WHO Grade IV). It is a highly malignant tumor of the cerebellum occurring predominantly in children and accounting for 12-25% of all pediatric CNS tumors.,,,, It is less frequent in adults, constituting only 0.5-1% of all intracranial neoplasms.,,,,
A. Risk stratification by clinical factors
Since the mid-1990s, the risk classification for relapse and selection of treatment of MB patients has remained strictly clinical, with cases stratified into two-risk groups, viz. 'average risk' and 'high risk,' based on the following criteria: (i) age, (ii) extent of resection, and (iii) Chang metastasis staging [Table - 1].,
According to this classification, average-risk patients are those older than 3 years of age with nonmetastatic disease and totally or near totally resected tumors (<1.5 cm of residual tumor on postoperative MR). Patients not fulfilling these criteria are regarded as high-risk . This clinical staging has been helpful as a broad guide for predicting prognosis. However a major drawback is that this does not differentiate high- from low-risk patients within the same clinical stage. It is a well-observed fact that patients with similar neoplasms and similar clinical stage, receiving identical therapies can have widely disparate clinical outcomes, owing to biological differences within the tumor. Further, two different trials, German trial HIT'91 and CCG 921, have established that overall survival (OS) is not significantly different between children staged as M0 vs those staged as M1. Also, brain stem invasion (stage III b), previously regarded as an indicator of high-risk, is now believed not to affect prognosis.
Based on this clinical staging system, a multimodality therapeutic approach has been designed for MBs, with maximum surgical resection, neuraxis radiation and chemotherapy. This has led to a reduction in the mortality rate by twofold in the last 30 years, with OS rates ranging from 50 to 60% at 5 years and 40-50% at 10 years. However, in long-term survivors of MBs, this aggressive protocol is associated with severe side effects in the form of neuropsychological sequelae and neurocognitive decline.,.,
In short, the major criticism of the current clinical staging is that it does not identify the 20-30% of average-risk patient with resistant disease or the average-risk patients who might be over treated with the current protocol. Hence, an important goal is to improve the chances of survival for all children with MB, and to tailor specific therapies to individual lesions based both on their degree of clinical as well as biological risk, so that patients are not over- or under-treated, and side effects are minimized.
All this has prompted search for new biological markers - histological and molecular - for MB stratification. It is hoped that a greater understanding of MB biology will not only translate into refinements in risk classification, but also lead to risk-based tailoring of therapies to individuals. It will also help in improvements in the way existing therapies are used, which is crucial in minimizing their devastating long-term side effects.
B. Risk stratification by histopathological factors
Recent studies have conclusively demonstrated that the following three histological factors have a distinct role in the determination of clinical outcome in MB viz. histopathological subtype, extent of nodularity and grade, as well as, extent of anaplasia [Table - 2]. The other factors implicated to have prognostic significance include desmoplasia, cell differentiation, proliferation, apoptosis, and ploidy. However, their definite role still remains controversial.
1. Histopathological subtypes
Six distinct histological subtypes of MB have been included in the current WHO classification.
Classic MBs are characterized by sheets of densely packed cells with hyperchromatic small round to oval nuclei, indiscernible cytoplasm, numerous mitoses, conspicuous apoptosis, and formation of occasional Homer Wright/neuroblastic rosettes.,,
Desmoplastic MBs, on the other hand, show typical nodular architecture comprising of reticulin-free pale nodules and reticulin-rich internodular regions.,,
Medulloblastomas with extensive nodularity and advanced neuronal differentiation (MBEN) are a distinct subtype, occurring in infants less than 3 years of age and demonstrating a striking grape-like nodularity on imaging. Histologically, they show a predominant nodular architecture with round uniform cells inside nodules arranged in a streaming pattern within a fine fibrillary neuropil-like matrix. Thus they differ from desmoplastic MBs in showing uniform neurocytic differentiation with little or no internodular component.,,
LC/A MBs comprise of large cells with pleomorphic nuclei, prominent nucleoli and more abundant cytoplasm than most MBs. High mitotic and apoptotic rate along with large areas of necrosis are also common.,,,
Melanotic MBs, are characterized by melanin production in scattered cells,, while medullomyoblastomas consist of cells displaying variable rhabdomyoblastic differentiation,,,, both in a background of classic MB.
Of all the six variants the best prognostic outcome is noted with MBENs., This is intriguing because it generally affects young infants who according to the clinical stage belong to the high-risk category. The worst outcome is associated with LC/A MBs, which are extremely aggressive with high incidence of local recurrence, CSF spread, systemic metastasis and death within 1-2 years of diagnosis.,
Difference in prognosis between the classic and desmoplastic variants remains controversial. Desmoplastic MBs have been variably correlated with better outcome,, by some, while others found it to be either associated with worse prognosis, or without any correlation with survival time.,,
Melanotic MBs and medullomyoblastomas have poor outcome, with survival ranging from 2 months to 2.5 years, in the former, and generally less than 1 year, in the latter subtype.,
2. Extent of nodularity
Eberhart et al demonstrated nodularity in 29% of 330 similarly treated cases of pediatric MB from the Pediatric Oncology Group (POG, USA). However, nodule formation in MBs can be variable - from diffuse to very focal. Hence, they graded the extent of nodularity into five categories - extensive (96-100%), widespread (51-95%), moderate (11-50%), slight (1-10%), and none (0%), and observed that only tumors with extensive nodules were associated with better survival. All other grades of nodularity showed no correlation with outcome.
The concept of anaplasia in MBs is relatively new and analogous to anaplasia in Wilm's tumor, which has well defined clinical implications. Anaplastic MBs have currently been proposed as the variant with most aggressive biological behavior.
Anaplastic MBs are characterized by markedly atypical cells having angular pleomorphic nuclei with coarse chromatin, wrapping around each other, with frequent moulding.,,, Earlier studies suggested that anaplasia was only confined to the large cell variant of MB. However, recent studies have shown that they can also arise by malignant progression of classic and desmoplastic MBs, as well as medullomyoblastomas.,, These cells are thought to represent focally aggressive clones capable of undergoing malignant progression, based on the observation that they often co-exist focally within MBs, or manifest only after recurrence or metastasis.,,,
Brown et al in a review of 474 MBs from POG patients, reported that the long-term survival of LC-MB with anaplasia was 10% compared to more than 50% in LC-MB without anaplasia. Eberhart et al on reevaluating 330 of the POG patients reported by Brown et al observed that while tumors with diffuse anaplasia were most aggressive, even focal anaplasia was significantly associated with poor outcome. Further patients with tumors having moderate to severe anaplasia (anaplastic group) had significantly shorter event-free survival (EFS) and OS as compared to those with slight to no anaplasia (nonanaplastic group). The 5-year survival probability was 42% inpatients with anaplastic variant in contrast to 68% for patients with nonanaplastic disease. In fact, on log-rank analysis, grade of anaplasia allowed better stratification of patients with respect to outcome than the current clinical stage, indicating that histological grading is not a surrogate for clinical staging, but rather an independent predictor of survival. Similar results of association of anaplasia with poor outcome have also been shown by MacManamy et al.
Conflicting reports on relationship of desmoplasia to outcome are chiefly attributable to different definitions of desmoplasia. In addition to conventional desmoplastic MBs, rarely MBs show an intense pericellular desmoplasia without any obvious nodule formation. Further invasion of leptomeninges by classic MB also produces intense desmoplasia.
In a retrospective review of 330 POG patients, Eberhart et al noted desmoplasia in 22% of cases. However there was no significant association of desmoplasia with clinical outcome (either EFS or OS).
5. Cell differentiation
Another histopathological prognostic parameter in MBs, which has received considerable attention but little agreement, is differentiation along glial or neuronal cell lines. Positivity for GFAP have been variably correlated with better prognosis, by some, while others found it to be either associated with poor prognosis,, or without any correlation with survival time.,
6. Proliferation/labeling index (LI)
Cell proliferation is another prognostic parameter whose significance is not clear. Ito et al showed that tumors with Bromodeoxyuridine (BudR) LI greater than 20% had a trend to worse prognosis. In contrast, Giordana et al and Schiffer et al showed no correlation in both adult and pediatric MBs. Studies of Sarkar et al suggested that MBs in children have higher MIB-I proliferative indices and lower apoptotic indices than those in adults.
7. Apoptotic index (AI)
Since it is the balance between cell proliferation and cell death that determines the rate of tumor growth, the impact of apoptosis on outcome has also been considered. Apoptosis has been suggested as a favorable prognostic feature by some and as a negative feature by others., Korshunov et al calculated AI of >1.5% to be associated with shorter survival, while Eggert et al found that expression of Apo3 was significantly associated with prolonged survival of MB patients. Haslam et al demonstrated that patients with a high AI had substantially improved outcome compared to all other patients, independently from the assignment to a high- or low-risk group at the time of diagnosis.
A more favorable prognosis has been associated with aneuploidy in MBs. Ramachandran et al found that patients with aneuploid tumors responded well to treatment regimens as compared to those with diploid tumors. Also, patients with progressive disease had a high S-phase fraction in the tumor cell population as compared with patients with favorable response to treatment.
C. Risk stratification by molecular and cytogenetic factors
It is widely accepted that identification of genetic and molecular alterations allows a clinically relevant subgrouping of MBs with particular profiles of biological behavior and outcome [Table - 2]. ,,,,,, The molecular genetic alterations in MBs have been worked out extensively and can be divided into three heads:
1. Nonrandom chromosomal abnormalities,
2. Gene profiling,
3. Abnormalities in signal transduction pathways.
1. Nonrandom chromosomal abnormalities
(i) Loss of 17p/isochromosome 17q
The most frequent genetic alteration present in 30-50% of MB cases is partial or complete deletion of the short arm of chromosome 17 (17p), ,,,, which may occur in isolation, but more frequently as a component of an isochromosome of 17q [i(17q)].,,, A recent study suggested that 17p loss /isochromosome 17q is more frequent in LC/A MBs than in classic MBs.
Several authors have observed that 17p deletion and/or i(17q) are prognostically unfavorable being associated with poor response to therapy, metastatic disease and shortened survival., However, other studies have refuted this suggestion., Scheurlen et al reported that MBs with concomitant 17p alterations and c-myc alterations have worse prognosis, indicating possible interaction between these two genetic alterations in promoting aggressive behavior.
Mutations of the tumor suppressor gene, p53 , located at 17p13.1 region are infrequent in MBs., However, an association of intense p53 immunostaining with significant reduced disease-free survival in MB patients has been shown by Woodburn et al Similarly, hypermethylation of the HIC-1 gene, on 17p13.3 region has been demonstrated to be a predictor of poor outcome in MB.
(ii) Myc gene (c-myc and N-myc) amplification
Amplification of c-myc and/or N-myc occurs in 5-10% of MBs, being most commonly associated with the LC/A variant.,,,,,, Eberhart et al found amplification of c-myc in 4 (12%) and N-myc in 5 (15%) of 33 MBs, all with anaplastic foci. A very high rate of c-myc amplification of 17% was reported by Scheurlen et al among a population of clinically high-risk MBs.
There is clear evidence that patients whose tumors show c - myc gene amplification have worse clinical outcome, being resistant to therapy and having an aggressive course with short survival and fatal outcome. Aldosari et al found 4 of 77 MBs with c-myc amplification (5.2%) all of whom died within 7 months of diagnosis. One case having amplification for both c-myc and N-myc and four cases with only N-myc amplification were also associated with short survival time. In the series of Badiali et al no long-term survivors were observed among cases with c-myc amplification. Similarly Scheurlen et al showed that all tumors with c-myc amplification were resistant to therapy and had fatal outcome.
A similar negative correlation of outcome with c-myc mRNA levels was shown by Herms et al and Grotzer et al Around 42% of MBs showed c-myc mRNA expression, and this parameter was found to be an independent prognostic criteria and more predictive than standard clinical factors.
High rate of immunopositivity for both c-myc protein (90%) and N-myc protein (84%) have also been reported in MBs. A tendency of N-myc immunopositive MBs to be associated with poor outcome was shown by Moriuchi et al. Hence there is a need of identifying MBs with myc gene amplification or myc mRNA over expression, since a large body of evidence now indicates its association with aggressive clinical behavior.
(iii) Other chromosomal abnormalities
In 20-40% of MB cases, loss of chromosomes 1q and 10q has been demonstrated., Isolated examples of deletions of 3q, 6q, 9q, 10q, 11p, 11q, and 16q as well as gains of distal regions of 4p, 5p, 5q, 7q, 8q, and 9p have also been detected in MBs.,, However, till date no prognostic correlation has been attached to any of these chromosomal abnormalities, with the exception of 9q loss (locus of PTCH Gene). Lusher et al has reported inactivation of the RASSF-1A gene on chromosome 3p21 in 79% of MBs (both in adult and pediatric MBs and in all histological variants).
Recently, Tong et al performed the first genomic survey of multiple oncogenes amplifications involved in the development of MBs. For the first time they identified gene amplifications involving PGY1 at 7q21.1, MDM2 at 12q14.3-q15, and Erb2 at 17q21.2, by performing comparative genomic hybridization (CGH) and array-based CGH, in a series of 14 cases. Overall the highest frequency of oncogene gains was observed in D17S1670 (61.5%), PIK3CA (46.2%), PGY1 (38.5%), MET (38.5%), and CSE1L (38.5%). Gene amplification in MBs was further confirmed by using fluorescence in-situ hybridization (FISH) analysis in 34 additional archival MB cases. In future, gains in these genes may possibly qualify as candidates for molecular markers and therapeutic targets of MBs.
2. Gene profiling
Pomeroy et al studied gene expression profile of MB cases using oligonucleotide microarrays. The genes most closely correlated with MBs were ZIC and NSCL1 , which encode transcription factors specific to cerebellar granule cells. They also identified a number of genes, which correlated with favorable outcome, including many genes characteristic of cerebellar differentiation ( vesicle coat protein b-NAP, NSCL1, TrkC, sodium channels ), and genes encoding extracellular matrix proteins ( procollagen-lysine-2-oxoglutarate 5-dioxygenase, lysyl hydroxylase, collagen type V a-I, elastin ). In contrast, genes related to cerebellar differentiation were underexpressed in poor prognosis tumors, which were dominated by the expression of genes related to cell proliferation and metabolism [ MYBL2, enolase I, LDH, HMG1 (Y), cytochrome C oxidase ] and multidrug resistance ( sorcin gene ).
Their study further demonstrated that outcome predictions based on gene expression (with a model made up of eight genes) was statistically significant: patients with a certain pattern, expected to have a good prognosis, had a 5-year OS of 80% compared with 17% for those not having that pattern, for whom a poor outcome was predicted.
In another study of gene expression profiles, MacDonald et al described that the platelet derived growth factor receptor alpha (PDGFR-a) and the Ras/mitogen-activated protein (MAP) kinase pathway genes were significantly upregulated in metastatic (M+) tumors but not in nonmetastatic (M0) MBs, This finding suggests that the PDGFR-a and Ras/MAP kinase signal transduction pathway may be rational therapeutic targets for M+ disease.
3. Abnormalities in signal transduction pathways
(i) Neurotrophin signaling pathway - TrkC expression and outcome
This pathway plays a major role in cerebellar development. It comprises of the neurotrophin family, which includes a set of ligands viz. nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin factors 3, 4, and 5 (NT3 and NT4/5). These are essentially trophic factors for the growth differentiation, survival and apoptosis of neurons. The other major constituent of this pathway are three members of the tyrosine kinase receptor family viz. TrkA, B, C. These Trk proteins function as classical growth factor receptors, each binding to one of the four neurotrophins resulting in their activation and upregulation of second messenger signaling pathway systems.,,
TrkC expression has been reported in 48-85% of MBs in different series., This high TrkC expression has been found to be the single most powerful independent predictor of favorable outcome in MBs, independent of other clinico-pathological variants. It was Segal et al who first reported 5-year survival rates as high as 89%, in patients having tumors with high TrkC expression, as compared to 46% for those with low TrkC expression levels. Subsequently Kim et al in a study of 42 cases of MB found that the median survival in high expressers of TrkC was 92 months, in contrast to only 39 months for the low expressers. In a larger study of 81 MBs and 6 PNETs, Grotzer et al reported a 4.8-fold greater risk of death in children with tumors having low TrkC mRNA expression. They identified TrkC mRNA expression as a powerful independent prognostic factor for predicting progression-free and OS. In another study, they showed 100% progression-free survival in a group of PNET/MB patients having combined low c-myc and high TrkC mRNA expression in their tumors after a median follow up time of 55 months. Contradictory results have been reported by Gajjar et al who found no correlation of TrkC expression with clinical outcome.
(ii) ErbB receptor signaling pathway - ErbB2 expression and outcome
The class-I receptor tyrosine kinases (RTK1), also termed ErbB/HER receptors constitute a signal transduction pathway that is important in both cerebellar development and MB tumorigenesis., Of the four members of this family viz. ErbB1, B2, B3, and B4, Erb B2 receptor appears to play a central role in MB tumorigenesis, along with neuregulin-1b (NRG-1b). ErbB2 expression has been reported in >80% of MBs, with co-expression of ErbB4 in 54% and expression of NRG-1b in 87.5% of tumors.,,,, However, Gajjar et al found ErbB2 expression in only 40% of tumors, most frequently in the LC/A variant.
Association between reduced patient survival and increased ErbB2 expression has been demonstrated by several workers.,,,, Gilbertson et al first reported a 48% 10-year survival rate in cases with less than 50% ErbB2-positive tumor cells, while the corresponding figures for cases ³ 50% positive cells was 10%. This prognostic significance was maintained in a further extension of the study to 70 cases, with 25-year survival rates for cases with < 50% and ³ 50 ErbB2 expression being 46 and 17%, respectively. In the same study, they also showed that co-expression of ErbB2 and ErbB4 significantly correlated with reduced OS, being independent of other clinical variables like age and tumor stage. Further, co-expression of all three components viz. ErbB2, ErbB4, and NRG-1b was significantly associated with presence of CNS metastasis at diagnosis.
It has been shown that combined analysis of molecular and clinical factors gives better risk stratification than clinical factors alone. Thus in an analysis of 41 MBs, Gilbertson et al found that sub-total tumor resection, metastatic disease at diagnosis, high expression of ErbB2 and isolated 17 p loss, all negatively correlated with survival. Similarly Gajjar et al in a study of clinical average-risk childhood MBs reported 100% 5-year survival in ErbB2-negative disease cases, as compared to only 54% in ErbB2-positive tumors.
(iii) Hedgehog - (SHH/PTCH) signaling pathway
Sonic hedgehog (SHH), the principal member of the hedgehog pathway, is a family of ligands, which are involved in cerebellar development by promoting replication of granule cells. PTCH (patched) is a tumor suppressor gene located on 9q22.3, which encodes a trans-membrane PTCH protein product. This is activated by SHH and functions as part of a signaling pathway controlling normal CNS development.,, The SHH/PTCH pathway has been implicated in the development of both sporadic and heritable forms of MB. Mutations in several components of the SHH pathway occur in about 25% of sporadic MB cases, commonest being mutation of the PTCH gene, reported in 8-12% of tumors.,, In patients with Gorlin's syndrome or NBCCS who have germ-line mutations of the PTCH gene the lifetime risk of developing MB is about 4%.,, It has been observed that MBs that carry mutations in the SHH/PTCH pathway preferentially but not exclusively show nodular desmoplastic morphology., However, till date no association has been found of alterations in this signaling pathway with prognosis in MBs.
(i) Wingless (WNT/WG) pathway
The WNT pathway co-ordinates a diverse array of developmental processes including the proliferation and fate of neural progenitor cells., The components of this pathway include b-catenin, the key transcriptional activator which in turn associates in the cytoplasm with a complex, which includes adenomatous polyposis coli ( APC ) gene, glycogen synthase kinase-3 (GSK3b) and AXIN-1.,
Mutations in proteins of the WNT pathway, especially of b-catenin and APC gene occur in about 15% of sporadic MBs. ,,,, Mutations of APC gene are also the cause of Turcot's syndrome, a tumor predisposition syndrome characterized by development of bowel tumors and MB.
No correlation again has been found with this pathway and prognosis. However an increasing number of anti-cancer drugs are being designed to target this pathway. Cyclopamine, is one example of a plant-derived teratogen, that specifically inhibits the SHH pathway in MB cells, causing anti-tumor activity.
| Conclusion|| |
There has been marked improvement in the 5-year survival rates in MBs from 2-30% in the 1970s to 50-70% currently. A major challenge, however, remains to differentiate high- and low-risk patients, and to individualize patient therapies, so as to prevent long-term side effects. In this regard, clinical staging alone has been shown in various studies to have its limitations. Two histological parameters currently assuming prognostic importance in MBs are the histopathological variant and grading of anaplasia. It is becoming apparent that homogenous lumping of all MBs as grade IV, highly aggressive neoplasms may be unjustified. The new concept therefore is to categorize MBs into favorable versus unfavorable histological groups, which is comparable to the classification used for peripheral neuroblastomas and Wilms' tumors. Molecular prognostic markers also hold promise, though global, multi-institutional studies with larger number of patients are required to prospectively validate their role as well as the methodologies used for the assessment of their expression levels.
The detailed mechanisms of how the different signaling pathways mediate an oncogenic effect need to be identified if we are to exploit these pathways fully for patient prognostication and management. Further, several questions need to be answered -which pathways initiate MB formation and which are involved in disease progression; how specific pathways affect MB histopathology and behavior; and whether any signal pathways mediate resistance to conventional treatments.
It is possible that in such a complex interaction of several factors, a final scenario will emerge where in a combination of clinical, histopathological and molecular factors will provide a more reliable means of disease stratification in patients of MB, rather than any single parameter alone. The role of the Pathologist will then assume great importance in guiding clinicians regarding biological risk assessment and tailoring therapeutic strategies.
| References|| |
|1.||Kleihues P, Cavenee WK (editors). World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000. p. 6-7. |
|2.||Arseni C, Ciurea AV. Statistical survey of 276 cases of medulloblastoma (1935-1978). Acta Neurchir (Wien) 1981;57:159-62. [PUBMED] |
|3.||Farwell JR, Dohrmann GJ, Flannery JT. Medulloblastoma in childhood: an epidemiological study. J Neurosurg 1984;61:657-64. [PUBMED] |
|4.||Giangaspero F, Bigner SH, Kleihues P, Pietsch T, Trojanowski JO. Medulloblastoma. In: Kleihues P, Cavenee WK (editors). World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000. p. 129-37. |
|5.||Roberts RO, Lynch CF, Jones MP, Hart MN. Medulloblastoma: a population-based study of 532 cases. J Neuropathol Exp Neurol 1991;50:134-44. [PUBMED] |
|6.||Sarkar C, Pramanik P, Karak AK, Mukhopadhyay P, Sharma MC, Singh VP, et al. Are childhood and adult medulloblastomas different? A comparative study of clinicopathological features, proliferation index and apoptotic index. J Neurooncol 2002;59:49-61. [PUBMED] [FULLTEXT]|
|7.||Ferrante L, Mastronardi L, Celli P, Acqui M, Cervoni L, Fortuna A. Medulloblastoma in adulthood. J Neurosurg Sci 1991;35:23-30. [PUBMED] |
|8.||Giordana MT, Schiffer P, Lanotte M, Girardi P, Chio A. Epidemiology of adult medulloblastomas. Int J Cancer 1999;80:689-92. [PUBMED] [FULLTEXT]|
|9.||Hubbard JL, Scheithauer BW, Kispert DB, Carpenter SM, Wick MR, Laws ER. Adult cerebellar medulloblastomas: the pathological, radiographic and clinical disease spectrum. J Neurosurg 1989;70:536-44. |
|10.||Muleci A, Cervoni L, Delfini R. Medulloblastomas in children and in adults:a comparative study. Acta Neurochir (Wien) 1992;119:62-7. |
|11.||Pramanik P, Sharma MC, Mukhopadhyay P, Singh VP, Sarkar C. A comparative study of classical vs. desmoplastic medulloblastomas. Neurol India 2003;51:27-34. [PUBMED] [FULLTEXT]|
|12.||Chang CH, Housepian EM, Herbert C. An operative staging system and a megavoltage radiotherpeutic technic for cerebellar medulloblastoma. Radiology 1969;93:1351-69. |
|13.||Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, et al. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children:Conclusions from the Children's Cancer Group 921 randomized phase II study. J Clin Oncol 1999;17:832-45. |
|14.||Eberhart CG, Burger PC. Anaplasia and grading in medulloblastomas. Brain Pathol 2003;13:376-85. [PUBMED] |
|15.||Kortmann RD, Kuhl J, Timmerman B, Mittler U, Urban C, Budach V, 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 Radit Oncol Biol Phys 2000;46:269-79. |
|16.||Saran F. Recent advances in paediatric neuro-oncology. Curr Opin Neurol 2002;15:671-7. [PUBMED] [FULLTEXT]|
|17.||Brandes AA, Palmisano V, Monfardini S. Medulloblastoma in adults: clinical characteristics and treatment. Cancer Treat Rev 1999;25:3-12. [PUBMED] [FULLTEXT]|
|18.||Gajjar A, Hernan R, Kocak M, Fuller C, Lee Y, McKinnon PJ, et al. Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 2004;22:984-93. |
|19.||Heikens J, Michiels EM, Behrendt H, Endert E, Bakker PJ, Fliers E. Long-term neuro-endocrine sequelae after treatment for childhood medulloblastoma. Eur J Cancer 1998;34:1592-7. [PUBMED] [FULLTEXT]|
|20.||Walter AW, Mulhern RK, Gajjar A, Heideman RL, Reardon D, Sanford RA, et al. Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children's Research Hospital. J Clin Oncol 1999;17:3720-8. |
|21.||Mulhern RK, Palmer SL, Reddick WE, Glass JO, Kun LE, Taylor J, et al. Risks of young age for selected neurocognitive deficits in medulloblastoma are associated with white matter loss. J Clin Oncol 2001;19:472-9. |
|22.||Ironside JW, Moss TH, Louis DN, Lowe JS, Weller RO (editors). Embryonal tumours. In : Diagnostic pathology of nervous system tumours. London: Churchill Livingstone; 2002. p. 185-215. |
|23.||Burger PC, Scheithauer BW, Vogel FS. Surgical Pathology of the Central Nervous System and Its Coverings, 4th edn. Philadelphia: Churchill Livingstone; 2002. p. 298-338. |
|24.||Giangaspero F, Perilongo G, Fondelli MP, Brisigotti M, Carollo C, Burnelli R, et al. Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 1999;91:971-7. |
|25.||Giangaspero F, Rigobello L, Badiali M, Loda M, Andreini L, Basso G, et al. Large-cell medulloblastomas. A distinct variant with highly aggressive behavior. Am J Surg Pathol 1992;16:687-93. [PUBMED] |
|26.||Kalimo H, Haapasalo H. Melanotic medulloblastoma. In : Kleihues P, Cavenee WK (editors). World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000. p. 140. |
|27.||Sharma MC, Agarwal M, Suri A, Gaikwad S, Mukhopadhyay P, Sarkar C. A melanotic desmoplastic medulloblastoma: report of a rare case and review of the literature. Brain Tumor Pathol 2002;19:93-6. [PUBMED] |
|28.||Chowdhury C, Roy S, Mahapatra AK, Bhatia R. Medullomyoblastoma. A teratoma. Cancer 1985;55:1495-500. [PUBMED] |
|29.||Giordana MT, Wiestler OD. Medullomyoblastoma. In : Kleihues P, Cavenee WK (editors). World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000. p. 138-9. |
|30.||Lata M, Mahapatra AK, Sarkar C, Roy S. Medullomyoblastoma. A case report. Indian J Cancer 1989;26:240-6. |
|31.||Mahapatra AK, Sinha AK, Sharma MC. Medullomyoblastoma. A rare cerebellar tumour in children. Childs Nerv Syst 1998;14:312-6. [PUBMED] [FULLTEXT]|
|32.||Suresh TN, Santosh V, Yasha TC, Anandh B, Mohanty A, Indiradevi B, et al. Medulloblastoma with extensive nodularity: a variant occurring in the very young-clinicopathological and immunohistochemical study of four cases. Childs Nerv Syst 2004;20:55-60. [PUBMED] [FULLTEXT]|
|33.||MacManamy CS, Lamont JM, Taylor RE, Cole M, Pearson AD, Clifford SC, et al. Morphophenotypic variation predicts clinical behaviour in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 2003;62:627-32. |
|34.||Bailey CC, Gnekow A, Wellek S, Jones M, Round C, Brown J, et al. Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II. Med Pediatr Oncol 1995;25:166-78. [PUBMED] |
|35.||Chatty EM, Earle KM. Medulloblastoma. A report of 201 cases with emphasis on the relationship of histological variants to survival. Cancer 1971;28:977-83. [PUBMED] |
|36.||Jenkin D, Shabanah MA, Shail EA, Gray A, Hassounah M, Khafaga Y, et al. Prognostic factors for medulloblastoma. Int J Radiat Oncol Biol Phys 2000;47:573-84. [PUBMED] [FULLTEXT]|
|37.||Giordana MT, Cavalla P, Chio A, Marino S, Soffietti R, Vigliani MC, et al. Prognostic factors in adult medulloblastoma. A clinico-pathologic study Tumori 1995;81:338-46. [PUBMED] |
|38.||Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, et al. Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer 2002;94:552-60. [PUBMED] |
|39.||Garton GR, Schomberger PJ, Scheithauer BW, Shaw EG, Ilstrup DM, Blackwell CR, et al. Medulloblastoma: Prognostic factors and outcome of treatment:review of the Mayo Clinic experience. Mayo Clin Proc 1990;65:1077-86. |
|40.||Beckwith JB. National Wilms Tumor Study: an update for pathologists. Pediatr Dev Pathol 1998;1:79-84. [PUBMED] [FULLTEXT]|
|41.||Brown HG, Kepner JL, Perlman EJ, Friedman HS, Strother DR, Duffner PK, et al. "Large cell/anaplastic" medulloblastomas:a Pediatric Oncology Group Study. J Neuropathol Exp Neurol 2000;59:857-65. [PUBMED] [FULLTEXT]|
|42.||Ellison D. Classifying the medulloblastoma: insights from morphology and molecular genetics. Neuropathol Appl Neurobiol 2002;28:257-82. [PUBMED] [FULLTEXT]|
|43.||Leonard JR, Cai DX, Rivet DJ, Kaufman BA, Park TS, Levy BK, et al. Large cell/anaplastic medulloblastomas and medullomyoblastomas: clinicopathological and genetic features. J Neurosurg 2001;95:82-8. [PUBMED] |
|44.||Eberhart CG, Cohen KJ, Tihan T, Goldthwaite PT, Burger PC. Medulloblastomas with systemic metastases: evaluation of tumor histopathology and clinical behavior in 23 patients. J Pediatr Hematol Oncol 2003;25:198-203. [PUBMED] [FULLTEXT]|
|45.||Eberhart CG, Kratz JE, Schuster A, Goldthwaite P, Cohen KJ, Perlman EJ, et al. Comparative genomic hybridization detects an increased number of chromosomal alterations in large cell/anaplastic medulloblastomas. Brain Pathol 2002;12:36-44. [PUBMED] |
|46.||Sarkar C, Roy S, Tandon PN. Primitive neuroectodermal tumours of the central nervous system--an electron microscopic and immunohistochemical study. Indian J Med Res 1989;90:91-102. [PUBMED] |
|47.||Caputy AJ, McCullough DC, Manz HJ, Patterson K, Hammock MK. A review of the factors influencing the prognosis of medulloblastoma. The importance of cell differentiation. J Neurosurg 1987;66:80-7. [PUBMED] |
|48.||Goldberg-Stern H, Gadoth N, Stern S, Cohen IJ, Zaizov R, Sandbank U. The prognostic significance of glial fibrillary acidic protein staining in medulloblastoma. Cancer 1991;68:568-73. [PUBMED] |
|49.||Janss AJ, Yachnis AT, Silber JH, Trojanowski JQ, Lee VM, Sutton LN, et al. Glial differentiation predicts poor clinical outcome in primitive neuroectodermal brain tumors. Ann Neurol 1996;39:481-9. [PUBMED] |
|50.||Packer RJ, Sutton LN, Rorke LB, Littman PA, Sposto R, Rosenstock JG, et al. Prognostic importance of cellular differentiation in medulloblastoma of childhood. J Neurosurg 1984;61:296-301. [PUBMED] |
|51.||Coffin CM, Braun JT, Wick MR, Dehner LP. A clinicopathologic and immunohistochemical analysis of 53 cases of medulloblastoma with emphasis on synaptophysin expression. Mod Pathol 1990;3:164-70. [PUBMED] |
|52.||Verma A, Sarkar C, Bhatia R, Banerji AK, Mehta VS, Mahapatra AK. Retrospective study of medulloblastoma with special reference to astrocytic differentiation - review of 63 cases. Neurol India 1993;41:7-12. |
|53.||Ito S, Hoshino T, Prados MD, Edwards MS. Cell kinetics of medulloblastomas. Cancer 1992;70:671-8. [PUBMED] |
|54.||Schiffer D, Cavalla P, Migheli A, Chio A, Giordana MT, Marino S, et al. Apoptosis and cell proliferation in human neuroepithelial tumors. Neurosci Lett 1995;195:81-4. [PUBMED] [FULLTEXT]|
|55.||Haslam RH, Lamborn KR, Becker LE, Israel MA. Tumor cell apoptosis present at diagnosis may predict treatment outcome for patients with medulloblastoma. J Pediatr Hematol Oncol 1998;20:520-7. [PUBMED] [FULLTEXT]|
|56.||Korshunov A, Golanov A, Ozerov S, Sycheva R. Prognostic value of tumor-associated antigens immunoreactivity and apoptosis in medulloblastomas. An analysis of 73 cases. Brain Tumor Pathol 1999;16:37-44. [PUBMED] |
|57.||Korshunov A, Savostikova M, Ozerov S. Immunohistochemical markers for prognosis of average-risk pediatric medulloblastomas. The effect of apoptotic index, TrkC and c-myc expression. J Neuro Oncol 2002;58:271-9. |
|58.||Eggert A, Grotzer MA, Zuzak TJ, Ikegaki N, Zhao H, Brodeur GM. Expression of Apo-3 and Apo-3L in primitive neuroectodermal tumours of the central and peripheral nervous system. Eur J Cancer 2002;38:92-8. [PUBMED] [FULLTEXT]|
|59.||Ramachandran C, Khatib Z, Escalon E, Fonseca HB, Jhabvala P, Medina LS, et al. Molecular studies in pediatric medulloblastomas. Brain Tumor Pathol 2002;19:15-22. [PUBMED] |
|60.||Brandes AA, Paris MK, Basso U. Medulloblastomas: do molecular and biologic markers indicate different prognoses and treatments? Expert Rev Anticancer Ther 2003;3:615-20. [PUBMED] [FULLTEXT]|
|61.||Ellison DW, Clifford SC, Gajjar A, Gilbertson RJ. What's new in neuro-oncology? Recent advances in medulloblastoma. Eur J Paediatr Neurol 2003;7:53-66. [PUBMED] [FULLTEXT]|
|62.||Gilbertson R, Wickramasinghe C, Hernan R, Balaji V, Hunt D, Jones-Wallace D, et al. Clinical and molecular stratification of disease risk in medulloblastoma. Br J Cancer 2001;85:705-12. |
|63.||Gilbertson R. Paediatric embryonic brain tumours biological and clinical relevance of molecular genetic abnormalities. Eur J Cancer 2002;38:675-85. |
|64.||Fisher PG, Burger PC, Eberhart CG. Biologic risk stratification of medulloblastoma: the real time is now. J Clin Oncol 2004;22:1-4. |
|65.||Packer RJ, Rood BR, Mac Donald TJ. Medulloblastoma: present concepts of stratification into risk groups. Pediatr Neurosurg 2003;39:60-7. |
|66.||Gilbertson RJ. Medulloblastoma: signalling a change in treatment. Lancet Oncol 2004;5:209-18. |
|67.||Cogen PH, Mc Donald JD. Tumour suppressor genes and medulloblastoma. J Neurooncol 1996;29:103-12. |
|68.||McDonald JD, Daneshvar L, Willert JR, Matsumura K, Waldman F, Cogen PH. Physical mapping of chromosome 17p13.3 in the region of a putative tumour suppressor gene important in medulloblastoma. Genomics 1994;23:229-32. |
|69.||Nicholson JC, Wickramasinghe CL, Ross FM, Crolla J, Ellison DW. Imbalances of chromosome 17 in medulloblastomas determined by comparative genomic hybridisation and fluorescence in situ hybridisation. Mol Path 2000;53:313-9. |
|70.||Scheurlen WG, Seranski P, Minchera A, Kuhl J, Sorensen N, Krauss J, et al. High resolution deletion mapping of chromosome arm 17p in childhood primitive neuroectodermal tumours reveals a common chromosomal disruption within the Smith-Magenis Region, an unstable region in chromosome band 17p11.2. Genes Chromosomes Cancer 1997;18:50-8. |
|71.||Steichen-Gersdorf E, Baumgartener M, Kerczy A, Maier H, Fink FM. Deletion mapping on chromosome 17p in medulloblastomas. Br J Cancer 1997;76:1284-7. |
|72.||Biegel JA, Janss AJ, Raffel C, Sutton L, Rorke LB, Harper JM, et al. Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumors (medulloblastomas) of the central nervous system. Clin Cancer Res 1997;3:473-8. |
|73.||Bigner SH, Mark J, Friedman HS, Biegel JA, Bigner DD. Structural chromosomal abnormalities in human medulloblastoma. Cancer Genet Cytogenet 1988;30:91-101. |
|74.||Vagner C, Zattara C, Gambarelli D, Gentet JC, Genitori L, Lena G, et al. Detection of i(17q) chromosome by fluorescent in situ hybridisation (FISH) with interphase nuclei in medulloblastoma. Cancer Genet Cytogenet 1994;78:1-6. |
|75.||Batra SK, McLendon RE, Koo JS, Castelino-Prabhu S, Fuchs HE, Krischer JP, et al. Prognostic implications of chromosome 17p deletions in human medulloblastoma. J Neurooncol 1995;24:39-45. |
|76.||Scheurlen WG, Schwabe GC, Joos S, Mollenhauer J, Sorensen N, Kuhl J. Molecular analysis of childhood primitive neuroectodermal tumours defines markers associated with poor outcome. J Clin Oncol 1998;16:2478-85. |
|77.||Emadian SM, Mc Donald JD, Gerken SC, Fults D. Correlation of chromosome 17p loss with clinical outcome in medulloblastoma. Clin Cancer Res 1996;2:1559-64. |
|78.||Adesina AM, Nalbantoglu J, Cavenee WK. p53 gene mutation and mdm2 gene amplification are uncommon in medulloblastoma. Cancer Res 1994;54:5649-51. |
|79.||Saylors P, Sidransky D, Friedman H, Bigner S, Bigner D. Infrequent p53 gene mutations in medulloblastoma. Cancer Res 1991;51:4721-3. |
|80.||Woodburn RT, Azzarelli B, Montebello JF, Goss IE. Intense p53 staining is a valuable prognostic indicator for poor prognosis in medulloblastoma/central nervous system primitive neuroectodermal tumors. J Neurooncol 2001;52:57-62. |
|81.||Rood BR, Zhang H, Weitman DM, Cogen PH. Hypermethylation of HIC-1 and 17p allelic loss in medulloblastoma. Cancer Res 2002;62:3794-7. |
|82.||Aldosari N, Bigner SH, Burger PC, Becker L, Kepner JL, Friedman HS, et al. MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group. Arch Pathol Lab Med 2002;126:540-4. |
|83.||Avet-Loiseau H, Venuat AM, Terrier-Lacombe MJ, Lellouch-Tubiana A, Zerah M, Vassal G. Comparative genomic hybridization detects many recurrent imbalances in central nervous system primitive neuroectodermal tumours in children. Br J Cancer 1999;79:1843-7. |
|84.||Badiali M, Pession A, Basso G, Andreini L, Rigobello L, Galassi E, et al. N-myc and c-myc oncogenes amplification in medulloblastoma. Evidence of particularly aggressive behaviour of a tumour with c-myc amplification. Tumouri 1991;77:118-21. |
|85.||Bigner SH, Friedman HS, Vogelstein B, Oakes WJ, Bigner DD. Amplification of the c-myc gene in human medulloblastoma cell lines and xenografts. Cancer Res 1990;50:2347-50. |
|86.||Jay V, Squire J, Bayani J, Alkhani AM, Rutka JT, Zielenska M. Oncogene amplification in medulloblastoma: analysis of a case by comparative genomic hybridization and fluorescence in situ hybridization. Pathology 1999;31:337-44. |
|87.||Herms J, Neidt I, Luscher B, Sommer A, Schurmann P, Schroder T, et al. C-MYC expression in medulloblastoma and its prognostic value. Int J Cancer 2000;89:395-402. |
|88.||Grotzer MA, Hogarty MD, Janss AJ, Liu X, Zhao H, Eggert A, et al. MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/ medulloblastoma. Clin Cancer Res 2001;7:2425-33. |
|89.||Bruggers CS, Tai KF, Murdock T, Sivak L, Le K, Perkins SL, et al. Expression of the c-Myc protein in childhood medulloblastoma. J Pediatr Hematol Oncol 1998;20:18-25. |
|90.||Moriuchi S, Shimizu K, Miyao Y, Hayakawa T. An immunohistochemical analysis of medulloblastoma and PNET with emphasis on N-myc protein expression. Anticancer Res 1996;16:2687-92. |
|91.||Blaeker H, Rasheed BK, McLendon RE, Friedman HS, Batra SK, Fuchs HE, et al. Microsatellite analysis of childhood brain tumours. Genes Chromosome Cancer 1996;15:54-63. |
|92.||Kraus JA, Koch A, Albrecht S, von Deimling A, Wiestler OD, Pietsch T. Loss of heterozygosity at locus F 13B on chromosome 1 Q in human medulloblastoma. Int J Cancer 1996;67:11-5. |
|93.||Reardon DA, Michalkiewicz E, Boyett JM, Sublett JE, Entrekin RE, Ragsdale ST, et al. Extensive genomic abnormalities in childhood medulloblastoma by comparative genomic hybridisation. Cancer Res 1997;57:4042-7. |
|94.||Thomas GA, Raffel C. Loss of heterozygosity on 6q, 16q and 17p in human central nervous system primitive neuroectodermal tumors. Cancer 1991;51:639-43. |
|95.||Lusher ME, Lindsey JC, Latif F, Pearson AD, Ellison DW, Clifford SC. Biallelic epigenetic inactivation of the RASSF1A tumor suppressor gene in medulloblastoma development. Cancer Res 2002;62:5906-11. |
|96.||Tong CY, Hui AB, Yin XL, Pang JC, Zhu XL, Poon WS, et al. Detection of oncogenes amplifications in medulloblastomas by comparative genomic hybridization and array-based comparative genomic hybridization. J Neurosurg Spine 2004;100:187-93. |
|97.||Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 2002;415:436-42. |
|98.||MacDonald TJ, Brown KM, LaFleur B, Peterson K, Lawlor C, Chen Y, et al. Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nat Genet 2001;29:143-52. |
|99.||Barbacid M. Neurotropic factors and their receptors. Curr Opin Cell Biol 1995;7:148-55. |
|100.||Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001;24:677-736. |
|101.||Minichiello L, Klein R. TrkB and TrkC neurotrophin receptors cooperate in promoting survival of hippocampal and cerebellar granule neurons. Genes Dev 1996;10:2849-58. |
|102.||Tajima Y, Molina RP Jr, Rorke LB, Kaplan DR, Radeke M, Feinstein SC, et al. Neurotrophins and neuronal versus glial differentiation in medulloblastomas and other pediatric brain tumors. Acta Neuropathol (Berl) 1998;95:325-32. |
|103.||Washiyama K, Muragaki Y, Rorke LB, Lee VM, Feinstein SC, Radeke MJ, et al. Neurotrophin and neurotrophin receptor proteins in medulloblastomas and other primitive neuroectodermal tumors of the pediatric central nervous system. Am J Pathol 1996;148:929-40. |
|104.||Segal RA, Goumnerova LC, Kwon YK, Stiles CD, Pomeroy SL. Expression of the neurotrophin receptor TrkC is linked to a favourable outcome in medulloblastoma. Proc Natl Acad Sci USA 1994;91:12867-71. |
|105.||Kim JY, Sutton ME, Lu DJ, Cho TA, Goumnerova LC, Goritchenko L, et al. Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. Cancer Res 1999;59:711-9. |
|106.||Grotzer MA, Janss AJ, Fung K, Biegel JA, Sutton LN, Rorke LB, et al. TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumours. J Clin Oncol 2000;18:1027-35. |
|107.||Gilbertson RJ, Clifford SC, MacMeekin W, Meekin W, Wright C, Perry RH, et al. Expression of the ErbB-neuregulin signalling network during human cerebellar development: implications for the biology of medulloblastoma. Cancer Res 1998;58:3932-41. |
|108.||Rio C, Rieff HI, Qi P, Khurana TS, Corfas G. Neuregulin and ErbB receptors play a critical role in neuronal migration. Neuron 1997;19:39-50. |
|109.||Gilbertson RJ, Jaros EB, Perry RH, Pearson AD. Prognostic factors in medulloblastoma. Lancet 1992;340:480. |
|110.||Gilbertson RJ, Pearson AD, Perry RH, Jaros E, Kelly PJ. Prognostic significance of the c-ErbB-2 oncogene product in childhood medulloblastoma. Br J Cancer 1995;71:473-7. |
|111.||Gilbertson RJ, Perry RH, Kelly PJ, Pearson AD, Lunec J. Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. Cancer Res 1997;57:3272-80. |
|112.||Herms JW, Behnke J, Bergmann M, Christen HJ, Kolb R, Wilkening M, et al. Potential prognostic value of C-ErbB-2 expression in medulloblastomas in very young children. J Pediatr Hematol Oncol 1997;19:510-5. |
|113.||Wechsler-Reya RJ, Scott MP. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 1999;22:103-14. |
|114.||Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, et al. Mutations of the human homologue of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996;85:841-51. |
|115.||Dean M. Polarity, proliferation and the hedgehog pathway. Nat Genet 1996;14:245-7. |
|116.||Reifenberger GJ, Wiestler OD, Chenevix-Trench G. NBCSS. In: Kleihues P, Cavenee WK (editors). World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000. p. 240-1. |
|117.||Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW, et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res 1997;57:842-5. |
|118.||Vorechovsky I, Tingby O, Hartman M, Stromberg B, Nister M, Collins VP, et al. Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours. Oncogene 1997;15:361-6. |
|119.||Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G. Mutations in the human homologue of the Drosophilia segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumours of the central nervous system. Cancer Res 1997;57:2581-5. |
|120.||Evans DG, Farndon PA, Burnell LD, Gattamaneni HR, Birch JM. The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer 1991;64:959-61. |
|121.||Pietsch T, Waha A, Koch A, Kraus J, Albrecht S, Tonn J, et al. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of the Drosophilia patched. Cancer Res 1997;57:2085-8. |
|122.||Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P. Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol 1998;8:573-81. |
|123.||Patapoutian A, Reichardt LF. Roles of Wnt proteins in neural development and maintenance. Curr Opin Neurobiol 2000;10:392-9. |
|124.||Eberhart CG, Tihan T, Burger PC. Nuclear localisation and mutation of beta-catenin in medulloblastomas. J Neuropathol Exp Neurol 2000;59:333-7. |
|125.||Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P, et al. APC mutations in sporadic medulloblastomas. Am J Pathol 2000;156:433-7. |
|126.||Mori T, Nagase H, Horii A, Miyoshi Y, Shimano T, Nakatsuru S, et al. Germ-line and somatic mutations of the APC gene in patients with Turcot syndrome and analysis of APC mutations in brain tumours. Genes Chromosomes Cancer 1994;9:168-72. |
|127.||Zurawel RH, Allen C, Chiappa S, Cato W, Biegel J, Cogen P, et al. Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma. Genes Chromosome Cancer 2000;27:44-51. |
|128.||Zurawel RH, Chiappa SA, Allen C, Raffel C. Sporadic medulloblastomas contain oncogenic beta-catenin mutations. Cancer Res 1998;58:896-9. |
|129.||Cavenee WK, Burger PC, van Meir EG. Turcot syndrome. In : Kleihues P, Cavenee WK (editors). World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000. p. 238-9. |
|130.||Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 2000;406:1005-9. |
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|[Pubmed] | [DOI]|
||Childhood tumors of the nervous system as disorders of normal development
| ||Grimmer, M.R., Weiss, W.A. |
| ||Current Opinion in Pediatrics. 2006; 18(6): 634-638 |
||Childhood tumors of the nervous system as disorders of normal development
| ||Matthew R Grimmer,William A Weiss |
| ||Current Opinion in Pediatrics. 2006; 18(6): 634 |
|[Pubmed] | [DOI]|