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TrkC Expression Predicts Good Clinical Outcome in Primitive Neuroectodermal Brain Tumors

From the Division of Oncology, Human Genetics, Biostatistics, and Neurosurgery and Department of Pathology, The Children’s Hospital of Philadelphia; and Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.

Address reprint requests to J.Q. Trojanowski, MD, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA 19104; email trojanow{at}mail.med upenn.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To identify biologic prognostic factors in childhood primitive neuroectodermal tumors (PNET), including medulloblastoma, that accurately define patient groups with sufficiently good prognosis to permit a reduction in treatment intensity.

PATIENTS AND METHODS: We determined expression levels of the neurotrophin receptor TrkC mRNA in formalin-fixed tumor samples from 87 well characterized PNET patients using in situ hybridization. Comparison of TrkC mRNA expression levels with clinical and other laboratory variables was performed using univariate and multivariate Cox regression analysis.

RESULTS: High TrkC mRNA expression was found to be associated more with higher 5-year cumulative survival rate than was low TrkC mRNA expression (89% v 46%, respectively). When compared with established clinical prognostic factors and laboratory variables of potential prognostic significance, TrkC mRNA expression, by univariate analysis, was found to be the single most powerful predictor of outcome (hazards ratio, 4.81; P < .00005), exceeding all clinical prognostic factors. In multivariate analysis, the hazards ratio remained significant (P < .00005).

CONCLUSION: High TrkC mRNA expression in PNET is a powerful independent predictor of favorable clinical outcome. Assessment of TrkC mRNA levels may aid in treatment planning for patients with PNETs and should be incorporated prospectively into PNET clinical trials.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PRIMITIVE neuroectodermal tumors (PNETs) of the cerebellum, also termed medulloblastomas (MBs), and supratentorial PNETs constitute more than 20% of all pediatric brain tumors and are the most common malignant brain tumors in children.¹ PNETs are characterized by their aggressive clinical behavior and high risk of leptomeningeal dissemination. Standard postoperative therapy for PNETs includes high-dose craniospinal radiotherapy and chemotherapy. Unfortunately, intensive therapy may cause severe late treatment complications, including second malignancies, endocrine and/or growth dysfunctions, and cognitive impairments, and thereby decrease quality of life for many long-term survivors.^2-7

Identification of prognostic factors that distinguish patients at relatively low risk of tumor recurrence from those at high risk have important implications for treatment planning. Accordingly, it is possible that lower risk patients may be treated with less intensive therapies that retain a high level of efficacy but reduce the toxicity caused by the most intensive treatments.⁸ Single-institution and collaborative group studies have identified clinical factors such as metastatic stage, patient age, tumor location, and extent of tumor resection as characteristics that have independent prognostic significance for PNET/MB survival outcomes.^9-20 These factors are currently used to distinguish children with a high risk of PNET/MB recurrence (eg, leptomeningeal metastasis, age < 3 years, or large postoperative residual tumor) from those with a lower risk.

In contrast to clinical prognostic factors, most efforts to identify biologic markers or predictors for PNET/MB have been inconclusive.^9,21-32 Either the results from these studies are contradictory, or the sample size is too small to establish the independent prognostic significance of the candidate biologic factor. In other childhood malignancies, biologic characteristics of the tumors add to the prognostic power of established clinical factors, identify clinically relevant subsets of high-, intermediate-, or low-risk patients, or may provide insight into patterns of treatment response, resistance, or metastatic potential. For example, N-myc amplification, deletion of chromosome 1p, and TrkA expression have independent prognostic significance for neuroblastomas that equals or exceeds that of any of the clinical prognostic factors for these tumors.^33-35

The development and survival of nervous system cells are regulated by various growth factors. Neurotrophins are a family of four related trophic factors that have pleiotropic effects on developing, mature, and injured cells of the central and peripheral nervous system (reviewed in^36-39 ). The classic neurotrophin is nerve growth factor (NGF), but three related neurotrophins have been cloned and sequenced and include brain-derived neurotrophic factor, neurotrophin-3 (NT3), and neurotrophin-4/5. All neurotrophins bind to the low-affinity NGF receptor; however, it is not clear what role the low-affinity NGF receptor plays in signal transduction. In contrast, the better understood functions of neurotrophins seem to be mediated by one or more members of a family of three high-affinity neurotrophin receptor kinases, ie, TrkA, TrkB, and TrkC. Each of the neurotrophins binds preferentially to a specific Trk receptor to initiate signal transduction. NGF binds TrkA, brain-derived neurotrophic factor and neurotrophin-4/5 bind TrkB, and NT3 binds TrkC.⁴⁰

Segal et al²⁸ reported in 1994 a possible association between TrkC mRNA expression and outcome by Northern blot analysis in 12 PNET/MB samples. This study was recently expanded by the addition of 42 patients.⁴¹ However, the sample size was not adequate to permit multivariate analysis. Therefore, it is not known if measurement of TrkC mRNA expression levels adds to the prognostic information provided by clinical variables.

To evaluate the potential prognostic significance of TrkC expression in a large, relatively uniformly treated patient population, we studied the expression of TrkC mRNA at a cellular level by in situ hybridization and compared the relative abundance of TrkC mRNA to clinical and biologic variables of known or suggested clinical significance. We found that TrkC mRNA expression is a robust prognostic marker that exceeds the prognostic power of any clinical or biologic factor and that identifies a favorable group of tumors.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients and Therapy
We studied PNET samples from 87 children diagnosed at The Children’s Hospital of Philadelphia between January 1981 and December 1996. The selection of tumors for this study was based on the availability of enough tumor tissue to perform in situ hybridization analysis. All diagnoses were confirmed by histologic assessment of tumor specimens obtained at surgery by the same neuropathologist (L.B.R.). Clinical information on the 87 patients, which is summarized in Table 1, included date of birth, date of diagnosis, extent of resection as determined by operative report (gross total resection 90% removal of tumor; partial resection 50%, but < 90% removal of tumor; and biopsy < 50% removal of tumor), metastatic stage,⁴² therapy received, follow-up, and survival outcomes. The median age at diagnosis for all patients was 6.5 years (range, 0.3 to 21.8 years). The median follow-up period after diagnosis for all patients was 4.7 years (range, 0.1 to 13.8 years). Median follow-up for the 59 patients who were alive and progression-free at the time of this report was 5.7 years (range, 0.1 to 13.8 years).

TrkC In Situ Hybridization
The relative abundance of TrkC mRNA expressed in PNETs was determined by in situ hybridization by use of a RNA probe (gift from D. Shelton), which spans nucleotides 795 to 1307 from the human TrkC cDNA and encodes for the TrkC extracellular domain in a region with relatively low homology to TrkA (38%) and TrkB (36%). The specificity of the probe has been demonstrated previously by in situ hybridization⁴⁴ and was confirmed by Northern blot analysis by use of NIH-3T3 cells transfected to express TrkA or TrkC⁴⁵ and SY5Y neuroblastoma cells transfected to express TrkB (gift from G. Brodeur).

Antisense and sense RNA probes for TrkC were produced by transcribing linearized cDNA with SP6 and T7 RNA polymerase in the presence of ³³P-uridine triphosphate (NEN Life Science Products, Boston, MA) and purified according to the instructions of the vendor (Promega Corporation, Madison, WI). Paraffin sections cut from formalin-fixed blocks of PNET/MB tumor samples were deparaffinized, rehydrated, digested with proteinase K (5 µg/mL) for 15 minutes at 37°C, treated with glycine (2mg/mL) in one times phosphate-buffered saline pH 7.1 for 5 minutes, with phosphate-buffered saline for 5 minutes, with 0.1 mol/L triethanolamine pH 8.0 for 5 minutes, and with two times standard saline citrate (SSC) for 2 minutes, and then dehydrated and air dried. Sections were then prehybridized at room temperature for 3 hours with 100 µL of hybridization solution (10% dextran sulfate, four times SSC, 50% formamide, 0.1% sodium dodecyl sulfate, two times Denhardt’s solution, and 1 mg/mL denatured salmon sperm DNA). Hybridization was performed in 100 µL of hybridization solution containing ³³P-labeled RNA probes. After an overnight incubation at 59°C, sections were washed at 69°C under increasingly stringent conditions with two times SSC/50% formamide up to 0.1 times SSC. Sections were dehydrated, air dried, and exposed for 3 days for autoradiography. Then, sections were processed for autoradiography using NTB-2 liquid photographic emulsion (Eastman Kodak, Rochester, NY) and were exposed for 14 days. Autoradiograms were developed, counterstained with hematoxylin and eosin, and coverslipped with cytoseal.

As positive controls for TrkC mRNA expression and to control for variance in the specific activity of probes, variability of the efficiency of hybridization, variability of washing, and variability of exposure to emulsion, formalin-fixed serial sections of adult human dorsal root ganglion were included in each batch of slides as a reference standard. To control for the specificity of the hybridization signal, sections adjacent to those hybridized with the antisense RNA probes were incubated with an equal amount of sense RNA probes.

To provide a semiquantitative assessment of in situ hybridization studies, we counted silver grains overlying 50 PNET cells in randomly chosen fields of each section at x1000 magnification by use of a Nikon light microscope equipped with a video screen (Nikon Corporation, Tokyo, Japan). After log transformation of this data, we found that one group of tumors showed an antisense-to-sense signal ratio of 1 and that a second group of tumors had an antisense-to-sense signal ratio of 1.7. PNETs with TrkC mRNA antisense-to-sense signal ratios of 1.7 were considered to express TrkC mRNA above background (TrkC mRNA high), whereas those with ratios less than 1.7 were considered to express TrkC mRNA at or below background (TrkC mRNA low). The analysis of in situ hybridization specimens was blinded to all clinical data.

Immunohistochemistry of NFP and GFAP and Evaluation of Chromosome 17p Deletion
The immunohistochemical assessment and quantification of neurofilament proteins (NFP) and glial fibrillary acidic protein (GFAP) expression has been described previously in a smaller cohort of our patients⁹; in the present study, we included the clinical data and survival outcomes for an additional 11 patients, and these data were correlated with the TrkC data. Cytogenetic and molecular methods to identify chromosome 17p deletions have also been described previously,³⁰ and information on 10 additional patients was included in this study.

Statistical Analysis
The following variables were used to create multiple regression models to evaluate overall survival and progression-free survival: age at diagnosis, sex, metastatic stage, tumor location, extent of surgical resection, treatment, expression of TrkC mRNA, expression of NFP and GFAP, apoptotic index, and chromosome 17p. Fisher’s exact test and t test were used to identify significant associations between the clinical and biologic variables listed above. Relative risk of progression or death was calculated by univariate and multivariate analyses using Cox regression. Initial regression analysis identified the clinical variables associated with increased risk of progression and death. To correct for the effect of clinical variables on survival outcome, these variables were included in the statistical models of subsequent regression analysis that identified the prognostic power of TrkC mRNA expression in PNETs/MBs. Progression-free survival and overall survival were determined by Kaplan-Meier analysis, and differences between survival curves were calculated using the log-rank test.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Expression of TrkC mRNA
High expression of TrkC mRNA in neoplastic cells was identified by in situ hybridization in 53 of the 87 PNETs (61%). Fifty of 81 posterior fossa PNETs/MBs and three of six supratentorial PNETs had high TrkC mRNA expression. The distribution of TrkC mRNA was homogeneous throughout the PNET samples (Fig 1) without evidence of specific patterns of expression within areas of neoplastic cells (Fig 2). In PNETs with high TrkC mRNA expression, tumor cells had markedly higher signal intensities than did stromal cells. The median value for antisense-to-sense signal ratio in PNETs with high TrkC mRNA expression was 3.9 (range, 2.1 to 13.0) and, for the PNETs with no or low TrkC mRNA expression, 1.1 (range, 0.7 to 1.6). Using quantitative duplex reverse transcriptase–polymerase chain reaction techniques with primers to the extracellular domain of TrkC, we studied 20 frozen PNET samples and found the reverse transcriptase–polymerase chain reaction results to be consistent with the in situ results (data not shown).

View larger version (85K): [in this window] [in a new window]   Fig 1. Macroscopic expression pattern of TrkC mRNA in 2 PNETs. (A) Macrographic hybridization patterns of a PNET with high TrkC mRNA expression using SP6 RNA polymerase-oriented antisense probe (as) show distinctly high signals, whereas those using T7 RNA sense probe (s) show no appreciable signals. (B) Macrographic hybridization patterns of a PNET with no or low TrkC mRNA expression.

View larger version (177K): [in this window] [in a new window]   Fig 2. Microscopic expression pattern of TrkC mRNA in 2 PNETs: (A) PNET with high TrkC mRNA expression and (B) PNET with no or low TrkC mRNA expression.

View larger version (12K): [in this window] [in a new window]   Fig 3. Cumulative survival curves of patients with PNETs, according to expression of TrkC mRNA. Kaplan-Meier curves show the probability of progression-free (A) and overall survival (B) in terms of the level of expression of TrkC mRNA. The survival curves were analyzed by the log-rank test.

View larger version (9K): [in this window] [in a new window]   Fig 4. Cumulative survival curves of patients younger than 3 years at diagnosis with PNETs, according to expression of TrkC mRNA. Kaplan-Meier curves show the probability of overall survival by expression of TrkC mRNA. There were no significant differences in metastatic stage, tumor location, extent of resection, or postoperative therapy between the 2 groups.

View larger version (11K): [in this window] [in a new window]   Fig 5. Cumulative survival curves of patients with PNETs, according to expression of TrkC mRNA and metastatic stage combined. Survival was significantly better in those with high TrkC mRNA expression (v low expression with M stage 0, P .0039, and with M stage 1, P < .00005) and within the low expression group in those with M stage 0 (v M stage 1, P = .018).

TrkC Expression and Metastatic Stage, Tumor Location, Age, Sex, and Chromosome 17p Deletion
High expression of TrkC mRNA was detected in 42 of 64 PNETs with M stage 0 (66%) and nine of 20 PNETs with M stage 1 (45%). The tendency of M0 tumors to have high TrkC mRNA expression was not significant (P = .12, Fisher’s exact test). There was no correlation between TrkC mRNA expression and tumor location. Three of six supratentorial PNETs had high expression of TrkC mRNA. There was no correlation of TrkC mRNA expression and age, sex, or chromosome 17p deletion (data not shown).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Neurotrophins activate Trk receptors to regulate cell proliferation, differentiation, and death in the developing and mature nervous system. PNETs are composed of morphologically undifferentiated cells that resemble neuroectodermal progenitor cells of the developing CNS,⁴⁶ and subsets of these tumors express neuronal and/or glial markers.⁴⁷ Studies of peripheral neuroblastomas and PNETs demonstrate that these tumors express one or more neurotrophins and neurotrophin receptors.^28,41,48-50 It is possible that the expression of TrkC serves as a marker for the cell of origin, but the receptor itself has no significant role in dictating tumor behavior. Alternatively, activation of TrkC through its ligand NT3 may activate pathways leading to differentiation, and decrease tumor growth.

Although the role neurotrophins may play in the induction and progression of tumors remains speculative, it is conceivable that at least some of these tumors respond to endogenous neurotrophins. Muragaki et al⁴⁵ have reported that TrkA transfected PNET cell lines undergo differentiation and apoptosis in response to TrkA activation. Kim et al⁴¹ recently reported that TrkC activation induces apoptosis in the DAOY PNET cell line. They also reported that overexpression of TrkC inhibits the growth of intracerebral DAOY xenografts and that the rate of apoptosis is significantly increased in these xenografts compared to DAOY wildtype xenografts.

In the present study, we found at a cellular level that TrkC mRNA expression is high in the majority of PNETs, particularly in PNETs with neuronal differentiation, although this observation did not reach statistical significance in this relatively small subgroup analysis. In addition, a high level of TrkC mRNA expression correlates strongly with a favorable outcome, independent of clinical factors.

A variety of clinical and biologic variables have been proposed as prognostic factors for PNETs. The established clinical prognostic factors alone are not sufficient to reliably define high- and low-risk groups of PNET patients. The likelihood of finding additional clinical prognostic factors is small, which thus encourages endeavors to find biologic prognostic factors. Chromosome 17p has been evaluated as one putative biologic factor of suggested prognostic significance. However, this could not been substantiated in a study of 56 PNET/MB patients.³⁰

Our studies indicate that the level of TrkC mRNA expression is the most robust single prognostic factor yet identified, that TrkC mRNA expression is an independent prognostic factor, and that the combined evaluation for TrkC mRNA expression and M stage clearly defines a high risk group (TrkC mRNA low; M stage 1), an intermediate group (TrkC mRNA low; M stage 0), and a group with favorable outcome (TrkC mRNA high; any M stage). TrkC mRNA expression was of clear prognostic influence also for children younger than 3 years at diagnosis. These are the patients who are most vulnerable to radiation therapy.

The tendency of M0 tumors to have high TrkC mRNA expression was not significant. Three of six supratentorial PNETs had high expression of TrkC mRNA. There was no correlation of TrkC mRNA expression and age, sex, or chromosome 17p deletion.

Radiation-related treatment complications, including growth dysfunctions, and cognitive impairments decrease substantially the quality of life for many long-term survivors. In PNETs with high TrkC mRNA expression and no evidence of leptomeningeal tumor dissemination, therapy with reduced craniospinal radiation might retain the efficacy but reduce the toxicity and, therefore, improve the quality of life for the survivors. As shown by a pilot study by Goldwein et al,⁸ therapy with reduced craniospinal radiation is feasible. With the addition of TrkC mRNA expression to clinical factors, the accuracy in defining this low-risk group increases substantially.

We conclude that TrkC mRNA expression is, at present, the most powerful predictor of a favorable clinical outcome in patients with PNET and that PNETs that express functional TrkC may be susceptible to programmed cell death or to terminal neuronal differentiation. We strongly recommend assessing prospectively TrkC mRNA levels and incorporating TrkC mRNA expression into future PNET/MB clinical trials.

	ACKNOWLEDGMENTS

 
Supported by grant no. NS34514 from the National Institute of Health, Bethesda, MD, and by grants from Stiftung zur Unterstützung des akademischen Nachwuchses of the University of Zurich and Zürcher Elternvereinigung für Krebskranke Kinder, Zurich, Switzerland (to M.A.G.), and Jeffrey Miller Neuro-Oncology Research Fund.

We are indebted to Dr David Shelton for supplying the cDNA for the TrkC Riboprobe (Promega Corporation), to Dr G. Brodeur for supplying the TrkB transfected SYS5 cell line, to Dr Vanessa Vogelsberg-Ragaglia and Dr C.D. Reddy for valuable suggestions, to Kathleen Gibbs for data management, and to Mary Quigley for aid in preparing the article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Packer RJ, Siegel KR, Sutton LN, et al: Efficacy of adjuvant chemotherapy for patients with poor-risk medulloblastoma: A preliminary report. Ann Neurol 24:503-508, 1988[Medline]

2. Olshan JS, Gubernick J, Packer R, et al: The effects of adjuvant chemotherapy on growth in children with medulloblastoma. Cancer 70:2013-2017, 1992[Medline]

3. Radcliffe J, Packer RJ, Atkins TE, et al: Three- and four-year cognitive outcome in children with noncortical brain tumors treated with whole-brain radiotherapy. Ann Neurol 32:551-554, 1992[Medline]

4. Silber JH, Radcliffe J, Peckham V, et al: Whole-brain irradiation and decline in intelligence: The influence of dose and age on IQ score. J Clin Oncol 10:1390-1396, 1992[Abstract/Free Full Text]

5. Dennis M, Spiegler BJ, Hetherington CR, et al: Neuropsychological sequelae of the treatment of children with medulloblastoma. Neurooncol 29:91-101, 1996

6. Chapman CA, Waber DP, Bernstein JH, et al: Neurobehavioral and neurologic outcome in long term survivors of posterior fossa brain tumors: Role of age and perioperative factors. J Child Neurol 10:209-212, 1996

7. Silverman CL, Palkes H, Talent B, et al: Late effects of radiotherapy of patients with cerebellar medulloblastoma. Cancer 54:825-829, 1984[Medline]

8. Goldwein JW, Radcliffe J, Johnson J, et al: Updated results of a pilot study of low dose craniospinal irradiation plus chemotherapy for children under five with cerebellar primitive neuroectodermal tumors (medulloblastoma). Int J Radiat Oncol Biol Phys 34:899-904, 1996[Medline]

9. Janss AJ, Yachnis AT, Silber JH, et al: Glial differentiation predicts poor clinical outcome in primitive neuroectodermal brain tumors. Ann Neurol 39:481-489, 1996[Medline]

10. Evans AE, Jenkin DT, Sposto R, et al: The treatment of medulloblastoma. J Neurosurg 72:572-582, 1990[Medline]

11. Garton GR, Schomberg PJ, Scheithauer BW, et al: Medulloblastoma: Prognostic factors and outcome of treatment—Review of the Mayo Clinic experience. Mayo Clin Proc 65:1077-1086, 1990[Medline]

12. Packer RJ, Sutton LN, Elterman R, et al: Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 81:690-698, 1994[Medline]

13. Weil MD, Lamborn K, Edwards MS, et al: Influence of a child’s sex on medulloblastoma outcome. JAMA 13:1474-1476, 1998

14. Albright AL, Wisoff JH, Zeltzer PM, et al: Effects of medulloblastoma resections on outcome in children: A report from the Children’s Cancer Group. Neurosurgery 38:265-271, 1996[Medline]

15. Cohen BH, Zeltzer PM, Boyett JM: Prognostic factors and treatment results for supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: A Childrens Cancer Group randomized trial. Clin Oncol 13:1687-1696, 1995

16. Berry MP, Jenkin RDT, Keen CW, et al: Radiation treatment for medulloblastoma. J Neurosurg 55:43-51, 1981[Medline]

17. Merchant TE, Wang M-H, Haida T, et al: Medulloblastoma: Long-term results for patients treated with definitive radiation therapy during the computed tomography era. Int J Radiat Oncol Biol Phys 36:29-35, 1996[Medline]

18. Pezzotta S, Cordero di Montezemolo L, Knerich R, et al: CNS-85 trial: A cooperative pediatric CNS tumor study—Results of treatment of medulloblastoma patients. Childs Nerv Syst 12:87-96, 1996[Medline]

19. Sure U, Berghorn WJ, Bertalanffy H, et al: Staging, scoring and grading of medulloblastoma: A postoperative prognosis predicting system based on the cases of a single institute. Acta Neurochir (Wien) 132:59-65, 1995[Medline]

20. Tait DM, Thornton-Jones H, Bloom HJG, et al: Adjuvant chemotherapy for medulloblastoma: The first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Eur J Cancer 26:464-469, 1990

21. Caputy AJ, McCullough DC, Manz HJ, et al: A review of the factors influencing the prognosis of medulloblastoma. J Neurosurg 66:80-87, 1987[Medline]

22. Tomita T, Yasue M, Engelhard HH, et al: Flow cytometric DNA analysis of medulloblastoma. Cancer 61:744-749, 1988[Medline]

23. Czerwionka M, Korf H-W, Hoffmann O, et al: Differentiation in medulloblastomas: Correlation between the immunocytochemical demonstration of photoreceptor markers (S-antigen, rod-opsin) and the survival rate in 66 patients. (Berl) 78:629-636, 1989

24. Goldberg-Stern H, Gadoth N, Stern S, et al: The prognostic significance of glial fibrillary acidic protein staining in medulloblastoma. Cancer 68:568-573, 1991[Medline]

25. Schofield DE, Yunis EJ, Geyer R, et al: DNA content and other prognostic features in childhood medulloblastoma: Proposal of a scoring system. Cancer 69:1307-1314, 1992[Medline]

26. Maraziotis T, Perentes E, Karamitopoulou E, et al: Neuron-associated class III beta-tubulin isotype, retinal S-antigen, synaptophysin, and glial fibrillary acidic protein in human medulloblastomas: A clinicopathological analysis of 36 cases. (Berl) 84:355-363, 1992

27. Zerbini C, Gelber RD, Weinberg D, et al: Prognostic factors in medulloblastoma, including DNA ploidy. J Clin Oncol 11:616-622, 1993[Abstract]

28. Segal RA, Goumnerova LC, Kwon YK, et al: Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. Proc Natl Acad Sci U S A 91:12867-12871, 1994[Abstract/Free Full Text]

29. Cogen PH, McDonald JD: Tumor suppressor genes and medulloblastoma. J Neurooncol 29:103-112, 1996[Medline]

30. Biegel JA, Janss AJ, Raffel C, et al: Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumors (medulloblastomas) of the central nervous system. Clin Cancer Res 3:473-478, 1997[Abstract]

31. Gilbertson RJ, Perry RH, Kelly PJ, et al: Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. Cancer Res 57:3272-3280, 1997[Abstract/Free Full Text]

32. Scheurlen WG, Schwabe GC, Joos S, et al: Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome. J Clin Oncol 16:2478-2485, 1998[Abstract]

33. Brodeur GM, Seeger RC, Schwab M, et al: Amplification of N-myc in untreated human neuroblastoma correlates with advanced disease stage. Science 224:1121-1124, 1984[Abstract/Free Full Text]

34. Nakagawara A, Arima-Nakagawara M, Scavarda NJ, et al: Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med 328:847-854, 1993[Abstract/Free Full Text]

35. Maris JM, White PS, Beltinger CP, et al: Significance of chromosome 1p loss of heterozygosity in neuroblastoma. Cancer Res 55:4664-4669, 1995[Abstract/Free Full Text]

36. Lindsay RM, Wiegand SJ, Altar CA, et al: Neurotrophic factors: From molecule to man. Trends Neurosci 17:182-190, 1994[Medline]

37. Chao MV: Neurotrophin receptors: A window into neuronal differentiation. Neuron 9:583-593, 1992[Medline]

38. Barbacid M: Nerve growth factor: A tale of two receptors. Oncogene 8:2033-2042, 1993[Medline]

39. Korsching S: The neurotrophic factor concept: A reexamination. J Neurosci 13:2739-2748, 1993[Abstract]

40. Barbacid M: The Trk family of neurotrophin receptors. J Neurobiol 25:1386-1403, 1994[Medline]

41. Kim JY, Sutton ME, Lu DJ, et al: Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. Res 59:711-719, 1999

42. Chang CH, Housepian EM, Herbert C: An operative staging system and a megavoltage radiotherapeutic technique for cerebellar medulloblastomas. Radiology 93:1351-1359, 1969[Medline]

43. Duffner PK, Horowitz ME, Krischer JP, et al: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328:1725-1731, 1993[Abstract/Free Full Text]

44. Shelton DL, Sutherland J, Gripp J, et al: Human trks: Molecular cloning, tissue distribution, and expression of extracellular domain immunoadhesins. J Neurosci 15:477-491, 1995 (1 pt 2)[Abstract]

45. Muragaki Y, Chou TT, Kaplan DR, et al: Nerve growth factor induces apoptosis in human medulloblastoma cell lines that express TrkA receptor. J Neurosci 17:530-542, 1997[Abstract/Free Full Text]

46. Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42:1-15, 1983[Medline]

47. Rorke LB, Trojanowski JQ, Lee VM, et al: Primitive neuroectodermal tumors of the central nervous system. Brain Pathol 7:765-784, 1997[Medline]

48. Tajima Y, Molina RP, Rorke LB, et al: Neurotrophins and neuronal versus glial differentiation in medulloblastomas and other pediatric brain tumors. Acta Neuropathol (Berl) 95:325-332, 1998[Medline]

49. Washiyama K, Muragaki Y, Rorke LB, et al: Neurotrophin and neurotrophin receptor proteins in medulloblastomas and other primitive neuroectodermal tumors of the pediatric central nervous system. Am J Pathol 148:929-940, 1996[Abstract]

50. Brodeur GM, Nakagawara A, Yamashiro DJ, et al: Expression of TrkA, TrkB, and TrkC in human neuroblastomas. J Neurooncol 31:49-55, 1997[Medline]

Submitted June 23, 1999; accepted October 5, 1999.

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				W. Jin, C. Yun, H.-S. Kim, and S.-J. Kim TrkC Binds to the Bone Morphogenetic Protein Type II Receptor to Suppress Bone Morphogenetic Protein Signaling Cancer Res., October 15, 2007; 67(20): 9869 - 9877. [Abstract] [Full Text] [PDF]

				S. Rutkowski, A. von Bueren, K. von Hoff, W. Hartmann, T. Shalaby, F. Deinlein, M. Warmuth-Metz, N. Soerensen, A. Emser, U. Bode, et al. Prognostic Relevance of Clinical and Biological Risk Factors in Childhood Medulloblastoma: Results of Patients Treated in the Prospective Multicenter Trial HIT'91 Clin. Cancer Res., May 1, 2007; 13(9): 2651 - 2657. [Abstract] [Full Text] [PDF]

				S. H. Ramkissoon, P. S. Patel, M. Taborga, and P. Rameshwar Nuclear Factor-{kappa}B Is Central to the Expression of Truncated Neurokinin-1 Receptor in Breast Cancer: Implication for Breast Cancer Cell Quiescence within Bone Marrow Stroma Cancer Res., February 15, 2007; 67(4): 1653 - 1659. [Abstract] [Full Text] [PDF]

				R. J. Packer, A. Gajjar, G. Vezina, L. Rorke-Adams, P. C. Burger, P. L. Robertson, L. Bayer, D. LaFond, B. R. Donahue, M. H. Marymont, et al. Phase III Study of Craniospinal Radiation Therapy Followed by Adjuvant Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma J. Clin. Oncol., September 1, 2006; 24(25): 4202 - 4208. [Abstract] [Full Text] [PDF]

				H. J. Patel, S. H. Ramkissoon, P. S. Patel, and P. Rameshwar Transformation of breast cells by truncated neurokinin-1 receptor is secondary to activation by preprotachykinin-A peptides PNAS, November 29, 2005; 102(48): 17436 - 17441. [Abstract] [Full Text] [PDF]

				D. W. Ellison, O. E. Onilude, J. C. Lindsey, M. E. Lusher, C. L. Weston, R. E. Taylor, A. D. Pearson, and S. C. Clifford {beta}-Catenin Status Predicts a Favorable Outcome in Childhood Medulloblastoma: The United Kingdom Children's Cancer Study Group Brain Tumour Committee J. Clin. Oncol., November 1, 2005; 23(31): 7951 - 7957. [Abstract] [Full Text] [PDF]

				J. R. Geyer, R. Sposto, M. Jennings, J. M. Boyett, R. A. Axtell, D. Breiger, E. Broxson, B. Donahue, J. L. Finlay, J. W. Goldwein, et al. Multiagent Chemotherapy and Deferred Radiotherapy in Infants With Malignant Brain Tumors: A Report From the Children's Cancer Group J. Clin. Oncol., October 20, 2005; 23(30): 7621 - 7631. [Abstract] [Full Text] [PDF]

				P. Brouwers Commentary: Study of the Neurobehavioral Consequences of Childhood Cancer: Entering the Genomic Era? J. Pediatr. Psychol., January 1, 2005; 30(1): 79 - 84. [Full Text] [PDF]

				A. Ray, M. Ho, J. Ma, R. K. Parkes, T. G. Mainprize, S. Ueda, J. McLaughlin, E. Bouffet, J. T. Rutka, and C. E. Hawkins A Clinicobiological Model Predicting Survival in Medulloblastoma Clin. Cancer Res., November 15, 2004; 10(22): 7613 - 7620. [Abstract] [Full Text] [PDF]

				J. M. Lamont, C. S. McManamy, A. D. Pearson, S. C. Clifford, and D. W. Ellison Combined Histopathological and Molecular Cytogenetic Stratification of Medulloblastoma Patients Clin. Cancer Res., August 15, 2004; 10(16): 5482 - 5493. [Abstract] [Full Text] [PDF]

				O. Ozen, B. Krebs, B. Hemmerlein, A. Pekrun, H. Kretzschmar, and J. Herms Expression of Matrix Metalloproteinases and Their Inhibitors in Medulloblastomas and Their Prognostic Relevance Clin. Cancer Res., July 15, 2004; 10(14): 4746 - 4753. [Abstract] [Full Text] [PDF]

				A. Fernandez-Teijeiro, R. A. Betensky, L. M. Sturla, J. Y.H. Kim, P. Tamayo, and S. L. Pomeroy Combining Gene Expression Profiles and Clinical Parameters for Risk Stratification in Medulloblastomas J. Clin. Oncol., March 15, 2004; 22(6): 994 - 998. [Abstract] [Full Text] [PDF]

				A. Gajjar, R. Hernan, M. Kocak, C. Fuller, Y. Lee, P. J. McKinnon, D. Wallace, C. Lau, M. Chintagumpala, D. M. Ashley, et al. Clinical, Histopathologic, and Molecular Markers of Prognosis: Toward a New Disease Risk Stratification System for Medulloblastoma J. Clin. Oncol., March 15, 2004; 22(6): 984 - 993. [Abstract] [Full Text] [PDF]

				P. G. Fisher, P. C. Burger, and C. G. Eberhart Biologic Risk Stratification of Medulloblastoma: The Real Time Is Now J. Clin. Oncol., March 15, 2004; 22(6): 971 - 974. [Full Text] [PDF]

				C. Pingoud-Meier, D. Lang, A. J. Janss, L. B. Rorke, P. C. Phillips, T. Shalaby, and M. A. Grotzer Loss of Caspase-8 Protein Expression Correlates with Unfavorable Survival Outcome in Childhood Medulloblastoma Clin. Cancer Res., December 15, 2003; 9(17): 6401 - 6409. [Abstract] [Full Text] [PDF]

				W. Q. Yang, D. Senger, H. Muzik, Z. Q. Shi, D. Johnson, P. M. A. Brasher, N. B. Rewcastle, M. Hamilton, J. Rutka, J. Wolff, et al. Reovirus Prolongs Survival and Reduces the Frequency of Spinal and Leptomeningeal Metastases from Medulloblastoma Cancer Res., June 15, 2003; 63(12): 3162 - 3172. [Abstract] [Full Text] [PDF]

				T. J. MacDonald, B. R. Rood, M. R. Santi, G. Vezina, K. Bingaman, P. H. Cogen, and R. J. Packer Advances in the Diagnosis, Molecular Genetics, and Treatment of Pediatric Embryonal CNS Tumors Oncologist, April 1, 2003; 8(2): 174 - 186. [Abstract] [Full Text] [PDF]

				Luis Del Valle, S. Enam, A. Lassak, J. Y. Wang, S. Croul, K. Khalili, and K. Reiss Insulin-like Growth Factor I Receptor Activity in Human Medulloblastomas Clin. Cancer Res., June 1, 2002; 8(6): 1822 - 1830. [Abstract] [Full Text] [PDF]

				M. A. Grotzer, M. D. Hogarty, A. J. Janss, X. Liu, H. Zhao, A. Eggert, L. N. Sutton, L. B. Rorke, G. M. Brodeur, and P. C. Phillips MYC Messenger RNA Expression Predicts Survival Outcome in Childhood Primitive Neuroectodermal Tumor/Medulloblastoma Clin. Cancer Res., August 1, 2001; 7(8): 2425 - 2433. [Abstract] [Full Text] [PDF]

				A. Eggert, M. A. Grotzer, N. Ikegaki, H. Zhao, A. Cnaan, G. M. Brodeur, and A. E. Evans Expression of the Neurotrophin Receptor TrkB Is Associated With Unfavorable Outcome in Wilms' Tumor J. Clin. Oncol., February 1, 2001; 19(3): 689 - 696. [Abstract] [Full Text] [PDF]

				J. A. Biegel, B. Fogelgren, J.-Y. Zhou, C. D. James, A. J. Janss, J. C. Allen, D. Zagzag, C. Raffel, and L. B. Rorke Mutations of the INI1 Rhabdoid Tumor Suppressor Gene in Medulloblastomas and Primitive Neuroectodermal Tumors of the Central Nervous System Clin. Cancer Res., July 1, 2000; 6(7): 2759 - 2763. [Abstract] [Full Text]

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