Pelloski, Christopher E.

Glioblastoma (GM) is one of the most common malignant parenchymal tumors in adults with the majority being supratentorial. Cerebellar GMs are far less common, comprising less than 1% of all intracranial GMs. To our knowledge, no large scale studies have been done to compare the survival outcome of cerebellar to cerebral GMs. Clinical characteristics of 42 patients with newly diagnosed cerebellar GMs from the files of M.D. Anderson Cancer Center between 1985 and 2005 were reviewed, and compared with 649 cerebral GMs. The median age of patients with cerebellar GM was 38.7, which was significantly younger than for cerebral GM (56.7, p<0.001). Survival outcome between the two patient populations was also compared. The median survival for the cerebellar GM group was 61.6 weeks, not significantly different from the cerebral GM group (81.3 weeks, p=0.156). However, long‐term survivorship, as defined by survival at 2 years was 17.5% and 28.6% for cerebral and cerebellar GMs, respectively (p<0.001). Cerebellar GMs occur in a younger patient population than cerebral GMs. The median survival does not appear to differ, but there is an increase in long‐term survivorship in cerebellar tumors. Comparison of molecular signatures, treatment modalities and tumor progression among the patients are under investigation to better stratify the patient populations.

Purpose The clinical significance of epidermal growth factor receptor variant III (EGFRvIII) expression in glioblastoma multiforme (GBM) and its relationship with other key molecular markers are not clear. We sought to evaluate the clinical significance of GBM subtypes as defined by EGFRvIII status. Patients and Methods The expression of EGFRvIII was assessed by immunohistochemistry in 649 patients with newly diagnosed GBM. These data were then examined in conjunction with the expression of phospho-intermediates (in a subset of these patients) of downstream AKT and Ras pathways and YKL-40 as well as with known clinical risk factors, including the Radiation Therapy Oncology Group's recursive partitioning analysis (RTOG-RPA) class. Results The RTOG-RPA class was highly predictive of survival in EGFRvIII-negative patients but much less predictive in EGFRvIII-positive patients. These findings were seen in both an initial test set (n = 268) and a larger validation set (n = 381). Similarly, activation of the AKT/MAPK pathways and YKL-40 positivity were predictive of poor outcome in EGFRvIII-negative patients but not in EGFRvIII-positive patients. Pair-wise combinations of markers identified EGFRvIII and YKL-40 as prognostically important. In particular, outcome in patients with EGFRvIII-negative/YKL-40–negative tumors was significantly better than the outcome in patients with the other three combinations of these two markers. Conclusion Established prognostic factors in GBM were not predictive of outcome in the EGFRvIII-positive subset, although this requires confirmation in independent data sets. GBMs negative for both EGFRvIII and YKL-40 show less aggressive behavior.

Abstract Purpose: YKL-40 is a secreted protein that has been reported to be overexpressed in epithelial cancers and gliomas, although its function is unknown. Previous data in a smaller sample set suggested that YKL-40 was a marker associated with a poorer clinical outcome and a genetically defined subgroup of glioblastoma. Here we test these findings in a larger series of patients with glioblastoma, and in particular, determine if tumor YKL-40 expression is associated with radiation response. Experimental Design: Patients (n = 147) with subtotal resections were studied for imaging-assessed changes in tumor size in serial studies following radiation therapy. An additional set (n = 140) of glioblastoma patients who underwent a gross-total resection was tested to validate the survival association and extend them to patients with minimal residual disease. Results: In the subtotal resection group, higher YKL-40 expression was significantly associated with poorer radiation response, shorter time to progression and shorter overall survival. The association of higher YKL-40 expression with poorer survival was validated in the gross-total resection group. In multivariate analysis with both groups combined (n = 287), YKL-40 was an independent predictor of survival after adjusting for patient age, performance status, and extent of resection. YKL-40 expression was also compared with genetically defined subsets of glioblastoma by assessing epidermal growth factor receptor amplification and loss at chromosome 10q, two of the common recurring aberrations in these tumors, using fluorescent in situ hybridization. YKL-40 was significantly associated with 10q loss. Conclusions: The findings implicate YKL-40 as an important marker of therapeutic response and genetic subtype in glioblastomas and suggest that it may play an oncogenic role in these tumors.