Tissues Harvested Using an Automated Surgical Approach Confirm Molecular Heterogeneity of Glioblastoma and Enhance Specimen's Translational Research Value.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Designing effective individualized therapies for GBM requires quality fresh tissue specimens, and a comprehensive molecular profile of this highly heterogenous neoplasm. Novel neuro-surgical approaches, such as the automated resection NICO Myriad™ system, are increasingly used by neurosurgeons to better reach the invasive front of tumors. However, no information exists on how harvesting GBM tissue using this approach may impact the translational research value of the sample. Here, we set out to characterize matched specimens from 15 patients, where one tissue sample was obtained using traditional tumor de-bulking (herein referred to as "en bloc" sample), and the other sample was obtained using the MyriadTM System (herein referred to as "Myriad" sample). We investigated the fidelity of patient derived xenografts (PDXs) for each sample type to the corresponding human tissues and evaluated the added value of sequencing both samples for each patient. Matched en bloc and Myriad samples processed in parallel, were subjected to the following assays: cell viability, self-renewal, in vivo tumorigenicity using an orthotopic model of glioma, genomic sequencing, and pharmacological testing using PI3K-MTOR pathway inhibitors. Our results demonstrate that primary GBM cultures derived from matched specimens grew at similar rates (correlation coefficient R = 0.72), generated equivalent number of neurospheres, and had equivalent tumorigenic potential in vivo (mouse survival correlation coefficient R = 0.93). DNA Sequencing using the Illumina tumor panel amplicons revealed over 70% concordance in non-synonymous mutations between matched human GBM specimens. PDX genomic profiles were also highly concordant with the corresponding patient tissues (>70%). RNA sequencing of paired GBM samples revealed unique genomic variants and differential gene expression between the en bloc and Myriad specimens, with the former molecularly resembling the "tumor core" and the latter resembling the "invasive tumor front" signature. Functionally, we show that primary-derived GBM cells-obtained after fresh specimen's dissociation-are more effectively growth-inhibited by co-targeting non-overlapping mutations enriched in each sample type, suggesting that profiling both specimens more adequately capture the molecular heterogeneity of GBM and may enhance the design accuracy and efficacy of individualized therapies.

Irinotecan and bevacizumab in progressive primary brain tumors, an evaluation of efficacy and safety.

Recurrent high-grade gliomas are resistant to chemotherapy and have poor prognosis. The combination of irinotecan and bevacizumab has been reported to be an active regimen in the treatment of this disease. Herein we report our experience with this regimen with the objective of evaluating its efficacy and examining its safety profile. We performed a retrospective review of 27 patients with recurrent or progressive high-grade gliomas treated at the Cleveland Clinic Brain Tumor and Neuro-Oncology Center from 7/2005 through 10/2006. Patients with at least one prior chemotherapy regimen were included. Patients with prior irinotecan or bevacizumab were excluded. Outcomes were analyzed on an intention-to-treat basis and estimated by the Kaplan-Meier method. The median age of the group was 46 years and the median number of prior therapies was two. Eighteen of 27 patients have progressed, and 11 patients have died at time of analysis. Progression-free survival at 6 months is 46% and overall survival at 6 months is 84% with a median overall survival of 12.6 months. Of 12 patients with pretreatment radiographic evidence of intracranial hemorrhage, only one developed symptomatic progression of hemorrhage that required termination of therapy. Our experience suggests that the combination of irinotecan and bevacizumab improves the outcome in progressive high-grade gliomas when compared to historical results. While the rate of severe toxicities is consistent with prior reports and mandates careful selection of patients, asymptomatic, stable intracranial blood products or hemorrhage is likely not an absolute contraindication to therapy.

Functional heterogeneity of prostatic intraepithelial neoplasia: the duration of hormonal therapy influences the response.

OBJECTIVES: To use a clinical model of androgen-deprivation therapy (ADT) followed by radical prostatectomy (RP) to test the hypothesis that prostatic intraepithelial neoplasia (PIN, a premalignant lesion of the prostate causally linked to prostate cancer) is heterogeneous for hormone responsiveness, which might explain aspects of the heterogeneity of the natural history of prostate cancer, for although ADT has been used to reduce prostate cancer, there are controversial data on the effect of ADT on PIN. PATIENTS AND METHODS: We assessed retrospectively patients with biopsy-confirmed prostate cancer who had RP; some patients had received >or=3 months of ADT at the discretion of their surgeons, and patients from the same cohort who did not have ADT were used as controls. Patients were sequentially selected from the database and their pathology slides were reviewed by a pathologist unaware of the initial presence of PIN (assessed by an independent observer). Fisher's exact test was used to compare the proportions of patients who had residual PIN in the study and control groups. Exact logistic regression was used to evaluate the duration of ADT on PIN regression. RESULTS: Eighteen patients initially diagnosed with PIN who had no ADT were identified, and 28 with PIN who had ADT were also assessed. All patients who had had no ADT had residual PIN, whereas seven of 28 receiving ADT had no residual PIN (P=0.043). The evaluation of ADT between responders and nonresponders showed a statistically significant association between PIN regression and the duration of ADT (P<0.001). However, the response of PIN to ADT was not uniform, as 16% of patients on ADT for >6 months had residual PIN, suggesting variable sensitivity of PIN to ADT. CONCLUSION: These results show that ADT causes PIN to regress, and that there is heterogeneity in this effect with the duration of ADT. We propose future prospective, multicentre, randomized trials in which the effect of ADT on PIN is characterized further.