A. H. Friedman

Outcome of Temporal Lobectomy in Adolescents

We performed temporal lobectomy in 23 young patients with intractable complex partial seizures (CPS) at an average age of 14.5 years. At a mean follow-up interval of 4.8 years, we reevaluated the patients to assess the surgical outcome; 74% were seizure-free. Cognitive testing showed slight improvement in Full-scale I.Q. scores and in some subtest scores. Wechsler Memory Scales had not changed significantly from the preoperative scores. Both pre- and postoperative Minnesota Multiphasic Personality Inventories 168 (MMPIs) were obtained in nine patients; and only postoperative MMPIs were obtained in 18. Pre- and postoperative social function, reported by the patients in a structured interview with a clinical psychologist (H.S.S.), was scored by a rating scale. All patients reported postoperative improvement in social function, although of variable degree. Patients were divided into a well-adjusted and a poorly adjusted group based on their postoperative social function. As compared with the well-adjusted group, the poorly adjusted group reported more preoperative social problems, had lower preoperative and postoperative I.Q. scores, had poorer postoperative seizure control, and had higher postoperative MMPI scores.

Abstract CT416: Intratumoral administration of an Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) in recurrent glioblastoma (GBM): Preliminary results of the Phase I clinical trial

Background: PVSRIPO is the live attenuated, oral (SABIN) serotype 1 poliovirus vaccine containing a heterologous internal ribosomal entry site stemming from human rhinovirus type 2. An oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy, nectin-like molecule-5, is recognized by PVSRIPO. We report the preliminary results of a phase I clinical trial evaluating the intratumoral administration via convection-enhanced delivery (CED) of PVSRIPO. Methods: Eligibility criteria for adult patients included: recurrent supratentorial GBM; 1-5 cm in diameter; ≥1cm away from the ventricles; ≥4 weeks after chemotherapy, bevacizumab (BEV) or study drug; adequate organ function; KPS >70%; and positive anti-poliovirus titer. Dose was rapidly escalated using a two-step continual reassessment method with anticipated accrual of 1 patient each on dose levels 1-4, and up to 21 patients at dose level 5. Results: Thus far, ten patients have been treated (1 each at levels 1 and 3, 2 at level 2, 2 at level 4, 4 at level 5). One dose limiting toxicity (patient #8) was observed at level 5, a grade 4 intracranial hemorrhage at the time of catheter removal, which required de-escalation to level 4. Grade 3 adverse events possibly related to study include hemiparesis (n=1) and lymphopenia (n=1). No grade 5 study related adverse events were observed. Eight patients remain alive, with two patients now 20 and 19 months post PVSRIPO, respectively. Two patients having previously failed BEV died six months post-infusion after initiating hospice care due to persistence of baseline neurologic deficits. After observing prolonged steroid use in 5 of 7 patients treated on dose levels 3 to 5 and after results of new immunogenic analysis became available, it was agreed upon that dose level 2 is probably the optimal dose level. The study has been amended to treat a total of 6 patients at dose level 2. Conclusion: Infusion of PVSRIPO via CED in the clinical setting is safe thus far and observed efficacy outcomes are intriguing. Dose expansion at dose level 2 is ongoing. Citation Format: Annick Desjardins, J H. Sampson, K B. Peters, T Ranjan, G Vlahovic, S Threatt, J E. Herndon, S Boulton, D Lally-Goss, F McSherry, A Friedman, H S. Friedman, D D. Bigner, M Gromeier. Intratumoral administration of an Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) in recurrent glioblastoma (GBM): Preliminary results of the Phase I clinical trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT416. doi:10.1158/1538-7445.AM2014-CT416

Abstract 1177: The mutational status of the p53 tumor suppressor gene is a determinant of GSTP1 expression and mediates GSTP1-dependent drug resistance in human glioblastoma

Mutations in the p53 tumor suppressor gene, a transcription factor activated by a variety of cellular stresses, including, those inflicted by anti-cancer agents, is a common genetic abnormality in GBMs. Although, p53 is involved in critical cellular processes, such as, cell cycle arrest, DNA repair and apoptosis, studies of p53 in tumor drug resistance and/or patient response to therapy have yielded mixed results. Thus, in gliomas and other cancers, such as, breast, bladder, and ovarian carcinomas, some studies have associated wild-type p53 with higher tumor drug resistance, while other studies indicate that mutant or functionally inactive p53, rather than wt p53, confers drug resistance. These observations indicate the significant complexity of the role of p53 in tumor response to therapy and suggest that other factors, including, downstream p53 pathways and/or regulation, may be important determinants of the p53 effects on the tumor drug resistance phenotype. We previously reported that the human GSTP1 gene, that encodes a major drug metabolizing protein, cell signaling regulator and a mediator of tumor drug resistance, is transcriptionally activated by p53 via a canonical p53 binding motif located in intron 4 of the GSTP1 gene. Our goal, in this study, is to gain further insight into the relationship between p53-dependent transcriptional control of GSTP1 in GBM and the extent to which it contributes to GSTP1 expression in primary patient tumor and, ultimately, to their response to therapy. For this, we sequenced the p53 gene across exons 2-11 in 42 primary GBM specimens quantified the level of GSTP1 gene expression by RNA-PCR and genotyped the allelic variants in them. The results showed, approx. half of the tumors to harbor wild-type p53. In those with mutant p53, the mutations spanned the entire p53 target region, the majority in the core DNA binding domain with the hot spots in codons 55, 72, 175, 245, 248, and 273. GSTP1 expression was significantly heterogeneous between the tumors, and with a few exceptions, correlated directly with the presence of wild-type p53. In representative tumors, the high GSTP1 gene expression was associated with resistance to cisplatin and temozolomide. These result suggest that, in GBM, transcriptional activation of GSTP1 by wild-type, and some mutant forms of p53, contributes to their resistance to therapy. Supported by NIH grants RO1 CA 153050, RO1CA127872, RO1 CA 112519, P50CA108786 and P30-CA14236. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1177. doi:1538-7445.AM2012-1177