Browsing by Author "Pinto, Navin"

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    Efficacy of Post-Induction Therapy for High-risk Neuroblastoma Patients with End-Induction Residual Disease
    (Wiley, 2022) Desai, Ami V.; Applebaum, Mark A.; Karrison, Theodore G.; Oppong, Akosua; Yuan, Cindy; Berg, Katherine R.; MacQuarrie, Kyle; Sokol, Elizabeth; Hall, Anurekha G.; Pinto, Navin; Wolfe, Ian; Mody, Rajen; Shusterman, Suzanne; Smith, Valeria; Foster, Jennifer H.; Nassin, Michele; LaBelle, James L.; Bagatell, Rochelle; Cohn, Susan L.; Radiology and Imaging Sciences, School of Medicine
    Background: High-risk neuroblastoma patients with end-induction residual disease commonly receive post-induction therapy in an effort to increase survival by improving response prior to autologous stem cell transplant (ASCT). We conducted a multi-center, retrospective study to investigate the efficacy of this approach. Methods: Patients diagnosed between 2008 and 2018 without progressive disease (PD) with ≤ partial response (PR) at end-induction were stratified according to post-induction treatment: i) no additional therapy prior to ASCT (Cohort 1); ii) post-induction “bridge” therapy prior to ASCT (Cohort 2); and iii) post-induction therapy without ASCT (Cohort 3). Chi-square tests were used to compare patient characteristics. Three-year event-free survival (EFS) and overall survival (OS) were estimated by the Kaplan-Meier method and survival curves were compared by log-rank test. Results: The study cohort consisted of 201 patients; Cohort 1 (n=123); Cohort 2 (n=51); and Cohort 3 (n=27). Although end-induction response was better for Cohort 1 than Cohorts 2 and 3, outcome for Cohort 1 and 2 was not significantly different (EFS; p=0.77 and OS; p=0.85). Inferior outcome was observed for Cohort 3 (EFS; p<0.001 and OS; p=0.06). Among patients with end-induction stable metastatic disease, 3-year EFS was significantly improved for Cohort 2 compared to Cohort 1 (p=0.04). Cohort 3 patients with complete response (CR) in metastatic sites following post-induction therapy had significantly better 3-year EFS compared to those with residual metastatic disease (p=0.01). Conclusions: Prospective studies to confirm the benefits of bridge treatment and the prognostic significance of metastatic response observed in this study are warranted.
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    A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors
    (Springer, 2018-08) Sehdev, Amikar; Karrison, Theodore; Zha, Yuanyuan; Janisch, Linda; Turcich, Michelle; Cohen, Ezra E. W.; Maitland, Michael; Polite, Blase N.; Gajewski, Thomas F.; Salgia, Ravi; Pinto, Navin; Bissonnette, Marc B.; Fleming, Gini F.; Ratain, Mark J.; Sharma, Manish R.; Medicine, School of Medicine
    Background Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis. Methods Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin). Results 24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (− 0.12 vs. − 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities. Conclusions Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers. Impact: Combining metformin with sirolimus did not improve mTOR inhibition.