Sorensen, Alma Gregory

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Sorensen, Alma Gregory

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Sorensen

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Alma Gregory

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Sorensen, Alma Gregory

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AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Patients
(Elsevier BV, 2007) Batchelor, Tracy; Sorensen, Alma Gregory; di Tomaso, Emmanuelle; Zhang, Wei-Ting; Duda, Dan; Cohen, Kenneth S.; Kozak, Kevin R.; Cahill, Daniel; Chen, Poe-Jou; Zhu, Mingwang; Ancukiewicz, Marek; Mrugala, Maciej M.; Plotkin, Scott; Drappatz, Jan; Louis, David; Ivy, Percy; Scadden, David; Benner, Thomas; Loeffler, Jay; Wen, Patrick; Jain, Rakesh
Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171—an oral tyrosine kinase inhibitor of VEGF receptors—has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.
Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma
(Springer Nature, 2009) Plotkin, Scott; Halpin, Chris; Blakeley, Jaishri O.; Slattery, William H.; Welling, Duane; Chang, Susan M.; Loeffler, Jay; Harris, Gordon; Sorensen, Alma Gregory; McKenna, Michael; Barker, Frederick
Neurofibromatosis type 2 (NF2) is a tumor suppressor gene syndrome characterized by multiple schwannomas, especially vestibular schwannomas (VS), and meningiomas. Anticancer drug trials are now being explored, but there are no standardized endpoints in NF2. We review the challenges of NF2 clinical trials and suggest possible response criteria for use in initial phase II studies. We suggest two main response criteria in such trials. Objective radiographic response is defined as a durable 20% or greater reduction in VS volume based on postcontrast T1-weighted MRI images collected with 3 mm or finer cuts through the internal auditory canal. Hearing response is defined as a statistically significant improvement in word recognition scores using 50-word recorded lists in audiology. A possible composite endpoint incorporating both radiographic response and hearing response is outlined. We emphasize pitfalls in response assessment and suggest guidelines to minimize misinterpretations of response. We also identify research goals in NF2 to facilitate future trial conduct, such as identifying the expectations for time to tumor progression and time to measurable hearing loss in untreated NF2-related VS, and the relation of both endpoints to patient prognostic factors (such as age, baseline tumor volume, and measures of disease severity). These data would facilitate future use of endpoints based on stability of tumor size and hearing, which might be more appropriate for testing certain drugs. We encourage adoption of standardized endpoints early in the development of phase II trials for this population to facilitate comparison of results across trials of different agents.
Hearing Improvement after Bevacizumab in Patients with Neurofibromatosis Type 2
(New England Journal of Medicine (NEJM/MMS), 2009) Plotkin, Scott; Stemmer-Rachamimov, Anat; Barker, Frederick; Halpin, Chris; Padera, Timothy; Tyrrell, Alex; Sorensen, Alma Gregory; Jain, Rakesh; di Tomaso, Emmanuelle
Background Profound hearing loss is a serious complication of neurofibromatosis type 2, a genetic condition associated with bilateral vestibular schwannomas, benign tumors that arise from the eighth cranial nerve. There is no medical treatment for such tumors. Methods We determined the expression pattern of vascular endothelial growth factor (VEGF) and three of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, in paraffinembedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas. Ten consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were treated with bevacizumab, an anti-VEGF monoclonal antibody. An imaging response was defined as a decrease of at least 20% in tumor volume, as compared with baseline. A hearing response was defined as a significant increase in the word-recognition score, as compared with baseline. Results VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26%. Three patients were not eligible for a hearing response; of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss. There were 21 adverse events of grade 1 or 2. Conclusions VEGF blockade with bevacizumab improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas.
Phase II Study of Cediranib, an Oral Pan–Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma
(American Society of Clinical Oncology (ASCO), 2010) Batchelor, Tracy; Duda, Dan; di Tomaso, Emmanuelle; Ancukiewicz, Marek; Plotkin, Scott; Gerstner, Elizabeth; Eichler, April; Drappatz, Jan; Hochberg, Fred H; Benner, Thomas; Louis, David; Cohen, Kenneth S.; Chea, Houng; Exarhopoulos, Alexis; Loeffler, Jay; Moses, Marsha; Ivy, Percy; Sorensen, Alma Gregory; Wen, Patrick; Jain, Rakesh
Purpose Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma. Methods Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points. Results Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell–derived factor-1α, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival. Conclusion Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.
Glioblastoma Recurrence after Cediranib Therapy in Patients: Lack of "Rebound" Revascularization as Mode of Escape
(American Association for Cancer Research (AACR), 2011) di Tomaso, E.; Snuderl, M.; Kamoun, W. S.; Duda, Dan; Auluck, P. K.; Fazlollahi, L.; Andronesi, Ovidiu; Frosch, Matthew; Wen, Patrick; Plotkin, Scott; Hedley-Whyte, E.; Sorensen, Alma Gregory; Batchelor, Tracy; Jain, Radhika
Recurrent glioblastomas (rGBM) invariably relapse after initial response to anti-VEGF therapy. There are two prevailing hypotheses on how these tumors escape antiangiogenic therapy: switch to VEGF-independent angiogenic pathways and vessel co-option. However, direct evidence in rGBM patients is lacking. Thus, we compared molecular, cellular and vascular parameters in autopsy tissues from five rGBM patients who had been treated with the pan-VEGF receptor tyrosine kinase inhibitor cediranib versus seven patients who received no therapy or chemoradiation but no antiangiogenic agents. After cediranib treatment, endothelial proliferation and glomeruloid vessels were decreased, and vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere. In addition, tumor endothelial cells expressed molecular markers specific to the blood-brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy. Surprisingly, in cediranib-treated GBM cellular density in the central area of the tumor was lower than in control cases and gradually decreased towards the infiltrating edge, indicative of a change in growth pattern of rGBMs after cediranib treatment, unlike that after chemo-radiation. Finally, cediranib treated GBMs showed high levels of PDGF-C and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy. In summary, we show that rGBMs switch their growth pattern after anti-VEGF therapy – characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis and blood vessels with normal molecular expression and morphology without a second wave of angiogenesis.
Stability of Large Diffusion/Perfusion Mismatch in Anterior Circulation Strokes for 4 or More Hours
(BioMed Central, 2010) González, R Gilberto; Hakimelahi, Reza; Schaefer, Pamela; Roccatagliata, Luca; Sorensen, Alma Gregory; Singhal, Aneesh
Background: The stability of hypoperfused brain tissue in stroke patients with major artery occlusions is unknown. The purpose of this study was to determine the persistence of a diffusion/perfusion mismatch in patients with ICA or proximal MCA occlusions. Methods: Fourteen patients with ICA and/or proximal MCA occlusion and a diffusion/perfusion mismatch at presentation were studied. All were enrolled in a pilot randomized study of normobaric oxygen therapy. None received thrombolytic therapy; 8 received normobaric oxygen and 6 room air. Diffusion/perfusion MRI was performed at baseline, 4 hours, 24 hours, and 1 week. Abnormal DWI, ADC, and MTT volumes were determined using standard image analysis methods. Results: The mean time from symptom onset to baseline MRI was 7.5 ± 1 hours. Across all 4 time points there was a significant difference in DWI lesion (ANOVA, P < 0.0001) and abnormal MTT volumes (ANOVA, P < 0.01) with the 24 hour and 1 week abnormal volumes different from the earlier studies. However, comparing baseline and 4 hour scans, there was no significant interval change in the mean abnormal DWI volume (29.4 ± 8.2 ml vs. 28.1 ± 7.4 ml) or abnormal MTT volumes (137 ± 17.7 ml vs. 130.9 ± 13.8). By 24 hours, only 2 patients did not maintain a mismatch of 20% or greater. Conclusions: Patients who present outside the time window for thrombolytic therapy, and who have a large diffusion/perfusion mismatch on MRI may have a stable mismatch for 4 or more hours.
Long-term Monitoring of Post-stroke Plasticity after Transient Cerebral Ischemia in Mice Using in vivo and ex vivo Diffusion Tensor MRI
(Bentham Science Publishers Ltd., 2007) Granziera, C; D’Arceuil, H; Zai, Laila; Magistretti, P.J; Sorensen, Alma Gregory; de Crespigny, A.J
We used a murine model of transient focal cerebral ischemia to study: 1) in vivo DTI long-term temporal evolution of the apparent diffusion coefficient (ADC) and diffusion fractional anisotropy (FA) at days 4, 10, 15 and 21 after stroke 2) ex vivo distribution of a plasticity-related protein (GAP-43) and its relationship with the ex vivo DTI characteristics of the striato-thalamic pathway (21 days). All animals recovered motor function. In vivo ADC within the infarct was significantly increased after stroke. In the stroke group, GAP-43 expression and FA values were significantly higher in the ipsilateral (IL) striatum and contralateral (CL) hippocampus compared to the shams. DTI tractography showed fiber trajectories connecting the CL striatum to the stroke region, where increased GAP43 and FA were observed and fiber tracts from the CL striatum terminating in the IL hippocampus. Our data demonstrate that DTI changes parallel histological remodeling and recovery of function.