Search

Purpose: Currently, radiologic response of brain tumors is assessed according to the Macdonald criteria 10 weeks from the start of therapy. There exists a critical need to identify nonresponding patients early in the course of their therapy for consideration of alternative treatment strategies. Our study assessed the effectiveness of the parametric response map (PRM) imaging biomarker to provide for an earlier measure of patient survival prediction. Experimental Design: Forty-five high-grade glioma patients received concurrent chemoradiation. Quantitative MRI including apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) maps were acquired pretreatment and 3 weeks midtreatment on a prospective institutional-approved study. PRM, a voxel-by-voxel image analysis method, was evaluated as an early prognostic biomarker of overall survival. Clinical and conventional MR parameters were also evaluated. Results: Multivariate analysis showed that PRMADC+ in combination with PRMrCBV− obtained at week 3 had a stronger correlation to 1-year and overall survival rates than any baseline clinical or treatment response imaging metric. The composite biomarker identified three distinct patient groups, nonresponders [median survival (MS) of 5.5 months, 95% CI: 4.4–6.6 months], partial responders (MS of 16 months, 95% CI: 8.6–23.4 months), and responders (MS has not yet been reached). Conclusions: Inclusion of PRMADC+ and PRMrCBV− into a single imaging biomarker metric provided early identification of patients resistant to standard chemoradiation. In comparison to the current standard of assessment of response at 10 weeks (Macdonald criteria), the composite PRM biomarker potentially provides a useful opportunity for clinicians to identify patients who may benefit from alternative treatment strategies. Clin Cancer Res; 17(14); 4751–60. ©2011 AACR.

Purpose: Functional imaging biomarkers of cancer treatment response offer the potential for early determination of outcome through the assessment of biochemical, physiologic, and microenvironmental readouts. Cell death may result in an immunologic response, thus complicating the interpretation of biomarker readouts. This study evaluated the temporal effect of treatment-associated inflammatory activity on diffusion magnetic resonance imaging and 2-[18F]-fluoro-2-deoxy-d-glucose-positron emission tomography imaging (FDG-PET) biomarkers to delineate the effects of the inflammatory response on imaging readouts. Experimental Design: Rats with intracerebral 9L gliosarcomas were separated into four groups consisting of control, an immunosuppressive agent dexamethasone (Dex), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and BCNU+Dex. Animals were imaged using diffusion-weighted magnetic resonance imaging and FDG-PET at 0, 3, and 7 days posttreatment. Results: In the BCNU- and BCNU+Dex-treated animal groups, diffusion values increased progressively over the 7-day study period to ∼23% over baseline. The FDG percentage change of standard uptake value decreased at day 3 (−30.9%) but increased over baseline levels at day 7 (+20.1%). FDG-PET of BCNU+Dex-treated animals were found to have percentage of standard uptake value reductions of −31.4% and −24.7% at days 3 and 7, respectively, following treatment. Activated macrophages were observed on day 7 in the BCNU treatment group with much fewer found in the BCNU+Dex group. Conclusions: Results revealed that treatment-associated inflammatory response following tumor therapy resulted in the accentuation of tumor diffusion response along with a corresponding increase in tumor FDG uptake due to the presence of glucose-consuming activated macrophages. The dynamics and magnitude of potential inflammatory response should be considered when interpreting imaging biomarker results. Clin Cancer Res; 16(5); 1542–52

The purpose of this study was to evaluate the diagnostic performance of MRI based T1 and relative cerebral blood volume (rCBV) maps analyzed a multi-modality voxel-based analysis referred to as multi-parametric response mapping (mPRM) for early chemoradiation response prediction in patients diagnosed with high-grade gliomas. Patients (n=23) with Grade III/IV glioma were recruited in a prospective imaging trial. Patients underwent MRI before RT, 1 and 3 weeks after RT. The MRI protocol included fluid-attenuated inversion recovery imaging (FLAIR), quantitative T1 mapping, dynamic contrast-susceptibility T2*-weighted imaging (rCBV) and contrast-enhanced T1-weighted imaging (CE-T1w). All images were co-registered to CE-T1w images acquired before RT. Following co-registration, the tumor VOIs were manually contoured either on the CE-T1w or on the FLAIR images and applied to the rCBV and T1maps. For each patient, mid-treatment time point and VOI the percentage change, PRM and mPRM techniques were used to analyze data. Briefly, PRM was performed by calculating the difference in the rCBV values of each voxel within the tumor at mid-treatment values with respective pre-treatment values. A threshold was then applied to the absolute difference of the rCBV in a voxel and all like voxels were summed to obtain tumor volume fractions that showed significantly increasing (PRMrCBV+), decreasing (PRMrCBV-), and unchanged (PRMrCBV0) rCBV values following therapy. We used the same procedure for determining the PRM of T1 maps. mPRMs maps were computed by combining both PRMs (T1 and rCBV) in a single color map. Receiver operator characteristic analysis (ROC), assessed for 12 month survival, was used to determine the optimal cutoff for each parameter. The patient population was then stratified based on the optimal cutoffs obtained from the ROC analysis. Overall survival for each parameter was determined using Kaplan-Meier curves and the log-rank test. Standard PRM, using T1or rCBV maps (specifically PRMT1+ and PRMrCBV- metrics) and percentage change methods were found to be predictive of survival only for specific time of acquisition and VOI used. It was determined that mPRMT1+/rCBV- significantly identified patients resistant to therapy irrespective of tumor volume delineation on CE-T1w or FLAIR images and the time point mid-treatment used. Our results show that mPRM improves the sensitivity of quantitative T1 and rCBV maps to predict overall patient survival. This study introduces a new approach for analyzing and combining multi-parametric MR images into a single multi-parametric response map. The mPRM metric showed promise as an early and robust imaging biomarker of treatment response in patients diagnosed with high grade gliomas. This novel approach is a very sensitive tool for analysis of multiparametric and/or multimodal data with enhanced sensitivity for early detection of therapy response. 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 4299. doi:1538-7445.AM2012-4299

Gliomas continue to be the most common form of brain malignancy in adult patients. Even with advancements in the clinical management of these patients, assessment of tumor recurrence continues to be based on late or serial changes in tumor volume as measured by CT or MRI [1; 2]. The purpose of this study was to develop and evaluate a new voxel-based method, referred as parametric response mapping (PRM), for early detection of brain tumor progression using standard MR images (FLAIR and contrast-enhanced T1-weighted). PRM results were evaluated relative to standard MRI-based criteria of clinical progression assessment in patients with Grade III/IV gliomas. Fourteen patients with grades III/IV glioma underwent MRI before and during treatment (every 2 months). MRI scans, acquired on a 1.5T or a 3T clinical scanner, consisted of fluid-attenuated inversion recovery imaging (FLAIR) and contrast-enhanced T1-weighted (CE-T1w) images. All images were spatially registered to CE-T1w pre-treatment scans and tumors were manually contoured on the T1w-Gd images. Subsequent to PRM analysis, FLAIR images were normalized to the signal using the white matter (rFLAIR). PRM, applied to the whole brain volume on rFLAIR, was performed by first generating voxel-based difference maps at each longitudinal follow-up scan using the baseline as the subtrahend. Baseline was defined as either the pre-treatment or subsequent rFLAIR image. Individual voxels were classified based on the extent of change observed in the rFLAIR difference maps. Three classifications were used: voxels with a significant increase in rFLAIR values (PRMrFLAIR+), significant decrease (PRMrFLAIR-) or statistically unchanged (PRMrFLAIR0). Disease recurrence was defined by PRM as the sum of red voxels that exceed 20% of the tumor volume as delineated on T1w-Gd. PRMrFLAIR detected tumor recurrence on average 18±3 weeks earlier than the MacDonald criteria. It was also observed that PRMrFLAIR+ found outside the tumor CE-T1w regions revealed the spatial location at which the tumor would progress on subsequent scans based on current standard progression criteria. These results show that the PRM approach provides for the early detection and spatial depiction of brain tumor progression prior to detection by currently available conventional MRI-based criteria. While further validation of PRM for detection of tumor recurrence is currently underway, the ability to detect tumor progression significantly earlier than currently possible is anticipated to have a major impact on patient care. [1] Macdonald, D. R., et al. (1990). J Clin Oncol 8(7): 1277-1280. [2] Wen, P. Y., et al. (2010). J Clin Oncol 28(11): 1963-1972. 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 452. doi:1538-7445.AM2012-452

Glioblastoma multiforme (GBM) remains a challenging malignancy due to intrinsic resistance to therapy. Pre-clinical mouse models which recapitulate the human disease provide an opportunity to identify and test novel agents that could be used alone or in combination with other systemic agents and/or radiation therapy. Here we describe the use of a genetically engineered murine GBM model [Ink4a-Arf-/- PtenloxP/loxp/ Ntv-a RCAS/PDGF(+)/Cre(+)] and functional magnetic resonance imaging (MRI) to evaluate systemic agents alone or in combination with radiation. The current standard therapy for patients bearing GBMs is Temozolomide (TMZ) combined with radiation yet recent analysis of O-6-methylguanine-DNA methyltransferase (MGMT) status in GBMs has linked unmethylated MGMT promoter with poor outcome. Thus we evaluated Gemcitabine (GEM) as a novel therapy for GBM concurrent with radiation and compared it to standard therapy. GEM, a deoxycytidine analog, is a potent radiosensitizer that demonstrates cytotoxic, anti-clonogenic, and radiosensitizing effects in GBM cell lines. Therapeutic efficacy was quantified by contrast-enhanced MRI and diffusion-weighted MRI (DW-MRI) for growth rate and tumor cellularity, respectively. Mice treated with GEM, TMZ or radiation alone showed a significant reduction in tumor volume compared to control mice as early as three days post treatment start. Both combined treatment (GEM+IR and TMZ+IR) resulted in improved effectiveness over single therapies. A significant reduction in tumor volume compared to GEM, TMZ or IR groups was observed. Furthermore, both combination therapies significantly prolonged survival compared to the other groups as early as day 7 after start of treatment. There was no significant difference between both combined treatments either in tumor growth or in survival. ADC values were found to increase immediately upon administration of GEM in both alone and combination therapies. In contrast, a gradual increase in ADC values was observed in tumors treated with IR and TMZ, both alone and in combination.GEM concurrent with radiation resulted in significant reduction in tumor volume and prolonged survival in this clinically-relevant GBM mouse model. GEM combined with radiation had the same effect GBM as compared to TMZ combined with radiation. We also demonstrated the successful implementation of an imaging biomarker surrogate (ADC) which correlated with efficacy. Ink4a-Arf-/- PtenloxP/loxP/ Ntv-a RCAS/PDGF(+)/Cre(+) mice serve as a valuable pre-clinical GBM model with the potential to identify novel therapeutics for early phase I/II testing for GBM patients. Based on these results, GEM combined with IR appears to be a suitable alternative to treat tumors that have a poor response to traditional therapies (eg. unmethylated MGMT). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5281. doi:10.1158/1538-7445.AM2011-5281

Fas-Associated protein with Death Domain (FADD) was originally reported as a pro-apoptotic adaptor molecule that mediates receptor induced apoptosis. Recent studies have revealed a potential role of FADD in NF-κB activation, embryogenesis, and cell cycle regulation and proliferation. Over-expression of FADD and its phosphorylation have been associated with the transformed phenotype in many cancers and is therefore a potential target for therapeutic intervention. In an effort to identify novel chemical entities that inhibit FADD phosphorylation, we screened an NCI diversity compound collection using a cell based assay recently developed in our laboratory for the detection of FADD-kinase activity (Khan, 2010). The screen resulted in the identification of NSC 47147 as a potent inhibitor of FADD phosphorylation. This compound was shown to be an inhibitor of CKIα, a previously described FADD kinase, with an IC50 = 1.5 µM. We demonstrate that inhibition of FADD phosphorylation by NSC 47147 results in a decrease in NF-κB activity, thereby potentially sensitizing tumor cells to chemotherapy. In support of this, treatment of lung cancer cells with NSC 47147 and cisplatin in culture as well as in a mouse xenograft model resulted in the synergistic induction of apoptosis and enhanced tumor control compared to either agent alone. These results provide evidence for the inhibition of FADD phosphorylation as a viable target for anti-cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2311. doi:10.1158/1538-7445.AM2011-2311

We assessed whether a new method of quantifying therapeutic-associated hemodynamic alterations may help to distinguish pseudoprogression from true progression in patients with high grade glioma. Patients from a prospective IRB-approved trial with high grade glioma received concurrent chemoradiation. Relative cerebral blood volume (rCBV) and blood flow (rCBF) maps were acquired prior and at week 3 mid-treatment. Pseudoprogression was defined as imaging changes 1-3 months after chemoradiation that mimic tumor progression but stabilized or improved without change in treatment or for which resection revealed radiation effects only. Clinical and conventional MR parameters, including average percent change of rCBV and CBF, were evaluated as potential predictors of pseudoprogression. Parametric response map (PRM), an innovative, voxel-by-voxel method of image analysis, was also performed. Median radiation dose was 72 Gy (range: 60-81). Of 27 patients, stable disease/partial response was noted in 13 and apparent progression in 14. Adjuvant temozolomide was continued in all patients. Pseudoprogression occurred in 6 patients. Based upon PRM analysis, a significant portion of the tumor volume had reduced rCBV (PRMrCBV) at week 3 in patients with progressive disease compared to those with pseudoprogression (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2698.

Genetically engineered mouse models combined with noninvasive functional imaging provide unique opportunities to evaluate molecularly targeted agents. To this end, we evaluated the effectiveness of targeted agents against the Ntv-a PtenloxP/loxp/Ink4a-Arf−/−RCAS/PDGF(+)/Cre(+) genetically engineered mouse glioma model. Agents targeting Akt (perifosine) and mTOR (CCI-779) were evaluated alone and in combination for their therapeutic effectiveness. Therapeutic efficacy was quantified using diffusion weighted magnetic resonance imaging (DW-MRI) and contrast-enhanced MRI to assess changes in tumor cellularity and growth rate, respectively. MRI scans were performed daily for the first week then every second day until the animals expired or become moribund in which case the animals were sacrificed. Two animals from each group were sacrificed for histological analysis of the tumors 24 hours following the final day of treatment using H&E, PCNA, pS6RP and TUNEL. Over the course of the study, CCI-779 treated animals either alone or in combination had statistically smaller tumor volumes versus controls. Tumors treated with perifosine alone were found to be statistically smaller than controls at day 5 but larger than CCI-779 alone and in combination at days 4 and 3, respectively. No difference was observed in tumor volumes between CCI-779 treatment alone or in combination. A 10-15% increase in tumor diffusion values were observed in perifosine and CCI-779 groups on days 3-6 post-treatment initiation. The combination therapy produced a 25-35% increased in tumor ADC values over this same time frame indicating that while each individual therapy provided some level of cell death, the combination was more effective. PCNA stains revealed a decrease in proliferation for perifosine treated tumors with a more profound decrease seen in CCI-779 and in the combination treatment group. Down regulation of the oncogenic signaling molecule pS6RP which is located downstream of mTOR and Ras was observed slightly for perifosine and nearly completely for the CCI-779 and combination treatment groups. Finally, TUNEL staining for the presence of apoptosis revealed slight positivity for perifosine and CCI-779, however, the combination treatment group appeared to have more TUNEL positivity than the other treatment groups. Improvement in overall survival was observed for all treatment groups versus control. Between treatments, CCI-779 and combination therapy were found to have a significant improvement in survival over perifosine. In conclusion, inhibition of mTor and Akt was found to elicit potent antitumor activity alone and were found to be more efficacious in combination. Finally, changes in tumor diffusion values as quantified using DW-MRI appeared to correlate and predict treatment effectiveness and may be useful as a molecular imaging biomarker for clinical translation of targeted agents for brain tumor trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4190.

We assessed whether quantification of therapeutic-associated tumor cellularity and hemodynamic alterations may help in the early assessment of treatment resistance in patients with high grade glioma. Patients with high grade glioma (n=45) received concurrent chemoradiation. Apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) maps were acquired prior to chemoradiation and at week 3 during treatment on a prospective IRB-approved study. Clinical and conventional MR parameters, including average baseline ADC and rCBV and radiological response, were evaluated as prognostic indicators of one-year survival. Parametric response map (PRM), an innovative, voxel-by-voxel method of image analysis, was also performed. Of 45 patients, median survival was found to be 14.9 months with 44% of patients living shorter than one year (median survival of 6.6 months). Baseline ADC was the only single model not found to be predictive of survival at one year, whereas in a multivariate analysis PRMADC+ and PRMrCBV- had a stronger correlation to survival than baseline rCBV. Overall, a composite model of PRMADC+ and PRMrCBV- was found to have the strongest correlation with one-year survival. This study demonstrates the potential of a composite parametric model sensitive to both tumor cellularity and hemodynamic alterations following first line therapy for providing an early assessment of patient resistant to chemoradiation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3754.

Introduction: Standard assessment of radiologic response in patients with malignant glioma is traditionally carried out using T1 gadolinium-enhanced MRI at approximately 10 weeks following treatment initiation. Diffusion-weighted MRI of gliomas, analyzed by the functional diffusion map (fDM), may provide an early measure of response during treatment to predict patient survival (OS). Tumor cells restrict the random diffusion of water molecules within a tumor; therefore, diffusion will increase during successful therapy. The fDM imaging biomarker is a voxel-wise method for analysis of DW-MRI data providing for quantification of treatment-associated spatial alterations in tumor diffusion values earlier than radiologic response. Methods: A prospective single-institution trial of early assessment of brain tumor response by MRI was performed early during radiation therapy. Sixty patients with high grade glioma undergoing radiation therapy were enrolled in an IRB-approved study of intra-treatment MRI 1, 3, and 10 weeks after the initiation of treatment. Receiver operating characteristic curve analysis was used to evaluate imaging parameters as a function of patient survival at one-year. Log Rank and Cox Proportional Hazards models were utilized to assess OS. Results: Measurable changes in diffusion MRI were observed as early as one week into treatment. The volume of tumor with increased diffusion as assessed by fDM 3 weeks after the start of therapy was the strongest predictor of patient survival at one year, with larger fDM predicting longer median survival [52.6 vs. 10.9 months, log-rank, P Conclusions: Compared to conventional neuro-imaging, fDM provided an earlier assessment of equal predictive value during the course of treatment, providing the opportunity to individualize therapy. The combination of fDM and RR provided a more accurate prediction of patient survival than either metric alone.