Search Results (6)

Tumor cells gain advantages in growth and survival by acquiring genotypic and phenotypic heterogeneity. Interactions with bystander cells in the tumor microenvironment contribute to the progression of heterogeneity. We have shown that fusion between tumor and bystander cells is one form of interaction, and that tumor–bystander cell fusion has contrasting effects. By trapping fusion hybrids in the heterokaryon or synkaryon state, tumor–bystander cell fusion prevents the progression of heterogeneity. However, if trapping fails, fusion hybrids will resume replication to form derivative clones with diverse genomic makeups and behavioral phenotypes. To determine the characteristics of bystander cells that influence the fate of fusion hybrids, we co-cultured prostate mesenchymal stromal cell lines and their spontaneously transformed sublines with LNCaP as well as HPE-15 prostate cancer cells. Subclones derived from cancer–stromal fusion hybrids were examined for genotypic and phenotypic diversifications. Both stromal cell lines were capable of fusing with cancer cells, but only fusion hybrids with the transformed stromal subline generated large numbers of derivative subclones. Each subclone had distinct cell morphologies and growth behaviors and was detected with complete genomic hybridization. The health conditions of the bystander cell compartment play a crucial role in the progression of tumor cell heterogeneity. Full article

Unlike medulloblastoma (MB) in children, robust prospective trials have not taken place for older patients due to the low incidence of MB in adults and adolescent and young adults (AYA). Current MB treatment paradigms for older patients have been extrapolated from the pediatric experience even though questions exist about the applicability of these approaches. Clinical and molecular classification of MB now provides better prognostication and is being incorporated in pediatric therapeutic trials. It has been established that genomic alterations leading to activation of the sonic hedgehog (SHH) pathway occur in approximately 60% of MB in patients over the age of 16 years. Within this cohort, protein patched homolog (PTCH) and smoothened (SMO) mutations are commonly found. Among patients whose tumors harbor the SHH molecular signature, it is estimated that over 80% of patients could respond to SHH pathway inhibitors. Given the advances in the understanding of molecular subgroups and the lack of robust clinical data for adult/AYA MB, the Alliance for Clinical Trial in Oncology group developed the AMBUSH trial: Comprehensive Management of AYA and Adult Patients with Medulloblastoma or Pineal Embryonal Tumors with a Randomized Placebo Controlled Phase II Focusing on Sonic Hedgehog Pathway Inhibition in SHH Subgroup Patients (Adult & Adolescent MedulloBlastoma Using Sonic Hedgehog Trial). This trial will enroll patients 18 years of age or older with MB (any molecular subgroup and risk stratification) or pineal embryonal tumor. Patients will be assigned to one of three cohorts: (1) average risk non-SHH-MB, (2) average risk SHH-MB, and (3) high risk MB or pineal embryonal tumors. All patients will receive protocol-directed comprehensive treatment with radiation therapy and chemotherapy. Patients with SHH-MB in cohort 1 will be randomized to a smoothened inhibitor or placebo as maintenance therapy for one year. Full article

We have previously characterized the reproducibility of brain tumor relative cerebral blood volume (rCBV) using a dynamic susceptibility contrast magnetic resonance imaging digital reference object across 12 sites using a range of imaging protocols and software platforms. As expected, reproducibility was highest when imaging protocols and software were consistent, but decreased when they were variable. Our goal in this study was to determine the impact of rCBV reproducibility for tumor grade and treatment response classification. We found that varying imaging protocols and software platforms produced a range of optimal thresholds for both tumor grading and treatment response, but the performance of these thresholds was similar. These findings further underscore the importance of standardizing acquisition and analysis protocols across sites and software benchmarking. Full article

The use of rCBV as a response metric in clinical trials has been hampered, in part, due to variations in the biomarker consistency and associated interpretation across sites, stemming from differences in image acquisition and post-processing methods. This study leveraged a dynamic susceptibility contrast magnetic resonance imaging digital reference object to characterize rCBV consistency across 12 sites participating in the Quantitative Imaging Network (QIN), specifically focusing on differences in site-specific imaging protocols (IPs; n = 17), and PMs (n = 19) and differences due to site-specific IPs and PMs (n = 25). Thus, high agreement across sites occurs when 1 managing center processes rCBV despite slight variations in the IP. This result is most likely supported by current initiatives to standardize IPs. However, marked intersite disagreement was observed when site-specific software was applied for rCBV measurements. This study's results have important implications for comparing rCBV values across sites and trials, where variability in PMs could confound the comparison of therapeutic effectiveness and/or any attempts to establish thresholds for categorical response to therapy. To overcome these challenges and ensure the successful use of rCBV as a clinical trial biomarker, we recommend the establishment of qualifying and validating site- and trial-specific criteria for scanners and acquisition methods (eg, using a validated phantom) and the software tools used for dynamic susceptibility contrast magnetic resonance imaging analysis (eg, using a digital reference object where the ground truth is known). Full article

With DSC-MRI, contrast agent leakage effects in brain tumors can either be leveraged for percent signal recovery (PSR) measurements or be adequately resolved for accurate relative cerebral blood volume (rCBV) measurements. Leakage effects can be dimished by administration of a preload dose before imaging and/or specific postprocessing steps. This study compares the consistency of both PSR and rCBV measurements as a function of varying preload doses in a retrospective analysis of 14 subjects with high-grade gliomas. The scans consisted of 6 DSC-MRI scans during 6 sequential bolus injections (0.05 mmol/kg). Mean PSR was calculated for tumor and normal-appearing white matter regions of interest. DSC-MRI data were corrected for leakage effects before computing mean tumor rCBV. Statistical differences were seen across varying preloads for tumor PSR (P value = 4.57E-24). Tumor rCBV values did not exhibit statistically significant differences across preloads (P value = .14) and were found to be highly consistent for clinically relevant preloads (intraclass correlation coefficient = 0.93). For a 0.05 mmol/kg injection bolus and pulse sequence parameters used, the highest PSR contrast between normal-appearing white matter and tumor occurs when no preload is used. This suggests that studies using PSR as a biomarker should acquire DSC-MRI data without preload. The finding that leakage-corrected rCBV values do not depend on the presence or dose of preload contradicts that of previous studies with dissimilar acquisition protocols. This further confirms the sensitivity of rCBV to preload dosing schemes and pulse sequence parameters and highlights the importance of standardization efforts for achieving multisite rCBV consistency. Full article

Relative cerebral blood volume (rCBV) is a magnetic resonance imaging biomarker that is used to differentiate progression from pseudoprogression in patients with glioblastoma multiforme, the most common primary brain tumor. However, calculated rCBV depends considerably on the software used. Automating all steps required for rCBV calculation is important, as user interaction can lead to increased variability and possible inaccuracies in clinical decision-making. Here, we present an automated tool for computing rCBV from dynamic susceptibility contrast-magnetic resonance imaging that includes leakage correction. The entrance and exit bolus time points are automatically calculated using wavelet-based detection. The proposed tool is compared with 3 Food and Drug Administration-approved software packages, 1 automatic and 2 requiring user interaction, on a data set of 43 patients. We also evaluate manual and automated white matter (WM) selection for normalization of the cerebral blood volume maps. Our system showed good agreement with 2 of the 3 software packages. The intraclass correlation coefficient for all comparisons between the same software operated by different people was >0.880, except for FuncTool when operated by user 1 versus user 2. Little variability in agreement between software tools was observed when using different WM selection techniques. Our algorithm for automatic rCBV calculation with leakage correction and automated WM selection agrees well with 2 out of the 3 FDA-approved software packages. Full article