Biology subjects

Singleton, K. W.

Publications and source records attributed to Singleton, K. W..

6 recordsLinked to original sources

bioRxiv2022

Glioblastoma states are defined by cohabitating cellular populations with progression-, imaging- and sex-distinct patterns

Background: Magnetic Resonance Imaging (MRI) is the mainstay for neurosurgical oncology but not for informing us about glioma biology. An obstacle to developing MR-based glioma biomarkers is the absence of rigorous correlation between MRI features and glioma biology as assessed in multi-regional biopsies, within and across patients. Methods: We directly addressed this obstacle by collating a unique cohort of 202 MRI-localized biopsies from 58 patients. We define a low-dimensional transcriptional pseudotime continuum along which heterogeneous high-grade glioma (HGG) samples organize both within and across patients. Results: We observe three polarized transcriptional tissue states: infiltrated brain, immune/inflammatory, and proliferative associated with patterns of cohabitation of cellular subpopulations. The states and deconvolved populations show correlation with enhancement status on T1Gd MRI. Moreover, discrete MRI habitats, regions sharing common imaging features, defined as combinations of high or low signal intensity across multiparametric MRI revealed 14 MRI habitats. We order the MRI habitats according to the average pseudotime on the transcriptional continuum. We find that MRI habitats with low pseudotime (associated with early tumor development and diffusely invaded brain tissue) localized at the periphery of the tumor whilst high pseudotime either proliferative or immune/inflammatory states were towards the core of the lesion. We find that composition of MRI habitats is impacted by MGMT status. Conclusion: This suggests that ongoing aggregation of MRI-localized biopsies may augment our projection of biology onto MRI habitats to support the noninvasive identification of cellular ecologies within and across each patient's tumor.

cancer biology↗

bioRxiv2019

Days Gained Response Discriminates Treatment Response in Patients with Recurrent Glioblastoma Receiving Bevacizumab-based Therapies

PurposeAccurate assessments of patient response to therapy are a critical component of personalized medicine. In glioblastoma multiforme (GBM), the most aggressive form of brain cancer, tumor growth dynamics are heterogenous across patients, complicating assessment of treatment response. This study aimed to analyze Days Gained (DG), a burgeoning model-based dynamic metric, for response assessment in patients with recurrent GBM who received bevacizumab-based therapies.\n\nExperimental DesignDays Gained response scores were calculated using volumetric tumor segmentations for patients receiving bevacizumab with and without concurrent cytotoxic therapy (N=62). Kaplan-Meier and Cox proportional hazards analyses were implemented to examine DG prognostic relationship to overall (OS) and progression-free survival (PFS) from the onset of treatment for recurrent GBM.\n\nResultsIn patients receiving concurrent bevacizumab and cytotoxic therapy, Kaplan-Meier analysis showed significant differences in OS and PFS at previously identified DG cutoffs consistent with previous DG analyses using gadolinium-enhanced T1 weighted MR imaging. DG scores for bevacizumab monotherapy only approached significance for PFS. Cox regression showed that increases of 25 DG were significantly associated with a 12.5% reduction in OS hazard for concurrent therapy patients and a 4.4% reduction in PFS hazard for bevacizumab monotherapy.\n\nConclusionDays Gained has significant meaning in recurrent therapy as a metric of treatment response, even in the context of anti-angiogenic therapies. This provides further evidence supporting the use of DG as an adjunct response metric that quantitatively connects treatment response and clinical outcomes.

cancer biology↗

bioRxiv2019

Sex differences in seizure at presentation in glioma population

Seizures are common presenting symptoms of primary brain tumors. Mechanisms of epileptogenesis are still unknown and are believed to be multifactorial. Previous studies have indicated correlation of seizure with tumor location. Recent investigations of our group have shown image-based parameters have sex-specific implications for patient outcome. In this retrospective study, we examined the association of tumor location with the probability and risk of seizure in male and female glioma patients.

cancer biology↗

bioRxiv2019

Image-based metric of invasiveness predicts response to adjuvant temozolomide for primary glioblastoma

Temozolomide (TMZ) has been the standard-of-care chemotherapy for glioblastoma (GBM) patients for more than a decade. Despite this long time in use, significant questions remain regarding how best to optimize TMZ therapy for individual patients. Understanding the relationship between TMZ response and factors such as number of adjuvant TMZ cycles, patient age, patient sex, and image-based tumor features, might help predict which GBM patients would benefit most from TMZ, particularly for those whose tumors are not MGMT methylated. Using a cohort of 90 newly-diagnosed GBM patients treated according to the Stupp protocol, we examined the relationships between several patient and tumor characteristics and volumetric and survival outcomes during adjuvant chemotherapy. Volumetric changes in MR imaging abnormalities during adjuvant therapy were used to assess TMZ response. T1Gd volumetric response is associated with younger patient age, increased number of TMZ cycles, longer time to nadir volume, and decreased tumor invasiveness. Moreover, increased adjuvant TMZ cycles corresponded with improved volumetric response only among more nodular tumors, and this volumetric response was associated with improved survival outcomes. Finally, in a subcohort of patients with known MGMT methylation status, MGMT methylated tumors were more diffusely invasive than unmethylated tumors, suggesting that the improved response in nodular tumors is not driven by a preponderance of MGMT methylated tumors. Our finding that less diffusely invasive tumors are associated with greater volumetric response to TMZ suggests that patients with these tumors may benefit from additional cycles of adjuvant TMZ, even for those without MGMT methylation.

cell biology↗

bioRxiv2018

Days Gained: A Simulation-Based, Response Metric in the Assessment of Glioblastoma

We show the application of a minimally based, patient-specific mathematical model in the evaluation of glioblastoma response to therapy. Days Gained uses computational models of glioblastoma growth dynamics derived from clinically acquired magnetic resonance imaging (MRI) to compare the post-treatment tumor lesion to the expected untreated tumor lesion at the same time point. It accounts for the inter-patient variability in growth dynamics and response to therapy. This allows for the accurate assessment of therapeutic response and provides insight into overall survival as it relates to treatment response.

bioinformatics↗

bioRxiv2017

Clinically Important sex differences in GBM biology revealed by analysis of male and female imaging, transcriptome and survival data

Sex differences in the incidence and outcome of human disease are broadly recognized but in most cases not adequately understood to enable sex-specific approaches to treatment. Glioblastoma (GBM), the most common malignant brain tumor, provides a case in point. Despite well-established differences in incidence, and emerging indications of differences in outcome, there are few insights that distinguish male and female GBM at the molecular level, or allow specific targeting of these biological differences. Here, using a quantitative imaging-based measure of response, we found that temozolomide chemotherapy is more effective in female compared to male GBM patients. We then applied a novel computational algorithm to linked GBM transcriptome and outcome data, and identified novel sex-specific molecular subtypes of GBM in which cell cycle and integrin signaling were identified as the critical determinants of survival for male and female patients, respectively. The clinical utility of cell cycle and integrin signaling pathway signatures was further established through correlations between gene expression and in vitro chemotherapy sensitivity in a panel of male and female patient-derived GBM cell lines. Together these results suggest that greater precision in GBM molecular subtyping can be achieved through sex-specific analyses, and that improved outcome for all patients might be accomplished via tailoring treatment to sex differences in molecular mechanisms.\n\nOne Sentence SummaryMale and female glioblastoma are biologically distinct and maximal chances for cure may require sex-specific approaches to treatment.

cancer biology↗