Microvesicles as a Biomarker for Tumor Progression versus Treatment Effect in Radiation/Temozolomide-Treated Glioblastoma Patients

Koch, Cameron J.; Lustig, Robert A.; Yang, Xiang-Yang; Jenkins, W. Timothy; Wolf, Ronald L.; Martinez‐Lage, Maria; Desai, Arati; Williams, Dewight; Evans, Sydney M.

doi:10.1016/j.tranon.2014.10.004

Cited by 46 publications

(53 citation statements)

References 29 publications

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“…Table 1 summarizes the demographics of the 16 newly diagnosed GB patients, their clinical and tumor findings, and their treatments. A subset of these patients was included in the previous report on MV number where we assessed the ability of MV to differentiate true progression from pseudoprogression (treatment effect) [15]. Data on the number of MV in normal volunteers was also included in that report.…”

Section: Methodsmentioning

confidence: 99%

“…The technical aspects of blood processing have been previously described [15]. Briefly, 0.9 mL blood was added to 0.1 mL of filtered Caltag A and allowed to sit at room temperature for 60 min.…”

Section: Methodsmentioning

confidence: 99%

“…The methods for preparation, running and analysis of flow cytometry of the HSP have been previously described [15]. Briefly, samples were thawed at 37 °C and gently vortexed.…”

Section: Methodsmentioning

confidence: 99%

“…Our recent published work showed that the mean number of Annexin V 1 positive (AnnV+) ECV > 300 nm diameter differs between GB patients treated with the Stupp protocol who go on to experience pseudoprogression versus true progression [15]. Herein, we describe an association between an increase in the number of AnnV + MV in the blood during chemoradiation therapy (CRT) and poor patient outcome.…”

Section: Introductionmentioning

confidence: 97%

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Initial evidence that blood-borne microvesicles are biomarkers for recurrence and survival in newly diagnosed glioblastoma patients

et al. 2016

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The purpose of this pilot study was to determine whether blood-borne microvesicles from newly diagnosed glioblastoma patients could be used as biomarkers. We collected 2.8 mL blood from 16 post-operative patients at the time that they were being simulated for chemoradiation therapy (radiation with concurrent temozolomide). Two additional samples were collected during chemoradiation therapy and a final sample was collected at the end of chemoradiation therapy. Patients continued with the therapy suggested by their physicians, based on tumor conference consensus and were followed for recurrence and overall survival. Microvesicles were isolated using serial centrifugation and stained for surface markers (Annexin V for phosphotidyl serine, CD41 for platelets, anti-EGFR for tumor cells, and CD235 for red blood cells). Flow cytometry analysis was performed. Our findings provide initial evidence that increases in Annexin V positive microvesicle levels during chemoradiation therapy are associated with earlier recurrence and shorter overall survival in newly diagnosed glioblastoma patients. The effect is dramatic, with over a four-fold increase in the hazard ratio for an individual at the 75th versus the 25th percentile. Moreover the pattern of Annexin V positive microvesicles remain significant after adjustment for confounding clinical variables that have previously been shown to be prognostic for recurrence and survival. Inclusion of neutrophil levels at the start of chemoradiation therapy in the model yielded the largest attenuation of the observed association. Further studies will be needed to verify and further investigate the association between these two entities.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The methods for preparation, running and analysis of flow cytometry of the HSP have been previously described [15]. Briefly, samples were thawed at 37 °C and gently vortexed.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Initial evidence that blood-borne microvesicles are biomarkers for recurrence and survival in newly diagnosed glioblastoma patients

et al. 2016

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“…Recent data indicate a function for Wnt exovesicles in cell-cell communication in tumorigenic tissues (Koch et al, 2014;Luga and Wrana, 2013;Menck et al, 2013). Thus, although Wnt proteins can be mobilized on exovesicles in healthy and diseased tissues, it is unclear whether this mode of transport contributes to the formation of a signaling gradient.…”

Section: Advances In Understanding Of Wnt Protein Transportmentioning

confidence: 99%

Role of cytonemes in Wnt transport

Stanganello

Scholpp

2016

Journal of Cell Science

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Wnt signaling regulates a broad variety of processes during embryonic development and disease. A hallmark of the Wnt signaling pathway is the formation of concentration gradients by Wnt proteins across responsive tissues, which determines cell fate in invertebrates and vertebrates. To fulfill its paracrine function, trafficking of the Wnt morphogen from an origin cell to a recipient cell must be tightly regulated. A variety of models have been proposed to explain the extracellular transport of these lipid-modified signaling proteins in the aqueous extracellular space; however, there is still considerable debate with regard to which mechanisms allow the precise distribution of ligand in order to generate a morphogenetic gradient within growing tissue. Recent evidence suggests that Wnt proteins are distributed along signaling filopodia during vertebrate and invertebrate embryogenesis. Cytoneme-mediated transport has profound impact on our understanding of how Wnt signaling propagates through tissues and allows the formation of a precise ligand distribution in the recipient tissue during embryonic growth. In this Commentary, we review extracellular trafficking mechanisms for Wnt proteins and discuss the growing evidence of cytoneme-based Wnt distribution in development and stem cell biology. We will also discuss their implication for Wnt signaling in the formation of the Wnt morphogenetic gradient during tissue patterning.

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Liquid Biopsy Strategies to Distinguish Progression from Pseudoprogression and Radiation Necrosis in Glioblastomas

et al. 2020

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despite aggressive treatment. [1] Currently, maximal resection followed by radiation therapy with concurrent temozolomide (TMZ) and adjuvant TMZ treatment is the standard of care. Post-treatment surveillance involves serial MRI. A challenge faced by clinicians is the diagnosis and management of a gadolinium enhancing lesion on a follow-up MRI post-treatment. This suspicious lesion could be progressive disease (PD) or a mere post-treatment radiation effects such as pseudoprogression or radiation necrosis (RN). Pseudoprogression and RN are distinct clinical entities, which when identified and managed appropriately result in better outcomes, while PD of the tumor is often dismal. Patients with PD have a median survival of 3-6 months, [2] and there is no standard of care. Systemic options include TMZ rechallenge, lomustine, and antiangiogenic therapy such as bevacizumab, but their effectiveness is limited. Reradiation and reresection can be considered depending on the location of the tumor and the condition of the patient. [3] Conversely, antiangiogenic drugs like bevacizumab or cediranib decrease contrast enhancement by altering permeability of tumor vasculature without actual reduction in tumor burden, referred to as pseudoresponse. Distinguishing these clinical entities from PD is crucial to avoid unnecessary reoperations, premature discontinuation of adjuvant TMZ or its substitution with second line agents. MR imaging based monitoring is the current standard of care for post-surgical monitoring. Contrast enhancement on imaging is indicative of disrupted blood brain barrier (BBB), but not tumor presence. [4] Currently, MRI-based Response Assessment in Neuro-Oncology (RANO) criteria is used to monitor treatment response in GBM patients. The criteria included T1 gadolinium enhancing disease, T2/FLAIR changes, new lesions, corticosteroid use, and clinical status. [5] Adoption of RANO criteria for monitoring response is not without limitations. There is ambiguity in identifying radiation effects, enrolling patients into clinical trials and monitoring immunotherapy response. [6] Advanced imaging modalities including diffusion-tensor imaging, perfusion imaging, MR spectroscopy (MRS), and positron emission tomography (PET) imaging Liquid biopsy for the detection and monitoring of central nervous system tumors is of significant clinical interest. At initial diagnosis, the majority of patients with central nervous system tumors undergo magnetic resonance imaging (MRI), followed by invasive brain biopsy to determine the molecular diagnosis of the WHO 2016 classification paradigm. Despite the importance of MRI for long-term treatment monitoring, in the majority of patients who receive chemoradiation therapy for glioblastoma, it can be challenging to distinguish between radiation treatment effects including pseudoprogression, radiation necrosis, and recurrent/progressive disease based on imaging alone. Tissue biopsy-based monitoring is high risk and not always feasible. However, distinguishing these entities is of critical im...

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Microvesicles as a Biomarker for Tumor Progression versus Treatment Effect in Radiation/Temozolomide-Treated Glioblastoma Patients

Cited by 46 publications

References 29 publications

Initial evidence that blood-borne microvesicles are biomarkers for recurrence and survival in newly diagnosed glioblastoma patients

Initial evidence that blood-borne microvesicles are biomarkers for recurrence and survival in newly diagnosed glioblastoma patients

Role of cytonemes in Wnt transport

Liquid Biopsy Strategies to Distinguish Progression from Pseudoprogression and Radiation Necrosis in Glioblastomas

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