Fluorescence-guided surgical sampling of glioblastoma identifies phenotypically distinct tumour-initiating cell populations in the tumour mass and margin

Piccirillo, Sara Grazia Maria; Dietz, Stefanie; Madhu, B; Griffiths, John R.; Price, Stephen J.; Collins, V. Peter; Watts, Colin

doi:10.1038/bjc.2012.271

Cited by 98 publications

(93 citation statements)

References 33 publications

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“…18 Higher levels of fluorescence have higher levels of ALA-induced protoporphyrin concentration and correlate strongly with increasing malignancy (histopathological score) and tissue proliferation. 2,31 To our knowledge, there are only 2 studies that have directly addressed the relationship of intraoperative ALA fluorescence intensity with degree of cellularity.…”

Section: Discussionmentioning

confidence: 99%

A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas

Lau

Hervey-Jumper

Chang

et al. 2016

JNS

141

110

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OBJECT There is evidence that 5-aminolevulinic acid (ALA) facilitates greater extent of resection and improves 6-month progression-free survival in patients with high-grade gliomas. But there remains a paucity of studies that have examined whether the intensity of ALA fluorescence correlates with tumor cellularity. Therefore, a Phase II clinical trial was undertaken to examine the correlation of intensity of ALA fluorescence with the degree of tumor cellularity. METHODS A single-center, prospective, single-arm, open-label Phase II clinical trial of ALA fluorescence-guided resection of high-grade gliomas (Grade III and IV) was held over a 43-month period (August 2010 to February 2014). ALA was administered at a dose of 20 mg/kg body weight. Intraoperative biopsies from resection cavities were collected. The biopsies were graded on a 4-point scale (0 to 3) based on ALA fluorescence intensity by the surgeon and independently based on tumor cellularity by a neuropathologist. The primary outcome of interest was the correlation of ALA fluorescence intensity to tumor cellularity. The secondary outcome of interest was ALA adverse events. Sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and Spearman correlation coefficients were calculated. RESULTS A total of 211 biopsies from 59 patients were included. Mean age was 53.3 years and 59.5% were male. The majority of biopsies were glioblastoma (GBM) (79.7%). Slightly more than half (52.5%) of all tumors were recurrent. ALA intensity of 3 correlated with presence of tumor 97.4% (PPV) of the time. However, absence of ALA fluorescence (intensity 0) correlated with the absence of tumor only 37.7% (NPV) of the time. For all tumor types, GBM, Grade III gliomas, and recurrent tumors, ALA intensity 3 correlated strongly with cellularity Grade 3; Spearman correlation coefficients (r) were 0.65, 0.66, 0.65, and 0.62, respectively. The specificity and PPV of ALA intensity 3 correlating with cellularity Grade 3 ranged from 95% to 100% and 86% to 100%, respectively. In biopsies without tumor (cellularity Grade 0), 35.4% still demonstrated ALA fluorescence. Of those biopsies, 90.9% contained abnormal brain tissue, characterized by reactive astrocytes, scattered atypical cells, or inflammation, and 8.1% had normal brain. In nonfluorescent (ALA intensity 0) biopsies, 62.3% had tumor cells present. The ALA-associated complication rate among the study cohort was 3.4%. CONCLUSIONS The PPV of utilizing the most robust ALA fluorescence intensity (lava-like orange) as a predictor of tumor presence is high. However, the NPV of utilizing the absence of fluorescence as an indicator of no tumor is poor. ALA intensity is a strong predictor for degree of tumor cellularity for the most fluorescent areas but less so for lower ALA intensities. Even in the absence of tumor cells, reactive changes may lead to ALA fluorescence.

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Section: Discussionmentioning

confidence: 99%

A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas

Lau

Hervey-Jumper

Chang

et al. 2016

JNS

141

110

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“…However, few cellular and molecular analyses have been performed in this area. Some studies have shown that residual, unresected tumor cells display alterations different from those of cells isolated from the corresponding tumor mass [12][13][14]. A better understanding of the characteristics of the PBZ and tumor cell infiltration in this region is critical to unravel the mechanisms underlying the recurrence of GB and to optimize the quality of surgical resection and the development of new therapies.…”

Section: Introductionmentioning

confidence: 98%

Characterizing the peritumoral brain zone in glioblastoma: a multidisciplinary analysis

et al. 2015

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Glioblastoma (GB) is the most frequent and aggressive type of primary brain tumor. Recurrences are mostly located at the margin of the resection cavity in the peritumoral brain zone (PBZ). Although it is widely believed that infiltrative tumor cells in this zone are responsible for GB recurrence, few studies have examined this zone. In this study, we analyzed PBZ left after surgery with a variety of techniques including radiology, histopathology, flow cytometry, genomic, transcriptomic, proteomic, and primary cell cultures. The resulting PBZ profiles were compared with those of the GB tumor zone and normal brain samples to identify characteristics specific to the PBZ. We found that tumor cell infiltration detected by standard histological analysis was present in almost one third of PBZ taken from an area that was considered normal both on standard MRI and by the neurosurgeon under an operating microscope. The panel of techniques used in this study show that the PBZ, similar to the tumor zone itself, is characterized by substantial inter-patient heterogeneity, which makes it difficult to identify representative markers. Nevertheless, we identified specific alterations in the PBZ such as the presence of selected tumor clones and stromal cells with tumorigenic and angiogenic properties. The study of GB-PBZ is a growing field of interest and this region needs to be characterized further. This will facilitate the development of new, targeted therapies for patients with GB and the development of approaches to refine the per-operative evaluation of the PBZ to optimize the surgical resection of the tumor.

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“…Therefore, it is still possible that GBM CSCs co-localize with the tumor and hence are accessible for a local therapy. This is also suggested by Piccirillo et al 112 showing the presence of cells within the tumor margin permitting high engraftment rates in vivo, so these cells appear not to enable the self-renewal of a major identi¯er of cancer stem cells.…”

Section: Discussionmentioning

confidence: 50%

Photodynamic therapy in the treatment of intracranial gliomas: A review of current practice and considerations for future clinical directions

Fisher

Lilge

2015

J. Innov. Opt. Health Sci.

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Invasive grade III and IV malignant gliomas remain di±cult to treat with a typical survival time post-diagnosis hovering around 16 months with only minor extension thereof seen in the past decade, whereas some improvements have been obtained towards¯ve-year survival rates for which completeness of resection is a prerequisite. Optical techniques such as°uorescence guided resection (FGR) and photodynamic therapy (PDT) are promising adjuvant techniques to increase the tumor volume reduction fraction. PDT has been used in combination with surgical resection or alternatively as standalone treatment strategy with some success in extending the median survival time of patients compared to surgery alone and the current standard of care. This document reviews the outcome of past clinical trials and highlights the general shift in PDT therapeutic approaches. It also looks at the current approaches for interstitial PDT and research options into increasing PDT's glioma treatment e±cacy through exploiting both physical and biological-based approaches to maximize PDT selectivity and therapeutic index, particularly in brain adjacent to tumor (BAT). Potential reasons for failing to demonstrate a signi¯cant survival advantage in prior PDT clinical trials will become evident in light of the improved understanding of glioma biology and PDT dosimetry.

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Fluorescence-guided surgical sampling of glioblastoma identifies phenotypically distinct tumour-initiating cell populations in the tumour mass and margin

Cited by 98 publications

References 33 publications

A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas

A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas

Characterizing the peritumoral brain zone in glioblastoma: a multidisciplinary analysis

Photodynamic therapy in the treatment of intracranial gliomas: A review of current practice and considerations for future clinical directions

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