Prognosis of patients with multifocal glioblastoma: a case-control study

Patil, Chirag G.; Yi, Anthony; Elramsisy, Adam; Hu, Jethro; Mukherjee, Debraj; Irvin, Dwain K.; Yu, John S.; Bannykh, Serguei; Black, Keith L.; Nuño, Miriam A

doi:10.3171/2012.7.jns12147

Cited by 103 publications

(94 citation statements)

References 24 publications

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“…The occurrence of such multifocal lesions has been reported in up to 10% of cases of GBM at initial presentation in older studies (27)(28)(29). The more recent study of Patil et al places the incidence at 12.8% (30). However, the incidence increases fully in keeping with the predictions of our model, where, with time, more of the distant migrated cells will be able proliferation term.…”

Section: Discussionsupporting

confidence: 76%

A novel bicompartmental mathematical model of glioblastoma multiforme

Hathout

Ellingson

Cloughesy

et al. 2014

International Journal of Oncology

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Abstract. Glioblastoma multiforme (GBM) is the most common primary CNS neoplasm, and continues to have a dismal prognosis. A widely-used approach to the mathematical modeling of GBM involves utilizing a reaction-diffusion model of cell density as a function of space and time, which accounts term, and the proliferation of tumor cells using a proliferation term. The current paper extends the standard models by incorporating an advection term to account for the so-called 'cell streaming' which is often seen with GBM, where some of the tumor cells seem to stream widely along the white matter pathways. The current paper introduces a bicompartmental GBM model in the form of coupled partial differential equations with a component of dispersive cells. The parameters needed for this model are explored. It is shown that this model can account for the rapid distant dispersal of GBM cells in the CNS, as well as such phenomena as multifocal gliomas with tumor foci distant from the core tumor site. The model suggests a higher percentage of tumor cells below the threshold of MRI images in comparison to the standard model. By incorporating an advection component, the proposed model is able to account for phenomena such as multicentric gliomas and rapid distant dispersion of a small fraction of tumor cells throughout the CNS, features important to the prognosis of GBM, but not easily accounted for by current models.

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Section: Discussionsupporting

confidence: 76%

A novel bicompartmental mathematical model of glioblastoma multiforme

Hathout

Ellingson

Cloughesy

et al. 2014

International Journal of Oncology

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“…Recent evidence suggests that there are several molecular subclasses of GBM with distinct molecular signatures [11]. A recent study from Cedars-Sinai Medical Center analyzed molecular markers from both multiple lesion GBM and single focus GBM showing no expression difference in a molecular panel including phosphorylated MAPK, PTEN, MGMT, laminin β1 and β2, and EGFR amplification between the tumor types [3]. While it remains unknown as to whether any particular subclasses of GBM or specific molecular pathways may influence multifocality of GBM, clinical trials have begun to target this possibility.…”

Section: Discussionmentioning

confidence: 99%

“…These multiple focus tumors represent between 0.5 and 20 % of all GBMs diagnosed, though some more recent reports indicate a higher incidence [1–3]. The population of multiple lesion GBM has previously been subdivided into multifocal and multicentric GBM.…”

Section: Introductionmentioning

confidence: 99%

Comparison of clinical outcomes and genomic characteristics of single focus and multifocal glioblastoma

et al. 2014

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We investigate the differences in molecular signature and clinical outcomes between multiple lesion glioblastoma (GBM) and single focus GBM in the modern treatment era. Between August 2000 and May 2010, 161 patients with GBM were treated with modern radiotherapy techniques. Of this group, 33 were considered to have multiple lesion GBM (25 multifocal and 8 multicentric). Patterns of failure, time to progression and overall survival were compared based on whether the tumor was considered a single focus or multiple lesion GBM. Genomic groupings and methylation status were also investigated as a possible predictor of multifocality in a cohort of 41 patients with available tissue for analysis. There was no statistically significant difference in overall survival (p < 0.3) between the multiple lesion tumors (8.2 months) and single focus GBM (11 months). Progression free survival was superior in the single focus tumors (7.1 months) as compared to multi-focal (5.6 months, p = 0.02). For patients with single focus, multifocal and multicentric GBM, 81, 76 and 88 % of treatment failures occurred in the 60 Gy volume (p < 0.5), while 54, 72, and 38 % of treatment failures occurred in the 46 Gy volume (p < 0.4). Out of field failures were rare in both single focus and multiple foci GBM (7 vs 3 %). Genomic groupings and methylation status were not found to predict for multifocality. Patterns of failure, survival and genomic signatures for multiple lesion GBM do not appreciably differ when compared to single focus tumors.

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“…Median survival for newly diagnosed GBM is still less than 2 years (5). Even with standard-of-care therapy with chemoradiation and adjuvant temozolomide, GBM patients with significant residual disease after surgery have an average survival that is on the order of 6 months, with even poorer survival observed when the disease recurs in a multifocal fashion (1, 6). GBM tumors with un-methylated O 6 -methylguanine methyltransferase (MGMT), a DNA repair enzyme, are also more resistant to radiation and temozolomide (7, 8), making unmethylated MGMT a poor prognostic marker.…”

Section: Introductionmentioning

confidence: 99%

A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma

et al. 2017

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We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)–EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up. All patients demonstrated detectable transient expansion of CART-EGFRvIII cells in peripheral blood. Seven patients had post–CART-EGFRvIII surgical intervention, which allowed for tissue-specific analysis of CART-EGFRvIII trafficking to the tumor, phenotyping of tumor-infiltrating T cells and the tumor microenvironment in situ, and analysis of post-therapy EGFRvIII target antigen expression. Imaging findings after CART immunotherapy were complex to interpret, further reinforcing the need for pathologic sampling in infused patients. We found trafficking of CART-EGFRvIII cells to regions of active GBM, with antigen decrease in five of these seven patients. In situ evaluation of the tumor environment demonstrated increased and robust expression of inhibitory molecules and infiltration by regulatory T cells after CART-EGFRvIII infusion, compared to pre–CART-EGFRvIII infusion tumor specimens. Our initial experience with CAR T cells in recurrent GBM suggests that although intravenous infusion results in on-target activity in the brain, overcoming the adaptive changes in the local tumor microenvironment and addressing the antigen heterogeneity may improve the efficacy of EGFRvIII-directed strategies in GBM.

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Prognosis of patients with multifocal glioblastoma: a case-control study

Cited by 103 publications

References 24 publications

A novel bicompartmental mathematical model of glioblastoma multiforme

A novel bicompartmental mathematical model of glioblastoma multiforme

Comparison of clinical outcomes and genomic characteristics of single focus and multifocal glioblastoma

A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma

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