scholarly journals CTNI-42. FIRST-IN-HUMAN FLUORESCENCE GUIDED SURGERY OF HIGH-GRADE GLIOMAS USING PANITUMUMAB-IRDYE800

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii51-ii52
Author(s):  
Quan Zhou ◽  
Nynke van den Berg ◽  
Naoki Nishio ◽  
Guolan Lu ◽  
Stefania Chirita ◽  
...  
Keyword(s):  
Near Infrared ◽  
Human Study ◽  
Closed Field ◽  
Normal Brain ◽  
High Grade ◽  
Viable Tumor ◽  
Flat Dose ◽  
Tumor Tissues ◽  
High Grade Gliomas ◽  
Brain Tissues

Abstract INTRODUCTION High-grade gliomas (HGGs) are malignant brain tumors with devastating prognosis. Extent of resection predicts survival in patients, but current neuroimaging approaches lack tumor specificity. The epidermal growth factor receptor (EGFR) is a biomarker heterogeneously expressed in HGGs. We assessed the feasibility of imaging HGGs using a near-infrared fluorescent anti-EGFR antibody. METHODS Nine patients with contrast enhancing HGGs on presurgical MRI scan were systemically infused with a flat dose of either 50mg (n = 4) or 100mg (n = 5) panitumumab-IRDye800, 1–5 days before surgery. Near-infrared fluorescence imaging of tumor and histologically normal brain tissues was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratio (TBR) were calculated by comparing MFIs of tumor and histologically uninvolved tissue. Immunohistopathological staining of EGFR was performed on formalin fixed paraffin embedded tissue sections. RESULTS Both MFI and TBR were positively correlated to panitumumab-IRDye800 dose per body weight (R2 = 0.59 and 0.07, P < 0.0001 and P = 0.046 respectively). The TBR was higher at a 100 mg dose than at 50 mg (2.1 vs. 1.5). The smallest detectable tumor volume in a closed-field setting was 21 mg with 50 mg of dye and 12 mg with 100 mg. On sections of paraffin embedded tissues, positive EGFR protein expression was observed in 88.9% ± 12.4% of tumor tissues and positively correlated with fluorescence. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (93%) and specific (81%) for viable tumor tissues while normal brain tissues showed minimal fluorescence. No adverse events related to the imaging probe was observed. CONCLUSION This first-in-human study demonstrates the feasibility and safety of antibody based imaging for contrast enhancing high-grade gliomas.

Survival and Failure Patterns of High-Grade Gliomas After Three-Dimensional Conformal Radiotherapy

2002 ◽  
Vol 20 (6) ◽  
pp. 1635-1642 ◽  
Author(s):  
June L. Chan ◽  
Susan W. Lee ◽  
Benedick A. Fraass ◽  
Daniel P. Normolle ◽  
Harry S. Greenberg ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Three Dimensional ◽  
Conformal Radiotherapy ◽  
High Dose ◽  
Normal Brain ◽  
High Grade ◽  
Significant Treatment ◽  
Failure Patterns ◽  
High Grade Gliomas ◽  
Three Dimensional Conformal Radiotherapy

PURPOSE: The goal of three-dimensional (3-D) conformal radiation is to increase the dose delivered to tumor while minimizing dose to surrounding normal brain. Previously it has been shown that even escalated doses of 70 to 80 Gy have failure patterns that are predominantly local. This article describes the failure patterns and survival seen with high-grade gliomas given 90 Gy using a 3-D conformal intensity-modulated radiation technique. PATIENTS AND METHODS: From April 1996 to April 1999, 34 patients with supratentorial high-grade gliomas were treated to 90 Gy. For those that recurred, failure patterns were defined in terms of percentage of recurrent tumor located within the high-dose region. Recurrences with more than 95% of their volume within the high-dose region were considered central; those with 80% to 95%, 20% to 80%, and less than 20% were considered in-field, marginal, and distant, respectively. RESULTS: The median age was 55 years, and median follow-up was 11.7 months. At time of analysis, 23 (67.6%) of 34 patients had developed radiographic evidence of recurrence. The patterns of failure were 18 (78%) of 23 central, three (13%) of 23 in-field, two (9%) of 23 marginal, and zero (0%) of 23 distant. The median survival was 11.7 months, with 1-year survival of 47.1% and 2-year survival of 12.9%. No significant treatment toxicities were observed. CONCLUSION: Despite dose escalation to 90 Gy, the predominant failure pattern in high-grade gliomas remains local. This suggests that close margins used in highly conformal treatments do not increase the risk of marginal or distant recurrences. Our results indicate that intensification of local radiotherapy with dose escalation is feasible and deserves further evaluation for high-grade gliomas.

scholarly journals EXTH-41. A NANOPARTICLE-BASED CANCER-SELECTIVE GENE TRANSFER STRATEGY FOR LOCALIZED THERAPY OF MALIGNANT HIGH GRADE GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi90-vi91
Author(s):  
Divya Rao ◽  
Ashish Phal ◽  
Varun Naga ◽  
Karina Negron ◽  
Yumin Oh ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Cancer Cells ◽  
Transgene Expression ◽  
Human Cancer ◽  
High Grade ◽  
Cmv Promoter ◽  
Survivin Promoter ◽  
Dna Nanoparticles ◽  
Tumor Tissues ◽  
High Grade Gliomas

Abstract Treatment for malignant high grade gliomas entails surgery, followed by chemotherapy and/or radiation. Despite the intensive care, there is a ~90% recurrence rate. This is attributed to suboptimal efficacy of treatments in tackling widespread cancer cells. We have previously developed nanoparticles that provide widespread therapeutic distribution both in healthy and tumor tissues, but are incapable of differentiating between them. This limitation applies to the current standard-of-care and state-of-the-art gene therapies. Here, we evaluate the efficacy of DNA nanoparticles carrying promoters that drive transgene expression specifically in tumor cells to achieve widespread yet cancer-selective gene transfer in high grade gliomas. To identify tumor-specific promoters, we used ELISA to confirm elevated expression of proteins previously reported to be upregulated in tumor tissue. We observed that expression of survivin in cancer cells was significantly greater than that of other cancer-rich proteins, exhibiting two orders of magnitude greater levels in rodent and human cancer cells compared to their respective healthy cells. Furthermore, the CMV promoter mediated similarly high expression in healthy cells, whereas the level achieved by the survivin promoter was significantly lower, if not negligible, suggesting its tumor specificity. Likewise, CMV-driven plasmids delivered into the brain by the nanoparticles mediated virtually identical volumetric distribution of transgene expression in both normal and tumor tissues in vivo. In contrast, nanoparticles carrying survivin-driven plasmids provided widespread transgene expression only in an orthotopically established tumor, but not healthy brain tissue. Additionally, we demonstrate therapeutic efficacy in an established brain tumor model using the DNA nanoparticles carrying survivin promoter-driven plasmids expressing a therapeutic protein. We identified survivin promoter as a lead TSP and confirmed its ability to mediate highly efficient and widespread but cancer-selective transgene expression with the aid of our nanoparticles uniquely designed to penetrate in healthy and tumor tissues.

scholarly journals Multiparameter quantitative histological MRI values in high-grade gliomas: a potential biomarker of tumor progression

2020 ◽  
Vol 7 (6) ◽  
pp. 646-655
Author(s):  
Gilles Reuter ◽  
Emilie Lommers ◽  
Evelyne Balteau ◽  
Jessica Simon ◽  
Christophe Phillips ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Relaxation Rate ◽  
Proton Density ◽  
Normal Brain ◽  
Transverse Relaxation Rate ◽  
High Grade ◽  
Conventional Mri ◽  
Initial Surgery ◽  
Potential Biomarker ◽  
High Grade Gliomas

Abstract Background Conventional MRI poorly distinguishes brain parenchyma microscopically invaded by high-grade gliomas (HGGs) from the normal brain. By contrast, quantitative histological MRI (hMRI) measures brain microstructure in terms of physical MR parameters influenced by histochemical tissue composition. We aimed to determine the relationship between hMRI parameters in the area surrounding the surgical cavity and the presence of HGG recurrence. Methods Patients were scanned after surgery with an hMRI multiparameter protocol that allowed for estimations of longitudinal relaxation rate (R1) = 1/T1, effective transverse relaxation rate (R2)*=1/T2*, magnetization transfer saturation (MTsat), and proton density. The initial perioperative zone (IPZ) was segmented on the postoperative MRI. Once recurrence appeared on conventional MRI, the area of relapsing disease was delineated (extension zone, EZ). Conventional MRI showing recurrence and hMRI were coregistered, allowing for the extraction of parameters R1, R2*, MTsat, and PD in 3 areas: the overlap area between the IPZ and EZ (OZ), the peritumoral brain zone, PBZ (PBZ = IPZ – OZ), and the area of recurrence (RZ = EZ – OZ). Results Thirty-one patients with HGG who underwent gross-total resection were enrolled. MTsat and R1 were the most strongly associated with tumor progression. MTsat was significantly lower in the OZ and RZ, compared to PBZ. R1 was significantly lower in RZ compared to PBZ. PD was significantly higher in OZ compared to PBZ, and R2* was higher in OZ compared to PBZ or RZ. These changes were detected 4 to 120 weeks before recurrence recognition on conventional MRI. Conclusions HGG recurrence was associated with hMRI parameters’ variation after initial surgery, weeks to months before overt recurrence.

scholarly journals Second window ICG predicts postoperative MRI gadolinium enhancement in high grade gliomas and brain metastases

2022 ◽  
Vol 6 (1) ◽  
pp. V8
Keyword(s):  
Brain Metastases ◽  
Near Infrared ◽  
Prospective Trial ◽  
High Grade ◽  
Gadolinium Enhancement ◽  
Postoperative Mri ◽  
Nir Imaging ◽  
Residual Neoplasm ◽  
High Grade Gliomas ◽  
Higher Sensitivity

A prospective trial evaluating the utility of second window indocyanine green (SWIG) in predicting postoperative MRI gadolinium enhancement was performed on high-grade gliomas (HGGs) and brain metastases. Compared to white light alone, SWIG demonstrated a higher sensitivity, negative predictive value, and accuracy in predicting residual neoplasm on MRI. The specificity of SWIG for predicting MRI enhancement was higher in HGGs than brain metastases. Clinically, near-infrared (NIR) imaging was better able to predict tumor recurrence than postoperative MRI. These results illustrate how SWIG is able to take advantage of gadolinium-like distribution properties to extravasate into the tumor microenvironment, enabling guidance in surgical resection. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21204

scholarly journals A retrospective comparison of intensity-modulated arc therapy and 3-dimensional conformal approaches in the planning of grade 3 gliomas

2018 ◽  
Vol 17 (3) ◽  
pp. 266-273
Author(s):  
Lubna Sheazadi ◽  
Robert Appleyard ◽  
Natalie Foley ◽  
Bernadette Foran
Keyword(s):  
Optic Chiasm ◽  
Rank Test ◽  
Normal Brain ◽  
High Grade ◽  
Optic Chiasma ◽  
Dose Volume Histograms ◽  
Intensity Modulated ◽  
Arc Therapy ◽  
High Grade Gliomas ◽  
Grade 3

AbstractPurposeTo evaluate the extent to which intensity-modulated arc therapy (IMAT) for high-grade gliomas is comparable with three-dimensional conformal radiotherapy (3DCRT) in relation to the dose delivered to normal brain tissue (NBT), planning target volume (PTV) conformity and the dose delivered to brainstem and optic chiasma.MethodA total of 16 randomly selected 3DCRT treatment plans of grade 3 gliomas were re-planned using an IMAT planning technique and dose–volume histograms were compared. Primary outcomes were maximum, mean, 1/3 and 2/3 doses to NBT outside the PTV. Also the maximum, mean, D50 and D20 doses to PTV. Secondary outcomes were maximum and mean doses to the brainstem and optic chiasm. Wilcoxon signed rank test was used to compare data.ResultsIMAT led to a statistically significant increase in mean dose to NBT (34·4 versus 33·3 Gy, (p=0·047) but a statistically significant reduction in maximum dose to NBT (62·7 versus 63·8 Gy, p=0·004) compared with 3DCRT. IMAT led to statistically significant reductions in maximum, D50 and D20 doses to the PTV (63·3 versus 64·7 Gy, p=0·001; 60·0 versus 60·7 Gy, p=0·001 and 60·5 versus 61·8 Gy, p=0·002, respectively). No statistically significant differences were seen in doses to brainstem and optic chiasm.ConclusionIMAT is at least comparable with 3DCRT in relation to minimising dose to NBT and ensuring good PTV conformity. Doses delivered to organs at risk using IMAT were also comparable with 3DCRT. This study supports the continued use of IMAT for the treatment of high-grade gliomas.

Nivolumab combined with hypofractionated stereotactic irradiation (HFSRT) for patients with recurrent high grade gliomas: A phase I trial (NCT02829931).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2084-TPS2084 ◽  
Author(s):  
Solmaz Sahebjam ◽  
Peter A. J. Forsyth ◽  
John Arrington ◽  
Nam D. Tran ◽  
Michael Vishal Jaglal ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Maximum Diameter ◽  
Imaging Biomarkers ◽  
High Grade ◽  
Who Grade ◽  
Flat Dose ◽  
High Grade Gliomas ◽  
Who Grade Iii ◽  
Grade Iii

TPS2084 Background: Nivolumab is an IgG4 monoclonal antibody that targets the PD-1 immune checkpoint pathway and prevents binding of PD-1 with PD-L1 and PD-L2. Expression of PD-1 and PD-L1 is found in the microenvironment of high grade gliomas and correlates with worse outcome providing a rationale for investigating nivolumab in this group of patients (pts) with very limited treatment options. Nivolumab monotherapy is well tolerated in recurrent glioblastoma pts. Preclinical studies have demonstrated that radiotherapy synergizes with anti PD-1/PD-L1 blockade and produces tumor regression and long-term survival in orthotopic murine models of glioma. This report describes an ongoing phase I trial of nivolumab in combination with HFSRT in pts with recurrent WHO grade III or IV gliomas. Methods: This phase I study includes a safety cohort of 6 pts followed by dose expansion cohort of 20 pts (NCT02829931). Pts with bevacizumab naïve recurrent WHO grade III or IV gliomas (maximum diameter of enhancing brain lesion ≤ 4 cm) are eligible. An interval of at least 6 months after the end of prior radiation therapy is required unless there is a new recurrence outside of the previous radiotherapy treatment field. Eligible patients will be treated with HFSRT to the recurrent tumor (30 Gy delivered in 5 fractions). Nivolumab will be started 5 days after HFSRT. It will be administered intravenously every 2 weeks (at 240 mg flat dose) for 4 months. After 4 months, nivolumab will be administered every 4 weeks at 480 mg flat dose. The primary study objectives are to determine safety and tolerability of nivolumab administered in combination with HFSRT to recurrent high grade gliomas. Secondary endpoints include determination of the preliminary antitumor activity (response rate, 6-months survival and 9-months survival rates), and exploring tissue and imaging biomarkers. Study Progress: At deadline for abstract submission, 5 patients have been treated on this study. Clinical trial information: NCT02829931.

scholarly journals Mechanisms of Glioma Invasion: Role of Matrix-Metalloproteinases

1997 ◽  
Vol 24 (1) ◽  
pp. 3-15 ◽  
Author(s):  
J.H. Uhm ◽  
N.P. Dooley ◽  
J.-G. Villemure ◽  
V.W. Yong
Keyword(s):  
Stromal Cells ◽  
Matrix Proteins ◽  
Normal Brain ◽  
High Grade ◽  
Cellular Mechanisms ◽  
Glioma Invasion ◽  
Kinase C ◽  
High Grade Gliomas ◽  
Peripheral Origin

ABSTRACT:One of the most lethal properties of high grade gliomas is their ability to invade the surrounding normal brain tissue, as infiltrated cells often escape surgical resection and inevitably lead to tumour recurrence. The consequent poor prognosis and survival rate underscore the need to further understand and target the cellular mechanisms that underly tumour invasiveness. Proteases which degrade the surrounding stromal cells and extracellular matrix proteins have been demonstrated to be critical effectors of invasion for tumours of both central and peripheral origin. Within the nervous system, the role of metalloproteinases as well as other classes of proteases in mediating the invasive phenotype of high grade gliomas has been an intense area of research. We present in this article a review of this literature and address the possibility that these proteases and the biochemical pathways that regulate their expression, such as protein kinase C, may represent potential targets in the therapy of high grade gliomas.

scholarly journals Peritumoral Microenvironment in High-Grade Gliomas: From FLAIRectomy to Microglia–Glioma Cross-Talk

2021 ◽  
Vol 11 (2) ◽  
pp. 200
Author(s):  
Roberto Altieri ◽  
Davide Barbagallo ◽  
Francesco Certo ◽  
Giuseppe Broggi ◽  
Marco Ragusa ◽  
...  
Keyword(s):  
Cross Talk ◽  
Near Infrared ◽  
Biologically Active ◽  
High Grade ◽  
Microglia Polarization ◽  
M1 Phenotype ◽  
High Grade Gliomas ◽  
Patient’S Outcome ◽  
Tumor Edge

Cellular composition and molecular signatures of the glioma core compared with infiltrative margins are different, and it is well known that the tumor edge is enriched in microglia. In this review of the literature, we summarize the role of the peritumoral area in high-grade gliomas (HGGs) from surgical and biological points of view. There is evidence on the dual role of microglia in HGGs—a scavenger-tumoricidal role when microglia are activated in an M1 phenotype and a role favoring tumor growth and infiltration/migration when microglia are activated in an M2 phenotype. Microglia polarization is mediated by complex pathways involving cross-talk with glioma cells. In this scenario, extracellular vesicles and their miRNA cargo seem to play a central role. The switch to a specific phenotype correlates with prognosis and the pathological assessment of a specific microglial setting can predict a patient’s outcome. Some authors have designed an engineered microglial cell as a biologically active vehicle for the delivery of intraoperative near-infrared fluorescent dye with the aim of helping surgeons detect peritumoral infiltrated areas during resection. Furthermore, the pharmacological modulation of microglia-glioma cross-talk paves the way to more effective therapies.

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