Surgical Resection Of Glioblastoma Research Articles

Surgical resection of glioblastoma in the very elderly: An analysis of survival outcomes using the surveillance, epidemiology, and end results database

ObjectivePatients with glioblastoma (GBM) often undergo surgery to prolong survival. However, the use of surgery, and more specifically achieving gross total resection (GTR), in patients >80 years old has yet to be fully assessed. Using the Surveillance, Epidemiology, and End Results (SEER) database, we aim to assess the efficacy of surgical resection, radiotherapy (RT) and chemotherapy (CT) on overall survival (OS) in very elderly GBM patients compared to elderly counterparts (age 65–79 years). MethodsThe SEER database was queried for all patients >65 years old with GBM (2000–2020). Patients not undergoing surgery or biopsy were excluded. Patients were stratified by age, and demographic relationships were assessed with chi-squared testing for categorical variables. Bivariable models were created using Kaplan-Meier survival estimates. All significant variables from bivariable analysis were included on multivariable Cox survival regression models to determine independent associations between clinical variables and OS. ResultsA total of 27,090 operative GBM patients were identified; 1868 patients (15.92 %) were very elderly and 10,092 patients (84.38 %) were elderly. Very elderly patients were less likely to undergo GTR (28 % vs 35 %, p<0.001), RT (59 % vs 78 %, p<0.001) and CT (40 % vs 66 %, p<0.001). In multivariable Cox regression analysis, very elderly patients who achieved GTR (HR=.696, p<0.001), received RT (HR=0.583, p<0.001) and underwent CT (HR=0.4197, p<0.001) had significantly improved OS compared to very elderly patients that did not undergo these treatment options. ConclusionCurrently, very elderly GBM patients undergo lower rates of aggressive surgery, RT and CT. However, very elderly patients that undergo surgery, RT and CT may have a survival advantage. These treatments should be considered as potential options for this patient population.

Prognostic value of surgical resection over biopsy in elderly patients with glioblastoma: a meta-analysis.

Maximal-safe resection has been shown to improve overall survival in elderly patients with glioblastoma in observational studies, however, the only clinical trial comparing resection versus biopsy in elderly patients with surgically-accessible glioblastoma showed no improvements in overall survival. A meta-analysis is needed to assess whether surgical resection of glioblastoma in older patients improves surgical outcomes when compared to biopsy alone. A search was conducted until October 9th, 2023, to identify published studies reporting the clinical outcomes of glioblastoma patients > 65 years undergoing resection or biopsy (PubMed, MEDLINE, EMBASE, and COCHRANE). Primary outcomes were overall survival (OS), progression-free survival (PFS), and complications. We analyzed mean difference (MD) and hazard ratio (HR) for survival outcomes. Postoperative complications were analyzed as a dichotomic categorical variable with risk ratio (RR). From 784 articles, 20 cohort studies and 1 randomized controlled trial met our inclusion criteria, considering 20,523 patients for analysis. Patients undergoing surgical resection had an overall survival MD of 6.13 months (CI 95%=2.43-9.82, p = < 0.001) with a HR of 0.43 (95% CI = 0.35-0.52, p = < 0.00001). The progression-free survival MD was 2.34 months (95%CI = 0.79-3.89, p = 0.003) with a 0.50h favoring resection (95%CI = 0.37-0.68, p = < 0.00001). The complication RR was higher in the resection group favoring biopsy (1.49, 95%CI = 1.06-2.10). Our meta-analysis suggests that upfront resection is associated with improved overall survival and progression-free survival in elderly patients with newly diagnosed glioblastoma over biopsy. However, postoperative complications are more common with resection. Future clinical trials are essential to provide more robust evaluation in this challenging patient population.

Treatment Strategies for Glioblastoma in the Elderly: What Should We Focus on Compared to Younger Patients.

(1) Background: Although the incidence of glioblastoma (GB) has a peak in patients aged 75-84 years, no standard treatment regimen for elderly patients has been established so far. The goal of this study was to analyze the outcome of GB patients ≥ 65 years to detect predictors with relevant impacts on overall survival (OS) and progression-free survival (PFS). (2) Methods: Medical records referred to our institution from 2006 to 2020 were analyzed. Adult GB patients with clinical data, postoperative MRI data, and ≥1 follow-up investigation after surgical resection were included. The complete cohort was divided into a younger (<65) and an elderly group (≥65 years). Multiple factors regarding OS and PFS were scanned using univariate and multivariable regression with p < 0.05. (3) Results: 1004 patients were included with 322 (61.0%) male individuals in the younger and 267 (56.1%) males in the older cohort. The most common tumor localization was frontal in both groups. Gross total resection (GTR) was the most common surgical procedure in both groups, followed by subtotal resection (STR) (145; 27.5%) in the younger group, and biopsy (156; 32.8%) in the elderly group. Multivariate analyses detected that in the younger cohort, MGMT promoter methylation and GTR were predictors for a longer OS, while MGMT methylation, GTR, and hypofractionated radiation were significantly associated with a longer OS in the elderly group. (4) Conclusions: Elderly patients benefit from surgical resection of GB when they show MGMT promoter methylation, undergo GTR, and receive hypofractionated radiation. Furthermore, MGMT methylation seems to be associated with a longer PFS in elderly patients. Further investigations are required to confirm these findings, especially within prospective radiation therapy studies and molecular examinations.

Postoperative disappearance of leptomeningeal enhancement around the brainstem in glioblastoma.

Leptomeningeal enhancement (LME) suggests leptomeningeal dissemination (LMD) of tumor cells, which is a complication of end-stage glioblastoma, and is associated with a poor prognosis. However, magnetic resonance imaging (MRI) occasionally indicates the disappearance of peri-brainstem LME after surgical resection of glioblastoma. Since preoperative LMD may affect treatment indications, we aimed to analyze the clinical significance of preoperative LME of the brainstem in glioblastoma. We retrospectively collected clinical and radiological data from consecutive patients with glioblastoma and preoperative LME of the brainstem, who were treated at our hospital between 2017 and 2020. Among 112 patients with glioblastoma, nine (8%) showed preoperative LME of the brainstem. In comparison with tumors without LME, tumor size was significantly associated with the preoperative LME of the brainstem (p = 0.016). In addition, there was a trend toward significance for a relationship between deep tumor location and preoperative LME of the brainstem (p = 0.058). Notably, among six patients who underwent surgical resection for glioblastoma with LME of the brainstem, four showed significant radiological disappearance of the LME on postoperative MRI. This suggests that the LME did not result from LMD in these cases. Moreover, these four patients lived longer than would be expected from the presence of LMD. However, this LME disappearance was not observed after biopsy or chemoradiotherapy. These findings suggest that preoperative LME does not necessarily indicate the presence of untreatable LMD; moreover, LME may disappear after surgical tumor resection. Thus, transient preoperative LME could be attributed to other mechanisms, including impaired venous flow due to intratumoral arteriovenous shunts, which can be resolved by reducing the tumor burden.

10077-NI-4 POSTOPERATIVE DISAPPEARANCE OF LEPTOMENINGEAL ENHANCEMENT AROUND THE BRAINSTEM IN GLIOBLASTOMA

Abstract BACKGROUND AND PURPOSE Leptomeningeal enhancement (LME) suggests leptomeningeal dissemination (LMD) of tumor cells, which is an end-stage glioblastoma complication associated with a poor prognosis. However, magnetic resonance imaging (MRI) occasionally indicates the disappearance of peri-brainstem LME after surgical resection of glioblastoma. Since preoperative LMD may affect treatment indication, we aimed to analyze the clinical significance of preoperative LME of the brainstem on glioblastoma, focusing on imaging examinations and patient outcomes. METHODS We retrospectively collected clinical and radiological data obtained from consecutive patients with glioblastoma and preoperative LME of the brainstem, who were treated at our hospital between 2017 and 2020. RESULTS AND CONCLUSIONS Among 112 patients with glioblastoma, nine (8%) showed preoperative LME of the brainstem. Tumors with LME were relatively large (median size, 59 cm; range, 47-83 cm) and frequently located in the temporal lobe (temporal lobe: n = 4, 44%; frontal lobe: n = 1; parietal lobe: n = 2; corpus callosum: n = 2). Notably, among six patients who underwent surgical resection for glioblastoma with peri-brainstem LME, four showed significant radiological disappearance of the LME on postoperative MRI. This suggests that the LME did not result from LMD in these cases. Moreover, these four patients lived longer than would be expected from the presence of LMD. This LME disappearance was not observed after biopsy or chemoradiotherapy. These findings suggest that preoperative LME does not necessarily indicate the presence of untreatable LMD; moreover, LME may disappear after surgical tumor resection. Thus, transient preoperative LME could be attributed to other mechanisms, including impaired venous flow due to intratumoral arteriovenous shunts, which can be resolved by reducing the tumor burden.

Clinical course of ventriculoperitoneal shunting for hydrocephalus following glioblastoma surgery: a systematic review and meta-analysis.

Surgical resection of glioblastoma (GBM) remains a cornerstone in the current treatment paradigm. The postoperative evolution of hydrocephalus necessitating ventriculoperitoneal shunting (VPS) continues to be defined. Correspondingly the objective of this study was to aggregate pertinent metadata to better define the clinical course of VPS for hydrocephalus following glioblastoma surgery in light of contemporary management. Searches of multiple electronic databases from inception to November 2023 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. Outcomes were pooled by random-effects meta-analyses where possible. A total of 12 cohort studies satisfied all selection criteria, describing a total of 6,098 glioblastoma patients after surgery with a total of 261 (4%) of patients requiring postoperative VPS for hydrocephalus. Meta-analysis demonstrated the estimated pooled rate of symptomatic improvement following VPS was 78% (95% CI 66-88), and the estimated pooled rate of VPS revision was 24% (95% CI 16-33). Pooled time from index glioblastoma surgery to VPS surgery was 4.1 months (95% CI 2.8-5.3), and pooled survival time for index VPS surgery was 7.3 months (95% CI 5.4-9.4). Certainty of these outcomes were limited by the heterogenous and palliative nature of postoperative glioblastoma management. Of the limited proportion of glioblastoma patients requiring VPS surgery for hydrocephalus after index surgery, 78% patients are expected to show symptom improvement, and 24% can expect to undergo revision surgery. An individualized approach to each patient is required to optimize both index glioblastoma and VPS surgeries to account for anatomy and goals of care given the poor prognosis of this tumor overall.

Inflammatory responsive neutrophil-like membrane-based drug delivery system for post-surgical glioblastoma therapy

Surgical resection of glioblastoma (GBM) causes brain inflammation that activates and recruits neutrophils (NEs) to residual GBM tissues. NE-based drug delivery using inflammatory chemotaxis is promising for the post-surgical treatment of residual GBM, but its clinical application is limited by the short life span of NEs and lack of in vitro propagation methods. HL60 cells are a type of infinitely multiplying tumor cells that can be induced to differentiate into NE-like cells. We developed a novel NE-like membrane system (NM-PD) by coating NE-like membranes on the surface of poly (lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG)-based doxorubicin (DOX)-loaded core (PLGA-PEG-DOX, PD) for post-surgical residual GBM treatment. Cell adhesion proteins were detected on NE-like membranes and endowed NM-PDs with inflammatory chemotaxis similar to mature NEs. The resulting NM-PD shows excellent inflamed in vitro blood-brain barrier (BBB) permeability and anti-proliferative effects on GBM cells. In our intracranial GBM resection model, NM-PD exhibited superior inflammatory chemotaxis and targeted residual GBM cells, thus remarkably improving antitumor capability and prolonging the survival time of the mice. These data suggest that NM-PD, which has sufficient sources and is easy to prepare, can efficiently suppress post-surgical residual GBM and holds potential for clinical transformation in GBM post-surgical adjuvant therapy.

Surgical resection of glioblastoma in basal ganglia and utility of exoscope: Technical case reports.

Due to the presence of many perforating arteries and the deep location of basal ganglia tumors, dissection of the perforating arteries is critical during tumor resection. However, this is challenging as these arteries are deeply embedded in the cerebrum. Surgeons need to bend their heads for a long time using operative microscope and it is uncomfortable for the operating surgeon. A high-definition (4K-HD) 3D exoscope system can significantly improve the surgeon's posture during resection and widen the operating view field considerably by adjusting the camera angle. We report two cases of glioblastoma (GBM) involving basal ganglia. We used a 4K-HD 3D exoscope system for resecting the tumor and analyzed the intraoperative visualization of the operative fields. We could approach the deeply located feeding arteries before successfully resecting the tumor using a 4K-HD 3D exoscope system which would have been difficult with the sole use of an operative microscope. The postoperative recoveries were uneventful in both cases. However, postoperative magnetic resonance imaging showed infarction around the caudate head and corona radiata in one of the cases. This study has highlighted using a 4K-HD 3D exoscope system in dissecting GBM involving basal ganglia. Although postoperative infarction is a risk, we could successfully visualize and dissect the tumors with minimal neurological deficits.

Immunostimulant In Situ Fibrin Gel for Post-operative Glioblastoma Treatment by Macrophage Reprogramming and Photo-Chemo-Immunotherapy.

Tumor recurrence remains the leading cause of treatment failure following surgical resection of glioblastoma (GBM). M2-like tumor-associated macrophages (TAMs) infiltrating the tumor tissue promote tumor progression and seriously impair the efficacy of chemotherapy and immunotherapy. In addition, designing drugs capable of crossing the blood-brain barrier and eliciting the applicable organic response is an ambitious challenge. Here, we propose an injectable nanoparticle-hydrogel system that uses doxorubicin (DOX)-loaded mesoporous polydopamine (MPDA) nanoparticles encapsulated in M1 macrophage-derived nanovesicles (M1NVs) as effectors and fibrin hydrogels as in situ delivery vehicles. In vivo fluorescence imaging shows that the hydrogel system triggers photo-chemo-immunotherapy to destroy remaining tumor cells when delivered to the tumor cavity of a model of subtotal GBM resection. Concomitantly, the result of flow cytometry indicated that M1NVs comprehensively improved the immune microenvironment by reprogramming M2-like TAMs to M1-like TAMs. This hydrogel system combined with a near-infrared laser effectively promoted the continuous infiltration of T cells, restored T cell effector function, inhibited the infiltration of myeloid-derived suppressor cells and regulatory T cells, and thereby exhibited a strong antitumor immune response and significantly inhibited tumor growth. Hence, MPDA-DOX-NVs@Gel (MD-NVs@Gel) presents a unique clinical strategy for the treatment of GBM recurrence.

Immunostimulant In Situ Hydrogel Improves Synergetic Radioimmunotherapy of Malignant Glioblastoma Relapse Post‐Resection

AbstractTumor recurrence remains the major cause of management failure after surgical resection of glioblastoma (GBM). Immunotherapy has the potential to effectively eradicate tumors and trigger immune memory to prevent tumor recurrence but not improve the outcomes of GBM patients. Here, an injectable, reactive oxygen species‐degradable therapeutic hydrogel (ADU‐AAV‐PD1@Gel), capable of sustained local release of soluble PD‐1 (sPD‐1) and stimulator of interferon gene (STING) agonist ADU‐S100 (ADU), is developed and applied in a GBM surgical resection model. Adeno‐associated virus serotype 9 is employed to stably express sPD‐1 blocking the PD‐1/PD‐L1 pathway. Concomitantly, the released ADU activates the STING pathway to improve tumor immunogenicity and response to therapy. This therapeutic hydrogel combined with radiotherapy (RT) effectively promotes sustained T cells infiltration and restores T cells effector function, which exhibits a robust antitumor immune response and significantly suppresses tumor growth. Moreover, ADU‐AAV‐PD1@Gel combined with RT treatment can also induce a long‐term immune memory to prevent GBM recurrence. As a result, ADU‐AAV‐PD1@Gel provides a novel strategy for effective radioimmunotherapy of GBM relapse post‐resection.

Abstract 904: Neural stem cells of the subventricular zone evolve into tumors around the resection cavity after surgical resection of glioblastoma via the CXCL12/CXCR4 axis

Abstract Glioblastoma multiforme (GBM) is the most common lethal primary brain tumor. Neural stem cells (NSCs) harboring cancer-driving mutations in the subventricular zone (SVZ) have recently been reported as the cells of origin for human glioblastoma (GBM) through migration. However, the pathological role of residual tumor-initiating NSCs (tNSCs) in the SVZ is undetermined for local recurrent tumor after surgical removal of the primary tumor. After the primary resection of GBM, most recurrences still appear as local tumors around the resection cavity (RC). Accordingly, we hypothesized that, after complete removal of the primary tumor, the tNSCs in SVZ might be the source for tumor construction at RC. Here, we examined the role of tNSCs in the development of local tumors around RC using a mouse model and genetic analysis of human tissues. First, cancer-driving mutations, including Trp53, Pten, and Egfr mutations, were introduced to NSCs in SVZ through in vivo electroporation, and the RC was generated in the remote cortex through stereotaxic resection. We found that the NSCs harboring driver mutations migrated specifically to the RC through the aberrant growth of oligodendrocyte-precursor cells (OPCs). Furthermore, the SVZ-originated cells constituted the GBM around the RC at four weeks post-resection in 64% of mouse models. Second, we performed deep sequencing of longitudinal matched tissues consisting of (i) normal SVZ away from the tumor, (ii) primary tumor, (iii) recurrent tumor, and (iv) blood in the patients with GBM, IDH wildtype. We found that the dominant clones of recurrent tumors genetically arose from the SVZ, not directly from the primary tumor. Third, the CXCR4/CXCL12 axis was upregulated through migration from the SVZ and tumor formation at the RC compared with primary tumors without the RC in mouse models. Blockage of the CXCR4/CXCL12 axis decreased the number of immigrating OPC lineage cells specifically and improved tumor control and survival rates. Taken together, our results reveal that the residual tNCSs harboring cancer-driving mutations in the SVZ can re-construct tumors after surgical resection of GBM. Blocking CXCL12/CXCR4 might be a potential treatment strategy for preventing the main local failures after resection. Citation Format: Xue Li, Hyun Jung Kim, Jeong Ho Lee, Hong-Gyun Wu, Joo Ho Lee. Neural stem cells of the subventricular zone evolve into tumors around the resection cavity after surgical resection of glioblastoma via the CXCL12/CXCR4 axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 904.

The potentiality of arterial spins labeling (ASL) magnetic resonance perfusion technique for the diagnosis of glioblastoma residual tissue

Background: Growing glioblastoma is associated with an impairment of the blood brain barrier and increased hemodynamic parameters (CBV, CBF), which is related to advanced tumor angiogenesis. Arterial spin labeling (ASL) perfusion, an additional study to the routine intravenous contrast-enhanced magnetic resonance imaging (MRI), may be a technique for assessment of hemodynamics and identification of the residual tumor tissue.Aim: To study the potential of native ASL to assess hemodynamic parameters and detect residual tumor tissue in the patients who had undergone surgical resection of glioblastoma.Materials and methods: At 2 to 4 weeks after surgery for glioblastoma grade IV, brain MRI with native ASL perfusion and subsequent intravenous contrast enhancement was performed in 63 patients. Cerebral blood flow (CBF) values were measured in three areas of interest: in the presumptive tumor tissue (PTT) with maximal perfusion, in the postoperative scar tissue (PST) and in the deep white matter (DWM) of the contralateral hemisphere.Results: According to their CBF values, all patients were categorized into two groups. Group 1 included 43 patients (68.3%) with mean CBF in PTT of 135.4±41.3 ml/100 Gr/min (min 73.9, max 255.9). These values were 5 to 6-fold higher than the CBF values in the PST and 6 to 8-fold higher than those in DWM. Group 2 included 20 patients (31.7%) without any areas of abnormal CBF increase in PST, with its mean value of 22.1±5.6 ml/100 Gr/min (min 13.9, max 37.1), which was close to the CBF level in DWM (19.8±4.6 ml/100 Gr/min, p=0.06). There were no between-group differences for the CBF values in PST (p=0.6), and DWM (p=0.7).Conclusion: ASL MR perfusion technique has good potential for the identification of residual tumor tissue after surgical resection of glioblastoma and can be an alternative to contrast enhancement during long-term follow up.

UPAR targeted phototheranostic metal-organic framework nanoprobes for MR/NIR-II imaging-guided therapy and surgical resection of glioblastoma

Glioblastoma (GBM) is the most malignant brain tumor. Owing to its highly infiltrative nature and restrictive blood-brain tumor barrier (BBTB), the current treatment strategies, including surgery and the following chemoradiotherapy, offer very low efficacy. Therefore, it is highly desirable to develop novel multifunctional theranostic agents for visualized diagnosis and treatment of GBM. In this work, a phototheranostic nanoprobe (CH4T@MOF-PEG-AE), constructed of Fe-based metal-organic framework (MOF) nanoparticles loaded with a small-molecule near-infrared II (NIR-II) fluorophore (CH4T), is rationally designed and modified with tumor-targeting AE105 peptide for efficiently targeting the over-expressed urokinase Plasminogen Activator Receptor (uPAR) on GBM. The nanoplatform combines advantages of high penetration depth of magnetic resonance (MR) imaging with high detection sensitivity and spatiotemporal resolution of NIR-II fluorescence imaging, enabling it to diagnose and delineate GBM accurately. Besides, in vivo studies reveal that CH4T@MOF-PEG-AE can realize MR/NIR-II imaging-guided photothermal therapy (PTT), achieving successful ablation of U87MG tumors. More importantly, the nanoprobes can efficiently transport across the BBTB facilitated by active tumor-targeting and enrich in the orthotopic GBM tumors, being capable of guiding the surgical resection of GBM via real-time intraoperative NIR-II imaging. Our work provides new insights into developing theranostic nanoplatforms for efficient diagnosis and treatment of GBM.

Optimal timing of chemoradiotherapy after surgical resection of glioblastoma: Stratification by validated prognostic classification.

Previous studies examining the time to initiate chemoradiation (CRT) after surgical resection of glioblastoma have been conflicting. To better define the effect that the timing of adjuvant treatment may have on outcomes, the authors examined patients within the National Cancer Database (NCDB) stratified by a validated prognostic classification system. Patients with glioblastoma in the NCDB who underwent surgery and CRT from 2004 through 2013 were analyzed. Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class (III, IV, V) was extrapolated for the cohort. Time intervals were grouped weekly, with weeks 4 to 5 serving as the reference category for analyses. Kaplan-Meier analysis, log-rank testing, and multivariate (MVA) Cox proportional hazards regression were performed. In total, 30,414 patients were included. RPA classes III, IV, and V contained 5250, 20,855, and 4309 patients, respectively. On MVA, no time point after week 5 was associated with a change in overall survival for the entire cohort or for any RPA class subgroup. The periods of weeks 0 to 1 (hazard ratio [HR], 1.18; 95% CI, 1.02-1.36), >1 to 2 (HR, 1.23; 95% CI, 1.16-1.31), and >2 to 3 (HR, 1.11; 95% CI, 1.07-1.15) demonstrated slightly worse overall survival (all P<.03). The detriment to early initiation was consistent across each RPA class subgroup. The current data provide insight into the optimal timing of CRT in patients with glioblastoma and describe RPA class-specific outcomes. In general, short delays beyond 5weeks did not negatively affect outcomes, whereas early initiation before 3weeks may be detrimental.

Radiomics in peritumoral non-enhancing regions: fractional anisotropy and cerebral blood volume improve prediction of local progression and overall survival in patients with glioblastoma.

The peritumoral non-enhancing region (NER) is frequently not removed during the surgical resection of glioblastoma, with most recurrences occurring within the original treatment field. This study determined whether radiomics analysis of the NER can predict local recurrence and overall survival in patients with glioblastoma. Preoperative magnetic resonance imaging (MRI) scans from 83 consecutive patients with glioblastoma were retrospectively reviewed and grouped into training (n = 59) and test sets (n = 24). A total of 6472 radiomic features were extracted from contrast-enhanced T1-weighted and fluid-attenuated inversion recovery images and from fractional anisotropy (FA) and normalized cerebral blood volume (CBV) maps. A diagnostic model to predict 6-month progression was tested using the area under the receiver operating characteristics curve (AUC) and compared with the single parameters of FA and CBV. A survival model was tested using Harrell's C-index and compared with clinical models that included age, sex, Karnofsky performance score, and extent of surgical resection. Four FA features and six CBV features were selected for the diagnostic model; no features were extracted from conventional MRI. Combined FA and CBV radiomics showed better predictive value for local progression (AUC, 0.79; 95% CI, 0.67-0.90) than single imaging radiomics (AUC, 0.70-0.76) or single imaging parameters (AUC, 0.51-0.54). The combined model (C-index, 0.87) improved prognostication when added to clinical models (C-index, 0.72). Radiomics features using FA and CBV in the NER have the potential to improve prediction of local progression and overall survival in patients with glioblastoma.

INtraoperative photoDYnamic Therapy for GliOblastomas (INDYGO): Study Protocol for a Phase I Clinical Trial.

Glioblastoma (GBM) is characterized by marked proliferation, major infiltration, and poor prognosis. Despite current treatments, including surgery, radiation oncology, and chemotherapy, the overall median survival is 15 mo and the progression-free survival is 7 to 8 mo. Because of systematic relapse of the tumor, the improvement of local control remains an issue. In this context, photodynamic therapy (PDT) may offer a new treatment modality for GBM. To assess the feasibility of intraoperative PDT early after surgical resection of GBM without unacceptable and unexpected toxicities. The INDYGO clinical trial (INtraoperative photoDYnamic Therapy for GliOblastomas) treatment will be carried out in addition to the current standard of care (SOC) of glioblastoma: maximum resection surgery followed by concomitant radio-chemotherapy and adjuvant chemotherapy. PDT treatment will be delivered during surgery early, after the fluorescence-guided resection. Immunological responses and biomarkers will also be investigated during the follow-up. A total of 10 patients will be recruited during this study. Clinical follow-up after the SOC with PDT is expected to be similar (no significant difference) to the SOC alone. This INDYGO trial assesses the feasibility of intraoperative 5-aminolevulinic acid PDT, a novel seamless approach to treat GBM. The technology is easily embeddable within the reference treatment at a low-incremental cost. The safety of this new treatment modality is a preliminary requirement before a multicenter randomized clinical trial can be further conducted to assess local control improvement by treating infiltrating and nonresected GBM cells.

Using the arterial spins labeling method (ASL-perfusion) for evaluation of glioblastoma residual tissue

Objective. To evaluate the efficiency of ASL-perfusion as a method of estimating of hemodynamics and detection of residual tumor tissue after surgical treatment of glioblastoma.Material and methods. 56 patients after brain tumor’s surgical resection of glioblastoma (GRADE IV). CBF values were determined in 3 different areas - in the presumed tumor tissue with maximum perfusion, in the postoperative scar tissue and in the deep white matter of the opposite hemisphere. All patients were divided into 2 groups according to CBF value.Results. 1st group: 38 (67.9%) patients - the average CBF in suspected tumor was 137.6±35.2 (79.6-227.6) ml/100 g/min. It was 6-8 times higher than CBF in the deep white matter of the opposite hemisphere, and 5-6 times higher than in the postoperative scars.2nd group: 18 (32.1%) patients with no pathological elevation of CBF in postoperative scar tissue. CBF there was 22.3±5.9 (13.9-37.1) ml/100 g/min. CBF in white matter in the contralateral hemisphere was similar.There was no significant differences in CBF of scar tissue (p=0,52) and in white matter of contralateral hemisphere (p=0,96) in both groups.Conclusion. The possibilities of ASL-perfusion are enough to estimating of hemodynamics and detection of residual tumor tissue after surgical removed glioblastoma.

Abstract 1933: A novel small molecule inhibitor of MRCK shows utility in blocking radiation induced invasion of glioblastoma cells in vitro and in vivo

Abstract Myotonic dystrophy kinase-related CDC42-binding kinases MRCKα and MRCKβ regulate actin-myosin contractility and are members of the AGC family of serine/threonine kinases. MRCKs are closely related to the Rho-regulated ROCK kinases, which is reflected in their shared abilities to phosphorylate a similar set of substrates, including myosin II light chain proteins (MLC) and myosin phosphatase target subunit 1 (MYPT1). However, MRCK and ROCK may phosphorylate these substrates at different subcellular localisations leading to diverging effects on cell invasion and migration. Glioblastoma (GBM) is an aggressive and incurable primary brain tumor. Patients are treated with surgery, radiotherapy and chemotherapy but prognosis remains poor, with a median survival of 15 months. Complete surgical resection of GBM is difficult because these tumours are frequently invasive. Recent research has indicated that, while radiotherapy extends life expectancy of patients, it can provoke a more infiltrative phenotype in those GBM cells that survive treatment. We have developed potent and selective small molecule MRCK inhibitors exemplified by BDP-9066, which inhibits pMLC in a selective cellular assay with an EC50 28.3 nM, whilst displaying high selectivity over ROCK1 where the EC50 10.6 µM. This compound, and others in the series, have been used in numerous cellular assay systems to demonstrate that MRCK inhibition suppresses the invasion and migration of cancer cells including, breast, skin SCC and glioblastoma. We have used BDP-9066 to demonstrate that MRCK inhibition is effective at perturbing radiation-induced migration of GBM cells in culture at concentrations that block phosphorylation of MLC. Using a clinically relevant intracranial mouse model that recapitulates key histological features of the disease, we have shown that BDP-9066 inhibits the invasion of G7 GBM cells into the contralateral hemisphere of the brain. These experiments highlight the potential utility of MRCK inhibition in the treatment of GBM in patients. Citation Format: Heather J. McKinnon, Joanna Birch, Laura McDonald, Mairi Sime, Daniel Croft, Diane Crighton, Martin Drysdale, Lesley Gilmore, Christopher Gray, Jennifer Konczal, Duncan McArthur, Patricia McConnell, Mokdad Mezna, Alexander Schuettelkopf, Karen Strathdee, Justin Bower, Michael F. Olson, Anthony J. Chalmers. A novel small molecule inhibitor of MRCK shows utility in blocking radiation induced invasion of glioblastoma cells in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1933.

Abstract 1869: Improved image-guided surgical resection of glioblastoma with [18F]-fluoroethyltyrosine Cerenkov luminescence imaging

Abstract The ability of a surgeon to completely resect a tumor is directly related to outcome in high- and low-grade gliomas. However current intraoperative navigational tools are useful only in a subset of glioma patients and do not detect the full extent of disease. We modelled orthotopic brain tumors by stereotactically implanting human U87, rat F98 and C6 glioblastoma cells into the forebrains of rats. We show here that a new hybrid PET-Cerenkov luminescence imaging approach using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) can accurately delineate tumor margins pre- and intra-operatively. We demonstrate consistency in the successful localisation and quantification of tumor burden using PET and Cerenkov luminescence imaging. The Cerenkov signal in individual tumors was directly proportional to the signal detected in corresponding FET PET scans (y = 1.06x - 0.01; R2 = 0.98; p &amp;lt; 0.0001) and subsequent autoradiography indicated equivalence between modalities. Cerenkov luminescence was better able to discriminate tumor from healthy brain tissue than the current ‘gold standard’ for intraoperative mapping, 5-ALA (5-aminolevulinic acid), indicated by a greater area under the ROC curve in human xenograft (0.968 ± 0.003 vs. 0.893 ± 0.019; p = 0.003) and syngeneic rat glioma models (0.970 ± 0.010 vs. 0.774 ± 0.046; p = 0.006). The quantitative accuracy of Cerenkov luminescence enabled us to determine a threshold of 2.1 x 102 p-1 sec-1 cm-2 sr-1 MBq-1 that separated U87 human glioblastoma and normal brain tissue, more precisely guiding tumor excision than 5-ALA. At the optimal threshold the specificity for detecting syngeneic rat and human xenograft gliomas was better with FET Cerenkov than 5-ALA (91.1 ± 2.7 % vs. 67.2 ± 5.2 %; p = 0.007 and 91.2 ± 1.0 % vs. 82.9 ± 1.8 %; p = 0.005 respectively). We confirmed and extended these findings at higher spatial resolution on cryosections using FET autoradiography and 5-ALA confocal microscopy, with FET demonstrating higher specificity and sensitivity for tumor detection than 5-ALA. FET PET-Cerenkov luminescence imaging has the potential for guiding resections in a much broader range of glioma patients than current approaches. Previous clinical experience with FET offers a facile route for clinical translation of this technology. Citation Format: David Y. Lewis, Richard Mair, Alan J. Wright, Kieren Allinson, Scott K. Lyons, Tom Booth, Robert Bielik, Dmitry Soloviev, Kevin M. Brindle. Improved image-guided surgical resection of glioblastoma with [18F]-fluoroethyltyrosine Cerenkov luminescence imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1869. doi:10.1158/1538-7445.AM2017-1869

PCN45 - In-Hospital Mortality and Complications Following Surgical Resection of Glioblastoma

PCN45 - In-Hospital Mortality and Complications Following Surgical Resection of Glioblastoma