Malignant Glioma Surgery Research Articles

Awake Surgery for Right Frontal Lobe Glioma: Preserving Emotional Recognition and Facilitating Early Return to Work.

Many glioma patients struggle to return to work after surgery because of higher brain dysfunction. Although the right frontal lobe has historically been considered functionally silent, reports of performing awake surgery to evaluate higher brain functions in patients with tumors in this area have increased. We present two cases of patients who underwent awake surgery for malignant glioma in the right frontal lobe to preserve emotional recognition and facilitate an early return to work. Case 1 was a 48-year-old right-handed woman employed as a nursery school teacher and case 2 was a 21-year-old right-handed man employed in sales. Both had contrast-enhancing right frontal lobe tumors exhibiting high signal intensity on fluid attenuated inversion recovery imaging and underwent awake surgery. During the operation, cortical mapping was performed using the Reading the Mind in the Eyes, calculation, and motor tasks. Resection of sites involved in motor and emotional recognition functions was avoided. In case 1, all regions of high signal intensity were completely resected; in case 2, all regions exhibiting enhancement were resected. Both patients were discharged home without neurological deficits and returned to work within 21 days after surgery. It may be important to focus not only on overall survival and progression-free survival in glioma patients, but also on factors associated with life satisfaction, such as time to return to work after surgery and time until work becomes difficult. Awake surgery aimed at preserving higher brain functions is useful and may also improve life satisfaction.

Survival Analysis of Patients Undergoing Intraoperative Contrast-enhanced Ultrasound in the Surgical Treatment of Malignant Glioma.

Complete resection of malignant gliomas is often challenging. Our previous study indicated that intraoperative contrast-enhanced ultrasound (ICEUS) could aid in the detection of residual tumor remnants and the total removal of brain lesions. This study aimed to investigate the survival rates of patients undergoing resection with or without the use of ICEUS and to assess the impact of ICEUS on the prognosis of patients with malignant glioma. A total of 64 patients diagnosed with malignant glioma (WHO grade HI and IV) who underwent surgery between 2012 and 2018 were included. Among them, 29 patients received ICEUS. The effects of ICEUS on overall survival (OS) and progression-free survival (PFS) of patients were evaluated. A quantitative analysis was performed to compare ICEUS parameters between gliomas and the surrounding tissues. The ICEUS group showed better survival rates both in OS and PFS than the control group. The univariate analysis revealed that age, pathology and ICEUS were significant prognostic factors for PFS, with only age being a significant prognostic factor for OS. In multivariate analysis, age and ICEUS were significant prognostic factors for both OS and PFS. The quantitative analysis showed that the intensity and transit time of microbubbles reaching the tumors were significantly different from those of microbubbles reaching the surrounding tissue. ICEUS facilitates the identification of residual tumors. Age and ICEUS are prognostic factors for malignant glioma surgery, and use of ICEUS offers a better prognosis for patients with malignant glioma.

P.111 5-ALA guided surgical resection of newly diagnosed high grade gliomas at Health Sciences North (HSN) in Sudbury, Ontario

Background: Since its approval by Health Canada in 2020, several neurosurgical centres across Canada have used 5-ALA, an oral drug that assists with surgical resection of malignant gliomas by causing tumour cells to fluoresce under the microscope. The study’s objective is to prospectively evaluate the extent of resection (EOR) and clinical outcomes in 5-ALA-guided surgery at HSN compared to historical controls. Methods: A retrospective analysis was performed of patients with malignant gliomas having undergone surgery at HSN from 2011 to December 2020, assessing the EOR (contrast-enhanced tumour on post-operative CT/MRI), progression-free survival (PFS), overall survival (OS). Results: 235 patients underwent surgery for malignant glioma including 51 newly-diagnosed patients felt to be surgically resectable and with post-operative imaging. 25/51 (49%) had no residual tumour. The median PFS and OS were 7.1 and 11.5 months respectively. To date, 3 patients have successfully undergone 5-ALA-guided surgery with complete resection of contrast-enhancing tumour and no new focal neurological deficit post-operatively. Conclusions: We continue to recruit and follow prospectively patients having undergone 5-ALA-guided resection of malignant gliomas at HSN. Patients living in Northern Ontario may derive significant benefits from the use of 5-ALA-guided surgery, particularly since other technologies, such as intraoperative MRI and ultrasound, are costly and not available.

Survival and Clinical Characteristics of Patients with Glioblastoma with Primitive Neuronal Component (P13-13.004)

<h3>Objective:</h3> Evaluate the survival and clinical characteristics of patients with diagnosis of glioblastoma with primitive neuronal component (GBM-PNC) on initial diagnosis compared to patients diagnosed with GBM-PNC at recurrence following prior diagnosis of malignant glioma without primitive component. <h3>Background:</h3> A subset of malignant gliomas are found to have solid-looking primitive nodules which confer a diagnosis of glioblastoma with primitive neuronal component (GBM-PNC). At initial diagnosis, GBM-PNC is associated with increased responsiveness to platinum-based therapies and high rates of cerebrospinal fluid dissemination. It is unknown if the same characteristics and risks exist when primitive neuronal component develops at recurrence after an initial diagnosis with a malignant glioma. <h3>Design/Methods:</h3> The University of Washington pathology database was queried between the years of 2005 to 2021 to identify patients with a pathological diagnosis of GBM-PNC. Clinical and radiographic data were abstracted. Descriptive statistics and survival analysis were preformed. <h3>Results:</h3> 20 patients with diagnosis of GBM-PNC were identified and 16 had appropriate clinical information for inclusion. 11 patients were diagnosed with GBM-PNC at initial surgery and 6 were diagnosed at surgery for presumed recurrent malignant glioma. For patients found to have GBM-PNC at recurrence, the median overall survival was 40months compared to only 17months for patients diagnosed at initial surgery. Patients diagnosed at recurrence, also had longer time to first progression of 26.5months compared to 12months for patients initially diagnosed with GBM-PNC. The 4 patients who had intracranial progression leading to diagnosis of GBM-PNC all had cystic appearance on MRI. 33% of patients diagnosed with GBM-PNC at recurrence developed leptomeningeal dissemination. <h3>Conclusions:</h3> Patients who are diagnosed at GBM-PNC at recurrence of a prior malignant glioma have improved survival compared to patients who have a primitive neuronal component of the malignant glioma diagnosed at initial resection. This pathology was associated with a cystic radiographic appearance when intracranial. <b>Disclosure:</b> Dr. McGranahan has nothing to disclose. Patrick Cimino has nothing to disclose. Ms. Costanza has nothing to disclose.

Haemostatic technique in malignant gliomas.

Haemostasis in brain surgery is mandatory to avoid postoperative re-bleeding and a poor outcome. Postoperative intra-cavity haemorrhage is a frequent complication, especially in surgery of malignant gliomas because of the fragility of pathological vessels. In this technical note, we describe our 'compression' technique used to achieve haemostasis in adult patients who underwent surgery for supratentorial malignant gliomas (GBM) at our Institute from January 2019 to January 2022. Peri-operative work-up included clinical status, laboratory data and contrast brain CT, performed at 24 hours after surgery, or earlier for patients with neurological worsening. A total of 82 patients was included in this study, 46 males (57%) and 36 females (43%). A post-operative intra-cavity haemorrhage was documented by postoperative CT-scan in 3/82 patients (3.65%), and the mean surgical time was 3.66 hours. No late bleeding was observed 48 hours after surgery. We have documented the good results of our technique to achieve haemostasis in patients operated for malignant glioma (GBM). The technique described in this study seems to be safe and useful to avoid post-operative bleeding in the surgery of cerebral GBM.

Surgical Management of Malignant Glioma in the Elderly.

BackgroundThe median age for diagnosis of glioblastoma is 64 years and the incidence rises with increasing age to a peak at 75-84 years. As the total number of high-grade glioma patients is expected to increase with an aging population, neuro-oncological surgery faces new treatment challenges, especially regarding aggressiveness of the surgical approach and extent of resection. In the elderly, aspects like frailty and functional recovery time have to be taken into account before performing surgery.Material & MethodsPatients undergoing surgery for malignant glioma (WHO grade III and IV) at our institution between 2015 and 2020 were compiled in a centralized tumor database and analyzed retrospectively. Karnofsky Performance Scale (KPS) and Clinical Frailty Scale (CFS) were used to determine functional performance pre- and postoperatively. Overall survival (OS) was compared between age groups of 65-69 years, 70-74 years, 75-79 years, 80-84 years and >85 years in view of extent of resection (EOR). Furthermore, we performed a literature evaluation focusing on surgical treatment of newly diagnosed malignant glioma in the elderly.ResultsWe analyzed 121 patients aged 65 years and above (range 65 to 88, mean 74 years). Mean overall survival (OS) was 10.35 months (SD = 11.38). Of all patients, only a minority (22.3%) received tumor biopsy instead of gross total resection (GTR, 61.2%) or subtotal resection (STR, 16.5%). Postoperatively, 52.9% of patients were treated according to the Stupp protocol. OS differed significantly between extent of resection (EOR) groups (4.0 months after biopsy vs. 8.3 after STR vs. 13.8 after GTR, p < 0.05 and p < 0.001 correspondingly). No significant difference was observed regarding EOR across different age groups.ConclusionGTR should be the treatment of choice also in elderly patients with malignant glioma as functional outcome and survival after surgery are remarkably better compared to less aggressive treatment. Elderly patients who received GTR of high-grade gliomas survived significantly longer compared to patients who underwent biopsy and STR. Age seems to have little influence on overall survival in selected surgically extensive treated patients, but high preoperative functional performance is mandatory.

Comparative analysis of 5-ALA and chlorin E6 fluorescence-guided navigation in malignant glioma surgery

To analyze specificity and sensitivity of 5-ALA and chlorin E6 fluorescence-guided navigation in malignant glioma surgery. Fluorescence-guided navigation was analyzed in 50 patients (2 groups) with high-grade glioma. All patients were treated at the Polenov Russian Neurosurgery Institute. Chlorin E6 1 mg/kg intravenously (Photoditazin) was used as a fluorescence inducer in 25 patients (the 1st group), 5-ALA 20 mg/kg orally (Alasens) - in other 25 patients (the 2nd group). Each group included 10 patients with glioma grade III and 15 patients with glioma grade IV. Both groups were statistically representative (p>0.05). In patients with glioma grade III, sensitivity of chlorin E6 fluorescence-guided navigation was 83.8%, 5-ALA fluorescence - 82.5%. Specificity was 66.7% and 64.1%, respectively. In patients with glioma grade IV, sensitivity was 87.7% for chlorin E6 and 88.3% for 5-ALA. Specificity was 85.2% and 88.1%, respectively. Statistical analysis confirmed comparable high efficacy of both agents in surgery of malignant gliomas. Sensitivity and specificity of fluorescence-guided navigation with chlorin E6 and 5-ALA were similar (p>0.05).

Complications of glioma surgery

Background. Nowadays extensive resection remains the best treatment for gliomas. However, postoperative complications can disturb the benefits of surgery. The risk of surgical complications must be assessed against the benefits of obtaining a total resection, especially for tumors of eloquent brain. Object. The goal of this study was to review present evidence of glioma resection concerning the frequency of complications,their causes, predictive risk factors and current methods of reducing the occurrence of these events. This review strives to consolidate information about complications and preventive measures as well as to establish the utility of tools to improve neurosurgical outcome. Methods. A review of the literature concerning the main postoperative complications in patients with glial tumors was done. We performed a search using key words "cerebral neoplasm", "cerebral tumor", "glioma" and "complications". Papers that namely discussed complications rates were included. Anatomic, physiologic, clinical features were taken into consideration in patients with postoperative complications as well as current methods of investigations. Results. Documented overall complication rates ranged from 10% to 35%, with overall mortality rates of 1.0%-15%. Studies of series undergoing surgery for malignant gliomas found at least one surgical complication in 3.4% of patients with a 4.5% risk in patients for hospital-associated complications such as surgical site infection. There was a wide range of types of complications. The presence of new or worsened neurological deficit was up to 20% as the highest reported rate for treatment of eloquent arias glioma. Relatively common complications were postoperative peritumoral edema (2%-10%), CSF fistula (1%-15%), wound infection (0%-4%), surgery-related hematoma (1%-5%) and early postoperative seizure (1%-12%). The risk for cardiac complications was 0.7%, for respiratory complications - 0.5%, for deep wound infection - 0.8%,for deep venous thromboses - 0.6%, for pulmonary embolus - 3.1%, for acute renal failure -1.3%. Infratentorial tumour location, reoperations and previous radiotherapy were factors related to the incidence of regional complications. Age over 60 and severe comorbidities were risk factors for systemic complications. Conclusion. Postoperative morbidity in glial tumor surgery may be reduced by: encouraging use of standardized protocols for regional and systemic complications, intraoperative navigation that allows surgeon to maximize resection while preserving neurological function, clinical vigilance and attention to details.

STMO-7 Usefulness of NU-KNIT in retractorless surgery for malignant glioma

On the removal of the brain tumor, securing of appropriate working corridor and the maintenance of the visibility are one of the most relevant elements regardless of tumor local existence. This is unchangeable extract in these days when a support apparatus such as navigation system and the nerve monitoring was enriched, and, in the malignant glioma that a tumor border is relatively indistinct, the importance does not change either.At our hospital, I protect the access route by two folds of coating of absorbable hemostat(Surgical NU-KNIT) and neurosurgical patties (Delicot) on the removal of the malignant brain tumor in the brain deep part instead without using as possible fixed retractor for the purpose of securing of working corridor under minimum retraction and extract deep part tumor. In this way, normal real protection, wet maintenance, maintenance of the visibility by the control of the bleeding and pressure reduction of the neighborhood organization extracting are provided, and postoperative function recovery gets an early impression. About a method of the securing of working corridor at our hospital, I inspect the usefulness and limit by showing representative cases and want to have an opinion, criticism.

Association of 5-aminolevulinic acid with intraoperative hypotension in malignant glioma surgery

BackgroundUse of 5-aminolevulinic acid for photodynamic malignant tumor diagnosis reportedly causes intraoperative hypotension (systolic blood pressure < 70 mmHg) during urologic surgery. However, its association with intraoperative hypotension in malignant glioma surgery and underlying mechanisms has not yet been elucidated.. This study aimed to investigate whether 5-aminolevulinic acid administration is associated with intraoperative hypotension in malignant glioma surgery and explore the mechanisms of 5-aminolevulinic acid-induced hypotension in vitro. MethodsIn this retrospective multicenter cohort study, we investigated intracellular nitric oxide as a candidate mediator of hypotension in response to 5-aminolevulinic acid in vitro in human umbilical vein endothelial cell cultures. ResultsOf 142 patients, 94 underwent 5-aminolevulinic acid-guided surgery. Systolic blood pressure was significantly lower throughout surgery with 5-aminolevulinic acid administration. 5-Aminolevulinic acid administration was an independent risk factor for intraoperative hypotension according to multivariable logistic regression analysis (89% vs. 56%; odds ratio = 6.72, 95% confidence interval [2.05–22.1], P = 002). In subgroup analysis of the 5-aminolevulinic acid group, increasing age and use of renin-angiotensin system inhibitors had a synergistic effect with 5-aminolevulinic acid on decreased blood pressure. In the vascular endothelial cell culture study, 5-aminolevulinic acid induced a significant increase in intracellular nitric oxide generation. Conclusions5-Aminolevulinic acid administration was associated with intraoperative hypotension in malignant glioma surgery, with increasing age and use of renin-angiotensin system inhibitors boosting the blood pressure-lowering effect of 5-aminolevulinic acid. According to in vitro results, the low blood pressure induced by 5-aminolevulinic acid may be mediated by a nitric oxide increase in vascular endothelial cells.

5-Aminolevulinic Acid-Induced Porphyrin Contents in Various Brain Tumors: Implications Regarding Imaging Device Design and Their Validation.

Fluorescence-guided resections using 5-aminolevulinic acid (5-ALA)-induced tumor porphyrins have been established as an adjunct for malignant glioma surgery based on a phase III study using specifically adapted microscopes for visualizing fluorescing protoporphyrin IX (PPIX). New hardware technologies are being introduced, which claim the same performance as the original technology for visualizing fluorescence. This assumes that qualitative fluorescence detection is equivalent to the established standard, an assumption that needs to be critically assessed. To determine PPIX concentrations (cPPIX) in tissue that can be detected visually using the established BLUE400 filter system (Carl Zeiss Meditec, Oberkochen, Germany) as a basis for defining the performance of this system. Utilizing a hyperspectral imaging system, tumor samples from patients harboring different tumor tissues, with or without visible fluorescence, were analyzed. Absolute values of cPPIX were calculated after calibrating the system with fluorescence phantoms with known cPPIX. A total of 524 tumor samples from 162 patients were analyzed. Visual fluorescence under the BLUE400 filter was documented by experienced neurosurgeons. A 0.9μg/ml threshold of cPPIX was defined as the minimal concentration required to detect and discriminate visual fluorescence. This is the first report providing data on the threshold of cPPIX, which is visually detected using the current generation of microscopes, thus defining the specificity and sensitivity of this technology as initially tested in a randomized trial. Novel technologies should show similar characteristics in order to be used safely and effectively. If more sensitive, such technologies require further assessments of tumor selectivity.

FLGS-01. Development of novel topical fluorescent probe for intraoperative rapid detection of glioma

Abstract PURPOSE Fluorescence imaging is an important surgical adjunct in malignant glioma surgery. 5-aminolevulinic acid (5-ALA) has been proven effective for radical tumor resection and extended progression-free survival in a phase III randomized trial and therefore integrated into surgery for malignant glioma. Importantly, however, some limitations still exist in its use, which include false positivity and false negativity as well as inability of re-administration. In this study, we aimed to develop a novel, spray-type fluorescent probe using hydroxymethyl rhodamine green (HMRG) as a fluorescent scaffold. METHODS We have previously established a fluorescent probe library comprised of more than 320 kinds of HMRG probes. They have HMRG as a fluorescent scaffold with various types of dipeptides attached to it. Primary probe screening was performed using the homogenized tumor samples from patients with glioblastoma operated at our institution. Secondary screening followed using the selected probes and fresh tumor samples obtained from patients with glioblastoma operated from 2016 until 2018. Diced electrophoresis gel (DEG) assay, two-dimensional gel electrophoresis followed by a multi-well plate-based fluorometric assay, was performed to identify responsible enzymes for the selected probe. Further experiments with inhibitors, real-time PCR, immunohistochemistry, and western blotting were performed for confirmation. RESULTS Proline-arginine-HMRG (PR-HMRG) was selected as a candidate probe based upon the above two-step screenings. It achieved 79.4% accuracy in receiver operating characteristic curve analysis. Calpain-1 was found to be responsible to cleave PR-HMRG probe by DEG-proteome analysis. Calpain-1 protein was highly expressed in tumor tissues which reacted to PR-HMRG probe. CONCLUSIONS Our innovative screening method was able to find PR-HMRG as a novel fluorescent probe effective for rapid detection of glioblastoma. A preclinical study is planned to assess the efficacy and safety of the selected probe.

SURG-10. DEVELOPMENT OF NOVEL TOPICAL FLUORESCENT PROBE FOR INTRAOPERATIVE RAPID DETECTION OF GLIOMA

Abstract PURPOSE Fluorescence imaging is an important surgical adjunct in malignant glioma surgery. 5-aminolevulinic acid (5-ALA) has been proven effective for radical tumor resection and extended progression-free survival in a phase III randomized trial and therefore integrated into surgery for malignant glioma. Importantly, however, some limitations still exist in its use, which include false positivity and false negativity as well as inability of re-administration. In this study, we aimed to develop a novel, spray-type fluorescent probe using hydroxymethyl rhodamine green (HMRG) as a fluorescent scaffold. METHODS We have previously established a fluorescent probe library comprised of more than 320 kinds of HMRG probes. They have HMRG as a fluorescent scaffold with various types of dipeptides attached to it. Primary probe screening was performed using the homogenized tumor samples from patients with glioblastoma operated at our institution. Secondary screening followed using the selected probes and fresh tumor samples obtained from patients with glioblastoma operated from 2016 until 2018. Diced electrophoresis gel (DEG) assay, two-dimensional gel electrophoresis followed by a multi-well plate-based fluorometric assay, was performed to identify responsible enzymes for the selected probe. Further experiments with inhibitors, real-time PCR, immunohistochemistry, and western blotting were performed for confirmation. RESULTS Proline-arginine-HMRG (PR-HMRG) was selected as a candidate probe based upon the above two-step screenings. It achieved 79.4% accuracy in receiver operating characteristic curve analysis. Calpain-1 was found to be responsible to cleave PR-HMRG probe by DEG-proteome analysis. Calpain-1 protein was expressed at significantly higher level in tumors that were fluoresced by PR-HMRG than in those that were not. CONCLUSIONS Our innovative screening method was able to find PR-HMRG as a novel fluorescent probe effective for rapid detection of glioblastoma. A preclinical study is planned to assess the efficacy and safety of the selected probe.

A Single-Center, Randomized, Double-Blind Study of 94 Patients Undergoing Surgery for Cerebral Glioma to Compare Postoperative Thromboprophylaxis with and without Rivaroxaban.

BackgroundVenous thrombosis (VTE) is a common adverse event among inpatients, which can cause pulmonary embolism, and greatly increases mortality. The effects of rivaroxaban in patients undergoing brain glioma surgery have still not been explored. This single-center study of 94 patients undergoing surgery for cerebral glioma aimed to compare postoperative thromboprophylaxis with and without rivaroxaban.Material/MethodsWe designed a randomized, controlled, double-blind study to evaluate the effect of rivaroxaban on 94 patients undergoing brain glioma surgery. These patients were divided into a rivaroxaban group (administered at 10 mg per day from admission to discharge) and a placebo group. The primary study endpoint was incidence of VTE at discharge. The secondary endpoints included safety outcomes of major bleeding, allergy, or VTE-related death.ResultsA total of 94 patients were enrolled in the study: 47 in the rivaroxaban group and 47 in the placebo group. Baseline characteristics of participants were well-matched in both groups. A significant reduction was found in the incidence of VTE in the rivaroxaban treatment group versus the placebo group (1/47 vs 10/47 patients, P=0.008). The rate of major bleeding events was quite low in both group (1/47 vs 1/47 patients). One patient in the placebo group died due to a pulmonary embolism and intractable concomitant underlying diseases.ConclusionsOur results indicate that treatment with rivaroxaban is a safe and effective thromboprophylaxis treatment in patients undergoing surgery for malignant cerebral glioma.

Characterization of autofluorescence and quantitative protoporphyrin IX biomarkers for optical spectroscopy-guided glioma surgery

5-Aminolevulinic acid (5-ALA)-mediated fluorescence does not effectively depict low grade gliomas (LGG) or the infiltrative tumor portion of high-grade gliomas (HGG). While spectroscopy improves sensitivity and precision, this is currently limited by autofluorescence and a second protoporphyrin IX (PpIX) fluorescence state at 620 nm. We investigated the autofluorescence to better characterize the present spectra and thus increase PpIX quantification precision and sensitivity. This study included 128 patients undergoing surgery for malignant glioma. 5-ALA (Gliolan) was administered before anesthesia, and fluorescence was measured using a hyperspectral device. It was found that all 2692 measured spectra consisted of contributions from 620 to 634 nm PpIX, NADH, lipofuscin, and flavins. The basis spectra were characterized and their use in spectral unmixing led to 82.4% lower fitting error for weakly fluorescing areas (p < 0.001), and 92.3% fewer false positive tumor identifications in control measurements (p = 0.0065) compared to previous works. They also decreased the PpIX620 contribution, thus halving the mean Ratio620/634 (p < 0.001). The ratio was approximately 0 for HGGs and increasing for LGGs, as demonstrated previously. Additionally, the Ratio620/634, the MIB-1/Ki-67 proliferation index, and the PpIX peak blue-shift were found to be significantly related to WHO grade, fluorescence visibility, and PpIX contribution (p < 0.001), and the value of these three as quantitative biomarkers is discussed.

P07.03 Fluorescence navigation in glioma surgery using 5 ALA and chlorin E6

Abstract BACKGROUND Metabolic navigation in the surgery of malignant gliomas is the most effective way to distinguish the border of the tumor during surgery and achieve a more radical resection, and as a result, to increase the recurrence interval and increase the life expectancy. MATERIAL AND METHODS A comparative analysis of fluorescent navigation was carried out in 50 patients (group 2) with glioma of a high degree of anaplasia, who were treated at the Department of Neurooncology of the A.L. prof. A.L. Polenov. In 25 patients (group 1), chlorin E6 1 mg / kg intravenously was used as a fluorescence inducer, the other 25 patients (group 2) received 5 ALA 20 mg / kg orally. Each group included 10 patients with Grade III anaplasia and 15 patients with Grade IV anaplasia. Both groups were statistically representative (p&amp;gt; 0.05). RESULTS For surgery of grade III glioma, the sensitivity of the method was 83.3% (chlorin E6), 82.9% (5ALA); specificity 66.7% (chlorin E6), 65.4% (5ALA). For grade IV glioma surgery, the sensitivity of the method is 87.5% (chlorin E6), 87.7% (5ALA); specificity - 85.7% (chlorin E6), 85.3% (5ALA). CONCLUSION Statistical analysis showed comparable high efficacy of the drugs in the surgery of malignant gliomas. The sensitivity and specificity of the method for fluorescent preparations of chlorin E6 and 5 ALA showed no statistically significant difference in the achievement of the result (p&amp;gt; 0.05)

Morphological evaluation of the effectiveness of fluorescence navigation with chlorin e6 in surgery for malignant gliomas

To evaluate the effectiveness of fluorescence navigation with chlorin e6 in surgery for malignant gliomas based on surgical material morphological and immunohistochemical data. The surgical material obtained from patients with high-grade (Grade III-IV) anaplastic glioma was examined. Along with histological examination, the proliferation marker Ki-67, the cell cycle transcription factor protein p53, and vascular endothelial growth factor (VEGF) were determined. A significant direct correlation was found between the expression of Ki-67, p53, and VEGF and the fluorescence intensity of tumor tissues (p<0.05). The technique of fluorescence navigation using chlorin e6 in comparative morphopathological analysis has confirmed its effectiveness in surgery for malignant gliomas.

STMO-08 Validation of the endoscopic 5-ALA fluorescence diagnosis for intraventricular tumors

Intraoperative 5-ALA fluorescence diagnosis (PDD) has been shown to improve tumor resection rates in surgery for malignant glioma. Recently, the usefulness of PDD has been reported in tumors other than malignant glioma. However, the fluorescence of intraventricular tumors is not easy to observe under the microscope, because excitation light could not reach enough to the deepest part of the brain. Therefore, we performed endoscopic 5-ALA fluorescence diagnosis of intraventricular tumors and evaluated its usefulness. Ten cases of intraventricular tumors were included in the study. There were 3 germ cell tumors, 2 metastatic brain tumors, 2 pilocytic astrocytomas, 1 malignant lymphoma, 1 subependymoma, and 1 medulloblastoma (recurrent). The tumors were located in the third ventricle in four cases, the lateral ventricle in three cases, the lateral ventricle and the third ventricle in two cases, and the aqueduct in one case. Tumor removal was performed in 6 cases and tumor biopsy in 4 cases. Intraoperative fluorescence could be observed in eight cases: three germ cell tumors, two metastatic brain tumors, two pilocytic astrocytomas, and one malignant lymphoma. Subependymoma and medulloblastoma did not show fluorescence. Among the cases with confirmed fluorescence, the fluorescent sites were targeted for biopsies for germ cell tumors and malignant lymphomas. For metastatic brain tumors and pilocytic astrocytomas, the extent of removal was determined at the time of removal, and the presence of residual tumor was confirmed by fluorescence after removal. Endoscopic 5-ALA fluorescence diagnosis for intraventricular tumors was useful in determining the target of biopsy or the extent of excision and in assessing residual tumors.

STEM-05. SINGLE CELL SEQUENCING CHARACTERIZES SPATIAL AND TEMPORAL RELATIONSHIPS OF ENHANCING AND NON-ENHANCING REGIONS IN HIGH-GRADE GLIOMA

Abstract INTRODUCTION Treatments of high grade glioma focus on the contrast enhancing (CE) portion of the tumor. However, given the invasive nature of glioma, residual tumor cells responsible for recurrence likely exist in the non-enhancing (NE) region. METHODS In 3 patients undergoing surgery for malignant glioma, we used pre-operative magnetic resonance images to prospectively identify biopsy targets in the CE region and locations 0.5-2.0cm beyond the CE edge. We carried out single cell sequencing on image guided biopsy specimens to generate 12,528 RNA profiles. RESULTS In all samples, tumor cells clustered into three predominant groups: tumor cells with astrocyte markers (ASC-like), tumor cells with oligodendrocyte markers (ODC-like), and tumor cells with neither marker. This last group consisted of a small proportion of tumor cells and expressed putative stem cell markers (PROM1, NES, SLC1A3, A2B5, ID1). A trajectory analysis consistently positioned this group as branching off into either ASC-like or ODC-like cells. CE regions had different cellular compositions than NE regions, with higher proportions of tumor, endothelial cells, T-cells, and NK cells. Using location and cell density data, we modeled expected tumor burden, predicting tumor cells up to 1.5cm beyond the CE region of the tumor. There were significant differences in gene expression between CE and NE tumor cells, with increased inflammation and hypoxia in the CE region versus increased proliferative markers in the NE region. Tumor cells in the NE region were characterized by increased proliferation, markers of invasion, and markers of self-renewal. CONCLUSIONS Single cell sequencing illustrates multiple glioma cell types and suggests a hierarchical relationship between tumor cell types. CE and NE regions exhibit different tumor and non-tumor cell populations as well as different gene expression profiles within individual cell types. There remains a significant tumor cell burden in the NE portion of tumor, including actively proliferating cells.

Validating a new generation filter system for visualizing 5-ALA-induced PpIX fluorescence in malignant glioma surgery: a proof of principle study

BackgroundThe BLUE 400 filter system (Carl Zeiss Meditec, Oberkochen, Germany) has provided visualization of 5-ALA-induced fluorescence-guided surgery for more than 20 years. Nevertheless, constraints, e.g., limited background discrimination during hemostasis, obstruct fluency of surgery. A novel filter with improved background visualization was developed, requiring validation regarding fluorescence discrimination. The aim of this article is to determine diagnostic accuracy and perception of protoporphyrin IX (PpIX) discrimination of a novel filter system with higher background illumination (BLUE 400 AR) compared with the gold standard, BLUE 400.MethodsA surgical microscope equipped with both BLUE 400 and BLUE 400 AR was used. Comparisons were performed on a biological basis and on the visual perception of margins. High-resolution images were compared during and after surgery by senior neurosurgeons. In a predefined biopsy algorithm, four biopsies per patient at tumor margins of PpIX fluorescence and adjacent brain were acquired using BLUE 400 AR only from regions intended for resection and assessed for cell count and density.ResultsThirty-two patients with malignant gliomas were included in this study. BLUE 400 AR markedly enhanced the brightness of the surgical field, allowing superior discrimination of brain anatomy. A total of 128 biopsies from fluorescence margins were collected. Positive predictive value (PPV) was 98.44% (95% CI, 90.06–99.77%) for malignant glioma. Residual median cell density in non-fluorescent tissue was 13% (IQR 13 to 31). Perception of the location of fluorescent margins on HD images was equivalent for both filter combinations.ConclusionsBLUE 400 AR demonstrated superior background compared with conventional BLUE 400 in malignant glioma surgery but comparable fluorescence margins and PPV. Therefore, BLUE 400 AR can be considered safe and effective in supporting malignant glioma surgery.