Current strategies for the treatment of malignant gliomas – experience of the Department of Neurosurgery, Brodno Masovian Hospital in Warsaw

Introduction: Malignant gliomas (HGG) are the most common primary malignant brain tumors arising from glial cells. Between HGG, glioblastoma is the most common and the most malignant histological subtype with only a 27% 2-year survival rate. Current standard medical treatment of malignant gliomas is still not satisfactory, and may need some development and modification. We presented and discussed the achievements of the Department of Neurosurgery at Brodno Masovian Hospital in the treatment of malignant gliomas. Material and methods: We step by step presented and discussed the policy in the treatment of malignant gliomas. We showed all steps starting from preparation of surgery (eg. neuroimaging) and finishing on the presentation the development of perioperative management – from intraoperative electrical stimulation mapping and monitoring which is nowadays already standard method to convection-enhanced delivery (CED) and gamma knife (GK) which are new and promising methods in the treatment of glioblastoma. Results: All surgical methods described in this manuscript were introduced to achieve maximal and safe resection of malignant glioma. CED and GK are the last resort methods for patients with recurrent HGG. Discussion: Department of Neurosurgery at Brodno Masovian Hospital deal with all types of brain tumors, including all types of high grade gliomas. As the first Department in Europe with close cooperation with the Department of Neurosurgery in San Francisco, we have started local infusions of drugs directly to the tumor in the real time of magnetic field, and we think that technology may change all approaches to the treatment of high grade gliomas.

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ATIM-04. PHASE I IMMUNOVIROTHERAPY TRIAL OF IL-12 EXPRESSING HSV-1 (M032) IN PET DOGS WITH SPONTANEOUS HIGH GRADE GLIOMAS: A PRELIMINARY REPORT

Neuro-Oncology ◽

10.1093/neuonc/noz175.004 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi2-vi2

Author(s):

M Renee Chambers ◽

David Crossman ◽

Jeremy Foote ◽

Jey Koehler ◽

James Markert ◽

...

Keyword(s):

Clinical Trial ◽

Brain Tumors ◽

Phase I ◽

Tumor Antigens ◽

Phase 1 ◽

Malignant Gliomas ◽

High Grade ◽

Pet Dogs ◽

High Grade Gliomas ◽

Hsv 1

Abstract Malignant gliomas are the most common primary brain tumors in humans, accounting for approximately 30% of all primary central nervous system (CNS) tumors in adults. Incidence and outcomes of gliomas in pet dogs are similar to humans. Previous methods of studying gliomas in rodent models do not adequately represent several features that define human cancers, most notably the sporadic nature of tumor development. Murine models lack intra-tumoral heterogeneity or hosts do not have an intact immune system. To overcome these rodent model deficiencies, many investigators have used canine models to study human diseases. We describe a prospective, phase I clinical trial in canine patients with sporadic high-grade gliomas to evaluate M032, a mutant HSV-1 expressing IL-12, alone or combined with a checkpoint inhibitor (Indoximod) to assess safety, tolerability and efficacy. M032 has been shown to infect and kill glioma cells, producing a virus and tumor cell antigen-rich debris field; will provide an increased adjuvant effect from released viral DNA recognized by TLR-9 receptors; and express IL-12 locally, stimulating activation of TH1 lymphocytes. The intratumoral inflammatory cell infiltration is expected to result in immune-related anti-viral responses with cross-epitope spreading to tumor antigens. Indoximod immunomodulation will be tested in latter cohorts to prolong anti-tumor responses. To date, six canines with high-grade gliomas have received intratumoral M032 without virus-related toxicities. Resected tumor and serial blood samples are being cryopreserved for analysis of lymphoid and monocyte/myeloid subset markers. This same virus is being tested in a phase 1 clinical trial in humans with high-grade malignant gliomas; eight human patients have received treatment at this writing without virus-related toxicities. The concurrent prosecution of both trials allows unprecedented real time comparison of safety and efficacy of immunovirotherapy as a stringent test of suitability of the dog as a valid and informative model of human brain tumors.

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Convection Enhanced Delivery in the Setting of High-Grade Gliomas

Pharmaceutics ◽

10.3390/pharmaceutics13040561 ◽

2021 ◽

Vol 13 (4) ◽

pp. 561

Author(s):

Chibueze D. Nwagwu ◽

Amanda V. Immidisetti ◽

Michael Y. Jiang ◽

Oluwasegun Adeagbo ◽

David C. Adamson ◽

...

Keyword(s):

Rapid Development ◽

Systemic Exposure ◽

Therapeutic Index ◽

High Grade Glioma ◽

High Grade ◽

Clinical Experiences ◽

Convection Enhanced Delivery ◽

Drug Concentrations ◽

Infiltrative Growth Pattern ◽

High Grade Gliomas

Development of effective treatments for high-grade glioma (HGG) is hampered by (1) the blood–brain barrier (BBB), (2) an infiltrative growth pattern, (3) rapid development of therapeutic resistance, and, in many cases, (4) dose-limiting toxicity due to systemic exposure. Convection-enhanced delivery (CED) has the potential to significantly limit systemic toxicity and increase therapeutic index by directly delivering homogenous drug concentrations to the site of disease. In this review, we present clinical experiences and preclinical developments of CED in the setting of high-grade gliomas.

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Sonodynamic Therapy for the Treatment of Intracranial Gliomas

Journal of Clinical Medicine ◽

10.3390/jcm10051101 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1101

Author(s):

Antonio D’Ammando ◽

Luca Raspagliesi ◽

Matteo Gionso ◽

Andrea Franzini ◽

Edoardo Porto ◽

...

Keyword(s):

Tumor Cells ◽

Therapeutic Option ◽

Malignant Gliomas ◽

Progression Free Survival ◽

High Grade ◽

Sonodynamic Therapy ◽

Treatment Protocols ◽

Ultrasound Waves ◽

High Grade Gliomas ◽

Preclinical And Clinical Studies

High-grade gliomas are the most common and aggressive malignant primary brain tumors. Current therapeutic schemes include a combination of surgical resection, radiotherapy and chemotherapy; even if major advances have been achieved in Progression Free Survival and Overall Survival for patients harboring high-grade gliomas, prognosis still remains poor; hence, new therapeutic options for malignant gliomas are currently researched. Sonodynamic Therapy (SDT) has proven to be a promising treatment combining the effects of low-intensity ultrasound waves with various sound-sensitive compounds, whose activation leads to increased immunogenicity of tumor cells, increased apoptotic rates and decreased angiogenetic potential. In addition, this therapeutic technique only exerts its cytotoxic effects on tumor cells, while both ultrasound waves and sensitizing compound are non-toxic per se. This review summarizes the present knowledge regarding mechanisms of action of SDT and currently available sonosensitizers and focuses on the preclinical and clinical studies that have investigated its efficacy on malignant gliomas. To date, preclinical studies implying various sonosensitizers and different treatment protocols all seem to confirm the anti-tumoral properties of SDT, while first clinical trials will soon start recruiting patients. Accordingly, it is crucial to conduct further investigations regarding the clinical applications of SDT as a therapeutic option in the management of intracranial gliomas.

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Roles of Extracellular Vesicles in High-Grade Gliomas: Tiny Particles with Outsized Influence

Annual Review of Genomics and Human Genetics ◽

10.1146/annurev-genom-083118-015324 ◽

2019 ◽

Vol 20 (1) ◽

pp. 331-357 ◽

Cited By ~ 4

Author(s):

Michael W. Graner

Keyword(s):

Extracellular Vesicles ◽

Standard Of Care ◽

High Grade ◽

Biological Processes ◽

Current Standard ◽

Endocrine Factors ◽

High Grade Gliomas ◽

Endosomal System ◽

Intercellular Communications

High-grade gliomas, particularly glioblastomas (grade IV), are devastating diseases with dismal prognoses; afflicted patients seldom live longer than 15 months, and their quality of life suffers immensely. Our current standard-of-care therapy has remained essentially unchanged for almost 15 years, with little new therapeutic progress. We desperately need a better biologic understanding of these complicated tumors in a complicated organ. One area of rejuvenated study relates to extracellular vesicles (EVs)—membrane-enclosed nano- or microsized particles that originate from the endosomal system or are shed from the plasma membrane. EVs contribute to tumor heterogeneity (including the maintenance of glioma stem cells or their differentiation), the impacts of hypoxia (angiogenesis and coagulopathies), interactions amid the tumor microenvironment (concerning the survival of astrocytes, neurons, endothelial cells, blood vessels, the blood–brain barrier, and the ensuing inflammation), and influences on the immune system (both stimulatory and suppressive). This article reviews glioma EVs and the ways that EVs manifest themselves as autocrine, paracrine, and endocrine factors in proximal and distal intra- and intercellular communications. The reader should note that there is much controversy, and indeed confusion, in the field over the exact roles for EVs in many biological processes, and we will engage some of these difficulties herein.

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ACTR-67. A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN (ONIVYDE) USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS: RESULTS THUS FAR

Neuro-Oncology ◽

10.1093/neuonc/noy148.097 ◽

2018 ◽

Vol 20 (suppl_6) ◽

pp. vi26-vi27 ◽

Cited By ~ 1

Author(s):

Karishma Kumar ◽

Susan Chang ◽

Nancy Ann Oberheim-Bush ◽

Jennifer Clarke ◽

Jennie Taylor ◽

...

Keyword(s):

Phase I ◽

Real Time ◽

Phase I Study ◽

High Grade ◽

Convection Enhanced Delivery ◽

Real Time Imaging ◽

High Grade Gliomas ◽

Liposomal Irinotecan

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Phase II Trial of Thalidomide and Carmustine for Patients With Recurrent High-Grade Gliomas

Journal of Clinical Oncology ◽

10.1200/jco.2003.08.045 ◽

2003 ◽

Vol 21 (12) ◽

pp. 2299-2304 ◽

Cited By ~ 132

Author(s):

Howard A. Fine ◽

Patrick Y. Wen ◽

Elizabeth A. Maher ◽

Elene Viscosi ◽

Tracy Batchelor ◽

...

Keyword(s):

Antitumor Activity ◽

Malignant Gliomas ◽

Cytotoxic Agents ◽

Clinical Activity ◽

Antiangiogenic Agents ◽

High Grade ◽

Antiangiogenic Agent ◽

Histologic Diagnosis ◽

Anaplastic Gliomas ◽

High Grade Gliomas

Purpose: The use of thalidomide as an antiangiogenic agent has met with only limited success in the treatment of malignant gliomas. On the basis of preclinical data demonstrating synergistic antitumor activity when antiangiogenic agents are combined with cytotoxic agents, we explored the clinical activity of the combination of thalidomide and carmustine (BCNU) in patients with recurrent high-grade gliomas. Patients and Methods: Patients with a histologic diagnosis of high-grade glioma and radiographic evidence of tumor progression after standard surgery, radiation, and chemotherapy were eligible for the study. Patients received BCNU 200 mg/m2 on day 1 of every 6-week cycle, and 800 mg/d of thalidomide that was escalated to a maximal dose of 1,200 mg/d as tolerated. Results: A total of 40 patients (38 with glioblastomas, two with anaplastic gliomas) were accrued to the study. The combination of thalidomide and BCNU was well tolerated; mild myelosuppression and mild to moderate sedation were the most common side effects. The median progression-free survival (100 days) and the objective radiographic response rate (24%) for patients with glioblastoma compared favorably with data from historical controls. Conclusion: This is one of the first clinical trials to evaluate the strategy of combining a putative antiangiogenic agent with a cytotoxic agent in patients with primary brain tumors. Our data demonstrate that thalidomide in combination with BCNU is well tolerated and has antitumor activity in patients with recurrent high-grade gliomas. Although the combination seems to be more active than either agent alone, such conclusions await confirmatory trials.

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Is Current Technology Improving Outcomes with Radiation Therapy for Gliomas?

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2014.34.e89 ◽

2014 ◽

pp. e89-e94 ◽

Cited By ~ 5

Author(s):

Michael Brada ◽

Brian Haylock

Keyword(s):

Normal Tissue ◽

Three Dimensional ◽

Principal Component ◽

High Grade ◽

Current Standard ◽

Heavy Charged Particles ◽

Novel Technologies ◽

Altered Fractionation ◽

Specialized Equipment ◽

High Grade Gliomas

Radiotherapy (RT) remains the principal component of glioma treatment, and three-dimensional conformal RT (3DCRT) is the current standard of RT delivery. Advances in imaging and in RT technology have enabled more precise treatment to defined targets combined with better means of avoiding critical normal structures, and this is complemented by intensive quality assurance, which includes on-treatment imaging. The refinements of 3DCRT include intensity modulated RT (IMRT), arcing IMRT, and high-precision conformal RT, formerly described as “stereotactic,” which can be delivered using a linear accelerator or other specialized equipment. Although proton therapy uses heavy charged particles, the principal application can also be considered as refinement of 3DCRT. The technologies generally improve the dose differential between the tumor and normal tissue and enable more dose-intensive treatments. However, these have not translated into improved survival outcome in patients with low- and high-grade gliomas. More intensive altered fractionation regimens have also failed to show survival benefit. Nevertheless, novel technologies enable better sparing of normal tissue and selective avoidance of critical structures, and these need to be explored further to improve the quality of life of patients with gliomas. Principal clinical advance in RT has been the recognition that less intensive treatments are beneficial for patients with adverse prognosis high-grade gliomas. We conclude that the principal gain of modern RT technology is more likely to emerge as a reduction in treatment related toxicity rather than as an improvement in overall survival; the optimal avoidance strategies remain to be defined.

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Differences in the distribution of methotrexate into high grade gliomas following intravenous administration, as monitored by microdialysis, are associated with blood brain barrier integrity

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.1548 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 1548-1548 ◽

Cited By ~ 5

Author(s):

J. J. Olson ◽

J. O. Blakeley ◽

S. A. Grossman ◽

J. Weingart ◽

A. Rashid ◽

...

Keyword(s):

Brain Tumors ◽

Blood Brain Barrier ◽

Half Life ◽

Extracellular Fluid ◽

Brain Barrier ◽

Published Data ◽

High Grade ◽

Blood Brain ◽

Drug Concentrations ◽

High Grade Gliomas

1548 Background: Microdialysis (MD) is an accepted technique to monitor neurochemicals in pts with traumatic brain injury. This study was conducted to evaluate the use of MD to define the time course of intratumoral drug concentrations in pts with high grade gliomas (HGG) receiving systemic chemotherapy. Methods: MD catheters were placed in residual HGG following tumor debulking and infused with Ringer’s solution at 1 μL/min. MD probe location and integrity of the blood brain barrier (BBB) in adjacent tissue were determined by fused MRI/CT. Highdose (12g/m2) methotrexate (MTX), was given as a 4 h iv infusion the next day. MTX was measured in plasma and dialysate samples, collected at 30 min intervals from 1 h before to 24 h after dosing, with an LC/MS assay. Results: Six pts have been enrolled without any adverse events attributed to the MD catheter. Adequate pharmacokinetics (PK) were obtained in 4/6pts. MTX plasma pharmacokinetics (PK) were very consistent between the 4 evaluable pts and similar to published data. Time courses of the uncorrected MTX concentration in extracellular fluid (CECF) exhibited two distinctly different kinetic profiles. For 2pts in whom the MD probe resided within contrast enhancing tumor, CECF increased and decreased in parallel with drug levels in plasma, with a peak CECF of 189 ± 6 μM, an apparent elimination half-life in ECF of 4.44 ± 0.07 h, and an ECF/plasma AUCratio of 0.13 ± 0.01. The other 2pts had a much lower peak CECF (10.4 ± 0.4 μM) and AUC ratio (0.028 ± 0.020), with a more prolonged ECF half-life (11.4 ± 4.5 h). Fused images from 2 of these pts showed that the MD probe was located in nonenhancing tissue. Conclusions: MD is a clinically practical technique to monitor the distribution of systemically administered drugs to brain tumors in pts. It has the capability to elucidate variations in kinetic behavior that are consistent with regional differences in BBB integrity. Appropriate interpretation of data from MD studies to evaluate the distribution of investigational new drugs into brain tumors necessarily requires radiographic determination of the region of the tumor into which the probe has been placed. No significant financial relationships to disclose.

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