Preclinical Studies with Glioblastoma Brain Organoid Co-Cultures Show Efficient 5-ALA Photodynamic Therapy.

BACKGROUND: The high recurrence of glioblastoma (GB) that occurs adjacent to the resection cavity within two years of diagnosis urges an improvement of therapies oriented to GB local control. Photodynamic therapy (PDT) has been proposed to cleanse infiltrating tumor cells from parenchyma to ameliorate short long-term progression-free survival. We examined 5-aminolevulinic acid (5-ALA)-mediated PDT effects as therapeutical treatment and determined optimal conditions for PDT efficacy without causing phototoxic injury to the normal brain tissue. METHODS: We used a platform of Glioma Initiation Cells (GICs) infiltrating cerebral organoids with two different glioblastoma cells, GIC7 and PG88. We measured GICs-5-ALA uptake and PDT/5-ALA activity in dose-response curves and the efficacy of the treatment by measuring proliferative activity and apoptosis. RESULTS: 5-ALA (50 and 100 µg/mL) was applied, and the release of protoporphyrin IX (PpIX) fluorescence measures demonstrated that the emission of PpIX increases progressively until its stabilization at 24 h. Moreover, decreased proliferation and increased apoptosis corroborated the effect of 5-ALA/PDT on cancer cells without altering normal cells. CONCLUSIONS: We provide evidence about the effectiveness of PDT to treat high proliferative GB cells in a complex in vitro system, which combines normal and cancer cells and is a useful tool to standardize new strategic therapies.

Photodynamic therapy in glioblastoma: Detection of intraoperative inadvertent 5-ALA mediated photodynamic therapeutical effect after gross total resection.

Introduction: Glioblastoma (GBM) remains the most frequent and lethal primary brain tumor in adults, despite advancements in surgical resection techniques and adjuvant chemo- and radiotherapy. The most frequent recurrence pattern (75-90%) occurs in the form of continuous growth from the border of the surgical cavity, thus emphasizing the need for locoregional tumor control. Fluorescence-guided surgical resection using 5-ALA has been widely implemented in surgical protocols for such tumors. Recent literature also highlights the applicability of 5-ALA-mediated photodynamic therapy to obtain locoregional tumor control further. This study aims to identify if 5-ALA mediated photodynamic therapeutic effect after gross total glioblastoma resection has inadvertently occurred due to the exposition of protoporphyrin IX charged peripheral tumoral cells to operative room light sources. Methods: Of 146 patients who were intervened from glioblastoma between 2015 and 2020, 33 were included in the present study. Strict gross total resection (without supralocal resection) had been accomplished, and adjuvant chemoradiotherapy protocol was administered. Two comparison groups were created regarding the location of the recurrence (group A: up to 1 centimeter from the surgical cavity, and group B: beyond 1 centimeter from the surgical cavity). The cutoff point was determined to be 1 centimeter because of the visible light penetrance to the normal brain tissue. Results: In univariate analysis, both groups only differed regarding 5-ALA administration, which was significantly related to a minor relative risk of presenting the recurrence within the first centimeter from the surgical cavity (Relative Risk = 0,655 (95% CI 0,442-0,970), p-value=0,046). Results obtained in univariate analysis were corroborated posteriorly in multivariate analysis (RR=0,730 (95% CI 0,340-0,980), p=0,017). Discussion: In the present study, a probable inadvertent 5-ALA photodynamic therapeutical effect has been detected in vivo. This finding widely opens the door for further research on this promising theragnostic tool.

Current and Future Frontiers of Molecularly Defined Oligodendrogliomas.

Oligodendrogliomas are a subtype of adult diffuse glioma characterized by their better responsiveness to systemic chemotherapy than other high-grade glial tumors. The World Health Organization (WHO) 2021 brain tumor classification highlighted defining molecular markers, including 1p19q codeletion and IDH mutations which have become key in diagnosing and treating oligodendrogliomas. The management for patients with oligodendrogliomas includes observation or surgical resection potentially followed by radiation and chemotherapy with PCV (Procarbazine, Lomustine, and Vincristine) or Temozolomide. However, most of the available research about oligodendrogliomas includes a mix of histologically and molecularly diagnosed tumors. Even data driving our current management guidelines are based on post-hoc subgroup analyses of the 1p19q codeleted population in landmark prospective trials. Therefore, the optimal treatment paradigm for molecularly defined oligodendrogliomas is incompletely understood. Many questions remain open, such as the optimal timing of radiation and chemotherapy, the response to different chemotherapeutic agents, or what genetic factors influence responsiveness to these agents. Ultimately, oligodendrogliomas are still incurable and new therapies, such as targeting IDH mutations, are necessary. In this opinion piece, we present relevant literature in the field, discuss current challenges, and propose some studies that we think are necessary to answer these critical questions.

Cost-Effectiveness of Low-Field Intraoperative Magnetic Resonance in Glioma Surgery.

OBJECT: Low-field intraoperative magnetic resonance (LF-iMR) has demonstrated a slight increase in the extent of resection of intra-axial tumors while preserving patient`s neurological outcomes. However, whether this improvement is cost-effective or not is still matter of controversy. In this clinical investigation we sought to evaluate the cost-effectiveness of the implementation of a LF-iMR in glioma surgery. METHODS: Patients undergoing LF-iMR guided glioma surgery with gross total resection (GTR) intention were prospectively collected and compared to an historical cohort operated without this technology. Socio-demographic and clinical variables (pre and postoperative KPS; histopathological classification; Extent of resection; postoperative complications; need of re-intervention within the first year and 1-year postoperative survival) were collected and analyzed. Effectiveness variables were assessed in both groups: Postoperative Karnofsky performance status scale (pKPS); overall survival (OS); Progression-free survival (PFS); and a variable accounting for the number of patients with a greater than subtotal resection and same or higher postoperative KPS (R-KPS). All preoperative, procedural and postoperative costs linked to the treatment were considered for the cost-effectiveness analysis (diagnostic procedures, prosthesis, operating time, hospitalization, consumables, LF-iMR device, etc). Deterministic and probabilistic simulations were conducted to evaluate the consistency of our analysis. RESULTS: 50 patients were operated with LF-iMR assistance, while 146 belonged to the control group. GTR rate, pKPS, R-KPS, PFS, and 1-year OS were respectively 13,8% (not significative), 7 points (p < 0.05), 17% (p < 0.05), 38 days (p < 0.05), and 3.7% (not significative) higher in the intervention group. Cost-effectiveness analysis showed a mean incremental cost per patient of 789 € in the intervention group. Incremental cost-effectiveness ratios were 111 € per additional point of pKPS, 21 € per additional day free of progression, and 46 € per additional percentage point of R-KPS. CONCLUSION: Glioma patients operated under LF-iMR guidance experience a better functional outcome, higher resection rates, less complications, better PFS rates but similar life expectancy compared to conventional techniques. In terms of efficiency, LF-iMR is very close to be a dominant technology in terms of R-KPS, PFS and pKPS.

Management in chordoid glioma: Avoiding the pitfalls in this rare and challenging entity.

Chordoid glioma (CG) of the third ventricle is an unusual neoplasm of glial nature, which is almost exclusively located in the anterior wall of the third ventricle, in close relation with the hypothalamus. Magnetic resonance images show CG as a suprasellar, hypo- to isointense mass, homogeneously enhancing after the administration of gadolinium. Since its description in 1998 by Brat et al., approximately 85 cases have been reported. Some of its pathological features are under discussion and its histological origin still remains unclear. In this study, we present a patient having this rare entity. We review the management of CG reported in literature. We also studied its pathological features, the postoperative mortality and morbidity related to radical surgical resection, and the implemented adjuvant therapies. Due to its classical clinical features and its close resemblance to other lesions in the region, it is an entity unlikely to be suspected prior to its histological diagnosis. Despite the benign nature of this tumor, the clinical outcome might be poor. Its treatment may represent a real challenge because it involves critical anatomical areas, leading to high postoperative morbidity and mortality rates. An initial minimally invasive management and adjuvant therapies, such as radiosurgery, in case of symptomatic recurrences, can be effective handling strategies.