Fluorescence-guided surgery combined with intraoperative photodynamic therapy for recurrent atypical and anaplastic intracranial meningiomas: a prospective feasibility study

Anastasiia Nechaeva¹Konstantin Kukanov¹Alexey Ulitin¹Victor Olyushin¹Darya Sitovskaya¹Danila Evhenjevich Bobkov²Vseslav Ushanov¹Stephanie E Combs³Konstantin Samochernykh¹Maxim Shevtsov^3*

• ¹Almazov National Medical Research Centre, St.Petersburg, Russia
• ²Institute of Cytology of the Russian Academy of Sciences (RAS), St.Petersburg, Russia
• ³Technical University of Munich, Munich, Germany

Objective: Recurrent intracranial meningiomas are a significant therapeutic challenge due to their invasive growth and high recurrence risk after surgery and radiotherapy. This study investigates the feasibility of a novel integrated approach combining 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery (FGS) with intraoperative photodynamic therapy (PDT) for recurrent atypical and anaplastic meningiomas. Methods: In a single-center, prospective cohort study, 23 patients with recurrent atypical and anaplastic meningiomas received the experimental treatment protocol (FGS+PDT). A retrospective control group (n=35) underwent conventional microsurgery. The intervention included preoperative 5-ALA administration, FGS with visual (Fluorescence Intensity Score, FIS) and quantitative biospectroscopy (Fluorescence Index, FI) guidance, tumor resection, and subsequent PDT (635 nm laser) applied to the resection cavity and tumor matrix. Biospectroscopy guided PDT endpoint (photobleaching and decreasing of FI). Primary outcomes included feasibility, safety, and extent of resection (Simpson Grade), short follow-up period. Histopathological and immunofluorescence analyses of paired pre-/post-PDT biopsies assessed biological effects. Results: The FGS+PDT protocol was successfully completed in all patients with an excellent safety profile; no adverse events were attributed to 5-ALA or PDT. All tumors exhibited visible 5-ALA fluorescence. Gross-total resection (Simpson I-II) was achieved in 95.6% (22/23) of the study group versus 77.1% (27/35) in controls (p<0.05). Biospectroscopy revealed significant PpIX accumulation even in visually low-fluorescence tumors. Over a median follow-up of 16 months, no recurrences were observed in the experimental group. Histopathological analysis demonstrated profound PDT-induced effects, including total ablation of progesterone receptor expression in the tumor matrix and a significant increase in caspase-3-mediated apoptosis in the peritumoral zone (36.3 ± 9.6 vs. 14.8 ± 2.2 cells/mm², p<0.0001). Confocal microscopy confirmed subcellular damage, including mitochondrial dysfunction, nuclear degradation, and Hsp70 overexpression. Conclusion: The integrated FGS and PDT protocol is feasible, safe, and demonstrates compelling preliminary efficacy for recurrent atypical and anaplastic meningiomas. It enhances resection and induces profound cytotoxic and apoptotic effects in the residual tumor bed and peritumoral zone. These results need to be further validated in larger, randomized controlled trials.