Beyond fluorescence-guided resection: 5-ALA-based glioblastoma therapies.

Glioblastoma is the most common primary malignant brain tumor. Despite advances in multimodal concepts over the last decades, prognosis remains poor. Treatment of patients with glioblastoma remains a considerable challenge due to the infiltrative nature of the tumor, rapid growth rates, and tumor heterogeneity. Standard therapy consists of maximally safe microsurgical resection followed by adjuvant radio- and chemotherapy with temozolomide. In recent years, local therapies have been extensively investigated in experimental as well as translational levels. External stimuli-responsive therapies such as Photodynamic Therapy (PDT), Sonodynamic Therapy (SDT) and Radiodynamic Therapy (RDT) can induce cell death mechanisms via generation of reactive oxygen species (ROS) after administration of five-aminolevulinic acid (5-ALA), which induces the formation of sensitizing porphyrins within tumor tissue. Preliminary data from clinical trials are available. The aim of this review is to summarize the status of such therapeutic approaches as an adjunct to current standard therapy in glioblastoma.

2-Hydroxyglutarate as an MR spectroscopic predictor of an IDH mutation in gliomas. / 2-Hydroxyglutarat als MR-spektroskopisch erfassbarer Prädiktor einer IDH-Mutation bei Gliomen.

The mutated enzyme isocitrate dehydrogenase (IDH) 1 and 2 has been detected in various tumor entities such as gliomas and can convert α-ketoglutarate into the oncometabolite 2-hydroxyglutarate (2-HG). This neuro-oncologically significant metabolic product can be detected by MR spectroscopy and is therefore suitable for noninvasive glioma classification and therapy monitoring.This paper provides an up-to-date overview of the methodology and relevance of 1H-MR spectroscopy (MRS) in the oncological primary and follow-up diagnosis of gliomas. The possibilities and limitations of this MR spectroscopic examination are evaluated on the basis of the available literature.By detecting 2-HG, MRS can in principle offer a noninvasive alternative to immunohistological analysis thus avoiding surgical intervention in some cases. However, in addition to an adapted and optimized examination protocol, the individual measurement conditions in the examination region are of decisive importance. Due to the inherently small signal of 2-HG, unfavorable measurement conditions can influence the reliability of detection. · MR spectroscopy enables the non-invasive detection of 2-hydroxyglutarate.. · The measurement of this metabolite allows the detection of an IDH mutation in gliomas.. · The choice of MR examination method is particularly important.. · Detection reliability is influenced by glioma size, necrotic tissue and the existing measurement conditions.. · Bauer J, Raum HN, Kugel H et al. 2-Hydroxyglutarate as an MR spectroscopic predictor of an IDH mutation in gliomas. Fortschr Röntgenstr 2024; DOI 10.1055/a-2285-4923.

Revitalizing neurosurgical frontiers: The EANS frontiers in neurosurgery committee's strategic framework.

Introduction: The field of neurosurgery faces challenges with the increasing involvement of other medical specialties in areas traditionally led by neurosurgeons. This paper examines the implications of this development for neurosurgical practice and patient care, with a focus on specialized areas like pain management, peripheral nerve surgery, and stereotactic radiosurgery. Research question: To assess the implications of the expanded scope of other specialties for neurosurgical practice and to consider the response of the EANS Frontiers in Neurosurgery Committee to these challenges. Materials and methods: Analysis of recent trends in neurosurgery, including the shift in various procedures to other specialties, demographic challenges, and the emergence of minimally invasive techniques. This analysis draws on relevant literature and the initiatives of the Frontiers in Neurosurgery Committee. Results: We explore a possible decrease in neurosurgical involvement in certain areas, which may have implications for patient care and access to specialized neurosurgical interventions. The Frontiers in Neurosurgery Committee's role in addressing these concerns is highlighted, particularly in terms of training, education, research, and networking for neurosurgeons, especially those early in their careers. Discussion and conclusion: The potential decrease in neurosurgical involvement in certain specialties warrants attention. This paper emphasizes the importance of carefully considered responses by neurosurgical societies, such as the EANS, to ensure neurosurgeons continue to play a vital role in managing neurological diseases. Emphasis on ongoing education, integration of minimally invasive techniques, and multidisciplinary collaboration is essential for maintaining the field's competence and quality in patient care.

ALA-RDT in GBM: protocol of the phase I/II dose escalation trial of radiodynamic therapy with 5-Aminolevulinic acid in patients with recurrent glioblastoma.

BACKGROUND: Despite improvements in surgical as well as adjuvant therapies over the last decades, the prognosis for patients with glioblastoma remains poor. Five-Aminolevulinic acid (5-ALA) induced porphyrins are already used for fluorescence-guided resection and as photosensitizer for photodynamic therapy. New findings reveal their potential use as sensitizing agents in combination with ionizing radiation. METHODS: We initiated a phase I/II dose escalation study, treating patients with recurrence of glioblastoma with oral 5-ALA concurrent to radiotherapy (RT). This prospective single-center study based in the University Hospital Münster aims to recruit 30 patients over 18 years of age with histologically verified recurrence of supratentorial glioblastoma in good performance status (KPS ≥ 60). Following a 3 + 3 dose-escalation design, patients having undergone re-resection will receive a 36 Gy RT including radiodynamic therapy fractions (RDT). RDT constitutes of oral administration of 5-ALA before the irradiation session. Two cohorts will additionally receive two fractions of neoadjuvant treatment three and two days before surgery. To determine the maximum tolerated dose of repeated 5-ALA-administration, the number of RDT-fractions will increase, starting with one to a maximum of eight fractions, while closely monitoring for safety and toxicity. Follow-up will be performed at two and five months after treatment. Primary endpoint will be the maximum tolerated dose (MTD) of repeated ALA-administration, secondary endpoints are event-free-, progression-free-, and overall-survival. Additionally, 5-ALA metabolites and radiobiological markers will be analysed throughout the course of therapy and tissue effects after neoadjuvant treatment will be determined in resected tissue. This protocol is in accordance with the SPIRIT guidelines for clinical trial protocols. DISCUSSION: This is the protocol of the ALA-RDT in GBM-study, the first-in-man evaluation of repeated administration of 5-ALA as a radiosensitizer for treatment of recurrent glioblastoma. TRIAL REGISTRATION: This study was approved by the local ethics committee of the Medical Association of Westphalia-Lippe and the University of Münster on 12.10.2022, the German federal institute for Drugs and medical devices on 13.10.2022 and the federal office for radiation protection on 29.08.2022. This trial was registered on the public European EudraCT database (EudraCT-No.: 2021-004631-92) and is registered under www.cliniclatrials.gov (Identifier: NCT05590689).

Does Early Mobilization Following Resection of Spinal Intra-Dural Pathology Increase the Risk of Cerebrospinal Fluid Leaks?-A Dual-Center Comparative Effectiveness Research.

Background and Objectives: Prolonged bed rest after the resection of spinal intradural tumors is postulated to mitigate the development of cerebrospinal fluid leaks (CSFLs), which is one of the feared postoperative complications. Nonetheless, the empirical evidence supporting this conjecture remains limited and requires further investigation. The goal of the study was to investigate whether prolonged bed rest lowers the risk of CSFL after the resection of spinal intradural tumors. The primary outcome was the rate of CSFL in each cohort. Materials and Methods: To validate this hypothesis, we conducted a comparative effectiveness research (CER) study at two distinct academic neurosurgical centers, wherein diverse postoperative treatment protocols were employed. Specifically, one center adopted a prolonged bed rest regimen lasting for three days, while the other implemented early postoperative mobilization. For statistical analysis, case-control matching was performed. Results: Out of an overall 451 cases, we matched 101 patients from each center. We analyzed clinical records and images from each case. In the bed rest center, two patients developed a CSFL (n = 2, 1.98%) compared to four patients (n = 4, 3.96%) in the early mobilization center (p = 0.683). Accordingly, CSFL development was not associated with early mobilization (OR 2.041, 95% CI 0.365-11.403; p = 0.416). Univariate and multivariate analysis identified expansion duraplasty as an independent risk factor for CSFL (OR 60.33, 95% CI: 0.015-0.447; p < 0.001). Conclusions: In this CER, we demonstrate that early mobilization following the resection of spinal intradural tumors does not confer an increased risk of the development of CSFL.

Mixed Reality as a Teaching Tool for Medical Students in Neurosurgery.

Background and Objectives: Simulation-based learning within neurosurgery provides valuable and realistic educational experiences in a safe environment, enhancing the current teaching model. Mixed reality (MR) simulation can deliver a highly immersive experience through head-mounted displays and has become one of the most promising teaching tools in medical education. We aimed to identify whether an MR neurosurgical simulation module within the setting of an undergraduate neurosurgical hands-on course could improve the satisfaction of medical students. Materials and Methods: The quasi-experimental study with 223 medical students [120 in the conventional group (CG) and 103 in the MR-group (MRG)] was conducted at the University Hospital Münster, Münster, Germany. An MR simulation module was presented to the intervention group during an undergraduate neurosurgical hands-on course. Images of a skull fracture were reconstructed into 3D formats compatible with the MR-Viewer (Brainlab, Munich, Germany). Participants could interact virtually with the model and plan a surgical strategy using Magic Leap goggles. The experience was assessed by rating the course on a visual analog scale ranging from 1 (very poor) to 100 (very good) and an additional Likert-scale questionnaire. Results: The satisfaction score for CG and MRG were 89.3 ± 13.3 and 94.2 ± 7.5, respectively. The Wilcoxon rank-sum test showed that MR users (Mdn = 97.0, IQR = 4, n = 103) were significantly more satisfied than CG users (Mdn = 93.0, IQR = 10, n = 120; ln(W) = 8.99, p < 0.001) with moderate effect size (r^biserial = 0.30, CI95 [0.15, 0.43]), thus indicating that the utilization of MR-simulation is associated with greater satisfaction. Conclusions: This study reports a positive response from medical students towards MR as an educational tool. Feedback from the medical students encourages the adoption of disruptive technologies into medical school curricula.

First clinical experience with fractionated intracavitary radioimmunotherapy using [177Lu]Lu-6A10-Fab fragments in patients with glioblastoma: a pilot study.

BACKGROUND: Following resection and standard adjuvant radio- and chemotherapy, approved maintenance therapies for glioblastoma are lacking. Intracavitary radioimmunotherapy (iRIT) with 177Lu-labeled 6A10-Fab fragments targeting tumor-associated carbonic anhydrase XII and injected into the resection cavity offers a novel and promising strategy for improved tumor control. METHODS: Three glioblastoma patients underwent tumor resection followed by standard radio- and chemotherapy. These patients with stable disease following completion of standard therapy underwent iRIT on compassionate grounds. After surgical implantation of a subcutaneous injection reservoir with a catheter into the resection cavity, a leakage test with [99mTc]Tc-DTPA was performed to rule out leakage into other cerebral compartments. IRIT comprised three consecutive applications over three months for each patient, with 25%, 50%, 25% of the total activity injected. A dosimetry protocol was included with blood sampling and SPECT/CT of the abdomen to calculate doses for the bone marrow and kidneys as potential organs at risk. RESULTS: All three patients presented without relevant leakage after application of [99mTc]Tc-DTPA. Two patients underwent three full cycles of iRIT (592 MBq and 1228 MBq total activity). One patient showed histologically proven tumor progression after the second cycle (526 MBq total activity). No relevant therapy-associated toxicities or adverse events were observed. Dosimetry did not reveal absorbed doses above upper dose limits for organs at risk. CONCLUSIONS: In first individual cases, iRIT with [177Lu]Lu-6A10-Fab appears to be feasible and safe, without therapy-related side effects. A confirmatory multicenter phase-I-trial was recently opened and is currently recruiting.

Conceptual development of an intensive exercise program for glioma patients (ActiNO): summary of clinical experience.

PURPOSE: Exercise proved to reduce cancer-related symptoms and prolong survival in some cancer types. However, brain tumor patients are often advised against strenuous exercise. Here, we summarize our experience with a submaximal exercise program for glioma patients: ActiNO (Active in Neuro-Oncology). METHODS: Glioma patients were invited to participate in the program. Since 2011, a sports scientist individualized two one-hour sessions per week adapted to the patients' symptoms. One session consisted of bicycle ergometry (average workload: 75% of maximum heart rate), the other of whole-body resistance training. Both sessions were further complimented by coordinative elements. Cardiorespiratory fitness was assessed using the "Physical Work Capacity" procedure. Patients were followed up regularly to assess adherence to the program and disease activity. RESULTS: Until December 2019, 45 glioma patients, median-aged 49 years (IQR 42-59), were included in the analysis. Most patients suffered from glioblastoma (58%), followed by diffuse lower-grade astrocytoma (29%). In overall 1828 training sessions, two minor epileptic events occurred (1 speech arrest; 1 focal seizure). During fitness assessment, all patients achieved at least 75% of their age-adjusted maximum heart rate. Peak workload averaged 172 W (95% CI 156-187). Median survival of participating glioblastoma patients was 24.1 months (95% CI 8.6-39.5). CONCLUSION: This supervised training program with submaximal exertion was feasible and safe in glioma regardless of WHO grading. Based on these experiences, we initiated a prospective multicenter study to objectify improvements in physical performance and quality of life in patients with glioblastoma.

Importance of interdisciplinarity in modern oncology: results of a national intergroup survey of the Young Oncologists United (YOU).

PURPOSE: Modern, personalized treatment concepts in oncology require an interdisciplinary and multiprofessional collaboration. In addition to its relevance in patient care, interdisciplinary collaboration is also becoming increasingly important in clinical research as well as medical education and resident training in oncology. METHODS: Between November 2021 and March 2022, an online survey was conducted among German early career research groups, represented by Young Oncologists United (YOU). The aim was to identify the status and need for interdisciplinarity at clinic, educational, and research levels. RESULTS: A total of 294 participants completed the questionnaire in full. 90.7% of the respondents fully or predominantly agreed with the statement that interdisciplinary work plays a major role in their daily clinical work. 78.9% wished for more interdisciplinary collaboration. Of the 49.7% of participants who have never participated in an interdisciplinary research project, 80.1% said they would like to participate in such a study project in the future. Lack of time resources, too much organizational effort, and possible political conflicts between institutions were identified as factors that make practical implementation difficult. 74.1% declared their willingness to become active in an oncology early career research group. CONCLUSION: Interdisciplinary collaboration has become increasingly important in oncology. Networks that span different disciplines could help to promote interdisciplinary research projects among young scientists and improve exchange in professional practice and education with the implication of improved patient care.

Adult intracranial ependymoma-relevance of DNA methylation profiling for diagnosis, prognosis, and treatment.

BACKGROUND: A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas. METHODS: Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from 8 diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS). RESULTS: The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6%, and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE, and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (GTR) (P = .009) and postoperative radiotherapy (P = .007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of the prognosis within molecularly defined ependymoma classes. CONCLUSIONS: DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. GTR and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.

Minimally Invasive Facetectomy and Fusion for Resection of Extensive Dumbbell Tumors in the Lumbar Spine.

Background and Objectives: Resection of dumbbell tumors can be challenging, and facet joint sparing approaches carry the risk of incomplete resection. In contrast, additional facetectomy may allow better surgical exposure at the cost of spinal stability. The aim of this study is to compare facet-sparing and facetectomy approaches for the treatment of lumbar spine dumbbell tumors. Materials and Methods: In a cohort study setting, we analyzed Eden type 2 and 3 tumors operated in our department. Conventional facet-sparing microsurgical or facetectomy approaches with minimally invasive fusions were performed according to individual surgeons' preference. Primary outcomes were extent of resection and tumor progression over time. Secondary outcomes were perioperative adverse events. Results: Nineteen patients were included. Nine patients were operated on using a facet-sparing technique. Ten patients underwent facetectomy and fusion. While only one patient (11%) in the facet-sparing group experienced gross total resection (GTR), this was achieved for all patients in the facetectomy group (100%). The relative risk (RR) for incomplete resection in the facet-sparing cohort was 18.7 (95% CI 1.23-284.047; p = 0.035). In addition, time to progression was shorter in the facet-sparing cohort (p = 0.022) and all patients with a residual tumor underwent a second resection after a median follow-up time of 42 months (IQR 25-66). Conclusions: Minimally invasive resection of lumbar Eden type 2 and 3 dumbbell tumors including facetectomy in combination with instrumentation appears to be safe and superior to the facet-sparing approach in terms of local tumor control.

5-ALA fluorescence in indeterminate grade gliomas.

5-Aminolevulinic acid (5-ALA) is a useful and well-established adjunct for glioblastoma surgery. A growing body of evidence has revealed the potential utility of 5-ALA in grade II and grade III glioma patients as well. However, reliable means of identifying in whom fluorescence will occur have not been established. The authors report the case of such an indeterminate-grade glioma highlighting two pearls of 5-ALA fluorescence in this subgroup of patients. Firstly, 5-ALA-guided tissue sampling helps to ensure that the true grade of the lesion is not underestimated. Secondly, intraoperative fluorescence can serve as a prognostic marker. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21196.

Intratumor heterogeneity and T cell exhaustion in primary CNS lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare lymphoma of the central nervous system, usually of diffuse large B cell phenotype. Stereotactic biopsy followed by histopathology is the diagnostic standard. However, limited material is available from CNS biopsies, thus impeding an in-depth characterization of PCNSL. METHODS: We performed flow cytometry, single-cell RNA sequencing, and B cell receptor sequencing of PCNSL cells released from biopsy material, blood, and cerebrospinal fluid (CSF), and spatial transcriptomics of biopsy samples. RESULTS: PCNSL-released cells were predominantly activated CD19+CD20+CD38+CD27+ B cells. In single-cell RNA sequencing, PCNSL cells were transcriptionally heterogeneous, forming multiple malignant B cell clusters. Hyperexpanded B cell clones were shared between biopsy- and CSF- but not blood-derived cells. T cells in the tumor microenvironment upregulated immune checkpoint molecules, thereby recognizing immune evasion signals from PCNSL cells. Spatial transcriptomics revealed heterogeneous spatial organization of malignant B cell clusters, mirroring their transcriptional heterogeneity across patients, and pronounced expression of T cell exhaustion markers, co-localizing with a highly malignant B cell cluster. CONCLUSIONS: Malignant B cells in PCNSL show transcriptional and spatial intratumor heterogeneity. T cell exhaustion is frequent in the PCNSL microenvironment, co-localizes with malignant cells, and highlights the potential of personalized treatments.

Andexanet-Alfa-Associated Heparin Resistance in the Context of Hemorrhagic Stroke.

BACKGROUND: With a growing number of patients on new oral anticoagulants, interest in reversal agents is rising. Andexanet alfa is used for reversal of factor Xa inhibitors in intracranial hemorrhage. METHODS: We provide a brief review on andexanet-alfa-associated heparin resistance and discuss potentially critical situations from different clinical perspectives. RESULTS: Case reports point out that andexanet alfa can cause unresponsiveness to heparin, leading to catastrophic events. As a result, regulatory bodies have issued warning notices to avoid heparinization parallel to the use of andexanet alfa. CONCLUSIONS: Although well known to hematologists, the phenomenon is underrecognized among stroke clinicians. However, patients with intracranial hemorrhage frequently undergo endovascular or surgical interventions that require periprocedural administration of heparin.

DNA methylation profiling of central nervous system hemangioblastomas identifies two distinct subgroups.

Hemangioblastomas (HBs) of the central nervous system are highly vascular neoplasms that occur sporadically or as a manifestation of von Hippel-Lindau (VHL) disease. Despite their benign nature, HBs are clinically heterogeneous and can be associated with significant morbidity due to mass effects of peritumoral cysts or tumor progression. Underlying molecular factors involved in HB tumor biology remain elusive. We investigated genome-wide DNA methylation profiles and clinical and histopathological features in a series of 47 HBs from 42 patients, including 28 individuals with VHL disease. Thirty tumors occurred in the cerebellum, 8 in the brainstem and 8 HBs were of spinal location, while 1 HB was located in the cerebrum. Histologically, 12 HBs (26%) belonged to the cellular subtype and exclusively occurred in the cerebellum, whereas 35 HBs were reticular (74%). Unsupervised clustering and dimensionality reduction of DNA methylation profiles revealed two distinct subgroups. Methylation cluster 1 comprised 30 HBs of mainly cerebellar location (29/30, 97%), whereas methylation cluster 2 contained 17 HBs predominantly located in non-cerebellar compartments (16/17, 94%). The sum of chromosomal regions being affected by copy-number alterations was significantly higher in methylation cluster 1 compared to cluster 2 (mean 262 vs. 109 Mb, p = 0.001). Of note, loss of chromosome 6 occurred in 9/30 tumors (30%) of methylation cluster 1 and was not observed in cluster 2 tumors (p = 0.01). No relevant methylation differences between sporadic and VHL-related HBs or cystic and non-cystic HBs could be detected. Deconvolution of the bulk DNA methylation profiles revealed four methylation components that were associated with the two methylation clusters suggesting cluster-specific cell-type compositions. In conclusion, methylation profiling of HBs reveals 2 distinct subgroups that mainly associate with anatomical location, cytogenetic profiles and differences in cell type composition, potentially reflecting different cells of origin.

A Data-Driven Approach to Predicting 5-Aminolevulinic Acid-Induced Fluorescence and World Health Organization Grade in Newly Diagnosed Diffuse Gliomas.

BACKGROUND: A growing body of evidence has revealed the potential utility of 5-aminolevulinic acid (5-ALA) as a surgical adjunct in selected lower-grade gliomas. However, a reliable means of identifying which lower-grade gliomas will fluoresce has not been established. OBJECTIVE: To identify clinical and radiological factors predictive of intraoperative fluorescence in intermediate-grade gliomas. In addition, given that higher-grade gliomas are more likely to fluoresce than lower-grade gliomas, we also sought to develop a means of predicting glioma grade. METHODS: We investigated a cohort of patients with grade II and grade III gliomas who received 5-ALA before resection at a single institution. Using a logistic regression-based model, we evaluated 14 clinical and molecular variables considered plausible determinants of fluorescence. We then distilled the most predictive features to develop a model for predicting both fluorescence and tumor grade. We also explored the relationship between intraoperative fluorescence and diagnostic molecular markers. RESULTS: One hundered seventy-nine subjects were eligible for inclusion. Our logistic regression classifier accurately predicted intraoperative fluorescence in our cohort with 91.9% accuracy and revealed enhancement as the singular variable in determining intraoperative fluorescence. There was a direct relationship between enhancement on MRI and the likelihood of observed fluorescence. Observed fluorescence correlated with MIB-1 index but not with isocitrate dehydrogenase (IDH) status, 1p19q codeletion, or methylguanine DNA methyltransferase promoter methylation. CONCLUSION: We demonstrate a strong correlation between enhancement on preoperative MRI and the likelihood of visible fluorescence during surgery in patients with intermediate-grade glioma. Our analysis provides a robust method for predicting 5-ALA-induced fluorescence in patients with grade II and grade III gliomas.

Combined Fluorescence-Guided Resection and Intracavitary Thermotherapy with Superparamagnetic Iron-Oxide Nanoparticles for Recurrent High-Grade Glioma: Case Series with Emphasis on Complication Management.

BACKGROUND: Concepts improving local tumor control in high-grade glioma (HGG) are desperately needed. The aim of this study is to report an extended series of cases treated with a combination of 5-ALA-fluorescence-guided resection (FGR) and intracavitary thermotherapy with superparamagnetic iron oxide nanoparticles (SPION). METHODS: We conducted a single-center retrospective review of all recurrent HGG treated with FGR and intracavitary thermotherapy (n = 18). Patients underwent six hyperthermia sessions in an alternating magnetic field and received additional adjuvant therapies on a case-by-case basis. RESULTS: Nine patients were treated for first tumor recurrence; all other patients had suffered at least two recurrences. Nine patients received combined radiotherapy and thermotherapy. The median progression-free survival was 5.5 (95% CI: 4.67-6.13) months and median overall survival was 9.5 (95% CI: 7.12-11.79) months. No major side effects were observed during active treatment. Thirteen patients (72%) developed cerebral edema and more clinical symptoms during follow-up and were initially treated with dexamethasone. Six (33%) of these patients underwent surgical removal of nanoparticles due to refractory edema. CONCLUSIONS: The combination of FGR and intracavitary thermotherapy with SPION provides a new treatment option for improving local tumor control in recurrent HGG. The development of cerebral edema is a major issue requiring further refinements of the treatment protocol.

Double dose of 5-aminolevulinic acid and its effect on protoporphyrin IX accumulation in low-grade glioma.

OBJECTIVE: Administration of 5-aminolevulinic acid (5-ALA) does not regularly elicit fluorescence in low-grade glioma (LGG) at currently established doses and timing of administration. One explanation may be differences in blood-brain barrier (BBB) integrity compared to high-grade glioma. The authors hypothesized that for a BBB semipermeable to 5-ALA there might be a relationship between plasma 5-ALA concentration and its movement into the brain. A higher dose would elicit more 5-ALA conversion into protoporphyrin IX (PPIX). The authors present a case series of patients harboring LGG who received higher doses of 5-ALA. METHODS: Patients undergoing surgery for indeterminate glioma later diagnosed as LGG were included in this study. 5-ALA was administered at a standard dose of 20 mg/kg body weight (bw) 4 hours prior to induction of anesthesia. A subgroup of patients received a higher dose of 40 mg/kg bw. Fluorescence was evaluated visually and PPIX concentration (cPPIX) was determined ex vivo by hyperspectral measurements in freshly extracted tissue. All adverse events were recorded. RESULTS: A total of 23 patients harboring diffuse low-grade astrocytomas (n = 19) and oligodendrogliomas (n = 4) were analyzed. Thirteen patients received 20 mg/kg bw, and 10 patients received 40 mg/kg bw of 5-ALA. In the 20 mg/kg group, 30.8% (4 of 13) of tumors harbored areas of visible fluorescence, compared to 60% of cases (n = 6 of 10) with 40 mg/kg bw. The threshold to visibility was 1 µg/ml in both groups. Measured over all biopsies, the mean cPPIX was significantly higher in the double-dose group (1.8 vs 0.45 µg/ml; p < 0.001). In non-visibly fluorescent tissue the mean cPPIX was 0.146 µg/ml in the 20 mg/kg and 0.347 µg/ml in the 40 mg/kg group, indicating an increase of 138% (p < 0.001). CONCLUSIONS: These observations demonstrate different regions with different levels of PPIX accumulation in LGG. With higher 5-ALA doses cPPIX increases, leading to more regions surpassing the visibility threshold of 1 µg/ml. These observations can be explained by the fact that the BBB in LGG is semipermeable to 5-ALA. Higher 5-ALA doses result in more PPIX conversion, an observation with implications for future dosing in LGG.