We followed a 36-year-old man with an atypical meningioma with somatic NF2 mutation and invasion into the bone, temporalis muscle, and pterygopalatine fossa, treated with surgical resection and adjuvant radiation therapy. His medical history included medulloblastoma treated with resection and adjuvant radiation therapy and a WHO Grade 1 meningioma treated with gross total resection. A brain MRI during routine follow-up revealed small enhancing foci in both internal auditory canals (IACs), which prompted concern for bilateral vestibular schwannomas and suspect NF2-related schwannomatosis (NF2-SWN). However, the lesions were symmetric, fundal, and nonnodular on high-resolution constructive interference in steady-state (CISS) imaging, with smooth vestibular nerve contours, long-term interval stability, and a lack of clinical symptoms, favoring physiologic enhancement of the vestibular ganglia (Scarpa's ganglia) rather than vestibular schwannomas. Recognition of these distinguishing features also helped avoid associating the IAC findings with the known NF2 mutation, which was determined to be somatic. While germline NF2 mutations (NF2-SWN) often lead to meningiomas and vestibular schwannomas, somatic NF2 mutations are common in sporadic meningiomas and should not suggest NF2-SWN. This case highlights the need to correlate small enhancing IAC foci with morphology on CISS MRI, symmetry, longitudinal stability, and NF2 pathology to avoid misdiagnosis of enhancing Scarpa's ganglia as vestibular schwannomas, as misdiagnosis can lead to increased patient anxiety and unnecessary follow-ups.

A newly developed noninvasive Oncomagnetic device (OMD) causes selective cytotoxicity in glioblastoma and diffuse intrinsic pontine glioma cells, providing a novel, non-toxic approach to anticancer therapy. Here, we report results in cultured glioma cells and in a syngeneic mouse model indicating that the immediate intracellular target mechanism of action of the spinning oscillating magnetic field (sOMF) produced by this device is reactive oxygen species-dependent persistent inhibition of mitochondrial complex I. Steps downstream of this mechanism involve the production of oxidative stress, DNA damage, G1 phase cell cycle arrest, and caspase-dependent apoptosis. We also show that sOMF does not produce these effects in normal human astrocytes and astroglial cells. These data provide a rationale for safe clinical use of OMD.

This case report details a 60-year-old man who presented with several spinal lesions after they were discovered incidentally during abdominal CT imaging. Lesions were observed in the cervical and thoracic spine and sacrum (C2-C3, C3-C4, C5-C6, T3, T4, T8-T9, S2-S3, and S4 levels) with varying bone involvement, soft tissue extension, and appearance on CT and MRI. The dominant lytic T8-T9 lesion was biopsied, resulting in a diagnosis of chordoma, yet 18F-FDG PET/CT showed no significant FDG activity in this lesion or elsewhere. Other lesions were not biopsied, and all lesions were subsequently monitored with routine imaging. Over the next several years, the lesions continued to show long-term stability on MRI with no symptomatic progression. Due to their longstanding benign nature, the unbiopsied lesions were reevaluated as a more benign etiology, such as benign notochordal cell tumors (BNCTs), which are also derived from notochordal remnants and are hypothesized as a precursor lesion to chordomas, but differ in their clinical behavior, histopathological characteristics, and imaging features. Accurate differentiation between BNCTs and chordomas is imperative for guiding treatment strategies, especially in the very rare case of multiple confounding lesions, as seen in this patient. This report underscores the diagnostic challenges in differentiating BNCTs and chordomas and highlights the importance of correlating histopathological findings with clinical and imaging features for accurate interpretation and intervention.

Glioblastoma (GBM) is the most lethal primary malignant brain tumor with a median survival of 15–20 months. Concurrent temozolomide (TMZ) chemotherapy and radiation (XRT) remain the current standard of care (SOC) treatment for newly diagnosed GBM. The addition of tumor treating fields (TTFs) improves median survival for newly diagnosed GBM from 16 to 20.9 months. This modest improvement underscores the urgent need to identify a new treatment modality as a safe and effective therapy. The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) in vitro. We studied the cellular and molecular effects of Oncomagnetic monotherapy (OMT) on GBM cell lines and investigated immune response in a syngeneic mouse model. OMT significantly reduces cell proliferation and cell survival in vitro. OMT induces persistent ROS primarily by increasing superoxide level in cancer cells and reduces mitochondrial-membrane potential and ATP production in GBM cells. OMT induces DNA damage and arrests cells in G1-phase of the cell cycle. The OMT markedly suppressed tumor growth and reduced contrast-enhanced tumor volume on 9.4T MRI, accompanied by a significant improvement in overall survival in treated mice. We also observed upregulated immune response indicated by RNA sequencing data obtained from OMT-treated GBM cells as well as in treated GBM mouse tumor sections by imaging mass cytometry analysis. The tSNE analysis of various immune clusters suggests significant increase in immune response by activating CD4+, CD8+, murine-macrophages and M1-macrophages located at tumor site in the treated group. The data demonstrate a significant anti-tumor effect through inhibition of cancer signaling pathways and enhanced immune activation. These findings highlight a distinct mechanism of OMT action and support its potential as a standalone therapy for GBM.

BackgroundMetabolic alterations during transformation of low-grade gliomas (LGGs) into high-grade glioblastomas (GBMs) remain incompletely understood. Particularly, IDH wildtype (IDHwt) diffuse astrocytomas harboring TERT promoter (TERTp) mutations, classified as molecular GBM under the 2021 WHO classification, may exhibit distinct metabolic and epigenetic features compared to histological WHO Grade 4 GBMs. Here, we conducted a detailed metabolomic comparison of tumor specimens from a patient initially diagnosed with WHO Grade 2 IDHwt diffuse astrocytoma carrying TERTp mutation, who subsequently progressed to a histologically confirmed WHO Grade 4 GBM upon recurrence.Case presentationA 66-year-old female patient underwent surgical resection of a WHO Grade 2 diffuse astrocytoma in April 2018. Molecular testing revealed IDH1-wildtype status and TERTp mutation, classifying the tumor as a molecular GBM. Following ~3.5 years of clinical stability, magnetic resonance imaging detected tumor recurrence. The patient underwent a second craniotomy in February 2022, with histopathology confirming progression to WHO Grade 4 GBM. Using untargeted proton nuclear magnetic resonance (1H NMR) spectroscopy, we analyzed aqueous-methanol and chloroform phases from methanol-chloroform-water extraction of tumor tissue from both time points. Compared to the primary tumor, the aqueous-methanol phase of the recurrent WHO Grade 4 GBM specimen showed decreased levels of neuronal and glial markers including N-acetylaspartate, myo-inositol, and scyllo-inositol. Elevated metabolites included phosphocholine, phosphoethanolamine, glycine, taurine, hypotaurine, branched-chain amino acids (leucine, isoleucine, valine), and notably alanine, which increased approximately 6-fold. Alanine likely serves as an alternative carbon source supporting tumor proliferation and aggressiveness. The chloroform phase showed the presence of cholesterol in both tumors; however, cholesteryl ester (CE) was detected only in the recurrent tumor. The CE-to-cholesterol ratio of 0.44 in the recurrent tumor suggests significant cholesterol esterification during malignant progression.ConclusionOur findings identify alanine accumulation and increased cholesterol esterification as key metabolic features accompanying malignant transformation from molecular GBM to histological WHO grade-4 GBM. These metabolic changes may serve as biomarkers of tumor progression and recurrence. Importantly, alanine detection via magnetic resonance spectroscopy offers promising potential for non-invasive glioma diagnostics. Furthermore, targeting cholesterol esterification pathways using Acyl-CoA:cholesterol acyltransferase inhibitors could provide a novel therapeutic approach, especially for low-grade astrocytomas with high risk of malignant progression and recurrence.

Diffuse midline glioma (DMG) is a malignant pediatric brain tumor with a median survival of <12 months. Radiotherapy is the mainstay of treatment, and there is no effective chemotherapy for DMG. New therapies are needed for the treatment of this deadly disease. Mitoquinone mesylate (MitoQ), a mitochondria-targeting antioxidant has shown some anti-cancer properties. In our preliminary studies, MitoQ inhibited migration and clonogenicity of DMG cells. In the current study, we investigated the effect of MitoQ on cellular metabolism in DMG cells. Patient-derived H3.3K27M mutant DMG (SF8628) cells were grown in DMEM media, supplemented with 10% FBS and L-glutamine, under humidified air with 5% CO2 at 37 °C. When confluent, cells in the test group were treated with MitoQ (2.5 μM). After overnight incubation, cells were harvested and extracted in perchloric acid (PCA). 1H NMR spectroscopic data were collected on cell extracts and metabolomic analysis was performed. We observed a >2-fold decrease (p-value, <0.03) in the levels of branch-chain amino acids (leucine/isoleucine/valine), lactate, glutamate, aspartate, creatine, phosphocreatine, phosphocholine, taurine, and glycine in MitoQ-treated DMG cells compared to the control group. About 74% and 80% decrease were observed in glutamate and aspartate levels in MitoQ-treated cells compared to the untreated group, suggesting that MitoQ almost completely inhibited mitochondrial metabolism of DMG cells. Moreover, lactate also decreased by 55%, suggesting that MitoQ also inhibits glycolysis indirectly. A decrease in creatine and phosphocreatine in MitoQ-treated group suggests that there is a decrease in ATP production by DMG cells. Glycine, taurine and phosphocholine are generally elevated in aggressive cancer cells, a significant decrease in the levels of these metabolites suggests anti-cancer effect of MitoQ on DMG cells. In conclusion, MitoQ inhibits cellular energy metabolism in DMG cells and it may have potential in metabolic therapy for the treatment of DMG tumors.

We have developed a novel technololgy to treat GBM and DIPG utilizing oscillating magnetic fields (OMF) to kill tumor cells. The mechanism of action is to increase reactive oxygen species in the mitochondria to toxic levels. Normal brain cells have low ROS levels and high antixoxidant defenses and are not affected by this therapy. This presentation provides updates regarding our work We delineated mechanisms of actions in cell culture studes assessing for reactive oxygen species and caspase 3 expression. Clonogenic assays, cell survival studies, flow cytometry, and RNA sequencing were utilized. Efficacy was assessed using syngeneic and PDX mouse models and expanded access treatment in 9 GBM and two DIPG patients. Cell culture studies documented elevation of ROS leading to apoptotic cell death. Optimal oscillating frequencies and on off parameters were determined. Six hours per day of treatment were sufficienct for optimal results. Effects were demonstrated in both syngeneic and PDX mouse glioma using 7T MRI scans.9 endstage GBM patients and two DIPG patients were treated using a removable helmet, six hours a day. No head shave or electrodes were required. Patients received treatment in two hour blocks, thrice daily. Dramatic reduction in contrast enhancement and improvement in OS were seen in 7/9 GBM patient & 1 DIPG patient. No adverse events occurred. OMF is a pwerful and disruptive technology for treatment of GBM. IDE studies in the US and clinical trials in Europe are underway to further study this potentially powerful technique, which may reduce the need for Chemoradiation and resulting toxicity.

INTRODUCTION: A new noninvasive cancer therapeutic device developed in our laboratory, the Oncomagnetic device, involves repeated stimulation with oscillating magnetic fields (sOMF) produced by spinning permanent magnets, distinct from the FDA-approved device Optune® . METHODS: In-vitro, GBM, astroglial SVGp12 and diffuse intrinsic pontine glioma (DIPG) cells were exposed to sOMF. Following this, mice with implanted mouse glioma cells were exposed, followed by end-stage patients. RESULTS: In-vitro, sOMF inhibited mitochondrial ETC complex-I and increased ROS levels in GBM cancer cells. Detection of g-H2AX and 53BP1 foci showed that sOMF caused significant DNA damage in GBM cells and diffuse intrinsic pontine glioma (DIPG) cells but not in normal astroglial SVGp12 cells. GBM cells exposed to sOMF for 4-h caused cell cycle arrest in G1 phase and 30%-40% loss of surviving colonies detected by clonogenic cell survival assay, while normal SVGp12 cells were not affected. This loss of survival in GBM cells was rescued by the antioxidant Trolox. Mice with implanted mouse glioma cells in their brains showed reduction in tumor size, increased survival (p< 0.05, n = 10) and higher DNA damage (g-H2AX foci) in implanted tumor after sOMF treatment. Normal mice exposed to sOMF for 4 months had no adverse effects on the brain and other organs. In a few end-stage glioblastoma (GBM) patients, this device reversed the progression of recurrent tumor, causing a >30% reduction in contrast-enhanced volume within 4 weeks of treatment. CONCLUSIONS: These results indicate that sOMF stimulation has high anticancer potency comparable to low dose radiation therapy at the cellular level with an underlying mechanism of action that is substantially different from that proposed for Optune® TTF.

BACKGROUND:Godtfredsen syndrome (GS), originally described by Dr. Erik Godtfredsen in 1946, is the combination of cranial nerve (CN) 6th and 12th palsies. The most common etiology of GS is a lesion of the clivus. METHODS:A retrospective case series of GS is described. RESULTS:Three patients were included: 1) a 38-year-old woman with a clival breast cancer metastasis; 2) a 35-year-old woman with a clival chordoma; and 3) a 72-year-old woman with a partially embolized dural arteriovenous fistula involving the hypoglossal canal. CONCLUSIONS:GS is a combination of CN 6th and 12th palsies and most commonly is due to a lesion in the clivus. Clinicians should be aware of this uncommon combination of cranial nerve findings, the localizing significance, and the differential diagnosis of clival lesions.

Brainstem gliomas have a poor prognosis and ineffective therapeutic options. We have developed a noninvasive device called an Oncomagnetic device that produces selective oncolysis of gliomas in vitro and marked reduction of contrast-enhanced tumor (CET) volume in end-stage recurrent glioblastoma (GBM) patients. Here we report Oncomagnetic treatment (OMT) of a 28-year-old woman who had undergone partial surgical excision and radiotherapy of a H3 K27M midline glioma in the mesencephalon and pons. OMT initiated after the first recurrence of the tumor was well tolerated for more than 694 days by the patient. There was near-complete regression of the CET at 145 days with symptomatic relief and a partial regression at 554 days after an apparent progression at 518 days. OMT was discontinued after 694 days because of hospital admission due to injuries from a fall and disease progression, which then led to her death. These findings demonstrate the potential of a new effective, nontoxic, and noninvasive wearable device-based treatment for the deadly diffuse midline glioma.

Diffuse midline glioma (DMG), also known as diffuse intrinsic pontine glioma (DIPG) is a malignant pediatric brain tumor that cannot be surgically resected due to its location in the brainstem. Currently available treatment options are ineffective, and the median overall survival is 8-12 months. Currently, radiotherapy is the mainstay of treatment which adds 3-4 months to survival, and there is a great need for novel therapies for the treatment of DMG patients. We have devised a new noninvasive wearable device known as the Oncomagnetic device (OMD) which generates spinning oscillatory magnetic fields (OMF). OMF produces anticancer effects by disrupting mitochondrial electron transport chain, generating elevated levels reactive oxygen species (ROS) and caspase-dependent cell death. We have previously shown that OMF treatment in GBM cells generates superoxide and H2O2. We have also observed ROS generation in DMG cells with OMF treatment. Here, we investigated the effect of OMF on the cellular metabolism of H3.3K27M mutant DMG cells. Patient-derived H3.3K27M mutant DMG (SF8628) cells were grown in DMEM media, supplemented with 10% FBS and L-glutamine, under humidified air with 5% CO2 at 37 °C. When confluent, cells in the treatment group were stimulated with OMF for 4 hours. Cells in both control and test groups were harvested and extracted in 5% perchloric acid. 1H NMR spectroscopic data were collected on the cell extracts for metabolomic analysis. We observed a 3-fold increase in the glutathione (GSH) levels and a 2-fold increase in protein synthesis in OMF-treated DMG cells compared to the control group. The increase in the GSH levels is in response to the ROS generation in the DMG cells due to OMF treatment. On the other hand, the increase in protein levels could be attributed to the response of DMG cells to OMF-induced DNA damage and apoptosis. In conclusion, OMF treatment in DMG cells leads to ROS generation and apoptotic changes, resulting in metabolic changes including GSH production and protein synthesis.

Rhabdoid meningioma is a rare meningeal tumor, considered to be an aggressive meningioma subtype (WHO Grade-III) if the tumor is associated with highly elevated mitotic activity (≥20 mitoses/10 HPFs) and formation of pseudopapillary growth or rhabdoid cells. With 2016 WHO classification of CNS tumors, these tumors have been placed under WHO grade-I (with rhabdoid features) if the above-mentioned grade-III criteria are lacking. Although rhabdoid meningiomas are well characterized immunohistochemically, there are no reports on the 1H MRS based metabolic profiling of these tumors. Here, we report 1H MRS metabolic profiling of a rhabdoid meningioma. The tumor specimen was collected from a rhabdoid meningioma patient undergoing surgery for the resection of the tumor mass. Tumor sample was extracted in 5% perchloric acid, resulting extract was vacuum dried and reconstituted in D2O containing 1.0 mM DSS-d6 (internal standard). Previously, we have identified the following metabolites in grade-I meningioma tumors: lactate, alanine, acetate, glutamate, succinate, glutamine, aspartate, creatine, phosphocreatine, phosphocholine, glycerophosphocholine, myo-inositol, scyllo-inositol, taurine, hypotaurine, glycine, and phosphoethanolamine. The rhabdoid tumor showed a distinct metabolic profile when compared to the grade-I meningioma. This tumor is characterized by relatively higher levels of lactate (9.48 µmol/g, wet tissue) and very low levels of glutamate (0.55 µmol/g, wet tissue) compared to the grade-I meningiomas (lactate = 5.89 µmol/g, and glutamate = 4.06 µmol/g), suggesting that the meningioma tumors with rhabdoid features are glycolytic in nature with dysregulated mitochondrial metabolism. In addition to the above-mentioned metabolites, rhabdoid meningioma also showed low levels of taurine, glycine, phosphocholine and phosphoethanolamine compared to grade-I meningiomas. Relatively low levels of these metabolites further confirm the less aggressive nature of rhabdoid meningioma. In conclusion, rhabdoid meningioma has a distinct metabolic profile which can be detected by 1H MRS. These findings will help in the differential diagnosis of rhabdoid meningiomas and other histologic subtypes of meningiomas.

Background: Glioblastoma (GBM) uses Glut3 and/or Glut14 and the Leloir pathway to catabolize D-Galactose (Gal). UDP-4-deoxy-4-fluorogalactose (UDP-4DFG) is a potent inhibitor of the two key enzymes, UDP-galactose-4-epimerase (GALE) and UDP-Glucose 6-dehydrogenase (UGDH), involved in Gal metabolism and in glycan synthesis. The Gal antimetabolite 4-deoxy-4-fluorogalactose (4DFG) is a good substrate for Glut3/Glut14 and acts as a potent glioma chemotherapeutic. Methods: Primary GBM cell cultures were used to examine toxicity and alterations in glycan composition via lectin binding in fixed cells and by Western blots. Toxicity/efficacy in vivo data was performed in mouse flank and intracranial models. The effect of 4DFG on D-glucose (Glc) metabolism in GBM cells was assessed by using 13C NMR-based tracer studies. Results: 4DFG is moderately potent against GBM cells (IC50: 125–300 µM). GBM glycosylation is disrupted by 4DFG. Survival analysis in an intracranial mouse model showed that treatment with 4DFG (6 × 25 mg/kg of 4DFG, intravenously) improved outcomes by three-fold (p < 0.01). Metabolic flux analysis revealed that both glycolytic and mitochondrial metabolic fluxes of [U-13C]Glc were significantly decreased in the presence of 4DFG in GBM cells. Conclusion: A functional Gal-scavenging pathway in GBM allows Gal-based antimetabolites to act as chemotherapeutics. 4DFG is metabolized by GBM in vitro and in vivo, is lethal to GBM tumors, and is well tolerated in mice.

Abstract BACKGROUND Resection and intraoperative brachytherapy for operable recurrent brain metastasis allows for pathologic confirmation of recurrent disease, mass effect relief, and immediate initiation of radiotherapy (RT). In this analysis, we report patterns-of-use and treatment-related adverse events (AEs) for rBM patients treated with Cs-131 collagen tiles, an FDA-cleared intracranial brachytherapy device. METHODS Patients with rBM who underwent resection and surgically-targeted radiation therapy (GammaTile, GT Medical Technologies Inc., Tempe, AZ USA) on a prospectively enrolling phase 4 registry study (NCT04427384) were analyzed. AEs were graded per CTCAE v5.0. RESULTS Between 11/2020 and 2/2024, 56 rBM in 51 consecutive patients underwent STaRT at 19 centers, with 5 patients having 2 metastases implanted concurrently. 44 patients (86%) had prior same-site RT (median interval 14.5 mo, range 3-56). Primary tumor histologies were lung (27), melanoma (8), breast (7), renal (4), colon (2), and “other” (3). Median pre-operative maximum diameter was 3.0 cm (range 1.4-5.7); age 63 (range 28-81); 53% females; KPS median 90 (range 40-100); and median implantation time 3 minutes. 26 patients were implanted at a 1st, 15 at a 2nd, and 10 at ≥ 3rd same-site recurrence (range 1-9). At a median follow-up of 6.2 months (range <1-35.1), 6/51 patients (11.8%) experienced ≥Gr 3 AEs at a median of 12 (range 1-69) days postoperatively (POD). No radiation necrosis (RN) events were observed, and no AEs occurred in multi-implant cases or where STaRT was the initial form of RT. CONCLUSIONS In this prospective multi-institutional study, STaRT demonstrated an excellent safety profile in a cohort of larger rBM, even in the setting of multi-recurrent disease. Accrual and follow-up are on-going and will provide data on tumor control and long-term RN rates.

Abstract INTRO This is the first observational registry study of R+STaRT, delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers, for patients with intracranial tumors. METHODS Since October 2020, 37 sites to-date have enrolled 359 patients with primary & metastatic intracranial tumors into the R+STaRT registry to assess the safety & efficacy of the addition of Gamma Tile to medically needed resection. Local control, overall survival, QOL, neurocognition, functional decline, and surgical and radiation associated AE’s are collected at 1, 3, 6, 9,12, 18 and 24 months, then every 6 months through 5 years. RESULTS Demographics include 359 patients, avg. age 57 y.o.. 162 malignant gliomas, 125 metastatic tumors, 38 meningiomas, and 34 rare other tumors. 197 Males (163 White, 23 Black, 5 Asian, and other races) and 157 Females (White 121, 28 Black, 0 Asian, and 8 other races). No unexpected outcomes reported in the hands of experienced providers have occurred, although close clinical-radiographic follow-up, to ensure early detection of possible treatment-effects, is paramount. Steroid-use, and above endpoints, continue to be collected. CONCLUSIONS In this observational registry of Gamma Tiles (Cs-131 source brachy-therapy) added to medically needed resections for patients with primary and metastatic intracranial tumors continues. Data will be used to benchmark clinical outcomes of R+STaRT therapy and allow for comparisons to existing standard-of-care treatments. The outcome measures captured will allow for evaluation of the potential risks and benefits of this treatment approach for patients in a real-world setting.