Abstract Background Primary central nervous system lymphoma (PCNSL) can be differentiated from glioblastoma multiforme (GBM) using positron emission tomography (PET) with [18F]fluoro-2-deoxy-D-glucose (FDG). However, differentiation is often difficult with magnetic resonance imaging (MRI) or FDG PET alone. We have used various PET tracers to aid glioma diagnosis; here, we assessed whether multiple PET tracers improve the distinction between GBM and PCNSL. Methods We studied 148 patients with newly diagnosed brain tumors: 96 with GBM and 52 with PCNSL (according to the 2016 World Health Organization classification). Tumor-to-normal tissue ratios (TNRs) were calculated for FDG, L[methyl[11C]]methionine, and 3′deoxy3′[18F]fluorothymidine (FLT). Tumor-to-blood ratio (TBR) was measured for [18F]fluoromisonidazole (FMISO). Results Median FDG TNR was 1.52 (interquartile range [IQR], 1.13–2.13) for GBM and 2.89 (IQR, 1.95–3.85) for PCNSL. MET TNR was 6.38 (IQR, 4.68–7.48) for GBM and 4.01 (IQR, 3.28–7.52) for PCNSL. FLT TNR was 17.35 (IQR, 11.10–22.28) for GBM and 25.61 (IQR, 15.91–55.30) for PCNSL. FMISO TBR was 2.72 (IQR, 2.22–3.62) for GBM and 1.58 (IQR, 1.04–1.93) for PCNSL. Receiver operating characteristic analysis showed areas under the curve of 0.78 (FDG), 0.62 (MET), 0.69 (FLT), and 0.85 (FMISO). FLT TNR had the highest sensitivity of 83.2% while FMISO TBR had the highest specificity of 84.2%. Among the four tracers, FLT showed the highest sensitivity and FMISO showed the highest specificity. Dual‑tracer combinations did not improve overall diagnostic accuracy beyond the best single tracers. Conclusions Among four PET tracers, FMISO was most effective in distinguishing GBM from PCNSL. Diagnostic accuracy was highest when each tracer was used individually.

BACKGROUND:Lymphomas originating from the dura mater of the skull, known as primary dural lymphomas (PDLs), are rare. Among these, cases of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are exceptionally uncommon, and no standardized treatment protocols have been established. The authors report a rare case of CLL/SLL manifesting as PDL mimicking a skull base meningioma and review the relevant literature. OBSERVATIONS:A 71-year-old male presented with an extra-axial tumor extending from the petroclival to middle cranial fossa, which demonstrated progressive enlargement over the course of 1 year. The preoperative diagnosis was meningioma, and the patient subsequently underwent preoperative embolization followed by partial tumor resection. Histological examination revealed CLL/SLL. Postoperatively, the residual lesion was treated with radiation therapy, and no recurrence has been observed for > 3 years. LESSONS:CLL/SLL arising as PDL is difficult to distinguish from meningioma based on clinical and radiological findings. However, it generally shows favorable outcomes when treated with a combination of surgery and low-dose radiation therapy. https://thejns.org/doi/10.3171/CASE25831.

As glioblastoma IDH-wild type (GBM) patients age, preserving cognitive function is as crucial as improving prognosis. At our institution, 46% of GBM cases since 2020 involved patients aged 75 or older. However, comprehensive cognitive assessment is often impractical in this population. We examined whether PET imaging could serve as a noninvasive, objective proxy for evaluating cognitive function. We retrospectively reviewed 27 GBM patients (mean age: 71.6; 12 aged ≥75; 14 men, 13 women) treated from February 2020 to April 2025. Diagnoses were biopsy-confirmed. Patients were categorized into three groups: KPS <60 (n=12), KPS ≥60 (n=8), and neoadjuvant (n=7), defined as KPS <60 with bevacizumab prior to tumor resection. PET tracers included FDG, MET, FLT, and THK5351 (tumor-to-normal ratio) and FMISO (tumor-to-blood ratio). Metabolic Tumor Volume (MTV) was defined as uptake >42% of SUV max. MTV/FLAIR and MTV/T1Gd ratios were calculated. Cognitive function was assessed using MMSE, TMT-A/B, and FAB. MMSE improvement was noted in 4, 5, and 5 patients; TMT-A in 3, 4, and 6; TMT-B in 1, 6, and 3; and FAB in 2, 2, and 3 patients, respectively, in the KPS <60, KPS ≥60, and neoadjuvant groups. MMSE correlated with FDG and FLT MTV/FLAIR and THK5351 MTV (p<0.05). TMT-A correlated with FDG MTV/FLAIR, TMT-B with THK5351 MTV, and FAB with FDG, MET, THK5351 MTV/T1Gd, and FMISO MTV. FDG and THK5351 PET imaging may offer a practical, noninvasive alternative for assessing cognitive function in elderly GBM patients.

With the aging of glioblastoma (GBM) patients, maintaining QOL and higher-order cognitive function has become increasingly important. However, evaluating these aspects and providing ongoing support is often challenging. This study investigated whether serial changes in tau PET imaging using THK5351 could serve as a surrogate marker for cognitive function during treatment in elderly GBM patients, and whether PET uptake patterns might influence prognosis and the need for care support. We retrospectively analyzed 14 patients aged ≥75 years who received bevacizumab (Bev) as initial therapy between February 2020 and March 2025. All patients were diagnosed with GBM via biopsy and were classified into two groups based on KPS: ≥60 and <60. Patients with KPS <60 who underwent tumor resection after Bev were defined as the neoadjuvant group. Cognitive function was evaluated after Bev and before discharge using the MMSE, TMT, and FAB, and findings were correlated with clinical course and support systems. The KPS ≥60 group included 2 patients (mean age 77.5), the KPS <60 group 9 patients (82.6), and the neoadjuvant group 3 patients (76.3). No post-Bev KPS deterioration was observed. Among KPS <60 patients, 4 with THK5351 uptake in the corpus callosum or hippocampus showed declines in MMSE. In contrast, the neoadjuvant group showed no hippocampal uptake and MMSE improvement. TMT-A was improved in 2 neoadjuvant cases. All KPS <60 patients failed TMT-B. FAB showed impairment in 2 KPS <60 cases, while the neoadjuvant case improved in all domains. Seven KPS <60 patients died in long-term care; others died at home. THK5351 PET uptake in the corpus callosum or hippocampus may reflect cognitive decline and predict difficulty with home discharge, offering a useful tool for planning treatment and supportive care.

Abstract OBJECTIVE Positron Emission Tomography (PET) may be useful in diagnosing glioblastoma, determining resection areas, and evaluating therapeutic efficacy. This study evaluated the usefulness of PET scans using 11C-Methionine (MET) to assess amino acid metabolism and 18F-Fluoromisonidazole (FMISO) to assess hypoxic regions in glioblastoma treatment. METHODS Thirty glioblastoma patients who underwent MET and FMISO PET studies from July 2013 to March 2024 were included. Patients underwent the Stupp regimen post-tumor resection and were treated with temozolomide (TMZ) and bevacizumab (Bev) upon recurrence. PET scans were performed before and after two courses of Bev treatment. Changes in tumor to normal ratio (TNR) for MET, tumor to blood ratio (TBR) for FMISO, and metabolic tumor volume (MTV) for both MET and FMISO were evaluated. Progression-free survival (PFS) and overall survival (OS) were compared based on the rate of change in MTV for MET and FMISO. RESULTS The residual volumes (contrast-enhanced MRI, MET, and FMISO) with a MET removal rate of >90% were 0.08 ml, 0.1 ml, and 0.08 ml, respectively. For FMISO removal rates of >90%, residual volumes were 0.36 ml, 1.54 ml, and 0.05 ml, respectively. Groups with a decreased rate of change in MET MTV had significantly better outcomes: PFS (months) 10.7 vs. 2.8 (p=0.19) and OS (months) 18.6 vs. 4.9 (p=0.09). In the FMISO groups, decreased TBR change rates correlated with better outcomes: PFS (months) 16.6 vs. 2.5 (p<0.01) and OS (months) 22.8 vs. 4.9 (p<0.01). MTV change rates also showed significant differences in outcomes: PFS (months) 10.5 vs. 3.7 (p=0.76) and OS (months) 14.9 vs. 7.0 (p=0.87). CONCLUSION Higher MET removal rates correlate with fewer contrast-enhanced MRI and FMISO accumulation areas, suggesting MET as a reliable tumor removal indicator. Both MET and FMISO PET scans are valuable in determining glioblastoma treatment response.

BACKGROUND There is limited literature on the use of positron emission tomography (PET) for benign tumors originating in the brain ventricles, and the use of multiple tracers for subependymal giant cell astrocytoma (SEGA) has not been reported. The authors compared the PET findings in two SEGA cases with past reports and literature, exploring the distinctive characteristics of SEGA on PET. OBSERVATIONS In a 21-year-old female with SEGA, the authors utilized 18F-fluorodeoxyglucose (18F-FDG), 11C-methionine (11C-MET), 18F-fluorothymidine (18F-FLT), 18F-fluoromisonidazole, and 18F-THK5351 tracers. Additionally, in a 6-year-old girl, the authors performed 11C-MET PET. LESSONS The results indicated the accumulation of all tracers except 18F-FDG, with particularly intense accumulation noted with 18F-FLT. In particular, 18F-FLT demonstrated accumulation comparable to that observed in malignant tumors. This study suggests that multiple PET tracers can provide valuable insights into the characterization of SEGA, with 18F-FLT showing particular promise as a distinctive marker of blood-brain barrier disruption. Further research in larger cohorts may enhance our understanding of metabolic patterns in SEGA and aid in its diagnosis and treatment.

Abstract OBJECTIVE Meningiomas are the most common primary brain tumors, typically following a benign course. However, some cases recur after surgery, necessitating further treatment or reoperation. This study aims to examine the relationship between PET studies and pathological findings, and their impact on recurrence. METHODS We included cases of newly diagnosed meningiomas treated surgically in our department from August 2008 to August 2022. The correlation between preoperative FDG-PET and methionine-PET accumulations with pathological findings (WHO grade, Ki-67 index), as well as the impact on recurrence, was investigated. RESULTS The study included 55 cases (22 males, 33 females), aged 17-87 years (median 61.8). The WHO grade was grade 1 in 34 cases and grade 2 in 21 cases, with no grade 3 cases observed. Recurrence occurred in 20 cases during follow-up, necessitating additional treatment. A significant correlation was observed between the tumor T/N ratio and the Ki-67 index for both tracers. Regarding WHO grade, the T/N ratio for FDG was 0.64 in the grade 1 group and 1.04 in the grade 2 group (p<0.01), while for MET, it was 4.8 in the grade 1 group and 6.39 in the grade 2 group (p<0.01), with both tracers showing significantly higher values in the grade 2 group. For postoperative recurrence, the T/N ratio for FDG was 0.97 in the recurrence group and 0.69 in the non-recurrence group (p=0.01), while for MET, it was 6.38 in the recurrence group and 4.66 in the non-recurrence group (p<0.01), with both tracers showing significantly higher values in the recurrence group. CONCLUSION The study demonstrated a significant correlation between preoperative PET studies and pathological findings in meningiomas, as well as an association with recurrence. PET studies were significantly correlated with the tumor malignancy and were considered predictors of postoperative recurrence.

Abstract INTRODUCTION Cancer treatment-related higher brain dysfunction significantly impacts quality of life (QOL) and social life. This study investigates the relationship between PET accumulation areas and advancing cognitive assessment in glioblastoma IDH-wild type (GBM) patients using the PET tracer THK5351, developed to detect tau protein. METHODS Twenty-four GBM patients who underwent changes in tumor to normal ratio (TNR) and metabolic tumor volume (MTV) for THK5351 evaluation before and after temozolomide (TMZ), bevacizumab (Bev), and radiation therapy from February 2020 to March 2024 were included. Cognitive assessments included the Mini-Mental State Examination (MMSE), Trail Making Test (TMT), Frontal Assessment Battery (FAB), Raven’s Coloured Progressive Matrices (RCPM), and Kohs block-design test (Kohs), administered at admission and discharge. RESULTS The mean age of the patients was 70.5 years (14 males, 10 females). All patients were diagnosed with GBM and received TMZ, Bev, and radiation therapy. In 11 patients, a reduction in THK5351 MTV correlated with MMSE improvement. However, 5 patients showed TMT deterioration, with a significant increase in THK5351 TNR change. FAB scores increased in 3 patients, while RCPM and Kohs scores deteriorated in 1 patient, alongside an increase in THK5351 TNR change. Among the 13 patients with enlarged THK5351 MTV, 5 showed decreased MMSE scores, and 3 showed decreased TMT and FAB scores. These cases exhibited an increased THK5351 TNR change, with accumulation expanding from the medial thalamus to the anterior nuclei of the thalamus, hypothalamus, caudate nucleus, hippocampus, and corpus callosum. Patients with reduced THK5351 TNR but enlarged THK5351 MTV had improved MMSE scores but decreased motivation and cognitive function. CONCLUSION Improving the GBM removal rate and preserving function requires attention to THK5351 accumulation in the corpus callosum, hippocampus, and hypothalamus for advancing cognitive assessment.

BACKGROUND/AIM:We evaluated the treatment outcomes of intensity-modulated radiation therapy (IMRT) using a standard radiation dose in patients with high-grade glioma (HGG).PATIENTS AND METHODS:We conducted a prospective, single-institutional, single-arm trial. Patients aged 20-75 years with histologically proven HGG were enrolled. Surgical procedures and chemotherapy regimens were not regulated. The prescribed dose of postoperative IMRT was 60 Gy in 30 fractions over six weeks. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), completion rate of IMRT, and Grade 3 or higher non-hematological toxicity.RESULTS:Between 2016 and 2019, 20 patients were enrolled. According to the World Health Organization 2016 Classification, glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma were present in nine, six, and five of the recruited patients, respectively. Gross total resection, partial resection, and biopsy were performed in four, nine, and seven patients, respectively. All patients received concurrent and adjuvant chemotherapy using temozolomide with or without bevacizumab. The completion rate of IMRT was 100%. The median follow-up period was 29 months (range=6-68 months). Median OS and PFS were 30 and 14 months, respectively. No patients experienced Grade 3 or higher non-hematological toxicity. The 2-year OS rates were 100%, 57%, and 33% in Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) classes I/II, IV, and V, respectively (p=0.002; log-rank test).CONCLUSION:IMRT using the standard radiation dose in patients with HGG can be carried out safely. RTOG-RPA class appears to be useful to estimate patient prognoses.

Glioblastoma is characterized by a strong self-renewal potential and poor differentiated state. We have reported previously that the (pro)renin receptor [(P)RR] is a potential target for glioma therapy by silencing the (P)RR gene. Here, we have examined the effects of a monoclonal antibody against (P)RR on gliomagenesis. Human glioma cell lines (U251MG and U87MG) and a glioma stem cell line (MGG23) were used for the in vitro study. The expressions of the Wnt/β-catenin signaling pathway (Wnt signaling pathway) components and stemness markers were measured by Western blotting. The effects of the (P)RR antibody on cell proliferation, sphere formation, apoptosis and migration were also examined. Subcutaneous xenografts were also examined in nude mice. Treatment with the (P)RR antibody reduced expression of Wnt signaling pathway components and stemness markers. Furthermore, the (P)RR antibody reduced cell proliferation and decreased sphere formation significantly. The treatment also suppressed migration and induced apoptosis. In a subcutaneous xenograft model, systemic administration of the (P)RR antibody reduced tumor volume significantly. These data show that treatment with the (P)RR antibody is a potential therapeutic strategy for treating glioblastoma.

PDF file - 282K, SUPPLEMENTARY TABLE 1. List of EV proteins identified by mass spectrometry.

Abstract OBJECTIVE PET scans are crucial for glioma diagnosis and treatment planning, but assessing the efficacy of Bevacizumab (Bev) treatment using MRI alone is challenging. Our study aimed to evaluate the effectiveness of Bev-based glioblastoma treatment using PET scans. METHODS We included ninety glioblastoma patients treated with Bev between July 2013 and May 2023. Patients were divided into three groups: the first group received Bev in addition to the Stupp regimen after biopsy or subtotal resection (first-dose group), the second group received Bev after biopsy followed by tumor resection (neoadjuvant group), and the third group received the Stupp regimen followed by TMZ + Bev at recurrence (recurrent group). PET scans (FDG, MET, FLT, and FMISO) were performed before and 4 weeks after starting Bev treatment. Tumor-to-normal ratio (TNR) was calculated for FDG, MET, and FLT, and tumor-to-blood ratio (TBR) was determined for FMISO. We used the Cox proportional hazards model to assess the percent change in TNR, TBR, and metabolic tumor volume (MTV) as prognostic factors. RESULTS The median PFS and OS (month) from Bev treatment were as follows: first-dose group (PFS: 8.87, OS: 12.53), neoadjuvant group (PFS: 16.53, OS: 22.13), and recurrent group (PFS: 4.0, OS: 8.0). In the first-line group, significant differences were found in the percent change in MTV for MET, FLT, and FMISO. In the recurrent group, significant differences were observed in the percent change in MTV for FDG and MET, as well as in FDG TNR and FMISO TBR. In the neoadjuvant group, significant differences were found in the percent change in MTV for MET and FLT. CONCLUSION Neoadjuvant Bev treatment led to prolonged PFS and OS in glioblastoma patients. Decreases in MET MTV change rate and FMISO TBR change rate were identified as potential indicators for assessing Bev treatment efficacy after recurrence.

PDF file - 98K, FIGURE S4 related to FIGURE 5. Visualization of GBM-derived EVs uptake.

PDF file - 133K, FIGURE S5 related to FIGURE 6. Effect of miR-1 on GBM-derived EVs protein cargo.

BACKGROUND:Cancer stemness and immunosuppressive tumor microenvironment (TME) in accordance with tumor oxygenation are variable during bevacizumab (Bev) therapy for glioblastoma (GBM). Positron emission tomography (PET) using 18F-fluoromisonidazole (FMISO) reflects hypoxic TME. The aim of this study was to compare FMISO-PET and immunohistochemical findings of tumor oxygenation in the TME of GBM during Bev treatment. METHODS:Seven patients with newly diagnosed IDH-wildtype GBM underwent FMISO-PET during follow-up. Three patients received preoperative neoadjuvant Bev (neo-Bev) and subsequently underwent surgical resection. Reoperation was performed at the recurrence. FMISO-PET was performed before and after neo-Bev. Four patients who underwent tumor resection without neo-Bev were included as the control group. Expressions of hypoxic markers (carbonic anhydrase; CA9), stem cell markers (nestin, FOXM1), and immunoregulatory molecules (CD163, FOXP3, PD-L1) in tumor tissues were analyzed by immunohistochemistry (IHC). RESULTS:All 3 patients treated with neo-Bev showed decrease in FMISO accumulation in accordance with expressions of CA9 and FOXM1 compared with the control group. Two of these 3 patients at the recurrence showed increase in FMISO accumulation. IHC showed increased CA9-and FOXM1-positive cells in recurrent tumors. Expression of PD-L1 tended to be lower after neo-Bev compared with the control group. CONCLUSIONS:FMISO-PET effectively visualized TME oxygenation after neo-Bev. Increased FMISO accumulation at the time of recurrence, even under Bev treatment, suggests that FMISO-PET might be useful for monitoring the duration of Bev efficacy by reflecting tumor oxygenation.

Recent studies have shown that D-allose, a rare sugar, elicits antitumor effects on different types of solid cancers, such as hepatocellular carcinoma, non-small-cell lung cancer, and squamous cell carcinoma of the head and neck. In this study, we examined the effects of D-allose on the proliferation of human glioblastoma (GBM) cell lines (i.e., U251MG and U87MG) in vitro and in vivo and the underlying mechanisms. D-allose treatment inhibited the proliferation of U251MG and U87MG cells in a dose-dependent manner (3–50 mM). However, D-allose treatment did not affect cell cycles or apoptosis in these cells but significantly decreased the cell division frequency in both GBM cell lines. In a subcutaneous U87MG cell xenograft model, intraperitoneal injection of D-allose (100 mg/kg/day) significantly reduced the tumor volume in 28 days. These data indicate that D-allose-induced reduction in cell proliferation is associated with a subsequent decrease in the number of cell divisions, independent of cell-cycle arrest and apoptosis. Thus, D-allose could be an attractive additive to therapeutic strategies for GBM.

Abstract OBJECTIVE This study aims to assess the efficacy of Bevacizumab (Bev) therapy, ten years after its initiation in treating glioblastoma patients at our department. METHODS Eighty-four patients treated with Bev from July 2013 to December 2022 were classified into three groups: the initial treatment group given the Stupp regimen with Bev (first-dose group), the group given the Stupp regimen plus Bev followed by tumor resection (neoadjuvant group), and those receiving the Stupp regimen post tumor resection (recurrence group). PET scans were conducted pre- and post- Bev therapy, and variations in Tumor-to-Normal ratio (TNR), Tumor-to-Blood ratio (TBR), and Metabolic Tumor Volume (MTV) were investigated. RESULTS The median Progression-Free Survival (PFS) and Overall Survival (OS) rates in the first, neoadjuvant, and recurrence groups were respectively (7.86, 14.27, 4.33) and (12.53, 21.57, 13.23) months. Notably, changes in MET and FMISO MTV in the first-treatment group, MET MTV and FMISO TBR changes in the recurrence group, and MET MTV change in the neoadjuvant group significantly influenced prognosis. In the recurrence group, patients who underwent total resection during initial treatment experienced a prolonged period of 25.9 months from initial treatment to the administration of Bev due to recurrence. Furthermore, cases where the FMISO TBR at recurrence was higher than at the initial treatment observed an extended median OS of 18.63 months upon administering Bev treatment at recurrence. CONCLUSION Bev neoadjuvant therapy demonstrated a significant correlation with enhanced PFS and OS outcomes, notably in patients subjected to total resection. In the context of recurrent disease, while the initiation of Bev administration was delayed, a distinct elevation in treatment effectiveness was observed in patients exhibiting an augmented FMISO TBR at the point of recurrence. The observed decreases in MET MTV and FMISO TBR emerge as robust predictors of the efficacy of Bev treatment.

PDF file - 56K, SUPPLEMENTARY TABLE 2. Functional analysis of EV proteins identified by mass spectrometry.

PDF file - 154K, FIGURE S3 related to FIGURE 4. Characterization of GBM-derived EVs.