Newly emerged T2 high-signal intensity area mimicking oligodendroglioma expansion on intraoperative magnetic resonance imaging: A case report.

Magnetic resonance imaging (MRI) is an indispensable tool in neurosurgery, though it sometimes faces challenges such as "tumor mimicry." While intraoperative MRI (iMRI) is widely recognized for its usefulness in achieving maximal safe resection during glioma surgery, instances of tumor mimicry still occur on iMRI. Moreover, reports on tumor mimics observed through iMRI, particularly in low-grade gliomas, remain scarce. In this article, we present a case of oligodendroglioma, where a newly emerged T2 high-signal intensity region on iMRI necessitated differentiation from tumor expansion. A 23-year-old man presented with a newly diagnosed brain tumor and underwent surgical removal. An iMRI taken after tumor removal revealed a newly emerged T2 hyperintense area without diffusion restriction around the resection cavity, which was not observed in the preoperative MRI. Suspecting residual tumor, we performed additional resection. An MRI on the following day confirmed that the T2 hyperintense area identified on the iMRI had been completely resected but also revealed an enlarged T2 high-signal area over a wider region. Histopathology found no tumor cells in the additionally resected area, indicating that the iMRI finding was a tumor mimic. Six months later, the T2 high-signal area around the resection cavity had disappeared on MRI without any additional treatment. This case highlights the challenge of distinguishing between T2 hyperintense mimicry and tumor enlargement during glioma surgery seen on iMRI. Despite the significant value of iMRI, our report underscores the need for careful interpretation in neurosurgical practice, particularly with non-contrast-enhancing tumors.

Cost of medical care for malignant brain tumors at hospitals in the Japan Clinical Oncology Group brain-tumor study group.

BACKGROUND: This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved. METHODS: We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL. RESULTS: The most used regimen (46.8%) for GBM in patients aged ≤74 years was 'Surgery + radiotherapy concomitant with temozolomide'. This regimen's total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, 'Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy' was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month). CONCLUSIONS: Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors.

A retrospective cohort study of stereotactic radiosurgery for vestibular schwannomas: Comparison of two age groups (75 years or older vs. 65-74 years).

Background: Treatment outcome data of stereotactic radiosurgery (SRS) for vestibular schwannomas (VS) in patients ≥75 years (late elderly) are lacking. Approximately 39% of patients ≥75 years with VS were reported to experience severe facial palsy after surgical removal. This study compared the treatment outcomes post-SRS for VS between patients ≥75 and 65-74 years (early elderly). Methods: Of 453 patients who underwent gamma knife SRS for VS, 156 were ≥65 years old. The late and early elderly groups comprised 35 and 121 patients, respectively. The median tumor volume was 4.4 cc, and the median radiation dose was 12.0 Gy. Results: The median follow-up periods were 37 and 56 months in the late and early elderly groups, respectively. Tumor volume control was observed in 27 (88%) and 95 (83%) patients (P = 0.78), while additional procedures were required in 2 (6%) and 6 (6%) patients (P = 1.00) in the late and early elderly groups, respectively. At the 60th and 120th months post-SRS, the cumulative tumor control rates were 87%, 75%, 85%, and 73% (P = 0.81), while the cumulative clinical control rates were 93% and 87%, 95%, and 89% (P = 0.80), in the late and early elderly groups, respectively. In the early elderly group, two patients experienced facial pain, and one experienced facial palsy post-SRS; there were no adverse effects in the late elderly group (both P = 1.00). Conclusion: SRS is effective for VS and beneficial in patients ≥75 years old as it preserves the facial nerve.

The Safety of Intraoperative Photodynamic Diagnosis Using 5-Aminolevulinic Acid Combined with Talaporfin Sodium Photodynamic Therapy in Recurrent High-Grade Glioma.

BACKGROUND: Intraoperative photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) is a widely adopted technique to enhance the extent of resection during high-grade glioma (HGG) surgery. Recent updates to the package insert for 5-ALA in Japan now allow its use in combination with drugs that may induce photosensitivity, such as talaporfin sodium (TS). TS is employed in intraoperative photodynamic therapy (PDT) and has been shown to improve overall survival. The combination of 5-ALA with TS is expected to offer further benefits. However, the safety of this combination had not been established. This study reports on the safety of 5-ALA-PDD with TS-PDT in the treatment of recurrent HGG. METHODS: 7 patients with recurrent HGG underwent tumor resection using a combination of 5-ALA-PDD and TS-PDT. The incidence of photosensitivity as an adverse effect associated with 5-ALA and TS was evaluated as described in the package insert. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: Tumor-specific fluorescence intensity was strong in 4 cases and weak in 3. Photosensitivity occurred in only 1 patient (14.3%). Three patients exhibited CTCAE grade 1 or 2 abnormal liver function, and 1 patient experienced CTCAE grade 1 γ-GTP elevation. All abnormalities improved during follow-up. CONCLUSIONS: The combined use of 5-ALA-PDD and TS-PDT for HGG surgery did not increase the risk of serious adverse events in our study. Further investigations with a larger number of cases are needed for a more accurate assessment of its safety and efficacy.

An analytical method using salting-out assisted liquid-liquid extraction to quantify ceftriaxone from micro volumes of human serum.

Ceftriaxone (CTRX) is a commonly used cephalosporin antibiotic. It is suggested that monitoring plasma/serum concentrations is helpful for its safe use. This study aimed to develop and validate an analytical method for measuring CTRX concentrations in human serum according to International Conference on Harmonization guideline M10. Ten microliters of serum sample was purified using a salting-out assisted liquid-liquid extraction procedure with magnesium sulfate. The upper layer was then diluted threefold and analyzed using a liquid chromatography-tandem mass spectrometry-based method with a total run time of 12 min. The linear calibration curve was obtained over the concentration range 5-500 µg/ml. The within-run accuracy varied from 0.2 to 6.5%, and the precision was ≤8.0%. The between-run accuracy and precision ranged from 0.7% to 5.6% and ≤6.4%, respectively. Significant carryover was resolved by injecting four blanks after high-concentration CTRX samples. The recovery rates from spiked serum at low and high concentrations were 44.4 and 43.4%, respectively. Other factors, including selectivity, matrix effects, stability, dilution integrity and reinjection reproducibility also met the acceptance criteria. Serum concentrations in 14 samples obtained from two participants receiving 2 g/day of CTRX were successfully determined using this method.

Recent Status of Phase I Clinical Trials for Brain Tumors: A Regulatory Science Study of Exploratory Efficacy Endpoints.

BACKGROUND: Appropriate exploratory efficacy data from Phase I trials are vital for subsequent phases. Owing to the uniqueness of brain tumors (BTs), use of different strategies to evaluate efficacy is warranted. We studied exploratory efficacy evaluation in Phase I trials involving BTs. METHODS: Using Clarivate's Cortellis™, 42 Phase I trials of BT interventions conducted from 2020 to 2022 were analyzed for efficacy endpoints, which were set as primary endpoints (PEs) or secondary endpoints (SEs). Additionally, these metrics were compared in two subgroups: trials including only BTs (Group-A) and those including BTs among mixed solid tumors (Group-B). RESULTS: Selected studies included a median of 1.5 PEs (range, 1-6) and 5 SEs (range, 0-19). Efficacy endpoints were included as PEs and SEs in 2 (5%) and 31 (78%) trials, respectively. Among the latter 31 trials that included 94 efficacy endpoints, 24, 22, 20, 9, and 8 reflected overall response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and disease control rate (DCR), respectively. ORR for BT was determined using various methods; however, the Response Evaluation Criteria in Solid Tumors (RECIST) was used less frequently in Group-A than in Group-B (p = 0.0039). CONCLUSIONS: Recent Phase I trials included efficacy endpoints as SEs, with ORR, PFS, or OS included in ~ 50% trials and DOR or DCR in ~ 25%. No established criteria exist for imaging evaluation of BTs. Phase I trials involving mixed solid tumor cohorts revealed challenges in designing methods to assess the exploratory efficacy of BTs.

H3 K27-altered diffuse midline glioma in adults arising from atypical regions: Two case reports and literature review.

Diffuse midline glioma (DMG), H3 K27-altered, is a newly defined "pediatric-type," diffuse, high-grade glioma under current WHO classifications (updated in 2021). An essential diagnostic criteria of DMG is its occurrence in the midline structures; most intracranial DMG occurs in the brainstem or thalamus but can also occur in other midline structures. We experienced 2 adult cases of intracranial DMGs in areas other than the brainstem and thalamus that were initially difficult to diagnose. Case 1 was a 49-year-old man with extensive T2 high-signal lesions in the bilateral frontal lobes and corpus callosum on brain MRI. A Gd-based contrast medium partially enhanced the lesion and showed marked diffusion restriction, mimicking malignant lymphoma. Case 2 was a 24-year-old man who presented with paroxysmal olfactory abnormalities. The tumor extended mainly to the right temporal lobe, the right basal forebrain, and the bilateral hypothalamus, showing a T2/FLAIR mismatch sign suggestive of IDH-mutant astrocytoma without 1p/19q co-deletion. After a biopsy, both cases were properly diagnosed as DMG, H3 K27-altered (K27M-mutant). Diagnosing adult cases involving atypical midline structures is sometimes challenging before surgery; we discuss this phenomenon with both case details and a literature review.

P53-negative status and gross total resection as predictive factors for autologous tumor vaccine treatment in newly diagnosed glioblastoma patients.

Background: Among primary brain tumors, glioblastoma (GBM) is the most common and aggressive in adults, with limited treatment options. Our previous study showed that autologous formalin-fixed tumor vaccine (AFTV) contributed to prognostic improvements in newly diagnosed GBM patients. However, some patients died early despite the treatment. The discovery of predictive factors in the treatment was warranted for efficient patient recruitment and studies to overcome resistance mechanisms. Identifying prognostic factors will establish AFTV guidelines for patients who may respond to the therapy. Methods: Data from 58 patients with newly diagnosed GBM, including 29 who received standard therapy plus AFTV (AFTV group) and 29 who received standard treatment (control group) were analyzed. Several data including patient age, sex, the extent of removal, and various cell immunohistochemistry (IHC) parameters were also included in the analysis. Results: Both univariate and multivariate analyses revealed that gross total resection (GTR) and negative p53 were associated with a better prognosis only in the AFTV group. In the IHC parameters, CD8 staining status was also one of the predictive factors in the univariate analysis. For blood cell-related data, lymphocyte counts of 1100 or more and monocyte counts of 280 or more before chemo-radiotherapy were significant factors for good prognosis in the univariate analysis. Conclusions: A p53-negative status in IHC and GTR were the predictive factors for AFTV treatment in newly diagnosed GBM patients. Microenvironment-targeted treatment and pretreatment blood cell status may be key factors to enhance therapy effects.

Acute cerebral hemorrhage mimicking glioblastoma on intraoperative magnetic resonance imaging: A case report.

Intraoperative magnetic resonance imaging (iMRI) is important in neurosurgical practice, especially for glioma surgery. However, the well-reported possibility to mistake lesions for brain tumors (tumor mimics) with MRI also exists for iMRI. Here, we first report a case of glioblastoma with acute cerebral hemorrhage that mimicked a newly emerged brain tumor on iMRI. A 53-year-old man underwent a second surgery for recurrent glioblastoma. Intraoperatively, iMRI revealed a new, enhanced lesion near the resected area that was absent on preoperative MRI and difficult to differentiate from newly emerged tumors. Here, a recent preoperative MRI was helpful and the new lesion was actually a hematoma. Neurosurgeons must understand that, as acute intracerebral hemorrhaging can mimic brain tumors on iMRI, preoperative MRI should be conducted just before surgery to place iMRI findings in proper context and avoid unnecessary resections.

Sclerosing meningioma with a large peritumoral cyst: Case report.

Meningioma morphology is diverse. Although unlisted in the WHO classification, sclerosing meningioma is a rare variation featuring an extremely low signal intensity on MRI T2-weighted imaging. About 50 cases of sclerosing meningiomas, including spinal tumors, have been reported; however, cases with an accompanying large peritumoral cyst remain unreported. Here, we first report a rare case of sclerosing meningioma with a large peritumoral cyst and review relevant literature.

Hemorrhagic Complications After Brain Tumor Biopsy: Risk-Reduction Strategies Based on Safer Biopsy Targets and Techniques.

OBJECTIVE: Brain tumor biopsies are essential for pathologic diagnosis. However, hemorrhagic complications after biopsies may occur, leading to suboptimal outcomes. This study aimed to evaluate the associated factors of hemorrhagic complications after brain tumor biopsies and propose countermeasures. METHODS: We retrospectively collected data on 208 consecutive patients with brain tumors (malignant lymphoma or glioma) who underwent a biopsy from 2011-2020. We evaluated factors and microbleeds (MBs) in the tumor plus relative cerebral/tumoral blood flow (rCBF) at the biopsy site on preoperative magnetic resonance imaging (MRI). RESULTS: Postoperative all and symptomatic hemorrhage occurred in 21.6% and 9.6% of patients. In univariate analysis, a needle biopsy was significantly associated with the risk of all and symptomatic hemorrhages compared to techniques that allow adequate hemostatic manipulation (i.e., open and endoscopic biopsies). Multivariate analyses revealed that a needle biopsy and gliomas of World Health Organization (WHO) grade III/IV were significantly associated with postoperative all and symptomatic hemorrhages. Multiple lesions were also an independent risk factor for symptomatic hemorrhages. On preoperative MRI, abundant MBs in the tumor and MBs at the biopsy sites, in addition to high rCBF, were significantly associated with postoperative all and symptomatic hemorrhages. CONCLUSIONS: We recommend the following measures to prevent hemorrhagic complications: consider biopsy techniques that allow adequate hemostatic manipulation preferentially; perform more careful hemostasis in cases of suspected gliomas of WHO grade III/IV, multiple lesions, and abundant MBs in the tumors; and, if there are multiple candidate biopsy sites, select areas with lower rCBF and no MBs as a biopsy target.

High-dose proton beam therapy versus conventional fractionated radiation therapy for newly diagnosed glioblastoma: a propensity score matching analysis.

BACKGROUND: High-dose proton beam therapy (PBT) uses excellent dose concentricity based on the unique characteristic termed the Bragg peak. PBT is a highly feasible treatment option that improves survival in select patients with newly diagnosed glioblastoma (GBM). However, selection bias remains an issue in prior studies that evaluated the efficacy of PBT. The aim of the present study was to compare the survival outcomes and toxicities of high-dose PBT and conventional radiation therapy (CRT) using propensity score-matched treatment cohorts. METHODS: The analysis included patients with newly diagnosed GBM treated with high-dose PBT of 96.6 Gy (RBE) or CRT of 60 Gy from 2010 to 2020. Propensity score generation and 1:1 matching of patients were performed based on the following covariates: age, sex, tumor location, extent of resection, chemotherapy, immunotherapy, and pre-radiation Karnofsky performance scale score. RESULTS: From a total of 235 patients, 26 were selected in each group by propensity score matching. The median overall survival (OS) of the PBT group was 28.3 months, while the median OS of the CRT group was 21.2 months. Although acute radiation-related toxicities were equivalent between the PBT and CRT groups, radiation necrosis as a late radiation-related toxicity was observed significantly more frequently in the PBT group. CONCLUSIONS: High-dose PBT provided significant survival benefits for patients with newly diagnosed GBM compared to CRT as shown by propensity score matching analysis. Radiation necrosis remains an issue in high-dose PBT; thus, the establishment of an effective treatment strategy centered on bevacizumab would be essential.

Efficacy Endpoints in Phase II Clinical Trials for Meningioma: An Analysis of Recent Clinical Trials.

BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST)-based response rates are commonly used as efficacy endpoints in phase II clinical trials for solid tumors. However, no consensus has been reached concerning adequate efficacy endpoints for phase II clinical trials targeting meningioma. Irregularity of lesions after resection, and varying degrees of dysplasia and histologic subtypes make establishing an appropriate efficacy evaluation difficult. METHODS: We analyzed primary efficacy endpoints (PEEs) and background factors from 48 trials retrieved from ClinicalTrials.gov ( https://clinicaltrials.gov/ ) using the search criteria "meningioma," "interventional," "phase II," and "study start 4/1/2001 to 3/31/2021." Primary purpose of the study was efficacy endpoint setting in overall population and three subgroups. RESULTS: Among 45 PEEs set in the 39 trials included; 33 trials with single PEE, and six trials with double PEEs, 17/45 (38%) trials adopted progression-free survival (PFS) rate, 15/45 (33%) trials response rate (seven Macdonald criteria or modified, three RECIST, three volumetric estimation, one RANO criteria, one unknown), 10/45 (22%) PFS, 1/45 (2%) OS, and 2/45 (4%) other endpoints. Although 26 PEEs were time-to-event endpoints, 19 of the 26 PEEs were single-arm studies. CONCLUSIONS: Time-to-event efficacy endpoints were often compared to historical data, and two-dimensional evaluation is more suitable than one-dimensional one. Accumulation of prognostic data is essential to standardize time-to-event efficacy endpoints. Considering the difficulty of setting design for phase II clinical studies targeting meningioma, evaluation might be done with multiple efficacy endpoints.

Frontal sinus giant osteoma with radiologically unusual component suggesting blood supply: A case report.

Osteoma is a common, slow growing bone tumor, and often affects the paranasal sinus. Typically, it shows a very hyperdense osseous lesion on computed tomography (CT) scan and low-intensity change on T2-weighted image on magnetic resonance imaging (MRI). No report has mentioned osteomas in blood supply on MRI. A 57-year-old male patient presented with a prolonged declined activity and a gigantic osseous tumor that originated from the frontal sinus, which markedly compressed the bilateral frontal lobe. MRI revealed a slightly enhanced front basal part of the tumor by gadolinium, with blood supply from ethmoidal arteries. The patient underwent surgery, and the diagnosis of osteoma was made based on histological findings. We reported a case of giant osteoma originating from the frontal sinus with unusual blood supply on 4-dimensional MR angiography.

Levetiracetam Versus Levetiracetam Plus Sodium Channel Blockers for Postoperative Epileptic Seizure Prevention in Brain Tumor Patients.

Background Brain tumor patients tend to develop postoperative epileptic seizures, which can lead to an unfavorable outcome. Although the incidence of postoperative epileptic seizures and adverse events are improved with the advent of levetiracetam (LEV), postoperative epilepsy occurs at a frequency of 4.6% or higher. In brain tumor patients, the addition of sodium channel blockers (SCBs) to LEV significantly reduces seizures, though confirmed in a non-postoperative study. Thus, the combination of SCBs with LEV might be promising. Objective In this prospective randomized controlled trial we investigated the safety, evaluated by adverse events during one and two weeks after surgery, and the efficacy, evaluated by the incidence of early epilepsy, including non-convulsive status epilepticus (NCSE), of using LEV alone or SCBs added to LEV in patients who underwent craniotomy or biopsy for brain tumors or brain mass lesions. Methods Patients with brain tumors or brain mass lesions undergoing surgical interventions, excluding endoscopic endonasal surgery (EES), with a diagnosis of epilepsy were eligible for this study. Patients are randomized into either Group A or B (B1 or B2) after the informed consents are taken; LEV alone in Group A patients, while LEV and SCBs in Group B patients (GroupB1, intravenous fosphenytoin plus oral lacosamide (LCM) and GroupB2, intravenous LCM plus oral LCM) were administered postoperatively. Fifty-three patients were enrolled during the first two and a half years of the study and four of them were excluded, resulting in the accumulation of 49 patients' data. Results Postoperative epileptic seizures occurred only in three out of 49 patients during the first week (6.1%) and in seven patients within two weeks after surgery (14.3%, including the three patients during the first week). In Group A, epileptic seizures occurred in two out of 26 patients during the first week (7.7%) and in five patients within two weeks (19.2%) after surgery. In Group B, epileptic seizures occurred in one out of 23 patients during the first week (4.3%) and in two patients during the first two weeks (8.7%). Low complication grade of epileptic seizures was observed in Group B rather than in Group A, however, without significant difference (p=0.256). There was no difference in the frequency of adverse effects in each group. Conclusion Although not statistically significant, the incidence of epileptic seizures within one week after surgery was lesser in LEV+SCBs groups than in LEV alone. No hepatic damage or renal function worsening occurred with the addition of LCM, suggesting the safety of LEV+SCBs therapy.

Perioperative Deep Vein Thrombosis and D-dimer Measurement in Patients with Brain Tumor.

We investigated the appropriate D-dimer cutoff value for each brain tumor type for acute or subacute deep vein thrombosis (DVT) following transcranial brain tumor surgery.In this single-center retrospective study, a cumulative total of 128 patients who underwent transcranial brain tumor surgery were enrolled and classified into the glioma group, the other intracranial malignant tumor group, and the intracranial benign tumor group. Venous ultrasonography was performed if the D-dimer plasma levels were positive (≥1 µg/mL) before surgery and on postoperative day (POD) 3 or 7.Of the 128 cases, DVT developed in 32 (25.0%). Among those, acute or subacute DVT was diagnosed in 22 cases on POD 3 and in 8 cases on POD 7. Compared with DVT-negative cases on POD 3, acute or subacute DVT-positive cases on POD 3 revealed a significant increase in the D-dimer level in all groups combined and in the benign tumor group but not in the glioma group. With regard to DVT on POD 3 in all groups, the receiver operating characteristic curve for the D-dimer level on POD 3 demonstrated a cutoff value of 3.3 µg/mL (sensitivity [0.636] and specificity [0.750]). However, if this cutoff value was used in practice, eight cases would be false-negative with a minimum D-dimer level of 1.5 µg/mL.The D-dimer cutoff value for acute or subacute DVT on POD 3 could be set to 3.3 µg/mL; however, the setting resulted in several false-negative cases. Practically, 1.5 µg/mL of the D-dimer cutoff value on POD 3 might be appropriate to avoid false-negative results.

Maximum resection and immunotherapy improve glioblastoma patient survival: a retrospective single-institution prognostic analysis.

Glioblastoma (GBM) is a refractory disease with a poor prognosis and various methods, including maximum resection and immunotherapy, have been tested to improve outcomes. In this retrospective study we analyzed the prognostic factors of 277 newly diagnosed GBM patients over 11 years of consecutive cases at our institution to evaluate the effect of these methods on prognosis. Various data, including the extent of removal (EOR) and type of adjuvant therapy, were examined and prognostic relationships were analyzed. The median overall survival (OS) of the entire 277-case cohort, 200 non-biopsy cases, and 77 biopsy cases was 16.6 months, 19.7 months, and 9.7 months, respectively. Gross total removal (GTR; 100% of EOR) was achieved in 32.9% of the cases. Univariate analysis revealed younger age, right side, higher Karnofsky performance status, GTR, intraoperative magnetic resonance imaging (MRI) use for removal, proton therapy, combination immunotherapy, and discharge to home as good prognostic factors. Intraoperative MRI use and EOR were closely related. In the multivariate analysis, GTR, proton therapy, and a combination of immunotherapies, including autologous formalin-fixed tumor vaccine, were the significant prognostic factors. A multivariate analysis of 91 GTR cases showed that immunotherapy contributed to prognostic improvements. The median OS and 5-year OS % values were 36.9 months and 43.3% in GTR cases receiving immunotherapy. In conclusion, GTR, proton therapy, and immunotherapy were good prognostic factors in single-center GBM cases. Tumor vaccine therapy for GTR cases achieved a notably high median survival time and long-term survival ratio, indicating its usefulness in GTR cases.

Hemagglutinating virus of Japan-envelope containing programmed cell death-ligand 1 siRNA inhibits immunosuppressive activities and elicits antitumor immune responses in glioma.

The programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway is involved in preventing immune system-mediated destruction of malignant tumors including glioblastoma. However, the therapeutic influence of PD-1/PD-L1 inhibition alone in glioblastoma is limited. To develop effective combination therapy involving PD-1/PD-L1 inhibition, we used a non-replicating virus-derived vector, hemagglutinating virus of Japan-envelope (HVJ-E), to inhibit tumor cell PD-L1 expression by delivering siRNA targeting PD-L1. HVJ-E is a promising vector for efficient delivery of enclosed substances to the target cells. Moreover, HVJ-E provokes robust antitumoral immunity by activating natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and by suppressing regulatory T lymphocytes (Treg). We hypothesized that we could efficiently deliver PD-L1-inhibiting siRNAs to tumor cells using HVJ-E, and that synergistic activation of antitumoral immunity would occur due to the immunostimulating effects of HVJ-E and PD-1/PD-L1 inhibition. We used artificially induced murine glioma stem-like cells, TS, to create mouse (C57BL/6N) glioblastoma models. Intratumoral injection of HVJ-E containing siRNA targeting PD-L1 (siPDL1/HVJ-E) suppressed the expression of tumor cell PD-L1 and significantly suppressed tumor growth in subcutaneous models and prolonged overall survival in brain tumor models. Flow cytometric analyses of brain tumor models showed that the proportions of brain-infiltrating CTL and NK cells were significantly increased after giving siPDL1/HVJ-E; in contrast, the rate of Treg/CD4+ cells was significantly decreased in HVJ-E-treated tumors. CD8 depletion abrogated the therapeutic effect of siPDL1/HVJ-E, indicating that CD8+ T lymphocytes mainly mediated this therapeutic effect. We believe that this non-replicating immunovirotherapy may be a novel therapeutic alternative to treat patients with glioblastoma.

Therapeutic Strategies for Overcoming Immunotherapy Resistance Mediated by Immunosuppressive Factors of the Glioblastoma Microenvironment.

Various mechanisms of treatment resistance have been reported for glioblastoma (GBM) and other tumors. Resistance to immunotherapy in GBM patients may be caused by acquisition of immunosuppressive ability by tumor cells and an altered tumor microenvironment. Although novel strategies using an immune-checkpoint inhibitor (ICI), such as anti-programmed cell death-1 antibody, have been clinically proven to be effective in many types of malignant tumors, such strategies may be insufficient to prevent regrowth in recurrent GBM. The main cause of GBM recurrence may be the existence of an immunosuppressive tumor microenvironment involving immunosuppressive cytokines, extracellular vesicles, chemokines produced by glioma and glioma-initiating cells, immunosuppressive cells, etc. Among these, recent research has paid attention to various immunosuppressive cells-including M2-type macrophages and myeloid-derived suppressor cells-that cause immunosuppression in GBM microenvironments. Here, we review the epidemiological features, tumor immune microenvironment, and associations between the expression of immune checkpoint molecules and the prognosis of GBM. We also reviewed various ongoing or future immunotherapies for GBM. Various strategies, such as a combination of ICI therapies, might overcome these immunosuppressive mechanisms in the GBM microenvironment.

Infiltration of CD163-positive macrophages in glioma tissues after treatment with anti-PD-L1 antibody and role of PI3Kγ inhibitor as a combination therapy with anti-PD-L1 antibody in in vivo model using temozolomide-resistant murine glioma-initiating cells.

Although chemoimmunotherapy often lengthens glioblastoma (GBM) survival, early relapses remain problematic as immunosuppressive M2 macrophages (Mϕ) that function via inhibitory cytokine and PD-L1 production cause immunotherapy resistance. Here, we detail anti-PD-L1 antibody effects on the tumor microenvironment, including Mϕ infiltration, using a temozolomide (TMZ)-treated glioma model. In addition, we tested combinations of anti-PD-L1 antibody and the M2Mϕ inhibitor IPI-549 on tumor growth. We simulated late TMZ treatment or relapse stage, persistent GBM cells by generating TMZ-resistant TS (TMZRTS) cells. M2Mϕ-associated cytokine production and PD-L1 expression in these cells were investigated. TMZRTS cells were then subcutaneously implanted into C57BL/6 mice to determine the effectiveness of an anti-PD-L1 antibody and/or IPI-549 treatment on infiltration of CD163-positive Mϕ, usually considered as an M2Mϕ marker into tumor tissues. CD163 expression in samples from human GBM patients were also evaluated. CD163-positive Mϕ heavily infiltrated TMZRS tumor tissues after in vivo anti-PD-L1 antibody treatment. Tumor growth was strongly inhibited by anti-PD-L1 antibody and IPI-549 combination therapy. Anti-PD-L1 antibody treatment significantly reduced infiltration of CD163-positive Mϕ into tumors, while combined PD-L1 antibody and IPI-549 therapy remarkably inhibited tumor growth. These therapies may be useful for recurrent or chronic GBM after TMZ treatment, but clinical safety and effectiveness studies are needed.