bluuebunny/crossref_metadata_2025 huggingface dataset:
IM-1 THE IMMUNOSUPPRESSIVE ROLE OF MAIT CELLS AND MR1 IN GBM THROUGH THE INDUCTION OF NEUTROPHILS AND MDSCS
Authors: Hana Taijun , Terabe Masaki
Published: December 2022

Background

Glioblastoma (GBM) is a devastating brain tumor, and its immunosuppressive microenvironment has been implicated in the poor prognosis. However, the mechanism of the induction of the microenvironment is not well understood. MHC class I-related protein (MR1) is an antigen-presenting molecule for Mucosal-Associated Invariant T (MAIT) cells. Recently, MR1 transcriptomic level was reported to correlate with glioma’s poor survival, and the infiltration of MAIT cells in GBM was reported previously. However, the role of MAIT cells and MR1 in GBM is poorly understood. We aimed to understand the mechanism by which MR1 levels affect GBM patient survival and any potential involvement of MAIT cells.

Method

RNA-sequencing data from TCGA-GBM was subjected to multi-layered analysis. Multiple methods, including comprehensive gene expression analysis and direct alignment-search using FASTQ data, were used to assess the immunological impact of MAIT cells in GBM. Using data from Pan-cancer TCGA, the role of MAIT cells in other cancer types was assessed.

Result

The survival of GBM patients was negatively correlated with the level of MR1 expression. 8.3% of TCGA-GBM samples were identified to have MAIT cell infiltration, and the expression of MR1, the amount of MAIT cell infiltration, and the activity of tumor-associated neutrophils (TANs)/myeloid-derived suppressor cells (MDSCs) were significantly correlated. Simultaneously, the TAN/MDSC activity was significantly correlated with the poor survival of GBM patients. In four more cancer types, similar relationships between MAIT/MR1 and TANs/MDSCs were observed.

Conclusions

Our observations shed light on the possible immunosuppressive role of MAIT cells and MR1. It was shown that MR1 up-regulation causes MAIT cell activation, which in turn causes TAN/MDSC induction. The current study implied the existence of a novel MAIT/MR1-TAN/MDSC immunosuppressive pathway, whose activation is associated with a worse prognosis for GBM. It was also suggested that a similar pathway might exist in other cancer types.
IM-3 IDENTIFICATION OF THERAPEUTIC TARGET ANTIGENS USING PATIENT DERIVED GLIOBLASTOMA AND THEIR APPLICATION TO CAR-T THERAPY
Authors: Kuroda Hideki , Kijima Noriyuki , Tachi Tetsuro , Utsugi Rena , HIrayama Ryuichi , Okita Yoshiko , Kagawa Maoki , Hosen Naoki , Kishima Haruhiko
Published: December 2022

Introduction

Recently, CAR-T cell (chimertic antigen receptor T-cell) therapy has been attracting and has shown high therapeutic efficacy, especially in the hematological tumors. The T cells from patient are then genetically engineered to specifically bind to and attack the target tumor cell antigen. In the brain, EGFRvIII or HER2 have been used as antigens, but have yet to show positive results. It is necessary to find antibodies that are more specific and have a therapeutic effect.

Methods

A primary culture line was prepared from glioblastoma surgical specimens, and immunized to Balb/c mice with it.The B cells from the mice were fused with myeloma cells, immortalized, and cultured monoclonally to obtain a number of monoclonal antibodies reacted glioblastoma cells. The obtained antibodies were reacted with glioblastoma cells and normal brain cells, and those that specifically react to glioblastoma were selected by flowcytometry to obtain antibody candidates that could be specifically expressed on the surface of glioblastoma cells.

Results

Approximately 20,000 antibody-producing strains were generated. From these, about 3,200 strains were selected as the reacted with immunized glioblastoma. About 560 strains was selected that reacted with at least one other glioblastoma, and from these, we selected 30 strains that did not react with normal brain cells. Finally, the cells were frozen and thawed at least once, and 13 stably growing strains selected.

Discussion

We have been identified one antibody among approximately 500 strains in past our study, and have confirmed that it is B7H3, a pan-tumor antibody. We will generate more antibody candidates in the future, as well as identify antibodies in 13 strains that have already been selected and confirmed to be glioblastoma-specific antibodies. We will also create CAR-T cells targeting these antibodies and confirm their anti-tumor effects.
ACT-1 A PROSPECTIVE MULTICENTER PHASE I/IIA STUDY OF PREOPERATIVE NEOADJUVANT BEVACIZUMAB FOR NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Tanaka Toshihide , Tamura Ryota , Takei Jun , Morimoto Yukina , Teshigawara Akihiko , Tohmoto Kyoichi , Kuranari Yuki , Imai Ryotarou , Yamamoto Yohei , Hasegawa Yuzuru , Akasaki Yasuharu , Murayama Yuichi , Miyake Keisuke , Sasaki Hikaru
Published: December 2022

Background

Preoperative neoadjuvant bevacizumab (neoBev) reduces enhancement and perifocal edema by inhibition of angiogenesis and vascular permeability for glioblastoma (GBM). The aim of this study was to investigate safety and efficacy of neoBev for newly diagnosed GBM through an exploratory prospective multi-center study.

METHODS & PATIENTS

15 patients with newly diagnosed GBM were enrolled in the present study. Eligibility was a patient with a brain tumor representing with ring-shaped enhancement and perifocal edema on magnetic resonance imaging (MRI). Based on neuroimage of typical GBM, neoBev and temozolomide (TMZ) were administered prior to craniotomy. Two weeks after neoBev, the tumor volume on T1-weighted gadolinium enhancement (T1Gd) and fluid attenuated inversion recovery (FLAIR) were assessed. Three to four weeks after neoBev and TMZ administration, patients underwent surgical resection. The primary endpoint was feasibility and safety, and the secondary endpoint was efficacy. Adverse events including systemic toxicity and wound healing delay during radiation (RT), TMZ, and Bev combined therapy were carefully monitored throughout clinical course including extent of resection.

RESULTS

Average of tumor regression rate two weeks after neoBev on T1Gd and FLAIR were 37.0% and 54.0%, respectively. Cerebral blood flow and cerebral blood volume were reduced after neoBev. Patients underwent surgical resection safely without excess blood loss due to less vascular and less degree of brain swelling. Two patients underwent awake surgery without any complications. Postoperative MRI showed that the all tumors were totally removed except one with multiple invasive tumors. Histological diagnosis of all patients was GBM, IDH-1 wild-type. Postoperative course was uneventful without neurological deficit and adverse effects except one postoperative hematoma in the resection cavity and one wound infection due to wound dehiscence.

CONCLUSION

Preoperative neoBev for newly diagnosed GBM might contribute to safe surgery. Clinical outcome of this therapeutics is now currently under investigation.
ACT-2 JCOG0911A2 AND ESTABLISHING AN INFRASTRUCTURE FOR RADIOLOGICAL STUDIES FOR JCOG BRAIN TUMOR STUDY GROUP CLINICAL TRIALS
Authors: Kinoshita Manabu , Sasaki Keita , Natsume Atsushi , Wakabayashi Toshihiko , Arakawa Yoshiki , Narita Yoshitaka
Published: December 2022

Background

Radiological information is indispensable to understanding the pathology and correctly assessing the treatment response of malignant brain tumors. Clinical trials conducted outside of Japan have vigorously collected and investigated radiological images of the enrolled patients and published many significant findings, such as the RANO criteria. The authors initiated the JCOG0911A2 study, which is an ancillary analysis of JCOG0911, and established an infrastructure for collecting and analyzing raw radiological images of patients enrolled in clinical trials conducted by the JCOG brain tumor study group. JCOG0911A2 study design and infrastructure for radiological image storage: JCOG0911A2 aims to collect all radiological images related to the JCOG0911 study, conduct radiomics analysis, and complete general radiological research. Among 122 registered patients, 2532 series from 118 cases accounting for 237 GB of data were collected as of June 28, 2022. All collected data were anonymized and stored in Osirix MD with triple data backup. JCOG0911A2's treatment response assessment will be performed according to the RANO criteria. Thus, the authors developed a script in MATLAB that enables semi-automatic treatment response assessment according to the investigators' annotations on Osirix MD.

Data Management

The abovementioned “semi-automatic treatment response assessment script” was not necessary until up to a collection of 30 cases. However, manual management became impossible as more case data arrived, and establishing a sophisticated and systematic data management system was inevitable. The data management system developed for JCOG0911A2 is also used with minor modifications for the ongoing JCOG study.

Conclusion

JCOG0911A2 study established a reliable infrastructure capable of handling radiological images from patients enrolled in JCOG brain tumor study group clinical trials.
ACT-8 A RANDOMIZED PHASE III STUDY OF HYPOFRACTIONATED RADIOTHERAPY COMBINED WITH TEMOZOLOMIDE IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA: JCOG1910 (AGEDGLIO-PIII)
Authors: Mineharu Yohei , Uto Megumi , Ichimura Koichi , Matsushita Yuko , Ono Tomohiro , Ito Yoshinori , Nishikawa Ryo , Nishimura Yasumasa , Narita Yoshitaka , Mizowaki Takashi , Arakawa Yoshiki
Published: December 2022

Background

The current standard treatment for elderly patients with newly diagnosed glioblastoma is surgery followed by short-course radiotherapy (40 Gy in 15 fractions) with temozolomide. Further reduction of fractionation is expected to reduce the burden for elderly patients without decreasing therapeutic efficacy.

Methods

This multi-institutional randomized phase III trial was commenced to confirm the non-inferiority of radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant and adjuvant temozolomide in terms of overall survival (OS) in elderly patients aged 71 or older with newly diagnosed glioblastoma. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, and proportion of health-related quality of life preservation. MGMT promoter methylation was included as an adjustment factor, and tumor specimen have been collected soon after the tumor resection and molecular diagnosis has been made centrally before randomization. A total of 270 patients will be accrued from 55 Japanese institutions in 4 years and follow-up will last 2 years.

Results

More than a half of patients (160 /270 cases) have been recruited between August 2020 and July 2022. Molecular diagnosis was made all but one cases, and diagnosis was made centrally within around 7 days after receiving the tumor specimen. There were one grade 4 severe adverse event and one treatment related death.

Discussion

Registration has been made smoothly without substantial delay due to central molecular diagnosis. The study has been safely performed for elderly patients. If the primary endpoint is met, hypofractionated radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be a standard of care for elderly patients with newly diagnosed glioblastoma.
ACT-11 CLINICAL BENEFIT OF ADD-ON BEVACIZUMAB FOR NEWLY DIAGNOSED GLIOBLASTOMA IN ELDERLY PATIENTS WITH UNRESECTABLE AND POOR PERFORMANCE STATUS
Authors: Tomoto Kyoichi , Yamamoto Yohei , Tanaka Toshihide , Suzuki Tomoya , Teshigawara Akihiko , Takei Jun , Koseki Hirokazu , Mori Ryosuke , Akasaki Yasuharu , Murayama Yuichi
Published: December 2022

Background

Since phase 3 randomized clinical trials failed to show the benefit of bevacizumab(Bev) from the induction therapy, Bev was widely used for the recurrence glioblastoma(GBM) cases. Given that Bev treatment for newly diagnosed GBM(nd-GBM) is permitted only in Japan, we could confirm the appropriate usage and timing of Bev for the GBM patient clinically. Here, we report the clinical benefit of Bev for nd-GBM based on the retrospective cohort study.

Methods

We retrospectively investigated 172 GBM patients who were treated with surgery, radiation therapy(RT) and temozolomide(TMZ) at our hospitals in 2006 to 2020. We classified with and without Bev patients for age, Karnofsky performance status(KPS) and extent of resection(EOR). Kaplan-Meier survival analysis was used to compare median overall survival(mOS) between patients who were treated with Bev simultaneously during Stupp regimen(S-Bev) and without Bev(NS-Bev).

Results

Bev provided prolonged mOS in the elderly(>60 years old)(p<0.01), poor KPS(<70)(p=0.015) and low EOR(<90%)(p<0.01) groups. In addition, mOS was longer in S-Bev compared with NS-Bev in the elderly and low EOR groups, and there was statistically significant difference in low EOR group(p<0.01). S-Bev tended to prolong mOS in elder patients(p=0.06) and NS-Bev tended to prolong in young patients(p=0.31).

Conclusion

Bev therapy commenced simultaneously with concurrent RT and TMZ might contribute to improve mOS for patients with high risk including the elderly, poor KPS and low EOR. Stratification based on risk factors including age and EOR might be effective for patients in whom Bev should be preferentially used as a first-line therapy.
ACT-13 DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA: A FIRST-IN-HUMAN, PHASE 1 STUDY
Authors: Yoshiki Arakawa , Reardon David , Narita Yoshitaka , Goldlust Samuel , Anstass George , McMullen Dragana , Dow Edward , Seki Masataka , Furuta Yudai , Song Gregory , Colman Howard
Published: December 2022

Background

The brain's cells are fully dependent on their own de novo biosynthesis of cholesterol as the blood-brain barrier prevents its uptake from the circulation. In normal glial cells, proper regulation of cholesterol synthesis depends on its cell density and is turned off when the cell density exceeds a certain level. On the other hand, gliomas maintain high levels of cholesterol synthesis to support abnormal growth under any condition. Upregulation of cholesterol synthesis genes is associated with decreased survival in patients with glioblastoma (GBM). Therefore, gliomas are potentially sensitive to cholesterol synthesis inhibition. DSP-0390 is an investigational small molecule inhibitor of EBP, an enzyme in one of the last steps of cholesterol biosynthesis. By inhibiting de novo cholesterol synthesis, cytotoxicity can be induced more selectively against hyperproliferative GBM cells. DSP-0390 has shown significant antitumor activity in orthotopic xenograft GBM models (data on file).

Methods

DSP-0390 will be evaluated in a phase 1 study in patients with recurrent high-grade glioma (NCT05023551). Key eligibility criteria: age ≥18 years; KPS score ≥70%; and adequate organ and hematologic function. Patients must not have multifocal disease, leptomeningeal metastasis, extracranial metastasis. In Dose Escalation, 21-30 patients with World Health Organization (WHO) grade III or IV malignant glioma who progressed after ≥1 prior therapy will be enrolled. Dose escalation will be guided by a Bayesian Logistic Regression Model until identification of the maximum tolerated dose or recommended dose for expansion. Dose Expansion will enroll approximately 20-40 patients with WHO grade IV GBM who progressed after primary therapy and have measurable disease. Study endpoints include safety (treatment-emergent adverse events [AEs], serious AEs, and dose-limiting toxicities), efficacy (6-month progression-free survival [PFS], objective response, PFS, duration of response, and 12-month overall survival), pharmacokinetics (PK), and pharmacodynamic biomarkers. This study is currently recruiting in the United States and Japan.
ACT-15 EFFICACY AND SAFETY OF SUBTOTAL RESECTION, 'FLAIRECTOMY' FOR RECURRENT GLIOBLASTOMA
Authors: Saito Kuniaki , Sasaki Nobuyoshi , Sasaki Yuta , Yamagishi Yuki , Kobayashi Keiichi , Shiokawa Yoshiaki , Nakatomi Hirofumi , Nagane Motoo
Published: December 2022

Background

Aggressive resection of recurrent glioblastoma has been reported to prolong survival and should be considered for resectable recurrences. In recent years, expanded resection for primary glioblastoma, especially removal of the FLAIR hyperintensity region beyond the contrast-enhancing lesion (FLAIRectomy; FR), has been reported, but there are no reports of FR for recurrent glioblastomas. In this study, we examined the efficacy and safety of FR for recurrent glioblastoma.

Methods

Recurrent glioblastoma operated on at our institution from January 2014 to July 2022 were included. The extent of resection (EOR) of contrast-enhancing lesions and FLAIR hyperintensity lesion was measured. Progression-free survival (PFS), overall survival (OS), surgical morbidity, KPS, and MMSE were analyzed retrospectively. Removal of at least 20% of the FLAIR hyperintensity lesion was defined as FR.

Results

Thirty-five surgeries in 28 patients (age at surgery 15-81 years; median 54 years, male 20/female 15) were included. The EOR of the contrast-enhancing lesion was 96.6± 7.4%, with GTR in 28 cases and non-GTR in 7. The EOR of the lesion with FLAIR hyperintensity was 33.2±36.5% and FR was achieved in 15 cases (42.9%). The median preoperative KPS was 90 (50-100; mean 83.3 ) in the FR group and 80 (60-100; mean 81) in the non-FR group. Both PFS and OS from surgery at recurrence were significantly prolonged in the FR group (median PFS; 8.1 months vs. 4.6 months, p=0.032, median OS; 36.1 months vs. 15.9 months, p=0.009); there was no difference in PFS or OS between the GTR and non-GTR groups (p=0.33, 0.79). There were significantly fewer patients in the FR group having a decrease in KPS of 20 or more at 30/90 days postoperatively (p=0.037, 0.020).

Conclusion

In our retrospective analysis, FR prolongs PFS and OS without decreasing KPS for resectable recurrent glioblastoma. Further validation in prospective studies is warranted.
ACT-19 A REPORT OF PHASE I PART OF PHASE I/II STUDY OF MAINTENANCE THERAPY WITH METFORMIN AND TEMOZOLOMIDE FOR GLIOBLASTOMA
Authors: Ohno Makoto , Kitanaka Chifumi , Miyakita Yasuji , Tanaka Shota , Takahashi Masamichi , Yanagisawa Shunsuke , Sonoda Yukihiko , Matsuda Kenichiro , Mishima Kazuhiko , Suzuki Tomonari , Shirahara Mitsuaki , Ishikawa Eiichi , Ohashi Ken , Nagane Motoo , Narita Yoshitaka
Published: December 2022

Background

Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. One strategy for overcoming resistance is developing a new therapy targeting the cancer stem/initiating cells. We have shown that the antidiabetic drug metformin (MF) can induce differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. We conducted a phase I/II study to examine the clinical effect of MF combined with standard maintenance temozolomide (TMZ). Here, we report the result of phase I part and the current status of phase II part.

Patients and Methods

Patients between 20 and 74 years of age with supratentorial GBM histologically diagnosed according to the World Health Organization 2016 classification were eligible. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first 6 weeks after MF initiation.

Results

Between February 2021 and January 2022, the first three patients were treated with 1,500 mg/day MF and the next four patients were treated with 2,250 mg/day MF, which is the maximum dose approved in Japan. The median age of the patients was 41 years. Three tumors (42.9 %) were IDH1/2 mutants and 4 (57.1 %) were IDH1/2 wild-types. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, which were observed in three patients. All of them were manageable, with grade 1 or 2. Only one grade 3 seizure was reported, which was likely related to the tumor. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up.

Conclusion

MF dose of up to 2,250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to phase II study with 2,250 mg/day MF.
ACT-24 LONG TERM CLINICAL RESULTS OF NEWLY DIAGNOSED GLIOBLASTOMA BY AGE AND TREATMENT STRATEGY
Authors: Nitta Masayuki , Muragaki Yoshihiro , Saito Taiichi , Tsuzuki Shunsuke , Koriyama Shunichi , Kuwano Atsushi , Kawamata Takakazu
Published: December 2022

Introduction

Glioblastoma has the poorest prognosis among brain tumors, and most cases recur. On the other hand, evidence of prognosis improvement by maximal surgical removal of the tumor is being established, and in recent years, new treatments such as temozolomide (2006), photodynamic therapy (2014), and TTF therapy (2018) were approved by insurance. and patient outcome has improved. In addition, molecular targeted therapy (bevacizumab approved in 2011) and immunotherapy are also used in clinical practice. In this study, we retrospectively analyzed the long-term treatment results of newly diagnosed glioblastoma cases treated at our facility, the correlation with the resection rate, and the treatment results by age and treatment method.

Methods

We retrospectively analyzed the clinical characteristics, resection rate, and treatment outcomes of adult patients with primary supratentorial glioblastoma who underwent surgery and treatment at our institution during the 20-year period from 2001 to 2021.

Results

493 cases, median age 58 years (18-85 years), 293 males and 200 females. The median and mean contrast-enhanced lesion resection rates in resection cases were 98% and 96.6%, respectively. Median PFS and OS for all patients (including biopsies) were 9.4 months and 22.7 months, respectively. The median OS for each age was 12.9 months, 22.9 months, 23 months, and 31.1 months when analyzed separately for 2001-2006, 2007-2010, 2011-2015, and 2016-2021 before TMZ. (p<0.0001), and treatment results improved with age. In particular, the median OS of 23 patients who combined PDT and autologous tumor vaccine (AFTV) was 63.1 months.

Conclusion

Treatment results for glioblastoma improve with age, and the time has come when we can aim for a 5-year survival rate of 50% by combining a high resection rate with multidisciplinary therapy including intraoperative MRI, PDT, AFTV and TTF.
ACT-26 PATTERN OF RECURRENCE IN NEWLY DIAGNOSED GLIOBLASTOMA TREATED WITH PHOTODYNAMIC THERAPY
Authors: Nakayama Noriyuki , Yamada Tetsuya , Ohe Naoyuki , Yano Hirohito , Iwama Toru
Published: December 2022

In 2016, photodynamic therapy (PDT) system using talaporfin sodium was introduced to our hospital. By December 2021, we have experienced 22 cases (15 males, 7 females, 57.9±18.6 years old) of newly diagnosed glioblastoma (GBM) treated with PDT. The recurrence pattern of 22 cases was retrospectively examined. In August 2022, 7 cases are still alive. Laser irradiation was performed at an average of 7.6±3.4 sites. Tumor localization was solitary and superficial in 14 cases. Extent of tumor resection was 89.3±18.5%, and the postoperative KPS was 86.4±15.0%. Median PFS was 11 months, median OS was 18 months, and 5 patients survived for more than 3 years. Recurrences were observed in 16 cases, and the recurrence types were local (LR) in 9 cases, distant (DR) in 3 cases, and both in 4 cases. Two of the remaining 6 cases, which were judged to have no recurrence at present, had Gd-enhancing lesions locally and were judged to have LR. Therefore, re-resection was performed in both cases, but the pathological diagnosis was gliosis. Fujita et al. (J Neurooncol 155:81-92, 2021) reported that acute response of high-grade glioma to PDT can be detected as linear transient hyperintense signal (LTHS) on diffusion-weighted imaging (DWI), and that All of the LRs arose from areas that did not show LTHS on DWI obtained on day 1 after PDT. Furthermore, they reported that this characteristic finding is useful for monitoring LR after PDT. In our cases, 3 DRs and 4 existing long-term survivors (including 2 with local gliosis) showed nearly LTHS throughout the resected wall. On the other hand, partial absence of LTHS was confirmed in 13 cases containing LR. PDT provides effective local control, but it requires careful irradiation planning to avoid missing areas of irradiation, and LTHS on DWI could indicate whether effective irradiation has been achieved.
PEDT-5 PREOPERATIVE MAGNETIC RESONANCE IMAGING AND INTRAOPERATIVE BLOOD LOSS IN CHILDHOOD POSTERIOR FOSSA TUMORS
Authors: Okamoto Takanari , Yamanaka Takumi , Takahashi Yoshinobu , Takeuchi Hayato , Tanigawa Seisuke , Teramukai Satoshi , Hashimoto Naoya
Published: December 2022

Background and Purpose

For removal of childhood posterior fossa tumors, it is important to control bleeding while internally decompressing the tumor. Evaluation of tumor vascularity by preoperative magnetic resonance imaging (MRI) is thought to be effective in predicting and controlling blood loss. In this study, we evaluated the relationship between imaging features, mainly susceptibility-weighted imaging (SWI), and the amount of intraoperative blood loss.

Methods

Among childhood posterior fossa tumors operated on by the same surgeon between January 2016 and March 2022, 9 cases in which preoperative MRI data could be analyzed and total or subtotal resection was achieved were included. The SWI: intratumoral susceptibility signals (ITSS) grade, an index of tumor vascularity, was used to evaluate the association between the degree of vascularity (ITSS: 0-2 vs. ITSS: 3) and multiple factors, including intraoperative blood loss, in a univariate analysis. In addition, the intraoperative blood loss was analyzed by multivariate analysis.

Results

There were 3 males and 6 females with a median age of 6 years (5-11). Seven medulloblastomas, one atypical teratoid/rhabdoid tumor, and one ependymoma were included. Univariate analysis showed that patients with higher vascularity (ITSS: 3) had significantly higher intraoperative blood loss (p=0.016) and larger tumor volume (p=0.032). In multivariate analysis with age, degree of contrast enhancement, degree of vascularity, tumor volume, and degree of tumor resection as independent variables, the degree of vascularity was not significantly associated with intraoperative blood loss (p=0.477), but only with tumor volume (p=0.036).

Conclusion

Although the degree of tumor vascularity may be related to intraoperative blood loss, there was a strong correlation between the degree of vascularity and tumor volume, and multivariate analysis of intraoperative blood loss showed that only tumor volume was a significant factor. Higher tumor vascularity was associated with larger tumor volume, which may result in increased intraoperative bleeding.
PEDT-6 A RANDOMIZED CONTROLLED CLINICAL STUDY OF RADIOTHERAPY COMBINED WITH CHEMOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED CENTRAL NERVOUS SYSTEM GERM CELL TUMOR, JCCG CNSGCT2021
Authors: Arakawa Yoshiki , Takami Hirokazu , Isobe Kiyotaka , Yamasaki Kai , Maebayashi Katsuya , Hashimo Takayuki , Tarashima Keita , Ichimura Koichi , Yoshioka Takako , Takimoto Tetsuya , Kato Miho , Yoshimura Kenichi , Nishikawa Ryo , Hara Junichi , Kumabe Toshihiro
Published: December 2022

Background

Central nervous system (CNS) germ cell tumors account for 15.3% of all CNS tumors in children and adolescents and young adults. Five histologic types and mixed types exist and can be classified into the following clinical risk groups: germinomas, malignant germ cell tumors, and other germ cell tumors. In germinomas, platinum-based chemotherapy and whole ventricle/brain irradiations 23.4 Gy/13 fraction are the standard of care, but late adverse events related to radiation therapy are a problem. In malignant germ cell tumors, chemotherapy with alkylating agents and platinum, craniospinal irradiation (CSI), and local radiation therapy (local dose 50-59.4 Gy/25-33 fractions) have become the standard of care, but the 10-year OS is poor at about 60% and late radiation therapy-related adverse events are an issue. For various reasons, it is not easy to establish a standard of care for mature teratomas and immature teratomas, which constitute the other germ cell tumors, but it is essential to collect knowledge on tumor characteristics and prognosis.

Methods and Patients

The Japan Children's Cancer Group Brain Tumor Committee has planned a study to validate the classification by histological diagnosis and ancillary tumor markers, a phase III study to test the non-inferiority of radiation dose reduction to standard therapy for germinomas, a phase II study to test the superiority of high-dose chemoradiation with methotrexate intrathecal injection excluding CSI to standard therapy for malignant germ cell tumors, observational studies to elucidate pathogenesis of other germ cell tumors.

Discussion

If these hypotheses are proven, it is expected to reduce late adverse events and prolong survival with radiotherapy in children and adolescent/young adult generation patients.
PEDT-10 PHASE II TRIAL OF PATHOLOGY-BASED THREE-GROUP TREATMENT STRATIFICATION FOR PATIENTS WITH CNS GERM CELL TUMORS: A LONG-TERM FOLLOW-UP STUDY
Authors: Takami Hirokazu , Suzuki Tomonari , Takabatake Kazuhiko , Fujimaki Takamitsu , Okamoto Michinari , Yamaguchi Shigeru , Kanamori Masayuki , Matsuda Kenichiro , Sonoda Yukihiko , Natsumeda Manabu , Ichinose Junya , Nakada Mitsutoshi , Muroi Ai , Ishikawa Eiichi , Takahashi Masamichi , Narita Yoshitaka , Higuchi Fumi , Shin Masahiro , Mineharu Yohei , Arakawa Yoshiki , Kagawa Naoki , Kawabata Shinji , Wanibuchi Masahiko , Takayasu Takeshi , Yamasaki Fumiyuki , Fujii Kentaro , Ishida Joji , Date Isao , MIyake Keisuke , Fujioka Hiroshi , Kuga Daisuke , Yamashita Shinji , Takeshima Hideo , Shinojima Naoki , Mukasa Akitake , Tanaka Shota , Asai Akio , Nishikawa Ryo , Matsutani Masao
Published: December 2022

Background

Phase II clinical trial funded by Ministry of Health, Labour and Welfare from 1995 to 2003 evaluated efficacy of pathology-based three-group treatment stratification for CNS germ cell tumors (GCTs). We here present long-term follow-up results.

Methods

Total 228 cases were registered. Germinoma was treated with carboplatin+etoposide (CARE) and extended-local irradiation, local irradiation was added for intermediate-prognosis-group, and poor-prognosis-group was treated with ifosfamide+cisplatin+etoposide (ICE) and whole-brain or craniospinal irradiation.

Results

Mean/median ages at diagnosis were 16.8/16 years and female-to-male ratio was 40-188. Registry included 123 germinomas, 76 intermediate-prognosis-group cases (including 38 germinoma with STGC), 28 poor-prognosis-group cases and 1 mature teratoma. Median 222-months follow-up was conducted, and 56 recurrences and 39 deaths were recorded. 10 and 20-year recurrence-free survival (RFS) for germinoma, intermediate and poor-prognosis-groups were 84/79%, 83/76% and 59/59%, respectively, and overall survival (OS) for each were 97/91%, 92/85% and 57/53%, respectively. Prognosis for germinoma with or without STGC was the same. Basal ganglia germinoma showed significantly shorter RFS but OS was not different from other locations. Median age at death was 24 years, and ages were significantly different depending on causes, such as disease-related (14 years on average) and complications (29 years). OS after recurrence at 5/10/20 years were 64/62/48%.Hormonal supplementation was seen in 82% for neurohypophyseal cases and antidiuretic hormone supplementation was most frequent (82%). Among available cases, 20-out-of-155 cases showed neoplastic/vascular complications, among which cavernous malformation was the most (n=9). Median period until complication presentation was 235 months, and the rate at 20 years was 11%.

Conclusions

Germinoma and intermediate-prognosis-group cases showed long-term survival for approximately 90%, while more intensive treatment would be necessitated for poor-prognosis-group. Long-term survivors often required hormonal supplementation, and increasing frequency of treatment-related complications was observed. There is no end of outpatient follow-up for CNS GCT patients.
PEDT-12 NATIONWIDE LANDSCAPE OF GENOMIC ANALYSIS OF PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: Watanabe Yuko , Takahashi Masamichi , Koyama Takafumi , Sunami Kuniko , Kubo Takashi , Cho Hourin , Hirata Makoto , Tao Kayoko , Sudo Kazuki , Kohsaka Shinji , Yanagisawa Shunsuke , Ohno Makoto , Miyakita Yasuji , Yamamoto Noboru , Narita Yoshitaka
Published: December 2022

Background and Purpose

In Japan, cancer-gene profiling (CGP) tests, such as the OncoGuide NCC Oncopanel System, FoundationOne CDx Cancer Genome Profile (F-one), and FoundationOne Liquid CDx Cancer Genome Profile, are covered by insurance and clinically applied to promote cancer genomic medicine. Information from CGP tests is managed at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) and shared with clinicians after discussions at the Expert Panel (EP). We provide an overview of the registered pediatric CNS tumors.

Methods

We extracted and analyzed CNS/brain data from the C-CAT registry from June 2019 to June 2022 for ages 0–19 years. Variables such as age, gender, histopathological diagnosis, CGP test type, ECOG Performance Status (PS), registration status, genetic abnormalities, and treatments were analyzed.

Results

Among 1133 patients of all ages with CNS tumors, 361 (31.9%) were aged 0–19 years; Of the 918 patients aged 0-19 years with any type of cancer, those with CNS tumors accounted for 34.2%; 188 patients were aged under 10 years, 173 patients were teenagers, 174 patients were males, 187 patients were females; PS was 0 in 47.9% of patients. The most common histopathological diagnoses were medulloblastoma, diffuse midline glioma and glioblastoma. Genetic abnormalities included TP53 mutations in 85 cases, H3F3A mutations in 38 cases, STK11 mutations in 36 cases, BRAF mutations in 33 cases, BRAF-KIAA1549 fusions in 24 cases, and TMB high in 16 cases. Seventy-six patients (21.1%) were offered treatment options in the EP, and 26 patients (7.2%) received the recommended treatment, including two in physician-initiated trials, four in company trials, eleven in treatments within insurance coverage, and eleven in others.

Discussion

This is the first report of genetic analysis of pediatric CNS tumors on a nationwide scale. Pediatric CNS tumors have a large number of registered cases; thus, drug development for them is urgently needed.
PEDT-18 PHASE I/II TRIAL OF OP-10 (ONC201) IN JAPANESE PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE MIDLINE GLIOMA
Authors: Okada Keiko , Narita Yoshitaka , Koga Yuhki , Nishikawa Ryo , Koh Katsuyoshi , Manabe Atsushi , Terashima Keita , Miyairi Kazunari , Taguchi Fumi , Hara Junichi
Published: December 2022

Background

Diffuse midline glioma (DMG) occurs mainly in the brain stem and most of patients have the mutation of histone (H3K27M). The prognosis is poor, and median overall survival (OS) is less than 12 months. OP-10 (ONC201) have antagonistic activity against dopamine D2 ha and to activate ClpP, a mitochondrial protease, leading tumor cells to apoptosis. We conducted a multicenter, single-arm, open-label phase I/II study of OP-10 in Japan.

Methods

A 3 + 3 design was used to determine the recommended dose of OP-10 for nine patients with recurrent or refractory glioma in the phase-I trial. Patients with recurrent or refractory DMG in the phase-II trial orally received OP-10 once weekly until discontinuation because of progression or adverse events. The efficacy and safety of OP-10 were evaluated in the phase-II part. The tumor objective response rate (ORR), the primary endpoint of the phase-II trial, was assessed through a blinded, independent central review according to RANO-LGG criteria.

Results

A total of 9 (age: 24-72 years) and 31 (age: 4-39 years) patients were administered in the phase-I and phase-II trials, respectively. Although the lower limit of the 90% confidence interval for ORR did not exceed the pre-specified threshold (5%), nine of 31 patients showed tumor regression on T2/FLAIR images. In the phase-II trial, the median OS was 28.4 weeks, and the OS rate at 6 months was 54.8%. Adverse events of grade ≥ 3 were reported in five of 31 (16.1%) patients in the phase-II part, with death of disease, hyperuricemia, malaise, pyrexia, alanine transaminase elevation, and aspartate transaminase elevation.

Conclusion

The results of this study suggested that OP-10 might be efficacious in some patients with recurrent or refractory DMG, without major safety concerns.
PEDT-19 RECENT PROGRESS IN CHILDHOOD BRAIN TUMORS RESEARCH
Authors: Terashima Keita
Published: December 2022

The multidisciplinary standard of care for medulloblastoma, a typical pediatric malignant brain tumor of cerebellar primary origin, has been established by large RCTs in the United States. The results of the Phase III RCTs sponsored by Children's Oncology Group's for newly-diagnosed medulloblastoma in children 3 years of age and older, ACNS0331, which attempted radiotherapy reduction for the average-risk group, and ACNS0332, which attempted intensified treatment with carboplatin as a radiosensitizer and isotretinoin as an apoptosis inducer for high-risk group are discussed.It has recently been reported that some infantile glioma cells have activating fusion genes with tyrosine kinase receptor genes, including NTRK, and that TRK inhibitors are effective against these tumors, and two TRK inhibitors have been used with cancer genome panel tests as companion diagnostics, Two TRK inhibitors can now be available for glioma treatment in Japanese practice. The results of clinical trials on the efficacy of these targeting agents in brain tumors with NTRK mutations will be presented.CAR-T cell therapy was developed for GD2 following HER2, which had attracted attention as an immunotherapeutic target for pediatric glioma, and its efficacy was demonstrated in clinical trials. We will examine the results of clinical trials of this immunotherapy, a promising treatment for DMS/DIPG, the disease with absolutely poor prognosis with no effective drug therapy, although it is used in a small number of cases.
IMT-1 PROS AND CONS OF SURGICAL INTERVENTION FOR DIFFUSE MIDLINE GLIOMA AIMED AT DENDRITIC CELL IMMUNOTHERAPY
Authors: Akasaki Yasuharu , Suzuki Tomoya , Takei Jun , Tanak Toshihide , Mori Ryosuke , Koseki Hirokazu , Yamamoto Yohei , Teshigawara Akihiko , Kamata Yuko , Yanagisawa Takaaki , Murayama Yuichi
Published: December 2022

Since a diffuse midline glioma (DMG) has no effective therapy, it is an urgent need to develop new therapeutic strategy. We performed immunotherapy using fusions of autologous dendritic cells (DC) with tumor cells in DMG cases in which tumor tissue was collected by surgery aimed at biopsy, and evaluate the effectiveness and examine the pros and cons of surgical intervention against DMG. Among the patients with basal ganglia or brain stem tumors received surgery at our hospital, 5 adult cases of DMG with H3K27M gene mutation were registered. All patients received radiation therapy and temozolomide chemotherapy. 4 cases received bevacizumab chemotherapy when the patients had recurrence or progression of the disease. The tumor-fused DCs (TFDC) were made by DCs induced from autologous peripheral blood mononuclear cells and tumor cells established from surgical specimens. They were injected subcutaneously into the neck 3 ~ 6 times in a 14 ~ 28 day cycle as the immunotherapy. The adverse events, PFS, and OS were evaluated. A transient complication of facial numbness was observed in one case on right after surgery. Although two patients had CR in those therapies, both of them died of disease (OS at 18 and 32 months, respectively). Since the remaining three cases were registered very recently, adverse event or treatment efficacy judgment have not been determined at the time of submission of the abstract. Serious surgical complications have not been observed in the presented cases. Surgery may be acceptable for DMG as long as the surgery is performed by sufficiently experienced surgeon in an appropriate environment. The TFDC immunotherapy, which can be performed only by collecting a small amount of tumor tissue, expects to be a novel treatment for MDG. In this presentation, the pros and cons of surgical intervention aimed at TFDC immunotherapy for DMG will be examined.
STMO-4 INITIAL EXPERIENCE WITH BRAIN TUMOR SURGERY USING STEALTH AUTOGUIDE
Authors: Kobayashi Yusuke , Satou Yosuke , Kon Takashi , Tanioka Daisuke , Shimizu Katsuyoshi , Mizutani Tohru
Published: December 2022

Tissue sampling of brain tumors is generally performed by biopsy with large or small craniotomy and stereotaxic brain biopsy. Recently, Stealth Autoguide, a robotic system for stereotactic deep electrode implantation and brain tumor biopsy in epilepsy, has become available. We report the initial experience of brain tumor surgery using stealth Autoguide in our hospital.Case: A man in his 70s. Left paralysis occurred during chemotherapy for esophageal cancer. Magnetic resonance imaging (MRI) revealed a ring-enhanced lesion from the right basal ganglia to the coronal radiatum. Because he was under steroid administration, he was diagnosed with metastatic brain tumor, malignant lymphoma, malignant glioma, or demyelinating disease. Since paralysis was progressing and MRS was suspected to be a malignant tumor, a stereotactic biopsy using a stealth autoguide was performed. Biopsies were performed with skin incisions of 1 cm or less from two locations that were automatically positioned based on the preoperative planning, and a sufficient amount of tissue was collected from the lesions. No complications such as bleeding were observed. Since the histological diagnosis was glioblastoma, chemotherapy with temozolomide and radiotherapy were promptly started.Brain tumor biopsy using stealth Autoguide allows accurate tissue sampling in a short period of time, and is a very useful tool for brain tumor diagnosis in the future.
STMO-13 PATHOLOGICAL EVALUATION AND ONCOLOGICAL OUTCOME OF FLAIRECTOMY IN PATIENTS WITH IDH1 WILD-TYPE GLIOBLASTOMA
Authors: Hirono Seiichiro , Kouchi Yusuke , Kishimoto Takashi , Kobayashi Masayoshi , Matsutani Tomoo , Iwadate Yasuo
Published: December 2022

Purpose

The pathological significance as well as oncological outcome of FLAIRectomy in patients with IDH1 wild-type Glioblastoma are unknown.

Methods

We conducted a retrospective review in newly-diagnosed, IDH1 wild-type glioblastoma who achieved gross total resection (GTR) of enhancing tumor. Pre- and post-operative volume of FLAIR abnormal area were also calculated. All patients underwent standard radiotherapy and temozolomide treatment, and monitored for tumor recurrence and overall survival (OS).

Results

A total of 25 GTR patients were included in the study, and the median FLAIRectomy and residual FLAIR volume were 51.5% and 19.6cc respectively. More than 80% of GTR patients unintentionally achieved 20% and more of FLAIRectomy. The pathological specimen of FLAIR abnormal area without gadolinium enhancement was obtained in 6 out of 25, and the typical features of GBM was found in only one. Following FLAIRectomy >20%, majority of recurrence was local. The progression-free and overall survival of those 25 patients were 14.9 months and 30.5 months respectively.

Conclusion

Although this study confirmed the unintentional FLAIRectomy >20% in most of GTR patients, the improvement of local control and survival was not clarified, necessitating prospective study with pathological and neurofunctional evaluation.
STMO-14 VALIDATION OF SURGICAL METHODS FOR GLIOMA AROUND THE MOTOR CORTEX
Authors: Nakahara Yukiko , Ito Hiroshi , Yoshioka Fumitaka , Masuoka Jun , Abe Tatsuya
Published: December 2022

Surgery for glioma around the primary motor area (primary MA) including premotor area (PA) and supplementary motor area (SMA) is performed by general anesthesia with motor evoked potential, called asleep surgery (Asleep S) or awake surgery (Awake S). The literature has shown that there is no difference in tumor removal rate and preservation of neurological function between the two methods. We retrospectively studied 14 patients who underwent craniotomy for glioma of the frontal lobe at our hospital, and 19 surgeries with contrast-enhancing lesions or T2 high-signal areas in the motor area. Tumor primary location was PMA: 6, PMA/ primary MA: 5, primary MA: 2, SMA 6 surgeries. All surgeries identified central sulcus by SEP and monitored transcranial and transcortical MEP. 11 surgeries were Asleep S and 8 were Awake S. Of the 11 Asleep S surgeries, 10 were high grade glioma with contrast on preoperative imaging. Of the 8 Awake S surgeries, 7 were lower grade gliomas, and most of these surgeries were performed for multiple recurrences. In Awake S, difficulties of assessment of motor function arose when the PMA and SMA were removed early in the surgery. In the case of Asleep S, to clarify the criteria for MEP warning signs is necessary, while in Awake S, the knowledge that how much motor decline is tolerated in voluntary movements need. In the case of Asleep S, to clarify the criteria for MEP warning signs is necessary, while in Awake S, the knowledge that how much motor decline is tolerated in voluntary movements need. In addition, the order of resection to avoid SMA syndrome and to evaluate motor function is important. We summarize the literatures and discuss these points for surgical strategy in glioma around motor area.
STMO-15 THE CLINICAL IMPACT OF VENTRICULAR OPENING IN THE IMPLANTATION OF BCNU WAFERS FOR MALIGNANT GLIOMA
Authors: Matsuda Ryosuke , Maeoka Ryosuke , Morimoto Takayuki , Yamada Shuichi , Nishimura Fumihiko , Nakagawa Ichiro , Park Young-Su , Nakase Hiroyuki
Published: December 2022

Objective

To evaluate the safety profile of bis-chloroethyl-nitrosourea (BCNU) wafer implantation after malignant glioma resection with or without ventricular opening (VO).

Methods

This single-center retrospective study included 61 consecutive patients with BCNU wafer implantation after malignant glioma resection between March 2013 and April 2021. The patients were categorized into two groups based on whether VO occurred during the malignant glioma resection. Fifty-three patients had glioblastoma, and eight had anaplastic astrocytoma or oligodendroglioma. Forty-five patients underwent an initial treatment, and 16 underwent recurrent surgeries. Symptomatic edema, newly occurring seizures within one month of the surgery, wound infection, brain abscess, hydrocephalus, cerebrospinal fluid leak, postoperative hemorrhage, and cyst formation were defined as adverse events (AEs).

Results

Twenty-nine patients underwent resection with VO, and 32 without. The median survival time was 28 months in the initial treatment group and 11.5 months in the recurrent treatment group. The with and without VO groups had similar median survival times. Postoperative AEs occurred in 7/29 patients (24.1%) with VO and 11/32 (34.4%) without VO, with no difference between them (p = 0.414).

Conclusions

This study showed that VO during surgery with BCNU wafer implantation might not influence the occurrence of postoperative AEs. If VO happens, BCNU wafer implantation can be performed safely with accurate closing of the ventricle.