bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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(&gt;60 years old)(p&lt;0.01), poor KPS(&lt;70)(p=0.015) and low EOR(&lt;90%)(p&lt;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&lt;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

Abstract

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

Abstract

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

Abstract

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

Abstract

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&lt;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

Abstract
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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.