bluuebunny/crossref_metadata_2025_split huggingface dataset:
IM-01 PI3K GAMMA INHIBITOR FOR OVERCOMING TREATMENT RESISTANCE IN COMBINATION THERAPY OF TEMOZOLOMIDE AND ANTI-PDL1 ANTIBODY FOR GLIOBLASTOMA PATIENTS
Authors: Ishikawa Eiichi , Miyazaki Tsubasa , Matsuda Masahide , Takano Shingo , Matsumura Akira 
Published: December 2019

Abstract

PURPOSE
Multidisciplinary therapies including immunotherapy in glioblastoma (GBM) patients often cause long survivor, while early relapse of GBM still remains. We should find factors associated with the immunotherapy-resistance for overcoming it. We previously reported that the infiltration of PD-1 positive cells and M2 macrophages (M2M&phi) increased in recurrent specimens compared to the initial specimens of GBMs treated with chemo-radiotherapy and autologous formalin-fixed tumor vaccine. Here we evaluate whether combination of novel immunotherapies, anti-PD-L1 antibody and M2M&phi inhibitor (IPI-549) inhibits growth of temozolomide (TMZ)-treated glioma cells rather than monotherapy.

METHODS
Using murine glioma initiating cells (TS) and TMZ-resistant TS (TMZRTS) cells, PD-L1 expression and cytokine production associated with M2M&phi were evaluated. TMZRTS cells were implanted in mice flank, followed by anti-PD-L1 antibody and / or IPI-549 administration.

RESULTS
Relative cell proliferation rate of TMZRTS cells was lower than TS cells, while PD-L1 mRNA expression was higher. Treatment with PD-L1 antibody caused marked infiltration of M2M&phi in glioma tissue. The combination therapy strongly inhibited tumor growth in TMZRTS murine model.

CONCLUSION
The anti-PD-L1 antibody treatment altered tissue microenvironment including marked infiltration of macrophages in glioma tissue, probably associated with clinical immunotherapy-resistance in GBM. Combination therapy with anti-PD-L1 antibody and M2M&phi inhibitor could overcame it.
BOT-01 BLOOD-BRAIN BARRIER OPENING USING 220-KHZ TRANSCRANIAL MRI-GUIDED FOCUSED ULTRASOUND AND MICROBUBBLES IN MOUSE AND RAT
Authors: Yoshida Michiharu , Maruyama Kazuo , Kato Yasutaka , Itay Rachmilevitch , Suzuki Syuji , Brockman Omer , Shapira Yeruham , Moriyama Kenji , Omata Daiki , Suzuki Ryo , Kamada Hajime 
Published: December 2019

Abstract

OBJECTIVE
In neuro-oncology, it is believed that one major obstacle to effective chemotherapy is the high vascularity and heterogenous permeability of brain tumors. Focused ultrasound (FUS) exposure with the microbubbles has been shown to transiently open the blood-brain barrier (BBB) without depositing thermal energy, and thus may enhance the delivery of various therapeutic drugs into brain tumors. The aim of this study was to evaluate the BBB opening using 220-kHz transcranial MRI-guided FUS (TcMRgFUS) device and microbubbles in mouse and rat.

METHODS
The experiments were performed with the 220-kHz ExAblate Neuro TcMRgFUS system (InSightec) and novel lipid bubbles (LB, Teikyo Univ.). Normal mouse and rat brains were irradiated with TcMRgFUS (output power, 5W; duration of irradiation, 30 s; duty cycle 100%) following intravenous injection of 6x107 LB per mouse and rat, respectively. On irradiation, target temperature rise & cavitation signal were monitored by MR thermometry and cavitation receiver, respectively. Immediately after irradiation, BBB opening and complications were detected based on T1, T2, T2*, and Gadolinium (Gd) enhanced T1-weighted images.

RESULTS
The maximum temperature of brain tissue was under 42 C. There were no risky-cavitation signals causing hemorrhage. The FUS-LB exposure induced successful BBB opening effect in both mouse and rat, confirmed by Gd enhancement in the target region, lateral ventricles, and sulcus. In addition, there were no complications such as edema, coagulation, and hemorrhage.

CONCLUSIONS
Although there remain many conditions to be optimized, BBB opening using a 220-kHz TcMRgFUS device and LB can offer a non-invasive and feasible drug delivery for brain malignancies.
BOT-04 POSSIBLE INVOLVEMENT OF CHLORIDE INTRACELLULAR CHANNEL PROTEIN 2 (CLIC2) IN THE SUPPRESSION OF INVASIVE ACTIVITY OF BRAIN TUMORS
Authors: Ozaki Saya , Inoue Akihiro , Nishikawa Masahiro , Suehiro Satoshi , Kunieda Takeharu 
Published: December 2019

Abstract
Chloride intracellular channel protein 2 (CLIC2) belongs to the CLIC family of conserved metazoan proteins. However, CLIC2 is the least studied among its family members, and its function remains to be elucidated. Recently, we have shown that CLIC2 is correlated with the development and/or maintenance of tight junctions in blood vessel endothelial cells in human non-cancer tissues. CLIC2-expressing endothelial cells supposedly prevent hematogenous spread of cancer cells. In this study, we investigated CLIC2 expression in human brain tumor tissues and also addressed its function by employing human meningioma cells, rat glioma cells and rat malignant brain tumor model. Thirty-one meningioma cases, six SFT/HPC cases, twelve pituitary adenoma cases and twenty-three glioblastoma cases who underwent surgery at Ehime University Hospital were included. CLIC2 mRNA expression levels were investigated with immunoblotting and quantitative RT-PCR. Cells from the meningiomas were cultured and their CLIC2 expression was knockdown. Filter-based invasion assays and gelatin zymography were performed using the knocked-down meningioma cells. Rat C6 glioma cells stably expressing rat CLIC2 were established and transplanted into the right striatum of neonatal Wistar rats. Effects of CLIC2 on the survival periods of the animals were investigated. CLIC2 expression levels were high in the low-grade cases but low in the high-grade cases and highly invasive cases. Meningioma cells, of which CLIC2 expression was knocked-down, showed higher invasive activity than control cells. The CLIC2-knock down cells displayed increased activities of MMP-2 and MMP-9. Rat brain tumor models revealed that high expression of CLIC2 was correlated with smaller and less invasive brain tumors compared with those consisted of control cells. The rats transplanted with CLIC2-expressing cells survived longer periods than the rats with control C6 cells. These results suggest that CLIC2 plays a role in suppression of invasive activities of tumor cells.
ACT-10 TREATMENT FOR GLIOBLASTOMA RECURRED AFTER CONCOMITANT CHEMORADIATION THERAPY WITH TEMOZOLOMIDE AND THEIR PROGNOSIS
Authors: Mori Kanji , Shofuda Tomoko , Mano Masayuki , Kodama Yoshinori , Kinoshita Manabu , Arita Hideyuki , Moriuchi Shusuke , Uda Takehiro , Taki Takuyu , Fukai Junya , Nonaka Masahiro , Ishibashi Kenichi , Sakamoto Daisuke , Izumoto Shuichi , Nishida Namiko , Okita Yoshiko , Nakajima Yoshikazu , Takano Koji , Hashimoto Naoya , Tsuyuguchi Naohiro , Okuda Takeshi , Achiha Takamune , Hayashi Nobuhide , Dehara Makoto , Kanemura Yonehiro 
Published: December 2019

Abstract
There are few data about treatment for glioblastoma recurred after concomitant chemoradiation therapy with temozolomide (TMZ). We retrospectively examined treatment and prognosis of recurred glioblastoma patients who registered Kansai molecular diagnosis network for central nervous system tumors, and whose clinical information were available. One hundred and fifty-seven patients that were clinically diagnosed as recurrence between November 2007 and April 2019 were included. Their median age at primary diagnosis was 52 years old and median KPS was 80%. Proportion of methylated MGMT promoter was 43.3% (65 patients), and mutated IDH was 5.4% (8 patients). Median overall survival after recurrence (mSAR) was 8.2 months. One hundred and sixteen patients (73.9%) were received any anticancer treatment and their mSAR was 10.5m. Combination of TMZ and bevacizumab (Bev) were most frequently used for 33 patients, followed by Bev monotherapy for 17 patients, surgery + TMZ + Bev for 15 patients, surgery + TMZ for 12 patients, and TMZ monotherapy for ten. Their mSAR were 8.0m, 7.5m, 10.5m, 13.0m, and 8.0m, respectively. Using univariate analysis, MGMT promoter methylation (p=0.0007), TMZ (p=0.00933), surgery (p=0.0126), re-radiation (p=0.0367), and surgery+TMZ+Bev (p=0.0493) significantly affected prognosis. By multivariate analysis, MGMT promoter methylation, TMZ, and re-radiation were statistically significant (p=0.000138, 0.00161, 0.00403, respectively). These data showed that relatively young patients with good performance status would receive anti-cancer treatment beyond progression and MGMT promoter methylation might be one of prognostic factor for longer survival. In this cohort, re-radiation was performed for few patients and nitrosourea such as nimustine was almost not used. Further study would be needed whether these treatments have any positive effect or not.
ACT-15 AD-SGE-REIC GENE THERAPY FOR MALIGNANT GLIOMA
Authors: Kurozumi Kazuhiko , Fujii Kentarou , Shimazu Yosuke , Tomita Yusuke , Matsumoto Yuji , Uneda Atsuhito , Tsuboi Nobushige , Kaneda Keisuke , Makino Keigo , Kumon Hiromi , Date Isao 
Published: December 2019

Abstract

INTRODUCTION
Malignant gliomas are one of the most common and aggressive intracranial neoplasms in humans. Expression of the gene encoding reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is reduced in a variety of human cancer cells. We previously showed the antitumor effect of an adenoviral vector carrying REIC/Dkk-3 gene (Ad-CAG-REIC). Recently, we have also developed a novel adenoviral vector expressing REIC/Dkk-3 (Ad-SGE-REIC). We assessed the anti-glioma effect of the Ad-SGE-REIC and planned a clinical trial of Ad-SGE-REIC for malignant glioma.

MATERIALS AND METHODS
We evaluated a cytotoxicity assay to treatments with Ad-SGE-REIC, Ad-CAG-REIC, or Ad-LacZ (control) using malignant glioma cells. The survival of mice in each group was analyzed by the Kaplan-Meier method. We also performed Good Laboratory Practice (GLP) toxicology tests and prepared a protocol for this clinical trial.

RESULTS
The treatment with Ad-SGE-REIC showed the number of malignant glioma cells attached to the bottom of culture wells was significantly reduced in a time-dependent manner. Mice treated with Ad-SGE-REIC significantly prolonged survival time more than those treated with other vectors. A cGMP product of Ad-SGE-REIC was developed and supplied by a startup biotech company, Momotaro-Gene Inc. We conducted GLP toxicology tests using the intracranial injection of higher doses of Ad-SGE-REIC at Shin Nippon Biomedical Laboratories (SNBL Japan). After finishing the consultation with Pharmaceuticals and Medical Devices Agency (PMDA), we prepared a protocol for a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma with our academic research organization (ARO), supported by Japan Agency for Medical Research and Development (AMED). This protocol was reviewed by our institution review board in March 2019. We submitted a notification of this trial in April 2019.

CONCLUSIONS
We demonstrated the anti-glioma effect of Ad-SGE-REIC. We start a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma (https://jrct.niph.go.jp/en-latest-detail/jRCT2063190013).
ACT-25 CLINICAL TRIALS BY THE JCOG BRAIN TUMOR STUDY GROUP
Authors: Nishikawa Ryo 
Published: December 2019

Abstract
Ongoing brain tumor clinical trials by the Japan Clinical Oncology Group (JCOG) are:JCOG1016, phase III randomized study in patients with anaplastic glioma of radiotherapy with temozolomide versus nimustine hydrochloride (ACNU) followed by temozolomide, is to prove superiority of post-operative radiotherapy with ACNU. JCOG1114, phase III study of high-dose methotrexate and whole brain radiotherapy with or without concomitant and adjuvant temozolomide in patients with primacy CNS lymphoma, is to prove usefulness and get insurance approval of TMZ for primary CNS lymphoma. JCOG1303, randomized phase III study for unresectable WHO Grade II diffuse astrocytoma with radiotherapy alone or chemoradiotherapy with temozolomide, is to prove superiority of STUPP regimen over simple radiotherapy for newly diagnosed and unresectable diffuse astrocytoma. JCOG1308, a multicenter randomized phase III study for recurrent glioblastoma comparing bevacizumab alone with dose-dense temozolomide followed by bevacizumab, is to prove usefulness of dose-dense, 7 days on/7 days off, TMZ, and to approve insurance coverage for recurrent GBM. JCOG1703, a multicenter randomized phase III study for newly-diagnosed maximally resected glioblastoma comparing carmustine wafer implantation followed by Stupp regimen with Stupp regimen alone, is to prove the survival advantage of surgery of GBM using carmustine wafer.
PEDT-05 USEFULNESS OF BEVACIZUMAB IN MAINTAINING QOL AT DIPG RELAPSE
Authors: Gomi Akira , Uchiyama Taku , Oguma Hirofumi , Yamaguchi Takashi , Kawai Kensuke 
Published: December 2019

Abstract

INTRODUCTION
Even in the age of molecular diagnosis, diffuse intrinsic pontine glioma (DIPG) is still a dismal disease, and there is no effective treatment. The usefulness of bevacizumab for DIPG relapse is reported.

SUBJECTS AND METHODS
The treatment and outcomes of 10 patients with DIPG who were treated at our institute since 2001 were retrospectively reviewed. All patients were diagnosed with DIPG by MRI imaging and underwent radiation therapy first. Chemotherapy was performed in combination with radiation therapy in 4 cases, and 3 of them did not receive chemotherapy at the time of relapse (Untreated Group). In 7 cases, chemotherapy was performed at the time of relapse with ACNU/vincristine or interferon beta (Other Treatment Group), and 2 cases with bevacizumab (Bv Group). The change in the Karnofsky Performance Status Scale (KPS) from the time of relapse was compared.

RESULTS
The average overall survival (OS) for all 10 cases was 10.0 months, 8.1 months in the Untreated Group, 9.5 months in the Bv Group, and 11.4 months in the Other Treatment Group. No prolongation of OS by bevacizumab was observed. However, it was only in the Bv Group that the KPS increased from the time of relapse. Comparison of the KPS at the time of relapse and the KPS after 4 months showed that the Bv Group remained unchanged or increased from 80 to 90, while the Untreated Group decreased by 60–100, and the Other Treatment Group also decreased by 20–50. In the Other Treatment Group, hospitalization was required for treatment, and side effects of bone marrow suppression were observed. However, in the Bv Group, outpatient treatment was possible, there were no side effects, and all could be observed at home.

CONCLUSION
From the above results, bevacizumab appears useful for palliative treatment for maintaining quality of life after DIPG relapse.
IMT-01 THERAPEUTIC EFFECT AGAINST LOWER GRADE GLIOMA INDUCED BY DENDRITIC CELL BASED IMMUNOTHERAPY
Authors: Akasaki Yasuharu , Takei Jun , Kamata Yuko , Yamamoto Yohei , Mori Ryosuke , Tanaka Toshihide , Yanagisawa Takaaki , Murayama Yuichi 
Published: December 2019

Abstract

BACKGROUND
This trial was designed to evaluate the safety and clinical responses to an immunotherapy with fusions of dendritic and glioma cells in patients with lower grade glioma (LGG; WHO grade II-III glioma).

METHOD
Autologous cultured glioma cells obtained from surgical specimens were fused with autologous dendritic cells (DC) using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region of subjects. Toxicity, progression-free survival (PFS), overall survival (OS), and MRI findings were evaluated. DNA for whole exome and RNA for whole transcriptome extracted from HLA-A*24:02 positive glioma cells were analyzed by next generation sequencer. Variant peptides showing strong binding affinity to HLA-A*24:02 but not the corresponding wild type peptides were selected as candidate of neo-antigens.

RESULTS
The number of subjects of this trial were 24 (initially diagnosed cases: 20, recurrence cases: 4). WHO grade III cases were 20, and grade II cases were 4. Male were 15, and female were 9. Mean of follow up periods were 53.0 months (the longest follow up period: 1322 months). The number of events on PFS and OS were 8 and 6, respectively. Mean of candidate of neo-antigen peptides in HLA-A*24:02 positive patients (n=8) was 34. Among these candidates, twelve types of common neo-antigen peptide were identified. Neo-antigen peptides specifically expressed in the glioma cells from the effective group were not identified.

CONCLUSIONS
These results indicate that the efficacy of FC-immunotherapy may not always depend on the number of gene mutations or the expression of the specific neo-antigens. FC-immunotherapy, as a means of producing specific immunity against neo-antigens may safely induce anti-tumor effects in patients with LGG. Analysis of prognostic factor in glioma immunotherapy may be the next area of major interest.
IMT-07 CLINICAL TRIAL OF A COCKTAIL WILMS’ TUMOR 1 (WT1) VACCINATION USING TWO HLA CLASS I PEPTIDES AND ONE CLASS II PEPTIDE FOR RECURRENT MALIGNANT GLIOMAS
Authors: Kagawa Naoki , Oji Yusuke , Tsuboi Akihiro , Hirayama Ryuichi , Kijima Noriyuki , Kinoshita Manabu , Oka Yoshihiro , Sugiyama Haruo , Kishima Haruhiko 
Published: December 2019

Abstract

PURPOSE
Our clinical trials shows the safety and clinical efficacy of Wilms’ tumor 1 (WT1) human leukocyte antigen (HLA) class I (Izumoto S et al. J Neurosurg. 2008) and class II (Tsuboi A et al. Cancer Immunol Immunother. 2019) peptide vaccination for recurrent malignant gliomas have been established. We have developed a cocktail vaccine (WT1 trio) containing two class I peptides (HLA-A*24:02 and HLA-A*02:01) and one II class peptide to improve more effective immunological response and improve patient’s prognosis. Clinical trial of a cocktail vaccination using WT1 HLA class I and II peptides for recurrent malignant gliomas is planned to verify its safety, clinical efficacy and usefulness of surrogate markers.

PATIENTS AND METHODS
Twenty-three patients with recurrent malignant gliomas, which showed WT1-positive in tumor samples and HLA-A*24:02 or HLA-A*02:01-positive in blood sample, were enrolled. These patients (age: 26–72 years old, average: 49.4) included 15 cases of glioblastomas and 8 of anaplastic astrocytomas. Patients received a WT1 trio vaccine intradermally, 7 times at 2-week intervals during 3 months.WT1-DTH and WT1-IgG antibody were regularly measured. Vaccine-related adverse events, best clinical response and the transfer rate of long-term administration of WT1 trio vaccination were estimated.

RESULTS
WT1-DTH positive cases were 12, WT1-IgG antibody positive were in 11. In most patients, WT1 -DTH positiveness coincided with that of WT1-IgG antibody. 9 of 11 cases showed stable disease at 3 months and transferred long-term administration of WT1 trio vaccination. Transfer rate in GBM and AA of long-term administration was 33% and 25%, respectively. Grade1 skin eruption was observed at the injection sites in 15 cases, but no significant adverse events related with vaccination were shown.

CONCLUSION
the safety and clinical efficacy of WT1 trio vaccination was verified for recurrent malignant gliomas. WT1-DTH and WT1-IgG antibody may be useful surrogate markers.
STMO-02 PREOPERATIVE FENCE-POST METHOD PLANNING WITH 3D-FUSION IMAGING
Authors: Sadahiro Hirokazu , Goto Hisaharu , Nomura Sadahiro , Suzuki Michiyasu 
Published: December 2019

Abstract
The fence-post method has been used for removal of intra-axial tumors. Preoperative detailed planning with only navigation work system is sometimes difficult to identify actual brain surface, small feeding artery and passing artery. Recently, 3-dementional imaging is well developed to integrate various anatomical findings. The purpose of this study is pursuit of perfect preoperative planning for removal intra-axial tumors with 3D-fusion imaging. From May 2017 to June 2019, 21 patients with intra-axial tumor were included. The software “AZE” was used to create 3D-fusion imaging. The brain tumor, brain surface and tractography were built from MRI, artery from digital angiography and vein from subtraction enhanced computed tomography. Then detailed preoperative planning was planned including how many fence-posts, procedure of cutting feeder, making sulcotomy or corticotomy, and finally cutting drainer. The average bleeding volume was 101±129cc, and there were no patients who had transfusion. All patients did not show additional neurological impairment after surgery. Detailed and perfect preoperative planning with 3D-sufion imaging should be effective for secure neurosurgery.
STMO-06 SMART CYBER OPERATING THEATER REALIZED BY INTERNET OF THINGS - RESULTS OF CLINICAL STUDY FOR 56 CASES
Authors: Yoshihiro Muragaki , Okamoto Jun , Saito Taiichi , Usui Satoshi , Yonezawa Ushio , Kurisu Kaoru , Goto Tetsuya , Fujii Yu , Hongo Kazuhiro , Horisawa Shiro , Taira Takaomi , Nitta Masayuki , Maruyama Takashi , Fukui Atsushi , Tsuzuki Shunsuke , Masamune Ken , Kawamata Takakazu , Iseki Hiroshi 
Published: December 2019

Abstract

PURPOSE
Unlike conventional operating rooms that provide a sterilized space, we have developed a Smart Cyber Operating Theater (SCOT) in which the room itself performs treatment as a single medical device. We report the clinical results of 3 types of SCOT.

METHODS
Basic SCOT packaged with intraoperative MRI (0.4Tesla) was introduced in Hiroshima University in 2016. Standard SCOT networked with middleware OPeLiNK was introduced to Shinshu University in 2018, and Hyper SCOT introduced to Tokyo Women’s Medical University in 2019.

RESULTS
The average of all 56 patients was 44 years old. There were 38 brain tumors (68%), 11 functional diseases (19%), and 7 orthopedic diseases (13%). Basic SCOT is used for 41 cases (/56; 73%) with 22 gliomas, 10 epilepsies, 7 bone tumors, and 2 benign brain tumors. Standard SCOT with 20 networked devices is used for 14 cases (/56; 25%) with 6 gliomas including brain stem and thalamus, 6 pituitary tumors and 2 benign brain tumors. The strategy desk can display a variety of digital data synchronized in time, and the review and comment functions also operate. It is useful for remote advice through mutual communication via strategy desk. Hyper SCOT was used in February 2019 for the first case (1/56 cases; 2%). MRI images were taken with an average of 1.3 shots with good image quality. For 46/56 neoplastic lesions (82%), additional removal of residual tumor was performed in 31/46 cases (67%), and 26/46 cases (57%) were totally removed, with an average removal rate of 89.2%. There was no reoperation (0%) within 1 month in all cases.

CONCLUSIONS
Three types of SCOT contributed to planned surgical outcome including maximal tumor resection without serious related complications. We will proceed with verification of clinical effects, and develop robotized devices, and utilize AI for strategy desk at Hyper SCOT.