bluuebunny/crossref_metadata_2025_split huggingface dataset:
EL2 CHANGES IN JAPANESE ACADEMIC CLINICAL TRIALS AND FRAMEWORKS FOR PLANNING CLINICAL TRIALS
Authors: Nakamura Kenichi 
Published: December 2019

Abstract
After the enforcement of the Japanese Clinical Trials Act, the number of investigator-initiated registration-directed trials (IIRDT, Chiken) is increasing while the number of non-registration academic trials is decreasing. Pharmaceutical companies tend to make an investment in IIRDT because the data derived from IIRDT can be utilized for new drug application for PMDA, which means the goals and return are clear for industries. On the other hand, the reason of the decrease of non-registration academic trials is the burden of cost and procedures specified in the Clinical Trials Act. In order to start academic trials, certain amount of research budget is indispensable due to the cost for certified review board and clinical trial insurance. Also, even minor changes of site information in jRCT should be submitted to certified review board and the hospital directors of all participating sites, which is one of the most serious burden for investigators. Confirmation of COI declaration in participating sites is another burden for investigators/sites. Under these circumstances, the number of non-registration academic trials will be decreasing for the time being.
In the Clinical Trials Act era, investigators must prepare some budget to start clinical trials. In order to obtain public funding, social/scientific value and scientific validity are substantially important. To express the social value sufficiently, the purpose of the trial should focus not on the researcher’s interest but on the contribution for patients. In terms of scientific validity, the framework of PICO is useful; PICO means Patient, Intervention, Control and Outcome. Utilization of this framework and the consistency of these four factors are essential to make the trial design sound.
CBMS-08 INVESTIGATION FOR NICOTINIC EFFECTS ON STEM CELL’S PROPERTY IN HSV-TK/GCV GENE THERAPY
Authors: Kenmochi Hiroaki , Yamasaki Tomohiro , Oishi Tomoya , Horikawa Makoto , Yamamoto Taisuke , Koizumi Shinichiro , Sameshima Tetsuro , Namba Hiroki 
Published: December 2019

Abstract

BACKGROUND
Herpes simplex virus-thymidine kinase/ganciclovir (HSV-tk/GCV) system is one of feasible therapeutic strategies for defeating malignant gliomas. Stem cells with intrinsic tumor tropism are used for suicide gene vehicles, which make this therapy further realistic. Nicotine is known to affect cellular migration capacity in variety types of cells but whether nicotine impacts on stem cells’ migration capacity to gliomas is not scrutinized. In this research, we investigated nicotinic impact on stem cells’ properties including tumor tropism and gap junctional intercellular communication (GJIC), which is crucial to this therapeutic strategy.

METHODS
Mouse induced pluripotent stem cell (iPSC)-derived neural stem cells (miPS-NSCs) and human dental pulp mesenchymal stem cells (hDPSCs) were used. Nicotine cytotoxicity for 24 hours was evaluated by MTT assay for stem cells and glioma cells; GS-9L and C6 (rat), GL261 (mouse), U251 and U87 (human). Tumor tropism to glioma-conditioned medium (CM) with or without non-toxic nicotine concentrations was assessed using Matrigel Invasion Chamber. Nicotine effect on GJIC was assessed with scrape loading/dye transfer assay (SL/DT assay) for co-culture of stem cells and glioma cells (stem cell/glioma cell) or parachute assay for glioma cells alone using high-content analysis.

RESULTS
MTT assay revealed 1 μM of nicotine, equivalent to serum nicotine concentration in habitual smoking, is the maximum safe concentration for stem cells and glioma cells. Tumor tropism (miPS-NSCs to GL261-CM, hDPSCs to U251- or U87-CM) and GJIC of co-culture of stem cells and glioma cells (miPS-NSC/GL261, hDPSC/U251) or glioma cells alone (GS-9L, C6, GL261 and U251) were not affected by 1 μM of nicotine.

CONCLUSIONS
Physiological nicotine presence did not affect (1) stem cell’s tumor tropism to gliomas and (2) GJIC between stem cells and glioma cells or within glioma cells. HSV-tk/GCV therapy may retain its therapeutic efficacy against gliomas even under physiological nicotine concentrations.
CBMS-10 FUNCTIONAL ROLE OF MYCN IN SHH TYPE TP53 MUTATED MB’S METABOLISM
Authors: Yokogami Kiyotaka , Watanabe Takashi , Yamashita Shinji , Mizuguchi Asako , Takeshima Hideo 
Published: December 2019

Abstract

BACKGROUND
Medulloblastoma is classified in 4 subgroups. Prognosis and therapeutic option were different from each subgroups. Thus, we need subgroup-specific in vitro models for investigating new therapeutic targets. Little established medulloblastoma cell-lines, which have been subgrouped is available. Especially, commercially available SHH type TP53 mutated cell-line is only DAOY. We established new cell lines 505CSC / 507FBS from the patient with SHH type with TP53 mutated MB. This matched pair cell line showed high expression of MYCN in serum free conditioned medium. To know the functional role of N-MYC in MB, we used 507CSC and DAOY.

MATERIAL AND METHODS
Using chemical inhibitor of MYCN in 507CSC and DAOY, proliferation assay, mRNA expression and measurements of ex-vivo metabolic phenotype were performed.

RESULTS
MYCN inhibition leads to cell death in both cell lines. MYCN regulated glucose, glutamine and methionine metabolism. Especially the targets were PKM2, GLS2, MAT2A, DNMT1 and 3A.

CONCLUSION
MYCN is a target of therapy in a patient with SHH type TP53 mutated medulloblastoma.
CBMS-12 PENTAMIDINE; TRANSLATIONAL RESEARCH FOR A NEW CHEMOTHERAPY TARGETING ON GLIOMA CELLS AND GLIOMA STEM CELLS USING DRUG REPOSITIONING
Authors: Tamai Sho , Hemragul Sabit , Shabierjiang Jiapaer , Zhang Guangtao , Zhang Jiakang , Wang Yi , Tanaka Shingo , Kinoshita Masashi , Hirao Atsushi , Nakada Mitsutoshi 
Published: December 2019

Abstract

INTRODUCTION
Glioblastoma (GBM) is primary malignant brain tumor with poor prognosis. Despite aggressive chemoradiotherapies, GBM has resistance and finally relapses. Recently, it is revealed that glioma stem cells (GSCs) are forming tumors and induce the recurrence. However, there is no effective therapy for GSCs. Herein, we newly identified pentamidine, an antiprotozoal drug, is effective for not only glioma cells but also GSCs by using drug repositioning approach.

METHOD
We used two glioma cell lines, A172 and T98, and patient-derived glioma stem cell lines KGS01, KGS07 which were established at Kanazawa University. We investigated proliferation ability, stemness and intracellular signal change by proliferation assay, sphere forming assay and western blotting, respectively. RESULT Proliferation ability was prohibited by pentamidine in both glioma cell lines and GSC lines. The half maximal inhibitory concentrations were 5–10 μM in glioma cell lines and 1–5 μM in GSC lines. Sphere forming assay revealed that size and number of spheres were reduced in both GSC lines, depending on concentration of pentamidine. In all cell lines, phosphorylation of extracellular signal-related kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) were suppressed by pentamidine.

DISCUSSION
Pentamidine is known as the therapeutic drug for pneumocystis jirovecii. In this study, pentamidine suppressed proliferation activity in all cell lines, and stemness in both GSCs. Previous papers revealed pentamidine had anti-tumor effects for some types of tumor cell lines, however, therapeutic effect for tumor stem cells have never been mentioned.

CONCLUSION
These results suggest that pentamidine would be therapeutic drug for not only glioma cells but also GSCs by suppressing phosphorylation of ERK and STAT3.
GEN-06 CLINICAL COURSE AFTER TUMOR RECURRENCE OF MGMT HYPERMETHYLATED GLIOBLASTOMA
Authors: Adachi Junichi , Shirahata Mitsuaki , Suzuki Tomonari , Mishima Kazuhiko , Fujimaki Takamitsu , Nishikawa Ryo 
Published: December 2019

Abstract
MGMT methylation in glioblastoma is a biomarker for determining treatment responsiveness and predicting prognosis. We analyzed whether there were differences in the prognosis between glioblastoma with MGMT hypermethylation and other glioblastomas after tumor recurrence. We enrolled 184 patients who underwent radiation therapy and temozolomide chemotherapy after tumor resection for newly diagnosed glioblastoma. MGMT methylation was quantitatively analyzed using methylation-specific high resolution melting analysis. The cut-off value for MGMT methylation had a difference of 35% from the previous values. The subjects were split into three groups according to their MGMT methylation levels, 122 in the low (L) methylation group (levels of 0–34%), 40 in the medium (M) methylation group (levels of 35–69%), and 22 in the high (H) methylation group (levels of 70% or more). We mainly focused on and compared the progression after recurrence. The progression-free survival (PFS) rate and overall survival (OS) rate were significantly longer in the M and H groups than in the L group. There was no difference in PFS between group M and group H, but OS was significantly longer in group H. The details of treatment for the 16 of 22 patients who had recurrences in group H are as follows: temozolomide, n = 1; bevacizumab, n = 8; investigational drugs (peptide vaccines and immune checkpoint inhibitors), n = 3; and supportive care, n = 4. The median survival rate for these 16 patients after recurrence was 18 months. Even patients who received only supportive care had a median survival time ranging between 9 and 17 months. Our results indicate that MGMT hypermethylation in glioblastoma is effective to a certain degree with other treatments even after recurrence. Even patients who underwent only supportive care survived for a relatively longer period of time. Biologically, MGMT hypermethylation may be associated with a moderately slow-growing tumor.
ACT-21 PRIMARY EXPERIENCE OF NOVOTTF THERAPY FOR THE PATIENTS WITH GBM IN OUR INSTITUTION
Authors: Yamaguchi Shigeru , Motegi Hiroaki , Ishi Yukitomo , Okamoto Michinari , Terasaka Shunsuke 
Published: December 2019

Abstract

BACKGROUND
Based on EF-14 clinical trial, NovoTTF therapy prolong overall survival in the patients with GBM. However, NovoTTF treatment does not become standard therapy because treatment procedures are cumbersome and potentially impose psychological burden on patients who suffer from dismal disease. In our institution, we can choose NovoTTF therapy as one of the treatment options for GBM patients since June 2018. In this report, we summarized primary experience of this novel treatment.

MATERIALS AND METHODS
Adult patients with primary GBM diagnosed after June 2018 were retrospectively reviewed. We investigated the suggestion of NovoTTF, patients’ acceptance, the reason of rejection of NovoTTF, and the condition of NovoTTF treatment.

RESULTS
Among 22 GBM patients, 12 cases were proposed NovoTTF treatment in actual. In 10 cases who were not proposed NovoTTF, the reasons were 1) poor performance status (KPS 50% or less); 7 cases, oldest-old; 1 case, unavailable care person; 2 cases. In 12 cases who were proposed NovoTTF, 5 cases (42%) accepted and performed this therapy. Remaining 7 cases did not accept NovoTTF because rejection of shaving hair; 1 case, troublesome for daily work; 2 cases, refusal due to cumbersome procedure; 2 cases, unavailable cooperation with care person(s); 2 cases. 5 cases treated NovoTTF were 3 males and 2 females, and the median age was 67yo (range 25yo-69yo). All patients were continued NovoTTF for 1–7 months without major complication. In two cases, minor skin trouble was observed, but easy to handle by putting ointment.
PEDT-02 DIAGNOSIS, TREATMENT AND CLINICAL OUTCOME OF ATYPICAL BRAINSTEM TUMOUR IN CHILDHOOD
Authors: Yanagisawa Takaaki , Honda Takaya , Yamaoka Masatada , Akiyama Masaharu , Fukuoka Kohei , Suzuki Tomonari , Adachi Junichi , Mishima Kazuhiko , Nishikawa Ryo , Masumoto Ai , Nonaka Yuichiro , Takei Jun , Mori Ryosuke , Ishi Yudo , Akasaki Yasuharu , Murayama Yuichi 
Published: December 2019

Abstract

BACKGROUND
Brainstem tumours account for 10–15% of brain tumors in childhood. Diffuse intrinsic pontine glioma (DIPG) accounts for 60–80% of them and are diagnosed based on clinical findings and radiologic features. All the rest of tumours excluding DIPG are very rare, heterogeneous group of tumours including low-grade glioma and malignant embryonal tumors. It is often difficult to diagnose and decide treatment strategy for their rarity.

METHODS
To present our experience with atypical brainstem tumours, a retrospective chart review was conducted to identify eligible cases treated over a ten-year period. All tumors involving brainstem, felt not to be DIPGs for absence of clinical/neuroimaging features were included. Demographic information, pathological findings, neuroimaging characteristics, surgical and nonsurgical management plans, and survival data were collected for analysis.

RESULTS
Between April 2007 and March 2017, 16 patients (14 initial and 2 recurrent) aged from 3 to 20 years were identified. 14 of them were symptomatic and 4 of them were asymptomatic at reference. Of 10 symptomatic cases, 10 were biopsied and pathological diagnosis was low-grade glioma in 8, glioblastoma in 2 cases. They had treatment depending on the pathological diagnosis. Of 4 asymptomatic cases, one with small focal tumour, with no findings suggesting malignant tumour with 11C-methioninePET or MRS, progressed to show typical clinical and image findings of DIPG in a year. For other three, they remain asymptomatic without progression with no treatment for 25months, 60months, and 65 months respectively. Malignant transformation was observed in one with biopsy-conformed oligoastrocytoma with no K27M-H3 mutations treated with chemotherapy and another with pilocytic astrocytoma treated with chemotherapy and radiotherapy.

CONCLUSIONS
Though molecular findings such as K27M-H3 mutations can predict clinical outcome in some cases, it still remains difficult to diagnose and find treatment strategy of atypical brainstem tumours. The need and usefulness of nationwide registry study is warranted.
PEDT-04 SIX CASES OF RETINOBLASTOMA WITH CNS INVOLVEMENT
Authors: Kiyotani Chikako , Tsujimoto Shinichi , Isshiki Kyohei , Sugawa Masahiro , Azuma Noriyuki , Usami Kenichi , Ogiwara Hideki , Yosioka Takako , Tsutsumi Yoshiyuki , Fuji Hiroshi , Terashima Keita , Matsumoto Kimikazu 
Published: December 2019

Abstract
Although the survival rate of intraocular retinoblastoma (RB) is nearly 100%, the outcome of central nervous system (CNS) involvement or Trilateral retinoblastoma (TRb: very rare RB which associated with brain tumor) is dismal. We retrospectively reviewed our six cases of these rare tumors. Their ages at diagnosis are 0y3m-1y10m (median 1y3m) (Male 4, Female 2). Only one had RB family history. Their affected eyes were bilateral 2, unilateral 3 and no 1. Their CNS diseases were suprasellar tumor 3, pineal tumor 1 and cerebrospinal fluid (CSF) cytology positive 2. Two of the suprasellar tumor patients had spinal metastasis. Three of the six patients were TRb. One TRb patient was treated with chemotherapy and high-dose chemotherapy without radiotherapy. Although he suffered with secondary osteosarcoma seven years later, he got complete remission and alive 5 years more without any tumor recurrence. The second TRb patient was treated with chemotherapy and local radiotherapy but relapsed 20 months later. The third TRb patient was chemotherapy resistant. Two CSF positive patients had optic nerve invasion. One patient with chiasm invasion died 11 months later because of treatment resistance. The other patient with optic nerve invasion before optic canal had no CNS tumor nor CSF involvement at diagnosis. Chemotherapy before enucleation was given to avoid dissemination. However, CSF cytology became positive after enucleation and remained even with intensified chemotherapy. Finally, he got remission with radiotherapy and high-dose chemotherapy, and alive without disease for 3.8 years. The last patient had suprasellar genetically classified retinoblastoma tumor and cerebrospinal metastasis. This patient showed good chemotherapy response and is still under treatment. Even with &quotso called° fatal RB cases, some case could survive with intensified therapy. Data accumulation is necessary for better survival of these tumors.
STMO-04 LOCAL CONVECTION-ENHANCED DELIVERY OF CHEMOTHERAPY AS TREATMENT FOR BRAIN TUMORS
Authors: Saito Ryuta , Kanamori Masayuki , Tominaga Teiji 
Published: December 2019

Abstract

BACKGROUND
Convection-enhanced delivery (CED) of therapeutic agents is a promising local delivery technique that has been extensively studied as a treatment for CNS diseases over the last 2 decades. Applying this technique to treat brain tumors, we have been working to develop novel local chemotherapy against brain tumors. In the meanwhile, clinical trial against diffuse intrinsic brain tumor aiming at Japanese “shonin” approval is recruiting patients. In this study, potential of local CED based chemotherapy against supratentorial brain tumor is discussed.

METHODS
Until today, we have evaluated the safety and efficacy of local CED of nimustine hydrochloride against supratentorial malignant glioma patients in the three prospective, single institute, nonrandomized, open-label studies. Among those, one study recruited the recurrent malignant glioma patients whose enhanced tumor can be surgically resected. After the resection of the tumor, CED of ACNU was performed targeting the surrounding brain. Temozolomide was also given for 5 days during this trial.

RESULTS
Seven patients; 4 male and 3 female, age 33–71 y.o. (median 54 y.o.), were treated in this study. Five patients suffered glioblastoma and two suffered anaplastic astrocytoma. After the treatment, all seven patients lived longer than a year; one survived three years, one survived four and a half years, and one with glioblastoma is still alive after 5 years.

DISCUSSION
Potential efficacy of local chemotherapy delivering nimustine hydrochloride with CED against recurrent malignant glioma was suggested. Further study is required to pave the way for this strategy against supratentorial malignant gliomas.
STMO-14 SURGICAL MANAGEMENT OF DEEP-SEATED GLIOMA AROUND THALAMUS
Authors: Saito Kuniaki , Kobayashi Keiichi , Shimada Daisuke , Iijima Shohei , Shiokawa Yoshiaki , Nagane Motoo 
Published: December 2019

Abstract

BACKGROUND
Higher extent of resection contributes to better prognosis of the patients with glioma. However, resection of deep-seated glioma represents a surgical challenge not only because of the depth but because of adjacent eloquent structures such as pyramidal tract, deep venous system, and brainstem.

METHODS
We performed a retrospective review of patients with deep-seated glioma around thalamus who underwent surgery between March 2014 and February 2019. The tumors were removed with use of neuronavigation, DTI tractography, electrophysiological monitoring and photo dynamics diagnosis using aminolevulinic acid via interhemispheric or transcortical approach. Volumetric analysis of preoperative tumor volume as well as postoperative residual volumes was performed.

RESULTS
A total of 17 patients, ages ranged from 13–79 years (median; 51) were eligible. Twelve patients underwent radical resection and 5 underwent biopsy (2 with craniotomy, 2 with endoscopy, and 1 stereotactic biopsy). Pathological diagnosis consisted of glioblastoma (GBM) in 10, diffuse midline glioma (DMG) in 3, anaplastic astrocytoma in 3, and diffuse astrocytoma in 1. Extent of resection of the patients attempted radical resection was 96.7%±6.4%. Postoperatively, 12 patients developed hemianopsia, 2 had hemiparesis because of corticospinal tract injury, 2 sensory disturbance, and 3 cognitive dysfunction. At 1 month after surgery, Karnofsky performance status (KPS) worsened in 5 GBM patients and 1 DMG patient, while improved or stable in the rest 11 patients.

CONCLUSION
Resection of deep-seated glioma around thalamus accompanies a high risk of neurological deficits. Nevertheless, radical resection without KPS decline can be achieved by preserving the corticospinal tract, deep venous system, and brainstem and minimizing damages of surrounding brain.
MPC-09 THE OPTIMIZATION OF TREATMENTS FOR SO-CALLED PRIMITIVE NEUROECTODERMAL TUMORS WITH MOLECULAR ANALYSIS
Authors: Suzuki Mario , Fujita Naohide , Ogino Ikuko , Fujimura Junya , Kondo Akihide 
Published: December 2019

Abstract

INTRODUCTION
In the previous WHO classification of central nervous tumors, the supratentorial tumors comprise small round blue cells with aggressive clinical features had been defined as primitive neuroectodermal tumor (PNET). Recent molecular analysis revealed that they do not belong to a single entity, but they are re-classified as the tumors of other well-defined tumors and newly defined tumor species. These facts were reflected to the new classifications. While, there are few studies those showed the re-consideration of treatments for tumors diagnosed as so-called PNET. In this study, we propose the optimization of treatments for tumors diagnosed by the new classification to clarify which treatments were effective for the tumors those were diagnosed as PNET.

MATERIALS AND METHODS
The tumor samples diagnosed as so-called PNETs were analyzed. The molecular information was extracted from tumor specimens. We used high throughput analysis with microarray, FISH, and immunohistochemistry. They all had treated in our institution in last 6 years and their clinical courses were followed by medical records. Informed parental consent was obtained from their guardians and this study was approved by the institutional review board of Juntendo university.

RESULTS
Nine tumor samples were able to be analyzed and they are re-classified into high-grade glioma, neuroblastoma, sarcoma, embryonal tumors with multilayered rosettes, C19MC altered (ETMR). They resembled each other closely in morphology, and therefore, it was not able to be classified by histopathological findings. There was a case of pineoblastoma, whose molecular background suggested that the tumor was re-classified into neuroblastoma. In terms of treatments, we have succeeded in neuroblastoma cases so far, ETMRs were required multiple surgeries and radiations to maintain remissions.

CONCLUSIONS
Re-classification of diagnosis based on the molecular background is necessary to clarify the optimization of treatments for pediatric brain tumors, and the comprehensive methods is required. We present our methods for molecular diagnosis in clinical field and future plans.