bluuebunny/crossref_metadata_2025_split huggingface dataset:
GEN-03 GENOTYPE-PHENOTYPE CORRELATION IN 111 FAMILIES OF VON HIPPEL-LINDAU DISEASE IN JAPAN
Authors: Kanno Hiroshi , Yoshizumi Tetsuya , Shinonaga Masamichi , Yao Masahiro 
Published: December 2019

Abstract

BACKGROUND AND AIM
von Hippel-Lindau (VHL) disease is a hereditary disease which manifest central nervous system (CNS) hemangioblastoma, retinal angioma, renal cell carcinoma (RCC), pheochromocytoma, endolymphatic sac tumor, and pancreas cyst. The VHL gene is located at 3p25.3 and is corresponding to 213 amino acids. Genotype-phenotype correlation analyses of VHL disease have been recently reported from several foreign countries, but the genotype-phenotype correlation has not been characterized since above 10 years ago. Therefore, this study aimed to evaluate the VHL mutation spectrum and genotype-phenotype correlations in Japanese VHL patients.

METHODS
Blood samples of 111 unrelated families of VHL disease were collected and DNAs were extracted. Direct sequencing and real-time PCR analysis were performed. Consequently, the clinical manifestations and family histories of the subjects were evaluated.

RESULTS
We identified VHL mutations as follows: missense 47; deletion 17; insertion 5; nonsense 8; splice-site 9; larger deletion 25. At hot-spot codon 167, 4 minsense mutations were identified, with Arg167Trp, 4 cases; Arg167Gln2, 2 cases. At codon 155, splice-site mutations were identified at 6 cases. Mutation sites were distributed in exon 1, 45; exon 2, 21; exon 3, 36. Large deletions were distributed in exon 1 & 2, 1; exon 2& 3, 1; all exons, 11. Genotype-phenotype correlation analysis revealed that age-specific risk and number of CNS hemangioblastoma were significantly higher in subjects carrying missense mutation within HIF-α binding site or non-missense mutation (P &lt; 0.05). In addition, penetrance of RCC was significantly higher in subjects carrying non-missense mutation (P &lt; 0.05).

CONCLUSIONS
The results of this study were similar to the previous foreign studies. This study provides insight into the genotype-phenotype correlation in that amino acids substitutions in the HIF- α binding and non-sense mutations may predispose VHL patients to age-related risk and number of CNS hemangioblastoma.
ET-11 ANALYSIS OF ANTI-GLIOMA EFFECT BY PROINFLAMMATORY CYTOKINES
Authors: Adachi Koji , Yamaguchi Fumio , Higuchi Tadashi , Takahashi Hirosi , Morita Akio 
Published: December 2019

Abstract

OBJECT
Antiglioma activity of proinflammatory cytokines, (TNF-alpha, IL-2, IL-12 related cytokines, IL-18, IL-32) are analyzed. Most effective combinations of cytokines are investigated.

MATERIAL & METHOD
Antitumor activity against U373MG, U87MG were measured by co-culture with PBMC and by nude mouse subcutaneous transplantation model. Cytokine receptors on PBMC and glioma cell lines were examined by IHC and mRNA expression. Anti-tumor activity was measured by local injection and systemic administration of proinflammatory cytokines. Cell cycle alteration and expression of apoptosis-related genes after cytokine administration was analyzed. Serum concentraion of cytokines is measured by ELISA.

RESULT
Cytokine receptors were not expressed on glioma cells but were present on intratmoral mononuclear cells. Anti-tumor activity against transplanted tumor is strongly observed by focal administration. Expression of apoptosis-related genes were augmented. IFN-gamma was strongly induced by TNF-alpha, IL-2 and IL-12 administration. IFN-gamma, IL-17, TNF-alpha were also induced. IL-27 and IL-32 per se did not induce IFN-gamma. Simultaneous IL-27 and IL-12 induced strong IFN-gamma induction. Anti-glioma activity of IL-12 and IL-23 were higher than the same dose of exogenous IFN-gamma. IFN-gamma, IL-2 plus IL-12 in U373MG, and IFN-gamma, IL-2 plus IL-18 in U87MG seemed to be the best combination.

CONCLUSIONS
Strong anti-glioma activity was induced by proinflammatory cytokines at least partially through IFN-gamma. There may be another factors. IL-2 and IL-23 showed anti-tumor activity through IFN-gamma, IL-17, TNF-alpha. IFN-gamma + IL-2 + IL-12/-18 seems to be the best combination.
TB-04 TERT PROMOTER MUTATION AS A SUSCEPTIBLE MOLECULAR MARKER OF BCNU LOCAL THERAPY
Authors: Miyake Shigeta , Tateishi Kensuke , Sasame Joe , Miyake Yohei , Matsuyama Shinichirou , Nakamura Taishi , Yamamoto Tetsuya 
Published: December 2019

Abstract

INTRODUCTION
Alkylating agents, including Temozolomide (TMZ) and CCNU (ACNU) have been widely accepted as a standard treatment in malignant gliomas. Several studies also demonstrated that BCNU wafer placement extended survival in glioblastoma patients. However, little study demonstrated gene-specific efficacy of BCNU local therapy in malignant gliomas. Herein, we investigated BCNU sensitivity for patient-derived primary cultured glioma cells.

MATERIALS AND METHODS
From January 2017 to July 2019, 58 gliomas (grade III, IV) were tested genomic analysis and ATP-based cell viability after BCNU treatment. IDH1/2 mutation and TERT promoter mutation status was determined by Sanger sequencing. MGMT methylation status were evaluated by methylation specific PCR.

RESULTS
Of 58 cases,10 cases (17.2%) and 32 (55.2%) cases harbored IDH1/2 mutation and TERT mutation (C228T, C250T), respectively. Among them, co-mutation was identified in 5/58 cases (8.6%). MGMT was methylated in 17/58 cases (29.3%). Interestingly, the presence of TERT promoter mutation was positively correlated with BCNU sensitivity, particularly in IDH1/2 wild-type tumors (p&lt;0.05). In contrast, there was no significant relationship between TMZ sensitivity and IDH mutation/MGMT methylation status.

CONCLUSION
Although sample size is small, our results imply TERT promoter mutations might be a predictive molecular marker for BCNU sensitivity in malignant gliomas. Since TERT mutations are located at two hot spot loci (C228T and C250T), vast majority of TERT promoter mutations can be evaluated during surgery, which may contribute tailored therapeutic strategy in malignant gliomas.
ACT-16 THE POTENTIAL OF HYPOFRACTIONATED RADIOTHERAPY AND BEVACIZUMAB FOR GLIOBLASTOMA TREATMENT
Authors: Hata Nobuhiro , Mizoguchi Masahiro , Kuga Daisuke , Hatae Ryusuke , Sangatsuda Yuhei , Akagi Yojiro , Amemiya Takeo , Fujioka Yutaka , Takigawa Kosuke , Yoshitake Tadamasa , Yoshimoto Koji , Iihara Koji 
Published: December 2019

Abstract

INTRODUCTION
First-line bevacizumab (BEV) is now available as a treatment option for glioblastoma (GBM) patients with severe clinical conditions in Japan. However, the survival benefits remain controversial. As we have emphasized the combined effect of BEV and radiation therapy, the strategies; 1) first-line add-on BEV to TMZ-radiation for unresectable GBMs and 2) re-irradiation using IMRT under BEV administration for recurrent GBMs, have been positively applied. To elucidate these potential survival benefits, we retrospectively analyzed survival in GBM patients.

METHODS
We analyzed survival in 101 patients with IDH-wild type GBM treated from 2006 to 2018. PFS and OS were assessed in two subgroups (TMZ and TMZ-BEV eras), and the correlations of prognostic factors with survival were evaluated.

RESULTS
After BEV approval, OS prolongation tendency (median OS: 14.9 vs. 22.1 months; P = 0.52) was observed, and this tendency was clearer in unresectable cases (10.1 vs 16.1 m P = 0.38). Subanalysis showed a significant prolongation of prognosis in the MGMT unmethylated group (12.2 vs 16.7 m; P = 0.04). In 10 patients of recurrent GBMs receiving BEV combined re-irradiation, adverse events of Grade 3 or higher did not occur. All patients showed PR (N=5) or CR (N=5) after treatment. The mPFS and mOS from the recurrence were 4.3 and 9.4 months, however, no local relapse was observed at their second recurrences.

CONCLUSIONS
Our treatment strategy has improved the outcome of high-risk cases after BEV approval. These results implied that hypofractionated radiotherapy under BEV administration might be an efficient treatment protocol as a first-line for high-risk cases, such as after partial excision and MGMT unmethylation.
PEDT-07 RECURRENT MEDULLOBLASTOMA 9 YEARS AFTER THE PRIMARY TUMOR
Authors: Hiraki Takamasa , Fukuoka Kouhei , Tsumura Yusuke , Inoue Kyohei , Tomita Osamu , Mitani Yuichi , Ohshima Kouichi , Mori Makiko , Arakawa Yuki , Tanami Yutaka , Nakazawa Atsuko , Kurihara Jun , Koh Katsuyoshi 
Published: December 2019

Abstract
Medulloblastoma is one of the most common malignant brain tumors in children. Despite multi-disciplinary treatment for medulloblastoma, including surgery, chemotherapy, and radiation, which have resulted in significant improvement of the prognosis, about 30% of patients still experience recurrence. Most recurrences occur within the first 15 months from diagnosis and late relapse of the tumor is quite rare. We report a case of a 15-year-old female patient with recurrent medulloblastoma 9 years after the primary tumor. At the age of 6, this patient developed a posterior fossa tumor without metastasis and underwent near-total resection. The pathological diagnosis was medulloblastoma with focal desmoplasia. After the surgery, she received multi-agent chemotherapy and radiation therapy consisting of 18 Gy craniospinal irradiation and 51.2 Gy local irradiation. She was in complete remission for 9 years after the treatment. However, gait disturbance began to gradually appear, and magnetic resonance imaging (MRI) showed an intradural lesion in her thoracic spine. The lesion was biopsied, and the pathological findings confirmed the recurrence of medulloblastoma. Currently, we plan to administer local radiation therapy concomitantly with temozolomide to the patient. The case reminds us of the importance of long-term careful follow-up of patients with medulloblastoma. Further studies are warranted for the treatment of relapsed medulloblastomas due to the limited information available at present.
IMT-05 PHASE III RANDOMIZED CLINICAL TRIAL OF AFTV FOR NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Nitta Masayuki , Muragaki Yoshihiro , Ishikawa Eiichi , Maruyama Takashi , Ikuta Soko , Saito Taiichi , Tsuzuki Shunsuke , Fukui Atsushi , Mastumura Akira , Kawamata Takakazu 
Published: December 2019

Abstract

BACKGROUND
The highly fatal glioblastoma has an extremely poor prognosis and development of a new treatment is desired. Local treatment is limited due to its high invasiveness, and immunotherapy utilizing self-immune mechanism is theoretically expected. An autologous formalin-fixed tumor vaccine (AFTV) is a vaccine that is prepared using formalin-fixed tumor tissue and recognizes tumor antigen peptides to induce cytotoxic T cells. We have previously conducted three clinical trials using AFTV for patients with newly diagnosed glioblastoma since 2004. The third trial was a double-blind multicenter phase IIb/III trial with 63 case registries, which did not make a significant difference in OS (study group 25 months, placebo group 31 months), the total removal group showed excellent clinical results (3-year survival rate; 65%, median survival; not reached). Since the study was designed to go to Phase III if the test group was not inferior to the placebo group, so it went on to go to Phase III.

METHODS
Target patients will be 80 patients with newly diagnosed glioblastoma undergoing pathologic diagnosis, who have undergone total removal of contrast-enhanced lesions and receive standard chemoradiation therapy.

STUDY DESIGN
Double-blind, 3-year enrollment period, 18-month observation period. Stratification factor: Photodynamic therapy (PDT), facility, age, KPS. Administration method: After standard chemoradiotherapy, in parallel with maintenance chemotherapy, a total of 9 times intradermal administration of vaccine. Primary endpoint: PFS of FAS patients, Secondary endpoints: 18 months PFS of the FAS patient, OS, PFS of the ITT analysis target case. Based on the results of the IIb trial, we limited the registered patients with total tumor removal, and in view of the fact that the prognosis of patients with combined PDT and AFTV were excellent, PDT was added to the stratification factor. We outline our efforts and problems aimed at clinical approval of AFTV for glioblastoma.
STMO-03 ROLE OF INTRAOPERATIVE COMPUTED TOMOGRAPHY IN GLIOBLASTOMA RESECTION GUIDED BY 5-ALA
Authors: Yamauchi Takahiro , Kitai Ryuhei , Shibaike Yoshinori , Oiwa Mizuki , Yamada Shintaro , Kawajiri Satoshi , Isozaki Makoto , Tsunetoshi Kenzo , Matsuda Ken , Arishima Hidetaka , Kodera Toshiaki , Kikuta Ken-Ichiro 
Published: December 2019

Abstract

OBJECTIVE
To improve resection rate, multiple operative modalities have been essential for glioblastoma (GBM) surgery. Aim of this study is to clarify the impact of intraoperative computed tomography (i-CT) for GBM surgery with 5-aminolevulinic acid photodynamic diagnosis (5-ALA PDD).

METHODS
Consecutive 24 patients newly diagnosed GBM were analyzed, retrospectively. To exclude 6 patients decided timing for i-CT based on neural monitoring, 18 patients performed i-CT after total resection of 5-ALA positive lesion were included, finally.

RESULTS
The median age was 58 years old, and average preoperative tumor volume was 47.78 cm3. Tumor locations were frontal lobe 5 (27%), parietal lobe 3 (17%), temporal lobe 9 (50%), and corpus callosum 1 (6%). Seventeen tumors (78%) harbored in eloquent area. After i-CT performed, 7 (39%) were confirmed residual tumor, and additional resections were needed. Subtotal resection (STR) was 5 and partial resection (PR) was 2 on volumetry in i-CT before additional resection. After additional resection, those cases were judged as 2 gross total resection (GTR), 4 STR and 1 PR in postoperative magnetic resonance imaging (MRI). 11 cases without additional resection were judged as 4 GTR, 3 STR and 4 PR in postoperative MRI. In 18 patients confirmed total resection of 5-ALA positive lesion, i-CT and postoperative MRI revealed 14 (78%) residual tumors. I-CT revealed 7 (50%) in all residual tumor.

DISCUSSION
Hemorrhage, brain edema, air, invasive lesion, and limitation of resolution of CT might make difficult to detect residual tumor.

CONCLUSION
I-CT may be useful to detect residual tumor even with 5-ALA and improve resection rate.
STMO-08 INFLUENCE OF WIDE OPENING OF THE LATERAL VENTRICLE ON SURVIVAL FOR SUPRATENTORIAL GLIOBLASTOMA PATIENTS WITH RADIOTHERAPY AND CONCOMITANT TEMOZOLOMIDE-BASED CHEMOTHERAPY
Authors: Saito Taiichi , Muragaki Yoshihiro , Maruyama Takashi , Komori Takashi , Nitta Masayuki , Tsuzuki Shunsuke , Fukui Atsushi , Kawamata Takakazu 
Published: December 2019

Abstract

BACKGROUND
The prognosis for glioblastoma (GBM) varies among patients. Ventricular opening during surgery has been reported as a prognostic factor for GBM patients, but the influence of ventricular opening itself on patient prognosis remains controversial.

OBJECTIVE
Accumulating evidence has suggested that the subventricular zone (SVZ) harbors a neural stem cell niche and is associated with gliomagenesis. Several reports have hypothesized that aggressive characteristics of GBM in contact with the SVZ may be associated with the recruitment of neural stem cells from the SVZ that have abilities associated with invasive proliferation, leading to poor prognosis. We presumed that the degree of ventricular opening would correlate with the degree of SVZresection and with prognosis in GBM patients. This study therefore investigated whether the degree of ventricular opening correlates with prognosis in GBM patients treated with the standard protocol of chemo-radiotherapy.

METHODS
Participants comprised 111 patients with newly diagnosed GBM who underwent surgery and postoperative radiotherapy and TMZ-based chemotherapy from 2005 to 2018. We classified 111 patients into “No ventricular opening” (NVO), “Ventricular opening, small” (VOS; distance &lt; 21 mm) and “Ventricular opening, wide” (VOW; distance &gt; 21 mm) groups. We evaluated the relationship between degree of ventricular opening and prognosis using survival analyses that included other clinicopathological factors.

RESULTS
Log-rank testing revealed age, KPS, extent of resection, MGMT status, IDH1 mutation, and degree of ventricular opening correlated significantly with overall survival. Multivariate analysis identified the degree of ventricular opening (small vs. wide) as the most significant prognostic factor (hazard ratio = 3.674; p &lt; 0.0001).

CONCLUSIONS
We demonstrated that wide opening of the lateral ventricle (LV) contributes to longer survival compared with small opening among GBM patients. Our results indicate that wide opening of the LV may correlate with the removal of a larger proportion of tumor stem cells from the SVZ.
STMO-18 SUBPIAL RESECTION OF GLIOMA USING CUSA CLARITY
Authors: Saito Kuniaki , Kobayashi Keiichi , Iijima Shohei , Matsumoto Yoshie , Shimada Daisuke , Shiokawa Yoshiaki , Nagane Motoo 
Published: December 2019

Abstract

BACKGROUND
Maximum safe resection is a primary goal of glioma surgery. Ultrasonic aspiration is commonly used technique in neurosurgery, as it allows for safely debulking of tumors without damaging the adjacent brain tissue. CUSA Clarity helps to avoid damage to blood vessels and nerve fibers due to its original function, ‘Tissue Select’. Here we introduce glioma surgery using CUSA Clarity.

METHODS
We used CUSA Clarity in three cases with glioma at Kyorin University Hospital. According to fragility of the tissues and hardness of the tumor, we adjusted power, irrigation, and Tissue Select level of CUSA Clarity. We also introduce subpial aspiration technique in glioma surgery using normal CUSA.

RESULTS
Histological diagnoses of the three patients were WHO grade IV glioblastoma, grade III anaplastic astrocytoma, and grade II oligodendroglioma. All patients underwent successful maximum safe resection without ischemic complication. CUSA Clarity allowed for safe subpial dissection and preservation of pia and small vessels more perfectly than surgery using normal CUSA. CUSA Clarity also contributed to bloodless dissection of the tumor margin due to avoidance of feeder injury. When using Tissue Select mode, the power of the CUSA was elevated by 10 or 20 to aspirate the tumor effectively.

CONCLUSION
CUSA Clarity contributes to safe resection of glioma due to selective tumor aspiration by Tissue Select.
RT-02 POTENTIAL OF PROTON BEAM THERAPY FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Matsuda Masahide , Ishikawa Eiichi , Mizumoto Masashi , Kohzuki Hidehiro , Sugii Narushi , Matsumura Akira 
Published: December 2019

Abstract

INTRODUCTION
Recently, proton beam therapy has attracted increasing interest in the Japanese neuro-oncological field because of the insurance approval for pediatric brain tumor, chordoma, and chondrosarcoma. We have developed the high dose radiotherapeutic strategy using proton beam for malignant glioma in our institution since long before. Here we retrospectively analyzed the efficacy of this treatment strategy.

METHODS
Thirty-four patients with newly diagnosed GBM who underwent high dose proton beam therapy were investigated. All patients received hyperfractionated concomitant radiotherapy consisting of X-ray radiotherapy (50.4Gy in 28 fractions) and proton beam therapy (46.2Gy [RBE] in 28 fractions). Concurrent chemotherapy consisted of ACNU in the early 6 cases or TMZ in the late 28 cases. The survival outcome and adverse events were analyzed.

RESULTS
The median overall survival time and progression free survival time for all 34 patients were 35.7 months (95%CI, 28.1–43.4) and 11.2 months (95%CI, 6.8–15.7), respectively. No significant survival difference according to the chemotherapy regimen was shown. Failure patterns after proton beam therapy include 19 cases of local recurrence, 3 cases of distant recurrence, and 5 cases of dissemination. Although there was no significant difference in time to recurrence according to the failure pattern, there was a tendency of longer survival in the local recurrence group. As for adverse events, symptomatic radiation necrosis was observed in 9 cases. The median time to onset of necrosis after radiation was 18.2 months (95%CI, 10.2–26.2). There were 8 cases of long survivors over 5 years out of 34 cases (23.5%). Of these, 6 cases developed symptomatic radiation necrosis.

CONCLUSIONS
Our results indicate that high dose proton beam therapy of 96.6Gy (RBE) prolonged survival in selected GBM patients. With appropriate patient selection and potent treatment for radiation necrosis, high dose proton beam therapy has a great potential to improve survival in GBM patients.
RT-03 POSTOPERATIVE CYBERKNIFE HYPOFRACTIONATED RADIOTHERAPY FOR THE ELDERLY PATIENTS WITH GLIOBLASTOMA
Authors: Tabei Yusuke , Sato Kengo , Kimura Toshikazu , Irie Koreaki , Ichi Shunsuke 
Published: December 2019

Abstract

INTRODUCTION
In recent years, hypofractionated radiotherapy (HRT) 40Gy in 15 fractions with concomitant temozolomide(TMZ) has come to be used as standard treatment for elderly glioblastoma. However, the treatment duration of 3–4 weeks for radiation is not enough short, and there is also a problem of radiation sickness. We performed hypofractionated stereotactic radiotherapy with CyberKnife (CK) for less than 2weeks. We retrospectively analyzed eight newly diagnosed elderly patients with glioblastoma treated by CK.

METHODS
Surgical cavity, contrast enhanced lesion, FLAIR high signal intensity area were set as gross tumor volume (GTV). To planned target volume (PTV) as GTV + 2 mm, Marginal dose (D95) 35 Gy in 5 fractions (Fr) was prescribed. The dose prescription and number of fractions were adjusted taking into consideration dose distribution, dose-limiting for important organs such as optic chiasm and brainstem.

RESULTS
The eight patients consisted of 3 men and 5 women. The median age was 78 (range 68–84) years old. All patients were pathologically diagnosed as glioblastoma. Two of 8 cases had undergone gross total removal of contrast area. Median postoperative KPS was 70 (40–80). Thirty three (28–33.5) Gy was administered in 5 (3–10) Fr to PTV 117 (44–243) ml. TMZ was used in 7 patients. Bevacizumab (BEV) was used together from 4 weeks after surgery in 5 patients. Progression-free survival was 6.5 (2.9–10.6) months and overall survival was 17.5 (7.1–28.5) months. 7 patients had experienced controllable hypertension with antihypertensive agents, Two patients had suffered from deep vein thrombosis, and anticoagulation therapy was used. One patient had nausea and malaise due to TMZ and had continue BEV alone. Asymptomatic cerebral infarction in the radiation field was observed in a patient.

CONCLUSION
CK treated in less than half duration of conventional HRT is expected as less invasive treatment.