bluuebunny/crossref_metadata_2025_split huggingface dataset:
ET-9 Development of photosensitive antibodies for near-infrared light immunotherapy targeting EGFR and IL13Rα2 of malignant gliomas and investigation of their photodynamic cytotoxic activity in vitro
Authors: Nonoguchi Naosuke , Kambara Akihiro , Kimura Seigo , Kawabata Shinji , Yagi Ryokichi , Ikeda Naokado , Furuse Motomasa , Wanibuchi Masahiko 
Published: December 2021

Abstract
Introduction: Near-Infrared Photoimmunotherapy (NIR-PIT) is a recently developed hybrid cancer therapy based on photodynamic cytotoxicity and anti-tumor immunopotentiation, utilizing a photosensitive antibody drug (PSAD). A global Phase III trial of NIR-PIT with an anti-EGFR-PSAD in patients with recurrent head and neck squamous cell carcinoma (HNSCC) is already underway, and NIR-PIT is expected to have therapeutic applications also in malignant gliomas. Methods: In this study, monoclonal antibodies to EGFR and IL13Rα2 were conjugated to the photosensitive dye IRDye700DX (IR700) to produce PSADs (EGFR-Ab/IR700 and IL13Rα2-Ab/IR700) and in vitro PDT assays using these PSADs were performed on four human glioma cell lines (U87MG, U251, U138, A172).Five groups were studied: EGFR-Ab/IR700 monotherapy: 5 μg/ml or 10 μg/ml, IL13Rα2-Ab/IR700 monotherapy: 5 μg/ml or 10 μg/ml, and EGFR-Ab/IR700: 5 μg/ml + IL13Rα2-Ab/IR700: 5 μg/ml combination therapy. The cytotoxic activity of each group was compared after irradiation with 690 nm light at 16 J/cm2. Results: Significantly higher cytotoxic activity was observed in all four glioma cell lines when EGFR-Ab/IR700 and IL13Rα2-Ab/IR700 were used in combination at 5 μg/ml each, than when each PSAD was treated with a doubled dose (10 μg/ml).Conclusion: Malignant gliomas show extensive cellular heterogeneity with diverse expression of cell surface antigens. The present results suggest that a therapeutic strategy using several different photosensitive antibodies simultaneously may lead to the release of tumor antigens from a greater number of tumor cells, resulting in a more efficient host immune response for therapeutic purposes.
TB-6 Experimental evaluation of the therapeutic potential of boron neutron capture therapy in primary central nervous system lymphoma
Authors: Yoshimura Kohei , Kashiwagi Hideki , Kawabata Shinji , Fukuo Yusuke , Takeuchi Koji , Hiramatsu Ryo , Hu Naonori , Tanaka Hiroki , Suzuki Minoru , Miyatake Shin-Ichi , Wanibuchi Masahiko 
Published: December 2021

Abstract
Background: High-dose methotrexate and whole brain radiation therapy (WBRT) is the recommended treatment for primary central nervous system lymphoma (PCNSL). Although the initial treatment is successful, the recurrence rate is high and the prognosis is poor. Boron neutron capture therapy (BNCT) is a nuclear reaction-based tumor cell-selective particle irradiation that occurs when non-radioactive boron-10 is irradiated with neutrons to produce α particles (10B [n, α] 7Li). In this study, we conducted a basic research to explore the possibility of BNCT as a treatment option for PCNSL. Methods: Cellular uptake of boron using human lymphoma cell-lines after exposure to boronophenylalanine (BPA) were evaluated. The cytotoxicity of lymphoma cells by photon irradiation or neutron irradiation with BPA were also evaluated. The lymphoma cells were implanted into the mouse brain and the bio-distribution of boron after administration of BPA were measured. In neutron irradiation studies, the therapeutic effect of BNCT on mouse CNSL models were evaluated in terms of survival time. Results: The boron concentration in lymphoma cells after BPA exposure was sufficiently high, and lymphoma cells showed cytotoxicity by photon irradiation, and also by BNCT. In in vivo bio-distribution study, lymphoma cells showed enough uptake of BPA with well contrasted to the brain. In the neutron irradiation experiment, the BNCT group showed a significant prolongation in their survival time compared to the control group. Conclusions: In our study, BNCT showed its effectiveness for PCNSL in a mouse brain tumor model. PCNSL is a radio-sensitive tumor with a extremely good response rate, but it also has a high recurrence rate / a high rate of adverse events, so there is no effective treatment for recurrence after treatment. Our translational study showed that BNCT is possibly have an important role against PCNSL during the therapy lines as a new treatment option for PCNSL patients.
IM-2 Possibility of immunotherapy for the glioblastoma patients with O6-methyl-guanine DNA methyltransferase (MGMT) expression or promoter unmethylated
Authors: Kushihara Yoshihiro , Tanaka Shota , Nanbu Shohei , Kugasawa Kazuha , Yamasawa Erika , Takami Hirokazu , Takayanagi Shunsaku , Kakimi Kazuhiro , Saito Nobuhito 
Published: December 2021

Abstract
Background: MGMT is a DNA repair protein that removes the cytotoxic O6-methylguanine (O6MG) DNA lesions generated by TMZ; thereby, MGMT expression is mechanistically linked to TMZ resistance. However, thus far, there is no effective treatment for these patients with MGMT promoter unmethylated. Therefore, a new treatment for GBM patients with MGMT expression is urgently needed. To this end, we examined the tumor microenvironment in GBM with or without MGMT expression. Methods: Based on The Cancer Genome Atlas (TCGA) primary GBM cohort, the tumor-infiltrating lymphocytes (TILs) expression level was calculated using the CIBERSORTx algorithms and the single-sample Gene Set Enrichment Analysis (ssGSEA) method. Furthermore, the differential expression gene analysis was conducted and pathway analysis was performed using Ingenuity Pathway Analysis (IPA). The results were validated using the GBM cohort from the Chinese Glioma Genome Atlas (CGGA) database. In addition, TILs were isolated from 13 surgically removed primary GBM tumors in our institution. Their responses to autologous tumors were evaluated by IFNγ ELISA. Results: T cells CD8 score by CIBERSORTx was significantly higher in the MGMT-high tumor. Similarly, ssGSEA scores for activated CD8 T cell, Macrophage, activated B cell, and Type 1 T helper cell were significantly higher in the MGMT-high tumor. Conversely, T cells CD4 naive was significantly higher in the MGMT-low tumor. Consistently, tumor-reactive TILs were detected in the MGMT-high tumor. Pathway analysis showed that Rictor was highly enriched in the MGMT-high tumor and Rictor inhibited lymphocyte activation. Coclusion: In this study, we demonstrated that macrophage was highly activated in the MGMT-high tumors. Thus, CSF-1R inhibitor can be combined with immunotherapy in these MGMT-high tumors to enhance anti-tumor immune responses. In addition, TMZ + mTOR2 inhibitors + PD-1 inhibitors may be effective against the MGMT-L group.
PEDT-3
Authors: Kanamori Masayuki , Shimoda Yoshiteru , Shibahara Ichiyo , Saito Ryuta , Sonoda Yukihiko , Kumabe Toshihiro , Tominaga Teiji 
Published: December 2021

Abstract
Background: Germ cell tumors (GCTs) containing a teratoma component is a group of diseases consisting of various pathological conditions such as mature teratoma, immature teratoma, teratoma with malignant transformation, and mixed tumor with other GCTs. There is controversy about the efficacy and safety of radiation and chemotherapy for GCTs with teratoma component other than mature teratomas. Methods: Of 212 cases of GCTs treated at Tohoku University Hospital Neurosurgery from January 1990 to March 2021. In this study, 23 histologically verified GCTs containing teratoma components were included. Pathological findings, recurrence, survival, and late complications were examined. Results: The age of onset was 2 months-21 years (median 10.5 years). Histological diagnosis was mature teratoma alone in 5 cases, mixed GCTs with mature teratoma in 11 cases, immature teratoma in 5 cases, and mixed tumor with mature teratoma and germinoma in 2 cases. Patients except mature teratoma were treated by chemotherapy alone or radiochemotherapy. During follow-up for 7–362 months (median 135 months), 3 patients relapsed. One of these patients was diagnosed with mature teratoma at the time of treatment and did not receive post-treatment, but relapsed as germinoma 21 years later. A review of pathological specimens at the time of initial onset revealed immature teratomas in addition to mature teratomas. Recurrent lesions in 3 cases were controlled by additional treatment, and no deaths due to tumor progression were observed. On the other hand, of the 18 patients who underwent radiochemotherapy, 1 developed primary hypothyroidism and 2 developed thyroid cancer and leukemia. Conclusion: GCTs with teratoma component often contain malignant histological types and require caution when making a pathological diagnosis. In these cases, tumor control can be expected by radiation or chemotherapy, but there is a risk of developing endocrine disorders and secondary tumors, and further studies are needed to optimize treatment.
PEDT-5 Problem for the guideline of CNS germ cell tumors
Authors: Nakamura Hideo , Yanagisawa Takaaki , Soejima Toshinori , Yokoo Hideaki , Nishikawa Ryo , Fujimaki Takamitsu , Hara Junichi , Terashima Keita , Sonoda Yukihiko , Arakawa Yoshiki , Kumabe Toshihiro , Sugiyama Kazuhiko , Fukuoka Kohei , Takami Hirokazu , Sakurada Kaori , Mineharu Yohei , Fujii Motoaki , Shinojima Naoki , Yamasaki Kai , Fujimura Junya , Yamasaki Fumiyuki , Takahashi Mayu , Suzuki Tomonari , Sato Iori 
Published: December 2021

Abstract
Primary CNS germ cell tumors (GCTs) are rare neoplasms, therefore, a clinical guideline has not been established so far. While better management has been achieved over recent decades by modifying radiation coverage and selecting appropriate chemotherapy, standardization of treatment remains challenging, partly due to the low volume of cases encountered in each institution. As the incidence is higher in East Asia, including Japan, the Japan Society for Neuro-Oncology established a multidisciplinary task force to create an evidence-based guideline for CNS GCTs. The Medical Information Network Distribution Service (Minds) guideline was referred to and utilized in the course of creating this guideline. We chose 6 topics and 10 clinical questions. This guideline provides recommendations for multiple dimensions of clinical management for CNS GCTs, with particular focus on diagnostic measures including serum markers, treatment algorithms including surgery, radiotherapy and chemotherapy, and under-investigated but important areas such as treatment for recurrent cases, long-term follow-up protocols and long-term sequelae. International collaborations to set standards of clinical management for this rare tumor have proven fruitful, concurrently, many fields continue to show variance in clinical practice, partly due to the rarity of clinical encounters and the absence of documented standards. There still seem to be differences in the treatment concept between Japan and North America or Europe countries. This guideline serves the purpose of helping healthcare professionals keep up to date with current knowledge and standards of management for patients with this rare disease in daily clinical practice, as well as driving future translational and clinical research by recognizing unmet needs concerning this tumor. We discuss about the issues both already clarified and should be cleared in the future.
STMO-16 The usability of Detailed pre-operative 3D simulation image for Tumor Resection of High grade glioma
Authors: Tsukamoto Yoshihiro , Natsumeda Manabu , Oishi Makoto , Fujii Yukihiko 
Published: December 2021

Abstract

Introduction
Understanding micro structures is important for the safety and reliable tumor resection for high grade glioma(HGG). The high-resolution 3-demension pre-operative simulation image (3D simulation imege) provides the useful information to the operators. We will report the outcome and the device of 3D simulation image at our single institute.

Material and Method
From April 2019 to July 2021, 56 cases of HGG (grade III: 18 cases, grade IV: 38 cases, initial cases: 49 cases, recurrent cases: 7) were included retrospectively. Zedview, Horos, and Freeform were used to create 3D simulation image from conventional clinical images as CT, MRI, and angiography. The evaluations of anatomical structures were 9 items: cerebral arteries (A), cerebral veins (V), perforators (Per), passing arteries (Pass), feeders (F), drainers (D), sylvian fissure vessels (SV), brain structures (B), and ventricles (Vent). After determining the necessity of 3D visualization for operative planning and evaluating whether it was possible to create the 3D image, the consistency with the anatomical structure and the usefulness for surgery were scored (Excellent 3 points / Good 2 points / Poor 1 point) respectively.

Result
A: 56 out of 56 cases (100%) was judged as necessary, and the average score was 2.73 points. V: 56/56 cases (100%), 2.70 points. Per: 7/7 cases (100%), 1.80 points. Pass: 7/7 cases (100%), 2.86 points. F: 34/36 cases (94.5%), 2.56 points. D: 22/22 cases (100%), 2.36 points. SA: 7/7 cases (100%), 2.43 points. B: 53/54 (98.1%), 2.70 points. Vent: 27/28 cases (96.5%), 2.50 points. The average score of all structures was 2.59 points.

Discussion and Conclusion
3D imaging of the required anatomical structures was possible in almost all cases, and consistency and usefulness in most items were highly scored. Although the evaluation of the perforators was low, the 3D simulation image seemed to be useful for surgical planning.
RT-4 Treatment outcome of proton beam therapy for glioblastoma
Authors: Matsuda Masahide , Mizumoto Masashi , Kohzuki Hidehiro , Sugii Narushi , Ishikawa Eiichi 
Published: December 2021

Abstract
Introduction: Proton beam therapy enables high dose irradiation for tumors while reducing the dose to surrounding normal tissue due to the sharp energy peak called the Bragg peak. We retrospectively analyzed the efficacy of the high dose radiotherapeutic strategy using proton beam for glioblastoma (GBM) in our institution. Methods: Twenty-nine patients with newly diagnosed GBM who underwent high dose proton beam therapy concomitant with temozolomide 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). The survival outcome and adverse events were analyzed. Results: The median overall survival time and progression free survival time for all 29 patients were 31.0 months (95%CI, 25.9–36.1) and 11.0 months (95%CI, 7.8–14.2), respectively. No significant survival difference according to the MGMT methylation status was shown. Failure patterns after proton beam therapy included 17 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. Regarding adverse events, radiation necrosis was observed in 8 cases (including 2 asymptomatic cases). The median time to onset of necrosis after radiation was 18.2 months (95%CI, 10.3–26.2). There were 5 cases of long survivor over 5 years out of 29 cases (17.2%). Of these, 4 cases developed radiation necrosis. Conclusions: Our results indicate that high dose proton beam therapy of 96.6Gy (RBE) prolonged survival in selected GBM patients. Particularly in long survivors, special attention and effective treatment to radiation necrosis is a remaining problem.
RT-5 Boron Neutron Capture Therapy has extended progression-free survival about recurrent malignant peripheral nerve sheath tumor - A case report
Authors: Watanabe Yuko , Igaki Hiroshi , Arakawa Ayumu , Yanagisawa Shunsuke , Takahashi Masamichi , Ohno Makoto , Miyakita Yasuji , Satomi Kaishi , Yoshida Akihiko , Isohashi Kayako , Ono Koji , Miyatake Shin-Ichi , Chen Yi-Wei , Ogawa Chitose , Narita Yoshitaka 
Published: December 2021

Abstract
Introduction: Recurrent malignant peripheral nerve sheath tumor (MPNST) is intractable. Boron neutron capture therapy (BNCT) is a treatment using tumor-selective particle radiation, and is indicated for medical treatment for head and neck cancer, and also used for malignant glioma and malignant meningioma.&lt;Case&gt;20-year-old woman who has MPNST that extends from the subcutaneous tissue of the right neck to the posterior fossa. &lt;Medical History&gt;Chemotherapy and local irradiation(50.4Gy/28fr) for primary embryonal rhabdomyosarcoma of the right ear canal at the age six.&lt;Current medical history&gt;Right cervical tumor developed at 17-year-old, some chemotherapy regimens and tumor resections were performed as recurrence of rhabdomyosarcoma at the previous hospital. After she was diagnosed with MPNST in the pathology consultation at our hospital, she was irradiated with heavy ion beam 70.8Gy(RBE)/16fr and received additional chemotherapies at our department, but her tumor was refractory. Although BNCT for MPNST is not covered by health insurance in Japan, she wanted to try to be treated for BNCT. After confirming boron accumulation in the tumor (SUVmax 4.28) by FBPA-PET, tumor growth and hydrocephalus occurred while waiting for travel to Taiwan due to the spread of COVID-19 infection. She was performed tumor resection(NTR) and irradiated with SRS 20Gy/fr for the residual lesion, but tumor had a rapid recurrence from the margin of the excision cavity. Finally, she could travel about 3 months after the operation and underwent BNCT, that used neutrons and 10B-boronophenylalanine from the Tsinghua University research reactor in Taiwan. No serious adverse events including cerebral edema were observed, and dramatic tumor shrinkage was maintained after treatment. FBPA-PET of 3 months later showed accumulation in the part of the margin of the cavity, the recurrence was observed on MRI after 3 and a half months. Discussion: BNCT for refractory/recurrent MPNST showed acceptable safety and was able to prolong progression-free survival.
MPC-7 Clinical features of Diffuse hemispheric glioma, H3 G34-mutant in children and young adults
Authors: Takeshima Yuki , Kuroda Jyun-Ichiro , Kawano Tatsuya , Matsuura Jin , Matsuzaki Hiroaki , Itoyama Takashi , Kai Keitarou , Takezaki Tatsuya , Shinojima Naoki , Mukasa Akitake 
Published: December 2021

Abstract
INTRODUCTION: H3F3A G34R/V mutated gliomas are seen predominantly in children and young adults, and have been proposed as “Diffuse hemispheric glioma, H3 G34-mutant” in cIMPACT-NOW Update 6. However, the clinical features of the tumor have not been fully elucidated.
METHODS: We retrospectively reviewed 4 cases with H3G34R mutation among 40 cases diagnosed as glioblastoma under 30 years old or primitive neuroectodermal tumor (PNET) in our hospital.
RESULTS: There were one male and three female patients with a median age of 21.5 years (range: 17–27 years). All lesions were localized in the cerebral hemispheres, and the initial symptoms were headache in two cases and seizures in two cases. On imaging, there was one case with poor contrast, and unlike the infiltrative growth pattern of the other three contrasted cases, it showed a well-defined mass lesion. DWI showed high signal in all four cases, reflecting the high cell density in histopathology. All cases were IDH-wildtype.
CONCLUSION: Although the patient background and genetic characteristics of the glioma with H3 G34R/V mutation at our institution were generally consistent with previous reports, there were some cases with atypical imaging findings. Further investigation is required for a deeper understanding of the clinical features of this tumor.
MPC-8 Serum anti-zinc finger FYVE domain-containing protein 21 (ZFYVE21) autoantibody as a novel biomarker for oligodendroglioma IDH-mutant and 1p/19q co-deletion
Authors: Matsutani Tomoo , Boshi Zhang , Hirono Seiichiro , Nagane Motoo , Yoshino Atsuo , Tanaka Shouta , Ishikawa Eiichi , Fukami Shinziro , Yamaguchi Fumio , Li Shuyang , Watanabe Yousuke , Kobayashi Masayoshi , Ikegami Shiro , Hiwasa Takaki , Iwadate Yasuo 
Published: December 2021

Abstract
Background: Glioma is one of the most challenging diseases to cure, and it would be beneficial to discover new serum biomarkers for early diagnosis. Moreover, zinc finger FYVE domain-containing protein 21 (ZFYVE21) was a regulator of tumor invasion and migration. In this study, we examined the levels of serum anti-ZFYVE21 antibodies in patients with glioma.
Methods: This is a multicenter observational prospective study to discover a novel serum autologous antibody marker. We analyzed 286 pre-surgically collected sera of CNS tumors and compared them to healthy donors(HD). Bacterially expressed glutathione-S-transferase-fused ZFYVE21 protein was purified, and its antibody levels were measured by amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA).
Results: The anti-ZFYVE21 antibody levels were significantly elevated in patients with gliomas (P&lt;0.001) than those in HD, instead of patients with other CNS tumors. Among gliomas, the highest sensitivity was observed for oligodendroglioma containing IDH mutation and 1p/19q co-deletion to HD (sensitivity: 72.00%, specificity: 67.71%, AUC: 0.7565, P&lt;0.0001), while there is no significance in astrocytoma containing only IDH mutation. In comparing 1p/19q co-deleted oligodendroglioma with IDH-mutated astrocytoma, the sensitivity and specificity were 50% and 100%, respectively.
Conclusion: Serum anti-ZFYVE21 antibodies might be a novel diagnostic marker distinguishing 1p/19q co-deleted oligodendroglioma from IDH-mutant astrocytoma.
NI-6 Preoperative differential diagnosis of grade II and grade III in cases with astrocytoma, IDH mutant
Authors: Yano Hirohito , Miwa Kazuhiro , Nakayama Noriyuki , Maruyama Takashi , Ohe Naoyuki , Ikuta Souko , Ikegame Yuka , Owashi Etsuko , Ohmura Kazufumi , Yokoyama Kazutoshi , Kumagai Morio , Muragaki Yoshihiro , Iwama Toru , Shinoda Jun 
Published: December 2021

Abstract
Purpose: We attempted to differentiate between IDH-mutant astrocytoma Grade II and grade III by using methionine (MET) positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). Subjects and Methods: We retrospectively analyzed 41 adult supratentorial glioma cases with confirmed histological diagnosis and IDH status from June 2015 to June 2020. These included 21 males, with an average age of 38.5 years (19–59 years), including seven astrocytoma grade II (A-II) and 34 grade III (A-III) cases. We determined the accumulation value rate of the maximum tumor to normal cortex accumulation value (T/N ratio) in MET-PET. We obtained the peak ratios of N-acetyl aspartate (NAA)/ creatine (Cr), choline (Cho)/Cr, and Cho/NAA. We investigated the correlation between the T/N ratios and MRS parameters and examined the contrast effects on MRI. Results: There were no significant differences in the T/N ratio and MRS parameters between A-IIs and A-IIIs. Only Cho/NAA ratios were significantly correlated with the T/N ratios (r = 0.443, P = 0.0037). We divided the distribution map into four areas with the highest T/N ratio of AII (1.59) and the highest Cho/NAA ratio (3.66). That is, 1) T/N ratio ≤ 1.59 & Cho/NAA ≤ 3.66, 2) &gt;1.59 & ≤ 3.66, 3) ≤1.59 & &gt; 3.66, 4) &gt 1.59 & &gt 3.66. The diagnostic rates for A-III were 1) 61.1% (11/18), 2) 100% (7/7), 3) 100% (9/9), and 4) 100% (7/7). We found the contrast effects in only 7 cases (20.6%) of A-III, which were distributed in areas 2) to 4). Conclusion: A-IIs and A-IIIs distributed in area 1) were difficult to distinguish, and they need careful observation as a step before the transition to areas 2)-4). Meanwhile, A-IIIs reaching widespread distribution to areas 2)-4) because of their wide range of malignancies require clinically aggressive treatment. The method might be beneficial in grade analysis of IDH-mutant astrocytomas.