bluuebunny/crossref_metadata_2025 huggingface dataset:
Eccentric debris disc morphologies – I. Exploring the origin of apocentre and pericentre glows in face-on debris discs
Authors: Lynch Elliot M , Lovell Joshua B
Published: December 2021

The location of surface brightness maxima (e.g. apocentre and pericentre glow) in eccentric debris discs are often used to infer the underlying orbits of the dust and planetesimals that comprise the disc. However, there is a misconception that eccentric discs have higher surface densities at apocentre and thus necessarily exhibit apocentre glow at long wavelengths. This arises from the expectation that the slower velocities at apocentre lead to a ‘pile up’ of dust, which fails to account for the greater area over which dust is spread at apocentre. Instead we show with theory and by modelling three different regimes that the morphology and surface brightness distributions of face-on debris discs are strongly dependent on their eccentricity profile (i.e. whether this is constant, rising, or falling with distance). We demonstrate that at shorter wavelengths the classical pericentre glow effect remains true, whereas at longer wavelengths discs can either demonstrate apocentre glow or pericentre glow. We additionally show that at long wavelengths the same disc morphology can produce either apocentre glow or pericentre glow depending on the observational resolution. Finally, we show that the classical approach of interpreting eccentric debris discs using line densities is only valid under an extremely limited set of circumstances, which are unlikely to be met as debris disc observations become increasingly better resolved.
IL-3 Changing Cancer Genomics and Cancer Genomic Medicine by Artificial Intelligence and Large-Scale Data Analysis
Authors: Miyano Satoru
Published: December 2021

In MEXT Program for Scientific Research on Innovative Areas “Systems Cancer” and “Systems Cancer in Neo-Dimension” (2010-2019), we developed a large-scale genome data analysis pipeline called Genomon in collaboration with Professor Seiji Ogawa (Kyoto University). Our efforts successfully produced innovative results on cancer genomics. This system is implemented on the supercomputers SHIROKANE and FUGAKU. One of the contributions unraveled the overall picture of genetic abnormalities in malignant brain tumors (Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 2015) that exploited Genomon on SHIROKANE. However, with the spread of new measurement technology and new computing environments, no one thinks that the future can be figured on this simple extension. On the other hand, for cancer genomic medicine, Institute of Medical Science University of Tokyo made a research team analyzing whole genome sequences. The challenge we faced was to transform thousands to millions of genomic aberrations per case into precision medicine. It is what we now call “digital transformation.” IBM’s Watson for Genomics was introduced for our research purpose. In the process, we identified the effectiveness of AI, the indispensability of specialist intervention, and bottlenecks. We recognized that natural language processing technology such as BERT and Google Knowledge Graph AI technology will open up the future. Automatic document creation is also a realistic issue. Cancer research is getting more difficult and larger in scale. For example, analysis of genomic data from 60, 954 cases revealed a new underlying mechanism in which multiple mutations within the same oncogene synergistically work (Nature 2021). AI with an accuracy of X% does not seem to be the goal. What is needed is not a black box, but explainable AI that explains “why” in a human-understandable way. We are currently conducting research with Fujitsu Laboratories for this direction.
ANGI-1 Impact of neoadjuvant bevacizumab on transcriptional factor for stemness, macrophage polarization, and oxygenation of tumor microenvironment in glioblastoma
Authors: Tanaka Toshihide , Takei Jun , Teshigawara Akihiko , Tohmoto Kyoichi , Yamamoto Yohei , Hasegawa Yuzuru , Tamura Ryouta , Sasaki Hikaru , Akasaki Yasuharu , Murayama Yuichi
Published: December 2021

Background: Previously we reported that bevacizumab (Bev) produces tumor oxygenation with immunosupportive tumor microenvironment (TME) and inhibition of stemness. To confirm whether those effects might contribute prolongation of clinical outcome, in the present study paired samples from same patients with newly diagnosed GBM who received Bev during its effectiveness and refractoriness were investigated by immunohistochemistry. Methods: Eighteen samples from 9 patients with newly diagnosed GBM who received preoperative neoadjuvant Bev (neoBev) followed by surgical operation and chemoradiotherapy in addition to salvage surgery after recurrence were investigated. Expressions of FOXM1, HIF-1, and CD163 were evaluated by immunohistochemistry. Overall survial (OS) were analyzed with the present cohort divided into two groups between good and poor responder (GR and PR, respectively) of Bev defined as tumor regression rate judged by T1 gadolinium enhancement (T1Gd) and fluid attenuated inversion recovery (FLAIR) images. Results: In the group of good responder of T1Gd (T1Gd-GR; defined as >38% of regression rate after neoBev), OS was prolonged compared with T1Gd-PR along with inhibition of FOXM1 expression and HIF-1a. In contrast, in the group of good responder of FLAIR (FLAIR-GR; defined as >54% of regression rate after neoBev), there were no significant differences of OS and FOXM1 expression between GR and PR. HIF-1a expression tended to be elevated in T1Gd-PR of initial tumors, T1Gd-GR of recurrent tumors, and FLAIR-PR of both initial and recurrent tumors.Conclusion: T1Gd-GR after neoBev might attribute to inhibition of FOXM1 and oxygenation. Bev might provide tumor oxygenation, leading to inhibition of stemness and M2 TAM infiltration during its effectiveness. These results suggested that Bev combined with immunotherapy for newly diagnosed GBM might provide clinical benefits including inhibition of stemness and induction of immunosupportive TME, when tumor volume assessed by T1 Gd. was significantly decreased following neoBev.
ANGI-2 Identification and functions of CD44 as a predictor for bevacizumab-resistant glioblastoma to optimally treat the tumor with bevacizumab
Authors: Inoue Akihiro , Nishikawa Masahiro , Ohnishi Takanori , Yano Hajime , Ohtsuka Yoshihiro , Suehiro Satoshi , Yamashita Daisuke , Watanabe Hideaki , Tanaka Junya , Kunieda Takeharu
Published: December 2021

Anti-angiogenic therapy with bevacizumab (Bev), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is a common treatment for recurrent glioblastoma (GBM), but its survival benefit is limited. Resistance to Bev is thought to be a major cause of ineffectiveness on Bev therapy. To optimize Bev therapy, identification of a predictive biomarker for responsiveness to Bev is required. Based on our previous study, we focused on the expression and functions of CD44 and VEGF in the Bev therapy. Here, we analyze a relationship between CD44 expression and responsiveness to Bev and elucidate the role of CD44 in anti-VEGF therapy. CD44 and VEGF expression in the tumor core and periphery of 22 GBMs was examined, and the relationship between expression of these molecules and progression-free time on Bev therapy was analyzed. The degree of CD44 expression in the tumor periphery was evaluated by the ratio of the mRNA expression in the tumor periphery to that in the tumor core (P/C ratio). VEGF expression was evaluated by the amount of the mRNA expression in the tumor periphery. To elucidate the roles of CD44 in the Bev therapy, in vitro and in vivo studies were performed using glioma stem-like cells (GSCs) and a GSC-transplanted mouse xenograft model, respectively. GBMs expressing high P/C ratio of CD44 were much more refractory to Bev than those expressing low P/C ratio of CD44, and the survival time of the former was much shorter than that of the latter. In vitro inhibition of VEGF with siRNA or Bev activated CD44 expression and increased invasion of GSCs. Bev showed no anti-tumor effects in mice transplanted with CD44-overexpressing GSCs. The P/C ratio of CD44 expression may become a useful biomarker predicting responsiveness to Bev in GBM. CD44 reduces the anti-tumor effect of Bev, resulting in much more highly invasive tumors.
CBMS-3 Potent bystander effect in suicide gene therapy using genetically engineered stem cells from human exfoliated deciduous teeth
Authors: Horikawa Makoto , Koizumi Shinichiro , Oishi Tomoya , Yamamoto Taisuke , Ikeno Masashi , Ito Masahiko , Yamasaki Tomohiro , Amano Shinji , Sameshima Tetsuro , Suzuki Tetsuro , Namba Hiroki , Kurozumi Kazuhiko
Published: December 2021

HSV thymidine kinase (TK)/ganciclovir (GCV) has a long history of application in malignant glioma and we have previously demonstrated its bystander effect on gliomas using several stem cell types as a vehicle. The main reason for applying stem cells is that they have a unique tumor-trophic activity that allows them to deliver TK genes efficiently to nearby the tumor. Stem cells from human exfoliated deciduous teeth (SHED) are mesenchymal stem cells easily harvested from dental pulp and no studies have reported suicide gene therapy using SHED as a carrier for malignant gliomas. For transduction of SHED with the HSVTK gene (SHEDTK), we used HSVTK retrovirus-producing cells.In vitro experiments showed a significant migration ability of SHEDTK toward tumor-conditioned medium and representative tumor growth factors. We also detected a significant bystander effect of SHEDTK on gliomas in the presence of GCV. In vitro time-lapse imaging showed that both SHEDTK and glioma cells underwent gradual morphological apoptosis and activation of caspase 3/7 was observed in both cell types. In intracranial tumor models using nude mice, SHEDTK migrated around the U87 cell mass implanted in the contralateral hemisphere. Additionally, coculture suspensions of SHEDTK and U87-luciferase cells were xeno-transplanted followed by intraperitoneal administration of GCV for 10 days. All mice of treatment group survived for more than 100 days, whereas those treated without GCV died of tumor growth with median survival of 42 days after tumor implantation. Furthermore, pre-existing intracranial U87 model mice were injected intratumorally with SHEDTK followed by GCV administration as described above. The tumor volume was significantly reduced during the treatment period, and over-all surivial in treatment group is prolonged significantly to that of control groups. These results indicate that SHEDTK-based suicide gene therapy might offer a new promising therapeutic modality for human malignant gliomas.
CBMS-7 IGF1/N-cadherin/Clusterin signaling axis mediates adaptive radioresistance of glioma stem cells
Authors: Osuka Satoru , Zhu Dan , Zhang Zhaobin , Li Chaoxi , Stackhouse Christian T , Sampetrean Oltea , Olson Jeffrey J , Gillespie Yancey , Saya Hideyuki , Willey Christopher D , Van Meir Erwin G
Published: December 2021

Glioblastoma (GBM) is composed of a variety of tumor cell populations including those with stem cell properties, known as glioma stem cells (GSCs). GSCs are innately less sensitive to radiation than the tumor bulk and are believed to drive GBM formation and recurrence following repeated irradiation. However, it is unclear how GSCs adapt to avoid the toxicity of repeated irradiation used in clinical practice. We established radioresistant human and mouse GSCs by exposing them to repeated rounds of irradiation in order to uncover critical mediators of adaptive radioresistance. Surviving subpopulations acquired strong radioresistance in vivo, which was accompanied by increased cell-cell adhesion, slower proliferation, an elevation of stemness properties and N-cadherin expression. Increasing N-cadherin expression rendered parental GSCs radioresistant, reduced their proliferation, and increased their stemness and intercellular adhesive properties. Conversely, radioresistant GSCs reduced their acquired phenotypes upon CRISPR/Cas9-mediated knockout of N-cadherin. Mechanistically, elevated N-cadherin expression resulted in the accumulation of β-catenin at the cell surface, which decreased Wnt/ β-catenin proliferative signaling, reduced neural differentiation, and protected against apoptosis through Clusterin secretion. Restoration of wild type N-cadherin, but not mutant N-cad lacking β-catenin binding region, led to increased radioresistance in N-cadherin knockout GSCs, indicating the importance of the binding between N-cadherin and β-catenin. We also demonstrated that N-cadherin upregulation was induced by radiation-induced IGF1 secretion, and the radiation resistance phenotype can be reversed with picropodophyllin (PPP), a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor, supporting clinical translation. Moreover, the elevation of N-cad and Clusterin are related to prognosis of GBM in the TCGA dataset. In conclusion, our data indicate that IGF1R inhibitor can block the N-cadherin-mediated resistance pathway. Our research provides a deeper understanding of adaptive radioresistance after repeated irradiation, and validates the IGF1/N-cadherin/β-catenin/Clusterin signaling axis as a novel target for radio-sensitization, which has direct therapeutic applicability.
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

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

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

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

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

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

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

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

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.20-year-old woman who has MPNST that extends from the subcutaneous tissue of the right neck to the posterior fossa. Chemotherapy and local irradiation(50.4Gy/28fr) for primary embryonal rhabdomyosarcoma of the right ear canal at the age six.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

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

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<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<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

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) >1.59 & ≤ 3.66, 3) ≤1.59 & > 3.66, 4) > 1.59 & > 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.
NI-7 Diffusion-weighted imaging for monitoring acute response and recurrence after photodynamic therapy in malignant gliomas
Authors: Fujita Yuichi , Nagashima Hiroaki , Tanaka Kazuhiro , Hashiguchi Mitsuru , Itoh Tomoo , Sasayama Takashi
Published: December 2021

Background

Photodynamic therapy (PDT) subsequent to surgical tumor removal is a novel light-activated localized treatment for malignant glioma. Although PDT provides effective local control, even PDT cannot completely suppress local recurrence of malignant glioma. We previously reported that the acute response of malignant glioma to PDT could be detected as linear hyperintense signals on diffusion-weighted imaging (DWI) and a decline in apparent diffusion coefficient (ADC) values that were asymptomatic and transient. However, their long-term clinical significance has not yet been examined. This study aimed to clarify the link between the hyperintense signal on DWI as an acute response and recurrence after PDT in malignant glioma.

Methods

Thirty consecutive patients (16 men, 14 women; median age 60.5 years) underwent PDT for malignant glioma at our institution between 2017 and 2020. We analyzed signal changes on DWI after PDT and the link between these findings and the recurrence pattern.

Results

In all patients, linear hyperintense signals of 5–7 mm on DWI were detected at the surface of the resected cavity from day 1 after PDT. These changes matched the PDT-irradiated area and disappeared in about 30 days without any neurological deterioration. Of the 30 patients, 19 (63%) exhibited recurrence: local recurrence in 10 (33%), distant recurrence in 1 (3%), and dissemination in 8 (27%). All local recurrences arose from areas that did not show a hyperintense signal on DWI obtained on day 1 after PDT. Patients with distant recurrence or dissemination tended to have uninterrupted hyperintense signal on DWI obtained on day 1 after PDT.

Conclusion

The local recurrence in malignant glioma after PDT occurred in the areas without hyperintense signal on DWI as the acute response to PDT. This characteristic finding could aid in the monitoring of not only PDT-irradiated area but also local recurrence site after PDT.
NI-13 Prediction of outcome at the time of discontinuing TMZ-adjuvant therapy in IDH-mutant lower grade glioma using 11C-methinine PET
Authors: Beppu Takaaki , Sato Yuichi , Sasaki Toshiaki , Terasaki Kazunori , Iwaya Takeshi , Ogasawara Kuniaki
Published: December 2021

Purpose: This study aimed to clarify whether positron emission tomography with 11C-methyl-L-methionine (11C-met PET) can predict consequential outcomes at the time of discontinuing temozolomide (TMZ)-adjuvant chemotherapy in patients with residual isocitrate dehydrogenase gene (IDH)-mutant lower-grade glioma.Methods: In 30 patients showing residual lesions of IDH-mutant lower grade glioma (16 with diffuse astrocytoma and 14 with anaplastic astrocytoma), we performed 11C-met PET, and calculated the tumor-to-normal brain tissue ratio of standardized uptake values (SUVT/N) at the time of discontinuing TMZ-adjuvant chemotherapy. We determined cutoff values to predict tumor relapse using the receiver operating characteristic curve for various prognostic factors including age, Karnofsky performance scale, number of courses of therapy, residual tumor size, and SUVT/N. The promotor methylation status of O6-methylguanine-DNA methyl-transferase gene (MGMT) was assessed using methylation-specific polymerase chain reaction. Progression-free survival (PFS) was compared between groups divided by cutoff values. Uni- and multivariate analyses were conducted using log-rank testing and Cox regression analysis, respectively.Results: Univariate analysis identified MGMT methylation status (p = 0.04) and an SUVT/N of 1.27 (p = 0.02) as predictors of PFS after TMZ discontinuation. In multivariate analysis, both unmethylated MGMT and SUVT/N ≥ 1.27 remained as strong predictors of unfavorable outcome. Conclusion: The present study suggested that 11C-met PET allows prediction of outcomes comparable to MGMT promotor methylation status at the time of discontinuing TMZ-adjuvant chemotherapy in patients with residual IDH-mutant lower-grade glioma.
NI-15 Comparison of amide proton transfer imaging with perfusion imaging of using arterial spin-labeling for evidence of tumor cells in glioma
Authors: Yamauchi Takahiro , Kitai Ryuhei , Umeda Hideto , Tsukinowa Yu , Hagihara Ryota , Shibaike Yoshinori , Kawajiri Satoshi , Kidoguchi Masamune , Yamada Shinsuke , Isozaki Makoto , Arishima Hidetaka , Kodera Toshiaki , Kimura Hirohiko , Kikuta Ken-Ichiro
Published: December 2021

BACKGROUND: Infiltrative gliomas show cerebral edema and tumor infiltration as areas of hyperintensity in FLAIR image. Amide proton transfer (APT) and cerebral blood flow (CBF) are useful for evaluating the tumor invasion. In this study, arterial spin-labeling (ASL)-CBF and APT were compared to determine which method was superior for predicting tumor infiltration in gliomas, pathologically. METHODS: Fifteen specimens from 5 glioma patients with confirmed selective sampling were obtained. Based on APT signal intensity (SI), regions of interests (ROIs) were selected for biopsy. Same regions of these ROIs were marked on the same slice of ASL imaging. Samples were pathologically assessed for cell density and vessel density. APT SI and ASL-CBF were analyzed for each specimen. RESULTS: APT signal intensity (SI) showed a strong correlation with cell density (R = 0.887, P < 0.0001). ASL-CBF showed no correlation with cell density (R = 0.240; P = 0.3836) but a correlation with vessel density (R = 0.697; P = 0.0038). In linear regression analysis, APT SI showed a positive relationship with cell density (R2 = 0.787, P < 0.0001, linear regression; y = 30.70 + 6.24E-3*x). CONCLUSIONS: APT imaging was superior in predicting cellular proliferation than ASL-CBF and a powerful predictor of cell density. APT imaging allowed revelation of novel clues reflecting tumor proliferation in brain tumor; to date, this is the first known report to assess cell density among various brain tumors and conditions after treatment.
NQPC-10 (Rare) Cancer patients’ unmet needs (patient-focused healthcare needs) survey
Authors: Gatellier Laureline , Moue Yuko , Matsuda Tomohiro
Published: December 2021

Background: Rare Cancers Japan (RCJ) consists of members of 20 rare cancer patient groups and individual rare cancer patients, including the Japan Brain Tumor Alliance (JBTA), the Pediatric Brain Tumor Network, and the DIPG Symposium Organizing Committee, and aims to solve the challenges of rare cancers. RCJ, together with the National Cancer Center Japan and the Japan Federation of Cancer Patient Groups is currently conducting a survey to clarify unmet needs of patients, as a follow-up survey to surveys conducted in 2018. Since then, a major paradigm shift happened in Japan, with the advent of genomic medicine and development of new treatments. This study plans to identify the latest unmet needs of cancer patients and to clarify the differences between cancer types to provide data for the improvement of healthcare systems.Purpose: Focusing on unmet needs of cancer patients, we conduct an online questionnaire survey of a total of 1,600 cancer patients (including brain tumor patients) regarding the following endpoints (1) detection and diagnosis, (2) treatment, (3) genomic medicine (access to genetic mutation testing), (4) clinical trials, (5) necessary information, medical care and support systems and (6) quality of life. The collected information will be analyzed to clarify the needs of patients and the nature of patient-centered healthcare. Method: The survey will be administered online, including a mix of open-ended and multiple-choice questions. The total number of questions, including respondent demographics, is 38, and the time required to answer them is expected to be between 15 and 20 minutes. Data analysis will take into account cancer type of cancer, gender, age group and region of residence of the respondent.Expected results: By February 2022, the results of the survey are expected to be available, as basis of discussion to improve brain tumor treatment and follow up, from a multidisciplinary perspective.
MET-6 Neoadjuvant fractionated stereotactic radiotherapy followed by piecemeal resection for metastatic brain tumor
Authors: Mitsuya Koichi , Deguchi Shoichi , Muto Manabu , Yasui Kazuaki , Onoe Tsuyoshi , Ogawa Hirofumi , Hayashi Kenji , Asakura Hirofumi , Harada Hideyuki , Hayashi Nakamasa
Published: December 2021

BACKGROUND: Large brain metastases which require resection are treated with surgery followed by whole brain radiation therapy or postoperative stereotactic radiosurgery (SRS). Recently a novel strategy using neoadjuvant stereotactic radiosurgery (Na-SRS) followed by surgery was reported, demonstrating lower rates of postoperative leptomeningeal dissemination (LMD) and symptomatic radiation necrosis (RN). We treated with neoadjuvant fractionated stereotactic radiotherapy (Na-fSRT) followed by surgery for large brain metastasis with piecemeal resection.

METHODS: Twelve patients received Na-fSRT followed by surgery between July 2019 and April 2021. Na-fSRT dose was based on lesion size and was standard dosing. Surgery generally followed within 7 days after radiotherapy.

RESULTS: The mean age was 68 years (51–79). Sixteen men and five women. Mean follow-up period was 8.5 months (1–24.9). Primary were lung; 10 (NSCLC; 9, SCLC (recurrence); 1), esophagus; 3, colon; 2, melanoma; 2, kidney; 2 (recurrence1), uterus body; 1, and liver; 1. The median maximum tumor diameter was 3.6 cm (2.6–4.9). Median PTV, GTV volume were 21.7ml, 15.5ml, respectively. The median fSRT dose was 30Gy/5fr, and the median time from fSRT to surgery was 4 days (1–7). As preoperative adverse event, intracranial hypertension and partial seizure grade 2 (CTCAE ver.5) were occurred, but controlled with steroid and osmotic diuretics and anticonvulsant. Grade 3 and more adverse events were not occurred. Gross total removal was performed in 95.2%. Event cumulative incidence as follows: cavity local recurrence 4.8% (subtotal removal case); distant brain failure 33%; LMD 4.8%; and symptomatic RN 0%. The median intracranial progression free survival was 7 months, and median overall survival was 8.4 months.

CONCLUSIONS: Na-fSRT followed by piecemeal resection is safety and feasible, and may have therapeutic value for deep large brain metastasis and eloquent lesion. Further prospective investigations in multi-institutional settings are warranted.