bluuebunny/crossref_metadata_2025 huggingface dataset:
SS-1 Therapeutic challenges for glioblastoma: Temozolomide and its issues?
Authors: Nagane Motoo
Published: November 2020

Glioblastoma (GBM), the most malignant form (WHO grade IV) of gliomas, remains incurable despite recent advances in medical technologies and molecular knowledge, with 5-year survival rate being just beyond 10%, thus undoubtedly leaving unmet needs to develop effective therapeutics to improve outcome. Current standard of care for patients with newly diagnosed GBM is maximum safe resection of the enhancing tumor bulk, followed by involved-field radiotherapy with temozolomide (TMZ) given concomitantly and as an adjuvant therapy thereof with or without Tumor-Treating Fields (TTF). The efficacy of TMZ for GBM was proved in 2005 by a randomized phase III trial (EORTC25981) for the first time ever in history, since then, however, any other agents have failed to show benefit to improve survival until now. O6-methylguanine-DNA methyltransferase (MGMT), a specific DNA repair enzyme, has been shown to restore the cytotoxic O6-methylguanine lesion induced by TMZ to normal, responsible for a major reason of TMZ resistance. Expression of MGMT is tightly regulated by methylation of the promoter region of the MGMT gene, where promoter methylation results in suppression of its expression. Accordingly, the promoter methylation of the MGMT gene (meth-MGMT) has been consistently associated with a better response to and outcome by TMZ treatment, and furthermore a favorable prognostic factor for patients with newly diagnosed GBM in a number of prospective clinical trials. In this line, efforts have been made to overcome TMZ resistance including intensifying dose schedulings of TMZ, one of which has been currently tested in a multi-institutional prospective phase III trial in Japan (JCOG1308C). TMZ has also been investigated in lower grade gliomas. A major issue in treating lower grade glioma with TMZ is potential development of the hypermutated tumors by virtue of O6-methylguanine-induced mutagenesis. The clinical and molecular consideration related to TMZ in glioma treatment will be presented.
SS-3 Tumor Treating Fields: from the Petri dish to the patient
Authors: Giladi Moshe
Published: November 2020

Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, antineoplastic treatment modality targeting rapidly dividing cancer cells using low intensity, alternating electric fields at cell-type-specific intermediate frequencies (100–500 kHz). TTFields therapy is approved for the treatment of newly-diagnosed and recurrent glioblastoma as well as malignant pleural mesothelioma, following clinical trials demonstrating efficacy and a favorable safety profile. Using novel in vitro and in vivo systems for TTFields application, research activities are being conducted to extend the understanding of the underlying mechanisms of action (MoA) and to assess additional means to improve treatment outcomes. The demonstrated antimitotic effects of TTFields discerned the positive combinatorial potential of TTFields with other agents targeting the division process. Subsequent to elucidation of anti-mitotic effects, other downstream effects of TTFields include induction of endoplasmic reticulum stress, up-regulation of autophagy and cell death, thus driving immunogenic cell death. Indeed, in several preclinical models, combining TTFields with immunotherapeutics demonstrated enhanced efficacy. Recently, additional novel effects of TTFields were characterized, including inhibition of DNA damage repair responses and induction of transient and reversible permeabilization of the blood brain barrier (BBB). These new findings offer potentially innovative means to optimize treatment outcomes by combining TTFields with radiation therapy and DNA damaging agents, as well as improved delivery of impermeant agents across the BBB. These scientific findings were instrumental in advancing the clinical pipeline of TTFields, which includes conduct of ongoing trials combining TTFields with a variety of modalities, in approved indications and in other solid malignant tumor types. The aim of this talk is to describe TTFields’ preclinical research activities and tools, and to specify how these study outcomes have defined and advanced the clinical pipeline.
SS-4 High dose chemotherapy with autologous hematopoietic stem cell transplantation for CNS lymphoma
Authors: Kondo Eisei
Published: November 2020

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDT-ASCT) is listed as a consolidation therapy option for primary central nervous system (CNS) lymphoma in the guidelines of western countries. The advantages of HDT-ASCT for primary CNS lymphoma as consolidation are believed to be high rates of long-term remission and lower neurotoxicity, even though its eligibility is limited to younger fit patients. In the Japanese guideline, HDT-ASCT for primary CNS lymphoma is however not recommended in daily practice, mainly because thiotepa was unavailable since 2011. The Japanese registry data for hematopoietic transplantation have shown that primary CNS lymphoma patients were treated with various HDT regimens and thiotepa-containing HDT was associated with better progression free survival (P=.019), lower relapse (P=.042) and a trend toward a survival benefit (Kondo E et al, Biol Blood Marrow Transplant 2019). A pharmacokinetic study of thiotepa(DSP-1958) in HDT-ASCT for lymphoma was conducted in 2017, and thiotepa was approved for HDT-ASCT in lymphoma this March, meaning that optimal HDT regimen for CNS lymphoma is now available in Japan. The treatment strategy of CNS lymphoma needs further development to improve survival and reduce toxicity.
KNL-1 Pathologic diagnosis of brain tumors in the molecular era
Authors: Hirose Takanori
Published: November 2020

The WHO Classification of CNS Tumors, first published in 1979, was revised four times during the recent four decades. The revision was based on the refinement of tumor entities and introduction of new entities, which were facilitated by the development of new investigative techniques, such as immunohistochemistry and molecular cytogenetics. More sophisticated approaches including NGS and methylation analysis will introduce more molecularly defined entities in the next WHO Classification. The molecular analyses are a very powerful tool for brain tumor research. They have disclosed molecular mechanisms of several tumors and discovered unrecognized tumor entities till then. More precise biologic behavior could be estimated by molecular profiles. Furthermore, the development of novel molecular-targeted therapies will be expected. In the clinical practice, brain tumors should be diagnosed stepwise. First, clinical and image information is mandatory. Histopathologic and immunohistochemical findings should be evaluated within the clinical context. For molecularly defined tumors, genetic analyses are necessary. Following the stepwise procedures, the risk of falling in pit-falls may be decreased. In the molecular era, the integrated diagnosis, combined histopathologic and molecular information, of brain tumors is necessary. Recently, the Japanese Society of Pathology (JSP) has started the project which foster next-generation pathologists interested in rare cancers including brain tumors. In addition, some molecular information could be gained through the consultation system run by JSP and the National Cancer Center Japan. To adapt the next, more detailed molecular classification, it may be necessary that the cancer genome panel test become available within the national health insurance system.
ES-1 Clinical results of tumor treating fields in patients with glioblastoma in Japan, compared with global surveillance
Authors: Muragaki Yoshihiro , Nitta Masayuki , Saito Taiichi , Tutsuki Shunichi , Fukui Atsushi , Kawamata Takakazu
Published: November 2020

INTRODUCTION: The tumor treatment field induces apoptosis of tumor cells by providing a low intensity, intermediate frequency, alternating current electric field via a transducer array. TTFields is based on Phase 3 EF-11 and EF-14 trials for glioblastoma in the US FDA and Japan PMDA. Therefore, I will report the statistics of TTFields use in Japan along with recent papers. METHODS: 410 patients were treated with TTFields in Japan (December 2017-), of which 17 were at Tokyo Women’s Medical University. We also referred to papers about global post-marketing surveillance and recent studies. RESULTS: Of the 410 patients, 409 (99.8%) were diagnosed with ndGBM(male: female, 66.8%: 33.2%). As of June 2020, 222 patients (54.1%) were on treatment and 188 (45.9%) were discontinued. In 17 cases at TWMU, the average age was 46.3 years. The average treatment period was 218 days, with 6 patients (35%) continuing treatment, 6 patients (35%) discontinuing due to patient wishes, and 5 patients (30%) discontinuing treatment due to recurrence. Side effects were contact dermatitis under the array in 9 patients (57%) and mild malaise in 7 patients (43%). We experienced long-term progression-free cases with TTF use of 25 months (survival 30 months after surgery) with a glioma partially resected and 21 months (survival 27 months after surgery) with a biopsied glioma. In the biopsy case, bevacizumab was used in combination during the treatment. Conclusion: In global surveillance, use for rGBM accounts for 39%, but Japan is limited to use for ndGBM due to insurance coverage. In terms of side effects, it showed a good safety profile comparable to previous trials. Long-term progression-free cases have been observed, and it is necessary to examine the characteristics of patients who respond to treatment and the effect of concomitant use with bevacizumab by prospective studies
SPDR-01 Paired epithelioid glioblastoma patient-derived xenograft models to evaluate resistant mechanism for molecular target therapy
Authors: Sasame Jo , Tateishi Kensuke , Ikegaya Naoki , Miyake Yohei , Nakamura Taishi , Udaka Naoko , Yamanaka Shoji , Yamamoto Tetsuya
Published: November 2020

Epithelioid glioblastoma (E-GBM) arises at younger age, commonly disseminates to cerebrospinal fluid, and results in dismal prognosis. About half of E-GBM harbors BRAF V600E mutation, thus BRAF/MEK inhibitors are expected to be specifically sensitive to E-GBM like other BRAF V600E mutant carcinomas. However, therapeutic effect is limited by the emergence of drug resistance. To overcome this issue, it is crucial to elucidate the treatment resistance mechanisms by clinically representative models. Herein, we establish 2 paired E-GBM patient-derived xenograft (PDX) models from young adult patients (YMG62 and YMG89) with BRAF V600E, TERT promoter mutations and CDKN2A homozygous deletions. The YMG62 patient received dabrafenib with trametinib, while YMG89 patient received dabrafenib monotherapy after recurrence with standard treatment. The YMG62 patient was refractory to combination therapy. The YMG89 patient was initially responded to dabrafenib, but gradually became resistant and the 2 patients died due to CNS dissemination. Paired PDX models were established from tumors prior and after molecular target therapy. All PDXs were formed as CNS dissemination model, which were recapitulated to the patient characteristics. BRAF/MEK inhibitors strongly suppressed cell viability in primary tumor (YMG89P). However, BRAF/MEK inhibitors became resistant in recurrent tumor (YMG89R). YMG62 paired PDXs were resistant to molecular target therapy. Western blotting indicated retained MAPK signaling pathway and/or increased AKT phosphorylation after BRAF/MEK inhibitors treatment in refractory and recurrent cells, which indicates crucial role of re-activation in the MAPK signaling pathway and/or PI3 kinase pathway for tumor maintenance in BRAF V600E mutant E-GBM. We have done high throughput drug screening to identify compounds to overcome resistant to molecular target therapy. Our established E-GBM paired PDX models recapitulate patient characteristics, which may uncover treatment resistant mechanism and novel therapeutic target in E-GBM.
GEN-09 Pursuing the function of microRNA targeting (Pro)renin receptor against glioma
Authors: Ogawa Daisuke , Fujimori Takeshi , Toyota Yasunori , Hatakeyama Tetsuhiro , Okauchi Masanobu , Kawanishi Masahiko , Miyake Keisuke , Masaki Tsutomu , Nishiyama Akira , Tamiya Takashi
Published: November 2020

(Pro)renin receptor((P)RR) is a part of the Wnt receptor complex. Wnt/β-catenin signaling pathway (Wnt signaling) plays important role in pathogenesis and self-renewal of glioblastoma (GBM), or differentiation of glioma stem cell. We previously reported that (P)RR activated Wnt signaling, (P)RR expression correlated with malignancy of glioma, and treatment with (P)RR siRNA reduced the proliferative capacity. This time, we have searched for over 2632 microRNAs by microRNA microarray that its expression is affected by (P)RR whether overexpressed or suppressed and examined their effects in GBM cell lines or its glioma stem cells.
ET-03 Convection-enhanced delivery of EZH2 inhibitor for the treatment of diffuse midline glioma
Authors: Sasaki Takahiro , Katagi Hiroaki , Oren Becker , Stewart Goldman , Nakao Naoyuki , Hashizume Rintaro
Published: November 2020

Background: Diffuse midline glioma (DMG) is a fatal childhood brain tumor and the majority of patients die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which precludes total surgical resection, and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities. Objective: This study aims to assess the efficacy of enhancer of zeste homolog-2 (EZH2) inhibitor by CED against human DMG xenograft models. Methods: The concentration of EZH2 inhibitor (EPZ-6438) in the brainstem tumor was evaluated by liquid chromatography mass spectrometry (LC/MS). We treated mice bearing human DMG xenografts with EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence image and the therapeutic response was evaluated by animal survival. Results: LC/MS analysis showed that the concentration of EPZ-6438 in the brainstem tumor was 3.74% of serum concentration after systemic administration. CED of EPZ-6438 suppressed tumor growth and significantly extended animal survival when compared to systemic administration of EPZ-6438 (P = 0.0475). Conclusion: Our results indicate that CED of an EZH2 inhibitor is a promising strategy to bypass the BBB and to increase the efficacy of an EZH2 inhibitor for the treatment of DMG.
ET-05 Alectinib and ceritinib, the second-generation ALK inhibitors, effectively induce glioblastoma cell death
Authors: Kawauchi Daisuke , Takahashi Masamichi , Yamamuro Shun , Kobayashi Tatsuya , Uchida Eita , Iwadate Yasuo , Ichimura Koichi , Tomiyama Arata
Published: November 2020

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that only expresses in the developmental stage of the central and peripheral nervous system. A variety of ALK gene alterations, such as oncogenic fusion, activating point mutation, or wild type gene amplification, have been recently discovered as the powerful oncogene in various tumors. These ALK mutations are expected as potential therapeutic targets. Some ALK inhibitors have already been approved and used for the clinical treatment of non-small cell lung cancers harboring oncogenic ALK fusion.

Previously, we reported classical ALK inhibitors triggered cell death in human glioblastoma (GBM) cells, which did not express ALK, via suppression of transcription factor STAT3 activation but not in normal tissue-derived cells.

In this study, we investigated the anti-tumor effect of newly-developed ALK inhibitors in GBM cells. As a result, second-generation ALK inhibitors, alectinib and ceritinib, induced cell death in various human GBM cell lines with lower concentrations than other ALK inhibitors. Also, alectinib and ceritinib suppressed STAT family activity in these GBM cell lines. We consider alectinib and ceritinib might be a novel therapeutic agent against GBMs. Further investigation about the specific anti-tumor mechanism of these second-generation ALK inhibitors in GBM cells is currently on-going.
ET-06 Suppression of glioblastoma through novel drug based on “Gene Switch Technology”
Authors: Yamamoto Etsuko , Arakawa Yoshiki , Mineharu Youhei , Mikami Masamitsu , Matsui Yasuzumi , Sugiyama Hiroshi , Miyamoto Susumu , Adachi Souichi , Kamikubo Yasuhiko
Published: November 2020

Glioblastoma (GBM) is the most common and aggressive malignancy primarily affecting adults. Despite intensive multimodal therapies, the prognosis of GBM is dismal and a novel therapy is needed. Here, we focused on RUNX, a transcription factor involved in the malignant transformation of GBM, and developed a novel Chlorambucil-conjugated PI-polyamides (Chb-M’), which “switches off” RUNX family. Chb-M’ specifically recognizes the consensus RUNX-binding sequences (TGTGGT) and alkylates it to inhibit transcription of the downstream gene of RUNX family. Chb-M’ has been shown to induce apoptosis and suppress proliferation in a variety of cancers including leukemia, and in this study, similar results were found for glioblastoma cells in vitro. Specific inhibition of RUNX1 led to a marked inhibition of tumor growth through cell cycle arrest and apoptosis. By using apoptosis array, we isolated several candidate genes which regulated by RUNX1. And some types of glioblastoma cell lines treated with Chb-M’ showed elevated expression of p21 and decreased survivin. From in silico analysis using glioma patient cohorts, survivin expression was significantly higher in GBM and it was possibly involved in maintaining the malignancy of GBM. Mechanistically survivin was found to be directly transcriptionally regulated by RUNX1 through ChIP assay and reporter assay. In addition, survivin K/D cells upregulated p21 expression and accelerated apoptosis. Taken together, we hypothesized that the RUNX1-survivin-p21 pathway can potentially be exploited in the management of this malignancy. Chb-M’ mediated regulation of RUNX1 can be a novel therapeutic strategy against GBM.
ACT-02 Changes in Recurrence Pattern and Prognosis of Glioblastoma after Approval of Bevacizumab as First-line Application
Authors: Funakoshi Yusuke , Hata Nobuhiro , Kuga Daisuke , Hatae Ryusuke , Sangatsuda Yuhei , Fujioka Yutaka , Takigawa Kosuke , Mizoguchi Masahiro
Published: November 2020

Introduction: There exist controversies on recurrence and aggressiveness after use of first-line bevacizumab (BEV) which has been approved in Japan and proven to be beneficial. Therefore, we analyzed the clinical impact of BEV approval by investigating the overall clinical course and glioblastoma (GBM) relapse pattern.

Methods: We included 100 patients with IDH-wildtype GBM between September 2006 and February 2018 from our institution. They were subdivided into pre-BEV (n=51) and post-BEV (n=49) groups. Overall, progression-free, deterioration-free, and post-progression survivals (OS, PFS, DFS, and PPS, respectively) were compared. We analyzed the relapse pattern of 72 patients, whose radiographic progressions were confirmed.

Results: Significant improvements in DFS (median DFS in the pre-BEV and post-BEV eras: 8.5 and 13.8 months, P=0.0046), and PFS (7.5 and 9.9 months, P=0.0153) after BEV approval were observed. These survival prolongations were strongly correlated (r: 0.91, P<0.0001). Non-enhancing tumor emerged as a novel recurrence pattern in the post-BEV era (five of 33; 15.2%). Changes in relapse pattern did not significantly impact OS, PFS, and DFS. No significant difference in PPS between pre-BEV and post-BEV eras was observed (6.7 and 5.5 months, P=0.2319). The rate of early (within 6 months) focal recurrence was significantly lower (P=0.0155) in the post-BEV era (four of 33; 12.1%) than in the pre-BEV era (18 of 39; 46.2%). A significant decrease in early focal recurrence after BEV approval was observed exclusively in patients with unresectable tumors (P=0.0110). Treatment era was the only parameter significantly correlated with decreased early focal recurrence rate (P=0.0021, univariate analysis; P=0.0144, multivariate analysis).

Conclusions: We found that, first-line BEV in Japan for unresectable tumors has a positive impact on the prevention of early progression and clinical deterioration of GBM without accelerating the clinical course after recurrence.
ACT-05 Present and future of precision-based medicine using cancer genome panels
Authors: Natsumeda Manabu , Kanemaru Yu , On Jotaro , Saito Shoji , Tsukamoto Yoshihiro , Okada Masayasu , Hiraishi Tetsuya , Oishi Makoto , Fujii Yukihiko
Published: November 2020

Background: Two cancer genome panels were approved for use in Japan in 2019, and their application in brain tumors are awaited. We have used CANCERPLEXR and FoundationOne CDx (F1) panels for the realization of precision-based medicine in brain tumors. Patients and methods: From August 2017 to present, we have applied cancer genome panels in 11 times to tumors in 9 patients. We assessed patient data including age, sex, pathology, reason for using the panel and actionability. Results: The range of age of 4 to 69 years (mean 45.2 years), and 5 men and 4 women were studied. Pathological diagnosis was epithelioid glioblastoma (GBM), giant cell GBM, anaplastic ependymoma, anaplastic meningioma, anaplastic large cell type lymphoma, meningeal melanomatosis, enterogeneous carcinoma, choroid plexus carcinoma and pineoblastoma. CANCERPLEXR was performed 7 times and F1 panel 4 times and the reasons included confirmation specific gene mutations such as BRAF V600E and TP53, young (pediatric) age and patient request. In one patient, by analyzing primary and recurrent tissue, we were able to assess genetic hits involved in malignant transformation. Actionable targets were found in 4 (44%) of cases, and action was taken in only 1 epithelioid GBM patient with BRAF V600E mutation, albeit with dramatic response (Kanamaru et al., Acta Neuropathol Commun, 2019). All tumors were microsatellite stable. Conclusions: We were able to understand tumor biology in rare brain tumors using 2 genome panels. We need to increase the percentage of patients actually treated. I will also like to touch briefly on how use genome panels for translational research on brain tumors.
ACT-07 Clinical Trials of 11C-Methionine PET for brain tumors
Authors: Yamaguchi Shigeru , Shiga Tohru , Hirata Kenji , Terasaka Shunsuke , Kobayashi Hiroyuki , Shimosegawa Eku , Kagawa Naoya , Hirayama Ryuichi , Kinoshita Manabu , Kijima Haruhiko , Fujii Masazumi , Ichikawa Masahiro , Oriuchi Noboru , Kuge Yuji , Tamaki Nagara
Published: November 2020

Background: Although 11C-Methionine (MET) PET has widely used, 11C-MET tracer has not been approved in Japan. We conducted multi-center prospective clinical trials using MET for drug approval in diagnosis of brain tumors[Methods] Two trials using 11C-MET PET were performed in Hokkaido University, Osaka University and Fukushima Medical University; 1) Diagnostic accuracy in differentiating tumor recurrence from radiation injury after radiotherapy in brain tumors, 2) The diagnostic efficacy in newly-diagnosed gliomas. 1) The patients with suspected brain tumor recurrence underwent MET and 18F-Fluorodeoxyglucose (FDG) PET. When the target lesion showed MET and/or FDG uptake, the patients underwent target resection for pathological confirmation. Positive prediction values of each tracer uptake were assessed as primary outcome measure, and the sensitivities and specificities of each PET exams were also assessed. 2) The patients with suspected gliomas underwent MET PET. Tissue samplings were performed from MET uptake lesions without contrast-enhancement on MRI in each patient, and evaluated the existence of tumor cells. Diagnostic additional values of MET PET on contrast-enhanced MRI was also investigated. Safety of MET PET was also assessed in each trial.[Result] 1) 57 cases were investigated. 38 cases underwent surgery and 32 cases (84%) were confirmed tumor recurrence histopathologically. MET and FDG uptake in 32 recurrence cases were 100% and 50%, respectively. Sensitivities and specificities of tumor recurrence were 84% and 89% in MET, and 100% and 56% in FDG. 2) 53 glioma cases were enrolled. Viable tumor cells were proven in 98% in MET uptake lesion without contrast-enhancement. In 42 out of 53 cases (78%), MET PET depicted tumor area beyond the contrast-enhancement area on MRI. No severe adverse events were observed in both trials. [Conclusions] MET PET were effective in diagnosis of brain tumors, and safety of MET was demonstrated.
PEDT-03 A clinical trial of dendritic cell-based immunotherapy for refractory brain tumors in children
Authors: Akasaki Yasuharu , Yamaoka Masayoshi , Takei Jun , Nonaka Yuichirou , Hirotsu Tatsuya , Akiyama Masaharu , Yanagisawa Takaaki , Ohashi Touya , Ida Hiroyuki , Murayama Yuichi
Published: November 2020

Background/Objectives: Relapse or refractory brain tumor in childhood continue to have a dismal prognosis in spite of developing multidisciplinary treatment. Cancer immunotherapy is newly expected as next promising treatment for highly aggressive pediatric cancer. This trial was designed to evaluate the safety and clinical responses to an immunotherapy with fusions of dendritic cells (DCs) and tumor cells in patients with malignant brain tumors. Design/Methods: Patients with histopathologically confirmed high-grade or recurrent brain tumor were eligible for our immunotherapy. Autologous cultured tumor cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region and repeated 3–10 times in each 28–84 days cycle. Toxicity, progression-free survival (PFS), and overall survival (OS) of this trial were evaluated. Results: Six patients were enrolled, three with high grade glioma and three with ependymoma. Median age at first course of immunotherapy was 10 years (range 8–25 years) and median time of follow-up from first course of immunotherapy was 13.5 months (range 3–33 months). All patients with immunotherapy were well tolerated and no adverse event without local erythema in injected site. Median progression free survival and overall survival were 18 months and 18.5 months, respectively. Conclusions: FC immunotherapy with autologous DCs and tumor cells for brain tumor in children and young adults were extremely well tolerated and encouraging. Further phase II study of FC immunotherapy is planned to improve prognosis and overcome treatment related neurological sequelae for highly malignant tumors.
STMO-08 Validation of the endoscopic 5-ALA fluorescence diagnosis for intraventricular tumors
Authors: Nonaka Masahiro , Takeda Junichi , Hashiba Tetsuo , Asai Akio
Published: November 2020

Intraoperative 5-ALA fluorescence diagnosis (PDD) has been shown to improve tumor resection rates in surgery for malignant glioma. Recently, the usefulness of PDD has been reported in tumors other than malignant glioma. However, the fluorescence of intraventricular tumors is not easy to observe under the microscope, because excitation light could not reach enough to the deepest part of the brain. Therefore, we performed endoscopic 5-ALA fluorescence diagnosis of intraventricular tumors and evaluated its usefulness. Ten cases of intraventricular tumors were included in the study. There were 3 germ cell tumors, 2 metastatic brain tumors, 2 pilocytic astrocytomas, 1 malignant lymphoma, 1 subependymoma, and 1 medulloblastoma (recurrent). The tumors were located in the third ventricle in four cases, the lateral ventricle in three cases, the lateral ventricle and the third ventricle in two cases, and the aqueduct in one case. Tumor removal was performed in 6 cases and tumor biopsy in 4 cases. Intraoperative fluorescence could be observed in eight cases: three germ cell tumors, two metastatic brain tumors, two pilocytic astrocytomas, and one malignant lymphoma. Subependymoma and medulloblastoma did not show fluorescence. Among the cases with confirmed fluorescence, the fluorescent sites were targeted for biopsies for germ cell tumors and malignant lymphomas. For metastatic brain tumors and pilocytic astrocytomas, the extent of removal was determined at the time of removal, and the presence of residual tumor was confirmed by fluorescence after removal. Endoscopic 5-ALA fluorescence diagnosis for intraventricular tumors was useful in determining the target of biopsy or the extent of excision and in assessing residual tumors.
STMO-09 Recovery from speech deficit after injury to frontal aslant tract in glioma surgery
Authors: Saito Kuniaki , Kobayashi Keiichi , Shimada Daisuke , Iijima Shohei , Sasaki Nobuyoshi , Sasaki Yuta , Shiokawa Yoshiaki , Nagane Motoo
Published: November 2020

BACKGROUND: The frontal aslant tract (FAT) is a white matter fiber connecting the superior frontal gyrus to the lateral inferior frontal gyrus. Damage to FAT in dominant hemisphere can lead to speech deficits which, in most cases, resolve within weeks to months. However, little is known about mechanisms of recovery and factors for predicting permanent language deficits. METHODS: Eighteen patients with glioma (age ranged 24 to 78, 10 glioblastomas and 8 lower grade gliomas) located in the medial frontal lobe in the dominant hemisphere involving the supplementary motor area (SMA) and FAT were included. FAT was visualized using diffusion tensor imaging tractography in pre- and postoperative MRI. Postoperative language deficit, resected area of FAT and surrounding brain regions including the cingulate gyrus and corpus callosum (CC) were retrospectively reviewed. RESULTS: In 17 of 18 cases, postoperative language deficits were observed. Speech deficits resolved within a month in 12 cases, while recovery was incomplete in five cases. In two patients without complete recovery, CC located beneath SMA was removed because of tumor infiltration. Other two patients had substantial injury of middle third portion of FAT. The last case had preceding infarction in the contralateral frontal white matter including FAT. In cases with complete language recovery, transcallosal fibers connecting the contralateral SMA to the ipsilateral inferior frontal gyrus were detected by postoperative DTI-tractography. These fibers were damaged anywhere along its length in patients without complete language recovery, indicating that they may play an important role in recovery after FAT injury. CONCLUSION: Injury to CC or middle third portion of FAT can cause permanent language disorder. Transcallosal fibers from contralateral SMA seems to be involved in the recovery from language deficit after injury to FAT. In glioma surgery involving dominant SMA or FAT, these fibers should be preserved to avoid permanent speech deficit.
STMO-11 Supratotal resection of Glioblastoma with Methionine PET
Authors: Ko Ozaki , Hirono Seiichiro , Matsutani Tomoo , Iwadate Yasuo
Published: November 2020

Objective: To assess the resection of both of contrast-enhanced (CE) and methionine-uptake (MU) and the oncological outcome in newly diagnosed glioblastoma. Methods: This retrospective study included a glioblastoma cohort from Chiba University who met the two criteria, i) total resection of CE tumor, ii) preoperative evaluation with methionine positron emission tomography (Met-PET). Data regarding the pattern of recurrence and overall survival were collected. Results: Among 247 cases with glioblastoma, total resection of CE was achieved in 112. Preoperative Met-PET was performed in 30 out of 112. The median age at operation, a period of follow-up, and the preoperative tumor volume in 30 patients were 56 year-old, 17.9 months, and 18.8 cc respectively. The promoter region of the O6-methylguanine-DNA methyltransferase was methylated in 37%. Radiological comparison revealed that Met uptake was detected beyond the CE area in 13 out of 30, and the Met uptake was also resected with awake mapping technique in 7 patients (supratotal resection group; STR). The median progression-free survival (PFS) in STR was 23 months, and all the patterns of recurrence were distant recurrence. In contrast, the PFS in total resection group (TRG) was 9 months (p=0.09, Wilcoxon). Furthermore, 14 out of 17 recurrence were local in TRG subgroup. While the median OS in TRG was 18 months, it has not reached in STR (p=0.04, Wilcoxon). Conclusions: The resection of both of CE and MU was associated with better PFS and OS. This finding must be validated in a larger cohort with a multicenter study.
MPC-04 Utility of comprehensive cancer genome analysis for brain tumors
Authors: Miwa Kazuhiro , Takei Hiroaki , Ito Takeshi , Yokoyama Kazutoshi , Yano Hirohito , Shinoda Jun , Ishihara Satoshi , Nakayama Noriyuki , Iwama Toru , Kato Yasutka
Published: November 2020

Objective: Our hospital has been designated as a cancer genome medical cooperation hospital, and it is our responsibility to play a central role in cancer medicine. We were one of the first local hospitals to clinically apply cancer genome analysis, and in January 2019, we started PleSsision-Rapid testing as a clinical study without patient burden. This study examines data from patients with brain tumors, subjects it to cancer genome analysis, and reports on its utility and efficacy.

Method: Genome analysis was performed by PleSsision-Rapid examination for patients with brain tumors who underwent surgery between January 2019 and July 2020. Tissue DNA extracted from pathological specimens was used to perform next-generation sequencing (NGS) analysis. In the PleSsision-Rapid test, 160 genes are comprehensively analyzed, examined by genomics, and evaluated for the presence or absence of actionable and druggable mutations, and the mutation rate is determined.

Results: There were 15 cases total. Histopathological diagnoses included glioblastoma (n=5), diffuse astrocytoma (n=1), metastatic brain tumor (n=4), meningioma (n=2), central nervous system primary malignant lymphoma (n=1), germinoma (n=1), and Langerhans cell histiocytosis (n=1). Of these 15 brain tumor cases, actionable mutations were detected in 80.0% of cases and druggable mutations were detected in 66.6%. The average mutation rate was 8.59±5.32 (range, 1.3 to 22.8) per patient.

Conclusion: Although future improvements will be needed for cancer genome analysis in brain tumors, this strategy may be useful for the selection of molecularly targeted drugs with high antitumor efficacy. We will continue to accumulate and study such cases in the future.
MPC-06 Cutting-edge of Cancer Genomic Medicine for brain tumors
Authors: Mizoguchi Masahiro , Hata Nobuhiro , Kuga Daisuke , Hatae Ryusuke , Sangatsuda Yuhei , Fujioka Yutaka , Takigawa Kosuke , Funakoshi Yusuke , Koga Yuhki
Published: November 2020

Kyushu University Hospital was designated a Cancer Genome Core Hospital in April 2018, and the multi-gene panel test has been introduced since August 2019. The expert panel has been held for 21 cases of the central nervous system (11 adult glioma, 5 pediatric brain tumors, 5 extramedullary tumors). Actionable gene abnormalities were newly detected in two cases. First case is epithelioid glioblastoma with BRAF V600E mutation, and second is embryonal tumor with VCL-ALK fusion. For the first case, BRAF/MEK inhibitor can be used by the prospective trial of patient-proposed healthcare services with multiple targeted agent based on the result of gene profiling by multigene panel test (NCCH1901). For the second case, we are planning to introduce ALK inhibitor by indicator-initiated clinical trial while continuing ICE therapy. The current approved agents for tumor-agnostic treatment are immune checkpoint inhibitors for mismatch repair deficient (dMMR) cases and TRK inhibitors for NTRK fusion gene-positive cases. We selected microsatellite instability (MSI) test and immunostaining of MMR gene for the indication of immune checkpoint inhibitor for recurrent glioma and Lynch syndrome that require dMMR evaluation, but FoundationOne CDx (F1CDx) allows simultaneous evaluation of MSI and MMR gene abnormalities. Regarding the indication of TRK inhibitors, F1CDx assay is selected as a companion diagnosis for ALK, NTRK1/2/3 fusion gene analysis for pediatric cases. At present, the actionable gene abnormalities are detected by multi-gene panel tests in about 10% of brain tumors. Development of tumor-agnostic treatment will expand the molecular target therapy for brain tumor in the future. Based on the experience of different schemes for molecular targeted therapy, it became clear that it is necessary to establish a cancer genome medical system for prompt introduction of precision medicine for highly malignant brain tumors.
MPC-08 Molecular risk stratification using genome-wide DNA methylation data of standard-risk medulloblastomas treated with 18-Gy craniospinal irradiation
Authors: Irikura Tomoya , Fukuoka Kohei , Mori Makiko , Oshima Koichi , Arakawa Yuki , Tanami Yutaka , Ichimura Koichi , Nakazawa Atsuko , Kurihara Jun , Koh Katsuyoshi
Published: November 2020

A novel risk stratification of medulloblastoma has been proposed based on retrospective data from patients undergoing standard treatment. However, it remains unclear whether the classification is applicable to patients receiving reduced-dose craniospinal irradiation (CSI). We performed molecular diagnosis and copy number analysis using methylation array on patients with standard-risk medulloblastoma treated with 18 Gy CSI at our institution. Nine tumor samples were available for analysis from seven patients who had a median age of 7.4 years at disease onset and a median observation period of 73 months. Three patients had recurrence, and another patient developed radiation-induced glioblastoma. From the three recurrent cases, one was molecularly diagnosed as SHH subtype with MYCN amplification; another case was a Group 4 tumor without favorable prognostic chromosomal aberrations, and the remaining patient experienced a very late relapse despite low-risk stratification. Of the recurrence-free cases, one was classified as WNT subtype, and another was a Group 4 tumor with chromosome 7 gain, and loss of chromosomes 8 and 11, both of which were associated with good prognosis. Methylation analysis also unveiled the fact that the recurrent tumor diagnosed as relapsing medulloblastoma by conventional diagnostic tools was in fact a radiation-induced glioblastoma. Our data suggested that the new risk stratification may be useful for cases treated with CSI reduced to 18 Gy. However, due to the presence of the late-relapsed case stratified to low risk, further investigations with a larger cohort should be required to confirm the data.
ML-04 The influence of surgical intervention for high-dose Methotrexate chemotherapy in the patients with primary central nervous system lymphoma
Authors: Okamoto Michinari , Yamaguchi Shigeru , Ishi Yukitomo , Motegi Hiroaki , Kobayashi Hiroyuki , Terasaka Shunsuke , Houkin Kiyohiro
Published: November 2020

Object: Surgical resection is not the standard of treatment for primary central nervous system lymphoma (PCNSL). Some recent studies suggest that resection might be beneficial. The aim of this study was to examine the effect of surgical treatment in terms of the time from surgery to chemotherapy.

Methods: We retrospectively analyzed all patients with PCNSL treated at Hokkaido University Hospital between 2001 and 2018 to assess the effect of selection for resection on the response of Methotrexate chemotherapy. We identified the days from surgery to chemotherapy, complications, the response of Methotrexate (CR/CRu rate) and prognostic factors including progression free survival (PFS) and overall survival (OS).

Results: A total 105 patients were identified. 84 patients underwent biopsy and 21 patients underwent surgical resection. Their median age were 63 [31–78] and 68 [44–77], respectively. Their Karnofsky Performance Status (KPS) were 70 [30–100] and 70 [40–100]. There were any significant difference. Patients undergoing biopsy and those undergoing resection had comparable rates of complications for all complication type. Overall, 4 biopsy patients and 5 resection patients experienced at least one complication. They were composed of 2 asymptomatic bleeding, 1 wound abscess, 1 hydrocephalus in biopsy patients, 1 epidural abscess, 1 epilepsy, 1 chronic subdural hematoma, 2 temporary hemiparesis. Although the days from surgery to chemotherapy were significantly shorter in patients underwent biopsy than in those underwent resection (P=0.0015), PFS was significantly longer in patients underwent resection than in those underwent biopsy (P=0.0403), whereas there was no difference in OS.

Discussion: Resection could delay the postoperative treatment. In this study, there was a significant delay of postoperative treatment in resection patients, however, CR/CRu rate after MTX was significantly better in those underwent resection than biopsy. We can see that resection for PCNSL might not necessarily worsen the prognosis.
ML-06 Diagnostic value of liquid biopsy for CNS lymphoma by detection of specific gene mutations in the cerebrospinal fluid
Authors: Yamagishi Yuki , Sasaki Nobuyoshi , Matsushita Yuko , Shimizu Saki , Saito Kuniaki , Kobayashi Keiichi , Shiokawa Yoshiaki , Nagane Motoo , Ichimura Koichi
Published: November 2020

Backgrounds & Purpose: Central nervous system lymphoma (CNSL) is the second most common primary malignant brain tumor. Brain biopsy is indispensable to confirm the diagnosis of CNSL, but has a potential risk of inducing hemorrhagic complications in the brain. Therefore, liquid biopsy using the cerebrospinal fluid (CSF) has attracted an attention as a less invasive diagnostic method. In this study, we established a digital PCR-based method to detect MYD88 mutations in CSF and evaluated its efficacy. Methods: Matched CSF and biopsy samples from CNSL patients collected before the start of chemotherapy were used. Cellular DNA and cell free DNA (cfDNA) of CSF were separately extracted from the pellet and the supernatant fraction of CSF, respectively. Presence of the MYD88 L265P mutation was examined in each fraction by the digital PCR. The mutational status obtained by liquid biopsy was compared with that of the matched biopsy specimen examined by pyrosequencing. Result: A total of 36 paired samples were used. When the cutoff value of Target/Total ratio was 0.25%, sensitivity, specificity, and area under the curve (AUC) of the digital PCR detection using cellular DNA were 92.9%, 100%, and 0.95, respectively, while they were 100%, 100%, and 1.00 using cfDNA. Conclusion: We showed that the digital PCR method was highly sensitive and specific in detecting MYD88 mutations in the CSF. We propose that CSF liquid biopsy may serve a clinically applicable surrogate to make a diagnosis of CNSL.
ML-07 High expression of PD-L1 on tumor-associated macrophage is a predictive factor for favorable prognosis in PCNSL
Authors: Furuse Motomasa , Kuwabara Hiroko , Ikeda Naokado , Hattori Yasuhiko , Ichikawa Tomotsugu , Kagawa Naoki , Kikuta Kenichiro , Tamai Sho , Nakada Mitsutoshi , Wakabayashi Toshihiko , Kuroiwa Toshihiko , Wanibuchi Masahiko , Miyatake Shin-Ichi
Published: November 2020

PD-L1 and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we investigated the expressions of PD-L1 and PD-L2 in surgical specimens from needle biopsies and craniotomies to compare tumor tissue with surrounding tumor tissue (peritumoral tissue) and analyzed the correlation between expression of PD-L1/PD-L2 and survival in patients with PCNSL. We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1- and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. The tumor cells did not express very much PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95%CI: 0–94.6) than intratumoral macrophages (27.5%; 95%CI: 0–81.1, p=0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2-positive peritumoral macrophages (p=0.0429), with very low coefficient correlation (ρ=0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p=0.0008; better MSKCC score, p=0.0103; peritumoral macrophages: low proportion of LDH elevation, p=0.0064) and longer OS (for intratumoral macrophages: high PD-L1=60 months, 95%CI=30–132.6; low PD-L1=24 months, 95%CI=11–48; p=0.032; for peritumoral macrophages: high PD-L1=60 months, 95%CI=30.7-NR; low PD-L1=14 months, 95%CI=3–26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR=0.30, 95%CI=0.12–0.77, p=0.0129). Macrophages in intratumoral and peritumoral tissue expressed PD-L1 and PD-L2 at a higher rate than tumor cells. PD-L1 expression, especially on peritumoral macrophages, seems to be an important prognostic factor in PCNSL.
ML-14 Re-challenge and maintenance therapy of methotrexate for elderly PCNSL patients with low scored KPS
Authors: Yamaguchi Takashi , Nagayama Rie , Gomi Akira , Kawai Kensuke
Published: November 2020

Purpose: The delayed neuronal toxicity after high dose methotrexate (HD-MTX) followed by radiotherapy (RT) is a serious problem for elderly primary CNS lymphoma patients. We started maintenance therapy (MT) with MTX after achieving complete remission (CR) to defer RT for elderly and poor Karnofsky Performance Scale (KPS) patients.

Methods: We performed HD-MTX (3.5g/m2) therapy until achieving CR for the patients over 70 years whose KPS were equal to or less than 60%. After having CR, 3 courses of MT of MTX (3g/patient) for 3 weeks were introduced every 3–4 months for 2 years. At the time of recurrence, HD-MTX was repeated. But when CR was not achieved by HD-MTX alone, RT was introduced. Moreover, additional use of rituximab was considered if patients’ condition became better.

Results: Number of patients was 9. Median age, median KPS, and median follow up periods were 73y.o. (71–78), 40% (30–60), and 14.0 months (1–55), respectively. CR rate was 78% and two patients were not achieved CR due to the adverse events (AEs) which were acute tubular necrosis and pneumocystis pneumonia. But meanwhile, there was no AE by MT. Median OS, median PFS, median time of radiation free period and delayed neuronal toxicity were 19.5 months (95%CI 3-NA), 5.0 months (95%CI 2–22), 2.5 months, and 8.2 months, respectively.

Discussion: The results of this study might be inferior to other reports of elderly patients due to poor median KPS. And low introduction rate of MT was undesirable. However, once MT was introduced, MT itself was safe and easy to manage and the long-term prognosis was excellent.

Conclusion: Rechallenge of HD-MTX and maintenance therapy of MTX might be promising but the problems of some serious AEs and low CR rate with HD-MTX alone should be resolved.