bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebral Blood Flow and Stroke in Patients with Left Ventricular Assist Devices
Authors: Kiyatkin Michael Eugene , Willey Joshua Zebadiah
Published: December 2019

The left ventricular assist device (LVAD) is increasingly used to treat end-stage heart failure and cardiogenic shock. Stroke is a leading complication of LVAD implantation, with an annual incidence of up to 20%, even with the latest models. The pathogenesis of ischemic and hemorrhagic stroke during LVAD support is multifactorial, with possible contributions including pump thrombosis, coagulopathy, and endothelial dysfunction secondary to pathological continuous flow. Strategies to prevent or minimize the risk of stroke have included preventing hypertension, using fewer thrombogenic materials in pump designs, optimizing anticoagulation, and implementing artificial pulsatility. In patients with LVADs, stroke is diagnosed from history, physical examination, and imaging (most importantly, computed tomography). Targeted endovascular therapy is preferred for treating ischemic stroke, and cautious reversal of anticoagulation is indicated for treating hemorrhagic stroke. The incidence of ischemic and hemorrhagic stroke after LVAD implantation continues to be unacceptably high. Further research in the pathophysiology, diagnosis, and treatment of stroke in patients with LVADs is needed, especially as these devices become more prevalent.
Aortic Regurgitation in Patients with Left Ventricular Assist Devices
Authors: Cevasco Marisa , Takeda Koji , Ando Masahiko , Naka Yoshifumi
Published: December 2019

Aortic insufficiency (AI) occurs as a complication in 25% to 37% of cases that receive left ventricular assist devices (LVAD). The incidence increases after implant by 1% to 6% per month of continued support. Uncertainty remains over the appropriate management of pump speeds to help delay this deterioration (complete emptying versus allowing native ventricular function open the aortic on a regular basis). Significant AI can lead to hemodynamic impairment with adverse outcomes over time. Due to the recirculation of blood, the calculated cardiac output of the LVAD may be markedly skewed. A number of surgical techniques have been proposed for the prevention and management of AI in the setting of LVAD therapy. This chapter details the causes, treatment strategies, and outcomes associated with this complication.
Chronic pain across the life span
Authors: Wainwright Elaine
Published: December 2019

Pain can be thought about at individual, social, and global levels and discursively defined in different ontological and epistemological ways. There is presently no absolute agreement about how to define it. However, there are movements to bridge the sufferer–observer, subjective–objective gap, and to think about pain from a functional perspective as opposed to conceptualizing it simply as an experience. Key conceptualizations of pain focus on its embodied nature and its extant function in protecting the organism from threat. Many epidemiological studies and systematic reviews define pain via International Association for the Study of Pain and International Classification of Diseases criteria, and show the extent of the global pain burden. Pain has many negative consequences across the life span, including a distinct impact on people’s working lives. How pain is conceptualized has important implications for clinical, research, and policy agendas. The embodied view of pain as an action against uncertainty means that if we are to reduce pain intrusion and interference (including whilst we work, or more broadly occupy ourselves) we must attend more deeply to how people manage threats to identity and coherence. We need clearer agendas to seek better pain-relieving resolutions than we achieve today.
Opportunities and Pitfalls of Quality Management
Authors: Verhoeven Didier , Siesling Sabine , Tucker Lee
Published: December 2019

Abstract: Quality of care is the degree to which health services are in accordance with the desired outcome and consistent with current professional knowledge and standards of care. Overuse, underuse, and misuse of diagnostic and treatment modalities may harm patients. Difficulties are present in defining the right standard. Quality indicators try to measure the quality management of the patients. Many challenges and opportunities are present in their development: they must be defined correctly and calculated using accurate data sources. Overall quality of care depends on the optimal quality at any stage of the health care process. Registration and monitoring must be done by an ‘independent’ trusted third party. Differences in quality indicators can lead to benchmarking, learning from best practices, and to better outcome at a lower cost. Following the Plan–Do–Check–Act cycle helps reduce unwanted clinical variation.
Examples of National Programmes on Quality Management
Authors: Siesling Sabine , Mensah Jumana , Brucker Sara Y. , Wesselmann Simone , Vrancken Peeters Marie-Jeanne , Honkoop Aafke , Terrier Francisco , Coló Federico , Matsuda Tomiro
Published: December 2019

Abstract: In several countries throughout the world, national accreditation programmes aim to standardize and improve the quality of care for breast cancer patients. All these national programmes stimulate the development of clinical practice guidelines, foster the implementation of these guidelines in multidisciplinary breast cancer units, and monitor aid implementation through guideline-derived quality indicators (QIs). This requires a well-defined set of quality requirements and indicators to which breast cancer centres adhere as well as a transparent auditing and data verification process. Breast cancer care should be delivered within the scope of a multidisciplinary treatment network and include all medical specialties and professions essential to providing optimal care. National programmes for quality assurance vary in their strategies for obtaining ideal quality of breast cancer care, and these range from auditing, certification, to accreditation. All hospitals should monitor their performance on a regular basis, and QI results as declared by the centres must be reliable and validated in the framework of on-site audits.
Reconstructive and Oncoplastic Surgery
Authors: Costa Mauricio Magalhães , van Dam Peter , Danaei Mahmoud , Leal Paulo Roberto , Leal Daniel
Published: December 2019

Abstract: Breast reconstruction has evolved over the last century, especially with the advent of new technologies including anatomical implants, expanders, and, most recently, acellular dermal matrix. The development of techniques ranging from free/pedicle flaps, implant-based reconstruction, fat grafting, and oncoplastic surgery have also played a major part in the success of this field. It is important that patients are informed about the possibility of having some type of reconstructive surgery in a second stage. The surgery should be performed by someone with the required training, either a plastic or oncoplastic surgeon, and this is an important quality assurance issue for the patient. Immediate breast reconstruction is gaining wide acceptance. However, secondary reconstruction is also a valid instrument, and in many cases, it is a reference standard procedure.
Teleoncology
Authors: Parham Groesbeck , Junkermann Hans , Van den Eynden Gert , van Diest Paul
Published: December 2019

Abstract: Teleoncology is defined as delivery of clinical oncology services from a distance for diagnosis, treatment, and patient follow-up using information and communication technology. Quality cancer care is often unavailable in low- and middle-income countries but also in remote areas of high-income countries. To reach its full transformational potential, it is in these areas where this technology is most needed. Areas where teleoncology has been most successfully applied are surgery, radiology, and pathology. Best practices must be identified for each local setting.
Optimization of Breast Cancer Management in Low- and Middle-Income Countries
Authors: Duggan Catherine , Anderson Benjamin O. , Cazap Eduardo , El-Tomb Paul A. , El Saghir Nagi S.
Published: December 2019

Abstract: Breast cancer mortality can be decreased by increasing awareness, and by improving access to early detection, screening programmes, and advanced care, as long as appropriate infrastructure and properly trained health care professionals are available. Low-income countries face many challenges, including spreading community awareness that breast cancer is a treatable disease. It must be clear that it is potentially curable, when discovered early enough and with the presence of basic pathology services and treatment options. The Breast Health Global Initiative consensus made clear recommendations to optimize breast care in low- and middle-resource countries.
SS1-KL-1 APPLICATION OF AI TECHNOLOGIES FOR MEDICAL CARE
Authors: Hamamoto Ryuji
Published: December 2019

On the basis of progress of the Machine Learning algorithm mainly on the Deep Learning, improvement of the GPU performance, the large-scale public database such as TCGA is available, big attention recently gathers in the AI technology. While large countries such as the United States or China vigorously promote AI research and development by a national policy, Cabinet Office, Government of Japan, also emphasized the importance of AI technologies in the 5th Science and Technology Basic Plan in 2016. As for the AI development, it is wrestled relatively for a long time; the word “Artificial Intelligence” was firstly used in the Dartmouth workshop in 1956. However, the AI development has not been promoted smoothly until now and repeats the active state period and the period of depression. As the current active state period of AI is called as the third AI boom, the most different point of this boom and the other booms is that AI technologies have already been involved in our social life such as the AI-based face authentication device in this period. Indeed, The US Food and Drug Administration (FDA) has already authorized around 30 AI-based medical instruments, and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan also authorized the first AI-based medical instrument last year. Therefore, now is the important time that we need to consider deeply for the creation of an affluent society, which enables coexistence of human being and AI. In this lecture, I particularly focus on medical imaging analysis using AI technologies and, would like to lecture on an action to the medical care application of the AI technology based on the experience that promoted medical AI research as the leader of two national projects relevant to medical AI called CREST and PRISM, and RIKEN AIP center.
SL2 ADVANCES IN MOLECULAR BIOLOGY AND GENETICS IN GLIOMA RESEARCH AND THERAPY
Authors: Cavenee Webster K
Published: December 2019

The most recent version of the WHO Classification of Tumours of the Central Nervous System includes, for the first time, the joint consideration of tumor pathology with tumor genetics as measured in various ways. This has come decades after the first recognition of genetic lesions in tumor genomes as discerned by cytogenetics and more than 30 years after the first reports of specific and recurrent genetic abnormalities in human tumors, particularly gliomas. This information is vitally important because it is now being used not just for tumor diagnosis but also to indicate specific therapies. In this lecture, I will review the increasingly precise methodologies being employed, the resultant genetic lesions being uncovered and the increasing import of such information for therapeutic selection.
MS3-1 IMPLEMENTATION OF GENE PANEL TESTING USING NEXT-GENERATION SEQUENCING
Authors: Sakai Kazuko
Published: December 2019

The advance of next-generation sequencers (NGS) has dramatically improved the performance of genomic analysis of clinical samples in cancer precision medicine. The practical use of gene panel testing for clinical applications has begun in Japan. At present, “OncomineTM Dx Target Test” is listed as a companion diagnostic system using NGS, and “FoundationOne CDx Cancer Genomic Profile” and “OncoGuide™ NCC Oncopanel System” are listed as gene panel testing under insurance coverage. Formalin-fixed paraffin-embedded specimen have been routinely used for molecular diagnosis testing, therefore quality control such as formalin fixation time and tumor contents is important to ensure validity of diagnostic results. In this presentation, the issue to obtain evaluable results of gene panel testing using formalin-fixed paraffin-embedded specimen will be discussed.

Due to evolution of detection technologies, we can detect gene mutation with high sensitivity. Detection of gene mutation in circulating tumor DNA is feasible approach for diagnostic testing in cancer treatment. Liquid biopsy has been approved as a companion diagnostic testing to detect EGFR mutations in NSCLC. Examples of the clinical utility of plasma testing in cancer treatment will be presented.
S4-KL-1 UPDATE OF WHO2016 CLASSIFICATION OF ADULT DIFFUSE GLIOMAS
Authors: Komori Takashi
Published: December 2019

The World Health Organization (WHO) central nervous system (CNS) tumor classification has represented the primary source of diagnosis and grading criteria of brain tumors. Nonetheless, recent advances of studies on their molecular alterations require more rapid update of recommendations for clinical practice. To accomplish this, cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established in 2016 and has published four updates. For adult gliomas, update 1 clarified the use of the term NOS (Not Otherwise Specified) and proposed a new term NEC (Not Elsewhere Classified); update 2 revised clarifications regarding diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant; update 3 proposed molecular criteria for an IDH-wildtype diffuse or anaplastic astrocytic glioma without histological features of glioblastoma, which would behave similarly to a grade IV glioblastoma. Nonetheless, no consensus on pathologic or molecular markers that could be incorporated into a more clinically relevant grading scheme for IDH-mutant gliomas has been reached. The molecular alterations previously studied using relatively large cohorts include CDKN2A/B homozygous deletion, CDK4 amplification, RB1 mutation/homozygous deletion, PIK3CA or PIK3R1 mutations, PDGFRA amplification, NMYC amplification, global hypomethylation, genomic instability and chromosome 14 loss. The proliferative activity, based on the mitotic count or Ki67 indices, and other morphologic features typical of a high grade that might stratify the risk better than the current criteria have also been evaluated. Despite the discordance among the results of previous studies, CDKN2A/2B homozygous deletions have been shown prognostic significance in high-grade IDH-mutant astrocytomas and microvascular proliferation stratifies IDH-mutant gliomas lacking a CDKN2A homozygous deletion, suggesting that the integration of molecular information and traditional histological findings is still essential for achieving maximum risk stratification of adult cases of IDH-mutant diffuse gliomas. The grading scheme for adult IDH-mutant as well as wild-type gliomas should therefore be revised in the next WHO update.
CBMS-04 SIGNIFICANT ROLE OF HYPOXIA IN THE EXPRESSION AND FUNCTION OF OSTEOPONTIN IN CD44-HIGHLY EXPRESSED GLIOMA STEM-LIKE CELLS IN TUMOR PROGRESSION OF GLIOBLASTOMA
Authors: Nishikawa Masahiro , Inoue Akihiro , Ohtsuka Yoshihiro , Ozaki Saya , Matsumoto Shirabe , Suehiro Satoshi , Yano Hajime , Kanemura Yonehiro , Tanaka Junya , Ohnishi Takanori , Kunieda Takeharu
Published: December 2019

The poor prognosis of glioblastoma multiforme (GBM) may be due to the surviving glioma stem-like cells (GSCs) in the tumor periphery after tumor resection. We demonstrated that CD44-expressed GSCs existed much more in the tumor periphery of high invasive (HI) type GBM than low invasive (LI) type GBM. The HI type was significantly associated with worse outcome, but how GSCs with high CD44 expression relate to tumor progression remains unknown. In this study, we investigated effects of hypoxia on CD44-directed signal pathways, leading to tumor invasion and proliferation in GBM. We focused on the CD44 ligand osteopontin (OPN) because it is known hypoxia affects the interaction of CD44 and OPN which promotes stemness and proliferation of cancer stem cells. We examined mRNA expressions of hypoxia inducible factor (HIF)-1a, HIF-2a, CD44 and OPN in tumor tissues of GBM and investigated effects of hypoxia (1%O2:severe or 5%O2:moderate) on the expression of these molecules using cultured GSCs that were established from tumor tissues showing high CD44 expression in the periphery of GBMs. In addition, we analyzed the effects of OPN on invasive, migratory and proliferative activities of GSCs under the hypoxic conditions. OPN was much higher expressed in the tumor periphery of LI type GBM than HI type GBM. Severe hypoxia significantly increased the expressions of HIF-1a and CD44 but did not OPN. On the other hands, moderate hypoxia promoted the expressions of HIF-2a and OPN. Knockdown of HIF-2a significantly inhibited OPN expression. In addition, the more OPN was expressed in the cultured GSCs under moderate hypoxia, the more the GSCs proliferated and decreased their invasive and migratory activities. In conclusion, GSCs existing in the tumor periphery of GBM can migrate or proliferate by changing CD44-directed signal pathways. Moderate hypoxia promoted HIF-2a/OPN/CD44 pathway, resulting in phenotypic transition to high proliferative tumors.
SPDR-06 PROTEIN DEUBIQUITINATION PATHWAY IS A NOVEL THERAPEUTIC TARGET AGAINST MALIGNANT CNS NON-GERMINOMATOUS GERM CELL TUMORS
Authors: Tomiyama Arata , Uchida Eita , Kobayashi Tatsuya , Wada Kojiro , Ichimura Kouichi
Published: December 2019

Central nervous system germ cell tumors (CNSGCTs) are rare intracranial neoplasm usually developed in adolescents and young adults. However, in East Asia including Japan, incidence of CNSGCTs is considerably higher compare with other regions of the world. Whereas germinomas generally respond to chemo-radiotherapy well, malignant subtypes of non-germinomatous germ cell tumors (NGGCT) are refractory, and development of novel therapy against NGGCTs is urgently needed. To develop a new therapeutic strategy against aggressive NGGCTs, we have investigated novel molecular targets for NGGCT treatment. We screened a total of 120 CNSGCT tumor tissues (including 55 NGGCT), which were registered to the Intracranial Germ Cell Tumor Consortium (iGCT), and discovered multiple mutations of a molecule that regulates protein ubiquitination and degradation specifically in NGGCT cases (5 of 55 cases; 1 immature teratoma, 3 mixed gem cell tumors, and 1 embryonal carcinoma). An in vitro ubiquitination assay revealed the mutations of this molecule discovered in NGGCT cases were loss of function mutations. Reduced expression of this molecule by knockdown in an established human seminoma cell line Tcam2 or a human yolk sac tumor cell line YST1, which was recently established in our institute, resulted in enhanced proliferation as well as upregulation of MEK-ERK activation. Importantly, treatment of these two GCT cell lines with reduced expression of this molecule by MEK inhibitor trametinib suppressed augmented proliferation of these cells. Taken together, these results suggest that protein ubiquitination-related pathways as well as MEK-ERK cascade may serve as a novel therapeutic target against NGGCTs.
ET-02 EFFICACY OF THE SALVAGE THERAPY VIA LOMUSTINE AND NIMUSTINE FOR RECURRENT GLIOBLASTOMA WITH TEMOZOLOMIDE RESISTANCE
Authors: Yamamuro Shun , Ichimura Koichi , Takahashi Masamichi , Tomiyama Arata
Published: December 2019

Temozolomide (TMZ) is widely used as a part of the standard treatment of glioblastomas (GBMs). However, GBM often acquires resistance for TMZ after continuous treatment with TMZ and recurs as TMZ resistance GBM (TMZ-R GBM). Other alkylating agents such as lomustine (CCNU) or nimustine (ACNU) have been sometimes used as a salvage therapy for those TMZ-R GBMs, however, their efficacy against TMZ-R GBMs has not been thoroughly investigated yet. In this study, we investigated anti-tumor effects of CCNU and ACNU for TMZ-R GBM cell lines in vitro to examine whether these agents could become alternative to TMZ in the therapy of TMZ-R GBMs. TMZ resistant clones of human GBM cell lines U87 MG (U87-R cells) and U251 MG (U251-R cells) were established as the TMZ-R GBM cell lines by cultivating U87 MG cells and U251 MG cells under continuous TMZ treatment for at least 1 year. Induction of growth arrest and apoptosis by TMZ, CCNU or ACNU against these cells were analyzed by dye exclusion assay, vital dye staining assay, and immunoblotting. The results showed that growth arrest and apoptosis were triggered upon these cells after administration of each drugs. As expected, the anti-tumor effects of TMZ for U87-R cells or U251-R cells were significantly reduced compared with those for parental U87 MG cells or U251 MG cells, respectively. On the other hand, CCNU and ACNU showed similar growth suppressive effect upon U87-R cells or U251-R cells as compared with U87 MG cells or U251 MG cells. Throughout these experiments, CCNU demonstrated strongest anti-tumor effects for all cell lines, both parental and TMZ-R GBM cell lines, and ACNU also demonstrated stronger effects than TMZ. These results suggest that CCNU or ACNU may serve as a drug of choice for salvage treatment of TMZ-R GBM.
TB-03 THE SURVIVAL PROLONGATION EFFECT OF NOVEL BORON COMPOUND FOR BNCT USING RAT BRAIN TUMOR MODEL
Authors: Fukuo Yusuke , Kawabata Shinji , Kashiwagi Hideki , Kanemitsu Takuya , Takeuchi Kouji , Hiramatsu Ryo , Wanibuchi Masahiko , Ono Kouji , Miyatake Shinichi
Published: December 2019

INTRODUCTION

Boron neutron capture therapy (BNCT) is form of tumor-cell selective particle irradiation. Although novel boron compounds have been developed, BPA (boronophenylalanine) and BSH (borocaptate sodium) are used in the clinical practice. The development of effective boron compounds is a major theme. We used Dodecaborate-containing BPA (AAL) which is combined the characteristics of both BPA and BSH. We have been conducting research on how the new compound for BNCT will affect rat brain tumor model.

MATERIALS AND METHODS

We evaluated the boron concentration of F98 glioma cells for BPA and AAL, and the biodistribution of these following BPA administrated intravenously (i.v.) or AAL administrated by convection-enhanced delivery (CED) in F98 glioma bearing rats. In BNCT study, the therapeutic effect was evaluated in terms of the survival time for all rats divided into six groups.

RESULTS

The uptake of boron showed almost the same value at all exposure times in high concentration. In biodistribution study, the AAL(CED) 6h after the termination group attained the highest boron concentrations of the tumor (59.9 ± 18.2 μg/g). In the BNCT study, the median survival time in the AAL(CED) group (31(29–35) days) was shorter than that in the BPA(i.v.) group(34(33–36) days). And the combination group of AAL(CED) and BPA(i.v.) gave the most significant prolongation of survival(38(36–40) days).

DISCUSSION

AAL(CED) and BPA(i.v.) combined group had a significant survival prolongation compared with the single-agent group. It is thought that AAL irradiated by thermal neutron had a cell-killing effect on cells in which BPA was not taken up. The combination uses of AAL (CED) provides additional BNCT effects. The mechanism by which AAL is incorporated has not been clarified, and further experiments including the influence on normal cells are in progress.

CONCLUSION

Dodecaborate-containing BPA (AAL) is a novel boron compound for BNCT that can be expected to prolong the survival time in combination with BPA.
IM-01 PI3K GAMMA INHIBITOR FOR OVERCOMING TREATMENT RESISTANCE IN COMBINATION THERAPY OF TEMOZOLOMIDE AND ANTI-PDL1 ANTIBODY FOR GLIOBLASTOMA PATIENTS
Authors: Ishikawa Eiichi , Miyazaki Tsubasa , Matsuda Masahide , Takano Shingo , Matsumura Akira
Published: December 2019

PURPOSE

Multidisciplinary therapies including immunotherapy in glioblastoma (GBM) patients often cause long survivor, while early relapse of GBM still remains. We should find factors associated with the immunotherapy-resistance for overcoming it. We previously reported that the infiltration of PD-1 positive cells and M2 macrophages (M2M&phi) increased in recurrent specimens compared to the initial specimens of GBMs treated with chemo-radiotherapy and autologous formalin-fixed tumor vaccine. Here we evaluate whether combination of novel immunotherapies, anti-PD-L1 antibody and M2M&phi inhibitor (IPI-549) inhibits growth of temozolomide (TMZ)-treated glioma cells rather than monotherapy.

METHODS

Using murine glioma initiating cells (TS) and TMZ-resistant TS (TMZRTS) cells, PD-L1 expression and cytokine production associated with M2M&phi were evaluated. TMZRTS cells were implanted in mice flank, followed by anti-PD-L1 antibody and / or IPI-549 administration.

RESULTS

Relative cell proliferation rate of TMZRTS cells was lower than TS cells, while PD-L1 mRNA expression was higher. Treatment with PD-L1 antibody caused marked infiltration of M2M&phi in glioma tissue. The combination therapy strongly inhibited tumor growth in TMZRTS murine model.

CONCLUSION

The anti-PD-L1 antibody treatment altered tissue microenvironment including marked infiltration of macrophages in glioma tissue, probably associated with clinical immunotherapy-resistance in GBM. Combination therapy with anti-PD-L1 antibody and M2M&phi inhibitor could overcame it.
BOT-01 BLOOD-BRAIN BARRIER OPENING USING 220-KHZ TRANSCRANIAL MRI-GUIDED FOCUSED ULTRASOUND AND MICROBUBBLES IN MOUSE AND RAT
Authors: Yoshida Michiharu , Maruyama Kazuo , Kato Yasutaka , Itay Rachmilevitch , Suzuki Syuji , Brockman Omer , Shapira Yeruham , Moriyama Kenji , Omata Daiki , Suzuki Ryo , Kamada Hajime
Published: December 2019

OBJECTIVE

In neuro-oncology, it is believed that one major obstacle to effective chemotherapy is the high vascularity and heterogenous permeability of brain tumors. Focused ultrasound (FUS) exposure with the microbubbles has been shown to transiently open the blood-brain barrier (BBB) without depositing thermal energy, and thus may enhance the delivery of various therapeutic drugs into brain tumors. The aim of this study was to evaluate the BBB opening using 220-kHz transcranial MRI-guided FUS (TcMRgFUS) device and microbubbles in mouse and rat.

METHODS

The experiments were performed with the 220-kHz ExAblate Neuro TcMRgFUS system (InSightec) and novel lipid bubbles (LB, Teikyo Univ.). Normal mouse and rat brains were irradiated with TcMRgFUS (output power, 5W; duration of irradiation, 30 s; duty cycle 100%) following intravenous injection of 6x107 LB per mouse and rat, respectively. On irradiation, target temperature rise & cavitation signal were monitored by MR thermometry and cavitation receiver, respectively. Immediately after irradiation, BBB opening and complications were detected based on T1, T2, T2*, and Gadolinium (Gd) enhanced T1-weighted images.

RESULTS

The maximum temperature of brain tissue was under 42 C. There were no risky-cavitation signals causing hemorrhage. The FUS-LB exposure induced successful BBB opening effect in both mouse and rat, confirmed by Gd enhancement in the target region, lateral ventricles, and sulcus. In addition, there were no complications such as edema, coagulation, and hemorrhage.

CONCLUSIONS

Although there remain many conditions to be optimized, BBB opening using a 220-kHz TcMRgFUS device and LB can offer a non-invasive and feasible drug delivery for brain malignancies.
BOT-04 POSSIBLE INVOLVEMENT OF CHLORIDE INTRACELLULAR CHANNEL PROTEIN 2 (CLIC2) IN THE SUPPRESSION OF INVASIVE ACTIVITY OF BRAIN TUMORS
Authors: Ozaki Saya , Inoue Akihiro , Nishikawa Masahiro , Suehiro Satoshi , Kunieda Takeharu
Published: December 2019

Chloride intracellular channel protein 2 (CLIC2) belongs to the CLIC family of conserved metazoan proteins. However, CLIC2 is the least studied among its family members, and its function remains to be elucidated. Recently, we have shown that CLIC2 is correlated with the development and/or maintenance of tight junctions in blood vessel endothelial cells in human non-cancer tissues. CLIC2-expressing endothelial cells supposedly prevent hematogenous spread of cancer cells. In this study, we investigated CLIC2 expression in human brain tumor tissues and also addressed its function by employing human meningioma cells, rat glioma cells and rat malignant brain tumor model. Thirty-one meningioma cases, six SFT/HPC cases, twelve pituitary adenoma cases and twenty-three glioblastoma cases who underwent surgery at Ehime University Hospital were included. CLIC2 mRNA expression levels were investigated with immunoblotting and quantitative RT-PCR. Cells from the meningiomas were cultured and their CLIC2 expression was knockdown. Filter-based invasion assays and gelatin zymography were performed using the knocked-down meningioma cells. Rat C6 glioma cells stably expressing rat CLIC2 were established and transplanted into the right striatum of neonatal Wistar rats. Effects of CLIC2 on the survival periods of the animals were investigated. CLIC2 expression levels were high in the low-grade cases but low in the high-grade cases and highly invasive cases. Meningioma cells, of which CLIC2 expression was knocked-down, showed higher invasive activity than control cells. The CLIC2-knock down cells displayed increased activities of MMP-2 and MMP-9. Rat brain tumor models revealed that high expression of CLIC2 was correlated with smaller and less invasive brain tumors compared with those consisted of control cells. The rats transplanted with CLIC2-expressing cells survived longer periods than the rats with control C6 cells. These results suggest that CLIC2 plays a role in suppression of invasive activities of tumor cells.
ACT-10 TREATMENT FOR GLIOBLASTOMA RECURRED AFTER CONCOMITANT CHEMORADIATION THERAPY WITH TEMOZOLOMIDE AND THEIR PROGNOSIS
Authors: Mori Kanji , Shofuda Tomoko , Mano Masayuki , Kodama Yoshinori , Kinoshita Manabu , Arita Hideyuki , Moriuchi Shusuke , Uda Takehiro , Taki Takuyu , Fukai Junya , Nonaka Masahiro , Ishibashi Kenichi , Sakamoto Daisuke , Izumoto Shuichi , Nishida Namiko , Okita Yoshiko , Nakajima Yoshikazu , Takano Koji , Hashimoto Naoya , Tsuyuguchi Naohiro , Okuda Takeshi , Achiha Takamune , Hayashi Nobuhide , Dehara Makoto , Kanemura Yonehiro
Published: December 2019

There are few data about treatment for glioblastoma recurred after concomitant chemoradiation therapy with temozolomide (TMZ). We retrospectively examined treatment and prognosis of recurred glioblastoma patients who registered Kansai molecular diagnosis network for central nervous system tumors, and whose clinical information were available. One hundred and fifty-seven patients that were clinically diagnosed as recurrence between November 2007 and April 2019 were included. Their median age at primary diagnosis was 52 years old and median KPS was 80%. Proportion of methylated MGMT promoter was 43.3% (65 patients), and mutated IDH was 5.4% (8 patients). Median overall survival after recurrence (mSAR) was 8.2 months. One hundred and sixteen patients (73.9%) were received any anticancer treatment and their mSAR was 10.5m. Combination of TMZ and bevacizumab (Bev) were most frequently used for 33 patients, followed by Bev monotherapy for 17 patients, surgery + TMZ + Bev for 15 patients, surgery + TMZ for 12 patients, and TMZ monotherapy for ten. Their mSAR were 8.0m, 7.5m, 10.5m, 13.0m, and 8.0m, respectively. Using univariate analysis, MGMT promoter methylation (p=0.0007), TMZ (p=0.00933), surgery (p=0.0126), re-radiation (p=0.0367), and surgery+TMZ+Bev (p=0.0493) significantly affected prognosis. By multivariate analysis, MGMT promoter methylation, TMZ, and re-radiation were statistically significant (p=0.000138, 0.00161, 0.00403, respectively). These data showed that relatively young patients with good performance status would receive anti-cancer treatment beyond progression and MGMT promoter methylation might be one of prognostic factor for longer survival. In this cohort, re-radiation was performed for few patients and nitrosourea such as nimustine was almost not used. Further study would be needed whether these treatments have any positive effect or not.
ACT-15 AD-SGE-REIC GENE THERAPY FOR MALIGNANT GLIOMA
Authors: Kurozumi Kazuhiko , Fujii Kentarou , Shimazu Yosuke , Tomita Yusuke , Matsumoto Yuji , Uneda Atsuhito , Tsuboi Nobushige , Kaneda Keisuke , Makino Keigo , Kumon Hiromi , Date Isao
Published: December 2019

INTRODUCTION

Malignant gliomas are one of the most common and aggressive intracranial neoplasms in humans. Expression of the gene encoding reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is reduced in a variety of human cancer cells. We previously showed the antitumor effect of an adenoviral vector carrying REIC/Dkk-3 gene (Ad-CAG-REIC). Recently, we have also developed a novel adenoviral vector expressing REIC/Dkk-3 (Ad-SGE-REIC). We assessed the anti-glioma effect of the Ad-SGE-REIC and planned a clinical trial of Ad-SGE-REIC for malignant glioma.

MATERIALS AND METHODS

We evaluated a cytotoxicity assay to treatments with Ad-SGE-REIC, Ad-CAG-REIC, or Ad-LacZ (control) using malignant glioma cells. The survival of mice in each group was analyzed by the Kaplan-Meier method. We also performed Good Laboratory Practice (GLP) toxicology tests and prepared a protocol for this clinical trial.

RESULTS

The treatment with Ad-SGE-REIC showed the number of malignant glioma cells attached to the bottom of culture wells was significantly reduced in a time-dependent manner. Mice treated with Ad-SGE-REIC significantly prolonged survival time more than those treated with other vectors. A cGMP product of Ad-SGE-REIC was developed and supplied by a startup biotech company, Momotaro-Gene Inc. We conducted GLP toxicology tests using the intracranial injection of higher doses of Ad-SGE-REIC at Shin Nippon Biomedical Laboratories (SNBL Japan). After finishing the consultation with Pharmaceuticals and Medical Devices Agency (PMDA), we prepared a protocol for a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma with our academic research organization (ARO), supported by Japan Agency for Medical Research and Development (AMED). This protocol was reviewed by our institution review board in March 2019. We submitted a notification of this trial in April 2019.

CONCLUSIONS

We demonstrated the anti-glioma effect of Ad-SGE-REIC. We start a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma (https://jrct.niph.go.jp/en-latest-detail/jRCT2063190013).
ACT-25 CLINICAL TRIALS BY THE JCOG BRAIN TUMOR STUDY GROUP
Authors: Nishikawa Ryo
Published: December 2019

Ongoing brain tumor clinical trials by the Japan Clinical Oncology Group (JCOG) are:JCOG1016, phase III randomized study in patients with anaplastic glioma of radiotherapy with temozolomide versus nimustine hydrochloride (ACNU) followed by temozolomide, is to prove superiority of post-operative radiotherapy with ACNU. JCOG1114, phase III study of high-dose methotrexate and whole brain radiotherapy with or without concomitant and adjuvant temozolomide in patients with primacy CNS lymphoma, is to prove usefulness and get insurance approval of TMZ for primary CNS lymphoma. JCOG1303, randomized phase III study for unresectable WHO Grade II diffuse astrocytoma with radiotherapy alone or chemoradiotherapy with temozolomide, is to prove superiority of STUPP regimen over simple radiotherapy for newly diagnosed and unresectable diffuse astrocytoma. JCOG1308, a multicenter randomized phase III study for recurrent glioblastoma comparing bevacizumab alone with dose-dense temozolomide followed by bevacizumab, is to prove usefulness of dose-dense, 7 days on/7 days off, TMZ, and to approve insurance coverage for recurrent GBM. JCOG1703, a multicenter randomized phase III study for newly-diagnosed maximally resected glioblastoma comparing carmustine wafer implantation followed by Stupp regimen with Stupp regimen alone, is to prove the survival advantage of surgery of GBM using carmustine wafer.
PEDT-05 USEFULNESS OF BEVACIZUMAB IN MAINTAINING QOL AT DIPG RELAPSE
Authors: Gomi Akira , Uchiyama Taku , Oguma Hirofumi , Yamaguchi Takashi , Kawai Kensuke
Published: December 2019

INTRODUCTION

Even in the age of molecular diagnosis, diffuse intrinsic pontine glioma (DIPG) is still a dismal disease, and there is no effective treatment. The usefulness of bevacizumab for DIPG relapse is reported.

SUBJECTS AND METHODS

The treatment and outcomes of 10 patients with DIPG who were treated at our institute since 2001 were retrospectively reviewed. All patients were diagnosed with DIPG by MRI imaging and underwent radiation therapy first. Chemotherapy was performed in combination with radiation therapy in 4 cases, and 3 of them did not receive chemotherapy at the time of relapse (Untreated Group). In 7 cases, chemotherapy was performed at the time of relapse with ACNU/vincristine or interferon beta (Other Treatment Group), and 2 cases with bevacizumab (Bv Group). The change in the Karnofsky Performance Status Scale (KPS) from the time of relapse was compared.

RESULTS

The average overall survival (OS) for all 10 cases was 10.0 months, 8.1 months in the Untreated Group, 9.5 months in the Bv Group, and 11.4 months in the Other Treatment Group. No prolongation of OS by bevacizumab was observed. However, it was only in the Bv Group that the KPS increased from the time of relapse. Comparison of the KPS at the time of relapse and the KPS after 4 months showed that the Bv Group remained unchanged or increased from 80 to 90, while the Untreated Group decreased by 60–100, and the Other Treatment Group also decreased by 20–50. In the Other Treatment Group, hospitalization was required for treatment, and side effects of bone marrow suppression were observed. However, in the Bv Group, outpatient treatment was possible, there were no side effects, and all could be observed at home.

CONCLUSION

From the above results, bevacizumab appears useful for palliative treatment for maintaining quality of life after DIPG relapse.
IMT-01 THERAPEUTIC EFFECT AGAINST LOWER GRADE GLIOMA INDUCED BY DENDRITIC CELL BASED IMMUNOTHERAPY
Authors: Akasaki Yasuharu , Takei Jun , Kamata Yuko , Yamamoto Yohei , Mori Ryosuke , Tanaka Toshihide , Yanagisawa Takaaki , Murayama Yuichi
Published: December 2019

BACKGROUND

This trial was designed to evaluate the safety and clinical responses to an immunotherapy with fusions of dendritic and glioma cells in patients with lower grade glioma (LGG; WHO grade II-III glioma).

METHOD

Autologous cultured glioma cells obtained from surgical specimens were fused with autologous dendritic cells (DC) using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region of subjects. Toxicity, progression-free survival (PFS), overall survival (OS), and MRI findings were evaluated. DNA for whole exome and RNA for whole transcriptome extracted from HLA-A*24:02 positive glioma cells were analyzed by next generation sequencer. Variant peptides showing strong binding affinity to HLA-A*24:02 but not the corresponding wild type peptides were selected as candidate of neo-antigens.

RESULTS

The number of subjects of this trial were 24 (initially diagnosed cases: 20, recurrence cases: 4). WHO grade III cases were 20, and grade II cases were 4. Male were 15, and female were 9. Mean of follow up periods were 53.0 months (the longest follow up period: 1322 months). The number of events on PFS and OS were 8 and 6, respectively. Mean of candidate of neo-antigen peptides in HLA-A*24:02 positive patients (n=8) was 34. Among these candidates, twelve types of common neo-antigen peptide were identified. Neo-antigen peptides specifically expressed in the glioma cells from the effective group were not identified.

CONCLUSIONS

These results indicate that the efficacy of FC-immunotherapy may not always depend on the number of gene mutations or the expression of the specific neo-antigens. FC-immunotherapy, as a means of producing specific immunity against neo-antigens may safely induce anti-tumor effects in patients with LGG. Analysis of prognostic factor in glioma immunotherapy may be the next area of major interest.
IMT-07 CLINICAL TRIAL OF A COCKTAIL WILMS’ TUMOR 1 (WT1) VACCINATION USING TWO HLA CLASS I PEPTIDES AND ONE CLASS II PEPTIDE FOR RECURRENT MALIGNANT GLIOMAS
Authors: Kagawa Naoki , Oji Yusuke , Tsuboi Akihiro , Hirayama Ryuichi , Kijima Noriyuki , Kinoshita Manabu , Oka Yoshihiro , Sugiyama Haruo , Kishima Haruhiko
Published: December 2019

PURPOSE

Our clinical trials shows the safety and clinical efficacy of Wilms’ tumor 1 (WT1) human leukocyte antigen (HLA) class I (Izumoto S et al. J Neurosurg. 2008) and class II (Tsuboi A et al. Cancer Immunol Immunother. 2019) peptide vaccination for recurrent malignant gliomas have been established. We have developed a cocktail vaccine (WT1 trio) containing two class I peptides (HLA-A*24:02 and HLA-A*02:01) and one II class peptide to improve more effective immunological response and improve patient’s prognosis. Clinical trial of a cocktail vaccination using WT1 HLA class I and II peptides for recurrent malignant gliomas is planned to verify its safety, clinical efficacy and usefulness of surrogate markers.

PATIENTS AND METHODS

Twenty-three patients with recurrent malignant gliomas, which showed WT1-positive in tumor samples and HLA-A*24:02 or HLA-A*02:01-positive in blood sample, were enrolled. These patients (age: 26–72 years old, average: 49.4) included 15 cases of glioblastomas and 8 of anaplastic astrocytomas. Patients received a WT1 trio vaccine intradermally, 7 times at 2-week intervals during 3 months.WT1-DTH and WT1-IgG antibody were regularly measured. Vaccine-related adverse events, best clinical response and the transfer rate of long-term administration of WT1 trio vaccination were estimated.

RESULTS

WT1-DTH positive cases were 12, WT1-IgG antibody positive were in 11. In most patients, WT1 -DTH positiveness coincided with that of WT1-IgG antibody. 9 of 11 cases showed stable disease at 3 months and transferred long-term administration of WT1 trio vaccination. Transfer rate in GBM and AA of long-term administration was 33% and 25%, respectively. Grade1 skin eruption was observed at the injection sites in 15 cases, but no significant adverse events related with vaccination were shown.

CONCLUSION

the safety and clinical efficacy of WT1 trio vaccination was verified for recurrent malignant gliomas. WT1-DTH and WT1-IgG antibody may be useful surrogate markers.
STMO-02 PREOPERATIVE FENCE-POST METHOD PLANNING WITH 3D-FUSION IMAGING
Authors: Sadahiro Hirokazu , Goto Hisaharu , Nomura Sadahiro , Suzuki Michiyasu
Published: December 2019

The fence-post method has been used for removal of intra-axial tumors. Preoperative detailed planning with only navigation work system is sometimes difficult to identify actual brain surface, small feeding artery and passing artery. Recently, 3-dementional imaging is well developed to integrate various anatomical findings. The purpose of this study is pursuit of perfect preoperative planning for removal intra-axial tumors with 3D-fusion imaging. From May 2017 to June 2019, 21 patients with intra-axial tumor were included. The software “AZE” was used to create 3D-fusion imaging. The brain tumor, brain surface and tractography were built from MRI, artery from digital angiography and vein from subtraction enhanced computed tomography. Then detailed preoperative planning was planned including how many fence-posts, procedure of cutting feeder, making sulcotomy or corticotomy, and finally cutting drainer. The average bleeding volume was 101±129cc, and there were no patients who had transfusion. All patients did not show additional neurological impairment after surgery. Detailed and perfect preoperative planning with 3D-sufion imaging should be effective for secure neurosurgery.
STMO-06 SMART CYBER OPERATING THEATER REALIZED BY INTERNET OF THINGS - RESULTS OF CLINICAL STUDY FOR 56 CASES
Authors: Yoshihiro Muragaki , Okamoto Jun , Saito Taiichi , Usui Satoshi , Yonezawa Ushio , Kurisu Kaoru , Goto Tetsuya , Fujii Yu , Hongo Kazuhiro , Horisawa Shiro , Taira Takaomi , Nitta Masayuki , Maruyama Takashi , Fukui Atsushi , Tsuzuki Shunsuke , Masamune Ken , Kawamata Takakazu , Iseki Hiroshi
Published: December 2019

PURPOSE

Unlike conventional operating rooms that provide a sterilized space, we have developed a Smart Cyber Operating Theater (SCOT) in which the room itself performs treatment as a single medical device. We report the clinical results of 3 types of SCOT.

METHODS

Basic SCOT packaged with intraoperative MRI (0.4Tesla) was introduced in Hiroshima University in 2016. Standard SCOT networked with middleware OPeLiNK was introduced to Shinshu University in 2018, and Hyper SCOT introduced to Tokyo Women’s Medical University in 2019.

RESULTS

The average of all 56 patients was 44 years old. There were 38 brain tumors (68%), 11 functional diseases (19%), and 7 orthopedic diseases (13%). Basic SCOT is used for 41 cases (/56; 73%) with 22 gliomas, 10 epilepsies, 7 bone tumors, and 2 benign brain tumors. Standard SCOT with 20 networked devices is used for 14 cases (/56; 25%) with 6 gliomas including brain stem and thalamus, 6 pituitary tumors and 2 benign brain tumors. The strategy desk can display a variety of digital data synchronized in time, and the review and comment functions also operate. It is useful for remote advice through mutual communication via strategy desk. Hyper SCOT was used in February 2019 for the first case (1/56 cases; 2%). MRI images were taken with an average of 1.3 shots with good image quality. For 46/56 neoplastic lesions (82%), additional removal of residual tumor was performed in 31/46 cases (67%), and 26/46 cases (57%) were totally removed, with an average removal rate of 89.2%. There was no reoperation (0%) within 1 month in all cases.

CONCLUSIONS

Three types of SCOT contributed to planned surgical outcome including maximal tumor resection without serious related complications. We will proceed with verification of clinical effects, and develop robotized devices, and utilize AI for strategy desk at Hyper SCOT.