bluuebunny/crossref_metadata_2025 huggingface dataset:
MPF–BML: a standalone GUI-based package for maximum entropy model inference
Authors: Quadeer Ahmed A , McKay Matthew R , Barton John P , Louie Raymond H Y
Published: December 2019

Learning underlying correlation patterns in data is a central problem across scientific fields. Maximum entropy models present an important class of statistical approaches for addressing this problem. However, accurately and efficiently inferring model parameters are a major challenge, particularly for modern high-dimensional applications such as in biology, for which the number of parameters is enormous. Previously, we developed a statistical method, minimum probability flow–Boltzmann Machine Learning (MPF–BML), for performing fast and accurate inference of maximum entropy model parameters, which was applied to genetic sequence data to estimate the fitness landscape for the surface proteins of human immunodeficiency virus and hepatitis C virus. To facilitate seamless use of MPF–BML and encourage more widespread application to data in diverse fields, we present a standalone cross-platform package of MPF–BML which features an easy-to-use graphical user interface. The package only requires the input data (protein sequence data or data of multiple configurations of a complex system with large number of variables) and returns the maximum entropy model parameters.

Availability and implementation

The MPF–BML software is publicly available under the MIT License at https://github.com/ahmedaq/MPF-BML-GUI.

Supplementary information

Supplementary data are available at Bioinformatics online.
A comprehensive analysis of methods for assessing polygenic burden on Alzheimer’s disease pathology and risk beyond APOE
Authors: Altmann Andre , Scelsi Marzia A , Shoai Maryam , de Silva Eric , Aksman Leon M , Cash David M , Hardy John , Schott Jonathan M ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2019

Genome-wide association studies have identified dozens of loci that alter the risk to develop Alzheimer’s disease. However, with the exception of the APOE-ε4 allele, most variants bear only little individual effect and have, therefore, limited diagnostic and prognostic value. Polygenic risk scores aim to collate the disease risk distributed across the genome in a single score. Recent works have demonstrated that polygenic risk scores designed for Alzheimer’s disease are predictive of clinical diagnosis, pathology confirmed diagnosis and changes in imaging biomarkers. Methodological innovations in polygenic risk modelling include the polygenic hazard score, which derives effect estimates for individual single nucleotide polymorphisms from survival analysis, and methods that account for linkage disequilibrium between genomic loci. In this work, using data from the Alzheimer’s disease neuroimaging initiative, we compared different approaches to quantify polygenic disease burden for Alzheimer’s disease and their association (beyond the APOE locus) with a broad range of Alzheimer’s disease-related traits: cross-sectional CSF biomarker levels, cross-sectional cortical amyloid burden, clinical diagnosis, clinical progression, longitudinal loss of grey matter and longitudinal decline in cognitive function. We found that polygenic scores were associated beyond APOE with clinical diagnosis, CSF-tau levels and, to a minor degree, with progressive atrophy. However, for many other tested traits such as clinical disease progression, CSF amyloid, cognitive decline and cortical amyloid load, the additional effects of polygenic burden beyond APOE were of minor nature. Overall, polygenic risk scores and the polygenic hazard score performed equally and given the ease with which polygenic risk scores can be derived; they constitute the more practical choice in comparison with polygenic hazard scores. Furthermore, our results demonstrate that incomplete adjustment for the APOE locus, i.e. only adjusting for APOE-ε4 carrier status, can lead to overestimated effects of polygenic scores due to APOE-ε4 homozygous participants. Lastly, on many of the tested traits, the major driving factor remained the APOE locus, with the exception of quantitative CSF-tau and p-tau measures.
Association between Anterior Cingulate Neurochemical Concentration and Individual Differences in Hypnotizability
Authors: DeSouza Danielle D , Stimpson Katy H , Baltusis Laima , Sacchet Matthew D , Gu Meng , Hurd Ralph , Wu Hua , Yeomans David C , Willliams Nolan , Spiegel David
Published: December 2019

Hypnosis is the oldest form of Western psychotherapy and a powerful evidence-based treatment for numerous disorders. Hypnotizability is variable between individuals; however, it is a stable trait throughout adulthood, suggesting that neurophysiological factors may underlie hypnotic responsiveness. One brain region of particular interest in functional neuroimaging studies of hypnotizability is the anterior cingulate cortex (ACC). Here, we examined the relationships between the neurochemicals, GABA, and glutamate, in the ACC and hypnotizability in healthy individuals. Participants underwent a magnetic resonance imaging (MRI) session, whereby T1-weighted anatomical and MEGA-PRESS spectroscopy scans were acquired. Voxel placement over the ACC was guided by a quantitative meta-analysis of functional neuroimaging studies of hypnosis. Hypnotizability was assessed using the Hypnotic Induction Profile (HIP), and self-report questionnaires to assess absorption (TAS), dissociation (DES), and negative affect were completed. ACC GABA concentration was positively associated with HIP scores such that the higher the GABA concentration, the more hypnotizable an individual. An exploratory analysis of questionnaire subscales revealed a negative relationship between glutamate and the absorption and imaginative involvement subscale of the DES. These results provide a putative neurobiological basis for individual differences in hypnotizability and can inform our understanding of treatment response to this growing psychotherapeutic tool.
Over-diagnosis of Rotavirus Infection in Infants Due to Detection of Vaccine Virus
Authors: Whiley David M , Ye Suifang , Tozer Sarah , Clark Julia E , Bletchly Cheryl , Lambert Stephen B , Grimwood Keith , Nimmo Graeme R
Published: December 2019

An accurate rotavirus diagnosis is important for clinical management and monitoring active disease and vaccine effectiveness. Between 2016–2018, rotavirus-positive results in our laboratory were from vaccine virus shedding in 71/152 (46.7%) infants with a request for rotavirus testing. Routine infant diagnostic testing should ideally distinguish vaccine from wild-type viruses.
Improvement of global longitudinal strain following high-dose chemotherapy and autologous peripheral blood stem cell transplantation in patients with amyloid light-chain cardiac amyloidosis: a case report
Authors: Hirata Yukina , Kusunose Kenya , Miki Hirokazu , Yamada Hirotsugu
Published: December 2019

Background

Cardiac amyloidosis (CA) is a secondary form of cardiomyopathy where abnormal accumulation of amyloid protein in the myocardial interstitium causes cardiac hypertrophy and myocardial fibrosis. If primary CA advances to heart failure, most patients do not survive for very long after the diagnosis.

Case summary

A 40-year-old man was admitted to our hospital for dyspnoea, progressive anaemia, and decreased appetite. He has diagnosed with amyloid light-chain (AL) amyloidosis. Although BD treatment (bortezomib + dexamethasone) and medical treatment were started, there was no sign of improvement. Then, high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) was initiated. Pretreatment echocardiography revealed typical findings of CA, such as ventricular wall thickening, valvular thickening, diastolic dysfunction, and pericardial effusion. Global longitudinal strain (GLS) was significantly reduced, and bull's-eye mapping showed typical apical sparing. After auto-PBSCT, GLS gradually improved and was almost normal after 2 years. Other echocardiographic parameters, functional status, and laboratory data also showed that there was significant regression of CA.

Discussion

Although the prognosis in primary CA is extremely poor, we achieved long-term survival in a patient with effective high-dose chemotherapy and auto-PBSCT. Global longitudinal strain may be a useful marker of prognosis, regression, and recovery.
Benefits of juvenile stand management in Finland—impacts on wood production based on scenario analysis
Authors: Huuskonen Saija , Haikarainen Soili , Sauvula-Seppälä Tiina , Salminen Hannu , Lehtonen Mika , Siipilehto Jouni , Ahtikoski Anssi , Korhonen Kari T , Hynynen Jari
Published: December 2019

We evaluated the impacts of juvenile stand management on wood production based on a nationwide scenario analysis. Measured plot-level information of the Finnish 11th National Forest Inventory (NFI) from juvenile stands formed the initial data for the analysis. To represent a total of 2.5 million hectares of productive forest land available for wood production, 6900 sample plots were selected. We predicted the development of the sample-plot stands for the next 100 years using the Motti stand simulator. We examined the impacts of juvenile stand management, including early cleaning and precommercial thinning, with three scenarios of different intensities of early-stage management (intensive, no management and business-as-usual). The results showed the benefits of juvenile stand management: earlier harvesting revenues, larger total removals, more valuable wood in the removals, and additional benefits that are associated with the first commercial thinning (i.e. no need for clearing before thinning, a larger stem size of removed trees). The main downside of juvenile stand management was the cost of the early cleaning and precommercial thinning. According to the results, a €560 million increase in costs would result in a €1700 million increase in stumpage earnings in Finnish forests during the next 100-year period. The 34 million m3 increase in the sawlog yield together with 28 million m3 decrease in the pulpwood yield also demonstrated the nationwide potential for increasing valuable sawlog production by intensive management of juvenile stands.
Nano-emulsification Enhances the Larvicidal Potential of the Essential Oil of Siparuna guianensis (Laurales: Siparunaceae) Against Aedes (Stegomyia) aegypti (Diptera: Culicidae)
Authors: Ferreira Ricardo Marcelo dos Anjos , D’haveloose Naima Pontes , Cruz Rodrigo Alves Soares , Araújo Raquel Silva , Carvalho José Carlos Tavares , Rocha Leandro , Fernandes Laís Pinho , Da Costa Tiago Silva , Fernandes Caio Pinho , Souto Raimundo Nonato Picanço
Published: December 2019

Siparuna guianensis (Laurales: Siparunaceae) has a terpene-rich essential oil with great potential for larvicides. The poor water miscibility of their compounds makes nano-emulsions of great interest for novel bioactive systems, including for control of Aedes aegypti (Diptera: Culicidae). This species is adapted to urban environments with important role in the epidemiology of some arboviruses such as dengue, chikungunya fever, zika, and urban yellow fever. The aim of the present study was to evaluate the feasibility of nano-emulsification to affect Ae. aegypti larvae. An optimal system was achieved by using a nonionic single surfactant, highlighted by its satisfactory size distribution profile. Moreover, improved larvicidal activity in comparison to bulk essential oil can be observed for the nano-emulsions. The estimated LC50 and LC90 values after 24 h of treatment of larvae with the essential oil were, respectively, 86.5232 and 134.814 µg/ml, while the estimated LC50 and LC90 value after treatment with the nano-emulsion were 24.7572 and 75.2452 µg/ml, respectively. The utilization of a simple technique to produce a fine nano-emulsion opens perspective for further integrative practices of mosquito control and giving value to this Amazon plant species may encourage its sustainable use and contribute to conservation policies.
Investigating the spectral age problem with powerful radio galaxies
Authors: Mahatma Vijay H , Hardcastle Martin J , Croston Judith H , Harwood Jeremy , Ineson Judith , Moldon Javier
Published: December 2019

The ‘spectral age problem’ is our systematic inability to reconcile the maximum cooling time of radiating electrons in the lobes of a radio galaxy with its age as modelled by the dynamical evolution of the lobes. While there are known uncertainties in the models that produce both age estimates, ‘spectral’ ages are commonly underestimated relative to dynamical ages, consequently leading to unreliable estimates of the time-averaged kinetic feedback of a powerful radio galaxy. In this work, we attempt to solve the spectral age problem by observing two cluster-centre powerful radio galaxies; 3C 320 and 3C 444. With high-resolution broad-band Karl G. Jansky Very Large Array observations of the radio sources and deep XMM–Newton and Chandra observations of their hot intracluster media, coupled with the use of an analytic model, we robustly determine their spectral and dynamical ages. After finding self-consistent dynamical models that agree with our observational constraints, and accounting for sub-equipartition magnetic fields, we find that our spectral ages are still underestimated by a factor of two at least. Equipartition magnetic fields will underestimate the spectral age by factors of up to ∼20. The turbulent mixing of electron populations in the radio lobes is likely to be the main remaining factor in the spectral age/dynamical age discrepancy, and must be accounted for in the study of large samples of powerful radio galaxies.
Streaming classification of variable stars
Authors: Zorich L , Pichara K , Protopapas P
Published: December 2019

In the last years, automatic classification of variable stars has received substantial attention. Using machine learning techniques for this task has proven to be quite useful. Typically, machine learning classifiers used for this task require to have a fixed training set, and the training process is performed offline. Upcoming surveys such as the Large Synoptic Survey Telescope will generate new observations daily, where an automatic classification system able to create alerts online will be mandatory. A system with those characteristics must be able to update itself incrementally. Unfortunately, after training, most machine learning classifiers do not support the inclusion of new observations in light curves, they need to re-train from scratch. Naively re-training from scratch is not an option in streaming settings, mainly because of the expensive pre-processing routines required to obtain a vector representation of light curves (features) each time we include new observations. In this work, we propose a streaming probabilistic classification model; it uses a set of newly designed features that work incrementally. With this model, we can have a machine learning classifier that updates itself in real time with new observations. To test our approach, we simulate a streaming scenario with light curves from Convention, Rotation and planetary Transits (CoRoT), Orbital Gravitational Lensing Experiment (OGLE), and Massive Compact Halo Object (MACHO) catalogues. Results show that our model achieves high classification performance, staying an order of magnitude faster than traditional classification approaches.
An NMF-based approach to discover overlooked differentially expressed gene regions from single-cell RNA-seq data
Authors: Matsumoto Hirotaka , Hayashi Tetsutaro , Ozaki Haruka , Tsuyuzaki Koki , Umeda Mana , Iida Tsuyoshi , Nakamura Masaya , Okano Hideyuki , Nikaido Itoshi
Published: December 2019

Single-cell RNA sequencing has enabled researchers to quantify the transcriptomes of individual cells, infer cell types and investigate differential expression among cell types, which will lead to a better understanding of the regulatory mechanisms of cell states. Transcript diversity caused by phenomena such as aberrant splicing events have been revealed, and differential expression of previously unannotated transcripts might be overlooked by annotation-based analyses. Accordingly, we have developed an approach to discover overlooked differentially expressed (DE) gene regions that complements annotation-based methods. Our algorithm decomposes mapped count data matrix for a gene region using non-negative matrix factorization, quantifies the differential expression level based on the decomposed matrix, and compares the differential expression level based on annotation-based approach to discover previously unannotated DE transcripts. We performed single-cell RNA sequencing for human neural stem cells and applied our algorithm to the dataset. We also applied our algorithm to two public single-cell RNA sequencing datasets correspond to mouse ES and primitive endoderm cells, and human preimplantation embryos. As a result, we discovered several intriguing DE transcripts, including a transcript related to the modulation of neural stem/progenitor cell differentiation.
AS2-2 NEUROCOGNITIVE AND PSYCHOSOCIAL DISORDERS IN CHILDREN WITH BRAIN TUMORS
Authors: Yoshihashi Manabu
Published: December 2019

The survival rate of children with brain tumors has been improving in the recent times. However, treatment outcomes should also include improved functional prognosis, considering motor dysfunction and sensory disorders, such as vision, and neurocognitive and psychosocial disorders, such as impaired intelligence, memory disorders, impaired attention, and impaired social behavior. In children with brain tumors, neurocognitive and psychosocial disorders easily occur due to various factors such as effect of the tumor, complications such as hydrocephalus, and impact of surgical treatment or radiotherapy. In addition, neurocognitive and psychosocial disorders are associated with decreasing quality of life (QoL) of pediatric patients with brain tumors.

When assessing neurocognitive and psychosocial disorders, objective assessments such as a neuropsychological assessment that includes an academic achievement test and an intelligence test, and subjective assessments such as observing behaviors need to be included. However, limited pediatric neuropsychological tests available in Japan.

Little evidence is available on the direct intervention methods that aim to improve neurocognitive and psychosocial disorders. Medical management for epilepsy, hydrocephalus, and endocrine disorders is performed while carefully considering cognitive function even in patients with neurocognitive and psychosocial disorders. Patients’ symptoms and QoL can be improved through cognitive rehabilitation, environmental adjustments such as an intervention in their educational environment, and family support. To integrate these medical and social models, a multidisciplinary team approach is required.

There is limited data on the assessment and intervention methods available for neurocognitive and psychosocial disorders of children with brain tumors. Currently, only a few facilities are equipped to provide expert treatment. The Neuropsychological Assessment Subcommittee (Brain Tumor Committee, the Japanese Children’s Cancer Group (JCCG)) aims to standardize the evaluation of neurocognitive and psychosocial disorders and intervention methods. These will be presented in line with the medical care provided at our hospital.
MS2 BRAIN TUMORS AND EPILEPSY
Authors: Iuchi Toshihiko
Published: December 2019

A brain tumor is one of the major causes of epilepsy, and glioma patients frequently exhibit seizures. Epileptic seizure, one of the features of glioma, is also known to be correlated with better outcome of patients. One of the reasons why patients with seizures have a good prognosis is that oligodendroglial tumors tends to cause epilepsy. However, even if limited to glioblastomas, the prognosis with epilepsy is still better than the others. Recently, the association between IDH mutations and epilepsy had been reported. IDH is an enzyme which converts isocitrate to alpha-ketoglutarate, but when this enzyme is mutated, 2-hydroxyglutarate (2HG) is produced instead of alpha-ketoglutarate. The molecular structure of 2HG is similar to glutamate, and it had been also reported that 2HG binds to the NMDA receptor. Indeed, in our cases, the IDH-mutation rate was higher in cases with epilepsy than the others. From our study of gene expression profiles, it was also clarified that the expressions of neuron-related genes were higher in cases with epileptic seizures, suggesting that many tumors classified as pro-neural type were included in this subset. As described, epilepsy phenotype is important, even in daily practice, because it predict the molecular status of gliomas and estimates the prognosis of the patients.

On the other hand, control of the seizures is important to keep patients’ QoL and to provide effective treatment. In this seminar, the control of epilepsy during and early after surgery, and how to manage status epilepticus will be reviewed.
SL3 PRIMARY CNS LYMPHOMA: CURRENT CONCEPTS AND THERAPEUTIC PERSPECTIVES
Authors: Grommes Christian
Published: December 2019

The lecture will summaries current standards of disease staging and treatment of Primary Central Nervous System Lymphoma (PCNSL). Concepts underlying the current first-line treatment regimen will be presented and current controversies in the treatment of PCNSL, including choice of induction regimen, choice of consolidation, and the roles of surgery/radiation/intrathecal therapy, will be discussed. In additional, the presentation will summarize novel insights into the pathophysiology of PCNSL, particularly the B-cell receptor signaling pathway (BCR). Results of completed and ongoing clinical trials targeting the BCR will be presented. The treatment standards in the recurrent setting will be summarized and additional novel therapeutic avenues, eg. immune checkpoint inhibition will be discussed. Furthermore, novel combinational clinical trials in recurrent/refractory setting will be discussed. Moreover, the diagnostic and prognostic value of novel, genomic testing and their integration into clinical trial development and clinical decision making will be discussed.
S5-KL-1 CURRENT TREATMENT FOR DLBCL AND PROPHYLAXIS AND TREATMENT FOR SECONDARY CNS LYMPHOMA
Authors: Izutsu Koji
Published: December 2019

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma, comprising 30% of all lymphoma cases. More than 60% of patients can be cured with current standard treatment, R-CHOP. On the other hand, prognosis of patients with relapsed or refractory DLBCL is disappointing with less than 10% being cured with salvage chemotherapy followed by high-dose chemotherapy with autologous stem cell transplantation. Prognosis of patients with central nervous system (CNS) relapse is especially poor because of a limited treatment option. Thus, evaluating risks of CNS relapse at diagnosis and administering prophylaxis including intrathecal methotrexate (MTX) or systemic high-dose MTX concurrently with R-CHOP or as consolidation therapy in high-risk patients are often-used approach. Clinically, higher risk according to the International Prognostic Index and extranodal involvement in organs such as kidney, adrenal gland, breast, testis, or bone marrow are considered to be high-risk for CNS relapse. Recently, CNS-International Prognostic Index has been proposed to integrate aforementioned risk factors. Moreover, patients with intravascular large B-cell lymphoma, CD5+ DLBCL, double hit lymphoma are reported as high-risk for CNS relapse. Further, the MYD88 L265P mutation, a common mutation in primary CNS DLBCL (PCNSL) is also common in DLBCL of testis or breast, which are the sites associated with CNS relapse.

Strategies for CNS prophylaxis have not established yet, and it is still unclear whether intrathecal MTX or high-dose MTX can prevent CNS relapse. Moreover, treatment for secondary CNS relapse have not been established. In particular, for those with both CNS and extra-CNS lesions, effective treatment options are very limited. The role of novel agents such as BTK inhibitors, lenalidomide, and immune check point inhibitors, whose efficacy have been shown for PCNSL, should be investigated further in the management of secondary CNS lymphoma.
ANGI-05 PATHOGENESIS OF RESISTANCE (MIMICRY AND CO-OPTION) TO ANTI-ANGIOGENIC TREATMENT FOR GLIOBLASTOMA
Authors: Takano Shingo , Tanaka Toshihide , Ishikawa Eiichi , Yamamoto Youhei , Takai Jun , Matsuda Masahide , Tsurubuchi Takao , Akutsu Hiroyoshi , Matsumura Akira
Published: December 2019

PURPOSE

Vessel co-option and vascular mimicry are important resistant factors with ant-angiogenic treatment for glioblastoma, but those precise evaluation is not clear. We had three types of glioblastoma surgically removed specimens treated with / without bevacizumab (Bev). Using these samples, pathogenesis of co-option and mimicry was morphometrically clarified.

MATERIALS / METHODS

Three types of glioblastoma specimens were analyzed; 1) Bev naive (N group, n 14), 2) Bev effective that was treated preoperative neoadjuvant Bev (E group, n 5), 3) Bev refractory that recurred with continuous Bev treatment for paired E group (R group, n 5). Vascular density was defined as a number of type IV collagen covered lumen. Vascular mimicry was measured as a ratio of CD34 negative / type IV collagen positive lumen. Vessel co-option was graded to 3 degrees (-), (+), (++) at tumor margin.

RESULTS

(1)Vascular density was significantly lower with E group (p<0.01) and R gr up (p<0.02) compared to N group. (2)Mimicry was significantly higher with R group compared to N and E group (p<0.01). Between paired samples, refractory case was constantly higher than effective sample. (3) Co-option was increases with R group compared to N group.

DISCUSSION/CONCLUSION

The effect of Bev for glioblastoma was investigated on three points (vascular density, vascular mimicry and vessel co-option) and two pathogeneses were clarified. In Bev refractory case, density was decreased, but mimicry and co-option were increased compared to Bev naive case. In Bev effective case, density was decreased, but mimicry and co-option were unchanged. Anti-angiogenic treatment for initial and Bev refractory glioblastoma should consider targeting co-option and mimicry in addition to Bev.
CBMS-01 AGE-DEPENDENT GLIOBLASTOMA PROGRESSION SUPPRESSED BY NAD+
Authors: Yamashita Daisuke , Ozaki Saya , Suehiro Satoshi , Sonomura Kazuhiro , Kondo Toru , Sato Taka-Aki , Kunieda Takeharu , Nakano Ichiro
Published: December 2019

The rise in population aging worldwide is causing an unparalleled increase in death from many cancers, including glioblastoma (GBM). Here, we have explored the impact of aging and rejuvenation on GBM tumorigenesis. Compared with old GBM, young GBM displayed elevated neuronal/synaptic signaling via brain-derived neurotrophic factor (BDNF) and SLIT and NTRK like-family member 6 (SLITRK6), promoting favorable survival rates. These effects were attributed to the rise in nicotinamide adenine dinucleotide (NAD+) levels, as brain rejuvenation by parabiosis or administration of nicotinamide mononucleotide (NMN) in mice elicited a younger phenotype with activated neuronal/synaptic signaling and improved outcomes. Our data indicate that age-associated NAD+ loss contributes to the highly aggressive GBM in the elderly. These findings have therapeutic implications in GBM and provide mechanistic insights into the exacerbation of GBM tumorigenesis with age.
CBMS-02 CROSSTALK WITH ASTROCYTES ESTABLISHES TUMOR EDGE IN GLIOBLASTOMA
Authors: Yamashita Daisuke , Ozaki Saya , Kondo Toru , Kunieda Takeharu , Nakano Ichiro
Published: December 2019

Clinical outcomes for patients with glioblastoma (GBM) are extremely poor due to inevitable tumor recurrence even after extensive treatments. These recurrences are thought to manifest from cells located within the tumor edge. Despite this, the precise molecular mechanism governing GBM spatial phenotypic heterogeneity (e.g. edge vs. core) and subsequent tumor recurrence remains poorly elucidated. Here, using patient-derived GBM core and edge tissues, we analyzed transcriptional and metabolic signatures in an effort to determine how GBM facilitates the edge phenotype and its associated recurrence-initiating cells (RICs). In so doing, we unexpectedly identified CD38 as an essential protein in the formation of the edge phenotype and found a CD38-driven interaction between edge GBM cells and neighboring astrocytes that communally develops a GBM edge that is unresectable by surgery and retains RICs. These findings have profound implications for future clinical therapies and provide new mechanistic insights into both tumor progression and recurrence.
GEN-03 GENOTYPE-PHENOTYPE CORRELATION IN 111 FAMILIES OF VON HIPPEL-LINDAU DISEASE IN JAPAN
Authors: Kanno Hiroshi , Yoshizumi Tetsuya , Shinonaga Masamichi , Yao Masahiro
Published: December 2019

BACKGROUND AND AIM

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

METHODS

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

RESULTS

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

CONCLUSIONS

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

OBJECT

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

MATERIAL & METHOD

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

RESULT

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

CONCLUSIONS

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

INTRODUCTION

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

MATERIALS AND METHODS

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

RESULTS

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

CONCLUSION

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

INTRODUCTION

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

METHODS

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

RESULTS

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

CONCLUSIONS

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

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

BACKGROUND

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

METHODS

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

STUDY DESIGN

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

OBJECTIVE

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

METHODS

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

RESULTS

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

DISCUSSION

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

CONCLUSION

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

BACKGROUND

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

OBJECTIVE

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

METHODS

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

RESULTS

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

CONCLUSIONS

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

BACKGROUND

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

METHODS

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

RESULTS

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

CONCLUSION

CUSA Clarity contributes to safe resection of glioma due to selective tumor aspiration by Tissue Select.