bluuebunny/crossref_metadata_2025_split huggingface dataset:
ML-12 Clinical impact and management of skin-related disorders during treatment of relapsed PCNSL by tirabrutinib
Authors: Sasaki Nobuyoshi , Kobayashi Keiichi , Saito Kuniaki , Onoda Ryo , Seiya Yosuke , Suzuki Saki , Yamagishi Yuki , Nakatomi Hirofumi , Shiokawa Yoshiaki , Nagane Motoo 
Published: December 2021

Abstract
BACKGROUNDS: Tirabrutinib is a second-generation Bruton’s tyrosine kinase (BTK) inhibitor, approved by the Japanese Pharmaceutical and Medical Devices Agency (PMDA) for relapsed and refractory PCNSL in March 2020. Skin-related disorder (SRD)s are the most prevalent adverse events in tirabrutinib, which accounted for 54.5% in a phase I/II trial. While the use of tirabrutinib is increasingly considered in clinical practice, the prevalence and clinical impact of tirabrutinib-related SRDs in real-world practice remains unclear. METHODS: Relapsed PCNSL patients treated with tirabrutinib at the author’s institution were identified, and divided into those with SRDs (SRD group), and without SRDs (non-SRD group). Response rate and progression-free survival (PFS) were retrospectively analyzed and compared between the two groups. RESULTS: Eleven patients were identified (median age: 73 [range: 50–83], median KPS: 70 [range: 40–90]), which included six (54.5%) from the SRD group and five (45.5%) from the non-SRD group. Response rate was 100% in the SRD group and 60% in the non-SRD group. Median PFS was 2.8 months in the SRD group and 36.3 months in the non-SRD group, which yielded no significant difference (p=0.446). While antihistamine prophylaxis using fexofenadine was performed in seven patients, among them SRDs were observed in three (27.3%). SRDs lead to tirabrutinib interruption (for seven days or more) in two (18.2%), dose reduction in three (27.3%), and discontinuation in two (18.2%) patients. Four patients in whom tirabrutinib was interrupted or discontinued due to SRDs had shorter PFS, compared with the two patients from the SRD group in whom tirabrutinib was continued (median PFS: 2.3 and 29.6 months, respectively) (p=0.049). CONCLUSIONS: SRDs substantially lead to tirabrutinib interruption or discontinuation, which could result in early PD. Since fexofenadine prophylaxis seems ineffective for preventing SRDs, other antihistamines should be considered. Establishment of the optimal management of tirabrutinib-related SRDs is warranted.
ML-17 Clinical usefulness of Tirabrutinib in recurrent PCNSL: single institute experience
Authors: Matsuura Jin , Kuroda Jun-Ichiro , Takezaki Tatsuya , Shinojima Naoki , Mukasa Akitake 
Published: December 2021

Abstract
Background: Primary central nervous system lymphoma (PCNSL) is a lymphoma whose primary lesion is localized in the brain and spinal cord. Treatment is a combination of high-dose methotrexate-based chemotherapy and whole-brain irradiation, often leading to recurrence. Pathologically, non-GCB type diffuse large B-cell lymphoma (DLBCL) predominates. In DLBCL, constitutive activation of B cell receptor signal (BCR) is the tumor mechanism of tumor development and growth. Tirabrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK) located downstream of BCR. In a phase I / II study, an overall response rate was 64%. Currently, Tirabrutinib is used to treat relapsed or refractory PCNSL. Purpose: Tirabrutinib is a drug that has just been approved, and there are few reports of its use in clinical practice. We report on our experience with Tirabrutinib with a review of the literature. Methods: We retrospectively examined the clinical course of 11 recurrent PCNSL patients treated with Tirabrutinib at our institution. Results: The average age of the subjects was 68.7 years, and 7 cases were male. Tirabrutinib 480 mg was administered in all cases. The response rate was 60% (6/10 cases). The median progression-free survival was 4.3 months. The adverse events were Grade 3 neutropenia in 1 patient and Grade 2 skin disorder in 4 patients. Treatment was discontinued in 5 of the 11 patients due to the progression of the disease. Due to the eruption, Tirabrutinib was reduced to 320 mg in 1 patient and discontinued in 1 patient. Treatment was discontinued at the request of the patient in 1 case, and four patients are still on medication. Summary: According to the results we obtained, the response rate was the same as that in the phase I / II study, and the progression-free survival was slightly longer.
BT-1 An autopsy case of multicentric malignant glioma, H3K27M mutant
Authors: Hayashi Nobuhide , Enomoto Hiroki , Kubo Kenji , Nakanishi Yuta , Ishii Kenji , Kawaguchi Takumi , Okada Hideo , Kuwata Toshikazu , Tsubota Yukari , Kanemura Yonehiro 
Published: December 2021

Abstract
Introduction: In 2016, the World Health Organization (WHO) defined diffuse midline glioma, H3K27M mutant (WHO Grade 4) as a tumor with K27M mutation in histone H3.3 (H3F3A) or H3.1 (HIST1H3B/C) that develops mainly in the midline regions of the central nervous system. Here, we report a rare case of the abovementioned disease with remote multiple lesions in addition to the midline regions that was diagnosed on the initial visit. Case: The 52-year-old man, suffered from dysarthria, dysphagia, gait disturbance, and headache that gradually worsened over several months. Non-contrast-enhanced lesions were noted in the pons(swelling and involvement of the basilar artery trunk), cerebellum, thalamus, fornix, periventricular area, hippocampus, medial aspect of bilateral frontal lobes, and distally in the right frontal cortex and apical region of the left temporal lobe. The open biopsy was performed for left cerebellar surface lesion, and the pathological and genetic diagnosis was diffuse midline glioma, H3K27M mutant. Extended focal radiation at 50Gy/25fr and corpus callosal/cerebellar boost at 10Gy/5fr were performed. The lesions were markedly reduced, and neurological symptoms were also alleviated. However, 20 months after the initial visit, neurological symptoms had worsened and cerebrospinal fluid dissemination occurred, after that died at 29 months. An autopsy revealed tumor invasion mainly in the midline regions of the cerebrum and in the cerebellum, brain stem, pituitary gland, entire spinal cord, and cauda equina. Immunostaining of the distally cerebral cortex lesions showed that with a negative result for H3G34V. Discussion/Conclusion: It was suggested that caution is required for primary differential diagnosis may be presented at multiple lesions such as remote cerebral cortex of diffuse midline glioma, H3K27M-mutant.
BT-4 The treatment history of long-term survivors of Optic Pathway Glioma in Kobe Children’s Hospital
Authors: Kawamura Atsufumi , Koyama Junji , Akutsu Nobuyuki , Higashino Masashi , Fujita Kenji 
Published: December 2021

Abstract
Optic pathway glioma(OPG) is almost recognized in childhood and about 0.01–0.02% of whole brain tumor in Japan. Because of the rare tumor, there are few reports about results of its treatment. In 2021, Guideline of Optic pathway/hypothalamic glioma is indicated from The japan Society for Neuro-Oncology. We retrospectively study 9 cases history of OPG who have treated for more than 5 years from January 2005 to March 2021 in Kobe Children’s Hospital. Cases are 4 boys and 5 girls. Average age at diagnosis is 3.8 years old and average follow up term is 11 years 10 months. They are 4 Pilocytic astrocytoma, 3 Pilomyxoid astrocytoma, and 1 Fibrillary astrocytoma. Al l cases have survived. There are only 2 cases who could be controlled with single series of surgical treatment and chemotherapy. Most cases need several times of resection and chemotherapy and uncontrollable 5 cases required radiological treatment. 2 cases are still under treatment for over 10 years. For OPG, partial resection to control hydrocephalus is recommended and several trial of chemotherapy must be carried out. There exist a few cases who need continuous treatment for long term. The other side, a few cases are uncontrollable those need radiotherapy to manage tumor volume. Because the history of OPG would be long term, we should adjust the treatment plan to environment of patients.
BT-7 Long-term outcome and late adverse effects of intracranial primary germ cell tumor
Authors: Hanihara Mitsuto , Kawataki Tomoyuki , Saito Ryu , Ogiwara Masakazu , Kinouchi Hiroyuki 
Published: December 2021

Abstract
Background: Current standard of care for intracranial germ cell tumor (IGCT) have favorable cure rates. However, long-term treatment-related adverse event data are limited. The present study examined the long-term outcome of IGCT.Methods: The data from 27 patients with IGCT treated at our institutes from 1993 to 2020 were retrospectively analyzed. The patients were divided into two groups: group A; who received whole-ventricle RT (30 Gy) or focal RT (40-50Gy) from 1993 to 2012, group B; who received whole-ventricle RT (23.4 Gy) from 2013 to 2020. Complications and physical-activity level after treatment were retrospectively analyzed.Results: Pathological diagnosis was germinoma in all cases, and chemotherapy was CARE in 19 cases and ICE in 2 cases. Radiation therapy was performed in 15 cases in group A and 6 cases in group B. The follow-up period was 8–19 years (mean 11.3 years) in group A and 0.4–7 years (mean 3.6 years) in group B. Radiological cure was obtained in all cases, there was no recurrence. Hypopituitarism requiring hormone replacement therapy was observed in 53% of patients in group A and 50% of patients in group B. Late complications were cerebral hemorrhage from venous malformation (4 years after treatment), symptomatic cerebral atrophy in 2 cases (3 years / 6 years after treatment), radiation induced malignant glioma (19 years after treatment) in group A. The rate of good physical-activity was 71% of group A and 100% of group B.Discussion/Conclusions: CARE + whole-ventricle radiation therapy is appropriate as a standard treatment for ICGT. Late complications are directly linked to poor quality of life and may be radiation dose dependent. Optimize radiation therapy to further improve outcomes is required.
CS-1 Cerebellar liponeurocytoma; Report of two cases with detailed metabolic, immunohistochemical, and genetic evaluations
Authors: Shimizu Miyuki , Origuchi Shinichi , Hirono Seiichiro , Matsutani Tomoo , Oota Masayuki , Ikeda Jun-Ichiro , Yokoo Hideaki , Iwadate Yasuo 
Published: December 2021

Abstract
Cerebellar liponeurocytoma (cLNC), World Health Organization grade II neoplasm, is a rare brain tumor characterized by advanced neuronal/neurocytic differentiation and focal lipid accumulation in neuroepithelial tumor cells. However, the expression and genetic profiling of cLNC, as well as metabolic imaging characteristics, have been poorly studied. Two patients with lower vermian tumors were operated on with telovelar approach. Moderate methionine uptake in positron emission tomography was observed in both cases. Histologically, the tumor was composed of small, uniform cells with round nuclei in a sheet-like fashion. Vacuolate cells with displacement of nuclei suggested the lipid accumulation, which was further supported by immunohistochemical staining of S-100. Although the extent of lipidization was relatively low compared with the reported cLNC cases, the immunohistochemical findings confirmed the diagnosis of cLNC. Next-generation sequencing of tumoral DNA in one case detected a splice site mutation of the ATRX gene, which is the first observation in the literature. Neither chemotherapy nor radiotherapy were administered postoperatively in both cases. In one case with spinal dissemination, residual tumor demonstrated progression 7 months after the resection. Long term follow-up data of cLNC cases with detailed expression and genetic profiles are essential for precise diagnosis and better understanding of the oncogenic pathway as well as the natural history of cLNC.
COT-3 Exosomal microRNA expression signature in blood and cerebrospinal fluid of glioblastoma patients
Authors: Yamashita Daisuke , Suehiro Satoshi , Ohtsuka Yoshihiro , Ozaki Saya , Nishikawa Masahiro , Inoue Akihiro , Kohno Shohei , Ohue Shiro , Ohnishi Takanori , Kunieda Takeharu 
Published: December 2021

Abstract
Analysis of exosomes derived from plasma or cerebrospinal fluid (CSF) has emerged as a promising biomarker platform for therapeutic monitoring in glioblastoma patients. However, the contents of the various subpopulations of exosomes in these clinical specimens remain poorly defined. Here we characterize the relative abundance of miRNA species in exosomes derived from the plasma and CSF of glioblastoma patients. To this end, we first employed miRNA arrays to measure the expression of exosomal miRNAs in the plasma from glioblastoma patients (n = 24) and healthy volunteers (n = 7) as control. In addition, we performed global miRNA profiling of exosomal miRNAs in the CSF from glioblastoma patients (n = 5) and non-tumoral patients (n = 3; hydrocephalus patients) as control. In plasma derived exosomes, 80 miRNAs were altered by &gt;2-fold in glioblastoma patients compared to controls. In CSF, 92 miRNAs were altered by &gt;2-fold in glioblastoma patients compared to controls. Combined analysis of plasma and CSF revealed a similar fold difference in eight miRNAs. Next, we measured these eight miRNAs expression in in the plasma from pre- and post-operative glioblastoma patients (n = 9). Among these eight miRNAs, we identified only one miRNA (miR-34b-3p) that was upregulated in exosomes from pre-operative glioblastoma patients. Our results suggest that miR-34b-3p might have a potential as a novel diagnostic marker or a therapeutic tool for glioblastoma patients.
COT-11 Relationship between preoperative liquid biopsy and prognosis of glioblastoma -Next Generation Sequencing of small noncoding RNA-
Authors: Onishi Shumpei , Yamasaki Fumiyuki , Takayasu Takeshi , Takano Motoki , Yonezawa Ushio , Taguchi Akira , Kanda Miyuki , Sugiyama Kazuhiko , Tahara Hidetoshi 
Published: December 2021

Abstract

Background
Non-invasive biomarkers are required in clinical practice of glioblastoma (GBM). We have previously reported the liquid biopsy for differentiating glioblastoma, central nervous system primary lymphoma and healthy control. In this study, we analyzed the relationship between the preoperative serum expression of circulating small non-coding RNAs and the prognosis of GBM patients.

Methods
Preoperative blood samples of GBM, IDH-wildtype patients (N=26) were centrifuged and collected all small RNAs in serum. The expression of small non-coding RNAs were analyzed using a next-generation sequencing system. The small non-coding RNAs that could predict short-term survivals in GBM patients were selected by the stepwise analysis. A diagnostic model was created using the combination of these RNAs and evaluated with ROC curve.

Results
GBM patients treated with adjuvant therapy of temozolomide and radiotherapy were divided into two groups: (1) a short-term survival group (N=11) with a survival time less than 15 months and (2) a long-term survival group (N=15) with a survival time more than 15 months. In the short-term survival group, the preoperative serum expression levels of small RNA-X and small RNA-Y were high, and the expression levels of small RNA-Z and small RNA-W were low. Using these four small non-coding RNAs, a prognostic model was created. The model was able to predict the short-term survival group of GBM patients with a sensitivity of 90.9% and specificity of 93.3% (AUC: 0.969).

Conclusion
The prognostic model developed with preoperative small non-coding RNA in GBM patients may be useful for estimating the survival of GBM patients treated with adjuvant therapy of temozolomide and radiotherapy.
COT-31 Risk Factors for the Development of Skin Rash with Levetiracetam and Lacosamide in Patients with Glioma
Authors: Onodera Mikoto , Muragaki Yoshihiro , Fukui Atsushi , Nitta Masayuki , Saito Taiichi , Tsuzuki Syunsuke , Kooriyama Syunichi , Tamura Manabu , Kimura Toshimi , Kawamata Takakazu 
Published: December 2021

Abstract
Introduction: Seizure control of in glioma patients is essential for quality of life. The new generation anti-seizure drug (ASD) is represented by lacosamide (LCM) and levetiracetam (LEV), and is said to have few side effects of eruption. We retrospectively analyzed the incidence of rash and related factors of the ASD, evaluated the safety of patients with glioma, and conducted a comparison with the evaluation of patients with meningioma. Method: We calculated the incidence of rash in patients who underwent glioma resection at our Hospital from January 2017 to December 2019 and were prescribed LEV or LCM, and compared it with the same incidence in meningioma patients. Multivariate logistic regression analysis was used to analyze the risk factors for the ASD-related eruption. Result: The subjects were 353 gliomas and 125 meningiomas who received LEV or LCM.The median ages are 44 ± 14.8 and 58 ± 13.2, respectively, and the male-female ratio is 203/150 and 53/72. There was no difference in the incidence of eruptions between the two groups, LEV and LCM, and the incidence of ASD-related eruptions was 11% (39/353) for gliomas, significantly higher than 1.6% (2/125) for meningiomas (p = 0.006). The incidence of ASD-related eruptions in glioma patients was not significantly different between the LEV group (10% (21/216)) and the LCM group (13% (20/154)) (p = 0.53). In a multivariate analysis of risk factors for eruption, chemoradiotherapy (p = 0.01), history of drug allergy (p = 0.039) was significantly higher. Conclusion: The incidence of LEV and LCM eruptions in glioma patients was higher than that in meningioma patients, and it was speculated that the treatment course specificity was more important than the disease-specific factors. Patients with glioma, especially those who have undergone chemoradiotherapy or have a history of drug allergies, require careful confirmation of the eruption.
UK infrastructure after Brexit
Authors: Rosewell Bridget , Hargreaves John 
Published: December 2021

AbstractInfrastructure is central to many aspects of policy, and this focus has survived the impact of Covid-induced expenditure. The paper examines the scope for Brexit to allow infrastructure planning to be more devolved, consider demand-side and nature-based solutions, and become more competitive. It concludes that Brexit offers the opportunity for a more system-based approach to infrastructure planning and delivery.
Moral Testimony and Re-Conceived Understanding: A Reply to Callahan
Authors: Slome Emily 
Published: December 2021

Abstract
In the article ‘Moral Testimony: A Re-Conceived Understanding Explanation’, Callahan argues that her re-conceived view of understanding can explain the issue with deference to moral testimony better than the more traditional understanding-based accounts. In this paper, I argue that Callahan fails to give a more successful explanation of the problem with moral testimony for two reasons. First, I argue that Callahan fails to adequately prove her claim that deference to testimony disincentivizes her re-conceived understanding. Second, I take issue with Callahan's claim that this re-conceived understanding is distinctly important in the moral domain. I also offer a more promising route for Callahan to take in explaining the problem with moral testimony.
Advancing diagnostic performance and clinical applicability of deep learning-driven generative adversarial networks for Alzheimer's disease
Authors: Qu Changxing , Zou Yinxi , Dai Qingyi , Ma Yingqiao , He Jinbo , Liu Qihong , Kuang Weihong , Jia Zhiyun , Chen Taolin , Gong Qiyong 
Published: December 2021

Abstract
Alzheimer's disease (AD) is a neurodegenerative disease that severely affects the activities of daily living in aged individuals, which typically needs to be diagnosed at an early stage. Generative adversarial networks (GANs) provide a new deep learning method that show good performance in image processing, while it remains to be verified whether a GAN brings benefit in AD diagnosis. The purpose of this research is to systematically review psychoradiological studies on the application of a GAN in the diagnosis of AD from the aspects of classification of AD state and AD-related image processing compared with other methods. In addition, we evaluated the research methodology and provided suggestions from the perspective of clinical application. Compared with other methods, a GAN has higher accuracy in the classification of AD state and better performance in AD-related image processing (e.g. image denoising and segmentation). Most studies used data from public databases but lacked clinical validation, and the process of quantitative assessment and comparison in these studies lacked clinicians' participation, which may have an impact on the improvement of generation effect and generalization ability of the GAN model. The application value of GANs in the classification of AD state and AD-related image processing has been confirmed in reviewed studies. Improvement methods toward better GAN architecture were also discussed in this paper. In sum, the present study demonstrated advancing diagnostic performance and clinical applicability of GAN for AD, and suggested that the future researchers should consider recruiting clinicians to compare the algorithm with clinician manual methods and evaluate the clinical effect of the algorithm.
Non-flooded riparian Amazon trees are a regionally significant methane source
Authors: Gauci Vincent , Figueiredo Viviane , Gedney Nicola , Pangala Sunitha Rao , Stauffer Tainá , Weedon Graham P. , Enrich-Prast Alex 
Published: December 2021

Inundation-adapted trees were recently established as the dominant egress pathway for soil-produced methane (CH4) in forested wetlands. This raises the possibility that CH4produced deep within the soil column can vent to the atmosphere via tree roots even when the water table (WT) is below the surface. If correct, this would challenge modelling efforts where inundation often defines the spatial extent of ecosystem CH4production and emission. Here, we examine CH4exchange on tree, soil and aquatic surfaces in forest experiencing a dynamic WT at three floodplain locations spanning the Amazon basin at four hydrologically distinct times from April 2017 to January 2018. Tree stem emissions were orders of magnitude larger than from soil or aquatic surface emissions and exhibited a strong relationship to WT depth below the surface (less than 0). We estimate that Amazon riparian floodplain margins with a WT < 0 contribute 2.2–3.6 Tg CH4 yr−1to the atmosphere in addition to inundated tree emissions of approximately 12.7–21.1 Tg CH4 yr−1. Applying our approach to all tropical wetland broad-leaf trees yields an estimated non-flooded floodplain tree flux of 6.4 Tg CH4 yr−1which, at 17% of the flooded tropical tree flux of approximately 37.1 Tg CH4 yr−1, demonstrates the importance of these ecosystems in extending the effective CH4emitting area beyond flooded lands.This article is part of a discussion meeting issue 'Rising methane: is warming feeding warming? (part 2)'.