Haruo Nakayama

The International Conference on Sports Concussion, held every four years since 2001, has been instrumental in forming the international consensus on sports-related concussions. However, due to the unprecedented global pandemic of COVID-19, not only the Tokyo Olympics 2020, but also the initially scheduled sixth conference was postponed multiple times. Finally, the 6th International Conference on Sports Concussion took place in Amsterdam at the end of October 2022. In July 2023, the Amsterdam Declaration, reflecting the outcomes of this sixth conference, was released. This paper provides an overview of the conference, in which significant updates were revealed and introduced, including revisions to the definition of sports-related concussions, as well as the latest version of the Sports Concussion Assessment Tool (SCAT), known as SCAT6, the Office Assessment Tool (SCOAT), and the updated staged return-to-play protocol.

The aim of the present study is to conduct a trauma and disability survey in amateur boxers and show the actual conditions of injuries based on the current situations. We have obtained 663 valid responses from male and female boxers. In the questionnaire survey who was carried out on a Web questionnaire form. The questions involve that Face Sheet (gender, height, weight, athletic experience, etc.) and prepared 10 questions about trauma and impairment, 7 questions with concussion or damage on head. and, set 11 self-evaluations, which the boxers assessed their boxing skills. The subjects include amateur boxers who are all high school students (15 years old) and retired boxers. We had analyzed relation between the skills and the injuries. And, main outcome was that make a measure to setting whether or not questionnaires have been knockout (KO) as a variable, we applied a method of multiple logistic regression analysis. Moreover, as for the group who got KO in the past, we have also applied multiple regression analysis by using stepwise regression to factors affecting numbers of symptoms. The number of hits they experienced was smaller in international tournament matches, and the odds rate for KO was 0.669. And, KO experience group was compared with non-KO experience group, and the factors influencing the number of severity symptoms were examined. As a result, 2 factors were selected what “Seriousness in practice” and “Fighting spirit in games”. It might be possible that the relation between the experience of being KO and self-assessment of boxing performance.

Glioblastoma is the most common and aggressive primary brain tumor, and even with the best treatment, the tumor repeatedly recurs and grows, eventually invading the entire brain. There are few reports on the pathogenesis and pathological search in the terminal stage of glioblastoma. In this study, we report the pathological analysis of glioblastoma cases that we were able to perform from initial treatment to confirmation of death at our hospital. We analyzed 26 glioblastoma cases (including 18 autopsied cases) treated at our hospital from initial treatment to death. The mean age of the 26 patients was 60.7 years, and the mean overall survival was 16.7 months. The duration of clinical symptoms was 36.2 days from coma to death, and 12 days from the appearance of respiratory depression to death. Psychiatric symptoms and central fever were observed in patients with intrathecal dissemination. Steroids and antiepileptic drugs were often continued after completion of active treatment. Patients with intrathecal dissemination progressed rapidly and presented with a variety of symptoms, including psychiatric symptoms, headache, neck pain, and central fever. In addition, there was a case of diffuse infiltration from the brain parenchyma to the periventricular area in a patient treated with bevacizumab, suggesting the possibility of a change in the form of recurrence. In the terminal stage of glioblastoma, hypoxemia due to disturbance of respiratory center progresses from impaired consciousness to death. Convulsive seizures are rare in the dying stage, and continuation of antiepileptic drugs should be considered. Although many patients develop from local recurrence, it was suggested that new treatment may change the mode of recurrence or alter the trait of tumor cells. In recent years, the number of patients receiving home care and end-of-life care has been increasing due to the improvement of medical systems such as home care. Further investigation of the pathophysiology is necessary for better end-of-life care. Citation Format: Norihiko Saito, Nozomi Hirai, Naoki Kushida, Sho Sato, Yu Hiramoto, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Keisuke Ito, Takatoshi Sakurai, Satoshi Iwabuchi. Clinical feature of end-stage cerebral glioblastomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5259.

The Cancer Genome Atlas (TCGA) project described a robust gene expression-based molecular classification of glioblastoma (GBM), but the functional and biological significance of the subclasses has not been determined. The present comprehensive analysis of 25 glioma-initiating cell (GIC) lines classifies GIC lines into four subtypes (classical, mesenchymal, proneural, and neural) that are closely related to the TCGA GBM subclasses and display distinct lineage characteristics and differentiation behavior that recapitulate neural development. More importantly, the GIC subtypes exhibit distinct biological phenotypes in relation to self-renewal capacity, proliferation, invasiveness, and angiogenic potential in vitro and in vivo. In addition, the GIC subtypes exhibit divergent patterns of signaling pathway activation and deactivation of the Wnt, Notch, and TGF-β pathways. These results will improve drug discovery targeting certain genetic mutation in glioblastoma and improve the development of precision medicine.

The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with γ-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH activity. Here we report loss of PTEN function as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of oncogene addiction from the NOTCH pathway to the PI3K pathway. Drug cytotoxicity testing of eight GICs showed a differential growth response to GSI, and the GICs were thus stratified into two groups: sensitive and resistant. In the sensitive group, GICs with loss of PTEN function appeared less sensitive to GSI treatment. Here we show that NOTCH regulates PTEN expression and the activity of the PI3K pathway in GICs, as treatment with GSI attenuated the NOTCH pathway and increased PTEN expression. NOTCH regulates PTEN expression via Hes-1, as knockdown of Notch or Hes1 increased expression of PTEN. This novel observation suggests that both pathways must be simultaneously inhibited in order to improve therapeutic efficacy in human glioblastomas (GBMs).

Glioblastoma, the most common adult glioma, is associated with a dismal prognosis. Treatment with bevacizumab has not significantly prolonged overall patient survival times. Glioblastoma resistance to angiogenesis inhibitors is attributed to multiple interacting mechanisms. We have thus embarked on a comprehensive effort to detecting expression signatures that are associated with response to the therapy and these signatures may allow prospective selection of patients with high likelihood of responding to therapy. Notch signaling pathway is an evolutionarily conserved pathway that plays an important role in multiple cellular and developmental processes including cell fate decision, differentiation, proliferation, survival, angiogenesis and migration. Analysis of The Cancer Genome Atlas expression dataset identified a group (43.9%) of tumors with proneural signature showing high Notch pathway activation. In this study, we compared CD133, Notch, and VEGF expressions in histological sections of primary and recurrent glioblastomas after radiotherapy and chemotherapy. Tumor samples were collected from 27 patients at the time of tumor recurrence. We used immunohistochemical techniques to compare expression of CD133, Notch-1 and VEGF. Expressions of CD133-, Notch-1-, and VEGF-positive glioma cells were higher in recurrent glioblastoma after radiotherapy and chemotherapy. To determine the clinical importance of Notch-1 expression in glioblastoma, we analyzed 15 patients who had received bevacizumab therapy followed by a second surgery at recurrence. OS was significantly longer in cases with Notch-1 negativity (8.8 months) than in those with Notch-1 positivity (6.8 months). Electron microscopic observation of two autopsy cases revealed the effects of blood vessel normalization in Notch-1 positive glioblastoma. Electron microscopic images confirmed the presence of pericytes surrounding the vascular endothelium. Autopsied tumors exhibited marked proliferation of Notch-1 and VEGF positive cells around vessels. In tumor angiogenesis, vascular endothelial growth factor and Notch signaling induce sprouting angiogenesis and recruitment of vascular endothelial cells such as tip cells, stalk cells, and phalanx cells. Fully mature phalanx cells are in close contact with pericytes. These findings indicate that bevacizumab treatment promotes vascular normalization by recruiting mature pericytes and associated with resistance to bevacizumab therapy in glioblastoma with high Notch pathway activation. Citation Format: Norihiko Saito, Kazuya Aoki, Nozomi Hirai, Satoshi Fujita, Junya Iwama, Masashi Ikota, Haruo Nakayama, Morito Hayashi, Keisuke Ito, Takatoshi Sakurai, Satoshi Iwabuchi. Notch pathway activation predicts resistance to bevacizumab therapy in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 774. doi:10.1158/1538-7445.AM2017-774

Idiopathic pulmonary arterial hypertension (IPAH) is a rare, fatal disease of unknown pathogenesis. Evidence from our recent study suggests that IPAH pathogenesis is related to upregulation of the Wnt/planar cell polarity (Wnt/PCP) pathway. We used microscopic observation and immunohistochemical techniques to identify expression patterns of cascading proteins—namely Wnt-11, dishevelled-2 (Dvl-2), and dishevelled-associated activator of morphogenesis 1 (Daam-1)—in pulmonary arteries. We analyzed sections of formalin-fixed and paraffin-embedded autopsied lung tissues obtained from 9 IPAH cases, 7 associated pulmonary arterial hypertension cases, and 16 age-matched controls without pulmonary arterial abnormalities. Results of microscopic observation were analyzed in relation to the cellular components and size of pulmonary arteries. Varying rates of positive reactivity to Dvl-2 and Daam-1 were confirmed in all cellular components of pulmonary arteries, namely, endothelial cells, myofibroblasts, and medial smooth muscle cells. In contrast, none of these components was reactive to Wnt-11. No specific expression patterns were observed for endothelial cells or myofibroblasts under any experimental conditions. However, marked expression of Dvl-2 and Daam-1 was confirmed in smooth muscle cells. In addition, Dvl-2 was depleted while Daam-1 expression was elevated in IPAH, in contrast with specimens from associated pulmonary arterial hypertension cases and controls. High Daam-1 expression may upregulate the Wnt/PCP pathway and cause IPAH.