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A woman in her 90s presented with loss of appetite, lower back pain, abdominal pain, and fever. Physical examination and subsequent blood tests indicated an inflammatory process, and computed tomography (CT) scans revealed gallbladder torsion with necrosis and abscess formation. The case involved successful management of this rare condition through percutaneous drainage without the need for surgical intervention, avoiding complications during follow-up. Remarkably, post-treatment CT showed complete resolution of the gallbladder abscess and the gallbladder itself was no longer visible. This case highlights the effectiveness of minimally invasive treatment for gallbladder torsion in elderly patients and underscores the potential for non-surgical intervention in managing complex abdominal conditions.

A bidirectional approach is necessary for treating critical limb ischemia with complex, multiple lesions. We report an ultrasound-guided bidirectional puncture through an occluded vessel to treat an obstruction extending from the anterior tibial artery to the dorsal foot artery in a patient with toe gangrene and rest pain. This technique effectively restored arterial patency and is a promising approach for managing challenging critical limb ischemia occlusions.

Abstract Epidural spinal cord stimulation (SCS) is indicated for the treatment of intractable pain and is widely used in clinical practice. In previous basic research, the therapeutic effects of SCS have been demonstrated for epileptic seizure. However, the mechanism has not yet been elucidated. In this study, we investigated the therapeutic effect of SCS and the influence of epileptic seizure. First, SCS in the cervical spine was performed. The rats were divided into four groups: control group and treatment groups with SCS conducted at 2, 50, and 300 Hz frequency. Two days later, convulsions were induced by the intraperitoneal administration of kainic acid, followed by video monitoring to assess seizures. We also evaluated glial cells in the hippocampus by fluorescent immunostaining, electroencephalogram measurements, and inflammatory cytokines such as C–C motif chemokine ligand 2 (CCL2) by quantitative real-time polymerase chain reaction. Seizure frequency and the number of glial cells were significantly lower in the 300 Hz group than in the control group. SCS at 300 Hz decreased gene expression level of CCL2, which induces monocyte migration. SCS has anti-seizure effects by inhibiting CCL2-mediated cascades. The suppression of CCL2 and glial cells may be associated with the suppression of epileptic seizure.

Abstract Accumulating evidence suggests that endothelial cells can be useful therapeutic targets. One of the potential targets is an endothelial cell-specific protein, Roundabout4 (ROBO4). ROBO4 has been shown to ameliorate multiple diseases in mice, including infectious diseases and sepsis. However, its mechanisms are not fully understood. In this study, using RNA-seq analysis, we found that ROBO4 downregulates prostaglandin-endoperoxide synthase 2 (PTGS2), which encodes cyclooxygenase-2. Mechanistic analysis reveals that ROBO4 interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1) and TNF receptor-associated factor 7 (TRAF7), a ubiquitin E3 ligase. In this complex, ROBO4 enhances IQGAP1 ubiquitination through TRAF7, inhibits prolonged RAC1 activation, and decreases PTGS2 expression in inflammatory endothelial cells. In addition, Robo4-deficiency in mice exacerbates PTGS2-associated inflammatory diseases, including arthritis, edema, and pain. Thus, we reveal the molecular mechanism by which ROBO4 suppresses the inflammatory response and vascular hyperpermeability, highlighting its potential as a promising therapeutic target for inflammatory diseases.

This study aimed to identify the reasons for transferring athletes to local medical facilities during the Olympic and Paralympic Games. Data on 567 injuries and other illnesses of athletes treated at the on-site clinics were collected from the Tokyo 2020 Organizing Committee. Of these, 84 athletes who required outpatient care during the Games were registered for this survey. During the Olympic and Paralympic Games, 66 (8.3/1 000) and 18 (7.2/1 000) athletes, respectively, consulted external medical facilities. In the Olympic Games, the reasons for these visits included 48 cases (72.7%) of injuries, 13 (19.7%) cases of illnesses, and 5 (7.6%) cases of heat stroke illness (HSI). Of these patients, 56 (84.9%) were treated as outpatients and 10 (15.1%) were hospitalized, while three of these patients required hospitalization for > 7 days. On the other hand, in the Paralympics Games, there were 7 (38.8%) cases of injuries, 9 (50.0%) other illnesses, 1 (5.6%) case of HSI, and 1 (5.6%) other cases, of which 11 (61.1%) were treated as outpatients and 7 (38.9%) were hospitalized, but none was hospitalized for > 7 days. Injuries accounted for 70% of the total cases at the 2021 Olympic Games, but only three (0.05%) were severe cases that required hospitalization for more than 1 week. In contrast, in the Paralympic Games, other illnesses accounted for approximately half of the total cases. This study provides details on the extent of injuries and other illnesses that were transferred to outside facilities, which has not been documented in previous games.

Surgical resection is considered for most brain tumors to obtain tissue diagnosis and to eradicate or debulk the tumor. Glioma, the most common primary malignant brain tumor, generally has a poor prognosis despite the multidisciplinary treatments with radical resection and chemoradiotherapy. Surgical resection of glioma is often complicated by the obscure border between the tumor and the adjacent brain tissues and by the tumor's infiltration into the eloquent brain. 5-aminolevulinic acid is frequently used for tumor visualization, as it exhibits high fluorescence in high-grade glioma. Here, we provide an overview of the fluorescent probes currently used for brain tumors, as well as those under development for other cancers, including HMRG-based probes, 2MeSiR-based probes, and other aminopeptidase probes. We describe our recently developed HMRG-based probes in brain tumors, such as PR-HMRG, combined with the existing diagnosis approach. These probes are remarkably effective for cancer cell recognition. Thus, they can be potentially integrated into surgical treatment for intraoperative detection of cancers.

Summary: Background: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations. Methods: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)]. Findings: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2–7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5–12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs. Interpretation: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. Funding: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).

BackgroundGlioblastoma (GBM) is a highly lethal brain tumor. The effectiveness of temozolomide (TMZ) treatment in GBM is linked to the methylation status of O6-methyl-guanine DNA methyltransferase (MGMT) promoter. Patients with unmethylated MGMT promoter have limited treatment options available. Consequently, there is a pressing need for alternative therapeutic strategies for such patients.MethodsData, including transcriptomic and clinical information, as well as information on MGMT promoter methylation status in primary GBM, were obtained from The Cancer Genome Atlas (TCGA) (n=121) and Chinese Glioma Genome Atlas (CGGA) (n=83) datasets. Samples were categorized into high and low MGMT expression groups, MGMT-high (MGMT-H) and MGMT-low (MGMT-L) tumors. A comprehensive transcriptome analysis was conducted to explore the tumor-immune microenvironment. Furthermore, we integrated transcriptome data from 13 GBM patients operated at our institution with findings from tumor-infiltrating lymphocyte (TIL) cultures, specifically investigating their response to autologous tumors.ResultsGene signatures associated with various immune cells, including CD8 T cells, helper T cells, B cells, and macrophages, were noted in MGMT-H tumors. Pathway analysis confirmed the enrichment of immune cell-related pathways. Additionally, biological processes involved in the activation of monocytes and lymphocytes were observed in MGMT-H tumors. Furthermore, TIL culture experiments showed a greater presence of tumor-reactive T cells in MGMT-H tumors compared to MGMT-L tumors. These findings suggest that MGMT-H tumors has a potential for enhanced immune response against tumors mediated by CD8 T cells.ConclusionOur study provides novel insights into the immune cell composition of MGMT-H tumors, which is characterized by the infiltration of type 1 helper T cells and activated B cells, and also the presence of tumor-reactive T cells evidenced by TIL culture. These findings contribute to a better understanding of the immune response in MGMT-H tumors, emphasizing their potential for immunotherapy. Further studies are warranted to investigate on the mechanisms of MGMT expression and antitumor immunity.

Abstract We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without (p = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer (p = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup.

Abstract Background Lymphoproliferative disorder represents a heterogeneous clinicopathological spectrum characterized by uncontrolled proliferation of lymphocytes. Immunodeficiency is a major trigger of its development. While induction of immunodeficiency is a well-known adverse effect of temozolomide therapy, development of lymphoproliferative disorder following temozolomide therapy has not previously been described. Case presentation A patient with brainstem glioma developed constitutional symptoms, pancytopenia, splenomegaly and generalized lymphadenopathy during the 2nd cycle of maintenance therapy following induction therapy with temozolomide. Epstein-Barr virus-infected lymphocytes were observed histopathologically and “other iatrogenic immunodeficiency-associated lymphoproliferative disorder” (OIIA-LPD) was diagnosed. Although discontinuation of temozolomide led to rapid remission, relapse was observed 4 months later. CHOP chemotherapy was induced, resulting in secondary remission. Vigilant follow-up for another 14 months showed radiologically stable brainstem glioma and no further recurrence of OIIA-LPD. Conclusions This is the first report documenting OIIA-LPD during temozolomide administration. Timely diagnosis of the disease and discontinuation of the causative agent were considered to be the management of choice. Close monitoring for relapse should be continued. Finding a balance between glioma management and controlling the remission of OIIA-LPD remains to be clarified.

Abstract Though it is well known that mammalian cardiomyocytes exit cell cycle soon after birth, the mechanisms that regulate proliferation remain to be fully elucidated. Recent studies reported that cardiomyocytes undergo dedifferentiation before proliferation, indicating the importance of dedifferentiation in cardiomyocyte proliferation. Since Runx1 is expressed in dedifferentiated cardiomyocytes, Runx1 is widely used as a dedifferentiation marker of cardiomyocytes; however, little is known about the role of Runx1 in the proliferation of cardiomyocytes. The purpose of this study was to clarify the functional significance of Runx1 in cardiomyocyte proliferation. qRT‐PCR analysis and immunoblot analysis demonstrated that Runx1 expression was upregulated in neonatal rat cardiomyocytes when cultured in the presence of FBS. Similarly, STAT3 was activated in the presence of FBS. Interestingly, knockdown of STAT3 significantly decreased Runx1 expression, indicating Runx1 is regulated by STAT3. We next investigated the effect of Runx1 on proliferation. Immunofluorescence microscopic analysis using an anti‐Ki‐67 antibody revealed that knockdown of Runx1 decreased the ratio of proliferating cardiomyocytes. Conversely, Runx1 overexpression using adenovirus vector induced cardiomyocyte proliferation in the absence of FBS. Finally, RNA‐sequencing analysis revealed that Runx1 overexpression induced upregulation of cardiac fetal genes and downregulation of genes associated with fatty acid oxidation. Collectively, Runx1 is regulated by STAT3 and induces cardiomyocyte proliferation by juvenilizing cardiomyocytes.

BackgroundDespite accumulating research on the molecular characteristics of meningiomas, no definitive molecularly targeted therapy for these tumors has been established to date. Molecular mechanisms underlying meningioma progression also remain unclear. Comprehensive genetic testing approaches can reveal actionable gene aberrations in meningiomas. However, there is still limited information on whether profiling the molecular status of subsequent recurrent meningiomas could influence the choice of molecular-targeted therapies.Case presentationWe report a case of meningioma with malignant progression and multiple recurrences. We performed matched tumor pair analysis using the Todai OncoPanel to investigate the possibility of additional standard treatments. The loss of several chromosomal regions, including NF2 and CDKN2A, which is associated with aggressive meningiomas, was considered a significant driver event for malignant progression. Using additional matched tumor pair analysis, mutations in TRAF7, ARID1A, and ERBB3 were identified as subclonal driver events at the time of recurrence. No genetic aberrations were found for which evidence-based targeted therapy was applicable. We also reviewed previous reports of molecular therapies in meningioma to discuss issues with the current molecular testing approach.ConclusionGene panel testing platforms such as the Todai OncoPanel represent a powerful approach to elucidate actionable genetic alterations in various types of tumors, although their use is still limited to the diagnosis and prediction of prognosis in meningiomas. To enable targeted molecular therapy informed by gene-panel testing, further studies including matched tumor pair analyses are required to understand the molecular characteristics of meningiomas and develop treatments based on genetic abnormalities.

Despite a long history of research, neurodegenerative diseases and malignant brain tumor gliomas are both considered incurable, facing challenges in the development of treatments. Recent evidence suggests that RNA modifications, previously considered as static components of intracellular RNAs, are in fact dynamically regulated across various RNA species in cells and play a critical role in major biological processes in the nervous system. Innovations in next-generation sequencing have enabled the accurate detection of modifications on bases and sugars within various RNA molecules. These RNA modifications influence the stability and transportation of RNA, and crucially affect its translation. This review delves into existing knowledge on RNA modifications to offer a comprehensive inventory of these modifications across different RNA species. The detailed regulatory functions and roles of RNA modifications within the nervous system are discussed with a focus on neurodegenerative diseases and gliomas. This article presents a comprehensive overview of the fundamental mechanisms and emerging roles of RNA modifications in these diseases, which can facilitate the creation of innovative diagnostics and therapeutics for these conditions.

Aim: The purpose of this study was to stratify patients who achieved return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA) with bystander procedures pre-emergency medical service (EMS) arrival and those who achieved ROSC with procedures post-EMS arrival, compare outcomes at 1-month, and identify factors associated with pre-EMS-arrival-ROSC. Methods: A retrospective cohort analysis of OHCAs occurring at stations in the Tokyo metropolitan area between 2014 and 2018 was conducted. Subjects were stratified by ROSC phase (categorized as pre- and post-EMS arrival and non-ROSC). Survival at 1-month post-OHCA and the percentage of favourable neurological function in each ROSC phase were analysed. In addition, factors associated with Pre-EMS-arrival-ROSC were identified using multivariable logistic regression analysis. The time of occurrence of OHCA was classified into four-time categories as follows. Rush hour on morning [7:00–9:00], Rush hour on evening [17:00–21:00], Daytime [9:00–17:00], and Night or Early morning [21:00–7:00]. Results: Among the 63,089 OHCA in the dataset, 702 were analysed. At 1-month after OHCA occurrence, Pre-EMS-arrival ROSC had higher survival rates than post-EMS-arrival ROSC (86.8% vs. 54.1%) and CPC1-2 rates (73.6% vs. 38.5%). Pre-EMS-arrival ROSC was associated (adjusted odds ratio [95% confidence interval]) with non-older-adult patients (1.59 [1.05–2.43]), witnessed OHCA (1.82 [1.03–3.31]), evening rush-hour (17:00–21:00; 2.08 [1.05–4.11]), conventional CPR (33.42 [7.82–868.44]), hands-only CPR (17.06 [4.30–436.48]), bystander defibrillation performed once (3.31 [1.59–6.99]). Conclusions: In an OHCA at a station in Tokyo, ROSC achieved with bystander treatment alone had a better outcome at 1-month compared to ROSC with EMS intervention

Abstract Runt-related transcription factor 2 (Runx2), a regulator of osteoblast differentiation, is pathologically involved in vascular calcification; however, the significance of Runx2 in cardiac homeostasis remains unclear. Here, we investigated the roles of Runx2 in cardiac remodeling after myocardial infarction (MI). The expression of Runx2 mRNA and protein was upregulated in murine hearts after MI. Runx2 was expressed in heart-infiltrating myeloid cells, especially in macrophages, at the border zone of post-infarct myocardium. To analyze the biological functions of Runx2 in cardiac remodeling, myeloid cell-specific Runx2 deficient (CKO) mice were exposed to MI. After MI, ventricular weight/tibia length ratio was increased in CKO mice, concomitant with severe cardiac dysfunction. Cardiac fibrosis was exacerbated in CKO mice, consistent with the upregulation of collagen 1a1 expression. Mechanistically, immunohistochemical analysis using anti-CD31 antibody showed that capillary density was decreased in CKO mice. Additionally, conditioned culture media of myeloid cells from Runx2 deficient mice exposed to MI induced the tube formation of vascular endothelial cells to a lesser extent than those from control mice. RNA-sequence showed that the expression of pro-angiogenic or anti-angiogenic factors was altered in macrophages from Runx2-deficient mice. Collectively, Runx2 + myeloid cells infiltrate into post-infarct myocardium and prevent adverse cardiac remodeling, at least partially, by regulating endothelial cell function.

To assess the clinicopathological features and prognostic factors of pediatric intracranial ependymomas and to explore the current diagnostic practice, we analyzed clinical data from the Brain Tumor Registry of Japan (BTRJ). Data of fifty children under 18 years of age diagnosed with intracranial ependymoma were extracted from the BTRJ database. Cases were reviewed for overall survival (OS) and progression-free survival (PFS), with attention to gender, preoperative Karnofsky performance status score, location of the tumor, the extent of resection, World Health Organization (WHO) histopathological grading, and adjuvant therapy. The median age at diagnosis was 6.1 years, ranging from 7 months to 17.6 years. Based on the WHO histopathological grading, 27 patients were classified under grade 2 (54%) and 23 patients were classified under grade 3 (46%). Gross total resection (GTR) was achieved in 30 patients (60%). The median follow-up time was 65 months. Five-year PFS and OS were 47.2 ± 7.3% and 73.3 ± 6.7%, respectively. GTR was associated with longer OS (P = 0.02). The histopathological grading was not an independent prognostic factor for the OS. Mitosis and microvascular proliferation were higher among patients with grade 3 than in those with grade 2, which aided in deciding the WHO grade. This nationwide study revealed the characteristics and outcomes of patients with childhood ependymomas. GTR was the factor most consistently associated with improved survival. In contrast, the histopathological grading in this cohort was not a significant prognostic factor. More reproducible and practical criteria for the diagnosis of intracranial ependymomas should be further pursued in future studies.

Upregulation of transcription factor OASIS in podocytes contributes to podocyte and/or tubular injury through decreased PRKCi expression and is a critical event for the disturbance of kidney homeostasis.

Introduction Among the 43 venues of Tokyo 2020 Olympic Games (OG) and 33 venues of Paralympic Games (PG) were held, the heat island effect was highly expected to cause heat-related illnesses in the outdoor venues with maximum temperatures exceeding 35°C. However, the actual number of heat-related illness cases during the competition was lower than that was initially expected, and it was unclear under what conditions or environment-related heat illnesses occurred among athletes.Object To clarify the cause and factors contributing to the occurrence of heat-related illness among athletes participating in the Tokyo 2020 Olympic and Paralympic Games.Method This retrospective descriptive study included 15 820 athletes from 206 countries. From 21 July 2021 to 8 August 2021 for the Olympics, and from 24 August 2021 to 5 September 2021 for the Paralympics. The number of heat-related illness cases at each venue, the incidence rate for each event, gender, home continent, as well as the type of competition, environmental factors (such as venue, time, location and wet-bulb globe temperature (WBGT)), treatment factor and the type of competition were analysed.Results More number of heat-related illnesses among athletes occurred at the OG (n=110, 76.3%) than at the PG (n=36, 23.7%). A total of 100 cases (100%) at the OG and 31 cases (86.1%) at the PG occurred at the outdoors venues. In the OG, a total of 50 cases (57.9%) occurred during the competition of marathon running and race walking at Sapporo Odori Park. Six of those, were diagnosed with exertional heat illness and treated with cold water immersion (CWI) at OG and one case at PG. Another 20 cases occurred in athletics (track and field) competitions at Tokyo National Olympic Stadium. In total, 10 cases (10.0%) were diagnosed with severe heat illness in the OG and 3 cases (8.3%) in the PG. Ten cases were transferred to outside medical facilities for further treatment, but no case has been hospitalised due to severe condition. In the factor analysis, venue zone, outdoor game, high WBGT (

Stereotactic frame-based brain tumor biopsy (SFB) is a potent diagnostic tool considering its minimal invasiveness, though its diagnostic power and safety for brainstem lesions remain to be discussed. Here, we aimed to examine the usefulness of SFB for brainstem tumors. Twenty-two patients with brainstem tumors underwent 23 SFBs at our institution during 2002–2021. We retrospectively analyzed patient characteristics, tumor pathology, surgical procedures, and outcomes, including surgery-related complications and the diagnostic value. Seven (32%) tumors were located from the midbrain to the pons, eleven (50%) in the pons only, and four (18%) from the pons to the medulla oblongata. The target lesions were in the middle cerebellar peduncles in sixteen procedures (70%), the cerebellum in four (17%), the inferior cerebellar peduncles in two (9%), and the superior cerebellar peduncles in one (4%). A definitive diagnosis was made in 21 patients (95%) at the first SFB. The diagnoses were glioma in seventeen (77%) cases, primary central nervous system lymphoma in four (18%), and a metastatic brain tumor in one (5%). The postoperative complications (cranial nerve palsy in three [13%] cases, ataxia in one [4%]) were all transient. SFB for brainstem tumors yields a high diagnostic rate with a low risk of morbidity.

BackgroundGlioblastoma is a malignant tumor, and its prognosis is as poor as 1.5 to 2 years. Most cases recur within one year even under the standard treatment. The majority of recurrences are local, and in rare cases, metastasize mostly within the centra nervous system. Extradural metastasis of glioma is exceedingly rare. Here, we present a case of vertebral metastasis of glioblastoma.Case presentationWe present a 21-year-old man post total resection of the right parietal glioblastoma, diagnosed with lumbar metastasis. He originally presented with impaired consciousness and left hemiplegia and underwent gross total resection of the tumor. Given the diagnosis of glioblastoma, he was treated with radiotherapy combined with concurrent and adjuvant temozolomide. Six months after tumor resection, the patient presented with severe back pain, and was diagnosed as metastatic glioblastoma on the first lumbar vertebrae. Posterior decompression with fixation and postoperative radiotherapy were conducted. He went on to receive temozolomide and bevacizumab. However, at 3 months after the diagnosis of lumbar metastasis, further disease progression was noted, and his care was transitioned to best supportive care. Comparison on copy number status between primary and metastatic lesions on methylation array analysis revealed more enhanced chromosomal instability including 7p loss, 7q gain and 8 gain in the metastatic lesion.ConclusionBased upon the literature review and our case, younger age of initial presentation, multiple surgical interventions, and long overall survival seem to be the risk factors of vertebral metastasis. As the prognosis of glioblastoma improves over time, its vertebral metastasis is seemingly more common. Therefore, extradural metastasis should be kept in mind in the treatment of glioblastoma. Further, detailed genomic analysis on multiple paired specimens is mandated to elucidate the molecular mechanisms of vertebral metastasis.

The onset and exacerbation of dementia have been observed in elderly patients with type 2 diabetes. However, the underlying mechanism remains unclear. In this study, we investigated the effects of aging on the cognitive function in a mouse model of type 2 diabetes. Pathogen-free KK-Ay/TaJcl mice were used in this study. The cognitive abilities and memory declined in the mice and worsened in the 50-week-olds. The levels of advanced glycation end products (AGEs), receptor for AGE (RAGE), and Iba1 in the hippocampus were increased in the mice compared to those in the control mice. Hippocampal levels of CC-chemokine receptor 7 and inducible nitric oxide synthase, which are from M1-type macrophages that shift from microglia, were higher in KK-Ay/TaJcl mice than in control mice. Tumor necrosis factor (TNF)-α and nitric oxide (NO) levels secreted by M1-type macrophages were similarly elevated in the mice and were even higher at the age of 50 weeks. NO levels were markedly elevated in the 50-week-old mice. In contrast, differentiation of CD163 and arginase-1 did not change in both mouse types. Memory and learning declined with age in diabetic mice, and the AGEs/RAGE/M1-type macrophage/NO and TNF-α pathways played an important role in exacerbating memory and learning in those mice.

Primary intracranial spindle cell sarcoma is an extremely rare mesenchymal tumor, the molecular pathogenesis of which is poorly understood. Because of the lack of specific markers, diagnosis sometimes relies on ruling out all possible differential diagnoses, often making it difficult to reach a definitive diagnosis. In this case study, we report a 69 year-old female patient for whom the integration of multi-layered molecular analyses contributed to making the diagnosis. The disease exhibited aggressive clinical behavior, requiring two sequential surgeries because of rapid regrowth within a short period. Primary and recurrent tumors exhibited similar histological features, in which spindle-shaped cells arranged in interlacing fascicles without any specific architectures, implicating sarcomatous tumors. In immunohistochemistry testing, tumor cells were immunopositive for vimentin but lacked any specific findings that contribute to narrowing down the differential diagnoses. Seeking further diagnostic clues, we performed DNA methylation-based analysis. The copy number analysis revealed MDM2 gene amplification and loss of heterozygosity of 22q. Moreover, dimension reduction clustering analysis implicated a methylation pattern comparable to aggressive types of sarcomas. In addition, an in-house next-generation sequencing panel (“Todai-OncoPanel”) analysis identified somatic mutations in DICER1, NF2 , and ATRX genes. Taken all together, we finally made the diagnosis of primary intracranial spindle cell sarcoma, DICER1 -mutant, with MDM2 gene amplification. This case report suggests that even for the tumors with insufficient morphological and immuno-histological diagnostic clues, integration of multi-layered molecular analyses can contribute to making the diagnoses as well as to understanding the rare tumors by elucidating unexpected genetic and epigenetic features.

Skin dryness associated with type 2 diabetes worsens with age; however, the underlying mechanisms remain unclear. Herein, we investigated the effects of aging on skin dryness using a type 2 diabetes mice model. Specific pathogen-free KK-Ay/TaJcl mice of different ages (10, 27, 40, and 50 weeks) were used in this study. The results confirmed that skin dryness worsens with age. Furthermore, increased levels of advanced glycation end products (AGE), prostaglandin E2 (PGE2), and tumor necrosis factor (TNF)-α, along with an increased expression of the major AGE receptor (RAGE), an increased macrophage number, and decreased collagen expression were observed in the skin of aged KK-Ay/TaJcl mice. In conclusion, dry skin conditions worsen with age in diabetic mice, and the AGE/RAGE/PGE2 and TNF-α pathways play an important role in exacerbating skin dryness during aging in these mice.

Abstract Tumor suppressor protein p53 plays crucial roles in the onset of heart failure. p53 activation results in cardiac dysfunction, at least partially by suppressing angiogenesis. Though p53 has been reported to reduce VEGF production by inhibiting hypoxia‐inducible factor, the anti‐angiogenic property of p53 remains to be fully elucidated in cardiomyocytes. To explore the molecular signals downstream of p53 that regulate vascular function, especially under normoxic conditions, DNA microarray was performed using p53‐overexpressing rat neonatal cardiomyocytes. Among genes induced by more than 2‐fold, we focused on CXCL10, an anti‐angiogenic chemokine. Real‐time PCR revealed that p53 upregulated the CXCL10 expression as well as p21, a well‐known downstream target of p53. Since p53 is known to be activated by doxorubicin (Doxo), we examined the effects of Doxo on the expression of CXCL10 and found that Doxo enhanced the CXCL10 expression, accompanied by p53 induction. Importantly, Doxo‐induced CXCL10 was abrogated by siRNA knockdown of p53, indicating that p53 activation is necessary for Doxo‐induced CXCL10. Next, we examined the effect of hypoxic condition on p53‐mediated induction of CXCL10. Interestingly, CXCL10 was induced by hypoxia and its induction was potentiated by the overexpression of p53. Finally, the conditioned media from cultured cardiomyocytes expressing p53 decreased the tube formation of endothelial cells compared with control, analyzed by angiogenesis assay. However, the inhibition of CXCR3, the receptor of CXCL10, restored the tube formation. These data indicate that CXCL10 is a novel anti‐angiogenic factor downstream of p53 in cardiomyocytes and could contribute to the suppression of vascular function by p53.

We evaluated the efficacy and safety of bevacizumab beyond progression (BBP) in Japanese patients with newly diagnosed glioblastoma and explored predictors of response to bevacizumab. This phase II study evaluated a protocol-defined primary therapy by radiotherapy with concurrent and adjuvant temozolomide plus bevacizumab, followed by bevacizumab monotherapy, and secondary therapy (BBP: bevacizumab upon progression). Ninety patients received the protocol-defined primary therapy (BBP group, n = 25). Median overall survival (mOS) and median progression-free survival (mPFS) were 25.0 and 14.9 months, respectively. In the BBP group, in which O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated tumors predominated, mOS and mPFS were 5.8 and 1.9 months from BBP initiation and 16.8 and 11.4 months from the initial diagnosis, respectively. The primary endpoint, the 2-year survival rate of the BBP group, was 27.0% and was unmet. No unexpected adverse events occurred. Expression profiling using RNA sequencing identified that Cluster 2, which was enriched with the genes involved in macrophage or microglia activation, was associated with longer OS and PFS independent of the MGMT methylation status. Cluster 2 was identified as a significantly favorable independent predictor for PFS, along with younger age and methylated MGMT. The novel expression classifier may predict the prognosis of glioblastoma patients treated with bevacizumab.

Type 2 diabetes is a lifestyle-related disease that affects people worldwide and is especially prevalent in the elderly. Many elderly people with diabetes also complain of dry skin; however, the relationship between aging and dry skin in type 2 diabetes is unknown. The purpose of this study was to examine the interaction between aging and dry skin using the specific pathogen-free KK-Ay/TaJcl type 2 diabetes mouse model. Skin dryness in this model increases with age and was evaluated at 10, 27, 40, and 50 weeks. We observed increased mast cell expression, increased histamine and matrix metalloproteinase-1 levels, and decreased collagen expression in the skin of aging KK-Ay/TaJcl mice. In addition, the increased expression of angiopoietin 2, interleukin-6, tumor necrosis factor-α, and endostatin in the blood indicated kidney damage in this model. Aging KK-Ay/TaJcl mice also showed fatty liver pathology, which led to increased reactive oxygen species in the blood and liver, as well as the increased expression of M1 macrophages in the liver. These results showed that dry skin is associated with skin, kidney, and liver interactions in an aging type 2 diabetes mouse model.

microRNAs (miRNAs) contained in small extracellular vesicles (sEVs) are candidates for non-invasive biomarkers. Oxaliplatin (L-OHP) has been approved for advanced colorectal cancer (CRC) chemotherapy. However, the response to L-OHP differs among CRC patients. In addition, CRC cells often acquire the resistance to L-OHP. This study aimed at the prediction of L-OHP sensitivity by measuring extracellular miRNAs levels. Firstly, we compared intracellular miRNAs expressions in L-OHP-sensitive CRC cells (SW620 and HCT116 cells) with those in acquired and intrinsic L-OHP-resistant cells. In microarray and real-time RT-PCR analyses, the intracellular miR-33a-5p, miR-210–3p, and miR-224–5p expressions were lower in acquired and intrinsic L-OHP-resistant CRC cells than sensitive cells. Furthermore, in SW620 cells, L-OHP sensitivity was decreased by miR-33a-5p inhibitor. On the other hand, miR-210–3p or miR-224–5p inhibitor did not affect L-OHP sensitivity in SW620 cells. Secondly, the amount of miR-33a-5p, miR-210–3p, and miR-224–5p in sEVs was compared. The amount of miR-33a-5p and miR-210–3p in sEVs secreted from acquired and intrinsic L-OHP-resistant cells tended to be small. miR-224–5p was not detected in sEVs secreted from three types of CRC cells examined. To the best of our knowledge, this is the first study demonstrating that miR-33a-5p and/or miR-210–3p in sEVs would be candidates for biomarkers of L-OHP sensitivity. In particular, miR-33a-5p is a promising candidate because it would be directly involved in L-OHP sensitivity.

Background: In neurosurgery, it is important to inspect the spatial correspondence between the preoperative medical image (virtual space), and the intraoperative findings (real space) to improve the safety of the surgery. Navigation systems and related modalities have been reported as methods for matching this correspondence. However, because of the influence of the brain shift accompanying craniotomy, registration accuracy is reduced. In the present study, to overcome these issues, we developed a spatially accurate registration method of medical fusion 3-dimensional computer graphics and the intraoperative brain surface photograph, and its registration accuracy was measured. Methods: The subjects included 16 patients with glioma. Nonrigid registration using the landmarks and thin-plate spline methods was performed for the fusion 3-dimensional computer graphics and the intraoperative brain surface photograph, termed mixed-reality computer graphics. Regarding the registration accuracy measurement, the target registration error was measured by two neurosurgeons, with 10 points for each case at the midpoint of the landmarks. Results: The number of target registration error measurement points was 160 in the 16 cases. The target registration error was 0.72 ± 0.04 mm. Aligning the intraoperative brain surface photograph and the fusion 3-dimensional computer graphics required ∼10 minutes on average. The average number of landmarks used for alignment was 24.6. Conclusions: Mixed-reality computer graphics enabled highly precise spatial alignment between the real space and virtual space. Mixed-reality computer graphics have the potential to improve the safety of the surgery by allowing complementary observation of brain surface photographs and fusion 3-dimensional computer graphics.

Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF.

Chordoma and chondrosarcoma share common radiographic characteristics yet are distinct clinically. A radiomic machine learning model differentiating these tumors preoperatively would help plan surgery. MR images were acquired from 57 consecutive patients with chordoma (N = 32) or chondrosarcoma (N = 25) treated at the University of Tokyo Hospital between September 2012 and February 2020. Preoperative T1-weighted images with gadolinium enhancement (GdT1) and T2-weighted images were analyzed. Datasets from the first 47 cases were used for model creation, and those from the subsequent 10 cases were used for validation. Feature extraction was performed semi-automatically, and 2438 features were obtained per image sequence. Machine learning models with logistic regression and a support vector machine were created. The model with the highest accuracy incorporated seven features extracted from GdT1 in the logistic regression. The average area under the curve was 0.93 ± 0.06, and accuracy was 0.90 (9/10) in the validation dataset. The same validation dataset was assessed by 20 board-certified neurosurgeons. Diagnostic accuracy ranged from 0.50 to 0.80 (median 0.60, 95% confidence interval 0.60 ± 0.06%), which was inferior to that of the machine learning model (p = 0.03), although there are some limitations, such as the risk of overfitting and the lack of an extramural cohort for truly independent final validation. In summary, we created a novel MRI-based machine learning model to differentiate skull base chordoma and chondrosarcoma from multiparametric signatures.

Purpose: This study aimed to examine the effectiveness of cardiopulmonary resuscitation (CPR) directions by dispatchers. We analysed the relationship of dispatcher-assisted bystander cardiopulmonary resuscitation (DA-BCPR) with favourable cerebral function, shockable rhythm rate, and emergency medical service (EMS) arrival time. Methods: This nationwide study was based on CPR statistical data of out-of-hospital cardiac arrest (OHCA) patients (n = 629,471) from 1 January 2011 to 31 December 2015, and included 107,669 patients with bystander-witnessed cardiogenic cardiac arrest.The primary outcome was good brain function prognosis after 1 month, while the secondary outcome was the rate of shockable rhythm on ECG at the time of EMS arrival.EMS arrival time at the site was stratified into 7 min, 8−10 min, and 11−20 min using tertiles. Adjusted odds ratios (AORs) and 95% confidence intervals (95% CIs) were estimated using multivariate logistic regression analysis to assess the association between DA-BCPR and outcomes in each tertile. Results: There were 37,269 (35%), 18,109 (17%), and 52,291 (49%) patients in the DA-BCPR, Only-BCPR, and no-BCPR groups, respectively. Compared to No-BCPR, DA-BCPR was associated with favourable neurological outcomes regardless of the time from 119 call to EMS contact (AOR, 1.56, 2.01, 1.82; 95% CI, 1.43−1.71, 1.80–2.24, 1.52−2.19; ≤7 min, 8–10 min, and 11–20 min, respectively). DA-BCPR showed association with the shockable rhythm rate upon EMS arrival regardless of the time 119 call to EMS contact (AOR, 1.30, 1.60, 1.90; 95% CI, 1.23−1.38, 1.51−1.70, 1.75–2.06; ≤7 min, 8–10 min, and 11–20 min, respectively). Conclusion: Providing dispatcher assistance with CPR to 119 callers improves the long-term outcome regardless of the patient’s age and EMS response time. Thus, encouraging dispatchers to promote BCPR is important for increasing the shockable rhythm rate and improving the brain function prognosis.

Electrical stimulation of specific small fibers (Aδ- and C-fibers) is used in basic studies on nociception and neuropathic pain and to diagnose neuropathies. For selective stimulation of small fibers, the optimal stimulation waveform parameters are an important aspect together with the study of electrode design. However, determining an optimal stimulation condition is challenging, as it requires the characterization of the response of the small fibers to electrical stimulation. The perception thresholds are generally characterized using single-pulse stimulation based on the strength-duration curve. However, this does not account for the temporal effects of the different waveforms used in practical applications. In this study, we designed an experiment to characterize the effects of multiple pulse stimulation and proposed a computational model that considers electrostimulation of fibers and synaptic effects in a multiscale model. The measurements of perception thresholds showed that the pulse dependency of the threshold was an exponential decay with a maximum reduction of 55%. In addition, the frequency dependence of the threshold showed a U-shaped response with a reduction of 25% at 30 Hz. Moreover, the computational model explained the synaptic effects, which were also confirmed by evoked potential recordings. This study further characterized the activation of small fibers and clarified the synaptic effects, demonstrating the importance of waveform selection.

Abstract Background Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a useful tool in pancreatic cancer diagnosis. However, the procedure itself may cause peritoneal dissemination and needle tract seeding at the puncture site. We herein report two cases of gastric wall metastasis due to needle tract seeding after EUS-FNA. Case presentation Case 1: A 68-year-old woman was admitted to our hospital for persistent cough. Computed tomography (CT) scan revealed inflammatory changes in the left lung field, and incidentally, a 15-mm hypovascular mass was detected in the pancreatic body. She underwent EUS-FNA and was diagnosed as pancreatic adenocarcinoma. She underwent distal pancreatectomy with splenectomy; however, a small hard mass was observed in the posterior gastric wall during surgery. We performed partial gastrectomy, and the resected specimen was diagnosed as a needle tract seeding following EUS-FNA. She then underwent adjuvant chemotherapy with TS-1, but the pancreatic cancer showed recurrence 6 months after surgery. She died due to peritoneal dissemination 18 months after surgery. Case 2: A 70-year-old man was incidentally detected with a pancreatic body mass on a CT scan as part of his follow-up for recurrence of basal cell carcinoma. He underwent EUS-FNA and was diagnosed as pancreatic adenocarcinoma. He had nodules in both lungs, and it was difficult to differentiate them from lung metastasis of pancreatic cancer. Therefore, he underwent neoadjuvant chemoradiotherapy, and thereafter, the lung nodules showed no changes; hence, he underwent distal pancreatectomy with splenectomy. During surgery, we observed a hard mass in the posterior gastric wall. We performed partial gastrectomy, and the resected specimen was diagnosed as needle tract seeding due to EUS-FNA. He underwent chemotherapy with TS-1, and he is still alive 18 months after surgery at the time of writing. Conclusion For resectable pancreatic body or tail tumors, EUS-FNA should be carefully performed to prevent needle tract seeding and intraoperative as well as postoperative assessment for gastric wall metastasis is mandatory.

Abstract Phosphatidylinositol 3-kinase signaling promotes cell growth and survival and is frequently activated in infiltrative gliomas. Activating mutations in PIK3CA gene are observed in 6–15% of glioblastomas, although their clinical significance is largely undescribed. The objective of this study was to examine whether PIK3CA mutations are associated with a specific clinical phenotype in glioblastoma. We retrospectively reviewed 157 consecutive newly diagnosed glioblastoma patients from December 2009 to June 2012 who underwent molecular profiling consisting of targeted hotspot genotyping, fluorescence in situ hybridization for gene amplification, and methylation-specific PCR for O6-methylguanine-DNA methyltransferase promoter methylation. Molecular alterations were correlated with clinical features, imaging and outcome. The Cancer Genome Atlas data was analyzed as a validation set. There were 91 males; median age was 58 years (range, 23–85). With a median follow-up of 20.9 months, median progression-free survival (PFS) and estimated overall survival (OS) were 11.9 and 24.0 months, respectively. Thirteen patients (8.3%) harbored PIK3CA mutation, which was associated with younger age (mean 49.4 vs. 58.1 years, p = 0.02). PIK3CA mutation correlated with shorter PFS (median 6.9 vs. 12.4 months, p = 0.01) and OS (median 21.2 vs. 24.2 months, p = 0.049) in multivariate analysis. A significant association between PIK3CA mutation and more disseminated disease at diagnosis, as defined by gliomatosis, multicentric lesions, or distant leptomeningeal lesions, was observed (46.2% vs. 11.1%, p = 0.004). In conclusion, despite the association with younger age, PIK3CA activating mutations are associated with earlier recurrence and shorter survival in adult glioblastoma. The aggressive course of these tumors may be related to their propensity for disseminated presentation.

Electrical stimulation of small fibres is gaining attention in the diagnosis of peripheral neuropathies, such as diabetes mellitus, and pain research. However, it is still challenging to characterise the electrical characteristics of axons in small fibres (Aδ and C fibres). In particular, in vitro measurement for human Aδ-fibre is difficult due to the presence of myelin and ethical reason. In this study, we investigate the in vivo electrical characteristics of the human Aδ-fibre to derive strength–duration (S–D) curves from the measurement. The Aδ-fibres are stimulated using coaxial planar electrodes with intraepidermal needle tip. For human volunteer experiments, the S–D curve of Aδ-fibre is obtained in terms of injected electrical current. With the computational analysis, the standard deviation of the S–D curve is mostly attributed to the thickness of the stratum corneum and depth of the needle tip, in addition to the fibre thickness. Then, we derive electrical parameters of the axon in the Aδ-fibre based on a conventional fibre model. The parameters derived here would be important in exploring the optimal stimulation condition of Aδ-fibres.

Aim Wearing personal protective equipment (PPE) is essential to prevent infection transmission, but the risk of heatstroke increases with wearing PPE in a humid and hot environment. Therefore, we aimed to examine how environmental parameters change the body physiology in a hot environment during the coronavirus disease (COVID‐19) pandemic. Methods This was a retrospective cohort study extracted from the MEDIC Japan heatstroke prevention database, which was recorded between 1 August and 7 September, 2020. Its database is a registry collection from seven healthy health‐care providers. Subjects recorded their own vital signs (forehead and tympanic temperature, blood pressure, pulse rate, and oxygen saturation) and environmental factors (type of weather, wet‐bulb globe temperature [WBGT], air temperature, humidity, and location) every hour during their working shift. Results From 323 records, a weak positive but statistically significant correlation was observed between WBGT and pulse rate (correlation coefficient [95% confidence interval], r = 0.34 [0.23, 0.45]) and between WBGT and core body temperature. Forehead temperature had a stronger correlation than tympanic temperature (forehead, r = 0.33 [0.21, 0.43]; tympanic, r = 0.17 [0.05, 0.28]), which also showed a larger effect (forehead, η2 = 0.08; tympanic, η2 = 0.05). The effect size of oxygen saturation measured outdoors was large (η2 = 0.30). Forehead temperature increased abruptly at 28°C WBGT and at 33°C air temperature. Conclusion A hot environment significantly affected forehead temperature, and the daytime imposed a high risk of heatstroke. To avoid heatstroke, environmental parameters are important to note as outdoor environments had a large effect on vital sign changes depending on the time of day.

Aim It is unclear whether endotracheal intubation in the prehospital setting improves outcomes following out‐of‐hospital cardiac arrest. The purpose of this study was to evaluate the association between endotracheal intubation time (time from patient contact to endotracheal intubation) and favorable neurological outcomes on out‐of‐hospital cardiac arrest. Methods We extracted patients who underwent endotracheal intubation on the scene from a nationwide out‐of‐hospital cardiac arrest database registered between 2014 and 2017 in Japan. We included 14,969 witnessed and intubated adult out‐of‐hospital cardiac arrest cases. Patients were divided into Shockable (n = 1,102) and Non‐shockable (n = 13,867) cohorts. We first drew the logistic curve due to predicting the association between endotracheal intubation time and favorable neurological outcome defined as Cerebral Performance Category (CPC) 1 or 2. Secondary, multivariable logistic regressions were used to estimate the association between the endotracheal intubation time (1‐min unit increase), CPC 1 or 2. Results The logistic curve for CPC 1 or 2 showed similar shapes and indicated a decreasing outcome over time. From the results of multivariable logistic regression, in the Shockable cohort, endotracheal intubation time delay was correlated with decreasing favorable outcomes: CPC 1 or 2 (adjusted odds ratio, 0.89; 95% confidence interval, 0.82–0.87). Results were the same for the Non‐shockable cohort: CPC 1 or 2 (adjusted odds ratio, 0.94; 95% confidence interval, 0.89–0.99). Conclusion Early endotracheal intubation was correlated with favorable neurological outcome. Training for intubation skills and improving protocols are needed for carrying out early endotracheal intubation.

Medical care-related decision-making among patients with malignant brain tumors has not been sufficiently discussed. This study aimed to develop a framework for understanding patients’ experiences in the decision-making process. Semi-structured interviews with 14 patients were analyzed using a grounded theory approach, focusing on their 48 decision-making points. Additionally, interviews with two family members and seven healthcare providers, and participant observations were used to gain contextual insight into patients’ experiences. Patients faced decisions while they struggled in vulnerability under shock, fear, and anxiety while hoping. Under this context, they showed four decision-making patterns: (1) led by the situation , (2) controlled by others , (3) entrusted someone with the decision , and (4) myself as a decision-making agent . Across these patterns, the patients were generally satisfied with their decisions even when they did not actively participate in the process. Healthcare providers need to understand patients’ contexts and their attitudes toward yielding decision-making to others.

Abstract Background and Purpose In cardiovascular diseases, cardiac fibroblasts (CFs) participate in the myocardial inflammation by producing pro‐inflammatory cytokines, worsening the prognosis. β2‐adrenergic receptor (AR) and β3AR are expressed in CFs, and β‐adrenergic stimulation promotes CFs to produce pro‐inflammatory cytokines. However, the mechanism of the expression of pro‐inflammatory cytokines in response to β‐adrenergic stimulation remains to be fully elucidated. Experimental Approach CFs were isolated from adult wild‐type or AT‐rich interactive domain‐containing protein 5A (Arid5a) knockout mice. The expression of mRNA was measured by real‐time RT‐PCR. Interleukin (IL)‐6 protein was measured by ELISA. The activity of nuclear factor‐κB (NF‐κB) and cyclic AMP (cAMP) response element binding protein (CREB) was assessed by ELISA‐like assay or Western blotting. Key Results The β‐adrenergic stimulation remarkably induced IL‐6 mRNA and protein through β2AR in CFs. The activation of adenylate cyclase and the enhancement of intracellular cAMP resulted in the upregulation of IL‐6 mRNA expression. The induction of IL‐6 transcript by β2AR signaling was independent of NF‐κB. Concomitant with IL‐6, the expression of Arid5a, an IL‐6 mRNA stabilizing factor, was enhanced by β2‐adrenergic stimulation and by cAMP increase. Importantly, β2AR signaling‐mediated IL‐6 induction was suppressed in Arid5a knockout CFs. Finally, β2AR stimulation phosphorylated CREB via PKA pathway, and the activation of CREB was essential for the induction of Arid5a and IL‐6 mRNA. Conclusion and Implications β2‐adrenergic stimulation post‐transcriptionally upregulates the expression of IL‐6 by the induction of Arid5a through cAMP/PKA/CREB pathway in adult CFs. β2AR/Arid5a/IL‐6 axis could be a therapeutic target against cardiac inflammation.

Abstract Background The effect of bystander interventions has been extensively evaluated by cerebral function after 1 month post-resuscitation. However, patients who received bystander cardiopulmonary resuscitation (BCPR) and achieved the return of spontaneous circulation (ROSC) before the arrival of the emergency medical system (EMS) are routinely defined with an unknown electrocardiogram (ECG) and are usually excluded before analysis. The aim is to determine the influence of excluding patients with unknown first monitored rhythm, which includes cases of bystander ROSC, from the out-of-hospital cardiac arrest (OHCA) database. Methods This nationwide population-based observational study was conducted in Japan using Utstein data from 2011 to 2014. In total, 91,995 patients with bystander-witnessed cardiogenic OHCA received resuscitation attempts in the pre-hospital setting. These patients were divided into three groups by the first monitored rhythm upon EMS arrival. We analysed the differences of datasets that included and excluded the unknown group and determined the effect on outcomes by multivariate logistic regression and odds ratios (ORs) with 95% confidence intervals (95% CIs). Results When the unknown group was excluded from the data, the adjusted odds ratio (AOR) of cardiopulmonary resuscitation (CPR) to favourable cerebral performance category (CPC) 1 or 2 was decreased (conventional CPR: AOR, 1.90 to 1.58; chest-compression-only CPR: AOR, 2.08 to 1.69) compared to the unknown group’s inclusion. Conversely, the AOR of public-access defibrillation (PAD) was increased (AOR, 4.51 to 6.13). Conclusions The exclusion of unknown ECGs from a dataset may lose ROSC patients by bystander CPR, causing selection bias to affect outcomes.

The lack of available tumor antigens with strong immunogenicity, human leukocyte antigen restriction, and immunosuppression via regulatory T-cells (Tregs) and myeloid-derived suppressor cells are limitations for dendritic cell (DC)–based immunotherapy in patients with advanced head and neck cancer (HNC). We sought to overcome these limitations and induce effective antitumor immunity in the host. The effect of low-dose docetaxel (DTX) treatment on DC maturation was examined in an ex vivo study, and a phase I clinical trial of combination therapy with direct peritumoral immature DC (iDC) injection with OK-432 and low-dose cyclophosphamide (CTX) plus DTX was designed. Low-dose DTX did not negatively affect iDC viability and instead promoted maturation and IL-12 production. Five patients with metastatic or recurrent HNC were enrolled for the trial. All patients experienced grade 1 to 3 fevers. Intriguingly, elevated CD8+ effector T-cells and reduced Tregs were observed in four patients who completed two treatment cycles. All patients were judged to have progressive disease, but tumor regressions were observed in a subset of targeted metastatic lesions in two of five patients. Our results show that the combination of direct peritumoral iDC injection with OK-432 and low-dose CTX plus DTX is well tolerated and should give rise to changing the immune profile of T-cell subsets and improvement of immunosuppression in advanced HNC patients. Additionally, our ex vivo data on the effect of low-dose DTX treatment on DC maturation may contribute to developing new combination therapies with low-dose chemotherapy and immunotherapy.

Small-bowel feces sign is useful to detect the corresponding site of stenosis or obstruction in patients with moderate and high degrees of small-bowel obstruction. The CT findings of kitchen sponge are very similar to small-bowel feces sign. With careful image interpretation, it is possible to judge whether the cause of obstruction is sponge. We report a case of a 26-year-old man small-bowel obstruction due to kitchen sponge eating as pica behavior, focusing on image findings. Keywords: CT, Small-bowel obstructions, Pica, Sponge eating

Primary anaplastic large cell lymphoma (ALCL) of the central nervous system (CNS) is a subtype of primary CNS lymphoma (PCNSL). There are very few comprehensive reports on this extremely rare tumor. Therefore, it is necessary to investigate the clinical features and prognostic factors for primary ALCL of the CNS. We performed a systematic review of the published literature. Past cases were comprehensively searched using PubMed, Cochrane Library, and Web of Science. Clinical information, such as age, sex, anaplastic lymphoma kinase (ALK) status, lesion sites, treatment methods, and survivorship were extracted. Thirty-nine cases with information on ALK status and treatment course were identified. The average observation period was 13 months, and the overall 2-year survival rate was 58%. Univariate analyses showed a statistically significantly better prognosis among patients < 40 years of age (p = 0.039, HR 0.32 (0.11–0.95)) and in relation to ALK positivity (p = 0.010, HR 0.24 (0.08–0.71) and methotrexate treatment (p = 0.003, HR 0.17 (0.05–0.56)). Because of the sparsity of cases, it is necessary to accumulate cases in order to perform more detailed analyses.

Although the incidence of central nervous system (CNS) cancers is not high, it significantly reduces a patient’s quality of life and results in high mortality rates. A low incidence also means a low number of cases, which in turn means a low amount of information. To compensate, researchers have tried to increase the amount of information available from a single test using high-throughput technologies. This approach, referred to as single-omics analysis, has only been partially successful as one type of data may not be able to appropriately describe all the characteristics of a tumor. It is presently unclear what type of data can describe a particular clinical situation. One way to solve this problem is to use multi-omics data. When using many types of data, a selected data type or a combination of them may effectively resolve a clinical question. Hence, we conducted a comprehensive survey of papers in the field of neuro-oncology that used multi-omics data for analysis and found that most of the papers utilized machine learning techniques. This fact shows that it is useful to utilize machine learning techniques in multi-omics analysis. In this review, we discuss the current status of multi-omics analysis in the field of neuro-oncology and the importance of using machine learning techniques.

Abstract Background Mass Cardio-Pulmonary Resuscitation (CPR) training using less expensive and easily portable manikins is one way to increase the number of trained laypeople in a short time. The easy-to-carry, low-cost CPR training model called Push Heart (PH) is widely used in Japan. The aim of this study was to examine if PH can achieve chest compression quality that is similar to that using more conventional Little Anne (LA) manikins for training laypersons. Methods This prospective randomized crossover study was done during routine community CPR training of laypersons in Singapore. The participants were randomly allocated into two groups, using the PH and LA models respectively. They crossed over during the training so that both groups had measurements using both models. Chest compression data were collected using blinded CPRcards, which are credit card-sized devices with accelerometers and data capture. Participants did not receive any CPR feedback during measurement. Results Forty-two people had data captured for the study with 15 males. The median compression depth was 41.5 mm on LA and 38.0 mm on PH (p = 0.0664), and median compression rate was 105 cpm on LA and 103 cpm on PH (p = 0.2429). Overall, only 1.5% of compressions performed on the PH achieved adequate depth of between 50–70 mm compared to 5.5% achieved on LA (p = 0.049). In contrast, 84% of all compressions performed on the PH were within the adequate rate of 100–120 cpm compared to 79.5% on LA (p = 0.457). Only the under 20-year-old group was able to achieve adequate median compression depth (50.5 mm) on LA, while the older age groups did not (p = 0.0024). The other age groups performed similar quality of chest compression regardless of the model used. 73.8% of participants preferred the LA for training. After the training, participants felt similarly well-prepared with either model with a median score of 8/10 on LA compared to 7/10 on PH (p = 0.0011). Conclusions The PH can be an alternative mass CPR training model. Both models achieved satisfactory chest compression rates, but the majority of participants, especially the elderly, had difficulty achieving adequate depth.

Objectives‘Quality Cardiopulmonary Resuscitation (QCPR) Classroom’ was recently introduced to provide higher-quality Cardiopulmonary Resuscitation (CPR) training. This study aimed to examine whether novel QCPR Classroom training can lead to higher chest-compression quality than standard CPR training.DesignA cluster randomised controlled trial was conducted to compare standard CPR training (control) and QCPR Classroom (intervention).SettingLayperson CPR training in Japan.ParticipantsSix hundred forty-two people aged over 15 years were recruited from among CPR trainees.InterventionsCPR performance data were registered without feedback on instrumented Little Anne prototypes for 1 min pretraining and post-training. A large classroom was used in which QCPR Classroom participants could see their CPR performance on a big screen at the front; the control group only received instructor’s subjective feedback.Primary and secondary outcome measuresThe primary outcomes were compression depth (mm), rate (compressions per minute (cpm)), percentage of adequate depth (%) and recoil (%). Survey scores were a secondary outcome. The survey included participants’ confidence regarding CPR parameters and ease of understanding instructor feedback.ResultsIn total, 259 and 238 people in the control and QCPR Classroom groups, respectively, were eligible for analysis. After training, the mean compression depth and rate were 56.1±9.8 mm and 119.2±7.3 cpm in the control group and 59.5±7.9 mm and 116.8±5.5 cpm in the QCPR Classroom group. The QCPR Classroom group showed significantly more adequate depth than the control group (p=0.001). There were 39.0% (95% CI 33.8 to 44.2; p

Brain metastasis frequently develops in non-small-cell lung cancer (NSCLC). Here, we report a patient who developed brain metastasis from ALK-positive NSCLC which mimicked brain abscess. He was admitted for suspected obstructive pneumonia nine months after curative lung resection. Head magnetic resonance imaging revealed a cavitary lesion, which was compatible with brain abscess but rare in brain metastasis. However, after treatment with antibiotics, the brain lesion increased in size. Aspiration of the liquid content of the brain lesion revealed cancer cells. When a brain lesion suggestive of abscess develops in a patient with ALK-positive NSCLC, aspiration may be necessary to differentiate metastasis from abscess.

Machine learning models for automated magnetic resonance image segmentation may be useful in aiding glioma detection. However, the image differences among facilities cause performance degradation and impede detection. This study proposes a method to solve this issue. We used the data from the Multimodal Brain Tumor Image Segmentation Benchmark (BraTS) and the Japanese cohort (JC) datasets. Three models for tumor segmentation are developed. In our methodology, the BraTS and JC models are trained on the BraTS and JC datasets, respectively, whereas the fine-tuning models are developed from the BraTS model and fine-tuned using the JC dataset. Our results show that the Dice coefficient score of the JC model for the test portion of the JC dataset was 0.779 ± 0.137, whereas that of the BraTS model was lower (0.717 ± 0.207). The mean Dice coefficient score of the fine-tuning model was 0.769 ± 0.138. There was a significant difference between the BraTS and JC models (p < 0.0001) and the BraTS and fine-tuning models (p = 0.002); however, no significant difference between the JC and fine-tuning models (p = 0.673). As our fine-tuning method requires fewer than 20 cases, this method is useful even in a facility where the number of glioma cases is small.

Glioma is characterized by a high heterogeneity in the brain tumor. Abundant tumor-associated macrophages (TAMs) exist as neoplastic tissues, implicating tumor plasticity and thus leading to therapeutic challenges. Vascular adhesion protein (VAP-1) potentially serves as a mediator for TAM immunity in tumor milieu. We previously demonstrated that VAP-1 could contribute to tumor malignancy, but its characteristics in TAM immunity of glioma progression are still unclear. This study explored the association of VAP-1 expression with TAM distribution as well as the resulting clinical significance and prognostic value in human gliomas. An in-depth analysis of AOC3 (VAP-1) gene expression was performed using 695 glioma samples derived from the cancer genome atlas (TCGA)-lower grade glioma and glioblastoma (GBMLGG) cohort. Bioinformatic analysis confirmed that VAP-1 expression is associated with poor prognosis of glioma patients (p = 0.0283). VAP-1 and TAM biomarkers (CD68, iNOS, and CD163) were evaluated by immunohistochemistry in 108 gliomas from Kaohsiung Medical University Hospital. VAP-1+ was expressed in 56 (51.85%) cases and this phenotype revealed a significant association with overall survival in Kaplan–Meier analysis (p < 0.0001). Immunohistochemical double staining showed that VAP-1 immunoreactivity was present around CD163+ M2 infiltration location, including aggressive lesions and neighboring neovasculature. We demonstrated that high VAP-1 expression levels positively correlated with CD163+ M2 activation and coexpression of these two proteins was associated with worse survival in gliomas (p < 0.0001). Multivariate analysis indicated that VAP-1 alone and co-expressed with CD163 were the significantly independent indicators (both p < 0.0001). Furthermore, VAP-1/CD163 coexpression exhibited excellent diagnostic accuracy in gliomas (AUC = 0.8008). In conclusion, VAP-1 and TAM CD163 M2 coexpression was found in glioma tissues belonging to a highly malignant subgroup that was associated with poor prognosis. These results implied VAP-1 abundance is closely linked to alternative M2 activation during glioma progression. From the aforementioned data, a reasonable inference is that VAP-1 combined with targeting M2 immunity might be an effective therapeutic target for human gliomas.