Language：Japanese   Publisher：(一社)日本臨床神経生理学会  

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Intraventricular haemorrhage (IVH) is a key prognostic factor for subarachnoid haemorrhage (SAH). However, no simple or rapid scoring method for its evaluation exists. We aimed to modify and validate a simple scale for rapid IVH grading. We engaged two study groups to generate scores and examine their utility. Study 1 identified prognostic factors in poor-grade SAH and developed a prognostic scoring system. Study 2 evaluated the utility of the score by analysing data from a multicentre patient registry, including all severity levels, and confirmed its generalisability. Outcomes were defined using the modified Rankin scale (score ≥ 3: poor outcome). Study 1 (including 110 patients with poor-grade SAH) created a simple IVH score (IVHAge) based on two slices of computed tomography images and confirmed that it was as predictive as the modified Graeb score (area under the curve: IVHAge score, 0.815; modified Graeb score, 0.752). Study 2 examined 493 patients and found that for each 1-unit increase in the IVHAge score, the odds of a poor outcome increased by 37% (unit odds ratio, 1.37; 95% confidence interval 1.10-1.70; P = 0.005). The IVHAge score, which comprises a simplified IVH score and age-related factors, has prognostic value and is suitable for rapid clinical application.

DOI： 10.1038/s41598-025-99132-3

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Mary Ann Liebert Inc  

DOI： 10.1089/neur.2024.0167

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Other Link： https://www.liebertpub.com/doi/pdf/10.1089/neur.2024.0167

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

AIM: To evaluate the prognostic factors in severe head trauma patients (Glasgow Coma Score (GCS) ≤ 8) with all trauma, including those with trunk injury as well as single severe head trauma (abbreviated injury scale (AIS) ≥ 3). METHODS: We included 152 consecutive patients with head trauma (AIS ≥ 3) and consciousness disorders (GCS ≤ 8) who were transported to our institute from January 2017 to October 2022. Data on the patients' background, vital signs at presentation, multiple trauma (AIS ≥ 3 in two or more locations), surgical intervention, and hematological findings were examined; a retrospective analysis was conducted with the modified Rankin Scale score after 3 months assigned as the primary outcome. RESULTS: The patients' mean age was 57.6 ± 23.4 years (0-89), 49 patients (32.2%) had multiple trauma, and 25 patients (16.4%) had accompanying shock vital signs. In the multivariate analysis of prognosis, age (p = 0.0007) and D-dimer levels (p = 0.0007) were independent poor prognostic factors. On the contrary, patients with multiple trauma (p = 0.027) and shock vital signs at presentation (p = 0.037) had a significantly better prognosis. In the non-shock group, 97.6% (41/42) of patients aged ≥50 years and with D-dimer level of 40 μg/mL or higher had a poor prognosis after 3 months. CONCLUSION: Advanced age and high D-dimer levels are important independent associated factors in patients with severe consciousness disorder associated with head trauma; meanwhile, the prognosis is more favorable in patients whose consciousness disorders are associated with multiple trauma or circulatory failure, indicating that rapid improvement of circulatory failure may lead to better outcomes.

DOI： 10.1002/ams2.70058

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Language：English   Publishing type：Research paper (scientific journal)  

Reversible cerebral vasoconstriction syndrome is characterized by severe headaches and diffuse, segmental constriction of cerebral arteries. We report a rare pediatric case of triptan-induced reversible cerebral vasoconstriction syndrome, complicated by both subarachnoid hemorrhage and cerebral infarction. A 10-year-old boy presented with persistent severe headaches initially suspected to be migraines, for which he was prescribed rizatriptan. Five days after starting rizatriptan, he developed impaired consciousness (Japan Coma Scale 10) and partial right-sided hemiparesis, prompting emergency hospitalization. A head computed tomography scan revealed subarachnoid hemorrhage in the left frontal cortical region. Cerebral angiography showed stenotic changes in the internal carotid artery, middle cerebral artery, anterior cerebral artery, and posterior cerebral artery. Suspecting triptan-induced reversible cerebral vasoconstriction syndrome, rizatriptan was discontinued, and verapamil treatment was initiated. Subsequent magnetic resonance imaging and magnetic resonance angiography revealed cerebral infarction in the right cerebellum, left middle cerebral artery territory, and right occipital lobe, with persistent stenotic changes from earlier findings. Edaravone was added to the treatment regimen. The patient's condition gradually improved, and follow-up magnetic resonance angiography showed almost complete resolution of the prior stenotic changes. His partial right-sided hemiparesis nearly resolved, and he was discharged home. Triptans should be used with caution, as they may precipitate reversible cerebral vasoconstriction syndrome or exacerbate cerebral vasoconstriction. Careful monitoring and vascular imaging are essential for patients presenting with symptoms following triptan administration.

DOI： 10.2176/jns-nmc.2025-0023

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Background and purpose The risk of rupture increases with advancing age. However, the risk-benefit of coil embolization for elderly patients with unruptured aneurysms is controversial. This study aimed to identify factors associated with treatment primary outcomes, including risk factors for complications and aneurysm recurrence requiring re-treatment in the endovascular treatment of unruptured aneurysms in elderly patients. In addition, deterioration of the modified Rankin Scale (mRS) was examined as a secondary outcome. Materials and methods This retrospective three-center study examined 112 cases of coiled unruptured aneurysms in patients aged ≥ 60 years using endovascular registry data from January 2018 to March 2022. We examined patient background, aneurysm characteristics, adjuvant technique, symptomatic complications, and mRS scores. Results The average age of the patients was 72.5±6.9 years, and 83 cases (74.1%) were female. During the postoperative follow-up period (six to 36 months), no deaths occurred, one case of postoperative rupture was observed, and nine patients (5.4%) were re-treated. Notably, age, underlying disease, aneurysm location, and re-treatment were not associated with complications. In the multivariate logistic analysis for re-treatment, symptomatic complications [odds ratio (OR) 11.01; 95% confidence interval (CI), 3.68-52.5; p < 0.001] and re-treatment (OR 3.25; 95% CI, 1.04-10.7; p = 0.039) were independently associated with mRS score deterioration. The risk factors for re-treatment were maximum aneurysm diameter and aneurysm neck diameter; aneurysms with neck diameters and maximum diameters > 5.0 mm and > 9.0 mm, respectively, had a higher rate of need for re-treatment (33%) and mRS score deterioration (33%) due to re-enlargement of the aneurysm. Conclusion In this study, complications did not increase with age in those aged 60 and older. However, prioritizing the avoidance of complications in elderly patients is important. Elderly patients with aneurysms larger than 9 mm have a poor prognosis and require additional attention for re-treatment.

DOI： 10.7759/cureus.75759

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Mary Ann Liebert Inc  

DOI： 10.1089/neur.2024.0133

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Other Link： https://www.liebertpub.com/doi/pdf/10.1089/neur.2024.0133

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Application of physical forces, ranging from ultrasound to electric fields, is recommended in various clinical practice guidelines, including those for treating cancers and bone fractures. However, the mechanistic details of such treatments are often inadequately understood, primarily due to the absence of comprehensive study models. In this study, we demonstrate that an alternating magnetic field (AMF) inherently possesses a direct anti‐cancer effect by enhancing oxidative phosphorylation (OXPHOS) and thereby inducing metabolic reprogramming. We observed that the proliferation of human glioblastoma multiforme (GBM) cells (U87 and LN229) was inhibited upon exposure to AMF within a specific narrow frequency range, including around 227 kHz. In contrast, this exposure did not affect normal human astrocytes (NHA). Additionally, in mouse models implanted with human GBM cells in the brain, daily exposure to AMF for 30 min over 21 days significantly suppressed tumor growth and prolonged overall survival. This effect was associated with heightened reactive oxygen species (ROS) production and increased manganese superoxide dismutase (MnSOD) expression. The anti‐cancer efficacy of AMF was diminished by either a mitochondrial complex IV inhibitor or a ROS scavenger. Along with these observations, there was a decrease in the extracellular acidification rate (ECAR) and an increase in the oxygen consumption rate (OCR). This suggests that AMF‐induced metabolic reprogramming occurs in GBM cells but not in normal cells. Our results suggest that AMF exposure may offer a straightforward strategy to inhibit cancer cell growth by leveraging oxidative stress through metabolic reprogramming.

DOI： 10.1111/cas.16243

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

SIGNIFICANCE: The initiation of goal-directed actions is a complex process involving the medial prefrontal cortex and dopaminergic inputs through the mesocortical pathway. However, it is unclear what information the mesocortical pathway conveys and how it impacts action initiation. In this study, we unveiled the indispensable role of mesocortical axon terminals in encoding the execution of movements in self-initiated actions. AIM: To investigate the role of mesocortical axon terminals in encoding the execution of movements in self-initiated actions. APPROACH: We designed a lever-press task in which mice internally determine the timing of the press, receiving a larger reward for longer waiting periods. RESULTS: Our study revealed that self-initiated actions depend on dopaminergic signaling mediated by D2 receptors, whereas sensory-triggered lever-press actions do not involve D2 signaling. Microprism-mediated two-photon calcium imaging further demonstrated ramping activity in mesocortical axon terminals approximately 0.5 s before the self-initiated lever press. Remarkably, the ramping patterns remained consistent whether the mice responded to cues immediately for a smaller reward or held their response for a larger reward. CONCLUSIONS: We conclude that mesocortical dopamine axon terminals encode the timing of self-initiated actions, shedding light on a crucial aspect of the intricate neural mechanisms governing goal-directed behavior.

DOI： 10.1117/1.NPh.11.3.033408

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BACKGROUND: The increasing prevalence of heated tobacco products (HTPs) has heightened concerns regarding their potential health risks. Previous studies have demonstrated the toxicity of cigarette smoke extract (CSE) from traditional tobacco's mainstream smoke, even after the removal of nicotine and tar. Our study aimed to investigate the cytotoxicity of CSE derived from HTPs and traditional tobacco, with a particular focus on the role of reactive oxygen species (ROS) and intracellular Ca2+. METHODS: A human oral squamous cell carcinoma (OSCC) cell line, HSC-3 was utilized. To prepare CSE, aerosols from HTPs (IQOS) and traditional tobacco products (1R6F reference cigarette) were collected into cell culture media. A cell viability assay, apoptosis assay, western blotting, and Fluo-4 assay were conducted. Changes in ROS levels were measured using electron spin resonance spectroscopy and the high-sensitivity 2',7'-dichlorofluorescein diacetate assay. We performed a knockdown of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) by shRNA lentivirus in OSCC cells. RESULTS: CSE from both HTPs and traditional tobacco exhibited cytotoxic effects in OSCC cells. Exposure to CSE from both sources led to an increase in intracellular Ca2+ concentration and induced p38 phosphorylation. Additionally, these extracts prompted cell apoptosis and heightened ROS levels. N-acetylcysteine (NAC) mitigated the cytotoxic effects and p38 phosphorylation. Furthermore, the knockdown of CaMKK2 in HSC-3 cells reduced cytotoxicity, ROS production, and p38 phosphorylation in response to CSE. CONCLUSION: Our findings suggest that the CSE from both HTPs and traditional tobacco induce cytotoxicity. This toxicity is mediated by ROS, which are regulated through Ca2+ signaling and CaMKK2 pathways.

DOI： 10.1186/s12576-024-00928-1

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.inat.2024.101974

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：eLife Sciences Publications, Ltd  

Midbrain dopamine neurons impact neural processing in the prefrontal cortex (PFC) through mesocortical projections. However, the signals conveyed by dopamine projections to the PFC remain unclear, particularly at the single-axon level. Here, we investigated dopaminergic axonal activity in the medial PFC (mPFC) during reward and aversive processing. By optimizing microprism-mediated two-photon calcium imaging of dopamine axon terminals, we found diverse responses in dopamine axons, with some preferring reward and others preferring aversive stimuli, with a strong bias for the latter at the population level. Long-term longitudinal imaging revealed that the preference was maintained in reward- and aversive-preferring axons throughout classical conditioning in which rewarding and aversive stimuli were paired with preceding auditory cues. However, as mice learned to discriminate reward or aversive cues, a cue activity preference gradually developed only in aversive-preferring axons, becoming more selective for aversive processing. We inferred the trial-by-trial cue discrimination based on machine learning using anticipatory licking or facial expressions, and found that successful discrimination was accompanied by sharper selectivity for the aversive cue in aversive-preferring axons. Our findings implicate mesocortical dopamine axon activity in the encoding of aversive processing that is modulated by both classical conditioning across days and trial-by-trial discrimination within a day.

Two-photon calcium imaging revealed that many mesocortical dopamine axons show enhanced selectivity for aversive cue processing during classical conditioning.

DOI： 10.7554/eLife.91136

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BACKGROUND: Takotsubo cardiomyopathy (TC) is a well-known complication of subarachnoid haemorrhage (SAH), often accompanied by neurogenic myocardial dysfunction. Although TC has been reported to be associated with higher morbidity and mortality among patients with aneurysmal SAH (aSAH), some patients have been reported to recover, the profiles and follow-up outcomes of these survivors remain unclear. MATERIALS AND METHODS: To characterize the profiles of patients with aSAH complicated by TC who experienced favourable outcomes using long-term follow-up data, a consecutive series of patients with aSAH were enrolled and TC diagnosis was based on the revised version of the Mayo Clinic criteria. Clinical outcomes were assessed at 6 months according to modified Rankin Scale scores. RESULTS: Among 165 consecutive patients with aSAH, 15 cases were complicated by TC, corresponding to an occurrence rate of 9.0%. Five patients with aSAH complicated by TC (33.3%) experienced a favourable outcome, and the mean value of systolic blood pressure on arrival was significantly lower than in those who experienced an unfavourable outcome (p = 0.032). CONCLUSION: According to analysis, it is possible cardiac dysfunction with decreased cerebral perfusion pressure and catecholamine toxicity transiently worsens conscious disturbance in aSAH complicated by TC. Therefore, it is important to carefully screen patients with aSAH to identify those complicated by TC, and for close collaboration of the multidisciplinary team to design appropriate treatment strategies.

DOI： 10.1080/02688697.2024.2334432

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.7759/cureus.52874

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Language：English  

UNLABELLED: Midbrain dopamine neurons impact neural processing in the prefrontal cortex (PFC) through mesocortical projections. However, the signals conveyed by dopamine projections to the PFC remain unclear, particularly at the single-axon level. Here, we investigated dopaminergic axonal activity in the medial PFC (mPFC) during reward and aversive processing. By optimizing microprism-mediated two-photon calcium imaging of dopamine axon terminals, we found diverse responses in dopamine axons, with some preferring reward and others preferring aversive stimuli, with a strong bias for the latter at the population level. Long-term longitudinal imaging revealed that the preference was maintained in reward- and aversive-preferring axons throughout classical conditioning in which rewarding and aversive stimuli were paired with preceding auditory cues. However, as mice learned to discriminate reward or aversive cues, a cue activity preference gradually developed only in aversive-preferring axons, becoming more selective for aversive processing. We inferred the trial-by-trial cue discrimination based on machine learning using anticipatory licking or facial expressions, and found that successful discrimination was accompanied by sharper selectivity for the aversive cue in aversive-preferring axons. Our findings implicate mesocortical dopamine axon activity in the encoding of aversive processing that is modulated by both classical conditioning across days and trial-by-trial discrimination within a day. IMPACT STATEMENT: Two-photon calcium imaging revealed that many mesocortical dopamine axons show enhanced selectivity for aversive cue processing during classical conditioning.

DOI： 10.1101/2023.08.23.554475

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Subarachnoid hemorrhage and thyroid storm are similar in their clinical symptomatology, and diagnosis of these conditions, when they occur simultaneously, is difficult. Here, we report a rare case of concurrent subarachnoid hemorrhage and thyroid storm we encountered at our hospital. CASE PRESENTATION: The patient was a 52-year-old woman. While bathing at home, the patient experienced a sudden disturbance of consciousness and was brought to our hospital. The main physical findings upon admittance were Glasgow Coma Scale score of E1V2M4, elevated blood pressure (208/145 mmHg), and tachycardia with atrial fibrillation (180 bpm) along with body temperature of 36.1 °C. Brain computed tomography revealed subarachnoid hemorrhage associated with a ruptured aneurysm of the posterior communicating artery branching from the left internal carotid artery, and aneurysm clipping was performed. Blood tests upon admission revealed high levels of free T3 and free T4 and low levels of thyroid-stimulating hormone. Upon determining that the patient had hyperthyroidism, thiamazole was administered. However, due to continuous impaired consciousness, fever, and persistence of tachycardia, the patient was diagnosed with thyroid storm. Oral potassium iodide and hydrocortisone were added to the treatment. The treatment was successful as the patient's symptoms improved, and she became lucid. In this case, we believe that in the presence of untreated hyperthyroidism, the onset of subarachnoid hemorrhage induced thyroid storm. Tachycardia of 130 bpm or higher, which is the diagnostic criterion for thyroid storm, rarely occurs with subarachnoid hemorrhage. Therefore, we believe it is an important factor for recognizing the presence of the thyroid storm. In this case, clipping surgery was prioritized which resulted in a favorable outcome. However, it is possible that invasive surgery may have exacerbated thyroid storm, suggesting that treatment should be tailored as per patient's condition. CONCLUSION: If a pulse rate of 130 bpm or higher is observed alongside subarachnoid hemorrhage, we recommend considering the possibility of concomitant thyroid storm and testing for thyroid hormone. If concomitant thyroid storm is present, we believe that a treatment plan tailored to the patient's condition is critical, and early diagnosis will lead to a favorable outcome for the patient.

DOI： 10.1186/s12245-023-00490-4

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: There have been several reports of central nervous system impairments associated with severe coronavirus disease 2019 (COVID-19) infection on head magnetic resonance imaging and angiography (MRI/A). However, head MRI/A is rarely performed in mild cases, and there have been few reports on intracranial changes after COVID-19 infection in these cases. Here, we report a comparative examination of the findings seen in common head MRI/A sequences in mild cases of COVID-19. METHODS: Of the 15,376 patients who underwent head MRI/A examination called "Brain Dock" between June 2020 and June 2021, 746 patients who received a COVID-19 antibody test were evaluated. Positive and negative patients were comparatively examined for head MRI/A findings such as cerebral white matter lesions, ischemic changes, cerebral microbleeds, cerebral aneurysms, arterial stenosis, sinusitis, and other abnormal findings. RESULTS: Overall, 31 (4.2%) patients were COVID-19 positive, and all of them had mild infections not requiring hospitalization. There was no significant difference in patient characteristics and head MRI/A findings between positive and negative patients. All positive patients showed no particular abnormalities in the nasal findings such as olfactory bulb atrophy or thickening of the olfactory mucosa. CONCLUSION: Intracranial lesions in mild patients do not show a clear difference from those in negative patients. This indicates that findings seen in common MRI/A sequences of severe patients are not likely in mild patients, supporting that there is relatively no damage to the central nervous system in mild patients.

DOI： 10.7759/cureus.34229

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Neuroendovascular Therapy  

DOI： 10.5797/jnet.oa.2022-0043

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PURPOSE: Observation is the first management option in asymptomatic meningiomas, but when an enlargement or mass effect is observed, surgery is indicated. This study is aimed at exploring risk factors for complications and recurrence after surgery for asymptomatic meningioma. We also examined the impact of preoperative tumor embolization, which is considered controversial. METHODS: We retrospectively reviewed 109 patients with primary asymptomatic meningiomas surgically treated at our institute between April 2007 and March 2021. Patients who only had headaches as a nonspecific complaint were included in the asymptomatic group. Complications, time to recurrence, and Glasgow Outcome Scale (GOS) score were the endpoints of the study. Risk factors for complications and recurrence were explored. Moreover, the effect of the resection on nonspecific headaches was also explored. RESULTS: The permanent postoperative complication rate related to the surgical procedure was 1.8%. Of the total, 107 patients (98.2%) with asymptomatic meningiomas who were surgically treated achieved a GOS score of 5 1 year after the operation. Preoperative headache was present in 31 patients and improved postoperatively in 21 patients. Multivariate analysis using the Cox proportional hazard model showed that preoperative tumor embolization with > 80% resolution of tumor staining (p < 0.001) was negatively related to recurrence, whereas age (p = 0.046) and Simpson grade IV resection (p = 0.041) were positively related to recurrence. CONCLUSION: Although surgery for asymptomatic meningiomas can, in many cases, be safe, it is not free of complications Thus, surgical intervention for asymptomatic meningiomas should be considered cautiously. However, more than half the patients with headaches showed improvement. Simpson grade IV resection cases should be assessed for recurrence, and preoperative tumor embolization might be effective in controlling recurrence.

DOI： 10.1007/s00701-022-05420-6

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BACKGROUND: Meningiomas are often embolized preoperatively to reduce intraoperative blood loss and facilitate tumor resection. However, the procedure is controversial and its effects have not yet been reported. We evaluated preoperative embolization for meningiomas and its effect on postoperative outcome and recurrence. METHODS: We retrospectively reviewed the medical records of 186 patients with WHO grade I meningiomas who underwent surgical treatment at our hospital between January 2010 and December 2020. We used propensity score matching to generate embolization and no-embolization groups (42 patients each) to examine embolization effects. RESULTS: Preoperative embolization was performed in 71 patients (38.2%). In the propensity-matched analysis, the embolization group showed favorable recurrence-free survival (RFS) (mean 49.4 vs 24.1 months; Wilcoxon p=0.049). The embolization group had significantly less intraoperative blood loss (178±203 mL vs 221±165 mL; p=0.009) and shorter operation time (5.6±2.0 hours vs 6.8±2.8 hours; p=0.036). There were no significant differences in Simpson grade IV resection (33.3% vs 28.6%; p=0.637) or overall perioperative complications (21.4% vs 11.9%; p=0.241). Tumor embolization prolonged RFS in a subanalysis of cases who experienced recurrence (n=39) among the overall cases before variable control (mean RFS 33.2 vs 16.0 months; log-rank p=0.003). CONCLUSIONS: After controlling for variables, preoperative embolization for meningioma did not improve the Simpson grade or patient outcomes. However, it might have effects outside of surgical outcomes by prolonging RFS without increasing complications.

DOI： 10.1136/neurintsurg-2022-019080

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.inat.2022.101583

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Language：Japanese   Publisher：横浜市立大学医学会  

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Language：Japanese   Publisher：横浜市立大学医学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The occipital transtentorial approach (OTA) is a very useful but challenging approach to expose the pineal region because the deep-seated arachnoid membranes usually fold and extend over the great vein of Galen (GVG), leading to dense and poor visibility. In addition, the practical aspects of arachnoid anatomy are not well understood. We aimed to develop a safe surgical procedure for the OTA according to the practical aspects of arachnoid anatomy. METHODS: The procedure is shown through an illustrative video of surgery and cadaver. Five cadavers were analyzed for their arachnoid structures and the surgical procedures via the OTA, in strict compliance with legal and ethical requirements. RESULTS: All cadavers showed a 2-layered arachnoid structure-one belonging to the occipital lobe, and the other to the cerebellum. According to our cadaveric analysis, the arachnoid attachment of the tentorial apex can be peeled bluntly, with an average distance of 10.2 mm. For our clinical presentation, a pineal tumor with hydrocephalus was detected in a 14-year-old boy. While using the OTA and expanding the deep surgical field, we detached the membrane from the tentorial apex and bluntly peeled it to reveal the deep veins. Finally, gross total removal of the tumor was achieved. CONCLUSIONS: A 2-layered arachnoid structure interposes the GVG from above and below the tentorium. The arachnoid membrane below the tentorium can be peeled off bluntly from the GVG to the attachment bundle limited by the penetrating veins. This detachment technique is useful for safe enlargement of the surgical field for the OTA.

DOI： 10.1016/j.wneu.2021.04.041

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Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein-Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease. SIGNIFICANCE: A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5330/F1.large.jpg.

DOI： 10.1158/0008-5472.CAN-20-2425

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Thiel's embalming method provides natural coloration, flexibility, and tissue plasticity, and is used widely to prepare specimens for cadaver surgical training. However, this method causes brain softening, thereby restricting the cadaver surgical training of intra-cranial procedures. In this study, three cadavers were embalmed using formalin fixation, Thiel's embalming method, and Thiel's embalming method with additional intra-cerebral ventricular formalin injection, respectively. We also established rat models of the three embalming methods to develop and determine the best method for retaining adequate brain elasticity. The intra-ventricular formalin injection in the cadaver was performed through the Kocher's point, as in the classical external ventricular drain procedure. Both, the cadaver brains and rat models yielded consistent shear wave measurements and brain surface stiffness data. Notably, the Thiel's embalming method with additional intra-cerebral ventricular formalin injection yielded suitable elasticity for brain cadaver surgical training in terms of brain mobilization and surgical field deployment, and also discharged formaldehyde in undetectable quantities. To our knowledge, this is the first report in which a fixed quality, namely, brain elasticity for the performance of head and brain cadaver surgical training, has been evaluated in a cadaver subjected to the Thiel's embalming method with immersion fixation in the cerebrospinal fluid space. We conclude that the Thiel's embalming method with additional intra-cerebral ventricular formalin injection can maintain the brain elasticity, and may therefore improve the quality of head and brain cadaver surgical training safely and easily.

DOI： 10.1007/s12565-020-00545-z

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OBJECTIVE: This study aimed to clarify the relationship between tumor redox reaction evaluated by Cu-diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) PET/computed tomography (CT) and disease-free survival (DFS) in patients with primary diffuse large B-cell lymphoma of the central nervous system (DLBCL-CNS). METHODS: Fifteen consecutive patients with histologically confirmed DLBCL-CNS underwent preoperative Cu-ATSM PET/CT and F-fluorodeoxyglucose (FDG) PET/CT. Statistical features of seven first-order parameters, including the standardized uptake value (SUV); 12 second-order parameters, including gray-level co-occurrence matrices and gray-level zone size matrices; and 5 high-order parameters, including neighborhood gray-tone difference matrices, were calculated from the volume of interest. We compared DFS with parameters, including SUVmax and tumor-to-background (T/B) ratio of FDG, and SUVmax, T/B ratio, and other textural features of Cu-ATSM. RESULTS: The mean follow-up duration after PET/CT was 458 (range, 41-1071) days. The SUVmax of FDG was significantly higher than that of Cu-ATSM (P = 0.001), but the T/B ratio was not significantly different between the scans (3.49 ± 2.29 vs 2.48 ± 1.18; P = 0.244). A Mantel-Cox log-rank test revealed no significant association between SUVmax of FDG and DFS (P = 0.641). A high SUVmax of Cu-ATSM had a tendency of shorter DFS (P = 0.055). Total lesion reduction, reductive tumor volume, and T/B ratio of Cu-ATSM were significantly correlated with poor DFS by univariate analysis (P = 0.049, 0.031, and 0.007, respectively). Neighborhood gray-level co-occurrence matrix dissimilarity was significantly correlated with poor DFS (P = 0.015). CONCLUSIONS: Metabolic and textural features derived from pretreatment Cu-ATSM PET/CT could be used for predicting DFS and establishing a novel treatment strategy in DLBCL-CNS patients.

DOI： 10.1097/MNM.0000000000001197

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Cortical plasticity is fundamental to motor recovery following cortical perturbation. However, it is still unclear how this plasticity is induced at a functional circuit level. Here, we investigated motor recovery and underlying neural plasticity upon optogenetic suppression of a cortical area for eye movement. Using a visually-guided eye movement task in mice, we suppressed a portion of the secondary motor cortex (MOs) that encodes contraversive eye movement. Optogenetic unilateral suppression severely impaired contraversive movement on the first day. However, on subsequent days the suppression became inefficient and capability for the movement was restored. Longitudinal two-photon calcium imaging revealed that the regained capability was accompanied by an increased number of neurons encoding for ipsiversive movement in the unsuppressed contralateral MOs. Additional suppression of the contralateral MOs impaired the recovered movement again, indicating a compensatory mechanism. Our findings demonstrate that repeated optogenetic suppression leads to functional recovery mediated by the contralateral hemisphere.

DOI： 10.7554/eLife.50855

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Language：Japanese   Publisher：(一社)日本臨床神経生理学会  

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We previously identified a novel nanomagnetic particle, N,N'-bis(salicylidene)ethylenediamine iron [Fe(Salen)]. Fe(Salen) not only shows antitumor effects but also magnetic properties. We found that Fe(Salen) can be used for magnet-guided drug delivery and visualization of accumulated drug by magnetic resonance imaging (MRI) because of its magnetism. In addition, Fe(Salen) can generate heat by itself when exposed to an alternating current magnetic field (AMF), resulting in a hyperthermia effect. Herein, we partly elucidated the antitumor mechanism of Fe(Salen) and carried out an i.v. repeated dose toxicity study to decide the therapeutic amount. Furthermore, we evaluated the antitumor effect of selective intra-arterial injection or i.v. injection of Fe(Salen) by catheter and the hyperthermia effect of Fe(Salen) when exposed to AMF in vivo. We used a rabbit model grafted with VX2 cells (rabbit squamous cell carcinoma) on the right leg. Intra-arterial injection of Fe(Salen) showed a greater antitumor effect than did i.v. injection. The combination of Fe(Salen) intra-arterial injection and AMF exposure showed a greater antitumor effect than did either Fe(Salen) or methotrexate (MTX) without AMF exposure, suggesting that AMF exposure greatly enhanced the antitumor effect of Fe(Salen) by arterial injection by catheter. This is the first report that the effectiveness of Fe(Salen) was evaluated in the point of administration route; that is, selective intra-arterial injection by catheter. Taken together, these results indicate a new administration route; that is, selective arterial injection of Fe(Salen) by catheter, and the development of a new strategy of simultaneous hyperthermia-chemotherapy in the future.

DOI： 10.1111/cas.13851

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Erythropoietin (EPO) is a clinically available hematopoietic cytokine. EPO has shown beneficial effects in the context of spinal cord injury and other neurological conditions. The aim of this study was to evaluate the effect of EPO on a rat model of spinal cord compression-induced cervical myelopathy and to explore the possibility of its use as a pharmacological treatment. METHODS: To develop the compression-induced cervical myelopathy model, an expandable polymer was implanted under the C5-C6 laminae of rats. EPO administration was started 8 weeks after implantation of a polymer. Motor function of rotarod performance and grip strength was measured after surgery, and motor neurons were evaluated with H-E, NeuN and choline acetyltransferase staining. Apoptotic cell death was assessed with TUNEL and Caspase-3 staining. The 5HT, GAP-43 and synaptophysin were evaluated to investigate the protection and plasticity of axons. Amyloid beta precursor protein (APP) was assessed to evaluate axonal injury. To assess transfer of EPO into spinal cord tissue, the EPO levels in spinal cord tissue were measured with an ELISA for each group after subcutaneous injection of EPO. RESULTS: High-dose EPO maintained motor function in the compression groups. EPO significantly prevented the loss of motor neurons and significantly decreased neuronal apoptotic cells. Expression of 5HT and synaptophysin was significantly preserved in the EPO group. APP expression was partly reduced in the EPO group. The EPO levels in spinal cord tissue were significantly higher in the high-dose EPO group than other groups. CONCLUSION: EPO improved motor function in rats with compression-induced cervical myelopathy. EPO suppressed neuronal cell apoptosis, protected motor neurons, and induced axonal protection and plasticity. The neuroprotective effects were produced following transfer of EPO into the spinal cord tissue. These findings suggest that EPO has high potential as a treatment for degenerative cervical myelopathy.

DOI： 10.1371/journal.pone.0214351

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We previously reported the efficacy of anti-cancer therapy with hyperthermia using an alternating magnetic field (AMF) and a magnetic compound. In the course of the study, unexpectedly, we found that an AMF enhances the cytotoxicity of Compound C, an activated protein kinase (AMPK) inhibitor, although this compound is not magnetic. Therefore, we examined the cellular mechanism of AMF-induced cytotoxicity of Compound C in cultured human glioblastoma (GB) cells. An AMF (280 kHz, 250 Arms) for 30 minutes significantly enhanced the cytotoxicity of Compound C and promoted apoptosis towards several human GB cell lines in vitro. The AMF also increased Compound C-induced cell-cycle arrest of GB cells at the G2 phase and, thus, inhibited cell proliferation. The AMF increased Compound C-induced reactive oxygen species production. Furthermore, the AMF decreased ERK phosphorylation in the presence of Compound C and suppressed the protective autophagy induced by this compound. The application of an AMF in cancer chemotherapy may be a simple and promising method, which might reduce the doses of drugs used in future cancer treatment and, therefore, the associated side effects.

DOI： 10.1111/cas.13781

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BACKGROUND: Paragangliomas are generally benign, slow-growing tumors. However, approximately 10%-20% are malignant, characterized by distant metastasis. Recently, a germ line mutation in succinate dehydrogenase B subunit (SDHB) has been shown to be associated with malignant behavior in paraganglioma. Here we present a case of SDHB-negative malignant paraganglioma of the jugular foramen with a pseudohypoxic microenvironment and unique imaging features on [18F]-fluoro-2-deoxy-d-glucose positron emission tomography ([18F]-FDG PET), and discuss the significance of SDHB immunohistochemistry and the potential of [18F]-FDG PET for clinical management. CASE DESCRIPTION: A 55-year-old woman was diagnosed with jugular foramen paraganglioma. Initial surgical resection was performed; however, follow-up [18F]-FDG PET indicated multiple uptake regions throughout the body. Biopsies for multiple recurrent lesions revealed consistent pathological features, suggesting distant metastasis. Immunohistochemical analysis revealed a lack of SDHB immunostaining in all specimens. Pseudohypoxic markers, including hypoxia-inducible factor-1α and downstream glycolysis enzymes, were strongly expressed. [18F]-FDG PET demonstrated increased uptake in the lesions, and the patient died 3 years after initial metastasis. CONCLUSION: In patients with head and neck paraganglioma without SDHB expression, close follow-up should be considered because of the risk for metastasis. In such cases, [18F]-FDG PET might be useful for detecting metastasis due to atypical accumulation from pseudohypoxia-induced glycolysis.

DOI： 10.1016/j.wneu.2018.02.147

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

DOI： 10.1007/s12149-018-1241-4

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DOI： 10.1016/j.wneu.2017.07.016

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Language：English   Publisher：(一社)日本癌学会  

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DOI： 10.1016/j.jphs.2017.07.002

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DOI： 10.1007/s12576-016-0480-1

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Language：Japanese   Publisher：(株)医学書院  

60歳女性。左顔面痙攣を主訴とした。頭部単純MRI/MRAにて左後下小脳動脈(左PICA)による左顔面神経の圧迫所見を認めたため、治療目的に入院となった。左顔面痙攣に対し、異常筋反応モニタリング(AMR)併用下に動脈刺激筋反応モニタリング(AWS-EMG)を行い、術中に異常波形を確認し、微小血管減圧術を施行した。術後AMR、AWS-EMGの異常波形は消失し、顔面痙攣も改善が得られた。

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

DOI： 10.11477/mf.1436203487

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DOI： 10.1038/srep42783

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：(一社)日本脳卒中の外科学会  

Adequate operative field and preservation of perforating arteries is necessary for successful, safe clipping of cerebral aneurysm. However, it is often difficult to avoid multiple perforators adjacent or dorsal to the aneurysm even if they could be separated from the aneurysm. Here, we used a polyglactin mesh (Vicryl mesh®) for aneurysmal clipping surgery. The polyglactin mesh is made of glycolic-lactic acid polyester and can be hydrolyzed within a living body. It is very thin, about 0.1 mm, without being fuzzy, and can be cut freely into any size and shape. Because of its consistency, it can hold dissected perforators off the aneurysm while clipping the neck, thus facilitating safe and successful maneuvers. It can also be retrieved safely and easily because it does not adhere to the surrounding structures. We used them in 45 cases of aneurysm. We could clip the cerebral aneurysms safely while avoiding perforators, other critical arteries, and cranial nerves around the aneurysm. No complications like vasospasm and perforator injuries were noted. Eighty-seven percent of the clipping procedures were accomplished by junior neurosurgeons under the guidance of senior instructors using the polyglactin mesh. This procedure is useful and safe in preserving critical arteries and structures like perforators and cranial nerves around the cerebral aneurysm.

DOI： 10.2335/scs.44.81

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Other Link： https://search.jamas.or.jp/link/ui/2016193880

Language：Japanese   Publisher：The Japanese Society on Surgery for Cerebral Stroke  

The basic procedure of carotid endarterectomy (CEA) has been almost established. However, beginners sometimes have difficulty dissecting the plaque at the same plane and treating the distal end of the plaque, even in typical cases. A simple, safe, and standardized procedure is important for beginners. We use the internal shunt in all cases to secure adequate blood flow and take advantage of the shunt tube as the tool for plaque dissection at the distal end.<br>We introduce our surgical technique and review our procedure from a beginner's point of view. We tack up the skin, muscle, and carotid sheath by using sutures to make wide and shallow operative fields without retractors. We insert the internal shunt tube after arteriotomy. Beginners need to rehearse the tube insertion before the procedure. At the proximal side of the plaque, we connect both sides of the dissection plane across the shunt to secure the same plane.<br>The distal end of the intima of the internal carotid artery (ICA) is fastened by using a shunt tube and tourniquet. The plaque can be easily cut off at the position of the tourniquet. If the plaque remains, we can peel off the plaque remnant like peeling onion skin. A shunt tube is used as the template of the ICA lumen in the distal end.<br>Beginners can easily master these procedures, which can be performed safely without distress, even in high-positioned stenosis. These procedures enable the beginners to accomplish CEA securely.

DOI： 10.2335/scs.44.352

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DOI： 10.1007/s00259-014-2714-x

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DOI： 10.3174/ajnr.A3679

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DOI： 10.1016/j.ijrobp.2012.03.008

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DOI： 10.3171/2012.6.GKS12318

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DOI： 10.1016/j.jocn.2011.06.036

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Language：Japanese   Publisher：(一社)日本臨床神経生理学会  

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DOI： 10.2335/scs.46.58

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Language：Japanese   Publisher：一般社団法人 日本脳卒中の外科学会  

We report herein five cases of symptomatic brainstem cavernous malformations (CM). Specific surgical approaches were designed to directly access each lesion. Neuronavigation and intraoperative monitoring were used. Four lesions underwent gross total resection, and one was subtotally partially removed. None of the patients developed new neurological deficits and all cases showed an improvement based on the modified Rankin Scale and the Karnofsky Performance Status. Although brainstem CM have a relatively high rate of re-bleeding, thus adversely affecting the neurological status of the patient, recent reports have demonstrated favorable outcomes after their resection. Hence, surgical removal can be recommended for cases of symptomatic brainstem CM, particularly those with re-bleeding. An optimal surgical approach, providing direct access to the lesion, is critical for successfully resecting brainstem CM.

DOI： 10.2335/scs.46.58

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Language：English   Publishing type：Research paper, summary (international conference)  

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DOI： 10.1158/1538-7445.AM2015-4371

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Language：English   Publishing type：Research paper, summary (international conference)  

DOI： 10.1158/1538-7445.AM2015-4548

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DOI： 10.1158/1538-7445.AM2015-4398

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Language：English   Publishing type：Research paper, summary (international conference)  

DOI： 10.1158/1538-7445.AM2014-5399

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Language：Japanese   Publisher：(株)メディカ出版  

穿頭血腫ドレナージ術を施行した109例のうち再発した11例(男8例、女3例、年齢51〜91歳)を対象に、再発に影響を及ぼす因子について多変量解析を用いて検討した。11例中6例に先行する頭部打撲があり、抗血栓・凝固薬使用では抗凝固薬1例、高血圧あり2例、糖尿病あり2例であった。その結果、「手術翌日の残存空気が1/4(25%)以上」と「1週間後の脳の膨張率が悪い」のみが有意な因子であった。年齢、性別、先行する頭部打撲、抗血栓・凝固療法の有無、高血圧・糖尿病の既往については再発因子としては有意ではなかった。また、手術翌日に残存空気が25%以上ある群は、残存空気が少ない群と比較して優位に1週間後の脳の膨張率が悪い結果となった。

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Language：Japanese   Publisher：(株)癌と化学療法社  

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