Oligodendroglioma, IDH-mutant and 1p/19q-codeleted-prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted is known for their relative chemosensitivity and indolent clinical course among diffuse gliomas of adult type. Based on the data from phase 3 clinical trials, the standard of post-surgical care for those tumors is considered to be initial chemoradiotherapy regardless of histopathological grade, particularly with PCV. However, partly due to its renewed definition in late years, prognostic factors in patients with those tumors are not well established. Moreover, the survival rate declines over 15 years, with only a 37% OS rate at 20 years for grade 3 tumors, even with the current standard of care. Given that most of this disease occurs in young or middle-aged adults, further improvements in treatment and management are necessary. Here, we discuss prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy in those tumors.

Prevention of Cerebrospinal Fluid Leakage in the Anterior Transpetrosal Approach.

Background: The anterior transpetrosal approach (ATPA) is effective for reaching petroclival lesions, and it allows for complications such as impaired venous return and neuropathy to be resolved. However, there is still room for improvement regarding cerebrospinal fluid (CSF) leakage. Here, we aim to focus on describing specific preoperative, intraoperative, and postoperative countermeasures for preventing CSF leakage when using the ATPA. Methods: Eleven patients treated using the ATPA, who were treated at our hospital from June 2019 to February 2023, were included in this descriptive study. Preoperatively, we performed a 3D simulation of the opened air cells. Then, we classified patterns of dural closure into three types based on intradural manipulation and whether it involved opened air cells or not. Intraoperatively, we performed a dural closure that included the use of more-watertight sutures (DuraGen®) and an endoscope. Furthermore, temporal bone air cell volume measurements were performed to confirm the correlation between the volume and factors related to CSF leakage. Results: No postoperative CSF leakage was observed in any patient. The temporal bone air cell volumes significantly corelated with the air cells of the petrous apex, the high-risk tract in the petrous apex, and postoperative fluid collection in mastoid air cells. Conclusions: We have described countermeasures for preventing CSF leakage when using the ATPA. Preoperative simulations and the use of multiple-layered dural reconstructions with endoscopes could be considered more reliable methods for preventing CSF leakage when using the ATPA.

Prevalence of Psychotropic Medication Use and Psychotropic Polypharmacy in Autistic Adults With or Without Intellectual Disability.

The aim of this study was to compare the rates of psychotropic medication use and psychotropic polypharmacy between autistic adults with and without intellectual disability (ID) and to examine factors associated with psychotropic medication use and psychotropic polypharmacy in autistic adults, stratified by the presence of ID. We conducted a retrospective medical chart review of outpatients with an autism diagnosis aged 18 years and older. The rates of psychotropic medication use and psychotropic polypharmacy were compared between autistic adults with and without ID. Subsequently, logistic regression analyses were performed to identify factors associated with psychotropic medication use and psychotropic polypharmacy in autistic adults with ID and those without ID, respectively. The rates of prevalence of psychotropic medication use and polypharmacy were significantly higher in participants with ID than those without ID (78.6% vs. 58.8% and 49.3% vs. 31.2%; p-values < 0.05). Age, gender, race, residence, presence of mood disorders, presence of schizophrenia, absence of anxiety disorder, number of psychiatric comorbidities, and presence of behaviors that challenge were significantly associated with these outcomes, depending on the presence/absence of ID. The need to optimize pharmacotherapy in autistic adults, stratifying by the presence of ID, is highlighted.

Anterior transpetrosal approach and the tumor removal rate, postoperative neurological changes, and complications: experience in 274 cases over 33 years.

OBJECTIVE: The authors report on the anterior transpetrosal approach (ATPA) and the results of surgeries performed over a 33-year period for petroclival tumors, including meningioma, trigeminal schwannoma, chordoma, and epidermoid tumor. They analyze early postoperative neurological changes, surgical complications, and trends over the decades. METHODS: A retrospective analysis of 274 surgical cases that had undergone the ATPA from January 1984 to March 2017 was conducted. Data were collected from charts, clinical summaries, operative records, and operative videos. The analyzed parameters included patient diagnosis, tumor size, disease location, operation date, tumor removal rate, pre- and postoperative neurological symptoms (consciousness level, motor and sensory deficits of the limbs, sensory aphasia, and cranial nerve III-VIII injuries), surgical deaths, and radiologically recognized brain injuries after the operation (contusion, infarction, hemorrhage). RESULTS: Gross-total resection (GTR) was achieved in 53.5% of the 243 tumors with available data. The GTR rate for meningiomas (148 cases) was 54.1%. Trigeminal schwannomas had a high GTR rate of 87.1%, whereas chordomas had a low GTR rate of 14.3%. The rate of early neurological deterioration immediately after the ATPA, referred to as "early neurological change," was as follows: consciousness disturbance in 1.9% of cases (5 cases), improvement of hemiparesis in 45.0% of cases but deterioration in 8.1% of cases, sensory aphasia in 2.3% of cases due to temporal lobe injury, improvement of cerebellar symptoms in 39.3% of cases with rare deterioration (1.9% of cases), worsening of preoperative diplopia in 49.4% of patients and rarely improving, improvement of trigeminal symptoms in 19.1% of cases (mostly trigeminal neuralgia) among the 43.7% of patients who had them preoperatively, and deterioration of facial hypesthesia and/or paresthesia in 27.4% of cases. Early neurological deterioration was monitored in 183 patients for 6 months to determine the surgical complications of ATPA. Consciousness disturbance recovered in half of the cases but persisted in 3 (1.5%). Hemiparesis fully recovered in 63.2% of cases, resulting in a complication rate of 3.0%. The most frequent complication was diplopia (36.4%), with a complete remission rate of 26.4%. The second most frequent complication was facial hypesthesia (24.0%), with a recovery rate of 16.1%. Facial nerve palsy improved in 63.0% of cases and had a complication rate of 4.9%. Cerebellar symptoms showed complete recovery in all cases. CONCLUSIONS: The ATPA allows the removal of petroclival tumors extending into Meckel's cave and the middle fossa, making it preferred for dumbbell trigeminal schwannomas and meningiomas. However, the ATPA's aggressive tumor removal can risk a lower recovery of cranial nerve IV-VI deficits. For benign meningiomas, initial observation with regular follow-up is recommended. Surgery is appropriate for high-growth cases aiming for total removal, accompanied by a thorough explanation of the risks. If the risks are not accepted, subtotal removal can be considered, and radiosurgery is suggested for residual tumor.

Transcranial magnetic stimulation neurophysiology in patients with non-Alzheimer's neurodegenerative diseases: A systematic review and meta-analysis.

Non-Alzheimer's dementia (NAD) accounts for 30% of all neurodegenerative conditions and is characterized by cognitive decline beyond mere memory dysfunction. Diagnosing NAD remains challenging due to the lack of established biomarkers. Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological tool that enables the investigation of cortical excitability in the human brain. Paired-pulse TMS paradigms include short- and long-interval intracortical inhibition (SICI/LICI), intracortical facilitation (ICF), and short-latency afferent inhibition (SAI), which can assess neurophysiological functions of GABAergic, glutamatergic, and cholinergic neural circuits, respectively. We conducted the first systematic review and meta-analysis to compare these TMS indices among patients with NAD and healthy controls. Our meta-analyses indicated that TMS neurophysiological examinations revealed decreased glutamatergic function in patients with frontotemporal dementia (FTD) and decreased GABAergic function in patients with FTD, progressive supranuclear palsy, Huntington's disease, cortico-basal syndrome, and multiple system atrophy-parkinsonian type. In addition, decreased cholinergic function was found in dementia with Lewy body and vascular dementia. These results suggest the potential of TMS as an additional diagnostic tool to differentiate NAD.

Efficacy and moderators of prevention and treatment of delirium with melatonin receptor agonists: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Delirium is a complex and heterogeneous condition that significantly affects patient outcome. This study aimed to conduct a systematic review and meta-analysis to investigate the effects of melatonin and melatonin receptor agonists (MRAs) on delirium prevention and treatment. METHOD: Randomized controlled studies, using MRAs as an intervention and placebo as a control were included. We conducted meta-analyses with random-effects model and trial sequential analysis. RESULTS: A total of 33 studies involving 4850 participants were included. The meta-analysis revealed a significant preventive effect of MRAs on delirium (risk ratio = 0.65, p < 0.01), while no significant therapeutic effect was observed. Additionally, MRAs were associated with a significant reduction in mortality rate (risk ratio = 0.90, p = 0.02) in delirium prevention studies. Furthermore, subgroup analyses revealed that assessment scales and the frequency of delirium detection may be significant moderators of the delirium-preventive efficacy of MRAs. CONCLUSION: This study provides evidence of the potential effects of MRAs in preventing delirium and reducing mortality. Further research is required to elucidate the therapeutic potential of MRAs for delirium and identify specific patient populations that may benefit from this agent.

Gene therapy using genome-edited iPS cells for targeting malignant glioma.

Glioblastoma is characterized by diffuse infiltration into the normal brain. Invasive glioma stem cells (GSCs) are an underlying cause of treatment failure. Despite the use of multimodal therapies, the prognosis remains dismal. New therapeutic approach targeting invasive GSCs is required. Here, we show that neural stem cells (NSCs) derived from CRISRP/Cas9-edited human-induced pluripotent stem cell (hiPSC) expressing a suicide gene had higher tumor-trophic migratory capacity compared with mesenchymal stem cells (MSCs), leading to marked in vivo antitumor effects. High migratory capacity in iPSC-NSCs was related to self-repulsive action and pathotropism involved in EphB-ephrinB and CXCL12-CXCR4 signaling. The gene insertion to ACTB provided higher and stable transgene expression than other common insertion sites, such as GAPDH or AAVS1. Ferroptosis was associated with enhanced antitumor immune responses. The thymidylate synthase and dihydroprimidine dehydrogenase expressions predicted the treatment efficacy of therapeutic hiPSC-NSCs. Our results indicate the potential benefit of genome-edited iPS cells based gene therapy for invasive GSCs. Furthermore, the present research concept may become a platform to promote clinical studies using hiPSC.

Psychiatric manifestations of Kleefstra syndrome: a case report.

Background: Kleefstra syndrome is a rare genetic condition, which affects at least 1 in 120,000 individuals who have a neurodevelopmental disorder, characterized by the core clinical phenotype of intellectual disability, hypotonia, severe speech delay, and distinct facial characteristics with additional clinical features including sleep disturbance, overweight, psychiatric disorders, and autism spectrum disorder. To date, a limited number of case reports of Kleefstra syndrome with psychiatric manifestations have been reported. Case presentation: We reported a case of a 35-year-old male diagnosed with Kleefstra syndrome, who also had diagnoses of autism spectrum disorder and moderate to severe intellectual disability. He exhibited various psychiatric manifestations, including temporarily manic-like symptoms, excessive eating/overweight, addictive/gambling behaviors, inappropriate and unsafe internet use, sleep disturbance, rigid routines, and behaviors that challenged in the form of meltdowns. These symptoms were eventually relatively successfully managed with a combination of non-pharmacological and pharmacological treatments. Conclusion: To our knowledge, there is only a limited number of case reports that detail patients with Kleefstra syndrome exhibiting various psychiatric manifestations. Our report adds further knowledge to the paucity of literature and highlights the effectiveness of a combination of non-pharmacological and pharmacological treatments for behavioral/psychiatric difficulties in Kleefstra syndrome.

Polygenic risk scores analyses of psychiatric and metabolic traits with antipsychotic-induced weight gain in schizophrenia: an exploratory study.

Given the polygenic nature of antipsychotic-induced weight gain (AIWG), we investigated whether polygenic risk scores (PRS) for various psychiatric and metabolic traits were associated with AIWG. We included individuals with schizophrenia (SCZ) of European ancestry from two cohorts (N = 151, age = 40.3 ± 11.8 and N = 138, age = 36.5 ± 10.8). We investigated associations of AIWG defined as binary and continuous variables with PRS calculated from genome-wide association studies of body mass index (BMI), coronary artery disease (CAD), fasting glucose, fasting insulin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, type 1 and 2 diabetes mellitus, and SCZ, using regression models. We observed nominal associations (uncorrected p < 0.05) between PRSs for BMI, CAD, and LDL-C, type 1 diabetes, and SCZ with AIWG. While results became non-significant after correction for multiple testing, these preliminary results suggest that PRS analyses might contribute to identifying risk factors of AIWG and might help to elucidate mechanisms at play in AIWG.

Simplified anterior transpetrosal approach without superior petrosal sinus and tentorial incision for lesions centered in Meckel's cave.

OBJECTIVE: The anterior transpetrosal approach (ATPA) is an effective method to reach lesions in the petroclival region. This approach involves many steps, including superior petrosal sinus (SPS) ligation and tentorial cutting. It is sometimes unnecessary to perform all procedures in the ATPA for certain lesions, especially those centered in the Meckel's cave. Here, we present a simplified anterior transpetrosal approach (SATPA) without superior petrosal sinus and tentorial incision for lesions centered in the Meckel's cave as a modified ATPA. METHODS: This study included 13 patients treated with SATPA. The initial steps of SATPA are similar to ATPA, excluding a middle cranial fossa dural incision, SPS dissection, or tentorial incision. Histological examination was performed to understand the membrane structure of the trigeminal nerve, which runs through the Meckel's cave. RESULTS: Pathology revealed trigeminal schwannoma (n=11), extraventricular central neurocytoma (n=1), and a metastatic tumor (n=1). The average tumor size was 2.4 cm. The total removal rate was 76.9% (10/13). Permanent complications included trigeminal neuropathy in four cases and cerebrospinal fluid leakage in one case. Histological examination revealed the trigeminal nerve traverses the subarachnoid space from the posterior fossa subdural space to the Meckel's cave and is covered with the epineurium in the inner reticular layer. CONCLUSIONS: We used SATPA for lesions located in the Meckel's cave identified using histological examination. This approach may be considered for small- to medium-sized lesions centered in the Meckel space. CLINICAL TRIAL REGISTRATION NUMBER: None.

Clinical, histopathological and molecular risk factors for recurrence of pilocytic astrocytomas: brainstem/spinal location, nestin expression and gain of 7q and 19 are associated with early tumor recurrence.

Pilocytic astrocytomas (PAs) are benign tumors. However, clinically aggressive PAs despite benign histology have been reported, and histological and molecular risk factors for prognosis have not been elucidated. 38 PAs were studied for clinical, histological, and molecular factors, including tumor location, extent of resection, post-operative treatment, glioma-associated molecules (IDH1/2, ATRX, BRAF, FGFR1, PIK3CA, H3F3A, p53, VEGF, Nestin, PD-1/PD-L1), CDKN2A/B deletion, and chromosomal number aberrations, to see if there is any correlation with patient's progression-free survival (PFS). Brainstem/spinal location, extent of resection and post-operative treatment, and VEGF-A, Nestin and PD-L1 expression, copy number gain of chromosome 7q or 19, TP53 mutation were significantly associated with shorter PFS. None of the histological parameters was associated with PFS. Multivariate analyses demonstrated that high Nestin expression, gain of 7q or 19, and extent of removal were independently predictive for early tumor recurrence. The brainstem/spinal PAs appeared distinct from those in the other sites in terms of molecular characteristics. Clinically aggressive PAs despite benign histology exhibited high Nestin expression. Brainstem/spinal location, extent of resection and some molecular factors including Nestin expression and gains of 7q and 19, rather than histological parameters, may be associated with early tumor recurrence in PAs.

Glutamatergic Neurometabolite Levels in Bipolar Disorder: A Systematic Review and Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies.

BACKGROUND: The glutamatergic system is thought to play an important role in the pathophysiology of bipolar disorder (BD). While there has been an increase in proton magnetic resonance spectroscopy studies examining this neurotransmission system, the results are inconsistent. Possible reasons for the inconsistency, including clinical features such as mood state and childhood versus adulthood age, were not addressed in previous meta-analyses. METHODS: This systematic review and meta-analysis of proton magnetic resonance spectroscopy studies of BD included 40 studies, with 1135 patients with BD and 964 healthy control (HC) subjects. RESULTS: Glutamate plus glutamine and glutamine levels in the anterior cingulate cortex of patients with BD were significantly elevated compared with those of HC subjects (standardized mean difference = 0.42, 0.48, respectively). Subgroup analyses showed that adult BD patients had significantly higher levels of glutamate plus glutamine than adult HC subjects, but this was not the case in pediatric patients. For mood states, anterior cingulate cortex glutamate plus glutamine levels were higher in patients with bipolar depression than those in HC subjects. CONCLUSIONS: Our results imply that glutamatergic dysfunction in the anterior cingulate cortex may be implicated in the pathophysiology of BD, which is most evident in adult BD patients and patients with bipolar depression.

Changes in spike protein antibody titer over 90 days after the second dose of SARS-CoV-2 vaccine in Japanese dialysis patients.

OBJECTIVES: There is no report on antibody titers after vaccination against SARS-CoV-2 in Japanese dialysis patients. As dialysis is different between Japan and other countries, changes in antibody titers were examined. METHODS: Baseline characteristics and anti-spike protein antibody titers (Roche) over 90 days after administration of the BNT162b2 messenger RNA vaccine were investigated in dialysis patients. RESULTS: The maximum anti-spike protein antibody titer after the second dose was 738 (327 to 1143) U/mL and was reached at 19 (17 to 24) days after the second dose. Antibody titers decreased over time, with titers of 770 (316 to 1089) U/mL at 15 days, 385 (203 to 690) U/mL at 30 days, 254 (138 to 423) U/mL at 60 days, and 208 (107 to 375) U/mL at 90 days after the second dose. When an antibody titer of 137 U/mL was assumed to be a measure related to breakthrough infection, the proportion of subjects with antibody titers exceeding this level was 90.1% at 15 days, 85.3% at 30 days, 75.0% at 60 days, and 65.4% at 90 days after the second dose. When a decrease in antibody titers below the assumed breakthrough level was defined as an event, subjects with a pre-dialysis albumin ≥ 3.5 g/dL were significantly less likely to experience an event than subjects with a pre-dialysis albumin < 3.5 g/dL. CONCLUSIONS: The presence of anti-spike protein levels ≥ 313 U/mL at 30 days after the second vaccine dose might be a factor in maintaining enough antibody titers at 90 days after. Whether an additional vaccine dose is needed should be determined based on indicators serving as factors in maintaining antibody titers as well as the status of the spread of infection.

Establishment of an oral squamous cell carcinoma cell line expressing vascular endothelial growth factor a and its two receptors.

Background/purpose: Vascular endothelial growth factor receptor (VEGFR) expression in oral squamous cell carcinoma (OSCC) promotes tumor growth through both autocrine and paracrine signaling. VEGF-positive OSCC cases are associated with a high depth of invasion, increased metastasis, and poor prognosis. In this study we established and then molecularly and functionally analyzed an OSCC cell line that co-expresses VEGF-A, VEGFR-1, and VEGFR-2, termed HCM-SqCC010 cells. Materials and methods: VEGF-A, VEGFR-1, and VEGFR-2 expression in HCM-SqCC010 cells were examined by immunohistochemistry and immunoblotting. Expression and inhibition of VEGF-A, VEGFR-1, and VEGFR-2 in HCM-SqCC010 cells were verified by quantitative real-time PCR. Results: Our analysis of HCM-SqCC010 cells revealed that their proliferation depended on VEGF-A, and selective inhibition of VEGFR-1 or VEGFR-2 resulted in decreased cell growth. Conclusion: We established an OSCC cell line, HCM-SqCC010, that expresses VEGF-A, VEGFR-1, and VEGFR-2. This triple-positive cell line showed no effect from a molecular targeted drug toward VEGF-A, but it did show strong cell growth inhibition in response to a VEGFR inhibitor. Thus, new therapeutic strategies against OSCC should include a VEGFR inhibitor.

A nationwide registry study: The 5-factor modified frailty index of meningioma surgery in non-elderly and elderly patients.

OBJECTIVES: The simplified 5-factor modified frailty index (mFI-5) is a useful indicator of outcome for patients undergoing surgeries as frailty is considered an important risk factor in elderly patients. However, its usefulness has not been validated based on age groups. Therefore, we aimed to investigate risk factors, including the mFI-5, across age groups for complications and worse outcomes in meningioma surgery using data obtained from the nationwide database in Japan. METHODS: We extracted data from the nationwide registry database in Japan between 2010 and 2015. Age (< 65, 65-74, and ≥ 75 years), sex, Barthel Index (BI), mFI-5 scores, and complications were evaluated. Multivariate logistic regression analyses identified risk factors for worsening BI scores and complications after surgery across all age groups. RESULTS: Among 8138 included patients, an mFI-5 score ≥ 2 items was a significant risk factor for worsening BI scores in patients aged < 65 years (odds ratio: 2.3; 95 % confidence interval: 1.5-3.4), but not in patients aged 65-74 years and those aged ≥ 75 years, contrary to chronological age. Similar results were noted for any complications in patients aged < 65 years (2.5; 1.8-3.6) and aged 65-74 years (1.5; 1.1-2.1), but not in patients aged ≥ 75 years. CONCLUSION: Although the mFI-5 scores could predict the risk of in-hospital worsening outcomes, mortality, and complications, it was more useful in non-elderly patients aged < 65 years rather than in elderly patients aged ≥ 75 years, contrary to chronological age. Further prospective studies should be performed in the future to clarify the utility of the mFI-5.

Meningiomas Involving the Hypoglossal Canal: A Case Report and Literature Review.

We report a rare case of hypoglossal canal meningioma in a 65-year-old woman who presented with dysphagia. Neurological examination revealed left hypoglossal nerve palsy. Head computed tomography and magnetic resonance imaging revealed a lesion around the left hypoglossal canal. She underwent a total resection with a midline suboccipital transcondylar approach. There were no postoperative complications, and the hypoglossal nerve palsy improved. There was no recurrence nine months after the surgery. Choosing a surgical approach that considers the site of origin and extent of tumor extension is important.

[The Anterior Transpetrosal Approach].

The Anterior transpetrosal approach is a skull base surgical procedure that can provide a wide operative view of the petroclival and the prepontine region. This approach requires one to accurately understand the anatomy of the anterior part of the temporal bone and the histological structure of the dura mater. In addition, it is necessary to learn operative techniques for venous preservation, accurate hemostasis at each step, and prevention of cerebrospinal fluid leakage. In this article, the anatomy and surgical techniques that are required for a beginner to master the anterior transpetrosal approach are explained step by step.