Development of extended pharmacokinetic models for propofol based on measured blood and brain concentrations.

Propofol's pharmacokinetics have been extensively studied using human blood samples and applied to target-controlled infusion systems; however, information on its concentration in the brain remains scarce. Therefore, this study aimed to simultaneously measure propofol plasma and brain concentrations in patients who underwent awake craniotomy and establish new pharmacokinetic model. Fifty-seven patients with brain tumors or brain lesions who underwent awake craniotomy were sequentially assigned to model-building and validating groups. Plasma and brain (lobectomy or uncapping margins) samples were collected at five time-points. The concentration of propofol was measured using high-performance liquid chromatography. Population pharmacokinetic analysis was conducted through a nonlinear mixed-effects modeling program using a first-order conditional estimation method with interactions. Propofol's brain concentrations were higher than its plasma concentrations. The measured brain concentrations were higher than the effect site concentrations using the previous models. Extended models were constructed based on measured concentrations by incorporating the brain/plasma partition coefficient (Kp value). Extended models showed good predictive accuracy for brain concentrations in the validating group. The Kp value functioned as a factor explaining retention in the brain. Our new pharmacokinetic models and Kp value can predict propofol's brain and plasma concentrations, contributing to safer and more stable anesthesia.

Irreversible postoperative cognitive impairment after unruptured intracranial aneurysm treatment in the elderly.

PURPOSE: Postoperative cognitive dysfunction and recovery remain unclear in older patients undergoing interventional therapies for unruptured intracranial aneurysms (UIAs). This study aimed to compare changes in postoperative cognitive function between younger and older patients and to detect factors associated with non-recovery from postoperative cognitive dysfunction. METHODS: This study reviewed 59 consecutive patients with UIAs who underwent interventional therapies, including microsurgical clipping or endovascular treatment, from 2021 to 2022. All patients were divided into the older (aged ≥ 70 years) and younger (aged < 70 years) groups. Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) were performed within 2 months before interventions, at 1 week postoperatively (POW1), and 3-6 months postoperatively (POM3-6). RESULTS: MMSE and FAB scores decreased more frequently in the older group than in the younger group at POW1 (older vs. younger: MMSE: 48% vs. 21%, p < 0.05; FAB: 56% vs. 18%, p < 0.01). In the older group, the FAB Z-score decreased in POW1 and recovered by POM3-6 (p < 0.01), while the MMSE Z-score continued to decrease (p = 0.04). Age and the preoperative MSME Z-score were significantly associated with non-recovery from decreased MMSE score at POM3-6 (recovery vs. non-recovery, age: 62 years old vs. 72 years old, p = 0.03, preoperative MMSE Z-score: 0.16 vs. - 0.90, p < 0.01). CONCLUSIONS: This retrospective study found that older patients were more likely to have a postoperative cognitive decline after UIA treatment and implicated that global cognitive function tended to decline more than executive function in the long term. In addition, this study demonstrated that lower preoperative cognitive function was associated with inadequate postoperative cognitive recovery. The findings potentially contribute to the establishment of indications for treating UIAs in older patients.

Seizure control by adding on other anti-seizure medication on seizure during levetiracetam administration in patients with glioma-related epilepsy.

BACKGROUND: Epilepsy is a major symptom in patients with glioma. Levetiracetam (LEV) is recognized as a first-line treatment for glioma-related epilepsy. Increasing the LEV dose is allowed into patients with seizure occurrence against its initial dose. However, the therapeutic efficacy of increasing the LEV dose in response to seizure occurrence remains unclear. METHODS: We retrospectively analyzed 236 glioma patients who were treated with antiseizure medications (ASMs) internally at our institute between September 2010 and December 2017. Of these, the analysis focused on 156 patients treated with LEV who had a clear history of administration. RESULTS: Seizure occurrences were observed in 21 of 75 patients (26.7%) who received LEV as first-line therapy and in 33 of 81 patients (40.7%) who received LEV as non-first-line treatment. The seizure control rate for seizure occurrence with LEV as first-line treatment was significantly higher in patients treated with addition of other ASMs (72.7%) than in those treated with increasing dose of LEV (20.0%) (p = 0.016). The seizure control rate for seizure occurrence with LEV as non-first-line treatment did not differ significantly between patients with addition of other ASMs (58.3%) and those treated with increasing dose of LEV (47.6%) (p = 0.554). CONCLUSIONS: Adding other ASMs was more effective than increasing the LEV dose for seizure control in patients treated with LEV as first-line treatment, but they demonstrated comparable efficacy in patients treated with LEV as non-first-line treatment.

Impact of Morphological Factors on the Future Growth of Unruptured Posterior Communicating Artery Aneurysms.

BACKGROUND: No previous study has established the factors associated with intracranial aneurysm growth using imaging data obtained before the appearance of morphological changes. Therefore, we investigated the factors related to future aneurysm growth in posterior communicating artery (Pcom) aneurysms. METHODS: Using a longitudinal database of intracranial aneurysm cases, we reviewed the findings for consecutive patients with unruptured Pcom aneurysms admitted to our institute from 2012 to 2021. Magnetic resonance images obtained over time were used to evaluate aneurysm growth. Aneurysms showing growth over time (group G) and unchanged aneurysms (group U) were compared in terms of background data and morphological factors. RESULTS: 93 Pcom aneurysms (group G: 25 aneurysms, 25%; group U: 68 aneurysms, 75%) were eligible for the present study. Six aneurysm rupture events occurred in group G (24%). Among morphological factors, Pcom diameter (1.2 ± 0.3 mm vs. 0.8 ± 0.7 mm, P < 0.01), bleb formation (group G: 39% vs. group U: 10%; odds ratio, 5.6; P = 0.01), and the lateral projection of the dome (group G: 52% vs. group U: 13%; odds ratio, 3.2; P = 0.023) were significantly different between the 2 groups. The sensitivity and specificity of a cutoff Pcom diameter of 0.73 mm for predicting enlargement were 96% and 53%, respectively. CONCLUSIONS: Pcom diameter, bleb formation, and lateral dome projection were associated with growth of Pcom aneurysms. Aneurysms with these risk factors require careful follow-up imaging, which may facilitate early detection of aneurysm growth and prevention of rupture through therapeutic interventions.

RUNX1-Survivin Axis Is a Novel Therapeutic Target for Malignant Rhabdoid Tumors.

Malignant rhabdoid tumor (MRT) is a highly aggressive pediatric malignancy with no effective therapy. Therefore, it is necessary to identify a target for the development of novel molecule-targeting therapeutic agents. In this study, we report the importance of the runt-related transcription factor 1 (RUNX1) and RUNX1-Baculoviral IAP (inhibitor of apoptosis) Repeat-Containing 5 (BIRC5/survivin) axis in the proliferation of MRT cells, as it can be used as an ideal target for anti-tumor strategies. The mechanism of this reaction can be explained by the interaction of RUNX1 with the RUNX1-binding DNA sequence located in the survivin promoter and its positive regulation. Specific knockdown of RUNX1 led to decreased expression of survivin, which subsequently suppressed the proliferation of MRT cells in vitro and in vivo. We also found that our novel RUNX inhibitor, Chb-M, which switches off RUNX1 using alkylating agent-conjugated pyrrole-imidazole polyamides designed to specifically bind to consensus RUNX-binding sequences (5'-TGTGGT-3'), inhibited survivin expression in vivo. Taken together, we identified a novel interaction between RUNX1 and survivin in MRT. Therefore the negative regulation of RUNX1 activity may be a novel strategy for MRT treatment.

A RUNX-targeted gene switch-off approach modulates the BIRC5/PIF1-p21 pathway and reduces glioblastoma growth in mice.

Glioblastoma is the most common adult brain tumour, representing a high degree of malignancy. Transcription factors such as RUNX1 are believed to be involved in the malignancy of glioblastoma. RUNX1 functions as an oncogene or tumour suppressor gene with diverse target genes. Details of the effects of RUNX1 on the acquisition of malignancy in glioblastoma remain unclear. Here, we show that RUNX1 downregulates p21 by enhancing expressions of BIRC5 and PIF1, conferring anti-apoptotic properties on glioblastoma. A gene switch-off therapy using alkylating agent-conjugated pyrrole-imidazole polyamides, designed to fit the RUNX1 DNA groove, decreased expression levels of BIRC5 and PIF1 and induced apoptosis and cell cycle arrest via p21. The RUNX1-BIRC5/PIF1-p21 pathway appears to reflect refractory characteristics of glioblastoma and thus holds promise as a therapeutic target. RUNX gene switch-off therapy may represent a novel treatment for glioblastoma.

Chlorambucil-conjugated PI-polyamides (Chb-M'), a transcription inhibitor of RUNX family, has an anti-tumor activity against SHH-type medulloblastoma with p53 mutation.

Malignancy of medulloblastoma depends on its molecular classification. Sonic Hedgehog (SHH)-type medulloblastoma with p53 mutation was recognized as one of the most aggressive types of tumors. We developed a novel drug, chlorambucil-conjugated PI-polyamides (Chb-M'), which was designed to compete with the RUNX consensus DNA-binding site. Chb-M' specifically recognizes this consensus sequence and alkylates it to inhibit the RUNX transcriptional activity. In-silico analysis showed all the RUNX families were upregulated in the SHH-type medulloblastoma. Thus, we tested the anti-tumor effects of Chb-M' in vitro and in vivo using Daoy cell lines, which belong to SHH with p53 mutation. Chb-M' inhibited tumor growth of Daoy cells by inducing apoptosis. The same inhibitory effect was also observed by knocking down of RUNX1 or RUNX2, but not RUNX3. Apoptosis array analysis showed that Chb-M' treatment induced phosphorylation of p53 serine 15 residues. In a subcutaneous tumor model, intratumoral injection of Chb-M' induced tumor growth retardation. Chb-M' mediated inhibition of RUNX1 and RUNX2 can be a novel therapeutic strategy for SHH-type medulloblastoma with p53 mutation.

Factors associated with somnolence during brain function mapping in awake craniotomy.

Somnolence during brain function mapping is one of the factors that inhibit the accomplishment of the goals of awake craniotomy. We examined the effect of anesthesia depth measured by bispectral index (BIS) during pre-awake phase on somnolence during brain function mapping and also explored the factors associated with somnolence. We examined the association between BIS values during pre-awake phase and somnolence during the first 30 min of brain function mapping in 55 patients who underwent awake craniotomy at Kyoto University Hospital from 2015 to 2018. The pre-awake BIS value was defined as the mean BIS value for 60 min before the removal of the airway. Somnolence during brain function mapping was the primary outcome, defined as either of the following conditions: inability to follow up, disorientation, or inability to assess speech function. Additionally, we compared patient or perioperative variables between patients with/without somnolence. Somnolence occurred in 14 patients (25.5%), of which 6 patients (10.9%) were unable to complete brain function mapping. There was no significant difference in the pre-awake BIS value between patients with/without somnolence (median: 46 vs. 49, P = 0.192). Somnolence was not significantly associated with age, gender, and the number of preoperative anticonvulsive drugs, but patients with somnolence had a significantly lower preoperative Western Aphasia Battery (WAB) aphasia quotient score (median 93.8 vs. 98.6, P = 0.011). We did not find an association between pre-awake BIS value and somnolence during brain function mapping. Somnolence likely occurs in patients with a low preoperative WAB aphasia quotient score.