Endoscopic Evacuation of Acute Subdural Hematomas: A New Selection Criterion.

Introduction Acute subdural hematomas (ASDHs) have a high mortality rate and unfavorable outcomes especially in the elderly population even after surgery is performed. The conventional recommended surgeries by the Brain Trauma Foundation in 2006 were craniotomies or craniectomies for ASDH. As the world population ages, and endoscopic techniques improve, endoscopic surgery should be utilized to improve the outcomes in elderly patients with ASDH. Materials and Methods This was a single-center retrospective report on our series of six patients that underwent endoscopic ASDH evacuation (EASE). Demographic data, the contralateral global cortical atrophy (GCA) score, evacuation rates, and outcomes were analyzed. Results All patients' symptoms and Glasgow Coma Scale improved or were similar after EASE with no complications. Good outcome was seen in 4 (66.7%) patients. Patients with poor outcome had initial low Glasgow Coma Scale scores on admission. The higher the contralateral GCA score, the higher the evacuation rate ( r = 0.825, p ≤ 0.043). All the patients had a GCA score of ≥7. Conclusion EASE is at least not inferior to craniotomy for the elderly population in terms of functional outcome for now. Using the contralateral GCA score may help identify suitable patients for this technique instead of just using a cut-off age as a criteria.

C-X-C domain ligand 14-mediated stromal cell-macrophage interaction as a therapeutic target for hand dermal fibrosis.

Dupuytren's contracture, a superficial dermal fibrosis, causes flexion contracture of the affected finger, impairing hand function. Specific single-nucleotide polymorphisms within genes in the Wnt signalling pathway are associated with the disease. However, the precise role of Wnt signalling dysregulation in the onset and progression of Dupuytren's contracture remains unclear. Here, using a fibrosis mouse model and clinical samples of human Dupuytren's contractures, we demonstrate that the activation of Wnt/ß-catenin signalling in Tppp3-positive cells in the dermis of the paw is associated with the development of fibrosis. Fibrosis development and progression via Wnt/ß-catenin signalling are closely related to stromal cell-macrophage interactions, and Wnt/ß-catenin signalling activation in Tppp3-positive stromal cells causes M2 macrophage infiltration via chemokine Cxcl14, resulting in the formation of a TGF-ß-expressing fibrotic niche. Inhibition of Cxcl14 mitigates fibrosis by decreasing macrophage infiltration. These findings suggest that Cxcl14-mediated stromal cell-macrophage interaction is a promising therapeutic target for Wnt/ß-catenin-induced fibrosis.

Reprogramming of pancreatic islet cells for regeneration and rejuvenation.

The pancreatic ß cell, which produces insulin, is a terminally differentiated cell type that divides rarely. Consequently, the regenerative ability of ß cells is limited and irreversible diabetes occurs after severe loss of ß-cell function. In view of such poor regenerative capacity, considerable research efforts have been made to promote the expansion of functional insulin-producing cells as a regenerative therapy for diabetes. Here, we discuss recent findings regarding the robust expansion of functional mature islet cells both in vivo and ex vivo through MYCL-mediated reprogramming. We also describe the potential prospects for the application of reprogramming technologies to regenerative therapy and rejuvenation of islet cells.

Preoperative detailed evaluation intracranial artery stenosis using three-dimensional visualization analysis reduces the invasiveness of superficial temporal artery-middle cerebral artery bypass.

Objectives: Superficial temporal artery (STA) to middle cerebral artery (MCA) bypass surgery is a common treatment for preventing cerebral ischemia in patients with intracranial artery stenosis. The aim of this study was to analyze the surgical outcomes of the STA-MCA bypass procedure, particularly with regard to the invasiveness of targeted bypass (TB) with preoperative planning using Amira® software. Methods: Consecutive patients with single STA-MCA bypass performed by a single neurosurgeon from January 2019 to May 2022 were included. The clinical parameters of seven TB patients were compared with those of 11 patients treated with the conventional method (CM). Results: Compared with CM patients, TB using Amira® software patients had a shorter scalp incision (median [interquartile range]=11.2 [9.7-12.7] cm vs. 16.9 [16.0-17.7] cm, respectively; p=0.004], smaller craniotomy size (11.8 [11.5-14.4] cm2 vs. 20.9 [17.1-22.2] cm2, respectively; p=0.01], shorter surgery duration (201 [195-218] min vs. 277 [229-310] min, respectively; p=0.003], and less intraoperative bleeding (10 [10-20] g vs. 23 [20-50] g, respectively; p=0.033]. However, there were no differences in surgical complications between the two groups. Conclusions: Detailed preoperative evaluation using Amira® software can reduce the invasiveness of the STA-MCA bypass procedure.

Exploring the potential of in vivo reprogramming for studying embryonic development, tissue regeneration, and organismal aging.

Forced expression of a specific set of transcription factors can reprogram terminally differentiated cells and convert them into induced pluripotent stem cells that correspond to cells in the inner cell mass of the developing embryo. It is now recognized that the scope of the reprogramming factors extends far beyond the stem cell biology. Studies using mouse models demonstrated that the induction of the reprogramming factors promotes cellular reprogramming in vivo. Closer inspection of these mice has revealed that expression of the reprogramming factors results in unique consequences that are not seen when cells are reprogrammed ex vivo, and can provide insights into development, tissue regeneration, cancer, and aging.

Complementary role of Indocyanine green video angiography, dual-image video angiography and flow-800.

BACKGROUND: Visualization of cerebral vessels, their branches and the surrounding structures are essential during cerebrovascular surgery. Indocyanine green dye-based video angiography is a commonly used technique in cerebrovascular surgery. This paper aims to analyze the real-time imaging of ICG-AG, DIVA, and the use of ICG-VA with Flow 800 to compare their usefulness in surgery. METHODS: Intraoperative real-time identification of vascular and surrounding structures in twenty nine anterior circulation aneurysms and three posterior circulation aneurysm clipping, one STA-MCA bypass, and two carotid endarterectomies were performed in patients using ICG-VA alone, DIVA, ICG-VA with Flow 800 to analyze and compare each of these methods in details. RESULTS: ICG-VA and DIVA couldn't visualize perforators in twenty-three cases of cerebral aneurysms clipping when used alone. Compared to that by adding Flow 800 perforators were easily visualized. In three cases, occlusion of perforators after clip application was visualized by DIVA and solved by repositioning surgical clips. In one STA-MCA bypass surgery, adequate blood flow to cortical branches of MCA (M4) from STA branches was assessed with ICG-VA, DIVA, and the use of ICG-VA with Flow 800 color mapping. ICG-VA, DIVA, and Flow 800 observed the lack of blood flow and fluttering atherosclerotic plaques in carotid endarterectomy. In one case of basilar tip aneurysm, we used ICG-VA with Flow 800; the intensity diagram drawn after determining regions of interest showed that there was no flow within the aneurysm sac after clipping. CONCLUSION: In real-time surgery, a multimodal approach using ICG-VA, DIVA, and ICG-VA with Flow 800 colour mapping can serve as useful tools for better visualization of vascular and surrounding structures. The benefits of flow 800 color mapping, such as determining regions of interest, intensity diagrams, and color-coded images, outweigh the advantages over the ICG-VA and DIVA in the visualization of critical vascular anatomy in humans during surgical procedures.

Predicting Morphological Changes to Vessel Walls Adjacent to Unruptured Cerebral Aneurysms Using Computational Fluid Dynamics.

Objective This study compared intraoperative findings with preoperative computed tomography angiography (CTA) and computational fluid dynamics (CFD) analysis of perianeurysmal findings for the indication of possible vessel wall thinning. Materials and Methods Participants comprised 38 patients with unruptured middle cerebral artery aneurysms treated by surgical clipping at our hospital between May 2020 and April 2021. We defined parent artery radiation sign (PARS) as the presence of each of the following three findings in CFD analysis based on preoperative CTA: (1) impingement of the stream line on the outer parent vessel wall of the aneurysm; (2) radiation of wall shear stress vectors outwards from the same site; and (3) increased wall pressure compared with the surrounding area. CFD analysis showing PARS was compared with intraoperative findings. Results In all nine cases with PARS, no morphological abnormalities were found in the same area on CTA. However, intraoperative findings showed thinning of the parent artery wall in one of the nine cases and formation of a very small mass in three cases, differing from CTA findings. All nine patients underwent additional clipping and/or wrapping and coating at the site of PARS. Conclusion Detecting thinning of the vessel wall or the presence of a microaneurysm may be difficult in endovascular therapy, which is based on the visualization of the vessel lumen. CFD analysis suggests the necessity of confirming findings for the vessel wall around an aneurysm by direct manipulation, as the presence of PARS may indicate partial thinning of the vessel wall or formation of a microaneurysm.

Coexistence of neurovascular compression syndrome and unruptured cerebral aneurysm.

Unruptured cerebral aneurysms (UCAs) are usually asymptomatic and detected incidentally by intracranial examinations. The coexistence of neurovascular compression syndrome (NVCS) and UCAs has not been well described. The aim of this study was to clarify the characteristics of UCAs with the NVCS. A total of 103 cases that underwent microvascular decompression (MVD) for trigeminal neuralgia (TN) or hemifacial spasm (HFS) were assigned to the NVCS group. The prevalence of UCAs in the NVCS group was compared retrospectively to that in 110 control cases (a control group) by neuro-imaging. Overall treatment courses for NVCS and UCAs were investigated in the NVCS group. Sixteen (15.3%; TN 11 cases, HFS 5 cases) of 103 MVD cases had 19 UCAs, a significantly higher prevalence than the 3.6% in the control group. Binomial logistic regression showed that NVCS is a significant factor for predicting the presence of UCAs, with an odds ratio of 4.80. In the NVCS group, 18 UCAs (94.7%) were supratentorial aneurysms, and 17 UCAs (89.5%) were less than 5 mm in size. Nine UCAs were surgically treated with clipping or coiling. Of the surgical cases, 2 UCAs were treated before MVD for NVCS, whereas the other 7 UCAs were treated after MVD. No aneurysms ruptured during the treatment course. The NVCS occurred with UCAs at a significantly higher rate than in the control group. Most UCAs with the NVCS were supratentorial, small aneurysms that did not affect the surgical treatment of NVCS.

Efficacy of tadalafil on symptom-specific bother in men with lower urinary tract symptoms.

INTRODUCTION: This multicenter and prospective study was performed to evaluate the efficacy of tadalafil on patient-reported bother for each symptom in men with lower urinary tract symptoms (LUTS). METHODS: Men with LUTS received 5 mg of tadalafil daily for 4 weeks. We assessed change in symptom severity using both international prostate symptom score (IPSS), and overactive bladder symptom score (OABSS), as well as patient-reported quality of life (QOL: bother or satisfaction) for each symptoms using IPSS-visual analog scale (IPSS-VAS) and OABSS-VAS. RESULTS: We found significant improvements in total IPSS (P < 0.001), including voiding symptoms (P < 0.001), storage symptoms (P < 0.001), and QOL (P < 0.001). All VAS measures corresponding to symptoms in IPSS and OABSS also significantly improved (P < 0.001). The most bothersome symptoms for each patient at baseline evaluated by VAS measures significantly improved (P < 0.001). Patients whose most bothersome symptoms at baseline included IPSS-Q7 (nocturia) showed significantly smaller improvement of VAS measure after treatment than those without it (P = 0.024). CONCLUSIONS: Daily tadalafil significantly improved not only symptom severity of LUTS but also patient-reported QOL on each symptom.

Preoperative 3D Image Evaluation of EC-IC Bypass by 3D Visualization Analysis Software Amira®.

Background: Careful evaluation of the preoperative imaging for extracranial-intracranial bypass performed for conditions like intracranial stenosis and Moya disease is important. The traditional use of 2D imaging has a significant limitation for neurosurgeons, primarily to determine the optimal location of the recipient artery for performing the surgical bypass. Therefore, many neurosurgeons use 3D angiograms more frequently to overcome these shortcomings. Materials And Methods: We performed the preoperative evaluation of the possibility of performing an anastomosis between the superficial temporal artery and the middle cerebral artery (STA-MCA) bypass by synthesizing images of computerized tomography (CT), magnetic resonance imaging (MRI), and digital subtraction angiography (DSA) using Amira® of 3D visualization analysis software (Thermo Scientific Co.). Results: The 3D images prepared before surgery using this software showed good agreement with the intraoperative findings. Conclusion: Preoperative image processing using tools like Amira provide optimal information for good planning and communication for performing STA-MCA bypass and may become a helpful tool.

YAP1/TAZ activity maintains vascular integrity and organismal survival.

Radiation therapy is one of the major treatment modalities for patients with cancers. However, ionizing radiation (IR) damages not only cancer cells but also the surrounding vascular endothelial cells (ECs). Hippo pathway effector genes Yap1 and Taz are the two transcriptional coactivators that have crucial roles in tissue homeostasis and vascular integrity in various organs. However, their function in adult ECs at the steady state and after IR is poorly understood. Here, we report sex- and context-dependent roles of endothelial YAP1/TAZ in maintaining vascular integrity and organismal survival. EC-specific Yap1/Taz deletion compromised systemic vascular integrity, resulting in lethal circulation failure preferentially in male mice. Furthermore, EC-specific Yap1/Taz deletion induced acute lethality upon sublethal IR that was closely associated with exacerbated systemic vascular dysfunction and circulation failure. Consistent with these findings, RNA-seq analysis revealed downregulation of tight junction genes in Yap1/Taz-deleted ECs. Collectively, our findings highlight the importance of endothelial YAP1/TAZ for maintaining adult vascular function, which may provide clinical implications for preventing organ injury after radiation therapy.

The oncogene-dependent resistance to reprogramming unveils cancer therapeutic targets.

The resistance to transcription factor-mediated reprogramming into pluripotent stem cells is one of the distinctive features of cancer cells. Here we dissect the profiles of reprogramming factor binding and the subsequent transcriptional response in cancer cells to reveal its underlying mechanisms. Using clear cell sarcomas (CCSs), we show that the driver oncogene EWS/ATF1 misdirects the reprogramming factors to cancer-specific enhancers and thereby impairs the transcriptional response toward pluripotency that is otherwise provoked. Sensitization to the reprogramming cue is observed in other cancer types when the corresponding oncogenic signals are pharmacologically inhibited. Exploiting this oncogene dependence of the transcriptional "stiffness," we identify mTOR signaling pathways downstream of EWS/ATF1 and discover that inhibiting mTOR activity substantially attenuates the propagation of CCS cells in vitro and in vivo. Our results demonstrate that the early transcriptional response to cell fate perturbations can be a faithful readout to identify effective therapeutics targets in cancer cells.

Microwave focal therapy of prostate cancer: a non-clinical study and exploratory clinical trial.

OBJECTIVE: To examine the safety and efficacy of microwave tissue coagulation (MTC) for prostate cancer and assess its use in lesion-targeted focal therapy in a non-clinical study and a clinical phase II trial. METHODS: In the non-clinical study using Microtaze® -AFM-712 (Alfresa Pharma Corporation, Osaka, Japan) with an MTC needle, MTC was performed using a transperineal approach to targeted canine prostatic tissue under real-time ultrasonography guidance. Using various MTC output and irradiation time combinations, the targeted and surrounding tissues (rectum, bladder and fat) were examined to confirm the extent of coagulative necrosis or potential cell death, and to compare intra-operative ultrasonography and pathology findings. The exploratory clinical trial was conducted to examine the safety and efficacy of MTC. Five selected patients underwent transperineal MTC to clinically single lesion magnetic resonance imaging (MRI)-visible lesions with Gleason score 3 + 4 or 4 + 4. Prostate-specific antigen (PSA), MRI and Expanded Prostate Cancer Index Composite questionnaire findings were compared before and 6 months after surgery. RESULTS: The region of coagulative necrosis was predictable by monitoring of ultrasonically visible vaporization; thus, by placing the MTC needle at a certain distance, we were able to perform a safe procedure without adverse events affecting the surrounding organs. Based on the non-clinical study, which used various combinations of output and irradiation time, MTC with 30-W output for 60-s irradiation was selected for the prostate. Based on the predictable necrosis, the therapeutic plan (where to place the MTC needle to achieve complete ablation of the target and how many sessions) was strictly determined per patient. There were no serious adverse events in any patient and only temporary urinary symptoms related to MTC therapy were observed. Furthermore, post-treatment satisfaction was very high. All preoperative MRI-visible lesions disappeared, and PSA decreased by 55% 6 months after surgery. CONCLUSION: Microwave tissue coagulation may be an option for lesion-targeted focal therapy for prostate cancer.

Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats.

Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted studies on the responsible mechanisms to provide clues for human cancer prevention. However, it remains unknown whether and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration. NMRs harbour loss-of-function mutations in RIPK3 and MLKL genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. In mice, disruption of Ripk3 reduced immune cell infiltration and delayed carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs.

Comparison of toxicities between ultrahypofractionated radiotherapy versus brachytherapy with or without external beam radiotherapy for clinically localized prostate cancer.

To compare gastrointestinal (GI) and genitourinary (GU) toxicities in patients with localized prostate cancer treated with ultrahypofractionated radiotherapy (UHF) or brachytherapy [BT; low dose rate, LDR or high dose rate (HDR) with or without external beam radiotherapy (EBRT)]. We compared 253 UHF and 1664 BT ± EBRT groups. The main outcomes were the incidence and severity of acute and late GU and GI toxicities. The secondary endpoint was biochemical control rate. Cumulative late actuarial GU toxicity did not differ for grade ≥ 2 (8.6% at 5-years in UHF and 13.3% in BT ± EBRT, hazard ratio [HR], 0.7066; 95% CI, 0.4093-1.22, p = 0.2127). Actuarial grade ≥ 2 late GI toxicity was higher in UHF (5.8% at 5-years, HR: 3.619; 95% CI, 1.774-7.383, p < 0.001) than in BT ± EBRT (1.1%). In detailed subgroup analyses, the high-dose UHF group (H-UHF) using BED ≥ 226 Gy1.5, showed higher GI toxicity profiles than the other subgroups (HDR + EBRT, LDR + EBRT, and LDR monotherapy, and L-UHF BED < 226 Gy1.5) with equivalent GU toxicity to other modalities. With a median follow-up period of 32 months and 75 months, the actuarial biochemical control rates were equivalent between the UHF and BT ± EBRT groups. UHF showed equivalent efficacy, higher GI and equivalent GU accumulated toxicity to BT ± EBRT, and the toxicity of UHF was largely dependent on the UHF schedule.

Generation of mice for evaluating endogenous p16Ink4a protein expression.

The cyclin-dependent kinase inhibitor p16Ink4a plays a central role in cellular senescence in vitro. Although previous studies suggested cellular senescence is integrated in the systemic mechanisms of organismal aging, the localization and the dynamics of p16Ink4a in tissues remain poorly understood, which hinders uncovering the role of p16Ink4a under the in vivo context. One of the reasons is due to the lack of reliable reagents; as we also demonstrate here that commonly used antibodies raised against human p16INK4A barely recognize its murine ortholog. Here we generated a mouse model, in which the endogenous p16Ink4a is HA-tagged at its N-terminus, to explore the protein expression of p16Ink4a at the organismal level. p16Ink4a was induced at the protein level along the course of senescence in primary embryonic fibroblasts derived from the mice, consistently to its transcriptional level. Remarkably, however, p16Ink4a was not detected in the tissues of the mice exposed to pro-senescence conditions including genotoxic stress and activation of oncogenic signaling pathways, indicating that there is only subtle p16Ink4a proteins induced. These results in our mouse model highlight the need for caution in evaluating p16Ink4a protein expression in vivo.

The phosphorylated retinoid X receptor-α promotes diethylnitrosamine-induced hepatocarcinogenesis in mice through the activation of ß-catenin signaling pathway.

Previous studies have shown that phosphorylation of the retinoid X receptor-α (RXRα) is associated with the development of hepatocellular carcinoma (HCC). However, these findings were revealed using HCC cell lines that express phosphorylated-RXRα (p-RXRα) proteins; therefore, it remains unclear whether p-RXRα affects hepatocarcinogenesis in vivo. Therefore, to investigate the biological function of p-RXRα in vivo, we developed a doxycycline-inducible ES cell line and transgenic mouse, both of which overexpress the phosphomimetic mutant form of RXRα, T82D/S260D, in a doxycycline-dependent manner. We found that the development of liver tumors, especially high-grade adenoma and HCC, was enhanced in diethylnitrosamine (DEN)-treated T82D/S260D-inducible mice. Moreover, the increased incidence of liver tumors in the transgenic mice was attributable to the promotion of cell cycle progression. Interestingly, the expression of ß-catenin protein and its target gene cyclin D1 was elevated in the liver tumors of DEN-treated T82D/S260D-inducible mice, concurrent with increased cytoplasmic and nuclear ß-catenin protein expression, indicating its stabilization and transcriptional activation. These results indicate that p-RXRα promotes DEN-induced hepatocarcinogenesis in mice through the activation of the ß-catenin signaling pathway, suggesting that p-RXRα may serve as a possible therapeutic target for HCC.

The Use of Fusion Images as a Diagnostic and Neurosurgical Planning Tool in Microvascular Decompression.

Preoperative assessment of surgery using high-quality images can help surgeons to achieve best result of treatment. With the advances in computer technology, interactive multimodality fusion images have been developed. The use of fusion images as a preoperative planning tool is described with its examples in illustrative cases of trigeminal neuralgia and hemifacial spasm microvascular decompression (MVD). Interactive computer graphics such as multimodality fusion method is a useful tool to preoperatively predict the need of bone exposure and configuration of blood vessels with its correlation to cranial nerves in MVD.

Impact of prostate-specific antigen screening on tumor size in patients with prostate cancer in a super-aging district in Kyoto, Japan.

BACKGROUND: Population-based prostate-specific antigen (PSA) screening is effective for reducing prostate cancer (PCa)-related mortality rates. In this study, we assessed biopsy-proven maximum cancer core length (MCCL) and maximum cancer diameter on magnetic resonance imaging (MRI; MCDM) in prostate biopsy and multiparametric MRI (mp-MRI) by PCa detection. METHODS: We retrospectively assessed 214 male PCa patients and 187 PCa patients with Prostate Imaging Reporting and Data System version 2 (PI-RADS) category 3-5 lesions in pre-biopsy mp-MRI and targeted biopsy characteristics. The mean biopsy-proven MCCL and MCDM were compared among three PSA screening groups, namely the population-based PSA screening (PBS), opportunistic PSA screening (OPS), and symptomatic outpatient PSA examination (SOP) groups. RESULTS: The median age and PSA value of the 214 participants were 75 years and 7.9 ng/mL, respectively. In the PBS, OPS, and SOP groups, the median ages were 73, 76, and 76 years, respectively (p = 0.046); PSA values were 7.2, 9.5, and 11.5 ng/mL, respectively (p < 0.001); and biopsy-proven MCCL and MCDM were significantly increased to 7, 10, and 14 mm (p < 0.001) and to 11, 15, and 17 mm (p < 0.001), respectively. In the 187 PCa patients with PI-RADS category 3-5 lesions on mp-MRI, MCDM were 11, 14, and 17 mm (p < 0.001), respectively. CONCLUSIONS: The biopsy-proven MCCL and MCDM were significantly smaller in the PBS and OPS groups than in the SOP group, which suggests that PSA screening detected PCa earlier than in symptomatic patients. PSA screening with MRI could objectively lead to earlier diagnosis based on tumor size.