Neuro-Restorative Effect of Nimodipine and Calcitriol in 1-Methyl 4-Phenyl 1,2,3,6 Tetrahydropyridine-Induced Zebrafish Parkinson's Disease Model.

Objective: Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The treatment of PD aims to alleviate motor symptoms by replacing the reduced endogenous dopamine. Currently, there are no disease-modifying agents for the treatment of PD. Zebrafish (Danio rerio) have emerged as an effective tool for new drug discovery and screening in the age of translational research. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to cause a similar loss of dopaminergic neurons in the human midbrain, with corresponding Parkinsonian symptoms. L-type calcium channels (LTCCs) have been implicated in the generation of mitochondrial oxidative stress, which underlies the pathogenesis of Parkinson's disease. Therefore, we investigated the neuro-restorative effect of LTCC inhibition in an MPTP-induced zebrafish PD model and suggested a possible drug candidate that might modify the progression of PD. Methods: All experiments were conducted using a line of transgenic zebrafish, Tg (dat:EGFP), in which green fluorescent protein (GFP) is expressed in dopaminergic neurons. The experimental groups were exposed to 500µã– MPTP from 1 to 3 days post fertilization (dpf). The drug candidates: Levodopa 1m㏖, Nifedipine 10µã–, Nimodipine 3.5 µã–, Diethylstilbestrol 0.3 µã–, Luteolin 100 µã–, Cacitriol 0.25 µã– were exposed from 3 to 5 dpf. Locomotor activity was assessed by automated tracking and dopaminergic neurons were visualized in vivo by confocal microscopy. Results: Levodopa, Nimodipine, Diethylstilbestrol, and Calcitriol had significant positive effects on the restoration of motor behavior, which was damaged by MPTP. Nimodipine and Calcitriol have significant positive effects on the restoration of dopaminergic neurons, which were reduced by MPTP. Through locomotor analysis and dopaminergic neuron quantification, we identified the neuro-restorative effects of Nimodipine and Calcitriol in Zebrafish MPTP-induced PD model. Conclusion: The present study identified the neuro-restorative effects of nimodipine and calcitriol in an MPTP-induced zebrafish model of Parkinson's disease. They restored dopaminergic neurons which were damaged due to the effects of MPTP and normalized the locomotor activity. LTCCs have potential pathological roles in neurodevelopmental and neurodegenerative disorders. Zebrafish are highly amenable to high-throughput drug screening and might, therefore, be a useful tool to work towards the identification of disease-modifying treatment for PD. Further studies including zebrafish genetic models to elucidate the mechanism of action of the disease-modifying candidate by investigating Ca2+ influx and mitochondrial function in dopaminergic neurons, are needed to reveal the pathogenesis of PD and develop disease-modifying treatments for PD.

Simulation Method for the Physical Deformation of a Three-Dimensional Soft Body in Augmented Reality-Based External Ventricular Drainage.

OBJECTIVES: Intraoperative navigation reduces the risk of major complications and increases the likelihood of optimal surgical outcomes. This paper presents an augmented reality (AR)-based simulation technique for ventriculostomy that visualizes brain deformations caused by the movements of a surgical instrument in a three-dimensional brain model. This is achieved by utilizing a position-based dynamics (PBD) physical deformation method on a preoperative brain image. METHODS: An infrared camera-based AR surgical environment aligns the real-world space with a virtual space and tracks the surgical instruments. For a realistic representation and reduced simulation computation load, a hybrid geometric model is employed, which combines a high-resolution mesh model and a multiresolution tetrahedron model. Collision handling is executed when a collision between the brain and surgical instrument is detected. Constraints are used to preserve the properties of the soft body and ensure stable deformation. RESULTS: The experiment was conducted once in a phantom environment and once in an actual surgical environment. The tasks of inserting the surgical instrument into the ventricle using only the navigation information presented through the smart glasses and verifying the drainage of cerebrospinal fluid were evaluated. These tasks were successfully completed, as indicated by the drainage, and the deformation simulation speed averaged 18.78 fps. CONCLUSIONS: This experiment confirmed that the AR-based method for external ventricular drain surgery was beneficial to clinicians.

Outcomes Following Carotid Endarterectomy and Carotid Artery Stenting in Patients with Carotid Artery Stenosis: A Retrospective Study from a Single Center in South Korea.

BACKGROUND Previous randomized controlled trials and meta-analyses comparing carotid endarterectomy (CEA) and carotid artery stenting (CAS) included a large number of patients, but the diagnosis, treatment selection, and performance were heterogeneous. This retrospective study from a single center in South Korea aimed to evaluate outcomes following CEA and CAS in patients with carotid artery stenosis. MATERIAL AND METHODS A retrospective analysis was performed using the data of patients who underwent carotid revascularization between September 2016 and June 2021 at a single institution. The primary outcomes were stroke, myocardial infarction (MI), and death during the periprocedural period. RESULTS We enrolled a total of 61 (44 symptomatic and 17 asymptomatic) patients who underwent CEA or CAS. Among them, 36 (59%) underwent CEA and 25 (41%) underwent CAS. Statistically significant differences were found between the groups in degree of carotid stenosis (CEA: 87.0±9.1, CAS: 80.5±9.3, P=0.007). All patients with confirmed plaque ulceration before carotid revascularization underwent CEA. Two (3.3%) periprocedural strokes occurred, 1 in each group, on the ipsilateral side. There were no significant differences between CEA and CAS in the event-free survival rate for stroke during the follow-up (log-rank test=0.806). CONCLUSIONS Favorable outcomes in terms of periprocedural stroke were observed. We found no significant difference between the 2 carotid revascularization techniques in the incidence of periprocedural stroke in symptomatic and asymptomatic patients. To confirm our findings, further studies involving a larger number of patients and continuous follow-up are necessary.

Comparison of Single-Session, Neoadjuvant, and Adjuvant Embolization Gamma Knife Radiosurgery for Arteriovenous Malformation.

BACKGROUND: The purpose of intracranial arteriovenous malformations (AVMs) treatment is to prevent bleeding or subsequent hemorrhage with complete obliteration. For large, difficult-to-treat AVMs, multimodal approaches including surgery, endovascular embolization, and gamma knife radiosurgery (GKRS) are frequently used. OBJECTIVE: To analyze the outcomes of AVMs treated with single-session, neoadjuvant, and adjuvant embolization GKRS. METHODS: We retrospectively reviewed a database of 453 patients with AVMs who underwent GKRS between January 2007 and December 2017 at our facility. The obliteration rate, incidence of latent period bleeding, cyst formation, and radiation-induced changes were compared among the 3 groups, neoadjuvant-embolized, adjuvant-embolized, nonembolized group. In addition, the variables predicting AVM obliteration and complications were investigated. RESULTS: A total of 228 patients were enrolled in this study. The neoadjuvant-embolized, adjuvant-embolized, and nonembolized groups comprised 29 (12.7%), 19 (8.3%), and 180 (78.9%) patients, respectively. Significant differences were detected among the 3 groups in the history of previous hemorrhage and the presence of aneurysms ( P < .0001). Multivariate Cox regression analyses revealed a significant inverse correlation between neoadjuvant embolization and obliteration occurring 36 months after GKRS (hazard ratio, 0.326; P = .006). CONCLUSION: GKRS with either neoadjuvant or adjuvant embolization is a beneficial approach for the treatment of AVMs with highly complex angioarchitectures that are at risk for hemorrhage during the latency period. Embolization before GKRS may be a negative predictive factor for late-stage obliteration (>36 months). To confirm our conclusions, further studies involving a larger number of patients and continuous follow-up are necessary.

Differences in intrinsic functional networks in patients with essential tremor who had good and poor long-term responses after thalamotomy performed using MR-guided ultrasound.

OBJECTIVE: Thalamotomy at the nucleus ventralis intermedius using MR-guided focused ultrasound has been an effective treatment method for essential tremor (ET). However, this is not true for all cases, even for successful ablation. How the brain differs in patients with ET between those with long-term good and poor outcomes is not clear. To analyze the functional connectivity difference between patients in whom thalamotomy was effective and those in whom thalamotomy was ineffective and its prognostic role in ET treatment, the authors evaluated preoperative resting-state functional MRI in thalamotomy-treated patients. METHODS: Preoperative resting-state functional MRI data in 85 patients with ET, who were experiencing tremor relief at the time of treatment and were followed up for a minimum of 6 months after the procedure, were collected for the study. The authors conducted a graph independent component analysis of the functional connectivity matrices of tremor-related networks. The patients were divided into thalamotomy-effective and thalamotomy-ineffective groups (thalamotomy-effective group, ≥ 50% motor symptom reduction; thalamotomy-ineffective group, < 50% motor symptom reduction at 6 months after treatment) and the authors compared network components between groups. RESULTS: Seventy-two (84.7%) of the 85 patients showed ≥ 50% tremor reduction from baseline at 6 months after thalamotomy. The network analysis shows significant suppression of functional network components with connections between the areas of the cerebellum and the basal ganglia and thalamus, but enhancement of those between the premotor cortex and supplementary motor area in the noneffective group compared to the effective group. CONCLUSIONS: The present study demonstrates that patients in the noneffective group have suppressed functional subnetworks in the cerebellum and subcortex regions and have enhanced functional subnetworks among motor-sensory cortical networks compared to the thalamotomy-effective group. Therefore, the authors suggest that the functional connectivity pattern might be a possible predictive factor for outcomes of MR-guided focused ultrasound thalamotomy.

Clinical application of deep learning-based synthetic CT from real MRI to improve dose planning accuracy in Gamma Knife radiosurgery: a proof of concept study.

Dose planning for Gamma Knife radiosurgery (GKRS) uses the magnetic resonance (MR)-based tissue maximum ratio (TMR) algorithm, which calculates radiation dose without considering heterogeneous radiation attenuation in the tissue. In order to plan the dose considering the radiation attenuation, the Convolution algorithm should be used, and additional radiation exposure for computed tomography (CT) and registration errors between MR and CT are entailed. This study investigated the clinical feasibility of synthetic CT (sCT) from GKRS planning MR using deep learning. The model was trained using frame-based contrast-enhanced T1-weighted MR images and corresponding CT slices from 54 training subjects acquired for GKRS planning. The model was applied prospectively to 60 lesions in 43 patients including benign tumor such as meningioma and pituitary adenoma, metastatic brain tumors, and vascular disease of various location for evaluating the model and its application. We evaluated the sCT and compared between treatment plans made with MR only (TMR 10 plan), MR and real CT (rCT; Convolution with rCT [Conv-rCT] plan), and MR and synthetic CT (Convolution with sCT [Conv-sCT] plan). The mean absolute error (MAE) of 43 sCT was 107.35 ± 16.47 Hounsfield units. The TMR 10 treatment plan differed significantly from plans made by Conv-sCT and Conv-rCT. However, the Conv-sCT and Conv-rCT plans were similar. This study showed the practical applicability of deep learning based on sCT in GKRS. Our results support the possibility of formulating GKRS treatment plans while considering radiation attenuation in the tissue using GKRS planning MR and no radiation exposure.

Antibody-mediated blockade for galectin-3 binding protein in tumor secretome abrogates PDAC metastasis.

The major challenges in pancreatic ductal adenocarcinoma (PDAC) management are local or distant metastasis and limited targeted therapeutics to prevent it. To identify a druggable target in tumor secretome and to explore its therapeutic intervention, we performed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis of tumors obtained from a patient-derived xenograft model of PDAC. Galectin-3 binding protein (Gal-3BP) is identified as a highly secreted protein, and its overexpression is further validated in multiple PDAC tumors and primary cells. Knockdown and exogenous treatment of Gal-3BP showed that it is required for PDAC cell proliferation, migration, and invasion. Mechanistically, we revealed that Gal-3BP enhances galectin-3-mediated epidermal growth factor receptor signaling, leading to increased cMyc and epithelial-mesenchymal transition. To explore the clinical impact of these findings, two antibody clones were developed, and they profoundly abrogated the metastasis of PDAC cells in vivo. Altogether, our data demonstrate that Gal-3BP is an important therapeutic target in PDAC, and we propose its blockade by antibody as a therapeutic option for suppressing PDAC metastasis.

Microbiological contamination of fresh-cut produce in Korea.

This study evaluated the microbiological contamination of fresh-cut produce in Korea. A total of 108 fresh-cut vegetables and fruits were surveyed for the aerobic mesophilic (AM) count, aerobic psychrophilic (AP) count, total coliform, generic Escherichia coli, yeast and mold, and foodborne pathogens. AM counts ranged from 1.00 to 7.36 log CFU/g, and AP counts showed very similar results as AM counts. For total coliform and generic E. coli, 53.7% and 9.3% of the samples were detected, respectively. For foodborne pathogens, none of the samples were identified as E. coli O157:H7 or Salmonella spp. However, S. aureus and B. cereus was detected in 5.6% and 6.5% of the samples, respectively. Although the contamination level has varied widely, samples with high bacterial counts, such as julienned green onion, bell pepper, carrot, and mixed sprout, should be implemented with strict control measures.

Dual Pallidal and Thalamic Deep Brain Stimulation for Complex Ipsilateral Dystonia.

PURPOSE: Globus pallidus pars interna (GPi) has become an established target for deep brain stimulation (DBS) in dystonia. Previous studies suggest that targeting the ventralis oralis (Vo) complex nucleus improves dystonic tremor or even focal dystonia. Research has also demonstrated that multi-target DBS shows some benefits over single target DBS. In this study, we reviewed patients who had undergone unilateral DBS targeting the GPi and Vo. MATERIALS AND METHODS: Five patients diagnosed with medically refractory upper extremity dystonia (focal or segmental) underwent DBS. Two DBS electrodes each were inserted unilaterally targeting the ipsilateral GPi and Vo. Clinical outcomes were evaluated using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Disability Rating Scale. RESULTS: BFMDRS scores decreased by 55% at 1-month, 56% at 3-month, 59% at 6-month, and 64% at 12-month follow up. Disability Rating Scale scores decreased 41% at 1-month, 47% at 3-month, 50% at 6-month, and 60% at 12-month follow up. At 1 month after surgery, stimulating both targets improved clinical scores better than targeting GPi or Vo alone. CONCLUSION: Unilateral thalamic and pallidal dual electrode DBS may be as effective or even superior to DBS of a single target for dystonia. Although the number of patients was small, our results reflected favorable clinical outcomes.

Aberrant Transcript Usage Is Associated with Homologous Recombination Deficiency and Predicts Therapeutic Response.

BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors that cause low precision in predicting samples that will respond to PARP inhibitors and DNA damaging agents. Here we present molecular and clinical evidence of transcriptional HRD (tHRD) that is based on aberrant transcript usage (aTU) of minor isoforms. Specifically, increased TU of nonfunctional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Functional assays validated the association of aTU with impaired HR activity. Machine learning-based tHRD detection by the transcript usage (TU) pattern of key genes was superior to directly screening for gHRD or BRCA1/2 mutations in accurately predicting responses of cell lines and patients with cancer to PARP inhibitors and genotoxic drugs. This approach demonstrated the capability of tHRD status to reflect functional HR status, including in a cohort of olaparib-treated ovarian cancer with acquired platinum resistance. Diagnostic tests based on tHRD are expected to broaden the clinical utility of PARP inhibitors. SIGNIFICANCE: A novel but widespread transcriptional mechanism by which homologous recombination deficiency arises independently of BRCA1/2 mutations can be utilized as a companion diagnostic for PARP inhibitors.

Predictive Factors of Surgical Site Infection Following Cranioplasty: A Study Including 3D Printed Implants.

In patients who have undergone decompressive craniectomy (DC), subsequent cranioplasty is required to reconstruct cranial defects. Surgical site infection (SSI) following cranioplasty is a devastating complication that can lead to cranioplasty failure. The aim of the present study, therefore, was to identify predictive factors for SSI following cranioplasty by reviewing procedures performed over a 10-year period. A retrospective analysis was performed for all patients who underwent cranioplasty following DC between 2010 and 2020 at a single institution. The patients were divided into two groups, non-SSI and SSI, in order to identify clinical variables that are significantly correlated with SSI following cranioplasty. Cox proportional hazards regression analyses were then performed to identify predictive factors associated with SSI following cranioplasty. A total of 172 patients who underwent cranioplasty, including 48 who received customized three-dimensional (3D) printed implants, were enrolled in the present study. SSI occurred in 17 patients (9.9%). Statistically significant differences were detected between the non-SSI and SSI groups with respect to presence of fluid collections on CT scans before and after cranioplasty. Presence of fluid collections on computed tomography (CT) scan before (p = 0.0114) and after cranioplasty (p < 0.0000) showed significant association with event-free survival rate for SSI. In a univariate analysis, significant predictors for SSI were fluid collection before (p = 0.0172) and after (p < 0.0001) cranioplasty. In a multivariate analysis, only the presence of fluid collection after cranioplasty was significantly associated with the occurrence of SSI (p < 0.0001). The present study investigated predictive factors that may help identify patients at risk of SSI following cranioplasty and provide guidelines associated with the procedure. Based on the results of the present study, only the presence of fluid collection on CT scan after cranioplasty was significantly associated with the occurrence of SSI. Further investigation with long-term follow-up and large-scale prospective studies are needed to confirm our conclusions.

Metagenomic analysis of gut microbiome reveals a dynamic change in Alistipes onderdonkii in the preclinical model of pancreatic cancer, suppressing its proliferation.

Pancreatic cancer is a lethal cancer with aggressive and invasive characteristics. By the time it is diagnosed, patients already have tumors extended to other organs and show extremely low survival rates. The gut microbiome is known to be associated with many diseases and its imbalance affects the pathogenesis of pancreatic cancer. In this study, we established an orthotopic, patient-derived xenograft model to identify how the gut microbiome is linked to pancreatic ductal adenocarcinoma (PDAC). Using the 16S rDNA metagenomic sequencing, we revealed that the levels of Alistipes onderdonkii and Roseburia hominis decreased in the gut microbiome of the PDAC model. To explore the crosstalk between the two bacteria and PDAC cells, we collected the supernatant of the bacteria or cancer cell culture medium and treated it in a cross manner. While the cancer cell medium did not affect bacterial growth, we observed that the A. onderdonkii medium suppressed the growth of the pancreatic primary cancer cells. Using the bromodeoxyuridine/7-amino-actinomycin D (BrdU/7-AAD) staining assay, we confirmed that the A. onderdonkii medium inhibited the proliferation of the pancreatic primary cancer cells. Furthermore, RNA-seq analysis revealed that the A. onderdonkii medium induced unique transcriptomic alterations in the PDAC cells, compared to the normal pancreatic cells. Altogether, our data suggest that the reduction in the A. onderdonkii in the gut microbiome provides a proliferation advantage to the pancreatic cancer cells. KEY POINTS: • Metagenome analysis of pancreatic cancer model reveals A. onderdonkii downregulation. • A. onderdonkii culture supernatant suppressed the proliferation of pancreatic cancer cells. • RNA seq data reveals typical gene expression changes induced by A. onderdonkii.

siRNA Nanoparticle Targeting PD-L1 Activates Tumor Immunity and Abrogates Pancreatic Cancer Growth in Humanized Preclinical Model.

Pancreatic cancer is characterized by late detection, frequent drug resistance, and a highly metastatic nature, leading to poor prognosis. Antibody-based immunotherapy showed limited success for pancreatic cancer, partly owing to the low delivery rate of the drug into the tumor. Herein, we describe a poly(lactic-co-glycolic acid;PLGA)-based siRNA nanoparticle targeting PD-L1 (siPD-L1@PLGA). The siPD-L1@PLGA exhibited efficient knockdown of PD-L1 in cancer cells, without affecting the cell viability up to 6 mg/mL. Further, 99.2% of PDAC cells uptake the nanoparticle and successfully blocked the IFN-gamma-mediated PD-L1 induction. Consistently, the siPD-L1@PLGA sensitized cancer cells to antigen-specific immune cells, as exemplified by Ovalbumin-targeting T cells. To evaluate its efficacy in vivo, we adopted a pancreatic PDX model in humanized mice, generated by grafting CD34+ hematopoeitic stem cells onto NSG mice. The siPD-L1@PLGA significantly suppressed pancreatic tumor growth in this model with upregulated IFN-gamma positive CD8 T cells, leading to more apoptotic tumor cells. Multiplex immunofluorescence analysis exhibited comparable immune cell compositions in control and siPD-L1@PLGA-treated tumors. However, we found higher Granzyme B expression in the siPD-L1@PLGA-treated tumors, suggesting higher activity of NK or cytotoxic T cells. Based on these results, we propose the application of siPD-L1@PLGA as an immunotherapeutic agent for pancreatic cancer.

Stimulation-Induced Side Effects of Deep Brain Stimulation in the Ventralis Intermedius and Posterior Subthalamic Area for Essential Tremor.

Deep brain stimulation (DBS) targeting the ventralis intermedius (VIM) nucleus of the thalamus and the posterior subthalamic area (PSA) has been shown to be an effective treatment for essential tremor (ET). The aim of this study was to compare the stimulation-induced side effects of DBS targeting the VIM and PSA using a single electrode. Patients with medication-refractory ET who underwent DBS electrode implantation between July 2011 and October 2020 using a surgical technique that simultaneously targets the VIM and PSA with a single electrode were enrolled in this study. A total of 93 patients with ET who had 115 implanted DBS electrodes (71 unilateral and 22 bilateral) were enrolled. The Clinical Rating Scale for Tremor (CRST) subscores improved from 20.0 preoperatively to 4.3 (78.5% reduction) at 6 months, 6.3 (68.5% reduction) at 1 year, and 6.5 (67.5% reduction) at 2 years postoperation. The best clinical effect was achieved in the PSA at significantly lower stimulation amplitudes. Gait disturbance and clumsiness in the leg was found in 13 patients (14.0%) upon stimulation of the PSA and in significantly few patients upon stimulation of the VIM (p = 0.0002). Fourteen patients (15.1%) experienced dysarthria when the VIM was stimulated; this number was significantly more than that with PSA stimulation (p = 0.0233). Transient paresthesia occurred in 13 patients (14.0%) after PSA stimulation and in six patients (6.5%) after VIM stimulation. Gait disturbance and dysarthria were significantly more prevalent in patients undergoing bilateral DBS than in those undergoing unilateral DBS (p = 0.00112 and p = 0.0011, respectively). Paresthesia resolved either after reducing the amplitude or switching to bipolar stimulation. However, to control gait disturbance and dysarthria, some loss of optimal tremor control was necessary at that particular electrode contact. In the present study, the most common stimulation-induced side effect associated with VIM DBS was dysarthria, while that associated with PSA DBS was gait disturbance. Significantly, more side effects were associated with bilateral DBS than with unilateral DBS. Therefore, changing active DBS contacts to simultaneous targeting of the VIM and PSA may be especially helpful for ameliorating stimulation-induced side effects.

Predictive Factors of Radiation-Induced Changes Following Single-Session Gamma Knife Radiosurgery for Arteriovenous Malformations.

We evaluated for possible predictors of radiation-induced changes (RICs) after gamma knife radiosurgery (GKRS) for arteriovenous malformations (AVMs). We identified the nidal component within AVMs to analyze the correlation between the volume of brain parenchyma within the 50% isodose line (IDL) and RICs. We retrospectively reviewed patients with AVMs who underwent a single-session of GKRS at our institution between 2007 and 2017 with at least a 2-year minimum follow-up. Follow-up magnetic resonance images were evaluated for newly developed T2 signal changes and the proportions of nidus and intervening parenchyma were quantified. A total of 180 AVM patients (98 males and 82 females) with a median age of 34 years were included in the present study. The overall obliteration rate was 67.8%. The median target volume was 3.65 cc. The median nidus and parenchyma volumes within the 50% IDL were 1.54 cc and 2.41 cc, respectively. RICs were identified in 79 of the 180 patients (43.9%). AVMs associated with previous hemorrhages showed a significant inverse correlation with RICs. In a multivariate analysis, RICs were associated with a higher proportion of brain parenchyma within the 50% IDL (hazard ratio (HR) 169.033; p < 0.001) and inversely correlated with the proportion of nidus volume within the 50% IDL (HR 0.006; p < 0.001). Our study identified that a greater proportion of brain tissue between the nidus within the 50% IDL was significantly correlated with RICs. Nidus angioarchitectural complexity and the absence of a prior hemorrhage were also associated with RICs. The identification of possible predictors of RICs could facilitate radiosurgical planning and treatment decisions as well as the planning of appropriate follow-up after GKRS; this could minimize the risk of RICs, which would be particularly beneficial for the treatment of incidentally found asymptomatic AVMs.

Technical and operative factors affecting magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor: experience from 250 treatments.

OBJECTIVE: Magnetic resonance imaging-guided focused ultrasound (MRgFUS) provides real-time monitoring of patients to assess tremor control and document any adverse effects. MRgFUS of the ventral intermediate nucleus (VIM) of the thalamus has become an effective treatment option for medically intractable essential tremor (ET). The aim of this study was to analyze the correlations of clinical and technical parameters with 12-month outcomes after unilateral MRgFUS thalamotomy for ET to help guide future clinical treatments. METHODS: From October 2013 to January 2019, data on unilateral MRgFUS thalamotomy from the original pivotal study and continued-access studies from three different geographic regions were collected. Authors of the present study retrospectively reviewed those data and evaluated the efficacy of the procedure on the basis of improvement in the Clinical Rating Scale for Tremor (CRST) subscore at 1 year posttreatment. Safety was based on the rates of moderate and severe thalamotomy-related adverse events. Treatment outcomes in relation to various patient- and sonication-related parameters were analyzed in a large cohort of patients with ET. RESULTS: In total, 250 patients were included in the present analysis. Improvement was sustained throughout the 12-month follow-up period, and 184 (73.6%) of 250 patients had minimal or no disability due to tremor (CRST subscore < 10) at the 12-month follow-up. Younger age and higher focal temperature (Tmax) correlated with tremor improvement in the multivariate analysis (OR 0.948, p = 0.013; OR 1.188, p = 0.025; respectively). However, no single statistically significant factor correlated with Tmax in the multivariate analysis. The cutoff value of Tmax in predicting a CRST subscore < 10 was 55.8°C. Skull density ratio (SDR) was positively correlated with heating efficiency (ß = 0.005, p < 0.001), but no significant relationship with tremor improvement was observed. In the low-temperature group, 1-3 repetitions to the right target with 52°C ≤ Tmax ≤ 54°C was sufficient to generate sustained tremor suppression within the investigated follow-up period. The high-temperature group had a higher rate of balance disturbances than the low-temperature group (p = 0.04). CONCLUSIONS: The authors analyzed the data of 250 patients with the aim of improving practices for patient screening and determining treatment endpoints. These results may improve the safety, efficacy, and efficiency of MRgFUS thalamotomy for ET.

The Establishment of a Fast and Safe Orthotopic Colon Cancer Model Using a Tissue Adhesive Technique.

PURPOSE: We aimed to develop a novel method for orthotopic colon cancer model, using tissue adhesive in place of conventional surgical method. MATERIALS AND METHODS: RFP HCT 116 cell line were used to establish the colon cancer model. Fresh tumor tissue harvested from a subcutaneous injection was grafted into twenty nude mice, divided into group A (suture method) and group B (tissue adhesive method). For the group A, we fixed the tissue on the serosa layer of proximal colon by 8-0 surgical suture. For the group B, tissue adhesive (10 µL) was used to fix the tumor. The mortality, tumor implantation success, tumor metastasis, primary tumor size, and operation time were compared between the two groups. Dissected tumor tissue was analyzed for the histology and immunohistochemistry. Also, we performed tumor marker analysis. RESULTS: We observed 30% increase in graft success and 20% decrease in mortality, by using tissue adhesive method, respectively. The median colon tumor size was significantly increased by 4 mm and operation time was shortened by 6.5 minutes. The H&E showed similar tumor structure between the two groups. The immunohistochemistry staining for cancer antigen 19-9, carcinoembryonic antigen, cytokeratin 20, and Ki-67 showed comparable intensities in both groups. Real-time quantitative reverse transcription analysis showed eight out of nine tumor markers are unchanged in the tissue adhesive group. Western blot indicated the tissue adhesive group expressed less p-JNK (apototic marker) and more p-MEK/p-p38 (proliferation marker) levels. CONCLUSION: We concluded the tissue adhesive method is a quick and safe way to generate orthotopic, colon cancer model.

One-Year Outcome of Multiple Blood-Brain Barrier Disruptions With Temozolomide for the Treatment of Glioblastoma.

Introduction: To overcome the blood-brain barrier (BBB) which interferes with the effect of chemotherapeutic agents, we performed multiple disruptions of BBB (BBBD) with magnetic resonance-guided focused ultrasound on patients with glioblastoma (GBM) during standard adjuvant temozolomide (TMZ) chemotherapy [clinical trial registration no.NCT03712293 (clinicaltrials.gov)]. We report a 1-year follow-up result of BBBD with TMZ for GBM. Methods: From September 2018 to January 2019, six patients were enrolled (four men and two women, median age: 53 years, range: 50-67 years). Of the six patients, five underwent a total of six cycles of BBBD during standard TMZ adjuvant therapy. One patient underwent three cycles of BBBD but continued with TMZ chemotherapy. The 1-year follow-up results of these six patients were reviewed. Results: The mean follow-up duration was 15.17 ± 1.72 months. Two patients showed a recurrence of tumor at 11 and 16 months, respectively. One underwent surgery, and the other patient was restarted with TMZ chemotherapy due to the tumor location with a highly possibility of surgical complications. The survival rate up to 1 year was 100%, and the other four patients are on observation without recurrence. None of the six patients had immediate or delayed BBBD-related complications. Conclusion: Multiple BBBDs can be regarded as a safe procedure without long-term complications, and it seems to have some survival benefits. However, since TMZ partially crosses the BBB, a further extended study with large numbers would be needed to evaluate the benefits of BBBD resulting in an increase of TMZ concentration. This study opened a new therapeutic strategy for GBM by combining BBBD with a larger molecular agent.

Functional Neural Changes after Low-Frequency Bilateral Globus Pallidus Internus Deep Brain Stimulation for Post-Hypoxic Cortical Myoclonus: Voxel-Based Subtraction Analysis of Serial Positron Emission.

Post-hypoxic myoclonus (PHM) and Lance-Adams syndrome (LAS) are rare conditions following cardiopulmonary resuscitation. The aim of this study was to identify functional activity in the cerebral cortex after a hypoxic event and to investigate alterations that could be modulated by deep brain stimulation (DBS). A voxel-based subtraction analysis of serial positron emission tomography (PET) scans was performed in a 34-year-old woman with chronic medically refractory PHM that improved with bilateral globus pallidus internus (Gpi) DBS implanted three years after the hypoxic event. The patient required low-frequency stimulation to show myoclonus improvement. Using voxel-based statistical parametric mapping, we identified a decrease in glucose metabolism in the prefrontal lobe including the dorsolateral, orbito-, and inferior prefrontal cortex, which was suspected to be the origin of the myoclonus from postoperative PET/magnetic resonance imaging (MRI) after DBS. Based on the present study results, voxel-based subtraction of PET appears to be a useful approach for monitoring patients with PHM treated with DBS. Further investigation and continuous follow-up on the use of PET analysis and DBS treatment for patients with PHM are necessary to help understanding the pathophysiology of PHM, or LAS.

Gamma Knife Radiosurgery Followed by Flow-Reductive Embolization for Ruptured Arteriovenous Malformation.

: Background: Aggressive treatment to achieve complete obliteration of brain arteriovenous malformation (AVM) is necessary in patients with a recent history of hemorrhage. The major drawback of Gamma knife radiosurgery (GKRS) alone for AVM is risk of bleeding during the latent period until the AVM occludes. At our center, patients who present with ruptured AVMs are frequently offered GKRS followed by embolization. The goal of this study was to compare outcomes of embolization for patients who have previously undergone GKRS for ruptured AVMs. METHODS: A database including 150 GKRS for ruptured AVMs between November 2008 and October 2017 was reviewed. The embolized group was selected by including AVMs with post-GKRS embolization. The non-embolized group was defined as AVMs treated by GKRS alone. Outcomes including obliteration rate, incidence of repeat hemorrhage, and delayed cyst formation were compared between two groups. The predictive factors related to AVM obliteration and complications were analyzed. RESULTS: The study consisted of 81 patients in the non-embolized group and 17 patients in the embolized group. Statistically significant differences were detected between the two groups with respect to age, Pollock-Flickinger score, Spetzler-Martin (SM) grade, eloquence of adjacent brain, and presence of aneurysms. The embolized group included more AVMs with larger median nidus volume. The predictive factors for the obliteration of ruptured AVMs were nidus volume, SM grade, Virginia Radiosurgery AVM Scale (VRAS), and Pollock-Flickinger score and for the subsequent hemorrhage were marginal dose, nidus volume, SM grade, VRAS, and Pollock-Flickinger score. The obliteration rates and complication rates after GKRS between groups were not significantly different. However, this study demonstrated statistically significant difference in the cumulative incidence of obliteration in AVMs with SM grade III and IV (p = 0.037). CONCLUSION: Although the current study demonstrated similar results in patients who underwent GKRS with and without embolization, the embolized group included more AVMs with larger nidus volume, higher SM grade, Pollock-Flickinger score, and aneurysm, which have a lower chance of obliteration and a higher probability of repeat hemorrhage. GKRS followed by embolization appears to be a beneficial approach for the treatment of ruptured AVMs that are at risk for obliteration failure and repeat hemorrhage during the latency period after single-session GKRS alone. Further studies involving a larger number of cases and continuous follow-up are necessary to confirm our conclusions.