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Background: Contemporary thrombolytics in acute ischemic stroke are limited to administration within 4.5 hours of last known normal. JX10 (formerly TMS-007), a Stachybotrys microspora triprenyl phenol family member, may extend this therapeutic window., Methods: In this multicenter, randomized, double-blind, placebo-controlled, dose-escalation phase 2a study, JX10 or placebo was administered as a single intravenous infusion to Japanese patients with acute ischemic stroke who were unable to receive tissue-type plasminogen activator or thrombectomy within 12 hours of last known normal. Primary end point was incidence of symptomatic intracranial hemorrhage with a worsening National Institutes of Health Stroke Scale score of ≥4 points within 24 hours of drug administration (symptomatic intracranial hemorrhage incidence)., Results: Ninety patients received either placebo (n=38; female 26.3%) or JX10 at 1, 3, or 6 mg/kg (n=6, 18, 28; female 0%, 33.3%, and 42.9%, respectively). Median age (range) and baseline median (range) National Institutes of Health Stroke Scale scores were respectively 76.5 (42-87) and 8 (6-21) for the combined JX10 cohort (JX10 Cohorts) and 75.0 (34-85) and 8 (6-22) for placebo. Median (range) dosing time since last known normal was 9.5 (5.0-12.1) and 10.0 (3.7-12.0) hours for JX10 Cohorts and placebo, respectively. Symptomatic intracranial hemorrhage incidence was 0% (0/52 [95% CI, 0.0-5.6]) for JX10 Cohorts versus 2.6% (1/38 [95% CI, 0.1-13.8]) for placebo ( P =0.42). Vessel patency at 24 hours (secondary end point) in patients with baseline arterial occlusive lesion score <3 (39/90) improved in 58.3% (14/24) of patients in JX10 Cohorts versus 26.7% (4/15) for placebo (odds ratio, 4.23 [95% CI, 0.99-18.07]). In JX10 Cohorts, a significantly higher proportion of patients had modified Rankin Scale scores of 0 to 1 on day 90 (secondary end point) versus placebo (JX10: 21/52, 40.4% versus placebo: 7/38, 18.4%; P =0.03)., Conclusions: JX10 was well tolerated and may expand the acute ischemic stroke therapeutic window as a novel thrombolytic agent., Registration: URL: https://rctportal.niph.go.jp/en; Unique identifier: jRCT2080223786., Competing Interests: Dr Niizuma reports study funding and article processing charges from TMS Co, Ltd. Dr Nishimura was a TMS Co, Ltd, employee during the conduct of the study, owns TMS Co, Ltd, stocks and stock options, and reports consulting fees from TMS Co, Ltd, as well as recipient of license fees for JX10-related patents. K. Hasegawa is an employee and shareholder of TMS Co, Ltd, and reports license fees for JX10-related patents. Dr Hasumi is a Director of the Board and shareholder of TMS Co, Ltd, an employee of Tokyo University of Agriculture and Technology, and reports grants from TMS Co, Ltd, and EPS Corporation, as well as license fees for JX10-related patents. Dr Wald is an employee and shareholder of Biogen. Dr Bell is a former employee of Biogen Inc. Drs Kuribayashi and Toda are employees of Biogen Japan Ltd and shareholders of Biogen Inc. Dr Tominaga declares consulting fees and license fees for a JX10-related patent from TMS Co, Ltd. The other authors report no conflicts.

Superficial epithelial gastric neoplasms can be divided into adenomas and early carcinomas. Histological diagnosis by endoscopic forceps biopsy is crucial for the diagnosis and management of gastric neoplasms. It is difficult to distinguish features of gastric neoplasms in small biopsy specimens; hence, gastric carcinomas can be underdiagnosed as adenomas. Recent developments in image-enhanced endoscopy have improved the ability to differentiate between carcinomatous and non-carcinomatous lesions. To investigate the prevalence of gastric carcinoma in lesions initially diagnosed as adenomas by forceps biopsy and assess the usefulness of image-enhanced endoscopy in distinguishing carcinomas. A total of 142 lesions of gastric adenomas, diagnosed by biopsy and resected endoscopically between January 2010 and May 2020, were retrospectively evaluated. Images were captured by white-light endoscopy (WLE), magnifying endoscopy with narrow-band imaging (M-NBI), and magnifying endoscopy with acetic acid and narrow-band imaging (M-AANBI); they were analyzed and compared with histopathological results. The diagnostic performance of M-AANBI was compared with that of M-NBI. Of the 142 lesions, 58 (40.8%) were pathologically diagnosed as adenocarcinomas. On WLE images, a depressed macroscopic type and size ≥20 mm were significant predictors of carcinoma (P < .001); however, they displayed low sensitivities (32.8% and 41.4%, respectively). M-AANBI displayed significantly higher sensitivity, specificity, and accuracy for distinguishing carcinomas than M-NBI (94.8% vs 74.1%, 81.0% vs 72.6%, and 86.6% vs 73.2%, P < .05). In conclusion, carcinoma was prevalent in 40.8% of gastric lesions initially diagnosed as adenomas by forceps biopsy. M-AANBI may be more useful than M-NBI and WLE in distinguishing gastric carcinomas from adenomas., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Thymic carcinoma (TC) presenting with cardiac tamponade has a poor prognosis because of the difficulty in controlling malignant pericardial effusion using conventional chemotherapy. Lenvatinib, a multitargeted kinase inhibitor of vascular endothelial growth factor receptor and other kinases, has recently been proven effective against TC. As the inhibition of vascular endothelial growth factor signaling is effective in malignant pericardial effusion, lenvatinib may also be effective in TC presenting with cardiac tamponade. However, no reports have shown that lenvatinib is effective in such cases. Herein, we present a case of successful treatment with lenvatinib in a patient with TC presenting with cardiac tamponade. The present case suggests that lenvatinib should be considered an effective treatment option for such cases., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Adoption of interventional endoscopic procedures is increasing with increasing prevalence of diseases. However, medical radiation exposure is concerning; therefore, radiation protection for medical staff is important. However, there is limited information on the usefulness of an additional lead shielding device during interventional endoscopic procedures. Therefore, we aimed to determine whether an additional lead shielding device protects medical staff from radiation.An X-ray unit (CUREVISTA; Hitachi Medical Systems, Tokyo, Japan) with an over-couch X-ray system was used. Fluoroscopy-associated scattered radiation was measured using a water phantom placed at the locations of the endoscopist, assistant, nurse, and clinical engineer. For each location, measurements were performed at the gonad and thyroid gland/eye levels. Comparisons were performed between with and without the additional lead shielding device and with and without a gap in the shielding device. Additionally, a clinical study was performed with 27 endoscopic retrograde cholangiopancreatography procedures.The scattered radiation dose was lower with than without additional lead shielding at all medical staff locations and decreased by 84.7%, 82.8%, 78.2%, and 83.7%, respectively, at the gonad level and by 89.2%, 86.4%, 91.2%, and 87.0%, respectively, at the thyroid gland/eye level. Additionally, the scattered radiation dose was lower without than with a gap in the shielding device at all locations.An additional lead shielding device could protect medical staff from radiation during interventional endoscopic procedures. However, gaps in protective equipment reduce effectiveness and should be eliminated.

Rationale: Although metastases to the oral and maxillofacial region (OMR) are rare, the lung is the most common primary site metastasizing to the OMR., Patient Concerns: An 83-year-old woman presented with reports of trismus, occlusal discomfort, swelling, and spontaneous pain in the right buccal region. Despite the absence of abnormal chest imaging findings, immunohistochemical analysis of biopsy specimens of the mandible and the thyroid indicated that the patient had multiple metastases from a lung poorly differentiated adenocarcinoma., Diagnoses: Metastases to the OMR and the thyroid from an undiscovered lung adenocarcinoma., Interventions: Gefitinib was started as first-line chemotherapy, and zoledronic acid was administered for bone metastases., Outcomes: Follow-up imaging examinations showed ossification and deformation of the right mandibular ramus and the condylar process. Although 2 years have passed since the first visit to our hospital, lung lesions have not been confirmed by imaging examinations., Lessons: Clinicians should consider the possibility that symptoms in the OMR may be the first clinical sign of an undiscovered distant primary tumor, and the primary tumors may not be detected by imaging examinations even when metastases to the OMR are revealed.

Background: Nanoparticle albumin-bound paclitaxel (nab-PTX), which avoids toxicities associated with a vehicle used in solvent-based PTX, has already shown safety and efficacy in patients with non-small cell lung cancer (NSCLC)., Methods: A phase II study was performed to assess the safety and efficacy of nab-PTX monotherapy as second-line chemotherapy after cytotoxic anticancer drugs for previously treated advanced NSCLC. Thirty-two patients with advanced NSCLC who had previously undergone 1 regimen of cytotoxic anticancer drugs were enrolled. Nab-PTX was administered intravenously at a dose of 100 mg/m on days 1, 8, and 15 of a 28-day cycle. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and toxicity profile were evaluated., Results: The ORR was 28.1%, the DCR was 71.9%, median PFS was 3.9 months (95% confidence interval [CI] 2.7-5.1 months), and median OS was 10.9 months (95% CI 9.5-12.3 months). The mean relative dose intensity of nab-PTX was 77%. Grade 3 or 4 neutropenia, and grade 3 febrile neutropenia were observed in 11 and 1 of 32 patients, respectively. As nonhematologic toxicities, grade 3 peripheral sensory neuropathy and pneumonitis were each observed in 2 of 32 patients., Conclusion: Nab-PTX is an active and well-tolerated regimen in patients with previously treated NSCLC., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Post orthotopic liver transplantation (OLT) viral hepatitis is an immunological condition where immune cells induce hepatitis during conditions of immune-suppression. The immune-regulatory programmed death-1 (PD-1)/PD-ligand 1 system is acknowledged to play important roles in immune-mediated diseases. However, the PD-1/PD-L2 interaction is not well characterized, with PD-L2 also exhibiting an immunostimulatory function. We hypothesized that this atypical molecule could affect the recurrence of post-OLT hepatitis. To test this hypothesis, we conducted immunohistochemical staining analysis and in vitro analysis of PD-L2., Methods: The expression of PD-L2 was evaluated in liver biopsy specimens from patients with chronic hepatitis B (n = 15), post-OLT hepatitis B (n = 8), chronic hepatitis C (n = 48), and post-OLT hepatitis C (CH-C-OLT) (n = 14). The effect of calcineurin inhibitors (CNIs) and hepatitis C virus (HCV) on PD-L2 expression was investigated in hepatoma cell lines., Results: The PD-L2 was highly expressed on CH-C-OLT hepatocytes. Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein. Transfection of cell lines with PD-L2 containing plasmid resulted in high intercellular adhesion molecule-1 (ICAM-1) expression, which might enhance hepatitis activity., Conclusions: The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1. These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C.

Background and Purpose: We determined which hemodynamic parameter independently characterizes the rupture status of middle cerebral artery (MCA) aneurysms using computational fluid dynamics analysis., Methods: In 106 patient-specific geometries of MCA aneurysms (43 ruptured, 63 unruptured), morphological and hemodynamic parameters were compared between the ruptured and unruptured groups. Multivariate logistic regression analysis was performed to determine parameters that independently characterized the rupture status of MCA aneurysms., Results: Univariate analyses showed that the aspect ratio, wall shear stress (WSS), normalized WSS, oscillatory shear index, WSS gradient, and aneurysm-formation index were significant parameters. The size of the aneurysmal dome and the gradient oscillatory number were not significantly different between the 2 groups. With multivariate analyses, only lower WSS was significantly associated with the rupture status of MCA aneurysms., Conclusions: WSS may be the most reliable parameter characterizing the rupture status of MCA aneurysms.

Background and Purpose: Preventing cerebral embolisms is a major concern with carotid artery stenting (CAS). This study evaluated 3-dimensional T1-weighted gradient echo (3D T1GRE) sequence to predict cerebral embolism related to CAS., Methods: We performed quantitative analyses of the characteristics of 47 carotid plaques before CAS by measuring the signal intensity ratio (SIR) and plaque volume using 3D T1GRE images. We used T1-weighted turbo field echo sequence to obtain 3D T1GRE images. We also evaluated diffusion-weighted images (DWI) of the brain before and after CAS to detect ischemic lesions (DWI lesions) from cerebral emboli., Results: SIR (2.17 [interquartile range 1.50-3.07] versus 1.35 [interquartile range 1.08-1.97]; P=0.010) and plaque volume (456 mm(3) [interquartile range 256-696] versus 301 mm(3) [interquartile range 126-433]; P=0.008) were significantly higher in the group of patients positive for DWI lesions (P-group: n=26) than DWI lesion-negative patients (N-group: n=21). In multivariate logistic regression analysis, SIR (P=0.007) and plaque volume (P=0.042) were independent predictors of DWI lesions with CAS. Furthermore, SIR (rs=0.42, P=0.005) and plaque volume (rs=0.36, P=0.012) were positively correlated with the number of DWI lesions. From analysis of a receiver-operating characteristic curve, the most reliable cutoff values of SIR and plaque volume to predict DWI lesions related to CAS were 1.80 and 373 mm(3), respectively., Conclusions: Quantitative evaluation of carotid plaques using 3D T1GRE images may be useful in predicting cerebral embolism related to CAS.

Background and Purpose: We developed a novel dynamic 4-dimensional CT angiography to accurately evaluate dynamics in cerebral aneurysm., Methods: Dynamic 4-dimensional CT angiography achieved high-resolution 3-dimensional imaging with temporal resolution in a beating heart using dynamic scanning data sets reconstructed with a retrospective simulated R-R interval reconstruction algorithm., Results: Movie artifacts disappeared on dynamic 4-dimensional CT angiography movies of 2 kinds of stationary phantoms (titanium clips and dry bone). In the virtual pulsating aneurysm model, pulsation on the dynamic 4-dimensional CT angiography movie resembled actual movement in terms of pulsation size. In a clinical study, dynamic 4-dimensional CT angiography showed 2-type motions: pulsation and anatomic positional changes of the cerebral artery., Conclusions: This newly developed 4-dimensional visualizing technique may deliver some clues to clarify the pathophysiology of cerebral aneurysms.

Background: The small-for-size (SFS) syndrome is caused by excessive portal inflow into a small-sized liver graft. Various approaches for portal decompression have been used, but details of their impact on liver regeneration in SFS graft remain unclear. We examined the effect of prophylactic splenic artery modulation (SAM)., Methods: We conducted a retrospective cohort study. The study group was 39 consecutive adult-to-adult living liver transplantation recipients, with a graft-to-recipient body weight ratio of less than 0.8. Patients were assigned into the non-SAM group (n=18, without any portal inflow attenuation) or SAM group (n=21, preoperative embolization in 15 patients and intraoperative ligation in 6 patients). Hepatic hemodynamics, graft function, liver regeneration, and outcome were evaluated., Results: In the SAM group, the excessive portal flow was significantly reduced (P<0.01) and the effect of embolization on portal decompression was equivalent to that of ligation. In the acute postoperative phase, serum transaminases, interleukin-6, and tumor necrosis factor-alpha, were lower in the SAM group than in non-SAM group. In both groups, a negative correlation was observed between graft-to-recipient body weight ratio and liver regeneration rate at 2 weeks after living donor liver transplantation. Splenic artery modulation was advantageous for liver regeneration, and significantly improved clinical features, hyperbilirubinemia, and prolonged ascites. Small-for-size syndrome occurred in five patients of the non-SAM group, and only one of SAM group (P=0.038)., Conclusion: In SFS graft with severe portal hypertension, prophylactic splenic embolization/ligation seems to relieve portal overperfusion injury and contributes in improvement of posttransplantation prognosis through liver regeneration.

Background: The negative effects of increased donor age on liver transplantation became evident in deceased donor liver transplantation. In living donor liver transplantation (LDLT), the details remain unclear., Methods: Initially, 137 adult LDLT recipients from August 1996 to May 2005 were divided into two groups (donors <50 years of age: n=99, donors >or= 50 years of age: n=38) for the retrospective study. Then, 24 recipients who received LDLT from June 2005 to July 2006 were divided into two groups: group 1 (donors <50 years of age, n=14) and group 2 (donors >or= 50 years of age, n=10) and enrolled in the prospective study to analyze their clinical course and prognostic factors in the aged graft., Results: In the retrospective study, the younger donor group had significantly better survival than that of the aged donor group (P=0.015, Log rank test). In the prospective study, the postoperative graft functions showed that the serum total bilirubin levels were significantly lower in group 1 (P<0.02, by ANOVA analysis). The phosphorylated-Signal Transducer and Activator of Transcription3 expression at 4 hr after reperfusion (RT2) in group 2 was significantly lower than that in group 1. At RT2, the expressions were up-regulated in group 1, but were down-regulated in group 2. The serum 8-hydroxydeoxyguanosine value became significantly higher in group 1 two weeks after LDLT., Conclusions: In the near term, Signal Transducer and Activator of Transcription3 gene induction during cold preservation may be of great use in improving the outcome of aged grafts in LDLT.

Hepatitis B immunoglobulin (HBIg) and lamivudine combination has been accepted as the best way to control hepatitis B recurrence after liver transplantation. However, the optimal dose of HBIg and the target titer of hepatitis B surface antibody (HBsAb) remain unclear. We report our satisfactory experience with high-dose HBIg in the early period followed by low-dose HBIg with lamivudine. Subjects comprised five patients with fulminant hepatitis (FH) and 18 patients with liver cirrhosis (LC) who underwent liver transplantation. HBIg at a dosage of 200 IU/kg per day was administered for one week postoperatively. Thereafter, HBIg was administered only for HBsAb titer <100 IU/L. After six months, HBIg was withdrawn in FH and administered in LC only for HBsAb titer <10 IU/L. Lamivudine was administered to two FH and all LC cases. Although two patients with LC showed transient hepatitis B surface antigen (HBsAg) recurrence, all patients remained HBsAg-negative at the final follow-up date. This method allows reliable and cost-effective control of hepatitis B recurrence.

Objective: The purposes of this study were to establish a quantitative method for evaluating rabbit tear film status and investigate the efficacy of artificial tear preparations through ocular surface bathing or eye drop application., Methods: The rabbit tear film was evaluated using a noninvasive specular reflection video recording system. The appearance of a tear break area (TBA) on the tear film images (7.4 mm2/mm) after 30 seconds of eye opening was quantified by image analysis. To induce disruption of the rabbit tear film, the ocular surface was challenged for 60 minutes with 1 ppm hypochloric acid (HOCl). Immediately after irrigation, artificial tear preparations composed of viscosity agents sodium hyaluronate (SH), hydroxypropylmethycellulose (HPMC), hydroxyethylcellulose (HEC), or chondroitin sulfate (CS) were applied to the rabbit eye through ocular surface bathing or eye drop application, and the recovery of the disrupted tear film was compared for each preparation., Results: A dramatic increase in TBA was observed immediately after the ocular surface was challenged with HOCl, and it returned to the initial level after 6 hours. Immediately after ocular surface bathing and eye drop application, a dramatic recovery of TBA was observed in all the test solution-treated eyes. One hour after treatments, prolonged amelioration of the tear film instability was observed after ocular surface bathing, but not by eye drop application, with the artificial tear preparations composed of HPMC or SH., Conclusion: Ocular surface bathing with artificial tear preparations composed of a suitable viscosity agents could be useful in managing tear film instability.

Several techniques for gene transfer into the heart have been developed, including direct injection of naked plasmid DNA into the myocardium and coronary infusion of various viral vectors. However, complications and side effects with those methods have been reported. In this study, to resolve these problems, the authors investigated the feasibility of nonviral gene transfer into the beating heart with the hand held gene gun. The genes pCAGGS/CTLA4-EGFP were coated around the surface of gold particles. Three sizes of gold particles (0.6, 1.0, and 1.6 microm in diameter) and three settings of helium gas pressure (200, 250, and 300 psi) were examined. Gene transfer into the rat beating heart was performed using the hand held gene gun. EGFP expressions were detected by fluorescence microscopy from day 1 to 3 weeks after bombardment. The most prominent expressions were detected with the combination of 1.0 microm gold particles and 300 psi helium gas pressure. In this study, the present authors showed that non-viral gene transfer into the beating heart was feasible with the hand held gene gun. This technique is effective for gene transfer into the heart and may be one of the most useful methods for gene therapy for many cardiovascular diseases in the future.

Early-morning blood pressure is generally viewed as an important therapeutic target, for two reasons. First, for antihypertensive agents taken once daily in the morning, the timing of the trough plasma drug level, and thereby the lowest pharmacodynamic effect, often coincides with the early morning rise in blood pressure and heart rate. Evidence has been accumulated to suggest that blood pressure control throughout the 24 h period may be necessary to gain complete benefit from antihypertensive medication. In fact, in a longitudinal study, the regression of cardiac hypertrophy in patients with hypertension was more accurately predicted by treatment-induced changes in average 24 h ambulatory blood pressure than by clinic or home-monitored blood pressure readings. The other reason for the importance of morning blood pressure is that cardiovascular risk is heightened at this time of day. A morning surge in sympathetic activity alters haemodynamic forces and predisposes vulnerable coronary atherosclerotic plaques to rupture. At the same time as this risk of plaque rupture is greatest, circadian variations in haemostatic and fibrinolytic factors result in morning hypercoagulability and hypofibrinolysis, promoting the formation of intraluminal thrombi. We recently showed that, in older hypertensives, a greater morning blood pressure surge, mediated at least in part by an exaggerated alpha-sympathetic activity, is associated with more advanced silent cerebrovascular disease as well as a higher future incidence of stroke. The early morning surge in blood pressure could become a new therapeutic target for preventing target-organ damage and subsequent cardiovascular events in hypertension. Of greatest interest is the potential benefit of a chronotherapeutic approach, involving, for example, long-acting chronoformulations, which has not yet been extensively studied.

The specific vasopressin receptor of V1 vascular subtype, which mediates platelet aggregation, has been found on human platelets. We investigated the binding characteristics using tritiated arginine vasopressin [3H]-AVP and platelet aggregation with AVP turbidometrically in normal subjects, patients with WHO class II essential hypertension and patients with malignant-phase hypertension. In essential hypertensives Bmax was significantly higher than that in normal subjects, but there were no differences in affinity and the maximal percentage aggregation between them. In malignant-phase hypertensives Bmax and maximal percentage aggregation were significantly lower than those in normals and essential hypertensives, although there was no difference in the affinity between them. With radio-immunoassay, the mean platelet-free plasma AVP level was significantly higher in malignant-phase hypertensives than those in normals and essential hypertensives, whereas there was no difference in mean platelet AVP levels between them. In essential hypertensives Bmax and maximal percentage aggregation did not change, but in malignant-phase hypertensives Bmax increased significantly and maximal percentage aggregation tended to normalize after treatment.