Clinicopathological features of immunoglobulin G4-related constrictive pericarditis.

AIM: Constrictive pericarditis (CP) is characterised by scarring fibrosis and a loss of pericardial elasticity, which causes heart failure. IgG4 (immunoglobulin G4)-related disease (IgG4-RD) is a systemic fibro-inflammatory disease characterised by the infiltration of IgG4-immunopositive plasmacytes and high serum IgG4 levels that frequently shape tumorous lesions. Although pericardial involvement of IgG4-RD is rare, with indications of CP, pericardial effusion and irregular masses, the clinical and pathological features remain unclear. In this study, we examined the relationship between CP and IgG4-RD. METHODS: Among 35 thick-walled CP cases (histologically pericardial thickening ≥2 mm), eight cases were aetiology identified. Using the diagnostic criteria for IgG4-RD, 11 cases were classified as IgG4-CP, whereas the remainder were considered true idiopathic CP (16 cases) and the clinical pathological features were evaluated. RESULTS: Compared with the other groups, the IgG4-CP group was more common in men and associated with low-grade fever and massive pericardial effusion with frequent recurrence. Deaths resulting from heart failure occurred in a few cases of the IgG4-CP group, but not in other groups. An increase in C-reactive protein and a high positivity rate of anti-nuclear antibodies frequently occurred in the IgG4-CP group. Histologically, the IgG4-CP group included lymphoid follicle, eosinophil infiltration and few calcifications. CONCLUSIONS: Pericardial IgG4-RD occurs not only as nodular lesions, but also as thick-walled CP, and accounts for approximately 40% of thick-walled CP cases of unknown cause. The predominant clinical characteristic was refractory and recurrent pericardial effusion. Recognising IgG4-RD as a cause of CP is important to initiate appropriate therapy.

Trends and Progress in Neuroendovascular Treatment in Japan: Japanese Registry of Neuroendovascular Therapy (JR-NET) 4. Main Report.

We reported the main results of the Japanese Registry of Neuroendovascular Therapy (JR-NET) 4, a nationwide surveillance of therapy (NET) in Japan from January 2015 to December 2019. JR-NET 4 registered consecutive patients who underwent NETs by Japan Society of Neuroendovascular Therapy (JSNET) -certified specialists. The primary endpoint was functional independence (mRS score of 0-2) at 30 days post-NET, with secondary endpoints focusing on technical success and major adverse events within 30 days.A total of 63,230 patients and 60,354 NET procedures from 166 participating centers were analyzed. During the study period, NET cases have consistently increased, with an increase in the proportion of elderly patients. A significant trend shift was observed in the distribution of NET procedures, with endovascular treatment for acute ischemic stroke that showed a dramatic increase in 5 years. This trend aligns with key randomized clinical trials from 2015 that presented the efficacy of this treatment. Clinical outcomes at 30 days posttreatment revealed that endovascular treatment for acute ischemic stroke and other NETs maintained safety and effectiveness despite varying prevalence of functional independence between target diseases. The study also observed a steady increase in emergency treatment cases, reflecting the increase in acute ischemic stroke, a time-sensitive medical condition.This comprehensive surveillance highlights the trend of NET practices in Japan, driven by clinical evidence and advancements in treatment devices. Although these findings were specific to Japan, they offer valuable insights into the broader trends in NETs and acute stroke care.

Expanding the Treatable Imaging Profile in Patients With Large Ischemic Stroke: Subanalysis From a Randomized Clinical Trial.

BACKGROUND: We aimed to examine the boundary of the ischemic core volume in patients undergoing endovascular thrombectomy (EVT) versus those receiving medical management to determine the minimum optimal size for favorable treatment outcomes. METHODS: This is a prespecified substudy of the RESCUE-Japan LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Large Ischemic Core Trial). Patients with large vessel occlusion were enrolled between November 2018 and September 2021 with a National Institutes of Health Stroke Scale score of at least 6 on admission and an Alberta Stroke Program Early Computed Tomography Score value of 3 to 5. We investigated the correlation between optimal quantified ischemic core volume, assessed solely using magnetic resonance diffusion-weighted imaging, and functional outcomes (modified Rankin Scale score, 0-3) at 90 days by predictive marginal plots. Final infarct volume and safety outcomes (symptomatic intracerebral hemorrhage and mortality) were also assessed. RESULTS: Of the 203 cases, 168 patients (85 in the EVT group versus 83 in the medical management group) were included. The median (interquartile range) core volume was 94 (65-160) mL in patients with EVT and 115 (71-141) mL in the medical management group (P=0.72). The predictive marginal probabilities of the 2 groups intersected at 128 mL for estimating functional outcomes. Symptomatic intracerebral hemorrhage and mortality within 90 days had overlay margins through all core volumes in both groups. The median final infarct volume (interquartile range) was smaller in the EVT group (142 [80-223] mL versus 211 [123-289] mL in the medical management group; P<0.001). CONCLUSIONS: In this prespecified analysis of a randomized clinical trial involving patients with large ischemic strokes, patients with an estimated core volume of up to 128 mL on diffusion-weighted imaging benefit from EVT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03702413.

Super-selective injection of propofol into the intracranial arteries enables Patient's self-evaluation of expected neurological deficit.

INTRODUCTION: It is hard to realize the extent of the expected postoperative neurological deficit for patients themselves. The provision of appropriate information can contribute not only to examining surgical indications but also to filling the gap between patient and expert expectations. We hypothesized that propofol infusion into the intracranial arteries (ssWada) could induce focal neurological symptoms with preserved wakefulness, enabling the patients to evaluate the postsurgical risk subjectively. METHODS: Presurgical evaluation using ssWada was performed in 28 patients with drug-resistant epilepsy. Based on anatomical knowledge, propofol was super-selectively infused into the intracranial arteries including the M1, M2, and M3 segments of the middle cerebral artery (MCA), A2 segment of the anterior cerebral artery, and P2 segment of the posterior cerebral artery to evaluate the neurological and cognitive symptoms. We retrospectively analyzed a total of 107 infusion trials, including their target vessels, and elicited symptoms of motor weakness, sensory disturbance, language, unilateral hemispatial neglect (UHN), and hemianopsia. We evaluated preserved wakefulness which enabled subjective evaluations of the symptoms and comparison of the subjective experience to the objective findings, besides adverse effects during the procedure. RESULTS: Preserved wakefulness was found in 97.2% of all trials. Changes in neurological symptoms were positively evaluated for motor weakness in 51.4%, sensory disturbance in 5.6%, language in 48.6%, UHN in 22.4%, and hemianopsia in 32.7%. Six trials elicited seizures. Multivariate analysis showed significant correlations between symptom and infusion site of language and left side, language and MCA branches, motor weakness and A2 or M2 superior division, and hemianopsia and P2. Transient adverse effect was observed in 8 cases with 12 infusion trials (11.2 %). CONCLUSION: The ssWada could elicit focal neurological symptoms with preserved wakefulness. The methodology enables specific evaluation of risk for cortical resection and subjective evaluation of the expected outcome by the patients.

Endovascular Treatment of Wide-Neck Bifurcation Aneurysm: Recent Trends in Coil Embolization with Adjunctive Technique.

Wide-neck bifurcation aneurysms (WNBAs) are sometimes challenging to treat. During endovascular treatment, it is important to prevent coil deviation and preserve normal vessels. Adjunctive balloon- and stent-assisted techniques have been developed. A meta-analysis of endovascular treatments of WNBAs revealed that only 40% of patients had complete occlusion. Recently, novel devices have been developed to expand the range of treatment options. Flow-diverter stents and intra-aneurysmal flow disruption devices do not require coils; however, coil embolization remains the standard procedure used by many neurointerventionists. This review describes the recent trends in adjunctive techniques for supporting coil embolization for WNBAs. We referred to literature on balloon-assisted techniques, stent-assisted techniques, Y-stenting, PulseRider, Barrel stents, Comaneci temporary stents, pCONUS, and eCLIPs. These reports showed that adequate embolization rates were generally greater than 80%, and the complete occlusion rate was as high as 94.6%. All devices had a relatively high occlusion rate; however, it may be inaccurate to simply compare each device because of the heterogeneity of the studies. It is important to select the best treatment for each individual case by considering not only literature-based efficacy and safety but also patient background, aneurysm characteristics, and operator experience.

Validation of the Diagnostic Criteria for IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis (IgG4PA/RPF) 2018, and Proposal of a Revised 2023 Version for IgG4-Related Cardiovascular/Retroperitoneal Disease.

BACKGROUND: In 2018, diagnostic criteria were introduced for IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis (PA/RPF). This study assessed the existing criteria and formulated an improved version.Methods and Results: Between August 2022 and January 2023, we retrospectively analyzed 110 Japanese patients diagnosed with IgG4-related disease (IgG4-RD) involving cardiovascular and/or retroperitoneal manifestations, along with 73 non-IgG4-RD patients ("mimickers") identified by experts. Patients were stratified into derivation (n=88) and validation (n=95) groups. Classification as IgG4-RD or non-IgG4-RD was based on the 2018 diagnostic criteria and various revised versions. Sensitivity and specificity were calculated using experts' diagnosis as the gold standard for the diagnosis of true IgG4-RD and mimickers. In the derivation group, the 2018 criteria showed 58.5% sensitivity and 100% specificity. The revised version, incorporating "radiologic findings of pericarditis", "eosinophilic infiltration or lymphoid follicles", and "probable diagnosis of extra-PA/-RPF lesions", improved sensitivity to 69.8% while maintaining 100% specificity. In the validation group, the original and revised criteria had sensitivities of 68.4% and 77.2%, respectively, and specificities of 97.4% and 94.7%, respectively. CONCLUSIONS: Proposed 2023 revised IgG4-related cardiovascular/retroperitoneal disease criteria show significantly enhanced sensitivity while preserving high specificity, achieved through the inclusion of new items in radiologic, pathological, and extra-cardiovascular/retroperitoneal organ categories.

Injury to the Muscle Layer and Risk of Non-cardiac Chest Pain after Endoscopic Submucosal Dissection for Esophageal Cancer.

BACKGROUND AND AIMS: Non-cardiac chest pain (NCCP) is a frequent complication of endoscopic submucosal dissection (ESD) for early-stage esophageal cancer. However, little is known about relationships between ESD findings and NCCP. This study aims to evaluate the risk factors for NCCP, including ESD findings related to injury to the muscle layer. METHODS: We enrolled a total of 296 lesions from 270 patients with esophageal squamous cell carcinoma (ESCC), who underwent ESD in our center. The grade of injury to the muscle layer caused by ESD was categorized as follows: grade 0: no exposure of muscularis propria; grade 1: muscularis propria exposure and/or whitish color change by the electrocoagulation; grade 2: torn muscularis propria with whitish color change by the electrocoagulation; and grade 3, esophageal perforation. The risk factors for NCCP, including ESD findings, were analyzed by univariate and multivariate analyses. RESULTS: NCCP occurred in 89 patients (33.0%) after esophageal ESD. Multivariate analysis demonstrated that younger age [odds ratio (OR) 0.95, 95% confidence interval (95%CI) 0.92-0.98, p=0.003), postoperative fever (>= 38°C) (OR=25.9, 95%CI: 2.89-232.10, p=0.004), ESD findings (grade 1: OR=3.99, 95%CI: 1.63-9.75, p=0.003 and grade 2: OR=3.18, 95%CI: 1.54-6.57, p=0.002) were independently associated with the incidence of post ESD NCCP. CONCLUSIONS: ESD findings relate to slight Injury to the muscle layer, such as muscularis propria exposure and whitish color change by the electrocoagulation were identified as risk factor for post ESD NCCP. We should therefore perform esophageal ESD carefully to avoid injuring the muscle layers.

Short- versus long-term Dual AntiPlatelet Therapy for Stent-Assisted treatment of CErebral aneurysm (DAPTS ACE): a multicenter, open-label, randomized clinical trial.

BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) after stent-assisted coil embolization (SACE) for cerebral aneurysm remains uncertain. This randomized trial of short- versus long-term Dual AntiPlatelet Therapy for Stent-Assisted treatment of CErebral aneurysm (DAPTS ACE) aimed to clarify whether long-term DAPT can reduce the occurrence of ischemic stroke in patients with cerebral aneurysms treated by SACE compared with short-term DAPT. METHODS: Patients treated for cerebral aneurysm with SACE were enrolled from 17 hospitals in Japan. Patients were enrolled within 30 days after SACE and assigned in a 1:1 ratio to receive long-term (12 months) or short-term (3 months) DAPT with aspirin and clopidogrel. Randomization was performed centrally through a web-based system. The primary outcome was the time to ischemic stroke event during 3 to 12 months after SACE. This trial was registered with the Japan Registry of Clinical Trials (jRCTs051180141). RESULTS: A total of 142 patients were recruited from November 4, 2016 to January 7, 2019. Among them, 65 and 68 patients assigned to the long- and short-term DAPT groups, respectively, were included in the full analysis set. Ischemic stroke occurred in no patients in the long-term DAPT group and in one patient in the short-term DAPT group. The incidence rate did not differ between the groups (0.0 vs 2.1/100 person-years; log rank test, P=0.33). CONCLUSIONS: In this multicenter randomized controlled trial, there was not a statistically significant difference in the rate of ischemic strokes between long- and short-term DAPT.

Disordered Balance of T-Cell Subsets in Arterial Tertiary Lymphoid Organs in Immunoglobulin G4-Related Vascular Disease.

BACKGROUND: Arterial/aortic tertiary lymphoid organs (ATLOs), characterized by germinal centers, control local arterial immune responses. T follicular helper cells (Tfh), resident in germinal centers, regulate immunoglobulin production and germinal center development. They consist of Tfh1, Tfh2, and Tfh17 subsets. T follicular regulatory (Tfr) cells possess suppressive functions as regulatory T cells and migrate into germinal centers. Immunoglobulin G4 (IgG4)-related diseases manifest in vascular lesions as frequently formed inflammatory aneurysms (IgG4-related abdominal aortic aneurysm [IgG4-AAAs]). IgG4-AAAs contain several ATLOs. METHODS AND RESULTS: We performed whole-slide immunohistochemical image analysis in surgical specimens of IgG4-AAAs (n=21), non-IgG4-related inflammatory AAAs (n=17), atherosclerotic AAAs (n=10), and Takayasu arteritis (n=5). IgG4-AAA was characterized by numerous, large, irregular-shaped ATLOs, and higher numbers of Tfr and Tfh2 cells than Tfh1 cells were present compared with others. The morphologic abnormalities (in number, area, and form) of ATLOs in IgG4-AAAs and the increased number of Tfr cells are closely related to the activity of IgG4-related diseases. All T-cell subsets were more enriched within ATLOs than outside ATLOs. In particular, an increase in Tfr cells in IgG4-AAAs was associated with ATLO formation. Increased Tfh17 cells were found in Takayasu arteritis, and atherosclerotic AAA and non-IgG4-related inflammatory AAAs were characterized by increased Tfh1 cells. CONCLUSIONS: In the classification of vascular lesions, considering the imbalance in T-cell subsets, IgG4-AAA should be positioned as adventitial vasculitis with predominant Tfr and Tfh2 cells, accompanied by the abnormal appearance of ATLOs.

Solitary recurrence of IgG4-related giant coronary aneurysm: Case report and review of the literature focusing on treatment strategies and complications.

Coronary periarteritis is a dangerous manifestation of IgG4-related disease, because it forms coronary artery aneurysms, which may cause sudden cardiac death. We report the case of a 78-year-old woman with IgG4-related coronary periarteritis and a coronary aneurysm, which showed progressive enlargement despite maintenance therapy for Type 1 autoimmune pancreatitis. This case was unique, in that coronary periarteritis was the only active lesion that recurred. Low-dose glucocorticoids suppressed the progression of periarterial lesions but led to rapid thinning of the aneurysmal wall and an increase in the size of mural thrombi, which pose a risk of myocardial infarction. Our systematic literature review including 98 cases of 86 articles was performed to examine its treatment strategies and complications. Among the cases in which the effect of immunosuppressive therapy could be followed radiologically, 33 of 37 (89.1%) cases showed improvement in wall thickening/periarterial soft tissue, while 6 of 13 (46.2%) showed worsening increase in the outer diameter of the coronary aneurysms. We propose a draft treatment algorithm and suggest that immunosuppressive therapy for IgG4-related coronary periarteritis with coronary aneurysms should be conducted only after the therapeutic benefit has been determined to outweigh the risks. Because coronary periarteritis can occur without other organ involvement, as in our case, all cases of IgG4-related disease require careful monitoring of coronary artery lesions.

Intravenous alteplase before endovascular therapy for acute large vessel occlusion with large ischemic core: subanalysis of a randomized clinical trial.

BACKGROUND: The efficacy of endovascular therapy (EVT) in patients with large ischemic core has been reported, but it remains unclear whether IV alteplase (IVT) has beneficial effects in addition to EVT in such patients. We evaluated the efficacy and safety of EVT with or without IVT. METHODS: The RESCUE-Japan LIMIT was an open-label, prospective, multicenter, randomized clinical trial to evaluate the efficacy and safety of EVT in stroke patients with large ischemic core, defined as Alberta Stroke Program Early CT Score (ASPECTS) 3-5. This subanalysis evaluated the differences in the effects of EVT with medical care (EVT group) compared with medical care alone (No-EVT group) between those who received IVT (IVT stratum) and those who did not (No-IVT stratum) before EVT. RESULTS: Among 202 enrolled patients, 147 (73%) did not receive IVT. In the No-IVT stratum, the modified Rankin Scale (mRS) score of 0-3 at 90 days was significantly higher in the EVT group than in the No-EVT group (31.1% vs 12.3%, OR 3.21 (95% CI 1.37 to 7.53)). In the IVT stratum, the mRS score of 0-3 was 30.8% in the EVT group and 13.8% in the No-EVT group (OR 2.78 (95% CI 0.72 to 10.7)) (interaction p=0.77). The incidence of symptomatic intracranial hemorrhage was not different between the two groups in the No-IVT stratum (OR 1.20 (95% CI 0.35 to 4.12)), but it was significantly higher in the EVT group than in the No-EVT group in the IVT stratum (11.5% vs 0%, p=0.03). CONCLUSIONS: There was no difference in efficacy of EVT with or without IVT, while IVT before EVT might increase symptomatic intracranial hemorrhage in patients with large ischemic core. TRIAL REGISTRATION INFORMATION: NCT03702413.

Mode of Imaging Study and Endovascular Therapy for a Large Ischemic Core: Insights From the RESCUE-Japan LIMIT.

BACKGROUND AND PURPOSE: Differences in measurement of the extent of acute ischemic stroke using the Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) by non-contrast computed tomography (CT-ASPECTS stratum) and diffusion-weighted imaging (DWI-ASPECTS stratum) may impact the efficacy of endovascular therapy (EVT) in patients with a large ischemic core. METHODS: The RESCUE-Japan LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism Japan-Large IscheMIc core Trial) was a multicenter, open-label, randomized clinical trial that evaluated the efficacy and safety of EVT in patients with ASPECTS of 3-5. CT-ASPECTS was prioritized when both CT-ASPECTS and DWI-ASPECTS were measured. The effects of EVT on the modified Rankin Scale (mRS) score at 90 days were assessed separately for each stratum. RESULTS: Among 183 patients, 112 (EVT group, 53; No-EVT group, 59) were in the CT-ASPECTS stratum and 71 (EVT group, 40; No-EVT group, 31) in the DWI-ASPECTS stratum. The common odds ratio (OR) (95% confidence interval) of the EVT group for one scale shift of the mRS score toward 0 was 1.29 (0.65-2.54) compared to the No-EVT group in CT-ASPECTS stratum, and 6.15 (2.46-16.3) in DWI-ASPECTS stratum with significant interaction between treatment assignment and mode of imaging study (P=0.002). There were significant interactions in the improvement of the National Institutes of Health Stroke Scale score at 48 hours (CT-ASPECTS stratum: OR, 1.95; DWIASPECTS stratum: OR, 14.5; interaction P=0.035) and mortality at 90 days (CT-ASPECTS stratum: OR, 2.07; DWI-ASPECTS stratum: OR, 0.23; interaction P=0.008). CONCLUSION: Patients with ASPECTS of 3-5 on MRI benefitted more from EVT than those with ASPECTS of 3-5 on CT.

Six-month Outcomes after PulseRider- and Conventional Single Stent-assisted Embolization for Bifurcation Aneurysms: A Propensity-adjusted Comparison.

Endovascular treatment of wide-necked bifurcation aneurysms (WNBAs) remains challenging despite using a stent. PulseRider is a novel device specifically designed to treat WNBAs, protecting both daughter branches, but the outcomes have not been compared with conventional single stent-assisted embolization. This study aimed to compare the six-month outcomes of PulseRider and single stent-assisted embolization for intracranial unruptured WNBAs using propensity score adjustment. Between February 2012 and October 2021, 46 unruptured WNBAs (34 basilar and 12 middle cerebral arteries) smaller than 10 mm in diameter were treated with PulseRider-assisted embolization (n = 17) or single stent-assisted embolization (n = 29). The immediate and six-month outcomes were compared using inverse probability of treatment weighting analysis. The immediate adequate occlusion rates for the PulseRider- and single stent-assisted embolization were similar (47.1% vs. 62.1%). At six months, adequate occlusion rates for the two groups were also similar (94.1% vs. 86.2%). However, the complete obliteration rate was significantly high after PulseRider-assisted embolization (88.2% vs. 41.4%, adjusted OR 10.54, 95% CI 1.93-57.63). The angiographical improvement rate was also significantly high after PulseRider-assisted embolization (70.6% vs. 37.9%, adjusted OR 6.06, 95% CI 1.54-23.76). The neurologic thromboembolic complication rate was 0% after PulseRider-assisted embolization and 3.4% after single stent-assisted embolization. PulseRider-assisted embolization of WNBAs smaller than 10 mm in diameter was associated with complete obliteration and angiographical improvement at six months. The unique shape of the PulseRider might contribute to the improved midterm aneurysm occlusion.

Microarchitectures of Barrett's esophagus associated with DNA methylation status.

Aim: DNA methylation is involved in esophageal adenocarcinoma (EAC) and Barrett's esophagus (BE). Microarchitectures of on-neoplastic BE associated with DNA methylation status were examined using magnifying narrow-band imaging (NBI) endoscopy. Patients and methods: Using biopsies from non-neoplastic BE without cancer (n = 66; N group), with EAC (n = 27; ADJ group) and EAC tissue (n = 22; T group), methylation of N33, DPYS, SLC16A12, miR124a3 and miR34bc genes were quantified. Magnifying NBI features of non-neoplastic BE were classified according to their morphologies. Results: The ADJ and T groups presented higher DNA methylation compared with the N group. Magnifying NBI endoscopic features of non-neoplastic BE also correlated with DNA methylation as an independent factor. Conclusion: Microarchitectures of BE visualized by magnifying NBI endoscopy correlated with DNA methylation.

Endovascular therapy for acute intracranial large vessel occlusion due to atherothrombosis: Multicenter historical registry.

BACKGROUND: Atherothrombotic stroke-related large vessel occlusion (AT-LVO) is caused by two etiologies, the intracranial artery occlusion due to in situ occlusion (intracranial group) or due to embolism from cervical carotid occlusion or stenosis (tandem group). The prognosis and reocclusion rate of each etiology after endovascular therapy (EVT) is unclear. METHODS: We conducted a historical multicenter registry study at 51 Japanese centers to compare the prognoses of AT-LVO between two etiologies. The primary outcome was the incidence of recurrent ischemic stroke or reocclusion of the treated vessels within 90 days after EVT. Each of the primary outcome means the incidence of recurrent ischemic stroke and reocclusion of the treated vessels within 90 days after EVT. RESULTS: We analyzed 582 patients (338 in the intracranial group and 244 in the tandem group). Patients in the intracranial group were younger (mean 71.9 vs 74.5, p=0.003), more of them were female and fewer of them were current smokers than those in the tandem group. In the tandem group, the patients' National Institutes of Health Stroke Scale score on admission was higher (13 vs 15, p=0.006), onset to puncture time was shorter (299 [145-631] vs 232 [144-459] minutes, p=0.03) and Alberta Stroke Program Early CT Score (ASPECTS) was lower (8 [7-9] vs 8 [6-9], p=0.0002). The primary outcome was higher in the intracranial group (22.5% vs 8.2%, p<0.0001). However, any ICH and death were not significantly different in the two groups. CONCLUSIONS: The incidence of recurrent ischemic stroke or reocclusion after EVT for AT-LVO was higher in the intracranial group.

Intravenous injection of tumor extracellular vesicles suppresses tumor growth by reducing the regulatory T cell phenotype.

BACKGROUND: Colorectal cancer is a disease of unmet medical need. Although extracellular vesicles (EVs) have been implicated in anti-tumor responses, discrepancies were observed among studies. We analyzed the role of tumor-derived EVs (TEVs) in tumor progression in vivo by focusing on regulatory T (Treg) cells, which play essential roles in tumor development and progression. METHODS: A mouse model of colorectal cancer lung metastasis was generated using BALB/c mice by tail vein injection of the BALB/c colon adenocarcinoma cell line Colon-26. TEVs derived from Colon-26 and BALB/c lung squamous cell carcinoma ASB-XIV were retrieved from the culture media supernatants. A TEV equivalent to 10 µg protein was injected every other day for 2 weeks. RESULTS: Histology and immunohistochemistry studies revealed that lung tumors reduced in the Colon-26-EV group when compared to the phosphate-buffered saline (PBS) group. The population of CD4 + FoxP3 + cells in the lung was upregulated in the PBS group mice when compared to the healthy mice (P < 0.001), but was significantly downregulated in the Colon-26-EV group mice when compared to the PBS group mice (P < 0.01). Programmed cell death protein 1, glucocorticoid-induced TNFR-related protein, and CD69 expression in lung Treg cells were markedly upregulated in the PBS group when compared to the healthy mice, but downregulated in the Colon-26-EV group when compared to the PBS group. The changes in expression were dose-dependent for Colon-26-EVs. ASB-EVs also led to significantly downregulated Treg cell expression, although non-cancer line 3T3-derived EVs did not. CONCLUSION: Our study suggests that TEVs possess components for tumor suppression.

A Short-Term Model of Colitis-Associated Colorectal Cancer That Suggests Initial Tumor Development and the Characteristics of Cancer Stem Cells.

The mechanisms underlying the transition from colitis-associated inflammation to carcinogenesis and the cell origin of cancer formation are still unclear. The azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model reproduces human colitis-associated colorectal cancer. To elucidate the mechanisms of cancer development and dynamics of the linker threonine-phosphorylated Smad2/3 (pSmad2/3L-Thr)-positive cells, we explored the early stages of colitis-associated colorectal cancer in AOM/DSS mice. The AOM/DSS mice were sacrificed at 4 to 6 weeks following AOM administration. To analyze the initial lesions, immunofluorescence staining for the following markers was performed: ß-catenin, Ki67, CDK4, Sox9, Bmi1, cyclin D1, and pSmad2/3L-Thr. Micro-neoplastic lesions were flat and unrecognizable, and the uni-cryptal ones were either open to the surfaces or hidden within the mucosae. These neoplastic cells overexpressed ß-catenin, Sox9, Ki67, and Cyclin D1 and had large basophilic nuclei in the immature atypical cells. In both the lesions, pSmad2/3L-Thr-positive cells were scattered and showed immunohistochemical co-localization with ß-catenin, CDK4, and Bmi1 but never with Ki67. More ß-catenin-positive neoplastic cells of both lesions were detected at the top compared to the base or center of the mucosae. We confirmed initial lesions in the colitis-associated colorectal cancer model mice and observed results that suggest that pSmad2/3L-Thr is a biomarker for tissue stem cells and cancer stem cells.

Relation between duration of dual antiplatelet therapy and risk of ischemic stroke after stent-assisted treatment of cerebral aneurysm (DAPTS ACE-registry).

BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) in patients with cerebral aneurysm who undergo stent-assisted coil embolization (SACE) has not been established. We aimed to clarify the association between duration of DAPT and incidence of ischemic stroke in patients with cerebral aneurysm. METHODS: We registered patients with cerebral aneurysm who underwent SACE in 27 hospitals in Japan. Those treated with DAPT (aspirin and clopidogrel) were eligible for inclusion in a previously reported randomized control trial (RCT). Patients who were ineligible or refused to participate to the RCT were followed-up for 15 months after SACE as the non-RCT cohort. Our study examined both the RCT and non-RCT cohorts. The primary and secondary outcomes were ischemic stroke and hemorrhagic events. RESULTS: Among the 313 patients registered, 296 were included for analysis (of these, 136 were RCT patients and 160 were non-RCT patients). Patients who were treated with DAPT for more than 6 months (n=191) were classified as the long-term DAPT group. Those treated less than 6 months (n=105) were classified as the short-term group. The incidence of ischemic stroke did not significantly differ between the long-term group (2.5 per 100 person-years) and the short-term group (3.2 per 100 person-years); nor did incidence of hemorrhagic events (0.8 and 3.2 per 100 person-years, respectively). The period of DAPT was not significantly associated with incidence rates of ischemic stroke or hemorrhagic events. CONCLUSIONS: Duration of DAPT was not associated with the incidence of ischemic stroke in the first 15 months after SACE.

Number of Passes of Endovascular Therapy for Stroke With a Large Ischemic Core: Secondary Analysis of RESCUE-Japan LIMIT.

BACKGROUND: The increased risk of intracranial hemorrhage with multiple passes in endovascular therapy (EVT) for large vessel occlusion with a large ischemic core is a concern. We explored the effect of the number of EVT passes on patients in a randomized clinical trial. METHODS: This post hoc study was the secondary analysis of RESCUE-Japan LIMIT, which was a randomized clinical trial comparing EVT and medical treatment alone for large vessel occlusion with large ischemic core. We grouped patients according to the number of passes with successful reperfusion (modified Thrombolysis in Cerebral Infarction score, ≥2b) in 1, 2, and 3 to 7 passes and failed reperfusion (modified Thrombolysis in Cerebral Infarction score, 0-2a) after any pass in the EVT group, and these groups were compared with medical treatment group. The primary outcome was modified Rankin Scale score of 0 to 3 at 90 days. Secondary outcomes were improvement in National Institutes of Health Stroke Scale score of ≥8 at 48 hours, mortality at 90 days, symptomatic intracranial hemorrhage, and any intracranial hemorrhage within 48 hours. RESULTS: The number of patients who received EVT with successful reperfusion after 1, 2, and 3 to 7 passes and failed reperfusion were 44, 23, 19, and 14, respectively, and 102 received medical treatment alone. The adjusted odds ratios (95% CIs) for the primary outcome relative to medical treatment were 5.52 (2.23-14.28) after 1 pass, 6.45 (2.22-19.30) after 2 passes, 1.03 (0.15-4.48) after 3 to 7 passes, and 1.17 (0.16-5.37) if reperfusion failed. The adjusted odds ratios (95% CIs) for any intracranial hemorrhage within 48 hours relative to medical treatment were 1.88 (0.90-3.93) after 1 pass, 5.14 (1.97-14.72) after 2 passes, 3.00 (1.09-8.58) after 3 to 7 passes, and 6.16 (1.87-24.27) if reperfusion failed. CONCLUSIONS: The successful reperfusion within 2 passes was associated with better clinical outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03702413.

Comprehensive DNA methylation profiling of Barrett's esophagus and esophageal adenocarcinoma in Japanese patients.

Molecular mechanisms of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remain unclear in Japanese patients. Japanese EACs frequently have underlying short length BE: short-segment BE (SSBE), for which, neoplastic potential remains unclear. We performed comprehensive methylation profiling of EAC and BE in Japanese patients, mostly comprised with SSBE. Using three different groups of biopsies obtained from non-neoplastic BE from patients without cancer (n = 50; N group), with EAC (n = 27; ADJ group) and EAC (n = 22; T group), methylation statuses of nine candidate genes (N33, DPYS, SLC16A12, CDH13, IGF2, MLF1, MYOD1, PRDM5, and P2RX7) were examined by the bisulfite pyrosequencing. Reduced representation bisulfite sequencing was performed to characterize the genome-wide methylation status in 32 samples (12 from N, 12 ADJ, and 8 from T groups). In the candidate approach, methylation levels of N33, DPYS, and SLC16A12 were higher in ADJ and T groups compared to that in N group. The ADJ group was an independent factor for higher DNA methylation in non-neoplastic BE. The genome-wide approach demonstrated an increase of hypermethylation from ADJ to T groups relative to N group near the transcription start sites. Among gene groups hypermethylated in ADJ and T groups (n = 645) and T group alone (n = 1438), 1/4 and 1/3 were overlapped with downregulated genes in the microarray data set, respectively. Accelerated DNA methylation is observed in EAC and underlying BE in Japanese patients, mostly comprised with SSBE, highlighting the potential impact of methylation in early carcinogenesis.