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Background and Objectives: Transient neurological deficits (TNDs) in patients with chronic subdural hematoma (CSDH), such as fluctuating aphasia, hemiparesis, or sensory disturbances, present diagnostic and treatment challenges as their pathophysiology remains unclear. The aim of this study was to investigate the association between specific MRI findings and TNDs in patients with CSDH and explored their relationship through intraoperative observation., Methods: We retrospectively evaluated 72 patients with CSDH who underwent preoperative MRI among 251 CSDH patients treated from January 2020 to December 2023. Sulcal hyperintensity (SHI) on fluid-attenuated inversion recovery images and web/net appearance (W/N) on T2*-weighted images were assessed and their association with TNDs was analyzed. Flexible neuroendoscopic surgery (FNS) was performed on 8 patients with TNDs exhibiting these MRI findings, allowing intraoperative observation of intrahematoma conditions. Histopathological examination was performed on hematoma samples., Results: Thirteen patients (5.2%) presented with preoperative TNDs. Diffuse SHI and W/N were strongly associated with preoperative TNDs (odds ratio = 150.0, P < .001). FNS revealed organized hematomas with inflammatory changes corresponding to the SHI and W/N seen on MRI. Patients who underwent FNS experienced complete resolution of TNDs postprocedure, with diffuse SHI disappearing by one month. No recurrence was observed at a mean follow-up of 5.9 months., Conclusion: This study provided the first evidence that the combination of diffuse SHI and W/N on MRI strongly correlates with TNDs in patients with CSDH, serving as valuable diagnostic indicators. These findings will aid in guiding surgical approach selection and facilitate more personalized treatment strategies for patients with CSDH presenting with TNDs., (Copyright © Congress of Neurological Surgeons 2025. All rights reserved.)

Background: Limited large-scale, real-world data exist on the prevalence and clinical impact of discordance between fractional flow reserve (FFR) and nonhyperemic pressure ratios (NHPRs)., Methods: The J-PRIDE registry (Clinical Outcomes of Japanese Patients With Coronary Artery Disease Assessed by Resting Indices and Fractional Flow Reserve: A Prospective Multicenter Registry) prospectively enrolled 4304 lesions in 3200 patients from 20 Japanese centers. The lesions were classified into FFR+/NHPR-, FFR-/NHPR+, FFR+/NHPR+, or FFR-/NHPR groups according to cutoff values of 0.89 for NHPRs and 0.80 for FFR. The primary study end point was the cumulative 1-year incidence of target vessel failure (a composite of cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization) on a lesion basis., Results: An NHPR cutoff value of 0.89, determined using online software, predicted an FFR of 0.80 across various NHPR types. Discordance between FFR and NHPRs was observed in 20% of lesions (FFR+/NHPR-, 11.2%; FFR-/NHPRs+, 8.8%). Revascularization was deferred in 42.9% and 88.4% of the FFR+/NHPR- and FFR-/NHPR+ groups, respectively. In deferred vessels, the FFR+/NHPR- and FFR-/NHPR+ groups showed a higher 1-year incidence of target vessel failure compared with the FFR-/NHPR- group (7.9% versus 5.5% versus 1.7%; for FFR+/NHPR-, adjusted hazard ratio [aHR], 4.89 [95% CI, 2.68-8.91]; P <0.001; for FFR-/NHPR+, aHR, 2.64 [95% CI, 1.49-4.69]; P <0.001). In revascularized vessels, the 1-year target vessel failure rate was numerically higher in the FFR-/NHPR+ group than in the FFR+/NHPR+ group (9.6% versus 3.4%; aHR, 2.27 [95% CI, 0.70-7.34]; P =0.17), although with similar outcomes between the FFR+/NHPR- and FFR+/NHPR+ groups (2.3% versus 3.4%; aHR, 0.96 [95% CI, 0.37-2.38]; P =0.93). The FFR+/NHPR- group benefited from revascularization compared with medical treatment (aHR, 0.26 [95% CI, 0.08-0.86]; P =0.027); the FFR-/NHPR+ group did not (aHR, 2.39 [95% CI, 0.62-9.21]; P =0.20)., Conclusions: Discordance between FFR and NHPRs was noted in 20% of lesions, and discordant deferred lesions resulted in worse outcomes than concordant negative lesions. Although the outcomes after deferring revascularization were comparable between the FFR+/NHPR- and FFR-/NHPR+ lesions, only FFR+/NHPR- lesions showed a benefit from revascularization compared with medical treatment, suggesting that an FFR-guided strategy is superior to an NHPR-guided strategy in discordant lesions., Registration: URL: https://www.umin.ac.jp; Unique identifier: UMIN000038403.

Limited evidence exists regarding the long-term outcomes of true versus nontrue coronary bifurcation lesions (CBLs) treated with current-generation drug-eluting stents and intravascular imaging guidance. The Sapporo Cardiovascular Clinic (SCVC) registry was a prospective, single-center, all-comers registry enrolling 1,727 consecutive patients treated with bioresorbable polymer sirolimus-eluting stent under complete imaging guidance. From this registry, 440 patients with CBLs (25.5%) were analyzed. Patients were categorized into the true and nontrue CBL groups according to the Medina classification (n = 234 and 206, respectively). The primary end point was the cumulative incidence of target vessel failure (TVF) (a composite of cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization). The 1-stent strategy was predominantly chosen for the true and nontrue CBL groups (93.9% and 96.2%, respectively). During the median follow-up of 5.4 years, the cumulative incidence of TVF did not differ between true and nontrue CBL groups after adjustment for baseline differences (5-year incidence 22.0% vs 17.7%, adjusted hazard ratio 1.27, 95% confidence interval 0.79 to 2.05, p = 0.32). Although the Medina 0.0.1 lesions were very rare (1.1%), they had the highest rate of TVF among the Medina subtypes. Final kissing balloon inflation technique was associated with a lower incidence of TVF (p = 0.036). In conclusion, imaging-guided percutaneous coronary intervention with bioresorbable polymer sirolimus-eluting stent resulted in comparable long-term clinical outcomes between true and nontrue CBLs, primarily using the 1-stent technique., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/objectives: Tumor-infiltrating B cells (TIBs) and tissue-resident memory T cells (TRMs) play significant roles in antitumor immunity. However, their prognostic relevance in brain metastases (BMs) derived from gastrointestinal (GI) cancers remains unclear. This study aimed to investigate the prognostic significance of TIBs and TRMs in GI cancer-derived BMs (GIBMs)., Methods: Retrospective histopathological analyses were performed on surgically resected GIBM tissues from 13 patients. The densities of tumor-infiltrating lymphocytes (TIL) subsets (TIBs, CD4 + T cells, CD8 + CD103 + TRMs, and CD8 + CD103 - non-TRMs) were quantified and correlated with clinical parameters and overall survival (OS) including the Graded Prognostic Assessment (GPA)., Results: TIBs and CD4 + T cells were predominantly accumulated in the tumor stroma, particularly around blood vessels, where they formed lymphocyte clusters without characteristics of tertiary lymphoid structures (TLSs). In contrast, TRMs more deeply infiltrated into the tumor epithelium than their counterpart non-TRMs. Positive correlations were found between TIB density and both the prognostic prediction of GPA and overall survival (OS) after BM diagnosis or surgery. Furthermore, increased densities of TIBs and TRMs were associated with enhanced survival after BM diagnosis., Conclusions: TIB and TRM densities in BM tissues could serve as reliable prognostic indicators for survival in patients with GIBMs. This study provides crucial insights for the development of novel immunotherapeutic strategies against this lethal disease.

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Tip detection-antegrade dissection and re-entry (TD-ADR) technique allows operators to accurately observe both guidewire tip direction and a true lumen in chronic total occlusion (CTO) lesions, while the torque direction of the guidewire on IVUS images does not invariably correspond to that on fluoroscopic images., Case Summary: A 41-year-old man with hypertension who smokes presented with sudden onset of dyspnoea, acute heart failure, and ischaemic findings on electrocardiogram; we performed percutaneous coronary intervention (PCI) for a sub-totally occluded mid-left anterior descending artery lesion. All antegrade wiring attempts failed to enter the distal true lumen followed by subintimal tracking and re-entry technique. Since the lesion re-occluded the next day, we treated the lesion using a novel TD-ADR technique, termed the 'integrated TD-ADR', because of no interventional retrograde channel. This method integrates fluoroscopic and intravascular ultrasound (IVUS) images, ensuring congruence in the torque direction of the guidewire across both modalities and enabling vertical puncture of the stiff guidewire from the extraplaque space to the distal true lumen quickly and precisely. Final angiography showed good results. Five months later, coronary angiography showed that the lesion remained open., Discussion: The integrated TD-ADR technique merges fluoroscopic and IVUS images, allowing operators to torque the guidewire in the same direction on both images. This approach might be more user-friendly than the original technique and has the potential to enhance the success rate of PCI in complex CTO cases. However, further investigations are warranted to address the clinical feasibility and applicability of this technique., Competing Interests: Conflict of interest: T.F. serves as a technical consultant for Terumo; S.K. receives lecture fees from Terumo. The other authors report no conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background/aim: The prognosis of patients with brain metastases (BMs) originating from lung cancer remains poor, despite advancements in treatment strategies. The role of tertiary lymphoid structures (TLSs) within the tumor immune microenvironment of BMs has not been extensively explored., Patients and Methods: This study utilized patient-derived clinical samples from 17 patients with histologically confirmed BMs of lung cancer, undergoing surgical resection. Immunohistochemistry was employed to analyze the presence and characteristics of TLS and tumor-infiltrating lymphocytes (TILs) within BM tissues, correlating these with clinical outcomes., Results: TLSs, albeit in their immature form, were identified within BM tissues, distinguishing them from their mature counterparts in primary lung cancer tissues. A significant correlation between TLS density (but not TIL density) and improved postoperative survival was observed, underscoring the potential of TLS density as an independent prognostic marker. Furthermore, TLS density did not correlate with the Graded Prognostic Assessment (GPA) index, suggesting its unique prognostic value beyond conventional predictors., Conclusion: Our findings reveal the presence of TLSs in lung cancer-derived BMs and highlight their prognostic significance, independent of the GPA index. The identification of TLS within the unique central nervous system tumor microenvironment offers new insights into the immune landscape of BMs and suggests potential avenues for immunotherapeutic interventions targeting these structures to improve patient outcomes., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Incomplete revascularization (ICR) has been associated with a worse prognosis after a percutaneous coronary intervention (PCI). In NSTEMI patients with multivessel disease (MVD) however, the benefit of a complete revascularization (CR) remains unclear., Methods: Patients presenting with an NSTEMI and MVD were selected from the global e-ULTIMASTER registry and grouped according to completeness of revascularization at index hospitalization discharge. The primary endpoint was the patient oriented composite endpoint (POCE) defined as all death, any myocardial infarction, and any revascularization at 1 year. Target lesion failure (TLF) was defined as the composite of cardiac death, target vessel related myocardial infarction and clinically driven target lesion revascularization. Inverse propensity score weighting (IPSW) was performed to harmonize the patient's baseline characteristics between the groups., Results: CR was achieved in 1800 patients (47.0 %) and ICR in 2032 patients (53.0 %). The incidence of POCE at 1 year was lower in the CR group compared to the ICR group: 7.0 % vs. 12.9 %, p < 0.0001. Similarly for TLF at 1 year: 3.6 % vs. 5.5 %, p < 0.01. After IPSW, the incidence of POCE was 7.7 % vs. 12.0 %, p < 0.0001, due to a lower all-cause mortality: 2.7 % vs. 4.2 %, p = 0.02 and less revascularizations: 4.9 % vs. 7.9 %, p < 0.001. The incidence of TLF was no longer statistically significant: CR 3.9 % vs. IR 5.0 %, p = 0.10., Conclusions: Patients with a NSTEMI and multi vessel disease undergoing a percutaneous coronary revascularization with a complete revascularization during index hospitalization have better 1-year clinical outcomes. Randomized studies are warranted to confirm these results., Competing Interests: Declaration of competing interest None of the authors reported a conflict of interest related to this manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Because the clinical benefit of antiplatelet therapy (APT) for patients with nonsignificant coronary artery disease (CAD) remains poorly understood, we evaluated it in patients after fractional flow reserve (FFR)-guided deferral of revascularization., Methods and Results: From the J-CONFIRM (Long-Term Outcomes of Japanese Patients with Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), we investigated 265 patients with deferred lesions who did not require APT for secondary prevention of cardiovascular disease. A 2-year landmark analysis assessed the relationship between APT at 2 years and 5-year major cardiac adverse events (MACE: composite of all-cause death, target vessel-related myocardial infarction, clinically driven target vessel revascularization). Of the 265 patients, 163 (61.5%) received APT. The 5-year MACE did not significantly differ between the APT and non-APT groups after adjustment for baseline clinical characteristics (9.2% vs. 6.9%, inverse probability weighted hazard ratio, 1.40 [95% confidence interval, 0.53-3.69]; P=0.49). There was a marginal interaction between the effect of APT on MACE and FFR values (< or ≥0.84) (P for interaction=0.066)., Conclusions: The 5-year outcomes after FFR-guided deferral of revascularization did not significantly differ between the APT and non-APT groups, suggesting that APT might not be a critical requirement for nonsignificant obstructive CAD patients not requiring APT for secondary prevention of cardiovascular disease., Competing Interests: S.K. receives lecture fees from Abbott Vascular Japan and Boston Scientific Japan; H.M. receives lecture fees from Abbott Vascular Japan, Boston Scientific Japan, and Phillips Japan; Y.K. receives lecture fees from Abbott Vascular Japan and Phillips Japan; Y.S. receives lecture fees from Abbott Vascular Japan and Phillips Japan; T.A. receives lecture fees from Abbott Vascular Japan and Phillips Japan; K.T. is a member of Circulation Journal’s and Circulation Reports’ Editorial Team; N.T. receives lecture fees from Abbott Vascular Japan and Boston Scientific Japan; H.Y. receives lecture fees from Boston Scientific Japan. The other authors report no conflicts., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Vessel-level physiological data derived from pressure wire measurements are one of the important determinant factors in the optimal revascularisation strategy for patients with multivessel disease (MVD). However, these may result in complications and a prolonged procedure time., Aims: The feasibility of using the quantitative flow ratio (QFR), an angiography-derived fractional flow reserve (FFR), in Heart Team discussions to determine the optimal revascularisation strategy for patients with MVD was investigated., Methods: Two Heart Teams were randomly assigned either QFR- or FFR-based data of the included patients. They then discussed the optimal revascularisation mode (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) for each patient and made treatment recommendations. The primary endpoint of the trial was the level of agreement between the treatment recommendations of both teams as assessed using Cohen's kappa., Results: The trial included 248 patients with MVD from 10 study sites. Cohen's kappa in the recommended revascularisation modes between the QFR and FFR approaches was 0.73 [95% confidence interval {CI} : 0.62-0.83]. As for the revascularisation planning, agreements in the target vessels for PCI and CABG were substantial for both revascularisation modes (Cohen's kappa=0.72 [95% CI: 0.66-0.78] and 0.72 [95% CI: 0.66-0.78], respectively). The team assigned to the QFR approach provided consistent recommended revascularisation modes even after being made aware of the FFR data (Cohen's kappa=0.95 [95% CI:0.90-1.00])., Conclusions: QFR provided feasible physiological data in Heart Team discussions to determine the optimal revascularisation strategy for MVD. The QFR and FFR approaches agreed substantially in terms of treatment recommendations.

Background: von Hippel-Lindau disease-associated hemangioblastomas (HBs) account for 20%-30% of all HB cases, with the appearance of new lesions often observed in the natural course of the disease. By comparison, the development of new lesions is rare in patients with sporadic HB., Observations: A 65-year-old man underwent clipping for an unruptured aneurysm of the anterior communicating artery. Fourteen years later, follow-up magnetic resonance imaging (MRI) revealed a strongly enhanced mass in the right cerebellar hemisphere, diagnosed as a sporadic HB. A retrospective review of MRI studies obtained over the follow-up period revealed the gradual development of peritumoral edema and vascularization before mass formation., Lessons: Newly appearing high-intensity T2 lesions in the cerebellum may represent a preliminary stage of tumorigenesis. Careful monitoring of these patients would be indicated, which could provide options for early treatment to improve patient outcomes.

Background: Melanoma metastases to the CNS rank third in frequency, just after lung and breast metastases. There is controversy regarding the factors predisposing to developing CNS metastases in patients with cutaneous melanoma and their survival with conventional treatments., Methods: We carried out a retrospective analysis in a third-level hospital in Mexico to determine epidemiological aspects of melanoma metastases to the central nervous system, factors related to its appearance, clinical presentation, and survival in three treatment groups: surgery, radiotherapy, and conservative management., Results: We found that the nodular variant has the most significant association with CNS metastases. In addition, the superficial spreading variant has the highest risk of presenting a more substantial number of lesions, up to seven for each case and predominantly in the infratentorial space. On the other hand, we found more remarkable survival in patients treated only with surgery than those treated with radiotherapy or conservatively., Conclusions: This study lays the foundations for future prospective survival analysis of the different current treatment modalities for metastatic melanoma in the brain and spine. It also highlights the clinical risk factors for metastatic brain and spine tumors of melanoma., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: The relationship between sex differences and long-term outcomes after fractional flow reserve (FFR)- and instantaneous wave-free ratio (iFR)-guided deferral of revascularization has yet to be elucidated. Methods and Results: From the J-CONFIRM registry (long-term outcomes of Japanese patients with deferral of coronary intervention based on FFR in a multicenter registry), this study included 432 lesions from 385 patients (men, 323 lesions in 286 patients; women, 109 lesions in 99 patients) with paired data of FFR and iFR. The primary endpoint was the cumulative 5-year incidence of target vessel failure (TVF), including cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization. The median FFR value was lower in men than in women (0.85 [0.81, 0.88] vs. 0.87 [0.83, 0.91], P=0.002), but the iFR value was comparable between men and women (0.94 [0.90, 0.98] vs. 0.93 [0.89, 0.98], P=0.26). The frequency of discordance between FFR and iFR was comparable between men and women (19.5% vs. 23.9%, P=0.34), although with different discordance patterns (P=0.036). The cumulative incidence of 5-year TVF did not differ between men and women after adjustment for baseline characteristics (13.9% vs. 6.9%, adjusted hazard ratio 1.82 [95% confidence interval: 0.44-7.56]; P=0.41). Conclusions: Despite sex differences in the results for physiological indexes, the 5-year TVF in deferred lesions did not differ between men and women after adjustment for baseline characteristics., Competing Interests: S.K. receives lecture fees from Abbott Vascular Japan, Boston Scientific Japan, and Phillips Japan; H.M. serves as advisory board member for Zeon Medical and receives lecture fees from Abbott Vascular Japan, Boston Scientific Japan, and Phillips Japan; Y.K. receives lecture fees from Abbott Vascular Japan and Phillips Japan; Y.S. receives lecture fees from Abbott Vascular Japan and Phillips Japan; T.A. receives lecture fees from Abbott Vascular Japan and Phillips Japan; N.T. serves as advisory board member for Abbott Vascular Japan and Boston Scientific Japan; H.Y. receives lecture fees from Boston Scientific Japan. K.T. is a member of Circulation Reports’ Editorial Team. The other authors report no conflicts., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Background: His bundle pacing (HBP) and left bundle branch area pacing (LBBAP) emerge as better alternatives to right ventricular apical pacing (RVAP) in patients with bradycardia requiring permanent cardiac pacing. We aimed to compare the clinical outcomes of LBBAP, HBP, and RVAP in Japanese patients with bradycardia., Methods: A total of 424 patients who underwent successful pacemaker implantation (HBP, n  = 53; LBBAP, n  = 75; and RVAP, n  = 296) were retrospectively enrolled in this study. The primary study endpoint was the cumulative incidence of heart failure hospitalization (HFH) during the follow-up., Results: The success rate for implantation was higher in the LBBAP group than in the HBP group (94.9% and 81.5%, respectively). Capture threshold increase >1V during the follow-up occurred in the HBP and RVAP groups (9.4% and 5.1%, respectively), while it did not in the LBBAP group. The cumulative incidence of HFH was significantly lower in the LBBAP group than the RVAP (adjusted hazard ratio, 0.12 [95% confidence interval: 0.02-0.86]; p  = .034); it did not differ between the HBP and RVAP groups (adjusted hazard ratio, 0.48 [95% confidence interval: 0.17-1.34]; p  = .16). Advanced age, mean percent right ventricular pacing (per 10% increase), left ventricular ejection fraction <50%, and RVAP were associated with HFH., Conclusions: Compared to RVAP and HBP, LBBAP appeared more feasible and effective in patients with bradycardia requiring permanent cardiac pacing., Competing Interests: All authors have no relevant financial or nonfinancial interests to disclose., (© 2024 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Background: The surgical techniques for treatment of chronic subdural hematoma (CSDH), a common neurosurgical condition, have been discussed in a lot of clinical literature. However, the recurrence proportion after CSDH surgery remains high, ranging from 10 to 20%. The standard surgical procedure for CSDH involves a craniostomy to evacuate the hematoma, but irrigating the hematoma cavity during the procedure is debatable. The authors hypothesized that the choice of irrigation fluid might be a key factor affecting the outcomes of surgery. This multicenter randomized controlled trial aims to investigate whether intraoperative irrigation using artificial cerebrospinal fluid (ACF) followed by the placement of a subdural drain would yield superior results compared to the placement of a subdural drain alone for CSDH., Methods: The study will be conducted across 19 neurosurgical departments in Japan. The 1186 eligible patients will be randomly allocated to two groups: irrigation using ACF or not. In either group, a subdural drain is to be placed for at least 12 h postoperatively. Similar to what was done in previous studies, we set the proportion of patients that meet the criteria for ipsilateral reoperation at 7% in the irrigation group and 12% in the non-irrigation group. The primary endpoint is the proportion of patients who meet the criteria for ipsilateral reoperation within 6 months of surgery (clinical worsening of symptoms and increased hematoma on imaging compared with the postoperative state). The secondary endpoints are the proportion of reoperations within 6 months, the proportion being stratified by preoperative hematoma architecture by computed tomography (CT) scan, neurological symptoms, patient condition, mortality at 6 months, complications associated with surgery, length of hospital stay from surgery to discharge, and time of the surgical procedure., Discussion: We present the study protocol for a multicenter randomized controlled trial to investigate our hypothesis that intraoperative irrigation with ACF reduces the recurrence proportion after the removal of chronic subdural hematomas compared with no irrigation., Trial Registration: ClinicalTrials.gov jRCT1041220124. Registered on January 13, 2023., (© 2023. The Author(s).)

Background: Whether drug-coated balloon (DCB) angioplasty would be effective in spiral dissection (SD) lesions with no flow impairment has been thoroughly investigated., Aims: The present study sought to assess the clinical outcomes of non-flow-limiting SD after DCB angioplasty for de novo femoropopliteal lesions in patients with symptomatic lower extremity artery disease., Method: This single-center retrospective study enrolled 497 patients with non-flow-limiting SD (n = 92) or non-SD (n = 405) without bailout stenting. The primary endpoint was 1-year primary patency, with the secondary endpoints including freedom from target lesion revascularization (TLR), major adverse limb event (MALE), all-cause death, and 30-day restenosis., Results: The 1-year primary patency and freedom from TLR were significantly lower in the SD group than in the non-SD group (69.8% vs. 83.3%, p = 0.004; 78.7% vs. 93.0%, p = 0.007, respectively). The SD group had a higher incidence of MALE and 30-day restenosis than the non-SD group (24.6% vs. 11.9%, p = 0.001; 4.3% vs. 0.5%, p = 0.002, respectively). All-cause death was comparable. One-year restenosis after SD was associated with chronic limb-threatening ischemia (CLTI) (hazard ratio, 3.36 [95% confidence interval, 1.21-9.36]; p = 0.020), TASC Ⅱ D (hazard ratio, 3.97 [95% confidence interval, 1.02-15.52]; p = 0.047), and residual stenosis ≥50% (hazard ratio, 4.92 [95% confidence interval, 1.01-23.94]; p = 0.048). The incidence of restenosis after SD increased with the number of these risk factors., Conclusions: Despite normal antegrade flow, the 1-year primary patency rate after DCB angioplasty for de novo femoropopliteal lesions was significantly lower in lesions with SD than those without SD. CLTI, TASC II D, and residual stenosis ≥50% were risk factors associated with 1-year restenosis after DCB angioplasty for non-flow-limiting SD lesions., (© 2023 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Intravascular lithotripsy (IVL) has emerged as a novel therapy for the treatment of coronary calcification. Numerous studies have reported the safety and efficacy of IVL in calcified coronary lesions, while IVL balloon-uncrossable calcified coronary lesions are sometimes encountered in clinical practice. This case report represents a novel technique called "modified leopard-crawl" to advance the IVL balloon antegradely by creating significant calcium cracking forward when the enhanced stent visualization system reveals that the distal emitter seems adjacent to calcification. This technique might be a valuable alternative when conventional procedures fail and has the potential to enhance the clinical applicability of IVL in daily practice., (© 2023 Wiley Periodicals LLC.)

Background Chronic kidney disease (CKD) might influence fractional flow reserve (FFR) value, potentially attenuating its prognostic utility. However, few large-scale data are available regarding clinical outcomes after FFR-guided deferral of revascularization in patients with CKD. Methods and Results From the J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), 1218 patients were divided into 3 groups according to renal function: (1) non-CKD (estimated glomerular filtration rate ≥60 mL/min per 1.73 m 2 ), n=385; (2) CKD (estimated glomerular filtration rate 15-59 mL/min per 1.73 m 2 , n=763); and (3) end-stage renal disease (ESRD) (eGFR <15 mL/min per 1.73 m 2 , n=70). The primary study end point was the cumulative 5-year incidence of target vessel failure (TVF), defined as a composite of cardiac death, target vessel myocardial infarction, and clinical driven target vessel revascularization. Cumulative 5-year incidence of TVF was significantly higher in the ESRD group than in the CKD and non-CKD group, whereas it did not differ between the CKD and non-CKD groups (26.3% versus 11.9% versus 9.5%, P <0.001). Although the 5-year TVF risk increased as the FFR value decreased regardless of renal function, patients with ESRD had a remarkably higher risk of TVF at every FFR value than those with CKD and non-CKD. Conclusions At 5 years, patients with ESRD showed a higher incidence of TVF than patients with CKD and non-CKD, although with similar outcomes between patients with CKD and non-CKD. Patients with ESRD had an excess risk of 5-year TVF at every FFR value compared with those with CKD and non-CKD. Registration URL: https://www.umin.ac.jp; Unique identifier: UMIN000014473.

Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has achieved tremendous success treating B cell malignancies; however, some patients fail to respond due to poor autologous T cell fitness. To improve response rates, we investigated whether disruption of the co-inhibitory receptors CTLA4 or PD-1 could restore CART function. CRISPR-Cas9-mediated deletion of CTLA4 in preclinical models of leukemia and myeloma improved CAR T cell proliferation and anti-tumor efficacy. Importantly, this effect was specific to CTLA4 and not seen upon deletion of CTLA4 and/or PDCD1 in CAR T cells. Mechanistically, CTLA4 deficiency permitted unopposed CD28 signaling and maintenance of CAR expression on the T cell surface under conditions of high antigen load. In clinical studies, deletion of CTLA4 rescued the function of T cells from patients with leukemia that previously failed CAR T cell treatment. Thus, selective deletion of CTLA4 reinvigorates dysfunctional chronic lymphocytic leukemia (CLL) patient T cells, providing a strategy for increasing patient responses to CAR T cell therapy., Competing Interests: Declaration of interests A.J.R. is a consultant for Affini-T Therapeutics. M.R. is the scientific founder of viTToria bio and is an inventor of intellectual property (IP) managed by Penn and licensed to Novartis, Tmunity, and viTToria. M.R. is part of the SAB of ABClon, viTToria bio, and Scailyte and has served as a consultant for GLG, BMS, GSK, nanoString, Sana, Bayer. M.M.D. is a consultant and has received research funding from Tmunity Therapeutics and is a consultant and member of the scientific advisory board for Cellares Corporation. J.A.F. is a member of the Scientific Advisory Boards of Cartography Bio. and Shennon Biotechnologies Inc. and has patents, royalties, and other intellectual property. D.L.P. has a consulting or advisory role at Novartis, Kite/Gilead, Incyte, Gerson Lehrman Group, Janssen (Johnson and Johnson), BMS, Bluebird Bio, Angiocrine, Mirror Biologics, Capstan Therapeutics, Instill Bio, Sana Biotherapeutics, and Verismo Therapeutics and research support from Novartis. D.L.P. is a patent inventor for use of CAR T cells in CD19+ malignancies. D.L.P. served as Chair of Board of Directors for National Marrow Donor Program from October 2018 to October 2020. D.L.P. is Associate Editor for Am J Hematology, Wiley and Deputy editor for Transplant and Cell Therapy (ASTCT Journal), Elsevier. D.L.P. spouse has stock and other ownership interests with Genentech and Roche from former employment. C.H.J. is an inventor of patents related to the CAR therapy product, which is the subject of this paper, as well as other CAR therapy products, and may be eligible to receive a select portion of royalties paid from Kite to the University of Pennsylvania. C.H.J. is a scientific co-founder and holds equity in Capstan Therapeutics, Dispatch Biotherapeutics, and Bluewhale Bio. C.H.J. serves on the board of AC Immune and is a scientific advisor to BluesphereBio, Cabaletta, Carisma, Cartography, Cellares, Cellcarta, Celldex, Danaher, Decheng, ImmuneSensor, Kite, Poseida, Verismo, Viracta, and WIRB-Copernicus group. C.H.J., R.M.Y., M.M.D., M.R., and D.L.P. are inventors on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and Kite and may receive license revenue from such licenses., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Coronary physiologic assessment is performed to measure coronary pressure, flow, and resistance or their surrogates to enable the selection of appropriate management strategy and its optimization for patients with coronary artery disease. The value of physiologic assessment is supported by a large body of clinical data that has led to major recommendations in all practice guidelines. This expert consensus document aims to convey practical and balanced recommendations and future perspectives for coronary physiologic assessment for physicians and patients in the Asia-Pacific region, based on updated information in the field that includes both wire- and image-based physiologic assessment. This is Part 2 of the whole consensus document, which provides theoretical and practical information on physiologic indexes for specific clinical conditions and patient statuses., Competing Interests: This work is supported by the grant from the Patient-Centered Clinical Research Coordinating Center (grant number HC19C0305). Dr Koo has received Institutional Research Grants from Abbott Vascular, Boston Scientific, Philips, and HeartFlow. Dr Wang has received institutional research grants from Boston Scientific. Dr Harding has received proctoring fees and speaker honoraria from Abbott Vascular, Boston Scientific, Medtronic, and Terumo Medical. Dr Fearon has received institutional research support from Abbott, Boston Scientific, and Medtronic; has consulting relationships with CathWorks and Siemens; and has stock options with HeartFlow. Dr Lee has received institutional research grants from Abbott Vascular, Boston Scientific, Philips Volcano, Terumo Corporation, Zoll Medical, and Donga-ST. Dr Hu has received institutional research grants from Boston Scientific. Dr Yong has received minor honoraria from Abbott Vascular and institutional research grants and support from Abbott Vascular and Philips. Dr Kuramitsu has received lecture fees from Abbott Medical Japan and Boston Scientific Japan. Dr Jeong has received honoraria for lectures from Daiichi Sankyo, Sanofi-Aventis, Han-mi Pharmaceuticals, and JW Pharmaceuticals and research grants or support from Han-mi Pharmaceuticals, Samjin Pharmaceuticals, Yuhan Pharmaceuticals, Biotronik, Dio Medical, and U and I Corporation. Dr Escaned has received personal fees as speaker or advisory board member from Abbott, Boston Scientific, Medis, RainMed, and Philips; he has reported joint ownership of angio-IMR patent. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Arginase is a manganese-dependent metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. The product L-ornithine is an important component which has wide applications in the healthcare and pharmaceutical industry. Enzymatic biosynthesis of L-ornithine is one of the effective methods in which arginase is used as a bio-catalyst. Here, we report the crystal structure of arginase from Thermus thermophilus ( Tt Arginase) in three different crystal forms. All structures were solved by molecular replacement and refined at 2.0 Å, 2.3 Å and 2.91 Å resolution respectively. Tt Arginase is compared with other structural homologs and the putative catalytic site residues were identified. To understand the thermophilic nature of Tt Arginase, the sequence and structural factors of Tt Arginase was compared with its mesophilic counterpart Bacillus subtilis arginase (Bs Arginase). To get insights on structural stability, molecular dynamics (MD) simulations were carried for Tt Arginase and Bs Arginase at three different temperatures (300 K, 333 K and 353 K). The results indicate that Tt Arginase is comparatively more stable than Bs Arginase. MD simulations were carried out in the absence of the metal ions at the active site which revealed high plasticity of the active site. The results suggest that metal ions are critical not only for the catalytic function, but also required for the maintenance of the proper active site geometry. Since arginase can be employed for large-scale industrial production of L-ornithine, the structural details of thermophilic arginases such as Tt Arginase will be helpful to engineer the protein to optimize its enzymatic action in a variety of conditions.Communicated by Ramaswamy H. Sarma.

A challenge when targeting T-cell lymphoma with chimeric antigen receptor (CAR) T-cell therapy is that target antigens are often shared between T cells and tumor cells, resulting in fratricide between CAR T cells and on-target cytotoxicity on normal T cells. CC chemokine receptor 4 (CCR4) is highly expressed in many mature T-cell malignancies, such as adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphoma (CTCL), and has a unique expression profile in normal T cells. CCR4 is predominantly expressed by type-2 and type-17 helper T cells (Th2 and Th17) and regulatory T cells (Treg), but it is rarely expressed by other T helper (Th) subsets and CD8+ cells. Although fratricide in CAR T cells is generally thought to be detrimental to anticancer functions, in this study, we demonstrated that anti-CCR4 CAR T cells specifically depleted Th2 and Tregs, while sparing CD8+ and Th1 T cells. Moreover, fratricide increased the percentage of CAR+ T cells in the final product. CCR4-CAR T cells were characterized by high transduction efficiency, robust T-cell expansion, and rapid fratricidal depletion of CCR4-positive T cells during CAR transduction and expansion. Furthermore, mogamulizumab-based CCR4-CAR T cells induced superior antitumor efficacy and long-term remission in mice engrafted with human T-cell lymphoma cells. In summary, CCR4-depleted anti-CCR4 CAR T cells are enriched in Th1 and CD8+ T cells and exhibit high antitumor efficacy against CCR4-expressing T-cell malignancies., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Large-scale registries can provide valuable complementary data to randomized controlled trials (RCT) for the postmarketing evaluation of coronary stents, but their scientific relevance remains debated., Methods: We sought to compare the evidence on the performance of a single coronary stent platform generated by the RCT for its regulatory approval and a well-conducted international registry. Patients treated with the Ultimaster coronary stent in the CENTURY II (CII-UM) trial (n = 551) were compared to patients in the real-world e-ULTIMASTER (e-UM) registry (n = 35,389). All major events were adjudicated by an independent clinical event committee in both studies. Propensity weighted analysis was used to balance baseline and procedural differences between the 2 populations., Results: Coronary artery disease was more complex in e-UM compared to CII-UM, including more acute coronary syndromes, multivessel disease, left main, arterial, or venous grafts, and chronic total occlusions (P < .005 for all). At one-year follow-up and after excluding periprocedural myocardial infarction (MI) there was no statistically significant difference between CII-UM and e-UM regarding all-cause death (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.26-1.20, P = .14), cardiac death (HR 0.71, 95% CI 0.29-1.72, P = .45), target lesion failure (HR 1.18, 95% CI 0.78-1.78, P = .44), and target vessel MI (HR 0.76, 95% CI 0.24-2.38, P = .63). However, target vessel revascularization rate was significantly higher in CII-UM than in e-UM, HR 1.78, 95% CI 1.23-2.56, P = .002., Conclusions: A well-conducted large-scale registry can provide valuable complementary evidence to RCTs on the postmarket performance of new coronary stents, across a wider range of uses and various geographic areas., Competing Interests: Conflict of interest A. Gautier, P. Laanmets, S. Munir, F.T. Malik, A.R. Iniguez, G. Maluenda and S. Saito have no conflict of interest to declare. M. Roffi received institutional reports grants from Terumo and Biotronik outside the submitted work, S. Kuramitsu received a consultant fee from Terumo outside the submitted work, M. Angioi received consulting fees from Terumo and BBraun outside the submitted work. W. Wijns received research grant and honoraria from MicroPort; medical advisor Rede Optimus Research and Corrib Core Laboratory outside the submitted work. B. Chevalier reports grants from Terumo during the conduct of the e-ULTIMASTER registry; personal fees from Terumo, outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cancer-associated thrombosis is a frequent complication of cancer; however, little evidence is available regarding the association between cancer history and coronary artery stent thrombosis (ST). We aimed to investigate the relationship between cancer history and second-generation drug-eluting stent thrombosis (G2-ST)., Methods: From the REAL-ST (Retrospective Multicenter Registry of ST After First- and Second-Generation Drug-Eluting Stent Implantation) registry, this study evaluated 1265 patients (G2- ST cases, n = 253; controls, n = 1012) with cancer-related information available., Results: The prevalence of patients with cancer history was higher (12.3% vs. 8.5%, p = 0.065), and that of currently diagnosed and currently treated cancer was significantly higher in ST cases than controls (3.6% vs. 1.4%, p = 0.021; 3.2% vs. 1.3%, p = 0.037, respectively). Multivariable logistic regression analysis revealed that cancer history was associated with late ST (odds ratio [OR]: 2.80, 95% confidence intervals [CI]: 0.92-8.55, p = 0.071) and very late ST (OR: 2.40, 95% CI: 1.02-5.65, p = 0.046), but not with early ST (OR: 1.01, 95% CI: 0.51-2.00, p = 0.97). During the median follow-up period of 872 days after the index ST events, patients with cancer history showed a higher mortality than those without, among both ST cases (hazard ratio [HR]: 1.93, 95% CI: 1.06-3.51, p = 0.031) and controls (HR: 1.93, 95% CI: 1.09-3.40, p = 0.023)., Conclusion: A post hoc analysis of REAL-ST registry revealed that patients with G2-ST had a higher prevalence of currently diagnosed and currently treated cancer. Notably, cancer history was associated with the occurrence of late and very late ST, but not with early ST., (© 2023. The Author(s).)

Background: Little evidence is available about the long-term safety of fractional flow reserve (FFR)-guided deferral of revascularization in infarct-related artery (IRA) lesions, especially when measuring FFR in the late setting after myocardial infarction (MI). This study aimed to assess the long-term outcomes after deferral of revascularization in IRA lesions based on FFR assessed in the late phase of post-MI., Methods: From the J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), data on 1447 lesions (1263 patients) were divided into 2 groups: the IRA and non-IRA groups. The primary study end point was the cumulative 5-year incidence of target vessel failure (TVF), such as cardiac death, target vessel-related MI, and clinically driven target vessel revascularization., Results: Of the 1447 lesions, 138 (9.5%) were classified into the IRA group. The median duration of FFR measurement was 716 days after MI. The frequency of visual-functional mismatches (ie, FFR >0.80 and percent diameter stenosis ≥50% or FFR ≤0.80 and percent diameter stenosis <50%) was comparable between the IRA and non-IRA groups (31.9% vs 36.3%). The cumulative 5-year incidence of TVF did not differ between the groups (9.2% vs 11.8%; inverse probability-weighted hazard ratio, 1.18, 95% confidence intervals, 0.48-2.91, P = .71). Similar results were observed irrespective of regional wall motion assessed by ultrasonic cardiography and acute MI type., Conclusions: The 5-year TVF rate did not differ between the IRA and non-IRA lesions when deferring revascularization guided by FFR in the late setting of post-MI., (© 2023 The Authors.)

Background: It remains unclear whether the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria could apply to peripheral artery disease (PAD) patients undergoing endovascular therapy (EVT)., Aims: We sought to evaluate the application of the ARC-HBR criteria to PAD patients undergoing EVT with contemporary drug-coated devices (DCD) for femoropopliteal artery lesions., Methods: Between May 2012 and December 2019, 542 consecutive patients undergoing EVT with DCD for femoropopliteal artery lesions were retrospectively analysed. The primary study endpoint was major bleeding events, defined as Bleeding Academic Research Consortium type 3 or 5., Results: Of 542 patients, 435 (80.3%) were stratified into the HBR group. The cumulative 5-year incidence of major bleeding events was significantly higher in the HBR group than in the non-HBR group (31.9% vs 2.3%; p<0.001). The 5-year major bleeding event rate gradually increased with the number of ARC-HBR criteria (≥2 major criteria: 48.6%, 1 major: 33.1%, ≥2 minor: 12.9%, and non-HBR: 2.3%; p<0.001). Major bleeding events were associated with a 5.4-fold increased risk of mortality (adjusted hazard ratio: 5.42, 95% confidence interval: 2.91-10.1; p<0.001). Severe chronic kidney disease, heart failure, and severe anaemia were predictors of major bleeding events., Conclusions: 80.3% of PAD patients undergoing EVT for femoropopliteal artery lesions with contemporary drug-coated devices met the ARC-HBR criteria. Given that major bleeding events remarkably increased the risk of mortality after EVT, the ARC-HBR criteria might be helpful for the risk stratification of PAD patients who undergo EVT with contemporary DCD.

Pyrrolidone carboxyl peptidase (PCP) hydrolytically removes the L-pyroglutamic acid from the amino terminal region of pyroglutamyl proteins or peptides. So far, only a limited number of structures of PCP have been solved. Here we report the crystal structure of pyrrolidone carboxyl peptidase from Thermus thermophilus (TtPCP) which has been solved using the molecular replacement method and refined at 1.9 Å resolution. TtPCP follows the α/β/α architecture in which the central β-sheets are surrounded by α-helices on both sides. The inter subunit contact between two monomers consists of two short antiparallel β-strands and part of a long protrusion loop. By comparing the TtPCP with its structural homologs, we identified the putative catalytic triad residues as Glu76, Cys139 and His160. A unique disulfide link found in some homologs of TtPCP, formed between two monomers that provide thermal stability to the protein, is not observed in TtPCP. Hence, being a thermophilic protein, the putative thermal stability of TtPCP could be due to more intra and inter-molecular hydrogen bonds, hydrophobic and ion pair interactions when compared with its mesophilic counterpart. The structural details of TtPCP will be helpful to understand the basis of the intrinsic stability of thermophilic proteins. Also, it could be useful for protein engineering., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Paclitaxel-coated balloon (PCB) angioplasty emerges as an effective therapeutic option for in-stent restenosis (ISR). However, whether PCB angioplasty would be effective for in-stent calcified nodule (ISCN) lesions remain fully understood. This study aimed to evaluate the frequency and outcomes of ISCN in patients undergoing PCB angioplasty for ISR after second-generation drug-eluting stents (G2-DES) implantation., Methods: This study enrolled 179 lesions (160 patients) undergoing PCB angioplasty for G2-DES restenosis with optical coherence tomography guidance. According to the presence of ISCN at the minimum lumen area, the lesions were divided into two groups: the ISCN (n = 16) and the non-ISCN groups (n = 163). The primary study endpoint was the cumulative 3-year incidence of target lesion failure (TLF; a composite of cardiac death, clinically driven target vessel revascularization, and definite stent thrombosis) on a lesion basis., Results: ISCN was observed in 16 of 179 lesions (8.9%). Cumulative 3-year incidence of TLF was significantly higher in the ISCN group than in the non-CN group (85.3% vs. 16.9%, inverse probability weighted hazard ratio [HR] 4.46, 95% confidence intervals [CIs]: 2.42-8.22, p < 0.001). Risk factors associated with TLF were ISCN (HR 4.55, 95% CI: 1.56-13.3, p = 0.005), recurrent ISR (HR 2.82, 95% CI: 1.50-3.30, p = 0.001), and early ISR (HR 2.18, 95% CI: 1.21-3.92, p = 0.009)., Conclusion: ISCN was observed in 8.3% of G2-DES restenosis. PCB angioplasty had little effect on ISCN lesions compared with non-ISCN lesions, suggesting the need for careful clinical follow-up of patients with ISCN lesions after PCB angioplasty., (© 2022 Wiley Periodicals LLC.)

Background: The relationship between in-stent calcified nodules (IS-CN) and second-generation drug-eluting stent (G2-DES) stent thrombosis (ST) remains uncertain., Aims: We aimed to evaluate the prevalence, clinical demographic and long-term clinical outcomes after G2-DES ST with IS-CN., Methods: The prespecified substudy of the REAL-ST registry (a retrospective, multicentre registry of patients with definite ST after first- and G2-DES implantation) enrolled patients who experienced definite G2-DES ST and who underwent pre-intervention intravascular ultrasound imaging at index ST events., Results: IS-CN was observed in 15 out of 118 (13%) definite G2-DES ST cases. The multiple logistic regression model demonstrated that haemodialysis (odds ratio [OR] 12.27, 95% confidence interval [CI]: 1.56-94.54; p=0.02), proximal or mid-right coronary artery lesions (OR 12.79, 95% CI: 1.78-92.13; p=0.01) and severe calcification (OR 13.01, 95% CI: 1.18-142.94; p=0.04) were independently associated with ST with IS-CN. The cumulative 5-year incidence of target lesion revascularisation (TLR) after ST was significantly higher in the IS-CN group than in the non-IS-CN group (p=0.02). Independent predictors of TLR after the index ST events were female sex (hazard ratio [HR] 3.05, 95% CI: 1.20-7.74; p=0.02), diabetes mellitus (HR 3.26, 95% CI: 1.26-8.41; p=0.01) and IS-CN (HR 3.07, 95% CI: 1.16-8.14; p=0.02)., Conclusions: IS-CN may be one of the underlying mechanisms of G2-DES ST. Notably, IS-CN was associated with a higher TLR rate after the index ST events, suggesting the need for careful clinical follow-up of ST patients with IS-CN.

Aims: Guideline-directed medical therapy (GDMT) is essential to prevent future cardiovascular events in chronic coronary syndrome (CCS) patients. However, whether achieving optimal GDMT could improve clinical outcomes in CCS patients with deferred lesions based on fraction flow reserve (FFR) remains thoroughly investigated. We sought to evaluate the association of GDMT adherence with long-term outcomes after FFR-based deferral of revascularization in a real-world registry., Methods and Results: This is a post-hoc analysis of the J-CONFIRM registry (long-term outcomes of Japanese patients with deferral of coronary intervention based on fractional flow reserve in multicentre registry). Optimal GDMT was defined as combining four types of medications: antiplatelet drug, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, beta-blocker, and statin. After stratifying patients by the number of individual GDMT agents at 2 years, landmark analysis was conducted to assess the relationship between GDMT adherence at 2 years and 5-year major adverse cardiac events (MACEs), defined as a composite of all-cause death, target vessel-related myocardial infarction, clinically driven target vessel revascularization. Compared with the suboptimal GDMT group (continuing ≤3 types of medications, n = 974), the optimal GDMT group (n = 139) showed a lower 5-year incidence of MACE (5.2% vs. 12.4%, P = 0.02). The optimal GDMT was associated with a lower risk of MACE (hazard ratio: 0.41; 95% confidence interval: 0.18 to 0.92; P = 0.03)., Conclusion: Patients with optimal GDMT were associated with better outcomes, suggesting the importance of achieving optimal GDMT on long-term prognosis in CCS patients after FFR-guided deferral of revascularization., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Little evidence is available regarding the long-term outcome in elderly patients after deferral of revascularization based on fractional flow reserve (FFR)., Methods and results: From the J-CONFIRM registry (long-term outcomes of Japanese patients with deferral of coronary intervention based on fractional flow reserve in multicenter registry), 1,262 patients were divided into 2 groups according to age: elderly and younger patients (aged ≥75 or <75 years, respectively). The primary endpoint was the cumulative 5-year incidence of target vessel failure (TVF), defined as a composite of cardiac death, target vessel-related myocardial infarction (TVMI), and clinically driven target vessel revascularization (CDTVR). Cumulative 5-year incidence of TVF was not significantly different between elderly and younger patients (14.3% vs. 10.8%, P=0.12). Cardiac death occurred more frequently in elderly patients than younger patients (4.4% vs. 0.8%, P<0.001), whereas TVMI and CDTVR did not differ between groups (1.3% vs. 0.9%, P=0.80; 10.7% vs. 10.1%, P=0.80, respectively). FFR values in lesions with diameter stenosis <50% were significantly higher in elderly patients than in younger patients (0.88±0.07 vs. 0.85±0.07, P=0.01), whereas this relationship was not observed in those with diameter stenosis ≥50%., Conclusions: Elderly patients had no excess risk of ischemic events related to the deferred coronary lesions by FFR, although FFR values in mild coronary artery stenosis were modestly different between elderly and younger patients.

Background: Although the risk of developing malignant lymphoma is higher in patients with rheumatoid arthritis (RA) than in the general population, primary central nervous system lymphoma (PCNSL) in patients with RA is extremely rare. In recent years, there has been concern that biological disease-modifying antirheumatic drugs (bDMARDs), widely administered to patients with RA, might increase the risk of cancer development. The authors report the first case of PCNSL in a patient with RA receiving the bDMARD tocilizumab., Observations: A 70-year-old man who was diagnosed with RA in 2010 was treated with low-dose methotrexate (MTX) from 2010 to 2015. Tocilizumab was commenced in 2012. In 2018, he developed gait disturbances, and gadolinium-enhanced magnetic resonance imaging showed multiple contrast-enhanced lesions in the basal ganglia and brain stem. Stereotactic brain biopsy led to the diagnosis of diffuse large B-cell lymphoma, and finally PCNSL was diagnosed. He was treated with five courses of MTX 3.5 g/m2, and his disease has been in remission for 34 months., Lessons: Low-dose MTX and bDMARDs are associated with the concern of increased cancer risk in patients with RA. Because tocilizumab has been in use for a relatively short time, further accumulation of cases and careful follow-up are necessary.

Objective: The primary objective was to assess the performance of a new generation thin-strut sirolimus-eluting coronary stent with abluminal biodegradable polymer in an all comer population. The secondary objective was to detail differences in contemporary percutaneous coronary intervention (PCI) practice worldwide., Methods: e-Ultimaster was an all-comer, prospective, global registry (NCT02188355) with independent event adjudication enrolling patients undergoing PCI with the study stent. The primary outcome measure was target lesion failure (TLF) at 1 year, defined as the composite of cardiac death, target vessel myocardial infarction and clinically driven target lesion revascularisation. Data were stratified according to 4 geographical regions., Results: A total of 37 198 patients were enrolled (Europe 69.2%, Asia 17.8%, Africa/Middle East 6.6% and South America/Mexico 6.5%) and 1-year follow-up was available for 35 389 patients (95.1%). One-year TLF occurred in 3.2% of the patients, ranging from 2% (Africa/Middle East) to 4.1% (South America/Mexico). In patients with acute coronary syndrome, potent P2Y 12 inhibitors were prescribed in 48% of patients at discharge, while at 1 year 72% were on any dual antiplatelet therapy. Lipid-lowering treatment was administered in 80.9% and 75.5% of patients at discharge and 1 year, respectively. Regional differences in the profile of the treated patients as well as in PCI practice were reported., Conclusions: In this investigation with worldwide representation, contemporary PCI using a new generation thin-strut sirolimus-eluting coronary stent with abluminal biodegradable polymer was associated with low 1-year TLF across clinical presentations and continents. Suboptimal adherence to current recommendations around antiplatelet and lipid lowering treatments was detected., Competing Interests: Competing interests: The following authors declare a competing interest with Terumo, the sponsor of the study: JP declared consulting fees; MM declared consulting fees and research grants; AA declared consulting fees; MA declared consulting fees; SK declared consulting fees; DJRH-S declared speaking fees and research grants; MR declared research grants. LJ and RD are employees of Terumo. All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Glioblastoma is a devastating malignant brain tumor with a poor prognosis despite standard therapy. Podoplanin (PDPN), a type I transmembrane mucin-like glycoprotein that is overexpressed in various cancers, is a potential therapeutic target for the treatment of glioblastoma. We previously reported the efficacy of chimeric antigen receptor (CAR)-T cells using an anti-pan-PDPN monoclonal antibody (mAb; NZ-1)-based third-generation CAR in a xenograft mouse model. However, NZ-1 also reacted with PDPN-expressing normal cells, such as lymphatic endothelial cells, pulmonary alveolar type I cells, and podocytes. To overcome possible on-target-off-tumor effects, we produced a cancer-specific mAb (CasMab, LpMab-2)-based CAR. LpMab-2 (Lp2) reacted with PDPN-expressing cancer cells but not with normal cells. In this study, Lp2-CAR-transduced T cells (Lp2-CAR-T) specifically targeted PDPN-expressing glioma cells while sparing the PDPN-expressing normal cells. Lp2-CAR-T also killed patient-derived glioma stem cells, demonstrating its clinical potential against glioblastoma. Systemic injection of Lp2-CAR-T cells inhibited the growth of a subcutaneous glioma xenograft model in immunodeficient mice. Combination therapy with Lp2-CAR-T and oncolytic virus G47Δ, a third-generation recombinant herpes simplex virus (HSV)-1, further inhibited the tumor growth and improved survival. These findings indicate that the combination therapy of Lp2-CAR-T cells and G47Δ may be a promising approach to treat glioblastoma., Competing Interests: The authors have no conflict of interest to declare., (© 2022 The Author(s).)

Background: Optic pathway gliomas are uncommon, accounting for 3-5% of childhood brain tumors, and are mostly classified as pilocytic astrocytomas (PAs). PAs of the optic nerve are particularly rare in adults., Observations: The authors presented the case of PA of the left optic nerve in a 49-year-old woman along with detailed pathological and molecular analyses and sequential magnetic resonance imaging. The tumor had progressed during 5 years of follow-up along with cyst formation and intracystic hemorrhage; it had a thick capsule and contained xanthochromic fluid. The boundary between tumor and optic nerve was unclear. B-type Raf kinase ( BRAF ) V600E point mutations or translocations, IDH1-R132H mutations, loss of alpha-thalassemia/mental retardation X-linked, and 1p/19q codeletion were negative., Lessons: BRAF alterations in pediatric PAs of the optic nerve are less frequent than those observed in PAs in other lesions; the same molecular pattern was observed in the adult case, without changes in BRAF . Surgical management should be indicated only in cases with severely impaired vision or disfigurement because there is no clear border between the tumor and optic nerve. Further discussion is needed to optimize the treatment for adult optic pathway gliomas, including radiotherapy, chemotherapy, and molecular-targeted therapies, in addition to surgical intervention., Competing Interests: Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper., (© 2022 The authors.)

Fractional flow reserve and instantaneous wave-free ratio are widely accepted and recommended in Western and Japanese guidelines for appropriate percutaneous coronary intervention. There are, however, many differences in clinical situations between Japan and Western countries. Therefore, the Task Force on coronary physiology of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) has proposed an expert consensus document to summarize current evidence and suggest the practical use of physiological lesion assessment in Japan., (© 2022. The Author(s) under exclusive licence to Japanese Association of Cardiovascular Intervention and Therapeutics.)

In patients with multivessel disease (MVD), functional information on lesions improves the prognostic capability of the SYNTAX score. Quantitative flow ratio (QFR®) is an angiography-derived fractional flow reserve (FFR) that does not require a pressure wire or pharmacological hyperemia. We aimed to investigate the feasibility of QFR-based patient information in Heart Teams' discussions to determine the optimal revascularization strategy for patients with MVD. We hypothesized that there is an acceptable agreement between treatment recommendations based on the QFR approach and recommendation based on the FFR approach. The DECISION QFR study is a prospective, multicenter, randomized controlled trial that will include patients with MVD who require revascularization. Two Heart Teams comprising cardiologists and cardiac surgeons will be randomized to select a revascularization strategy (percutaneous coronary intervention or coronary artery bypass graft) according to patient information either based on QFR or on FFR. All 260 patients will be assessed by both teams with reference to the anatomical and functional SYNTAX score/SYNTAX score II 2020 derived from the allocated physiological index (QFR or FFR). The primary endpoint of the trial is the level of agreement between the treatment recommendations of both teams, assessed using Cohen's κ. As of March 2022, the patient enrollment has been completed and 230 patients have been discussed in both Heart Teams. The current trial will indicate the usefulness of QFR, which enables a wireless multivessel physiological interrogation, in the discussions of Heart Teams to determine the optimal revascularization strategy for MVD., (© 2022 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

The purpose of this study was to assess early and late vascular healing in response to bioresorbable-polymer sirolimus-eluting stents (BP-SESs) for the treatment of patients with ST-elevation myocardial infarction (STEMI) and stable coronary artery disease (CAD). A total of 106 patients with STEMI and 101 patients with stable-CAD were enrolled. Optical frequency-domain images were acquired at baseline, at 1- or 3-month follow-up, and at 12-month follow-up. In the STEMI and CAD cohorts, the percentage of uncovered struts (%US) was significantly and remarkably decreased during early two points and at 12-month (the STEMI cohort: 1-month: 18.75 ± 0.78%, 3-month: 10.19 ± 0.77%, 12-month: 1.80 ± 0.72%; p < 0.001, the CAD cohort: 1-month: 9.44 ± 0.78%, 3-month: 7.78 ± 0.78%, 12-month: 1.07 ± 0.73%; p < 0.001 respectively). The average peri-strut low-intensity area (PLIA) score in the STEMI cohort was significantly decreased during follow-up period (1.90 ± 1.14, 1.18 ± 1.25, and 1.01 ± 0.72; p ≤ 0.001), whereas the one in the CAD cohort was not significantly changed (0.89 ± 1.24, 0.67 ± 1.07, and 0.64 ± 0.72; p = 0.59). In comparison with both groups, differences of %US and PLIA score at early two points were almost disappeared or close at 12 months. The strut-coverage and healing processes in the early phase after BP-SES implantation were significantly improved in both cohorts, especially markedly in STEMI patients. At 1 year, qualitatively and quantitatively consistent neointimal coverage was achieved in both pathogenetic groups., (© 2021. The Author(s).)

Background: Adenoid cystic carcinoma (ACC) of the external auditory canal (EAC) is a rare tumor that accounts for approximately 5% of all EAC tumors. ACC is generally known as a slow-growing tumor, but patients often experience recurrence or distant metastasis in the long clinical course. While the major pattern of recurrence is pulmonary metastasis, brain metastasis of ACC of the EAC is rare., Observations: The authors describe the case of a 72-year-old male who was diagnosed with ACC of the EAC. Approximately 7 years later, brain magnetic resonance imaging revealed an intra-axial homogenously enhancing mass lesion that had no direct connection with the skull base in the left frontal lobe. The patient underwent tumor resection and histopathological examination revealed a mixture of cribriform and tubular patterns. The image and pathological characteristics of the tumor were similar to those of primary ACC or ACC from other sites of origin., Lessons: While patients with ACC of the EAC often experience recurrence or distant metastasis in the long clinical course, they survive for a relatively long period of time, even though an optimal treatment has not been established. The authors therefore recommend surgical resection for brain metastasis of ACC of the EAC to improve neurological symptoms.

Objectives: The aim of this study was to evaluate the impact of thrombotic risk on the occurrence of cardiovascular events in patients with coronary artery disease with deferred revascularization after fractional flow reserve (FFR) measurements., Background: Deferral of revascularization on the basis of FFR is generally considered to be safe, but after deferral, some patients have cardiovascular events over time., Methods: From J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), 1,263 patients with deferral of revascularization on the basis of FFR were evaluated. The association between thrombotic risk as assessed by CREDO-Kyoto (Coronary Revascularization Demonstrating Outcome Study in Kyoto) thrombotic score and 5-year target vessel failure (TVF) and major adverse cardiac and cerebrovascular events (MACCE) was investigated., Results: FFR and high thrombotic risk (HTR) were associated with increased risk for 5-year TVF (FFR per 0.01-unit decrease: HR: 1.08; 95% CI: 1.05-1.11; P < 0.001; HTR: HR: 2.16; 95% CI: 1.37-3.39; P < 0.001) and MACCE (FFR per 0.01-unit decrease: HR: 1.05; 95% CI: 1.02-1.06; P < 0.001; HTR: HR: 2.11; 95% CI: 1.56-2.84; P = 0.001). Patients with HTR had higher risk for 5-year TVF (HR: 2.30; 95% CI: 1.45-3.66; P < 0.001) and MACCE (HR: 2.34; 95% CI: 1.75-3.13; P < 0.001) than those without HTR, even when they had negative FFR., Conclusions: Assessment of thrombotic risk provides additional prognostic value to FFR in predicting 5-year TVF and MACCE in patients with deferral of revascularization after FFR measurements. (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry; UMIN000014473)., Competing Interests: Funding Support and Author Disclosures This work was supported by Abbott Medical Japan, Phillips Japan, and Boston Scientific Japan. The funders of the study had no role in the study design, data collection, data analysis, interpretation of the data, writing of the report, or decision to submit the paper for publication. Dr Shiono has received lecture fees from Abbott Medical Japan and Phillips Japan. Dr Kuramitsu has received lecture fees from Abbott Medical Japan and Boston Scientific Japan. Dr Matsuo serves as an advisory board member for Zeon Medical; and has received lecture fees from Abbott Medical Japan, Phillips Japan, and Boston Scientific Japan. Dr Kikuta has received lecture fees from Abbott Medical Japan and Phillips Japan. Dr Asano has received lecture fees from Abbott Medical Japan and Phillips Japan. Dr Tanaka serves as advisory board member for Abbott Medical Japan and Boston Scientific Japan. Dr Yokoi has received lecture fees from Boston Scientific Japan. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Little large-scale data is available about the long-term (beyond 3 years) clinical outcomes after fractional flow reserve (FFR)-based deferral of revascularization in clinical practice. We sought to assess the 5-year outcomes after deferral of revascularization based on FFR., Methods: The J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry) prospectively enrolled 1263 patients with 1447 lesions in whom revascularization was deferred based on FFR from 28 Japanese centers. The primary study end point was the cumulative 5-year incidence of target vessel failure (TVF), including cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization., Results: Five-year follow-up was completed in 92.2% of patients. The 5-year TVF rate was 11.6% in deferred lesions, mainly driven by clinically driven target vessel revascularization (9.8%). Cardiac death and target vessel-related myocardial infarction were 1.9% and 0.95%, respectively. Cumulative 5-year incidence of TVF was similar between the FFR 0.75 to 0.80 and 0.81 to 0.85 groups even after adjustment for baseline characteristics (12.2% versus 13.0%, inverse probability-weighted hazard ratio, 0.86 [95% CI, 0.46-1.60]; P =0.63). Compared with the almost normal FFR (0.86-1.00) group, the significant (<0.75) and borderline (0.75-0.85) FFR groups showed a higher incidence of TVF at 5 years (29.9% versus 12.8% versus 8.6%, P <0.001). Independent predictors of the 5-year TVF were hemodialysis, FFR value, left main coronary artery lesion, prior percutaneous coronary intervention, and male sex., Conclusions: The 5-year TVF rate was 11.6% in deferred lesions, mainly driven by clinically driven target vessel revascularization. Notably, cardiac death and target vessel-related myocardial infarction rarely occurred during the follow-up. Our findings highlight the long-term safety of FFR-based deferral of revascularization in patients with chronic coronary syndrome. Registration: URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000014473.

Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction., Competing Interests: Declaration of interests R.M.Y., S.G., S.F.L., S.M.A., M.R., and C.H.J. are inventors on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receive license revenue from such licenses. R.M.Y. is an inventor on patents and/or patent applications licensed to Tmunity Therapeutics and receives license revenue from such licenses. C.H.J. is a scientific founder of Tmunity Therapeutics and DeCART Therapeutics, and is a member of the scientific advisory boards of AC Immune, BluesphereBio, Cabaletta, Carisma, Cartography, Cellares, Celldex, Decheng, Poseida, Verismo, WIRB-Copernicus, and Ziopharm. S.J.S. is a consultant, on the scientific advisory board, and receives research support from Genentech/Roche, Novartis, and Juno Therapeutics. S.J.S. is a consultant for AlloGene, AstraZeneca, BeiGene, Regeneron, and Tesa Therapeutics. S.J.S. is a consultant and on the scientific advisory board for Loxo Oncology. S.J.S. is on the scientific advisory board for Nordic Nanovector. S.J.S. is a consultant and receives research support from Celgene. S.F.L. receives research funding from Tmunity Therapeutics and Cabaletta. M.R. is on the scientific advisory board of AbClon Inc. and consulted for BMS, nanoString, GSK, and Bayer. M.R. is the scientific founder of viTToria Biotherapeutics. L.L.L. is on the scientific advisory boards for Alector, Atreca, Dragonfly, DrenBio, Morphosys, Nkarta, Obsidian Therapeutics, Rubius, SBI, and Innovent. S.M.A. receives research funding from Tmunity Therapeutics, RAPT, and Incyte Corporation and is scientific advisor for Trizell, BioArdis, and Verismo., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Limited data are available regarding the vascular response after fluoropolymer paclitaxel-eluting stent (FP-PES) implantation. This study sought to assess the vascular response at 6 and 12 months after FP-PES implantation for femoropopliteal artery lesions using serial optical coherence tomography (OCT) examination., Methods and results: From the IMPERIAL trial, this study evaluated 10 de novo femoropopliteal lesions treated with FP-PES. The primary study endpoint was neointimal tissue coverage at a 6- and 12-month follow up, as assessed by serial OCT examination. The incidence of peri-strut low-intensity area (PLIA) and extra-stent lumen (ESL) was also assessed. A total of 203 matched cross-sectional images were evaluated at 6 and 12 months (5,615 and 5,763 struts, respectively). From 6 to 12 months, the mean neointimal thickness tended to increase from 198 µm to 233 µm, with a significant reduction in the incidence of malapposed struts (0.59% vs. 0.28%, P=0.039). Conversely, uncovered struts and PLIA were more frequently observed at 12 months (4.4% vs. 7.8%, P=0.01; 12.7% vs. 21.0%, P<0.001, respectively). The ESL area significantly increased over time without any difference in its incidence (0.24±0.32 mm 2 vs. 0.38±0.36 mm 2 , P=0.009)., Conclusions: Neointimal proliferation was markedly inhibited from 6 to 12 months after FP-PES implantation, whereas the incidence of uncovered struts and PLIA significantly increased over time with the enlargement of ESL.

Background The subintimal approach (SA) is widely used in endovascular therapy for femoropopliteal chronic total occlusion lesions. However, when compared with the intraluminal approach (IA), the safety and efficacy of SA in real-world practice are not well characterized. Furthermore, there is a paucity of data on the clinical impact of subintimal and intraluminal wire passage (SWP and IWP, respectively) assessed by intravascular ultrasound. Methods and Results From the IVORY (Intravascular Ultrasound-Supported Endovascular Therapy in Superficial Femoral Artery) registry, this study included 500 patients undergoing endovascular therapy for femoropopliteal chronic total occlusion lesions (SA, n=67; IA, n=433; and SWP, n=186; IWP, n=314). The primary end point was the cumulative 1-year incidence of restenosis. The rate of perioperative complications was also assessed. Propensity score matching analysis was performed to adjust for the intergroup differences. After propensity score matching, the final study population consisted of 59 pairs (SA, n=59; IA, n=348) and 170 pairs (SWP, n=170; IWP, n=293), respectively. Cumulative 1-year incidence of restenosis was comparable between the SA and IA groups (41.0% versus 43.4%, P =0.40). No significant difference in 1-year restenosis rate between the SWP and IWP groups was observed (48.2% versus 40.8%, P =0.40), although the SWP group tended to be a higher rate of perioperative complications than the IWP group (8.2% versus 4.1%, P =0.07). Conclusions At 1 year, both SA and IA showed acceptable results for femoropopliteal chronic total occlusion lesions. Cumulative 1-year incidence of restenosis was not significantly different between SWP and IWP, whereas perioperative complications occurred more frequently in SWP than in IWP. Registration URL: https://www.umin.ac.jp; Unique identifier: UMIN000020472.

Gastric cancer (GC) is one of the most lethal malignant tumors. To improve the prognosis of GC, the identification of novel driver genes as therapeutic targets is in urgent need. Here, we aimed to identify novel driver genes and clarify their roles in gastric cancer. OSBPL3 was identified as a candidate driver gene by in silico analysis of public genomic datasets. OSBPL3 expression was analyzed by RT-qPCR and immunohistochemistry in GC cells and tissues. The biological functions and mechanisms of OSBPL3 in GC were examined in vitro and in vivo using GC cells. The association between OSBPL3 expression and clinical outcome in GC patients was also evaluated. Overexpression of OSBPL3 was detected in GC cells with OSBPL3 DNA copy number gains and promoter hypomethylation. OSBPL3-knockdown reduced GC cell growth in vitro and in vivo by inhibiting cell cycle progression. Moreover, an active Ras pull-down assay and western blotting demonstrated that OSBPL3 activates the R-Ras/Akt signaling pathway in GC cells. In a clinical analysis of two GC datasets, high OSBPL3 expression was predictive of a poor prognosis. Our findings suggest that OSBPL3 is a novel driver gene stimulating the R-Ras/Akt signaling pathway and a potential therapeutic target in GC patients., (© 2021. The Author(s).)

Microtubules are among the most successful targets for anticancer therapy because they play important roles in cell proliferation as they constitute the mitotic spindle, which is critical for chromosome segregation during mitosis. Hence, identifying new therapeutic targets encoding proteins that regulate microtubule assembly and function specifically in cancer cells is critical. In the present study, we identified a candidate gene that promotes tumor progression, ribonucleic acid export 1 (RAE1), a mitotic checkpoint regulator, on chromosome 20q through a bioinformatics approach using datasets of colorectal cancer (CRC), including The Cancer Genome Atlas (TCGA). RAE1 was ubiquitously amplified and overexpressed in tumor cells. High expression of RAE1 in tumor tissues was positively associated with distant metastasis and was an independent poor prognostic factor in CRC. In vitro and in vivo analysis showed that RAE1 promoted tumor growth, inhibited apoptosis, and promoted cell cycle progression, possibly with a decreased proportion of multipolar spindle cells in CRC. Furthermore, RAE1 induced chemoresistance through its anti-apoptotic effect. In addition, overexpression of RAE1 and significant effects on survival were observed in various types of cancer, including CRC. In conclusion, we identified RAE1 as a novel gene that facilitates tumor growth in part by inhibiting apoptosis and promoting cell cycle progression through stabilizing spindle bipolarity and facilitating tumor growth. We suggest that it is a potential therapeutic target to overcome therapeutic resistance of CRC., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: Peritoneal dissemination (PD) occurs frequently in gastric cancer (GC) and is fatal. The interactions between tumor cells and stromal cells are critical for cancer progression. Our aim was to identify a novel PD-associated gene derived from stromal cells in GC., Materials and Methods: Among the candidate PD-associated genes identified in our previous study, we focused on spondin-2 (SPON2), an extracellular matrix-secreted protein. Clinicopathological and prognostic analyses of SPON2 mRNA expression were performed using GC datasets. Localization of SPON2 expression was assessed by immunohistochemistry. In vitro migration assay and immunofluorescence staining were also conducted using GC cell lines., Results: SPON2 was expressed in and secreted from cancer-associated fibroblasts in GC. High expression of SPON2 in tumor tissues was correlated with PD, tumor size and poor prognosis in GC. The motility of GC cells was increased by treatment with a SPON2 recombinant protein in vitro., Conclusion: Cancer-associated fibroblast-derived SPON2 may promote PD, in part, by facilitating GC cell motility and serve as a predictive marker for PD in GC., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The aim of this study was to evaluate the predictive ability of frailty for bleeding after percutaneous coronary intervention (PCI). In 2439 patients who underwent their PCI, frailty was prospectively assessed according to the Canadian Study of Health and Aging clinical frailty scale (CFS). Patients were divided into three groups according to the CFS: low (CFS levels 1 to 3; 1748 patients, 71.7%), intermediate (CFS levels 4 to 6; 519 patients, 21.3%), and high CFS groups (CFS levels 7 to 9; 172 patients, 7.1%). Academic Research Consortium High Bleeding Risk (ARC-HBR) was present in 47.3% in the low CFS group, in 83.2% in the intermediate CFS group and in 89.0% in the high CFS group (p <0.001). Patients in the intermediate and high CFS groups were associated with higher 1-year major bleeding risk after PCI in the overall cohort (HR 3.82, 95% CI 2.65 to 5.51, p <0.001, and HR 7.81, 95% CI 5.07 to 12.0, p <0.001, respectively). Patients in the high CFS group were also associated with higher 1-year major bleeding risk regardless of having the high bleeding risk (HBR) according to ARC-HBR. In conclusion, the association of frailty with 1-year major bleeding was consistently observed in patients with and without HBR, indicating that frailty per se might be a predictor for major bleeding after PCI on top of HBR criteria., (Copyright © 2021 Elsevier Inc. All rights reserved.)