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Objectives This study sought to evaluate the impact of post-stent optical coherence tomography (OCT) findings, including severe malapposition, on long-term clinical outcomes. Background Suboptimal OCT findings following percutaneous coronary intervention (PCI) are highly prevalent; however, their clinical implications remain controversial. Methods Of the patients registered in the Yonsei OCT registry, a total of 1,290 patients with 1,348 lesions, who underwent OCT immediately post-stenting, were consecutively enrolled for this study. All patients underwent implantation of drug-eluting stents. Post-stent OCT findings were assessed to identify predictors of device-oriented clinical endpoints (DoCE), including cardiac death, target vessel-related myocardial infarction (MI) or stent thrombosis, and target lesion revascularization (TLR). Significant malapposition criteria associated with major safety events (MSE) were also investigated, such as cardiac death, target vessel-related MI, or stent thrombosis. Results The median follow-up period was 43.0 months (interquartile range [IQR] 21.4 to 56.0 months). The incidence rates of stent edge dissection, tissue prolapse, thrombus, and malapposition after intervention were not associated with occurrence of DoCE. However, patients with significant malapposition (total malapposition volume [TMV] ≥7.0 mm3] exhibited more frequent MSE. A smaller minimal stent area (MSA) was identified as an independent predictor for DoCE (hazard ratio [HR]: 1.20 [95% confidence interval [CI]: 1.00 to 1.43]; p = 0.045). Malapposition with TMV ≥7.0 mm3 was found to be an independent predictor of MSE (HR: 6.12 [95% CI: 1.88 to 19.95]; p = 0.003). Follow-up OCT at 3, 6, or 9 months after PCI showed that post-stent TMV ≥7.0 mm3 was related to a greater occurrence of late malapposition and uncovered struts. Conclusions Although most suboptimal OCT findings were not associated with clinical outcomes, a smaller MSA was associated with DoCE, driven mainly by TLR, and significant malapposition with TMV ≥7.0 mm3 was associated with more MSE after PCI. (Yonsei OCT [Optical Coherence Tomography] Registry for Evaluation of Efficacy and Safety of Coronary Stenting; Yonsei OCT registry; NCT02099162 )

BackgroundTumour-unrelated, virus-specific bystander CD8+T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet.MethodsWe studied the characteristics of bystander CD8+TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy.ResultsWe show that bystander CD8+TILs specific to various viruses are present in human NSCLC tissues. We stimulated CD8+TILs ex vivo using IL-15 without cognate antigens and found that IL-15 treatment upregulated NKG2D expression on CD8+TILs, resulting in NKG2D-dependent production of interferon (IFN)-γ (p=0.0006). Finally, we tested whether IL-15 treatment can control tumour growth in a murine NSCLC model with or without a history of murine cytomegalovirus (MCMV) infection. IL-15 treatment reduced the number of tumour nodules in the lung only in mice with MCMV infection (p=0.0037). We confirmed that MCMV-specific bystander CD8+TILs produced interferon (IFN)-γ after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-α and IFN-γ responsive genes in tumour microenvironment.ConclusionThus, the study demonstrates that bystander CD8+TILs can be repurposed by IL-15 for tumour immunotherapy.

BACKGROUND The heterogeneous immune landscapes of intrahepatic cholangiocarcinoma (ICC) remain largely unknown. Here we aimed to investigate the implications of tissue-resident memory (TRM)-related features of tumour-infiltrating CD8+ T cells (CD8+ TILs) from ICC patients. METHODS From ICC patients, we obtained blood samples and ICC surgical specimens (n = 33). We performed multicolour flow cytometry, multiplexed immunohistochemistry and RNA sequencing. RESULTS When compared to peripheral CD8+ T cells, the CD8+ TILs included significantly higher proportions of the CD69+ CD103- and CD69+ CD103+ TRM-like subsets (P

Background & Aims Human liver CD69+CD8+ T cells are ~95% CD103- and ~5% CD103+. Although CD69+CD103+CD8+ T cells show tissue residency and robustly respond to antigens, CD69+CD103-CD8+ T cells are not yet well understood. Methods Liver perfusate and paired peripheral blood were collected from healthy living donors and recipients with cirrhosis during liver transplantation. Liver tissues were obtained from patients with acute hepatitis A. Phenotypic and functional analyses were performed by flow cytometry. Gene expression profiles were determined by microarray and quantitative reverse transcription PCR. PT-2385 was used to inhibit hypoxia-inducible factor (HIF)-2α. Results Human liver CD69+CD103-CD8+ T cells exhibited HIF-2α upregulation with a phenotype of tissue residency and terminal differentiation. CD103- cells comprised non-hepatotropic virus-specific T cells as well as hepatotropic virus-specific T cells, but CD103+ cells exhibited only hepatotropic virus specificity. Although CD103- cells were weaker effectors on a per cell basis than CD103+ cells, following T cell receptor or interleukin-15 stimulation, they remained the major CD69+CD8+ effector population in the liver, surviving with less cell death. An HIF-2α inhibitor suppressed the effector functions and survival of CD69+CD103-CD8+ T cells. In addition, HIF-2α expression in liver CD69+CD103-CD8+ T cells was significantly increased in patients with acute hepatitis A or cirrhosis. Conclusions Liver CD69+CD103-CD8+ T cells are tissue resident and terminally differentiated, and their effector functions depend on HIF-2α. Furthermore, activation of liver CD69+CD103-CD8+ T cells with HIF-2α upregulation is observed during liver pathology. Lay summary The immunologic characteristics and the role of CD69+CD103-CD8+ T cells, which are a major population of human liver CD8+ T cells, remain unknown. Our study shows that these T cells have a terminally differentiated tissue-resident phenotype, and their effector functions depend on a transcription factor, HIF-2α. Furthermore, these T cells were activated and expressed higher levels of HIF-2α in liver pathologies, suggesting that they play an important role in immune responses in liver tissues and the pathogenesis of human liver disease.

Background For diabetic patients with multivessel coronary artery disease (MVD), limited data exist on the long-term outcomes of percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) according to clinical presentation [stable coronary artery disease (SCAD) or non-ST-elevation acute coronary syndrome (NSTE-ACS)]. Patients and methods From a Korean multicenter registry, we analyzed 1135 diabetic patients with MVD treated with PCI (n = 660) or CABG (n = 475). After propensity score matching, 8-year major adverse cardiovascular and cerebrovascular events [MACCE; composite of all-cause death, myocardial infarction (MI), or stroke] were compared between PCI and CABG according to clinical presentation. Results After matching, MACCE was not different between PCI and CABG for SCAD patients [15.6 vs. 17.2%, hazard ratio (HR) = 0.94, 95% confidence interval (CI) = 0.55-1.63, P = 0.837], whereas it was higher in PCI than in CABG for NSTE-ACS patients (31.1 vs. 22.4%, HR = 1.63, 95% CI = 1.03-2.59, P = 0.036), mainly driven by the higher MI occurrence (HR = 2.18, 95% CI = 1.04-4.59, P = 0.035). A significant interaction between revascularization strategy and clinical presentation was observed for MACCE (P-interaction = 0.022). However, when PCI was further classified according to revascularization completeness, the treatment gap between PCI and CABG with respect to MI in NSTE-ACS patients was improved by complete-revascularization PCI. Conclusion Among diabetic patients with MVD, the long-term outcomes of PCI versus CABG differed according to clinical presentation. CABG may be more beneficial for NSTE-ACS patients with MVD in reducing MACCE and MI, whereas PCI was as effective as CABG for SCAD patients with MVD. Therefore, clinical presentation must be considered when choosing revascularization strategies in these patients.

The aim of this study was to investigate the optimal strategy for antiplatelet therapy in patients with lower extremity peripheral artery disease (PAD) after endovascular revascularization.The optimal strategy for antiplatelet therapy in patients with PAD after endovascular revascularization has not been established.From March 2008 to February 2013, 693 patients with lower extremity PAD treated with different antiplatelet therapies, such as mono-antiplatelet therapy (MAPT) and dual-antiplatelet therapy (DAPT), of various durations after endovascular revascularization were analyzed. They were classified into 2 groups (DAPT 6 months or MAPT vs. DAPT ≥6 months). The primary outcomes were major adverse cardiovascular events and major adverse limb events. The safety outcome was major bleeding.During 5-year follow-up, major adverse cardiovascular events occurred less frequently in the DAPT ≥6-month group than the DAPT 6-month or MAPT group (17.3% vs. 31.3%; hazard ratio: 0.44; 95% confidence interval: 0.30 to 0.65; p 0.001). Major adverse limb events also occurred less frequently in the DAPT ≥6-month group than the DAPT 6-month or MAPT group (21.5% vs. 43.7%; hazard ratio: 0.42; 95% CI: 0.30 to 0.58; p 0.001). However, major bleeding events were infrequent, with no signal toward harm with DAPT ≥6 months. Results were consistent after inverse probability-weighted adjustment and propensity score matching.Following endovascular revascularization for lower extremity PAD, DAPT ≥6 months was associated with decreased 5-year major adverse cardiovascular events and major adverse limb events.

Background: Although stent underexpansion on intravascular ultrasound (IVUS) has been a major predictor for adverse outcomes in previous studies, these studies have primarily focused on angiographic restenosis or repeat revascularization with short-term follow-up. This study sought to evaluate the long-term benefit of different criteria for IVUS-defined optimal stent expansion on hard clinical outcomes. Methods: From the pooled data of 2 randomized trials, IVUS-XPL (Impact of Intravascular Ultrasound Guidance on the Outcomes of Xience Prime Stents in Long Lesions) and ULTIMATE (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in All-Comers Coronary Lesions) that compared IVUS- versus angiography-guided drug-eluting stent implantation, a total of 1254 patients with IVUS-guided drug-eluting stent implantation into 1484 long lesions (implanted stent length, ≥28 mm) were included. Different criteria for IVUS-defined optimal stent expansion based on minimum stent area (MSA) as an absolute measure or MSA relative to reference lumen area were applied and validated. The primary end point was composite of cardiac death, target lesion–related myocardial infarction, or stent thrombosis at 3 years. Results: The rate of the primary end point was lower in patients with optimal stent expansion versus those without optimal stent expansion according to 3 IVUS-defined optimal stent expansion criteria: MSA >5.5 mm 2 (0.5% versus 2.2%; hazard ratio, 0.21 [95% CI, 0.06–0.75]; P =0.008), MSA >5.0 mm 2 (0.6% versus 2.6%; hazard ratio, 0.24 [95% CI, 0.09–0.68]; P =0.003), and MSA/distal reference lumen area >90% (0.5% versus 2.4%; hazard ratio, 0.32 [95% CI, 0.12–0.88]; P =0.019). Achieving other relative expansion criteria, MSA/distal reference lumen area >100% or 80% or MSA/average reference lumen area >90% or 80%, was not associated with a reduction in hard clinical events. Conclusions: In patients undergoing IVUS-guided drug-eluting stent implantation for long lesions, achieving optimal stent expansion of MSA >5.5 mm 2 , >5.0 mm 2 , or MSA/distal reference lumen area >90% was associated with improved long-term hard clinical outcomes.

Background: In patients with acute coronary syndrome (ACS) with a high risk of ischemia, the impact of ticagrelor monotherapy after short-term dual antiplatelet therapy (DAPT) has not been clearly elucidated. Methods: This post hoc analysis of the TICO trial (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus-Eluting Stent for Acute Coronary Syndrome) compared the impact of ticagrelor monotherapy after 3-month DAPT versus ticagrelor-based 12-month DAPT in patients with high-ischemic risk ACS, defined as any of the following: number of stents implanted ≥3, total stent length >60 mm, complex procedures (chronic total occlusion, left main occlusion, or bifurcation plaques remedied using the 2-stent technique), or a history of diabetes or chronic kidney disease. Ischemic (composite of death, myocardial infarction, stent thrombosis, stroke, and target vessel revascularization) and bleeding outcomes (major bleeding) were evaluated at 12 months. Results: Of the total population (N=3056), 1473 (48.2%) patients were identified as having high-ischemic risk ACS. The rate of the ischemic outcome was significantly higher in high-ischemic risk ACS patients than in nonhigh-ischemic risk ACS patients (3.9% versus 1.9%, hazard ratio, 2.14 [95% CI, 1.37–3.35], P =0.001). Furthermore, the risk of major bleeding (3.2% versus 1.5%, hazard ratio, 2.23 [95% CI, 1.36–3.68], P =0.001) and the composite ischemic and bleeding outcome (6.6% versus 3.3%, hazard ratio, 2.02 [95% CI, 1.44–2.84], P P int =0.718), bleeding ( P int =0.092), and composite outcomes ( P int =0.094) without significant interactions. Conclusions: There were no significant heterogeneities in the impact of ticagrelor monotherapy after 3-month DAPT compared with that of ticagrelor-based 12-month DAPT on clinical outcomes according to the presence of high-ischemic risk. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02494895.

Atherectomy as a pretreatment has the potential to improve the outcomes of drug-coated balloon (DCB) treatment by reducing and modifying atherosclerotic plaques. The present study investigated the outcomes of atherectomy plus DCB (A+DCB) compared with DCB alone for the treatment of femoropopliteal artery disease.A total of 311 patients (348 limbs) underwent endovascular therapy using DCB for native femoropopliteal artery lesions at two endovascular centers. Of these, 82 limbs were treated with A+DCB and 266 limbs with DCB alone. After propensity score matching based on clinical and lesion characteristics, a total of 82 pairs was compared for immediate and mid-term outcomes.For the matched study groups, the lesion length was 172.7±111.2 mm, and severe calcification was observed in 43.3%. The technical success rate was higher in the A+DCB group than in the DCB group (80.5% vs. 62.2%, p=0.015). However, the A+DCB group showed more procedure-related minor complications (37.0% vs. 13.4%, p=0.047). At 2-year follow-up, primary clinical patency (73.8% vs. 82.6%, p=0.158) and the target lesion revascularization (TLR)-free survival (84.3% vs. 88.2%, p=0.261) did not differ between the two groups. In Cox proportional hazard analysis, atherectomy showed no significant impact on the outcome of DCB treatments.The pretreatment with atherectomy improved technical success of DCB treatment; however, it was associated with increased minor complications. In this study, A+DCB showed no clinical benefit in terms of TLR-free survival or clinical patency compared with DCB treatment alone.

Oxidative stress can induce covalent disulfide bond formation between protein-protein thiol groups and generate hydroxyl free radicals that damage DNA. HMGB1 is a DNA chaperone and damage-associated molecular pattern molecule. As a redox-sensitive protein, HMGB1 contains three cysteine residues: Cys23, Cys45, and Cys106. In this study, we focused on the relationship between HMGB1 dimerization and DNA stabilization under oxidative stress conditions. HMGB1 dimerization was positively modulated by CuCl2 and H2O2. Mutation of the Cys106 residue blocked dimer formation. Treatment of HEK293T cells with CuCl2 and H2O2 enhanced the oxidative self-dimerization of HMGB1, whereas this dimerization was inhibited in mutant HMGB1C106A cells. Furthermore, we performed a bimolecular fluorescence complementation assay to visualize Cys106 oxidation-induced HMGB1 dimerization in live cells exposed to oxidative stress and were able to reproduce the dimerization effect of HMGB1 in fluorescence resonance energy transfer analysis. Interestingly, dimerized HMGB1 bound to DNA with higher affinity than monomeric HMGB1. Dimerized HMGB1 protected DNA from damage due to hydroxyl free radicals and prevented cell death. In conclusion, dimerized HMGB1 may play a regulatory role in DNA stabilization under oxidative stress., Graphical abstract Image 1, Highlights • Accumulation of excessive ROS induces DNA damage, causing cell death. • HMGB1 dimerizes in the presence of excessive ROS and binds DNA with high affinity. • Binding of dimerized HMGB1 (Di-HMGB1) protects DNA from ROS action. • We prepared an in vitro HMGB1 dimerization due to excessive ROS. • Di-HMGB1 protected against DNA damage induced by radiation exposure.

Skin perfusion pressure (SPP) has been proposed as a method to predict wound healing in chronic limb threatening ischaemia (CLTI). However, studies regarding the impact of SPP before and after endovascular therapy (EVT) on wound healing are limited. This study sought to evaluate the predictive value of SPP for early wound healing in CLTI treated by EVT.Between January 2018 and June 2020, 236 limbs (172 patients) with CLTI that underwent SPP measurement before and after EVT were included. SPP was measured before and 24 - 48 hours after the procedure. Early wound healing was defined as the achievement of complete epithelisation of all wounds without major amputation within three months of EVT.Early wound healing was achieved in 145 (61.4%) limbs after EVT. Baseline SPP (44.1 ± 21.0 mmHg vs. 33.5 ± 21.7 mmHg; p.001) and post-procedural SPP (61.8 ± 18.5 mmHg vs. 37.4 ± 19.9 mmHg; p.001) were significantly higher in the wound healing (+) group than in the wound non-healing (-) group. The area under the receiver operating characteristics curve for early wound healing was 0.82 for post-procedural SPP with a cutoff value of 50 mmHg (sensitivity 74.5%, specificity 78.0%). The early wound healing rate was significantly higher with a post-procedural SPP ≥ 50 mmHg compared with a SPP50 mmHg (84.4% vs. 35.0%; p.001).Post-procedural SPP with a cutoff value of 50 mmHg was capable of predicting early wound healing after EVT in CLTI.

Background and aims The prognosis of stented lesions differs according to in-stent neointimal characteristics on optical coherence tomography (OCT). In particular, patients who show in-stent heterogeneous neointima are associated with a higher incidence of target lesion revascularization (TLR) compared with those who show in-stent non-heterogeneous neointima. However, the relationship between in-stent neointimal characteristics and native coronary atherosclerosis progression has not been clearly elucidated. The study aimed to investigate the relationship between in-stent neointimal characteristics and progression of native atherosclerosis. Methods The neointimal characteristics of 377 patients with 377 drug-eluting stents (DESs) were quantitatively and qualitatively assessed using OCT. The OCT-based neointima was categorized as homogeneous (n = 207), heterogeneous (n = 93), and layered (n = 77). The relationship of non-target lesion revascularization (non-TLR) with neointimal characteristics was evaluated after OCT examination of the stents. Results After a median follow-up duration of 40.0 months, patients with heterogeneous neointima showed significantly higher non-TLR rates than those with homogeneous neointima and tended to have higher non-TLR rates than those with layered neointima (heterogeneous vs. homogeneous:14.0% vs. 8.7%, p = 0.046; heterogeneous vs. layered neointima:14.0% vs. 7.8%, p = 0.152). Multivariate analysis showed that the independent determinants for non-TLR were heterogeneous neointima (HR: 2.237, 95% CI: 1.023–4.890, p = 0.044) and chronic kidney disease (hazard ratio [HR]: 8.730, 95% CI: 2.175–35.036, p = 0.002). Conclusions The heterogeneous neointima in DES-treated lesions was associated with a higher incidence of non-TLR and target lesion failure. This finding suggests that the neointimal pattern may reflect the progression of the native lesion.

Background and objectives Transcatheter aortic valve replacement (TAVR) has been reported as a good alternative for surgical aortic valve replacement in patients with small aortic annulus. Head-to-head comparisons of different transcatheter aortic valves in these patients are insufficient. We compared the outcomes after TAVR between two different types of recent transcatheter aortic valves (self-expanding vs. balloon-expandable) in patients with small aortic annulus. Methods A total of 70 patients with severe aortic stenosis and small annulus (mean diameter ≤23 mm or minimal diameter ≤21 mm on computed tomography) underwent TAVR with either a self-expanding valve with supra-annular location (n=45) or a balloon-expandable valve with intra-annular location (n=25). The echocardiographic hemodynamic parameters after TAVR and 1-year follow-up were compared. Results Between the self-expanding and balloon-expandable valve-treated patients, the clinical outcomes including permanent pacemaker implantation (11.1% vs. 8.0%), acute kidney injury stage 2 or 3 (4.4% vs. 4.0%), and major vascular complication (4.4% vs. 0.0%) were similar without all-cause mortality, stroke, and life-threatening bleeding during 30-day follow-up. Compared with the balloon-expandable valve-treated patients, the self-expanding valve-treated patients presented larger effective orifice area (EOA) (1.46±0.28 vs. 1.75±0.42 cm², p=0.002) and indexed EOA (0.95±0.21 vs. 1.18±0.28 cm²/m², p=0.001), whereas mean aortic valve gradient (11.7±2.9 vs. 8.9±5.2 mmHg, P=0.005) and incidence of ≥moderate prosthesis-patient mismatch (36.0% vs. 8.9%, p=0.009) were lower. These hemodynamic differences were maintained at 1-year follow-up. Conclusions TAVR with self-expanding valves was associated with superior hemodynamic outcomes compared with balloon-expandable valves in patients with small aortic annulus.

Few studies have presented evidence pertaining to the adequate minimum number of adjuvant chemotherapy (AC) cycles required to achieve an oncologic benefit for gastric cancer. From January 2012 to December 2013, data from patients who underwent curative radical gastrectomy and consequently received AC for pathologic stage 2 or 3 gastric cancer at 27 institutions in South Korea were analyzed. The study enrolled 925 patients, 661 patients (71.5%) who completed 8 cycles of AC and 264 patients (28.5%) who did not. Compared with the mean disease-free survival (DFS) of the patients who completed 8 AC cycles (69.3 months), the mean DFS of patients who completed 6 AC cycles (72.4 months; p = 0.531) and those who completed 7 AC cycles (63.7 months; p = 0.184) did not differ significantly. However, the mean DFS of the patients who completed 5 AC cycles (48.2 months; p = 0.016) and those who completed 1–4 AC cycles (62.9 months; p = 0.036) was significantly lower than the DFS of those who completed 8 AC cycles. In the multivariate Cox proportional hazards analysis, the mean DFS was significantly affected by advanced stage, large tumor size, positive vascular invasion, and number of completed AC cycles (1–5 cycles: hazard ratio 1.45; 95% confidence interval 1.01–2.08; p = 0.041). The current multicenter observational cohort study showed that the mean DFS for 6 or 7 AC cycles was similar to that for 8 AC cycles as an adjuvant treatment for gastric cancer.

There have been limited clinical trials comparing drug eluting stents (DESs) and drug coated balloons (DCBs) in the treatment of femoropopliteal artery disease. This two centre retrospective and prospective cohort study sought to compare DES with DCB for the treatment of native femoropopliteal artery disease.A total of 288 limbs (242 patients) with native femoropopliteal artery disease were treated with DESs (Zilver PTX; 102 limbs) or DCBs (IN.PACT Admiral; 186 limbs) in two Korean endovascular centres between 19 January 2013 and 5 May 2018 and followed for a median duration of 19.6 months. The primary endpoint was primary clinical patency. Propensity score matching (PSM, 162 limbs) and inverse probability weighted (IPW) adjustment were performed to adjust for confounding baseline characteristics.The DCB group had fewer lesions with Trans-Atlantic Inter-Society Consensus (TASC) II type C/D (55.9% vs. 70.6%, p = .021) or total occlusions (43.5% vs. 77.5%, p .001) and showed shorter lesion lengths (164.2 ± 105.4 mm vs. 194.8 ± 86.8 mm, p = .009) than the DES group. After PSM, baseline clinical and lesion characteristics of the two groups were comparable except for larger reference vessel diameter in the DES group (5.4 ± 0.6 vs. 5.1 ± 0.7, p = .025). Adjunctive atherectomy was performed in 32.1% of the DCB group and in 2.5% of the DES group (p .001). The provisional stenting was required in 14.8% of the DCB group. At two year follow up, the DCB group showed higher primary clinical patency (74.6% vs. 56.7%, hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.27-0.96, p = .032) and freedom from target lesion revascularisation (85.9% vs. 71.3%, HR 0.39, 95% CI 0.17-0.89, p = .021) than the DES group. Survival from all cause death did not differ between groups (87.6% vs. 92.1%, HR 1.85, 95% CI 0.62-5.52, p = .26).In this two centre cohort, DCBs with selective use of adjunctive atherectomy achieved more favourable outcomes than DESs for native femoropopliteal artery disease.

Background and aims Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4-1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor-infiltrating CD8+ T cells (CD8+ tumor-infiltrating lymphocytes [TILs]) and its association with distinct T-cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC). Approach and results Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA-sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4-1BB was most prominently expressed on CD8+ TILs. 4-1BB expression was almost exclusively detected on CD8+ T cells in the tumor-especially on programmed death 1 (PD-1)high cells and not PD-1int and PD-1neg cells. Compared to PD-1int and 4-1BBneg PD-1high CD8+ TILs, 4-1BBpos PD-1high CD8+ TILs exhibited higher levels of tumor reactivity and T-cell activation markers and significant enrichment for T-cell activation gene signatures. Per-patient analysis revealed positive correlations between percentages of 4-1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T-cell activation. Among highly exhausted PD-1high CD8+ TILs, 4-1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4-1BB-related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4-1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti-PD-1-mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T-cell activation. Conclusion 4-1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4-1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T-cell activation.

Tissue-resident memory CD8+ T cells (TRMs), marked by expression of CD103, are considered to play a key role as anti-tumor immune response in breast cancer. However, prognostic value of TRMs and heterogeneity in CD103+ TRMs of breast cancer in terms of tumor-specificity needs further understanding to establish immuno-therapeutic implications. Here, we isolated tumor-infiltrating CD103+TRMs in breast cancer samples and matched peripheral blood mononuclear cells (PBMCs) which were prospectively collected from 127 patients who underwent surgical resection between July 2016 and May 2020 at Severance Hospital, Seoul, Republic of Korea. Multi-color flow cytometry analyses were performed.CD103+TRMs consist of both tumor-antigen specific CD8+ T cells and bystander CD8+ T cells, such as viral antigen-specific CD8+ T cells. Dissection of CD103+TRMs with CD39 expression reveals a clonally-distinct subpopulation exhibiting tumor-antigen specificity and reactivity with transcriptionally and phenotypically exhaustive features. CD39+CD103+ TRMs were enriched in HER2 enriched and triple-negative breast cancer(TNBC) subtypes, but not in Hormone receptor(HR) positive/HER2 not enriched subtypes, implying that the role of tumor-infiltrating CD8+ T cells in eliciting anti-tumor immune response differ among molecular subtypes. In line with early-exhaustive features of CD39+CD103+TRMs, inhibition of either PD-1 alone or both PD-1 and CTLA-4 reinvigorate the proliferation and the cytokine production of CD8+ TILs in HER2 and TNBC subtypes. Our findings indicate that different immuno-therapeutic strategies should be considered to different subtypes of breast cancer. Citation Format: Jee Ye Kim, Yong Joon Lee, Seung hyuck Jeon, Heejin Nam, Jae Hyung Jung, Seung Il Kim, Eui-Cheol Shin. Tumor-specificity of tumor-infiltrating CD8+ t cells determines the potential of immune checkpoint inhibitors in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1666.

Purpose Previous studies have demonstrated the prognostic impact of the prognostic nutritional index (PNI), a proposed indicator of immunonutritional statuses of surgical patients, on patients with various gastrointestinal cancers. Although the prognostic impact of the PNI on patients with colorectal cancer has been well established, its value has not been studied in patients treated with preoperative chemoradiation (pCRT). This study aimed to evaluate the prognostic impact of PNI on patients receiving pCRT for locally advanced rectal cancer (LARC). Methods Patients with LARC who underwent curative pCRT followed by surgical resection were enrolled. The PNI was measured in all patients before and after pCRT, and the difference in values was calculated as the PNI difference (dPNI). Patients were classified according to dPNI (10). Clinicopathologic parameters and long-term oncologic outcomes were assessed according to dPNI classification. Results No significant intergroup differences were observed in clinicopathologic parameters such as age, histologic grade, tumor location, tumor-node-metastasis stage, and postoperative complications. Approximately 53% of the patients had a mild dPNI (10). Univariate and multivariate analyses identified the dPNI as an independent prognostic factor for disease-free status (P < 0.01; hazard ratio [HR], 2.792; 95% confidence interval [CI], 1.577–4.942) and for cancer-specific survival (P = 0.012; HR, 2.469; 95%CI, 1.225–4.978). Conclusion The dPNI is predictive of long-term outcomes in pCRT-treated patients with LARC. Further prospective studies should investigate whether immune-nutritional status correction during pCRT would improve oncologic outcomes.

Background The efficacy of oral anticoagulation therapy (OAT) has not been revealed in atrial fibrillation (AF) patients with newly diagnosed cancers. This study evaluated the thromboembolic and bleeding events in AF patients with malignancies according to OAT. Methods and results In 2168 consecutive non-valvular AF patients with newly diagnosed malignancies, we analyzed the composite endpoints including major adverse cardiac events (MACEs) and major bleeding. Based on a propensity score matching, two groups with 690 matched pairs were created. Patient baseline characteristics were comparable between the matched groups. During a follow-up period of 3.9±2.8years, 72 (10%) and 65 (9%) patients had MACEs in the propensity score-matched OAT+ and OAT− groups, respectively (p=0.461). There was no significant difference in the major bleeding (10% vs. 8%, p=0.300) and composite endpoints (18% vs. 16%, p=0.181) between OAT+ and OAT− patients. During the first year after the cancer diagnosis, 66 (48%) MACEs, 52 (41%) major bleedings, and 116 (49%) composite end points of all events occurred. The optimal international normalized ratio (2.0 to 3.0) level was achieved in only 85 (12%) patients. However, 1year after cancer diagnosis, OAT+ patients with the target therapeutic range of ≥60% demonstrated better cumulative survival free of composite end point than OAT− patients (p=0.026). Conclusion During the first year after the cancer diagnosis, OAT did not improve the composite end point because of poor INR control caused by cancer treatment. However, after 1year after diagnosis of cancer, optimal anticoagulation significantly reduced the composite end point.

We measured systemic changes in the immune response in 92 patients receiving preoperative chemoradiation therapy (CRT) and subsequent surgery for rectal cancer. The peripheral blood was sampled five times from the onset of CRT until surgery. Lymphocytes decreased continuously during CRT but increased after CRT. The increased lymphocyte population was predominantly CD8+ T lymphocytes, which accounted for a significantly larger proportion in patients without residual lymph node metastasis than in those with residual lymph node metastasis. Neutrophils and monocytes decreased during the initial two weeks of CRT but were maintained or increased afterwards. Neutrophil and monocyte counts were significantly lower in patients with a pCR (pathologic complete response) than in those without a pCR two weeks after CRT began but not at the initiation of CRT. All cytokines showed dramatic changes one month after the termination of CRT. Cytokines related to the antitumour immune response increased, and those related to tumour progression decreased. The predictive value of cytokines was not clear. In short, we observed that immune components in peripheral blood are affected by CRT and show dynamic changes over time. We identified biomarker candidates to predict the pathologic response in the future.

Implantable cardioverter-defibrillator (ICD) therapy is acknowledged as a valid treatment method for the effective prevention of sudden cardiac death, which is a major cause of mortality in adult congenital heart disease patients. But ICD implantation by the conventional transvascular approach is not always possible in patients who have undergone palliative surgery due to congenital and structural heart disease. Here, we report a case in which an ICD was transvascularly implanted in an arrhythmogenic right ventricular cardiomyopathy patient who had undergone a one-and-a-half ventricle repair.

Intramural duodenal hematoma (IDH) is a rare disease which defined a hematoma formation localized within the wall of the duodenum. The most common cause of IDH is due to blunt abdominal trauma while most of other cases of IDH are more related to the use of anticoagulants or coagulation disorders such as haemophilia and Von Willebrand disease. We report a very rare case of a large IDH caused by acute alcoholic pancreatitis without any kind of anticoagulation therapies nor coagulopathies. The patient was recovered by only medical treatment and observation without surgical intervention. Korean J Pancreas Biliary Tract 2014;19(3):132-136

Copyright©2014 Korean Geriatric Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/). Successful Treatment of Severe Aortic Stenosis With Transcatheter Aortic Valve Implantation in a Centenarian Patient Yong-Joon Lee, MD, Young-Ju Kim, MD, Jung-Hee Lee, Young-Guk Ko, MD, Sanghoon Shin, MD, Geuru Hong, MD, Sak Lee, MD, Byung-Chul Chang, MD, Jae-Kwang Shim, MD, Young-Ran Kwak, MD, Myeong-Ki Hong, MD Divisions of Cardiology, Thoracic and Cardiovascular Surgery, and Anesthesiology and Pain Medicine, Severance Cardiovascular Hospital, Yonsei University Health System, Seoul, Korea

BACKGROUND AND OBJECTIVES There are limited data on the use of non-vitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with cancer. We aimed to assess the efficacy and safety of NOACs in AF patients with cancer in this study. METHODS In 2,568 consecutive non-valvular AF patients with newly diagnosed cancer, we analyzed ischemic stroke/systemic embolism (SE), major bleeding, and all-cause death. Based on propensity score matching, 388 matched pairs were included in the NOAC and warfarin groups. RESULTS Patient baseline characteristics were comparable between the matched groups. During median follow-up of 1.8 years, the NOAC group had significantly lower incidences of ischemic stroke/SE (p

Background: High mobility group box-1 (HMGB1), a proinflammatory cytokine, plays a pivotal role in tissue remodeling and angiogenesis, both of which are crucial for the pathogenesis of pulmonary arterial hypertension. In this study, we explored the relationship between HMGB1 and pulmonary hypertension and whether glycyrrhizin, an inhibitor of HMGB1, attenuates disease progression in an animal model of pulmonary hypertension induced by monocrotaline sodium (MCT). Methods: After inducing pulmonary hypertension through a single subcutaneous injection of MCT (60 mg/kg) to Sprague–Dawley rats, we administered daily intraperitoneal injections of either glycyrrhizin (GLY, 50 mg/kg), an inhibitor of HMGB1, or saline (control) for either 4 or 6 weeks. Results: Expression levels of HMGB1 in serum increased from the second week after MCT injection and remained elevated throughout the experiment periods. Lung tissue levels of HMGB1 assessed by immunohistochemical staining at 4 weeks after MCT injection also increased. Chronic inhibition of HMGB1 by GLY treatment reduced the MCT-induced increase in right ventricular (RV) systolic pressure, RV hypertrophy (ratio of RV to [left ventricle+septum]), and pulmonary inflammation. MCT-induced muscularization of the pulmonary artery was also attenuated in the GLY-treated group. As assessed 6 weeks after MCT injection, the GLY-treated group exhibited increased survival (90% [18 of 20]) when compared with the control group (60% [12 of 20]; p =0.0027). Conclusions: Glycyrrhizin, an inhibitor of HMGB1, attenuates pulmonary hypertension progression and pulmonary vascular remodeling in the MCT-induced pulmonary hypertension rat model. Further studies are needed to confirm the potential of HMGB1 as a novel therapeutic target for pulmonary hypertension.

Bis (Bag-3, CAIR), a Bcl-2-interacting protein, promotes the anti-apoptotic activity of Bcl-2 and increased levels of Bis have been observed in several disease models. The involvement of Bcl-2 and some Bcl-2-binding proteins in differentiation has recently been reported. However, the relevance of Bis to cellular differentiation remains unknown. The findings herein show that Bis expression is up-regulated during the differentiation of HL-60 cells. To investigate the effect of Bis expression on differentiation, we established Bis-overexpressing HL-60 cells (HL-60-bis). HL-60-bis cells have a low nuclear: cytoplasmic ratio and indented nucleus in Wright- Giemsa staining, and an increased expression of CD11b in immunofluorescence study, indicating the promotion of differentiation. The overexpression of Bis also resulted in a retarded cell growth rate, accompanied by the accumulation of HL-60 cells at the G0/G1 phase of the cell cycle, which was sustained during the differentiation process. Western blot analysis revealed that the expression of p27, a representative inducer of cell cycle arrest at the G1 phase, was increased 2.5-fold in HL-60-bis cells compared to HL-60-neo cells. These results suggest that the Bis induced growth inhibition of HL-60 cells promotes G0/G1 phase arrest via up-regulation of p27, which seems to be a prerequisite for differentiation. Further studies will be required to define the exact roles of Bis on cellular differentiation more precisely.

Primary stenting in femoropopliteal lesions of intermediate length has recently shown favorable outcomes. However, stent fractures are a concern after bare metal stent implantation. The incidence of stent fracture varies widely (ranging from 2% to 65%) depending on factors such as the treated lesions or stent type and may potentially lead to various complications. We reported a case of stent fracture with complete dislocation combined with recurrent in-stent reocclusion and aneurysm formation in a patient with occlusive disease of the femoropopliteal artery, which was successfully treated with self-expandable endovascular stent graft.

Plasma angiotensin-converting enzyme activity was measured by spectrophotometer in normal subjects and in patients with end stage renal failure, serially during a routine hemodialysis. Patients on maintenance hemodialysis tended to be associated with elevated plasma angiotensin-converting enzyme activity versus normal subjects. Plasma angiotensin-converting enzyme activity was significantly elevated in patients with chronic renal failure after 5 hours of hemodialysis(p

Background High mobility group box-1 (HMGB1), a proinflammatory cytokine, plays a pivotal role in tissue remodeling and angiogenesis, both of which are crucial for the pathogenesis of pulmonary arterial hypertension. In this study, we explored the relationship between HMGB1 and pulmonary hypertension and whether glycyrrhizin, an inhibitor of HMGB1, attenuates disease progression in an animal model of pulmonary hypertension induced by monocrotaline sodium (MCT). Methods After inducing pulmonary hypertension through a single subcutaneous injection of MCT (60 mg/kg) to Sprague–Dawley rats, we administered daily intraperitoneal injections of either glycyrrhizin (GLY, 50 mg/kg), an inhibitor of HMGB1, or saline (control) for either 4 or 6 weeks. Results Expression levels of HMGB1 in serum increased from the second week after MCT injection and remained elevated throughout the experiment periods. Lung tissue levels of HMGB1 assessed by immunohistochemical staining at 4 weeks after MCT injection also increased. Chronic inhibition of HMGB1 by GLY treatment reduced the MCT-induced increase in right ventricular (RV) systolic pressure, RV hypertrophy (ratio of RV to [left ventricle + septum]), and pulmonary inflammation. MCT-induced muscularization of the pulmonary artery was also attenuated in the GLY-treated group. As assessed 6 weeks after MCT injection, the GLY-treated group exhibited increased survival (90% [18 of 20]) when compared with the control group (60% [12 of 20]; p =0.0027). Conclusions Glycyrrhizin, an inhibitor of HMGB1, attenuates pulmonary hypertension progression and pulmonary vascular remodeling in the MCT-induced pulmonary hypertension rat model. Further studies are needed to confirm the potential of HMGB1 as a novel therapeutic target for pulmonary hypertension.