The Risk and Reversibility of Osimertinib-related Cardiotoxicity in a Real-World Population.

INTRODUCTION: While osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, as the first-line therapy for metastatic non-small cell lung cancer (NSCLC) has shown significant survival benefits, concerns have arisen regarding its potential cardiotoxicity, particularly in real-world clinical settings. We aimed to investigate the incidence, risk factors, and reversibility of osimertinib-related cardiotoxicity. METHODS: We analyzed 1,126 NSCLC patients treated with osimertinib from May 2016 to April 2023 in two cancer centers. Osimertinib-related cardiotoxicity was defined as a composite of osimertinib-related cardiac dysfunction (ORCD), newly developed arrhythmia, and cardiac death. Total follow-up duration was 20.6 (10.8-35.2) months. RESULTS: The osimertinib was administered for a median of 12.4 months. The incidence of osimertinib-related cardiotoxicity was 4.7%. Advanced age (adjusted hazard ratio with 95% confidence interval; 1.07 [1.04-1.09], P < 0.001), a history of heart failure (HF; 3.35 [1.67-9.64], P = 0.025), atrial fibrillation (AF; 3.42 [1.27-9.22], P = 0.015), and baseline low left ventricle strain (0.87 [0.79-0.96], P = 0.005) were independently associated with development of cardiotoxicity. The recovery rate of ORCD was 82.4%, which did not differ between patients who discontinued medication and those who did not. CONCLUSION: In real-world practice, the incidence of osimertinib-related cardiotoxicity was 4.7%, including 3.4% for ORCD requiring cardiologic intervention, which is higher than previously reported. Given the long-term medication of osimertinib and increased mortality associated with cardiotoxicity, vigilant monitoring is crucial, especially in patients with advanced age, history of HF, AF, or decreased baseline LV strain.

Survival predictors in patients with pancreatic cancer on liposomal irinotecan plus fluorouracil/leucovorin: a multicenter observational study.

Background: Approximately half of the patients with advanced pancreatic ductal adenocarcinoma (PDAC) receive subsequent lines of chemotherapy. Recently, the liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) regimen is recommended as subsequent lines of chemotherapy. However, little is known about the predictive factors for the nal-IRI + 5-FU/LV regimen, especially in patients with previous irinotecan (IRI) exposure. Objectives: We investigated the predictive factors associated with nal-IRI + 5-FU/LV treatment in patients with PDAC. Design: Multicenter, retrospective cohort study. Methods: This study included patients with advanced PDAC who received the nal-IRI + 5-FU/LV regimen for palliative purposes. Results: Overall, 268 patients were treated with nal-IRI + 5-FU/LV. The median overall survival (OS) was 7.9 months (95% confidence interval (CI): 7.0-8.8), while the median progression-free survival (PFS) was 2.6 months (95% CI: 1.9-3.2). An albumin level of<4.0 g/dL, neutrophil-to-lymphocyte ratio (NLR) of ⩾3.5, liver or peritoneal metastasis, and a history of >3 lines of palliative chemotherapy were associated with worse OS. An NLR of ⩾3.5 and liver metastasis were significant predictive factors for worse PFS. Previous exposure to IRI was not a significant predictor. Patients without prior IRI (no-IRI) treatment showed relatively longer OS and PFS compared to IRI responders and nonresponders, but these differences were not significant when compared specifically to the responders (OS: 8.8 vs 8.1 months, p = 0.388; PFS: 3.6 vs 2.6 months, p = 0.126). Conclusion: An NLR of ⩾3.5 and liver metastasis were associated with worse PFS. Prior IRI exposure was not a significant predictive factor for OS and PFS, especially in IRI responders.

Effect of Evogliptin on the Progression of Aortic Valvular Calcification.

BACKGROUND: Medical therapy for aortic stenosis (AS) remains an elusive goal. OBJECTIVES: This study sought to establish whether evogliptin, a dipeptidyl peptidase-4 inhibitor, could reduce AS progression. METHODS: A total of 228 patients (age 67 ± 11 years; 33% women) with AS were randomly assigned to receive placebo (n = 75), evogliptin 5 mg (n = 77), or evogliptin 10 mg (n = 76). The primary endpoint was the 96-week change in aortic valve calcium volume (AVCV) on computed tomography. Secondary endpoints included the 48-week change in active calcification volume measured using 18F-sodium fluoride positron emission tomography (18F-NaF PET). RESULTS: There were no significant differences in the 96-week changes in AVCV between evogliptin 5 mg and placebo (-5.27; 95% CI: -55.36 to 44.82; P = 0.84) or evogliptin 10 mg and placebo (-18.83; 95% CI: -32.43 to 70.10; P = 0.47). In the placebo group, the increase in AVCV between 48 weeks and 96 weeks was higher than that between baseline and 48 weeks (136 mm3; 95% CI: 108-163 vs 102 mm3; 95% CI: 75-129; P = 0.0485). This increasing trend in the second half of the study was suppressed in both evogliptin groups. The 48-week change in active calcification volume on 18F-NaF PET was significantly lower in both the evogliptin 5 mg (-1,325.6; 95% CI: -2,285.9 to -365.4; P = 0.008) and 10-mg groups (-1,582.2; 95% CI: -2,610.8 to -553.5; P = 0.0038) compared with the placebo group. CONCLUSIONS: This exploratory study did not demonstrate the protective effect of evogliptin on AV calcification. Favorable 18F-NaF PET results and possible suppression of aortic valve calcification with longer medication use in the evogliptin groups suggest the need for larger confirmatory trials. (A Multicenter, Double-blind, Placebo-controlled, Stratified-randomized, Parallel, Therapeutic Exploratory Clinical Study to Evaluate the Efficacy and Safety of DA-1229 in Patients With Calcific Aortic Valve Disease; NCT04055883).

Perioperative Risk of Noncardiac Surgery in Patients With Asymptomatic Significant Aortic Stenosis: A 10-Year Retrospective Study.

BACKGROUND: Aortic stenosis (AS) is a representative geriatric disease, and there is an anticipated rise in the number of patients requiring noncardiac surgeries in patients with AS. However, there is still a lack of research on the primary predictors of noncardiac perioperative complications in patients with asymptomatic significant AS. METHODS AND RESULTS: Among the cohort of noncardiac surgeries under general anesthesia, with an intermediate to high risk of surgery from 2011 to 2019, at Samsung Medical Center, 221 patients were identified to have asymptomatic significant AS. First, to examine the impact of significant AS on perioperative adverse events, the occurrences of major adverse cardiovascular events and perioperative adverse cardiovascular events were compared between patients with asymptomatic significant AS and the control group. Second, to identify the factors influencing the perioperative adverse events in patients with asymptomatic significant AS, a least absolute shrinkage and selection operator regression model was used. There was no significant difference between the control group and the asymptomatic significant AS group in the event rate of major adverse cardiovascular events (4.6% at control group versus 5.5% at asymptomatic significant AS group; P=0.608) and perioperative adverse cardiovascular events (13.8% at control group versus 18.3% at asymptomatic significant AS group; P=0.130). Cardiac damage stage was a significant risk factor of major adverse cardiovascular events and perioperative adverse cardiovascular events. CONCLUSIONS: There was no significant difference in major postoperative cardiovascular events between patients with asymptomatic significant AS and the control group. Advanced cardiac damage stage in significant AS is an important factor in perioperative risk of noncardiac surgery.

Transgelin-2, a novel cancer stem cell-related biomarker, is a diagnostic and therapeutic target for biliary tract cancer.

BACKGROUND: Biliary tract cancer (BTC) is a relatively rare but aggressive gastrointestinal cancer with a high mortality rate. Cancer stem cell (CSC) populations play crucial roles in tumor biology and are responsible for the low response to anti-cancer treatment and the high recurrence rate. This study investigated the role of Transgelin-2 (TAGLN2), overexpressed in CSC in BTC cells, and analyzed its expression in patient tissues and serum to identify potential new targets for BTC. METHODS: TAGLN2 expression was suppressed by small-interfering or short hairpin RNAs, and its effects on tumor biology were assessed in several BTC cell lines. Furthermore, the effects of TAGLN2 silencing on gemcitabine-resistant BTC cells, differentially expressed genes, proteins, and sensitivity to therapeutics or radiation were assessed. TAGLN2 expression was also assessed using western blotting and immunohistochemistry in samples obtained from patients with BTC to validate its clinical application. RESULTS: Suppression of TAGLN2 in BTC cell lines decreased cell proliferation, migration, invasion, and tumor size, in addition to a reduction in CSC features, including clonogenicity, radioresistance, and chemoresistance. TAGLN2 was highly expressed in BTC tissues, especially in cancer-associated fibroblasts in the stroma. Patients with a low stromal immunohistochemical index had prolonged disease-free survival compared to those with a high stromal immunohistochemical index (11.5 vs. 7.4 months, P = 0.013). TAGLN2 expression was higher in the plasma of patients with BTC than that in those with benign diseases. TAGLN2 had a higher area under the curve (0.901) than CA19-9, a validated tumor biomarker (0.799; P < 0.001). CONCLUSION: TAGLN2 plays a critical role in promoting BTC cell growth and motility and is involved in regulating BTC stemness. Silencing TAGLN2 expression enhanced cell sensitivity to radiation and chemotherapeutic drugs. The expression of TAGLN2 in patient tissue and plasma suggests its potential to serve as a secretory biomarker for BTC. Overall, targeting TAGLN2 could be an appropriate therapeutic strategy against advanced cancer following chemotherapy failure.

Prognostic implication of left atrial strain in patients experiencing early recurrence of atrial fibrillation after totally thoracoscopic ablation.

Background: Although early atrial fibrillation (AF) events during the blanking period after AF ablation are risk factors for late recurrence, data on predictors of late recurrence in patients who experience early AF events are limited. In this study, we investigated the implications of left atrial (LA) strain with respect to long-term outcomes in patients experiencing early AF during the blanking period after totally thoracoscopic ablation (TTA). Methods: A total of 128 patients who underwent TTA between 2012 and 2015 were enrolled from a tertiary center. Peak longitudinal LA strain was measured preoperatively. Early recurrence (ER) was defined as any AF within the 3-month blanking period after TTA. The primary outcome was late recurrence of AF for 5 years, detected on 12-lead electrocardiogram or 24-hour Holter monitoring, excluding the blanking period. Results: Out of 128 patients, 42 (32.8%) experienced ER during the blanking period. Patients who experienced ER had a significantly higher risk of 5-year AF recurrence compared with those who did not [72.7% vs. 29.6%, hazard ratio (HR) =3.69, 95% confidence interval (CI): 2.14-6.36, P<0.001]. Within the group of 42 patients experiencing ER, LA strain with a best cutoff value of 18.6% was the only independent predictor of 5-year AF recurrence (adjusted HR =4.20, 95% CI: 1.08-16.29, P=0.038). Patients with ER and LA strain ≥18.6% had a risk of 5-year AF recurrence, similar to those without ER (35.2% vs. 29.6%, HR =1.21, 95% CI: 0.36-4.04, P=0.755). Patients with ER and LA strain <18.6% had a significantly higher risk of 5-year AF recurrence compared to those without ER (83.0% vs. 29.6%, HR =4.83, 95% CI: 2.75-8.48, P<0.01). Conclusions: Early AF during the blanking period is common in patients undergoing TTA. In patients with ER, LA strain was an independent predictor of long-term AF recurrence.

Uncovering the clinicopathological features of early recurrence after surgical resection of pancreatic cancer.

To identify risk factors and biomarker for early recurrence in patients diagnosed with pancreatic cancer who undergo curative resection. Early recurrence after curative resection of pancreatic cancer is an obstacle to long-term survival. We retrospectively reviewed 162 patients diagnosed with pancreatic cancer who underwent curative resection. Early recurrence was defined as recurrence within 12 months of surgery. We selected S100A2 as a biomarker and investigated its expression using immunohistochemistry. Of the total, 79.6% (n = 129) of patients received adjuvant chemotherapy after surgery and 117 (72.2%) experienced recurrence, of which 73 (45.1%) experience early recurrence. In multivariate analysis, age < 60 years, presence of lymph node metastasis, and no adjuvant chemotherapy were significantly associated with early recurrence (all P < 0.05). The proportion of patients with high S100A2 expression (H-score > 5) was significantly lower in the early recurrence group (41.5% vs. 63.3%, P = 0.020). The cumulative incidence rate of early recurrence was higher in patients with an S100A2 H-score < 5 (41.5% vs. 63.3%, P = 0.012). The median overall survival of patients with higher S100A2 expression was longer than those with lower S100A2 expression (median 30.1 months vs. 24.2 months, P = 0.003). High-risk factors for early recurrence after surgery for pancreatic cancer include young age, lymph node metastasis, and no adjuvant therapy. Neoadjuvant treatment or intensive adjuvant therapy after surgery may improve the prognosis of patients with high-risk signatures. In patients who receive adjuvant therapy, high S100A2 expression is a good predictor.

Integrative analysis of spatial and single-cell transcriptome data from human pancreatic cancer reveals an intermediate cancer cell population associated with poor prognosis.

BACKGROUND: Recent studies using single-cell transcriptomic analysis have reported several distinct clusters of neoplastic epithelial cells and cancer-associated fibroblasts in the pancreatic cancer tumor microenvironment. However, their molecular characteristics and biological significance have not been clearly elucidated due to intra- and inter-tumoral heterogeneity. METHODS: We performed single-cell RNA sequencing using enriched non-immune cell populations from 17 pancreatic tumor tissues (16 pancreatic cancer and one high-grade dysplasia) and generated paired spatial transcriptomic data from seven patient samples. RESULTS: We identified five distinct functional subclusters of pancreatic cancer cells and six distinct cancer-associated fibroblast subclusters. We deeply profiled their characteristics, and we found that these subclusters successfully deconvoluted most of the features suggested in bulk transcriptome analysis of pancreatic cancer. Among those subclusters, we identified a novel cancer cell subcluster, Ep_VGLL1, showing intermediate characteristics between the extremities of basal-like and classical dichotomy, despite its prognostic value. Molecular features of Ep_VGLL1 suggest its transitional properties between basal-like and classical subtypes, which is supported by spatial transcriptomic data. CONCLUSIONS: This integrative analysis not only provides a comprehensive landscape of pancreatic cancer and fibroblast population, but also suggests a novel insight to the dynamic states of pancreatic cancer cells and unveils potential therapeutic targets.

Phenotypic characteristics of circulating tumor cells and predictive impact for efficacy of chemotherapy in patients with pancreatic cancer: a prospective study.

Objective: Early chemoresistance and tumor mass progression are associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Circulating tumor cells (CTCs) have been studied as potential predictors of treatment response and prognosis in PDAC; however, this approach has yet to be applied in clinical practice. The aim of our study was to investigate the phenotypic characteristics of CTCs and determine their predictive value for PDAC progression. Methods: We prospectively enrolled 40 patients who were pathologically diagnosed with PDAC and collected blood samples at diagnosis, 2 months after diagnosis, and during disease progression or recurrence. We used a microfabricated filter-based enrichment system to retrieve and analyze CTCs, which were classified using immunofluorescence staining (CD45, EpCAM, and vimentin). Results: Our study included 20 women and 20 men (median age, 66 years). Overall, 45% of the patients (18/40) had disseminated disease, and 77.5% (31/40) received chemotherapy. Multivariate analysis revealed that the total CTC count and carbohydrate antigen 19-9 level at 2 months after diagnosis were associated with disease progression (P<0.05). Linear mixed model analysis revealed that the total CTC count and vimentin-positive CTCs were significantly correlated with treatment response during chemotherapy (P=0.024 and 0.017, respectively). Kaplan-Meier analysis showed that total CTC positivity at 2 months was significantly associated with poor progression-free survival (P=0.038). Conclusion: Our study's findings suggest that CTCs can serve as predictive biomarkers of clinical outcomes in patients with PDAC receiving palliative chemotherapy. In particular, the total CTC count and vimentin-positive CTCs showed changes associated with the chemotherapy response.

Predictors of embolism and death in left-sided infective endocarditis: the European Society of Cardiology EURObservational Research Programme European Infective Endocarditis registry.

BACKGROUND AND AIMS: Even though vegetation size in infective endocarditis (IE) has been associated with embolic events (EEs) and mortality risk, it is unclear whether vegetation size associated with these potential outcomes is different in left-sided IE (LSIE). This study aimed to seek assessing the vegetation cut-off size as predictor of EE or 30-day mortality for LSIE and to determine risk predictors of these outcomes. METHODS: The European Society of Cardiology EURObservational Research Programme European Infective Endocarditis is a prospective, multicentre registry including patients with definite or possible IE throughout 2016-18. Cox multivariable logistic regression analysis was performed to assess variables associated with EE or 30-day mortality. RESULTS: There were 2171 patients with LSIE (women 31.5%). Among these affected patients, 459 (21.1%) had a new EE or died in 30 days. The cut-off value of vegetation size for predicting EEs or 30-day mortality was >10 mm [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.13-1.69, P = .0015]. Other adjusted predictors of risk of EE or death were as follows: EE on admission (HR 1.89, 95% CI 1.54-2.33, P < .0001), history of heart failure (HR 1.53, 95% CI 1.21-1.93, P = .0004), creatinine >2 mg/dL (HR 1.59, 95% CI 1.25-2.03, P = .0002), Staphylococcus aureus (HR 1.36, 95% CI 1.08-1.70, P = .008), congestive heart failure (HR 1.40, 95% CI 1.12-1.75, P = .003), presence of haemorrhagic stroke (HR 4.57, 95% CI 3.08-6.79, P < .0001), alcohol abuse (HR 1.45, 95% CI 1.04-2.03, P = .03), presence of cardiogenic shock (HR 2.07, 95% CI 1.29-3.34, P = .003), and not performing left surgery (HR 1.30 95% CI 1.05-1.61, P = .016) (C-statistic = .68). CONCLUSIONS: Prognosis after LSIE is determined by multiple factors, including vegetation size.

Antiplatelet therapy and long-term mortality in patients with myocardial injury after non-cardiac surgery.

BACKGROUNDS: Myocardial injury after non-cardiac surgery (MINS) has recently been accepted as a common complication associated with increased mortality. However, little is known about the treatment of MINS. The aim of this study was to investigate an association between antiplatelet therapy and long-term mortality after MINS. METHODS: From 2010 to 2019, patients with MINS, defined as having a peak high-sensitivity troponin I higher than 40 ng/L within 30 days after non-cardiac surgery, were screened at a tertiary centre. Patients were excluded if they had a history of coronary revascularisation before or during index hospitalisation. Clinical outcomes at 1 year were compared between patients with and without antiplatelet therapy at hospital discharge. The primary outcome was death, and the secondary outcome was major bleeding. RESULTS: Of the 3818 eligible patients with MINS, 940 (24.6%) received antiplatelet therapy at hospital discharge. Patients with antiplatelet therapy had a significantly lower mortality at 1 year than those without antiplatelet therapy (7.5% vs 15.9%, adjusted HR 0.60, 95% CI 0.45 to 0.79, p<0.001). A risk of major bleeding at 1 year was not significantly different between the patients with and without antiplatelet therapy (6.6% vs 7.6%, adjusted HR 0.85, 95% CI 0.62 to 1.17, p=0.324). In propensity score-matched analysis of 886 pairs, patients with antiplatelet therapy had a significantly lower risk of 1-year mortality (adjusted HR 0.53, 95% CI 0.39 to 0.73, p<0.001) than those without antiplatelet therapy. CONCLUSIONS: In patients with MINS, antiplatelet therapy at discharge was associated with decreased 1-year mortality.

Left atrial strain predicts fibrosis of left atrial appendage in patients with atrial fibrillation undergoing totally thoracoscopic ablation.

Background: Left atrial (LA) fibrosis is related with development and severity of atrial fibrillation (AF). The aim of this study was to investigate the association between LA strain and LA fibrosis in patients undergoing totally thoracoscopic ablation (TTA) for AF. Methods: Between February 2012 and March 2015, a total of 128 patients who underwent TTA were enrolled from a tertiary hospital. Left atrial appendage (LAA) was harvested during surgery to determine the degree of fibrosis. LAA fibrosis was classified as mild (1st quartile), moderate (2nd and 3rd quartile), or severe (4th quartile). Clinical outcome was 5-year recurrence rate of AF detected on electrocardiogram or 24 h Holter monitoring. Results: The mean age was 54.3 ± 8.8 years and 18.8% had paroxysmal AF. Patients with mild LAA fibrosis had a significantly lower rate of recurrent AF (23.3%) at 5 years after TTA compared with those with moderate (51.4%; hazard ratio [HR] 2.69; 95% confidence interval [CI] 1.19-6.12) or severe (53.2%; HR 2.84; 95% CI 1.16-6.97) fibrosis. Among clinical and echocardiographic parameters, peak LA strain was the only predictor of mild LAA fibrosis (coefficient 0.10, p = 0.005) with the best cutoff value of 14.7% (area under the curve 0.732). The prevalence of mild LAA fibrosis was 40.6% in patients with peak LA strain ≥14.7%, but only 6.8% in those with peak LA strain <14.7%. Conclusions: In patients undergoing TTA for AF, mild LAA fibrosis was associated with a lower risk of 5-year AF recurrence. LA strain was the only predictor of mild LAA fibrosis that reflects a lower risk of 5-year AF recurrence.

Difference of Risk of Pancreatic Cancer in New-Onset Diabetes and Long-standing Diabetes: A Population-based Cohort Study.

CONTEXT: Considering the absence of methods to find pancreatic cancer early, surveillance of high-risk groups is needed for early diagnosis. OBJECTIVE: The study aimed to investigate the effect in the incidence of pancreatic cancer and the differences between new-onset diabetes mellitus (NODM) and long-standing DM (LSDM) since NODM group is a representative high-risk group. METHODS: The Korean National Health Insurance Service-National Sample Cohort between 2002 and 2013 data were used. Regarding 88 396 people with DM (case group), we conducted a 1:1 propensity score matching to select a matched non-DM population (control group). To investigate the interaction between DM and the time variable distinguishing NODM and LSDM, we performed a multivariate time-dependent Cox regression analysis. RESULTS: The incidence of pancreatic cancer was higher in the DM group compared to the non-DM group (0.52% vs 0.16%; P < .001). The DM group had shown different risk of pancreatic cancer development according to the duration since the DM diagnosis (NODM hazard ratio (HR): 3.81; 95% CI, 2.97-4.88; P < .001; LSDM HR: 1.53; 95% CI, 1.11-2.11; P < .001). When the NODM and the LSDM groups were compared, the risk of pancreatic cancer was higher in the NODM group than in the LSDM group (HR: 1.55; P = .020). In subgroup analysis, NODM group showed that men (HR = 4.42; 95% CI, 3.15-6.19; P < .001) and patients who were in their 50 seconds (HR = 7.54; 95% CI, 3.24-17.56; P < .001) were at a higher risk of developing pancreatic cancer than matched same sex or age control group (non-DM population), respectively. CONCLUSION: The risk of pancreatic cancer was greater in people with DM than in a non-DM population. Among people with DM, NODM showed a higher risk of pancreatic cancer than LSDM.

The Expression of Programmed Death-Ligand 1 on Immune Cells Is Related to a Better Prognosis in Biliary Tract Cancer.

Background/Aims: Programmed death-ligand 1 (PD-L1) expression in tumor cells is associated with a poor biliary tract cancer (BTC) prognosis; tumor-infiltrating immune cells in the tumor microenvironment are associated with a better prognosis. The effect of PD-L1 expression on immune cells on survival is unclear. We investigated the relationship between PD-L1 expression in immune cells and BTC prognosis. Methods: PD-L1 expression was evaluated using an anti-PD-L1 22C3 mouse monoclonal primary antibody, and its relationships with clinical characteristics and prognosis were analyzed using the Cox proportional hazard model to investigate the prognostic performance of PD-L1 in BTC. Results: Among 144 analyzed cases, patients with positive PD-L1 expression in tumor cells and negative PD-L1 expression in immune cells showed poorer overall survival rates than those exhibiting other expressions (tumor cells: hazard ratio [HR]=1.023, p<0.001; immune cells: HR=0.983, p=0.021). PD-L1 expression in tumor cells was an independent predictor of poor overall survival (HR=1.024, p<0.001). In contrast, PD-L1 expression in immune cells was a predictive marker of good prognosis (HR=0.983, p=0.018). Conclusions: PD-L1 expression in immune cells may be used as an independent factor to evaluate the prognosis of patients with BTC.

Covered versus uncovered double bare self-expandable metal stent for palliation of unresectable extrahepatic malignant biliary obstruction: a randomized controlled multicenter trial.

BACKGROUND AND AIMS: In a recent randomized controlled trial, a double bare metal stent (DBS) showed better stent patency than single-layer metal stents. However, clear evidence comparing the efficacy of uncovered (UCDBS) and partially covered (PCDBS) DBSs for distal malignant biliary obstruction (MBO) is lacking. Therefore, we compared the clinical outcomes including stent patency of UCDBSs versus PCDBSs. METHODS: A multicenter, randomized study was performed in patients with distal MBO. The primary endpoint was stent patency. Secondary endpoints were the proportion of patients with patent stents at 6 months, risk factors for stent dysfunction, overall survival, technical and clinical success rates of stent placement, and other adverse events (AEs). RESULTS: Among 258 included patients, 130 were randomly assigned to the PCDBS group and 128 to the UCDBS group. The mean duration of stent patency of the PCDBS (421.2 days; 95% confidence interval [CI], 346.7-495.7) was longer than that of the UCDBS (377.4 days; 95% CI, 299.7-455.0), although total stent dysfunction and stent dysfunction within 6 months were not different between groups. Multivariate analysis indicated that chemotherapy after stent placement was a significant factor for overall survival (hazard ratio, .570; 95% CI, .408-.796) and had a marginal impact on stent patency (hazard ratio, 1.569; 95% CI, .923-2.667). There were no remarkable differences in AEs, including pancreatitis, cholecystitis, and stent migration, between the 2 groups. CONCLUSIONS: The use of PCDBSs compared with UCDBSs in patients with distal MBO has unclear benefits regarding stent patency and overall survival, although PCDBSs have a lower rate of tumor ingrowth. (Clinical trial registration number: NCT02937246.).

Evaluation of the 8th Edition AJCC Staging System for the Clinical Staging of Pancreatic Cancer.

The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for pancreatic cancer (PC) has been validated for pathological staging; however, its significance for clinical staging remains uncertain. We validated the prognostic performance and suitability of the current staging system for the clinical staging of PC. We identified 1043 patients from our PC registry who were staged by imaging according to the 8th edition staging system and conducted analysis, including overall survival (OS) comparison. Gradual prognostic stratification according to stage hierarchy yielded significant OS differences between stage groups, except between stage I and II (p = 0.193). A substage comparison revealed no survival differences between IB (T2N0) and IIA (T3N0), which were divided by the T3 criterion only (p = 0.278). A higher N stage had significantly shorter OS than a lower N stage (all pairwise p < 0.05). However, among the 150 patients who received upfront surgery, the pathological stage was more advanced than the clinical stage in 86 (57.3%), mostly due to a false-negative cN0 (70.9%). Our results suggest that the new definition of T3 and the number-based N criteria in the 8th edition AJCC staging system may be not adequate for clinical staging. Establishing separate criteria more suitable for clinical staging should be considered.

Safety and Efficacy of Allogeneic Natural Killer Cells in Combination with Pembrolizumab in Patients with Chemotherapy-Refractory Biliary Tract Cancer: A Multicenter Open-Label Phase 1/2a Trial.

BACKGROUND AND AIM: This study investigated the administration of combination therapy, allogeneic natural killer (NK) cells and pembrolizumab in the treatment of advanced biliary tract cancer to determine the safety and tolerability (phase 1) and the efficacy and safety (phase 2a). METHODS: Forty patients (phase 1, n = 6; phase 2a, n = 34) were enrolled between December 2019 and June 2021. The patients received highly activated allogeneic NK cells ("SMT-NK") on weeks 1 and 2 and pembrolizumab on week 1. This 3-week schedule (one cycle) was repeated until confirmed disease progression, intolerable adverse events (AEs), patient withdrawal, or finishing the maximum treatment schedule. The tumor response was evaluated after every three cycles. RESULTS: In phase 1, four patients (66.7%) experienced seven AEs, but no severe AE was observed. In phase 2a, 126 AEs occurred in 29 patients (85.3%). Severe AEs (≥grade 3) were reported in 16 patients (47.1%). The overall response rate (ORR) was 17.4% in the full analysis set and 50.0% in the per-protocol set. CONCLUSIONS: SMT-NKs plus pembrolizumab resulted in no severe AEs directly related to the drug combination. The combination therapy also exerted antitumor activity with improved efficacy compared to the recent monotherapy with pembrolizumab in patients with advanced biliary tract cancer.

Prognostic Factors in Patients Treated with Pembrolizumab as a Second-Line Treatment for Advanced Biliary Tract Cancer.

Some BTC types respond to pembrolizumab, but there are no known prognostic factors to predict its treatment benefits. In this study, we attempted to identify the prognostic factors associated with pembrolizumab as a second-line treatment for gemcitabine-refractory BTC. This retrospective and single tertiary-center study involved all the consecutive patients (n = 80) with refractory advanced BTC, who were diagnosed as programmed cell death ligand 1-positive and treated with pembrolizumab between August 2017 and February 2021. The overall survival (OS) was analyzed using Cox regression analysis. The median OS was 6.0 months [95% confidence interval (CI): 3.87−8.20]; median progression-free survival was 1.9 months (95% CI: 1.82−1.98); and the response rate was 15.9%. In the multivariate Cox regression analysis, the TB [adjusted hazard ratio (HR) = 2.286; 95% CI: 1.177−4.440; p = 0.015), albumin levels (adjusted HR = 0.392; 95% CI: 0.211−0.725; p = 0.003), ALP levels (adjusted HR = 1.938; 95% CI: 1.105−3.400; p = 0.021), and LMR (adjusted HR = 0.325; 95% CI: 0.173−0.609; p < 0.001) were identified as significant variables associated with the OS. High albumin levels and LMR and low ALP levels and TB were significantly associated with better OS in patients treated with pembrolizumab.

Association of longitudinal left atrial strain with mortality after tricuspid valve surgery.

AIMS: Tricuspid valve (TV) surgery for functional tricuspid regurgitation (TR) is becoming more common, but the associated mortality remains high. Therefore, we evaluated the clinical and echocardiographic parameters associated with all-cause mortality in patients with severe functional TR who underwent TV surgery. METHODS AND RESULTS: A total of 286 patients with severe functional TR who underwent TV replacement or repair was analysed between January 2006 and December 2017. We assessed changes in conventional echocardiographic parameters and strain, such as peak atrial longitudinal strain (PALS). During a median follow-up period of 5.3 years, 71 (24.8%) patients died due to any cause. When comparing groups with and without all-cause deaths, there were no significant differences in terms of sex, co-morbidities, medication use, and surgery type. However, patients who died were older and more likely to have refractory atrial fibrillation (AF). With multivariate Cox modelling, age >65 years (adjusted hazard ratio [HR], 2.81, 95% confidence interval [CI], 1.59-4.96; P < 0.001), refractory AF (adjusted HR, 2.84, 95% CI, 1.36-5.94; P = 0.006), lower albumin level (adjusted HR, 0.50, 95% CI, 0.31-0.82), and reduced PALS (adjusted HR, 1.87, 95% CI, 1.06-3.33; P = 0.032) were significant determinants of all-cause mortality. PALS decline was associated with refractory AF (adjusted HR, 5.74, 95% CI, 2.81-11.7; P < 0.001) and the absence of a Maze procedure (adjusted HR, 2.95, 95% CI, 1.51-5.78; P = 0.002). CONCLUSIONS: A reduction in PALS was significantly associated with all-cause mortality in our cohort of patients with severe functional TR who underwent TV surgery. This phenomenon is related to refractory AF and more aggressive intervention for AF is necessary concomitant with TV surgery.

Temporal trends in incidence, prevalence, and death of aortic stenosis in Korea: a nationwide population-based study.

AIMS: We aim to determine the temporal trends of incidence, prevalence, and death of aortic stenosis (AS, I35.0) in an East Asian population. METHODS AND RESULTS: Data for 3773 patients who were newly diagnosed with AS from 2006 through 2017 were extracted from the National Health Insurance Service in Korea. The age-standardized incidence rate, prevalence rate, and death rate, survival rate (SR), and death risk of AS were calculated. Overall, the mean (standard deviation) age of AS patients was 69.9 (15.3) years [66.2 (15.7) years for men and 72.7 (14.4) years for women (P = 0.007)], and the proportion of men was 42.7%. The proportion of AS patients ≥60 years old was 80% (71.8% in men and 86% in women, P < 0.001). The proportion of patients who died of AS was 36.4% during the period from 2006 through 2017. The most common causes of death were disease of the circulatory system. The age-standardized incidence, prevalence, and death rates in 2017 were 0.85, 2.79, and 0.58 persons per 100 000 persons, respectively. The 10 year SR was 49.2%. The higher adjusted HRs [95% CI] for AS were observed in 70- to 79-year-old people (9.08 [1.27, 64.7], P = 0.027), in individuals 80 years of age or older (22.7 [3.18, 161.9], P = 0.001), in men (1.46 [1.31, 1.63], P < 0.001), among the middle socioeconomic group (1.19 [1.03, 1.37], P = 0.016), among the lower income levels (1.32 [1.17, 1.49], P < 0.001), in those with myocardial infarction (1.57 [1.16, 2.13], P = 0.003), with heart failure (1.63 [1.44, 1.85], P < 0.001), with ischaemic stroke (3.26 [1.20, 8.85], P = 0.015), with haemorrhagic stroke (2.51 [1.94, 3.25], P = 0.02), with chronic kidney disease (2.51 [1.94, 3.25], P < 0.001), and with malignant neoplasm (2.33 [1.64, 3.31], P < 0.001). CONCLUSIONS: The proportion of AS at age ≥60 years was 80%. For AS, the age-standardized incidence rates were steady, prevalence rates increased, and death rates decreased by year over a decade. The 10 year SR of AS was about 50%. The most common cause of death in AS was disease of the circulatory system. Given the progressively higher incidence of AS with age continued efforts are required to increase awareness regarding AS-related symptoms and potential complications in aged people.