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Although angiotensin II receptor blockers (ARBs) are more effective in women for either reduction of blood pressure or heart failure (HF), the gender disparities and the impact of class/drug effects on ARBs in relation to cardiac hypertrophy and HF remain unclear. We aimed to investigate the sex-based and drug-specific differences in left ventricular (LV) mass reduction with ARBs. We employed the cohort of 193 hypertensive patients with HF and an LV ejection fraction of ≥ 45% treated with azilsartan or candesartan once daily for 48 weeks as a sub-analysis of the J-TASTE trial. After exclusion of patients without LV mass data nor the drugs, 170 patients were finally enrolled (azilsartan: male, n = 43, female, n = 39 and candesartan: male, n = 52; female, n = 36). We investigated the sex-based differences of the primary endpoint of the change in LV mass as assessed by echocardiography from baseline to the end of the study (48 weeks), and the secondary endpoint of the incidence of the composite cardiovascular endpoint (death from cardiovascular disease or hospitalization for heart failure). In the male stratum, the ratio of patients with > 10% LV mass reduction at 48 weeks was higher in the azilsartan group than candesartan group (40 vs. 19%, p = 0.029). There was no significant difference in LV mass reduction between two groups in the female stratum. There were no differences of the onset of the secondary endpoints between male and female groups, and azilsartan and candesartan groups. The event-free survival rate of the composite cardiovascular endpoints tended to be lower in patients with ≤ 10% than > 10% LV mass reduction (95.3 vs. 100% at 48 weeks, log-rank p = 0.11). In patients with HF, the effectiveness of either azilsartan or candesartan in achieving > 10% LV mass reduction depends on sex. Male is more sensitive to azilsartan than candesartan to achieve cardiac hypertrophy in HF patients., Competing Interests: Declarations. Conflict of interest: MA has nothing to disclose. CI reports personal fees from Daiichi Sankyo, Edwards Lifesciences, Bristol-Myers Squibb, Otsuka, Cannon Medical Systems, Sumitomo Dainippon, TOA EIYO, MSD, Pfizer, Boehringer Ingelheim, Teijin, Tsumura, and Novartis outside the submitted work. SI reports a grant from the Japan Society for the Promotion of Science outside the submitted work. MK reports grants from the Japanese government during the conduct of the study and the following outside the submitted work: grants from the Japanese government, grants from the Japan Heart Foundation, grants from the Japan Cardiovascular Research Foundation, grants and personal fees from Takeda, personal fees from Daiichi Sankyo, grants and personal fees from Pfizer, grants and personal fees from Ono, grants and personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, grants from Novartis, grants and personal fees from Mitsubishi Tanabe, personal fees from Kowa, personal fees from Otsuka, grants from Sanofi, personal fees from Amgen, personal fees from Toyama-Kagaku, and grants and personal fees from Kureha., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Background: Recent large clinical trials have revealed that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes not only in patients with heart failure with reduced ejection fraction, but also in patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF). However, the effect of SGLT2 inhibitors on left ventricular (LV) diastolic function is still controversial., Methods and Results: The TOP-HFPEF trial (Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus) is a multicenter, double-arm, open-label, confirmatory, investigator-initiated clinical study to investigate the effect of SGLT2 inhibitor on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus. The participants are randomly assigned (1:1) to the tofogliflozin group (20 mg once daily) or the control group (administration or continuation of antidiabetic drugs other than SGLT2 inhibitors). The estimated number of patients to be enrolled in this trial is 90 in total (45 in each group). The participants are followed up for 52 weeks with tofogliflozin or control drugs. The primary endpoint is the change in E/e' assessed by echocardiography from the baseline to the end of this study (52 weeks). This trial will also evaluate the effects of tofogliflozin on cardiovascular events, biomarkers, other echocardiographic parameters, the occurrence of atrial fibrillation, and renal function., Conclusions: The TOP-HFPEF trial will clarify the efficacy of an SGLT2 inhibitor, tofogliflozin, on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus., Competing Interests: Declarations. Ethical Approval: This study is conducted in compliance with the Declaration of Helsinki and Japan’s Clinical Trials Act. The study protocol was approved by the Certified Review Board of Osaka Metropolitan University, and written informed consent will be obtained from all patients before their enrollment. Consent to Participate: All eligible participants are required to provide written informed consent before enrollment in this study. Consent for Publication: All authors reviewed the manuscript and approved its submission. Conflict of Interest: Kowa Company will not have any role in the analysis or interpretation of the results of this study. SI reports receiving a lecture fee from Nippon Boehringer Ingelheim Co., Ltd. and a grant from the Japan Society for the Promotion of Science, outside the submitted work. YN reports receiving a grant from the Osaka Medical Research Foundation for Intractable Diseases, outside the submitted work. HF reports receiving funds from Kitano Cadet-Doctor program, outside the submitted work. CI reports personal fees from AstraZeneca K.K.; Medtronic Japan Co., Ltd.; Novartis Pharma K.K.; Kowa Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Daiichi Sankyo Co., Ltd.; Bayer Yakuhin, Ltd.; Otsuka Pharmaceutical Co., Ltd.; Pfizer Japan Inc.; Sumitomo Pharma Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Edwards Lifesciences Corp.; Nippon Boehringer Ingelheim Co., Ltd.; Tsumura & Co.; Philips Japan, Ltd.; Eisai Co., Ltd.; Canon Medical Systems Corp.; Alnylam Japan K.K.; Janssen Pharmaceutical K.K.; Kyowa Kirin Co., Ltd.; Abbott Medical Japan LLC; Eli Lilly Japan K.K.; Astellas Pharma Inc.; Nihon Medi-Physics Co., Ltd.; and Japan Lifeline Co., Ltd., outside the submitted work. GN has nothing to disclose. HY has nothing to disclose. HM has nothing to disclose. MI reports receiving scholarship funds and personal fees from Daiichi Sankyo Co., Ltd.; Novartis Pharma K.K.; Nippon Shinyaku Co., Ltd.; Bayer Yakuhin, Ltd.; Mitsubishi Tanabe Pharma Corp.; Nippon Boehringer Ingelheim Co., Ltd.; and Otsuka Pharmaceutical Co., Ltd.; receiving scholarship funds from Teijin Pharma, Ltd.; Public Research Center; Nihon Medi-Physics Co., Ltd.; and Mochida Pharmaceutical Co., Ltd.; receiving joint research funds from Mie University, Research Institute for Production Development Japan, Janssen Pharmaceutical K.K., Nihon Kohden Corp., Nara Medical University, National Cerebral and Cardiovascular Center, and IQVIA Japan K.K.; receiving joint research funds and personal fees from Amgen Inc.; receiving personal fees from Kowa Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; AstraZeneca K.K.; Pfizer Japan Inc.; Eli Lilly Japan K.K.; Ono Pharmaceutical Co., Ltd.; and Sumitomo Dainippon Pharma Co., Ltd., outside the submitted work. S Toyoda reports receiving funds from Assist Japan Inc.; Abbott Vascular Japan Co., Ltd.; Abbott Medical Japan LLC; EP-CRSU Co., Ltd.; Next Japan Medicalnext Co., Ltd..; GE Healthcare Pharma Ltd.; CVQuest K.K.; Cmic Co., Ltd.; Sumitomo Electric Group CSR Foundation; Life Science Institute, Inc.; Teijin Pharma, Ltd.; Terumo Corp.; Nipro Corp.; Japan Heart Foundation; Next Japan Medicalnext Co., Ltd.; Japan Lifeline Co., Ltd.; Boston Scientific Japan K.K.; and Roche Diagnostics K.K.; receiving funds and lecture fees from Astellas Pharma Inc.; Otsuka Pharmaceutical Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Kyowa Kirin Co., Ltd.; Kowa Co., Ltd.; Sanofi K.K.; Daiichi Sankyo Co., Ltd.; Sumitomo Pharma Co., Ltd.; Mitsubishi Tanabe Pharma Corp.; Tsumura & Co.; Abiomed Japan K.K.; Eli Lilly Japan K.K.; Nippon Shinyaku Co., Ltd.; Nippon Boehringer Ingelheim Co., Ltd.; Medtronic Japan Co., Ltd.; Novartis Pharma K.K.; and Mochida Pharmaceutical Co., Ltd.; and receiving lecture fees from Bayer Yakuhin, Ltd.; Viatris Inc.; Novo Nordisk Pharma, Ltd.; AstraZeneca K.K.; Takeda Pharmaceutical Co., Ltd.; Janssen Pharmaceutical K.K.; Fukuda Denshi Co., Ltd.; Protea Japan Co., Ltd.; Eisai Co., Ltd.; Edwards Lifesciences Corp.; Zeria Pharmaceutical Co., Ltd.; Pfizer Japan Inc.; Bristol Myers Squibb K.K.; MSD Inc.; Amicus Therapeutics Inc.; and Toa Eiyo, Ltd., outside the submitted work. S Takiuchi has nothing to disclose. TK reports receiving personal fees from Kaneka Corp. and Philips Japan, Ltd., and receiving lecture fees from Kowa Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; Novartis Pharma K.K.; Nippon Boehringer Ingelheim Co., Ltd.; Daiichi Sankyo Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Tsumura & Co.; Toa Eiyo, Ltd.; AstraZeneca K.K.; Bayer Yakuhin, Ltd.; Boston Scientific Japan K.K.; Terumo Corp.; Nipro Corp.; and Abbott Medical Japan LLC, outside the submitted work. YI reports receiving lecture fees from Pfizer Japan Inc.; Nippon Boehringer Ingelheim Co., Ltd.; Sanofi K.K.; Medtronic Japan Co., Ltd.; AstraZeneca K.K.; Toa Eiyo, Ltd.; Bayer Yakuhin, Ltd.; Takeda Pharmaceutical Co.; Ltd.; Sumitomo Pharma Co., Ltd.; Janssen Pharmaceutical K.K.; Otsuka Pharmaceutical Co., Ltd.; Kowa Co., Ltd.; Novartis Pharma K.K.; Mitsubishi Tanabe Pharma Corp.; Viatris Inc.; Nippon Shinyaku Co., Ltd.; Kyowa Kirin Co., Ltd.; Alnylam Japan K.K.; Eli Lilly Japan K.K.; JCR Pharmaceuticals Co., Ltd.; Amicus Therapeutics Inc.; Ono Pharmaceutical Co., Ltd.; Abbott Japan LLC; and GlaxoSmithKline Consumer Healthcare Japan K.K.; and receiving grants from Daiichi Sankyo Co., Ltd., outside the submitted work. YA reports receiving personal fees from Abbott Medical Japan LLC; Astellas Pharma Inc.; AstraZeneca K.K.; Bayer Yakuhin, Ltd.; Daiichi Sankyo Co., Ltd.; Edwards Lifesciences Corp.; Eli Lilly Japan K.K.; GE Healthcare Japan Corp.; Mallinckrodt Pharma K.K.; Nippon Boehringer Ingelheim Co., Ltd.; Novartis Pharma K.K.; Ono Pharmaceutical Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; and Toa Eiyo, Ltd., outside the submitted work. TS has nothing to disclose. YS reports receiving personal fees from Daiichi Sankyo Co., Ltd.; Novartis Pharma K.K.; Nippon Boehringer Ingelheim Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; AstraZeneca K.K.; and Bayer Yakuhin, Ltd., outside the submitted work. ME reports receiving grants from Mitsubishi Tanabe Pharma Corp.; Eisai Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; and Bayer Yakuhin, Ltd.; receiving personal lecture fees from Novo Nordisk Pharma, Ltd.; Sanofi K.K.; AstraZeneca K.K.; MSD Inc.; Kowa Co., Ltd.; Teijin Pharma, Ltd.; Sanwa Co., Ltd.; Eli Lilly Japan K.K.; and Astellas Pharma Inc.; and receiving grants and personal lecture fees from Nippon Boehringer Ingelheim Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Sumitomo Pharma Co., Ltd.; and Kyowa Kirin Co., Ltd., outside the submitted work. TI reports personal fees from Kowa Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Daiichi Sankyo Co., Ltd.; Mochida Pharmaceutical Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; AstraZeneca K.K.; Eisai Co., Ltd.; Mitsubishi Tanabe Pharma Corp.; Novo Nordic Pharma, Ltd.; and receiving grants from Fukuda Denshi Co., Ltd., outside the submitted work. MK reports receiving personal fees from Daiichi Sankyo Co., Ltd.; Viatris Inc.; Otsuka Pharmaceutical Co., Ltd.; and Eli Lilly Japan K.K.; receiving grants and personal fees from Ono Pharmaceutical Co., Ltd.; Mitsubishi Tanabe Pharma Corp.; AstraZeneca K.K.; and Nippon Boehringer Ingelheim Co., Ltd.; receiving grants from Novartis Pharma K.K.; Takeda Pharmaceutical Co., Ltd.; and Kowa Co., Ltd., outside the submitted work., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background & Aims: Enteral nutrition in older adults is often associated with intolerance, a phenomenon not well-understood in the context of gastroesophageal reflux disease (GERD). This observational study aimed to evaluate serum potassium levels as an independent prognostic factor for unplanned enteral nutrition discontinuation in older adults with GERD., Methods: We conducted a retrospective analysis of 213 consecutive patients with GERD who received enteral nutrition at our institution from April 2018 to March 2023. The dietary assessment involved extracting relevant nutritional information from the patients' medical records. The incidence of enteral nutrition discontinuation due to complications was monitored over a 30-day period after initiation., Results: Patients were categorized into three groups based on initial serum potassium levels: low (<4.0 mmol/L), intermediate (4.0-4.5 mmol/L), and high (≥4.5 mmol/L). During the follow-up, 35 % of patients experienced events leading to the discontinuation of enteral nutrition. Higher potassium levels correlated with an increased risk of unplanned discontinuation of enteral nutrition (log-rank P = 0.002). Multivariate Cox proportional hazards analysis identified serum potassium level as an independent predictor of unplanned discontinuation (hazard ratio: 1.700 [95 % confidence interval: 1.100-2.627] per 1 mmol/L, P = 0.017)., Conclusions: Serum potassium level is a robust independent predictor of unplanned enteral nutrition discontinuation in older adults with GERD. Our findings suggest that monitoring and adjusting potassium levels may be essential for improving outcomes in this vulnerable population., Competing Interests: Conflict of interest None., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The guidelines recommend the initiation or up-titration of heart failure (HF) treatments following an HF hospitalization; however, concerns about adverse events may limit the use of mineralocorticoid receptor antagonists (MRAs). Patient profiles or disease severity might impact adverse events associated with MRA therapy in acute HF., Methods: The EARLIER trial included patients with acute HF who were randomized to eplerenone or placebo over 6 months. Adverse events (i.e., worsening renal function [WRF], hyperkalemia, hypotension, and volume depletion/dehydration) were assessed. HF-related outcome included a composite of all-cause mortality, HF re-hospitalization, investigator-reported worsening HF and out-of-hospital diuretic intensification., Results: In 297 patients (mean age: 67 ± 13 years; 73% males), adverse events were observed: 44.4% experienced WRF (>20% drop in estimated glomerular filtration rate[eGFR] and/or investigator-reported WRF), 8.4% had hyperkalemia (potassium >5.5 mmol/L and/or investigator-reported hyperkalemia), 27.9% experienced hypotension (systolic blood pressure[SBP] <90 mmHg and/or investigator-reported hypotension), and 16.8% had investigator-reported volume depletion/dehydration. Eplerenone vs. placebo did not elevate the incidence of these events (all-p-values>0.0 5). Multivariable analyses revealed that, irrespective of treatment allocation, older age (>7 5 years), prevalent diabetes, symptomatic congestion, and microalbuminuria were associated with increased risk of WRF. Baseline eGFR<60 ml/min/1.73m 2 and SBP < 90 mmHg predicted hyperkalemia and hypotension, respectively, while older patients were more likely to experience volume depletion/dehydration. However, these patient profiles did not alter the benefit of eplerenone on outcomes (HR [9 5%CI] = 0.53 [0.29 to 0.97], P = 0.04; all-p-for-interaction>0.10)., Conclusion: Eplerenone did not increase adverse events compared with placebo in acute HF. Importantly, disease severity and comorbidity burden greatly influence adverse events, but not benefit from eplerenone., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Dysphagia caused by tumor strictures is a major symptom in patients with advanced esophageal cancer. However, the prognostic effect of dysphagia in resectable cases is insufficiently investigated. This study aimed to investigate the prognostic value of dysphagia scores in resectable advanced esophageal cancer who underwent radical esophagectomy after preoperative treatment., Methods: This retrospective study enrolled 302 consecutive patients with advanced resectable esophageal cancer who received preoperative treatment. The preoperative dysphagia score was used to assess the relationship between tumor stricture and clinical outcomes., Results: Almost half of the patients had dysphagia scores of 2 to 4 (n = 152 [50.3%]). Lower body mass index, circumferential tumors, and noncurative resection were significantly more common as dysphagia scores worsened. Patients with dysphagia had significantly more advanced ypT stage and worse histopathologic response than those without dysphagia. The 5-year disease-free survival and overall survival (OS) rates for dysphagia scores of 0 to 1, 2 to 3, and 4 were 52.9%, 35.3%, and 26.7% and 60.7%, 40.4%, and 26.7%, respectively. Multivariate analysis identified dysphagia score as an independent factor of OS, similar to surgical curability and ypN stage. The postoperative recurrence rate was significantly higher among patients with dysphagia scores of 2 to 3 (56%) and 4 (67%) than among those with dysphagia scores of 0 to 1 (36%) (P < .001 and P = .037, respectively). Furthermore, distant recurrence in dysphagia scores of 2 to 3 and 4 was higher than in dysphagia scores of 0 to 1 (26%, 46%, and 42%, respectively)., Conclusion: The dysphagia score before initial treatment is associated with postoperative survival in patients with resectable advanced esophageal cancer., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Purpose: Sentinel lymph node biopsy (SLNB) can detect occult nodal metastasis. We have previously reported the safety and feasibility of indocyanine green (ICG)-guided SLNB for clinical stage II/III lower rectal cancer (RC). However, little is known about the influence of lateral pelvic SLNB using ICG on oncological outcomes. The present study aimed to evaluate the prognostic impact of lateral pelvic SLNB on oncological outcomes compared with prophylactic lateral lymph node dissection (LLND)., Methods: Participants comprised consecutive patients with clinical stage II/III lower RC who underwent lateral pelvic SLNB or prophylactic LLND (Non-SLNB) between January 2010 and December 2020. The primary outcome measure was the 5-year cumulative incidence of local recurrence (LR). Secondary endpoints included cancer-specific survival (CSS), overall survival (OS), recurrence-free survival (RFS), local recurrence-free survival (LRFS), and distant recurrence-free survival (DRFS)., Results: Among the 150 eligible patients included, 79 patients underwent lateral pelvic SLNB. Of those 79 patients, 4 patients who were SLNB-positive underwent LLND. LLND was omitted for the 75 patients who were SLNB-negative. Median follow-up was 61.0 months (range, 1.3-143.2 months). The overall recurrence rate was 30.7% (46 patients), with LR in 12.0% (18 patients). LR comprised lateral lymph node recurrence in 2.6% and central pelvic recurrence in 9.4%. No significant differences were seen between groups in terms of the frequency of LR or in CSS, OS, RFS, LRFS, or DRFS., Conclusion: Oncological outcomes were not different between the SLNB and Non-SLNB groups. ICG-guided SLNB appears promising as a method for determining indications for LLND., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Since many people die of either cancers or cardiovascular diseases worldwide, it is important to find the clinical pitfall that provokes cardiovascular diseases and cancer overall. Since metabolic syndrome (MetS) is largely linked to cardiovascular diseases, we have come to consider that MetS, even in its early state, may prime the occurrence of cancers overall. Indeed, the importance of MetS in causing pancreatic cancer has been proved using our large medical database. We analyzed Japanese healthcare and clinical data in 2005, who were followed up until 2020 and we examined the incidence of major cancers. At the enrollment, we examined the presence or absence of MetS judged by either Japanese criteria or NCEP/ATPIII. Of 2.7 million subjects without missing data, 102,930; 200,231; 237,420; 63,435; 76,172; and 2,422 subjects suffered lung, stomach, colon, liver and prostate cancer, respectively, and myelogenous leukemia during follow-up. MetS, defined by Japanese criteria, increased (p < 0.005 each) the incidence of cancer with a hazard ratio (HR) of 1.03-1.47 for lung, stomach, colon, liver, prostate cancers, and myelogenous leukemia. According to Japanese criteria, cancer incidence in the pre-stage MetS group was comparable to the MetS group. The results were almost identical when we defined MetS using NCEP ATP III. Taken together, we conclude that MetS is linked to majority of cancers., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Background: The clinical significance of the lymph node ratio (LNR), the number of metastatic lymph nodes per dissected lymph node, has not been sufficiently clarified in ampullary cancer., Methods: Among patients diagnosed histopathologically with ampullary cancer between 1980 and 2018, the study included 106 who underwent pathological radical resection by pancreaticoduodenectomy. The relationships between the LNR and metastatic lymph node sites and prognosis were examined., Results: Multivariate analysis revealed that sex and lymph node metastasis were independent prognostic factors. In the 46 patients (43%) with metastatic lymph nodes, the LNR in the recurrence group was significantly higher than that in the non-recurrence group (0.15 ± 0.11 vs. 0.089 ± 0.071, p = 0.025). The receiver operating characteristic curve demonstrated that the LNR cut-off value, 0.07 (area under the curve = 0.70, sensitivity 81%, specificity 56%), was a significant indicator for recurrence (22% vs. 61%, p = 0.016) and prognosis (5-year survival: 48% vs. 83%, p = 0.028). Among the metastatic lymph node sites in the 46 positive cases, lymph node metastases developed from the peripancreatic head region (80%, 37/46) to the superior mesenteric artery (33%, 15/46) and para-aortic (11%, 5/46) regions., Conclusion: Lymph node metastasis is an independent prognostic factor, and the LNR is a significant indicator for recurrence and prognosis in patients with ampullary cancer., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Identifying patients who can be spared nonbeneficial surgery is crucial, as pancreatic cancer surgery is highly invasive, with substantial negative effects on quality of life. The study objective was to investigate a useful indicator of patients who do not gain prognostic benefit from radical surgery after neoadjuvant therapy for resectable and borderline resectable pancreatic cancer., Method: We compared factors among 609 patients with resectable or borderline resectable pancreatic cancer receiving neoadjuvant therapy during 2005-2019. Patients were divided into a poor-prognosis group (no surgery or postresection recurrence within a year) and a good-prognosis group (no recurrence or recurrence >1 year after resection)., Results: Patients who experience a recurrence within a year of resection (poor-prognosis group) did no better than patients who received neoadjuvant therapy and progressed but never made it to surgery. The value of carbohydrate antigen 19-9 after neoadjuvant therapy was the most significant indicator to predict the poor prognosis group and the elevation of carbohydrate antigen 19-9 (>200 U/mL) identified only poor prognosis group with high specificity of 96.6%. The overall survival of patients with more than 200 of carbohydrate antigen 19-9 after neoadjuvant therapy was significantly very poor and their 2-year survival rate was only 41.4%., Conclusion: A striking elevation of carbohydrate antigen 19-9 after neoadjuvant therapy for resectable or borderline resectable pancreatic cancer is a good indicator of poor prognosis. Patients with carbohydrate antigen 19-9 >200 U/mL after neoadjuvant therapy should not undergo radical surgery., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pembrolizumab plus chemotherapy has been indicated as the first-line treatment for metastatic or unresectable locally advanced esophageal cancer. However, pretreatment biomarkers for predicting clinical outcomes remain unclear. We investigated the predictive value of inflammation-based prognostic scores in patients treated with pembrolizumab and chemotherapy. The Prognostic Nutritional Index (PNI), C-reactive protein/albumin ratio (CAR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were calculated before initial treatment in 65 eligible patients with metastatic or unresectable locally advanced esophageal cancer receiving pembrolizumab plus CF therapy, and the relationship between these biomarkers and clinical outcomes was analyzed. The objective response rate (ORR) and progression disease (PD) were observed in 51% and 21% of all patients. Patients with PNI<39 have significantly worse treatment responses than those with PNI≥39 (ORR; 28% vs. 60%, PD; 44% vs. 13%, P =0.020). Progression-free survival (PFS) is significantly associated with the PNI and CAR ( P <0.001 and P =0.004, respectively). Overall survival (OS) is associated with PNI, CAR, and PLR ( P <0.001, P =0.008, and P =0.018, respectively). The PNI cutoff value of 39 is identified as an independent factor for PFS (odds ratio=0.27, 95% CI: 0.18-0.81, P =0.012) and OS (odds ratio=0.22, 95% CI: 0.08-0.59, P =0.003). Patients with PNI<39 have significantly worse 6-month PFS and 1-year OS than those with PNI≥39 (27.8% vs. 66.7%, 27.2% vs. 81.1%, respectively). In conclusion, inflammation-based prognostic scores are associated with survival in patients treated with pembrolizumab plus CF therapy. Pretreatment PNI is a promising candidate for predicting treatment response and survival., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Local recurrence is common after curative resections of rectal cancer. Surgical resection is considered a primary curative treatment option for patients with locally recurrent rectal cancer (LRRC). LRRC often requires a combined resection of other organs, especially in the case of posterior recurrence, which requires a combined resection of the sacrum, making the surgery highly invasive. Venous thromboembolism (VTE) is one of the lethal complications in the postoperative period, particularly in the field of pelvic surgery. We found no reports regarding the risks of postoperative VTE in surgery for LRRC, a typical highly invasive procedure in the field of colorectal surgery. This study aims to evaluate the risk of postoperative VTE in surgery for LRRC patients., Methods: From April 2010 to March 2022, a total of 166 patients underwent surgery for LRRC in the pelvic region at our institutions. Clinicopathological background and VTE incidence were compared retrospectively., Results: Among the 166 patients included in the study, 55 patients (33.1%) needed sacral resection. Pharmacological prophylaxis for prevention of VTE was performed in 121 patients (73.3%), and the incidence of VTE was 9.09% (5/55 patients) among those who underwent surgery for LRRC with sacral resection, while it was 1.8% (2/111 patients) in those without sacral resection. In univariate analysis, the combination with sacral resection was identified as a risk factor for VTE in surgery for LRRC (p = 0.047)., Conclusions: This study demonstrates that surgery for LRRC combined with sacral resection could be a significant risk factor for VTE., (© 2024. The Author(s).)

This study aims to investigate the role of claudin-5 (Cldn5) in cardiac structural integrity. Proteomic analysis was performed to screen the protein profiles in enlarged left atrium from atrial fibrillation (AF) patients. Cldn5 shRNA adeno-associated virus (AAV) or siRNA was injected into the mouse left ventricle or added into HL1 cells respectively to knockdown Cldn5 in cardiomyocytes to observe whether the change of Cldn5 influences cardiac morphology and function, and affects those protein expressions stem from the proteomic analysis. Mitochondrial density and membrane potential were also measured by Mitotracker staining and JC-1 staining under the confocal microscope in HL1 cells. Cldn5 was reduced in cardiomyocytes from the left atrial appendage of AF patients compared to non-AF donors. Proteomic analysis showed 83 proteins were less abundant and 102 proteins were more abundant in AF patients. KEGG pathway analysis showed less abundant CACNA2D2, CACNB2, MYL2 and MAP6 were highly associated with dilated cardiomyopathy. Cldn5 shRNA AAV injection caused severe cardiac atrophy, dilation and myocardial dysfunction in mice. The decreases in mitochondrial numbers and mitochondrial membrane potentials in HL1 cells were observed after Cldn5 knockdown. We demonstrated for the first time the mechanism of Cldn5 downregulation-induced myocyte atrophy and myocardial dysfunction might be associated with the downregulation of CACNA2D2, CACNB2, MYL2 and MAP6, and mitochondrial dysfunction in cardiomyocytes., 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 © 2024 Elsevier B.V. All rights reserved.)

Strain TC023 T , a Gram-positive, long, rod-shaped, spore-forming anaerobe, was isolated from the faeces of a heart failure mouse model. The strain formed greyish-white coloured colonies with a convex elevation on brain-heart infusion medium supplemented with 0.1 % sodium taurocholate, incubated at 37 °C for 2 days. Taxonomic analysis based on the 16S rRNA gene sequence showed that TC023 T belonged to the genus Turicibacter , and was closely related to Turicibacter bilis MMM721 T (97.6 %) and Turicibacter sanguinis MOL361 T (97.4 %). The whole genome of the strain has a G+C content of 37.3 mol%. The average nucleotide identity and genome-to-genome distance between TC023 T and Turicibacter bilis MMM721 T were 77.6 % and 24.3 %, respectively, and those with Turicibacter sanguinis MOL361 T were 75.4 % and 24.3 %, respectively. These genotypic, phenotypic, and biochemical analyses indicated that the isolate represents a novel species in the genus Turicibacter , and the name Turicibacter faecis sp. nov. is proposed. The type strain is TC023 T (RIMD 2002001 T =TSD 372 T ).

Background: Heart failure patients are deficient in B-type natriuretic peptide (BNP) but the significance of subclinical BNP deficiency is unclear. Methods and Results: A total of 1,398 subjects without cardiovascular disease, with left ventricular ejection fraction (LVEF) ≥50% and BNP level <100 pg/mL, were selected from a 2005-2008 health checkup in Arita-cho, Japan, and divided into 2 groups: with and without LV diastolic dysfunction (DD+ or DD-). We performed propensity score matching on non-cardiac factors affecting BNP levels and analyzed 470 subjects in each group (372/940 men; median age, 66 years). The DD(+) group showed higher lateral E/e', an index of estimated left ventricular filling pressure, and greater prevalence of concentric hypertrophy (CH) despite similar BNP levels, suggesting a relative deficiency of BNP in DD(+) compared with DD(-). Multivariable logistic regression analysis revealed an increase in BNP correlated with decreased odds of CH (adjusted odds ratio [aOR] 0.663, 95% confidence interval (CI) 0.484-0.909, P=0.011), whereas an increase in lateral E/e' was associated with increased odds of CH (aOR, 2.881; 95% CI, 1.390-5.973; P=0.004). Furthermore, CH in combination with diastolic dysfunction independently predicted major adverse cardiovascular events (hazard ratio 3.272, 95% CI 1.215-8.809; P=0.019). Conclusions: Relative BNP deficiency was associated with CH, which had a poor prognosis in patients with diastolic dysfunction., Competing Interests: O.T., S.I. are members of Circulation Reports’ Editorial Team. The other authors declare that there are no conflicts of interest., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Background/aim: Postoperative venous thromboembolism (VTE) is a well-recognized complication that leads to morbidity and mortality. Lateral lymph node dissection (LLND) for rectal cancer is thought to potentially increase the risk of VTE due to its technical complexity. However, the relationship between LLND and VTE remains inadequately understood. The aim of this study was to elucidate the impact of LLND on the incidence of postoperative VTE., Patients and Methods: This is a retrospective analysis of patients who underwent rectal cancer resection between 2010 and 2018 to identify the risk factors associated with postoperative VTE. Patients were divided into two groups: those who underwent surgery with LLND (LLND+ group) and those who underwent surgery without LLND (LLND- group)., Results: A total of 543 patients were enrolled in this study, and 113 patients underwent surgery for rectal cancer with LLND. VTE developed in 8 patients (1.47%), with the incidence rates being 4.42% in the LLND+ group and 0.69% in the LLND- group, respectively (p=0.012). Three of 8 patients had developed severe postoperative complications, and the other two patients needed intraoperative repair of the iliac vein during LLND procedure. Multivariate analysis identified the incidence of postoperative complications and LLND as the independent risk factors of VTE., Conclusion: Patients undergoing rectal cancer surgery with LLND should be closely monitored for signs of VTE., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The assessment of muscle mass loss, muscle strength, and physical function has been recommended in diagnosing sarcopenia. However, only muscle mass has been assessed in previous studies. Therefore, this study investigated the effect of comprehensively diagnosed preoperative sarcopenia on the prognosis of patients with esophageal cancer., Methods: The study analyzed 115 patients with esophageal cancer (age ≥ 65 years) who underwent curative esophagectomy. Preoperative sarcopenia was analyzed using the skeletal mass index (SMI), handgrip strength, and gait speed based on the Asian Working Group for Sarcopenia 2019 criteria. Clinicopathologic factors, incidence of postoperative complications, and overall survival (OS) were compared between the sarcopenia and non-sarcopenia groups. The significance of the three individual parameters also was evaluated., Results: The evaluation identified 47 (40.9%) patients with low SMI, 31 (27.0%) patients with low handgrip strength, and 6 (5.2%) patients with slow gait speed. Sarcopenia was diagnosed in 23 patients (20%) and associated with older age and advanced pT stage. The incidence of postoperative complications did not differ significantly between the two groups. Among the three parameters, only slow gait speed was associated with Clavien-Dindo grade 2 or greater complications. The sarcopenia group showed significantly worse OS than the non-sarcopenia group. Those with low handgrip strength tended to have worse OS, and those with slow gait speed had significantly worse OS than their counterparts., Conclusions: Preoperative sarcopenia diagnosed using skeletal muscle mass, muscle strength, and physical function may have an impact on the survival of patients with esophageal cancer., (© 2023. Society of Surgical Oncology.)

Purpose: Acid suppressive therapy using histamine H 2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) can be utilized for the prevention of gastrointestinal bleeding (GIB) among patients with cardiovascular disease receiving dual antiplatelet therapy (DAPT). However, emerging data suggests underlying associations between PPI or H2RA use and cardiovascular disease incidence, progression, and mortality. This review explores the history of acid suppressive therapies and their use in cardiovascular disease patients and the growing evidence in support of H2RA use., Recent Findings: PPIs were originally championed as better than H2RAs for preventing GIB events in cardiovascular disease patients on DAPT therapy, but there is evidence to suggest that drug-drug interactions between clopidogrel and PPIs may translate to worse cardiovascular outcomes. Studies demonstrating PPI superiority in the setting of DAPT were also limited due to small sample sizes and high levels of bias. Consequently, there is renewed interest in H2RAs for patients on DAPT with some data demonstrating similar or improved clinical outcomes over PPI therapy. Additionally, studies have discovered a possible role for H2RAs in the management of heart failure (HF) incidence, symptoms, and mortality. Studies comparing H2RAs and PPIs in patients on DAPT have demonstrated mixed results for cardiovascular and GIB outcomes, with several studies being underpowered and limited by biases. Recent clinical and pre-clinical studies now support the noninferiority of H2RAs for major outcomes and even utility in HF. These findings suggest that H2RAs may warrant reconsideration as an acid suppressive therapy over PPIs for patients on DAPT or with HF., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Metastatic or unresectable locally advanced oesophageal cancer remains a disease with high mortality. More recently, pembrolizumab plus chemotherapy has been indicated as the first-line treatment for those patients, but the predictive factors for treatment efficacy remain controversial. This study investigated the clinical utility of early tumour shrinkage (ETS) and depth of response (DpR) in metastatic or unresectable oesophageal cancer treated with pembrolizumab plus CF therapy., Methods: ETS and DpR, defined as the percent decreases at the second evaluation and the percentage of the maximal tumour shrinkage during treatment, were measured in 53 eligible patients. The ETS and DpR cut-off values were 20% and 30%, respectively, based on survival outcomes., Results: Twenty-seven patients (51%) were treatment naïve, while 26 (49%) had received any treatment before initiating pembrolizumab plus CF therapy. The median progression-free survival (PFS) and overall survival for ETS ≥20% and &lt;20% were 12.7 and 5.5 months and 14.4 and 8.2 months and 12.7 and 4.9 months and 14.4 and 8.0 months for DpR ≥30% and &lt;30%, respectively. ETS &lt;20% showed early tumour growth, whereas ETS ≥20% had a good response rate with sufficient longer response duration. In addition, an ETS cut-off of 20% predicted the best overall response and was not associated with prior treatment. In multivariable analysis, ETS ≥20% and DpR ≥30% were independent factors of longer PFS., Conclusion: Our findings suggest that an ETS is a promising on-treatment marker for early prediction of further sensitivity to pembrolizumab plus CF therapy., (© 2023 S. Karger AG, Basel.)

Background/aim: CheckMate 577 evaluated adjuvant nivolumab therapy after neoadjuvant chemoradiotherapy and surgery for esophageal cancers. However, the efficacy of this treatment in patients who received neoadjuvant chemotherapy remains unknown. This study investigated the short-term outcomes of adjuvant nivolumab therapy in patients with advanced esophageal squamous cell carcinoma post-neoadjuvant chemotherapy., Patients and Methods: Out of 956 patients with thoracic esophageal cancer who underwent radical esophagectomy, 227 who exhibited ypN1-3 after neoadjuvant chemotherapy and surgery were included in this study., Results: Among 227 patients, 30 received adjuvant nivolumab and 197 received non-nivolumab adjuvant therapy. The nivolumab group displayed a higher number of lymph node metastases compared to the control group. Patients with ypN1-2 tended to have longer recurrence-free survival (RFS) in the nivolumab group than in the non-nivolumab group (p=0.095). In the propensity score-matched cohort, no differences in patient characteristics were observed. Adjuvant nivolumab therapy significantly prolonged RFS in patients who received neoadjuvant chemotherapy (p=0.013). Patients with ypN1-2 in the nivolumab group had significantly longer RFS than their counterparts in the non-nivolumab group (p=0.001), but not in ypN3 (p=0.784). The 1-year postoperative recurrence rates were 59% for the non-nivolumab group and 24% for the nivolumab group (p=0.007). Nivolumab-related adverse events in patients receiving neoadjuvant chemotherapy were mostly consistent across all grades, while the frequency of increased aspartate aminotransferase (AST) levels was relatively higher compared to CheckMate577., Conclusion: Adjuvant nivolumab was more likely to prolong 1-year RFS in patients receiving neoadjuvant chemotherapy, especially in those with ypN1-2, and had acceptable adverse events., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Although previous studies have showed that metabolic syndrome is one of the contributors of pancreatic cancer, there is no clear consensus that early stages of metabolic syndrome are linked to increased incidence of pancreatic cancer. Therefore, we confirmed the linkage between metabolic syndrome and pancreatic cancer, and shown that even early stage of metabolic syndrome is linked to pancreatic cancer in the retrospective observational study., Methods: We recruited approximately 4.6 million Japanese in 2005 and followed up these subjects for more than 10 years. At the time of the enrollment, after obtaining clinical data with prescribed drugs and examining the presence or absence of metabolic syndrome (MetS), we followed up on these subjects with and without MetS to examine the incidence of pancreatic cancer. The modified criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATPIII) were used to define MetS., Findings: During the 40.7-month average follow-up period for 2,707,296 subjects with complete data for identifying MetS and important risk factors without pancreatic cancer before the enrollment, 87,857 suffered from pancreatic cancer. Pancreatic cancers occurred in 16,154 of 331,229 subjects (4.9%) in the MetS group and 71,703 of 2,376,067 patients (3.0%) in the non-MetS group (hazard ratio (HR), 1.37; 95% confidence interval [CI], 1.34-1.39; p < 0.0001 after the adjustment with age, smoking and sex). As the number of the constituent factors of MetS increased from one to five, the incidence of pancreatic cancer correspondingly increased (HR: 1.11, 1.23, 1.42, 1.66 and 2.03 using Cox proportional hazard models, p < 0.0001 each). When we defined MetS using the Japanese criteria, the results are in accord with the results using NCEP/ATPIII. Especially pre-metabolic syndrome (pre-MetS) in the Japanese criteria was tightly linked to the incidence of pancreatic cancers., Interpretation: MetS is confirmed to be linked to pancreatic cancer. Although we cannot conclude causality. We also demonstrated the link between pre-MetS and pancreatic cancer., Funding: The sponsors of the study were Japanese Heart Foundation and Japan Cardiovascular Research Foundation. This is also partially supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and Grants-in-Aid from the Japan Agency for Medical Research and Development., Competing Interests: Relationships to industry do not exist for YM, TH, HF, JK, NK, KK, YY, MY, and TW. SI reports grants from Japan Society for the Promotion of Science outside the submitted work. MK reports personal fees from Daiichi-sankyo, personal fees from Viatris, grants and personal fees from Ono, grants from Novartis, grants and personal fees from Tanabe-mitsubishi, grants from Takeda, grants and personal fees from Astra Zeneca, grants and personal fees from Boehringer-ingelheim, grants from Kowa, personal fees from Otsuka, personal fees from Eli Lilly outside the submitted work., (© 2023 The Author(s).)

Background: Patients with heart failure (HF) with mildly reduced or preserved ejection fraction in Asia may have different clinical characteristics and outcomes compared with patients from other parts of the world., Objectives: The purpose of this study was to investigate the clinical characteristics, safety, and efficacy of dapagliflozin in patients in Asia vs outside Asia in the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial., Methods: In the DELIVER trial, patients with HF and left ventricular ejection fraction >40% were enrolled across 353 sites in 20 countries. The effects of dapagliflozin vs placebo on primary (composite of worsening HF or cardiovascular death) and secondary outcomes were compared in patients from Asia vs outside Asia., Results: Among 6,263 participants, 1,226 (19.6%) were enrolled in Asia. Participants from Asia were less likely to have diabetes, hypertension, history of myocardial infarction, or obesity. After adjusting for clinically relevant characteristics, those in Asia had similar risks of primary composite outcome compared with those from outside Asia (HR: 0.97; 95% CI: 0.82-1.15). Those in Asia had a lower risk of all-cause mortality compared with those enrolled outside Asia (HR: 0.54; 95% CI: 0.44-0.66). Enrollment from Asia did not modify the effect of dapagliflozin on the primary outcome ( P interaction  = 0.54). Serious adverse events and rates of drug discontinuation were also balanced in both treatment arms, irrespective of enrollment in Asia vs outside Asia., Conclusions: In the global DELIVER trial, dapagliflozin reduced the risk of CV death or worsening HF events and was well tolerated among participants enrolled in both Asia and other geographic regions., Competing Interests: AstraZeneca was the sponsor and funder of the DELIVER trial. Dr Wang is supported by a T32 postdoctoral training grant from the National Heart, Lung, and Blood Institute (T32 HL094301), and by the Scott Schoen and Nancy Adams First.In.Women Cardiovascular Fellowship, Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital. Dr Lam has received research support from NovoNordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a co-founder and non-executive director of Us2.ai. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Kondo receives lecture fees from Abbott Medical Japan LLC, Ono Pharmaceutical Co, Ltd, Otsuka Pharmaceutical Co, Ltd, Novartis Pharma K.K., AstraZeneca K.K., Bristol Myers Squibb Co, and Abiomed Japan K.K. Dr Yang reports travel grants from AstraZeneca. Dr Vinh received financial support as PI of DAPA-HF, DELIVER trials from AZ, and honoraria as speakers from AZ, Boehringer Ingelheim, Servier, Roche, Abbott, and Menarini. Dr Chiang received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, Menarini, MSD, Novartis, Sanofi, and Viatris. Dr Kitakaze reports grants from the Japanese government, Japan Heart Foundation, Japan Cardiovascular Research Foundation, Kowa, Novartis, and Takeda; personal fees from Daiichi Sankyo, Eli Lilly, Otsuka, and Viatris; and grants and personal fees from Ono, Tanabe-Mitsubishi, AstraZeneca, and Boehringer Ingelheim, outside the submitted work. Dr Jhund reported speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc. Dr Jhund’s employer the University of Glasgow has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and NovoNordisk; Director Global Clinical Trial Partners (GCTP). Dr Desai reports being the named recipient on institutional research grants to Brigham and Women’s Hospital from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis as well as personal consulting fees from Abbott, Alnylam, AstraZeneca, Avidity Biopharma, Axon Therapeutics, Bayer, Biofourmis, Cytokinetics, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, River2Renal, Roche, Veristat, Verily, and Zydus. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Merck, Pfizer, and Bayer, and has delivered lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr De Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. Dr Martinez receives consulting fees from AstraZeneca. Dr Kosiborod receives consulting fees from Alnylam Pharmaceuticals, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Esperion Therapeutics, Janssen Global Services, Lexicon Pharmaceuticals, Merck, Novo Nordisk, Pharmacosmos, Sanofi, Vifor Pharma; he also receives grant/contract or travel fees from AstraZeneca and Boehringer Ingelheim. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic and Verily; and has served as a consultant or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Eidos, Intercept, Merck, and Novartis. Dr Claggett reported receiving consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, Intellia, and Rocket outside of the submitted work. Dr Langkilde is employed by and holds stock in AstraZeneca. Dr McMurray is supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217. He has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GSK, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; and personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, Global Clinical Trial Partners (GCTP). Dr Solomon has received research grants from Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Cytokinetics, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the urinary albumin-to-creatinine ratio (UACR) in patients with elevated levels of albuminuria in the presence or absence of heart failure (HF) or type 2 diabetes mellitus (T2D). However, these effects have not yet been reported in the presence of both HF and T2D. This lack of evidence prompted us to conduct a clinical trial on the effects of dapagliflozin on UACR in patients with HF and T2D., Methods: DAPPER is a multicentre, randomised, open-labeled, parallel-group, standard treatment-controlled trial that enrolled patients at 18 medical facilities in Japan. Eligible participants with both HF and T2D and aged between 20 and 85 years were randomly assigned to a dapagliflozin or control (anti-diabetic drugs other than SGLT 2 inhibitors) group with a 1:1 allocation. The primary outcome was changes in UACR from baseline after a two-year observation, and secondary endpoints were cardiovascular (CV) events and parameters related to HF. This trial was registered with the UMIN-CTR registry, UMIN000025102 and the Japan Registry of Clinical Trials, jRCTs051180135., Findings: Between 12 May 2017 and 31 March 2020, 294 patients were randomly assigned to the dapagliflozin group (n = 146) or control group (n = 148). The mean age of patients was 72.1 years and 29% were female. The mean glycated hemoglobin value was 6.9%, mean NT-proBNP was 429.1 pg/mL, mean estimated GFR was 65.7 mL/min/1.73 m 2 , and median UACR was 25.0 (8.8-74.6) mg/g Cr in the dapagliflozin group and 25.6 (8.2-95.0) mg/g Cr in the control group. Of the 146 patients in the dapagliflozin group, 122 completed the study, and 107 (87.7%) were taking 5 mg of dapagliflozin daily at the end of the observation period. The primary outcome did not significantly differ between the dapagliflozin and control groups. Among the secondary endpoints, the mean decrease in left ventricular end-diastolic dimensions as one of the echocardiographic parameters was larger in the dapagliflozin group than in the control group. The composite endpoint, defined as CV death or hospitalisation for CV events, hospitalisation for HF events, hospitalisation for all causes, and an additional change in prescriptions for heart failure in a two-year observation, was less frequent in the dapagliflozin group than in the control group., Interpretation: Although dapagliflozin at a dose of 5 mg daily did not reduce urinary albumin excretion in patients with HF and T2D from that in the controls, our findings suggest that dapagliflozin decreased CV events and suppressed left ventricular remodeling., Funding: AstraZeneca KK, Ono Pharmaceutical Co., Ltd., Competing Interests: FY reports grants and personal fees from AstraZeneca K.K. and Ono Pharmaceutical Co., LTD., during the conduct of the study. FY also has received grants from the Japanese government (KAKENHIPROJECT-17K09002, 20K07819, 23K09616) and personal fees from Daiichi Sankyo, National Agricultural Insurance Association, AstraZeneca, Kyowa-Kirin, Bayer, Astellas, Mochida, Teijin, Otsuka, Sumitomo Dainippon, Terumo, Novartis, Akahata, Tanabe Mitsubishi, Boehringer Ingelheim, and Sumitomo, outside the submitted work. MI has nothing to disclose. IS 3) reports grants and personal fees from the National Cerebral and Cardiovascular Centre during the conduct of the study. IS 3) also received grants from Ryukyu University, Soiken Co., Res. Inst. for Production Development and Nexis Co., and personal fees from Daiichi Sankyo, Kowa, AstraZeneca, Kyowa-Kirin, Bayer, Astellas, Mochida, Nipro, Otsuka, Sumitomo Dainippon, Eisai, Novartis, Glaxo Smith Kline, Toa Eiyo, Boehringer Ingelheim, Novo Nordisk, Bristol Myers Squibb, and Sanwa Kagaku, outside the submitted work. YH received grants from the Japanese government (AMED JP20ek0210152, and JP22ek21065) from the National Centre for Global Health and Medicine (21A1001, 21A2004, 21A2007, and 23A1019) and personal fees from AstraZeneca, Daiichi Sankyo, Bayer, Otsuka, Novartis, Tanabe Mitsubishi, Roche, Novo Nordisk, Mochida, Viatris, Kowa, Chugai, MSD, Boehringer Ingelheim, Takeda, Eisai, and Edwards Lifesciences outside the submitted work. HH reports grants and personal fees from AstraZeneca Plc. and Ono Pharmaceutical Co., LTD., during the conduct of the study. HH also received personal fees from Daiichi Sankyo, AstraZeneca, Bayer, and Terumo outside the submitted work. OO has nothing to disclose. CI 6) author, has nothing to disclose. CI 7) author reports grants from the Japanese government (KAKENHIPROJECT-22K08118), AMED (22ek0109539h0002, and 23ek0109629h0001), Daiichi Sankyo, Cannon Medical Systems, Teijin, Pfizer, Idorsia Pharmaceuticals Japan, LSI Medience and Shin Nippon PPD as well as personal fees from Daiichi Sankyo, Edwards Lifesciences, AstraZeneca, Cannon Medical Systems, Bayer, Astellas, Mochida, Teijin, Otsuka, Sumitomo Dainippon, Pfizer, Novartis, Bristol-Myers Squibb, Tanabe Mitsubishi, Boehringer Ingelheim, Tsumura, and MSD outside the submitted work. TN received grants from the Japanese government (KAKENHIPROJECT-22K08223, 22H03191, 21K08044, 20K08483, 20H03681, and 19K08571) and the Japan Agency for Medical Research and Development (AMED: 23811571, 20314990, 21453332, 21472516, and 17930494). TN received personal fees from AstraZeneca, Kyowa-Kirin, Bayer, Astellas, Mochida, Takeda, Otsuka, Sumitomo Dainippon, Boston-Scientific, Novartis, Daiichi Sankyo, Tanabe Mitsubishi, Boehringer Ingelheim, Kowa, Toaeiyo, Bristol Myers Squibb, Gwangju International Interventional Cardiology Symposium (GICS 2023), and Gwangju International Interventional Cardiology Symposium (GICS 2022) outside the submitted work. TS has nothing to disclose. NN has nothing to disclose. KF has nothing to disclose. KI reports honoraria from AstraZeneca, Ono Pharmaceutical, Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk A/S, Sumitomo Pharma, Amgen, Kowa Company, Bayer, Kyowa-Kirin, Daiichi Sankyo, Astellas, Mochida, Otsuka Pharmaceutical, Novartis, and Tanabe Mitsubishi, and support for attending meetings and travel from Novo Nordisk A/S. OT has nothing to disclose. KK receives personal fees from Otsuka, AstraZeneca, Kyowa-Kirin, Novartis, Amgen, and Abbott. MT received honoraria for lectures from AstraZeneca, Ono Pharmaceutical Co., Kyowa-Kirin, Kowa Company Limited, Sanofi K.K., Daiichi Sankyo, TAISHO PHARMACEUTICAL, Takeda Pharmaceutical, Tanabe Mitsubishi, Boehringer Ingelheim, Novo Nordisk Pharma, Sumitomo Dainippon, MSD, Astellas, Eli Lilly, KISSEI PHARMACEUTICAL, Teijin, Novartis, Mochida, Otsuka, SANWA KAGAKU KENKYUSHO, Sumitomo Pharma, NIPRO CORPORATION, and Bayer. KY received personal fees from Mochida Pharmaceutical Co., Ltd., Eisai Co., Ltd., Otsuka Pharmaceutical, Sanofi, Boston Scientific, Abbott Diagnostics Medical Co., Ltd., Bristol Myers Squibb, DAIICHI SANKYO COMPANY, LIMITED, Nippon Boehringer Ingelheim Co., Ltd., Janssen Pharmaceutical K.K., Kowa Company, Limited, Amgen K.K., Novartis Pharma K.K., AstraZeneca K.K., Edwards Lifesciences, and Mitsubishi Tanabe Pharma Corporation. HT receives personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Kowa, Mochida, Nippon Shinyaku, Novartis, Omron, Otsuka, PDRadiopharma, and Sumitomo Dainippon outside the submitted work. TH 16) has nothing to disclose. IS 17) reports honoraria from Kyowa-Kirin Terumo, Sumitomo, Novo Nordisk, Eli Lilly, AstraZeneca, Boehringer Ingelheim Sanofi, Otsuka, and MSD. TM receives grants from the Japanese government (KAKENHIPROJECT 18K15864, and 21K16068) and personal fees from Daiichi Sankyo, AstraZeneca, Bayer, Astellas, Mochida, Otsuka, Novartis, and Boehringer Ingelheim outside the submitted work. KW reports consulting fees from Terumo, Gadelius Medical, and ITI Co., LTD., during the conduct of the study. KW also received personal fees from OrbusNeich, Japan Medtronic, Ono Pharmaceutical Co., Daiichi-Sankyo, Dainihon Sumitomo, Amgen, Kowa, Japan Lifeline, Novartis, Toaeiyo, Otsuka Pharma, Mochida, Sumitomo Pharma, Fuji Yakuhin, and AstraZeneca outside the submitted work. KS has nothing to disclose. TH 21) has nothing to disclose. SA has nothing to disclose. SH receives personal fees from Daiichi Sankyo, AstraZeneca, Novartis, Nippon Boehringer Ingelheim, Kowa, Viatris, Actelion, Bayer, Amgen, Bristol Myers, Takeda, Termo, Ono, Janssen, Novo Nordisk, Tanabe, Otsuka, Astellas, and Edwards Lifesciences outside the submitted work. MA received grants from Daiichi Sankyo, Otsuka, Boehringer Ingelheim, and personal fees from AstraZeneca, Tanabe Mitsubishi, Daiichi Sankyo, Novartis, Byer, Boehringer Ingelheim, Nippon Shinyaku, Viatris, Janssen, Astellas, Eli Lilly, and Otsuka outside the submitted work. TK receives Grants-in-Aid for Scientific Research (KAKENHI 22K10547). KO receives personal fees from Nippon Boehringer Ingelheim Co., Ltd., outside the submitted work. SI reports a grant from the Japan Society for the Promotion of Science outside the submitted work. MK reports grants from the Japanese government, grants from the Japan Heart Foundation, grants from the Japan Cardiovascular Research Foundation, personal fees from Daiichi-Sankyo, personal fees from Viatris, grants and personal fees from Ono, grants from Novartis, grants and personal fees from Tanabe-Mitsubishi, grants from Takeda, grants and personal fees from Astra Zeneca, grants and personal fees from Boehringer-Ingelheim, grants from Kowa, and personal fees from Otsuka, and personal fees from Eli Lilly outside the submitted work., (© 2023 The Author(s).)

Background/aim: Locally recurrent rectal cancer (LRRC) involving the upper sacrum is generally considered a contraindication for curative surgery. In the surgical management of LRRC, sacrectomy is frequently performed to secure clear resection margins. Nonetheless, the indications for high sacrectomy remain controversial due to potential postoperative complications, questions about radicality, and the increased complexity of the operation. Furthermore, comprehensive studies addressing this issue are notably absent. This study aimed to assess the feasibility, safety, and surgical prognosis in high sacrectomy for LRRC., Patients and Methods: All patients with LRRC who required concomitant sacrectomy, but did not include the inferior margin of the second sacral vertebra, between 2003 and 2014, were reviewed retrospectively., Results: Eight patients with a median age of 59 years were included in this study. The proximal resection line for sacral bone resection was the central part of the S1 vertebra in one patient, lower edge of the S1 vertebra in six patients, and central part of the S2 vertebra in one patient. Negative margin resection was achieved in five out of the eight patients. The median operative time was 922 min, and the median operative blood loss volume was 6,370 ml. Major complications included pelvic abscess (n=5), ileus (n=1), and pulmonary vein embolism (n=1), none of which proved fatal during the postoperative period. Both the 5-year local re-recurrence-free survival rate and the 5-year distant metastasis-free survival rate were 50% (4/8)., Conclusion: High sacrectomy is safe and feasible to achieve negative margins in patients with LRRC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The enhanced recovery after surgery (ERAS) program is expected to improve perioperative outcomes in patients with esophageal cancer. However, how ERAS impacts the postoperative body composition and factors related to compliance rate of ERAS have not been fully investigated., Patients and Methods: The study included 252 consecutive patients with thoracic esophageal cancer who underwent minimally invasive esophagectomy. We compared the postoperative outcomes including body composition between the old perioperative program and the new one that aimed to shorten postoperative length of stay (LOS). Compliance-related clinical factors were also examined., Results: From 252 patients, 129 underwent the old program and 123 the new program. Postoperative LOS, postoperative complications, and hospital costs were reduced with the new program. Body weight loss was significantly improved with the new program at discharge and 3-months after esophagectomy (94.9% vs. 96.6%, p=0.013, 89.5% vs. 91.1%, p=0.028, respectively). Patients in the new program had better body composition at discharge than those in the old program [body fat mass (91.6% vs. 94.1%), lean body mass (95.2% vs. 97.2), and skeletal muscle mass (95.3% vs. 97.0%)]. Major reasons for incompliance were dysphagia, pneumonia, and anastomotic leakage. Multivariate analysis revealed that age ≥70 years at surgery and sex (male) were independent risk factors for incompliance with the postoperative program., Conclusion: The new ERAS program aimed to shorten postoperative LOS had clinical benefits in body composition early after esophagectomy. Personalized ERAS programs based on age might lead to better postoperative outcomes because of low compliance rates for older patients., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Characterized by ventricular and vascular stiffness, heart failure with preserved ejection fraction (HFpEF) has led to high morbidity and mortality. As azilsartan is an angiotensin receptor blocker with the highest myocardial and vascular affinities, azilsartan may improve the left ventricular (LV) diastolic function in patients with hypertension and either HFpEF or HF with mildly reduced ejection fraction (HFmrEF) more than candesartan. In this randomized, open-label trial, we randomly assigned 193 hypertensive patients with HF and LV ejection fraction ≥ 45% to 20 mg of azilsartan (n = 95) or 8 mg of candesartan (n = 98), once daily for 48 weeks. After the initiation of treatment, changes in the doses of the study drugs were permitted based on the patient's conditions, including blood pressure (median dose at 48 weeks: azilsartan 20.0 mg/day, candesartan 8.0 mg/day). The primary endpoint was the baseline-adjusted change in the ratio of peak early diastolic transmitral flow velocity (E) to early diastolic mitral annular velocity (e') (E/e'). Adjusted least-squares mean (LSM) change in E/e' was - 0.8 (95% confidence interval [CI] - 1.49 to - 0.04) in the azilsartan group and 0.2 (95% CI - 0.49 to 0.94) in the candesartan group, providing the LSM differences of - 1.0 (95% CI - 2.01 to 0.03, P = 0.057). The median change in left atrial volume index was - 2.7 mL/m 2 with azilsartan vs 1.4 mL/m 2 with candesartan (P = 0.091). The frequency of adverse events related to hypotension and hyperkalemia did not differ between the groups. The current study did not provide strong evidence that azilsartan improves LV diastolic dysfunction, and further confirmatory study is required., (© 2023. The Author(s).)

Background: Cardiac-specific myosin light chain kinase (cMLCK), encoded by MYLK3 , regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure., Methods: We generated the knock-in mice ( Mylk3 +/fs and Mylk 3 fs/fs ) with a familial dilated cardiomyopathy-associated MYLK3 frameshift mutation ( MYLK3 +/fs ) that had been identified previously by us (c.1951-1G>T; p.P639Vfs*15) and the human induced pluripotent stem cell-derived cardiomyocytes from the carrier of the mutation. We also developed a new small-molecule activator of cMLCK (LEUO-1154)., Results: Both mice ( Mylk3 +/fs and Mylk 3 fs/fs ) showed reduced cMLCK expression due to nonsense-mediated messenger RNA decay, reduced MLC2v (ventricular myosin regulatory light chain) phosphorylation in the myocardium, and systolic dysfunction in a cMLCK dose-dependent manner. Consistent with this result, myocardium from the mutant mice showed an increased ratio of cardiac superrelaxation/disordered relaxation states that may contribute to impaired cardiac contractility. The phenotypes observed in the knock-in mice were rescued by cMLCK replenishment through the AAV9&#95; MYLK3 vector. Human induced pluripotent stem cell-derived cardiomyocytes with MYLK3 +/fs mutation reduced cMLCK expression by 50% and contractile dysfunction, accompanied by an increased superrelaxation/disordered relaxation ratio. CRISPR-mediated gene correction, or cMLCK replenishment by AAV9&#95; MYLK3 vector, successfully recovered cMLCK expression, the superrelaxation/disordered relaxation ratio, and contractile dysfunction. LEUO-1154 increased human cMLCK activity ≈2-fold in the V max for ventricular myosin regulatory light chain phosphorylation without affecting the K m . LEUO-1154 treatment of human induced pluripotent stem cell-derived cardiomyocytes with MYLK3 +/fs mutation restored the ventricular myosin regulatory light chain phosphorylation level and superrelaxation/disordered relaxation ratio and improved cardiac contractility without affecting calcium transients, indicating that the cMLCK activator acts as a myotrope. Finally, human myocardium from advanced heart failure with a wide variety of causes had a significantly lower MYLK3 / PPP1R12B messenger RNA expression ratio than control hearts, suggesting an altered balance between myosin regulatory light chain kinase and phosphatase in the failing myocardium, irrespective of the causes., Conclusions: cMLCK dysregulation contributes to the development of cardiac systolic dysfunction in humans. Our strategy to restore cMLCK activity could form the basis of a novel myotropic therapy for advanced systolic heart failure., Competing Interests: Disclosures None.

Background: Tissue-resident memory T (Trm) cells are associated with cytotoxicity not only in viral infection and autoimmune disease pathologies but also in many cancers. Tumour-infiltrating CD103 + Trm cells predominantly comprise CD8 T cells that express cytotoxic activation and immune checkpoint molecules called exhausted markers. This study aimed to investigate the role of Trm in colorectal cancer (CRC) and characterise the cancer-specific Trm., Methods: Immunochemical staining with anti-CD8 and anti-CD103 antibodies for resected CRC tissues was used to identify the tumour-infiltrating Trm cells. The Kaplan-Meier estimator was used to evaluate the prognostic significance. Cells immune to CRC were targeted for single-cell RNA-seq analysis to characterise cancer-specific Trm cells in CRC., Results: The number of CD103 + /CD8 + tumour-infiltrating lymphocytes (TILs) was a favourable prognostic and predictive factor of the overall survival and recurrence-free survival in patients with CRC. Single-cell RNA-seq analysis of 17,257 CRC-infiltrating immune cells revealed a more increased zinc finger protein 683 (ZNF683) expression in cancer Trm cells than in noncancer Trm cells and in high-infiltrating Trm cells than low-infiltrating Trm in cancer, with an upregulated T-cell receptor (TCR)- and interferon-γ (IFN-γ) signalling-related gene expression in ZNF683 + Trm cells., Conclusions: The number of CD103 + /CD8 + TILs is a prognostic predictive factor in CRC. In addition, we identified the ZNF683 expression as one of the candidate markers of cancer-specific Trm cells. IFN-γ and TCR signalling and ZNF683 expression are involved in Trm cell activation in tumours and are promising targets for cancer immunity regulation., (© 2023. The Author(s).)

Endoscopic resection is typically performed for early T1 stage colorectal cancer (T1 CRC). Additional surgery is subsequently recommended based on pathological findings; however, the current criteria may result in overtreatment. The present study aimed to re-examine the reported risk factors for lymph node (LN) metastasis in T1 CRC and develop a prediction model using a large multi-institutional dataset. In this retrospective study, the medical records of 1,185 patients with T1 CRC who underwent surgery between January 2008 and December 2020 were investigated. Slides pathologically re-assessable for additional risk factors were re-examined. A total of 251 patients with inadequate data were excluded, and 934 patients were randomly assigned at a ratio of 3:1 to the training and validation datasets. In the univariate analysis, left-sided CRC (P=0.003), deep submucosal invasion depth (P=0.005), poor histological grade (P=0.020), lymphatic invasion (P<0.001), venous invasion (P<0.001) and tumor budding grade 2/3 (P<0.001) were significant risk factors for LN metastasis. A nomogram predicting LN metastasis was developed using these variables, with an area under the received operating characteristic curve (AUC) of 0.786. The nomogram was validated using a validation set with an AUC of 0.721, indicating moderate accuracy. No LN metastases were observed in patients with <90 points using the nomogram; therefore, patients with a low nomogram score may avoid undergoing surgical resection. Prediction of LN metastasis using this developed nomogram may help identify patients who are at high-risk who require surgery., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023, Spandidos Publications.)

We aimed to identify combinations of clinical factors that predict heart failure (HF) onset using a novel limitless-arity multiple-testing procedure (LAMP). We also determined if increases in numbers of predictive combinations of factors increases the probability of developing HF. We recruited people without HF who received health check-ups in 2010, who were followed annually for 4 years. Using 32,547 people, LAMP was performed to identify combinations of factors of fewer than four factors that could predict the onset of HF. The ability of the method to predict the probability of HF onset based on the number of matching predictive combinations of factors was determined in 275,658 people. We identified 549 combinations of factors for the onset of HF. Then we classified 275,658 people into six groups who had 0, 1-50, 51-100, 101-150, 151-200 or 201-250 predictive combinations of factors for the onset of HF. We found that the probability of HF progressively increased as the number of predictive combinations of factors increased. We identified combinations of variables that predict HF onset. An increased number of matching predictive combinations for the onset of HF increased the probability of HF onset., (© 2023. The Author(s).)

Background: Local recurrence is common after curative resection for rectal cancer. Although one expects radical resection of locally recurrent rectal cancer to be curative, the postoperative re-recurrence rate is relatively high. Therefore, identifying risk factors for recurrence may improve the prognosis of locally recurrent rectal cancer with early therapeutic intervention., Objective: This study aimed to evaluate the relationship between perioperative serum CEA/carbohydrate antigen 19-9 levels and prognosis in locally recurrent rectal cancer to validate their usefulness for postoperative surveillance in locally recurrent rectal cancer., Design: This was a single-center retrospective cohort study., Setting: The study is based on data obtained from procedures at the Osaka University Hospital., Patients: Ninety patients underwent radical resection for locally recurrent rectal cancer between January 2000 and January 2015., Main Outcome Measures: We evaluated the correlation between perioperative serum CEA/carbohydrate antigen 19-9 levels and prognosis after complete resection of locally recurrent rectal cancer and the serum CEA and carbohydrate antigen 19-9 levels at the diagnosis of postoperative re-recurrence., Results: The median preoperative serum CEA level was 4 ng/mL and carbohydrate antigen 19-9 level was 12 U/mL. Of the 90 patients, 43.3% had serum CEA ≥5 ng/mL, and 15.6% had serum carbohydrate antigen 19-9 ≥37 U/mL. Preoperatively, this serum carbohydrate antigen 19-9 level strongly correlated with poorer prognoses regarding cancer-specific survival. Postoperatively, serum CEA ≥5 ng/mL significantly correlated with a worse prognosis. At the time of diagnosis of re-recurrence after resection of locally recurrent rectal cancer, 53.2% of patients had serum CEA ≥5 ng/mL, and 23.4% of patients had serum carbohydrate antigen 19-9 ≥37 U/mL., Limitations: The study was limited by its single-center retrospective design, an insufficient sample size, and a relatively long study period., Conclusions: High serum levels of carbohydrate antigen 19-9 preoperatively and CEA postoperatively are associated with poor prognosis after locally recurrent rectal cancer. Furthermore, we found a high rate of serum CEA elevation in the diagnosis of postoperative re-recurrence. See Video Abstract at http://links.lww.com/DCR/C106 ., Importancia Clnica De Los Niveles Sricos Preoperatorios Y Posoperatorios De Cea Y Ca En Pacientes Sometidos a Reseccin Curativa De Cncer De Recto Localmente Recurrente: ANTECEDENTES:La recurrencia local es común después de la resección curativa del cáncer de recto. Aunque se espera que la resección radical del cáncer rectal localmente recurrente sea curativa, la tasa de recurrencia posoperatoria es relativamente alta. Por lo tanto, la identificación de los factores de riesgo de recurrencia puede mejorar el pronóstico del cáncer de recto localmente recurrente con una intervención terapéutica temprana.OBJETIVO:Evaluamos la relación entre los niveles séricos perioperatorios de CEA/CA19-9 y el pronóstico en el cáncer de recto localmente recurrente para validar su utilidad para la vigilancia posoperatoria en el cáncer de recto localmente recurrente.DISEÑO:Este fue un estudio de cohorte retrospectivo de un solo centro.AJUSTE:El estudio se basa en datos obtenidos de procedimientos en el Hospital Universitario de Osaka.PACIENTES:Noventa pacientes fueron sometidos a resección radical por cáncer de recto localmente recurrente entre Enero de 2000 y Enero de 2015.PRINCIPALES MEDIDAS DE RESULTADOS:Evaluamos la correlación entre los niveles séricos perioperatorios de CEA/CA19-9 y el pronóstico después de la resección completa del cáncer de recto localmente recurrente y los niveles séricos de CEA y CA19-9 en el diagnóstico de recurrencia posoperatoria.RESULTADOS:La mediana de los niveles séricos preoperatorios de CEA y CA19-9 fueron de 4 ng/mL y 12 U/mL, respectivamente. De los 90 pacientes, el 43,3 % tenía CEA sérico ≥5 ng/mL y el 15,6 % tenía CA19-9 sérico ≥37 U/mL. Antes de la operación, este nivel sérico de CA19-9 se correlacionó fuertemente con peores pronósticos con respecto a la supervivencia específica del cáncer. Después de la operación, el CEA sérico ≥5 ng/mL se correlacionó significativamente con un peor pronóstico. En el momento del diagnóstico de recurrencia después de la resección del cáncer de recto localmente recurrente, el 53,2 % de los pacientes tenían CEA sérico ≥5 ng/mL y el 23,4 % de los pacientes tenían CA19-9 sérico ≥37 U/mL.LIMITACIONES:El estudio estuvo limitado por su diseño retrospectivo de un solo centro, un tamaño de muestra insuficiente y un período de estudio relativamente largo.CONCLUSIONES:Los niveles séricos altos de CA19-9 antes de la operación y de CEA después de la operación están asociados con un mal pronóstico después del cáncer de recto localmente recurrente. Además, encontramos una alta tasa de elevación del CEA sérico en el diagnóstico de recurrencia posoperatoria. Consulte el Video Resumen en http://links.lww.com/DCR/C106 . (Traducción-Dr. Yesenia Rojas-Khalil )., (Copyright © The ASCRS 2022.)

Background: In the EARLIER (Efficacy and Safety of Early Initiation of Eplerenone Treatment in Patients with Acute Heart Failure) trial, eplerenone did not reduce heart failure (HF) hospitalizations or all-cause mortality in 300 patients admitted for acute HF (AHF). However, the trial might have been underpowered for these endpoints, and a comprehensive overview of the effect of eplerenone on diuretic doses and patients' clinical stability is warranted., Methods: The EARLIER trial included Japanese patients hospitalized for AHF randomly assigned to eplerenone or placebo over 6 months. Cox proportional hazards and mixed-effects models were used for analyses., Results: Three hundred patients were included (mean age, 67 ± 13 years; 73% males). The median furosemide equivalent dose was 40 (20-62) mg at randomization. Patients with higher furosemide-equivalent doses had more severe signs and symptoms of congestion and a higher risk of all-cause mortality or HF hospitalization during 6-month follow-up (adjusted-hazard ratio per 10 mg/day increase = 1.25, 95% confidence interval: 1.05-1.49). Eplerenone significantly decreased furosemide-equivalent diuretic doses and b-type natriuretic levels throughout the follow-up (overall-joint-p < 0.05 for both) and reduced E/e' and inferior vena cava diameter at 4 weeks (both p < 0.05). Additionally, eplerenone significantly reduced left ventricular (LV) end-diastolic diameter at 24 weeks (p < 0.05)., Conclusions: Eplerenone treatment improved the clinical stability particularly during short period following hospitalization for AHF, translated by lower diuretic doses, natriuretic peptide levels, indirect markers of filling pressure and venous congestion, and a smaller LV volume., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Approximately 10% of patients with colorectal cancer with submucosal invasion have lymph node metastasis. Pathological risk factors for lymph node metastasis have varying sensitivities and specificities. To predict the risk of lymph node metastasis, the identification of new risk factors is vital. Tumor-infiltrating T cells have been reported to improve the prognosis of many solid tumors. Therefore, the purpose of this study was to examine the relationship between lymph node metastasis and tumor-infiltrating T cells in patients with colorectal cancer with submucosal invasion. We examined CD8 + tumor-infiltrating T cells level as a risk factor for lymph node metastasis in patients with colorectal cancer with submucosal invasion. Using immunohistochemical staining, we identified CD8 + T cells in surgically resected specimens from 98 patients with SM-CRC. We showed that low CD8 + tumor-infiltrating T cells levels are positively correlated with lymph node metastasis. Furthermore, by combining the number of CD8 + tumor-infiltrating T cell and the number of CD103 + tumor-infiltrating T cells, the results showed a high positive predictive value for lymph node metastasis in cases with low numbers of both types of tumor-infiltrating T cells and a high negative predictive value in cases with high numbers of both types of tumor-infiltrating T cells., (© 2023. Crown.)

Aims: To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients., Methods and Results: In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0-10.0% (42-86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), -0.0155-0.0182] mm and 0.0015 (95% CI, -0.0155-0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of -0.0001 mm (95% CI, -0.0191-0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [-0.1% (95% CI, -0.2-0.1); P = 0.359]., Conclusion: Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

With modern treatments for heart failure with reduced ejection fraction (EF), indicative of impaired cardiac systolic function, patients may exhibit an increase in EF. Limited data are available regarding the clinical management of this growing population, categorized as heart failure with improved EF (HFimpEF), which has a high event rate and has been excluded from virtually all prior heart failure outcomes trials. In a prespecified analysis of the DELIVER trial ( NCT03619213 ), of a total of 6,263 participants with symptomatic heart failure and a left ventricular EF >40%, 1,151 (18%) had HFimpEF, defined as patients whose EF improved from ≤40% to >40%. Participants were randomized to 10 mg dapagliflozin or placebo daily and the primary outcome of the trial was a composite of cardiovascular death or worsening heart failure (heart failure hospitalization or an urgent heart failure visit). Participants with HFimpEF had similar event rates to those with an EF consistently >40%. In participants with HFimpEF, dapagliflozin reduced the primary composite outcome (hazard ratio (HR) = 0.74, 95% confidence interval (CI) = 0.56-0.97), first worsening heart failure events (HR = 0.78, 95% CI = 0.61-1.14), cardiovascular death (HR = 0.62, 95% CI = 0.41-0.96) and total worsening heart failure events (rate ratio = 0.68, 95% CI = 0.50-0.94) to a similar extent as for individuals with an EF consistently >40%. These data suggest that patients with HFimpEF who are symptomatic may benefit from the addition of a sodium/glucose cotransporter 2 inhibitor to previously instituted guideline-directed medical therapy to further reduce morbidity and mortality., (© 2022. The Author(s).)

Aspirin loading (chewable or intravenous) as soon as possible after presentation is a class I recommendation by current ST elevation myocardial infarction (STEMI) guidelines. Earlier achievement of therapeutic antiplatelet effects by aspirin loading has long been considered the standard of care. However, the effects of the loading dose of aspirin (alone or in addition to a chronic maintenance oral dose) have not been studied. A large proportion of myocardial cell death occurs upon and after reperfusion (reperfusion injury). Numerous agents and interventions have been shown to limit infarct size in animal models when administered before or immediately after reperfusion. However, these interventions have predominantly failed to show significant protection in clinical studies. In the current review, we raise the hypothesis that aspirin loading may be the culprit. Data obtained from animal models consistently show that statins, ticagrelor, opiates, and ischemic postconditioning limit myocardial infarct size. In most of these studies, aspirin was not administered. However, when aspirin was administered before reperfusion (as is the case in the majority of studies enrolling STEMI patients), the protective effects of statin, ticagrelor, morphine, and ischemic postconditioning were attenuated, which can be plausibly attributable to aspirin loading. We therefore suggest studying the effects of aspirin loading before reperfusion on the infarct size limiting effects of statins, ticagrelor, morphine, and/ or postconditioning in large animal models using long reperfusion periods (at least 24 h). If indeed aspirin attenuates the protective effects, clinical trials should be conducted comparing aspirin loading to alternative antiplatelet regimens without aspirin loading in patients with STEMI undergoing primary percutaneous coronary intervention., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To assess pain management in patients post-sacrectomy, focusing on opioid use, and to identify the factors associated with postoperative pain., Methods: Patients who underwent resection of locally recurrent rectal cancer (LRRC) with concomitant sacrectomy at one of two hospitals between 2007 and 2020 were reviewed retrospectively. We examined the use of opioids preoperatively and postoperatively. Patients were classified into high and low sacrectomy groups based on the sacral bone resection level passing through the S3 vertebra., Results: Sixty-four patients were enrolled. Opioid use was significantly higher in the high sacrectomy group than in the low sacrectomy group at all times assessed: on postoperative days 7, 14, 30, 90, 180, and 365. Opioid use 3 months after locally recurrent rectal cancer surgery was significantly higher in patients with local re-recurrence of the tumor than in those without re-recurrence (p < 0.05), and the median morphine-equivalent opioid use 3 months postoperatively was significantly higher in the high sacrectomy group (30 vs. 0 mg/day; p < 0.05)., Conclusions: Opioid use after concomitant sacrectomy for LRRC was higher in the high sacrectomy group. Prolonged postoperative pain or increasing pain was associated with local recurrence., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Frailty is increasing in prevalence. Because patients with frailty are often perceived to have a less favorable risk/benefit profile, they may be less likely to receive new pharmacologic treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure with mildly reduced or preserved ejection fraction randomized in DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure)., Methods: Frailty was measured using the Rockwood cumulative deficit approach. The primary end point was time to a first worsening heart failure event or cardiovascular death., Results: Of the 6263 patients randomized, a frailty index (FI) was calculable in 6258. In total, 2354 (37.6%) patients had class 1 frailty (FI ≤0.210; ie, not frail), 2413 (38.6%) had class 2 frailty (FI 0.211-0.310; ie, more frail), and 1491 (23.8%) had class 3 frailty (FI ≥0.311; ie, most frail). Greater frailty was associated with a higher rate of the primary end point (per 100 person-years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7; P <0.001). The effect of dapagliflozin (as a hazard ratio) on the primary end point from FI class 1 to 3 was 0.85 (95% CI, 0.68-1.06), 0.89 (0.74-1.08), and 0.74 (0.61-0.91), respectively ( P interaction =0.40). Although patients with a greater degree of frailty had worse Kansas City Cardiomyopathy Questionnaire scores at baseline, their improvement with dapagliflozin was greater than it was in patients with less frailty: placebo-corrected improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score at 4 months in FI class 1 was 0.3 (95% CI, -0.9 to 1.4); in class 2, 1.5 (0.3-2.7); and in class 3, 3.4 (1.7-5.1; P interaction =0.021). Adverse reactions and treatment discontinuation, although more frequent in patients with a greater degree of frailty, were not more common with dapagliflozin than with placebo irrespective of frailty class., Conclusions: In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with a higher level of frailty., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03619213.

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain., Methods: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis., Results: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups., Conclusions: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.)., (Copyright © 2022 Massachusetts Medical Society.)

Background and Aims: Recognition of heart failure with preserved ejection fraction (HFpEF) at an early stage in mass screening is desirable, but difficult to achieve. We examined whether the fibrosis (Fib)-4 index, a simple index of liver stiffness/fibrosis, could be used as a screening tool to select candidates requiring expert diagnostics., Methods: Individuals who participated in annual health checks between 2006 and 2007 in Arita-cho, Saga, Japan, with no history of cardiovascular disease and EF ≥ 50% were enrolled (total 710; 258 men; median age, 59 years)., Results: Participants were divided into 5 groups according to HFpEF risk: 215 (30%), 100 (14%), 171 (24%), 163 (23%), and 61 (9%) with Heart Failure Association (HFA)-PEFF scores of 0, 1, 2, 3, and 4-6 points, respectively. The highest HFpEF risk group (HFA-PEFF score, 4-6 points) showed poor prognosis for the clinical events of all-cause mortality and hospitalization for HF (log-rank test, P  = .002). The Fib-4 index was correlated with HFpEF risk stratification (r s  = 0.526), and increment in the Fib-4 index was independently linked to high HFpEF risk by multiple logistic regression analysis (adjusted odds ratio, 1.311; 95% confidence interval, 1.078-1.595; P  = .007). The Fib-4 index stratified clinical prognosis (log-rank test, P < .001) was an independent predictor of all-cause mortality and hospitalization for HF (hazard ratio, 1.305; 95% confidence interval, 1.139-1.495; P < .001)., Conclusion: The Fib-4 index can be used to select appropriate candidates for a detailed examination of HFpEF in a subclinical population., (© 2023 The Authors.)

Objectives: The cornerstone of treating colorectal cancer (CRC) is generally a surgical resection with lymph node (LN) dissection. The tools for predicting lymph node metastasis (LNM) in submucosal (SM) CRC are useful to avoid unnecessary surgical resection., Methods: Retrospectively, we analyzed 526 consecutive patients with SM CRC who underwent surgical resection at the Osaka International Cancer Institute, Osaka University Hospital, and Minoh City Hospital, Japan, between 1984 and 2012. The Osaka International Cancer Institute group and the Osaka University Hospital group were randomly divided into a training set and a test set of 2:1. The prediction model was validated in Minoh City Hospital., Results: We partitioned patients using three risk factors involved in the presence or absence of LNM in SM CRC: lymphatic invasion (Ly), budding grade (BD) and the depth of submucosal invasion (DSI) (cut-off value 2789 μm) that were significantly different in the multivariate analysis. As a result, a predictive model of "LNM <5%" when "Ly negative and DSI <2789 μm" was evaluated. We similarly partitioned by DSI 3000 μm as easy-to-evaluate values in clinical use. We developed the additional model for predicting LNM is 1.05%, that is, LNM <5%, when there are "Ly negative and DSI <3000 μm.", Conclusions: As a limitation, only patients who underwent surgical resection were included in this study. This predictive model could help clinicians and CRC patients decide on the additional surgery required after endoscopic resection., Competing Interests: Conflicts of Interest There are no conflicts of interest., (Copyright © 2022 by The Japan Society of Coloproctology.)

Hypertension is a major risk factor for cardiovascular diseases, and behavior modification has been shown to improve blood pressure (BP). We investigated whether daily self-monitoring of systemic BP and other factors related to cardiovascular events decreased BP in hypertensive participants. In this prospective, randomized, open, blinded-endpoint trial, we assigned 161 participants with hypertension to monitor their BP daily (BP-measurement group) or, in addition to BP, monitor their body fat, sleeping time, and daily step count (multiple-measurement group) or no self-monitoring (control group) for 2 months. The primary endpoint was the absolute change in systolic BP from baseline to 2 months after assignment. There were no differences in the baseline age and gender ratios among the three groups. After 2 months, systolic BP in the morning was unchanged in the control group, at a median of 149 mmHg [interquartile range (IQR) 136-164] from 150 mmHg (IQR 138-164), and was significantly decreased to 139 mmHg (IQR 125-148) from 142 mmHg (IQR 131-157) in the BP-measurement group. BP did not further decrease in the multiple-measurement group, 134 mmHg (IQR 121-146) from 141 mmHg (IQR 131-157). Daily self-monitoring of BP decreased the BP of participants with hypertension, but additional daily self-monitoring of body fat, sleeping time, and daily step count did not further decrease BP. This behavior modification merits use as a nonpharmacological hypertension treatment., (© 2021. Springer Japan KK, part of Springer Nature.)