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Pancreatic cancer remains a highly lethal disease, largely attributed to the rapid development of resistance against standard chemotherapy regimens. Although an acidic tumor microenvironment (TME) has been implicated in this resistance, the molecular mechanisms involved are not fully understood. In this study, we identified Family with Sequence Similarity 111 Member B (FAM111B) as significantly upregulated in pancreatic cancer cells under acidic conditions through RNA sequencing and validated. Functional analyses revealed that FAM111B regulates intracellular pH (pHi). Moreover, combining gemcitabine with α‐cyano‐4‐hydroxycinnamic acid, a lactate transporter inhibitor known to decrease pHi, markedly suppressed pancreatic cancer cell viability compared to gemcitabine alone, thereby enhancing the sensitivity under acidic conditions in both in vitro and in mouse xenograft models. Clinically, elevated FAM111B expression correlated with significantly poorer overall survival in pancreatic cancer patients receiving gemcitabine‐based chemotherapy (median OS: 2.05 vs. 3.66 years, p = 0.038). Multivariate analysis identified FAM111B expression as an independent predictor of poor prognosis (HR = 3.05, p = 0.032). These findings highlight the crucial role of FAM111B in maintaining pHi homeostasis under acidic TME conditions and contributing to gemcitabine resistance. Targeting FAM111B may represent a novel therapeutic strategy to overcome chemotherapy resistance and improve clinical outcomes in pancreatic cancer. Family with Sequence Similarity 111 Member B (FAM111B), cysteine/serine peptidase with molecular targets, are upregulated under acidic conditions. FAM111B suppression increased the sensitivity to gemcitabine through intracellular pH regulation. Moreover, FAM111B expression is correlated with poorer overall survival in pancreatic cancer patients.

Cell-based therapy using adipose-derived stem cells (ADSCs) has emerged as a novel therapeutic approach to treat heart failure after myocardial infarction (MI). The purpose of this study was to determine whether inhibition of α1-adrenergic receptors (α1-ARs) in ADSCs attenuates ADSC sheet-induced improvements in cardiac functions and inhibition of remodeling after MI. ADSCs were isolated from fat tissues of Lewis rats. In in vitro studies using cultured ADSCs, we determined the mRNA levels of vascular endothelial growth factor (VEGF)-A and α1-AR under normoxia or hypoxia and the effects of norepinephrine and an α1-blocker, doxazosin, on the mRNA levels of angiogenic factors. Hypoxia increased α1-AR and VEGF mRNA levels in ADSCs. Norepinephrine further increased VEGF mRNA expression under hypoxia; this effect was abolished by doxazosin. Tube formation of human umbilical vein endothelial cells was promoted by conditioned media of ADSCs treated with the α1 stimulant phenylephrine under hypoxia but not by those of ADSCs pretreated with phenylephrine plus doxazosin. In in vivo studies using rats with MI, transplanted ADSC sheets improved cardiac functions, facilitated neovascularization, and suppressed fibrosis after MI. These effects were abolished by doxazosin treatment. Pathway analysis from RNA sequencing data predicted significant upregulation of α1-AR mRNA expression in transplanted ADSC sheets and the involvement of α1-ARs in angiogenesis through VEGF. In conclusion, doxazosin abolished the beneficial effects of ADSC sheets on rat MI hearts as well as the enhancing effect of norepinephrine on VEGF expression in ADSCs, indicating that ADSC sheets promote angiogenesis and prevent cardiac dysfunction and remodeling after MI via their α1-ARs.

Background The Japanese registry for mechanical assisted circulatory support (J-MACS) is a prospective registry to collect all data of implantable left ventricular assist device (LVAD) (and part of paracorporeal VAD) established in 2010. The first analytical report was published in 2017. The organization running J-MACS was used to be the pharmaceuticals and medical devices agency (PMDA), but has been changed to the council for clinical use of ventricular assist device related academic societies in 2017. Methods Since 2018, we changed the analytical methods as follows: first, we eliminated paracorporeal VAD from the analysis. Second, we included not only primary implantation but bridge to bridge (BTB) implantation of LVAD. Third, we added the analyses of adverse events that were not included in the previous analysis. Results As of Oct 2018, 711 primary LVAD implants and 168 BTB implants were enrolled. Survival rate of primary LVAD was 93% at 360 days and 91% at 720 days, and that of BTB was 86% at 360 days and 82% at 720 days. Conclusion We first reported the results of BTB in the second official report of J-MACS. The prognosis after LVAD implantation has been kept good in Japanese circumstances.

Transcatheter aortic valve replacement (TAVR) has revolutionized the prognosis of intermediate- or high-risk patients with severe aortic stenosis, particularly among older adults. However, in possible candidates for surgical aortic valve replacement (SAVR), the implantation of expensive prostheses may be questionable in an era when healthcare costs are becoming a major concern. In this retrospective analysis of a single Japanese center, we focused on patients aged over 80 years; the objectives of this study were: (1) to compare TAVR and SAVR in terms of total hospitalization costs and (2) to describe the itemized cost of TAVR and SAVR to identify patients aged over 80 years in whom TAVR or SAVR would be cost-effective. A total of 146 patients aged over 80 years who underwent TAVR or SAVR for severe aortic stenosis were included. These patients were divided into a high-risk group (Society of Thoracic Surgeons [STS] mortality score > 8%; 36: TAVR and 12: SAVR) with 48 patients and a non-high-risk group (STS mortality score < 8%; 45: TAVR and 53 SAVR) with 98 patients. No 30-day mortality was observed in either group. In both groups, postoperative intensive care unit stay and hospital stay were longer with SAVR than with TAVR. In the non-high-risk group, the total cost was comparable for TAVR and SAVR; however, in the high-risk group, the total cost was significantly higher with SAVR than that with TAVR. A breakdown analysis of the total cost in the high-risk group showed both pre- and postoperative costs to be significantly higher with SAVR than with TAVR; however, operative costs were higher with TAVR. Up to 3 years, the overall survival in both groups did not significantly differ between TAVR and SAVR. Our findings suggest that from the perspective of total medical costs, TAVR is more suitable than SAVR for high-risk older adults.

PurposeThe purpose of this study was to investigate the impact of frailty on the clinical outcomes of hybrid aortic arch repair with debranching of the supra-aortic arteries.MethodsConsecutive patients ≥ 75 years old who underwent hybrid aortic arch repair from January 2010 to December 2019 were retrospectively analyzed. Using the Canadian Study of Health and Aging (CSHA) scale, all patients with a CSHA scale score > 4 were defined as frail. The frail patients (FP) group and the non-frail patients (NFP) group were compared regarding the early and mid-term outcomes of hybrid aortic arch repair.ResultsA total of 84 patients were included. The early postoperative results were not markedly different between the groups, except that the rate of transfer to a rehabilitation hospital was higher in the FP group than in the NFP group. The survival at 5 years was significantly lower in the FP group at 43.0% than in the NFP group at 67.7% (P = 0.015). However, the freedom from aorta-related death was not significantly different between the two groups.ConclusionFrailty did not affect the short-term outcomes of hybrid aortic arch repair; however, the mid-term outcomes, including the survival, of the frail patients were significantly worse than those of the non-frail patients, mostly because of non-aorta-related causes.

Robotically assisted mitral valve repair was approved by the Japanese government in April 2018. However, understanding robotic surgery involves steep learning curves of surgeons and dedicated cardiac teams. The Center for Minimally Invasive Surgery (CMIS) of Tottori University Hospital is a multidisciplinary organization established in 2011 with seven surgical departments. In this study, we report strategies for improving the safety of robotic surgery in the CMIS and early results of robotic mitral valve repair at our hospital. We reviewed the first 20 patients who underwent robotic primary mitral valve repair, including concomitant procedures, from October 2019 to September 2021 under the supervision of the CMIS. Before starting the program, the CMIS requires setting console time limit to 180 min and implementing risk management strategies through simulation training for various mechanical failures. Mitral valve repair was completed in all patients. There was no in-hospital or 30-day mortality. No conversion to median sternotomy was necessary. The analysis of mitral pathology revealed 1 case of functional mitral regurgitation, 12 cases of posterior lesions, 3 cases of anterior lesions, 3 cases of bileaflet lesions, and 1 case of commissural lesion. The average cross-clamp time was 133 ± 27 min. Sixteen cases had trace mitral regurgitation postoperatively, and 4 cases had mild mitral regurgitation. The median (interquartile range) postoperative hospital stay was 10 (8.5–12.5) days. Robotically assisted mitral valve repair was performed safely with assistance from the multidisciplinary CMIS, and the early results were satisfactory without compromising clinical outcomes.

Aims/Introduction We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P < 0.001 and hazard ratio 0.53, 95% confidence interval 0.28–0.998, P < 0.05, respectively). The incidence of adverse events was not different between treatment groups. Conclusions The risk of kidney events tended to decrease by IT, although it was not statistically significant. Lipid control using statin was associated with a lower risk of adverse kidney events. Further follow‐up study might show the effect of IT in patients with advanced diabetic kidney disease. The Diabetic Nephropathy Remission and Regression Team Trial in Japan was designed to clarify the beneficial effects of multifactorial intensified intervention by the team approach with medical staffs at each institution. There was an overall trend toward a lower risk on the development of kidney events in the intensive treatment group than in the conventional treatment group in this trial, but the benefit of intensive treatment could not be confirmed statistically. Lipid control by statin was associated with lower risk of kidney events in addition to strict control of blood glucose and blood pressure.

PurposeTolvaptan administration in the early postoperative period after cardiac surgery rapidly treats fluid retention without affecting the renal function. Tolvaptan also has the benefit of not stimulating the renin–angiotensin and sympathetic nervous systems, which are risk factors for postoperative paroxysmal atrial fibrillation. In this study, we examined the hypothesis that tolvaptan administration reduces postoperative paroxysmal atrial fibrillation and worsening of the renal function incidence in patients who have undergone open-heart surgery.MethodsFrom our previous randomized study, we selected 166 open-heart surgery patients, divided them into 2 groups [tolvaptan group, 83 patients; control (non-tolvaptan) group, 83 patients], and compared the incidence of postoperative paroxysmal atrial fibrillation and worsening of the renal function in the postoperative period between the groups.ResultsThe incidence of worsening of the renal function was significantly lower in the tolvaptan group than in the control group (4.8% vs. 15.7%; P = 0.04). The incidence of postoperative paroxysmal atrial fibrillation within 14 days was also significantly lower in the tolvaptan group than in the control group (26.5% vs. 42.2%; P = 0.011).ConclusionTolvaptan administration in the early postoperative period after open-heart surgery may reduce the incidence of postoperative paroxysmal atrial fibrillation and worsening of the renal function.

BackgroundSeveral clinical parameters and pathological findings are known to be predictors of the deterioration of diabetic nephropathy (DN). Glomerular basement membrane duplication (GBM-DP) is a pathological feature representing endothelial injury, which is commonly observed in DN. In the present study, we investigated the association between GBM-DP and the renal prognosis in DN.MethodsThe study enrolled 80 patients with renal biopsy-proven DN who were managed at Chiba-East Hospital from 2005 to 2012. We confirmed the pathological findings according to the Renal Pathology Society classifications, and we further evaluated the GBM-DP, which was defined as double contours of the GBM that expanded more than 10% of capillary loops in the most affected nonsclerotic glomerulus. We used Cox regression models to estimate hazard ratios (HRs) for end-stage renal disease (ESRD), with adjustment for age, sex, systolic blood pressure, HbA1c, estimated glomerular filtration rate (eGFR), and urinary protein excretion (UP) at baseline.ResultsOf the 80 patients, 56 were male (70.0%) and the mean age was 59.1 years. The median eGFR and UP were 42 ml/min/1.73 m2 (IQR 30, 59) and 3.1 g/gCr (IQR 1.2, 5.2). Twenty-seven patients progressed to ESRD and one patient died during the median observational period of 2.9 years (IQR 1.5, 4.3). The multivariable analyses showed that GBM-DP was significantly associated with ESRD (HR 3.18 [95% confidence interval (CI): 1.02–9.87], p = 0.045).ConclusionWe newly identified GBM-DP as a strong prognostic predictor in DN patients. Further study is needed to clarify the pathogenic mechanism of GBM-DP in DN.

Background We examined the outcome of debranching thoracic endovascular aortic repair (d-TEVAR) without sternotomy for distal aortic arch aneurysm in patients aged ≥75 years. Methods Patients who underwent d-TEVAR or TAR for aortic arch aneurysm between 2008 and 2015 at our hospital and aged ≥75 years were included. Age, sex, left ventricular ejection fraction, preoperative creatinine level, diabetes, cerebrovascular disease, and chronic obstructive pulmonary disease were matched using PS. Results Among 74 patients (d-TEVAR: 51, TAR: 23), 17 patients in each group were matched. No difference in surgical outcome was detected between the d-TEVAR and TAR groups, including 30-day death (0% vs. 0%), hospital death (5.8% vs. 0%: p  = 0.31) and incidence of cerebral infarction (5.8% vs. 7.6%: p  = 0.27) as well as the long-term outcomes of 5-year survival (92.8% vs. 74.8%: p  = 0.30) and 5-year aorta-related event-free rate (88.2% vs. 100%: p  = 0.15). Average duration of ICU stay (1.3 ± 1.1 days vs. 5.6 ± 1.3 days: p  = 0.025) and hospital stay (16.5 ± 5.2 days vs. 37.7 ± 19.6 days: p  = 0.017) were significantly shorter in the d-TEVAR group. Conclusion Our results indicated that d-TEVAR is less invasive without affecting long-term outcome up to 5 years. Although the number of the patients included in the study was small, debranching TEVAR could be one of the treatments of the choice in the elderly, especially with comorbidities.