Cardiac arrest and post-discharge mortality in patients with myocardial infarction: A large-scale nationwide registry analysis.

Background: Cardiac arrest is a serious complication of acute myocardial infarction. The implementation of contemporary approaches to acute myocardial infarction management, including urgent revascularization procedures, has led to significant improvements in short-term outcomes. However, the extent of post-discharge mortality in patients experiencing cardiac arrest during acute myocardial infarction remains uncertain. This study aimed to determine the post-discharge outcomes of patients with cardiac arrest. Methods: We analysed data from the J-PCI OUTCOME registry, a Japanese prospectively planed, observational, multicentre, national registry of percutaneous coronary intervention involving consecutive patients from 172 institutions who underwent percutaneous coronary intervention and were discharged. Patients who underwent percutaneous coronary intervention for acute myocardial infarction between January 2017 and December 2018 and survived for 30 days were included. Mortality in patients with and without cardiac arrest from 30 days to 1 year after percutaneous coronary intervention for acute myocardial infarction was compared. Results: Of the 26,909 patients who survived for 30 days after percutaneous coronary intervention for acute myocardial infarction, 1,567 (5.8%) had cardiac arrest at the onset of acute myocardial infarction. Patients with cardiac arrest were younger and more likely to be males than patients without cardiac arrest. The 1-year all-cause mortality was significantly higher in patients with cardiac arrest than in those without (11.9% vs. 2.8%, p < 0.001) for all age groups. Multivariable analysis showed that cardiac arrest was an independent predictor of all-cause long-term mortality (hazard ratio: 2.94; 95% confidence interval: 2.29-3.76). Conclusions: Patients with acute myocardial infarction and concomitant cardiac arrest have a worse prognosis for up to 1 year after percutaneous coronary intervention than patients without cardiac arrest.

Spatial and single-cell colocalisation analysis reveals MDK-mediated immunosuppressive environment with regulatory T cells in colorectal carcinogenesis.

BACKGROUND: Cell-cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival. METHODS: We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell-cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients. FINDINGS: CRC cells colocalised with regulatory T cells (Tregs) at the adenoma-carcinoma interface. At early-stage carcinogenesis, cell-cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients. INTERPRETATION: MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC. FUNDING: Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund.

Utility of new FDG-PET/CT guidelines for diagnosing cardiac sarcoidosis in patients with implanted cardiac pacemakers for atrioventricular block.

Diagnosing cardiac sarcoidosis (CS), especially in isolated cases, is challenging, particularly due to the limitations of endomyocardial biopsy, leading to potential undiagnosed cases in pacemaker-implanted patients. This study aims to provide real world findings to support new guideline for CS using 18F-fluoro-deoxyglucose positron-emission tomography computed tomography (FDG-PET/CT) which give a definite diagnosis of isolated CS (iCS) without histological findings. We examined consecutive patients with cardiac pacemakers for atrioventricular block (AV-b) attending our outpatient pacemaker clinic. The patients underwent periodical follow-up echocardiography and were divided into two groups according to echocardiographic findings: those with suspected CS and those without suspected CS. Patients suspected of having nonischemic cardiomyopathy underwent FDG-PET/CT for CS diagnosis. We investigated the utility of the new guideline for CS using FDG-PET/CT. Among the 272 patients enrolled, 97 patients were implanted with cardiac pacemakers for AV-b. Twenty-two patients were suspected of having CS during a median observation period of 5.4 years after pacemaker implantation. Of these, one did not consent, and nine of 21 cases (43%) were diagnosed with definite CS according to the new guidelines. Five of these nine patients were diagnosed with iCS using FDG-PET/CT. The number of patients diagnosed with definite CS using the new guidelines tended to be approximately 2.3 times that of the conventional criteria (p = 0.074). Three of the nine patients underwent steroid treatment. The composite outcome, comprising all-cause death, heart failure hospitalization, and a substantial reduction in left ventricular ejection fraction, were significantly lower in patients receiving steroid treatment compared to those without steroid treatment (p = 0.048). The utilization of FDG-PET/CT in accordance with the new guidelines facilitates the diagnosis of CS, including iCS, resulting in approximately 2.3 times as many diagnoses of CS compared to the conventional criteria. This guideline has the potential to support the early identification of iCS and may contribute to enhancing patient clinical outcomes.

Tumor suppressive role of the epigenetic master regulator BRD3 in colorectal cancer.

Bromodomain and extraterminal domain (BET) family proteins are epigenetic master regulators of gene expression via recognition of acetylated histones and recruitment of transcription factors and co-activators to chromatin. Hence, BET family proteins have emerged as promising therapeutic targets in cancer. In this study, we examined the functional role of bromodomain containing 3 (BRD3), a BET family protein, in colorectal cancer (CRC). In vitro and vivo analyses using BRD3-knockdown or BRD3-overexpressing CRC cells showed that BRD3 suppressed tumor growth and cell cycle G1/S transition and induced p21 expression. Clinical analysis of CRC datasets from our hospital or The Cancer Genome Atlas revealed that BET family genes, including BRD3, were overexpressed in tumor tissues. In immunohistochemical analyses, BRD3 was observed mainly in the nucleus of CRC cells. According to single-cell RNA sequencing in untreated CRC tissues, BRD3 was highly expressed in malignant epithelial cells, and cell cycle checkpoint-related pathways were enriched in the epithelial cells with high BRD3 expression. Spatial transcriptomic and single-cell RNA sequencing analyses of CRC tissues showed that BRD3 expression was positively associated with high p21 expression. Furthermore, overexpression of BRD3 combined with knockdown of, a driver gene in the BRD family, showed strong inhibition of CRC cells in vitro. In conclusion, we demonstrated a novel tumor suppressive role of BRD3 that inhibits tumor growth by cell cycle inhibition in part via induction of p21 expression. BRD3 activation might be a novel therapeutic approach for CRC.

Metastasis of cervical cancer indicated by elevation of serum CA125 produced by mediastinal lymph nodes: a case report.

BACKGROUND: In patient assessment for recurrence of neoplasia, a biomarker that shows an elevated serum value before the first treatment is a candidate for follow-up examination. The biomarker squamous cell carcinoma antigen is usually utilized for follow-up of squamous cell cancer of the cervix. CASE PRESENTATION: We herein report a 30-year-old Japanese woman of postoperative metastasis of cervical squamous cell cancer to the mediastinal and supraclavicular lymph nodes as indicated by an elevated serum cancer antigen 125 concentration and not by the squamous cell carcinoma antigen value. After chemoradiotherapy and chemotherapy, the serum cancer antigen 125 concentration decreased to a normal value. Squamous cell carcinoma antigen was found to be distributed in both the squamous cell cancer tissue of the cervix and the supraclavicular lymph node metastatic tissue. By contrast, cancer antigen 125 was distributed in the supraclavicular lymph node metastatic tissue but not in the original squamous cell cancer tissue of the cervix. CONCLUSION: In this case, metastasis of cervical cancer to the mediastinal and supraclavicular lymph nodes was shown by the biomarker cancer antigen 125, which was not present in the original neoplasia.

Mediastinal hematoma as an unusual intrathoracic manifestation of Boerhaave Syndrome: A case report.

INTRODUCTION: Boerhaave Syndrome (BS) is rare but life-threatening condition caused by a sudden increase in the intraluminal pressure due to vomiting. We present a case of BS manifesting as a posterior mediastinal hematoma, indicative of a potentially fatal condition. PRESENTATION OF CASE: A 51-year-old man presented with acute chest pain after vomiting. Enhanced Computed Tomography revealed mediastinal fluid with a left pleural effusion, leading to a diagnosis of BS. Emergency surgery revealed a posterior mediastinal hematoma with active bleeding due to a torn proper esophageal artery. Hemostasis and a wall repair were performed, and the patient was discharged uneventfully. DISCUSSION: This case highlights two important aspects. Firstly, a spontaneous esophageal perforation can manifest as a mediastinal hematoma due to the subpleural arterial injury, delaying bacterial spillage. While preoperative thoracentesis may not always diagnose BS accurately, bloody thoracic drainage can serve as an alternative diagnostic sign. Secondly, the mediastinal hematoma itself poses a serious risk, as it can lead to a catastrophic outcome even before bacterial contamination occurs, emphasizing the necessity of a timely surgical intervention in BS cases. CONCLUSION: BS can manifest as a mediastinal hematoma, and the absence of gastrointestinal content in the thoracic drainage does not rule out the possibility of BS. Prompt surgical intervention remains essential, as a mediastinal hematoma alone can result in a catastrophic outcome. This case highlights the significance of a comprehensive diagnostic assessment for BS.

Chronic Clinical Findings after Rheocarna® Therapy in a Chronic Limb-threatening Ischemia Patient with Inframalleolar Lesions: A Case Report.

An 87-year-old man was referred to our hospital for non-healing ulcers on the right third, fourth, and fifth toes. The patient was diagnosed with chronic limb-threatening ischemia. Pre-treatment angiography of the right lower extremity revealed inframalleolar lesions. We failed to perform endovascular treatment because of severe calcification. Therefore, we treated the patient with a novel low-density lipoprotein apheresis device (Rheocarna®; Kaneka Corporation, Osaka, Japan). Angiography performed four days after therapy revealed significant improvement in microcirculation. One year after therapy, he managed to avoid major amputation and achieve wound healing. In addition, angiography revealed that the microcirculation was maintained.

PIVKA­II is associated with liver function, bone metabolism, and muscle function in patients with liver disease.

Protein induced by vitamin K (VK) absence-II (PIVKA-II) is a sensitive marker for diagnosing hepatoma but is occasionally detected in patients without hepatoma Here, the clinical significance of serum PIVKA-II levels in patients who were not administered warfarin and did not have hepatoma or liver disease were evaluated. As VK is related to muscle and bone metabolism, PIVKA-II and clinical factors related to bone and muscle were compared. A total of 441 patients with various liver diseases were evaluated. Of these, 236 patients were female. Clinical factors and anthropometric measurements were obtained for each participant during outpatient visits. Among the clinical factors, type I procollagen N-propeptide (P1NP), a low titer of undercarboxylated osteocalcin (ucOC), and 25(OH) vitamin D (VD) were used as bone metabolic markers, and SARC-F and grip strength were used as muscle-related markers. Serum PIVKA-II levels above the upper limit were associated with Child B/C (Child-Pugh score), high titers of total P1NP, and low titers of ucOC in females, and alcohol-related liver disease and low VD in males. The titer of PIVKA-II were associated with immunoglobulin (Ig) A and prothrombin time (PT)-international normalized ratio (INR) in females, and fibrosis-4-4, IgG, total bilirubin, PT-INR, and SARC-F in males. Elevated PIVKA-II levels were associated with abnormal bone physiology in females, weak muscles in males, and severe liver disease in both sexes. Assessing PIVKA-II may assist in evaluating the clinical and bone-muscle metabolic stages in liver disease. Nutrition and supplementation with fat-soluble vitamins, including VK and VD may thus serve as a potential method to alleviate or prevent bone-muscle pathophysiology in patients with liver disease.

Impact of general anesthesia on ablation catheter stability during pulmonary vein isolation based on a novel measurement approach.

Catheter ablation for atrial fibrillation (AF) during pulmonary vein isolation (PVI) is performed under general anesthesia (GA) or conscious sedation (CS). GA during PVI may improve treatment outcomes by improving catheter stability. However, the magnitude of GA-derived catheter stability compared with that of CS is unclear. We directly assessed catheter movement and determined the impact of GA compared with that of CS on ablation catheter stability during PVI. Patients who underwent initial ablation using the EnSite Precision™ mapping system were recruited and divided into two groups (GA and CS groups). The two groups were compared for ablation catheter stability during PVI based on the distance traveled by the catheter distal tip per second, clinical periprocedural characteristics, and periprocedural complications. Among 69 consecutively admitted patients, data of 30 patients (17 in the GA group and 13 in the CS group) and the distance traveled per second by the catheter on 148,976 points/patient were evaluated. The GA group had a significantly smaller catheter tip travel distance than the CS group (0.92 [0.82‒1.16] vs. 1.25 [1.14‒1.38], p = 0.01). Therefore, GA during PVI for AF provides greater catheter stability than CS and will contribute to more accessible and safer PVI procedures.

Successful multidisciplinary treatment with complete response to atezolizumab plus bevacizumab in a 90-year-old patient with hepatocellular carcinoma recurrence.

Atezolizumab plus bevacizumab is the first-line regimen in Japan for hepatocellular carcinoma following the results of the IMbrave 150 trial. However, the safety and efficiency of atezolizumab plus bevacizumab in older patients, especially in the oldest-old patients aged over 80 years, have not been thoroughly studied and is still controversial. Eighteen months ago, a 90-year-old woman underwent a laparoscopic hepatectomy (S6) for her primary hepatocellular carcinoma (S6, 2 cm). Nine months after the first surgery, she received transcatheter arterial chemoembolization treatment for solitary hepatocellular carcinoma recurrence (S8, 2 cm). The subsequent recurrence (S3, 1 cm; S5, 2 cm; S8, 1 cm) was uncovered by radiological assessment 1 year after transcatheter arterial chemoembolization treatment. We then initiated chemotherapy treatment with lenvatinib at 8 mg daily. Despite reducing the lenvatinib dosage, the adverse event of severe fatigue and asitia did not resolve; therefore, the regimen of atezolizumab + bevacizumab combination therapy was changed to be started. After the first 2 months, tumor regression was observed on computed tomography; the patient tolerated the atezolizumab + bevacizumab combination regimen over 8 months for 10 cycles without any adverse effects. She finally showed a complete response; no recurrence developed 1 year after the complete response. Therefore, older adult patients may benefit highly from atezolizumab plus bevacizumab with appropriate patient selection.

Tumor Microenvironment Landscape of NSCLC Reveals Resistance Mechanisms for Programmed Death-Ligand 1 Blockade After Chemoradiotherapy: A Multicenter Prospective Biomarker Study (WJOG11518L:SUBMARINE).

INTRODUCTION: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE). METHODS: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers. RESULTS: The importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocyte density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17-14.04] for CD8+ tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity. CONCLUSIONS: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.

An infant with a vertical vein aneurysm in a supracardiac totally anomalous pulmonary venous connection.

Massive vertical vein aneurysm in a supracardiac total anomalous pulmonary venous connection is rare. Herein, vertical vein aneurysm with total anomalous pulmonary venous connection and additional pathological findings are reported in a young child.

Association between coronary flow and aortic stenosis during transcatheter aortic valve implantation.

AIMS: In patients with aortic stenosis (AS), the coronary flow reserve decreases even in the absence of epicardial coronary artery stenosis. Systolic coronary flow reversal (SFR) reflecting reduced coronary microcirculation, often seen in patients with severe AS, has a potential negative impact on the pathogenesis of cardiac dysfunction. However, there are limited data on the relationship between the severity of AS and SFR, as well as on the benefits of transcatheter aortic valve implantation (TAVI). The aim of this study was to evaluate the relationship between the severity of AS and efficacy of TAVI in improving SFR. METHODS AND RESULTS: Consecutive patients with AS who had undergone TAVI using transoesophageal echocardiography (TEE) from November 2020 to February 2022 were prospectively enrolled. Coronary flow in the left anterior descending artery as well as the aortic valve peak velocities, and the mean aortic valve pressure gradients (AVPGs), indicating the severity of AS, were measured using intraprocedural TEE before and after TAVI. The following parameters were measured as coronary flow: systolic and diastolic peak velocity (cm/s) and systolic and diastolic velocity-time integral (VTI) (cm). SFR was defined as the presence of a reversal coronary flow component in systole. The enrolled patients were classified into two groups according to the presence or absence of SFR before TAVI. A total of 25 patients were included: 13 had SFR and 12 who had no SFR, before TAVI. Patients with SFR had significantly higher aortic valve peak velocities (451.1 ± 45.9 vs. 372.1 ± 52.1 cm/s; P < 0.001) and mean AVPGs (49.2 ± 14.5 vs. 30.3 ± 11.6 mmHg; P = 0.002) than those without. The optimal binary cut-off aortic valve peak velocity values and the mean AVPG associated with the presence of SFR before TAVI were >410.0 cm/s (specificity, 75.0%; sensitivity, 92.3%) and >37.4 mmHg (specificity, 83.3%; sensitivity, 92.3%), respectively. After TAVI, SFR immediately disappeared in 11 of 13 patients with SFR (84.6%). Overall, the systolic coronary VTI significantly increased after TAVI (2.0 ± 4.7 vs. 6.4 ± 3.2 cm, P < 0.001), and this increase was greater in patients with SFR than in those without SFR before TAVI (interaction P = 0.035). CONCLUSIONS: SFR was found to be associated with the severity of AS and with a greater increase in systolic coronary flow immediately after TAVI.

Total body fluid is the factor that affects the pharmacokinetics of tolvaptan, and its efficacy, in acute worsening heart failure patients.

The optimal starting dose of tolvaptan to effectively improve fluid retention in patients with heart failure (HF) is unknown. This study explored the factors affecting the pharmacokinetics (PKs) and pharmacodynamics of tolvaptan in patients with decompensated HF. We prospectively enrolled patients who were slated to receive tolvaptan because of volume overload associated with chronic HF. Blood samples were collected to measure tolvaptan concentrations before and 4, 8, 12-15, 24, and 144 h after administration. Additionally, demographic parameters, coadministered drugs, and body fluid composition were evaluated. Multiple regression analysis to detect PK parameters for the prediction of body weight (BW) loss at day 7 after the initiation of tolvaptan treatment and PK analysis to explore the factors affecting the PKs of tolvaptan were performed. In total, 165 blood samples were obtained from 37 patients. The predictors of weight loss on day 7 were area under the curve (AUC0-∞ ) of tolvaptan. PK analysis of the data revealed a strong correlation between CL/F and Vd/F, but no correlation between CL/F and kel (r = .95 and .06, respectively). A significant correlation was observed between total body fluid and Vd/F, and this correlation remained statistically significant even after adjusting for BW (r = .49, p < .05). Fat was also significantly correlated with Vd/F before adjusting for BW, on the other the correlation disappeared after adjusting BW. The optimal dose of tolvaptan based on total body fluid levels in individual patients could result in the alleviation of fluid retention in patients with HF.

Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma.

BACKGROUND: Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity. METHODS: We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39-77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability. RESULTS: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of 'Val Leu Ile degradation pathway'. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival. CONCLUSIONS: We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.

Rheocarna® as an alternative therapeutic option for patients with chronic limb-threatening ischemia: A case report.

Recently, a new low-density lipoprotein apheresis device (Rheocarna®; Kaneka Corporation, Osaka, Japan), a blood purification therapy, was approved in Japan for managing chronic limb-threatening ischemia with refractory ulcers. Here, we describe a case of chronic limb-threatening ischemia that was treated with the Rheocarna. A 65-year-old Asian man with an ulcer on the right heel was admitted to our hospital. Angiography revealed chronic total occlusion with severe calcification of the anterior tibial, peroneal, and posterior tibial arteries. The patient underwent distal bypass of the saphenous vein; however, the bypass was occluded in the early postoperative period. The Rheocarna was used, and the ulcers improved significantly postoperatively. Although endovascular treatment was eventually performed on the occluded bypass graft to completely heal the ulcer, the Rheocarna could be an alternative treatment option in challenging cases of chronic limb-threatening ischemia.