Predictors of long-term survival in Japanese patients with heart failure with reduced ejection fraction (HFrEF) treated with cardiac resynchronization therapy-defibrillators (CRT-D).

BACKGROUND: Reports on the factors predicting long-term survival of CRT-D cases from Western countries are increasing, however, those from Asia including Japan are still sparse. We aimed to clarify the factors predicting long-term survival of Japanese CRT-D cases. METHODS: We retrospectively analyzed consecutive 133 patients who underwent CRT-D implantation between 2006 and 2021. We compared clinical factors between patients who died within 5 years after implantation (short-survival group: n = 31) and who had survived for more than 5 years (long-survival group: n = 36) after implantation. RESULTS: Major underlying heart diseases were dilated cardiomyopathy (45%) and ischemic heart disease (12%). There was no difference between the short-survival group and the long-survival group in incidence of CLBBB (32% vs. 30%), whereas CRBBB was more common in the short-survival group (26% vs. 0%, p = .004). Mechanical dyssynchrony at implantation was more frequent in the long-survival group (48% vs. 78%, p = .02). The incidence of response to CRT at 1 year after implantation was higher in long-survival group (19% vs. 50%, p = .02). Multiple logistic regression analysis identified NYHA class, mechanical dyssynchrony at implantation, and response at one year as predictors of long-term survival. CONCLUSIONS: In Japanese CRT-D cases, lower NHYA class, preexisting mechanical dyssynchrony, and 1-year response to CRT predict long-term survival.

Square-Planar Anionic Pt0 Complexes.

A T-shaped Pt0 complex with a diphosphine-borane (DPB) ligand was prepared. The Pt→B interaction enhances the electrophilicity of the metal and triggers the addition of Lewis bases to give the corresponding tetracoordinate complexes. For the first time, anionic Pt0 complexes are isolated and structurally authenticated. X-ray diffraction analyses show the anionic complexes [(DPB)PtX]- (X=CN, Cl, Br, I) to be square-planar. The d10 configuration and Pt0 oxidation state of the metal were unambiguously established by X-ray photoelectron spectroscopy and DFT calculations. The coordination of Lewis acids as Z-type ligands is a powerful mean to stabilize elusive electron-rich metal complexes and achieve uncommon geometry.

A microRNA-based liquid biopsy signature for the early detection of esophageal squamous cell carcinoma: a retrospective, prospective and multicenter study.

BACKGROUND: Currently, there is no clinically relevant non-invasive biomarker for early detection of esophageal squamous cell carcinoma (ESCC). Herein, we established and evaluated a circulating microRNA (miRNA)-based signature for the early detection of ESCC using a systematic genome-wide miRNA expression profiling analysis. METHODS: We performed miRNA candidate discovery using three ESCC tissue miRNA datasets (n = 108, 238, and 216) and the candidate miRNAs were confirmed in tissue specimens (n = 64) by qRT-PCR. Using a serum training cohort (n = 408), we conducted multivariate logistic regression analysis to develop an ESCC circulating miRNA signature and the signature was subsequently validated in two independent retrospective and two prospective cohorts. RESULTS: We identified eighteen initial miRNA candidates from three miRNA expression datasets (n = 108, 238, and 216) and subsequently validated their expression in ESCC tissues. We thereafter confirmed the overexpression of 8 miRNAs (miR-103, miR-106b, miR-151, miR-17, miR-181a, miR-21, miR-25, and miR-93) in serum specimens. Using a serum training cohort, we developed a circulating miRNA signature (AUC:0.83 [95%CI:0.79-0.87]) and the diagnostic performance of the miRNA signature was confirmed in two independent validation cohorts (n = 126, AUC:0.80 [95%CI:0.69-0.91]; and n = 165, AUC:0.89 [95%CI:0.83-0.94]). Finally, we demonstrated the diagnostic performance of the 8-miRNA signature in two prospective cohorts (n = 185, AUC:0.92, [95%CI:0.87-0.96]); and (n = 188, AUC:0.93, [95%CI:0.88-0.97]). Importantly, the 8-miRNA signature was superior to current clinical serological markers in discriminating early stage ESCC patients from healthy controls (p < 0.001). CONCLUSIONS: We have developed a novel and robust circulating miRNA-based signature for early detection of ESCC, which was successfully validated in multiple retrospective and prospective multinational, multicenter cohorts.

Comprehensive Analysis of Multiple Primary Cancers in Patients With Esophageal Squamous Cell Carcinoma Undergoing Esophagectomy.

OBJECTIVE: The aim of this study was to elucidate the latest epidemiology and risk factors for multiple primary cancers (MPCs), and the association between neoadjuvant chemotherapy (NAC) and postoperative metachronous cancer (PMC) in patients with esophageal squamous cell carcinoma (ESCC) who underwent esophagectomy. SUMMARY OF BACKGROUND DATA: Background data to derive appropriate screening strategies are insufficient. METHODS: This study consisted of 3 retrospective investigations. A total of 766 consecutive patients with ESCC who underwent esophagectomy between April 2005 and December 2019 were eligible for epidemiological analysis. Of these, 688 patients without missing data were analyzed for the risk of MPCs. In total, 364 patients who underwent NAC (115) and no preoperative treatments (249) were investigated for the association between NAC and PMC. RESULTS: Of 766 patients, 288 (38%) patients experienced 357 MPCs in their life. PMCs identified after the completion of 5-year postoperative follow-up were significantly more advanced (P = 0.019). Male sex [hazard ratio (HR) = 3.04, P = 0.038], older age (HR = 2.39, P < 0.001), and diabetes mellitus (HR = 1.76, P = 0.034) were risk factors for preoperative metachronous cancers. Heavy smoking (HR = 1.70, P = 0.014) and drinking (HR = 1.61, P = 0.029) were risk factors for synchronous cancers. NAC significantly reduced PMC incidence ( P = 0.043). NAC showed a trend to contribute to improved survival via reduced deaths from PMCs, although this did not reach significance ( P = 0.082). CONCLUSIONS: ESCC is associated with a high risk of MPCs. Continuing follow-up for PMCs after the completion of 5-year postoperative follow-up is important. NAC may reduce PMCs, representing a novel mechanism for improving survival in patients with locally advanced ESCC.

Clinical impact of nocturnal ventricular tachyarrythmias in electrical storm.

BACKGROUND: The incidence of electrical storm (ES) is significantly higher during the daytime. However, the association between nocturnal ventricular tachyarrythmias during ES and prognosis remains unclear. Therefore, this study aimed to investigate the clinical characteristics and outcomes of ES with midnight ventricular tachyarrythmias. METHODS: We included 48 consecutive patients who had an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator implanted between 2010 and 2020 and those who had experienced the onset of an out-of-hospital ES episode. According to the midnight (0:00 a.m.-6:00 a.m.) occurrence of ventricular arrythmia events consisting of ventricular tachycardia (VT) and ventricular fibrillation (VF), we divided them into two groups (with-midnight group: n = 27, without-midnight group: n = 21). The clinical characteristics and outcomes of the two groups were compared. RESULTS: The patients in the with-midnight group were mostly males, had longer QRS duration, and longer corrected QT-interval than those in the without-midnight group (p < .05). The incidence of all-cause death, especially heart failure death, was higher in the with-midnight group than in the without-midnight group (p < .01). Multivariate analysis showed that the presence of midnight VT/VF during ES was the only independent risk factors for heart failure death (HR = 18.9, 95%CI = 1.98-181, p = .011). CONCLUSIONS: The presence of midnight VT/VF during ES might be associated with the poor prognosis. The loss of a sympathetic circadian pattern of VT/VF distribution during ES might suggest advanced stages of the cardiac disease.

Increased Rate of Serum Prealbumin Level after Preoperative Enteral Nutrition as an Indicator of Morbidity in Gastrectomy for Gastric Cancer with Outlet Obstruction.

BACKGROUND: Preoperative malnutrition is believed to contribute to increased postoperative complications. Preoperative serum prealbumin level was reported to be a predictor of nutritional status and postoperative complications after gastrointestinal surgery, including gastrectomy. Gastric outlet obstruction caused by gastric cancer leads to insufficient nutritional status. However, the impact of preoperative enteral nutrition using naso-jejunal feeding tubes for patients with gastric outlet obstruction is not fully understood. METHODS: From July 2010 to June 2020, 50 patients with gastric cancer-induced outlet obstruction who underwent gastrectomy following preoperative enteral nutrition via feeding tube were included. We investigated the relationship between changes in nutritional status after preoperative enteral nutrition and postoperative complications. Postoperative complications were defined as grade ≥II based on the Clavien-Dindo classification. RESULTS: The median period of preoperative enteral nutrition was 10 days. The median increase rate of the serum prealbumin level was 10.5% (interquartile range, 0.63-38.2%), and patients with an increase rate ≥ 10% were defined as the elevated group. Postoperative morbidity was significantly higher in the non-elevated group (P = 0.0031). Univariate and multivariate analyses showed that an increased rate of the serum prealbumin level was an independent risk factor of postoperative complications for patients with gastric outlet obstruction caused by gastric cancer (P = 0.0025 and P = 0.009, respectively). CONCLUSIONS: Preoperative enteral nutrition improved the serum prealbumin level of patients with gastric cancer-induced outlet obstruction, and an increased rate of prealbumin can be an indicator of sufficient preoperative enteral nutrition and decreased postoperative morbidity.

The Risk of Ventricular Tachyarrhythmias in Patients with Antimitochondrial Antibodies-Related Noncardiac Diseases.

Antimitochondrial antibodies (AMA) are serum autoantibodies specific to primary biliary cholangitis and are linked to myopathy and myocardial damage; however, the presence of AMA as a risk factor for ventricular tachyarrhythmias (VTs) has remained unknown. This study aimed to elucidate whether the presence of AMA-related noncardiac diseases indicates VTs risk.This cohort study enrolled 1,613 patients (883 females) who underwent AMA testing to assess noncardiac diseases. The incidence of VTs and supraventricular tachyarrhythmias (SVTs) from a year before the AMA testing to the last visit of the follow-up were retrospectively investigated as primary and secondary objectives. Using propensity score matching, we extracted AMA-negative patients whose covariates were matched to those of 152 AMA-positive patients. In this propensity score-matched cohort, the incidence of VTs and SVTs in the AMA-positive patients were compared with that in AMA-negative patients.The AMA-positive patients had higher estimated cumulative incidence (log-rank, P = 0.013) and prevalence (5.9% versus 0.7%, P = 0.020) of VTs than the AMA-negative patients. The presence of AMA was an independent risk factor for VTs (hazard ratio, 4.02; 95% CI, 1.44-20.01; P = 0.005). Meanwhile, AMA were associated with atrial flutter and atrial tachycardia development. In AMA-positive patients, VTs were associated with male sex, underlying myopathy, high creatine kinase levels, presence of chronic heart failure or ischemic heart disease, left ventricular dysfunction, presence of SVTs, and the electrocardiographic parameters indicating atrial disorders.The presence of AMA-related noncardiac diseases is an independent risk factor for VTs.

Progressive increase in activation delay during premature stimulation is related to ventricular fibrillation in Brugada syndrome.

INTRODUCTION: The local conduction delay has been deemed to play an important role in the perpetuation of ventricular fibrillation (VF) in Brugada syndrome (BrS). We evaluated the relationship between the activation delay during programmed stimulation and cardiac events in BrS patients. METHODS: This study included 47 consecutive BrS patients who underwent an electrophysiological study and received implantable cardiac defibrillator therapy. We divided the patients into two groups based on whether they had developed VF (11 patients) or not (36 patients) during the follow-up period of 89 ± 53 months. The activation delay was assessed using the interval between the stimulus and the QRS onset during programmed stimulation. The mean increase in delay (MID) was used to characterize the conduction curves. RESULTS: The MID at the right ventricular outflow tract (RVOT) was significantly greater in patients with VF (4.5 ± 1.2 ms) than in those without VF (2.2 ± 0.9 ms) (p < .001). A receiver operating characteristics curve analysis indicated that the optimal cut-off point for discriminating VF occurrence was 3.3 with 88.9% sensitivity and 91.3% specificity. Furthermore, patients with an MID at the RVOT ≥ 3.3 ms showed significantly higher rates of VF recurrence than those with an MID at the RVOT < 3.3 ms (p < .001). The clinical characteristics, including the signal-averaged electrocardiogram measurement and VF inducibility were similar between the two groups. CONCLUSION: A prolonged MID at the RVOT was associated with VF and maybe an additional electrophysiological risk factor for VF in BrS patients.

A multicenter retrospective study of the esophageal triamcinolone acetonide-filling method in patients with extensive esophageal endoscopic submucosal dissection.

OBJECTIVE: Endoscopic submucosal dissection (ESD) for extensive esophageal cancer is sometimes associated with post-ESD stenosis, despite preventative steroid therapy. In this retrospective multicenter analysis, we evaluated the factors associated with therapy resistance. MATERIALS AND METHODS: We enrolled 73 patients with 75 extensive esophageal cancers treated with ESD. Stenosis prevention was performed using two esophageal triamcinolone acetonide (TA)-fillings, and repeated if stenosis was found on follow-up. Therapy-resistance factors associated with incidence of severe stenosis requiring endoscopic balloon dilation (EBD) were evaluated, including age, gender, previous treatment history, tumor location, morphology, resection size, histologic type, invasion depth, and horizontal resection grade (HR-grade 1, ≥ 9/12 and <10/12 of the circumference; grade 2, ≥ 10/12 and <11/12; grade 3, ≥ 11/12 but not circumferential; and grade 4, entirely circumferential). RESULTS: Severe stenosis occurred in 17.3%(13/75) of cases, with a median of two EBDs (range, 1-6 times). Severe stenosis was significantly associated with HR-grade elevation and previous treatment history (p < .05); multivariate analysis showed both as independent therapy-resistance factors (p < .05). Patients without previous treatment history demonstrated severe stenosis at 12.9%(9/70): 0%(0/26) HR-grade 1, 18.8%(3/16) grade 2, 17.6%(3/17) grade 3, and 27.3%(3/11) grade 4, showing a risk of HR-grade 2 or more resection but an acceptable stenosis prevention even after entirely circumferential resection. Conversely, patients with previous treatment history demonstrated severe stenosis at a high frequency of 80%(4/5). CONCLUSIONS: Esophageal TA-filling is a promising stenosis-preventive steroid therapy, even in entirely circumferential ESD cases. However, HR-grade 2 or more elevation and previous treatment history were independently associated with therapy resistance.

Efficacy of antitachycardia pacing alert by remote monitoring of implantable cardioverter-defibrillators for out-of-hospital electrical storm.

BACKGROUND: Remote monitoring (RM) has been shown to reduce all-cause mortality in patients with implantable cardioverter-defibrillators or cardiac resynchronization therapy defibrillators (ICD/CRT-D). Not all devices transmit an alert for antitachycardia pacing (ATP) therapy, and it is unknown whether differences of RM alert affect the outcomes of electrical storm (ES). METHODS: We enrolled 42 patients with ICD/CRT-D whose out-of-hospital ES were detected by RM between 2013 and 2020. We divided their 54 episodes into two groups (ATP-alert-on; 22, ATP-alert-off; 32), and clinical outcomes were compared between the two groups. RESULTS: In 35 of 54 episodes of ES, ventricular tachycardia (VT) could be terminated within 24 h of ES onset just by ATP (ATP-alert-on: 14, ATP-alert-off: 21); however, many patients subsequently received shock delivery for VT. Among the 35 episodes, only in ATP-alert-on group, seven patients were prompted to visit our hospital without ICD shock through confirmation of ES by ATP-alert. Episodes that led to shock delivery 24 h or longer after the ES onset were significantly less common in the ATP-alert-on group (ATP-alert-on: 1/14, ATP-alert-off: 9/21, p = .03). Although there were no significant differences in the number of shock deliveries between episodes in the two groups, the number of ATP deliveries were significantly fewer in the ATP-alert-on group (12[7-26] vs. 29[16-53] in ATP-alert-off group, p = .03). Multivariate logistic regression analyses showed that the only ATP-alert significantly reduced ATP deliveries (HR = 0.14, 95%CI = 0.04-0.57, p = .003). CONCLUSION: Remote monitoring with an ATP-alert function during electrical storm may reduce appropriate ICD therapy through prompting early review.

J point elevation in high precordial leads associated with risk of ventricular fibrillation.

INTRODUCTION: The significance of high precordial electrocardiograms in idiopathic ventricular fibrillation (IVF) is unknown. METHOD: This study included 50 consecutive patients (48 men; age, 42 ± 18 years) who had spontaneous ventricular fibrillation not linked to structural heart disease and received implantable cardiac defibrillator therapy. IVF was diagnosed in 35 patients and Brugada syndrome was diagnosed in other 15 patients. Electrocardiograms in high intercostal space were compared between 35 patients with IVF and 105 age- and sex-matched healthy controls (patient: control ratio, 1:3). RESULTS: The frequency of J point elevation ≥ 0.1 mV in the 4th intercostal spaces was similar between patients with IVF (14%) and healthy controls (7%). However, the frequency of J point elevation ≥ 0.1 mV in the 3rd intercostal space was higher in patients with IVF (40%) than controls (11%) (p < .01). J point elevation was present only in the 3rd intercostal space but not in the 4th intercostal space in 30% of patients with IVF but only in 6% of controls (p < .01). During follow-up, the recurrence of ventricular fibrillation was higher in patients with IVF who had J point elevation in the 3rd intercostal space (36%) and Brugada syndrome(40%) than those with IVF who did not have J point elevation in the 3rd intercostal space(11%) (p < .05 for both). CONCLUSION: J point elevation in the 3rd intercostal space was associated with IVF and recurrences of ventricular fibrillation. Electrocardiogram recordings in the high intercostal space may be useful to identify risk of sudden death.

12-Chemokine signature, a predictor of tumor recurrence in colorectal cancer.

Tertiary lymphoid structures (TLSs) provide an immunological antineoplastic effect. Recent evidences link a unique 12-chemokine (CCL2, -3, -4, -5, -8, -18, -19, -21, CXCL9, -10, -11, -13) signature status from tumor tissue and the TLS expression. However, the potential significance of 12-chemokine signature status for clinical use is unknown. We aimed to evaluate the association of 12-chemokine signature status with patient outcomes in colorectal cancer (CRC). We used integrated data of resected 975 CRC cases within three independent cohorts from France, Japan and the United States (GSE39582, KUMAMOTO from Kumamoto university hospital and TCGA). The association of 12-chemokine signature status with clinicopathological features, patient outcome, TLS expression status and key tumor molecular features was analyzed. Patients with low 12-chemokine signature status had a significant shorter relapse-free survival in discovery cohort (HR: 1.61, 95% CI: 1.11-2.39, p = 0.0123), which was confirmed in validation cohort (HR: 3.31, 95% CI: 1.33-10.08, p = 0.0087). High 12-chemokine signature status had significant associations with right-sided tumor, high tumor-localized TLS expression, BRAF mutant, CIMP-high status and MSI-high status. Furthermore, RNA-seq based analysis showed that high 12-chemokine signature status was strongly associated with inflammation-related, immune cells-related and apoptosis pathways (using gene set enrichment analysis), and more tumor-infiltrating immune cells, such as cytotoxic T lymphocytes and myeloid dendritic cells (using MCP-counter analysis). We investigated a promising effect of 12-chemokine signature status in CRC patients who underwent resection. Our data may be helpful in developing novel immunological treatment strategies for CRC.

Prospective multicenter study of the esophageal triamcinolone acetonide-filling method in patients with subcircumferential esophageal endoscopic submucosal dissection.

BACKGROUND AND AIM: The esophageal triamcinolone acetonide (TA)-filling method is a novel local approach for stenosis prevention after extensive esophageal endoscopic submucosal dissection (ESD). We evaluated this method after subcircumferential ESD. METHODS: We enrolled 20 patients with esophageal cancer requiring subcircumferential ESD in a prospective multicenter study. Esophageal TA filling was carried out 1 day and 1 week after ESD, with follow-up endoscopy every 2 weeks. We treated severe stenosis preventing endoscope passage with endoscopic balloon dilatation (EBD) and additional TA filling, and mild stenosis allowing endoscope passage with additional TA filling only. Primary endpoint was incidence of severe stenosis; secondary endpoints were total number of EBD, rate of additional TA filling, time to stenosis and complete re-epithelialization, dysphagia score, and adverse events. Horizontal resection grade was divided into grades 1 (≥ 9/12 and <10/12 of the circumference), 2 (≥ 10/12 and <11/12), and 3 (≥ 11/12 but not circumferential) and analyzed statistically for correlation with endpoints. RESULTS: Incidence of severe stenosis was 5.0% (1/20; 0.1-24.8%) and was treated with three EBD. Six patients showed mild stenosis. Additional TA filling was carried out in these seven patients: 0% (0/9) for grade 1 resection, 40% (2/5) for grade 2, and 83% (5/6) for grade 3 (P < 0.05). Median time to stenosis and re-epithelialization was 3 and 7 weeks, respectively. Dysphagia score deteriorated in one patient. No adverse events occurred. CONCLUSIONS: The esophageal TA-filling method prevented stenosis after subcircumferential ESD. Grade ≥2 resection showed a high risk for stenosis, but additional TA filling for mild stenosis inhibited stenosis progression (UMIN000024384).

A MicroRNA Signature Associated With Metastasis of T1 Colorectal Cancers to Lymph Nodes.

Most T1 colorectal cancers treated by radical surgery can now be cured by endoscopic submucosal dissection. Although 70%-80% of T1 colorectal cancers are classified as high risk, <16% of these patients actually have lymph node metastases. Biomarkers are needed to identify patients with T1 cancers with the highest risk of metastasis, to prevent unnecessary radical surgery. We collected data from The Cancer Genome Atlas and identified 5 microRNAs (MIR32, MIR181B, MIR193B, MIR195, and MIR411) with significant changes in expression in T1 and T2 colorectal cancers with vs without lymph node metastases. Levels of the 5 microRNAs identified patients with lymph node invasion by T1 or T2 cancers with an area under the receiver operating characteristic curve (AUROC) value of 0.84. We validated these findings in 2 cohorts of patients with T1 cancers, using findings from histology as the reference. The 5-microRNA signature identified T1 cancers with lymph node invasion in cohort 1 with an AUROC value of 0.83, and in cohort 2 with an AUROC value of 0.74. When we analyzed biopsy samples from untreated patients, the 5-microRNA signature identified cancers with lymph node metastases with an AUROC value of 0.77. The 5-microRNA therefore identifies high-risk T1 colorectal cancers with a greater degree of accuracy than currently used pathologic features.

Early repolarization and risk of lone atrial fibrillation.

INTRODUCTION: Early repolarization syndrome is a recently proposed condition characterized by an early repolarization pattern in the electrocardiogram (ECG) and ventricular fibrillation in the absence of structural heart abnormalities. Although some studies have suggested that early repolarization is associated with frequency of atrial fibrillation, the association of early repolarization with atrial fibrillation is not well known. HYPOTHESIS: Early repolarization indicates the substrate for atrial fibrillation in addition to that for ventricular fibrillation. METHOD: This study included 79 patients (57 men [72%]; age, 45 ± 12 years) aged less than 60 years who had paroxysmal lone atrial fibrillation and 395 age- and sex-matched healthy controls (patient:control ratio, 1:5). Patients who had structural heart disease, hypertension, diabetes, hyperthyroidism, history of successful resuscitation, or the Brugada type ECG were excluded. ECGs recorded during sinus rhythm were compared between patients with atrial fibrillation and healthy controls. RESULTS: Early repolarization in the inferior and/or lateral leads was more common in patients with atrial fibrillation (25%) than controls (10%; P = 0.001). The location and magnitude of early repolarization were similar between the two groups. Other electrocardiographic measurements were not different between the two groups. Among patients with atrial fibrillation, there was no difference in clinical characteristics including age at atrial fibrillation development, sex, and body mass index between patients with early repolarization and those without early repolarization. Electrocardiographic measurements were not different between patients with early repolarization and those without early repolarization. CONCLUSION: Early repolarization was associated with lone atrial fibrillation. Early repolarization may indicate increased susceptibility to atrial fibrillation.

Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression.

RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus with pyrosequencing technology detected RNF43 hotspot mutations in one (0.88%) of 113 colorectal polyp cases and in 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harbouring mutated RNF43 experienced a higher recurrence rate than those harbouring non-mutated RNF43. In addition, the growth of RNF43 wild-type colorectal cancer cell lines was significantly increased by RNF43 silencing. We generated Rnf43 knockout mice in a C57BL/6 N background by using the CRISPR-Cas9 system. Although intestinal organoids from Rnf43 knockout mice did not show continuous growth in the absence of R-spondin, an azoxymethane/dextran sodium sulphate mouse model demonstrated that tumours were markedly larger in Rnf43 knockout mice than in wild-type mice. These findings provide evidence that Wnt signalling activation by RNF43 mutations during the tumourigenic stage enhances tumour growth and promotes a high recurrence rate in colorectal cancer patients. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A Steam Pop Detected by Intracardiac Echocardiography During Catheter Ablation of the Left Ventricular Papillary Muscle.

A 60-year-old female with premature ventricular contractions (PVCs) originating from the bottom of the posteromedial papillary muscle of the left ventricle underwent radiofrequency catheter ablation (RFCA) using an irrigated-tip catheter. During ablation of the PVCs, a loud steam pop was observed. Intracardiac echocardiography (ICE) revealed a growing, hyperechogenic intramyocardial microbubble formation around the catheter tip. The formation disappeared slowly and completely, leaving an endocardial laceration without pericardial effusion. ICE imaging is valuable during a difficult RFCA procedure, because ICE reveals the exact anatomical position of the catheter and thus allows rapid evaluation of the occurrence of steam popping and any possible subsequent complication.

Replacement of an Implantable Cardioverter-Defibrillator (ICD) with a New Standard Subcutaneous ICD System in a Patient with Jervell and Lange-Nielsen Syndrome.

A 7-year-old female suffering from syncope attacks and deafness was genetically diagnosed with Jervell and Lange-Nielsen syndrome (JLNS). A transvenous-designed shock lead and implantable cardioverter-defibrillator (ICD) were atypically implanted subcutaneously, because the patient's body was small. Six years after implantation, we confirmed the patient's eligibility for a subcutaneous ICD (S-ICD) based on electrocardiogram screening. The implanted ICD system was replaced with a new standard S-ICD system. Implantation of the S-ICD may be considered a reliable and safe option in young patients with JLNS, even if their electrocardiograms show remarkable prolongation of the QT interval and T-wave alternans.

Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells.

BACKGROUND & AIMS: Fibroblasts that interact with cancer cells are called cancer-associated fibroblasts (CAFs), which promote progression of different tumor types. We investigated the characteristics and functions of CAFs in diffuse-type gastric cancers (DGCs) by analyzing features of their genome and gene expression patterns. METHODS: We isolated CAFs and adjacent non-cancer fibroblasts (NFs) from 110 gastric cancer (GC) tissues from patients who underwent gastrectomy in Japan from 2008 through 2016. Cells were identified using specific markers of various cell types by immunoblot and flow cytometry. We selected pairs of CAFs and NFs for whole-exome and RNA sequencing analyses, and compared expression of specific genes using quantitative reverse transcription PCR. Protein levels and phosphorylation were compared by immunoblot and immunofluorescence analyses. Rhomboid 5 homolog 2 (RHBDF2) was overexpressed from a transgene in fibroblasts or knocked down using small interfering RNAs. Motility and invasiveness of isolated fibroblasts and GC cell lines (AGS, KATOIII, MKN45, NUGC3, NUGC4, OCUM-2MD3 and OCUM-12 cell lines) were quantified by real-time imaging analyses. We analyzed 7 independent sets of DNA microarray data from patients with GC and associated expression levels of specific genes with patient survival times. Nude mice were given injections of OCUM-2MD3 in the stomach wall; tumors and metastases were collected and analyzed by immunohistochemistry. RESULTS: Many of the genes with increased expression in CAFs compared with NFs were associated with transforming growth factor beta 1 (TGFB1) activity. When CAFs were cultured in extracellular matrix, they became more motile than NFs; DGC cells incubated with CAFs were also more motile and invasive in vitro than DGC cells not incubated with CAFs. When injected into nude mice, CAF-incubated DGC cells invaded a greater number of lymphatic vessels than NF-incubated DGC cells. We identified RHBDF2 as a gene overexpressed in CAFs compared with NFs. Knockdown of RHBDF2 in CAFs reduced their elongation and motility in response to TGFB1, whereas overexpression of RHBDF2 in NFs increased their motility in extracellular matrix. RHBDF2 appeared to regulate oncogenic and non-canonical TGFB1 signaling. Knockdown of RHBDF2 in CAFs reduced cleavage of the TGFB receptor 1 (TGFBR1) by ADAM metallopeptidase domain 17 (ADAM17 or TACE) and reduced expression of genes that regulate motility. Incubation of NFs with in interleukin 1 alpha (IL1A), IL1B or tumor necrosis factor, secreted by DGCs, increased fibroblast expression of RHBDF2. Simultaneous high expression of these cytokines in GC samples was associated with shorter survival times of patients. CONCLUSIONS: In CAFs isolated from human DGCs, we observed increased expression of RHBDF2, which regulates TGFB1 signaling. Expression of RHBDF2 in fibroblasts is induced by inflammatory cytokines (such as IL1A, IL1B, and tumor necrosis factor) secreted by DGCs. RHBDF2 promotes cleavage of TGFBR1 by activating TACE and motility of CAFs in response to TGFB1. These highly motile CAFs induce DGCs to invade extracellular matrix and lymphatic vessels in nude mice.

Colorectal Cancer Stem Cells Acquire Chemoresistance Through the Upregulation of F-Box/WD Repeat-Containing Protein 7 and the Consequent Degradation of c-Myc.

The cancer stem cell (CSC) paradigm suggests that tumors are organized hierarchically. Chugai previously established an LGR5+ human colorectal cancer (CRC) stem-cell-enriched cell line (colorectal CSCs) that expresses well-accepted colorectal CSC markers and that can dynamically switch between proliferative and drug-resistant noncycling states. We performed this study to elucidate the molecular mechanisms responsible for evading cell death in colorectal CSCs mediated by anticancer agents. During the cell cycle arrest caused by anticancer agents, we found that c-Myc expression was substantially decreased in colorectal CSCs. The c-Myc expression alterations were mediated by upregulation of F-box/WD repeat-containing protein 7 (FBXW7), as evidenced through FBXW7-small interfering RNA knockdown experiments that resulted in enhanced cell sensitivity to anticancer agents. Upregulation of FBXW7 following drug treatment was not evident in commercially available cancer cell lines. Colorectal CSCs were induced to differentiation by Matrigel and fetal bovine serum. Differentiated CSCs treated with anticancer agents did not show upregulation of FBXW7 and were more sensitive to irinotecan (CPT-11), highlighting the potential CSC-specific nature of our data. The FBXW7 over-expression was further validated in resected liver metastatic sites in CRC patients after chemotherapy. In conclusion, our study revealed that a CSC-specific FBXW7-regulatory mechanism is strongly associated with resistance to chemotherapeutic agents. Inhibition of FBXW7-upregulation in CSCs following chemotherapy may enhance the response to anticancer agents and represents an attractive strategy for the elimination of colorectal CSCs. Stem Cells 2017;35:2027-2036.