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We treated a female patient known to have a double-chambered right ventricle (DCRV) who presented with symptoms of an acute myocardial infarction (AMI). Emergent coronary artery catheterization revealed acute right coronary artery (RCA) occlusion and proximal left anterior descending (LAD) stenosis. We performed percutaneous coronary intervention (PCI) for the RCA occlusion. Right heart catheterization revealed a pressure gradient across the mid-RV of 58 mmHg. Computed tomography and magnetic resonance imaging revealed no other congenital cardiac abnormalities. She underwent surgical repair of the RV stenosis and coronary artery bypass surgery for LAD stenosis.

We herein report a very unusual case of small bowel obstruction caused by phytobezoar in a 69-year-old woman who consumed a large amount of bracken. The patient presented with nausea and vomiting. Computed tomography revealed an air-filled foreign body in the jejunum that had likely caused the small bowel obstruction. A fibrous foreign body diagnosed as a phytobezoar was detected using double-balloon enteroscopy. The obstruction was successfully resolved by crushing the phytobezoar repeatedly using a snare. Small bowel obstructions caused by phytobezoars are often treated with surgical interventions. However, endoscopic fragmentation using a snare is a minimally invasive treatment alternative.

Recently, myocardial extracellular volume (ECV) analysis has been measurable on computed tomography (CT) using new software. We evaluated the use of cardiac CT to estimate the myocardial ECV of left ventricular (LV) myocardium (LVM) to predict reverse remodeling (RR) in cases of atrial fibrillation (AF) after catheter ablation (CA). Four hundred and seven patients underwent CA for AF in our institution from April 2014 to Feb 2021. Of these, 33 patients (8%) with an LVEF ≤ 50% and who had undergone CT were included in our study. We estimated the LVM ECV using commercial software to analyze the CT data. RR was defined as an improvement in LVEF to 50% after CA. LVEF increased to 50% in 24 patients (73%) after CA. In all 24 patients, LVM ECV, LV end-diastolic and end-systolic volumes (LVEDV and LVESV), and the n-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) were significantly lower than in the other nine patients (P = 0.0037, 0.0273, 0.0443, and 0.0001). On receiver operating characteristic curve analysis, the best cut-off of ECV, LVEDV, LVESV and NT-proBNP for the prediction of RR were 37.73%, 120 mL, 82 mL, and 1267 pg/mL, respectively. We newly defined the ENL (ECV, NT-proBNP, and LVEDV) score as the summed score for the presence or absence (1 or 0; maximum score = 3) of ECV, NT-proBNP, and LVEDV values less than or equal to each best cut-off value, and found that this score gave the highest area under the curve for the prediction of RR (0.9583, P 0.0001). The ENL score may be useful for predicting RR in patients with AF undergoing CA.

The atrial defibrillation threshold (ADFT) for internal cardioversion is theoretically related to the critical mass for sustaining atrial fibrillation (AF).This study aimed to investigate the association of ADFT for internal cardioversion with the outcome of catheter ablation for non-paroxysmal AF (non-PAF).We included 368 consecutive patients who underwent first-time catheter ablation for non-PAF. Based on the degree of ADFT recorded by the internal cardioversion before pulmonary vein isolation, we divided the patients into low ADFT (20 J) and high ADFT (≥20 J) groups and analysed the association between ADFT and atrial tachyarrhythmia recurrence.There were 234 and 134 patients in the low and high ADFT groups, respectively. Of these, 39 patients (16.7%) and 41 (30.6%) patients, respectively, had atrial tachyarrhythmia recurrence during the 2.6±1.0 year follow-up. The high ADFT group showed a significantly higher atrial tachyarrhythmia recurrence than the low ADFT group (p=0.002). This finding was also noted in patients with long-standing persistent AF (p=0.032) but not in patients with persistent AF (p=0.159). The significant predictors of arrhythmia recurrence on multivariate analysis were high ADFT (p=0.004) and long-standing persistent AF (p=0.011). In multivariate analysis within the long-standing persistent AF group, only ADFT remained a significant risk factor for AF recurrence (p=0.035).The high ADFT of internal cardioversion was found to be a risk factor for post-catheter ablation recurrence in patients with long-standing persistent AF but not in those with persistent AF.

Supplementary Table from HER3 Augmentation via Blockade of EGFR/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non–Small Cell Lung Cancer

Targeting collateral deletion of housekeeping genes caused by the loss of tumor suppressor genes is a potential strategy to identify context-specific, molecular-targeted therapies in cancer. In mammals, phosphatidylserine (PS) synthesis depends on two redundant PS synthetases, PTDSS1 and PTDSS2, and PTDSS2 is located at a tumor-suppressive locus, 11p15.5. Here, we sought to determine whether PTDSS2 loss would confer vulnerability to disruption of PTDSS1 function. PTDSS2 was lost in a wide range of cancer types, and PTDSS1 depletion specifically suppressed growth in PTDSS2-deficient cancer cell lines. Potent and selective PTDSS1 inhibitors were developed whose activity phenocopied the effect of PTDSS1 depletion, and in vivo treatment of PTDSS2-deleted tumors with these inhibitors led to tumor regression. Whole-transcriptome analysis revealed that inhibition of PTDSS1 in PTDSS2-depleted cells activated the endoplasmic reticulum (ER) stress response downstream of PS depletion. ER stress-mediated cell death induced by PTDSS1 inhibitors activated tumor immunity through the secretion of HMGB1 protein followed by activation of bone marrow-derived dendritic cells. PTDSS2 loss showed intratumoral heterogeneity in clinical samples, raising concerns about resistance to PTDSS1 inhibition. However, the PTDSS1 inhibitor effectively suppressed the growth of tumor containing both PTDSS2 wild-type and knockout cells in immunocompetent mice, showing potency for overcoming tumor heterogeneity by modulating the tumor immune microenvironment. Thus, these newly developed PTDSS1 inhibitors provide a therapeutic option for treating cancer with PTDSS2 loss, harnessing the synthetic lethality of PTDSS1/2.Significance:This study identifies a specific dependency on PTDSS1 for phosphatidylserine synthesis following PTDSS2 deletion and introduces novel PTDSS1 inhibitors as a therapeutic option to induce collateral lethality in cancer with PTDSS2 loss.

Supplementary Figure from HER3 Augmentation via Blockade of EGFR/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non–Small Cell Lung Cancer

Purpose:EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated EGFR-mutated non–small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance. Clinical trials of the HER3-targeting antibody–drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated its anticancer activity in EGFR-mutated NSCLC; however, the mechanisms that regulate HER3 expression are unknown. This study was conducted with the aim to clarify the mechanisms underlying HER3 regulation in EGFR-mutated NSCLC tumors and explored the strategy for enhancing the anticancer activity of HER3-DXd in EGFR-mutated NSCLC.Experimental Design:Paired tumor samples were obtained from 48 patients with EGFR-mutated NSCLC treated with EGFR-TKI(s). HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pretreatment to post-EGFR-TKI resistance acquisition. The anticancer efficacy of HER3-DXd and osimertinib was evaluated in EGFR-mutated NSCLC cells.Results:We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples. RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation, especially in tumors from patients who received continuous EGFR-TKI therapy. An in vitro study also showed that EGFR-TKI increased HER3 expression, repressed AKT phosphorylation in multiple EGFR-mutated cancers, and enhanced the anticancer activity of HER3-DXd.Conclusions:Our findings help clarify the mechanisms of HER3 regulation in EGFR-mutated NSCLC tumors and highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC.

The present study aimed to identify useful biomarkers to predict deterioration in patients with coronavirus disease 2019 (COVID‑19). A total of 201 COVID‑19 patients were classified according to their disease severity into non‑severe (n=125) and severe (n=76) groups, and the behavior of laboratory biomarkers was examined according to the prognosis. Neutrophil count, aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase (LDH), C‑reactive protein (CRP), sialylated carbohydrate antigen KL‑6 (KL‑6), procalcitonin (PCT), presepsin (PSP) and D‑dimer levels were significantly higher, and lymphocyte count and platelet count were significantly lower in the non‑severe group compared with the severe group. In the non‑severe group, ROC analysis demonstrated that only four biomarkers, CRP, PSP, AST and LDH were useful for differentiating the prognosis between improvement and deterioration subgroups. No strong correlation was revealed for any of the markers. Multivariate analysis identified CRP as a significant prognostic factor in non‑severe cases (odds ratio, 41.45; 95% confidence interval, 4.91‑349.24; P0.001). However, there were no blood biomarkers that could predict the outcome of patients in the severe group. Overall, several blood markers changed significantly according to disease severity in the course of COVID‑19 infection. Among them, CRP, PSP, LDH and AST were the most reliable markers for predicting the patient's prognosis in non‑severe COVID‑19 cases.

Purpose: Clinical outcomes regarding the efficacy of excimer laser coronary angioplasty (ELCA) in real-world cases of acute myocardial infarction (MI) are limited. We evaluated the impact of ELCA on myocardial salvage and left ventricular (LV) systolic/diastolic function in patients with ST-segment elevation MI (STEMI) compared with manual aspiration thrombectomy using nuclear scintigraphy.Methods: We enrolled 143 consecutive STEMI patients treated with ELCA (63 patients) or manual aspiration thrombectomy (80 patients) between September 2016 and December 2020 in a single-center hospital. We checked peak creatine kinase (CK)/ creatine kinase-myocardial band (CK-MB) level and demonstrated single-photon emission computed tomography (SPECT) analyses with Quantitative Gated SPECT and Quantitative Perfusion SPECT (Auto QUANT 7.2) at 3–10 days using 123I-BMIPP and 3 months after percutaneous coronary intervention using 99mTc-tetrofosmin to evaluate myocardial salvage and LV systolic/diastolic function. Results: There was no significant difference in patients’ and periprocedural characteristics. Peak CK-MB level was significantly different between the groups (ELCA group, 190.0 [70.5–342.0] IU/L vs. aspiration group, 256.5 [157.0–354.8] IU/L, p=0.047). Although there was no significant difference in myocardial salvage, significant improvement in the LV ejection fraction (14.1 [6.2-19.8]% vs. 9.5 [3.9-15.3]%, respectively, p=0.017) and peak emptying rate (-0.54 [-1.02–-0.27] mL/s vs. -0.38 [-0.76–-0.05] mL/s, respectively, p=0.017) were detected.Conclusion: ELCA could suppress myocardial deviation enzymes and potentially improve systolic function in STEMI patients compared to manual aspiration thrombectomy.

Purpose High-quality images can be obtained with 320-slice computed tomography (CT) with model-based iterative reconstruction (MBIR). We therefore investigated the diagnostic accuracy of 320-slice CT with MBIR for detecting significant coronary artery stenosis. Methods This was a retrospective study of 160 patients who underwent coronary CT and invasive coronary angiography (ICA). The first 100 consecutive patients (Group 1) underwent 320-slice CT without MBIR or small-focus scanning. The next 60 consecutive patients (Group 2) underwent 320-slice CT with both MBIR and small-focus scanning. Patients who underwent coronary artery bypass surgery were excluded. The diagnostic performance of 320-slice CT without MBIR or small-focus scanning and 320-slice CT with both of them, with ICA regarded as a reference standard, was compared to detect significant coronary artery stenosis (≥70% on CT, ≥75% on ICA). Results In a patient-based analysis, the sensitivity, specificity, and overall accuracy of detection of significant stenosis on CT against ICA were 95%, 85%, and 91% in Group 1, and 93%, 83%, and 90% in Group 2, respectively. No significant differences were observed between the two groups in the patient- and segment-based analyses. However, among cases with a severe coronary artery calcium score400 (31 cases in Group 1 and 28 in Group 2), the specificity and overall accuracy were significantly higher (all p0.01) in Group 2 than in Group 1 according to the segment-based analysis. Conclusion The diagnostic accuracy of the detection of coronary artery stenosis on CT was improved using 320-slice CT with MBIR.

Cardiac computed tomography (CT) is useful for the screening of coronary artery stenosis, and extracellular volume fraction (ECV) analysis by CT using new dedicated software is now available. Here, we evaluated the utility of ECV analysis using cardiac CT to predict patient prognosis in cases with dilated cardiomyopathy (DCM). We analyzed 70 cases with DCM and cardiac computed tomography (CT) with available late-phase images. We evaluated the ECV of the left ventricular myocardium (LVM) using commercially available software (Ziostation 2, Ziosoft Inc, Japan). ECV on LVM was 33.96 ± 5.04%. Major adverse cardiac events (MACE) occurred in 21 cases (30%). ECV of the LVM on CT, endo-systolic volume, and rate of significant valvular disease were significantly higher in cases with MACE than in those without (37.16 ± 5.91% vs. 32.59 ± 3.95%, 194 ± 109 vs. 138 ± 78 ml and 57% vs. 20%, all P values 0.05). LVEF was significantly lower in cases with MACE than in those without (23 ± 8 vs. 31 ± 11%, P = 0.0024). The best cut-off value of ECV on LVM for prediction of MACE was 32.26% based on receiver operating characteristics analysis. Cases with ECV ≥ 32.26% had significantly higher MACE based on Kaplan-Meier analysis (P = 0.0032). Only ECV on LVM was an independent predictor of MACE based on a multivariate Cox proportional hazards model (P = 0.0354). Evaluation of ECV on LVM by CT is useful for predicting MACE in patients with DCM.

Targeting collateral deletion of housekeeping genes caused by the loss of tumor suppressor genes is a potential strategy to identify context-specific, molecular-targeted therapies in cancer. In mammals, phosphatidylserine (PS) synthesis depends on two redundant PS synthetases, PTDSS1 and PTDSS2, and PTDSS2 is located at a tumor-suppressive locus, 11p15.5. Here, we sought to determine whether PTDSS2 loss would confer vulnerability to disruption of PTDSS1 function. PTDSS2 was lost in a wide range of cancer types, and PTDSS1 depletion specifically suppressed growth in PTDSS2-deficient cancer cell lines. Potent and selective PTDSS1 inhibitors were developed whose activity phenocopied the effect of PTDSS1 depletion, and in vivo treatment of PTDSS2-deleted tumors with these inhibitors led to tumor regression. Whole-transcriptome analysis revealed that inhibition of PTDSS1 in PTDSS2-depleted cells activated the endoplasmic reticulum (ER) stress response downstream of PS depletion. ER stress-mediated cell death induced by PTDSS1 inhibitors activated tumor immunity through the secretion of HMGB1 protein followed by activation of bone marrow-derived dendritic cells. PTDSS2 loss showed intratumoral heterogeneity in clinical samples, raising concerns about resistance to PTDSS1 inhibition. However, the PTDSS1 inhibitor effectively suppressed the growth of tumor containing both PTDSS2 wild-type and knockout cells in immunocompetent mice, showing potency for overcoming tumor heterogeneity by modulating the tumor immune microenvironment. Thus, these newly developed PTDSS1 inhibitors provide a therapeutic option for treating cancer with PTDSS2 loss, harnessing the synthetic lethality of PTDSS1/2. Significance: This study identifies a specific dependency on PTDSS1 for phosphatidylserine synthesis following PTDSS2 deletion and introduces novel PTDSS1 inhibitors as a therapeutic option to induce collateral lethality in cancer with PTDSS2 loss.

Visible-light- and thermal-stimuli-responsive properties of a host–guest system were investigated based on ruthenium aqua complexes bearing two alkyl chains.

e21175 Background: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is a standard first-line therapy for activated EGFR-mutated non-small-cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance and is hence a promising target for anticancer treatment. Patritumab deruxtecan (HER3-DXd) is an antibody drug conjugate comprised of a fully human anti-HER3 IgG1 monoclonal antibody, covalently linked to a topoisomerase 1 inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker. Clinical trials of theHER3-DXd demonstrated its anticancer activity in EGFR-mutated NSCLC. However, the genomic background that regulates HER3 expression is unknown. This study was conducted with the aim to clarify the genomic background for HER3 regulation in EGFR-mutated NSCLC tumors and to explore the strategy for enhancing the anticancer activity of HER3-DXd. Methods: 48 paired samples were obtained before EGFR-TKI treatment and after the acquisition of EGFR-TKI resistance from patients with EGFR-mutated NSCLC. HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pre-treatment to post-EGFR-TKI resistance acquisition. For statistical tests, linear regression analysis was performed to investigate whether a factor, including EGFR-TKI administration, affected HER3 expression. Pearson correlation coefficients were calculated to explore the relationships between HER3 expression level and other genomic expression in the tumors. Results: We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared to paired pretreatment samples (mean H-score 100.8 vs. 155.9, paired t-test p = 0.0007). Although genomic alterations including EGFR secondary T790M mutation did not correlate with HER3 augmentation, RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation (GSEA; normalized enrichment score -1.78, p = 0.004). Multivariable regression analysis of HER3 augmentation revealed that re-biopsy under continuing EGFR-TKI treatment independently effected HER3 augmentation. Indeed, an in-vitro study also showed that EGFR-TKI increased HER3 expression via repressed AKT phosphorylation in multiple EGFR-mutated cancers, and it finally enhanced the anticancer activity of HER3-DXd. Conclusions: Our findings highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC that is currently being evaluated in a clinical trial for patients with EGFR-mutated NSCLC tumors, not only with regard to an acquired resistance to EGFR-TKI but also in EGFR-TKI-naïve tumors (NCT04676477).