The effect of axial length on the short-term outcomes of cataract surgery combined with ab interno trabeculotomy.

PURPOSE: Minimally invasive glaucoma surgery is safer and effective surgical modality for patients with glaucoma. To compare the effect of axial length (AL) on the surgical outcomes of combined cataract surgery and ab interno trabeculotomy (phaco-LOT), a retrospective, non-randomized comparative study was performed. METHODS: In total, 458 eyes of 458 open-angle glaucoma patients who underwent phaco-LOT and were followed-up without any intervention for at least 6 months were enrolled. All were divided into a long-AL group (AL ≥ 26.0 mm, 123 eyes) and a not-long-AL group (AL < 26.0 mm, 335 eyes). The principal outcomes were the changes in intraocular pressure (IOP) and medication scores. We also sought a correlation between postoperative IOP spike and hyphema. RESULTS: Significant postoperative reductions in IOP and medication scores were apparent in all subjects. The IOP reductions were significant at all timepoints in the not-long-AL group, but not until 1 month postoperatively in the long-AL group, and the IOP change was significantly lower in the long-AL group from postoperative day 1 to 3 months. On subanalysis of subjects by age, the microhook used, the pre-operative IOP, and the medication score, a significantly higher incidence of IOP spike was observed in the long-AL group in weeks 1 and 2 (both p < 0.05), but this did not correlate with hyphema status, implying that a different mechanism was in play. CONCLUSION: Phaco-LOT was effective regardless of AL, but the postoperative IOP decrease was lower and the early postoperative incidence of IOP spike was higher in long-AL eyes.

Recent preclinical and clinical advances in radioimmunotherapy for non-Hodgkin's lymphoma.

Radioimmunotherapy (RIT) is a therapy that combines a radioactive nucleotide with a monoclonal antibody (mAb). RIT enhances the therapeutic effect of mAb and reduces toxicity compared with conventional treatment. The purpose of this review is to summarize the current progress of RIT for treating non-Hodgkin's lymphoma (NHL) based on recent preclinical and clinical studies. The efficacy of RIT targeting the B-lymphocyte antigen cluster of differentiation 20 (CD20) has been demonstrated in clinical trials. Two radioimmunoconjugates targeting CD20, yttrium-90 (90Y)-ibritumomab-tiuxetan (Zevalin) and iodine-131 (131I)-tositumomab (Bexxar), have been approved in the USA Food and Drug Administration (FDA) for treating relapsed/refractory indolent or transformed NHL in 2002 and 2003, respectively. Although these two radioimmunoconjugates are effective and least toxic, they have not achieved popularity due to increasing access to novel therapies and the complexity of their delivery process. RIT is constantly evolving with the identification of novel targets and novel therapeutic strategies using newer radionuclides such as alpha-particle isotopes. Alpha-particles show very short path lengths and high linear energy transfer. These characteristics provide increased tumor cell-killing activities and reduced non-specific bystander responses on normal tissue. This review also discusses reviewed pre-targeted RIT (PRIT) and immuno-positron emission tomography (PET). PRIT potentially increases the dose of radionuclide delivered to tumors while toxicities to normal tissues are limited. Immuno-PET is a molecular imaging tracer that combines the high sensitivity of PET with the specific targeting capability of mAb. Immuno-PET strategies targeting CD20 and other antigens are currently being developed. The theragnostic approach by immuno-PET will be useful in monitoring the treatment response.

PAX5 functions as a tumor suppressor by RB-E2F-mediated cell cycle arrest in Kaposi sarcoma-associated herpesvirus-infected primary effusion lymphoma.

Primary effusion lymphoma (PEL) is a malignant B-cell lymphoma attributable to Kaposi sarcoma-associated herpesvirus (KSHV) infection. PEL is characterized by invasive behavior, showing recurrent effusions in body cavities. The clinical outcome and typical prognosis in patients with PEL are poor and potentially lethal. Clarification of the pathogenesis in PEL is urgently needed in order to develop novel therapies. PEL cells generally lack B-cell surface markers, and we therefore hypothesized that the B-cell transcription factor, PAX5, would be down-regulated in PEL. The expression of PAX5 is detected from the pro-B to the mature B-cell stage and is indispensable for the differentiation of B-cells. PAX5 was silenced in PEL cells via its promoter methylation. Up-regulation of PAX5 induced several genes coding for B-cell surface marker mRNA, but not protein level. PAX5 inhibited cell growth via G1 cell cycle arrest. PAX5 bound to RB and increased its protein expression. RB/E2F-regulated genes were significantly down-regulated in microarray analysis and PCR experiments. To elucidate the in vivo role of PAX5, we examined the restoration of PAX5 in a PEL mouse model. The ascites volume and organ invasions were significantly suppressed by PAX5 restoration. Reduction of PAX5 has played a crucial role in the oncogenesis of PEL, and PAX5 is a tumor suppressor in PEL. Targeting PAX5 could represent a novel therapeutic strategy for patients with PEL.

Prognostic Impact of Previous Atherosclerotic Cardiovascular Disease on Short- and Long-Term Outcomes in Acute Myocardial Infarction.

Patients with previous atherosclerotic cardiovascular disease (ASCVD) are typically managed by secondary prevention modalities; however, they may experience recurrent events. In acute myocardial infarction (MI), the prognostic effect of preexisting ASCVD on the short- and long-term outcomes remains uncertain. This retrospective, multicenter registry included 2,475 patients with acute MI who underwent percutaneous coronary intervention. Previous ASCVD was defined as a history of ischemic events in the coronary, cerebral, and peripheral arterial territories. Patients were divided into 2 groups according to preexisting ASCVD. The primary end point was major adverse cardiovascular events (MACEs), defined as a composite of cardiovascular death, recurrent MI, and ischemic stroke during hospitalization and after discharge. The bleeding outcomes were also evaluated. Of the 2,475 patients, 475 (19.2%) had previous ASCVD. Patients with previous ASCVD were older and likely to have more co-morbidities than those without ASCVD. During hospitalization, the MACE rates were higher in the ASCVD group than in the non-ASCVD group (16.4% vs 9.6%, p <0.001). Similarly, during a median follow-up of 542 days after discharge, patients with previous ASCVD had an increased risk of MACEs than those without ASCVD (13.4% vs 5.6%, p <0.001). The multivariable analyses identified previous ASCVD as a factor that was significantly associated with MACEs after discharge. Major bleeding events occurred more frequently in the ASCVD group than in the non-ASCVD group. In conclusion, preexisting ASCVD was often observed in patients with acute MI and was particularly associated with long-term ischemic outcomes after discharge; thus, further clinical investigations are needed in this vulnerable patient subset.

Differential Prognostic Impact of Risk-Prediction Models for Heart Failure in Acute Myocardial Infarction: The Original and Revised Heart Failure Time-Points.

Background: We previously developed a risk-scoring system for heart failure (HF) in patients with acute myocardial infarction (MI), namely "HF time-points (HFTPs)". In the original HFTPs, the presence of HF on admission, during hospitalization, and at short-term follow-up was individually scored. This study examined whether the revised HFTPs, with additional scoring of previous HF, provide better predictivity. Methods: This multicenter registry included a total of 1331 patients with acute MI undergoing percutaneous coronary intervention. HF was evaluated at four time-points before and after acute MI onset: (1) a history of HF; (2) elevated natriuretic peptide levels on admission; (3) in-hospital HF events; and (4) elevated natriuretic peptide levels at a median of 31 days after the onset. When HF was present at each time-point, one point was assigned to a risk scoring system, namely the original and revised HFTPs, ranging from 0 to 3 and from 0 to 4. The primary endpoint was a composite of cardiovascular death and HF rehospitalization after discharge. Results: Of the 1331 patients, 65 (4.9%) had the primary outcome events during a median follow-up period of 507 (interquartile range, 335-1106) days. The increase in both original and revised HFTPs was associated with an increased risk of the primary outcomes in a stepwise fashion with similar diagnostic ability. Conclusions: The original and revised HFTPs were both predictive of long-term HF-related outcomes in patients with acute MI undergoing percutaneous coronary intervention. Yet, the original HFTPs may be sufficient to estimate HF risks after MI.

Cardiogenic shock in takotsubo syndrome: etiology and treatment.

Takotsubo syndrome (TTS) can mimic acute coronary syndrome despite being a distinct disease. While typically benign, TTS can lead to serious complications like cardiogenic shock. Cardiogenic shock occurs in 1-20% of TTS cases. Various mechanisms can cause shock, including pump failure, right ventricular involvement, left ventricular outflow tract obstruction, and acute mitral regurgitation. Because treatment depends on the mechanism, early identification of the mechanism developing cardiogenic shock is essential for optimal treatment and improved outcomes in TTS patients with cardiogenic shock. This review summarizes current knowledge on causes and treatment of cardiogenic shock in patients with TTS.

Impact of Cancer, Inflammation, and No Standard Risk Factors in Patients With Myocardial Infarction.

Background: The lack of standard modifiable cardiovascular risk factors (SMuRFs), including hypertension, diabetes, dyslipidemia, and smoking, is reportedly associated with poor outcomes in acute myocardial infarction (AMI). Among patients with no SMuRFs, cancer and chronic systemic inflammatory diseases (CSIDs) may be major etiologies of AMI. Objectives: The purpose of this study was to evaluate clinical characteristics and outcomes of patients with cancer, CSIDs, and no SMuRFs in AMI. Methods: This multicenter registry included 2,480 patients with AMI undergoing percutaneous coronary intervention. Patients were divided into 4 groups: active cancer, CSIDs, no SMuRFs, and those remaining. The coprimary endpoint was major adverse cardiovascular events (MACE) and major bleeding events, during hospitalization and after discharge. Results: Of 2,480 patients, 104 (4.2%), 94 (3.8%), and 120 (4.8%) were grouped as cancer, CSIDs, and no SMuRFs, respectively. During the hospitalization, MACE rates were highest in the no SMuRFs group, followed by the cancer, CSIDs, and SMuRFs groups (22.5% vs 15.4% vs 12.8% vs 10.2%; P < 0.001), whereas bleeding risks were highest in the cancer group, followed by the no SMuRFs, CSIDs, and SMuRFs groups (15.4% vs 10.8% vs 7.5% vs 4.9%; P < 0.001). After discharge, the rates of MACE (33.3% vs 22.7% vs 11.3% vs 9.2%; P < 0.001) and bleeding events (8.6% vs 6.7% vs 3.8% vs 2.9%; P = 0.01) were higher in the cancer group than in the CSIDs, no SMuRFs, and SMuRFs groups. Conclusions: Patients with active cancer, CSIDs, and no SMuRFs differently had worse outcomes after AMI in ischemic and bleeding endpoints during hospitalization and/or after discharge, compared with those with SMuRFs.

Long-term course of untreated asymptomatic esophageal eosinophilia and minimally symptomatic eosinophilic esophagitis.

Background and study aims The long-term course of untreated asymptomatic esophageal eosinophilia (aEE) and minimally symptomatic eosinophilic esophagitis (mEoE) are not well understood. This study aimed to clarify this course. Patients and methods A total of 36 patients with EE who were endoscopically followed up for more than 5 years, and who underwent more than one endoscopy evaluation after the first diagnosis, were investigated. These patients were divided into two groups according to the presence or absence of the continuous treatment: no treatment group (NT group, n=22) and proton pump inhibitor/potassium competitive acid blocker group (Tx group, n=14). Symptoms and endoscopic and histological findings were retrospectively reviewed according to endoscopic phenotypes. Endoscopic assessment was performed using the EoE endoscopic reference score (EREFS). Results The median follow-up period was 84.5 months in the Tx group and 92 months in the NT group. During the follow-up period, about half of the patients in the Tx-diffuse group persisted EREFS >3, while the remaining half had EREFS ≤2. The total EREFS in the NT-diffuse group remained almost unchanged (median: 2-4) without apparent exacerbation. In contrast, EREFS in the NT-localized group exhibited an unchanged or gradually decreasing trend, with statistical significance from the first diagnosis to 72 to 83 months after. Conclusions Untreated aEE and mEoE are not likely to worsen even without treatment at least for a median follow-up of 7 years. Instead, the localized type may spontaneously improve, implying a different pathogenesis in the presence of the diffuse type. Further studies should clarify the long-term prognosis.

Young Patient with X-linked Agammaglobulinemia Presents with Advanced Gastric Cancer and Extensive Atrophic Gastritis.

X-linked agammaglobulinemia (XLA) is associated with an increased risk of gastrointestinal cancers including gastric cancer (GC). We herein report the case of a 30-year-old male patient with XLA who developed GC and extensive atrophic gastritis. He tested positive in the urea breath test, thus indicating the presence of Helicobacter pylori. Distal gastrectomy and chemotherapy were performed without any complications; however, the died two years after this diagnosis. Immunoglobulin deficiency makes these patients susceptible to progressive atrophic gastritis and the associated risk of GC. Therefore, patients with XLA are advised to undergo an evaluation for Helicobacter pylori infection as well as monitoring for GC.

Effect of hyperuricemia on paroxysmal atrial fibrillation after catheter ablation and influence of alcohol consumption.

Background: Evidence regarding the association between hyperuricemia and arrhythmia recurrence after catheter ablation for paroxysmal atrial fibrillation (AF) is scarce. We investigated whether hyperuricemia predicts arrhythmia recurrence after catheter ablation for paroxysmal AF and the relationship between hyperuricemia and alcohol consumption in AF recurrence. Methods: Patients who underwent catheter ablation for paroxysmal AF were divided into the hyperuricemia (index serum uric acid [UA] >7.0 mg/dL; n = 114) and control (UA ≤7.0 mg/dL; n = 609) groups and were followed for a median of 24 (12-48) months after ablation. Results: The hyperuricemia group had more patients with an alcohol intake of ≥20 g/day (33.3% vs. 22.7%, p = .017) and a lower incidence of AF-free survival (p = .019). Similarly, those with an alcohol intake of ≥20 g/day had a lower incidence of AF-free survival than other patients. Multivariate Cox regression analysis revealed the following independent predictors of AF recurrence (adjusted hazard ratio, 95% confidence interval): hyperuricemia (1.64, 1.12-2.40), female gender (1.91, 1.36-2.67), brain natriuretic peptide level >100 pg/mL (1.59, 1.14-2.22), and alcohol consumption ≥20 g/day (1.49, 1.03-2.15) (all p < .05). In addition, causal mediation analysis revealed that alcohol consumption of ≥20 g/day directly affected AF recurrence, independent of hyperuricemia. Conclusions: Patients with hyperuricemia may be at a high risk of arrhythmia recurrence after catheter ablation for paroxysmal AF. Although high alcohol consumption may contribute to increased UA levels, the presence of hyperuricemia may independently predict AF recurrence.

Expression of fibroblast activation protein-α in human deep vein thrombosis.

BACKGROUND: Fibroblast activation protein-α (FAP), a type-II transmembrane serine protease, is associated with wound healing, cancer-associated fibroblasts, and chronic fibrosing diseases. However, its expression in deep vein thrombosis (DVT) remains unclear. Therefore, this study investigated FAP expression and localization in DVT. METHODS: We performed pathological analyses of the aspirated thrombi of patients with DVT (n = 14), classifying thrombotic areas in terms of fresh, cellular lysis, and organizing reaction components. The organizing reaction included endothelialization and fibroblastic reaction. We immunohistochemically examined FAP-expressed areas and cells, and finally analyzed FAP expression in cultured dermal fibroblasts. RESULTS: All the aspirated thrombi showed a heterogeneous mixture of at least two of the three thrombotic areas. Specifically, 83 % of aspirated thrombi showed fresh and organizing reaction components. Immunohistochemical expression of FAP was restricted to the organizing area. Double immunofluorescence staining showed that FAP in the thrombi was mainly expressed in vimentin-positive or α-smooth muscle actin-positive fibroblasts. Some CD163-positive macrophages expressed FAP. FAP mRNA and protein levels were higher in fibroblasts with low-proliferative activity cultured under 0.1 % fetal bovine serum (FBS) than that under 10 % FBS. Fibroblasts cultured in 10 % FBS showed a significant decrease in FAP mRNA levels following supplementation with hemin, but not with thrombin. CONCLUSIONS: The heterogeneous composition of venous thrombi suggests a multistep thrombus formation process in human DVT. Further, fibroblasts or myofibroblasts may express FAP during the organizing process. FAP expression may be higher in fibroblasts with low proliferative activity.

Time Course of Left Ventricular Strain Assessment via Cardiovascular Magnetic Resonance Myocardial Feature Tracking in Takotsubo Syndrome.

Background: Although takotsubo syndrome (TTS) is characterized by transient systolic dysfunction of the left ventricle (LV), the time course and mechanism of LV function recovery remain elusive. The aim of this study is to evaluate cardiac functional recovery in TTS via serial cardiac magnetic resonance feature tracking (CMR-FT). Methods: In this Japanese multicenter registry, patients with newly diagnosed TTS were prospectively enrolled. In patients who underwent serial cardiovascular magnetic resonance (CMR) imaging at 1 month and 1 year after the onset, CMR-FT was performed to determine the global circumferential strain (GCS), global radial strain (GRS) and global longitudinal strain (GLS). We compared LV ejection fraction, GCS, GRS and GLS at 1 month and 1 year after the onset of TTS. Results: Eighteen patients underwent CMR imaging in one month and one year after the onset in the present study. LV ejection fraction had already normalized at 1 month after the onset, with no significant difference between 1 month and 1 year (55.8 ± 9.2% vs. 58.9 ± 7.3%, p = 0.09). CMR-FT demonstrated significant improvement in GCS from 1 month to 1 year (-16.7 ± 3.4% vs. -18.5 ± 3.2%, p < 0.01), while there was no significant difference in GRS and GLS between 1 month and year (GRS: 59.6 ± 24.2% vs. 59.4 ± 17.3%, p = 0.95, GLS: -12.8 ± 5.9% vs. -13.8 ± 4.9%, p = 0.42). Conclusions: Serial CMR-FT analysis revealed delayed improvement of GCS compared to GRS and GLS despite of rapid recovery of LV ejection fraction. CMR-FT can detect subtle impairment of LV systolic function during the recovery process in patients with TTS.

Decreased Abundance of Genus Slackia in Individuals With Obesity and Colorectal Adenoma.

Background and Aims: The increasing prevalence of obesity has significantly contributed to the global burden of colorectal cancer and the precancerous colorectal adenoma (CRA). Gut microbiota vary at each stage of colorectal carcinogenesis and participate in energy homeostasis. Elucidating gut microbiotal characteristics in obesity-related CRA may help prevent and treat colorectal tumors; however, this remains unclarified. Therefore, this study investigated the gut microbiota profile of patients with obesity-related CRA. Methods: This hospital setting-based cross-sectional study included 113 participants (66 [without CRA control group] and 37 [with CRA group]; each group was divided into obese and nonobese groups) who underwent screening colonoscopy between June 2019 and January 2020. Gut microbiota were analyzed using 16S rRNA and polymerase chain reaction techniques and the data compared between the aforementioned groups. Results: No between-group difference was observed in the diversity index; however, α diversity was the lowest in the obese CRA group. The CRA group had significantly higher and lower numbers of 26 and 17 genera, respectively. Genus Slackia was significantly lower in the obese CRA group than in the nonobese CRA group. Multivariate analysis of the quartiles according to genus Slackia relative abundance rates revealed that the first quartile was an independent risk factor for CRA (odds ratio, 3.57; 95% confidence interval 1.19-10.7). The proportion of equol reductase-positive participants was lowest in the obese CRA group (P = .04). Multivariate odds ratio for CRA was 5.46 (95% confidence interval 1.35-22.0) for genus Slackia and equol reductase-negative participants. Conclusion: Decreased abundance of genus Slackia and absence of equol reductase potentially influence obesity-related CRA development.

Novel ERBB2 Variant Potentially Associated with Resistance against Anti-HER2 Monoclonal Antibody-Based Therapy in ERBB2-Amplified Metastatic Colorectal Cancer.

PURPOSE: HER2-targeted therapies in ERBB2-amplified metastatic colorectal cancer (mCRC) are effective; however, a notable portion of patients do not respond to treatment, and secondary resistance occurs in most patients receiving these treatments. The purpose of this study was to investigate determinants of treatment efficacy and resistance in patients with ERBB2-amplified mCRC who received HER2-targeted therapy by analyzing multiomics data. EXPERIMENTAL DESIGN: We investigated genomic data from a nationwide large cancer genomic screening project, the SCRUM-Japan project. We analyzed paired genome and transcriptome data of tissue and genomic data of ctDNA collected pre- and postprogression in patients enrolled in the related trial, TRIUMPH, in ERBB2-amplified mCRC. RESULTS: In 155 patients with ERBB2-amplified solid tumors who received HER2-targeted therapy based on the SCRUM-Japan project, the objective response rate was 50%, 51%, and 35% in ERBB2 wild-type, variant of unknown significance, and pathogenic variant groups, respectively. In the paired genome and transcriptome data analyses in TRIUMPH, we identified the novel splicing-associated variant c.644-66_-2del in one of the 11 patients with paired whole-exome sequencing and whole-transcriptome sequencing data sets, which lacks the binding domain of pertuzumab, in progressed metastatic tumor as a variant with potential pathogenicity. The time-course ctDNA analysis detected c.644-66_-2del as an acquired variant. CONCLUSIONS: This study highlighted the importance of ERBB2 genomic status when evaluating the efficacy of HER2-targeted therapies in ERBB2-amplified mCRC. The identification of a novel splicing-associated variant may provide insights into potential mechanisms of treatment resistance. Furthermore, we demonstrated the utility of ctDNA to follow the acquired genomic status of mCRC tumors.

Cationic indium catalysis as a powerful tool for generating α-alkyl propargyl cations for SN1 reactions.

Dehydration is an abundant and promising process in chemical, biochemical, and industrial fields. Dehydration methods can contribute to building a modern and sustainable society with minimal environmental impact. Breakthrough advances in the dehydrative SN1 reaction can be achieved through the discovery of new cationic indium catalysts. Here we show that the breakthrough advances in the dehydrative SN1 reaction can be achieved using the cationic indium catalysts. The dehydrative carbon-carbon bond formation of α-alkyl propargyl alcohols afforded a wide variety of α-aryl- and heteroaryl-propargyl compounds. Mechanistic investigations into this process revealed that the InCl3/AgClO4/Bu4NPF6/1,1'-binaphthol catalytic system generated a powerful cationic indium catalyst that could promote the dehydration of alcohols. Labile α-alkyl propargyl cations were found to self-condense, and the catalyst system efficiently regenerated propargyl cations for reaction with nucleophiles. This propargylation reaction directly proceeded from the corresponding alcohols under mild and open-air conditions and tolerated a broad scope of functional groups. Furthermore, a wide variety of nucleophiles, including aromatic and heteroaromatic compounds, phenols, alcohols, and sulfonamides, reacted with the corresponding cations to afford the propargyl compounds in good to high yields. Finally, the synthetic utility of this reaction was demonstrated by the synthesis of colchicine and allocolchicine analogues. The dehydration process could help create new compounds that were previously impossible to synthesize and is more eco-friendly and efficient than conventional methods.