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Abstract Background Although the incidence of lung cancer in elderly individuals has been increasing in recent years, the number of clinical trials designed specifically for elderly patients with advanced non‐small cell lung cancer (NSCLC) is still limited. To fulfill this unmet medical need, we conducted a phase II study to elucidate the efficacy of pemetrexed (PEM) plus bevacizumab (Bev) combination chemotherapy in elderly patients with nonsquamous NSCLC. Methods A total of 29 elderly patients (≥75 years old) with nonsquamous NSCLC were enrolled in this multicenter, open‐label, phase II study, and 27 patients were finally analyzed. PEM at 500 mg/m2 on day 1 plus Bev at 15 mg/kg on day 1 were administered triweekly. The primary endpoint was the investigator‐assessed objective response rate. Results The median age at initiating chemotherapy was 80 years old. Almost all patients (92.6%) had adenocarcinoma histology. The median number of cycles administered was 6, and the objective response rate was 40.7%. The median progression‐free survival, overall survival and 1‐year survival were 8.8 months, 27.2 months and 79%, respectively. The treatment was well‐tolerated, and no treatment‐related death was observed. Conclusion Combination chemotherapy with PEM plus Bev in elderly patients with previously untreated advanced non‐squamous NSCLC exhibited favorable antitumor activity and tolerability, suggesting that a combination of PEM plus Bev might be a promising treatment option for this population.

Aim: The 22q11.2 deletion syndrome (22q11DS) is associated with a high prevalence of mental health comorbidities. However, not enough attention has been paid to the elevated prevalence of high trait anxiety that begins early in life and may be enduring. We sought to identify specific medical, welfare, or educational difficulties associated with high trait anxiety in 22q11DS., Methods: A questionnaire-based survey was conducted for the parents of 22q11DS individuals ( N  = 125). First, a multiple regression analysis was conducted to confirm the hypothesis that high trait anxiety in individuals with 22q11DS would be associated with parents' psychological distress. This was based on 19 questionnaire options regarding what difficulties the parents currently face about their child's disease, characteristics, and traits. Next, we explored what challenges faced in medical, welfare, and educational services would be associated with the trait anxiety in their child., Results: The multiple regression analysis confirmed that the high trait anxiety was significantly associated with parental psychological distress ( β  = 0.265, p  = 0.018) among the 19 clinical/personal characteristics of 22q11DS. Furthermore, this characteristic was associated with various difficulties faced in the medical care, welfare, and education services, and the parent-child relationship., Conclusion: To our knowledge, this is the first study to clarify quantitatively how the characteristic of high anxiety level in 22q11DS individuals is related to the caregivers' perceived difficulties in medical, welfare, and educational services. These results suggest the necessity of designing service structures informed of the fact that high trait anxiety is an important clinical feature of the syndrome., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Background: Interatrial conduction time (IACT) prolongs in fibrotic left atrium. We tested the hypothesis that IACT is related to left atrial low voltage area (LVA) and predicts the recurrence after single atrial fibrillation (AF) ablation., Methods: One hundred sixty-four consecutive AF patients (79 non-paroxysmal) who underwent initial ablation in our institute were analyzed. IACT and LVA were defined as interval from the onset of P-wave to the basal left atrial appendage (P-LAA) activation, and area with bipolar electrogram < 0.5 mV covering over 5% of the total left atrial surface area during sinus rhythm, respectively. Pulmonary vein antrum isolation, non-PV foci ablation, and atrial tachycardia (AT) ablation were performed without substrate modification., Results: LVA was frequently identified in patients with prolonged P-LAA ≥ 84 ms ( n  = 28) compared with patients with P-LAA < 84 ms ( n  = 136). Patients with P-LAA ≥ 84 ms were older (71 ± 10 vs. 65 ± 10 years, p  = .0061), and had more frequent non-paroxysmal AF (75% vs. 43%, p  = .0018), larger left atrial diameter (43.5 ± 4.5 vs. 39.3 ± 5.7 mm, p  = .0003), and higher E/e' ratio (14.4 ± 6.5 vs. 10.5 ± 3.7, p  < .0001) compared with P-LAA < 84 ms patients. After a mean follow-up period of 665 ± 153 days, Kaplan-Meier curve analysis showed that AF/AT recurrences was more frequently observed in patients with prolonged P-LAA (Log-rank p  = .0001). Additionally, univariate analysis revealed that P-LAA prolongation (OR = 1.055 per 1 ms, 95% CI: 1.028-1.087, p  < .0001) and the existence of LVA (OR = 5.000, 95% CI: 1.653-14.485 p  = .0053) were predictors of AF/AT recurrences after single AF ablation., Conclusions: Our results suggested that prolonged IACT as measured by P-LAA was associated with LVA and predicts AT/AF recurrence after single AF ablation., Competing Interests: All authors have no conflict of interest related to the present study., (© 2023 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Background: Catheter ablation (CA) for atrial fibrillation (AF) can be associated with a risk of thromboembolism and bleeding. We recently demonstrated that uninterrupted edoxaban with one dose delayed on the CA procedural day is associated with a low risk of periprocedural complications. Previous reports have indicated that some specific subgroups of patients undergoing CA have an increased risk of bleeding and thromboembolic complications. This subanalysis of the KYU-RABLE study assessed the changes in plasma concentrations of edoxaban and coagulation biomarkers during the periprocedural period of CA in subgroups stratified by the risk of thromboembolism assessed by CHADS 2 score (<2 or ≥2) and AF type (paroxysmal AF [PAF] or non-PAF)., Methods: We evaluated changes in plasma concentrations of edoxaban and coagulation biomarkers (D-dimer and prothrombin fragment F1+2), by subgroup, during the periprocedural period of CA. Measurements were made prior to CA (procedure day)., Results: This subanalysis evaluated data from 343 patients with CHADS 2 score <2 and 134 patients with CHADS 2 score ≥2, and from 280 patients with PAF and 197 patients with non-PAF. Plasma edoxaban concentration decreased with time on the day of CA, while plasma concentrations of coagulation biomarkers remained unchanged. No significant differences were observed according to CHADS 2 score or type of AF., Conclusions: The changes in plasma concentrations of edoxaban and coagulation biomarkers in each subgroup were similar to those of the whole analysis, regardless of the thromboembolic risk (CHADS 2 <2 or ≥2) or AF type (PAF or non-PAF)., Competing Interests: NT has received remuneration from Daiichi Sankyo, Bristol‐Myers Squibb, Pfizer Japan, and received research funding from Ono Pharmaceutical. YM has received remuneration from Daiichi Sankyo, Bristol‐Myers Squibb, and Nippon Boehringer Ingelheim. KO has received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. TK, KY, and AT are employees of Daiichi Sankyo. TS and HO have nothing to disclose. IRB Approval number: B17‐021. IRB Approval date: 12 December 2017., (© 2020 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.)

Background: It is common to develop heart failure (HF) events even in respondents to cardiac resynchronization therapy (CRT) during a long-term observation period. We investigated the predictors for long-term outcome in responders in comparison with nonresponders in patients diagnosed with HF along with implanted CRT., Methods: We enrolled 133 consecutive patients (mean age, 70 ± 10 years; 72 males) implanted with CRT from April 2010 to July 2019. Accurate follow-up information (mean follow-up period, 983 ± 801 days) was obtained from 66 responders and 53 nonresponders., Results: Kaplan-Meier event-free curves showed that major adverse cerebral and cardiovascular event (MACCE)-free ratio was significantly lower as the stage of renal function progresses (log rank, 19.5; P  < .0001). The baseline estimated glomerular filtration rate (e-GFR) before CRT was not significantly different between nonresponders and responders. The e-GFR after judgment of CRT response was lower in patients with MACCEs than those without. Cox proportional hazards regression analysis revealed that low baseline e-GFR before CRT and after judgment of CRT response was closely related with MACCEs in responders, but not in nonresponders. The survival rate in responders without MACCEs assessed using Kaplan-Meier analysis was significantly larger in the preserved e-GFR (baseline value before CRT, >44 mL/min/1.73 m 2 ) group than in the depressed group (log rank, 20.29; P  < .0001)., Conclusion: We demonstrate that the factors for MACCEs during long follow-up periods were distinctively different between responders and nonresponders. Patients with depressed e-GFRs are suggested to have poor prognosis even if they are responders to CRT., Competing Interests: The authors have no conflict of interest. This study was approved by the institutional review board (IRB) of Oita University, and the IRB approval number was B11‐053., (© 2020 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.)

The aim of this study was to investigate whether a dual endothelin receptor antagonist bosentan modulates the kinetics of bone marrow-derived stem cells in inhibiting the development of pulmonary hypertension. Bone marrow chimeric mice, transplanted with enhanced green fluorescent protein (eGFP)-positive bone marrow mononuclear cells, were exposed to hypobaric hypoxia or kept in the ambient air, and were daily treated with bosentan sodium salt or saline for 21 days. After the treatment period, right ventricular pressure was measured and pulmonary vascular morphometry was conducted. Incorporation of bone marrow-derived cells was analyzed by immunohistochemistry. Gene expression and protein level in the lung tissue were evaluated by quantitative real-time PCR and western blotting, respectively. The results showed that, in hypoxic mice, right ventricular pressure and the percentage of muscularized vessel were increased and pulmonary vascular density was decreased, each of which was reversed by bosentan. Bone marrow-derived endothelial cells and macrophages in lungs were increased by hypoxia. Bosentan promoted bone marrow-derived endothelial cell incorporation but inhibited macrophage infiltration into lungs. Quantitative real-time PCR analysis revealed that interleukin 6, stromal cell-derived factor-1, and monocyte chemoattractant protein-1 were upregulated by hypoxia, in which interleukin 6 and monocyte chemoattractant protein-1 were downregulated and stromal cell-derived factor-1 was upregulated by bosentan. Protein level of endothelial nitric oxide synthase (eNOS) in the whole lung was significantly upregulated by hypoxia, which was further upregulated by bosentan. Bosentan modulated kinetics of bone marrow-derived ECs and macrophages and related gene expression in lungs in ameliorating pulmonary hypertension in mice. Altered kinetics of bone marrow-derived stem cells may be a novel mechanism of the endothelin receptor blockade in vivo and confer a new understanding of the therapeutic basis for pulmonary hypertension., (© The Author(s) 2020.)

Introduction: We examined the perinatal outcomes and right ventricular function before pregnancy, during pregnancy, and after delivery in women with Ebstein's anomaly., Material and Methods: We retrospectively investigated the clinical course and mode of delivery and monitored hemodynamic parameters throughout pregnancy in 17 women with Ebstein's anomaly who delivered at our institution during the period of 1995-2015., Results: Eight women, including nine pregnancies, underwent elective cesarean section, and nine women, including 14 pregnancies, underwent vaginal delivery. Elective cesarean section was performed in cases with significant heart failure or arrhythmias and in the presence of more than two of the following: cardiothoracic ratio ≥60%, moderate or severe tricuspid valve regurgitation, tricuspid valve regurgitation pressure gradient ≥35 mmHg during pregnancy. The cardiothoracic ratio and tricuspid valve regurgitation pressure gradient significantly increased during pregnancy compared with prepregnancy values. The New York Heart Association classification deteriorated from class I to class II or III in five cases during pregnancy., Conclusions: Although pregnancy was relatively safe among women with Ebstein's anomaly, some women developed cyanosis, arrhythmia, and heart failure, leading to elective cesarean section. Monitoring clinical and hemodynamic changes throughout pregnancy is advised to minimize maternal cardiac risk and select the appropriate mode of delivery., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

This case report describes a 19-year-old man with early repolarization (ER) in the inferolateral leads and a normal QT interval who survived a cardiac arrest that was likely related to polymorphic ventricular tachycardia (VT). Electrocardiograms (ECGs) also showed unifocal premature ventricular beats (PVBs) with a relatively narrow QRS duration. A Holter ECG documented occasional short-coupled PVBs following non-sustained VTs. Pharmacological stress testing was also performed to assess the effects of anti-arrhythmic drugs on ER (the J wave) and PVBs. We performed successful radiofrequency catheter ablation to prevent the recurrence of ventricular fibrillation after cardioverter-defibrillator implantation.

Background: Caveolin-1 plays a regulatory role in several signaling pathways. Recently caveolin-1 was identified as a metastasis-related gene in prostate carcinoma. However, the clinical impact of caveolin-1 expression in esophageal carcinoma remains unknown., Methods: One hundred thirty surgical specimens of esophageal squamous cell carcinoma were immunohistochemically assessed for caveolin-1 expression by polyclonal antibody. Caveolin-1 immunoreactivity was correlated with patients' clinicopathologic parameters and outcome., Results: Positive caveolin-1 immunostaining was detected in 58 patients (44.6%). Positive caveolin-1 immunostaining correlated positively with pathologic stage (P = 0.029), pN (P = 0.023), and pM (P = 0.018). The overall survival rate was worse in patients with caveolin-1-positive tumors than in patients with caveolin-1-negative tumors (P = 0.0215). Univariate analyses identified caveolin-1 positivity (P = 0.0238), pT (P = 0.0002), pN (P < 0.0001), pM (P = 0.0002), lymphatic invasion (P = 0.0021), and positive surgical margin (P < 0.0001) as negative prognostic predictors. Multivariate analyses indicated that pT (P = 0.0296), pN (P = 0.0003), and a positive surgical margin (P = 0.0452) were independent prognostic factors., Conclusions: Over-expression of caveolin-1 is associated with lymph node metastasis and a worse prognosis after surgery in esophageal squamous cell carcinoma., (Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10329)

Highly enantioselective asymmetric hydrogenation of readily accessible olefins, (E)- and (Z)-[1-(toluene-4-sulfonyl)-1,2,3, 4-tetrahydro-1H-benzo[b]azepin-5-ylidene]acetic acid (4a and 4b, respectively) and [1-(toluene-4-sulfonyl)-2, 3-dihydro-1H-benzo[b]azepin-5-yl]acetic acid (4c), is presented as an efficient and straightforward route to (R)-[1-(toluene-4-sulfonyl)-2,3,4, 5-tetrahydro-1H-benzo[b]azepin-5-yl]acetic acid [(R)-1] which is a key intermediate for the synthesis of non-peptide AVP V2-agonist. Hydrogenation of carboxylic acid 4c gave (R)-1 in quantitative yield and 85% ee using Ru(OAc)2[(S)-H8-BINAP], a Ru(II) complex of a partially hydrogenated BINAP (H8-BINAP), as a catalyst. When (R)-1 of 76% ee was transformed into the corresponding isopropylamide 6, pure enantiomer (R)-6 was obtained in 75% yield by recrystallization from MeOH., (Copyright 2000 Wiley-Liss, Inc.)

We discovered the first nonpeptide arginine-vasopressin (AVP) V(2)-receptor agonist, OPC-51803. Pharmacological properties of OPC-51803 were elucidated using HeLa cells expressing human AVP receptor subtypes (V(2), V(1a) and V(1b)) and compared with those of 1-desamino-8-D-arginine vasopressin (dDAVP), a peptide V(2)-receptor agonist. OPC-51803 and dDAVP displaced [(3)H]-AVP binding to human V(2)- and V(1a)-receptors with K(i) values of 91.9+/-10.8 nM (n = 6) and 3.12+/-0.38 nM (n = 6) for V(2)-receptors, and 819+/-39 nM (n = 6) and 41.5+/-9.9 nM (n = 6) for V(1a)-receptors, indicating that OPC-51803 was about nine times more selective for V(2)-receptors, similar to the selectivity of dDAVP. OPC-51803 scarcely displaced [(3)H]-AVP binding to human V(1b)-receptors even at 10(-4) M, while dDAVP showed potent affinity to human V(1b)-receptors with the K(i) value of 13.7+/-3.2 nM (n = 4). OPC-51803 concentration-dependently increased cyclic adenosine 3', 5'-monophosphate (cyclic AMP) production in HeLa cells expressing human V(2)-receptors with an EC(50) value of 189+/-14 nM (n = 6). The concentration-response curve for cyclic AMP production induced by OPC-51803 was shifted to the right in the presence of a V(2)-antagonist, OPC-31260. At 10(-5) M, OPC-51803 did not increase the intracellular Ca(2+) concentration ([Ca(2+)](i)) in HeLa cells expressing human V(1a)-receptors. On the other hand, dDAVP increased [Ca(2+)](i) in HeLa cells expressing human V(1a)- and V(1b)-receptors in a concentration-dependent fashion. From these results, OPC-51803 has been confirmed to be the first nonpeptide agonist for human AVP V(2)-receptors without agonistic activities for V(1a)- and V(1b)-receptors. OPC-51803 may be useful for the treatment of AVP-deficient pathophysiological states and as a tool for AVP researches.

Background: It has been suggested that the genetic abnormality responsible for von Recklinghausen neurofibromatosis (NF1) increases a patient's risk of various kinds of malignancies. The incidence of small cell lung carcinoma (SCLC) as a complication of NF1, however, is rare. To clarify the relationship between NF1 and SCLC, possible loss of heterozygosity of chromosome 17 in a patient with SCLC combined with NF1 was analyzed., Methods: Possible loss of heterozygosity for chromosome 17 was analyzed by a molecular genetic approach using several chromosome 17-specific polymorphic DNA markers., Results: In both primary tumor and metastatic tumors of SCLC, loss of heterozygosity was detected on chromosome arm 17p, but not on 17q. Loss of heterozygosity, however, was detected on neither 17p nor 17q in neurofibromas and normal tissue., Conclusions: The formation of SCLC may result from several genetic alterations, including inactivation of tumor-suppressor gene on chromosome 17p, most likely P53, although it still is unknown whether or not a mutation of the NF1 gene on 17q was involved in the development of SCLC in this patient.

The authors retrospectively searched for human papillomavirus (HPV) types 16 and 18 in 60 cases of carcinoma arising from the nasal cavities (NC) and paranasal sinuses (PS) by using the polymerase chain reaction (PCR) on DNA extracted from formalin-fixed, paraffin-embedded tissues. In cases of SCC (n = 49), the authors also compared the clinical features of patients with HPV-positive and HPV-negative results to determine the clinical significance of HPV. HPV 16 and 18 were detected in 7 of the 49 cases (14%) of SCC. In the other histologic types of carcinoma (n = 11), neither HPV 16 nor HPV 18 was detected. No significant differences in the clinical features were observed between patients with SCC with HPV-positive and HPV-negative results. The results suggest that HPV 16 and 18 are implicated in the pathogenesis of SCC arising from the NC and PS. However, the presence of HPV is not related to local progression, occurrence of metastases, or the prognosis of the patients.

The authors retrospectively analyzed epidermal growth factor receptor (EGFR) gene amplification in 49 cases of squamous cell carcinoma (SCC) arising from the nasal cavities (NC) and paranasal sinuses (PS) by using slot-blot analysis of DNA extracted from formalin-fixed, paraffin-embedded tissues. Also, the relationship between the results of gene analysis and the clinical features of the patients was studied to investigate the clinical significance of the EGFR in SCC of the NC and PS. Amplification of the EGFR gene was detected in 5 of the 49 cases (10%). No significant difference was observed between EGFR gene amplification and the presence of lymph node metastases, local recurrence, or prognosis. This suggests that EGFR gene amplification is not related to the local progression or metastasis of the SCC in the NC and PS. In addition, it appears that amplification of the EGFR gene is not a prognostic indicator for SCC in the NC and PS.

The complication of Sweet's syndrome and interstitial pneumonia occurred in a patient with myelodysplastic syndrome. Superoxide anion production by the patient's neutrophils was considerably higher than that by neutrophils obtained from normal controls after stimulation with opsonized zymosan, phorbol myristate acetate, or myristic acid. Prednisone, which a potent inhibitor of superoxide anion production by neutrophils, dramatically improved the skin and pulmonary lesions, suggesting that they were parts of the same clinical spectrum associated with the superoxide anion hyperproduction.

Analysis of recombinant DNAs provides new information on the basis of crystallin evolution and diversity. All crystallin genes contain introns. Two similar, tandemly linked chicken delta-crystallin genes, which probably arose by gene duplication, contain at least 16-17 introns. In the beta-crystallins three introns are situated between exons encoding the structural motifs of the protein, thus relating gene and protein structure. The structurally similar beta- and gamma-crystallins are coded by separate gene families which apparently arose by successive duplications of a common ancestral gene. The N-termini (5' end of gene) of the beta-crystallins appear to have diverged, while the 3' ends have been conserved. In the single murine alpha A-crystallin gene, coding information (the insert exon) for the alpha Ains peptide is contained within an intron. Alternative RNA splicing of this gene gives both the alpha A2 and the alpha Ains crystallin mRNAs. Thus, molecular genetics is providing a deeper appreciation of evolutionary events and is serving to redefine the crystallins in terms of their genes. Since the crystallins are so abundant in the lens, greater understanding of their polypeptide and gene structure should contribute to our understanding of and ability to treat cataract.