Causes of Death in Elderly Patients With Non-Valvular Atrial Fibrillation　- Results From the ANAFIE Registry.

BACKGROUND: Previous studies on mortality in atrial fibrillation (AF) included a limited number of elderly patients receiving direct oral anticoagulants (DOACs). This subanalysis of the ANAFIE Registry evaluated 2-year mortality according to causes of death of elderly non-valvular AF (NVAF) patients in the DOAC era.Methods and Results: The ANAFIE Registry was a multicenter prospective observational study. Mean patient age was 81.5 years and 57.3% of patients were male. Of the 32,275 patients completing the study, 2,242 died. The most frequent causes of death were cardiovascular (CV) death (32.4%), followed by infection (17.1%) and malignancy (16.1%). Incidence rates of CV-, malignancy-, and infection-related death were 1.20, 0.60, and 0.63 per 100 person-years, respectively. Patients aged ≥85 years showed increased proportions of non-CV and non-malignancy deaths and a decreased proportion of malignancy deaths compared with patients aged <85 years. The incidence of death due to congestive heart failure/cardiogenic shock, infection, and renal disease was higher in patients aged ≥85 than those aged <85 years. Compared with warfarin, DOACs were associated with a significantly lower risk of death by intracranial hemorrhage, ischemic stroke, and renal disease. CONCLUSIONS: This subanalysis described the mortality according to causes of death of Japanese elderly NVAF patients in the DOAC era. Our results imply that a more holistic approach to comorbid conditions and stroke prevention are required in these patients.

Clinical significance of spread of lipiodol marking for pulmonary nodules and its influence on surgery.

OBJECTIVE: Computed tomography (CT)-guided lipiodol marking is one of the targeting methods for resecting small pulmonary nodules or ground-glass nodules in video-assisted thoracic surgery (VATS). However, lipiodol spreading during marking has not been assessed, practically. In this study, we examined the clinical significance and the influence of lipiodol spreading on surgery. METHODS: From April 2010 to March 2021, 176 pulmonary nodules in 167 patients were marked with lipiodol under CT guided before VATS. The marking images after lipiodol injection were classified into "Spread" and "non-Spread." Lung resection was sequentially performed on the same day. RESULTS: All target nodules were successfully resected in VATS. In the classification of marking images, Spread was 32 (18%), non-Spread was 144 (82%). There was a significant difference in duration of surgery (mean; 138.7 min vs. 118.3 min, p = 0.0496) and amount of bleeding (mean; 32.7 g vs. 11.2 g, p = 0.0173). Provided that limited to the data of wedge resections without intrathoracic pleural adhesion (n = 117), there was no significant difference in duration of surgery (mean; 104.8 min vs. 99.6 min, p = 0.48), amount of bleeding (mean; 4.9 g vs. 5.3 g, p = 0.58). In the multivariate logistic regression analysis, the risk factor of lipiodol spreading was intrathoracic pleural adhesion (odds ratio: 3.16, 95% confidence interval: 1.12-8.97, p = 0.03). There was no relationship between marking image and complication rate. CONCLUSIONS: Lipiodol spreading did not directly influence surgery and complication. However, it was a sign of intrathoracic pleural adhesion, which could lead to increased duration of surgery and amount of bleeding.

A Randomized Phase II Study of S-1 Adjuvant Chemotherapy With or Without Hochu-ekki-to, a Japanese Herbal Medicine, for Stage II/III Gastric Cancer: The KUGC07 (SHOT) Trial.

Objectives: A multicenter randomized phase II study was conducted to evaluate the effects of Hochu-ekki-to (TJ-41) for reducing adverse reactions and increasing compliance with S-1 adjuvant therapy for advanced gastric cancer. Methods: The eligibility criteria were pathological stage II/III after R0 resection. Patients received adjuvant therapy with S-1 alone (group S) or S-1 with TJ-41 (group ST) for 1 year. The primary endpoint was the completion rate of S-1. Secondary endpoints were adverse events, relative dose intensity, relapse-free survival (RFS), and overall survival (OS). Results: We randomly assigned 56 patients to group ST and 57 patients to group S. The completion rates of S-1 were 54.5 and 50.9%, the median relative dose intensities were 89.2 and 71.9%, and adverse events of grade 3 or 4 occurred in 45.5 and 54.5% in groups ST and S, respectively. There was no significant difference in 3-year OS or RFS between the two groups. Conclusions: TJ-41 does not increase relative dose and completion rate of S-1 significantly. J-41 may reduce toxic effects, but our findings do not support routine use of TJ-41 after gastrectomy.

The Japanese Early-Stage Trial of High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis (JETALS): Protocol for a Randomized Controlled Trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months. OBJECTIVE: This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset. METHODS: The Japanese early-stage trial of high-dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase III study conducted at 24 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 128 ALS patients within one year of onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 16 weeks. If patients wish to receive E0302 50 mg after the double-blind administration period, E0302 will be provided to them until March 2020 during the continuous administration period. RESULTS: This study began in October 2017 and is being conducted at 24 participating institutions in Japan. The study is in progress and the patient enrollment period is scheduled to end in August 2019, with follow-up scheduled to end in March 2020. CONCLUSIONS: This study is being performed to revalidate the efficacy and safety of E0302 in patients with early-stage ALS in the first year of symptom onset. If positive results are obtained, the aim is to apply for E0302 approval as a new drug for the treatment of ALS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/12046.

Adjuvant chemotherapy with S-1 after curative chemoradiotherapy in patients with locoregionally advanced squamous cell carcinoma of the head and neck: Reanalysis of the ACTS-HNC study.

BACKGROUND: Chemoradiotherapy (CRT) has improved organ preservation or overall survival (OS) of locoregionally advanced head and neck squamous cell cancer (LAHNSCC), but in clinical trials of conventional CRT, increasing CRT intensity has not been shown to improve OS. In the Adjuvant ChemoTherapy with S-1 after curative treatment in patients with Head and Neck Cancer (ACTS-HNC) phase III study, OS of curative locoregional treatments improved more with adjuvant chemotherapy with S-1 (tegafur gimeracil oteracil potassium) than with tegafur/uracil (UFT). ACTS HNC study showed the significant efficacy of S-1 after curative radiotherapy in sub-analysis. We explored the efficacy of S-1 after curative CRT in a subset of patients from the ACTS-HNC study. METHODS: Patients with stage III, IVA, or IVB LAHNSCC were enrolled in this study to evaluate the efficacy of S-1 compared with UFT as adjuvant chemotherapy after curative CRT in the ACTS-HNC study. Patients received S-1 at 80-120 mg/day in two divided doses for 2 weeks, followed by a 1-week rest, or UFT 300 or 400 mg/day in two or three divided doses daily, for 1 year. The endpoints were OS, disease-free survival, locoregional relapse-free survival, distant metastasis-free survival (DMFS), and post-locoregional relapse survival. RESULTS: One hundred eighty patients (S-1, n = 87; UFT, n = 93) were included in this study. Clinical characteristics of the S-1 and UFT arms were similar. S-1 after CRT significantly improved OS (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.22-0.93) and DMFS (HR, 0.50; 95% CI, 0.26-0.97) compared with UFT. CONCLUSION: As adjuvant chemotherapy, S-1 demonstrated better efficacy for OS and DMFS than UFT in patients with LAHNSCC after curative CRT and may be considered a treatment option following curative CRT. For this study was not preplanned in the ACTS-HNC study, the results is hypothesis generating but not definitive.

Clinical Significance of Prognostic Nutritional Index After Surgical Treatment in Lung Cancer.

BACKGROUND: The prognostic nutritional index (PNI), calculated as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (cells/mm3), can reportedly predict postoperative complications and prognosis for various types of malignancy. However, the clinical significance and prognostic value of the PNI for both short- and long-term outcomes remains uncertain in patients with lung cancer. METHODS: We retrospectively reviewed 248 patients with completely resected non-small cell lung cancer (NSCLC). Clinicopathologic characteristics were evaluated according to the PNI, and the prognostic significance for postoperative outcomes was assessed using Cox proportional regression analysis. The survival rate was calculated using the Kaplan-Meier method. RESULTS: An optimal cutoff of 48 for recurrence-free survival (RFS) was determined using the minimum p value approach. Old age, low body mass index, large tumor size, and elevated C-reactive protein levels correlated significantly with low PNI. Logistic regression analysis demonstrated that low PNI status was statistically related to postoperative complications (Clavien-Dindo grade ≥II) and pulmonary air leakage. Five-year overall survival (OR) rates in the high- and low-PNI groups were 80.6% and 58.5%, respectively (p = 0.002). Five-year RFS rates were 73.6% and 48.6%, respectively (p < 0.001). Furthermore, PNI was identified as an independent prognostic factor for OS (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.08-4.21) and RFS (HR, 2.57; 95% CI, 1.46-4.38) by multivariate analysis. CONCLUSIONS: The PNI could represent a useful biomarker to predict postoperative complications and survival in patients with completely resected NSCLC.

Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety.

BACKGROUND: Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule. METHODS: Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m2/day) intravenously for 12 to 14 days. RESULTS: We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF. CONCLUSIONS: Intravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.

A 1-µT extremely low-frequency electromagnetic field vs. sham control for mild-to-moderate hypertension: a double-blind, randomized study.

The effects of extremely low-frequency electromagnetic fields (ELF-EMFs) on blood pressure (BP) are controversial. In this double-blind, randomized, sham-controlled study, we examined the effects of repeated exposure to a 1-µT ELF-EMF on BP in 20 humans with mild-to-moderate hypertension. Subjects were randomly assigned to either the ELF-EMF group or the sham group. Subjects in the ELF-EMF group were exposed to an ELF-EMF (6- and 8 Hz, respectively, peak magnetic field 1 µT, peak electric field 10 Vm(-1)) for at least two 10- to 15-min sessions per week, over a period of 4 weeks. In the sham group, the EMF-generating apparatus was not active. We obtained systolic and diastolic BP (SBP and DBP, respectively) measurements at registration and before and after each ELF-EMF exposure session. Subjects in the ELF-EMF and sham groups had mean ages of 52.8 and 55.1 years, and were exposed to a mean of 9.9 and 9.0 sessions, respectively. There was a significant difference between the ELF-EMF and sham groups with respect to change in SBP value between baseline and the end of the exposure regimen (P=0.02), but not with respect to change in DBP (P=0.21). There were no adverse events other than mild paresthesia of the hands of two subjects in the ELF-EMF group. Our results suggest that repeated exposure to an ELF-EMF has a BP-lowering effect on humans with mild-to-moderate hypertension.

Clinical effect of qigong practice on essential hypertension: a meta-analysis of randomized controlled trials.

OBJECTIVES: This study was designed to quantitatively assess the effectiveness of self-practiced qigong for treatment of essential hypertension. METHODS: Six major electronic databases were searched up to July 2006 to retrieve any potential randomized controlled trials designed to evaluate the clinical effectiveness of self-practiced qigong for essential hypertension reported in any language, with main outcome measures as systolic blood pressure (SBP) and diastolic blood pressure (DBP). The quality of included studies were assessed with the Jadad Scale and a customized standard quality assessment scale. RESULTS: Ninety-two (92) studies were identified. Nine (9) of these studies qualified for meta-analysis, comprising a total of 908 cases. Results were as follows: (1) The mean decrease of SBP in those practicing qigong was a 17.03 mm Hg reduction (95% confidence interval (CI) 11.53-22.52) compared with nonspecific intervention controls, but not superior to that in drug controls (1.19 mm Hg, 95% CI -5.40-7.79) and conventional exercise controls (-1.51 mm Hg, 95% CI -6.98-3.95). (2) Mean decrease of DBP in those practicing qigong was 9.98 mm Hg (95% CI 2.55-17.41) compared with nonspecific intervention controls, but not superior to that in drug controls (2.49 mm Hg, 95% CI -0.16-5.13) and conventional exercise controls (-1.59 mm Hg, 95% CI -4.91-1.74). (3) No obvious side effects were identified. CONCLUSIONS: Self-practiced qigong for less than 1 year is better in decreasing BP in patients with essential hypertension than in no-treatment controls, but is not superior to that in active controls. More methodologically strict studies are needed to prove real clinical benefits of qigong, and to explore its potential mechanism.