Four-year mortality and physical activity in Japanese patients with chronic obstructive pulmonary disease.

BACKGROUND: Physical activity (PA) is associated with the risk of mortality in patients with chronic obstructive pulmonary disease (COPD); however, evidence is limited to the Japanese population. This study aimed to evaluate the effects of PA on long-term mortality in Japanese patients with COPD. METHODS: We conducted a prospective observational study in a cohort of Japanese patients with COPD and assessed mortality during a 4-year follow-up period. The Cox proportional hazards model was used to evaluate the association between PA and mortality. RESULTS: Among 309 patients (294 men; median age, 76 years), 287 completed follow-ups while 45 died. The all-cause mortality rate was 27.5% in patients with low PA and 4.1% in those with high PA. Adjusted hazard ratios for all-cause mortality were associated with high PA. CONCLUSIONS: Higher PA levels are associated with a better prognosis across different settings and patient characteristics, even in Japanese patients with COPD.

A randomized double-blind placebo-controlled trial of an inhibitor of plasminogen activator inhibitor-1 (TM5614) in mild to moderate COVID-19.

An inhibitor of plasminogen activator inhibitor (PAI)-1, TM5614, inhibited thrombosis, inflammation, and fibrosis in several experimental mouse models. To evaluate the efficacy and safety of TM5614 in human COVID-19 pneumonia, phase IIa and IIb trials were conducted. In an open-label, single-arm trial, 26 Japanese COVID-19 patients with mild to moderate pneumonia were treated with 120-180 mg of TM5614 daily, and all were discharged without any notable side effects. Then, a randomized, double-blind, placebo-controlled trial was conducted in Japanese COVID-19 patients with mild to moderate pneumonia. The number of study participants was set to be 50 in each arm. Even after extension of the enrollment period, the number of study participants did not reach the initially intended sample size, and 75 patients were enrolled in the study. The total oxygenation scale from Day 1 to Day 14 as the primary endpoint was 1.5 in the TM5614 group vs 4.0 in the placebo group (p = 0.22), and the number of days of oxygen administration required as the secondary endpoint was 2.0 days in the TM5614 group vs 3.5 days in the placebo group (p = 0.34). Further studies will be necessary to verify the efficacy of PAI-1 inhibition for the treatment of COVID-19 pneumonia.Clinical trial registration: Two studies were conducted: a prospective, multicenter, open-label phase II study at https://jrct.niph.go.jp (jRCT2021200018) (First registration date 18/08/2020) and a prospective, multicenter, randomized, double-blind, placebo-controlled, phase II study at https://jrct.niph.go.jp (jRCT2021210006) (First registration date 28/05/2021).

Physical activity and outcomes in Japanese patients with chronic obstructive pulmonary disease: From the Ishinomaki COPD Network registry.

BACKGROUND: Low physical activity levels are associated with an increased risk of exacerbations and all-cause mortality in patients with chronic obstructive pulmonary disease (COPD); however, evidence is limited in a population with a low frequency of exacerbations, such as the Japanese population. This study investigated the effects of physical activity on outcomes in Japanese patients with COPD. METHODS: We conducted a prospective observational study in a cohort of Japanese patients with COPD between April 2018 and July 2020. Characteristics, frequency of exacerbations, and mortality were assessed during the 1-year follow-up period. Logistic regression analysis evaluated the relationship between physical activity and outcomes. RESULTS: A total of 309 patients (294 males; median age, 75 years) with stable COPD were included, and 307 completed follow-up. Patients with lower levels of physical activity were older, and showed increased airflow obstruction, limited exercise capacity, increased dyspnea, depressive state, poor health status, muscle weakness, and more information needs for the disease. Patients with high levels of physical activity had a lower risk of exacerbation, including hospital admission, compared to those with low levels of activity (odds ratio [OR], 0.46; 95 % confidence interval [CI], 0.22-0.97; and OR, 0.21; 95 % CI, 0.09-0.50, respectively). High physical activity was associated with a reduced risk of all-cause mortality (OR, 0.07; 95 % CI, 0.01-0.55) and respiratory mortality (OR, 0.16; 95 % CI, 0.02-1.47). CONCLUSIONS: These findings showed that higher physical activity is associated with better clinical outcomes, even in a COPD population with a low frequency of exacerbations.

Contribution of traditional Japanese Kampo medicines, kakkonto with shosaikotokakikyosekko, in treating patients with mild-to-moderate coronavirus disease 2019: Further analysis of a multicenter, randomized controlled trial.

We previously reported the finding of symptom relief in a randomized controlled trial with the combined use of kakkonto and shosaikotokakikyosekko added to conventional treatment in patients with coronavirus disease 2019 (COVID-19). For further evaluation, we performed post hoc analysis focused on symptom disappearance without recurrence, to determine a clearer effect of Kampo medicine. Patients with mild and moderate COVID-19 were randomly allocated to a control group receiving symptomatic therapy or a Kampo group receiving kakkonto (2.5 g) with shosaikotokakikyosekko (2.5 g) three times daily in addition to symptomatic therapy. The data of 161 patients (Kampo group, n = 81; control group, n = 80) were analyzed post hoc for the time to symptom disappearance. Kaplan-Meier and Cox proportional hazard estimates of disappearance of symptoms showed that all and each symptom targeted in this study disappeared faster in the Kampo group than in the control group, although not statistically significant (all symptomatic cases; hazard ratio [HR] 3.73, 95% confidence interval [CI] 0.46-29.98, log-rank p = 0.1763). In a supplemental assessment using covariate adjustment and competing risk analysis, fever disappeared faster in the Kampo group than in the control group (all symptomatic cases, HR 1.62, 95% CI 0.99-2.64, p = 0.0557; unvaccinated cases, HR 1.68, 95% CI 1.00-2.83, p = 0.0498) and shortness of breath disappeared significantly faster in Kampo group than in control group (all symptomatic cases, HR 1.92, 95% CI 1.07-3.42, p = 0.0278; unvaccinated cases, HR 2.15, 95% CI 1.17-3.96, p = 0.0141). These results demonstrate the advantages of Kampo treatment for acute COVID-19.

Multiple cavitary lung lesions from colorectal cancer responding to chemotherapy.

Lung metastasis is an uncommon cause of multiple cavitary lung lesions. Herein, we report a case of multiple cavitary lung lesions of colorectal cancer that responded to chemotherapy. An 81-year-old woman was referred to our hospital for abdominal pain. Computed tomography revealed multiple cavitary lung lesions. The patient was diagnosed with lung metastases from colorectal cancer with a lower gastrointestinal endoscopy and bronchoscopy. Following chemotherapy, the cavitary lung lesions shrank. Lung metastases from colorectal cancer may appear as multiple cavitary lung lesions, which may be misdiagnosed as infections. Clinicians should consider lung metastases when multiple cavitary lung lesions are detected.

Conventional and Kampo Medicine Treatment for Mild-to-moderate COVID-19: A Multicenter, Retrospective, Observational Study by the Integrative Management in Japan for Epidemic Disease (IMJEDI Study-observation).

Objective Patients in whom coronavirus disease 2019 (COVID-19) was suspected or confirmed between January 1, 2020, and October 31, 2021, were enrolled from Japanese hospitals in this multicenter, retrospective, observational study. Methods Data on the treatment administered (including conventional and Kampo medicine) and changes in common cold-like symptoms (such as fever, cough, sputum, dyspnea, fatigue, and diarrhea) were collected from their medical records. The primary outcome was the number of days without a fever (with a body temperature <37°C). The secondary outcomes were symptomatic relief and the worsening of illness, defined as the presence of a condition requiring oxygen inhalation. The outcomes of patients treated with and without Kampo medicine were compared. Patients We enrolled 962 patients, among whom 528 received conventional and Kampo treatment (Kampo group) and 434 received conventional treatment (non-Kampo group). Results Overall, after adjusting for the staging of COVID-19 and risk factors, there were no significant between-group differences in the symptoms or number of days being afebrile. After performing propensity score matching and restricting the included cases to those with confirmed COVID-19 who did not receive steroid administration and initiated treatment within 4 days from the onset, the risk of illness worsening was significantly lower in the Kampo group than in the non-Kampo group (odds ratio=0.113, 95% confidence interval: 0.014-0.928, p=0.0424). Conclusion Early Kampo treatment may suppress illness worsening risk in COVID-19 cases without steroid use. Further randomized controlled studies are needed to confirm the clinical benefit of Kampo medicine for COVID-19.

Multicenter, randomized controlled trial of traditional Japanese medicine, kakkonto with shosaikotokakikyosekko, for mild and moderate coronavirus disease patients.

The traditional Japanese (Kampo) medicine, kakkonto with shosaikotokakikyosekko, has antiviral and anti-inflammatory effects. In this randomized trial, patients with mild and moderate coronavirus disease (COVID-19) were randomly allocated to the control group receiving conventional treatment for symptom relief such as antipyretics and antitussives or the Kampo group receiving mixed extract granules of kakkonto (2.5 g) and shosaikotokakikyosekko (2.5 g) three times a day for 14 days in addition to conventional treatment. The main outcome was the number of days until total symptom relief. The secondary outcome was the number of days until each symptom's relief and whether the disease progressed to respiratory failure. We enrolled a total of 161 patients (Kampo group, n = 81; control group, n = 80). The results from Kaplan-Meier estimates of symptom relief showed that there are no significant differences between the groups. However, covariate-adjusted cumulative incidence of fever relief considering competitive risk showed that the recovery was significantly faster in the Kampo group than in the control group (HR 1.76, 95% CI 1.03-3.01). Additionally, the risk of disease progression to moderate COVID-19 requiring oxygen inhalation was lower in the Kampo group than in the control group (Risk Difference -0.13, 95% CI -0.27-0.01). No significant drug-related side effects were observed. Kakkonto with shosaikotokakikyosekko is effective for fever relief with suppression of disease progression in COVID-19 patients. Clinical Trial Registration: https://jrct.niph.go.jp/en-latest-detail/jRCTs021200020, identifier [jRCTs021200020].

A case of metastatic endobronchial tumor from uterine leiomyosarcoma.

A 54-year-old woman presented with persistent productive cough, found to have an endobronchial tumor which obstructed the left upper lobe bronchus. Histopathological examination of a transbronchial biopsy of the endobronchial tumor suggested leiomyosarcoma. A positron emission tomography (PET)-CT revealed uterus tumor with moderate uptake of 18F-fluorodeoxyglucose, suggesting uterine malignancies. From the results of histological findings of the resected uterus and the biopsied bronchial specimen, she was diagnosed with uterine leiomyosarcoma and endobronchial metastasis. The systematic use of PET-CT could be useful for patients presenting with tumors that cause endobronchial metastasis of leiomyosarcomas.

Mite allergen avoidance decreases allergic symptoms in children in Ishinomaki city of Japan after natural disasters.

OBJECTIVE: We investigated the prevalence of asthma, rhinitis, and atopic dermatitis in children, evaluated the mite allergen levels in their bedding after the Great East Japan Earthquake, and assessed changes in allergic symptoms in children and their families after allergen avoidance practices. METHODS: We performed a survey for the International Study of Asthma and Allergies in Childhood (ISAAC) comprising 1109 children, aged 7-8 years, living in Ishinomaki, Japan. We collected responses from 464 children, and in 2016, measured the level of Dermatophagoides group 1 (Der 1) in the bedding of 202 of these children. The intervention group of children attended at least one allergen avoidance seminar. The levels of Der 1 in their bedding were measured, along with changes in allergic symptoms, in 17 children in 2017 and 14 children in 2018. The nonintervention group comprised children who did not attend an allergen avoidance seminar at any time. RESULTS: Of the 464 children who participated in the ISAAC, 50 (10.8%) reported having asthma, 179 (38.8%) allergic rhinitis, and 126 (27.3%) atopic dermatitis. The average level of Der 1 measured in the bedding of the 202 children in 2016 was 295.8 ng/m2. The levels of Der 1 in the intervention group-but not in the nonintervention group-significantly decreased in 2017 and 2018. The symptoms of asthma, allergic rhinitis, and atopic dermatitis in the children of intervention group and their families decreased after allergen avoidance practices. CONCLUSIONS: Allergen avoidance practices relieved allergic symptoms in school children after the Great East Japan Earthquake.

Mite allergen avoidance decreases allergic symptoms in children in Ishinomaki city of Japan after natural disasters

Objective We investigated the prevalence of asthma, rhinitis, and atopic dermatitis in children, evaluated the mite allergen levels in their bedding after the Great East Japan Earthquake, and assessed changes in allergic symptoms in children and their families after allergen avoidance practices.Methods We performed a survey for the International Study of Asthma and Allergies in Childhood (ISAAC) comprising 1109 children, aged 7–8 years, living in Ishinomaki, Japan. We collected responses from 464 children, and in 2016, measured the level of Dermatophagoides group 1 (Der 1) in the bedding of 202 of these children. The intervention group of children attended at least one allergen avoidance seminar. The levels of Der 1 in their bedding were measured, along with changes in allergic symptoms, in 17 children in 2017 and 14 children in 2018. The nonintervention group comprised children who did not attend an allergen avoidance seminar at any time.Results Of the 464 children who participated in the ISAAC, 50 (10.8%) reported having asthma, 179 (38.8%) allergic rhinitis, and 126 (27.3%) atopic dermatitis. The average level of Der 1 measured in the bedding of the 202 children in 2016 was 295.8 ng/m2. The levels of Der 1 in the intervention group—but not in the nonintervention group—significantly decreased in 2017 and 2018. The symptoms of asthma, allergic rhinitis, and atopic dermatitis in the children of intervention group and their families decreased after allergen avoidance practices (AU)

Regional Antimicrobial Stewardship Program in a Provincial Medical Zone in Japan: a Multifaceted Approach.

Antimicrobial resistance (AMR) is a threat to patient health. However, data to optimize antimicrobial use are limited. Furthermore, reducing antibiotic use raises concerns regarding patient safety. The effectiveness of antibiotics in reducing the prevalence of AMR is controversial. Researchers at the Japanese Red Cross Ishinomaki Hospital (JRCIH), the only tertiary care hospital in the medical zone, along with local medical and pharmacy associations and public health centers have been leading the AMR control program since 2018. The program involves lectures aimed at optimizing antimicrobial use, regular publication of surveillance data of drug-resistant strains at the JRCIH, and presentation of first-line treatments for community-acquired infections. The delivery of oral antimicrobial agents across the region in 2020 was 28.7% lower than that in 2013, with delivery of cephalosporins, quinolones, and macrolides decreasing by 34.8%, 46.8%, and 56.0%, respectively. Despite these reductions, there has been no associated increase in the number of patients with severe infectious diseases admitted to the JRCIH. The rates of representative drug-resistant bacterial strains, such as extended-spectrum beta-lactamase-producing Escherichia coli and methicillin-resistant Staphylococcus aureus, decreased by half. Herein, we demonstrated the potential of collaborative efforts to optimize antimicrobial agent use and reduce the AMR prevalence without compromising patient safety.

Mite avoidance decreased mite-specific IgE levels and ameliorated asthma symptoms in subjects who lived in temporary housing after natural disasters

Background: We previously reported an increased prevalence of asthma among patients who had lived in temporary housing after the 2011 Great East Japan Earthquake. We investigated the prognosis of asthma in former residents of temporary housing after allergen avoidance. Methods: Asthma was diagnosed in adults ≥ 15 years from 2014 to 2019 who had lived in temporary housing in Ishinomaki City for at least 1 year. The disease prognosis after the intervention of allergen avoidance in cases that were followed for more than 3 years during the 6-year study period was analyzed. We measured the Dermatophagoides farinae -specific immunoglobulin E (IgE) levels in serum, and the amount of Dermatophagoides group 1 (Der 1) antigen on their futons or mattresses. We instructed residents in an allergen avoidance strategy that included 32 tasks, including using microfiber bedding covers. Results: Of the 202 examinees who were followed for at least 3 years during the 6-year study period, 72(35.6%) were asthmatic during at least one examination. Of these 72 asthmatics, 55(76.4%) developed the disease after the earthquake, and more than half of the cases that we diagnosed at the examination were mild intermittent asthma. After the allergen-avoidance intervention, both the Der 1 level on the futons or mattresses of residents who were diagnosed with asthma but who were nonasthmatic at the final screening and their serum Der f-specific IgE levels significantly decreased (P < 0.01) at the final examination. Conclusion: Antigen avoidance ameliorated mild asthma that was prevalent among residents of temporary housing after the earthquake (AU)

Association between Temporary Housing Habitation after the 2011 Japan Earthquake and Mite Allergen Sensitization and Asthma Development.

INTRODUCTION: We previously reported an increased prevalence of asthma in adults who lived in temporary housing after the 2011 Great East Japan Earthquake. The goal of the current study was to investigate changes in asthma prevalence and mite-specific immunoglobulin E (IgE) titers in temporary housing residents during 2014-2019. METHODS: By using the Global Initiative for Asthma guidelines, we diagnosed asthma in Ishinomaki city temporary housing residents aged 15 years or older. We then analyzed serum antigen-specific IgE levels to Dermatophagoides farinae (Der f), Dermatophagoides pteronyssinus (Der p), and Aspergillus fumigatus. RESULTS: The prevalence of asthma exceeded 20% across all age-groups throughout the study period. The proportion of study participants with a "positive" antigen-specific IgE titer (i.e., ≥0.35 IUA/mL) was higher in asthmatics than in nonasthmatics for Der f and Der p but not for Aspergillus fumigatus. Among residents ≥50 years old who were diagnosed with asthma, the percentage with a Der f-specific IgE titer ≥0.10 IUA/mL was higher than the proportion with ≥0.35 IUA/mL. Among study participants, asthma onset occurred before the earthquake, during residence in shelters or temporary housing, and (starting in 2016) after moving out of temporary housing. The Der p-specific IgE level was positively correlated with the duration of temporary housing (p < 0.05, r = 0.41) and inversely correlated with the time elapsed since moving out of temporary housing (p < 0.05, r = -0.35). CONCLUSION: Mite allergen sensitization was found in both asthmatic and nonasthmatic temporary housing residents after the 2011 Japan earthquake and tsunami; asthma developed even after subjects moved out of temporary housing.

Dynamic left ventricular outflow tract obstruction in a patient with acute coronary syndrome and without the apical akinesia: Potential alternative mechanisms causing a dynamic left ventricular outflow tract obstruction other than a compensatory basal hyperkinesis.

The mechanism for dynamic left ventricular outflow tract obstruction (LVOTO) after acute coronary syndromes (ACS) is thought to be apical infarction with compensatory hyperkinesia of the residual normally perfused basal segments of the myocardium. However, herein, we report a patient with ACS and dynamic LVOTO (peak gradient of 250 mm Hg at rest) that could not be secondary to apical akinesia. We propose a potential alternative mechanism leading to dynamic LVOTO in ACS, namely, the interplay between sigmoid septum, basal hyperkinesis, and outflow tract narrowing induced by afterload reduction due to acute myocardial ischemia itself.

Exhaled nitric oxide: A biomarker for chronic obstructive pulmonary disease.

The fractional concentration of exhaled nitric oxide (FeNO) is recognized as a biomarker of type 2 inflammation in asthma, which is related to airway eosinophilia. We conducted a prospective observational study in a cohort of Japanese patients with chronic obstructive pulmonary disease (COPD) to evaluate the relationship between FeNO and clinical features and patient outcomes over a 3-year period. Participants were categorized into two groups based on FeNO levels (high and low), and the clinical features and outcomes were compared between the groups. Patients with high FeNO levels showed features of asthma and eosinophilic inflammation compared to those with low levels. However, high FeNO levels were not associated with worse outcomes (exacerbations, hospital admissions, all-cause and disease-specific mortality) compared to low levels. These results provide evidence that baseline FeNO is related to eosinophilic inflammation; however, is not a predictor of future exacerbations or prognosis in patients with stable COPD.

Clinical characteristics of Japanese patients with chronic obstructive pulmonary disease (COPD) with comorbid interstitial lung abnormalities: A cross-sectional study.

Smoking-related interstitial lung abnormalities are different from specific forms of fibrosing lung disease which might be associated with poor prognoses. Chronic obstructive pulmonary disease with comorbid interstitial lung abnormalities and that with pulmonary fibrosis are considered different diseases; however, they could share a common spectrum. We aimed to evaluate the clinical characteristics of Japanese patients with chronic obstructive pulmonary disease and comorbid interstitial lung abnormalities. In this prospective observational study, we analyzed data from the Ishinomaki COPD Network Registry. We evaluated the clinical characteristics of patients with chronic obstructive pulmonary disease with and without comorbid interstitial lung abnormalities by comparing the annualized rate of chronic obstructive pulmonary disease exacerbations per patient during the observational period. Among 463 patients with chronic obstructive pulmonary disease, 30 (6.5%) developed new interstitial lung abnormalities during the observational period. After 1-to-3 propensity score matching, we found that the annualized rate of chronic obstructive pulmonary disease exacerbations per patient during the observational period was 0.06 and 0.23 per year in the interstitial lung abnormality and control groups, respectively (P = 0.043). Our findings indicate slow progression of interstitial lung abnormality lesions in patients with pre-existing chronic obstructive pulmonary disease. Further, interstitial lung abnormality development did not significantly influence on chronic obstructive pulmonary disease exacerbation. We speculate that post-chronic obstructive pulmonary disease interstitial lung abnormalities might involve smoking-related interstitial fibrosis, which is different from specific forms of fibrosing lung disease associated with poor prognoses.

Clinical Characteristics and Outcomes of Patients with Asthma-COPD Overlap in Japanese Patients with COPD.

Purpose: Asthma-COPD overlap (ACO) has been reported as an association with a lower quality of life, frequent exacerbations, and higher mortality than those with COPD alone. However, clinical characteristics and outcomes of ACO remain controversial. Patients and Methods: We conducted a prospective observational study analyzing data of patients with stable COPD enrolled from the Ishinomaki COPD Network Registry. Patients with features of asthma who had a history of respiratory symptoms that vary over time and intensity, together with documented variable expiratory airflow limitation, were identified, and then defined as having ACO. The characteristics, frequency of exacerbations, and mortality during the 3-year follow-up were compared between patients with ACO and patients with COPD alone. Results: Among 387 patients with COPD, 41 (10.6%) were identified as having ACO. Patients with ACO tended to be younger, have higher BMI, have a shorter smoking history, and use more respiratory medications, especially inhaled corticosteroids. Inflammatory biomarkers including fractional exhaled nitric oxide, blood eosinophil count, total immunoglobulin E (IgE) level, and presence of antigen-specific IgE were significantly higher in patients with ACO than in those with COPD alone. Lung function, mMRC score, CAT score, and comorbidity index were not different between the groups. The annual rate of all exacerbations and severe exacerbations required hospital admission were not different between ACO and COPD alone (0.20 vs 0.14, 0.12 vs 0.10, events per person, respectively). Mortality was significantly higher in patients with COPD alone compared with those with ACO during the study period (P=0.037). Conclusion: The results of our study indicate that ACO is not associated with poor clinical features nor outcomes in an outpatient COPD cohort receiving appropriate treatment.

A multi-center, randomized controlled trial by the Integrative Management in Japan for Epidemic Disease (IMJEDI study-RCT) on the use of Kampo medicine, kakkonto with shosaikotokakikyosekko, in mild-to-moderate COVID-19 patients for symptomatic relief and prevention of severe stage: a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: We aimed to test our hypothesis that additional administration of traditional Japanese (Kampo) medicine, kakkonto (kakkon-to: KT) and shosaikotokakikyosekko (sho-saiko-to-ka-kikyo-sekko: SSKKS), is more effective in relieving symptoms and preventing the onset of severe infection in mild-to-moderate COVID-19 patients compared to those treated only with conventional treatment. TRIAL DESIGN: The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator-sponsored, two-arm study. PARTICIPANTS: Patients and inpatients will be recruited from 8 Japanese academic and non-academic hospitals. The inclusion and exclusion criteria are as follows: Inclusion criteria: 1. Diagnosed as positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 2. Clinical stages of mild-to-moderate COVID-19 3. Symptomatic 4. ≥ 20 years of age 5. Male or female 6. Ability to communicate in Japanese 7. Outpatients and inpatients 8. Provided informed consent Exclusion criteria: 1. Difficulty in providing informed consent due to dementia, psychosis, or psychiatric symptoms 2. Allergic to Kampo or Western medicines used in this study 3. Pregnant and lactating 4. Unable to follow up 5. Participating in another clinical trial or interventional study 6. Hypokalemic or taking oral furosemide or steroids 7. Determined unsuitable for this study by the physician INTERVENTION AND COMPARATOR: Patients in the control group will receive conventional treatment with antipyretics, painkillers, or antitussives for symptoms that occurred after they contracted the SARS-CoV-2 infection. Patients in the Kampo group will receive 2.5 g of KT (TJ-1@TSUMURA and Co.) and 2.5 g of SSKKS (TJ-109@TSUMURA and Co.) 3 times a day, orally, for 14 days in addition to the conventional treatment as mentioned above. MAIN OUTCOMES: The number of days till at least one of the symptoms (fever, cough, sputum, malaise, shortness of breath) improves in the first 14 days of treatment. To assess the cough, sputum, malaise, and shortness of breath, a numeric rating scale will be used to define improvement in terms of a 2-point decrease in the number of days from the start of treatment for at least 2 days. Fever will be defined as an improvement when the temperature is less than 37 °C. RANDOMIZATION: Patients are randomized (1:1 ratio) to each group using the minimization method, with balancing of the arms with severity of disease stage and patient age (< 65, 65 to < 75, or ≥ 75 years). Computer-generated random numbers will be used for the minimization method. BLINDING (MASKING): Open-label with no blinding NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The main research hypothesis of this study is that the combination of Kampo medicine and conventional treatment will significantly improve the patients' symptoms (fever, fatigue, cough, sputum, and shortness of breath) during the first 14 days of treatment as compared with conventional treatment alone. Concerning the analysis of the primary endpoint, the duration of time before improvement of at least one of the common cold-like symptoms (fever, malaise, cough, sputum, and shortness of breath) will be estimated using the Kaplan-Meier method, and the survival curves will be compared between groups using the log-rank test. Assuming this method of analysis and based on previous studies reporting the efficacy of Kampo medicine for COVID-19 and H1N1 influenza patients, the median survival time in the Kampo medicine group is estimated as 3 days; this time will be 1.5 times longer in the control group. Assuming a one-sided significance level of 5%, a power of 70%, and an allocation ratio of 1:1, the required sample size is calculated as 126 cases. To compensate for a loss in follow-up, we plan to include 150 cases in both groups (Kampo group = 75, control group = 75). TRIAL STATUS: Protocol version 1.2 as of August 20, 2020 Recruitment start (expected): October 1, 2020 Recruitment finish (expected): October 31, 2023 TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) jRCTs021200020 . Registered on August 25, 2020 FULL PROTOCOL: The full protocol is attached as an additional file and is accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

CD45+CD326+ Cells are Predictive of Poor Prognosis in Non-Small Cell Lung Cancer Patients.

PURPOSE: The epithelial-to-mesenchymal transition, the major process by which some cancer cells convert from an epithelial phenotype to a mesenchymal one, has been suggested to drive chemo-resistance and/or metastasis in patients with cancer. However, only a few studies have demonstrated the presence of CD45/CD326 doubly-positive cells (CD45/CD326 DPC) in cancer. We deployed a combination of cell surface markers to elucidate the phenotypic heterogeneity in non-small cell lung cancer (NSCLC) cells and identified a new subpopulation that is doubly-positive for epithelial and non-epithelial cell-surface markers in both NSCLC cells and patients' malignant pleural effusions. EXPERIMENTAL DESIGN: We procured a total of 39 patients' samples, solid fresh lung cancer tissues from 21 patients and malignant pleural effusion samples from 18 others, and used FACS and fluorescence microscopy to check their surface markers. We also examined the EGFR mutations in patients with known acquired EGFR mutations. RESULTS: Our data revealed that 0.4% to 17.9% of the solid tumor tissue cells and a higher percentage of malignant pleural effusion cells harbored CD45/CD326 DPC expressing both epithelial and nonepithelial surface markers. We selected 3 EGFR mutation patients and genetically confirmed that the newly identified cell population really originated from cancer cells. We also found that higher proportions of CD45/CD326 DPC are significantly associated with poor prognosis. CONCLUSIONS: In conclusion, varying percentages of CD45/CD326 DPC exist in both solid cancer tissue and malignant pleural effusion in patients with NSCLC. This CD45/CD326 doubly-positive subpopulation can be an important key to clinical management of patients with NSCLC.