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Abstract Background There are currently no scoring-type predictive models using only easily available pre- and intraoperative data developed for assessment of the risk of advanced axillary lymph node metastasis (ALNM) in patients with breast cancer with metastatic sentinel lymph nodes (SLNs). We aimed to develop and validate a scoring system using only pre- and intraoperative data to distinguish between non-advanced (≤ 3 lymph nodes) and advanced (> 3 lymph nodes) ALNM in patients with breast cancer with metastatic SLNs. Methods We retrospectively identified 804 patients with breast cancer (cT1-3cN0) who had metastatic SLNs and had undergone axillary lymph node dissection (ALND). We evaluated the risk factors for advanced ALNM using logistic regression analysis and developed and validated a scoring system for the prediction of ALNM using training (n = 501) and validation (n = 303) cohorts, respectively. The predictive performance was assessed using the receiver operating characteristic (ROC) curve, area under the curve (AUC), and calibration plots. Results Ultrasound findings of multiple suspicious lymph nodes, SLN macrometastasis, the ratio of metastatic SLNs to the total number of SLNs removed, and the number of metastatic SLNs were significant risk factors for advanced ALNM. Clinical tumor size and invasive lobular carcinoma were of borderline significance. The scoring system based on these six variables yielded high AUCs (0.90 [training] and 0.89 [validation]). The calibration plots of frequency compared to the predicted probability showed slopes of 1.00 (training) and 0.85 (validation), with goodness-of-fit for the model. When the cutoff score was set at 4, the negative predictive values (NPVs) of excluding patients with advanced ALNM were 96.8% (training) and 96.9% (validation). The AUC for predicting advanced ALNM using our scoring system was significantly higher than that predicted by a single independent predictor, such as the number of positive SLNs or the proportion of positive SLNs. Similarly, our scoring system also showed good discrimination and calibration ability when the analysis was restricted to patients with one or two SLN metastases. Conclusion Our easy-to-use scoring system can exclude advanced ALNM with high NPVs. It may contribute to reducing the risk of undertreatment with adjuvant therapies in patients with metastatic SLNs, even if ALND is omitted.

Abstract Background The purpose of this study was to develop an objective, content-valid, and reliable assessment method for Kampo medicine using an objective structured clinical examination (OSCE) for the assessment of clinical competence in Kampo medicine. Methods We developed a blueprint followed by a list of 47 assessment items and three task scenarios related to clinical competence in Kampo medicine. An eight-member test committee checked the relevance of the assessment items on a Likert scale. We calculated a content validity index and content validity ratio, and used the Angoff method to set the passing threshold. We trained a total of nine simulated patients with three assigned to each scenario. We conducted an OSCE for 11 candidates with varying medical abilities, and conducted three stations per person, which were evaluated by one evaluator in one room by direct observation. We used video recordings to test the inter-rater reliability of the three raters. We used the test results to verify the reliability of the assessment chart. Results The inter-rater reliability (intraclass correlation coefficient [2,1]) was 0.973. The reliability of the assessment chart for each scenario (Cronbach’s α) was 0.86, 0.89, and 0.85 for Scenarios 1, 2, and 3, respectively. The reliability of the assessment chart for the whole OSCE (Cronbach’s α) was 0.90. Conclusions We developed a content-valid new OSCE assessment method for Kampo medicine and obtained high inter-rater and test reliabilities. Our findings suggest that this is one of the most reliable evaluation methods for assessing clinical competence in Kampo medicine.

Abstract Background Zinc is an essential micronutrient for maintaining biological activity. The level of zinc in the blood is known to decrease with age, especially in those over 75 years of age. In older adults patients with impaired functional status, aspiration pneumonia based on dysphagia often becomes problematic. However, the relationship between zinc deficiency and swallowing function has not been studied before. Methods A total of 52 older adults subjects (15 males and 37 females) living in a nursing home were enrolled for this study. At the time of enrollment, data of gender, age, body weight, serum zinc levels, serum albumin levels, and the time in a simple 2-step swallowing provocation test (S-SPT) were collected. In patients with serum zinc levels

Abstract Background Aciduria caused by urinary excretion of acidic metabolic wastes produced in daily life is known to be augmented in patients with chronic kidney disease (CKD). To evaluate the reno-protective effect of oral alkalizing agents for the improvement of metabolic acidosis and neutralization of intratubular pH in the patients with mild stages of CKD. Also, to identify reno-protective surrogate markers in the serum and urine that can closely associate the effect of urine alkalization. Methods In this single-centered, open-labeled, randomized cohort study, patients with CKD stages G2, G3a and G3b, who visited and were treated at Tohoku University Hospital during the enrollment period were registered. We administered sodium bicarbonate or sodium-potassium citrate as the oral alkalinizing agents. A total of 150 patients with CKD will be randomly allocated into the following three groups: sodium bicarbonate, sodium-potassium citrate and standard therapy group without any alkalinizing agents. The data of performance status, venous blood test, spot urine test, venous blood-gas test, electrocardiogram, renal arterial ultrasonography and chest X-ray will be collected at 0, 6, 12 and 24 weeks (short-term study) from starting the interventions. These data will be also collected at 1 and 2 years (long-term study). The samples of plasma and serum and early-morning urine at every visit will be acquired for the analysis of renal function and surrogate uremic biomarkers. The recruitment for this cohort study terminated in March, 2018, and the follow-up period for all the enrolled subjects will be terminated in December, 2020. The primary endpoint will be the development of originally-defined significant renal dysfunction or the occurrence of any cerebrovascular disease in the short-term study. The secondary endpoint will be the same endpoints as in the long-term study, or the patients with significant changes in the suggested the surrogate biomarkers. Discussion The findings of this study will address the importance of taking oral alkalizing agents in the patients with early stages of CKD, furthermore they could address any new surrogate biomarkers that can be useful from early stage CKD. Trial registration Registered Report Identifier: UMIN000010059 and jRCT021180043 . The trial registration number; 150. Date of registration; 2013/02/26.

Abstract Objective We aimed to test our hypothesis that traditional Japanese (Kampo) medicine, hochuekkito (Hochu-ekki-to: HET) has a preventive effect for the symptoms on COVID-19. Trial design The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator sponsored, two-arm study. Participants Six thousand participants will be recruited from healthy hospital workers in 7 Japanese University Hospitals. Inclusion criteria: 1. Age from 20 to 75 years old at the time of registration 2. Asymptomatic and body temperature below 37°C at the time of registration 3. Capable of eating orally Exclusion criteria: 1. Previous upper respiratory inflammation due to viral infection (including suspected COVID-19) 2. Taking immunosuppressants 3. Allergic to the Kampo medicines used in this study 4. History of hypokalaemia, severe hypertension, severe liver dysfunction, and interstitial pneumonia 5. Regularly taking other Kampo medicines 6. Pregnant or possibly pregnant 7. Participating in other research 8. Judged to be unsuitable for this study by the doctor in charge Intervention and comparator Kampo group: participants receive HET in 9 tablets 2 times per day for 8 weeks. Control group: participants receive placebo in the same dosage as the Intervention group - 9 tablets 2 times per day for 8 weeks. Placebo tablets are identical in appearance and package to HET. Taste of placebo is different from that of HET. The Ohsugi Pharmaceutical Co. Ltd, Osaka, Japan manufactured the placebo and HET. Main outcomes Primary outcome: Number of patients with a SARS-CoV-2 RNA by ploymerase chain reaction (PCR) positive result with at least one symptom (fever, cough, sputum, malaise, shortness of breath) during the 12-week study period (including the 4-week observation period after oral administration). Secondary outcomes: 1. Period from infection to onset 2. Period from the appearance of symptoms to the disappearance of PCR positive 3. Number of days until the appearance or improvement of symptoms 4. Severe stage: presence of hospitalization 5. Shock stage: ICU management required for mechanical ventilation, shock vitals or failure of organ(s) other than lungs Safety endpoints include numbness in the hands and/or feet, edema, skin rash or other allergic symptoms, and gastric discomfort. Randomisation Patients are randomized (1:1 ratio) to each group using minimization implemented with the Electric data capture system (DATATRAK Enterprise Cloud), with balancing of the arms with age range (under 50 years of age or not) and having a history of risk factors for COVID-19 (cardiovascular disease, hypertension, diabetes, respiratory diseases). Blinding (masking) Only participants will be randomized. Numbers to be randomised (sample size) The main research hypothesis of this study is that Kampo medicines significantly prevent the onset of COVID-19. It is assumed that the infection rate before the administration of the drug under consideration will be 0% and that the incidence of COVID-19 thereafter will be 2- 3%, of which 70%-80% will show symptoms of COVID-19. Assuming that the pharmaceutical effect of the drug will be effective in 50% of patients and that the incidence rates in the placebo and drug groups will be 1.4%-2.4% and 0.7%-1.2%, respectively, the placebo is calculated at 2%, and the study drug at 1%. Since the frequency of verification is low and the number of cases will be large, we set a total of 10 analyses (9 interim analyses and a final analysis). Since the number of cases at the time of the final analysis will be 4,986 under the conditions of α = 0.05 and a power of 80% by the Peto method. We set at 600 cases in each interim analysis with an estimated dropout rate of 16.9%. Finally, the total number of cases is set to 6,000 with 3,000 in the placebo group and 3,000 in the HET group. Trial status Protocol version 1.3 of October 23rd , 2020. Recruitment start (expected): December 1st, 2020. Recruitment finish (expected): December 31st, 2022. Trial registration This trial is registered in the Japan Registry of Clinical Trials (jRCT) ( jRCTs031200150 ) on 14 October 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Abstract 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 (

Abstract Background Eribulin mesylate is currently indicated as a sequential monotherapy to be administered after two chemotherapeutic regimens, including anthracycline and taxane treatments, for treatment of metastatic breast cancer. This open-label, multicenter phase II study was designed to evaluate the efficacy and safety of eribulin as a first- or second-line treatment for patients with metastatic breast cancer. Methods The primary objective was to determine the overall response rate. Secondary objectives were to evaluate progression-free survival and the safety profile. Patients were scheduled to receive eribulin mesylate 1.4 mg/m2 intravenously on days 1 and 8 of a 21-day cycle. Patients received the study treatment unless disease progression, unacceptable toxicity, or a request to discontinue from the patient and/or investigator eventuated. Results Between December 2012 and September 2015, 32 patients with metastatic breast cancer were enrolled at 10 participating clinical institutions in Japan, and toxicity and response rates were evaluated. The overall response rate was 43.8% (95% confidence interval [CI] 26.5–61.0). The clinical benefit and tumor control rates were 56.3% (95% CI 39.0–73.5) and 78.1% (95% CI 63.8–92.5), respectively. Median progression-free survival was 8.3 months (95% CI 7.1–9.4). A subgroup analysis did not identify any factors affecting the efficacy of eribulin. The most common adverse events were neutropenia (71.9%), alopecia (68.7%), and peripheral neuropathy (46.9%). As a first- or second-line therapy, eribulin showed sufficient efficacy for metastatic breast cancer compared with taxane and capecitabine treatment in previous clinical trials. The safety profile of eribulin was acceptable. Conclusions Eribulin may be another option for first-line chemotherapeutic regimens for metastatic breast cancer. Trial registrations This trial was retrospectively registered at the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (ID number: UMIN000010334). Date of trial registration: April 1st, 2013.