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Abstract Background The composite physiologic index (CPI) was developed to estimate the extent of interstitial lung disease (ILD) in idiopathic pulmonary fibrosis (IPF) patients based on pulmonary function tests (PFTs). The CALIPER-revised version of the CPI (CALIPER-CPI) was also developed to estimate the volume fraction of ILD measured by CALIPER, an automated quantitative CT postprocessing software. Recently, artificial intelligence-based quantitative CT image analysis software (AIQCT), which can be used to quantify the bronchial volume separately from the ILD volume, was developed and validated in IPF. The aim of this study was to develop AIQCT-derived CPI formulas to quantify CT abnormalities in IPF and to investigate the associations of these CPI formulas with survival. Methods The first cohort included 116 patients with IPF. In this cohort, ILD, bronchial, and hyperlucent volumes on CT were quantified using AIQCT. New CPI formulas were developed based on PFTs to estimate the volume fraction of ILD (ILD-CPI), the sum of the ILD and bronchial volume fractions (ILDB-CPI), and the sum of the ILD, bronchial and hyperlucent volume fractions (ILDBH-CPI). The associations of the original CPI, the CALIPER-CPI and the AIQCT-derived CPIs with survival were analyzed in the first cohort and in a second cohort of patients with IPF (n = 72). Results In the first cohort, over a median observation time of 92.8 months, 79 patients (68.1%) died, and one patient (0.9%) underwent living-donor lung transplantation. The original CPI, the CALIPER-CPI, and all AIQCT-derived CPIs were associated with overall survival (hazard ratios: 1.07–1.22). The C-index of the ILDB-CPI (0.759) was the highest among all AIQCT-derived CPIs and was comparable to that of the original CPI (0.765) and the CALIPER-CPI (0.749). The C-index of the ILDBH-CPI (0.729) was lower than that of the other CPI variables. The second cohort yielded similar C-indices as the first cohort for the original CPI (0.738), CALIPER-CPI (0.757) and ILDB-CPI (0.749). Conclusions The ILDB-CPI can predict the outcomes of IPF patients with a similar performance to that of the original CPI and the CALIPER-CPI. Adding the hyperlucent volume to the CPI formula did not improve its predictive accuracy for mortality. Trial registration None (no health care interventions were performed).

Abstract This study aims to identify factors influencing the alleviation of knee joint symptoms in patients with rheumatoid arthritis treated with biologic or target synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Among 2321 patients who started b/tsDMARDs between 2010 and 2023, we focused on 295 patients who had knee swelling or tenderness at the initiation of b/tsDMARDs and continued b/tsDMARDs at least 3 months, with recorded knee symptoms 6 months later. Symptom relief after 6 months was 78.2% for interleukin 6 (IL-6) inhibitors, 68.6% for Janus kinase (JAK) inhibitors, 65.8% for tumor necrosis factor (TNF) inhibitors, and 57.6% for cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig). The initial use of b/tsDMARDs and the use of IL-6 inhibitors in comparison to CTLA4-Ig emerged as a significant factor associated with the improvement of knee joint symptoms. Among 141 patients who underwent knee radiography at baseline and two years later, the deterioration in knee joint radiographs was 7.7% for IL-6 inhibitors, 6.3% for JAK inhibitors, 21.9% for TNF inhibitors, and 25.9% for CTLA4-Ig. The use of IL-6 inhibitors was a significant factor associated with the improvement of knee joint symptoms and the inhibition of joint destruction compared to CTLA4-Ig.

Abstract Background Patients with rheumatoid arthritis (RA) are prone to muscle atrophy due to inflammatory cytokines and corticosteroid use and immobility due to joint pain and deformity. Although resistance training is effective and safe in reversing muscle atrophy in RA, some patients are unable to perform a conventional high-load exercise program due to disease-related limitations. This study aims to examine the efficacy of individualized exercise therapy on physical function in elderly patients with RA who are at a high risk for sarcopenia. Methods This study is a single-center, parallel-group, two-arm, healthcare provider- and outcome assessor-blinded, superiority randomized controlled trial with a 1:1 allocation ratio. A total of 160 participants with RA between 60 and 85 years of age with a positive screening test for sarcopenia will be included. The intervention group will receive nutritional guidance and a four-month individualized exercise program in addition to the usual treatment. The control group will receive nutritional guidance in addition to the usual care. The primary endpoint will be physical function assessed using the Short Physical Performance Battery (SPPB) at 4 months. The data on outcome measures will be collected at baseline and at the two- and four-month follow-ups. Linear mixed-effects models for repeated measures will be conducted using the modified intention-to-treat analysis population. Discussion This study will provide evidence on whether a personalized exercise program can improve physical function and quality of life in elderly patients with RA. Some limitations include limited generalizability due to the single-center study and lack of blinding of the patients to the intervention assignment because of the nature of the exercise. Physical therapists may use this knowledge in their daily practice to improve RA treatment. Tailored exercise may enhance the health outcomes of the RA population and contribute to a reduction in healthcare costs. Trial registration The study protocol was retrospectively registered at the University hospital Medical Information Network-Clinical Trial Repository (UMIN-CTR) (registration number: UMIN000044930, https://www.umin.ac.jp/ctr/index-j.htm ) on January 4, 2022.

The Mann–Whitney effect is a measure for comparing survival distributions between two groups. The Mann–Whitney effect is interpreted as the probability that a randomly selected subject in a group survives longer than a randomly selected subject in the other group. Under the independence assumption of two groups, the Mann–Whitney effect can be expressed as the traditional integral formula of survival functions. However, when the survival times in two groups are not independent of each other, the traditional formula of the Mann–Whitney effect has to be modified. In this article, we propose a copula-based approach to compute the Mann–Whitney effect with parametric survival models under dependence of two groups, which may arise in the potential outcome framework. In addition, we develop a Shiny web app that can implement the proposed method via simple commands. Through a simulation study, we show the correctness of the proposed calculator. We apply the proposed methods to two real datasets.

Abstract Radiation therapy (RT) can enhance the abscopal effect of immune checkpoint blockade. This phase I/II study investigated the efficacy and safety of nivolumab plus RT in HER2-negative metastatic breast cancer requiring palliative RT for bone metastases. Cohort A included luminal-like disease, and cohort B included both luminal-like and triple-negative disease refractory to standard systemic therapy. Patients received 8 Gy single fraction RT for bone metastasis on day 0. Nivolumab was administered on day 1 for each 14-day cycle. In cohort A, endocrine therapy was administered. The primary endpoint was the objective response rate (ORR) of the unirradiated lesions. Cohorts A and B consisted of 18 and 10 patients, respectively. The ORR was 11% (90% CI 4–29%) in cohort A and 0% in cohort B. Disease control rates were 39% (90% CI 23–58%) and 0%. Median progression-free survival was 4.1 months (95% CI 2.1–6.1 months) and 2.0 months (95% CI 1.2–3.7 months). One patient in cohort B experienced a grade 3 adverse event. Palliative RT combined with nivolumab was safe and showed modest anti-tumor activity in cohort A. Further investigations to enhance the anti-tumor effect of endocrine therapy combined with RT plus immune checkpoint blockade are warranted. Trial registration number and date of registration UMIN: UMIN000026046, February 8, 2017; ClinicalTrials.gov: NCT03430479, February 13, 2018; Date of the first registration: June 22, 2017.

Background: Radiation or hormonal therapy is considered for prostate cancer patients with biochemical recurrence (BCR) after radical prostatectomy (RP). However, these therapies have their own complications. To delay the start of these therapies, we investigated the efficacy and safety of Brazilian green propolis for the treatment for BCR after RP. Materials and Methods: This single-center, single-arm open trial included 22 patients who experienced BCR after RP between 2016 and 2019. The patients received nine softgels of Brazilian green propolis (containing 40 mg propolis per capsule) daily for 6 months. The primary outcome was the prostate-specific antigen (PSA) response rate. The secondary outcomes included progression-free time, PSA slope (1/PSA doubling time) response rate, quality of life, and safety profile. Results: The PSA response rate was 0%. The mean PSA slopes before and after baseline were 0.12 month−1 and 0.08 month−1, respectively. Fifteen patients (68%) showed a decreased PSA slope after treatment. There were no negative effects on quality of life or serious adverse events leading to treatment discontinuation. Conclusion: There was no significant anticancer response in patients who received Brazilian green propolis. However, the PSA slope was decreased after propolis administration. Further, Brazilian green propolis may be safely consumed by patients.

Abstract The association between capecitabine efficacy and proton pump inhibitors (PPIs) is controversial. Here, we determined whether co-administration of PPIs affects the real-world effectiveness of capecitabine. This retrospective observational study included consecutive patients with stage II–III colorectal cancer (CRC) who received adjuvant capecitabine monotherapy or CapeOX (capecitabine and oxaliplatin) between January 2009 and December 2014 at nine participating institutions. The primary endpoint was the difference in relapse-free survival (RFS) between patients who received PPIs and those who did not and was estimated using the Kaplan–Meier method. Overall survival (OS) was the secondary endpoint. Multivariable analysis of RFS and OS was performed using a Cox proportional hazards model, propensity score adjustment, and inverse probability of treatment weighting (IPTW) analyses. Data from 606 patients were evaluated, 54 of whom had received a PPI. PPI-treated patients tended to have poorer RFS and OS than patients treated without PPIs. The hazard ratio for RFS with capecitabine monotherapy was 2.48 (95% confidence interval: 1.22–5.07). These results were consistent with sensitivity analyses performed using propensity score adjustment and IPTW methods. Co-administration of PPIs may reduce the effectiveness of capecitabine and negatively impact patients with stage II–III CRC.

Abstract Background Olanzapine has been reported to be an effective antiemetic in patients receiving carboplatin-based chemotherapy. However, the efficacy of a neurokinin-1 receptor antagonist (NK1RA) added to olanzapine, a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA), and dexamethasone (DEX) has not been proven. This study aimed to assess the efficacy and safety of NK1RA, in combination with three-drug antiemetic regimens containing olanzapine, in preventing nausea and vomiting induced by carboplatin-based chemotherapy. Methods Data were pooled for 140 patients receiving carboplatin-based chemotherapy from three multicenter, prospective, single-arm, open-label phase II studies that evaluated the efficacy and safety of olanzapine for chemotherapy-induced nausea and vomiting. The propensity score of the co-administration of NK1RA was estimated for each patient using a logistic regression model that included age, sex, and carboplatin dose. We analyzed a total of 62 patients, who were treated without NK1RA (non-NK1RA group: 31 patients) and with NK1RA (NK1RA group: 31 patients). The patients were selected using propensity score matching. Results The complete response rate (without emetic episodes or with no administration of rescue medication) in the overall period (0–120 h post carboplatin administration) was 93.5% in the non-NK1RA group and 96.8% in the NK1RA group, with a difference of -3.2% (95% confidence interval, -18.7% to 10.9%; P = 1.000). In terms of safety, there was no significant difference between the groups in daytime sleepiness and concentration impairment, which are the most worrisome adverse events induced by olanzapine. Conclusions The findings suggest that antiemetic regimens consisting of olanzapine, 5HT3RA, and DEX without NK1RA may be a treatment option for patients receiving carboplatin-based chemotherapy.

Abstract Background The management of anxiety and depression symptoms in rheumatoid arthritis (RA) patients is vital. Previous study findings on this topic are conflicting, and the topic remains to be thoroughly investigated. This study aimed to clarify the association of RA disease activity with anxiety and depression symptoms after controlling for physical disability, pain, and medication. Methods We conducted a cross-sectional study of RA patients from the XXX Rheumatoid Arthritis Management Alliance cohort. We assessed patients using the Disease Activity Score (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), and Hospital Anxiety and Depression Scale (HADS). Anxiety and depression symptoms were defined by a HADS score ≥ 8. We analyzed the data using multivariable logistic regression analyses. Results Of 517 participants, 17.6% had anxiety symptoms and 27.7% had depression symptoms. The multivariable logistic regression analysis demonstrated that DAS28 was not independently associated with anxiety symptoms (odds ratio [OR] [95% confidence interval; CI] 0.93 [0.48–1.78]; p = 0.82) and depression symptoms (OR [95% CI] 1.45 [0.81–2.61]; p = 0.22). However, DAS28 patient global assessment (PtGA) severity was associated with anxiety symptoms (OR [95% CI] 1.15 [1.02–1.29]; p = 0.03) and depression symptoms (OR [95% CI] 1.21 [1.09–1.35]; p

Abstract Background The efficacy of olanzapine as an antiemetic agent in cancer chemotherapy has been demonstrated. However, few high-quality reports are available on the evaluation of olanzapine’s efficacy and safety at a low dose of 5 mg among patients treated with carboplatin regimens. Therefore, in this study, we investigated the efficacy and safety of 5 mg olanzapine for managing nausea and vomiting in cancer patients receiving carboplatin regimens and identified patient-related risk factors for carboplatin regimen-induced nausea and vomiting treated with 5 mg olanzapine. Methods Data were pooled for 140 patients from three multicenter, prospective, single-arm, open-label phase II studies evaluating the efficacy and safety of olanzapine for managing nausea and vomiting induced by carboplatin-based chemotherapy. Multivariable logistic regression analyses were performed to determine the patient-related risk factors. Results Regarding the endpoints of carboplatin regimen-induced nausea and vomiting control, the complete response, complete control, and total control rates during the overall study period were 87.9, 86.4, and 72.9%, respectively. No treatment-related adverse events of grade 3 or higher were observed. The multivariable logistic regression models revealed that only younger age was significantly associated with an increased risk of non-total control. Surprisingly, there was no significant difference in CINV control between the patients treated with or without neurokinin-1 receptor antagonist. Conclusions The findings suggest that antiemetic regimens containing low-dose (5 mg) olanzapine could be effective and safe for patients receiving carboplatin-based chemotherapy.

Abstract Runt-related transcription factor 2 (Runx2)-deficient mice can be used to model congenital tooth agenesis in humans. Conversely, uterine sensitization-associated gene-1 (Usag-1)-deficient mice exhibit supernumerary tooth formation. Arrested tooth formation can be restored by crossing both knockout-mouse strains; however, it remains unclear whether topical inhibition of Usag-1 expression can enable the recovery of tooth formation in Runx2-deficient mice. Here, we tested whether inhibiting the topical expression of Usag-1 can reverse arrested tooth formation after Runx2 abrogation. The results showed that local application of Usag-1 Stealth small interfering RNA (siRNA) promoted tooth development following Runx2 siRNA-induced agenesis. Additionally, renal capsule transplantation of siRNA-loaded cationized, gelatin-treated mouse mandibles confirmed that cationized gelatin can serve as an effective drug-delivery system. We then performed renal capsule transplantation of wild-type and Runx2-knockout (KO) mouse mandibles, treated with Usag-1 siRNA, revealing that hindered tooth formation was rescued by Usag-1 knockdown. Furthermore, topically applied Usag-1 siRNA partially rescued arrested tooth development in Runx2-KO mice, demonstrating its potential for regenerating teeth in Runx2-deficient mice. Our findings have implications for developing topical treatments for congenital tooth agenesis.

Abstract Allogenic hematopoietic stem cell transplantation (allo‐HCT) is the standard treatment for acute myeloid leukemia (AML) in non‐complete remission (non‐CR); however, the prognosis is inconsistent. This study aimed to develop and validate nomograms and a web application to predict the overall survival (OS) of patients with non‐CR AML undergoing allo‐HCT (cord blood transplantation [CBT], bone marrow transplantation [BMT], and peripheral blood stem cell transplantation [PBSCT]). Data from 3052 patients were analyzed to construct and validate the prognostic models. The common significant prognostic factors among patients undergoing allo‐HCT were age, performance status, percentage of peripheral blasts, cytogenetic risk, chemotherapy response, and number of transplantations. The conditioning regimen was a significant prognostic factor only in patients undergoing CBT. Compared with cyclophosphamide/total body irradiation, a conditioning regimen of ≥3 drugs, including fludarabine, with CBT exhibited the lowest hazard ratio for mortality (0.384; 95% CI, 0.266–0.554; p

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients. Methods A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed. Results In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01–1.07; IL-8, HR = 1.04, 95% CI 1.01–1.08; MIP-1α, HR = 1.19, 95% CI 1.00–1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02–1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01–1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls. Conclusions CTACK is a novel prognostic biomarker of IPF. Trial registration None (because of no healthcare intervention)

Abstract Background Overactive bladder (OAB) symptoms affect daily life by decreasing health-related quality of life (HRQol). However, there remain no very effective treatment for OAB. Pharmacotherapy is one of the best treatments, but it is not always efficient and may incur adverse events. Although behavioral therapy is another effective treatment, there are very few structured treatment manuals on how to prescribe behavioral therapy to treat OAB for whom. Cognitive behavioral therapy (CBT) is a psychotherapy consisting of structured sessions to solve problems with the collaborative empiricism between therapists and patients. OAB symptoms are supposed to worsen with cognitive distortion, and CBT is expected to be effective in treating OAB by modifying such cognitive processes. In this trial, we will evaluate the efficacy of CBT for OAB. Methods A randomized, controlled, open-label, multicenter parallel-group superiority trial will be conducted. Participants with moderate to severe OAB symptoms with or without pharmacotherapy will be recruited and will be randomly allocated 1:1 to two different groups by minimization (age, baseline OAB severity, treatment status, types of intervention, and treating institutions). The intervention group will be prescribed an individual CBT program covering six techniques in 4 sessions (30 min each), with or without pharmacotherapy. The primary outcome is the change scores in an OAB-questionnaire (OAB-q) from baseline to the end of the trial (week 13). Secondary outcomes will include other patient reported outcome measures and the frequency volume chart. All analyses will be conducted on an intention-to-treat principle. Discussion This trial will determine the efficacy of CBT to treat OAB using a rigorous methodology. The effectiveness of CBT with a structured manual may not only lead to a new treatment option for patients suffering from OAB symptoms, but may also reduce the social burden by OAB. Trial registration UMIN-CTR Clinical Trial, CTR-UMIN000038513 . Registered on November 7, 2019.

Objectives: To improve patient safety, information regarding errors must be collected. This practice constitutes one of the strategies that hospital managers use to understand the types of errors that occur at their hospitals. This pilot study aimed to evaluate an intervention designed to improve error reporting percentage among physicians. Methods: The study was conducted at University Hospital A, where data were collected from April 2017 to March 2019. The intervention began in April 2018 and involved the following steps: receiving support and appropriate feedback from the hospital administrator, defining reporting standards, improving the incident reporting system, and having the hospital administrators set clear goals and begin a visualized feedback process. Physicians were the main target for these steps in this study. Results: The percentage of reports submitted by physicians relative to nonphysicians increased from fiscal year (FY) 2017 to FY 2018, with the largest monthly increase within 2018 occurring in November. Physician reporting was higher in FY 2018 than in FY 2017, with the greatest difference observed for December of the respective FYs (p < 0.001, analyzed using Fisher’s exact test). The percentage of reports submitted by physicians increased by 2.6% (95% confidence interval [CI]: 1.7, 3.5) from FY 2017 to FY 2018, raising the percentage to 9%. Conclusions: Based on these results, it can be said that the intervention effectively increased incident reporting among not only physicians but also nonphysician staff members. In this regard, reporting barriers were broken when hospital administrators encouraged staff to submit incident reports. Active feedback by hospital administrators—the executive class of the hospital—may encourage not only physicians, but also staff members to submit incident reports, thus effectively removing reporting barriers.

Choking can lead to mortality and residual impairments. This study aimed to determine the factors associated with choking among acute hospital patients and examine error-producing conditions to suggest choking-prevention policies. Among 36,364 cases reported by hospital staff at an acute university hospital from 2012 to 2018 were examined using a retrospective study, 35,440 were analysis as the number of cases analysed for the study. We used descriptive statistics to present patient characteristics and conducted univariable and multivariable logistic regression analyses to identify factors associated with choking. Additionally, we conducted content analysis (root cause analysis) to examine error-producing conditions and prevention policies. Sixty-eight cases were related to choking injuries; of these, 43 patients (63.2%) were male, and 38 (55.9%) were aged 65 years and older. Choking cases had a high percent of adverse outcomes involving residual impairment or death (n = 23, 33.8%). Mental illness (adjusted odds ratio [95% confidence interval]: 3.14 [1.39-7.08]), and hospitalisation in the general wards (adjusted odds ratio [95% confidence interval]: 3.13 [1.70-5.76]) were associated with an increased probability of choking. Error production was caused by food (n = 25, 36.8%) and medical devices or supplies (n = 13, 19.1%). Almost all contributory factors were associated with inadequate checking (n = 66, 97.1%) and misperception of risk (n = 65, 95.6%). Choking poses a highly significant burden on patients, and hospital administrators should minimise the risk of choking to prevent related injuries. Hospital administrators should provide training and education to their staff and develop adequate protocols and procedures to prevent choking.

Reminiscence therapy is garnering attention for stimulating seniors’ cognitive functions. It could be inferred that that synergistic effects could be created by combining virtual reality (VR), which can project realistic images, with recall, which stimulates memory. We hypothesized that by projecting realistic memories to stimulate recall, VR-based reminiscence therapy would stimulate cognitive function better than conventional photo-based reminiscence therapy. We randomly assigned total 52 people with mild cognitive impairment to eight weeks of reminiscence therapy using either tablet VR panoramas or conventional still photos with 26 participants in each group. Before and after therapy, we tested their cognitive functions with the mini-mental state examination (MMSE), the revised PGC morale scale, multidimensional observation scale for elderly subjects, trail making tests A and B, and the word fluency test. The total scores of MMSE showed improvement for both groups, but did not show statistical significance of the VR panoramas group over the conventional still photos group. However, of the two groups, only the VR panoramas group showed considerable improvement from the baseline. In addition, the analysis of secondary outcome showed that the revised PGC morale scale scores rose considerably higher in the VR panoramas group than in the still photos group. No definite differences were observed in other scales. Contrary to our primary hypothesis, reminiscence therapy produced cognitive improvement regardless of whether its stimuli were still photos or VR panoramas. However, the greater improvement in VR participants’ revised PGC morale scale scores shows enhancement of patients’ subjective well-being.

Abstract Background The aim of this study was to evaluate the efficacy and safety of nab-paclitaxel plus cisplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer (NSCLC). Methods Chemotherapy-naïve patients with advanced NSCLC were eligible. In the phase I dose-escalation cohort (3 + 3 design), patients received nab-paclitaxel (80 or 100 mg/m2 given intravenously on days 1, 8 and 15) plus cisplatin (60 or 75 mg/m2 given intravenously on day 1) every 4 weeks. The maximum tolerated dose was not reached. Nab-paclitaxel (100 mg/m2 given intravenously on days 1, 8 and 15) plus cisplatin (75 mg/m2 given intravenously on day 1) every 4 weeks was selected for the phase II cohort. The primary endpoint was the objective response rate (ORR). Results Twenty-three patients (phase I, n = 6; phase II, n = 17) were enrolled, and 22 patients were eligible. The median age was 67.5 years (range 37–75), 90.9% were males, 45.5% had adenocarcinoma and 81.8% had stage IV disease. The ORR was 59.1% (90% confidence interval (CI); 41.8–74.4), and the disease control rate was 86.4% (95% CI; 66.7–95.3). The median progression-free survival was 5.1 months (95% CI; 4.0–6.7), and the median overall survival was 24.2 months (95% CI; 8.4 months to not estimable). The common grade ≥ 3 adverse events were neutropenia (31.8%), leukopenia (27.3%), lung infection (18.2%) and hyponatremia (18.2%). There was one instance of grade 2 interstitial pneumonia and no treatment-related death. Conclusions Nab-paclitaxel plus cisplatin was well tolerated and associated with encouraging response outcomes in chemotherapy-naïve patients with advanced NSCLC. Further investigation is warranted. Trial registration UMIN Clinical Trials Registry: UMIN000011776; Date of registration: 17 September 2013; Date of enrolment of the first participant to the trial: 23 January 2014.

Abstract Background Human papilloma viruses (HPVs) infect squamous epithelial cells and form verrucous lesions, or warts. Besides the psychosocial problems caused by the disfiguring warts, a subset of HPVs can be the primary etiologic agent for malignancies such as cervical cancer. However, there is no curative antiviral therapy for HPV infection. We recently found that the viral RNA transcription of DNA viruses requires cyclin dependent kinase 9 (CDK9) in the host cells, and that FIT039, a specific inhibitor of CDK9, suppressed the proliferation of DNA viruses such as herpes simplex virus 1 (HSV-1), HSV-2, human adenovirus, human cytomegalovirus, hepatitis virus B, and HPVs. Here, we describe a protocol to evaluate the safety and antiviral effect of FIT039 on common warts in human skin. Methods and design A multi-institutional, single-blind, placebo-controlled randomized phase I/II clinical trial was designed to evaluate the safety and efficacy of FIT039 on common warts on the extremities. A total of 44 adults with a primary diagnosis of verruca vulgaris on the extremities without serious comorbidities will be randomized into either the intervention group with an FIT039-releasing transdermal patch or a control group for a duration of 14 days. Outcomes will be assessed at baseline and postintervention. Participants will be further assessed at 2 months follow-up. The primary endpoint for efficacy is the resolution of the warts. The safety endpoint is the incidence of adverse events and adverse drug reactions. The secondary endpoints are changes in the dimensions of the wart, the cross-sectional area of the wart, and the number of clots within the area of the wart. Discussion This study is the first to assess the efficacy of FIT039 and will contribute to the development of antiviral agents that can cure refractory common warts in immunocompromised patients. Trial registration UMIN Clinical Trials, UMIN000029695. Registered on 1 November 2017.

Abstract Background Adaptive enrichment designs for clinical trials have great potential for the development of targeted therapies. They enable researchers to stop the recruitment process for a certain population in mid-course based on an interim analysis. However, adaptive enrichment designs increase the total trial period owing to the stoppage in patient recruitment to make interim decisions. This is a major drawback; it results in delays in the submission of clinical trial reports and the appearance of drugs on the market. Here, we explore three types of patient recruitment strategy for the development of targeted therapies based on the adaptive enrichment design. Methods We consider recruitment methods which provide an option to continue recruiting patients from the overall population or only from the biomarker-positive population even during the interim decision period. A simulation study was performed to investigate the operating characteristics by comparing an adaptive enrichment design using the recruitment methods with a non-enriched design. Results The number of patients was similar for both recruitment methods. Nevertheless, the adaptive enrichment design was beneficial in settings in which the recruitment period is expected to be longer than the follow-up period. In these cases, the adaptive enrichment design with continued recruitment from the overall population or only from the biomarker-positive population even during the interim decision period conferred a major advantage, since the total trial period did not differ substantially from that of trials employing the non-enriched design. By contrast, the non-enriched design should be used in settings in which the follow-up period is expected to be longer than the recruitment period, since the total trial period was notably shorter than that of the adaptive enrichment design. Furthermore, the utmost care is needed when the distribution of patient recruitment is concave, i.e., when patient recruitment is slow during the early period, since the total trial period is extended. Conclusions Adaptive enrichment designs that entail continued recruitment methods are beneficial owing to the shorter total trial period than expected in settings in which the recruitment period is expected to be longer than the follow-up period and the biomarker-positive population is promising.

Trial design: Human papillomavirus infection causes verruca vulgaris. CDK9 inhibitor FIT039 inhibits DNA virus proliferation in animal models. We conducted a multicenter, single-blind, placebo-controlled, randomized phase I/II clinical trial evaluating the safety and efficacy of FIT039 against verruca vulgaris. Methods: Target lesions were treated with liquid nitrogen once, and a FIT039 patch or placebo patch was applied for 14 days. The primary endpoint was lesion disappearance. The secondary endpoints were safety and changes in dimension, cross-sectional area, and the number of petechial lesions. Results: A total of 24 participants were randomly allocated to the FIT039 (n = 13, median age, 54 years) and placebo (n = 11, median age, 62 years) groups. Verruca vulgaris did not disappear. FIT039 decreased the dimension to 76% of the initial value on day 29, followed by an increase to 98% on day 57. Placebo showed a monotonic increase to 107% on day 57. Changes in the cross-sectional area and petechiae number were comparable between the groups. Conclusions: No drug-related adverse reactions occurred. FIT039 efficacy was not determined in this study.

Introduction Alzheimer’s disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD.Methods and analysis This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted.Ethics and dissemination The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process.Trial registration number jRCT2041200008, NCT04413344.

BackgroundAmong patients with advanced non-small-cell lung cancer who were treated with nivolumab monotherapy, the association of peripheral blood count data (at baseline and 2 weeks after treatment initiation) with the early onset of immune-related adverse events (irAEs) and treatment efficacy has not been clearly established. This study aimed to identify peripheral blood count data that may be predictive of the development of nivolumab-induced irAEs in a real-world clinical setting.Materials and MethodsThis multicenter observational study retrospectively evaluated consecutive patients with advanced non-small-cell lung cancer undergoing nivolumab monotherapy in the second- or later-line setting between December 2015 and November 2018 at the National Cancer Center Hospital and Keio University Hospital in Japan. The primary endpoint was the association between peripheral blood count data and irAEs during the 6-week study period. Receiver operating characteristic curve and multivariable logistic regression analyses were performed.ResultsOf the 171 patients evaluated, 73 (42.7%) had ≥1 irAE during the first 6 weeks following treatment initiation. The median time to irAEs from the initiation of nivolumab was 15 (interquartile range: 13–28) days. Receiver operating characteristic curve analyses revealed that the optimal cut-off values of the absolute lymphocyte count, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio 2 weeks after treatment initiation for early irAE onset were 820, 4.3, and 2.2, respectively. In multivariable logistic regression analyses, absolute lymphocyte count >820 at 2 weeks after treatment initiation was significantly associated with an increased risk of early onset of any irAE. In contrast, no significant association was observed for the neutrophil-to-lymphocyte ratio (>4.3) or the lymphocyte-to-monocyte ratio (>2.2) at 2 weeks following treatment initiation.ConclusionsThe absolute lymphocyte count >820 at 2 weeks following nivolumab initiation predicts early onset of irAEs during a 6-week study period. Routinely available absolute lymphocyte count, which is measured after the initiation of nivolumab, may be useful for identifying patients at risk of early onset of irAEs.

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is an adverse event induced by antiresorptive agents (ARAs). The purpose of this study was to evaluate variables, mainly surgery and hyperbaric oxygen (HBO) therapy, associated with treatment outcomes in patients with a diagnosis of ARONJ at a single center. We enrolled consecutive patients who presented to our hospital for the management of stage 2 or 3 ARONJ between January 2003 and December 2019. The relationship between potentially predictive factors and outcome variables was examined using statistical analyses, along with a subgroup analysis based on disease stage. Of 252 patients included in this study, 206 had stage 2 ARONJ and 46 had stage 3 ARONJ. There were 119 patients with osteoporosis and 133 with malignant disease. In total, 139 patients were healed, and the healing rate of patients with stage 3 ARONJ was lower than that of patients with stage 2 ARONJ. With regard to the combination of surgery and HBO therapy, most patients underwent HBO before and after surgery. In the univariable analysis, surgery showed a therapeutic effect in both stage 2 and 3 ARONJ, whereas HBO showed a therapeutic effect in stage 2 ARONJ. In the multivariable analysis for stage 2 ARONJ, extensive surgery showed a stronger association with healing than conservative surgery, whereas ≥46 sessions of HBO therapy was less associated with healing than was non-HBO therapy. Our findings suggest that extensive surgery is highly effective against ARONJ regardless of disease stage if there is a sequestrum separation and systemic tolerance, whereas HBO therapy before and after surgical approach can be effective. Further studies are needed to identify treatment strategies for patients with treatment-refractory ARONJ who may be forced to undergo long-term HBO therapy with the expectation of sequestrum separation.

Background and objective A high frequency of infections complicating rheumatoid arthritis (RA) has been reported due to the immunomodulatory effect of RA or to agents with immunosuppressive effects used in its treatment. We aimed to assess clinical and radiological characteristics of pulmonary cryptococcosis in patients with and without RA.Methods We retrospectively reviewed the medical records of 52 patients with pulmonary cryptococcosis and divided them into two groups, those with RA and without RA, and compared clinical characteristics and radiological findings between them.Results Eleven (21.2%) of the 52 patients had RA. Median follow-up periods were 51.2 (range: 1.1–258.7) months for patients with RA and 19.1 (range: 0.63–246.9) months for patients without RA. Among the patients with RA, 81.8% were women, with a mean age of 68.1 years. Female sex and respiratory comorbidities were significantly more frequent in patients with RA than in patients without RA. Frequencies of concomitant cryptococcal meningitis and respiratory failure were not different between the groups. There were no significant differences in frequency of any radiological findings, locations and number between the two groups. Among patients with RA, all but one responded well to antifungal treatment. During the antifungal treatment course, one (9.1%) patient with RA died of cryptococcosis. Despite continuing antirheumatic drugs, no patients had recurrence of pulmonary cryptococcosis during follow-up.Conclusion Other than some differences in background, there were no clinical, radiological or prognostic differences between the patients with and without RA with pulmonary cryptococcosis. The administration of antirheumatic therapy had no negative effect on the clinical course of antifungal treatment.

Abstract Background Clinical remission can be maintained after the discontinuation of biological disease-modifying antirheumatic drugs (bDMARDs) in some patients with rheumatoid arthritis (RA) (bDMARD-free remission (BFR)). It is unknown which bDMARD is advantageous for achieving BFR or under which conditions BFR can be considered. This study aimed to determine the factors associated with BFR achievement in clinical practice. Methods Patients with RA were enrolled from a Japanese multicenter observational registry. Patients with RA who achieved clinical remission (Disease Activity Score 28—C-reactive protein 6 months), Boolean remission, no glucocorticoid use at the time of bDMARD discontinuation, and use of TNFi(mAb) or CTLA4-Ig remained as independent factors associated with BFR. Conclusions BFR can be achieved in some patients with RA after bDMARD discontinuation in clinical practice. Use of TNFi(mAb) or CTLA4-Ig, sustained remission, Boolean remission, and no glucocorticoid use at the time of bDMARD discontinuation are advantageous for achieving BFR.

Abstract Background Planar cell polarity (PCP) coordinates the patterning and orientation of cells and their structures along tissue planes, and although its acquisition during the formation of airway epithelium has been described, the mechanisms for its maintenance and reconstruction are poorly understood. We aimed to clarify whether ambient environment change by orthotropic autologous transplantation affected PCP at the cellular level. Methods We performed orthotropic autologous transplantation by inverting tracheal segments in rats, and then performed morphological evaluation by microscopy. The PCP of the tracheal epithelium was assessed over time by analyzing the directions of mucociliary transport and ciliary beat, the positional relationship between the basal body and basal foot, and the bias of Vang-like protein 1 (Vangl1) at 2, 4, and 6 months postoperatively. Results After 2 months, the directions of mucociliary transport and ciliary beat were preserved toward the lung in the inverted tracheal segments. The positional relationship between the basal body and the basal foot, and the bias of Vangl1, also indicated preservation of PCP in the inverted tracheal segments. Similar results were obtained at 6 months. Conclusion The PCP of ciliated epithelium was preserved in reversed trachea, even after long-term observation.

Introduction Amyotrophic lateral sclerosis (ALS) is a progressive and severe neurodegenerative disease caused by motor neuron death. There have as yet been no fundamental curative medicines, and the development of a medicine for ALS is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified an Src/c-Abl inhibitor, bosutinib, as a candidate molecular targeted therapy for ALS. The objectives of this study are to evaluate the safety and tolerability of bosutinib for the treatment of patients with ALS and to explore the efficacy of bosutinib on ALS. This study is the first clinical trial of administered bosutinib for patients with ALS.Methods and analysis An open-label, multicentre phase I dose escalation study has been designed. The study consists of a 12-week observation period, a 1-week transitional period, a 12-week study treatment period and a 4-week follow-up period. After completion of the transitional period, subjects whose total ALS Functional Rating Scale-Revised (ALSFRS-R) score decreased by 1–3 points during the 12-week observation period receive bosutinib for 12 weeks. Three to six patients with ALS are enrolled in each of the four bosutinib dose levels (100, 200, 300 or 400 mg/day) to evaluate the safety and tolerability under a 3+3 dose escalation study design. Dose escalation and maximum tolerated dose are determined by the safety assessment committee comprising oncologists/haematologists and neurologists based on the incidence of dose-limiting toxicity in the first 4 weeks of the treatment at each dose level. A recommended phase II dose is determined by the safety assessment committee on completion of the 12-week study treatment in all subjects at all dose levels. The efficacy of bosutinib is also evaluated exploratorily using ALS clinical scores and biomarkers.Ethics and dissemination This study received full ethical approval from the institutional review board of each participating site. The findings of the study will be disseminated in peer-reviewed journals and at scientific conferences.Trial registration number UMIN000036295; Pre-results, JMA-IIA00419; Pre-results.

The aim of this study was to evaluate the effect of an oral care intervention program on the incidence of pneumonia and fever as a surrogate endpoint. In addition, we tried to determine the oral care risk factors for the incidence of fever. We provided an oral care program for the elderly at one private nursing home in July 2013. The maximum capacity of the nursing home was 60 residents. The body temperatures of all residents were measured twice a day and were summarized as the incidence of fever over a one-month period, which was used as the dependent variable. The residents’ life conditions, number of teeth, and prescribed diet were used as independent variables. The factors that affected the incidence of fever were the number of remaining teeth, a prescribed diet of sliced food, the meal care level, and the oral Candida levels. These risk factors affected the incidence of fever independently or interactively with oral care. Some risk factors for the incidence of fever were enhanced by the oral care program. It is important to evaluate and control these factors before the implementation of an oral care program.