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Study Design Retrospective cohort study. Purpose This study aimed to compare data from patients who received intradiscal condoliase (chondroitin sulfate ABC endolyase) injection for primary lumbar disc herniation (LDH) and recurrent LDH. Overview of Literature Chemonucleolysis with condoliase for LDH is a treatment with relatively good results and a high safety profile; however, few studies have reported recurrence after LDH surgery. Methods The study participants were 249 patients who underwent intradiscal condoliase injection for LDH at nine participating institutions, including 241 patients with initial LDH (group C) and eight with recurrent LDH (group R). Patient characteristics including age, sex, body mass index, disease duration, intervertebral LDH level, smoking history, and diabetes history were evaluated. Low back pain/leg pain Numerical Rating Scale (NRS) scores and the Oswestry Disability Index (ODI) were used to evaluate clinical symptoms before treatment and at 6 months and 1 year after treatment. Results Low back pain NRS scores (before treatment and at 6 months and 1 year after treatment, respectively) in group C (4.9 → 2.6 → 1.8) showed significant improvement until 1 year after treatment. Although a tendency for improvement was observed in group R (3.5 → 2.8 → 2.2), no significant difference was noted. Groups C (6.6 → 2.4 → 1.4) and R (7.0 → 3.1 → 3.2) showed significant improvement in the leg pain NRS scores after treatment. Group C (41.4 → 19.5 → 13.7) demonstrated significant improvement in the ODI up to 1 year after treatment; however, no significant difference was found in group R (35.7 → 31.7 → 26.4). Conclusions Although intradiscal condoliase injection is less effective for LDH recurrence than for initial cases, it is useful for improving leg pain and can be considered a minimally invasive and safe treatment method.

Abstract The KOJI AWARENESS (KA) screening test assesses motor function in humans. We aimed to analyze the correlation between age and KA screening scores and to identify the specific age at which a significant decline occurs. A total of 793 healthy participants (234 females) were interviewed for basic information on age and sex and completed the KA screening test. In addition to calculating the total score from the KA test, the scores were calculated for the neck-scapula-upper extremity-complex (NSU), trunk, and lower extremity (LE) segments. Spearman’s rank correlation coefficient was used to assess the validity of the test. Additionally, Bayesian linear regression was employed to estimate the change point in KA scores, facilitating the identification of a critical age associated with a notable decline in motor function. KA screening total and separate body segment scores were negatively correlated with age in both gender (for female and male, KA total score, ρ = − 0.443, ρ = − 0.344; NSU segment, ρ = − 0.431, ρ = − 0.427; trunk segment, ρ = − 0.210, ρ = − 0.473; LE segment: ρ = − 0.43, ρ = − 0.507). Furthermore, a change-point analysis using linear regression analysis showed that KA screening total scores declined sharply at the age of 49.1(95% credible interval: 37.503, 68.366). The result show that total KA scores decrease − 0.196 (95% credible interval: − 0.335, − 0.049) for every 1 year of age increase, and for ages over 49.1, total KA scores additionally decrease − 0.255 (95% credible interval: − 0.485, − 0.054) for every 1 year of age increase. In the NSU segment, females showed a more rapid decline than males from the age of 50 years. KA screening test total scores declined sharply at the age of 49.1. These results may be useful in setting treatment goals, exercise, and lifestyle programs for age-related decline in motor function.

Background: Allergen immunotherapy (AIT) is the only disease-modifying treatment for immunoglobulin (Ig) E-mediated allergy. Owing to the high prevalence and early onset of hay fever and pollen-food allergy syndrome (PFAS), a safer and simpler treatment method than conventional AIT is needed. To develop a local nasal immunotherapy using an ointment containing hypoallergenic pollen and assess its efficacy in mice and healthy humans. Methods: Hypoallergenicity was achieved by combining pollen and galactomannan through the Maillard reaction to create birch pollen-galactomannan conjugate (BP-GMC). The binding of galactomannan to Bet v 1 was confirmed using electrophoresis and Western blotting (WB). Binding of specific IgE antibodies to BP-GMC was verified using enzyme-linked immunosorbent assay (ELISA) and basophil activation test (BAT). The localization of BP-GMC absorption was confirmed using a BALB/c mouse model. BP-GMC mixed with white petrolatum was intranasally administered to 10 healthy individuals (active drugs, 8; placebo, 2) for 14 days. Results: In electrophoresis and WB, no 17-kDa band was observed. In ELISA and BAT, BP-GMC did not react to specific IgE but was bound to IgA and IgG. In the mouse model, BP-GMC was detected in nasopharyngeal-associated lymphoid tissues. In the active drug group, the salivary-specific IgA level significantly increased on day 15 (p = 0.0299), while the serum-specific IgG level significantly increased on day 85 (p = 0.0006). Conclusions: The BP-GMC ointment rapidly produced antagonistic antibodies against IgE; it is safe and easy to use and might serve as a therapeutic antigen for hay fever and PFAS.

Abstract Dupuytren’s contracture, a superficial dermal fibrosis, causes flexion contracture of the affected finger, impairing hand function. Specific single-nucleotide polymorphisms within genes in the Wnt signalling pathway are associated with the disease. However, the precise role of Wnt signalling dysregulation in the onset and progression of Dupuytren’s contracture remains unclear. Here, using a fibrosis mouse model and clinical samples of human Dupuytren’s contractures, we demonstrate that the activation of Wnt/β-catenin signalling in Tppp3-positive cells in the dermis of the paw is associated with the development of fibrosis. Fibrosis development and progression via Wnt/β-catenin signalling are closely related to stromal cell–macrophage interactions, and Wnt/β-catenin signalling activation in Tppp3-positive stromal cells causes M2 macrophage infiltration via chemokine Cxcl14, resulting in the formation of a TGF-β-expressing fibrotic niche. Inhibition of Cxcl14 mitigates fibrosis by decreasing macrophage infiltration. These findings suggest that Cxcl14-mediated stromal cell–macrophage interaction is a promising therapeutic target for Wnt/β-catenin-induced fibrosis.

Abstract Background Racial differences have been reported in toxicity outcomes for anticancer drug treatments. However, these observations were often from studies with small sample sizes, and many only reported the maximum grade of toxicity and no longitudinal information. This current analysis aims to investigate racial differences in longitudinal toxicities using a large‐scale clinical trials database. Methods Early‐phase clinical trials sponsored by the Cancer Therapy Evaluation Program at the National Cancer Institute, USA, that evaluated cytotoxic drugs and molecularly targeted agents between March 2000 and December 2012 were studied. Race was categorized as White, Black or African‐American, and Asian. Each toxicity's grade prevalence, mean grade at each cycle, and time to develop grade 2 or higher toxicity was evaluated. Results In total, 25,442 patients from 697 trials were included in this study. The number of patients categorized as White, Black, and Asian designations was 22,756 (89%), 1874 (7%), and 812 (3%), respectively. Notable findings include the rate of any grade of diarrhea in Black people was 26% and 21% lower than that of White and Asian people. The median time to the first grade 2 or higher event was 6 cycles in White people, 8 in Black people, and 6 in Asian people. The rate of any grade hyperglycemia was significantly higher in Asian people. Conclusions Although we identified several racial differences in longitudinal toxicities, most were of generally lower grade. Further study is needed to clarify the cause of racial differences in treatment‐associated toxicities.

BackgroundThrombosis is a unique complication of coronavirus disease 2019 (COVID-19). Although antiphospholipid antibodies (aPL) are detected in COVID-19 patients, their clinical significance remains elusive. We evaluated the prevalence of aPL and serum concentrations of beta-2 glycoprotein I (β2GPI), a major self-antigen for aPL, in Japanese COVID-19 patients with and without thrombosis.MethodsThis retrospective single-center nested case-control study included 594 hospitalized patients with COVID-19 between January 2020 and August 2021. Thrombotic complications were collected from medical records. Propensity score-matching method (PSM) (1:2 matching including age, sex, severity on admission, and prior history of thrombosis) was performed to compare the prevalence and titer of aPL (anti-cardiolipin (aCL) IgG/IgM, anti-β2GPI IgG/IgM/IgA, and anti-phosphatidylserine/prothrombin antibody (aPS/PT) IgG/IgM) and serum β2GPI concentration. In addition, PSM (1:1 matching including age and sex) was performed to compare the serum β2GPI concentration between COVID-19 patients and healthy donors.ResultsAmong the patients, 31 patients with thrombosis and 62 patients without were compared. The prevalence of any aPLs was indifferent regardless of the thrombosis (41.9% in those with thrombosis vs. 38.7% in those without, p =0.82). The positive rates of individual aPL were as follows: anti-CL IgG (9.7% vs. 1.6%, p =0.11)/IgM (0% vs. 3.2%, p =0.55), anti-β2GP1 IgG (22.6% vs. 9.7%, p =0.12)/IgA (9.7% vs. 9.7%, p =1.0)/IgM (0% vs. 0%, p =1.0), and anti-PS/PT IgG (0% vs. 1.6%, p =1.0)/IgM (12.9% vs. 21.0%, p =0.41), respectively. The aPL titers were also similar regardless of thrombosis. The levels of β2GPI in COVID-19 patients were lower than those in the healthy donors.ConclusionAlthough aPLs were frequently detected in Japanese COVID-19 patients, their prevalence and titer were irrelevant to thrombotic complications. While COVID-19 patients have lower levels of serum β2GPI than healthy blood donors, β2GPI levels were indifferent regardless of thrombosis. Although most of the titers were below cut-offs, positive correlations were observed among aPLs, suggesting that the immune reactions against aPL antigens were induced by COVID-19. We should focus on the long-term thromboembolic risk and the development of APS in the aPL-positive patients with high titer or multiple aPLs.

Summary: Background: Pediatric patients with certain rare diseases are at increased risk of severe respiratory syncytial virus (RSV) infection. However, the prophylactic use of anti-RSV antibody (palivizumab) in these patients is not indicated at present in Japan. Methods: This first-in-the-world multicenter, uncontrolled, open-label, phase II clinical trial was carried out between 28 July 2019 and 24 September 2021 at seven medical institutions in Japan to investigate the efficacy, safety, and pharmacokinetics of palivizumab in 23 subjects recruited from among neonates, infants, or children aged 24 months or younger who had any of the following conditions: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. At least four continuous doses of palivizumab were administered intramuscularly at 15 mg/kg at intervals of 30 days. Findings: Twenty-three enrolled subjects completed the study. No subject required hospitalization for RSV. Adverse events (AE) did not notably differ from the event terms described in the latest interview form. Five severe AEs required unplanned hospitalization, but resolved without RSV infection. Therapeutically effective concentrations of palivizumab were maintained throughout the study period. Interpretation: Palivizumab might be well tolerated and effective in preventing serious respiratory symptoms and hospitalization due to severe RSV infection, indicating the prophylactic use in the pediatric patients included in this study. Funding: Japan Agency for Medical Research and Development (AMED), grant numbers 19lk0201097h0001 (to MM), 20lk0201097h0002 (to MM), 21lk0201097h0003 (to MM), and 22lk0201097h0004 (to MM). AMED did not have any role in the execution of this study, analysis and interpretation of the data, or the decision to submit the results.

Abstract Background The significance of metastasis-directed therapy for oligometastatic prostate cancer has been widely discussed, and targeted therapy for progressive sites is a feasible option as a multidisciplinary treatment for castration-resistant prostate cancer (CRPC). When oligometastatic CRPC with only bone metastases progresses after targeted therapy, it tends to progress as multiple bone metastases. The progression of oligometastatic CRPC after targeted therapy may be due in part to the presence of micrometastatic lesions that, though undetected on imaging, were present prior to targeted therapy. Thus the systemic treatment of micrometastases in combination with targeted therapy for progressive sites is expected to enhance the therapeutic effect. Radium-223 dichloride (radium-223) is a radiopharmaceutical that selectively binds to sites of increased bone turnover and inhibits the growth of adjacent tumor cells by emitting alpha rays. Therefore, for oligometastatic CRPC with only bone metastases, radium-223 may enhance the therapeutic effect of radiotherapy for active metastases. Methods This phase II, randomized trial of Metastasis-Directed therapy with ALpha emitter radium-223 in men with oligometastatic CRPC (MEDAL) is designed to assess the utility of radium-223 in combination with metastasis-directed radiotherapy in patients with oligometastatic CRPC confined to bone. In this trial, patients with oligometastatic CRPC with three or fewer bone metastases on whole-body MRI with diffusion-weighted MRI (WB-DWI) will be randomized in a 1:1 ratio to receive radiotherapy for active metastases plus radium-223 or radiotherapy for active metastases alone. The prior use of androgen receptor axis-targeted therapy and prostate-specific antigen doubling time will be used as allocation factors. The primary endpoint will be radiological progression-free survival against progression of bone metastases on WB-DWI. Discussion This will be the first randomized trial to evaluate the effect of radium-223 in combination with targeted therapy in oligometastatic CRPC patients. The combination of targeted therapy for macroscopic metastases with radiopharmaceuticals targeting micrometastasis is expected to be a promising new therapeutic strategy for patients with oligometastatic CRPC confined to bone. Trial registration Japan Registry of Clinical Trials (jRCT) (jRCTs031200358); Registered on March 1, 2021, https://jrct.niph.go.jp/latest-detail/jRCTs031200358

Abstract Background A basket trial is a type of clinical trial in which eligibility is based on the presence of specific molecular characteristics across subpopulations with different cancer types. The existing basket designs with Bayesian hierarchical models often improve the efficiency of evaluating therapeutic effects; however, these models calibrate the type I error rate based on the results of simulation studies under various selected scenarios. The theoretical control of family-wise error rate (FWER) is important for decision-making regarding drug approval. Methods In this study, we propose a new Bayesian two-stage design with one interim analysis for controlling FWER at the target level, along with the formulations of type I and II error rates. Since the difficulty lies in the complexity of the theoretical formulation of the type I error rate, we devised the simulation-based method to approximate the type I error rate. Results The proposed design enabled adjustment of the cutoff value to control the FWER at the target value in the final analysis. The simulation studies demonstrated that the proposed design can be used to control the well-approximated FWER below the target value even in situations where the number of enrolled patients differed among subpopulations. Conclusions The accrual number of patients is sometimes unable to reach the pre-defined value; therefore, existing basket designs may not ensure defined operating characteristics before beginning the trial. The proposed design that enables adjustment of the cutoff value to control FWER at the target value based on the results in the final analysis would be a better alternative.

Abstract Objective Patients with spinal and bulbar muscular atrophy (SBMA) often experience muscular weakness under cold exposure. Methods In our previously conducted observational study, we assessed nerve conduction and grip strength to examine the effect of cold exposure on motor function, based on which we conducted a randomized controlled trial to evaluate the efficacy and safety of mexiletine hydrochloride in SBMA (MEXPRESS). Results In the observational study, 51 consecutive patients with SBMA and 18 healthy controls (HCs) were enrolled. Of the patients with SBMA, 88.0% experienced cold paresis. Patients with SBMA exhibited greater prolongation of ulnar nerve distal latency under cold (SBMA, 5.6 ± 1.1 msec; HC, 4.3 ± 0.6 msec; p

Abstract This study aimed to develop a functional measurement that combines quantitative motor evaluation index of various body regions in patients with spinal and bulbar muscular atrophy (SBMA). We assessed subjects with SBMA and healthy controls with quantitative muscle strength measurements and functional scales. We selected tongue pressure, grip power, % peak expiratory flow (%PEF), timed walking test, and % forced vital capacity (%FVC) as components. By combining these values with Z-score, we created a functional composite (SBMA functional composite: SBMAFC). We also calculated the standardized response mean to compare the sensitivity of SBMAFC with that of existing measurements. A total of 97 genetically confirmed patients with SBMA and 36 age- and sex-matched healthy controls were enrolled. In the longitudinal analysis, the standardized response mean of SBMAFC was larger than that of existing rating scales. Receiver operating characteristic (ROC) analysis demonstrated that the SBMAFC is capable of distinguishing between subjects with early-stage SBMA and healthy controls. SBMAFC is more sensitive to disease progression than existing functional rating scales and is a potential outcome measure in clinical trials of SBMA.

Abstract Background Lubricin, a proteoglycan encoded by the PRG4 gene, is synthesised by superficial zone (SFZ) chondrocytes and synovial cells. It reduces friction between joints and allows smooth sliding of tendons. Although lubricin has been shown to be effective against osteoarthritis and synovitis in animals, its clinical application remains untested. In this study, we aimed to induce lubricin-expressing cells from pluripotent stem cells (iPSCs) and applied them locally via cell transplantation. Methods To generate iPSCs, OCT3/4, SOX2, KLF4, and L-MYC were transduced into fibroblasts derived from Prg4-mRFP1 transgenic mice. We established a protocol for the differentiation of iPSC-derived Prg4-mRFP1-positive cells and characterised their mRNA expression profile. Finally, we injected Prg4-mRFP1-positive cells into the paratenon, surrounding the Achilles tendons and knee joints of severe combined immunodeficient mice and assessed lubricin expression. Result Wnt3a, activin A, TGF-β1, and bFGF were applied to induce the differentiation of iPSC-derived Prg4-mRFP1-positive cells. Markers related to SFZ chondrocytes and fibroblast-like synovial cells (FLSs) were expressed during differentiation. RNA-sequencing indicated that iPSC-derived Prg4-mRFP1-positive cells manifested expression profiles typical of SFZ chondrocytes and FLSs. Transplanted iPSC-derived Prg4-mRFP1-positive cells survived around the Achilles tendons and in knee joints. Conclusions The present study describes a protocol for the differentiation of iPSC-derived Prg4-positive cells with characteristics of SFZ chondrocytes and FLSs. Transplantation of lubricin-expressing cells offers promise as a therapy against arthritis and synovitis.

Arthrodesis is a reliable surgical procedure for treating thumb carpometacarpal osteoarthritis. However, the most frequent and problematic complication of arthrodesis is nonunion. Although postarthrodesis-related nonunion is a common complication, the indications and results of revision procedures for this pathological condition have not been well documented. A 59-year-old man underwent arthrodesis for thumb carpometacarpal osteoarthritis, which resulted in painful nonunion 7 months after the surgery. We performed revision surgery for this pathological condition, using first dorsal metacarpal artery-pedicled second metacarpal vascularized bone graft. This method resulted in successful bone union and pain relief. First dorsal metacarpal artery-pedicled second metacarpal vascularized bone grafting could be an alternative method for nonunion, which is a common complication after thumb carpometacarpal arthrodesis.

ObjectivesImproving the lifestyle of occupational workers is essential for extending healthy life expectancy. We investigated various lifestyle-related items in a rural Japanese population and compared them between agricultural and non-agricultural workers.MethodsThis cross-sectional study was conducted as a part of the "Iwaki Health Promotion Project." Lifestyle-related items such as sleep, work hours, nutrition, health-related quality of life, and proportion of time spent performing each daily activity were compared between agricultural and non-agricultural workers in the ≥60 years (n = 251) and ResultsAgricultural workers had significantly lower Pittsburgh Sleep Quality Index total scores than non-agricultural workers in the ConclusionsAgricultural workers have better sleep habits but work longer than non-agricultural workers, with some differences in energy intake and proportion of time spent on each daily activity. These differences should be considered when planning lifestyle intervention programs for agricultural workers.

Abstract Mesenchymal stem cells (MSCs) have immunomodulatory properties and support hematopoiesis in the bone marrow (BM). To develop a new strategy to not only prevent graft‐vs‐host disease (GVHD) but also to enhance engraftment, a phase I trial of cord blood transplantation (CBT) combined with intra‐BM injection of MSCs (MSC‐CBT) was designed. Third‐party BM‐derived MSCs were injected intra‐BM on the day of CBT. The conditioning regimen varied according to patient characteristics. GVHD prophylaxis was tacrolimus and methotrexate. The primary endpoint was toxicity related to intra‐BM injection of MSCs. Clinical outcomes were compared with those of six controls who received CBT alone. Five adult patients received MSC‐CBT, and no adverse events related to intra‐BM injection of MSCs were observed. All patients achieved neutrophil, reticulocyte, and platelet recoveries, with median times to recoveries of 21, 35, and 38 days, respectively, comparable with controls. Grade II‐IV acute GVHD developed in three controls but not in MSC‐CBT patients. No patients developed chronic GVHD in both groups. At 1 year after transplantation, all MSC‐CBT patients survived without relapse. This study shows the safety of MSC‐CBT, and the findings also suggest that cotransplantation of MSCs may prevent GVHD with no inhibition of engraftment. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as number 000024291.

Introduction Neonatal hypoxic-ischaemic encephalopathy (HIE) is an important illness associated with death or cerebral palsy. This study aims to assess the safety and tolerability of the allogenic human multilineage-differentiating stress-enduring cell (Muse cell)-based product (CL2020) cells in newborns with HIE. This is the first clinical trial of CL2020 cells in neonates.Methods and analysis This is a single-centre, open-label, dose-escalation study enrolling up to 12 patients. Neonates with HIE who receive a course of therapeutic hypothermia therapy, which cools to a body temperature of 33°C–34°C for 72 hours, will be included in this study. A single intravenous injection of CL2020 cells will be administered between 5 and 14 days of age. Subjects in the low-dose and high-dose cohorts will receive 1.5 and 15 million cells per dose, respectively. The primary outcome is the occurrence of any adverse events within 12 weeks after administration. The main secondary outcome is the Bayley Scales of Infant and Toddler Development Third Edition score and the developmental quotient per the Kyoto Scale of Psychological Development 2001 at 78 weeks.Ethics and dissemination This study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. The Nagoya University Hospital Institutional Review Board (No. 312005) approved this study on 13 November 2019. The results of this study will be published in peer-reviewed journal and reported in international conferences.Trial registration numbers NCT04261335, jRCT2043190112.

Abstract Background The prophylactic use of anti-respiratory syncytial virus (RSV) antibody (palivizumab) for severe RSV infection is not approved in Japan in specified groups of infants with neuromuscular diseases or other rare diseases associated with reduced ventilation competence or difficulty in expectoration, which increase the risk of exacerbation of severe RSV infection. The objective of this study is to investigate the efficacy, safety, and pharmacokinetics of palivizumab in pediatric patients with those rare diseases for which palivizumab is not indicated at present. Methods/design This study is a multicenter, uncontrolled, open-label study planned to be carried out between July 1, 2019 and June 30, 2022 at 7 medical institutions in Japan. The study population will be recruited from among neonates, infants, or children aged 24 months or younger with a condition falling under any of the following 5 disease groups: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. The planned sample size is 18 subjects, including at least 3 subjects per disease group. Throughout the RSV season, at least 4 continuous doses of palivizumab will be administered intramuscularly at 15 mg/kg at intervals of 30 days. The efficacy and safety of palivizumab will be comprehensively evaluated based on the incidence of RSV-related hospitalization, and serum palivizumab concentration, serum anti-palivizumab antibody concentration, and the occurrence of adverse events/reactions after the start of palivizumab treatment. Discussion This study will evaluate the efficacy and safety of palivizumab in pediatric patients with rare diseases which place them at high risk of severe RSV infection, but which fall outside the current indications for palivizumab prophylaxis. The generated data will have implications for the regulatory approval of prophylactic palivizumab treatment in this patient group. Trial registration This study has been prospectively registered in Japic Clinical Trials Information, which is managed and administered by the Japan Pharmaceutical Information Center (registration number: JapicCTI-194946 , registration date: September 10, 2019).

Abstract Parkinson’s disease (PD) is a debilitating neurodegenerative disorder in which nonmotor symptoms, such as constipation and hyposmia, precede the onset of motor symptoms by 20 years. The aim of this study was to identify biomarkers at the premotor stage of PD. We assessed the differences in longitudinal changes in anthropometric and serological indices obtained from health check-up data before and after the onset of motor symptoms between male and female PD patients and healthy subjects. We enrolled 22 male and 23 female PD patients and 60 male and 60 female healthy controls. A mixed-effects model was used to estimate the trajectory of each clinical marker over the years before and after motor symptoms onset in the PD subjects, which were then compared with the trajectories of the healthy controls. The results showed a premotor blood pressure increase in female PD patients and premotor decreases in haematocrit, total cholesterol and low-density lipoprotein cholesterol in the male patients. Our results indicated that blood pressure, haematocrit and serum cholesterol levels are potential premotor markers of PD. Additionally, the changes in anthropometric and serological indices before PD motor symptoms onset were sex specific.

Background: Thrombosis is a characteristic complication in coronavirus disease 2019 (COVID-19). Since coagulopathy has been observed over the entire clinical course, thrombosis might be a clue to understanding the specific pathology in COVID-19. Currently, there is limited epidemiological data of COVID-19-associated thrombosis in the Japanese population and none regarding variant strains of SARS-CoV-2. Here, we elucidate the risk factors and the pattern of thrombosis in COVID-19 patients.Methods: The patients consecutively admitted to Tokyo Medical and Dental University Hospital with COVID-19 were retrospectively analyzed. SARS-CoV-2 variants of concern/interest (VOC/VOI) carrying the spike protein mutants E484K, N501Y, or L452R were identified by PCR-based analysis. All thrombotic events were diagnosed by clinical symptoms, ultrasonography, and/or radiological tests.Results: Among the 516 patients, 32 patients experienced 42 thromboembolic events. Advanced age, severe respiratory conditions, and several abnormal laboratory markers were associated with the development of thrombosis. While thrombotic events occurred in 13% of the patients with a severe respiratory condition, those events still occurred in 2.5% of the patients who did not require oxygen therapy. Elevated D-dimer and ferritin levels on admission were independent risk factors of thrombosis (adjusted odds ratio 9.39 and 3.11, 95% confidence interval 2.08–42.3, and 1.06–9.17, respectively). Of the thrombotic events, 22 were venous, whereas 20 were arterial. While patients with thrombosis received anticoagulation and antiinflammatory therapies with a higher proportion, the mortality rate, organ dysfunctions, and bleeding complications in these patients were higher than those without thrombosis. The incidence of thrombosis in COVID-19 became less frequent over time, such as during the replacement of the earlier strains of SARS-CoV-2 by VOC/VOI and during increased use of anticoagulatory therapeutics.Conclusion: This study elucidated that elevated D-dimer and ferritin levels are useful biomarkers of thrombosis in COVID-19 patients. The comparable incidence of arterial thrombosis with venous thrombosis and the development of thrombosis in less severe patients required further considerations for the management of Japanese patients with COVID-19. Further studies would be required to identify high-risk populations and establish appropriate interventions for thrombotic complications in COVID-19.

PurposePatients with advanced/relapsed rare cancers have few treatment options. Analysis of circulating tumor DNA in plasma may identify actionable genomic biomarkers using a non-invasive approach.Patients and MethodsRare cancer patients underwent prospective plasma-based NGS testing. Tissue NGS to test concordance was also conducted. Plasma DNA alterations were assessed for incidence, functional impact, therapeutic implications, correlation to survival, and comparison with tissue NGS.ResultsNinety-eight patients were analyzed. Diseases included soft-tissue sarcoma, ovarian carcinoma, and others. Mean turn-around-time for results was 9.5 days. Seventy-six patients had detectable gene alterations in plasma, with a median of 2.8 alterations/patient. Sixty patients had a likely pathogenic alteration. Five received matched-therapy based on plasma NGS results. Two developed known resistance mutations while on targeted therapy. Patients with an alteration having VAF ≥5% had a significantly shorter survival compared to those of lower VAF. Tissue NGS results from eleven of 22 patients showed complete or partial concordance with plasma NGS.ConclusionPlasma NGS testing is less invasive and capable of identifying alterations in advanced rare cancers in a clinically meaningful timeframe. It should be further studied as a prospective enrollment assay in interventional studies for patients with rare advanced stage cancers.Clinical Registration[https://www.umin.ac.jp/ctr/index-j.htm], identifier UMIN000034394.

Abstract Background Maxillomandibular bone defects arise from maxillofacial injury or tumor/cyst removal. While the standard therapy for bone regeneration is transplantation with autologous bone or artificial bone, these therapies are still unsatisfactory. Autologous bone harvesting is invasive and occasionally absorbed at the implanted site. The artificial bone takes a long time to ossify and it often gets infected. Therefore, we have focused on regenerative therapy consisting of autologous bone marrow-derived mesenchymal cells (BM-MSCs), which decreases the burden on patients. Based on our previous research in patients with maxillomandibular bone defects or alveolar bone atrophy using a mixture of BM-MSCs, platelet-rich plasma (PRP), thrombin, and calcium, we confirmed the efficacy and acceptable safety profile of this treatment. In this investigator-initiated clinical study (the TEOM study), we intended to add β-tricalcium phosphate (β-TCP) owing to large defect with patients. The TEOM study aimed to evaluate the efficacy and safety of bone regeneration using mixtures of BM-MSCs in patients with bone defects resulting from maxillofacial injury, and tumor/cyst removal in the maxillomandibular region. Methods The TEOM study is an open-label, single-center, randomized controlled study involving a total of 83 segments by the Fédération Dentaire Internationale numbering system in maxillomandibular bone defects that comprise over 1/3 of the maxillomandibular area with a remaining bone height of ≤10 mm. The primary endpoint is rate of procedure sites with successful bone regeneration defined as a computed tomography (CT) value of more than 400 and a bone height of more than 10 mm. Our specific hypothesis is that the number of required regions was calculated assuming that the rate of procedure sites with successful bone regeneration is similar and the non-inferiority margin is 15.0%. Discussion The TEOM study is the first randomized controlled study of regenerative treatment using BM-MSCs for large maxillomandibular bone defects. We will evaluate the efficacy and safety in this study to provide an exploratory basis for the necessity of BM-MSCs for these patients. Trial registration This trial was registered at the University Hospital Medical information Network Clinical Trials Registry (UMIN-CTR Unique ID: UMIN000020398; Registration Date: Jan 15, 2016; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000016543).

In oncology, next generation sequencing and comprehensive genomic profiling have enabled the detailed classification of tumors using molecular biology. However, it is unrealistic to conduct phase I–III trials according to each sub-population based on patient molecular subtypes. Common protocols that assess the combination of several molecular markers and their targeted therapies by means of multiple sub-studies are required. These protocols are called “master protocols,” and are drawing attention as a next-generation clinical trial design. Recently, several reviews of clinical trials based on the master protocol design have been published, but their definitions of these such trials, including basket, umbrella, and platform trials, were not consistent. Concurrently, the acceleration of the development of new statistical designs for master protocol trials has been underway. This article provides an overview of recent reviews for master protocols, including their statistical design methodologies in Oncology. We also introduce several examples of previous and on-going master protocol trials along with their classifications by some recent studies. Keywords: Master protocol, Basket, Umbrella, Platform, Bayesian adaptive method

Aging of the population has led to an increase in the prevalence of cancer among older adults. In Japan, single agent chemotherapy was recommended for advanced non-small cell lung cancer (NSCLC) for those, who were aged ≥75 years, while the Western guidelines did not recommend a specific regimen. In clinical practice, physicians are required to decide the treatment based on a lack of enough evidence. This study aimed to examine the prescribing patterns of first-line chemotherapy according to age in the real-world practice. Data from the survey database of Diagnostic Procedure Combination and hospital-based cancer registries of designated cancer centers nationwide were used. The first-line chemotherapy regimens among 9,737 patients who were diagnosed with advanced lung cancer between January and December 2013, were identified and compared based on age. We found that the proportion of patients receiving chemotherapy decreased with age; 80.0%, 70.4%, 50.6%, and 30.2% of patients aged 70-74, 75-79, 80-84, and ≥ 85 years, respectively, received chemotherapy. Among them, platinum doublets were prescribed for 62.7% of the patients who were aged ≥ 70 years, and 60.7% of the patients who were aged ≥ 75 years with no driver mutations in NSCLC; only 37.6% of them received single agents. Patients who were aged ≥ 80 years also preferred platinum doublets (35.6%). Carboplatin was commonly prescribed in all age groups; only 28.4% of those receiving platinum doublets selected cisplatin. In this study, platinum doublets were identified as the most commonly prescribed regimen in those who were aged ≥ 70 years. Despite recommendations of Japanese guidelines for NSCLC, 60.7% of those who were aged ≥75 years received platinum doublets. Additionally, patients who were aged ≥ 80 years also received systemic chemotherapy, including platinum doublets; age did not solely influence regimen selection.

Fetal growth restriction (FGR) is a major complication of prenatal ischemic/hypoxic exposure and affects 5%–10% of pregnancies. It causes various disorders, including neurodevelopmental disabilities due to chronic hypoxia, circulatory failure, and malnutrition via the placenta, and there is no established treatment. Therefore, the development of treatments is an urgent task. We aimed to develop a new FGR rat model with a gradual restrictive load of uterus/placental blood flow and to evaluate the treatment effect of the administration of umbilical cord-derived mesenchymal stromal cells (UC-MSCs). To create the FGR rat model, we used ameroid constrictors that had titanium on the outer wall and were composed of C-shaped casein with a notch and center hole inside that gradually narrowed upon absorbing water. The ameroid constrictors were attached to bilateral ovarian/uterine arteries on the 17th day of pregnancy to induce chronic mild ischemia, which led to FGR with over 20% bodyweight reduction. After the intravenous administration of 1 × 105 UC-MSCs, we confirmed a significant improvement in the UC-MSC group in a negative geotaxis test at 1 week after birth and a rotarod treadmill test at 5 months old. In the immunobiological evaluation, the total number of neurons counted via the stereological counting method was significantly higher in the UC-MSC group than in the vehicle-treated group. These results indicate that the UC-MSCs exerted a treatment effect for neurological impairment in the FGR rats.

Abstract Introduction Possession of the apolipoprotein E (APOE) ε4 allele advances amyloid β (Aβ) deposition and symptomatic onset of Alzheimer's disease (AD), whereas its effect on the rate of cognitive decline remained controversial. We examined the effects of APOE ε4 allele on cognition in biomarker‐confirmed late mild cognitive impairment (LMCI) and mild AD subjects in the Japanese Alzheimer's Disease Neuroimaging Initiative (J‐ADNI) and North American ADNI (NA‐ADNI). Methods The “early AD” (ie, combined LMCI and mild AD) cohort of 649 subjects from J‐ADNI and NA‐ADNI were selected based on positivity of Aβ confirmed by amyloid positron emission tomography (PET) or cerebrospinal fluid testing. The rates of cognitive decline in the Mini Mental State Examination (MMSE), the Clinical Dementia Rating Sum of Boxes (CDR‐SB), and the Alzheimer's Disease Assessment Scale‐cognitive subscale 13 (ADAS‐Cog) from baseline were examined using mixed‐effects model. The effect of ε4 on time to conversion to dementia was also analyzed in LMCI using the Kaplan‐Meier estimator and log‐rank test. Results The rates of cognitive decline were not significantly different between ε4 carriers and ε4 non‐carriers in the total early AD cohort, which were affected neither by region nor by the number of ε4 alleles. In LMCI, ε4 carriers showed almost the same progression rates as ε4 non‐carriers, except for a significantly faster decline in MMSE (P = .0282). Time to conversion to demenita was not significantly different between ε4 carriers and ε4 non‐carriers. In ε4‐positive mild AD, the rates of decline in MMSE (P = .003) and CDR‐SB (P = .0071) were slower than those in ε4 non‐carriers. DISCUSSION The APOE ε4 allele had little effect on the rates of cognitive decline in the overall biomarker‐confirmed early AD, regardless of region and number of ε4 alleles, with a slight variability in different clinical stages, the ε4 allele being slightly accelerative in LMCI, while decelerative in mild AD.

Abstract Background The quality of cardiopulmonary resuscitation (CPR) performed by emergency medical services (EMS) personnel affects patient outcomes after cardiac arrest. A CPR feedback device with an accelerometer mounted on a defibrillator can monitor the motion of the patient’s sternum to display and record CPR quality in real time. To evaluate the utility of real-time feedback, debriefing, and retraining using a CPR feedback device outside of the hospital, an open-label, cluster randomized controlled trial will be conducted in five municipalities of Osaka Prefecture, Japan. Methods Each EMS station within a fire department will be randomly assigned to: 1) the treatment group with real-time feedback, debriefing, and retraining using the CPR feedback device (intervention group); or 2) the conventional treatment group without real-time feedback, debriefing, and retraining (control group). This trial will include 2850 to 3020 patients over about 4 years. The primary outcome of the trial is 1-month favorable neurological survival, defined as cerebral performance category scale score 1 or 2. Secondary outcomes are 1-month survival, survival to hospital discharge, return of spontaneous circulation, and quality of CPR including fraction, depth, tempo, and ventilation rate. Discussion The trial will assess whether treatment monitored by the CPR feedback device, which allows for real-time feedback, debriefing, and retraining using CPR quality data, outperforms conventional treatment without real-time feedback, debriefing, and retraining in terms of 1-month favorable neurological survival in cardiac arrest patients receiving CPR outside the hospital. Trial registration University Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000021431. Registered on 11 March 2016.

The recommended phase 2 doses of molecularly targeted agents, determined by using an ordinal dose-finding method that only uses toxicity data at first cycle, may not be optimal. Some researchers have proposed the use of relative dose intensity that can account for late-onset, cumulative, and low-grade toxicities to determine the recommended phase 2 dose (RP2D). In this study, we proposed two dose escalation methods based on the observed relative dose intensities (RDIs) between the pre-specified intervals (cycles) for toxicity evaluation used in combination with DLT evaluation in the first cycle. First, we propose the modified 3 + 3 design that incorporates longitudinal RDI assessment. Second, we propose the sequential assessment method for longitudinal RDI (SARDI) to achieve faster dose escalation compared to that of the modified 3 + 3 design. Simulation studies demonstrated that the SARDI was, in many cases, superior to the ordinal and modified 3 + 3 designs in respect to the selection rate of true RP2D and study period. The two proposed methods could also in some cases decrease the average number of patients enrolled in the trial compared to that of the ordinary 3 + 3 design. Incorporation of the RDI assessment into the 3 + 3 design is not difficult and does not require the use of complex statistical techniques. Therefore, we believe that investigators who routinely use the 3 + 3 design in practice can easily use our proposed methods. Keywords: Dose finding, Oncology, Relative dose intensity, Phase I trial

Concentrated growth factor (CGF) is 100% blood-derived, cross-linked fibrin glue with platelets and growth factors. Human CGF clot is transformed into membrane by a compression device, which has been widely used clinically. However, the mechanical properties of the CGF membranes have not been well characterized. The aims of this study were to measure the tensile strength of human CGF membrane and observe its behavior as a scaffold of BMP-2 in ectopic site over the skull. The tensile test of the full length was performed at the speed of 2mm/min. The CGF membrane (5 × 5 × 2 mm3) or the CGF/BMP-2 (1.0 μg) membrane was grafted onto the skull periosteum of nude mice (5-week-old, male), and harvested at 14 days after the graft. The appearance and size of the CGF membranes were almost same for 7 days by soaking at 4 °C in saline. The average values of the tensile strength at 0 day and 7 days were 0.24 MPa and 0.26 MPa, respectively. No significant differences of both the tensile strength and the elastic modulus were found among 0, 1, 3, and 7 days. Supra-periosteal bone induction was found at 14 days in the CGF/BMP-2, while the CGF alone did not induce bone. These results demonstrated that human CGF membrane could become a short-term, sticky fibrin scaffold for BMP-2, and might be preserved as auto-membranes for wound protection after the surgery.

Abstract Background Male stress urinary incontinence is a prevalent condition after radical prostatectomy. While the standard recommendation for the management of urine leakage is pelvic floor muscle training, its efficacy is still unsatisfactory. Therefore, we have focused on regenerative therapy, which consists of administering a periurethral injection of autologous regenerative cells from adipose tissue, separated using the Celution® system. Based on an interim data analysis of our exploratory study, we confirmed the efficacy and acceptable safety profile of this treatment. Accordingly, we began discussions with Japanese regulatory authorities regarding the development of this therapy in Japan. The Ministry of Health, Labour and Welfare suggested that we implement a clinical trial of a new medical device based on the Pharmaceutical Affaires Act in Japan. Next, we discussed the design of this investigator-initiated clinical trial (the ADRESU study) aimed at evaluating the efficacy and safety of this therapy, in a consultation meeting with the Pharmaceuticals and Medical Device Agency. Methods The ADRESU study is an open-label, multi-center, single-arm study involving a total of 45 male stress urinary incontinence patients with mild-to-moderate urine leakage persisting more than 1 year after prostatectomy, in spite of behavioral and pharmacological therapies. The primary endpoint is the rate of patients at 52 weeks with improvement of urine leakage volume defined as a reduction from baseline greater than 50% by 24-h pad test. Our specific hypothesis is that the primary endpoint result will be higher than a pre-specified threshold of 10%. Discussion The ADRESU study is the first clinical trial of regenerative treatment for stress urinary incontinence by adipose-derived regenerative cells using the Celution® system based on the Japanese Pharmaceutical Affaires Act. We will evaluate the efficacy and safety in this trial to provide an adequate basis for marketing approval with the final objective of making this novel therapy widely available for Japanese patients. Trial registration This trial was registered at the University Hospital Medical information Network Clinical Trial Registry (UMIN-CTR Unique ID: UMIN000017901 ; Registered July 1, 2015) and at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT02529865 ; Registered August 18, 2015).

We report the case of a wound complication that was reconstructed by reverse lateral arm flap after excision of heterotopic ossification (HO) of the elbow in a patient with severe burns. Careful attention should be paid to wound complication and HO recurrence in patients undergoing surgical treatment for elbow HO following burn injury. Keywords: Burn, Heterotopic ossification, Elbow, Complication

Background: In cluster randomized controlled trials (RCTs) for emergency medical services (EMS) system, we encounter the situation that the actual cluster size and ratio of allocated patients between two groups eventually differ from those used for sample size estimation because of the nature of patient enrollment. In such trials, estimations of effect size of test intervention and intra-cluster correlation coefficient (ICC) used for sample size estimation are also difficult. To improve efficient management on clinical cluster RCTs, we need to understand the effect of such inconsistencies of the design parameters on the type I error rate and statistical power of testing. Methods: We planned the trial which evaluated the 1-month favorable neurological survival of out-of-hospital cardiac arrest patients with or without real-time feedback, debriefing, and retraining system by EMS personnel. Under the conditions that we possibly encountered in this trial, we examined the effect of inconsistencies in the actual ICC, cluster size, and ratio of patient allocation with those expected for sample size estimation on the type I error rate and power, using simulation studies. We further investigated the contribution of incorporating sample size re-estimation, based on the results of interim analysis of the trial, on the power increase. Results: This simulation study showed that the inconsistencies of cluster size and patient allocation ratio decreased the power by 5–10% in some cases. In addition, the power decreased by 3–4% when the actual ICC was larger than that expected for sample size estimation. Furthermore, the use of a generalized estimating equation method to evaluate the difference in the 1-month favorable neurological survival between two groups caused inflation of type I error rate. Finally, the increase in power by incorporating sample size re-estimation was limited. Conclusions: We identified remarkable effects of sample size estimation and re-estimations in a cluster RCT for real-time feedback, debriefing, and retraining system of cardiopulmonary resuscitation for out-of-hospital cardiac arrests. The estimation of design parameters for sample size estimation is generally challenging in cluster RCTs for EMS system; therefore, it is important to conduct a trial simulation that assesses the statistical performances under sample sizes based on the various expected values of the design parameters before beginning the trial. Keywords: Cluster randomization, Emergency medical services, Intracluster correlation coefficient, Sample size re-estimation

Rupture of the flexor tendons is a rare complication following distal radius malunion after nonoperative management. This article presents 2 cases of delayed flexor tendon ruptures following malunited distal radius fracture and discusses the characteristics, operative management, and outcomes of this rare complication by reviewing the previous literature. Our analysis demonstrate that surgical reconstruction of ruptured tendons provides good outcomes when the number of tendon ruptures is small. If multiple tendon ruptures are present, surgical outcomes may be poor despite surgical reconstruction. Osseous surgery would be necessary to prevent additional tendon ruptures; however, less invasive and simple surgeries arrowing early rehabilitation would be preferable. Keywords: Distal radius fracture, Malunion, Nonoperative treatment, Flexor tendon rupture, Complication

[This corrects the article DOI: 10.1371/journal.pone.0192688.].

Background/Objective: Perinatal hypoxic-ischemia (HI) causes neonatal death and permanent neurological deficits. Cell therapy using various cell sources has been recently identified as a novel therapy for perinatal HI. Among the available types of cell sources, bone marrow-derived mononuclear cells (BMMNCs) have unique features for clinical application. For example, stem cells can be collected after admission, thus enabling us to perform autologous transplantation. This study aimed to investigate whether the administration of BMMNCs ameliorated HI brain injury in a neonatal rat model.Methods: Seven-day-old rats underwent left carotid artery ligation and were exposed to 8% oxygen for 60 min. BMMNCs were collected from the femurs and tibias of juvenile rats using the Ficoll–Hypaque technique and injected intravenously 24 h after the insult (1 × 105 cells). Active caspase-3, as an apoptosis marker, and ED1, as an activated microglia/macrophage marker, were evaluated immunohistochemically 48 h after the insult (vehicle, n = 9; BMMNC, n = 10). Behavioral assessments using the rotarod treadmill, gait analysis, and active avoidance tests were initiated 3 weeks after the insult (sham, n = 9, vehicle, n = 8; BMMNC, n = 8). After these behavioral tests (6 weeks after the insult), we evaluated the volumes of their hippocampi, cortices, thalami, striata, and globus pallidus.Results: The mean cell densities of the sum of four parts that were positive for active caspase-3 significantly decreased in the BMMNC group (p < 0.05), whereas in the hippocampi, cortices, thalami, and striata cell densities decreased by 42, 60, 56, and 47%, respectively, although statistical significance was not attained. The number of ED1 positive cells for the sum of the four parts also significantly decreased in the BMMNC group compared to the vehicle group (p < 0.05), whereas in each of the four parts the decrease was 35, 39, 47, and 36%, respectively, although statistical significance was not attained. In gait analysis, the BMMNC normalized the contact area of the affected hind paw widened by HI. The volumes of the affected striata and globus pallidus were significantly larger in the BMMNC group than in the control group.Conclusion: These results indicated that the injection of BMMNCs ameliorated HI brain injury in a neonatal rat model.

OBJECTIVE:The aim of this prospective multicenter randomized controlled trial was to compare the efficacy of silver nitrate cauterization against that of topical steroid ointment in the treatment of neonatal umbilical granuloma. METHODS:An open-label, non-inferiority randomized controlled trial was conducted from January 2013 to January 2016. The primary endpoint for the silver nitrate cauterization and topical steroid ointment groups was the healing rate after 2 weeks of treatment, applying a non-inferiority margin of 10%. The healing rate was evaluated until completion of 3 weeks of treatment. RESULTS:Participants comprised 207 neonates with newly diagnosed umbilical granuloma, randomized to receive silver nitrate cauterization (n = 104) or topical steroid ointment (n = 103). Healing rates after 2 weeks of treatment were 87.5% (91/104) in the silver nitrate cauterization and 82% (82/100) in the topical steroid ointment group group. The difference between groups was -5.5% (95% confidence interval, -19.1%, 8.4%), indicating that the non-inferiority criterion was not met. After 3 weeks of treatment, the healing rate with topical steroid ointment treatment was almost identical to that of silver nitrate cauterization (94/104 [90.4%] vs. 91/100 [91.0%]; 0.6% [-13.2 to 14.3]). No major complications occurred in either group. CONCLUSIONS:This study did not establish non-inferiority of topical steroid ointment treatment relative to silver nitrate cauterization, presumably due to lower healing rates than expected leading to an underpowered trial. However, considering that silver nitrate cauterization carries a distinct risk of chemical burns and that the overall efficacy of topical steroid ointment treatment is similar to that of silver nitrate cauterization, topical steroid ointment might be considered as a good alternative in the treatment of neonatal umbilical granuloma due to its safety and simplicity. To clarify non-inferiority, a larger study is needed.

Background and study aims Endoscopic ultrasound (EUS) elastography (EUS-E) and contrast-enhanced harmonic EUS (CH-EUS) are useful methods for the diagnosis of pancreatic lesions. This study aims to compare the accuracy of combined EUS-E and CH-EUS with that of EUS-E or CH-EUS alone in the differential diagnosis of pancreatic solid lesions. Patients and methods One hundred thirty-six patients with solid pancreatic lesions underwent EUS with both EUS-E and CH-EUS were included. Diagnoses were classified as adenocarcinoma, neuroendocrine tumor (NET), and inflammatory pseudotumor in 95, 22, and 19 patients, respectively. EUS records in each case were rearranged into 3 groups: EUS-E, CH-EUS, and combination. Each modality was randomly reviewed by 3 reviewers with different levels of clinical experience. Sensitivity, specificity, and accuracy of each modality according to each diagnosis group were evaluated. For the combined diagnosis populations, the proportions of correct diagnoses among the 3 modalities were compared by using the multivariate logistic regression analysis. Results The accuracies of EUS-E, CH-EUS, and the combination of them were 68.4 %, 65.4 %, and 75.7 %, respectively, for adenocarcinoma group; 83.8 %, 82.4 %, and 86.8 % for NET group; 80.1 %, 78.7 %, and 81.6 % for inflammatory pseudotumor group. The multivariate logistic regression analysis for the combined diagnosis populations showed that the proportion of correct diagnoses when EUS-E and CH-EUS were combined was slightly higher than with the other 2 modalities, although the significant differences among them were not observed. Conclusion EUS-E and CH-EUS combined may improve differential diagnosis of solid pancreatic lesions compared with use of the individual modalities.

Abnormal activation of the Wnt/β-catenin signaling is implicated in the osteoarthritis (OA) pathology. We searched for a pre-approved drug that suppresses abnormally activated Wnt/β-catenin signaling and has a potency to reduce joint pathology in OA. We introduced the TOPFlash reporter plasmid into HCS-2/8 human chondrosarcoma cells to estimate the Wnt/β-catenin activity in the presence of 10 μM each compound in a panel of pre-approved drugs. We found that fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI), down-regulated Wnt/β-catenin signaling in human chondrosarcoma cells. Fluoxetine inhibited both Wnt3A- and LiCl-induced loss of proteoglycans in chondrogenically differentiated ATDC5 cells. Fluoxetine increased expression of Sox9 (the chondrogenic master regulator), and decreased expressions of Axin2 (a marker for Wnt/β-catenin signaling) and Mmp13 (matrix metalloproteinase 13). Fluoxetine suppressed a LiCl-induced increase of total β-catenin and a LiCl-induced decrease of phosphorylated β-catenin in a dose-dependent manner. An in vitro protein-binding assay showed that fluoxetine enhanced binding of β-catenin with Axin1, which is a scaffold protein forming the degradation complex for β-catenin. Fluoxetine suppressed LiCl-induced β-catenin accumulation in human OA chondrocytes. Intraarticular injection of fluoxetine in a rat OA model ameliorated OA progression and suppressed β-catenin accumulation.

BACKGROUND:Data regarding the association between 24h urinary sodium and potassium excretion with kidney outcomes in patients with diabetes mellitus is currently scarce. METHODS:We conducted a single-center, retrospective cohort study in which 1230 patients with diabetes who had undergone a 24h urinary sodium and potassium excretion test were analyzed. Patients with incomplete urine collection were excluded based on 24h urinary creatinine excretion. Outcomes were the composite of a 30% decline in eGFR or death. Multivariate cox regression analysis was used to investigate the association between urinary sodium and potassium excretion and outcomes. RESULTS:With a mean follow up period of 5.47 years, 130 patients reached the outcomes (30% decline in eGFR: 124, death: 6). Mean (SD) eGFR and 24h urinary sodium and potassium excretion at baseline were 78.6 (19.5) ml/min/1.73m2, 4.50 (1.64) g/day, and 2.14 (0.77) g/day. Compared with sodium excretion < 3.0 g/day, no significant change in risk of outcomes was observed with increased increments of 1.0 g/day. Compared with potassium excretion of < 1.5 g/day, 2.0-2.5 g/day, and 2.5-3.0 g/day were significantly associated with a lower risk of outcomes (hazard ratio [HR], 0.49 and 0.44; 95% confidence interval [CI], 0.28 to 0.84 and 0.22 to 0.87). CONCLUSIONS:24h urinary sodium excretion was not significantly associated with a risk of 30% decline in eGFR or death in patients with diabetes. However, an increased risk of 30% decline in eGFR or death was significantly associated with 24h urinary potassium excretion < 1.5 g/day than with 2.0-2.5 g/day and 2.5-3.0 g/day.

Soft tissue metastases of prostate cancer to other sites are extremely rare, and, to our best knowledge, there have been no reports of metastasis to soft tissue of the hand. A 63-year-old man was diagnosed with prostatic cancer. During treatment, bone and soft tissue metastases to the right hand, appearing in the first web space, were observed. The tumor was resected, along with both the first and second metacarpal bones. The thumb was reconstructed by pollicization of the remaining index finger, enabling the patient to use the pollicized thumb for activities of daily living. This is the first case report of prostate cancer metastasizing to the soft tissue in hand. After wide resection, pollicization was able to reconstruct a functional hand and thumb.

The aim of this study was to characterize the respiratory function profile of subjects with spinal and bulbar muscular atrophy (SBMA), and to explore the underlying pathological mechanism by comparing the clinical and biochemical indices of this disease with those of amyotrophic lateral sclerosis (ALS). We enrolled male subjects with SBMA (n = 40) and ALS (n = 25) along with 15 healthy control subjects, and assessed their respiratory function, motor function, and muscle strength. Predicted values of peak expiratory flow (%PEF) and forced vital capacity were decreased in subjects with SBMA compared with controls. In SBMA, both values were strongly correlated with the trunk subscores of the motor function tests and showed deterioration relative to disease duration. Compared with activities of daily living (ADL)-matched ALS subjects, %PEF, tongue pressure, and grip power were substantially decreased in subjects with SBMA. Both immunofluorescence and RT-PCR demonstrated a selective decrease in the expression levels of the genes encoding the myosin heavy chains specific to fast-twitch fibers in SBMA subjects. The mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and peroxisome proliferator-activated receptor delta were up-regulated in SBMA compared with ALS and controls. In conclusion, %PEF is a disease-specific respiratory marker for the severity and progression of SBMA. Explosive muscle strength, including %PEF, was selectively affected in subjects with SBMA and was associated with activation of the mitochondrial biogenesis-related molecular pathway in skeletal muscles.

Choosing an appropriate statistic and precisely evaluating the false discovery rate (FDR) are both essential for devising an effective method for identifying differentially expressed genes in microarray data. The t-type score proposed by Pan et al. (2003) succeeded in suppressing false positives by controlling the underestimation of variance but left the overestimation uncontrolled. For controlling the overestimation, we devised a new test statistic (variance stabilized t-type score) by placing shrunken sample variances of the James-Stein type in the denominator of the t-type score. Since the relative superiority of the mean and median FDRs was unclear in the widely adopted Significance Analysis of Microarrays (SAM), we conducted simulation studies to examine the performance of the variance stabilized t-type score and the characteristics of the two FDRs. The variance stabilized t-type score was generally better than or at least as good as the t-type score, irrespective of the sample size and proportion of differentially expressed genes. In terms of accuracy, the median FDR was superior to the mean FDR when the proportion of differentially expressed genes was large. The variance stabilized t-type score with the median FDR was applied to actual colorectal cancer data and yielded a reasonable result.

The recent development of DNA microarray technology allows us to measure simultaneously the expression levels of thousands of genes and to identify truly correlated genes with anticancer drug response (differentially expressed genes) from many candidate genes. Significance Analysis of Microarray (SAM) is often used to estimate the false discovery rate (FDR), which is an index for optimizing the identifiability of differentially expressed genes, while the accuracy of the estimated FDR by SAM is not necessarily confirmed. We propose a new method for estimating the FDR assuming a mixed normal distribution on the test statistic and examine the performance of the proposed method and SAM using simulated data. The simulation results indicate that the accuracy of the estimated FDR by the proposed method and SAM, varied depending on the experimental conditions. We applied both methods to actual data comprised of expression levels of 12,625 genes of 10 responders and 14 non-responders to docetaxel for breast cancer. The proposed method identified 280 differentially expressed genes correlated with docetaxel response using a cut-off value for achieving FDR

Biopolymers consist of three major classes, i.e., polynucleotides (DNA, RNA), polypeptides (proteins) and polysaccharides (sugar chains). It is widely accepted that polynucleotides and polypeptides play fundamental roles in the pathogenesis of neurodegenerative diseases. But, sugar chains have been poorly studied in this process, and their biological/clinical significance remains largely unexplored. Amyotrophic lateral sclerosis (ALS) is a motoneuron-degenerative disease, the pathogenesis of which requires both cell autonomous and non-cell autonomous processes. Here, we investigated the role of keratan sulfate (KS), a sulfated long sugar chain of proteoglycan, in ALS pathogenesis. We employed ALS model SOD1(G93A) mice and GlcNAc6ST-1(-/-) mice, which are KS-deficient in the central nervous system. Unexpectedly, SOD1(G93A)GlcNAc6ST-1(-/-) mice exhibited a significantly shorter lifespan than SOD1(G93A) mice and an accelerated appearance of clinical symptoms (body weight loss and decreased rotarod performance). KS expression was induced exclusively in a subpopulation of microglia in SOD1(G93A) mice, and became detectable around motoneurons in the ventral horn during the early disease phase before body weight loss. During this phase, the expression of M2 microglia markers was transiently enhanced in SOD1(G93A) mice, while this enhancement was attenuated in SOD1(G93A)GlcNAc6ST-1(-/-) mice. Consistent with this, M2 microglia were markedly less during the early disease phase in SOD1(G93A)GlcNAc6ST-1(-/-) mice. Moreover, KS expression in microglia was also detected in some human ALS cases. This study suggests that KS plays an indispensable, suppressive role in the early phase pathogenesis of ALS and may represent a new target for therapeutic intervention.

In prognostic studies for breast cancer patients treated with neoadjuvant chemotherapy (NAC), the ordinary Cox proportional-hazards (PH) model has been often used to identify prognostic factors for disease-free survival (DFS). This model assumes that all patients eventually experience relapse or death. However, a subset of NAC-treated breast cancer patients never experience these events during long-term follow-up (>10 years) and may be considered clinically “cured.” Clinical factors associated with cure have not been studied adequately. Because the ordinary Cox PH model cannot be used to identify such clinical factors, we used the Cox PH cure model, a recently developed statistical method. This model includes both a logistic regression component for the cure rate and a Cox regression component for the hazard for uncured patients. The purpose of this study was to identify the clinical factors associated with cure and the variables associated with the time to recurrence or death in NAC-treated breast cancer patients without a pathologic complete response, by using the Cox PH cure model. We found that hormone receptor status, clinical response, human epidermal growth factor receptor 2 status, histological grade, and the number of lymph node metastases were associated with cure.

BACKGROUND: Development of tailored treatment based on immunohistochemical profiles (IPs) of tumors for cancers of unknown primary is needed. METHODOLOGY/PRINCIPAL FINDINGS: We developed an algorithm based on primary known adenocarcinoma for testing sensitivity and specificity. Formalin-fixed paraffin-embedded tissue samples from 71 patients of unfavorable subsets of unknown primary adenocarcinoma were obtained. We examined 15 molecular markers using the algorithm incorporating these IPs and classified the tumours into 9 subsets based on the primary tumour site. The sensitivity and specificity of this algorithm were 80.3% and 97.6%, respectively. Apparent primary sites were lung in 17 patients, digestive organs in 13, gynecological organs in 9, prostate in 7, liver or kidney in 6, breast in 4, urothelial organ in 2, biliary tract and pancreatic profile in none, and unclassified in 13. The response rate to chemotherapy was highest for the gynecological IPs. Patients with gynecological or lung cancer IPs had longer median progression-free survival than those with others: 11.2 months for gynecological IPs (p

BACKGROUND: The oncology market represents one of the largest pharmaceutical markets in any medical field, and printed advertising in medical journals is an important channel by which pharmaceutical companies communicate with healthcare professionals. The aim of the present study was to analyze the volume and content of and trends and changes in oncology-related advertising intended for healthcare professionals in a peer-reviewed medical journal. Information that could be included in advertisements to promote drug development and improve treatment strategies for cancer patients is discussed on the basis of the results of the analysis. METHODS/PRINCIPAL FINDINGS: Overall, 6,720 advertisements covering 13,039 pages in a leading oncology medical journal published (by the American Society of Clinical Oncology) between January 2005 and December 2009 were analyzed. The advertisements targeting pharmaceuticals and clinical trials, in particular, were reviewed. A total of 6,720 advertisements covering 13,039 pages were included in the analysis. For the years 2005-2009, the percentages of total journal pages dedicated to advertising were 24.0%, 45.7%, 49.8%, 46.8%, and 49.8%, respectively. Package insert information and efficacy and safety explanations appeared in more than 80% of advertisements intended for pharmaceutical promotion. From 2005 to 2009, the overall quantity of drug advertisements decreased by approximately 13%, whereas advertisements calling for the enrollment of patients into registration trials increased by approximately 11%. CONCLUSION/SIGNIFICANCE: Throughout the study period, oncology-related pharmaceutical advertisements occupied a considerable number of pages relative to other journal content. The proportion of advertisements on ongoing clinical trials increased progressively throughout the study period.

The recent development of DNA microarray technology allows us to measure simultaneously the expression levels of thousands of genes and to identify truly correlated genes with anticancer drug response (differentially expressed genes) from many candidate genes. Significance Analysis of Microarray (SAM) is often used to estimate the false discovery rate (FDR), which is an index for optimizing the identifiability of differentially expressed genes, while the accuracy of the estimated FDR by SAM is not necessarily confirmed. We propose a new method for estimating the FDR assuming a mixed normal distribution on the test statistic and examine the performance of the proposed method and SAM using simulated data. The simulation results indicate that the accuracy of the estimated FDR by the proposed method and SAM, varied depending on the experimental conditions. We applied both methods to actual data comprised of expression levels of 12,625 genes of 10 responders and 14 non-responders to docetaxel for breast cancer. The proposed method identified 280 differentially expressed genes correlated with docetaxel response using a cut-off value for achieving FDR

BACKGROUND: The clinical outcome of pulmonary vein isolation (PVI) for persistent atrial fibrillation (AF) is suboptimal. Mapping studies have demonstrated atrial sites outside of the pulmonary veins displaying focal activation patterns during AF. We sought to determine whether adding catheter ablation of focal activation sites to PVI improves clinical outcomes of catheter ablation for persistent AF. METHODS: In this multicenter, randomized, single-blinded trial, we assigned patients with persistent AF to either PVI alone or to mapping-guided ablation of focal activation sites in addition to PVI in a 1:1 ratio. In the mapping-guided group, both atria were mapped after PVI using a Pentaray catheter (Biosense-Webster) and focal activation sites identified by CARTOFINDER (Biosense-Webster) were ablated. The primary end point was freedom from AF or atrial tachycardia without antiarrhythmic drugs beyond a 90-day blanking period. RESULTS: A total of 98 patients were assigned to the mapping-guided group and 102 to the PVI alone group. In the mappingguided group, focal activation sites were identified at 2.6±0.3 and 2.5±0.2 sites per patient in the left and right atrium, respectively. Patients were followed up for 768.5 (interquartile range, 723.75--915.75) and 755.5 days (interquartile range, 728.5--913.75) in the mapping-guided ablation and the PVI alone groups, respectively. Freedom from AF/atrial tachycardia without antiarrhythmic drugs at 2-year follow-up was 66.8% and 75.2% in the mapping-guided ablation and the PVI alone groups, respectively (hazard ratio, 1.26 [95% CI, 0.76--2.10]; P=0.37). Adverse events occurred in 3 patients (3.0%) and none (0%) in the mapping-guided ablation and the PVI alone groups, respectively (P=0.12). CONCLUSIONS: In patients with persistent AF, the addition of mapping-guided ablation of focal activation sites to PVI did not improve clinical outcomes compared with PVI alone. [ABSTRACT FROM AUTHOR]