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Aims/Introduction Diabetic polyneuropathy (DPN) develops in the early stage of diabetes. However, no common diagnostic protocol has yet been established. Here, to verify that the flicker electroretinogram using a hand‐held device can detect the early dysfunction of the peripheral nervous system in patients with diabetes, we investigated the correlation between the progression of DPN and neuroretinal dysfunction. Materials and Methods In total, 184 participants with type 1 or 2 diabetes underwent a flicker electroretinogram (ERG) using a hand‐held device RETeval™ and nerve conduction study. Participants were also evaluated for intima‐media thickness, ankle‐brachial index, toe brachial index and brachial‐ankle pulse wave velocity. Parameters of the nerve conduction study were used to diagnose the severity according to Baba’s classification. A multiple regression analysis was used to examine the associations of ERG parameters with the severity of DPN categorized by Baba’s classification. Diagnostic properties of the device in DPN were evaluated using a receiver operating characteristic curve. Results A multiple regression model to predict the severity of DPN was generated using ERG. In the model, moderate‐to‐severe DPN was effectively diagnosed (area under the receiver operating characteristic curve 0.692, sensitivity 56.5%, specificity 78.3%, positive predictive value 70.6%, negative predictive value 66.1%, positive likelihood ratio 2.60, negative likelihood ratio 0.56). In the patients without diabetic retinopathy, the implicit time and amplitude in ERG significantly correlated with the parameters of the nerve conduction study, brachial‐ankle pulse wave velocity and intima‐media thickness. Conclusions Electroretinogram parameters obtained by the hand‐held device successfully predict the severity of DPN. The device might be useful to evaluate DPN., The progression of diabetic retinopathy and the dysfunction of neuroretina evaluated using the mydriasis‐free flicker electroretinogram showed a significant correlation. In patients without apparent diabetic retinopathy, the electroretinogram data correlated with parameters indicating vascular dysfunction, and with parameters indicating diabetic polyneuropathy, such as data of a nerve conduction study. Therefore, the electroretinogram data might reflect the neural and vascular impairments of the retina in patients with diabetes. The electroretinogram data were able to be used to predict the severity of diabetic polyneuropathy.

Objectives: Reticulated platelets circulating in the blood reflect megakaryopoietic activity and platelet turnover and can be automatically and low-invasively measured as the immature platelet fraction (IPF) using a Sysmex XN hematocytometer. The present study retrospectively investigated whether or not the IPF can predict the treatment response to corticosteroids in adult patients with primary immune thrombocytopenia (ITP). Methods: Forty-six patients who had been newly diagnosed with primary treatment-naïve ITP and started treatment with corticosteroids were analyzed. Results: Among the 46 primary ITP patients, 33 (72%) responded to the treatment and 13 (28%) did not. The percentage of IPF (IPF%) among the nonresponders was significantly lower than that of the responders (6.6 vs. 16.0%; p < 0.001). In the receiver operating characteristics analysis, the optimum IPF% cut-off value for predicting the treatment response was 12%, with a specificity of 85% and a sensitivity of 76%. Conclusions: Our findings thus suggest that measuring the IPF% as a surrogate of reticulated platelets is useful to identify patients likely to respond to corticosteroids.

Aims/Introduction A gold standard in the diagnosis of diabetic polyneuropathy (DPN) is a nerve conduction study. However, as a nerve conduction study requires expensive equipment and well‐trained technicians, it is largely avoided when diagnosing DPN in clinical settings. Here, we validated a novel diagnostic method for DPN using a point‐of‐care nerve conduction device as an alternative way of diagnosis using a standard electromyography system. Materials and Methods We used a multiple regression analysis to examine associations of nerve conduction parameters obtained from the device, DPNCheck™, with the severity of DPN categorized by the Baba classification among 375 participants with type 2 diabetes. A nerve conduction study using a conventional electromyography system was implemented to differentiate the severity in the Baba classification. The diagnostic properties of the device were evaluated using a receiver operating characteristic curve. Results A multiple regression model to predict the severity of DPN was generated using sural nerve conduction data obtained from the device as follows: the severity of DPN = 2.046 + 0.509 × ln(age [years]) − 0.033 × (nerve conduction velocity [m/s]) − 0.622 × ln(amplitude of sensory nerve action potential [µV]), r = 0.649. Using a cut‐off value of 1.3065 in the model, moderate‐to‐severe DPN was effectively diagnosed (area under the receiver operating characteristic curve 0.871, sensitivity 70.1%, specificity 87.7%, positive predictive value 83.0%, negative predictive value 77.3%, positive likelihood ratio 5.67, negative likelihood ratio 0.34). Conclusions Nerve conduction parameters in the sural nerve acquired by the handheld device successfully predict the severity of DPN., Currently, most diagnostic criteria for diabetic polyneuropathy consist of physical examinations; for example, Achilles tendon reflex or vibration sensation with a tuning fork. Therefore, the low diagnostic sensitivity of these criteria should be improved. Although the gold standard for quantitative evaluation of diabetic polyneuropathy is an electromyography system, these have not become widely used due to their high cost and necessity of an advanced examination technique. The current work verified the efficacy of a handheld nerve conduction device. If clinicians recognize the validity and reliability of the device, this simplified nerve conduction study could be carried out in various clinical settings, including clinics or hospitals in developing or developed countries. The worldwide utilization of the device would improve diagnostic sensitivity for diabetic polyneuropathy in the future.

Although patients with cancer and immunosuppression are at a risk of functional hyposplenism, how to detect it promptly remains unclear. Since hyposplenism allows erythrocytes with nuclear remnants (Howell-Jolly bodies [HJBs]) to appear in the peripheral blood, HJB detection by a routine microscopic examination may help identify patients with functional hyposplenism. This prospective study was thus performed to determine the underlying diseases in patients who presented with HJBs. Of 100 consecutive patients presenting with HJBs, 73 had a history of splenectomy. The remaining 27 had hematologic cancer (n = 6, 22%), non-hematologic cancer (n = 8, 30%), hepatic disorders (n = 4, 15%), premature neonates (n = 3, 11%), hemolytic anemia (n = 2, 7%), autoimmune disorders (n = 2, 7%) and miscellaneous diseases (n = 2, 7%), and their prior treatments included chemotherapy (n = 8, 30%), steroids (n = 7, 26%) and molecular-targeted therapy (n = 3, 11%). Among the 27 patients, 22 had computed tomography scans available: 3 (14%) had underlying diseases in the spleen, and the remaining 19 (86%) were all found to have a decreased splenic volume, including 11 (50%) with more than 50% of the ideal value. The present findings suggest that HJB detection identifies patients with potentially functional hyposplenism who should receive appropriate interventional treatment, such as vaccination and prophylactic antibiotics.

Perinatal bronchopulmonary dysplasia (BPD) is defined as lung injury in preterm infants caused by various factors, resulting in serious respiratory dysfunction and high mortality. The administration of mesenchymal stem/stromal cells (MSCs) to treat/prevent BPD has proven to have certain therapeutic effects. However, MSCs can only weakly regulate macrophage function, which is strongly involved in the development of BPD. 7ND-MSCs are MSCs transfected with 7ND, a truncated version of CC chemokine ligand 2 (CCL2) that promotes macrophage activation, using a lentiviral vector. In the present study, we show in a BPD rat model that 7ND-MSC administration, but not MSCs alone, ameliorated the impaired alveolarization evaluated by volume density and surface area in the lung tissue, as well as pulmonary artery remodeling and pulmonary hypertension induced by BPD. In addition, 7ND-MSCs, but not MSCs alone, reduced M1 macrophages and the messenger RNA expressions of interleukin-6 and CCL2 in the lung tissue. Thus, the present study showed the treatment effect of 7ND-MSCs in a BPD rat model, which was more effective than that of MSCs alone.

BACKGROUND: We examined the relationship between the tumour microenvironment and the clinical efficacy of neoadjuvant chemotherapy in patients with cT2-4aN0M0 bladder cancer using multiplex fluorescence immunohistochemistry. METHODS: The study retrospectively evaluated 51 patients who underwent radical cystectomy following neoadjuvant chemotherapy for cT2-4aN0M0 muscle-invasive bladder cancer. Patients were divided into responders (

Background Tumour-infiltrating lymphocyte (TIL)-high breast tumours have a high rate of pathological complete response (pCR) with neoadjuvant chemotherapy. In our routine pathological diagnoses of biopsy specimens from pCR cases, we have observed a high infiltration of plasma cells (PCs). A positive correlation of PCs with favourable patient outcome has recently been reported, but little is known about how PCs contribute to local tumour immunity. Methods We retrospectively examined biopsy specimens from 146 patients with invasive breast cancer who received neoadjuvant chemotherapy. CD138+ PC infiltration was assessed by immunohistochemistry. Multiplexed fluorescent immunohistochemistry (mfIHC) with T and B cell markers was also conducted to elucidate the profile of immune cells. Results Greater PC infiltration was observed in the pCR group (p = 0.028) and this trend was confirmed in another patient cohort. With mfIHC, we observed significantly more CD8+, T-bet+CD4+, and CD8+FOXP3+ T cells, total B cells and PCs in pCR cases. Such cases were also characterised by high expression of both PD-1 and PD-L1 on B cells and PCs. In patients with hormone receptor-negative tumours, high PC infiltration was correlated with significantly longer disease-free survival (p = 0.034). Conclusions We found that higher PC infiltration in biopsy specimens before neoadjuvant chemotherapy was associated with pCR. With mfIHC, we also revealed that the local cytotoxic immune response was clearly enhanced in pCR cases, as was the infiltration of B cells including PCs. Moreover, higher PC levels were correlated with favourable outcomes in hormone receptor-negative breast cancer patients.

Aims/Introduction Although nerve conduction study (NCS) using a standard electromyography system (EMGS) is considered to be the gold standard in evaluating diabetic polyneuropathy, this examination requires expensive equipment and well‐trained technicians. We aimed to validate a point‐of‐care device, NC‐stat/DPNCheck™, that has been developed for widespread use of NCS in diabetic polyneuropathy. Materials and Methods Diabetes patients underwent two kinds of NCS: DPNCheck™ and electromyography system. Inter‐/intrarater reliability of DPNCheck™ were also determined by the intraclass correlation coefficient. Results A total of 57 patients were evaluated. The parameters of NCS between the two methods correlated well (r = 0.7734 for the sural nerve conduction velocity, r = 0.6155 for the amplitude of sural nerve action potential). The intraclass correlation coefficients were excellent (intrarater: the velocity 0.767, the amplitude 0.811; interrater: the velocity 0.974, the amplitude 0.834). Conclusions The point‐of‐care device has excellent reproducibility and good agreement with standard electromyography system. The device might be useful to evaluate diabetic polyneuropathy.

The luminosity and the temperature are factors that act directly in the photosynthetic process, where an elevation of the luminous intensity can cause a reduction of the assimilation of carbon, which consequently lowers the development of the cotton. The objective of this work was to assess the response of physiological parameters of cotton when subjected to different artificial light intensities. Two varieties of cotton IMA5801B2RF and IACRDN, were interacting with five artificial light intensities: 0 (control); 500; 1000; 1500 and 2000 μmol m−2 s−1 of photosynthetically active radiation provided by LED bulbs. The experiment was set in a randomized complete block design using a 2x5 factorial scheme. The variables measured were the rate of CO2 assimilation, transpiration, stomatal conductance, inner CO2 concentration in the substomatic chamber, and efficient use of water (for which a portable device of gas exchange was used). The cotton varieties responded positively to different luminous intensities until reaching the point of maximum saturation between 1400 and 1600 µmol m-1 s-1 of light, which provided a better rate of CO2 assimilation, concentration of CO2 in the substomatic chamber, and efficient use of water. Leaf transpiration and stomatal conductance showed a positive linear response with increasing light intensity. The ideal luminous intensity for the use of Infra-Red Gas Analyzer - IRGA was 1500 µmol m-1 s-1 for the tested cotton varieties.

The present review provides an update about the major achievements and recent advances of immunotherapy in renal cell carcinoma, urothelial carcinoma, and prostate cancer. Although the treatment strategy for renal cell carcinoma and urothelial carcinoma includes traditional cancer immunotherapies, such as interleukin-2 and interferon-alfa, the clinical outcomes of these therapies are unsatisfactory. In recent years, the development of immune checkpoint inhibitors has drastically changed the treatment strategy for various cancers, including genitourinary cancer. The present review summarizes the approved cancer immunotherapies for renal cell carcinoma, urothelial carcinoma and prostate cancer. Furthermore, we review the response evaluation and biomarkers for immune checkpoint inhibitors with a distinctive mode of action that is different from cytotoxic agents. Finally, future perspectives for cancer immunotherapy are discussed.

Aims/Introduction Diabetic polyneuropathy (DPN) and diabetic retinopathy (DR) are traditionally regarded as microvascular complications. However, these complications may share similar neurodegenerative pathologies. Here we evaluate the correlations in the severity of DPN and changes in the thickness of neuroretinal layers to elucidate whether these complications exist at similar stages of progression. Materials and Methods A total of 43 patients with type 2 diabetes underwent a nerve conduction study (NCS), a macular optical coherence tomography, and a carotid artery ultrasound scan. Diabetic polyneuropathy was classified according to Baba’s classification using NCS. The retina was automatically segmented into four layers; ganglion cell complex (GCC), inner nuclear layer/outer plexiform layer (INL/OPL), outer nuclear layer/photoreceptor inner and outer segments, and retinal pigment epithelium (RPE). The thickness of each retinal layer was separately analyzed for the fovea and the parafovea. Results Fourteen patients were classified as having moderate to severe diabetic polyneuropathy. The thicknesses of the foveal and parafoveal INL/OPL increased in patients with diabetic polyneuropathy compared with patients without. The thickness of the parafoveal retinal pigment epithelium decreased in patients with diabetic polyneuropathy. The thinning of parafoveal ganglion cell complex and foveal and parafoveal retinal pigment epithelium were positively correlated with deterioration of nerve functions in the nerve conduction study, but the thickening of INL/OPL was positively correlated with the nerve function deterioration. The thinning of parafoveal ganglion cell complex and foveal retinal pigment epithelium were positively correlated with the thickening of the carotid intima‐media. Conclusions Depending on the progression of diabetic polyneuropathy, the ganglion cell complex and retinal pigment epithelium became thinner and the INL/OPL became thicker. These retinal changes might be noteworthy for pathological investigations and for the assessment of diabetic polyneuropathy and diabetic retinopathy., (1) The thickness of the foveal and parafoveal inner nuclear layer/outer plexiform layer increased in patients with clinical diabetic polyneuropathy compared with patients without clinical diabetic polyneuropathy. (2) A decrease in the thickness of the parafoveal ganglion cell complex correlated with deterioration of nerve functions in the nerve conduction study. (3) A decrease in the thickness of the parafoveal ganglion cell complex was positively correlated with an increase in the parameters of atherosclerosis and cardiovascular risk factors.

Objectives To evaluate the incidence and predictors of acute kidney injury after clampless partial nephrectomy, and its impact on intermediate-term renal function. Methods The incidence and severity of acute kidney injury were assessed for 262 patients undergoing clampless partial nephrectomy between 2010 and 2015. The association between perioperative covariates and acute kidney injury was evaluated using multivariate logistic regression analysis. An annual change in estimated glomerular filtration rate from 1 year after surgery was calculated according to the presence or absence of acute kidney injury. An impact of acute kidney injury on postoperative renal impairment, defined as a ≥25% estimated glomerular filtration rate decrease, was evaluated. Results Overall, 21 (8.0%) patients experienced grade 1 acute kidney injury after clampless partial nephrectomy, and grade ≥2 acute kidney injury was not observed. High tumor complexity was the only independent predictor of acute kidney injury. Estimated glomerular filtration rate in patients with acute kidney injury improved within 1 year, and annual estimated glomerular filtration rate changes were similar among patients with or without acute kidney injury. Ultimately, 13 (5.0%) patients showed postoperative renal impairment during the median follow-up period of 37 months. Advanced age and diabetes mellitus were independent risk factors for renal impairment, but acute kidney injury was not. Conclusions The incidence and severity of acute kidney injury after clampless partial nephrectomy are low. Low-grade acute kidney injury after clampless partial nephrectomy does not seem to affect intermediate-term renal function.

OBJECTIVE To investigate the prognostic significance of contact with the renal sinus in patients with clear cell renal cell carcinoma. METHODS A total of 787 pT1N0M0 clear cell renal cell carcinoma patients who had undergone radical or partial nephrectomy were reviewed retrospectively. A tumor in contact with the renal sinus was defined as a tumor radiologically attached to the renal sinus. Metastatic-free survival rates were analyzed in the total and propensity score-matched cohorts. A risk score model for metastasis after surgery was developed. RESULTS Of the 787 patients, 411 (52.2%) had tumors in contact with renal sinus. The contact with renal sinus group showed poorer metastatic-free survival in both total and matched cohorts. In multivariate analysis, contact with renal sinus was an independent prognostic factor of metastasis, as well as Fuhrman grade, microvascular invasion and age. The scoring model likewise consisted of Fuhrman grade, microvascular invasion, age and contact with renal sinus. Metastasis-free survival curves were clearly stratified according to risk, with 5-year metastasis-free survival rates of 95.7% and 65.2% in the low- and high-risk groups, respectively (P

Background Nivolumab is an immune checkpoint inhibitor specific to the programmed death 1 (PD-1) receptor. Nivolumab has shown clinical responses in many malignancies. Although immune-related adverse events (irAEs) associated with nivolumab are largely tolerable, severe irAEs have occurred in some patients. However, the mechanisms underlying the development of irAEs are not fully clarified. Case presentation We report 2 patients with metastatic melanoma who developed colitis, an irAEs caused by nivolumab. Both patients experienced colitis after nivolumab administration. Pathological examination of the colon showed robust infiltration of CD8+ cells and T-bet expressing CD4+ cells in both cases, indicating helper T cells (Th) 1 to be responsible for the dominant response. Additionally, we observed the serum C-reactive protein level (CRP) as well as interleukin-6 (IL-6) reflected the clinical course of irAEs clearly in the two cases. Conclusion Our two cases suggested that the development of irAEs due to nivolumab is associated with Th1 dominant response. CRP as well as IL-6 was found to be a potential biomarker for irAEs. Our findings may help to understand the mechanisms underlying irAEs caused by nivolumab and manage irAEs in clinical practice.

Background Transient CD4+ T cell depletion led to the proliferation of tumor-specific CD8+ T cells in the draining lymph node and increased infiltration of PD-1+CD8+ T cells into the tumor, which resulted in strong anti-tumor effects in tumor-bearing mice. This is a first-in-human study of IT1208, a defucosylated humanized anti-CD4 monoclonal antibody, engineered to exert potent antibody-dependent cellular cytotoxicity. Methods Patients with advanced solid tumors were treated with intravenous IT1208 at doses of 0.1 or 1.0 mg/kg. The first patient in each cohort received a single administration, and the other patients received two administrations of IT1208 on days 1 and 8. Results Eleven patients were enrolled in the 0.1 mg/kg (n = 4) and 1.0 mg/kg cohorts (n = 7). Grade 1 or 2 infusion-related reactions was observed in all patients. Decreased CD4+ T cells in peripheral blood due to IT1208 were observed in all patients and especially in those receiving two administrations of 1.0 mg/kg. CD8+ T cells increased on day 29 compared with baseline in most patients, resulting in remarkably decreased CD4/8 ratios. One microsatellite-stable colon cancer patient achieved durable partial response showing increased infiltration of both CD4+ and CD8+ T cells into tumors after IT1208 administration. Moreover, transcriptomic profiling of the liver metastasis of the patient revealed upregulation of the expression of interferon-stimulated genes, T cell activation-related genes, and antigen presentation-related genes after IT1208 administration. Two additional patients with gastric or esophageal cancer achieved stable disease lasting at least 3 months. Conclusions IT1208 monotherapy successfully depleted CD4+ T cells with a manageable safety profile and encouraging preliminary efficacy signals, which warrants further investigations, especially in combination with immune checkpoint inhibitors. Electronic supplementary material The online version of this article (10.1186/s40425-019-0677-y) contains supplementary material, which is available to authorized users.

Plasma removal by washing platelet concentrates (PCs) is effective in preventing adverse reactions to PC transfusions. The Japanese Red Cross Society (JRCS) started releasing washed PCs (WPCs) as a commercially approved blood product in September 2016. This retrospective multicenter study investigated the change in the number of transfused WPCs and the impact on the incidence of adverse reactions to PCs before and after the release. The numbers and types of transfused PCs and the adverse reactions to the PCs for a year before the start of the WPC release and for a year after the release were reported by 27 medical institutes in Japan. Transfusion information for approximately 8% of the amount of PCs supplied in Japan was analyzed during the study period. After the start of WPC release by the JRCS, the number of transfused WPCs doubled. The rate of adverse reactions to PCs decreased significantly (p = 0.0223), from 4.30% before the release to 4.05% after the release. The rates of adverse reactions to unwashed and WPCs were 4.13% and 0.84%, respectively. Allergic adverse reactions were significantly decreased after the release (3.60% before versus 3.37% after). No severe allergic reactions to WPCs were reported. The release of WPCs by the JRCS significantly reduced transfusion-related adverse reactions to PCs in Japan.

Immune checkpoint inhibitors have now become a standard therapy for malignant melanoma. However, as immunotherapies are effective in only a limited number of patients, biomarker development remains one of the most important clinical challenges. Biomarkers predicting clinical benefit facilitate appropriate selection of individualized treatments for patients and maximize clinical benefits. Many biomarkers derived from tumors and peripheral blood components have recently been reported, mainly in retrospective settings. This review summarizes the recent findings of biomarker studies for predicting the clinical benefits of immunotherapies in melanoma patients. Taking into account the complex interactions between the immune system and various cancers, it would be difficult for only one biomarker to predict clinical benefits in all patients. Many efforts to discover candidate biomarkers are currently ongoing. In the future, verification, by means of a prospective study, may allow some of these candidates to be combined into a scoring system based on bioinformatics technology.

C-reactive protein (CRP), a representative inflammatory marker, could serve as a biomarker in renal cell carcinoma because CRP is an important prognostic factor. However, its detailed mechanism remains unknown. This study showed that higher CRP levels correlated with the tumor immune microenvironment, which leads to a worse prognosis. These findings can help to clarify the underlying mechanisms between the presence of systemic inflammatory reaction and prognosis. The aim of this study is to investigate the association between tumor immune microenvironment and CRP in patients with renal cell carcinoma (RCC) to explore the underlying mechanisms between CRP level and prognosis.Immunohistochemical measurement of CD4, CD8, CD163 (M2 macrophages), and Foxp3 (Regulatory T [Treg] cells) was performed in patients with clear-cell RCC (n = 111) treated with radical or partial nephrectomy at our institution. The association between immunohistochemical status and preoperative serum CRP level and cancer-specific survival (CSS) was analyzed.Thirty-three patients (30%) had a high CRP level (≥ 5.0 mg/L), and the CSS rate was significantly worse among these patients than among the remaining patients (P .001). In patients with strong infiltration of CD8+, Foxp3+, or CD163+ cells, CRP levels were significantly higher (P = .041, P = .001, and P = .035, respectively), and CSS was significantly worse compared with patients with weak infiltration (P = .040, P = .026, and P .001, respectively). In multivariate analysis, strong CD163+ cells infiltration (P = .001) as well as pathologic T3 (P = .036), lymph-node involvement (P = .007), distant metastasis (P .001), and Fuhrman nuclear grade 4 (P = .003) were independent prognostic factors for CSS.Infiltration of the immunosuppressive cells known as Tregs and M2 macrophages in the tumor microenvironment is associated with higher CRP and poor prognosis in patients with clear-cell RCC. CRP could reflect an immunosuppressive microenvironment.

BACKGROUND The plasma fraction of blood components has an essential role in the etiology of allergic transfusion reactions (ATRs). The difference of incidences of ATRs between fresh-frozen plasma (FFP) and platelet concentrates (PCs), in which plasma is the main component, is not clearly understood. This study compares the frequency of ATRs to FFP versus PCs on both first and subsequent (nonfirst) transfusions and considers the factors influencing the risk of ATRs. STUDY DESIGN AND METHODS Five hospitals agreed to systematically collect and share 2 years of data (January 2010 through December 2011). This was a retrospective observational analysis of data including the number of transfusion episodes and ATRs for FFP and PCs on first-transfusion patients (without transfusion history) and previously transfused patients. RESULTS The incidence of ATRs to PCs (2.51%) was significantly higher than to FFP (1.68%) on subsequent transfusions (p

Chronic stress is closely linked to the metabolic syndrome, diabetes, hyperuricemia and thromboembolism, but the mechanisms remain elusive. We reported recently that stress targets visceral adipose tissue (VAT), inducing lipolysis, low-grade inflammation with production of inflammatory adipokines, metabolic derangements such as insulin resistance, and prothrombotic state. In the present study, we hypothesized the involvement of VAT xanthine oxidoreductase (XOR), a source of reactive oxygen species (ROS) and uric acid (UA) in the above processes. Restraint stress in mice resulted in upregulation of XOR and xanthine oxidase activity, accumulation of ROS in VAT as well as liver and intestine, increase in serum UA levels, upregulation of NADPH oxidase subunits and downregulation of antioxidant enzymes. Immunohistochemistry and RT-PCR analysis also showed that restraint stress induced VAT monocyte accumulation and proinflammatory adipokine production, resulting in reduced insulin sensitivity and induction of plasminogen activator inhibitor-1 and tissue factor in VAT. Treatment with febuxostat, a potent XO inhibitor, suppressed stress-induced ROS production and VAT inflammation, resulting in improvement of serum UA levels, insulin sensitivity, and prothrombotic tendency. Our results suggest that stress perturbs glucose and UA metabolism, and promotes prothrombotic status, and that XO inhibition by febuxostat might be a potential therapy for stress-related disorders.

2610 Background: C-REV, an oncolytic, spontaneous mutant of Herpes Simplex Virus type 1 (HSV-1), is a cancer immunotherapy agent that combine direct tumor cell killing with immune modulation. A phase I study for solid tumors with cutaneous and/or superficial lesions treated with C-REV monotherapy and a phase II study for unresectable or metastatic melanoma treated with C-REV and Ipi combination therapy were conducted. Immune status of cancer pts before and after administration of C-REV with/without Ipi has been unclear. Methods: A phase I study (n = 6) included solid tumor pts with cutaneous and/or superficial lesions treated with C-REV monotherapy (1 x 106 and 1 x 107 TCID50/mL/dose; 4 injections q2-4wk). In phase II study (n = 28), C-REV (1 x 107 TCID50/mL/dose; 4 injections q1wk; then up to 15 injections q3wk) was injected into each tumor for advanced melanoma pts. Four Ipi infusions (3 mg/kg) were administered at q3wk. Immune-monitoring was conducted before and after treatment in tumor microenvironment usingpaired biopsy samples by multiplex immunohistochemistry (mIHC) and in peripheral blood by flow cytometry (FCM). Results: In the phase I study, significant infiltrations of CD8+and CD4+ T cells were observed at tumor local site statistically in three pts (60%) among five pts. In the phase II study, FCM of peripheral blood (n = 10) showed that the responders (irSD, n = 7, 70%) tend to express the higher levels of ICOS on CD4+ T cells as a pharmacodynamic biomarker of ipi monotherapy reported previously (Ng Tang D, et al. Cancer Immunol Res. 2013) and lower levels of PD-L1 on monocyte after two months of treatment. Moreover, mIHC analysis of paired tumor biopsy samples (n = 11) revealed that five pts (45%) among 11 pts were confirmed persistent infection of C-REV at the injected site by qPCR. Disease control rate of pts with the virus DNA detected on Days 85/169 was higher than that without it (100% [n = 5, irPR; 1, irSD; 4] vs. 33% [n = 6, irSD; 2, irPD; 4]). Furthermore, median OS of pts with or without the DNA detected was 342 or 251 days respectively. Conclusions: Our results suggest C-REV injection in the tumor local site have potential to enhance systemic immune response of Ipi. Clinical trial information: NCT03153085.

Objectives To develop and validate predictive models for postoperative estimated glomerular filtration rate and risk of chronic kidney disease after radical nephrectomy in Japanese patients. Methods The present retrospective study included a development cohort of 209 patients without preoperative chronic kidney disease who underwent radical nephrectomy between 1994 and 2008, and were followed up for longer than 3 years, and a validation cohort of 144 similar such patients. Univariate and multivariate linear regression or logistic regression analyses were carried out to identify the independent predictors of estimated glomerular filtration rate or chronic kidney disease 3 years after radical nephrectomy. Incorporating all independent predictors, predictive models for postoperative renal function were developed and externally validated. Results Age, the presence of diabetes mellitus, and preoperative estimated glomerular filtration rate were independent predictors of both postoperative estimated glomerular filtration rate and chronic kidney disease. A formula for predicting the postoperative estimated glomerular filtration rate and a nomogram for predicting the risk of postoperative chronic kidney disease were developed. The adjusted R2 of the formula and area under the receiver operating characteristic curves of the nomogram were 0.446 and 0.865 in the development cohort, and 0.396 and 0.787 in the validation cohort, respectively. Conclusions We developed and validated novel predictive models for the postoperative renal function 3 years after radical nephrectomy in Japanese patients.

To assess whether there is an association between the apparent diffusion coefficient (ADC) value and the pathological characteristics of prostate cancer. The study cohort consisted of 29 consecutive patients with prostate cancer treated with radical prostatectomy. All patients underwent diffusion-weighted MRI before the prostate biopsy. In 42 tumor foci, the associations of the ADC values with the clinicopathological characteristics and Ki-67 labeling index (LI) were analyzed. High-grade cancers (Gleason score [GS] ≥ 4 + 3), larger cancers (maximum diameter (MD) ≥ 16 mm), and highly proliferating cancers (Ki-67 LI ≥ 4.43 %) had significantly lower ADC values, respectively (P

Livedoid vasculopathy (LV) is a chronic disease with recurrent reticularis and ulcers, mainly affecting the feet and lower legs. The pathogenesis of LV has not been yet thoroughly understood, but thrombosis is thought to play a major role because fibrin deposition within both the wall and lumen of affected vessels is pathologically detected. A 68-year-old woman first presented to our hospital in 2004 with a 6-year history of a reticular rash and ulceration on the lower legs. Screening tests for vasculitis and collagen disease were mostly normal, leading to diagnosis of LV. After failed treatment with steroid and aspirin, she was started on warfarin, to which she had a favorable response. However, she had to be admitted to the hospital because complication of swelling and infection in her left lower leg in 2004 + 10. Contrast-enhanced computed tomography showed thrombosis in the left popliteal artery. Screening tests for thrombotic tendency revealed that protein S activity was low (27%) although total protein S antigen was within normal range (73%). Analysis of protein S-alpha gene revealed 155 Lys>Glu mutation in exon VI, which was reported in 1994 and named as protein S Tokushima. Thus, we conclude that protein S deficiency could contribute to LV.

INTRODUCTION AND OBJECTIVES: Magnetic resonance imaging (MRI)-targeted prostate biopsy (MRBX) is an effective biopsy procedure for with suspicion of prostate cancer on MRI. However, some significant cancer (SC) is missed using MRBX. Use of systematic prostate biopsy (SBX) for negative areas on MRI to detect SC missed by MRBX is not established for this indication. In this study, we aimed to explore the optimal combination of SBX and MRBX in these patients. METHODS: Between 2014 and 2015 at our institution, 271 men underwent MRBX with or without SBX based on prebiopsy multiparametric 1.5T MRI. Of these, 52 were excluded from the analysis because of PSA levels>40 ng/ml, obvious clinical T3-4 disease or biopsy with an insufficient number of cores for severe comorbidity. The remaining 219 men who underwentMRBXandSBXinonesessionaccording toourbiopsyprotocolwere enrolled in this study. MRBX was performed under cognitive or MRI/transrectal ultrasound fusion. Using MRBX, four-core samples for one suspicious lesiononMRIwereperformed.TheSBXprotocolwasa transperineal18-core biopsy.SCwasdefinedasclinical stageT2borgreater,biopsyGleasonscore of 4+3orgreater, ormaximumcancer lengthof 5mmorgreater.Cancerother thanSCwasdefinedas indolent cancer (IC). SC thatwasnot detected or that wasdetectedas ICusingMRBX,but thatwasdetectedasSCusingSBXwas defined as MRBX-missed SC. The frequency of MRBX-missed SC was investigated. A SBX protocol that could sufficiently detect MRBX-missed SC with a minimum number of sampling cores was determined. RESULTS: The median PSA was 7.5 ng/ml, and one/two suspicious lesions were observed in 204/15 patients, respectively, using MRI. The detection rate of any cancer or SC using both MRBX and SBX was 76%or 61%, respectively. Frequency ofMRBX-missed SC to overall SC was 13% (21/135). MRBX results in MRBX-missed SC patients was no cancer in 8 and IC in 13. Of 21 MRBX-missed cancer, a maximum of 10, 13, 15, 17, 19, 20 and 21MRBX-missed SCwere detected using 2, 4, 6, 8, 10, 12and14SBXsamplingcores, respectively.Whenweset theSC detection rate using both MRBX and the transperineal 18-core SBX at 100%, aminimum of 6 sampling cores in SBX (in addition to MRBX) were required to detect 95% of overall SC as SC. The six SBX sampling locationswere bilateral transperineal anterior, posterior and far lateral sites. CONCLUSIONS: The combination of transperineal 6-core SBX and MRBX could be an optimal biopsy strategy that strikes a balance between SC detectability and sampling number for men with suspicion of prostate cancer on MRI.

Diffusion-weighted MRI (DW-MRI) is a functional imaging to assess molecular diffusion. We report a case in which treatment response to lymph node metastatic bladder cancer was monitored by DW-MRI. A 67-year-old man had paraaortic lymph node metastasis from bladder cancer; the paraaortic lymph node showed high signal intensity on DW-MRI. After four course treatment of gemcitabine and cisplatin, the lesion showed reduction of signal intensity on DW-MRI and increase of the apparent diffusion coefficient value. These signal changes were consistent with the change of morphological images (CT, MRI (T1-W, T2-W)), 18F-FDG PET and tumor markers. This case suggests that DW-MRI is useful in monitoring treatment response of metastatic bladder cancer.

Tendon driven robots can contact with environment softly at any time by grace of the intrinsic elasticity of actuators. Meanwhile it is difficult to manipulate them accurately due to their own flexibilities. In the biologic systems, the muscles are controlled by the spinal cord and cerebellum at the lowest level. Due to those control systems, we can manipulate our limbs as intended. Thus, this paper attempts to develop a new trajectory tracking controller for the tendon driven robot by integrating the computational models of the spinal cord and cerebellum in the same manner as the biological system. The proposed controller consists of the reflex control inputs composed of the delayed force feedback and PD position error feedback, and the adaptive controller which estimates and eliminates the excess reflex component of reflexes caused by the inertial force. The asymptotic stability of the controlled system is proven along the Liapunov-Krasovskii stability theorem. The effectiveness of the proposed controller and the dependence of the control performance on delays are examined through some computer simulations.

Purpose: To determine the predictive factors for postoperative urinary incontinence (UI) following holmium laser enucleation of the prostate (HoLEP) during the initial learning period. Patients and Methods: We evaluated 127 patients with benign prostatic hyperplasia who underwent HoLEP between January 2011 and December 2013. We recorded clinical variables, including blood loss, serum prostate-specific antigen levels, and the presence or absence of UI. Blood loss was estimated as a decline in postoperative hemoglobin levels. The predictive factors for postoperative UI were determined using a multivariable logistic regression analysis. Results: Postoperative UI occurred in 31 patients (24.4%), but it cured in 29 patients (93.5%) after a mean duration of 12 weeks. Enucleation time >100 min (p=0.043) and blood loss >2.5g/dL (p=0.032) were identified as significant and independent risk factors for postoperative UI. Conclusions: Longer enucleation time and increased blood loss were independent predictors of postoperative UI in patients who underwent HoLEP during the initial learning period. Surgeons in training should take care to perform speedy enucleation maneuver with hemostasis.

Background: In treatment of tumors, we usually reconstruct after resection of the entire femur using only metallic modular endoprostheses among many procedures and defined it as a total femur replacement. We studied the interrelation between the preservation of rectus femoris and the functional outcome after total femur replacement. Methods: We rated the functional outcomes of 21 patients who underwent total femur replacement. We categorized the subjects into 2 groups: group A (rectus femoris preserved) and group B (rectus femoris unpreserved). We examined them based on the Mann-Whitney U test between the 2 groups in average through the Musculoskeletal Tumor Society functional scores. Results: The average score of group A was 20 of 25 (11–25; 80%), whereas the average score of group B was 10 of 25 (4–13; 40%). There was significant difference between the groups (P = 0.00168877). Conclusion: We found that the preservation of rectus femoris is imperative for achieving the favorable functional outcome in total femur replacement.

In this paper, a trajectory tracking control method for the tendon-driven robot is presented. In the human motor control system, it is known that the spinal reflex and the cerebellum play a key role to achieve the desired limb motions and have some characteristic structures different from the conventional robot control systems, such as the internal positive feedback loops. From the viewpoint of control, the positive feedback is inconvenient since it might potentially destabilize the limb motion. However, in the biological system, the positive feedback is actively used rather than avoided and has significant role to achieve the natural human limb motions. Thus, in this paper, we attempted to establish a trajectory tracking controller for the tendon-driven robots with reference to the biological control system composed of the spinal cord and cerebellum. The stability of the controlled system was proven along the Popov's hyper-stability theory. The effectiveness of the proposed controller was demonstrated through some computer simulations and experiments using a 2 link tendon-driven robot.

Purpose We tested a new head-mounted display (HMD) system for surgery on the upper urinary tract. Surgical Technique Four women and one man with abnormal findings in the renal pelvis on computed tomography and magnetic resonance imaging underwent surgery using this new system. A high definition HMD (Sony, Tokyo, Japan) is connected to a flexible ureteroscope (Olympus, Tokyo, Japan) and the images from the ureteroscope are delivered simultaneously to various participants wearing HMDs. Furthermore, various information in addition to that available through the endoscope, such as the narrow band image, the fluoroscope, input from a video camera mounted on the lead surgeon’s HMD and the vital monitors can be viewed on each HMD. Results Median operative duration and anesthesia time were 53 and 111 minutes, respectively. The ureteroscopic procedures were successfully performed in all cases. There were no notable negative outcomes or incidents (Clavien-Dindo grade ≥1). Conclusion The HMD system offers simultaneous, high-quality magnified imagery in front of the eyes, regardless of head position, to those participating in the endoscopic procedures. This affordable display system also provides various forms of information related to examinations and operations while allowing direct vision and navigated vision.

Objective: The aim of this study is to identify the pre-operative prognostic factors and create a risk stratification model for patients with renal cell carcinoma with extension into the renal vein or inferior vena cava. Methods: The study cohort included 61 patients with renal cell carcinoma extending into the renal vein or inferior vena cava that underwent operations between 1993 and 2012. Cancerspecific survival rates were estimated, and univariate and multivariate analyses were carried out to determine the prognostic factors. A simple risk stratification model was developed for these patients. Results: The median follow-up period of the current patient cohort was 33.7 months. Their 1, 3 and 5-year cancer-specific survival were 89, 70 and 65%, respectively. On multivariate analysis, the level of tumor thrombus extension (extension into the supradiaphragm), presence of distant metastasis and elevation of lactate dehydrogenase and C-reactive protein were independent negative prognostic factors for cancer-specific survival. Cancer-specific survival rates were clearly discriminated by the stratification according to the scoring model (P , 0.001). The concordance index of the new model was 0.80. Conclusions: We demonstrated a simple risk stratification model with four pre-operative independent prognostic factors for patients with renal cell carcinoma with venous involvement. This may be a useful decision-making model in the management of such patients.

INTRODUCTION AND OBJECTIVES: The Michigan Urological Surgery Improvement Collaborative (MUSIC) is a state-wide consortium of 29 urology practices funded by Blue Cross Blue Shield with the goal of improving the quality of prostate cancer care in Michigan. As an initial priority we examined practice-level and temporal variations in the use of radiographic staging among men with newly diagnosed prostate cancer. METHODS: Practices submit standardized data, including use and results of staging computed tomography and bone scans, to a webbased clinical registry for all men with newly-diagnosed prostate cancer. We compared patterns of imaging utilization across patient risk groups before (Phase I, March-October 2012) and after (Phase II, November 2012-June 2013) practice-level performance feedback and guideline review provided at one of our tri-annual collaborative-wide meetings. RESULTS: Across all MUSIC practices in Phase I, imaging studieswereorderedwith significant variability amongpractices (p 0.001) for approximately 5%, 20%, and 70% of low, intermediate, and high risk patients, respectively. After practice-specific feedback there was a statistically significant decreased in imaging for low risk disease (Table 1). CONCLUSIONS: Although variability exists among urology practices in Michigan, patterns of care regarding the use of imaging studies seem to be quite appropriate and significantly improving for low risk disease based on collaborative education and performance feedback. Opportunities exist for further improvement in the rates of imaging and refinement of imaging criteria and risk classifications. Table 1 Rates of radiographic staging in phase I (March 2012 October 2012) compared to phase II (November 2012 June 2013)

Background and Objectives This study compares the frequency of adverse transfusion reactions (ATRs) after first transfusions with the frequency of ATRs for subsequent (non-first) transfusions. Materials and Methods Five hospitals agreed to systematically collect and share 2 years of data. This was a retrospective observational analysis of data including the number of transfusion episodes and ATRs for red blood cells (RBCs), fresh frozen plasma (FFP) and platelet concentrates (PCs) given to first-time transfusion recipients and to those previously transfused. Results First transfusion ATRs to RBCs, FFP and PCs were 1·08%, 2·84% and 3·34%, respectively. These are higher than ATR incidences to RBCs (0·69%), FFP (1·91%) and PCs (2·75%) on subsequent transfusions. Specifically, first transfusion incidences of febrile non-haemolytic transfusion reactions (FNHTRs) to RBCs (0·43%) and allergic reactions to FFP (2·51%) were higher than on subsequent transfusions (RBCs: 0·23%, FFP: 1·65%). Conclusion There are risks of ATRs on the first transfusion as well as transfusions of patients with transfusion history.

Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP), a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-α and IFN-γ, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type.

The artificial spawning material in which Japanese sandfish lays eggs was developed. The 1st purpose is development of the mitigation technology which complements a spawning function until natural seaweed is reproduced. The breakwater to which Japanese sandfish is laying eggs in the present at Tomakomai Higashi port will be moved in the future. The 2nd purpose is the technical development for adding the function of seaweed to a coast structure in the deep place of depth of water where natural seaweed cannot grow.The quality of the material is polypropylene of specific gravity 0.18. Therefore, it stands straight underwater by buoyancy. Although the form referred to the seaweed, the number of branches and the number of roots were made several times more than natural seaweed.Japanese sandfish laid eggs to all of the artificial spawning material installed in 2000.

In repetitive measurements of flow-mediated dilatation (FMD), the duration of the interval between measurements remains controversial. In this pilot study, we conducted three sequential measurements of low-flow-mediated constriction (L-FMC), FMD and flow-mediated total dilation (FMTD; L-FMC+ FMD) at baseline and intervals of 15 and 60 min in 30 healthy males. FMD15, L-FMC15, and FMTD15 were significantly lower than the respective first measurements, but all indices showed full recovery at 60 min in all subjects. The baseline diameter was slightly increased at 15 min and restored at 60 min, but the maximum diameter, and the baseline and reactive flow velocity unchanged. We examined the relationship between recovery rate of FMTD at 15 min (FMTD-R) and cardio-ankle vascular index (CAVI). Univariate analysis showed moderate correlation between FMTD-R, and CAVI and L-FMC0. Patients were divided according to FMTD-R value; the low-FMTD-R group [below the median value (-26.2%)] included a significantly higher proportion of smokers and higher CAVI values than the high-FMTD-R group. The reproducibility of FMTD and FMTD-R was evaluated in another group of 25 healthy subjects. The range of variation across measurements was 1.1% for FMTD and 4.6% for FMTD-R; with intraclass correlation coefficients of 0.93 and 0.95, respectively. The present study demonstrated blunted recovery of FMD within 15 min, suggesting the need for selection of a more adequate interval between measurements to avoid underestimation of FMD in subsequent measurements. The findings demonstrated the reproducibility of FMTD-R and FMTD measurements, and that FMTD-R might be involved in arterial stiffness and early vascular impairment in the healthy subjects.

A modified PID controller which feeds a saturated position error feeedback instead of proportional one guarantees the global asymptotic stability for setpoint position control. For this controller, this paper proposes an H∞ tuning method to realize the disturbance attenuation against unknown torque disturbances at each joint. In its stability analysis, the following facts are shown, 1)global asymptotic stability of the closed loop system and disturbance attenuation are feasible easily by taking account of physical properties of robot dynamics 2)disturbance attenuation with arbitrary gain can be established independently of the asymptotic stability. 3)as to robot dynamics, the storage function should be taken as a total internal energy and if the total internal energy is chosen as the storage function, the robot system has the KYP property which connects the passivity concept and dissipativity concept.