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Background: Lymphocytes are closely linked to mechanisms of action of immuno-oncology (IO) agents. We aimed to assess the prognostic significance of absolute lymphocyte count (ALC) in patients with metastatic renal cell carcinoma (mRCC)., Patients and Methods: Using the International mRCC Database Consortium (IMDC), patients receiving first-line IO-based combination therapy were analysed. Baseline patient characteristics, objective response rates (ORRs), time to next treatment (TTNT), and overall survival (OS) were compared., Results: Of 966 patients included, 195 (20%) had lymphopenia at baseline, and they had a lower ORR (37% versus 45%; P < 0.001), shorter TTNT (10.1 months versus 24.3 months; P < 0.001), and shorter OS (30.4 months versus 48.2 months; P < 0.001). Among 125 patients with lymphopenia at baseline, 52 (42%) experienced ALC recovery at 3 months, and they had longer OS (not reached versus 30.4 months; P = 0.012). On multivariable analysis for OS, lymphopenia was an independent adverse prognostic factor (hazard ratio 1.68; P < 0.001). Incorporation of lymphopenia into the IMDC criteria improved OS prediction accuracy (C-index from 0.688 to 0.707)., Conclusions: Lymphopenia was observed in one-fifth of treatment-naive patients with mRCC and may serve as an indicator of unfavourable oncologic outcomes in the contemporary IO era., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Topological data analysis (TDA) can generate patient-patient similarity networks by analyzing large, complex data and derive new insights that may not be possible with standard statistics., Objectives: The purpose of this paper was to discover novel phenotypes of chronic primary mitral regurgitation (MR) patients and to analyze their clinical implications using network analysis of echocardiographic data., Methods: Patients with chronic moderate to severe primary MR were prospectively enrolled from 11 Asian tertiary hospitals (n = 850; mean age 56.9 ± 14.2 years, 57.9% men). We performed TDA to generate network models using 14 demographic and echocardiographic variables. The patients were grouped by phenotypes in the network, and the prognosis was compared by groups., Results: The network model by TDA revealed 3 distinct phenogroups. Group A was the youngest with fewer comorbidities but increased left ventricular (LV) end-systolic volume, representing compensatory LV dilation commonly seen in chronic primary MR. Group B was the oldest with high blood pressure and a predominant diastolic dysfunction but relatively preserved LV size, an unnoticed phenotype in chronic primary MR. Group C showed advanced LV remodeling with impaired systolic, diastolic function, and LV dilation, indicating advanced chronic primary MR. During follow-up (median 3.5 years), 60 patients received surgery for symptomatic MR or died of cardiovascular causes. Kaplan-Meier curves demonstrated that although group C had the worst clinical outcome (P < 0.001), group B, characterized by diastolic dysfunction, had an event-free survival comparable to group A despite preserved LV chamber size. The grouping information by the network model was an independent predictor for the composite of MR surgery or cardiovascular death (adjusted HR: 1.918; 95% CI: 1.257-2.927; P = 0.003)., Conclusions: The patient-patient similarity network by TDA visualized diverse remodeling patterns in chronic primary MR and revealed distinct phenotypes not emphasized currently. Importantly, diastolic dysfunction deserves equal attention when understanding the clinical presentation of chronic primary MR., Competing Interests: Funding Support and Author Disclosures This work was supported by grants from the National Research Foundation of Korea; a grant funded by the Korean government (Ministry of Science and ICT) (No. 2019R1A2C2084099); and the Seoul National University Hospital research fund (03-2020-0430). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Limited data exist on the clinical effectiveness of second-line (2L) vascular endothelial growth factor (receptor) targeted inhibitor (VEGF(R)i) sunitinib after first-line (1L) immuno-oncology (IO) therapy for patients with metastatic renal cell carcinoma (mRCC) in real-world settings., Methods: A retrospective cohort study among adult patients with mRCC treated with 2L sunitinib following 1L IO was conducted from select International mRCC Database Consortium (IMDC) centers. All analyses were performed overall and by 1L ipilimumab + nivolumab (IPI+NIVO) or 1L IO+VEGF(R)i. Median overall survival (mOS) and time-to-treatment discontinuation (mTTD) in 2L were estimated using Kaplan-Meier analysis. The 2L objective response rate (ORR) (complete/partial response) was reported., Results: Among 102 patients on 2L sunitinib, mean age was 61.3 years. IMDC risk scores at 2L initiation was available for 83 patients: 8 (9.6%) were favorable, 45 (54.2%) were intermediate, and 30 (36.1%) were poor risk. The 1L consisted of IPI+NIVO in 62 (60.8%), IO+VEGF(R)i therapy in 27 (26.5%), and IO monotherapy in 13 (12.7%) patients. Among all patients, mOS was 15.6 months (95% confidence interval [CI], 9.8-21.7), with a 1-year OS rate of 57.5% (95% CI, 45.2-68.0). mTTD was 5.4 months (95% CI, 4.2-7.2) and ORR was 22.5%., Conclusion: Despite availability of effective 1L therapies in recent years, 2L sunitinib continues to have clinical activity after failure of 1L IO. Further studies on optimal treatment sequencing after 1L IO progression are needed., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

An association between the development of overall or specific immune-related adverse events (irAEs) and outcomes of immune checkpoint inhibitors has recently been suggested. To address this emerging association in patients with urothelial cancer receiving pembrolizumab, we conducted a multicenter retrospective analysis, which is the first and largest in an Asian cohort as well as a systematic literature review. We retrospectively evaluated 97 patients with advanced urothelial cancer treated with pembrolizumab as second- or later-line treatment between January 2018 and March 2019. irAEs were categorized by the involved organs and graded using Common Terminology Criteria for Adverse Events version 5.0. Associations between irAEs and pembrolizumab efficacy, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), were evaluated. In our review of the literature, 28 studies, including 9 studies involving patients with urothelial cancer and 19 studies reporting the association between outcomes and spectrum of irAEs, were analyzed. Patients with irAEs had significantly higher ORR (52% vs. 16%, P < .01), longer PFS (11.0 months vs. 3.6 months, P < .01) and OS (median not reached vs. 13.1 months, P = .12) than in patients without irAEs. Endocrine (P = .02), pneumological (P = .06), and other (gastrointestinal, hematological, hepatic) (P = .04) irAEs were associated with increased ORR, whereas skin irAEs were not. Endocrine irAEs (P = .04) was associated with improved OS, whereas pneumological and skin irAEs were not. The association between the occurrence of irAEs and clinical efficacy of immune checkpoint inhibitors was consistently supported by the multiple studies we reviewed. The association between clinical outcomes and the spectrum of organs/systems affected by irAEs seems to be inconsistent and could be dependent on tumor type. irAEs were associated with a higher ORR and better survival of patients with advanced urothelial cancer treated with pembrolizumab., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Older adults with metastatic renal cell carcinoma(mRCC) are underrepresented in immune-checkpoint inhibitor(ICI) registration trials. Here we compare the efficacy of ICI treatments in older vs. younger adults with mRCC., Methods: Using the International mRCC Database Consortium(IMDC), patients treated with a PD(L)-1 based ICI were identified. Older adult was defined as ≥70-years at the time of treatment. Descriptive statistics were summarized in means, medians, and proportions. Effectiveness endpoints included overall survival (OS), time-to-treatment failure(TTF), time-to-next treatment(TNT), and overall response rate(ORR). Hazards ratios were adjusted(aHR) for IMDC risk factors, histology, line of treatment and older age., Results: Of 1427 included patients, 397(28%) were older adults. ICI was used as 1st line(1 L) in 40%, 2nd line(2 L) in 49% and 3rd line(3 L) in 11% of patients. In univariable analysis, older adults had inferior OS compared to younger adults(25.1 m vs. 30.8 m, p < 0.01). There were no significant differences in TTF (6.9 m vs. 6.9 m, p = 0.4) or TNT(9.1 m vs 10 m, p = 0.3) between groups. In multivariable analyses, older age was not independently associated with worse OS(aHR = 1.02, p = 0.8), TTF(aHR = 0.95, p = 0.6) or TNT(aHR = 0.93, p = 0.5). Older adults had a lower ORR compared to younger adults(24% vs. 31%, p = 0.01), which was mainly driven by responses in 1 L(31% vs. 44%, p = 0.02) and not observed in 2 L/3 L., Conclusions: After multivariable analyses, older adults with mRCC treated with ICI had no difference in OS, TTF or TNT when compared to younger adults. Our data support that chronological older age should not preclude patients from receiving ICI based therapies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The modified Glasgow prognostic score (mGPS), which incorporates serum albumin and C-reactive protein levels, reflects systemic inflammation and nutritional status. In this study, we evaluate the role of mGPS as a predictor of prognosis in metastatic renal cell carcinoma treated with nivolumab., Patients and Methods: Forty-five consecutive patients with metastatic renal cell carcinoma receiving nivolumab therapy after tyrosine kinase inhibitor therapy between September 2013 and August 2019 at our institution were retrospectively analyzed. The prognostic factors associated with overall survival were statistically analyzed., Results: The median follow-up period was 26.4 months. The median progression-free survival and 1- and 3-year progression-free survival rates were 11.6 months, 48.9%, and 17.1%, respectively. The median overall survival and 1- and 3-year overall survival rates were not reached, 88.7%, and 62.3%, respectively. In multivariate analysis, mGPS at the time of nivolumab administration (P < .0001; hazard ratio [HR], 95.7; P = .0004 [Score 1 vs. 0]; HR, 98.9; P = .0002 [Score 2 vs. 0]; and HR, 1.03; P = .971 [Score 2 vs. 1]) was extracted as the strongest predictor for overall survival followed by duration from diagnosis to treatment (P = .0001), lactate dehydrogenase (P = .0005), and lymphocyte count (P = .021). Overall survival curves were distinctly separated between mGPS Score 0 and mGPS Score 1 + 2, with median overall survival periods being not reached and 32.4 months, respectively (P = .0004)., Conclusions: mGPS was the strongest significant prognostic biomarker in patients with metastatic renal cell carcinoma treated with nivolumab. This simple classification could be useful in clinical practice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Second-line salvage therapy for patients with metastatic germ-cell cancer (GCC) after the first-line combination of VIP (etoposide, ifosfamide, cisplatin) therapy has not been established. This study evaluated the efficacy and tolerability of the TGP (paclitaxel, gemcitabine, cisplatin) combination chemotherapy as a second-line salvage therapy., Patients and Methods: The medical records of 16 consecutive patients with metastatic GCC who had been treated with first-line VIP therapy followed by second-line TGP therapy between 2005 and 2019 were reviewed and statistically analyzed. Ten patients, excluding the 6 patients treated with TGP without unequivocal progression, were included in the efficacy analysis. All 16 patients were included in the safety analysis., Results: The median follow-up period from initial TGP administration was 78 months (interquartile range, 46-120 months). The estimated 5-year progression-free and overall survival rates for the 10 patients in the efficacy analysis were 70% and 100%, respectively. Grade 3/4 hematologic toxicity occurred in all 16 patients, but none developed uncontrollable infections or life-threatening bleeding. One patient died of treatment-related secondary leukemia, however., Conclusion: The present study is to our knowledge the first to examine the therapeutic outcomes and safety profile of second-line TGP chemotherapy. VIP followed by TGP might be an alternative first- and second-line conventional regimen for patients with metastatic GCC in this granulocyte colony-stimulating factor era, especially for patients at a high risk of bleomycin-induced pulmonary toxicity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: We think that it is necessary to evaluate whether the patient after total hip arthroplasty has achieved age-appropriate locomotor ability by improvement in hip joint function. The 25-question Geriatric Locomotive Function Scale (GLFS-25) have been determined age-specific standard values for the general population. The aim of this study was to compare postoperative hip muscle strength and functional performance at 3 months after THA with preoperative levels, and to compare the outcomes at 3 months after THA with the function of age-matched adults without hip disease., Methods: The GLFS-25 scores and muscle strength were investigated before THA and 3 months after surgery in 12 men and 75 women who underwent total hip arthroplasty., Results: The mean preoperative and postoperative GLFS-25 score was 55.4 and 19.1, respectively. With regard to the influence of age, the mean scores before and after THA were respectively 52.0 versus 18.2 for patients aged 60-69 years and 61.2 versus 17.3 for those aged 70-79 years in the normal/mild OA group. When female patients from the normal/mild OA group and the implant group classified into levels 4-7 after THA were combined (n = 15), their mean preoperative and postoperative straight leg raising (SLR) strength was 0.56 Nm/kg and 0.75 Nm/kg, respectively. On the other hand, the mean preoperative and postoperative SLR strength was respectively 0.54 Nm/kg and 0.86 Nm/kg for patients classified into levels 1-3 after THA (n = 45)., Conclusion: Before THA, 90% of the patients who has severe hip disturbance were in need of nursing care (levels 4-7), while the percentage decreased to 30% after surgery. There was a difference of SLR muscle strength between the patients in levels 4-7 and those in levels 1-3 after THA, suggesting that achieving levels 1-3 postoperatively might depend on whether SLR muscle strength shows improvement., (Copyright © 2018. Published by Elsevier B.V.)

Synchrotron-based XRD spectra from rat bone of different age groups (w, 56 w and 78w), lumber vertebra at early stages of bone formation, Calcium hydroxyapatite (HAp) [Ca 10 (PO 4 ) 6 (OH) 2 ] bone fill with varying composition (60% and 70%) and bone cream (35-48%), has been acquired with 15keV synchrotron X-rays. Experiments were performed at Desy, Hamburg, Germany, utilizing the Resonant and Diffraction beamline (P9), with 15keV X-rays (λ=0.82666 A 0 ). Diffraction data were quantitatively analyzed using the Rietveld refinement approach, which allowed us to characterize the structure of these samples in their early stages. Hydroxyapatite, received considerable attention in medical and materials sciences, since these materials are the hard tissues, such as bone and teeth. Higher bioactivity of these samples gained reasonable interest for biological application and for bone tissue repair in oral surgery and orthopedics. The results obtained from these samples, such as phase data, crystalline size of the phases, as well as the degree of crystallinity, confirm the apatite family crystallizing in a hexagonal system, space group P6 3 /m with the lattice parameters of a=9.4328Å and c=6.8842Å (JCPDS card #09-0432). Synchrotron-based XRD patterns are relatively sharp and well resolved and can be attributed to the hexagonal crystal form of hydroxyapatite. All the samples were examined with scanning electron microscope at an accelerating voltage of 15kV. The presence of large globules of different sizes is observed, in small age groups of the rat bone (8w) and lumber vertebra (LV), as distinguished from, large age groups (56 and 78w) in all samples with different magnification, reflects an amorphous phase without significant traces of crystalline phases. Scanning electron microscopy (SEM) was used to characterize the morphology and crystalline properties of Hap, for all the samples, from 2 to 100μm resolution., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Diagnosis and treatment of bone metastasis requires various types of measures, specialists and caregivers. To provide better diagnosis and treatment, a multidisciplinary team approach is required. The members of this multidisciplinary team include doctors of primary cancers, radiologists, pathologists, orthopaedists, radiotherapists, clinical oncologists, palliative caregivers, rehabilitation doctors, dentists, nurses, pharmacists, physical therapists, occupational therapists, medical social workers, etc. Medical evidence was extracted from published articles describing meta-analyses or randomised controlled trials concerning patients with bone metastases mainly from 2003 to 2013, and a guideline was developed according to the Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Multidisciplinary team meetings are helpful in diagnosis and treatment. Clinical benefits such as physical or psychological palliation obtained using the multidisciplinary team approaches are apparent. We established a guideline describing each specialty field, to improve understanding of the different fields among the specialists, who can further provide appropriate treatment, and to improve patients' outcomes., Competing Interests: S Kato, sponsored research (Chugai Pharmaceutical Co, Ltd); IO, honoraria (Taiho Pharmaceutical Co, Ltd); S Kinuya, data and safety monitoring board (Bayer Yakuhin, Ltd); NS, honoraria (Novartis Pharma); ST, honoraria (Astellas Pharma Inc, AstraZeneca plc, Daiichi Sankyo Co, Ltd, Novartis Pharma), sponsored research (Sanofi, Zenyaku Kogyo Co, Ltd, Taiho Pharmaceutical Co, Ltd, Boehringer Ingelheim Japan, Chugai Pharmaceutical Co, Ltd, Novartis Pharma); YT, honoraria (Janssen Pharma); K Takayama20, consultation and honoraria (Clinical Research Support Center Kyushu, AstraZeneca plc, Chugai Pharmaceutical Co, Ltd, Eli Lilly Japan, PfizerJapan Inc), sponsored research (Kyowa Hakko Kirin Co, Ltd, plc, Daiichi Sankyo Co, Ltd, Chugai Pharmaceutical Co, Ltd, Eli Lilly Japan, Novartis Pharma, Bristol-Myers Squibb); UT, consultation and honoraria (Micron Inc, SymBio Pharmaceutical Co, Ltd, Chugai Pharmaceutical Co, Ltd, Nihon Medi-Physics Co, Ltd); HM, sponsored research (Eisai Co, Ltd, Taiho Pharmaceutical Co, Ltd); T Yuasa, honoraria (Novartis Pharma, PfizerJapan Inc).

Background: Sarcomatoid renal cell carcinoma is associated with poor prognosis. Data regarding outcome in the targeted therapy era are lacking., Patients and Methods: Clinical, prognostic, and treatment parameters in metastatic renal cell carcinoma patients with and without sarcomatoid histology treated with targeted therapy were retrospectively analyzed., Results: Two thousand two hundred eighty-six patients were identified (sRCC: n = 230 and non-sRCC: n = 2056). sRCC patients had significantly worse IMDC prognostic criteria compared with non-sRCC (11% vs. 19% favorable risk; 49% vs. 57% intermediate risk, and 40% vs. 24% poor risk; P < .0001). Time from original diagnosis to relapse (excluding synchronous metastatic disease) was shorter in the sRCC group (18.8 vs. 42.9 months; P < .0001). There was no significant difference in the incidence of central nervous system metastases (6%-8%) or underlying clear cell histology (87%-88%). More than 93% of patients received VEGF inhibitors as first-line therapy; objective response was less common in sRCC whereas primary refractory disease was more common (21% vs. 26% and 43% vs. 21%; P < .0001, for both). sRCC patients had significantly less use of second- (P = .018) and third-line (P < .0001) systemic therapy. The median progression-free survival (PFS)/overall survival (OS) was 4.5/10.4 months in sRCC patients and 7.8/22.5 months in non-sRCC patients (P < .0001 for both). Sarcomatoid histology was associated with a significantly worse PFS and OS after adjusting for individual IMDC risk factors in multivariable analysis (hazard ratio, 1.5; P < .0001 for both)., Conclusion: Patients with sRCC have a shorter time to relapse, worse baseline prognostic criteria, and worse clinical outcome with targeted therapy. Additional insight into the biology of sRCC is needed to develop alternative therapeutics., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Targeted therapies improve survival in metastatic renal cell carcinoma (mRCC). However, survival patterns can be divergent, and patients at the 2 extremes of the survival spectrum need to be characterized., Patients and Methods: Data from 2161 patients included in the International mRCC Database Consortium (IMDC) were analyzed. We identified patients on the basis of their duration of survival. Long-term survival (LTS) was defined as overall survival (OS) of ≥ 4 years, and short-term survival (STS) was defined as OS of ≤ 6 months from the start of targeted therapy. Baseline characteristics, including demographic, clinicopathologic, and laboratory data, were compared between LTS and STS. Treatment response by the RECIST criteria was summarized for the 2 survival groups., Results: A total of 152 patients experienced LTS and 218 experienced STS. Adverse clinical and laboratory prognostic factors previously described in the IMDC prognostic model were significantly more frequent in the STS group (P < .0001). In the LTS group, 138 patients (91%) had nonprogressive disease (non-PD) as best response to first-line targeted therapy, and 56 (60%) of 94 patients who received second-line therapy had non-PD. In the STS group, only 51 patients (23%) had non-PD on first-line therapy. None of 21 the patients who received second-line therapy had non-PD as best response. In LTS, the median duration of therapy was 23.6 months (range 0.4 to 81.8+ months) for first-line therapy and 11.5 months (range 0.6 to 45.7 months) for second-line therapy, compared to 2.0 and 0.8 months for the STS group, respectively., Conclusion: Baseline prognostic criteria and absence of PD after first and second-line targeted therapy may characterize long-term survival., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction/background: Approval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting., Patients and Methods: We performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS)., Results: We identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients., Conclusion: Poor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Soluble insulin receptor (sIR), the ectodomain of IR, has been detected in human plasma, and its concentration parallels that of blood glucose in patients with diabetes. IR has a pivotal role in glucose homeostasis and diabetes development; therefore, cleavage of IR promoted by hyperglycemia is involved in insulin resistance and glucose toxicity. To elucidate the physiology of sIR, we developed an in vitro model mimicking the changes in sIR levels in plasma from patients with diabetes. Among four human cell lines that expressed IR, spontaneous cleavage of IR occurred only in HepG2 cells. The molecular characteristics of sIR derived from HepG2 cells were similar to those of sIR detected in human plasma. The concentration of sIR in the medium did not differ between basal and high-glucose conditions in the initial 24-h period, but increasing the duration of pre-stimulation (>48 h) led to a significant increase in sIR levels in cells exposed to high glucose. Additionally, glucose-dependent increment of sIR was reversible in this model. These results are consistent with the observation of plasma sIR in patients with diabetes. Using this model, O-linked N-acetylglucosamine modification was determined to be involved in high-glucose-induced IR cleavage. A calcium-dependent protease was shown to cleave IR extracellularly. These findings show that this in vitro model could be useful for determining the molecular mechanism underlying IR cleavage., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: This study sought to examine the combination chemotherapy of gemcitabine, etoposide, and cisplatin (GEP) as a first-line treatment for advanced urothelial carcinoma (UC) to assess its antitumor activity and toxicity., Methods and Materials: Eligible patients with advanced UC had undergone no previous chemotherapy. Advanced UC was defined as unresectable or metastatic disease. Subsequent recurrent disease, either locally or distantly following primary radical surgery, was not excluded. GEP was recycled every 4 weeks. Etoposide and cisplatin were given on days 1 through 3 at doses of 60 mg/m(2) and 20mg/m(2), respectively, and gemcitabine was given on days 1, 8, and 15 at a dose of 800 mg/m(2). The primary end point was objective response rate, and the secondary end points included progression-free survival, overall survival (OS), and toxicity., Results: Forty-two patients were enrolled and subsequently treated with GEP. Nineteen had visceral/bone metastases, 16 had disease restricted to the lymph nodes, and the remaining 7 had unresectable disease at the primary site. The median number of GEP courses was 4. Thirty of the 42 assessable patients (71.4%, 95% confidence interval [CI]: 56.4%-82.8%) demonstrated objective responses. At a median follow-up of 14.6 months, median progression-free survival and OS periods were 8.7 months (95% CI: 6.9-14.6 mo) and 16.2 months (95% CI: 13.1-25.4 mo), respectively. In the multivariate analysis, anemia and visceral/bone metastasis were significant pretreatment prognostic factors for OS. Grade 4 hematologic events were neutropenia (83.3%), thrombocytopenia (23.8%), and anemia (7.1%). There were no toxic deaths and no instances of severe nonhematologic toxicity., Conclusions: GEP as a first-line chemotherapy treatment was very active and moderately tolerable for advanced UC. Anemia and visceral/bone metastasis were important negative predictive factors of GEP for OS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown., Patients and Methods: mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3)., Results: Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001)., Conclusions: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

Idiopathic normal pressure hydrocephalus (iNPH) is an elderly dementia caused by abnormal metabolism in the cerebrospinal fluid (CSF). The tap test is the current basis for confirming iNPH, but it shows very low sensitivity, indicating that many patients who might be cured by a shunt operation will be missed. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we found two transferrin isoforms: one had a unique N-glycan (Tf-1) whereas the other had N-glycan similar to that of serum transferrin (Tf-2). Glycan analyses revealed that Tf-1 had branching (biantennary) asialo- and agalacto-complex type N-glycans (N-acetylglucosamine [GlcNAc]-terminated glycans), which carried bisecting β1,4-N-acetylglucosamine and core α1,6-fucose. To examine glycoform whether changes in iNPH, we introduced the Tf-2/Tf-1 ratio as a diagnostic index, which minimized blot-to-blot variations in measurement. The Tf-2/Tf-1 ratios of iNPH patients are significantly higher than those of controls (p = 0.0019) and Alzheimer's patients (p = 0.0010). This suggests that the Tf-2/Tf-1 ratio could distinguish iNPH from Alzheimer's disease, and possibly other dementias. In conclusion, glycoform analysis has diagnostic potential in neurological diseases., (Copyright © 2012. Published by Elsevier Inc.)

Background: Circulating cardiac troponin T is a marker of cardiomyocyte injury, and predicts adverse outcomes in patients with chronic heart failure. However, the significance of highly sensitive cardiac troponin T (hs-TnT) in cardiac dysfunction remains uncertain. The purpose of this study is to evaluate the correlation between hs-TnT and echocardiographic parameters or natriuretic peptides in patients with heart failure., Methods and Results: We analyzed 283 consecutive out- or in-patients who had B-type natriuretic peptide (BNP) ≥20 pg/mL and were examined by echocardiography (mean age 66.5±13.9 years old; 159 males). Hs-TnT, BNP, N-terminal pro-BNP (NT-proBNP), and creatinine levels were measured simultaneously. LVEDD (left ventricular end-diastolic dimension), LVEF (left ventricular ejection fraction), E', E/E', left ventricular (LV) Tei index, and right ventricular (RV) Tei index were determined with echocardiography. The linear regression analyses demonstrated that loghs-TnT correlated with LVEDD (R=0.242, p<0.0001), LVEF (R=-0.369, p<0.0001), E' (R=-0.447, p<0.0001), E/E' (R=0.364, p<0.0001), LV Tei index (R=0.303, p<0.0001), RV Tei index (R=0.443, p<0.0001), and estimated glomerular filtration rate (eGFR) (R=-0.489, p<0.0001). Using multiple variable regression analysis, loghs-TnT independently correlated with LVEF, E/E', RV Tei index, and eGFR. Furthermore, loghs-TnT significantly correlated with logBNP (R=0.567, p<0.0001) or logNT-proBNP (R=0.647, p<0.0001). Multiple variable regression analysis demonstrated that loghs-TnT independently correlated with logBNP, age, and eGFR, or with logNT-proBNP, age, sex, and eGFR., Conclusions: The hs-TnT correlated with cardiac dysfunction evaluated by echocardiography and natriuretic peptides in patients with heart failure. The elevation of hs-TnT levels in heart failure may represent cardiac dysfunction due to minor and ongoing myocardial injury., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Introduction: Effects of sodium fluoride (NaF) mouth rinse solutions on torsional properties of a miniscrew implant were investigated., Methods: As-received Ti-6Al-4V miniscrew implants (AbsoAnchor [Dentos, Inc., Daigu, Korea]) were immersed in 0.1% or 0.2% NaF mouth rinse solution (pH 5.12 and 5.14, respectively) for 1 hour or 24 hours. Miniscrew implants selected as controls were not immersed. Each implant was subjected to increasing torque until fracture (n = 5 in sample groups). Mean moment and twist angle for fracture were compared using 1-way analysis of variance (ANOVA). Surfaces of implants after immersion were observed with a scanning electron microscope (SEM). Electron microprobe and micro-x-ray diffraction analyses were performed to obtain composition information about deposits on implant surfaces., Results: Pits and cracks formed on the implant surfaces after immersion in both NaF mouth rinse solutions. Corrosion products, probably sodium aluminum fluoride (Na(3)AlF(6)), were observed on the implants after immersion in both NaF solutions for both time periods. There were no significant differences for mean torque (P = 0.063) and twist angle (P = 0.696) at fracture compared with control implants., Conclusions: Although titanium alloy miniscrew implants corroded slightly from immersion in 0.1% or 0.2% NaF solutions, mouth rinsing by patients with the same fluoride solution concentrations should not cause deterioration of their torsional performance., (Copyright © 2011 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

Introduction: Despite the clinical adoption of distraction osteogenesis (DO), studies examining the bone healing process at the distraction gap in osteoporotic bone are limited. We examined the effect of osteoporosis in the ovariectomized rat on DO., Material and Methods: Mid-diaphyseal osteotomies were performed on the femurs of ovariectomized (OVX) rats. External distractors were placed on these rats and also on sham-ovariectomized rats. After a 7-day latency period, distraction was carried out at a rate of 0.5mm/day for 10 days. The bone volume (BV) of the distraction gap was measured by Micro-focused X-ray computed tomography (micro-CT) at 0, 2, and 4 weeks after completion of the distraction, and the distraction gap was examined histologically., Results: The BV of the distraction gap in the OVX group was significantly lower than that in the sham group at 2 and 4 weeks after completion of distraction (p<0.01). On histological examination, the distraction gap in the OVX group was filled with scattered smaller bone trabeculae than those seen in the sham group at 4 weeks after completion of distraction. Osteoclast numbers at the distraction gap in the OVX group were significantly increased when compared to the sham group (p<0.01)., Conclusion: Bone turnover with osteoclast predominance in ovariectomized rats is likely to be the cause of a reduction in new bone formation at the distraction gap., (Copyright © 2010 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Introduction: In this study, we investigated the nanohardness and elastic modulus of enamel after debonding metal brackets., Methods: The surfaces of 3 maxillary premolars were subdivided into 3 regions. Two regions were exposed to a conventional etching system (Transbond XT, 3M Unitek, Monrovia, Calif) and a self-etching system (Transbond Plus primer, 3M Unitek); the third region was not etched. Metal brackets were bonded with Transbond XT composite to the 2 etched regions. After storage for 24 hours in distilled water, the brackets and residual adhesive were removed, and the teeth were sectioned transversely. Seven nanoindentations (2 mN load) were placed 1 to 25 μm from the surface in each region. Mean nanohardness and elastic modulus were compared with analysis of variance (ANOVA) and the Scheffé test., Results: Locations 1 and 5 μm from the enamel surface had significantly (P < 0.05) lower nanohardness and elastic modulus values for the conventional system compared with the self-etching system and the unetched region. All other locations for the conventional system and all locations for the self-etching system and unetched area had no significant differences. The nanohardness was much higher than the Vickers hardness for enamel., Conclusions: The minimal effect of the self-etching system on the nanomechanical properties of enamel arises from much lower chemical attack. The much greater effects of the conventional system require further study., (Copyright © 2010 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

Introduction: The purpose of this study was to investigate the effect of filler properties on the grindability of composite resin adhesives., Methods: Six composite resin products were selected: Transbond XT (3M Unitek, Monrovia, Calif), Transbond Plus (3M Unitek), Enlight (Ormco, Glendora, Calif), Kurasper F (Kuraray Medical, Tokyo, Japan), Beauty Ortho Bond (Shofu, Kyoto, Japan), and Beauty Ortho Bond Salivatect (Shofu). Compositions and weight fractions of fillers were determined by x-ray fluorescence analysis and ash test, respectively. The polished surface of each resin specimen was examined with a scanning electron microscope. Vickers hardness of plate specimens (15 × 10 × 3 mm) was measured, and nano-indentation was performed on large filler particles (>10 μm). Grindability for a low-speed tungsten-carbide bur was estimated. Data were compared with anlaysis of variance (ANOVA) and the Tukey multiple range test. Relationships among grindability, filler content, filler nano-indentation hardness (nano-hardness), filler elastic modulus, and Vickers hardness of the composite resins were investigated with the Pearson correlation coefficient test., Results: Morphology and filler size of these adhesives showed great variations. The products could be divided into 2 groups, based on composition, which affected grindability. Vickers hardness of the adhesives did not correlate (r = 0.140) with filler nano-hardness, which showed a significant negative correlation (r = -0.664) with grindability., Conclusions: Filler nano-hardness greatly influences the grindability of composite resin adhesives., (Copyright © 2010 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

Background: Previous studies showed that some parameters, including left atrium diameter and left atrium volume index (LAVI), predicted the success of sinus conversion. However, no previous studies have investigated the association of sinus conversion with LAVI and histopathological findings. This study was designed to investigate the relationship among LAVI, pathological assessment, and failure in sinus conversion after surgery for valvular atrial fibrillation (AF)., Methods and Results: A total of 78 patients with left atrium enlargement and valvular AF who underwent maze procedure concomitantly with various cardiac surgeries were classified into one of two groups: those who successfully underwent sinus conversion (Group 1; n=40) and those who did not achieve sinus conversion (Group 2; n=38). Histopathological assessment was performed in 9 cases using tissues derived from the left atrial appendage (LAA). The degree of histopathological change was classified into 1 of 4 grades. LAVI was significantly less in Group 1 than in Group 2 (81 + or - 22 ml/m(2) vs. 122 + or - 49 ml/m(2), p<0.001). Preoperative LAVI predicted 100% failure of sinus conversion after surgery with a cut-off value of 135 ml/m(2). Histopathological analyses clearly showed that the grades for intercellular fibrosis, fatty infiltration, endocardial thickening, and nuclear enlargement/abnormalities were significantly and positively correlated with LAVI (r=0.75, p<0.05; r=0.74, p<0.05; r=0.69, p<0.05; r=0.77, p<0.05, respectively)., Conclusions: LAVI associated with histopathological features of the resected LAA is a predictor of failure in sinus conversion following surgical intervention in patients with valvular AF., (Copyright 2009 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Wnt/beta-catenin signaling is required for skeletal development and organization and for function of the growth plate and articular cartilage. To further clarify these roles and their possible pathophysiological importance, we created a new transgenic mouse model in which Wnt/beta-catenin signaling can be activated in cartilage for specific periods of time. These transgenic mice expressed a constitutive active form of beta-catenin fused to a modified estrogen receptor ligand-binding domain under the control of cartilage-specific collagen 11alpha2 promoter/enhancer. Transient Wnt/beta-catenin signaling activation in young adult mice by tamoxifen injections induced growth retardation and severe deformities in knee joints. Tibial and femoral growth plates displayed an excessive number of apoptotic cells and eventually underwent abnormal regression. Articular cartilage exhibited an initial acute loss of proteoglycan matrix that was followed by increases in thickness, cell density, and cell proliferation. In reciprocal studies, we found that conditional ablation of beta-catenin in postnatal mice using a Col2-CreER strategy led to hypocellularity in articular cartilage, growth plate disorganization, and a severe reduction in bone volume. Together, these data provide evidence that Wnt/beta-catenin signaling has important and distinct roles in growth plate and articular cartilage and that postnatal dysregulation of this signaling pathway causes diverse structural and functional changes in the two cartilaginous structures.

Objectives: The purpose of this study was to re-assess the left ventricular (LV) systolic function in diastolic heart failure (DHF) using Doppler echocardiography., Background: Systolic function in DHF is defined as the preserved LV ejection fraction (EF). EF may not fully reflect the systolic function in DHF, especially in the presence of abnormalities during the isovolumetric contraction time (ICT)., Methods: We examined LV systolic and diastolic function in 80 consecutive patients with DHF, 30 patients with asymptomatic diastolic dysfunction (ADD), and 30 normal subjects (Control). The LV and left atrial volumes, LV EF, LV ICT, and isovolumetric relaxation time (IRT), early diastolic mitral flow velocity, systolic mitral annular velocity (S'), and early diastolic mitral annular velocity were obtained., Results: LV ICT in DHF (69+/-30 ms) was significantly increased compared to those with ADD (37+/-23 ms) and Control (35+/-26 ms) (P<0.0001). ICT in ADD was equal to that in Control. The LV end-diastolic volume index in DHF (49+/-14 ml/m(2)) was significantly increased compared to those with ADD (42+/-12 ml/m(2)) and Control (43+/-8 ml/m(2)) (P<0.05). S' in DHF (5.9+/-1.4 cm/s) and ADD (6.7+/-1.1 cm/s) was significantly decreased compared to that in Control (8.7+/-2.5 cm/s)., Conclusions: Our results revealed that the major differences between ADD and DHF were global and longitudinal LV systolic dysfunction and LV enlargement. This study suggests that LV systolic dysfunction plays an important role in the development of DHF.

X-ray crystal interferometer-based X-ray phase-contrast microtomography (phase-contrast microtomography) is able to image microstructures within soft tissue without the use of a contrast agent. Here we determined the feasibility of using this technique in the non-destructive inspection of formalin-fixed kidney tissue from certain hamsters that spontaneously develop mesangial thickening with focal and segmental glomerulosclerosis, and from age-matched Syrian hamsters. We used a triple Laue-case X-ray interferometer with a 40 microm-thick analyzer, a sample cell, and an X-ray charge-coupled-device camera with a 4.34 microm pixel size. Images of glomeruli and tubular structures were similar to those seen using 40-100 x magnification on an optical microscope. In samples from two female glomerulosclerotic hamsters, seven scattered lesions were detected. The wedge-shaped pathological lesions included mild atrophic tubular walls, markedly dilated tubular lumen, high-density glomeruli, and widening of Bowman's space. The microvasculature was distinctly visualized in the specimens without any contrast agents. Hence, phase-contrast microtomography can detect small scattered lesions in diseased kidney tissue and is a powerful auxiliary tool for pre-histological evaluations.

Purpose: To profile the detailed clinical features of sporadic amyotrophic lateral sclerosis (ALS) on large-scale samples in Japan., Methods: We assessed the clinical features of sporadic ALS patients in Japan, based on the nationwide registration system of the Ministry of Health, Labor and Welfare of Japan. We described 3,428 new cases registered cases between 2003 and 2006 to analyze initial symptoms and related clinical features, 4,202 cases registered in the single year of 2005 to describe the cross-sectional overview of the ALS patients, and a total of 2,128 cases with tracheostomy positive pressure ventilation (TPPV) from all of the registration data from 2003 to 2006 to describe the features of ALS patients with TPPV., Results: The patients with an older age at onset progressed more rapidly to the TPPV stage than those with a younger age at onset. The subpopulation of patients with long-standing TPPV showed ophthalmoplegia, while its appearance rate was less in the patients with an older age at onset than in those with a younger age at onset. Furthermore, age at onset strongly influenced the frequency of initial symptoms: dysarthria, dysphagia, neck weakness and respiratory disturbance were more frequent in patients with an older age at onset, while upper or lower limb weakness was observed more frequently in patients with a younger age at onset. In addition, those initial symptoms were still the most prominent at the follow-up stage, suggesting that the initial symptoms determine the major clinical features even in advanced illness., Conclusions: Our present study demonstrated that symptomatic features of ALS are strongly influenced by the age at onset by the large scale of samples.

Introduction: Titanium miniscrew implants are popular in orthodontics, but there is little information about their torsional performance., Methods: Four brands of miniscrew implants (A-D) with 1.6-mm diameters were compared, with miniscrew A implants also having diameters of 1.2 to 2.0 mm. Nominal compositions of the implants were determined by x-ray fluorescence (n = 8). The miniscrews were loaded to failure in torsion, and the mean moment and twist angle were determined for each group (n = 8). Data were compared by ANOVA and the Tukey multiple range tests. Micro x-ray diffraction (n = 3) was used to identify phases in the implants, and the phases were also examined in etched cross-sections with a scanning electron microscope., Results: Miniscrew A and C implants were pure titanium, whereas miniscrew B and D implants contained small amounts of vanadium, aluminum, iron, and manganese. Only alpha-titanium peaks were detected for all implants by micro x-ray diffraction, but beta titanium was observed in the microstructures of miniscrew B and D implants, which had significantly higher torsional moments at failure., Conclusions: Addition of small amounts of other elements to titanium yielded significantly improved torsional performance for miniscrew implants. Research to develop optimum compositions for mechanical properties and biocompatibility is needed.

Background and Purpose: To evaluate intramyocardial coronary flow velocity pattern by transthoracic Doppler echocardiography and its clinical significance in patients with hypertrophic cardiomyopathy (HCM)., Methods and Results: In 48 patients with HCM who had angiographically normal coronary artery, coronary flow velocity in the left anterior descending coronary artery (LAD) and intramyocardial coronary artery (IMCA) derived from LAD were evaluated using transthoracic Doppler echocardiography. Two clearly different flow patterns in the IMCA were observed in patients with HCM. Twenty-seven HCM patients (group A) had slow deceleration slope in the IMCA flow (average diastolic deceleration time, 989+/-338; range, 585-1680) and the remaining 21 patients (group B) had steep deceleration slope with diastolic deceleration time <300 ms, resulting in a no reflow-like pattern in the IMCA flow (average diastolic deceleration time, 166+/-67; range, 55-280). There were no significant differences in the clinical characteristics and LAD flow velocity profiles between the two groups. The incidence of cardiovascular symptoms (chest pain or syncope) was significantly higher in group B than in group A (67% vs. 26%, p<0.01). Additionally, exercise-induced ischemia as detected by thallium-201 scintigraphy was significantly more frequent in group B than in group A (6 of 9 (67%) vs. 0 of 9 (0%), p<0.01)., Conclusions: Two different intramyocardial coronary flow velocity patterns are observed in patients with HCM using transthoracic Doppler echocardiography. No reflow-like pattern in the IMCA is strongly related to myocardial ischemia in the absence of epicardial coronary artery stenosis, suggesting that coronary microvascular dysfunction may be a causative mechanism.

The origin, roles and fate of progenitor cells forming synovial joints during limb skeletogenesis remain largely unclear. Here we produced prenatal and postnatal genetic cell fate-maps by mating ROSA-LacZ-reporter mice with mice expressing Cre-recombinase at prospective joint sites under the control of Gdf5 regulatory sequences (Gdf5-Cre). Reporter-expressing cells initially constituted the interzone, a compact mesenchymal structure representing the first overt sign of joint formation, and displayed a gradient-like distribution along the ventral-to-dorsal axis. The cells expressed genes such as Wnt9a, Erg and collagen IIA, remained predominant in the joint-forming sites over time, gave rise to articular cartilage, synovial lining and other joint tissues, but contributed little if any to underlying growth plate cartilage and shaft. To study their developmental properties more directly, we isolated the joint-forming cells from prospective autopod joint sites using a novel microsurgical procedure and tested them in vitro. The cells displayed a propensity to undergo chondrogenesis that was enhanced by treatment with exogenous rGdf5 but blocked by Wnt9a over-expression. To test roles for such Wnt-mediated anti-chondrogenic capacity in vivo, we created conditional mutants deficient in Wnt/beta-catenin signaling using Col2-Cre or Gdf5-Cre. Synovial joints did form in both mutants; however, the joints displayed a defective flat cell layer normally abutting the synovial cavity and expressed markedly reduced levels of lubricin. In sum, our data indicate that cells present at prospective joint sites and expressing Gdf5 constitute a distinct cohort of progenitor cells responsible for limb joint formation. The cells appear to be patterned along specific limb symmetry axes and rely on local signaling tools to make distinct contributions to joint formation.

Objectives: Evaluation of left anterior descending coronary artery (LAD) flow by transthoracic Doppler echocardiography (TTDE) may allow assessment of anastomosis of the internal mammary artery (IMA) grafted to the LAD. This study tested the feasibility of TTDE to evaluate anastomotic stenosis of the IMA grafted to the LAD., Methods: TTDE was performed in 66 patients (48 men and 18 women, mean age 67 +/- 10 years) with left or right IMA grafts to the LAD. The distal IMA flow at the anastomosis was visualized and the percentage stenosis was evaluated by the continuity equation using the anastomotic and pre-anastomotic flow velocity measured by TTDE as well as by angiography. If the anastomotic flow was not visualized by TTDE, the absence of augmented diastolic flow of the proximal IMA, by using the supraclavicular approach, with diastolic to systolic mean velocity ratio < 0.25 was considered as anastomotic occlusion., Results: Anastomotic flow was visualized and the percentage stenosis was obtained by the continuity equation in 50 patients. In 4 of the remaining 16 patients, the proximal IMA flow by TTDE showed the occlusion pattern. In these 54 (82%) patients, the percentage stenosis by TTDE showed a significant correlation with that by angiography (r2 = 0.86, p < 0.0001). In all the remaining 12 patients with the patent proximal IMA pattern but without visualized anastomotic flow, the patency was confirmed by angiography., Conclusions: TTDE enables direct visualization and quantitative evaluation of the anastomotic patency in patients with IMA graft to the LAD.

Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region-Abl (Bcr-Abl)-positive leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib. We have identified a specific dual Abl-Lyn inhibitor, NS-187 (elsewhere described as CNS-9), which is 25 to 55 times more potent than imatinib in vitro. NS-187 is also at least 10 times as effective as imatinib in suppressing the growth of Bcr-Abl-bearing tumors and markedly extends the survival of mice bearing such tumors. The inhibitory effect of NS-187 extends to 12 of 13 Bcr-Abl proteins with mutations in their kinase domain but not to T315I. NS-187 also inhibits Lyn without affecting the phosphorylation of Src, Blk, or Yes. These results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Philadelphia-positive (Ph+) leukemia.

In order to determine the effect of pimobendan on sympathetic nerve activity and cardiopulmonary baroreflex (CPB), electrocardiogram, direct arterial pressure, central venous pressure (CVP) and cardiac output were recorded along with muscle sympathetic nerve activity (MSNA) in 8 healthy young men. CPB function was evaluated before and 60 min after oral administration of 5 mg pimobendan using the response of MSNA to lower body negative pressure (LBNP) of -5 and -10 mm Hg. The same protocol also was performed during handgrip exercise. Cardiac index, MSNA increased and CVP decreased significantly (p<0.01, respectively), but arterial pressure and heart rate unchanged after pimobendan administration. During LBNP, CVP decreased and MSNA increased significantly. CPB sensitivity was augmented from 5.53+/-0.75 to 8.59+/-0.78 burst incidence/mm Hg after pimobendan administration (p<0.01). Pimobendan did not alter the percentage increase of MSNA during handgrip exercise. In conclusion, pimobendan induces an increase in basal sympathetic nerve activity by decreasing CVP and augmenting CPB sensitivity without changing arterial pressure in healthy young men.

We herein report the case of a 46 year old man with chronic inflammatory demyelinating polyneuropathy (CIDP) with hyperIgEaemia. The patient presented with bilateral weakness, generalized hyporeflexia, and mild paresthesia of the fingers of both hands. Nerve conduction studies revealed multiple sites of motor conduction block in the absence of sensory abnormalities. Muscle strength increased, as did compound muscle action potential (CMAP) amplitude immediately after the intravenous infusion of immunoglobulin (IVIg). Serum IgE levels also fluctuated in parallel with his relapsing-remitting clinical course. We propose that pure motor CIDP may be immune mediated and suggest that IgE-mediated allergy may be one potential cause of this condition.

Early-onset sarcoidosis (EOS) and inheritable Blau syndrome (BS) share characteristic clinical features of juvenile-onset systemic granulomatosis syndrome that mainly affects skin, joints, and eyes. However, no direct evidence has been shown for the possible common origin of these 2 diseases. Recent discovery of CARD15 mutations in BS families encouraged us to investigate similar CARD15 mutations in EOS patients. Among 10 EOS cases retrospectively collected in Japan, heterozygous missense mutations were found in 9 cases; 4 showed a 1000C>T (R334W in amino acid change) that has been reported in BS, 4 showed novel 1487A>T (H496L), 1538T>C (M513T), 1813A>C (T605P), and 2010C>A (N670K), and 1 case showed double 1146C>G (D382E)/1834G>A (A612T) mutations on different alleles. All 6 of these variants of CARD15 showed increased basal nuclear factor (NF)-kappaB activity. These findings indicate that the majority of EOS and BS cases share the common genetic etiology of CARD15 mutations that cause constitutive NF-kappaB activation.

Background: In failing hearts, homeostatic mechanisms contrive to maximize stroke work and maintain normal arterial blood pressure at the expense of energetic efficiency. In contrast dobutamine reestablishes maximal mechanical efficiency by promoting energetically optimal loading conditions. However, dobutamine also wastefully increases nonmechanical oxygen consumption. We investigated whether direct mechanical cardiac compression would reestablish maximal mechanical efficiency without the oxygen-wasting effect., Methods: The pressure-volume relationship and myocardial oxygen consumption were derived in sheep using left ventricular pressure and volume from manometer-tipped and conductance catheters, and coronary flow from Transonics flow probe., Results: Propranolol hydrochloride and atropine sulfate were administered to reduce ejection fraction to 21% when ventricular elastance fell to 1.35 mm Hg/mL and mechanical efficiency to 79% of maximal. Low-pressure direct mechanical compression of the failing heart restored mechanical efficiency to 94% of maximal and realigned optimal left ventricular end-systolic pressure with operating left ventricular end-systolic pressure without altering nonmechanical oxygen consumption., Conclusions: We conclude that direct cardiac compression restores mechanical efficiency to normal maximum without wasting energy on additional nonmechanical activity.

Background: This study investigates the possibility of reducing myocardial oxygen consumption by dynamic cardiomyoplasty in chronic heart failure. The sheep model used is relevant for cardiac assist using direct mechanical cardiac compression., Methods: In 7 sheep, heart failure was induced by staged intracoronary microembolization followed by dynamic cardiomyoplasty. Six months later, the effect of latissimus dorsi muscle stimulation in the 2:1 mode (on, cardiomyoplasty; off, control) was studied. Left ventricular pressure-volume loops were obtained by conductance, micromanometer, and inferior vena cava occlusion catheter. Myocardial oxygen consumption was derived from left main coronary artery blood flow and oxygen content of arterial and coronary sinus blood., Results: Cardiomyoplasty had no significant effect on left ventricular hemodynamic variables such as end-systolic pressure. However, cardiomyoplasty increased stroke volume and ejection fraction significantly by 11% +/- 12% and 11% +/- 10%, respectively. Although pressure-volume area and external work did not increase with cardiomyoplasty, myocardial oxygen consumption decreased by 21% +/- 11%. Therefore, cardiomyoplasty increased myocardial efficiency (external work/myocardial oxygen consumption) by 16% +/- 13%., Conclusions: Despite limited hemodynamic improvement from dynamic cardiac compression by cardiomyoplasty in sheep with chronic heart failure, myocardial oxygen consumption was significantly reduced. These findings provide a rationale for reverse remodeling of the failing heart using direct mechanical compression.

Background: Dynamic cardiomyoplasty (d-CMP) encourages reverse remodeling and improved contractility and stroke work (SW) efficiency of the failing native heart. This contrasts with passive cardiomyoplasty (p-CMP), which provides "passive girdling." To further evaluate pump recovery we assessed native left ventricular performance (without assist) 6 months after dynamic and passive CMP in sheep with heart failure with acute volume loading., Methods: Heart failure (left ventricular ejection fraction 26%+/-8%) induced by coronary microembolization was followed by CMP in 11 sheep. After 8 weeks of muscle "training," paced cardiac assist was undertaken in the d-CMP group (n = 6). Five sheep with heart failure served as controls. Six months later the pressure-volume relationship was derived before and after volume loading by colloid solution. Latissimus dorsi muscle pacing was previously ceased in the d-CMP group., Results: Volume loading increased left ventricular end-diastolic volume and pressure in all groups. After volume loading in d-CMP, the SW and pressure-volume area were increased, and SW efficiency remained unchanged. In p-CMP neither variable changed, whereas in control heart failure SW efficiency decreased due to a rise in pressure-volume area with stable SW., Conclusions: Based on response to volume loading, the failing native heart after 6 months of d-CMP showed functional recovery from "active girdling," whereas p-CMP prevented functional deterioration through passive girdling. The failing control heart progressively deteriorated.