Published papers

© 2016 The Author(s). Background: As a sub-analysis of the PROLOGUE study, we evaluated the long-term effect of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on endothelial function in the conduit brachial artery in patients with type 2 diabetes. Methods: In the PROLOGUE study, patients were randomly assigned to either add-on sitagliptin treatment (sitagliptin group) or continued conventional antihyperglycemic treatment (conventional group). Among the 463 participants in the PROLOGUE study, FMD was measured in 17 patients in the sitagliptin group and 18 patients in the conventional group at the beginning and after 12 and 24 months of treatment. Results: HbA1c levels were significantly decreased after 12 and 24 months of treatment compared to baseline values in both groups (7.0 ± 0.4 vs. 6.6 ± 0.3 and 6.6 ± 0.4 % in the sitagliptin group; 7.0 ± 0.6 vs. 6.6 ± 0.7 and 6.6 ± 0.7 % in the conventional group; P < 0.05, respectively). There was no significant difference between FMD values at baseline and after 12 and 24 months in the sitagliptin group (4.3 ± 2.6 vs. 4.4 ± 2.1 and 4.4 ± 2.3 %, P = 1.0, respectively). Although FMD had a tendency to increase from 4.3 ± 2.4 % at baseline to 5.2 ± 1.9 % after 12 months and 5.1 ± 2.2 % after 24 months in the conventional group, there was no significant difference between FMD values at baseline and after 12 and 24 months (P = 0.36 and 0.33, respectively). Conclusions: Add-on sitagliptin to conventional antihyperglycemic drugs in patients with type 2 diabetes did not alter endothelial function in the conduit brachial artery measured by FMD during a 2-year study period. Sitagliptin may be used without concern for an adverse effect on endothelial function in patients with type 2 diabetes. Trial registration: University hospital Medical Information Network (UMIN) Center: ID UMIN000004490

Biomedical researchers usually test the null hypothesis that there is no difference of the population mean of pharmacokinetics (PK) parameters between genotypes by the Kruskal-Wallis test. Although a monotone increasing pattern with a number of alleles is expected for PK-related genes, the Kruskal-Wallis test does not consider a monotonic response pattern. For detecting such patterns in clinical and toxicological trials, a maximum contrast method has been proposed. We show how that method can be used with pharmacogenomics data to a develop test of association. Further, using simulation studies, we compare the power of the modified maximum contrast method to those of the maximum contrast method and the Kruskal-Wallis test. On the basis of the results of those studies, we suggest rules of thumb for which statistics to use in a given situation. An application of all three methods to an actual genome-wide pharmacogenomics study illustrates the practical relevance of our discussion.

© 2017, International League of Associations for Rheumatology (ILAR). T1 rho and T2 mapping are magnetic resonance imaging (MRI) techniques to detect early degenerative changes in cartilage. Recent advancements have enabled 3D acquisition for both techniques. The objective of the present study was to examine the correlation of 3D T1 rho and 3D T2 mapping with macroscopic and histological characteristics of knee cartilage. Twenty-one patients who underwent total knee arthroplasty due to osteoarthritis with involvement of the medial compartment but with minimum involvement of the lateral compartment were enrolled. Prior to surgery, five series of MRI were acquired with a 3-T scanner. 3D T1 rho/T2 analyses were performed following determination of regions to be assessed using in-house software that incorporated three series of MRI acquisitions data (3D-MERGE, 3D-SPGR, and 3D-CUBE). During surgery, the cartilage of the lateral compartment was macroscopically assessed with the International Cartilage Research Society (ICRS) articular classification system. The extracted specimens were histologically assessed using the OARSI histology score. Three regions of interest (ROI) were assessed for each slice (two slices per knee): the central lateral femoral condyle (cLFC), the posterior portion of the lateral femoral condyle (pLFC), and the lateral tibia plateau (LTP). For each ROI, the mean T1 rho and T2 relaxation time, the ICRS grade, and the OARSI score were compared. Neither the T1 rho nor the T2 reflected the macroscopic grading. The T1 rho could discriminate between histological grades 1 and 2. However, the T2 could not. The T1 rho relaxation time was higher in the pLFC than in the cLFC even in the same grade. Compared to T2 mapping, T1 rho mapping may have an advantage in differentiating grades I and II cartilage degeneration on OARSI histological grading system.

Interindividual variation in drug response among patients is well known and poses a serious problem in medicine. The variation could be due to multiple factors including those of the host (e. g., age, genetic and environmental factors) and disease (pathophysiological phenotypes). The complex interplay of these factors may influence pharmacodynamic responses such as adverse effects and efficacy, as well as pharmacokinetic manifestations. However, at present, few biomarkers can predict responders and non-responders, and those who might experience adverse reactions for the same medication and dose. In order to realize personalized medicine, rigorous development of biomarkers is required to identify new biomarkers that may change clinical practice. In this review, we first introduce how biomarkers may be used as targets and the difference between prognostic and predictive markers. Next, we focus on confirmatory clinical trial designs for biomarker development and introduce their application in actual studies. Finally, we introduce exploratory statistical screening techniques for detecting biomarkers in phase I and pharmacokinetics studies.

© 2014 EAN. Background and objectives: Several symptoms and signs are characteristic of multiple sclerosis (MS) such as Lhermitte's sign, Uhthoff's phenomenon and painful tonic seizure. Neuromyelitis optica (NMO) is another inflammatory disease of the central nervous system, and most of the opticospinal form of MS is thought to be NMO. This study aimed to investigate the frequencies of symptoms and signs, previously regarded as characteristic of MS, in NMO and MS patients. Methods: Consecutive Japanese NMO-plus patients [NMO (n = 30) or partial NMO (n = 18)] and MS patients (n = 128) seen at Chiba University Hospital between 2011 and 2012 were investigated for the frequencies of symptoms and signs characteristic of MS. Logistic regression analyses were used to identify factors that distinguished NMO-plus from MS. Results: Univariate analyses revealed that tonic seizures, Lhermitte's sign, persistent pain, fatigue and girdle sensation were more frequent in NMO-plus patients than in MS patients. Multivariate logistic regression analysis showed that paroxysmal itching, Uhthoff's phenomenon, Lhermitte's sign and girdle sensation were more characteristic of NMO-plus than of MS. Conclusions: Several classical MS symptoms and signs are more frequent in NMO patients than MS patients, which may be caused by the differences in the severity of inflammation, and localization and extensiveness of demyelinated lesions.

We assessed the efficacy and safety of sitagliptin compared with α-glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active-controlled, non-inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12weeks, sitagliptin reduced HbA1c by -0.44% (p<0.001) relative to αGI. At 24weeks, the reduction was almost identical between the groups (-0.091%, p=0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia. © 2014 John Wiley & Sons Ltd.

Because brainstem metastases are not deemed resectable, stereotactic radiosurgery (SRS) is the only treatment modality expected to achieve a radical cure. The authors describe their treatment results, focusing particularly on how long patients can survive without neurological deterioration following SRS for brainstem metastases. This was an institutional review board-approved, retrospective cohort study in which the authors pulled from their database information on 2553 consecutive patients with brain metastases who underwent Gamma Knife surgery (GKS) at the Mito GammaHouse between July 1998 and July 2011. Among the 2553 patients, excluding cases in which there was meningeal dissemination, 200 cases of brainstem metastases (78 women and 122 men with a mean age of 64 years [range 36-86 years]) were identified and analyzed. The most common primary site was the lung (137 patients) followed by the gastrointestinal tract (24 patients), breast (17 patients), kidney (12 patients), and others (10 patients). Among the 200 patients, 15 patients (7.5%) harbored at least 2 tumors in the brainstem: 11 patients had 2 tumors, 2 patients had 3 tumors, and 1 patient each had 4 or 5 tumors. Therefore, a total of 222 tumors were irradiated. These 222 tumors were located in the pons (121 lesions), the midbrain (65 lesions), and the medulla oblongata (36 lesions). The mean and median tumor volumes were 1.3 and 0.2 cm(3) (range 0.005-10.7 cm(3)), and the median peripheral radiation dose was 18.0 Gy (range 12.0-25.0 Gy). The overall median survival time (MST) was 6.0 months. Distribution of MSTs across Recursive Partitioning Analysis (RPA) classes showed that the MSTs were 9.4 months in Class I (20 patients), 6.0 months in Class II (171 patients), and 1.9 months in Class III (9 patients). Better Karnofsky Performance Scale score, single metastasis, and well-controlled primary tumor were significant predictive factors for longer survival. The neurological and qualitative survival rates were 90.8% and 89.2%, respectively, at 24 months post-GKS. Better KPS score and smaller tumor volume tended to be associated with prolonged qualitative survival. Follow-up imaging studies were available for 129 patients (64.5%). The tumor control rate was 81.8% at 24 months post-GKS. Smaller tumor volume tended to contribute to tumor control. The present results indicate that GKS is effective in the treatment of brainstem metastases, particularly from the viewpoint of maintaining a good neurological condition in the patient.

© 2014 Osteoarthritis Research Society International. Objective: To examine whether the detection of osteophytes anywhere in the knee could serve as a pre-radiographic biomarker for osteoarthritis (OA) development. Methods: Baseline magnetic resonance imaging (MRIs) of 132 participants in the Osteoarthritis Initiative (OAI) were studied. Based on radiographs, 66 knees were assessed as osteoarthritis-free (no-osteoarthritis [NOA], or Kellgren/Lawrence [K/L] severity grade 0/1 both at baseline and 48 months), and another 66 knees were assessed as having radiographic OA changes (pre-radiographic osteoarthritis [PROA], or with K/L grade 0/1at baseline and grade ≥2at 48 months). Using baseline MRI data, we examined eight sites of osteophyte formation: the medial and lateral femoral condyle (MFC and LFC, respectively); medial and lateral tibial plateau (MTP and LTP, respectively); medial and lateral facets of the patellofemoral joint (PM and PL, respectively); tibial spine (TS); and femoral intercondylar notch (IC). Knee joint osteophyte size was assessed via the 8-point marginal osteophytes item of the whole-organ magnetic resonance imaging score (WORMS). The frequencies and distributions of osteophytes were compared between groups. Results: Mild-size osteophytes (defined as score ≥2) were observed more frequently at the MFC (P=0.00278), MTP (P=0.0046), TS (P=0.0146), PM (P<0.0001), PL (P=0.0012), and IC (P<0.0001) in PROA knees than in NOA knees. Moderate-size osteophytes (defined as score ≥4) were more frequently observed in PROA knees than in NOA knees only at the IC (P<0.0001). Conclusion: Knees with osteophyte formation at the IC, even those of K/L severity grade 0/1, are at risk for the development of radiographic OA by 48 months.

腫瘍体積が10ml以上の大きな脳転移に対するガンマナイフによる三期的および二期的照射の治療成績を比較検討した。本試験参加19施設において総計1441例のガンマナイフによる段階的照射が施行され、このうち335例(三期114例、二期的照射221例)が登録された。生存期間中央値は三期群15.1ヵ月、二期群12.0ヵ月と三期群の方が長い傾向にあったが有意差を認めなかった。その他のすべての副次評価項目において両群間に有意差を認めなかった。Propensity score matchを用いて最終的に212例(両群106例)を選択し評価したところ、生存期間中央値は三期群15.9ヵ月、二期群11.7ヵ月と三期群の方が長い傾向にあったが有意差を認めなかった。1年における累積腫瘍増大発生頻度は三期群21.6%、二期群16.7%で有意差を認めなかった。その他、腫瘍再発、放射線壊死、神経死、有害事象においても両群間に有意差を認めなかった。

© 2015 Taylor & Francis. Diabetic nephropathy has dramatically increased worldwide. In this study, we measured urinary podocalyxin in 240 patients with diabetes. The relationship between urinary podocalyxin and clinical parameters and the effects of dipeptidyl peptidase-4 inhibitors (DPP4i) and alpha-glucosidase inhibitor (a-GI) on urinary podocalyxin levels were examined. Urinary podocalyxin levels were significantly higher in patients with microalbuminuria than in those with normoalbuminuria. Urinary podocalyxin levels were also significantly related to albumin-to-creatinine ratio. Neither DPP4i nor α-GI ameliorated the increase in urinary podocalyxin levels. Our results indicated that urinary podocalyxin will be not only an early marker but also a treatment target for DN.

Objective: POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome is a rare multisystem disease characterised by plasma cell dyscrasia and overproduction of vascular endothelial growth factor (VEGF). VEGF is assumed to be useful in monitoring disease activity, because VEGF levels usually decrease after treatment. However, there is no study to investigate whether the extent of decrease in VEGF correlates with clinical outcome. We tested the predictive efficacy of serum VEGF levels in POEMS syndrome. Method: This was an institutional review board approved retrospective observational cohort study of 20 patients with POEMS monitored regularly for more than 12 months (median follow-up, 87 months) after treatment onset using our prospectively accumulated database of POEMS from 1999 to 2015. Patients were treated by autologous peripheral blood stem cell transplantation or thalidomide administration. Serum VEGF was measured by ELISA. Outcome measures included clinical and laboratory findings and relapsefree survival. Results: Serum VEGF levels decreased rapidly after treatment, and stabilised by 6 months post treatment. Patients with normalised serum VEGF levels (<1040 pg/mL) at 6 months showed prolonged relapsefree survival (HR=12.81, 95% CI 2.691 to 90.96; p=0.0001) and greater later clinical improvement. The rate of serum VEGF reduction over the first 6 months post treatment correlated with increased grip strength, serum albumin levels, and compound muscle action potential amplitudes at 12 months. Conclusions: Serum VEGF level at 6 months post treatment is a predicative biomarker for disease activity and prognosis in POEMS syndrome. Serum VEGF could be used as a surrogate endpoint for relapse-free survival or clinical or laboratory improvement of POEMS syndrome for clinical trials.

日本先天性横隔膜ヘルニア(CDH)スタディグループ内の5施設で実施された栄養に関する追跡調査のデータを元に、CDH管理における急性期栄養が乳幼児期の成長に及ぼす影響について報告した。その結果、CDH軽症例では、積極的な経腸栄養(EN)が乳児期の体重増加に寄与することが示唆された。重症例では急性期におけるENが困難な場合が多く、静脈栄養によるサポートが体重増加に寄与する可能性が示唆された。

© Author(s) (or their employer(s)) 2019. Objective To propose the optimal diagnostic criteria for polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome using appropriate statistical methods and disease controls. Methods This retrospective cohort study included 104 consecutive patients with suspected POEMS syndrome, among whom a gold standard group of 60 patients with definitive POEMS syndrome diagnosis were followed for at least 12 months to strictly exclude other disorders mimicking POEMS syndrome and to confirm response to POEMS syndrome-specific treatment. Thirty patients with chronic inflammatory demyelinating polyradiculoneuropathy (demyelinating polyradiculoneuropathy controls) and 30 with multiple myeloma or immunoglobulin light chain amyloidosis (monoclonal plasma cell proliferation controls) were also included. Logistic regression analyses were performed to determine optimal combination of clinical and laboratory abnormalities, characteristic of POEMS syndrome. Results The diagnostic criteria were statistically defined as the presence of the three major criteria (polyneuropathy (typically demyelinating), monoclonal plasma cell proliferative disorder and elevated vascular endothelial growth factor) and at least two of the four minor criteria (oedema/effusion, skin changes, organomegaly and sclerotic bone lesions), based on best performance by area under the receiver operating characteristic curve analyses. The sensitivity and specificity were 100% and 100%, respectively; the diagnostic accuracy of the proposed criteria was equivalent to somewhat complicated previous criteria. Conclusions The statistically defined, simple diagnostic criteria for POEMS syndrome could accelerate early diagnosis and treatment, thereby contribute to better outcome in patients with this serious disease. Prospective larger studies are required to confirm the validity.

Copyright ©2019 Journal of Orthopaedic & Sports Physical Therapy. BACKGROUND: Radiographs of the feet are the reference standard for measuring the hallux valgus angle. However, the availability and use of radiographs are constrained due to cost and radiation exposure. Less invasive, nonradiographic assessments have been proposed, although measurement using self-photography has not been reported. t OBJECTIVES: To determine (1) reliability of photographic hallux valgus angle (pHVA) measurement using the same photographs of the feet, (2) reliability of repeated self-photography trials, and (3) measurement error when the radiographic hallux valgus angle (rHVA) is estimated using the pHVA. t METHODS: In this reliability study, participants took photographs of their own feet using a digital camera. The intrarater and interrater reliability of pHVA measurements were then assessed using the intraclass correlation coefficient (ICC) and 95% minimum detectable change (MDC). The participants took photographs twice, and the reliability of repeated self-photography trials was examined. Participants also received radiographs of their feet, from which the rHVA was measured. The measurement error was assessed using the mean difference and 95% limits of agreement. t RESULTS: The intrarater and interrater ICC of pHVA measurement was 0.99, with MDCs less tha 2°. The ICC of pHVA measurement for repeated self-photography was 0.96, and the MDC was 6.9° The pHVA was systematically lower than the rHVA by 5.3°. t CONCLUSION: Measurement of the pHVA using self-photography was reproducible, althoug pHVA measurement underestimated the rHVA. Th pHVA can be a useful nonradiographic method to uantify hallux valgus deformity.

Historically, whole brain radiotherapy was administered to most patients with brain metastases. However, over the past three decades, stereotactic radiosurgery (SRS), targeted at individual cranial lesions, has been accepted widely. In this study, based on the authors' experiences along with published data, recent trends in SRS for brain metastases are discussed. This article focuses on the following issues: 1) How many tumors can or should be treated with SRS? 2) Two-/three-staged SRS for relatively large tumors, 3) post- or preoperative SRS, and 4) repeat SRS.

© 2018, Springer Japan KK, part of Springer Nature. Home telemonitoring is becoming more important to home medical care for patients with heart failure. Since there are no data on home telemonitoring for Japanese patients with heart failure, we investigated its effect on cardiovascular outcomes. The HOMES-HF study was the first multicenter, open-label, randomized, controlled trial (RCT) to elucidate the effectiveness of home telemonitoring of physiological data, such as body weight, blood pressure, and pulse rate, for Japanese patients with heart failure (UMIN Clinical Trials Registry 000006839). The primary end-point was a composite of all-cause death or rehospitalization due to worsening heart failure. We analyzed 181 recently hospitalized patients with heart failure who were randomly assigned to a telemonitoring group (n = 90) or a usual care group (n = 91). The mean follow-up period was 15 (range 0–31) months. There was no statistically significant difference in the primary end-point between groups [hazard ratio (HR), 0.95; 95% confidence interval (CI), 0.548–1.648; p = 0.572]. Home telemonitoring for Japanese patients with heart failure was feasible; however, beneficial effects in addition to those of usual care were not demonstrated. Further investigation of more patients with severe heart failure, participation of home medical care providers, and use of a more integrated home telemonitoring system emphasizing communication as well as monitoring of symptoms and physiological data are required.

© 2018 Elsevier Ltd Background: Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. Methods: This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3–5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. Findings: Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42–78; n=14) in the eculizumab group, and 45% (20–73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. Interpretation: The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. Funding: The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.