オルプリノンはendothelial Nitric Oxide Synthaseを誘導し、ラット大量肝切除モデルにおける過度のシェアストレスを軽減する

京都大学0048新制・課程博士博士(医学)甲第16712号医博第3660号新制||医||992(附属図書館)29387京都大学大学院医学研究科医学専攻(主査)教授 川口 義弥, 教授 坂井 義治, 教授 芹川 忠夫学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

The correlation between the number of eligible patients in routine clinical practice and the low recruitment level in clinical trials: a retrospective study using electronic medical records.

[Background]A number of clinical trials have encountered difficulties enrolling a sufficient number of patients upon initiating the trial. Recently, many screening systems that search clinical data warehouses for patients who are eligible for clinical trials have been developed. We aimed to estimate the number of eligible patients using routine electronic medical records (EMRs) and to predict the difficulty of enrolling sufficient patients prior to beginning a trial. [Methods]Investigator-initiated clinical trials that were conducted at Kyoto University Hospital between July 2004 and January 2011 were included in this study. We searched the EMRs for eligible patients and calculated the eligible EMR patient index by dividing the number of eligible patients in the EMRs by the target sample size. Additionally, we divided the trial eligibility criteria into corresponding data elements in the EMRs to evaluate the completeness of mapping clinical manifestation in trial eligibility criteria into structured data elements in the EMRs. We evaluated the correlation between the index and the accrual achievement with Spearman's rank correlation coefficient. [Results]Thirteen of 19 trials did not achieve their original target sample size. Overall, 55% of the trial eligibility criteria were mapped into data elements in EMRs. The accrual achievement demonstrated a significant positive correlation with the eligible EMR patient index (r = 0.67, 95% confidence interval (CI), 0.42 to 0.92). The receiver operating characteristic analysis revealed an eligible EMR patient index cut-off value of 1.7, with a sensitivity of 69.2% and a specificity of 100.0%. [Conclusions]Our study suggests that the eligible EMR patient index remains exploratory but could be a useful component of the feasibility study when planning a clinical trial. Establishing a step to check whether there are likely to be a sufficient number of eligible patients enables sponsors and investigators to concentrate their resources and efforts on more achievable trials

[Galatasaray Lisesi 1909-1910 mezunları]

Taha Toros Arşivi, Dosya Adı: Galatasarayİstanbul Kalkınma Ajansı (TR10/14/YEN/0033) İstanbul Development Agency (TR10/14/YEN/0033

A single-center analysis of the survival benefits of adjuvant gemcitabine chemotherapy for biliary tract cancer.

[Background]Surgical resection is the only curative treatment of biliary tract cancer (BTC). However, the prognosis of BTC remains unsatisfactory. The aim of this study is to evaluate the benefits of adjuvant gemcitabine chemotherapy for BTC. [Methods]We performed a historical cohort study that involved 198 patients who underwent R0 surgical resection. Patients who underwent major hepatectomy were administered biweekly intravenous gemcitabine at a dose of 800 mg/m2. Otherwise, patients were administered intravenous gemcitabine at a dose of 1, 000 mg/m2 in 3 weekly infusions, which were followed by a 1-week pause. The primary outcome was overall survival. The hazard ratio (HR) of adjuvant chemotherapy was estimated by propensity score-stratified Cox regression that was adjusted for confounders. [Results]Forty patients received adjuvant chemotherapy. The HR of adjuvant chemotherapy was 0.47 [95 % confidence interval (CI) 0.28–0.95; P = 0.03]. Subgroup analysis showed that the survival benefits were possibly modified by lymph node positivity (HR 0.19; 95 % CI 0.07–0.58; interaction, P = 0.22), stage III (HR 0.11; 95 % CI 0.02–0.50; interaction, P < 0.01), intrahepatic cholangiocarcinoma (ICC) (HR 0.09; 95 % CI 0.01–0.67; interaction, P = 0.05), and poorly differentiated tumor (HR 0.16; 95 % CI 0.03–0.85; interaction, P = 0.13). [Conclusions]Adjuvant gemcitabine chemotherapy for BTC may be effective, particularly for patients with stage III and ICC

Study flow diagram included in the systematic review.

<p>Study flow diagram included in the systematic review.</p

Annotated forest plot for meta-analysis of risk ratio of seven-day-survival probability.

<p>Annotated forest plot for meta-analysis of risk ratio of seven-day-survival probability.</p

An eClinical trial system for cancer that integrates with clinical pathways and electronic medical records.

[Background] Various information technologies currently are used to improve the efficiency of clinical trials. However, electronic medical records (EMRs) are not yet linked to the electronic data capture (EDC) system. Therefore, the data must be extracted from medical records and transcribed to the EDC system. Clinical pathways are planned process patterns that are used in routine clinical practice and are easily applicable to the medical care and evaluation defined in a trial protocol. However, few clinical pathways are intended to increase the efficiency of clinical trials. [Purpose] Our purpose is to describe the design and development of a new clinical trial process model that enables the primary use of EMRs in clinical trials by integrating clinical pathways and EMRs. [Methods] We designed a new clinical trial model that uses EMR data directly in clinical trials and developed a system to follow this model. We applied the system to an investigator-initiated clinical trial and examined whether all data were extracted correctly. At the protocol development stage, our model measures endpoints based on clinical pathways with the same diagnosis. Next, medical record descriptions and the format of the statistical data are defined. According to these observations, screens for entry of data, which are used both in clinical practice and for study, are prepared into EMRs with an EMR template, and screens are prepared for data checks on our EMR retrieval system (ERS). In an actual trial, patients are registered and randomly assigned to a protocol treatment. The protocol treatment is executed according to clinical pathways, and the data are recorded to EMRs using EMR templates. The data are checked by a local data manager using reports created by the ERS. After edit checks and corrections, the data are extracted by the ERS, archived in portable document format (PDF) with an electronic signature, and transferred in comma-separated values (CSV) format to a coordinating centre. At the coordinating centre, the data are checked, integrated, and made available for a statistical analysis. [Results] We verified that the data could be extracted correctly and found no unexpected problems. [Limitation] To execute clinical trials in our system, the EMR template and efficient ERSs are required. Additionally, to execute multi-institutional clinical trials, it is necessary to create templates appropriate for EMRs at all participating sites and for the coordinating centre to validate local templates and procedures. [Conclusion] We proposed and pilot tested a new eClinical trial model. Because our model is integrated with routine documentation of clinical practice and clinical trials, redundant data entries were avoided and the burden on the investigator was minimised. The reengineering of the clinical trial process would facilitate the establishment of evidence in the future

Hepatoprotective effect by pretreatment with olprinone in a swine partial hepatectomy model.

Excessive portal flow to a small remnant liver or small-for-size graft is a primary factor of small-for-size syndrome. We demonstrated that olprinone (OLP), a phosphodiesterase III inhibitor, had a hepatoprotective effect in a rat extended hepatectomy model and a small-for-size liver transplantation model through a modification of the portal venous pressure (PVP). To identify the appropriate dose and duration of treatment for clinical applications, we conducted experiments with a swine partial hepatectomy model. Twenty microminipigs were divided into 4 groups that received the following treatments: (A) saline (control group), (B) OLP at 0.3 μg/kg/minute (preoperative and postoperative administration), (C) OLP at 0.1 μg/kg/minute (preoperative administration), and (D) OLP at 0.3 μg/kg/minute (preoperative administration). The pigs underwent 70% partial hepatectomy. Hemodynamic changes, including changes in PVP, were examined. Liver biopsy was performed 1 and 3 hours after hepatectomy. Blood samples were collected until postoperative day 7 (POD7). In comparison with group A, PVP elevations, periportal edema, and sinusoidal hemorrhaging were attenuated after left Glisson's ligation in groups C and D. Pretreatment with OLP in groups C and D preserved the microstructure of sinusoids and improved the prothrombin activity 1 and 3 hours after hepatectomy. These animals showed better recovery of the remnant liver volume and the plasma disappearance rate of indocyanine green on POD7. In contrast, group B showed exacerbation of liver damage. Measurements of the serum OLP concentration showed that 10 ng/mL OLP was appropriate for a hepatoprotective effect. In conclusion, pretreatment with OLP shows hepatoprotective effects in a swine partial hepatectomy model. OLP may have the potential to ameliorate patients' outcomes after hepatectomy or liver transplantation

Effect of olprinone on liver microstructure in rat partial liver transplantation.

[Background]Donor safety is a major concern in living-donor liver transplantation. However, partial grafts do not meet the functional demands of recipients and lead to small-for-size syndrome (SFSS). In a previous study, we showed that olprinone (OLP), a selective phosphodiesterase ІІІ inhibitor, up-regulates endothelial nitric oxide synthase level in the liver and attenuates shear stress, sinusoidal endothelial cell injury, and hepatocyte apoptosis after excessive liver resection in a rat model. We aimed to examine whether OLP treatment has beneficial effects on SFSS in a rat model of partial liver transplantation (PLT). [Methods]We performed experiments in a rat model of 30% PLT. In the OLP group, we inserted an osmotic pump with OLP into the peritoneal cavity 48 h before liver graft sampling. Recipient rats were not treated with OLP. We examined the liver microstructure by electron microscopy and biochemical examination, and determined the 7-d survival of recipients. [Results]In the OLP group 1 h after PLT, the sinusoidal endothelial cells of the liver were well preserved and we observed few vacuolar structures in hepatocytes. The total serum bilirubin level 1 wk after PLT tended to be lower in the OLP group than in the controls, and the liver microstructures were also well preserved in the OLP group. The probability of survival in the OLP group (100%; 14 of 14 rats) was significantly higher than that in the control group (75%; 15 of 20 rats). [Conclusions]Olprinone treatment was demonstrated to have therapeutic potential to overcome SFSS