Quality of life (QOL) evaluated by patients themselves has become one of the important outcomes in clinical practice as well as clinical trials. Recently clinicians have attempted to gather QOL evaluation data in their clinical practice setting and integrate the findings into the medical decision-making process. To date, several multidimensional generic questionnaires consisting of multiple domains such as functional, physical, mental and social well-being, have been developed and utilized for generic QOL evaluation in clinical trials, especially in the oncology area. To develop a well-constructed and valid QOL questionnaire, its psychometric characteristics such as reliability, validity, responsiveness and feasibility must be adequately assessed in the research setting.
In clinical trials, QOL data are generally measured in a longitudinal fashion and there are two prominent embarrassing statistical problems : one is the multiplicity due to replication (in time) of statistical tests and the other is the occurrence of missing data due to a variety of reasons. Non-random missing data which occurs because of any reasons related to a patient's present status and/or future prognosis possibly leads to bias and misinterpretation of the results of a trial. To solve the multiplicity problem, the repeated-measures ANOVA-type data analysis or summarization of a repeated measures into an appropriate summary measure can be applied. Missing data can be prevented to some extent by allocating/training coordinators at each participating institute and establishing a communication network between a data center and participating institutes. However, missing data will occur inevitably due to the deterioration of a patient's physical status in the area of life threatening diseases suchas advanced cancer or other diseases with poor prognosis. Although several statistical approaches to cope with missing data even including non-random one have been proposed, there is no single complete analytical solution that can handle the non-random missing problem. The best remedy would be to collect information about reasons why the missing data occurred so that we can identify the missing mechanism and take it into account in a statistical analysis. A so-called “sensitivity analysis” of comparing the results of several analytical methods suchas different imputation techniques or newly proposed ideas would also be a useful approach. The QALY (Quality Adjusted Life Year) used the idea of weighting life time by utility evaluated by patients themselves and is coined for incorporating a patient's judgment into the treatment selection. Ultimately, an assessment of QOL should be utilized for “individualized” or “tailor-made” treatment and statistical methodology should be developed further for gathering, analyzing and utilizing QOL data.

Background: Combination treatment with bevacizumab and paclitaxel has been approved for treating human epidermal growth factor receptor 2(HER2)-negative metastatic breast cancer(MBC) in Japan. Japan has no official economical guideline showing decision criteria for the approvals of new drugs. However, the National Institute for Health and Clinical Excellence(NICE) in UK hardly recommends the combinational use of bevacizumab for HER2-negative MBC, because of its poor cost-effectiveness.　Objective: The evaluation of the cost-effectiveness of additional bevacizumab as primary chemotherapy for HER2-negative MBC in accordance with the clinical practice guideline in JapanMethods: A Markov cohort simulation was used to follow the clinical course of typical patients with MBC. Transition probabilities were estimated from randomized clinical trials. Direct medical costs were assessed from the perspective of the Japanese health-care system. This study used quality-adjusted life year(QALY), and both costs and QALYs were discounted 3% annually. The time horizon was 10 years. Both a univariate and probabilistic sensitivity analyses were conducted. Results: The additional use of bevacizumab to paclitaxel required an additional cost of JPY 9.12 million(USD 114,000) for obtaining a gain of 0.26 QALYs, and the incremental cost effectiveness ratio was JPY 35 million(USD 437,000). Conclusion：By assuming of GBP 20,000-30,000(JPY 2.5-3.75 million and USD 31,000-46,900) to be an index value threshold by NICE, combination treatment with bevacizumab was found to be hardly cost-effective. Based on the fair and adequate distribution of medical resource, economical guidelines reflecting the Japanese health-care system are necessary. (Jpn J Pharmacoepidemiol 2013；18(1)：1-12)

Objective: To investigate the perception of the prevalence of mental diseases in breast cancer patients and the therapeutic approach to depression undertaken by oncologists. Method: Self-reported questionnaires were sent to 352 breast cancer specialists. The survey contains 11 categories to elicit the perception and identification of mental illnesses in patients, diagnostic procedure, and details of antidepressant prescribed. Logistic regression was used to explore the association of oncologists' characteristics and management of depression in breast cancer patients. Results: Survey response rate was 31.3%. Ninety percent of the oncologists perceived the prevalence of depression to be less than 20%, while half believed that the proportion was less than 5%. The most commonly-used medication for the treatment of depression was BZDs (41.5% [n=39]), followed by Selective Serotonin Reuptake Inhibitors (SSRIs) (30.9% [n=29]). Benzodiazepines (BZDs) were most frequently prescribed (41.5%) despite its known ineligible dependency, followed by Selective Serotonin Reuptake Inhibitors (SSRIs) (30.9%). Choice of BZDs was significantly associated with the career length of oncologists (Odds Ratio [OR]=8.20), and safety of drug (OR=5.57). Contrarily, prescription of SSRIs was associated with efficiency of drug (OR=7.07). Conclusion: Relative to anxiety and insomnia, a lower awareness regarding depression was common among study oncologists. In addition, the quality of care varied among these oncologists. It is necessary to improve both the awareness and management of mental illnesses in order to enhance the total clinical care of breast cancer patients.

Background : With a suppport from Ministry of Health and Welfare (MHW) Japan, we studied the feasibility of conducting event monitoring in Japan similar to Prescription-Event Monitoring in England. The manuscript presented is a report to MHW in 1996.
Methods : Means available in Japan to identify drug, patient and doctor are examined. In addition, any modification needed to make on a questionnaire sent to doctors in PEM conducted in Japan is examined.
Results and Conclusion : Monthly claims called as “Rezept” issued by individual hospitals and clinics and sent to insurers and outpatient prescriptions issued by hospitals to be dispensed by the pharmacies outside the hospitals are considered to be two available means to identify drug, patient and doctor. To have a sample representative of all drug users, the use of “Rezept” is needed as only a fraction of outpatient prescriptions are dispensed by independent pharmacies. However, the use of prescriptions dispensed by the independent pharmacies together with the cooperation of individual pharmacies is capable of finding a contemporary control which is a group of patients who have recently started “old” drugs comparable to the new “test drug”. In Japan no doctor may have a complete list of the hospitals and clinics a patient has visited and it is mandatory to ask doctors the last date when the patient visited the doctor. To clarify what problems arise when a PEM-like study is introduced to Japan, a pilot study is going to be done during 1997 and the feasibility will be examined further based on the results.

Objective : The incidence rate is used frequently in drug safety assessment. The incidence rate of adverse events is defined as the number of patients experiencing a certain adverse event divided by the number of patients administered a drug in spite of duration of administration (observation). In post-marketing surveillance, the duration of administration (observation) typically differs by patient and most of the analyses fail to take into account the differences in duration of administration (observation). Therefore, we investigated the usefulness of hazard functions in a drug safety assessment using the interim results from Clinical Experience Investigation of the oral anticancer drug, TS-1.
Methods : About three thousand patients with gastric cancer were enrolled in this Clinical Experience Investigation. TS-1 was administrated orally twice daily. One course consisted of consecutive administration for 28 days and 14 days rest. Administration was repeated in two courses. Hematological measurements, stomatitis, anorexia, nausea/vomiting, diarrhea, malaise were analyzed. Adverse events were evaluated in accordance with the criteria of the Japan Society for Cancer Therapy, which were established based on criteria established by the WHO. Time to occurrence of an adverse event was calculated from the first day of administration until the adverse event was first observed. Hazard functions were estimated by smoothing methods using kernel functions.
Results : The occurrence of adverse events using smoothed hazard functions had one peak around 10 days in the first course and decreased by administration rest. With the resumption of administration, the occurrence increased again. The occurrence in the second course were less than that of the first course.
Conclusion : The occurrence peaks of adverse events were estimated graphically by smoothed hazard functions. We conclude that hazard functions are useful as an analytical tool in drug safety assessment.

The purpose of this study was to examine the association between the pedometer-determined steps per day and physical fitness in order to evaluate the usefulness of the pedometer-determined physical activity to help individuals meet the recommended exercise target level of the Ministry of Health, Labour and Welfare (MHLW). The subjects consisted of 222 men and 172 women aged 71 years in community-dwelling elderly. The subjects wore a pedometer for 7 consecutive days to measure daily steps. The functional capacity was assessed based on the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) and self-reported performance of tasks (stair-climbing and chair-rising). Physical fitness tests included handgrip strength, knee extensor strength, leg extensor power, stepping, one-leg standing time with eyes open and maximal walking speed at 10 m. The men and women took on average 6,561±2,907 and 6,329±2,451 steps/day, respectively. Our subjects seemed to be highly functioning elderly, because the total scores of TMIG-IC (maximum : 13 scores) were on average 12 for men and women. The average of steps/day was significantly correlated with stair-climbing, chair-rising and knee extensor strength in men and women, and with body weight, body mass index (BMI), percent body fat (%Fat) and leg extensor power in women. The BMI and %Fat levels were significantly lower while the handgrip strength and knee extensor strength were significantly higher in women who attained to the level of the pedometer-determined physical activity as recommended by the MHLW.The present study suggests that both men and women who take a lot of steps on a daily basis tend to demonstrate excellent leg strength and thus have a good ability to perform the tasks of daily living. In addition, the degree of obesity tends to be lower in women who regularly take a lot of steps. In addition, the number of daily steps taken has been recognized to be linked to gender, and such a link has also been suggested to be stronger in women than in men.

OBJECTIVETo evaluate the statistical property of the estimators on exposure effect and value of propensity score methods in practical use.

METHODSSimulation data, propensity score methods (PSM) were conducted to assess bias and efficiency, under both with/without model misspecification conditions.

RESULTSUnder model misspecification conditions, propensity score methods had better robustness than model based methods.

CONCLUSIONFor large and complicated data, propensity score methods had more flexibility in practical use than model based methods.

The Standardized Structured Medical record Information eXchange (SS-MIX) was started in 2006 as the project supported by the Ministry of Health, Labour and Welfare (MHLW) for promoting the exchange of the standardized medical information. Free soft wares developed in the project allow the storage of medical information to receive HL7 messages for prescription, laboratory test results, diagnoses and patient demographics in the hospital information system (HIS). We encourage the use of the SS-MIX standardized storage for postmarketing surveys and clinical studies. The recommendations consist of the following 7 parts. [1] In surveys and clinical studies, the information of drugs and laboratory test results in the SS-MIX standardized storage can be directly transferred to the electronic questionnaire and the investigators may obtain the information with high accuracy and granularity. [2] The SS-MIX standardized storage works as the backup system for the HIS because it can provide the minimum information essential in patient care even under the disastrous condition like earthquake or unexpected network failure. [3] The SS-MIX standardized storage may be useful to conduct a good pharmacoepidemiology study not only because it provides the information in the storage efficiently but also it can be used to identify “new users” who started the drug after some period of non-use.The “new user” design is often essential to have the unbiased results. [4] When the drug company conducts postmarketing surveys according to the current regulation, the use of the SS-MIX standardized storage will facilitate the fast and efficient collection of data to develop the timely measure to minimize the drug-related risk. With the SS-MIX standardized storage, it is also expected that many types of study design can be employed and the quality of data is improved in the survey. [5] The SS-MIX standardized storage maybe also useful to evaluate the risk minimization action plan by comparing the prescription pattern or incidence of the targeted adverse event between two periods before and after the implementation of the action plan. [6] In planning clinical trials, the SS-MIX standardized storage may be used to estimate the size of eligible patients. The storage may also allow conducting cross-sectional studies to know characteristics of diseases or drug treatment. In addition, cohorts of those who had coronary artery angiography, new users of a drug and those with a rare disease may be readily identified. Using such cohorts, investigators can initiate a case-control study nested within the cohort, pharmacogenomic studies and comparative effectiveness researches. [7] The SS-MIX standardized storage may be used as the formal data source in clinical trials in the future when some conditions are satisfied. For instance, the formal agreement should be reached between industry, government and academia on the use of standards of data structure in Clinical Data Interchange Standards Consortium (CDISC) and on the operation of computerized system validation (CSV) in the clinical trials.

PURPOSE: Postoperative pancreatic fistula is a serious and fatal complication of gastrectomy for gastric cancer. Blunt trauma to the parenchyma of the pancreas can result from an assistant's forceps compressing and retracting the pancreas, which in turn may result in pancreatic juice leakage. However, no published studies have focused on blunt trauma to the pancreas during laparoscopic surgery. Our aim was to investigate the relationship between compression of the pancreas and pancreatic juice leakage in a swine model. MATERIALS AND METHODS: Three female pigs were used in this study. The pancreas was gently compressed dorsally for 15 minutes laparoscopically with gauze grasped with forceps. Pancreatic juice leakage was visualized by fluorescence imaging after topical administration of chymotrypsin-activatable fluorophore in real time. Amylase concentrations in ascites collected at specified times was measured. In addition, pancreatic tissue was fixed with formalin, and the histology of the compressed sites was evaluated. RESULTS: Fluorescence imaging enabled visualization of pancreatic juice leaking into ascites around the pancreas. Median concentrations of pancreatic amylase in ascites increased from 46 U/L preoperatively to 12,509 U/L 4 hours after compression. Histological examination of tissues obtained 4 hours after compression revealed necrotic pancreatic acinar cells extending from the surface to deep within the pancreas and infiltration of inflammatory cells. CONCLUSIONS: Pancreatic compression by the assistant's forceps can contribute to pancreatic juice leakage. These findings will help to improve the procedure for lymph node dissection around the pancreas during laparoscopic gastrectomy.
Acinar Cells ; Administration, Topical ; Amylases ; Ascites ; Female ; Formaldehyde ; Gastrectomy* ; Hand Strength ; Humans ; Laparoscopy ; Lymph Node Excision* ; Lymph Nodes* ; Optical Imaging ; Pancreas ; Pancreatic Fistula ; Pancreatic Juice ; Stomach Neoplasms ; Surgical Instruments ; Swine ; Wounds, Nonpenetrating