A 55-year old man was admitted to our hospital owing to endograft collapse after TEVAR. He had undergone total arch replacement for acute aortic type A dissection at age 39, and undergone thoracic endovascular aortic repair (TEVAR) for chronic aortic type B dissection at age 54. TEVAR was successfully performed and the false lumen was shrunk. However, one year after TEVAR, computed tomography showed endograft collapse. Technical success was not achieved by the balloon technique to treat endograft collapse, so we performed additional TEVAR. After this procedure, endograft collapse was repaired. The postoperative course was uneventful.

Those of us in the pharmaceutical industry are in favor of using SS-MIX standardized storage to alleviate the burden on medical professionals. As previously suggested, in addition to the benefits of reducing study periods, supporting a variety of investigative research and safety measures, and obtaining more accurate data on disease states and treatments, actively using this kind of new technology is a societal imperative in an information-driven society. Possible practical uses include (1) general application in drug use surveillance and special drug use surveillance, (2) appropriate sampling surveys, (3) patient monitoring, (4) observational studies with controls, such as those using disease registries, and (5) reviewing the results of safety measures. However, there is the issue of regulatory interpretation and consensus, with debate on information protection, and the issue of social infrastructure. Therefore, industry, government, and academia must continue its active, cooperative discussion to enable true implementation of this technology. (Jpn J Clin Pharmacoepidemiol 2013; 18(1): 57-64)

An in vitro infection system of Trypanosoma cruzi and HeLa cells was used to measure the anti-T. cruzi activities of various calcium antagonists classified into dihydropyridines, diphenylalkylamines, and benzothiazepines and of allopurinol and benznidazole as medium and highly effective reference compounds, respectively. Six dihydropyridines (10 μM each), i. e. nifedipine, nicardipine, nimodipine, nisoldipine, nitrendipine, and amlodipine, decreased the rates of infection of HeLa cells from 11.7% (control) to 5.8, 0.9, 1.2, 3.6, 5.9, and 1.7%, respectively. Nicardipine and amlodipine were highly toxic to HeLa cells, causing detachment of cells from coverslips. Nimodipine was thus the most effective inhibitor tested against T. cruzi infection in HeLa cells. Verapamil and gallopamil (diphenylalkylamines), diltiazem and midazolam (benzothiazepines), and allopurinol (positive control) were less effective than nimodipine. IC₅₀ values, the concentrations of compounds that elicited a 50% reduction in the infection rates of HeLa cells, were 2.5, 2.6, 1.3, 2.1, and 1.7 μM for nicardipine, nimodipine, amlodipine, verapamil, and benznidazole, respectively, while the values for nifedipine, diltiazem, and allopurinol were much higher. Nicardipine, amlodipine, and verapamil again showed significant cytotoxicities to HeLa cells. When Swiss 3T3 fibroblasts replaced HeLa cells, nimodipine markedly lowered the host-cell-infection rate, with an IC₅₀ value of 8.3 nM. Thus, nimodipine is expected to be a highly effective anti-T. cruzi lead compound, with low cytotoxicity to mammalian cells. Structural formulas of nimodipine and nicardipine in relation to their low and high cytotoxicities, respectively, against HeLa cells are discussed.

PURPOSE: The purpose of this retrospective study was to determine the effects of resistance training (RT) on myocardial infarction (MI) patients in phase II cardiac rehabilitation (CR) in our hospital.
METHODS: Twenty two outpatients who had participated in the phase II CR program more than three months at least were enrolled in this study. They were divided into control group (n＝8) and RT group (n＝14). We examined changes in the exercise capacity of these two groups. The traditional exercise programs which included aerobics and muscle strength exercise were run on the control group. Changes in exercise load for target heart rate measured with a bicycle ergometer as an indicator of exercise capacity were assessed in each patient 1,3 and 5 months after AMI onset.
RESULTS: The amounts of load and target heart rates recorded 1 month after the onset were not significantly different between the two groups. After 3,5 months of CR, the RT group showed no changes in the target heart rate but significant increase of the amount of load. The control group showed no change in the amount of load and target heart rate. In the amount of each load 3 and 5 months after, the RT group was significantly out did the control group.
CONCLUSIONS: These results suggested that RT was useful in the improvement of exercise capacity for patients with MI who participated in the phase II CR program provided by our hospital.

A Task Force team consisting of members from pharmaceutical companies --a central player to develop and implement RMP (Risk Management Plan)-- as well as health care professionals and members from academia was established in JSPE. The Task Force developed guidance for scientific approach to practical and ICH-E2E-compliant Pharmacovigilance Plan (PVP) stated in Japanese Risk Management Plan issued in April 2012 by the Ministry of Health, Labour and Welfare. The guidance contains the following topics.
1．Introduction: JSPE's activities and this task force's objectives for pharmacovigilance activities
2．How to select Safety Specification (SS) and describe its characteristics
・Selection of SS
・Characterization of SS
・Association with Research Questions (RQ)
3．How to define and describe RQ
・What is RQ ?
・RQ interpretation in other relevant guidelines
・Methodology to develop RQ for PVP with examples
・Best approach to integrating PVP for whole aspects of safety concern
4．How to optimize PVP for specific RQ
・Routine PVP or additional PVP ?
・Additional PVP design (RQ and study design, RQ structured with PICO or GPP's research objectives, specific aims, and rationale)
・Checklist to help develop PVP
5．Epilogue:
・What can/should be “Drug use investigation” in the context of ICH-E2E-compliant PVP.
・Significance of background incidence rate and needs for comparator group
・Infrastructure for the future PVP activities
6．Appendix: Checklist to help develop PVP activities in RMP
The task force team is hoping that this guidance help develop and conduct SS and PVP in accordance with ICH E2E, as stated in Japanese Risk Management Plan Guideline.

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.

OBJECTIVE: Reports on the repeated administration of medroxyprogesterone acetate (MPA) for intrauterine recurrence after fertility-preserving therapy for atypical endometrial hyperplasia (AEH) and early grade 1 endometrioid carcinoma (G1) are lacking. We aimed to clarify the outcomes of repeated MPA therapy in cases of intrauterine recurrence after fertility-preserving therapy with MPA against AEH/early G1. METHODS: Patients with AEH or stage IA well-differentiated endometrioid carcinoma without myometrial invasion who underwent first-line MPA therapy for primary lesions or intrauterine recurrence were divided into initial treatment and repeated treatment groups (162 and 82 patients, respectively). Oral MPA administration (400−600 mg/day) was continued until pathological tumor disappearance. Data regarding clinicopathological factors, adverse events, and outcomes following the initial and repeated hormonal treatments were extracted from medical records and analyzed. RESULTS: Complete response rates in the initial and repeated treatment groups were 98.5% and 96.4%, respectively, among patients with AEH, and were 90.7% and 98.1%, respectively, among patients with G1. In the initial treatment group, 5-year recurrence-free survival (RFS) rates were 53.7% and 33.2% among patients with AEH and G1, respectively. In the repeated treatment group, RFS rates were 14.0% and 11.2% among patients with AEH and G1, respectively. Among patients with AEH, the pregnancy rate tended to be lower in the repeated treatment group than in the initial treatment group (11.1% vs. 29.2%; p=0.107), while no significant group difference was observed among patients with G1 (20.8% vs. 22.7%). CONCLUSION: Repeated treatment is sufficiently effective for intrauterine recurrence after hormonal therapy for AEH/early G1.
Carcinoma, Endometrioid ; Endometrial Hyperplasia* ; Endometrial Neoplasms* ; Female ; Fertility Preservation ; Fertility* ; Hormone Replacement Therapy ; Humans ; Medical Records ; Medroxyprogesterone Acetate* ; Medroxyprogesterone* ; Pregnancy Rate ; Recurrence

Objective: The aim of this study was to establish criteria that would indicate whether fertility preservation therapy would likely be safe for patients aged 40 years or less with endometrioid endometrial cancer based on their DNA methylation profile. Methods: Forty-nine fresh-frozen tissue samples from patients with endometrial cancer from an initial cohort and 31 formalin-fixed paraffin-embedded tissue samples from a second cohort were subjected to genome-wide DNA methylation analysis using the Infinium MethylationEPIC BeadChip. Results: Epigenomic clustering of early-onset endometrial cancer was correlated with the widely used recurrence risk classification. Genes showing differences in DNA methylation levels between the low-recurrence-risk category and intermediate- and high-risk categories were accumulated in pathways related to fibroblast growth factor and nuclear factor-κB signaling. DNA hypomethylation and overexpression of ZBTB38 were frequently observed in the low-risk category. Eight hundred thirty-one marker CpG probes showed area under the curve values of >0.7 on the receiver operating characteristic curve for discrimination of patients belonging to the low-risk category. By combining marker CpG sites, seven panels for placing patients into the low-risk category with 91.3% or more sensitivity and specificity in both the initial and second cohorts were established. Conclusions DNA methylation diagnostics criteria using up to 6 of 8 CpG sites for LPP, FOXO1, RNF4, EXOC6B, CCPG1, RREB1 and ZBTB38 may be applicable to recurrence risk estimation for patients aged 40 years or less with endometrial cancer, regardless of tumor cell content, even if formalin-fixed paraffin-embedded biopsy or curettage materials are used.

STUDY DESIGN: Retrospective case series. PURPOSE: The purpose of this study was to examine changes in the ligamentum flavum thickness and remodeling of the spinal canal after anterior fusion during a 10-year follow-up. OVERVIEW OF LITERATURE: Extreme lateral interbody fusion provides minimally invasive treatment of the lumbar spine; this anterior fusion without direct posterior decompression, so-called indirect decompression, can achieve pain relief. Anterior fusion may restore disc height, stretch the flexure of the ligamentum flavum, and increase the spinal canal diameter. However, changes in the ligamentum flavum thickness and remodeling of the spinal canal after anterior fusion during a long follow-up have not yet been reported. METHODS: We evaluated 10 patients with L4 spondylolisthesis who underwent stand-alone anterior interbody fusion using the iliac crest bone. Magnetic resonance imaging was performed 10 years after surgery. The cross-sectional area (CSA) of the dural sac and the ligamentum flavum at L1–2 to L5–S1 was calculated using a Picture Archiving and Communication System. RESULTS: Spinal fusion with correction loss (average, 4.75 mm anterior slip) was achieved in all patients 10 years postsurgery. The average CSAs of the dural sac and the ligamentum flavum at L1–2 to L5–S1 were 150 mm² and 78 mm², respectively. The average CSA of the ligamentum flavum at L4–5 (30 mm²) (fusion level) was significantly less than that at L1–2 to L3–4 or L5–S1. Although patients had an average anterior slip of 4.75 mm, the average CSA of the dural sac at L4–5 was significantly larger than at the other levels. CONCLUSIONS: Spinal stability induced a lumbar ligamentum flavum change and a sustained remodeling of the spinal canal, which may explain the long-term pain relief after indirect decompression fusion surgery.
Decompression* ; Follow-Up Studies ; Humans ; Ligamentum Flavum* ; Magnetic Resonance Imaging ; Retrospective Studies ; Spinal Canal ; Spinal Fusion ; Spine ; Spondylolisthesis

STUDY DESIGN: Prospective study of changes in intervertebral disc degeneration after injection of bupivacaine. PURPOSE: To examine whether injection of bupivacaine into human intervertebral discs accelerates their degeneration. OVERVIEW OF LITERATURE: Bupivacaine is commonly used for therapy and diagnosis of discogenic low back pain. However, several in vitro studies have reported toxic effects of bupivacaine to disc cells. We sought to evaluate whether this finding is clinically relevant. METHODS: We selected 46 patients with low back pain who showed disc degeneration at only one level (L4-L5 or L5-S1) on magnetic resonance imaging (MRI) (discography group, n=18), discoblock group (injection of bupivacaine, n=18), and a control group, n=10). There were no significant differences in baseline characteristics across the 3 groups. The two experimental groups underwent either discography or anesthetic discoblock, respectively. All three groups were followed up 5 years after the examination. RESULTS: At 5 years follow-up, there was no significant difference in the rate of disc degeneration among the 3 groups (p>0.1). Moreover, X-ray images showed that there was no significant difference in disc height, range of motion, or translation between flex and extension position (p>0.1). CONCLUSIONS: In conclusion, radiologic and MRI findings did not show acceleration of intervertebral disc degeneration at 5 years after a single injection of bupivacaine into human discs.
Bupivacaine ; Follow-Up Studies ; Humans ; Intervertebral Disc ; Intervertebral Disc Degeneration ; Low Back Pain ; Lumbar Vertebrae ; Magnetic Resonance Imaging ; Prospective Studies ; Range of Motion, Articular