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Summary: Aims: A multi‐stakeholder consensus has proposed MASLD (metabolic dysfunction‐associated steatotic liver disease). We aimed to investigate the pathological findings related to the mid‐term mortality of patients with biopsy‐proven MASLD in Japan. Methods: We enrolled 1349 patients with biopsy‐proven MASLD. The observational period was 8010 person years. We evaluated independent factors associated with mortality in patients with MASLD by Cox regression analysis. We also investigated pathological profiles related to mortality in patients with MASLD using data‐mining analysis. Results: The prevalence of MASH and stage 3/4 fibrosis was observed in 65.6% and 17.4%, respectively. Forty‐five patients with MASLD died. Of these, liver‐related events were the most common cause at 40% (n = 18), followed by extrahepatic malignancies at 26.7% (n = 12). Grade 2/3 lobular inflammation and stage 3/4 fibrosis had a 1.9‐fold and 1.8‐fold risk of mortality, respectively. In the decision‐tree analysis, the profiles with the worst prognosis were characterised by Grade 2/3 hepatic inflammation, along with advanced ballooning (grade 1/2) and fibrosis (stage 3/4). This profile showed a mortality at 8.3%. Furthermore, the random forest analysis identified that hepatic fibrosis and inflammation were the first and second responsible factors for the mid‐term prognosis of patients with MASLD. Conclusions: In patients with biopsy‐proven MASLD, the prevalence of MASH and advanced fibrosis was approximately 65% and 20%, respectively. The leading cause of mortality was liver‐related events. Hepatic inflammation and fibrosis were significant factors influencing mid‐term mortality. These findings highlight the importance of targeting inflammation and fibrosis in the management of patients with MASLD. [ABSTRACT FROM AUTHOR]

Background and Aims: Both fibrosis status and body weight are important for assessing prognosis in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify population clusters for specific clinical outcomes based on fibrosis‐4 (FIB‐4) index and body mass index (BMI) using an unsupervised machine learning method. Methods: We conducted a multicenter study of 1335 biopsy‐proven NAFLD patients from Japan. Using the Gaussian mixture model to divide the cohort into clusters based on FIB‐4 index and BMI, we investigated prognosis for these clusters. Results: The cohort consisted of 223 cases (16.0%) with advanced fibrosis (F3–4) as assessed from liver biopsy. Median values of BMI and FIB‐4 index were 27.3 kg/m2 and 1.67. The patients were divided into four clusters by Bayesian information criterion, and all‐cause mortality was highest in cluster d, followed by cluster b (P = 0.001). Regarding the characteristics of each cluster, clusters d and b presented a high FIB‐4 index (median 5.23 and 2.23), cluster a presented the lowest FIB‐4 index (median 0.78), and cluster c was associated with moderate FIB‐4 level (median 1.30) and highest BMI (median 34.3 kg/m2). Clusters a and c had lower mortality rates than clusters b and d. However, all‐cause of death in clusters a and c was unrelated to liver disease. Conclusions: Our clustering approach found that the FIB‐4 index is an important predictor of mortality in NAFLD patients regardless of BMI. Additionally, non‐liver‐related diseases were identified as the causes of death in NAFLD patients with low FIB‐4 index. [ABSTRACT FROM AUTHOR]

Liver stiffness measurements (LSMs) and controlled attenuation parameters (CAPs) obtained using vibration-controlled transient elastography (VCTE) are recognized non-invasive methods of assessing liver histology. The usefulness of CAP for predicting liver-related events (LREs: hepatocellular carcinoma, decompensation, bleeding varices) is not well understood worldwide. Our aim was to re-evaluate the cutoff values of LSM/CAP in Japan and to examine whether LSM/CAP can predict LRE. Japanese NAFLD patients (n = 403) who underwent both liver biopsy and VCTE were enrolled. We determined optimal cutoff values of LSM/CAP diagnoses for fibrosis stage and steatosis grade and investigated their clinical outcome based on LSM/CAP values. The LSM cutoff values for F1 to F4 are 7.1, 7.9, 10.0 and 20.2 kPa, and the CAP cutoff values for S1 to S3 are 230, 282 and 320 dB/m. During a median follow-up of 2.7 y (range: 0.0–12.5 y), 11 patients developed LREs. The incidence of LREs in the LSM Hi (≥8.7) group was significantly higher than that in the LSM Lo (<8.7) group (p = 0.003), and the incidence in the CAP Lo (<295) group was higher than that in CAP Hi (≥295) group (p = 0.018). Considering LSM and CAP together, the risk of LRE was higher in the LSM Hi CAP Lo group than in the LSM Hi CAP Hi group (p = 0.03). We set LSM/CAP cutoff values to diagnose liver fibrosis and steatosis in Japan. Our study determined that NAFLD patients with high LSM and low CAP values are at high risk for LREs. [ABSTRACT FROM AUTHOR]

Aim: The enhanced liver fibrosis (ELF) test is a noninvasive method for diagnosing hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). This multicenter cohort study aimed to evaluate the accuracy of the ELF test and compare it with other noninvasive tests in Japan. Methods: We analyzed 371 Japanese patients with biopsy‐proven NAFLD. We constructed area under the receiver operator characteristic curves (AUROC) to determine the diagnostic accuracies of the ELF test, the Mac‐2‐binding protein glycosylation isomer (M2BPGi), the Fibrosis‐4 (FIB‐4) index, and combinations of these indices. Results: In patients with F0/F1/F2/F3/F4 fibrosis, the median values of the ELF test were 8.98/9.56/10.39/10.92/11.41, respectively. The AUROCs of the ELF test for patients with F0 versus F1–4, F0–1 versus F2–4, F0–2 versus F3–4, and F0–3 versus F4 fibrosis were 0.825/0.817/0.802/0.812, respectively. The AUROCs of the ELF test were greater than those of the FIB‐4 index and M2BPGi at each fibrosis stage. Respective low and high cut‐off values yielded sensitivities and specificities for predicting advanced fibrosis (≥F3) of 91.1% and 50.8%, and 38.5% and 92.8%, respectively. For F3 or F4 fibrosis, the combined values from the ELF test and FIB‐4 index showed a sensitivity of 98.5%, and the combined values from the ELF test and M2BPGi assay showed a specificity of 97.5%. Conclusions: In Japan, the ELF test predicts NAFLD‐related fibrosis from its early stages. The diagnostic ability of the ELF test was not inferior to that of other indices, and the combined values of ELF plus other indices were more accurate. [ABSTRACT FROM AUTHOR]

Introduction: Laparoscopic bariatric procedures have been performed in Japan since 2000. Laparoscopic sleeve gastrectomy (LSG) has been fully covered by National Health Insurance since 2014, and it has been increasingly performed recently. The Japan Consortium of Obesity and Metabolic Surgery conducts a nationwide survey on laparoscopic bariatric/metabolic surgery every 2 years. Methods: The survey was sent by post or email to 97 Japanese institutions in January 2020. Results: From 2000 to 2019, a total of 3669 laparoscopic bariatric/metabolic procedures were performed in 64 institutions. The most popular procedure was LSG (n = 2866), followed by LSG with duodenojejunal bypass (LSG‐DJB, n = 337) and laparoscopic Roux‐en‐Y gastric bypass (LRYGB, n = 280). Morbidity and reoperation rates were, respectively, 29.8% and 11.8% for LRYGB, 16.8% and 2.8% for LSG, and 13.6% and 6.6% for LSG‐DJB. At 5 years after the procedures, the percentage of excess weight loss was 78% for LRYGB, 66% for LSG, and 80% for LSG‐DJB. Conclusion: This nationwide survey clearly showed that laparoscopic bariatric/metabolic surgery has been safely and effectively performed for 20 years in Japan. [ABSTRACT FROM AUTHOR]

Summary: What is known and objective: The target trough concentration of tacrolimus for ulcerative colitis is recommended to be 10‐15 ng/mL in the initial two weeks and 5‐10 ng/mL in the later phase. However, the effectiveness of rapid attainment of these target trough concentrations of tacrolimus in patients with ulcerative colitis is still unclear. In the present study, we evaluated the clinical efficacy and safety of rapid attainment of target trough concentrations of tacrolimus in patients with ulcerative colitis. Methods: A prospective cohort was conducted at Gifu University Hospital in Gifu, Japan. Hospitalized patients who received tacrolimus for the treatment of ulcerative colitis between April 2009 and March 2017 were enrolled. Since June 2011, the initial loading dose of tacrolimus increased from 0.05 to 0.1‐0.2 mg/kg/d, and the maintenance dose to achieve the target trough concentration was determined to be 12.5 ng/mL by proportional calculation with measured blood concentration. The period required to attain target trough concentration and the clinical efficacy before and after dosage modification was compared. Results: The initial dose after dosage modification was significantly increased compared to that before dosage modification (0.10 [0.04‐0.22], median [range] mg/kg/d vs 0.05 [0.03‐0.05] mg/kg/d, P < 0.001). The period required to attain a target trough concentration over 10 ng/mL was significantly shortened by dosage modification (6 [4‐14] days before dosage modification vs 4.5 [2‐8] days after modification, P = 0.048). Further, stool frequency score was significantly improved after dosage modification, without affecting the incidence of adverse events. What is new and conclusion: Our findings suggest that rapid attainment of the target trough concentration of tacrolimus improves clinical symptoms in patients with ulcerative colitis. [ABSTRACT FROM AUTHOR]

Two huge earthquakes struck Kumamoto, Japan, in April 2016, forcing residents to evacuate. Few studies have reported early-phase disease and injury trends among evacuees following major inland earthquakes. We evaluated the trends among evacuees who visited a medical clinic in a shelter located at the epicenter of the 2016 Kumamoto earthquakes. The clinic opened on April 15, the day after the foreshock, and closed 3 weeks later. We reviewed medical charts related to 929 outpatient visits and conducted descriptive analyses. The evacuees experienced mild injuries and common diseases. The types of diseases changed weekly. Elderly people needed medical support for longer than other age groups. Future earthquakes may be inevitable, but establishing arrangements for medical needs or making precautions for infectious diseases in shelters could reduce the effects of earthquake-related health problems. [ABSTRACT FROM AUTHOR]

Background It is widely supposed that there has been no evidence of increased survival in patients with advanced dementia receiving enteral tube feeding. However, more than a few studies have reported no harmful outcome from tube feeding in dementia patients compared to in patients without dementia. Methods This was a retrospective study. Nine psychiatric hospitals in Okayama Prefecture participated in this survey. All inpatients fulfilling the entry criteria were evaluated. All subjects suffered from difficulty with oral intake. Attending physicians thought that the patients could not live without long-term artificial nutrition. The physicians decided whether to make use of long-term artificial nutrition between January 2012 and December 2014. Results We evaluated 185 patients. Their mean age was 76.6 ± 11.4 years. Of all subjects, patients with probable Alzheimer's disease ( n = 78) formed the biggest group, schizophrenia patients ( n = 44) the second, and those with vascular dementia ( n = 30) the third. The median survival times were 711 days for patients with tube feeding and 61 days for patients without tube feeding. In a comparison different types of tube feeding, median survival times were 611 days for patients with a nasogastric tube and more than 1000 days for those with a percutaneous endoscopic gastrostomy tube. Conclusion Patients with tube feeding survived longer than those without tube feeding, even among dementia patients. This study suggests that enteral nutrition for patients with dementia prolongs survival. Additionally, percutaneous endoscopic gastrostomy tube feeding may be safer than nasogastric tube feeding among patients in psychiatric hospitals. [ABSTRACT FROM AUTHOR]

Aim: Artificial nutrition, including tube feeding, continues to be given to dementia patients in numerous geriatric facilities in Japan. However, the clinical characteristics of patients receiving artificial nutrition have not been fully investigated. Therefore, we tried to evaluate the clinical features of those patients in this study. Methods: Various clinical characteristics of all inpatients at 18 of 20 psychiatric hospitals in Okayama Prefecture, Japan, with a percutaneous endoscopic gastrostomy tube, nasogastric tube, or total parenteral nutrition were evaluated. Results: Two hundred twenty ‐ one patients (5.4% of all inpatients) had been receiving artificial nutrition for more than 1 month, and 187 (130 women, 57 men; 84.6% of 221 patients) were fully investigated. The mean age was 78.3 years old, and the mean duration of artificial nutrition was 29.8 months. Eighty ‐ four patients (44.7% of 187 patients) were receiving artificial nutrition for more than 2 years. Patients with Alzheimer's disease (n = 78) formed the biggest group, schizophrenia (n = 37) the second, and vascular dementia (n = 26) the third. Conclusion: About one ‐ fifth of the subjects receiving artificial nutrition were in a vegetative state. More than a few patients with mental disorders, including schizophrenia, also received long ‐ term artificial nutrition. We should pay more attention to chronic dysphasia syndrome in mental disorders. [ABSTRACT FROM AUTHOR]

In this paper, a GaAs-AlGaAs double-heterostructure (DH) coupled-waveguide optical modulator, which is important as a multi-function optical component and for possible monolithic integration, has been studied in detail. A DH device with pn-junction structure, which is expected to have the lowest switching voltage, has been fabricated and the optical modulation characteristics have been measured at 1.06 μm wavelength. At a reverse bias of 13 V, an extinction ratio of 11 dB has been obtained. However, the cut-off frequency has been limited to about 250 MHz, which was lower than the calculated value of 1.1 GHz obtained using a simple lumped-element circuit analysis. Therefore, the optical modulation characteristics have been analyzed assuming the device as a distributed-element circuit line, and also taking into account the external parasitic impedancees. Thus it has been concluded that a reduction of the top-electrode resistance and an Increase of the conductance across the device cross-section are necessary to improve the high-frequency optical modulation characteristics. To verify these results, a DH Schottky contact structure, which essentially possesses no ohmic contact resistance with a thick top- electrode, has been fabricated on a MBE-grown wafer. At a reverse bias of 16 V, an extinction ratio of 12 dB and a cut-off frequency of 1.5 GHz have been obtained successfully. It has also been concluded that an even thicker top-electrode and an improved mounting method which minimizes the external parasitic elements are necessary for further improvement of the optical modulation frequency characteristics. [ABSTRACT FROM AUTHOR]

• How safe and effective is monotherapy with low-dose afatinib for patients with EGFR mutation positive, non-small cell lung cancer? • This multicenter, single-arm, open-label phase II trial involving 53 patients with EGFR positive non–small cell lung cancer revealed that the median PFS was 12.6 months, similar to that reported in previous studies. • In addition, the rate of adverse events was lower than that observed in previous phase III studies of 40 mg afatinib. • Based on its promising clinical efficacy and tolerability profile, monotherapy with low-dose afatinib should become one of the standard therapies for EGFR mutation-positive NSCLC. Afatinib is an effective treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, the toxicity associated with this agent often leads to dose modifications. The aim of this study was to assess the efficacy, safety and plasma concentrations of low dose afatinib monotherapy in patients with EGFR mutation-positive NSCLC. This was a multicenter, single-arm, open-label, phase II trial involving treatment-naïve patients with advanced EGFR mutation-positive NSCLC. From March 2017 to September 2018, 53 patients were enrolled from 21 institutions in Japan. Patients initially received afatinib 20 mg/day orally. For patients in whom the tumor progressed within stable disease, the investigators were able to increase the afatinib dose (10 mg increments). The primary endpoint was progression-free survival (PFS). The threshold and expected median PFS was 9.2 and 13.8 months, respectively. Additionally, the correlation of the plasma concentration of low-dose afatinib with clinical outcome and adverse events were evaluated. The median age of patients was 70 years (range: 37–85 years); 28 patients (52.8%) were females. The median duration of the follow-up was 20.8 months. The median PFS, and overall survival were 12.6 months (90% confidence interval [CI]: 9.7–14.3 months), and not reached, respectively. The primary endpoint was met. The objective response rate and disease control rate were 66.0% (95% CI: 51.7–78.5) and 92.5% (95% CI: 81.8–97.9), respectively. Grade ≥ 3 adverse events occurred in 12 patients (22.6%), including diarrhea in four patients (7.5%). The rate of adverse events was lower than that observed in previous phase III studies of 40 mg afatinib. Based on its promising clinical efficacy and tolerability profile, monotherapy with low-dose afatinib should become one of the standard therapies for EGFR mutation-positive NSCLC. [ABSTRACT FROM AUTHOR]

Background/aim: Sunitinib is used for the treatment of metastatic renal cell carcinoma (mRCC). Asian patients, including Japanese, tend not to tolerate long-term sunitinib therapy of 50 mg p.o. once daily for 4 weeks, followed by 2 week off treatment due to severe adverse events at this dosage level. The aim of this retrospective study was to investigate the optimal dose of sunitinib for long-term continuation in Asian patients with mRCC., Patients and Methods: The study cases were 50 patients with mRCC who were treated with sunitinib between June 2008 and December 2017. Risk analysis for "unacceptable" adverse events (depending on the physician, ranging from grade 2 to ≥ grade 3) leading to discontinuation of sunitinib was determined by time-dependent Cox proportional hazard regression analysis., Results: A total of 54 unacceptable adverse events leading to discontinuation occurred. Multivariable analysis indicated that a sunitinib dose of ≤ 37.5 mg/day significantly reduced the risk of discontinuation due to adverse events in comparison with 50 mg/day [hazard ratio (HR) 0.08, 95% confidence interval (CI) 0.03-0.21, p < 0.001). The progression-free survival (PFS) with a sunitinib dose ≤ 37.5 mg/day was longer than that associated with a dose of 50 mg/day, albeit not to a statistically significant degree (120 days for ≤ 37.5 mg/day vs 41 days for 50 mg/day, HR 0.39, 95% CI 0.10-1.44, p = 0.157)., Conclusion: Our findings suggest that the optimal dose of sunitinib for Asian, including Japanese, patients with mRCC is ≤ 37.5 mg/day.

Background: Because clinical data to confirm the safety and effectiveness of fosphenytoin, a prodrug of phenytoin, are insufficient, the length of administration of fosphenytoin is restricted. Nevertheless, some cases require fosphenytoin administration for more than a few days. The aim of this study was to retrospectively investigate the serum concentration of phenytoin in adult Japanese patients who received intravenous fosphenytoin therapy for more than 3 days., Methods: Patients injected with intravenous fosphenytoin for more than 3 days at Gifu University Hospital between January 2012 and September 2014 were enrolled. Individual pharmacokinetic parameters were predicted by Bayesian estimation using NONMEM software, and the maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration (10-20 mcg/mL) was calculated from the parameters., Results: Among a total of 8 patients, the serum trough concentration of phenytoin decreased with each day after repeated injection of fosphenytoin. The incidence rate of significant convulsive seizures was increased time dependently (0% on day 1, 12.5% on day 2, 25% on day 3, and 66.7% on day 4 and after). Phenytoin clearance showed a time-dependent increase. The maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration was simulated to be 779.8 ± 316.8 mg/d, a dose that was markedly higher than the actual maintenance dose (414.1 ± 55.7 mg/d)., Conclusions: Prolonged use of fosphenytoin, for such patients as those with autoimmune-mediated encephalopathy accompanied with reflux disease and/or ileus, time dependently decreased the serum concentration of phenytoin and increased the risk of convulsion. Therefore, the maintenance dose should be increased to maintain the therapeutic serum concentration.

Aim: Laparoscopic sleeve gastrectomy (LSG) has proven to be the most effective strategy for the treatment of morbid obesity, however its efficacy and safety in an aging population has not yet been confirmed. In this study, we evaluated the effectiveness and safety of LSG in elderly obese Japanese patients., Methods: Three obese individuals aged >60 years and 11 obese individuals aged <60 years who underwent LSG were enrolled. Pre- and postoperative changes after at least 12 months were examined, including bodyweight, body mass index, total weight loss, excess weight loss, bone mineral density and bone-related markers., Results: There were no significant differences between patients aged <60 years and >60 years in terms of percent total weight loss (24.4 ± 11 vs 23 ± 4.4%, respectively) and percent excess weight loss (49.1 ± 23.4 vs 47.6 ± 10 %, respectively). Dual-energy X-ray absorptiometry was carried out before and 12 months after LSG. There were no significant differences in bone mineral density changes at the lumbar spine and femoral neck between the two groups (0.01 ± 0.06 vs 0.02 ± 0.03 g/cm 2 , -0.03 ± 0.06 vs -0.08 ± 0.02 g/cm 2 , respectively). There were no peri- and postoperative complications. All three patients aged >60 years had reduced bone mineral density in the femoral neck after LSG; one was diagnosed with osteoporosis., Conclusions: Although the present results suggest that LSG could be of considerable benefit to elderly obese Japanese patients, long-term careful observation after bariatric surgery is especially important in elderly patients to prevent future osteoporosis. Geriatr Gerontol Int 2017; 17: 2068-2073., (© 2017 Japan Geriatrics Society.)

Background: J wave is known to be associated with increased risk of life-threatening ventricular arrhythmias in both structural and nonstructural heart disease. A documented history of ventricular tachycardia (VT) is also a known predictor for future arrhythmic events. The purpose of this study is to investigate prognostic factors in ventricular tachyarrhythmias in patients with an implanted defibrillator., Methods: Intracardiac electrograms were thoroughly analyzed in patients with either an implanted implantable cardioverter-defibrillator or with cardiac resynchronization therapy with a defibrillator. The relation between the clinical characteristics and the device interventions for ventricular tachyarrhythmias was evaluated retrospectively with multivariate Cox proportional hazards models., Results: This study enrolled a total of 160 patients who were followed for a mean period of 44 ± 28 months. Of these patients, 31 (19%) showed J wave and 77 (48%) showed documented VT before the device implantation. Multivariate Cox proportional hazards models revealed that the presence of J wave and the documented history of VT before the device implantation were independently associated with device intervention in patients with device implantation even after the adjustment of confounding factors (hazard ratio [HR], 2.90; 95% confidence interval [CI], 1.56-5.24; p=0.001 and HR, 4.34; 95% CI, 2.43-8.05; p<0.0001, respectively)., Conclusion: The presence of J wave and the documented history of VT prior to device implantation served as independent predictors of future device intervention for ventricular tachyarrhythmias., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Valproic acid, which is widely used to treat various types of epilepsy, may cause severe hyperammonemia. However, the mechanism responsible for this side effect is not readily apparent. Polymorphisms in the genes encoding carbamoyl-phosphate synthase 1 (CPS1) and N-acetylglutamate synthase (NAGS) were recently reported to be risk factors for the development of hyperammonemia during valproic acid-based therapy. This study aimed to examine the influence of patient characteristics, including polymorphisms in CPS1 4217C>A and NAGS -3064C>A, on the development of hyperammonemia in Japanese pediatric epilepsy patients. The study included 177 pediatric epilepsy patients. The presence of a 4217C>A polymorphism in CPS1 was determined using an allele-specific polymerase chain reaction (PCR)-based method, and the presence of a -3064C>A polymorphism in NAGS was determined using a PCR-based restriction fragment length polymorphism method. Hyperammonemia was defined as a plasma ammonia level exceeding 200 μg/dL. We observed a significant difference between the combination of valproic acid with phenytoin and the development of hyperammonemia in both univariate and multivariate analyses. With regard to the CPS1 4217C>A polymorphism, we did not observe a significant association with the development of hyperammonemia. In conclusion, CPS1 4217C>A polymorphism may not be associated with the development of hyperammonemia in Japanese population., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background/aims: It is important to retract the lateral liver segment during laparoscopic gastrectomy to achieve an optimal surgical field. Few retractors cause transient liver dysfunction after surgery; therefore, for an easier and safer procedure, we devised a new liver retractor and implemented a trial clinical application., Methodology: The novel liver retractor comprises a metallic, flexible arm retractor attached to the operating table and an air compressor which pneumatically moves and fixes the retractor. It was inserted directly into the abdominal cavity just below the xiphisternum to retract the left lobe of the liver anterosuperiorly, thereby exposing the hiatus. Blood samples were collected from the patients on days 1, 3, and 7 after surgery to assess the levels of the liver enzymes AST and ALT., Results: During laparoscopic gastrectomy, no liver damage was observed macroscopically. The surgical fields obtained were optimal and efficient for laparoscopic surgery. Notably, it was possible to retract the liver as often as needed. Further, none of the patients developed postoperative liver dysfunction., Conclusions: The novel flexible-arm retractor provided an optimal surgical field without inducing liver dysfunction.

Methotrexate (MTX) exhibits large inter-individual and inter-ethnic differences in the dose required for its anti-rheumatic effect. To maintain low disease activity, patients may require increased MTX doses or co-administration of biologic disease-modifying anti-rheumatic drugs (bDMARDs). The availability of a marker predicting the effect of MTX will make it possible to increase the MTX dose and prescribe bDMARDs to patients at an early stage. To establish individualized medication for rheumatoid arthritis (RA), we investigated genetic polymorphisms of the folate pathway in Japanese RA patients. Eighty-nine patients were treated with MTX alone (MTX group). MTX and bDMARDs were co-administered to 81 patients because of insufficient MTX efficacy (MTX + bDMARDs group); an equally stable therapeutic effect was achieved in both groups. Polymorphism analyses using bDMARD co-treatment as the objective variable revealed a significant association between age and the G80A polymorphism of the reduced folate carrier 1 gene (RFC1) as an explanatory variable. Compared to patients with the A allele, patients with the G allele may have less intracellular MTX uptake and, therefore, poor efficacy; a greater number of them were found to be bDMARD concomitant cases. The results of this study suggest that the RFC1 G80A polymorphism may be a useful marker for predicting MTX efficacy in Japanese patients with RA.

New-generation pharmacists who graduate from the 6-year pharmacy education program will come into being in Japan in 2 years' time. The new program regards technical skills and caring attitudes suitable for healthcare professionals as important, as well as expert knowledge. Pharmacists are expected to become more involved in pharmacotherapy and patient care to overcome rural physician shortage and achieve better outcomes in pharmacotherapy. Pharmacists themselves also want to contribute to improve pharmacotherapy and patient care. Pharmacists educated with the former 4-year education program, however, hardly had a chance to learn clinical pharmacy or pharmaceutical care when they were pharmacy students. They have so far studied clinical knowledge, skills, and attitudes by themselves mostly after graduation. Therefore most pharmacists have not received systematic education or training about clinical pharmacy. Pharmacy schools employ pharmacists and physicians as professors, and built practical rooms for pre-clinical training to study pharmacy practice in recent years. We should use those human resources and laboratory equipment in pharmacy schools to facilitate recurrent education for pharmacists. Internet-based real time remote lecture is also useful for pharmacists working far from pharmacy schools to attend a recurrent class. I propose an education system in which pharmacists who completed the recurrent education program teach students pharmacy practice in their worksites, and both pharmacists and students are developing their practical skills to a high degree together.

Dihydrofolate reductase gene (DHFR) 19-bp deletion polymorphisms result in varied DHFR enzymatic activity affecting the risk for preterm delivery, spina bifida, and the efficacy of methotrexate (MTX). Ethnic differences in DHFR 19-bp polymorphisms may be responsible for the divergent findings in previous genetic studies. We compared genotype and allele frequency of DHFR intronic 19-bp deletion polymorphisms in ethnically homogenous East Asians (from Japan) and others by polymerase chain reaction assay conducted on 277 healthy Japanese individuals. The genotype distribution was as follows: wild/wild, 11.9% (n=33); wild/deletion, 40.1% (n=111); deletion/deletion, 48.0% (n=133). The frequencies of wild type and deletion alleles were 0.32 and 0.68, respectively. The obtained genotype distribution was consistent with those calculated by Hardy-Weinberg equilibrium. The genotype distribution and allele frequencies in the Japanese population were significantly different from those previously reported for other ethnic populations. Determination of intronic 19-bp deletion polymorphisms of DHFR may be useful for monitoring the efficacy and side effects of MTX for the treatment of diseases such as rheumatoid arthritis and childhood acute leukemia in the Japanese population because the frequency of the deletion allele is higher.

Hyperhomocysteinemia is a known risk factor of cardiovascular disease. Homocysteine has been also linked to inflammation in rheumatoid arthritis (RA). In this study, we investigated the relationship between plasma homocysteine levels and single nucleotide polymorphism (SNP) of the gene coding for methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in the biosynthesis of homocysteine, and the correlation between the plasma homocysteine levels and generally used inflammatory markers (C-reactive protein, erythrocyte sedimentation rate and matrix metalloproteinase-3) in 96 Japanese patients with RA. Plasma homocysteine levels in patients with the MTHFR 677TT genotype were significantly higher than in those with the 677CC genotype (p < 0.05). In addition, plasma homocysteine levels were increased along with the elevation of general inflammatory markers. Therefore, we conclude that homocysteine might affect the inflammatory status of patients, and the MTHFR 677C>T SNP could be a predictive factor of hyperhomocysteinemia in patients with RA.

Background: Because invasion to an adjacent organ (T4) indicates highly advanced disease, and most surgeons avoid esophagectomy, the prognostic impact of clinicopathologic factors for survival of these patients after esophagectomy has rarely been analyzed., Study Design: From 1960 to 2005, a total of 268 patients with esophageal squamous cell carcinoma underwent esophagectomy for pathologic T4 disease (pT4). The impact of clinicopathologic factors on survival was evaluated by univariate and multivariate analysis. Changes in surgical outcomes and longterm survival between the earlier period (1960 to 1989) and the later period (1990 to 2005) were analyzed., Results: Overall survival rates of all patients were 25% at 1 year, 10% at 3 years, and 5% at 5 years. The survival curve of the later group was significantly better than that of the earlier group (p < 0.01). Multivariate analysis indicated that venous invasion (hazards ratio, 1.76; 95% CI, 1.33 to 2.33, p < 0.01) and presence of a postoperative complication (hazards ratio, 2.62; 95% CI, 1.96 to 3.51, p < 0.01) were independent risk factors for poor overall survival. Presence of residual cancer was also an independent risk factor for poor cause-specific survival (hazards ratio, 2.40; 95% CI, 1.23 to 4.69, p=0.01). Venous invasion and intramural metastasis were risk factors for residual cancer. A total of 38 (14%) patients, 15 in the early period and 23 in the later period, underwent complete resection (R0). Although overall survival after R0 resection in the later period improved slightly, cancer-related survival rates were similar in both periods., Conclusions: Although overall survival of patients with pT4 improved after 1990, this improvement might be mainly dependent on curability of the resection.

We investigated the genotype distribution and allele frequency of C452T polymorphism of gamma-glutamyl hydrolase (GGH) gene, which causes the decreased enzymatic activity affecting the efficacy of methotrexate (MTX), in a Japanese population. The polymerase chain reaction-restriction fragment length polymorphism assay was applied to determine the genotype of C452T polymorphism in 269 Japanese healthy individuals. The genotype distribution was as follows: C/C, 89.2% (n=240); C/T, 10.4% (n=28); T/T, 0.4% (n=1). The frequency of C and T allele was 0.944 and 0.056, respectively. The obtained genotype distribution was well agreed with those expected by Hardy-Weinberg equilibrium. The genotype distribution and allele frequency in a Japanese population were found to be similar to those of African-Americans but significantly different from Caucasians. Although the frequency of variant T allele in a Japanese population is not so high as compared to Caucasians, determination of C452T polymorphism of GGH may be useful for monitoring of efficacy and side-effects of MTX for treatment of diseases such as rheumatoid arthritis or childhood acute leukemia. To our knowledge, this is the first report about the examination of C452T polymorphism of GGH in a Japanese population.