Statin persistence and adherence among older initiators: A nationwide cohort study using the national health insurance claims database in Japan.

PURPOSE: This study clarifies the reality of persistence and adherence to statins in older Japanese people who initiated statin use and compares it between primary and secondary prevention cohorts. METHODS: The nationwide study using the national claims database targeted statin initiators aged ≥55 years from FY2014 to FY2017 in Japan. Persistence and adherence to statins were analyzed overall and according to subgroups based on sex, age stratum, and prevention cohorts. Permissible gap of median days that statins were supplied per prescription to an individual was employed. Persistence rates were estimated as Kaplan-Meier estimates. Poor adherence during persistence was evaluated and defined as <0.8 of the proportion of days covered. RESULTS: Of 3 675 949 initiators, approximately 80% initiated statin use with strong variants. The persistence rate at 1 year was 0.61. Poor adherence to statins during persistence was 8.0% in all patients and this value gradually improved with increasing age. Persistence rate and adherence were lower for the primary prevention cohort than for the secondary prevention cohort, and a notable sex difference was observed for the secondary prevention cohort, which was lower in females but was almost never and slightly observed in the primary prevention cohorts without and with high-risk factors, respectively. CONCLUSIONS: Many statin initiators discontinued statins shortly following statin initiation but adherence while on statin therapy was good. Attentively watching older patients not to discontinue statins and listening to their reasons for discontinuation are required, especially for initiators in primary prevention and females in secondary prevention.

Statin, Ezetimibe, or Fibrate Initiation and Subsequent Use for the Primary and Secondary Prevention of Cardiovascular Diseases among Japanese Patients Aged ≥55 Years: A Nationwide Cohort Study.

The use of lipid-modifying agents (LMAs) other than statins has rarely been reported in real clinical settings. We aimed to compare the initiation and subsequent use of LMA classes for prevention of cardiovascular diseases. Using the national claims database, this retrospective cohort study was conducted on patients aged ≥55 years who initiated to use statins, ezetimibe, or fibrates between Fiscal Years (FYs) 2014 and 2017 as the first pharmacotherapy for dyslipidemia in Japan. A permissible gap for defining persistence was set as the median days of supply of a class to an individual. Kaplan-Meier estimates were calculated for rates. Cohorts for primary prevention without/with risk and secondary prevention comprised 1307438, 908378, and 503059 initiators for statins; 44116, 34206, and 11373 for ezetimibe; and 124511, 96380, and 27751 for fibrates. The persistence rates declined shortly after the therapy initiation regardless of the classes, which was approximately 50% at 1 year for any class for primary prevention without risk. A notable sex difference in terms of persistence rates was observed only for statins of secondary prevention. The restarting rates were similar between prevention settings: approximately 50-60% for statins and 30-40% for ezetimibe and fibrates 1 year after first discontinuation. For ezetimibe and fibrates, approximately 10% of initiators were added or switched to statins within 1 year of initiation. Collectively, any class tended to be discontinued early and some restarted; however, there were some unique classes. The findings are useful for improvement of dyslipidemia therapy.

A novel weighting method to remove bias from within-subject exposure dependency in case-crossover studies.

BACKGROUND: Case-crossover studies have been widely used in various fields including pharmacoepidemiology. Vines and Farrington indicated in 2001 that when within-subject exposure dependency exists, conditional logistic regression can be biased. However, this bias has not been well studied. METHODS: We have extended findings by Vines and Farrington to develop a weighting method for the case-crossover study which removes bias from within-subject exposure dependency. Our method calculates the exposure probability at the case period in the case-crossover study which is used to weight the likelihood formulae presented by Greenland in 1999. We simulated data for the population with a disease where most patients receive a cyclic treatment pattern with within-subject exposure dependency but no time trends while some patients stop and start treatment. Finally, the method was applied to real-world data from Japan to study the association between celecoxib and peripheral edema and to study the association between selective serotonin reuptake inhibitor (SSRI) and hip fracture in Australia. RESULTS: When the simulated rate ratio of the outcome was 4.0 in a case-crossover study with no time-varying confounder, the proposed weighting method and the Mantel-Haenszel odds ratio reproduced the true rate ratio. When a time-varying confounder existed, the Mantel-Haenszel method was biased but the weighting method was not. When more than one control period was used, standard conditional logistic regression was biased either with or without time-varying confounding and the bias increased (up to 8.7) when the study period was extended. In real-world analysis with a binary exposure variable in Japan and Australia, the point estimate of the odds ratio (around 2.5 for the association between celecoxib and peripheral edema and around 1.6 between SSRI and hip fracture) by our weighting method was equal to the Mantel-Haenszel odds ratio and stable compared with standard conditional logistic regression. CONCLUSION: Case-crossover studies may be biased from within-subject exposure dependency, even without exposure time trends. This bias can be identified by comparing the odds ratio by the Mantel-Haenszel method and that by standard conditional logistic regression. We recommend using our proposed method which removes bias from within-subject exposure dependency and can account for time-varying confounders.

Prescription sequence symmetry analysis: assessing risk, temporality, and consistency for adverse drug reactions across datasets in five countries.

BACKGROUND: Prescription sequence symmetry analysis (PSSA) is a signal detection method for adverse drug events. Its capacity to consistently detect adverse drug events across different settings has not been tested. We aimed to determine the consistency of PSSA results for detecting positive and negative control adverse drug events across different settings. METHODS: Using a distributed network model, we analyzed prescription dispensing data using PSSA in Australia, Hong Kong, Japan, Korea, and Taiwan. Positive control was amiodarone and thyroxine, as a marker of amiodarone-induced hypothyroidism, a known adverse event with a clear temporal relationship to amiodarone initiation. Negative controls were amiodarone and allopurinol, as a marker of amiodarone-induced gout and thyroxine and allopurinol, as a marker of thyroxine-induced gout. Gout is not recorded as an adverse event in product information for either medicine. Adjusted sequence ratios (ASR) were calculated for each country. Pooled estimates were obtained by using the generic inverse variance method. RESULTS: A positive association was identified between amiodarone and thyroxine in all settings with a pooled ASR 2.63 (95% confidence interval (CI) 1.47-4.72). Temporal analysis showed the effect occurred within the first few weeks of treatment. No significant associations were found for the negative controls in any setting; pooled ASR were 0.76 (95%CI 0.62-0.93) and 0.98 (95%CI 0.85-1.12) for amiodarone-allopurinol and thyroxine-allopurinol, respectively. CONCLUSION: Despite different health settings, different populations, and different patterns of medicine utilization, PSSA gave consistent estimates across countries for a well-known positive association and two negative control adverse events.

Multi-country rapid adverse drug event assessment: the Asian Pharmacoepidemiology Network (AsPEN) antipsychotic and acute hyperglycaemia study.

PURPOSE: To undertake a multi-country study to investigate the risk of acute hyperglycaemia with antipsychotic use. METHODS: Using a distributed network model with a common minimal data set, we performed a prescription sequence symmetry analysis (PSSA) to investigate the risk of acute hyperglycaemia associated with antipsychotic initiation. Incident insulin prescriptions were used as a proxy indicator of acute hyperglycaemia. Participating countries and population datasets included Australia (300,000 persons), Japan I (300,000 persons), Japan II (200,000 persons), Korea (53 million persons) Taiwan (1 million persons), Sweden (9 million persons), USA-Public (87 million persons) and USA-Private (47 million persons). RESULTS: Olanzapine showed a trend towards increased risk in most databases, with a significant association observed in the USA-Public database (Adjusted sequence ratio (ASR) = 1.14; 95% Confidence Interval (CI) 1.10-1.17) and Sweden (ASR = 1.53; 95% CI 1.13-2.06). Null or negative associations were observed for haloperidol, quetiapine and risperidone. CONCLUSION: Acute hyperglycaemia appears to be associated with olanzapine use, however, this effect was only observed in two large databases. Despite different patterns of utilization of both antipsychotics and insulin, PSSA analysis results for individual antipsychotic medicines were qualitatively similar across most countries. PSSA, used in conjunction with existing methods, may provide a simple and timely method further supporting multi-national drug safety monitoring.

High SLC20A1 Expression Indicates Poor Prognosis in Prostate Cancer.

BACKGROUND/AIM: High expression of solute carrier family 20 member 1 (SLC20A1) indicates poor clinical outcomes for patients with breast cancer subtypes treated with endocrine therapy and radiotherapy. However, the association between SLC20A1 expression and clinical outcomes in prostate cancer remains to be determined. MATERIALS AND METHODS: Open-source datasets (The Cancer Genome Atlas prostate, Stand Up to Cancer-Prostate Cancer Foundation Dream Team, and The Cancer Genome Atlas PanCancer Atlas) were downloaded and analyzed. SLC20A1 expression was analyzed in prostate cancer and normal prostate tissue. Survival analysis using Kaplan-Meier curves and Cox regression analysis were performed to examine patient prognosis, as well as the effects of endocrine therapy and radiotherapy on high SLC20A1 expression in patients with prostate cancer. RESULTS: SLC20A1 was higher in prostate cancer than in normal prostate tissues. High SLC20A1 expression predicted poor disease-free and progression-free survival. Following endocrine therapy, no significant difference in prognosis was observed between patients with high SLC20A1 and those with low SLC20A1 expression. However, following radiotherapy, high SLC20A1 expression tended to be associated with a poor clinical outcome. CONCLUSION: SLC20A1 may serve as a prognostic biomarker for prostate cancer, and the recommended treatment for patients with high SLC20A1 expression is endocrine therapy.

High expression of SLC20A1 is less effective for endocrine therapy and predicts late recurrence in ER-positive breast cancer.

Estrogen receptor-positive (ER+) breast cancer intrinsically confers satisfactory clinical outcomes in response to endocrine therapy. However, a significant proportion of patients with ER+ breast cancer do not respond well to this treatment. Therefore, to evaluate the effects of endocrine therapy, there is a need for identification of novel markers that can be used at the time of diagnosis for predicting clinical outcomes, especially for early-stage and late recurrence. Solute carrier family 20 member 1 (SLC20A1) is a sodium/inorganic phosphate symporter that has been proposed to be a viable prognostic marker for the luminal A and luminal B types of ER+ breast cancer. In the present study, we examined the possible association of SLC20A1 expression with tumor staging, endocrine therapy and chemotherapy in the luminal A and luminal B subtypes of breast cancer. In addition, we analyzed the relationship between SLC20A1 expression and late recurrence in patients with luminal A and luminal B breast cancer following endocrine therapy. We showed that patients with higher levels of SLC20A1 expression (SLC20A1high) exhibited poorer clinical outcomes in those with tumor stage I luminal A breast cancer. In addition, this SLC20A1high subgroup of patients exhibited less responses to endocrine therapy, specifically in those with the luminal A and luminal B subtypes of breast cancer. However, patients with SLC20A1high showed good clinical outcomes following chemotherapy. Patients tested to be in the SLC20A1high group at the time of diagnosis also showed a higher incidence of recurrence compared with those with lower expression levels of SLC20A1, at >15 years for luminal A breast cancer and at 10-15 years for luminal B breast cancer. Therefore, we conclude that SLC20A1high can be used as a prognostic biomarker for predicting the efficacy of endocrine therapy and late recurrence for ER+ breast cancer.

High SLC20A1 Expression Is Associated With Poor Prognosis for Radiotherapy of Estrogen Receptor-positive Breast Cancer.

BACKGROUND/AIM: Radiotherapy is one of the main treatments for estrogen receptor-positive (ER+) breast cancer. However, in some ER+ breast cancer cases, radiotherapy is insufficient to inhibit progression and there is a lack of markers to predict radiotherapy insensitivity. Solute carrier family 20 member 1 (SLC20A1) is a sodium/inorganic phosphate symporter, which has been proposed to be a viable prognostic marker for luminal A and B types of ER+ breast cancer. The present study examined the possibility of SLC20A1 as a novel biomarker for the prediction of radiotherapy efficiency. PATIENTS AND METHODS: The Molecular Taxonomy of Breast Cancer International Consortium dataset was downloaded from cBioportal and the prognosis of patients with high SLC20A1 expression (SLC20A1 high ) was compared with that of patients with low SLC20A1 expression, without or with radiotherapy and tumor stages I, II, and III, using the Kaplan-Meier method and multivariate Cox regression analyses of disease-specific and relapse-free survival. RESULTS: Patients in the SLC20A1 high group with radiotherapy showed poor clinical outcomes in both luminal A and luminal B breast cancers. Furthermore, in luminal A breast cancer at tumor stage I, patients in the SLC20A1 high  group with radiotherapy also showed poor clinical outcomes. Therefore, these results suggest that radiotherapy is insufficient for patients in the SLC20A1 high group for both luminal A and B types, and especially for the luminal A type at tumor stage I. CONCLUSION: SLC20A1 can be used as a prognostic marker for the prediction of the efficacy of radiotherapy for luminal A and luminal B breast cancers.

Event Monitoring and Evaluation by Community Pharmacists in Japan: A Pilot Study on Fenofibrate and Pemafibrate.

BACKGROUND: The Japan Pharmaceutical Association has conducted drug event monitoring to detect drug events related to pemafibrate. As there are a few studies on the safety of pemafibrate in clinical settings, a pilot study evaluating the association between drug use and detected events was performed in Japan. AIMS: In this study, the association between detected events and the use of pemafibrate, utilizing pharmacy records maintained by community pharmacists, was investigated. We identified the newuser cohort using a test and active comparison drug and collected the baseline information. An active comparison group comprising new users was used to assess the events. METHODS: A retrospective cohort study using questionnaires regarding baseline and event data was conducted by community pharmacists belonging to the Japan Pharmaceutical Association. The incidence of event and estimated hazard ratio were calculated using the Cox proportional hazards model that was adjusted for confounding factors, such as age and sex. RESULTS: A total of 1294 patients using pemafibrate and 508 patients using fenofibrate were identified as new drug users. The most reported events involving suspected adverse reactions and add-on drugs were increased blood pressure and lipid-lowering effects with pemafibrate use, and nasopharyngitis, pruritus, dizziness, and lipid-lowering effects with fenofibrate use. No significant differences were found in commonly occurring events, except that an add-on anti-hypertensive drug has been used by pemafibrate users compared to fenofibrate users. CONCLUSION: This study conducted by pharmacists can facilitate the safety assessment of newly marketed drugs, as few drug use investigations with a comparator are carried out by the Japanese authority for pharmaceutical companies. However, further research is required.

High Expression of p62 and ALDH1A3 Is Associated With Poor Prognosis in Luminal B Breast Cancer.

BACKGROUND/AIM: p62 (also known as sequestosome 1) is involved in cancer progression, and high expression of p62 indicates poor clinical outcome in several cancer types. However, the association between p62 gene expression and cancer stem cells (CSCs) in breast cancer subtypes remains unclear. MATERIALS AND METHODS: In the present study, genomic datasets of primary breast cancer (The Cancer Genome Atlas, n=593; and Molecular Taxonomy of Breast Cancer International Consortium, n=2,509) were downloaded. p62 Expression was then examined in normal and breast cancer tissues derived from the same patients. Kaplan-Meier and multivariate Cox regression analyses were employed to evaluate disease-specific survival. Next, the effect on cell viability and in vitro tumor-sphere formation of p62 knockdown using targeted small interfering RNA was assessed by using cells with high activity of aldehyde dehydrogenase 1 (ALDH1high). RESULTS: Patients with normal-like, luminal A or luminal B breast cancer with p62high had poor prognosis. Furthermore, patients with p62high ALDH1A3high luminal B type also exhibited poor prognoses. Knockdown of p62 suppressed viability and tumor-sphere formation by ALDH1high cells of the luminal B-type cell lines BT-474 and MDA-MB-361. These results suggest that p62 is essential for cancerous progression of ALDH1-positive luminal B breast CSCs, and contributes to poor prognosis of luminal B breast cancer. CONCLUSION: p62 is potentially a prognostic marker and therapeutic target for ALDH1-positive luminal B breast CSCs.

Survival and prognostic factors in malignant pleural mesothelioma: a retrospective study of 314 patients in the west part of Japan.

OBJECTIVE: The objective in our study was to examine baseline and other characteristics associated with survival in patients with malignant pleural mesothelioma in Japan. METHODS: Three hundred and fourteen patients with an adjudicated diagnosis of mesothelioma were examined. Survival was evaluated by the Kaplan-Meier method with the log-rank test. The Cox model was used to estimate the hazard ratio for the possible prognostic factors. RESULTS: Of 314 patients, 223 (71%) died and only 40 (13%) were still alive at the end of the observation period starting from the day of diagnosis, while 51 (16%) were transferred to other hospitals or had the last health service contact before the end of the study period yielding the median survival of 308 days. In the multivariate analysis, age older than 70 years (hazard ratio = 2.17; 95% confidence interval, 1.36-3.46), non-epithelioid type (hazard ratio = 1.58; 95% confidence interval, 1.15-2.18), poor performance status (hazard ratio = 3.22; 95% confidence interval, 1.19-8.74), high white blood cell count (hazard ratio = 1.49; 95% confidence interval, 0.99-2.26) and high C-reactive protein level (hazard ratio = 1.80; 95% confidence interval, 1.06-3.06) were negatively associated with survival, after adjustment for other factors. CONCLUSIONS: Some baseline conditions including old age, poor performance status, non-epithelioid type, high white blood cell count and high C-reactive protein level were determinants of poor survival of patients with malignant mesothelioma.

Incidence of interstitial lung disease in patients with mesothelioma in the west part of Japan.

PURPOSE: In order to evaluate the incidence of an adverse event encountered when using a new therapeutic intervention, it is essential to know the background rate of this adverse event in the same patient population. Interstitial lung disease (ILD) often develops in Japanese patients receiving treatment with anti-neoplastic agents or other drugs. In our study, we estimated the background rate of ILD in patients with malignant mesothelioma (MM). METHODS: We conducted a retrospective cohort study of 328 Japanese patients diagnosed with MM during the period between 1996 and 2006. RESULTS: After the diagnosis of MM had been made, 21 (15 new and 6 exacerbation) of the 328 patients developed ILD. The crude baseline rate of ILD was estimated to be 0.023 (95%CI, 0.009-0.054) per patient-year, and the baseline rate using the Poisson regression model was estimated to be 0.032 (95%CI, 0.017-0.059) per patient-year where major therapeutic interventions were incorporated in the model. The risk of ILD was increased by surgical excision (rate ratio, 8.87; 95%CI, 2.39-33.0), pleurodesis with picibanil (rate ratio, 5.14; 95%CI, 1.63-16.3), and systemic chemotherapy using vinorelbine (rate ratio, 5.95; 95%CI, 1.22-29.0). CONCLUSIONS: Our results have implications for evaluating the safety outcomes of future studies in patients receiving treatment for MM. The development of ILD in such studies at an incidence rate higher than 0.02-0.03 per patient-year might indicate an excess occurrence as a result of a therapeutic intervention.

Safety of elobixibat and lubiprostone in Japanese patients with chronic constipation: a retrospective cohort study.

BACKGROUND: We aimed to discuss and compare reported adverse reactions and drug add-ons associated with elobixibat and lubiprostone use in chronic constipation treatment, as the safety of these drugs has not been well examined in post-marketing clinical settings. RESEARCH DESIGN AND METHODS: In this retrospective cohort study, using records of community pharmacies in Japan, we identified new users of elobixibat and lubiprostone. The Japan Pharmaceutical Association sent questionnaires regarding baseline and event data to community pharmacists. The incidence of events and hazard ratio (HR) associated with the study drugs were evaluated. RESULTS: New users of elobixibat (n = 979) and lubiprostone (n = 829) were identified (mean age: 74 and 77 years; females: 59% and 53%, respectively). Although the crude risk ratio of adverse events for elobixibat was 0.79 (95% confidence interval: 0.63-0.99), there was no significant difference in the HR for any of the common events, including drug add-ons (n ≥ 5), compared with those for lubiprostone. CONCLUSION: No new safety concerns have been raised in relation to elobixibat and lubiprostone use for treating chronic constipation, although the HR of different events varied. Further larger-scale study is needed as the estimates for events of small numbers were unstable.

Evaluation of rapid drug safety communication materials for patients in Japan.

Since 2011, pharmaceutical companies in Japan have been required to issue two types of documents regarding severe adverse drug reactions reported post-marketing, namely the Rapid Safety Communication Materials for Patients and the Related Materials. However, the adequacy of these documents has not yet been systematically assessed. The aim of this study was to evaluate the adequacy of these two types of materials. The Rapid Safety Communications for Patients were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website. The Related Materials were obtained from pharmaceutical companies or the PMDA website. Three assessors independently scored the Rapid Safety Communication for Patients and the Related Materials using the Centers for Disease Control and Prevention Clear Communication Index (CCI). In addition, the contents and descriptions of the materials were analyzed. In total, 13 materials for seven drugs were assessed. Almost all materials contained the "main message" and "call to action". However, the average CCI scores for the Rapid Safety Communication for Patients and Related Materials for Patients were 68.8 and 74.3 (out of 100), respectively. Further, none of the evaluated materials were scored above the CCI threshold score (i.e., ≥ 90%). Descriptions regarding "language", "state of science", and "risk" were not adequate. In particular, the terminology used in materials seemed difficult for patients to understand. In conclusion, the Japanese Rapid Communication Materials for Patients require improvement. Furthermore, a system for evaluating these materials prior to publication should be established.

High SLC20A1 Expression Is Associated With Poor Prognoses in Claudin-low and Basal-like Breast Cancers.

BACKGROUND/AIM: SLC20A1 has been identified as a prognostic marker in ER+ breast cancer. However, the role of SLC20A1 expression in breast cancer subtypes other than the ER+ types remains unclear. MATERIALS AND METHODS: Genomics datasets were downloaded and analyzed, and the effect of SLC20A1 knockdown using targeted siRNA on cell viability and tumor-sphere formation was assessed. RESULTS: SLC20A1high patients with ER+, claudin-low or basal-like breast cancers showed poor prognoses. SLC20A1high patients treated with radiotherapy had poor clinical outcomes. SLC20A1 knockdown suppressed the viability of MDA-MB 231 (claudin-low), MDA-MB 468 (basal-like) and MCF-7 (ER+) cells, and tumor-sphere formation by ALDH1high cells. These results suggest that SLC20A1 is involved in cancer progression and contributes to clinical outcomes in patients with ER+, claudin-low and basal-like breast cancers. CONCLUSION: SLC20A1 is a potential prognostic marker and therapeutic target in ER+, claudin-low and basal-like breast cancers.

Real-world evidence of population differences in allopurinol-related severe cutaneous adverse reactions in East Asians: A population-based cohort study.

Allopurinol-related severe cutaneous adverse reactions (SCARs) are strongly associated with HLA-B*58:01, the allele frequency (AF) of which is largely different among East Asians. However, evidence of population differences in SCAR development and relevance of genetic and/or other risk factors in the real-world remain unelucidated. This study aimed to evaluate population differences in allopurinol-related SCAR incidence related to genetic and/or other risk factors among East Asians in the real-world. A population-based cohort study was conducted using claims databases from Taiwan, Korea, and Japan. New users of allopurinol (311,846; 868,221; and 18,052 in Taiwan, Korea, and Japan, respectively) were followed up to 1 year. As control drugs, phenytoin and carbamazepine were used. The crude incidence rate ratios (IRRs) of SCARs for allopurinol against phenytoin or carbamazepine were the highest in Taiwan (IRR, 0.62 and 1.22; 95% confidence interval [CI], 0.54-0.72 and 1.01-1.47, respectively), followed by Korea (IRR, 0.34 and 0.82; 95% CI, 0.29-0.40 and 0.77-0.87), and the lowest in Japan (IRR, 0.04 and 0.16; 95% CI, 0.02-0.08 and 0.09-0.29). This order was accordant with that of AF ratios (AFRs) reported of HLA-B*58:01 against alleles responsible for phenytoin- or carbamazepine-related SCARs. The IRRs were higher in patients with chronic kidney disease, females, and elderly. This study demonstrated population differences in the risk of allopurinol-related SCAR development among East Asians based on genetic and other common risk factors. This finding will help to promote appropriate risk management for allopurinol-related SCARs based on ethnic origins. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THIS TOPIC? Allopurinol-related severe cutaneous adverse reactions (SCARs) are strongly associated with HLA-B*58:01, the allele frequency of which is largely different among East Asians. However, there is no direct real-world evidence of population differences in SCAR development and the influence of genetic factors and/or other risk factors. WHAT QUESTION DID THIS STUDY ADDRESS? Do population differences in development of allopurinol-related SCARs, depending on genetic factors and/or other risk factors, exist among three East Asians in the real-world? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The current analysis, based on comparisons of relative risks of SCAR incidence, provides real-world evidence of population differences in allopurinol-related SCAR development risk among East Asians, which was consistent with differences in reported HLA-B*58:01 frequencies, as well as identifying chronic kidney disease, female gender, and old age as common risk factors. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study helps to promote appropriate risk management strategies for allopurinol-related SCARs in the real-world considering risk factors based on the patients' ethnicity. Our approach is useful for evaluating population differences in the real-world.

Glyoxalase 1 and protein kinase Cλ as potential therapeutic targets for late-stage breast cancer.

Cancer cells upregulate the expression levels of glycolytic enzymes in order to reach the increased glycolysis required. One such upregulated glycolytic enzyme is glyoxalase 1 (GLO 1), which catalyzes the conversion of toxic methylglyoxal to nontoxic S-D-lactoylglutathione. Protein kinase Cλ (PKCλ) is also upregulated in various types of cancer and is involved in cancer progression. In the present study, the association between enhanced glycolysis and PKCλ in breast cancer was investigated. In human breast cancer, high GLO 1 expression was associated with high PKCλ expression at the protein (P<0.01) and mRNA levels (P<0.01). Furthermore, Wilcoxon and Cox regression model analysis revealed that patients with stage III-IV tumors with high GLO 1 and PKCλ expression had poor overall survival compared with patients expressing lower levels of these genes [P=0.040 (Gehan-Breslow generalized Wilcoxon test) and P=0.031 (hazard ratio, 2.36; 95% confidence interval, 1.08-5.16), respectively]. Treatment of MDA-MB-157 and MDA-MB-468 human basal-like breast cancer cells with TLSC702 (a GLO 1 inhibitor) and/or aurothiomalate (a PKCλ inhibitor) reduced both cell viability and tumor-sphere formation. These results suggested that GLO 1 and PKCλ were cooperatively involved in cancer progression and contributed to a poor prognosis in breast cancer. In conclusion, GLO 1 and PKCλ serve as potentially effective therapeutic targets for treatment of late-stage human breast cancer.

GLO 1 and PKCλ Regulate ALDH1-positive Breast Cancer Stem Cell Survival.

BACKGROUND/AIM: We examined the inhibitory effects of both glyoxalase 1 (GLO 1) and protein kinase C (PKC)λ in aldehyde dehydrogenase 1 (ALDH1)-positive breast cancer stem cells (CSCs). MATERIALS AND METHODS: Breast cancer genomics datasets (TCGA, n=593; METABRIC, n=1904) were downloaded and statistically analyzed. The effects of GLO 1 and PKCλ on trypan blue staining and tumor-sphere formation by ALDH1high cells derived from triple negative breast cancer (TNBC) and basal-like breast cancer were examined. RESULTS: GLO 1high, PKCλhigh, and ALDH1A3high tumors were enriched in stage I/II/III/IV samples, associated with the HER2 and TNBC subtypes according to receptor status, and associated with the HER2-enriched and basal-like subtypes according to PAM50. Inhibition of either GLO 1 (TLSC702) or PKCλ (ANF) suppressed tumor-sphere formation and enhanced death in ALDH1high cells. TLSC702 also effectively inhibited tumor-sphere formation and induced death in PKCλ knockout ALDH1high cells. CONCLUSION: GLO 1 and PKCλ are important for the survival of ALDH1-positive breast CSCs, and may represent potential therapeutic targets for the treatment of ALDH1-positive breast CSCs.

Examining the association between the "My Pharmacist" model and the service quality of community pharmacies.

BACKGROUND: In Japan, patients can freely choose medical facilities. Many visit different medical facilities for different diseases, and for convenience, often utilize the pharmacies neighboring these facilities. Accordingly, a "My Pharmacy" model was recommended, in which patients select a single pharmacy using their own judgement to receive proper medication services. A "My Pharmacist" model, in which the pharmacist is constantly involved in the treatment of a patient, was also proposed. However, patients' evaluations of pharmacist/pharmacy services under these models have not been investigated. OBJECTIVE: To examine how a patient's constant involvement with the same pharmacist and pharmacy is associated with their evaluation of the quality of pharmacy services. METHODS: A cross-sectional survey using a self-administered questionnaire was conducted among patients who used pharmacies periodically. Patients evaluated the pharmacist/pharmacy services and were classified into 4 groups ("My Pharmacy/My Pharmacist," "My Pharmacy/Multiple Pharmacists," "Multiple Pharmacies/My Pharmacist," and "Multiple Pharmacies/Multiple Pharmacists") according to the form of their usage of pharmacies and pharmacists. An intergroup comparison was then performed and correlations within each group analyzed. RESULTS: Data from 3,492 individuals using 147 pharmacies were analyzed. "My Pharmacy" users had significantly higher scores than did "Multiple Pharmacies" users on patient experience of proper medication services (e.g., identifying duplicate medication) (p < 0.001). "My Pharmacy/My Pharmacist" users scored higher than the other three groups on four evaluation factors, including "pharmacy/pharmacist's interpersonal services" ("sharing and utilizing patient information," "enhanced health support function," and "consideration towards patients"), "patient satisfaction with the pharmacy," "placing more emphasis on quality of interaction with pharmacist than on waiting time," and "attitude when visiting healthcare facilities" (all p < 0.001). CONCLUSION: The findings indicate that highly tailored, in-person services provided by "My Pharmacists" are associated with not only with the degree of patients' overall satisfaction, but also their evaluation of "the quality of pharmacist services."

High PKCλ expression is required for ALDH1-positive cancer stem cell function and indicates a poor clinical outcome in late-stage breast cancer patients.

Despite development of markers for identification of cancer stem cells, the mechanism underlying the survival and division of cancer stem cells in breast cancer remains unclear. Here we report that PKCλ expression was enriched in basal-like breast cancer, among breast cancer subtypes, and was correlated with ALDH1A3 expression (p = 0.016, χ2-test). Late stage breast cancer patients expressing PKCλhigh and ALDH1A3high had poorer disease-specific survival than those expressing PKCλlow and ALDH1A3low (p = 0.018, log rank test for Kaplan-Meier survival curves: hazard ratio 2.58, 95% CI 1.24-5.37, p = 0.011, multivariate Cox regression analysis). Functional inhibition of PKCλ through siRNA-mediated knockdown or CRISPR-Cas9-mediated knockout in ALDH1high MDA-MB 157 and MDA-MB 468 basal-like breast cancer cells led to increases in the numbers of trypan blue-positive and active-caspase 3-positive cells, as well as suppression of tumor-sphere formation and cell migration. Furthermore, the amount of CASP3 and PARP mRNA and the level of cleaved caspase-3 protein were enhanced in PKCλ-deficient ALDH1high cells. An Apoptosis inhibitor (z-VAD-FMK) suppressed the enhancement of cell death as well as the levels of cleaved caspase-3 protein in PKCλ deficient ALDH1high cells. It also altered the asymmetric/symmetric distribution ratio of ALDH1A3 protein. In addition, PKCλ knockdown led to increases in cellular ROS levels in ALDH1high cells. These results suggest that PKCλ is essential for cancer cell survival and migration, tumorigenesis, the asymmetric distribution of ALDH1A3 protein among cancer cells, and the maintenance of low ROS levels in ALDH1-positive breast cancer stem cells. This makes it a key contributor to the poorer prognosis seen in late-stage breast cancer patients.