A Multimodal Generative AI Copilot for Human Pathology.

The field of computational pathology[1,2] has witnessed remarkable progress in the development of both task-specific predictive models and task-agnostic self-supervised vision encoders[3,4]. However, despite the explosive growth of generative artificial intelligence (AI), there has been limited study on building general purpose, multimodal AI assistants and copilots[5] tailored to pathology. Here we present PathChat, a vision-language generalist AI assistant for human pathology. We build PathChat by adapting a foundational vision encoder for pathology, combining it with a pretrained large language model and finetuning the whole system on over 456,000 diverse visual language instructions consisting of 999,202 question-answer turns. We compare PathChat against several multimodal vision language AI assistants and GPT4V, which powers the commercially available multimodal general purpose AI assistant ChatGPT-4[7]. PathChat achieved state-of-the-art performance on multiple-choice diagnostic questions from cases of diverse tissue origins and disease models. Furthermore, using open-ended questions and human expert evaluation, we found that overall PathChat produced more accurate and pathologist-preferable responses to diverse queries related to pathology. As an interactive and general vision-language AI Copilot that can flexibly handle both visual and natural language inputs, PathChat can potentially find impactful applications in pathology education, research, and human-in-the-loop clinical decision making.

Using Automated Machine Learning to Predict the Mortality of Patients With COVID-19: Prediction Model Development Study.

BACKGROUND: During a pandemic, it is important for clinicians to stratify patients and decide who receives limited medical resources. Machine learning models have been proposed to accurately predict COVID-19 disease severity. Previous studies have typically tested only one machine learning algorithm and limited performance evaluation to area under the curve analysis. To obtain the best results possible, it may be important to test different machine learning algorithms to find the best prediction model. OBJECTIVE: In this study, we aimed to use automated machine learning (autoML) to train various machine learning algorithms. We selected the model that best predicted patients' chances of surviving a SARS-CoV-2 infection. In addition, we identified which variables (ie, vital signs, biomarkers, comorbidities, etc) were the most influential in generating an accurate model. METHODS: Data were retrospectively collected from all patients who tested positive for COVID-19 at our institution between March 1 and July 3, 2020. We collected 48 variables from each patient within 36 hours before or after the index time (ie, real-time polymerase chain reaction positivity). Patients were followed for 30 days or until death. Patients' data were used to build 20 machine learning models with various algorithms via autoML. The performance of machine learning models was measured by analyzing the area under the precision-recall curve (AUPCR). Subsequently, we established model interpretability via Shapley additive explanation and partial dependence plots to identify and rank variables that drove model predictions. Afterward, we conducted dimensionality reduction to extract the 10 most influential variables. AutoML models were retrained by only using these 10 variables, and the output models were evaluated against the model that used 48 variables. RESULTS: Data from 4313 patients were used to develop the models. The best model that was generated by using autoML and 48 variables was the stacked ensemble model (AUPRC=0.807). The two best independent models were the gradient boost machine and extreme gradient boost models, which had an AUPRC of 0.803 and 0.793, respectively. The deep learning model (AUPRC=0.73) was substantially inferior to the other models. The 10 most influential variables for generating high-performing models were systolic and diastolic blood pressure, age, pulse oximetry level, blood urea nitrogen level, lactate dehydrogenase level, D-dimer level, troponin level, respiratory rate, and Charlson comorbidity score. After the autoML models were retrained with these 10 variables, the stacked ensemble model still had the best performance (AUPRC=0.791). CONCLUSIONS: We used autoML to develop high-performing models that predicted the survival of patients with COVID-19. In addition, we identified important variables that correlated with mortality. This is proof of concept that autoML is an efficient, effective, and informative method for generating machine learning-based clinical decision support tools.

Concomitant lansoprazole ameliorates cisplatin-induced nephrotoxicity by inhibiting renal organic cation transporter 2 in rats.

Cisplatin is used widely for the treatment of multiple solid tumors. Cisplatin-induced nephrotoxicity is caused by renal accumulation of cisplatin via human organic cation transporter 2 (hOCT2). As lansoprazole, a proton pump inhibitor, is known to inhibit hOCT2 activity, lansoprazole might ameliorate cisplatin-induced nephrotoxicity. A previous study showed that concomitant lansoprazole administration ameliorated nephrotoxicity in patients receiving cisplatin. However, the detailed mechanism remains to be clarified. In the present study, the drug-drug interaction between lansoprazole and cisplatin was examined using hOCT2-expressing cultured cells and rat renal slices. Moreover, the effect of lansoprazole on cisplatin-induced nephrotoxicity and the pharmacokinetics of cisplatin in rats was investigated. In the uptake study, lansoprazole potently inhibited the uptake of cisplatin in hOCT2-expressing cultured cells and rat renal slices. The in vivo rat study showed that concomitant lansoprazole significantly ameliorated cisplatin-induced nephrotoxicity and reduced the renal accumulation of platinum up to approximately 60% of cisplatin alone at 72 h after cisplatin intraperitoneal administration. Furthermore, the renal uptake of platinum at 3 min after intravenous cisplatin administration in rats with cisplatin and lansoprazole decreased to 78% of rats with cisplatin alone. In addition, there was no significant difference in the plasma platinum concentration between rats treated with and without lansoprazole at 3 min after cisplatin intravenous administration. These findings suggested that concomitant lansoprazole ameliorated cisplatin-induced nephrotoxicity by inhibiting rOCT2-mediated cisplatin uptake in rats, thus decreasing cisplatin accumulation in the kidney. The present findings provided important information for the establishment of novel protective approaches to minimize cisplatin-induced nephrotoxicity.

Maternal Blood Concentration of Tadalafil and Uterine Blood Flow in Pregnancy.

: Background and Objectives: Tadalafil for treatment of fetal growth restriction (FGR) or preeclampsia is given once a day orally. The drug kinetics of tadalafil were investigated to determine the ideal dosage to promote uterine blood flow. Materials and Methods: We recruited five pregnant women with FGR or preeclampsia before administration of tadalafil, all of which were administered tadalafil (20 mg/day, once-daily dosing). The blood concentration of tadalafil was measured 1, 2, 4, 6, 8, and 24 h after administration, and uterine blood flow was measured before tadalafil administration and 2-4 and 20-24 h after. We then analyzed the correlation between tadalafil blood concentration and uterine artery blood flow. Results: The blood concentration of tadalafil correlated with uterine artery blood flow in pregnant women. The blood concentration of tadalafil and uterine artery blood flow decreased 5 h after administration of tadalafil. Conclusions: The blood concentration of tadalafil and uterine artery blood flow fluctuate in parallel, the latter was decreased by reduced blood concentration. Thus, a study of tadalafil administered twice a day in pregnant women will be needed to stabilize uterine artery blood flow.

Stereoselective Inhibition of Renal Basolateral Human Organic Anion Transporter 3 by Lansoprazole Enantiomers.

Lansoprazole, a proton pump inhibitor, potently inhibits human organic anion transporter, hOAT3 (SLC22A8). Lansoprazole has an asymmetric atom in its structure and is clinically administered as a racemic mixture of (R)-and (S)-enantiomers. However, little is known about the stereoselective inhibitory potencies of lansoprazole against hOAT3 and its homolog, hOAT1. In the present study, the stereoselective inhibitory effect of lansoprazole was evaluated using hOAT1-and hOAT3-expressing cultured cells. hOAT1 and hOAT3 transported [14C]p-aminohippurate and [3H]estrone-3-sulfate (ES) with Michaelis-Menten constants of 29.8 ± 4.0 and 30.1 ± 9.0 µmol/L respectively. Lansoprazole enantiomers inhibited hOAT1- and hOAT3-mediated transport of each substrate in a concentration-dependent manner. The IC50 value of (S)-lansoprazole against hOAT3-mediated transport of [3H]ES (0.61 ± 0.08 µmol/L) was significantly lower than that of (R)-lansoprazole (1.75 ± 0.31 µmol/L). In contrast, stereoselectivity was not demonstrated for the inhibition of hOAT1. Furthermore, (S)-lansoprazole inhibited hOAT3-mediated transport of pemetrexed and methotrexate (hOAT3 substrates) more strongly than the corresponding (R)-lansoprazole. This study is the first to demonstrate that the stereoselective inhibitory potency of (S)-lansoprazole against hOAT3 is greater than that of (R)-lansoprazole. The present findings provide novel information about the drug interactions associated with lansoprazole.

Endobronchial Metastasis from Extrapulmonary Neoplasms: Analysis of Clinicopathologic Features and Cytological Evaluation by Bronchial Brushing.

PURPOSE: Bronchial brushings (BB) commonly aid in the diagnosis of primary lung cancer. However, the utility of this method in diagnosing endobronchial metastases (EBM) from extrapulmonic malignancies has not been thoroughly evaluated. The purpose of this study is to evaluate the sensitivity of BB in diagnosing EBM. METHODS: An institutional database was queried for all patients with cytologically or histologically confirmed extrapulmonary EBM identified by endobronchial biopsy between 1978 and 2013. Data were collected on patient demographics, histologic and cytologic diagnoses, time from primary malignancy to identification of EBM, and location of EBM. The sensitivity of BB for the diagnosis of EBM and the clinicopathologic features of extrapulmonary EBM were assessed. RESULTS: Fifty-six patients (33 females, 23 males; mean age 53 years) were identified with EBM. Diagnoses included lymphoma (21), breast adenocarcinoma (11), colonic adenocarcinoma (7), melanoma (6), renal cell carcinoma (RCC, 5), embryonal carcinoma (2), and 1 case each of tonsillar squamous cell carcinoma, thymic carcinoma, leiomyosarcoma, and sarcoma, not otherwise specified. The sensitivity of BB for identifying EBM was 85% overall and 94% for non-hematologic malignancies. The mean interval between primary diagnosis and EBM was 59 months (range 0-264 months). Excluding ten patients who had EBM at their initial presentation, lymphoma had the shortest (10 months) and RCC had the longest (264 months) mean interval between primary diagnosis and EBM. The mean time between EBM identification and death was 22.4 months (n = 24). CONCLUSION: Bronchial brushing is a sensitive technique for diagnosing non-hematologic extrapulmonic endobronchial metastases.

Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3.

Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 µM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed.

Contribution of human organic anion transporter 3-mediated transport of a major linezolid metabolite, PNU-142586, in linezolid-induced thrombocytopenia.

Thrombocytopenia, a common adverse effect of linezolid, often occurs in patients lacking typical risk factors. In this study, we investigated the key risk factors for linezolid-induced thrombocytopenia using two real-world clinical databases and explored its underlying mechanism through in vitro and in vivo experiments. In a retrospective analysis of 150 linezolid-treated patients, multivariate analysis identified coadministration of lansoprazole, a proton pump inhibitor, as a significant independent risk factor for thrombocytopenia (odds ratio: 2.33, p = 0.034). Additionally, analysis of the Food and Drug Administration Adverse Event Reporting System database revealed a reporting odds ratio of thrombocytopenia for lansoprazole of 1.64 (95% CI: 1.25-2.16). In vitro studies showed that the uptake of PNU-142586, a major linezolid metabolite, was significantly higher in human organic anion transporter 3-expressing HEK293 (HEK-hOAT3) cells compared to HEK-pBK cells. The apparent IC50 value of lansoprazole against hOAT3-mediated transport of PNU-142586 was 0.59 ± 0.38 µM. In a pharmacokinetic study using rats, coadministration of linezolid with lansoprazole intravenously resulted in approximately a 1.7-fold increase in the area under the plasma concentration-time curve of PNU-142586, but not linezolid and PNU-142300. Moreover, PNU-142586, but not linezolid, exhibited concentration-dependent cytotoxicity in a human megakaryocytic cell line. These findings suggest that linezolid-induced thrombocytopenia should be due to delayed elimination of PNU-142586. Furthermore, delayed elimination of PNU-142586 due to renal failure and hOAT3-mediated transport inhibition by lansoprazole should exacerbate linezolid-induced thrombocytopenia.

Comparative Efficacy and Safety of Standard and Biweekly Trifluridine/Tipiracil Regimen in Patients With Colorectal Cancer.

BACKGROUND/AIM: Trifluridine/tipiracil (FTD/TPI) is used to treat metastatic colorectal cancer (mCRC). Since the standard regimen of FTD/TPI features a complex dosing schedule and frequently results in severe hematological toxicities, a simplified regimen has emerged, in which FTD/TPI is orally administered biweekly. However, the survival benefits and potential adverse events associated with the biweekly FTD/TPI regimen have not been fully evaluated in previous reports. Therefore, in this study, the differences in efficacy and safety between the standard and biweekly FTD/TPI regimens were retrospectively investigated in patients with mCRC. PATIENTS AND METHODS: Data from 90 patients who received FTD/TPI for mCRC were extracted from the electronic medical records at the Osaka University Hospital. According to the inclusion and exclusion criteria, 85 of the 90 patients were enrolled in the study. We compared patient characteristics, overall survival (OS), progression-free survival (PFS), and adverse events between the standard (n=56) and biweekly groups (n=29). RESULTS: The biweekly group exhibited prolonged OS and PFS compared to patients in the standard group. Multivariate analysis for OS and PFS demonstrated that the biweekly regimen was the only significant factor that affected OS, and not PFS (HR=0.561, p=0.049). Kaplan-Meier analysis indicated that neutropenia (grade ≥3) in the biweekly group was significantly prolonged compared to the standard group (p=0.012). However, there were no significant differences in adverse events between the two groups (p>0.999). CONCLUSION: The biweekly FTD/TPI regimen, compared to the standard regimen, should enhance both OS and PFS in patients with mCRC without escalating any adverse event.

General Applicability of Existing College of American Pathologists Accreditation Requirements to Clinical Implementation of Machine Learning-Based Methods in Molecular Oncology Testing.

CONTEXT.­: The College of American Pathologists (CAP) accreditation requirements for clinical laboratory testing help ensure laboratories implement and maintain systems and processes that are associated with quality. Machine learning (ML)-based models share some features of conventional laboratory testing methods. Accreditation requirements that specifically address clinical laboratories' use of ML remain in the early stages of development. OBJECTIVE.­: To identify relevant CAP accreditation requirements that may be applied to the clinical adoption of ML-based molecular oncology assays, and to provide examples of current and emerging ML applications in molecular oncology testing. DESIGN.­: CAP accreditation checklists related to molecular pathology and general laboratory practices (Molecular Pathology, All Common and Laboratory General) were reviewed. Examples of checklist requirements that are generally applicable to validation, revalidation, quality management, infrastructure, and analytical procedures of ML-based molecular oncology assays were summarized. Instances of ML use in molecular oncology testing were assessed from literature review. RESULTS.­: Components of the general CAP accreditation framework that exist for traditional molecular oncology assay validation and maintenance are also relevant for implementing ML-based tests in a clinical laboratory. Current and emerging applications of ML in molecular oncology testing include DNA methylation profiling for central nervous system tumor classification, variant calling, microsatellite instability testing, mutational signature analysis, and variant prediction from histopathology images. CONCLUSIONS.­: Currently, much of the ML activity in molecular oncology is within early clinical implementation. Despite specific considerations that apply to the adoption of ML-based methods, existing CAP requirements can serve as general guidelines for the clinical implementation of ML-based assays in molecular oncology testing.

MicroRNA-145 post-transcriptionally regulates the expression and function of P-glycoprotein in intestinal epithelial cells.

P-glycoprotein (P-gp/MDR1) is a multispecific efflux transporter regulating the pharmacokinetics of various drugs. Although P-gp expression in the small intestine is elevated after liver ischemia-reperfusion (I/R) injury, the regulatory mechanism remains to be clarified. MicroRNAs (miRNAs) play an important role in the post-transcriptional regulation of the expression of drug transporters. Here, we investigated the intestinal expression profile of miRNAs after liver I/R and the role of miRNAs in the post-transcriptional regulation of P-gp in intestinal epithelial cells. Microarray analysis showed that microRNA-145 (miR-145) level was decreased in the small intestine of I/R rats. This downregulation of miR-145 was further confirmed by real-time polymerase chain reaction. In silico analysis revealed that 3'-untranslated regions (UTRs) of rat Mdr1a, mouse Mdr1a, and human MDR1 mRNA retain binding sites for miR-145. Luciferase assays using MDR1 3'-UTR reporter plasmid in HEK293 cells showed that luciferase activity was decreased by the overexpression of miR-145, and the deletion of miR-145 binding site within MDR1 3'-UTR abolished this decreased luciferase activity. The downregulation of miR-145 in Caco-2 cells, an epithelial cell line derived from human colon, increased P-gp expression and efflux activity of rhodamine 123, but not MDR1 mRNA level. These findings demonstrated that miR-145 negatively regulates the expression and function of P-gp through the repression of mRNA by direct interaction on the 3'-UTR of MDR1 mRNA. In addition, the downregulation of miR-145 should significantly contribute to the elevated intestinal P-gp expression after liver I/R. Our results provide new insight into the post-transcriptional regulation of intestinal P-gp.

Proton Pump Inhibitors Ameliorate Oxaliplatin-induced Peripheral Neuropathy: Retrospective Analysis of Two Real-world Clinical Databases.

BACKGROUND/AIM: Chemotherapy-induced peripheral neuropathy (CIPN) due to oxaliplatin (L-OHP) is a major clinical problem. Effective and safe preventive strategies for CIPN are urgently needed. Although proton pump inhibitors (PPIs) have various off-target effects, their clinical impact on L-OHP-induced CIPN remains unclear. In the present study, we investigated the effects of PPIs on L-OHP-induced CIPN in patients using two real-world clinical databases. PATIENTS AND METHODS: We retrospectively analyzed the electronic medical records of Osaka University Hospital to examine the effect of PPIs on CIPN development in 217 patients who received XELOX (L-OHP plus capecitabine) therapy for colorectal cancer. In addition, the Japanese Adverse Drug Event Report (JADER) database was used to validate the effects of PPIs on L-OHP-induced CIPN. RESULTS: The incidences of CIPN (grade ≥2) and discontinuation of L-OHP were significantly lower in patients with PPIs than in those without PPIs. Multivariate analysis showed that concomitant PPIs use was an independent factor that significantly contributed to the prevention of grade ≥2 CIPN (odds ratio=0.054, p<0.001). Kaplan-Meier analysis showed that the time to onset of grade ≥2 CIPN was significantly prolonged in patients with PPIs without affecting the therapeutic efficacy of L-OHP (p=0.004). Moreover, JADER database analyses revealed that the reporting odds ratio of any PPI for L-OHP-induced CIPN was 0.485. CONCLUSION: Concomitant PPI use ameliorated L-OHP-induced CIPN in patients with colorectal cancer.

Proton Pump Inhibitors Ameliorate Capecitabine-induced Hand-Foot Syndrome in Patients With Breast Cancer: A Retrospective Study.

BACKGROUND/AIM: Hand-foot syndrome (HFS) is the most common adverse event associated with capecitabine, and its pathogenesis is known to be associated with inflammation. Proton pump inhibitors (PPIs) reportedly exert anti-inflammatory effects; however, the impact of PPIs on capecitabine-induced HFS needs to be clarified in the clinical setting. In the present study, we retrospectively investigated the efficacy and safety of PPIs in patients with breast cancer receiving capecitabine. PATIENTS AND METHODS: We analyzed the effects of PPIs on the development of severe HFS (grade ≥2), progression-free survival (PFS), and overall survival (OS) in 195 patients who received capecitabine chemotherapy for breast cancer. RESULTS: In total, 50 patients (26%) were treated with PPIs, while 145 patients (74%) did not receive PPIs. The incidence of severe HFS was significantly lower in patients who received PPIs (18%) than in patients who did not receive PPIs (43%, p=0.001), and the discontinuation rate of capecitabine therapy due to HFS was also lower in patients receiving PPIs than in those who did not receive PPIs (p=0.003). Multivariate analysis revealed that concomitant PPIs use was an independent factor that significantly contributed to the prevention of severe HFS (odds ratio (OR)=0.265, p=0.003). Meanwhile, no significant difference in median PFS and OS values was observed between patients treated with and without PPIs. CONCLUSION: Concomitant use of PPIs could ameliorate capecitabine-induced HFS in patients with breast cancer.

Repositioning of Lansoprazole as a Protective Agent Against Cisplatin-Induced Ototoxicity.

Cisplatin (CDDP) is a well-known chemotherapeutic drug approved for various cancers. However, CDDP accumulates in the inner ear cochlea via organic cation transporter 2 (OCT2) and causes ototoxicity, which is a major clinical limitation. Since lansoprazole (LPZ), a proton pump inhibitor, is known to inhibit OCT2-mediated transport of CDDP, we hypothesized that LPZ might ameliorate CDDP-induced ototoxicity (CIO). To test this hypothesis, we utilized in vivo fluorescence imaging of zebrafish sensory hair cells. The fluorescence signals in hair cells in zebrafish treated with CDDP dose-dependently decreased. Co-treatment with LPZ significantly suppressed the decrease of fluorescence signals in zebrafish treated with CDDP. Knockout of a zebrafish homolog of OCT2 also ameliorated the reduction of fluorescence signals in hair cells in zebrafish treated with CDDP. These in vivo studies suggest that CDDP damages the hair cells of zebrafish through oct2-mediated accumulation and that LPZ protects against CIO, possibly inhibiting the entry of CDDP into the hair cells via oct2. We also evaluated the otoprotective effect of LPZ using a public database containing adverse event reports. The analysis revealed that the incidence rate of CIO was significantly decreased in patients treated with LPZ. We then retrospectively analyzed the medical records of Mie University Hospital to examine the otoprotective effect of LPZ. The incidence rate of ototoxicity was significantly lower in patients co-treated with LPZ compared to those without LPZ. These retrospective findings suggest that LPZ is also protective against CIO in humans. Taken together, co-treatment with LPZ may reduce the risk of CIO.

Concomitant palonosetron ameliorates cisplatin-induced nephrotoxicity, nausea, and vomiting: a retrospective cohort study and pharmacovigilance analysis.

BACKGROUND: Cisplatin (CDDP)-induced nephrotoxicity is the most important complication of CDDP treatment. 5-Hydroxytryptamine type 3 receptor antagonists (5-HT3RAs) are widely used to prevent chemotherapy-induced nausea and vomiting (CINV). However, in patients with the triple antiemetic (neurokinin-1 receptor antagonist, 5-HT3RA, and dexamethasone) therapy, the advantage of palonosetron in comparison with other 5-HT3RAs on CDDP-induced nephrotoxicity and CINV remains unclear. In the present study, we investigated the effect of palonosetron on CDDP-induced nephrotoxicity and CINV in patients with the triple antiemetic therapy by a retrospective cohort study and a pharmacovigilance analysis. METHODS: We retrospectively analyzed the effect of 5-HT3RAs on the development of nephrotoxicity and CINV in 110 patients who received CDDP, fluorouracil, and triple antiemetic therapy for the treatment of esophageal cancer. Moreover, the effect of 5-HT3RAs on CDDP-induced nephrotoxicity was validated in patients with the triple antiemetic therapy using the Japanese Adverse Drug Event Report (JADER) database. RESULTS: In a retrospective study, the incidence of nephrotoxicity (≥ grade 1) in patients receiving palonosetron (18%) was significantly lower than that in patients receiving ramosetron (another 5-HT3RA) (36%, p = 0.044). Moreover, severe nephrotoxicity ≥ grade 3 was observed in one patient treated with ramosetron, whereas hematological toxicity was comparable between the two groups (p = 0.553). Furthermore, the incidence rate of CINV within 120 h following CDDP administration in patients treated with palonosetron (18%) was significantly lower than that in patients receiving ramosetron (39%, p = 0.026). JADER database analyses revealed that the reporting odds ratio of palonosetron for CDDP-induced acute kidney injury was 0.282 (95% confidence interval: 0.169-0.472). CONCLUSIONS: The findings of the present study suggested a greater potential of palonosetron against CDDP-induced nephrotoxicity and CINV than other 5-HT3RAs in patients with the triple antiemetic therapy.

A doxycycline-inducible CYP3A4-Caco-2 cell line as a model for evaluating safety of aflatoxin B1 in the human intestine.

Exposure of humans to aflatoxin B1 (AFB1) via ingestion of contaminated agricultural products is a major concern for human health throughout the world because epoxidized AFB1, biotransformed from AFB1 by hepatic CYP3A4, is strongly hepatotoxic and hepatocarcinogenic. Intestinal epithelial cells serve as a physical and physiological barrier against xenobiotics via their intercellular tight junction (TJ) seals and the metabolizing enzyme CYP3A4. However, the effect of AFB1 on the intestinal barrier remains unclear. Here, we investigated the influence of AFB1 on these physical and physiological intestinal barriers by means of an in vitro human intestinal model utilizing doxycycline-inducible CYP3A4-expressing Caco-2 cells, in which CYP3A4 activity is comparable to that in the adult human intestine. Cellular toxicity of AFB1 in induced Caco-2 cells (i.e., cells in which expression of CYP3A4 is induced by doxycycline) was approximately 5 times that of uninduced Caco-2 cells. Exposure to 16 µM AFB1 did not decrease the transepithelial electric resistance (TEER; a measure of TJ barrier integrity) in monolayers of uninduced Caco-2 cells to 95.8 % of that in vehicle-treated cells; in contrast, in induced Caco-2 cells, TEER was reduced to 28.8 %. Exposure to 16 µM AFB1 increased paracellular permeation of 4- and 20-kDa dextrans (paracellular permeation markers) through monolayers of induced Caco-2 cells to 5.4 and 5.2 times that through uninduced Caco-2 cells. These results together show that ingested AFB1 can modulate the intestinal barrier, and that inducible CYP3A4-expressing Caco-2 cells are a promising tool for evaluating the safety of food contaminants in the human intestine.

Effect of number of medications and complexity of regimens on medication adherence and blood pressure management in hospitalized patients with hypertension.

INTRODUCTION: Good adherence of antihypertensives is recommended for the accomplishment of hypertension therapy. The number of medications and characteristics contributing to medication regimen complexity, such as dosage forms and dosing frequency, are known to influence medication adherence. However, the effect of medication regimen complexity on the therapeutic efficacy of medicines remains to be clarified. In the present study, we retrospectively investigated the effect of number of medications and medication regimen complexity on medication adherence and therapeutic efficacy in patients with hypertension. METHODS: According to the inclusion and exclusion criteria, 1,057 patients, who were on medications including antihypertensives on admission at the Mie University Hospital between July 2018 and December 2018, were enrolled in this study. Poor blood pressure management was defined if the systolic or diastolic blood pressure were ≥140 mmHg or ≥ 90 mmHg. Medication regimen complexity was quantified using the medication regimen complexity index (MRCI) score. RESULTS: Among 1,057 patients, 164 and 893 patients were categorized into poor and good adherence groups, respectively. The multivariate analyses revealed that age ≥ 71 years and oral MRCI score ≥ 19.5 but not number of oral medications were extracted as risk factors for poor medication adherence. Medication adherence and blood pressure management were poor in the group with oral MRCI score ≥ 19.5, regardless of the age. The rate of readmission was similar. CONCLUSION: Our study is the first to demonstrate that medication regimen complexity rather than number of medications is closely related to medication adherence and blood pressure management. Hence, physicians and/or pharmacists should consider the complexity of medication regimens while modifying them.

Cytomegalovirus skin disease in a kidney transplant patient.

A 44-year-old man with a history of renal transplantation presented with right lower abdominal wall swelling, redness and pain. A bacterial abscess was drained, and he was discharged home with oral antibiotics. After failing to improve, he returned to the hospital, where he was briefly treated with intravenous antibiotics and discharged home again. The patient returned 5 days later, reporting worsening right groin swelling that extended into the ipsilateral scrotum. Imaging revealed a persistent fluid collection in the region, and he was taken for surgical debridement. Tissue immunochemistry and histopathological evaluation identified cytomegalovirus infection. Plasma quantitative PCR for cytomegalovirus demonstrated high viraemia. The patient was successfully treated with intravenous ganciclovir, followed by oral valganciclovir, with resolution of the skin changes. Persistent hydrocele with epididymitis on imaging suggests that this process may have been the source of the cutaneous cytomegalovirus infection.

Opioid therapy duration before naldemedine treatment is a significant independent risk of diarrhea: a retrospective cohort study.

BACKGROUND: The most common adverse event (AE) associated with opioid analgesics is opioid-induced constipation (OIC). Naldemedine (NAL) is widely used for the treatment of OIC. However, diarrhea has been reported as the most common treatment-emergent AE of NAL, and little is known about the risk factors associated with the development of diarrhea during NAL administration. This study examined the risk factors for NAL-induced diarrhea via a retrospective chart review of hospitalized patients. METHODS: The data of 101 hospitalized adult patients who received NAL for the first time for the treatment of OIC at Mie University Hospital between June 2017 and December 2018 were extracted from electronic medical records. According to the inclusion and exclusion criteria, 70 of the 101 patients were enrolled in this study. Diarrhea was defined as "diarrhea" on the medical record within 2 weeks of NAL administration. Univariate and multivariate analyses were performed to identify risk factors for the development of diarrhea in patients receiving NAL. RESULTS: Twenty-two of the 70 patients enrolled (31%) developed diarrhea within 2 weeks of NAL administration. The median duration (range) of NAL treatment before diarrhea onset was 3 (1-12) days. Patients with diarrhea had a significantly longer duration of opioid therapy before NAL administration than patients without diarrhea (P=0.002). Multivariate logistic regression analysis indicated that the independent risk factors for the development of NAL-induced diarrhea were NAL administration after more than 17 days of opioid therapy (odds ratio [OR]=7.539; P=0.016) and pancreatic cancer (OR=6.217; P=0.025). In fact, the incidence of diarrhea in patients who were administered NAL within a day of opioid therapy was significantly lower than that in patients who were administered NAL after more than 17 days of opioid therapy (13% vs. 54%, P=0.030). CONCLUSIONS: These results suggested that a prolonged duration of opioid therapy prior to NAL initiation is associated with increased incidence of diarrhea.

Temporary decrease in tacrolimus clearance in cytochrome P450 3A5 non-expressors early after living donor kidney transplantation: Effect of interleukin 6-induced suppression of the cytochrome P450 3A gene.

Tacrolimus is important for immunosuppression in kidney transplantation. In this historical cohort and in vitro study, we evaluated the changes in tacrolimus pharmacokinetics early after living donor kidney transplantation and the effects of interleukin (IL)-6 on cytochrome P450 3A4 (CYP3A4) and cytochrome P450 3A5 (CYP3A5) expression. In the historical cohort study, 22 patients who met the inclusion criteria were classified into CYP3A5 expressors and non-expressors (n = 16 and 6, respectively). The blood tacrolimus concentration per dose ratio (C/D) temporarily increased post-kidney transplantation on days 3-4 only in CYP3A5 non-expressors. The effects of IL-6 on CYP3A4 and CYP3A5 expression were also investigated in vitro using HepG2 and Caco-2 cells. IL-6 induced a significant concentration- and time-dependent decrease in CYP3A4 and CYP3A5 expression in both cells. The mean CYP3A4 expression level at 12 hours after IL-6 exposure (% of 0 hour) was 44.0 and 62.6 in HepG2 and Caco-2 cells, respectively, whereas the CYP3A5 expression level was 30.7 and 52.4, respectively. We hypothesize that CYP3A5 non-expressors might exhibit a temporary decrease in the oral clearance of tacrolimus via an increase in serum IL-6 concentrations early after kidney transplantation. These results may help develop strategies to improve kidney transplant outcome.