Published papers

PURPOSE: Capecitabine, an oral anticancer agent, frequently causes hand-foot syndrome (HFS), affecting patients' quality of life and treatment adherence. However, such symptomatic toxicities are often difficult to detect in structured electronic health record (EHR) data. This study primarily aimed to validate a natural language processing (NLP) approach to identifying capecitabine-induced HFS from unstructured clinical text and demonstrate its application in evaluating medication-associated adverse event trends in real-world settings. METHODS: We conducted a retrospective cohort study using EHRs from the University of Tokyo Hospital (2004-2021). HFS cases were identified using the MedNERN-CR-JA NLP model. After propensity score matching, we compared capecitabine users with and without celecoxib and assessed time to HFS onset using Cox proportional hazards models. NLP-based HFS detection was validated through manual annotation of aggregated clinical notes. Negative control and sensitivity analyses ensured robustness. RESULTS: Among 44,502 patients with cancer, 669 capecitabine users were analyzed. HFS incidence was significantly higher among capecitabine users (hazard ratio [HR], 1.93 [95% CI, 1.48 to 2.52]; P < .001) compared with nonusers. Celecoxib use showed a suggestive association with a reduced HFS risk (HR, 0.51 [95% CI, 0.24 to 1.07]; P = .073). The NLP model demonstrated high accuracy in identifying HFS, achieving a precision of 0.875, recall of 1.000, and F1 score of 0.933, based on manual annotation of patient-level clinical notes. Outcome trends remained consistent when using manually annotated HFS case labels instead of NLP-detected events, supporting the method's robustness. CONCLUSION: These findings demonstrate the effectiveness of NLP in detecting HFS from real-world clinical records. The application to celecoxib-HFS detection illustrates the potential utility of this approach for retrospective safety analysis. Further work is needed to evaluate generalizability across diverse clinical settings.

Background Androgen receptor axis-targeting reagents (ARATs) have become key drugs for patients with castration-resistant prostate cancer (CRPC). ARATs are taken long term in outpatient settings, and effective adverse event (AE) monitoring can help prolong treatment duration for patients with CRPC. Despite the importance of monitoring, few studies have identified which AEs can be captured and assessed in community pharmacies, where pharmacists in Japan dispense medications, provide counseling, and monitor potential AEs for outpatients prescribed ARATs. Therefore, we anticipated that a named entity recognition (NER) system might be used to extract AEs recorded in pharmaceutical care records generated by community pharmacists. Objective This study aimed to evaluate whether an NER system can effectively and systematically identify AEs in outpatients undergoing ARAT therapy by reviewing pharmaceutical care records generated by community pharmacists, focusing on assessment notes, which often contain detailed records of AEs. Additionally, the study sought to determine whether outpatient pharmacotherapy monitoring can be enhanced by using NER to systematically collect AEs from pharmaceutical care records. Methods We used an NER system based on the widely used Japanese medical term extraction system MedNER-CR-JA, which uses Bidirectional Encoder Representations from Transformers (BERT). To evaluate its performance for pharmaceutical care records by community pharmacists, the NER system was first applied to 1008 assessment notes in records related to anticancer drug prescriptions. Three pharmaceutically proficient researchers compared the results with the annotated notes assigned symptom tags according to annotation guidelines and evaluated the performance of the NER system on the assessment notes in the pharmaceutical care records. The system was then applied to 2193 assessment notes for patients prescribed ARATs. Results The F1-score for exact matches of all symptom tags between the NER system and annotators was 0.72, confirming the NER system has sufficient performance for application to pharmaceutical care records. The NER system automatically assigned 1900 symptom tags for the 2193 assessment notes from patients prescribed ARATs; 623 tags (32.8%) were positive symptom tags (symptoms present), while 1067 tags (56.2%) were negative symptom tags (symptoms absent). Positive symptom tags included ARAT-related AEs such as “pain,” “skin disorders,” “fatigue,” and “gastrointestinal symptoms.” Many other symptoms were classified as serious AEs. Furthermore, differences in symptom tag profiles reflecting pharmacists’ AE monitoring were observed between androgen synthesis inhibition and androgen receptor signaling inhibition. Conclusions The NER system successfully extracted AEs from pharmaceutical care records of patients prescribed ARATs, demonstrating its potential to systematically track the presence and absence of AEs in outpatients. Based on the analysis of a large volume of pharmaceutical medical records using the NER system, community pharmacists not only detect potential AEs but also actively monitor the absence of severe AEs, offering valuable insights for the continuous improvement of patient safety management.

The objective of this study was to investigate the effect of renin-angiotensin system inhibitors (RASIs) on bevacizumab (BV)-induced proteinuria in non-small cell lung cancer (NSCLC) patients.We retrospectively reviewed the medical records of NSCLC patients receiving BV between 2008 and 2014 at 11 hospitals. The patients were categorized into three groups according to their antihypertensive drug use: RASI user, non-RASI user, and non-user groups. The primary outcome was a proteinuria event of any grade during the first 6 cycles of BV treatment.A total of 211 patients were included, 89 of whom received antihypertensive drugs. Of these 89 patients, 49 were in the RASI user group, and 40 were in the non-RASI user group. The non-user group comprised 122 patients. The occurrence of proteinuria in the RASI user group was significantly lower than that in the non-RASI user group (P = 0.037) but was not significantly lower than that in the non-user group (P = 0.287). Patients using RASIs had a lower rate of proteinuria than those who did not use RASIs according to multivariate analysis (odds ratio 0.32; 95% confidence interval 0.12-0.86; P = 0.024).Our study suggests that RASI administration reduces the risk of proteinuria in patients receiving BV.

Tablets and capsules are widely used forms of oral medication, but some patients experience difficulty handling them, which can reduce medication adherence and affect health outcomes. This study aimed to identify factors contributing to perceived handling difficulty, using data from harmo®, a nationwide electronic medication notebook system. A questionnaire was distributed to adult users who had been prescribed oral medications, and the responses were linked with personal health records to analyze medication characteristics and patient backgrounds. Among the 1,230 respondents, 24% reported difficulty with small tablets or capsules. A size threshold was identified: a combined long and short diameter of 13.3 mm or less was most associated with handling problems (ROC-AUC = 0.834). Binomial logistic regression analysis revealed that difficulty in applying force with the hands (OR = 2.64), prescription of small tablets or capsules (OR = 2.52), and medical histories of hypertension (OR = 1.69) and osteoporosis (OR = 4.99) were significantly associated with reported difficulty. These results suggest that both the physical characteristics of formulations and individual patient factors influence medication usability. Our results provide evidence to inform more patient-centered approaches to oral formulation design and prescribing practices, ultimately supporting better adherence and medication safety.

Abstract Background Hospitals in Japan established the healthcare delivery system from FY 2018 to 2021 by acquiring an additional reimbursement for infection prevention (ARIP) of category 1 or 2. However, research on outcomes of ARIP applications related to the practice of hospital pharmacists is scarce. Methods This study assessed the activities performed by hospital pharmacists in hospitals with 100 to 299 beds, using ARIP acquirement as an indicator, using data from an annual questionnaire survey conducted in 2020 by the Japanese Society of Hospital Pharmacists on the status of hospital pharmacy departments. Out of the survey items, this study used those related to hospital functions, number of beds, number of pharmacists, whether the hospital is included in the diagnosis procedure combination (DPC) system, average length of stay, and nature of work being performed in the analysis. The relationship between the number of beds per pharmacist and state of implementation of pharmacist services or the average length of hospital stay was considered uncorrelated when the absolute value of the correlation coefficient was within 0–0.2, whereas the relationship was considered to have a weak, moderate, or strong correlation when the absolute value ranged at 0.2–0.4, 0.4–0.7, or 0.7–1, respectively. Results Responses were received from 3612 (recovery rate: 43.6%) hospitals. Of these, 210 hospitals meeting the criteria for ARIP 1 with 100–299 beds, and 245 hospitals meeting the criteria for ARIP 2 with 100–299 beds, were included in our analysis. There was a significant difference in the number of pharmacists, with a larger number in ARIP 1 hospitals. For the pharmacist services, significant differences were observed, with a more frequency in ARIP 1 hospitals in pharmaceutical management and guidance to pre-hospitalization patients, sterile drug processing of injection drugs and therapeutic drug monitoring. In DPC hospitals with ARIP 1 (173 hospitals) and 2 (105 hospitals), the average number of beds per pharmacist was 21.7 and 24.7, respectively, while the average length of stay was 14.3 and 15.4 d, respectively. Additionally, a weak negative correlation was observed between the number of pharmacist services with “Fairly well” or “Often” and the number of beds per pharmacist for both ARIP 1 (R = -0.207) and ARIP 2 (R = -0.279) DPC hospitals. Furthermore, a weak correlation (R = 0.322) between the average number of beds per pharmacist and the average length of hospital stay was observed for ARIP 2 hospitals. Conclusions Our results suggest that lower beds per pharmacist might lead to improved pharmacist services in 100–299 beds DPC hospitals with ARIP 1 or 2. The promotion of proactive efforts in hospital pharmacist services and fewer beds per pharmacist may relate to shorter hospital stays especially in small and medium-sized hospitals with ARIP 2 when ARIP acquisition was used as an indicator. These findings may help to accelerate the involvement of hospital pharmacists in infection control in the future.

BACKGROUND: In early December 2020, the antifungal medication, itraconazole (ITCZ), was mistakenly contaminated with rilmazafone in Japan. Healthcare professionals reported adverse drug reaction reports associated with ITCZ and included central nervous system-depression symptoms such as dizziness, lightheadedness, loss of consciousness, and intense drowsiness. OBJECTIVE: We examined ITCZ-associated suspicious cases using the Japanese Adverse Drug Event Report (JADER) database to determine the impact of adverse drug reaction reporting on post-marketing safety measures. METHODS: Adverse drug reaction reports in which the suspicious or concomitant medication was ITCZ or fluconazole (FLCZ) were extracted from the JADER dataset. The number of adverse drug reaction reports associated with central nervous system-depression adverse drug reactions were counted, and chronological changes were compared with ITCZ and FLCZ. RESULTS: Of the 713,893 adverse drug reaction reports in the JADER database, 5048 cases were associated with ITCZ and 6007 cases with FLCZ. When ITCZ contamination occurred, the number of adverse drug reaction reports associated with ITCZ increased rapidly, while those with FLCZ did not. In addition, the proportion of central nervous system-depression adverse drug reactions increased only in the ITCZ-associated report. CONCLUSIONS: An incident of ITCZ contamination with rilmazafone was detected on the JADER retrospectively. This case highlights the importance of spontaneous adverse drug reaction reporting, even if the causal relationship between the drug and adverse drug reaction is unknown.

BACKGROUND: Proton pump inhibitors (PPIs) reduce the bioavailability of several anticancer drugs. The impact of PPIs co-administered with cyclin-dependent kinase 4 and 6 inhibitors is controversial. We aimed to clarify whether the concomitant use of PPIs impacts palbociclib and abemaciclib effectiveness in breast cancer treatment. PATIENTS AND METHODS: This multicenter, retrospective, observational study, conducted across 4 medical institutions in Japan, consecutively included patients with endocrine-resistant metastatic breast cancer, receiving palbociclib or abemaciclib between December 2017 and August 2022. Propensity score-matched analyses were performed. Treatment efficacy and safety with and without PPIs were compared. Progression-free survival and overall survival were estimated using the Kaplan-Meier method and compared using a log-rank test. A Cox proportional hazards model was used to estimate the hazard ratio. RESULTS: The study included 240 patients. After 1:1 matching, 112 patients were treated with and without PPIs. The median progression-free survival period was 1.2 years in the PPI group and 1.3 years in the non-PPI group (hazard ratio, 1.19; 95% CI, 0.70-2.02). The median overall survival period was 3.6 years in the PPI group, whereas it was not reached in the non-PPI group (hazard ratio, 1.23; 95% CI, 0.61-2.47). Consistent results were obtained for subgroups receiving palbociclib (n = 177) and abemaciclib (n = 63) without propensity score matching. Adverse event incidence and severity were similar in both groups. CONCLUSION: The effectiveness of cyclin-dependent kinase 4/6 inhibitors is unlikely to be affected by concomitant PPI use. Future prospective pharmacokinetic studies are warranted.

PURPOSE: This study aimed to investigate the current status of end-of-life chemotherapy and targeted therapy and explore the aggressiveness of end-of-life care in Japan using the DeSC database, a large administrative claims database. METHODS: We identified fatal cases of at least one cancer-related diagnosis between April 2015 and November 2020. Patients prescribed at least one anticancer drug were analyzed, and chemotherapy regimens were categorized based on the combination of concomitant anticancer drugs prescribed. RESULTS: Among 1,095,713 individuals enrolled in the National Health Insurance database, 7,300 deaths with cancer-related diagnosis were identified. Of these, 4,010 cases were identified in which at least one anticancer drug was prescribed, and 11.6% of 7,300 death had been prescribed anticancer drugs in their last 30 days of life. The most commonly used regimen was S-1 (tegafur, gimeracil, and oteracil potassium combination) monotherapy, followed by nivolumab monotherapy and nab-paclitaxel plus gemcitabine. Immune checkpoint inhibitor monotherapy was more likely prescribed to patients whose last chemotherapy dose was in the last 30 days of life (p = 0.0066, chi-squared test). CONCLUSIONS: This study provides insights into the current status of end-of-life chemotherapy and targeted therapy in Japan, using a large administrative claims database. The results of this study will inform future research on end-of-life chemotherapy and targeted therapy, and help develop strategies to improve the quality of life of patients with advanced cancer.

PURPOSE: Denosumab is used to treat patients with bone metastasis from solid tumors, but sometimes causes severe hypocalcemia, so careful clinical management is important. This study aims to externally validate our previously developed risk prediction model for denosumab-induced hypocalcemia by using data from two facilities with different characteristics in Japan and to develop an updated model with improved performance and generalizability. METHODS: In the external validation, retrospective data of Kameda General Hospital (KGH) and Miyagi Cancer Center (MCC) between June 2013 and June 2022 were used and receiver operating characteristic (ROC)-AUC was mainly evaluated. A scoring-based updated model was developed using the same data set from a hospital-based administrative database as previously employed. Selection of variables related to prediction of hypocalcemia was based on the results of external validation. RESULTS: For the external validation, data from 235 KGH patients and 224 MCC patients were collected. ROC-AUC values in the original model were 0.879 and 0.774, respectively. The updated model consisting of clinical laboratory tests (calcium, albumin, and alkaline phosphatase) afforded similar ROC-AUC values in the two facilities (KGH, 0.837; MCC, 0.856). CONCLUSION: We developed an updated risk prediction model for denosumab-induced hypocalcemia with small interfacility differences. Our results indicate the importance of using data from plural facilities with different characteristics in the external validation of generalized prediction models and may be generally relevant to the clinical application of risk prediction models. Our findings are expected to contribute to improved management of bone metastasis treatment.

WHAT IS KNOWN AND OBJECTIVE: Adverse drug reactions (ADRs) are one of the primary reasons for hospitalization. The spontaneous reporting of ADRs by healthcare professionals is important for issuing post-marketing drug safety measures. The Japanese Society of Hospital Pharmacists (JSHP) conducts a nationwide survey annually. Using data from this large-scale survey, we identified the characteristics of hospitals that reported ADRs to regulatory authorities and pharmaceutical companies. METHODS: Data were obtained from annual surveys conducted by JSHP from 2015 to 2020. All variables were expressed as categorical variables and tabulated. The Chi-square test was used to compare the categorical variables. The Cochran-Armitage trend test was used to identify significant trends in the proportion of hospitals reporting ADRs. RESULTS AND DISCUSSION: From 2015 to 2020, 22,362 responses were recorded. There was a significant increase in the proportion of hospitals that reported ADRs with an increase in number of beds and pharmacists (p < 0.0001). The proportion of hospitals reporting ADRs to regulatory authorities was also significantly higher in those charging an additional fee for pharmacist-performed ward operations and in those with an ADR data management section than in hospitals without these attributes (p < 0.0001). WHAT IS NEW AND CONCLUSION: Hospitals that submitted ADR reports to the regulatory authorities and pharmaceutical companies charged an additional fee for pharmacist-performed ward operations, had a central ADR data management section, and had fewer beds per pharmacist. This trend was similar, regardless of the size of the hospital.

WHAT IS KNOWN AND OBJECTIVE: Continuing education is essential for pharmacists to acquire and maintain the knowledge, skills, and ethical attitudes necessary for clinical practice. However, with the emergence of COVID-19, the social circumstances and face-to-face learning environments have changed. The objectives of this study were to determine Japanese pharmacists' perception of a web-based educational programme in oncology, and assess changes in their understanding of pharmaceutical care in oncology before and after their participation in the webinar. METHODS: Questionnaire-based surveys were conducted for the participants of the web-based educational programme to determine their perspectives on the webinar, and their degree of comprehension of the five cancer types covered before and after watching the webinar. RESULTS AND DISCUSSION: Of the 1936 pharmacists taking the programme, all participated in the pre-webinar survey, and 1861 (96.1%) in the post-webinar survey. Compared with previous seminars that were held in the offline mode before the COVID-19 pandemic, 76.8% of respondents were significantly satisfied with the web-based educational programme. The median post-webinar comprehension scores in all modules were significantly higher than the median pre-webinar scores (p < 0.0001). A majority of the participants agreed that a web-based educational programme was satisfactory in acquiring knowledge. WHAT IS NEW AND CONCLUSION: This web-based educational programme was effective for Japanese pharmacists for postgraduate education in pharmaceutical care in oncology. To the best of our knowledge, our study is the first to report the effectiveness of a web-based educational programme for oncology pharmacists using a large population.

Aim: To describe real-world breast cancer medications among reproductive-age women. Patients & methods: Using data from a Japanese claims database, anticancer prescriptions were classified into seven categories of amenorrhea risk based on fertility preservation guidelines. Results: We identified 2999 women with records of breast cancer and anticancer prescription from 2005 to 2018. The proportions of prescriptions were as follows: high, 4.1-12.9%; intermediate, 6.0-16.3%; low, 0.4-2.3%; very low/no, 0.3-12.2%; unknown, 33.9-45.5%; unlisted combination, 12.2-23.4%; and unlisted drug, 12.5-26.7%. The common drugs in the unknown category were trastuzumab (n = 1527), docetaxel (n = 1014), and paclitaxel (n = 995). For medications unlisted in the guidelines, various drugs and drug combinations were observed. Conclusion: Numerous anticancer drugs are currently being prescribed with insufficient evidence regarding amenorrhea risk.

BACKGROUND: Trifluridine/tipiracil (TAS-102) is an oral anticancer drug with adequate efficacy in unresectable colorectal cancer, but frequently also induces chemotherapy-induced nausea and vomiting (CINV). To investigate the occurrence of CINV and antiemetic therapy in patients with colorectal cancer treated with TAS-102 (JASCC-CINV 2001). METHODS: We conducted a multicenter, prospective, observational study in patients with colorectal cancer who received TAS-102 without dose reduction for the first time. Primary endpoint was the incidence of vomiting during the overall period. Secondary endpoints were the incidence of nausea, significant nausea, anorexia, other adverse events (constipation, diarrhea, insomnia, fatigue, dysgeusia) and patient satisfaction. Patient diaries were used for primary and secondary endpoints. All adverse events were subjectively assessed using PRO-CTCAE ver 1.0. and CTCAE ver 5.0. RESULTS: Data from 100 of the 119 enrolled patients were analyzed. The incidence of vomiting, nausea, and significant nausea was 13%, 67%, and 36%, respectively. The incidence of vomiting in patients with and without prophylactic antiemetic therapy were 20.8% and 10.5%, respectively. Prophylactic antiemetics were given to 24% of patients, of whom 70% received D2 antagonists. Multivariate Cox proportional hazards analysis showed that experience of CINV in previous treatment tended to be associated with vomiting (hazard ratio [HR]: 7.13, 95% confidence interval [CI]: 0.87-58.5, P = 0.07), whereas prophylactic antiemetic administration was not (HR: 1.61, 95 CI: 0.50-5.21, P = 0.43). With regard to patient satisfaction, the proportion of patients who were "very satisfied," "satisfied," "slightly satisfied" or "somewhat satisfied" was 81.8%. CONCLUSIONS: The low incidence of vomiting and high patient satisfaction suggest that TAS-102 does not require the use of uniform prophylactic antiemetic treatments. However, patients with the experience of CINV in previous treatment might require prophylactic antiemetic treatment.

抗がん薬による職業的曝露と環境汚染低減のため、薬剤師に対して化学発光液を用いた抗がん薬の取扱いに関するトレーニングを行い、その前後に作業者の手袋の残留抗がん薬量を測定した。研究対象者5名が化学発光液を用いたトレーニングを行い、5名全員について薬液入りバイアルのゴム栓、輸液ボトルのゴム栓部への化学発光液の付着が確認された。1時間のトレーニング実施後には、すべての被験者で化学発光液の落下や付着が認められなくなった。トレーニング前後における手袋の残留抗がん薬量に関して、5-フルオロウラシルはトレーニング実施前では5名中3名で検出されたのに対し、トレーニング実施後では5名中5名が検出限界以下であった。ゲムシタビン塩酸塩はトレーニング前後でそれぞれ5名中1名から検出され、同一の研究対象者であった。手袋に付着した抗がん薬量の測定は、トレーニング方法の評価指標として適用可能であることが示唆された。