論文

© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press. Background: We previously reported the results of a prospective study of chemotherapy-induced nausea and vomiting (CINV) in a cohort of patients who received carboplatin-based chemotherapy and were selected from a nationwide registry of those scheduled for moderately (MEC) or highly emetogenic chemotherapy (HEC) by the CINV Study Group of Japan. Of 1,910 previously registered patients (HEC: 1,195; MEC: 715), 400 patients received carboplatin-based chemotherapy. The frequency of CINV was determined, and the risk factors for CINV were assessed. Materials and Methods: CINV data were collected from 7-day diaries. Risk factors for CINV were identified using logistic regression models. Results: Of 400 patients scheduled for carboplatin-based chemotherapy, 267 patients received two antiemetics (5-hydroxytryptamine-3 receptor antagonist [5-HT3 RA] and dexamethasone [DEX]), 118 patients received three antiemetics (5-HT3 RA, DEX, and neurokinin-1 receptor antagonist [NK1 RA]), and 15 were nonadherent to the treatment. In these patients, the CINV overall, acute, and delayed phase rates of complete response (CR), defined as no vomiting with no rescue medication, were 67.0%, 98.2%, and 67.5%, respectively. The rates of no nausea were 55.6%, 94.0%, and 56.1%, respectively, and those of no vomiting were 81.3%, 99.0%, and 81.8%, respectively. Older age was associated with a decreased non-CR, whereas female sex, history of pregnancy-related emesis, and dual antiemetic therapy were associated with an increased non-CR during the overall period. Conclusion: In a clinical practice setting, in patients who received carboplatin-based chemotherapy, adherence is quite high and appropriate antiemetic prophylaxis requires a triple antiemetic regimen including NK1 RA. Implications for Practice: For patients receiving carboplatin-based chemotherapy, triple antiemetic therapy with 5-hydroxytryptamine-3 receptor antagonist, dexamethasone, and neurokinin-1 receptor antagonist should be given prophylactically regardless of risk factor status.

Purpose: Venous pain induced by peripheral intravenous infusion of gemcitabine has remained an unresolved issue in clinical practice. This study aimed to identify differences between gemcitabine formulations as well as risk factors associated with gemcitabine-induced venous pain in patients with cancer. Methods: We retrospectively analyzed data from consecutive patients with cancer who had received chemotherapy including a lyophilized or liquid formulation of gemcitabine diluted with 5% glucose solution via a peripheral vein. The study was conducted at Ehime University Hospital using electronic medical records dated between January 2015 and July 2017. The primary end point was the prevalence of venous pain at the administration site during gemcitabine infusion, classified as injection site reaction of grade ≥2 according to the Common Terminology Criteria for Adverse Events, version 4.0. A multivariate logistic regression analysis with generalized estimating equations for longitudinal data was used to identify risk factors for venous pain during all courses of gemcitabine treatment. Findings: A total of 1150 treatment courses in 141 Japanese patients were evaluated in this study. Venous pain occurred in 115 courses (10.0%) and in 49 patients (34.8%). The multivariate logistic regression analysis with generalized estimating equations revealed that a dose increase of gemcitabine and use of the liquid formulation of gemcitabine were significantly associated with an increased risk for venous pain (dose increase, adjusted odds ratio [OR] = 1.25; 95% CI, 1.11–1.40 [P < 0.001]; and liquid formulation, adjusted OR = 12.43, 95% CI, 5.61–27.51 [P < 0.001]), whereas age, course number of gemcitabine, and use of the soft-back product of 5% glucose solution were significantly associated with a reduced risk for venous pain (age, adjusted OR = 0.75; 95% CI, 0.57–0.98 [P = 0.037]; course number, adjusted OR = 0.96; 95% CI, 0.92–0.99 [P = 0.023]; and soft back, adjusted OR = 0.39; 95% CI, 0.21–0.74 [P = 0.004]). Implications: The use of the liquid formulation of gemcitabine was associated with a significant increase in the frequency of gemcitabine-induced venous pain despite dilution with 5% glucose solution compared to that with the lyophilized formulation. The lyophilized formulation of gemcitabine should hence be used in peripheral intravenous infusion for the treatment of patients with cancer.

Purpose: This study aimed to identify patient-related risk factors for chemotherapy-induced nausea and vomiting (CINV) in patients with cancer receiving carboplatin in addition to standard antiemetics, using real-world data. Methods: In this single-center, observational study, data from electronic medical records of consecutive patients with solid tumors who had received their first cycle of a carboplatin-based regimen and were treated with a 2- or 3-drug combination of antiemetics from January 2014 to January 2019 at Toranomon Hospital were retrospectively analyzed. The primary end point was the occurrence of a complete response (CR) within 5 days after the first cycle, which was defined as no vomiting and no use of rescue medication for CINV. A receiver operating characteristic curve, univariable, and multivariable logistic regression analyses were used. Findings: A total of 314 patients were evaluated in this study. The proportion of patients who had a CR in the overall, acute, and delayed phases was 76.8% (n = 241), 98.7% (n = 310), and 77.4% (n = 243), respectively. Similar to univariable logistic regression analysis, multivariable logistic regression analysis revealed that age ≥70 years and total dexamethasone dose ≥14.6 mg were significantly associated with a non-CR in the overall phase, whereas female sex, history of habitual alcohol intake, and history of smoking were not associated with a non-CR in the overall phase. Implications: Our study findings suggest that a patient age of <70 years and a total dexamethasone dose of <14.6 mg are high-risk factors for carboplatin-induced CINV.

We developed an international journal club, using an online meeting tool, as an evidence-based medicine training program intended for healthcare professionals and students. This study aimed to evaluate the outcome of the journal club via a questionnaire survey. We administered the questionnaire to 53 healthcare professionals and students who participated in the journal club between February 2019 and April 2020. Respondents showed positive improvement scores after participating in the journal club, compared with those before, as conveyed through the use of a seven-point Likert scale. The median scores of critical thinking skills, discussion skills in English, evidence-based practice skills, and the sense of freedom to ask questions and make comments after participating in the journal club were significantly improved from 4 (interquartile range [IQR]: 2 - 5) to 5 (IQR: 4 - 6); 3 (IQR: 2 - 4) to 3 (IQR: 2 - 5); 3 (IQR: 2 - 5) to 4 (IQR: 3 - 6); and 3 (IQR: 1 - 5) to 3 (IQR: 2 - 6), respectively. Moreover, they expressed interest in the opportunity to share articles on topics of interest with other professionals from different disciplines, to exchange clinical practice ideas concerning topics of interest, and to explore differences in clinical settings between Asia and the MD Anderson Cancer Center. They also expressed great appreciation for the online meeting format, novelty, and overall qualities of the journal club. These findings suggest that an international journal club for healthcare professionals and students could be useful in an evidence-based medicine training program and communication in English.

The Model Core Curriculum for Pharmacy Education (2013 version) presents eight disease areas as the minimum medical conditions that require student trainees to be continuously engaged in pharmacotherapy, during practical training at a community pharmacy followed by a hospital-based pharmacy. However, the relationship of the number of those who continuously experienced the minimum medical conditions and the outcome of rubric assessment that is newly introduced in this study remain unknown. We clarify the effect of the number of those who continuously experienced the minimum medical conditions and pharmacy training on rubric assessment using the uniquely developed “Individual Student Report Form.” Twenty inexperienced students and 21 experienced students in pharmacy practice were evaluated on the following subjects related to medication guidance: “(2)-2 Medication Order Review and Medication Therapy Management,” “(2)-4 Professional Attitudes and Behaviors of Practice, Patient Education, and Counseling,” “(3)-1 Collection of Patient Information,” “(3)-2 Management of Drug Information,” “(3)-3 Pharmaceutical Care Plans and Recommendations,” and “(3)-4 Evaluation of Effectiveness and Safety.” The number of eight disease experiences in any subjects were not shown to affect the students’ rubric evaluation. On the other hand, the pharmacy practice experiences were significantly increased in the “(3)-1 Collection of Patient Information” (partial regression coefficient B = 1.305, P = 0.044; 95％CI: 0.036-2.575). It is important to be flexible in the eight disease areas as the minimum medical conditions and to practice the problem solving of the patient with a certified pharmacist.

Background: Pembrolizumab is currently the standard treatment for patients with advanced non-small cell lung cancer (NSCLC). However, the association between immune-related adverse events (irAEs) and peripheral blood cell counts remains unclear. We aimed at identifying peripheral blood cell counts that may predict the development of pembrolizumab-induced irAEs. Methods: We retrospectively analyzed data on consecutive patients with advanced NSCLC who received pembrolizumab monotherapy as first-line or later-line therapy at the National Cancer Center Hospital and Keio University Hospital. We used data between December 2015 and November 2018. The primary endpoint was the relationship between peripheral blood cell count data and early-onset irAEs during the 6-weeks study period. Receiver operating characteristic (ROC) curve and multivariable logistic regression analyses were performed. Results: In total, 92 patients were evaluated, of whom 45 (48.9%) had at least one irAE during the first 6-weeks after treatment initiation. The ROC curves revealed that the optimal cutoff of pretreatment absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) for onset of irAEs were 1459, 2.320, 1.538, and 165, respectively. Multivariable logistic regression analyses revealed that pretreatment ALC>1450 and LMR>1.6 were significantly associated with a reduced risk for onset of any irAEs, whereas pretreatment NLR>2.3 and PLR>165 were significantly associated with an increased risk. Conclusions: The findings suggest that considering the routine availability of blood cell count data before the initiation of treatment with pembrolizumab, it may be useful in identifying early-onset irAEs during the 6-weeks study period in clinical practice.

Background: Olanzapine is an inexpensive and durable agent for the treatment of chemotherapy-induced nausea and vomiting and is also superior to neurokinin-1 receptor antagonists in the control of nausea. This study aimed to investigate the efficacy and safety of a low dose of 5 mg olanzapine plus granisetron and dexamethasone for treatment of carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic malignancies. Materials and Methods: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four centers in Japan. Registered patients were scheduled to receive area under the curve (AUC) ≥5 mg/mL per minute of CBDCA and had never received moderately to highly emetogenic chemotherapy. Patients received olanzapine 5 mg/day orally after supper for 4 days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the overall phase (0–120 hours). Results: Between February 2018 and June 2020, 51 patients were enrolled, and 50 patients were evaluated. The CR rates in the overall (0–120 hours), acute (0–24 hours), and delayed phases (24–120 hours) were 94.0%, 100%, and 94.0%, respectively. No grade 3 or higher adverse effects of olanzapine were observed. Conclusion: Prophylactic antiemetic therapy with a low dose of 5 mg olanzapine plus granisetron and dexamethasone showed durable efficacy with an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic malignancies receiving an AUC ≥5 mg/mL per minute of CBDCA-based regimen. Clinical trial identification number: UMIN000031267. Implications for Practice: The results of this phase II trial indicated that the prophylactic administration of low-dose of 5 mg olanzapine combined with granisetron and dexamethasone has promising activity with acceptable safety profile in patients with thoracic malignancy receiving high-dose carboplatin chemotherapy.

Background: Among patients with advanced non-small-cell lung cancer who were treated with nivolumab monotherapy, the association of peripheral blood count data (at baseline and 2 weeks after treatment initiation) with the early onset of immune-related adverse events (irAEs) and treatment efficacy has not been clearly established. This study aimed to identify peripheral blood count data that may be predictive of the development of nivolumab-induced irAEs in a real-world clinical setting. Materials and Methods: This multicenter observational study retrospectively evaluated consecutive patients with advanced non-small-cell lung cancer undergoing nivolumab monotherapy in the second- or later-line setting between December 2015 and November 2018 at the National Cancer Center Hospital and Keio University Hospital in Japan. The primary endpoint was the association between peripheral blood count data and irAEs during the 6-week study period. Receiver operating characteristic curve and multivariable logistic regression analyses were performed. Results: Of the 171 patients evaluated, 73 (42.7%) had ≥1 irAE during the first 6 weeks following treatment initiation. The median time to irAEs from the initiation of nivolumab was 15 (interquartile range: 13–28) days. Receiver operating characteristic curve analyses revealed that the optimal cut-off values of the absolute lymphocyte count, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio 2 weeks after treatment initiation for early irAE onset were 820, 4.3, and 2.2, respectively. In multivariable logistic regression analyses, absolute lymphocyte count >820 at 2 weeks after treatment initiation was significantly associated with an increased risk of early onset of any irAE. In contrast, no significant association was observed for the neutrophil-to-lymphocyte ratio (>4.3) or the lymphocyte-to-monocyte ratio (>2.2) at 2 weeks following treatment initiation. Conclusions: The absolute lymphocyte count >820 at 2 weeks following nivolumab initiation predicts early onset of irAEs during a 6-week study period. Routinely available absolute lymphocyte count, which is measured after the initiation of nivolumab, may be useful for identifying patients at risk of early onset of irAEs.

We hypothesized that suppression of peripheral circulation via cryotherapy may be effective in preventing paclitaxel-induced peripheral neuropathy (PIPN). Therefore, this study aimed to clarify whether self-administered cryotherapy could prevent PIPN in patients with early-stage breast cancer, using real-world data. A single-center, retrospective, observational study was conducted. Data from the electronic medical records of consecutive patients aged ≥ 20 years with early-stage breast cancer who received a regimen containing paclitaxel for 12 cycles with or without self-administered cryotherapy at the National Cancer Center Hospital from March 2018 to May 2019 were evaluated. The primary endpoint was the cumulative dose of paclitaxel until the onset of grade ≥ 2 PIPN. To compare the difference between the two groups, multivariable Cox proportional hazards models adjusted for prognostically important variables were used. Ninety Japanese patients were included in this study. The estimated incidence of grade ≥ 2 PIPN was 26.9% and 37.7% in the self-administered cryotherapy group and control group, respectively (P = 0.314). The multivariable Cox proportional hazards model showed that the self-administered cryotherapy group had a decreased risk of onset of grade ≥ 2 PIPN (hazard ratio: 0.63, 95% confidence interval: 0.25 to 1.39; P = 0.281). Sensitivity analyses using multivariable Cox proportional hazards models along with two propensity score-adjusted methods demonstrated consistent results. The findings suggest that the methods of self-administered cryotherapy may prevent PIPN and should be reinforced appropriately in clinical practice. A randomized controlled multicenter trial of self-administered cryotherapy is warranted.

Hematological toxicities induced by pemetrexed plus platinum therapy remain a critical issue in clinical practice. We hypothesized that inhibition of the renin-angiotensin system (RAS) can ameliorate pemetrexed-induced hematological toxicities through drug-drug interactions involving organic anion transporters. Thus, this study aimed to clarify whether RAS inhibitors (RASIs) could prevent pemetrexed plus platinum-induced hematological toxicities. We retrospectively analyzed data from 305 consecutive patients with non-small cell lung cancer or malignant pleural mesothelioma who received their first cycle of a pemetrexed plus platinum regimen and were treated with or without RASIs. The primary endpoint was the incidence of severe myelosuppression after the first cycle. Propensity score (PS)-matched, PS-adjusted, and inverse probability of treatment weighting (IPTW) analyses were used. The number of patients with grade ≥3 hematological toxicities was 27 (8.9%). PS-matched analyses revealed that the concomitant use of RASIs was slightly associated with a lower risk of grade ≥3 hematological toxicities (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.20–2.32; p = 0.536). Additionally, sensitivity analyses using PS-adjusted and IPTW methods demonstrated similar results (OR, 0.63; 95% CI, 0.19–2.15; p = 0.463 and OR, 0.37; 95% CI, 0.11–1.29; p = 0.117, respectively). These findings suggest that RASIs might prevent pemetrexed plus platinum-induced hematological toxicities.

It is necessary to determine the expiration date and storage methods for in-hospital preparations. However, data on the physical properties and stability of in-hospital preparations for eye drops, especially in long-term storage, are limited. Therefore, the stability of in-hospital preparations for eye drops, 0.5％ vancomycin (VCM), 0.25％ DENOSINE® (GCV), 0.1％ Funguard® (MCFG), 1％ VFEND® (VRCZ), and 5％ sodium chloride (NaCl), were evaluated for long-term storage. All eye drops were stored for 12 weeks under the following conditions: cool (4℃)/darkness, room temperature(approximately 23℃)/darkness, room temperature (approximately 24℃)/scattered light (approximately 1,500 lx), or high temperature (37℃)/darkness. The concentration of eye drops over time was measured by high-performance liquid chromatography and automated clinical chemistry analyzer, and pH, appearance, and sterility were evaluated. As a result, 0.5％ VCM eye drops can be stored for 3 weeks at room temperature when placed in a light-shielding bag or for 12 weeks at 4℃. The 0.25％ GCV, 1％ VRCZ, and 5％ NaCl eye drops can be stored for 12 weeks at 4 - 37℃. The 0.1％ MCFG eye drops can be stored for 6 weeks at 37℃, or for 12 weeks at room temperature or 4℃. The stability of in-hospital preparations for eye drops during long-term storage under varying conditions was demonstrated. Therefore, the use of in-hospital preparations for eye drops is considered to be safer and more effective.

This study aimed to clarify whether the performance levels of pharmaceutical students could be measured by a rubric-based performance evaluation, which consists of a four-point score, during pharmacy practice experiences (PPEs) at both community and hospital pharmacies on a revised model core curriculum for pharmaceutical education in Japan. We assessed the changes in performance evaluation by mentors and students during PPEs, the correlation of their total scores, and those between community pharmacies and hospitals. Data from the electronic records of fifth-year students of the Keio University Faculty of Pharmacy, who did PPEs in 2019, were retrospectively analyzed. A total of 144 students were included in this study. The median scores of performance evaluation by mentors and students in all tasks significantly increased from the commencement to the end of training in community pharmacies and hospitals (P < 0.05). Consequently, there was a significant association of total scores of performance evaluation between mentors and students in the community pharmacies (ρ = 0.755) or hospitals (ρ = 0.724). In contrast, there was a poor association of total scores of performance evaluation by mentors between community pharmacies or hospitals (ρ = 0.209) and those between community pharmacies and hospitals (ρ = 0.409). In conclusion, these findings suggest that performance evaluation by mentors and students reflects the latter’s performance level and can measure their growth in the PPEs at a community pharmacy and a hospital.

We aimed to clarify whether various antipsychotics ameliorate cisplatin-induced pica behavior in mice using a drug repositioning approach. Mice were administered cisplatin (12.5 mg/kg, i.p.) with or without olanzapine (1 mg/kg, i.p.), asenapine (4 mg/kg, i.p.), mirtazapine (5 mg/kg, i.p.) or standard three-drug antiemetics (granisetron [0.5 mg/kg, i.p.], fosaprepitant [25 mg/kg, i.p.], and dexamethasone [3 mg/kg, i.p.]). Kaolin, food, and water intake, and spontaneous motor activity on the day before and seven consecutive days after the cisplatin administration were measured using a telemetry system. At the primary endpoint, kaolin intake was significantly higher at day three in the cisplatin group than in the pre-treatment and saline groups ( p < 0.05). Additionally, kaolin intake was not significantly higher in cisplatin with olanzapine, asenapine, and mirtazapine groups for seven days than in the pre-treatment group. At the secondary endpoint, cisplatin decreased the food and water intake, and spontaneous motor activity in a time-dependent manner. Three antipsychotics failed to improve the cisplatin-induced decrease in food and water intake, and spontaneous motor activity. The findings suggest that prophylactic administration of antipsychotics besides olanzapine may improve cisplatin-induced nausea and vomiting in a delayed phase and de-escalate standard 3-drug antiemetics.

Background: Nivolumab and pembrolizumab are the standard treatments for patients with advanced non-small-cell lung cancer (NSCLC). While there are reports on several inflammatory indices and the prognosis of patients with cancer, no study has combined baseline medication with the neutrophil-to-lymphocyte ratio (NLR) to predict clinical outcomes. This study investigated the efficacy of baseline medications plus NLR to predict the effectiveness of nivolumab and pembrolizumab in a real-world clinical setting. Methods: We conducted a single-center retrospective observational study of consecutive patients with advanced NSCLC who received nivolumab or pembrolizumab as first-line, second-line, or beyond treatment between December 2015 and November 2018 at the National Cancer Center Hospital in Japan. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The drug-based prognostic score for baseline medications plus NLR was weighed based on the regression β coefficients. The multivariable Cox proportional hazard model was used to assess the association between the prognostic score-stratified groups and survival outcomes. Results: In total, 259 patients were evaluated in this study. A prognostic score calculated from the baseline medications plus NLR was used to categorize the patients into good (score 0), intermediate (scores 1–2), and poor (scores 3–6) -prognosis groups. The multivariable Cox proportional hazard model revealed a significant association between the poor-prognosis group and reduced OS. The hazard ratio of OS was 1.75 (95% confidence interval: 1.07–2.99; P = 0.031). In contrast, no association between these prognosis groups and PFS was observed. Conclusions: The findings suggest that the baseline medications with nivolumab or pembrolizumab plus NLR could lead to progressively shorter survival outcomes in patients with advanced NSCLC and could be used as a prognostic index for poor outcomes. However, to ascertain the clinical application of these findings, these concomitant medications need further validation in a large-scale multicenter study.

Oxaliplatin (OXA) is used in chemotherapy for various cancer types and is associated with acute and chronic neurotoxicity. However, a preventive strategy for OXA-induced peripheral neuropathy (OIPN) and its underlying mechanism remain unclear. We examined the effects of renin-angiotensin-aldosterone system inhibitors (RAASIs) on OIPN by performing a retrospective multicenter study and an in vitro assay. We retrospectively evaluated electronic medical records of 976 patients who underwent one or more courses of OXA-containing regimens at Ehime, Okayama, and Tokushima University Hospitals. The primary endpoint was the incidence of OIPN during or after OXA administration. The effects of RAASIs and OXA on the neurite length in PC12 cells were determined. The combined administration of an OXA-containing regimen and RAASI significantly inhibited the cumulative incidence grade-2 or higher OIPN (log-rank test; p = 0.0001). RAASIs markedly suppressed the development of both acute and chronic OIPN (multivariate analysis; p = 0.017 and p = 0.011). In an in vitro assay, 10 µM OXA suppressed the neurite length; treatment with 1 µM aliskiren, spironolactone, 10 µM candesartan, and enalapril significantly restored neurite length to the control level. Moreover, 1 µM SCH772984 (a selective inhibitor of extracellular signal-regulated kinase, ERK1/2) and 500 µM SQ22536 (a cell-permeable adenylate cyclase (AC) inhibitor) markedly abolished neurite-extending effects of candesartan and enalapril. These results indicate that RAASIs possess preventive or therapeutic effects in acute and chronic OIPN, candesartan and enalapril may increase in the activity of ERK1/2 and AC in PC12 cells.

Introduction: Triple antiemetic therapy with neurokinin-1 receptor antagonist, 5-hydroxytryptamine type 3 receptor antagonist, and dexamethasone has been widely recommended for high emetogenic chemotherapeutic (HEC) agents and regimens, including anthracycline combined with cyclophosphamide (AC). The addition of olanzapine (OLZ) 5 mg or 10 mg to the recommended triple antiemetic therapy has demonstrated superiority in antiemetic efficacy compared with the standard triplet therapy for a cisplatin-based HEC regimen. Although OLZ plus the triple antiemetic treatment may also be effective for patients on an AC-based HEC regimen, no study has investigated its efficacy at a lower dose of 5 mg. Methods and analysis: To assess whether 5 mg OLZ, as compared with placebo, in combination with triple combination therapy, significantly improves nausea and vomiting, we are conducting a randomised, parallel-group controlled clinical trial with a total of 500 patients at 15 study centres in Japan. The primary outcome is the complete response rate, defined as no emetic episodes and no use of rescue medication during 120 hours after the initiation of chemotherapy. Treatment group comparison for the primary endpoint will be done by using the Cochran-Mantel-Haenszel test. Ethics and dissemination: The study was approved by the institutional review board of Juntendo University Hospital and relevant approval was obtained from all participating centres. All participants will be required to provide written informed consent. The trial results will be reported at conferences and in peer-reviewed journals. Trial registration number: Japan Registry of Clinical Trials (jRCT) jRCT1031200134; protocol date: 30 July 2020, version: 1.3, approval: 25 August 2020.

Reports on the therapeutic drug monitoring (TDM) of second- and third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer patients are limited and are required to improve the safety of EGFR-TKI therapy. Some EGFR-TKIs have active metabolites with similar or higher potency compared with the parent compounds; thus, monitoring the parent compound as well as its active metabolites is essential for truly effective TDM. In this study, we developed and validated a method that simultaneously quantifies second- and third-generation EGFR-TKIs (afatinib, dacomitinib, and osimertinib) and the active metabolites of osimertinib, AZ5104 and AZ7550, in the human serum using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The clinical application of the method was also evaluated. The analytes were extracted from a 100 μL serum sample using a simple protein precipitation method and analyzed using LC-MS/MS. Excellent linearity of calibration curves was observed at ranges of 2.5–125.0 ng/mL for afatinib, 2.5–125.0 ng/mL for dacomitinib, 4.0–800.0 ng/mL for osimertinib, 1.0–125.0 ng/mL for AZ5104, and 2.5–125.0 ng/mL for AZ7550. The precision and accuracy were below 14.9% and within ± 14.9% of the nominal concentrations, respectively. The mean recovery was higher than 94.7% and the coefficient of variation (CV) was lower than 8.3%. The mean internal-standard normalized matrix factors ranged from 94.6 to 111.9%, and the CVs were lower than 9.7%. This analytical method met the acceptance criteria of the U.S. Food and Drug Administration guidelines. The method was also successfully applied to the analysis of 45 clinical samples; it supports the efficient and valuable analysis for TDM investigations of EGFR-TKIs.

We newly introduced an on-site workshop of personality inventory, using the Myers-Briggs Type Indicator® (MBTI®) intended for pharmacy students in January 2022. The aim of this study was to evaluate the outcome of the MBTI® workshop to support pharmacy studentsʼ self-understanding via an online questionnaire survey. All third- to ?fth-year students of the Keio University Faculty of Pharmacy (n = 17) assessed the self-understanding, clarity of career path, and their own MBTI® type during the pre-workshop phase, and after the lecture of MBTI®, personality inventory of the MBTI®, and the MBTI® workshop. The recovery rate of the questionnaire was 100％. Notably, the self-guessed MBTI® typeafter the lecture of MBTI® was different from that after the personality inventory of the MBTI® and the MBTI® workshop (94.1％ and 88.2％, respectively). Respondents showed positive scores after participating in the workshop, compared with those before, as conveyed through the use of a seven-point Likert scale. The median scores of self-understanding and clarity of career path after participating in the workshop were signi?cantly improved from 5 (interquartile range [IQR]: 3.5 - 5.5) to 6 (IQR: 6 - 6) and 4 (IQR: 2 - 5) to 5 (IQR: 4 - 6), respectively. They also expressed high overallsatisfaction on the workshop (median 7 [IQR: 6.5 - 7]). In conclusion, this study demonstrated the usefulness of the MBTI® workshop as an educational program to support pharmacy studentsʼ self-understanding. The evaluation of their career path after the MBTI® workshop is warranted in the future.

This study aimed to clarify the attitudes toward career paths for pharmacists in Japan. A self-administered online questionnaire survey was delivered to the live and on-demand release attendees at the 31st annual meeting of the Japanese Society of Pharmaceutical Health Care and Sciences between October 14th and December 7th, 2021. A customer satisfaction (CS) analysis was performed to assess the association between the participants’ perspectives on career paths and satisfaction. The recovery rate was 90.3％ (65/72). The number of females and males was 57 and 8, respectively. The respondents were from diverse backgrounds of age, workplace, and position, etc. The median satisfaction scores of job, education & training system, research activities, relationships, management’s consideration of women, the presence of role models, salary, career path support by colleagues, career path support by supervisors, career path support by a family member, work-life balance, and career paths was 4 (interquartile range [IQR]: 3 - 5), 3 (IQR: 2 - 4), 3 (IQR: 2 - 4), 4 (IQR: 3 - 5), 4 (IQR: 2.5 - 5), 2 (IQR: 1 - 4), 4 (IQR: 2 - 5), 4 (IQR: 3 - 5), 4 (IQR: 2.5 - 5), 5 (IQR: 5 - 7), 4 (IQR: 3 - 5), and 4 (IQR: 3 - 5), respectively. CS analysis revealed that the education & training system, work-life balance, and research activities should be improved as a matter of highest priority for a career path. In conclusion, the findings may provide useful information to develop career paths for Japanese pharmacists in diverse careers and work styles in the future.

Background: The association between the effectiveness of capecitabine and the concomitant administration of gastric acid suppressants remains controversial. We aimed to clarify whether the effectiveness of capecitabine is affected by the co-administration of histamine H2 receptor antagonists (H2RAs) in early-stage colorectal cancer (CRC) patients using real-world data. Methods: This multicenter, retrospective, observational study included consecutive patients with stage II-III CRC who received either capecitabine monotherapy or the CapeOX regimen (capecitabine and oxaliplatin) as adjuvant therapy between January 2009 and December 2014 in Japan. Relapse-free survival (RFS) and overall survival were estimated using the Kaplan-Meier method. Additionally, multivariable Cox proportional hazards model, propensity score adjustment, and inverse probability of treatment weighting analyses were performed. Results: In total, 552 patients were included in this study, of which 30 were co-administered H2RAs. RFS at five years was 76.7% (95% confidence interval [CI]: 57.2-88.1%) and 79.8% (95% CI: 76.0-83.0%) in the H2RA and non-H2RA groups, respectively. Multivariable Cox proportional hazards model and propensity score-adjusted analyses showed that the co-administration of H2RAs was associated with a poor RFS among those receiving capecitabine monotherapy (hazard ratio [HR], 2.01; 95% CI: 0.86-4.70 and HR, 1.81; 95% CI: 0.77-4.22, respectively). In contrast, these results were inconsistent with the group receiving the CapeOX regimen. Conclusions: The study findings suggest that the co-administration of H2RAs may not reduce the effectiveness of capecitabine therapy in patients with early-stage CRC. To confirm this relationship, a prospective study with a pharmacokinetic approach is needed.