Published papers

A quantitative evaluation method has not yet been established for pharmacy students in relation to learning achievements and their hospital-based practical training. We therefore developed an outpatient chemotherapy educational program to address this issue. To assess the learning achievements quantitatively, we carried out four examinations - twice at the halfway point (first) and at the program's term-end (second); a perfect score was 100. This study was conducted between May and November 2013 and 24 pharmacy students participated. The results showed that the first and second mean scores relating to their cytotoxic agent handling knowledge were 91.5 ± 5.2 and 99.1 ± 1.8, respectively. The first and second mean scores relating to preparation skills for vials (how to handle anticancer drugs) were 68.5 ± 13.1 and 78.9 ± 18.5, respectively. For their preparation skills (using closed systems to handle anticancer drugs) the mean scores were 85.2 ± 13.1 (first) and 97.0 ± 3.7 (second). The first and second mean scores about the processes involved in solving chemotherapy-related patient problems were 52.1 ± 23.7 and 77.8 ± 21.9, respectively. All of the scores were significantly increased at the end of the program compared with scores halfway through. These results suggest that our program may be useful for supporting pharmacy students to learn more effectively during their hospital-based practical training in Japan.

The BD PhasealTM administration set, a new device for the BD PhasealTM closed system drug transfer device (CSTD), can prevent the occupational exposure of health caregivers to antineoplastic agents during all stages of the treatment process from preparation to administration. Further, a revised nursing approach for administration may prevent inadvertent antineoplastic agent spills. In this study, we compared the exposure levels of cyclophosphamide (CPA) and paclitaxel (PTX) between conventional methods and the new method described above; by sampling drug absorption sheets (a sampling sheet method) was used. In both methods, CPA was prepared using the BD PhasealTM CSTD and PTX was a plastic needle open system. For the new method, CPA was administered using the BD PhasealTM administration set and PTX was the revised nursing administration approach. Five pharmacists undertook the preparation process, and five nurses the administration process. Within the administration process using the conventional method, the following levels were detected: CPA 1.67 ng/cm2 and PTX 0.077 ng/cm2. No measurable levels were detected with the new method. For the preparation process, no CPA was detected, but PTX was detected. These results suggest that the use of the BD PhasealTM administration sets and the revised nursing administration approach is useful for preventing the occupational exposure of health caregivers to antineoplastic agents; this applies to both the preparation process and the administration processes.

We retrospectively evaluated the clinical outcomes of pharmaceutical interventions relating to outpatient chemotherapy and estimated their associated economic impact between August 2014 and August 2015. We developed a novel pharmaceutical system, involving JPY1,164,000 allocated to a total of 582 patients. There were 117 proposals for pharmaceutical interventions, 106 (90.6%) of which were accepted by physicians. The number of proposals for supportive therapy was 56, 29 (51.8%) of which significantly decreased the grade of chemotherapy-induced adverse events compared to before pharmaceutical interventions (P < 0.001). The number of reductions in grade 1, 2, and 3 events was 14, 11 and 4, respectively. In this study, the potential economic costs associated with reduction of grade 1, 2 and 3 chemotherapy-induced adverse events were calculated as JPY112,000, JPY112,000, and JPY2,140,000, respectively, based on the costs paid by the Adverse Drug Reaction Relief System of the Pharmaceuticals and Medical Devices Agency. According to this cost calculation, we estimated that the total cost saving associated with the clinical outcomes of pharmaceutical interventions was JPY11,360,000. This is the first study to estimate the economic impact associated with the clinical outcomes of pharmaceutical interventions for outpatient chemotherapy. These results suggest that pharmaceutical interventions contribute to the quality and safety of outpatient chemotherapy by decreasing chemotherapy-induced adverse events.

Following the publication of a guideline on the safe handling of hazardous drugs (HDs) in Japan, the issue of cost-effectiveness has been become a problem. We introduced the PhaSeal™ system in June 2015, a closed system drug transfer devices (CSTD) used for all outpatients, from preparation to administration. We retrospectively compared clinical outcomes before and after the introduction of CSTD of HDs included chemotherapy. Furthermore, we evaluated the medical fee income and the cost of providing CSTD between July and December 2015. The mean number of outpatient chemotherapy treatments per day before and after CSTD introduction was 15 ± 6 and 14 ± 5, respectively (P = 0.947). The mean preparation time by pharmacists before and after introduction was 21 ± 9 and 24 ± 9 minutes, respectively (P = 0.002). The mean time of nursing preparation before and after introduction was 29 ± 16 and 25 ± 14 minutes, respectively (P = 0.068). The mean time of patients waiting for chemotherapy before and after introduction was 36 ± 17 and 37 ± 17 minutes, respectively (P = 0.735). Based on the mean differences between the medical fee income and the cost of CSTD per month, we estimated that the annual cost associated with the introduction of CSTD for all outpatient to administer HDs was approximately JPY 21,000,000. After April 2016, we estimated that the amount of increase of the medical fee income of CSTD was approximately JPY 2,000,000 per year. These results suggest that the medical fee income should be increased so CSTD can be implemented for all outpatients.

Limited sharing of information occurs between hospitals and community pharmacies regarding outpatients receiving oral chemotherapy. We therefore developed the sharing system of patient information between hospital and community pharmacies using the monitoring sheet of tegafur/gimeracil/oteracil potassium (S-1). After October 2013, community pharmacies monitored adverse events in patients receiving S-1 using the monitoring sheet, and subsequently provided this information to our hospital by fax. A medical clerk entered the information into the electronic medical records, thus providing feedback to hospital physicians. In this study, we retrospectively investigated adverse events in outpatients who had received S-1 between September 2012 and October 2014. In total, sixty-seven patients were included in the study. The proportion of patients who experienced adverse events in the control group and the monitoring sheet group was 69.0％ and 76.0％, respectively. The proportion of patients who developed lacrimation in the control group and the monitoring sheet group was 11.9％ and 36.0％, respectively, which was statistically significant (P = 0.03). On the other hand, the proportion of patients who managed any adverse events in the control group and the monitoring sheet group was 45.2％ and 68.0％, respectively. The proportion of patients who managed lacrimation in the control group and the monitoring sheet group was 11.9％ and 32.0％, respectively, which was not statistically significant (P = 0.06). These results suggest that this sharing system contributed to the identification of adverse events induced by S-1, resulting in appropriate management for patients who developed these adverse events by hospital physicians and community pharmacists.

Treatment with antipsychotic drugs has been associated with hyperprolactinemia. The same antipsychotic drugs have also been associated with side effects such as menstruation disorders. The aim of this study was to evaluate the prevalence of hyperprolactinemia and menstruation disorders in women undergoing antipsychotic treatment. We performed a retrospective chart review study of psychiatric patients who underwent laboratory testing for serum prolactin (PRL) level between March 2011 and March 2015 in Ehime University Hospital. Patients presenting with and without menstruation disorders were evaluated to determine if they presented concomitant hyperprolactinemia. Patients with menstrual disorders had a significant increase in serum PRL level with a mean of approximately 90 ng/mL. Those with menstrual disorders presented increased PRL levels by 2-fold that of patients without menstrual disorder. However, there was no significant difference in the equivalent dose of chlorpromazine between these two groups. Additionally, about 70% of patients with menstrual disorders received risperidone treatment. The receiver operating characteristic curve showed that the optimal cutoff point of serum PRL level associated with the development of menstrual disorders was 60 ng/mL. Based on these results, we concluded that patients with menstrual disorders presented increased serum PRL, and that most of them underwent treatment with risperidone.

Background Venous pain induced by peripheral intravenous administration of oxaliplatin remains clinically unresolved. Objective The aim of this study was to determine the efficacy of comprehensive intervention care for venous pain in colorectal cancer patients receiving oxaliplatin. Setting A Japanese tertiary hospital. Method We treated all outpatients after April 2012 with comprehensive intervention care including pre-warming of the oxaliplatin solution, use of a hot compress, and pH adjustment by combination with dexamethasone. We retrospectively reviewed the electronic medical records from colorectal cancer patients who had received oxaliplatin via a peripheral vein between December 2009 and June 2014. Main outcome measures The primary endpoint of this study was the incidence of venous pain at the administration site during oxaliplatin infusion, according to injection site reaction grade ≥ 2. Results We evaluated 271 treatment courses in 59 patients. Venous pain occurred in 42 courses (15.5%) among 26 patients. Multivariate logistic regression analysis revealed that female gender and body mass index ≥ 25 kg/m2 were significantly associated with an increased risk of venous pain during all courses (adjusted odds ratio [OR]: 3.18, 95% confidence interval [CI] 1.35–7.92; P < 0.01; and adjusted OR: 3.37, 95% CI 1.26–9.40; P = 0.02, respectively), whereas comprehensive intervention care were significantly associated with reduced risk of venous pain during all courses (adjusted OR: 0.10, 95% CI 0.02–0.44; P < 0.01). Conclusion Comprehensive intervention care is a clinical treatment option for oxaliplatin-induced peripheral venous pain in patients with colorectal cancer, especially females with obesity.

A Japanese guideline for the safe handling of anticancer drugs recommends a closed system drug transfer device (CSTD). We gradually introduced the PhaSealTM system from preparation to administration of all anticancer drugs to inpatients on holidays as well as weekdays. We evaluated whether the CSTD handling of 36 pharmacists was appropriate or not and also retrospectively compared outcomes before and after the introduction of CSTD. In nine pharmacists who had more than 4 items of an inappropriate handling of CSTD, the median noncompliance ratio after re-training was significantly improved from 4 to 1 items (P = 0.008). We subsequently administered a questionnaire for 36 pharmacists. The customer satisfaction analysis indicated two issues for improvement: anxiety over appropriate preparation on the double audit system of pharmacists and anxiety over miss priming after liquid sensor. On the other hand, the median introduction ratio per day of CSTD between February and April 2016 and between September and October 2016 was significantly increased on weekdays and holidays (P < 0.001 and P < 0.001, respectively). In addition, the median preparation time per day between February and April 2016 and between September and October 2016 was not significantly increased on weekdays and holidays (P = 0.514 and P = 0.423, respectively). These results suggest that our training for pharmacists contributed to an appropriate handling of CSTD, resulting in the safe handling of all anticancer drugs to inpatients on weekdays as well as holidays and the risk management of pharmacists without increase of the preparation time.

© 2017 Background: The prognosis of diffuse large B-cell lymphoma (DLBCL) is remarkably improved after R-CHOP therapy. However, there are few detailed reports regarding very elderly DLBCL patients. We investigated relationships between prognostic factors and mortality risk in DLBCL patients, especially those aged 80 years or more. Methods: The study subjects consisted of 141 patients newly-diagnosed with de novo DLBCL. Information regarding age, sex, stage, performance status (PS), lactate dehydrogenase (LDH), extranodal (EN) involvement, and therapies was available. Results: For the 141 patients, the female sex was significantly inversely related to mortality, whereas age ≥80 years, PS ≥2, and non-standard therapy were significantly positively associated with death. No associations were observed between death and stage, LDH, or EN. When classifying patients by age (<80 [n = 108] and ≥80 [n = 33] years), a significant inverse association between female sex and mortality was found only in the latter (very elderly) group. Positive relationships of PS ≥2 with mortality was more pronounced in patients ≥80 years of age than in those <80 years of age. A significant positive relationship with non-standard therapy was found only in patients <80 years of age. Conclusion: PS ≥2 may be positively associated with mortality, regardless of age. Female sex may be inversely related to mortality only in DLBCL patients aged 80 years or more, possibly due to the difference in rituximab clearance between the two study groups.

© 2018 Elsevier Inc. Purpose: Oxaliplatin-induced peripheral neuropathy has remained an unresolved issue in clinical practice. Our previous study hypothesized that inhibition of the renin-angiotensin system (RAS) may produce a preventive effect on oxaliplatin-induced neuropathy. The aim of this study was to clarify whether RAS inhibitors prevent oxaliplatin-induced peripheral neuropathy. Methods: This study retrospectively analyzed data from cancer patients who had received chemotherapy including oxaliplatin and were treated with or without RAS inhibitors. This retrospective observational study was conducted at Ehime University Hospital using electronic medical records from May 2009 to December 2016. The primary end point was the incidence of severe peripheral neuropathy during or after oxaliplatin treatment, according to the Common Terminology Criteria for Adverse Events, version 4.0. A multivariate Cox proportional hazards model analysis was used to identify risk factors. Findings: A total of 150 patients were included in the study. The estimated incidence of peripheral neuropathy was 36.9% and 91.7% in the RAS inhibitor group and the non–RAS inhibitor group, respectively. The multivariate analysis using a Cox proportional hazards model showed that the RAS inhibitor group was slightly associated with a decreased risk of neurotoxicity (adjusted hazard ratio, 0.42 [95% CI, 0.18–0.99]; P = 0.048). Implications: The present findings suggest that RAS inhibitors have the ability to prevent oxaliplatin-induced peripheral neuropathy.

© 2018 Elsevier Inc. Purpose: The aim of this study was to identify a high-risk or low-risk population for chemotherapy-induced nausea and vomiting among patients with breast cancer treated with a current standard 3-drug antiemetic regimen and receiving anthracycline. Methods: We analyzed data from chemotherapy-naive Japanese patients with breast cancer, who had received the first cycle of anthracycline-based regimen and were treated with a 3-drug combination of aprepitant, palonosetron, and dexamethasone. This study was carried out at Ehime University Hospital (Toon, Japan) using electronic medical records from May 2011 to June 2017. The primary end point was complete response (CR), which was defined as no emesis and no use of rescue medication. Findings: A total of 103 patients were included in this study. The percentages of patients who had a CR in the overall, acute, and delayed phases were 35.0%, 40.8%, and 50.5%, respectively. Multivariate logistic regression analysis revealed that age <55 years and body mass index <27.5 kg/m2 were significantly associated with an increased risk for CR failure in the overall and acute phases. In contrast, a history of alcohol habit was significantly associated with a decreased risk for CR failure in overall phase. Implications: The present findings suggest that, among patients with breast cancer receiving anthracycline and treated with aprepitant, palonosetron, and dexamethasone, patients younger than 55 years and having a body mass index <27.5 kg/m2 are high-risk populations for chemotherapy-induced nausea and vomiting, whereas those with a history of habitual alcohol consumption is a low-risk one.

© 2018 Elsevier Inc. Purpose: Nivolumab, an anti–programmed death 1 antibody, produces antitumor effects by activating host immunity, which also causes immune-related adverse events (irAEs). The aim of this study was to analyze the association between antitumor effect and irAEs induced by nivolumab in patients with melanoma. Methods: Fifteen patients with melanoma who had received nivolumab at Tokushima University Hospital or Ehime University Hospital between January 2015 and December 2016 were enrolled in this study. Patients who had and did not have irAEs during nivolumab treatment were classified into an irAEs-positive group (n = 8) and an irAEs-negative group (n = 7), respectively. We compared the disease control rate (DCR) and overall survival (OS) between the 2 groups. Data on blood cell counts were also analyzed. Findings: After a median of 4 cycles of nivolumab treatment, irAEs occurred. The DCRs were 75% and 14% in the irAEs-positive and irAEs-negative groups, respectively (p < 0.05). OS in the irAEs-positive group was higher than that in the irAEs-negative group (p < 0.05). Multivariable Cox proportional hazards regression analysis revealed that irAE occurrence affected OS with nivolumab treatment. Moreover, the increase in baseline peripheral lymphocyte count at the time of onset of irAEs was significantly greater in the irAEs-positive group than in the irAEs-negative group after 4 cycles of nivolumab treatment (p < 0.05). Implications: Our study indicated that clinical response with nivolumab treatment improves with irAE occurrence in patients with melanoma. Moreover, the early increase in peripheral lymphocyte count may act as a biomarker for predicting the occurrence of irAEs induced by nivolumab.

ゲムシタビン誘発性血管痛は末梢静脈投与で生じ、臨床上未解決のままとなっている。エピルビシンとオキサリプラチンにおける先行研究によれば、抗炎症作用とpH調整目的にデキサメタゾンがオプションとなる。本研究の目的は、先発及び後発品のゲムシタビンとデキサメタゾン配合の製剤学的安定性を調査することであった。我々はデキサメタゾン配合後の凍結乾燥製剤及び液体製剤のゲムシタビン先発及び後発品11品目の濃度、pH及び外観変化を生理食塩液及び5%ブドウ糖液希釈において24時間後まで評価した。濃度とpHはそれぞれ高速液体クロマトグラフィーとpHメータで測定した。配合液の濃度及びpHは生理食塩液及び5%ブドウ糖液希釈において24時間後まで変化しなかった。ゲムシタビンの液体製剤のpHは凍結乾燥製剤と比較して、生理食塩液及び5%ブドウ糖液希釈においてわずかに低かった。さらに、生理食塩液及び5%ブドウ糖液希釈において外観変化はなかった。これらの結果は、すべての先発及び後発品のゲムシタビンの製剤学的安定性はデキサメタゾン配合によって影響を受けなかった。本研究は、実臨床においてゲムシタビン誘発性血管痛の可能性を減らすために、先発及び後発品のゲムシタビンはデキサメタゾンと配合投与できることを示唆する。(著者抄録)

愛媛大学医学部附属病院では、2016年6月より消化管・腫瘍外科の外来がん化学療法施行患者を対象に、薬剤師による面談を診察後から前へ変更した。そこで、診察前面談の有用性を評価し、改善点を明らかにすることを目的に変更前後6ヵ月間(前:2015年12月〜2016年5月、後:2016年7月〜12月)を比較検討した。変更前は延べ84名中47名、変更後は延べ139名中70名に面談を実施した。提案割合は変更前(23.4%、11/47名)と比較して変更後(40.0%、28/70名)で増加し、医師に当日採択された割合も変更後有意に上昇した(診察後面談:54.5%、6/11件vs診察前面談:100.0%、39/39件、p<0.001)。また、医師へのインタビューからも薬剤師の診察前面談内容が医師の診察時に共有されることで医師の業務負担軽減にも繋がり、患者の安全な薬物療法遂行に早期から貢献できていることが考えられた。(著者抄録)