Details of a Researcher - KAWAZOE Hitoshi

Papers - KAWAZOE Hitoshi

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Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum

Ishikawa E, Yokoyama Y, Chishima H, Kuniyoshi O, Satou I, Nakaya N, Nakajima H, Kimura M, Hakamata J, Suehiro N, Nakada H, Ikemura S, Jibiki A, Kawazoe H, Muramatsu H, Suzuki S, Nakamura T

Journal of Chromatography B (ELSEVIER ) 1199 123245 2022.04

Research paper (scientific journal), Joint Work, Accepted

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.

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Effects of adding a neurokinin-1 receptor antagonist to 5 mg olanzapine, a 5-hydroxytryptamine-3 receptor antagonist, and dexamethasone for preventing carboplatin-induced nausea and vomiting: a propensity score-matched analysis

Yamamoto S, Iihara H, Uozumi R, Kawazoe H, Tanaka K, Fujita Y, Abe M, Imai H, Karayama M, Hayasaki Y, Hirose C, Suda T, Nakamura K, Suzuki A, Ohno Y, Morishige K, Inui N

BMC Cancer (BMC) 22 310 2022.03

Research paper (scientific journal), Joint Work, Accepted

Background: Olanzapine has been reported to be an effective antiemetic in patients receiving carboplatin-based chemotherapy. However, the efficacy of a neurokinin-1 receptor antagonist (NK1RA) added to olanzapine, a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA), and dexamethasone (DEX) has not been proven. This study aimed to assess the efficacy and safety of NK1RA, in combination with three-drug antiemetic regimens containing olanzapine, in preventing nausea and vomiting induced by carboplatin-based chemotherapy.
Methods: Data were pooled for 140 patients receiving carboplatin-based chemotherapy from three multicenter, prospective, single-arm, open-label phase II studies that evaluated the efficacy and safety of olanzapine for chemotherapy-induced nausea and vomiting. The propensity score of the co-administration of NK1RA was estimated for each patient using a logistic regression model that included age, sex, and carboplatin dose. We analyzed a total of 62 patients, who were treated without NK1RA (non-NK1RA group: 31 patients) and with NK1RA (NK1RA group: 31 patients). The patients were selected using propensity score matching.
Results: The complete response rate (without emetic episodes or with no administration of rescue medication) in the overall period (0–120 h post carboplatin administration) was 93.5% in the non-NK1RA group and 96.8% in the NK1RA group, with a difference of -3.2% (95% confidence interval, -18.7% to 10.9%; P = 1.000). In terms of safety, there was no significant difference between the groups in daytime sleepiness and concentration impairment, which are the most worrisome adverse events induced by olanzapine.
Conclusions: The findings suggest that antiemetic regimens consisting of olanzapine, 5HT3RA, and DEX without NK1RA may be a treatment option for patients receiving carboplatin-based chemotherapy.

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Study protocol for a double-blind, comparative, randomized Japanese trial of triplet standard antiemetic therapies with or without 5 mg olanzapine to prevent chemotherapy-induced nausea and vomiting for patients with breast cancer treated with an anthracycline/cyclophosphamide regimen (JTOP-B)

Ozeki R, Iihara H, Shimokawa M, Hashimoto H, Abe M, Mukohara T, Bando H, Hayashi T, Kawazoe H, Komoda M, Yanai-Takahashi T, Saito M

BMJ Open (BMJ PUBLISHING GROUP ) 12 e058755 2022.03

Research paper (scientific journal), Joint Work, Accepted

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.

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Renin-Angiotensin-Aldosterone System Inhibitors Prevent the Onset of Oxaliplatin-Induced Peripheral Neuropathy: A Retrospective Multicenter Study and in Vitro Evaluation

Uchida M, Ushio S, Niimura T, Takechi K, Kawazoe H, Hidaka N, Tanaka A, Araki H, Zamami Y, Ishizawa K, Kitamura Y, Sendou T, Kawasaki H, Namba H, Shibata K, Tanaka M, Takatori S

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 45 ( 2 ) 226 - 234 2022.02

Research paper (scientific journal), Joint Work, Accepted

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.

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Prognostic Value of Baseline Medications plus Neutrophil-to-Lymphocyte Ratio in the Effectiveness of Nivolumab and Pembrolizumab in Patients with Advanced Non-Small-Cell Lung Cancer: A Retrospective Study

Ogiwara T, Kawazoe H*, Egami S, Hashimoto H, Saito Y, Sakiyama N, Ohe Y, Yamaguchi M, Furukawa T, Hara A, Hiraga Y, Jibiki A, Yokoyama Y, Suzuki S, Nakamura T

Frontiers in Oncology (FRONTIERS MEDIA SA) 11 770268 2021.11

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

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.

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Drug repositioning of antipsychotic drugs for cisplatin-induced pica behavior in mice

Sekiguchi M, Sagano N, Kawazoe H*, Hiraga Y, Jibki A, Yokoyama Y, Suzuki S, Nakamura T

Pharmazie (Avoxa - Mediengruppe Deutscher Apotheker GmbH) 76 ( 10 ) 484 - 487 2021.10

Research paper (scientific journal), Joint Work, Corresponding author, Accepted, ISSN 0031-7144

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.

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新型タバコの主観的有害性認識度の評価　松山大学在校生への喫煙防止・禁煙教育の結果

黒田　普, 河添　仁, 山内真央子, 井上捷人, 高橋芹奈, 武智研志, 高取真吾, 柴田和彦, 難波弘行

禁煙科学 (日本禁煙科学会) 15 ( 10 ) 1 - 8 2021.10

Research paper (scientific journal), Joint Work, Accepted

目的:紙巻タバコや新型タバコ(加熱式タバコ、電子タバコ)に対する大学生の主観的有害性認識度(以下、認識度)が、喫煙防止・禁煙教育を行うことでどの様に変化するか講義前後で評価した。方法:共通教育科目において、癌疾患、慢性閉塞性肺疾患等の喫煙が関係する病態や禁煙補助剤の説明、さらに紙巻きタバコや新型タバコの有害性に関する90分の講義を3回行った。講義終了後、学生にアンケートを配布し、年齢、性別、3種類のタバコに関する認識度の変化(1:少ない〜5:多いの5段階)の記載を求めた。結果と考察:大学生への喫煙防止・禁煙教育において、講義後に喫煙に対する認識度は上昇しており有意差が認められた。3種類のタバコの中で認識度が最も高いのは、紙巻タバコであり、加熱式タバコ、電子タバコの順であった。紙巻タバコの有害性に関しては、小学校より継続的に教育されているが、新型タバコは近年販売されたばかりであり、毒性が低い等の宣伝が原因と考えられる。また、全ての種類のタバコの有害性に関して、女性の方が男性よりも認識度が高い傾向にあった。この理由として、女性は妊娠・出産等の健康面を考慮しているためと考えられる。一方、講義前の加熱式タバコや電子タバコの認識度が紙巻タバコよりも低い結果であった。特にニコチンやタールが入っていない電子タバコに関しては、講義前の認識度が最も低いため、電子タバコなら喫煙しても良いと考える多くの学生がいると懸念される。結論:大学生に対する紙巻きタバコや新型タバコに関する有害性認識度の調査から、大学生への新型タバコの有害性に関して教育する必要がある。(著者抄録)

薬学教育モデル・コアカリキュラムに基づく実務実習におけるルーブリック形式の概略評価は実習生のパフォーマンスレベルを測定できるか？

河添　仁, 鈴木小夜, 平賀ゆい, 横山雄太, 地引　綾, 岩田紘樹, 小林典子, 藤本和子, 中田英夫, 青森　達, 山浦克典, 中村智徳

医療薬学 ((一社)日本医療薬学会) 47 ( 9 ) 513 - 524 2021.09

Research paper (scientific journal), Joint Work, Lead author, Accepted, ISSN 1346-342X

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.

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Efficacy and safety of 5 mg olanzapine for nausea and vomiting management in cancer patients receiving carboplatin: integrated study of three prospective multicenter phase II trials

Yamamoto S, Iihara H, Uozumi R, Kawazoe H, Tanaka K, Fujita Y, Abe M, Imai H, Karayama M, Hayasaki Y, Hirose C, Suda T, Nakamura K, Suzuki A, Ohno Y, Morishige K, Inui N

BMC Cancer (BMC) 21 832 2021.07

Research paper (scientific journal), Joint Work, Accepted

Background: The efficacy of olanzapine as an antiemetic agent in cancer chemotherapy has been demonstrated. However, few high-quality reports are available on the evaluation of olanzapine’s efficacy and safety at a low dose of 5 mg among patients treated with carboplatin regimens. Therefore, in this study, we investigated the efficacy and safety of 5 mg olanzapine for managing nausea and vomiting in cancer patients receiving carboplatin regimens and identified patient-related risk factors for carboplatin regimen-induced nausea and vomiting treated with 5 mg olanzapine.
Methods: Data were pooled for 140 patients from three multicenter, prospective, single-arm, open-label phase II studies evaluating the efficacy and safety of olanzapine for managing nausea and vomiting induced by carboplatin-based chemotherapy. Multivariable logistic regression analyses were performed to determine the patient-related risk factors.
Results: Regarding the endpoints of carboplatin regimen-induced nausea and vomiting control, the complete response, complete control, and total control rates during the overall study period were 87.9, 86.4, and 72.9%, respectively. No treatment-related adverse events of grade 3 or higher were observed. The multivariable logistic regression models revealed that only younger age was significantly associated with an increased risk of non-total control. Surprisingly, there was no significant difference in CINV control between the patients treated with or without neurokinin-1 receptor antagonist.
Conclusions: The findings suggest that antiemetic regimens containing low-dose (5 mg) olanzapine could be effective and safe for patients receiving carboplatin-based chemotherapy.

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院内製剤の抗微生物薬，抗ウイルス薬，塩化ナトリウム点眼液の長期保存における安定性の評価

武田真実, 横山雄太, 渡邉武明, 平賀ゆい, 地引　綾, 河添　仁, 鈴木小夜, 門田佳子, 中村智徳

医療薬学 ((一社)日本医療薬学会) 47 ( 6 ) 316 - 325 2021.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

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.

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Effect of renin-angiotensin system inhibitors on pemetrexed plus platinum-induced hematological toxicities: a multicenter retrospective study using three propensity score analyses

Arami T, Kawazoe H*, Uozumi R, Hashimoto H, Egami S, Sakiyama N, Ohe Y, Nakada H, Aomori T, Ikemura S, Yasuda H, Kawada I, Fukunaga K, Soejima K, Yamaguchi M, Nakamura T

Pharmazie (Avoxa - Mediengruppe Deutscher Apotheker GmbH) 76 ( 6 ) 266 - 271 2021.06

Research paper (scientific journal), Joint Work, Corresponding author, Accepted, ISSN 0031-7144

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.

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Preventive effects of self-administered cryotherapy on paclitaxel-induced peripheral neuropathy in patients with early-stage breast cancer: a propensity score analysis

Shimanuki Y, Hashimoto H, Kawazoe H*, Uozumi R, Udagawa R, Watabe D, Nakamura T, Yamaguchi M, Terakado H

Pharmazie (Avoxa - Mediengruppe Deutscher Apotheker GmbH) 76 ( 6 ) 261 - 265 2021.06

Research paper (scientific journal), Joint Work, Corresponding author, Accepted, ISSN 0031-7144

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.

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Absolute Lymphocyte Count Predicts Immune-related Adverse Events in Patients with Non-small-cell Lung Cancer Treated with Nivolumab Monotherapy: A Multicenter Retrospective Study

Egami S, Kawazoe H*, Hashimoto H, Uozumi R, Arami T, Sakiyama N, Ohe Y, Nakada H, Aomori T, Ikemura S, Fukunaga K, Yamaguchi M, Nakamura T

Frontiers in Oncology (FRONTIERS MEDIA SA) 11 618570 2021.05

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

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.

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Low-Dose Olanzapine Plus Graniseteron and Dexamethasone for Carboplatin-Induced Nausea and Vomiting in Patients with Thoracic Malignancies: A Prospective Multicenter Phase II Trial

Sakai C, Shimokawa M, Iihara H, Fujita Y, Ikemura S, Hirose C, Kotake M, Funaguchi N, Gomyo T, Imai H, Hakamata J, Kaito D, Minato K, Arai T, Kawazoe H, Suzuki A, Ohno Y, Okura H

Oncologist (WILEY) 26 ( 6 ) e1066 - e1072 2021.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 10837159

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.

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Peripheral blood biomarkers predict immune-related adverse events in non-small cell lung cancer patients treated with pembrolizumab: a multicenter retrospective study

Egami S, Kawazoe H*, Hashimoto H, Uozumi R, Arami T, Sakiyama N, Ohe Y, Nakada H, Aomori T, Ikemura S, Fukunaga K, Yamaguchi M, Nakamura T

Journal of Cancer (IVYSPRING INTERNATIONAL PUBLISHER) 12 ( 7 ) 2105 - 2112 2021.02

Research paper (scientific journal), Joint Work, Corresponding author, Accepted, ISSN 1837-9664

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.

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代表的8疾患と薬局実習が病院実習の到達度に与える影響

清宮啓介, 津田壮一郎, 池淵由香, 鈴木小夜, 地引　綾, 岩田紘樹，横山雄太, 河添　仁, 小林典子, 藤本和子, 山浦克典, 中村智徳, 村松　博, 青森　達, 望月眞弓

医療薬学 ((一社)日本医療薬学会) 46 ( 12 ) 715 - 721 2020.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

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.

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医療従事者および医療系学生に対する国際ジャーナルクラブ活動とそのアウトカム

土屋雅美†, 河添　仁†, 江面美緒, 橋口宏司, 飯原大稔, 橋本浩伸

医療薬学 ((一社)日本医療薬学会) 46 ( 11 ) 664 - 671 2020.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

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.

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Patient-related Risk Factors for Nausea and Vomiting with Standard Antiemetics in Patients with Cancer Receiving Carboplatin: A Retrospective Study

Nasu I†, Shimano R†, Kawazoe H†, Nakamura T, Miura Y, Takano T, Hayashi M

Clinical Therapeutics (ELSEVIER) 42 ( 10 ) 1975 - 1982 2020.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 0149-2918

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.

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ヒノキ科花粉大量飛散年における2019年の花粉情報メール配信の評価

岡田啓司, 河添　仁, 高取真吾, 豊田芳彦, 清水秀樹, 宮野良隆, 難波弘行

日本花粉学会会誌 (日本花粉学会) 66 ( 1 ) 25 - 31 2020.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 0387-1851

我々は,ヒノキ科花粉の飛散が多かった2019年の,メール配信の「登録群」と「非登録群」における初期療法の実施状況と花粉症症状の評価,および登録前後のセルフメディケーションを含めた花粉症治療の患者満足度を比較検討した.花粉症症状の評価が最も高かったのは,「登録+初期療法」群であり,「登録+非初期療法」群,「非登録+初期療法」群,「非登録+非初期療法」群の順であった.さらに,セルフメディケーションを含めた花粉症治療の患者満足度も,「登録後」が「登録前」より高かった.以上より,ヒノキ科花粉飛散情報メール配信は,ヒノキ科花粉大量飛散年においても,患者の花粉回避に対する意識を高め,患者満足度の向上に寄与すると考えられる.(著者抄録)

実務実習生の薬学専門科目に対する自己効力感は実務実習での成功体験に影響を与える

菊山史博, 鈴木小夜，地引　綾，横山雄太，河添　仁, 中村智徳

薬学雑誌 ((公社)日本薬学会) 140 ( 6 ) 799 - 808 2020.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 0031-6903

Pharmacy practice experience (PPE) is essential in the six-year course of pharmaceutical education in Japan. We previously found that PPE reinforced students' self-efficacy for curriculums (SECs), leading robust acquisition and reconstruction of pharmaceutical expertise. In this study, we aimed to clarify whether students' SECs affect successful experiences as enactive attainments in PPE. We distributed survey questionnaires to the fifth-year students in Keio University in 2016-2017 before and after PPE. The students made a self-assessment of their psychological state “expect to do well” on a seven-point Likert scale for each curriculum (C1 to C18), and their successful experiences were also collected from free description type questionnaire. We could follow up 139 students. The SEC scores increased from pre-PPE to post I (p<0.001) and II terms (p<0.01). The increase in SEC scores during PPE was associated with the rate of students' successful experiences in the first-term PPE (p=0.04). The path analysis revealed the following as significant predictive factors of SECs for successful experiences: basic sciences (C1, C2, C3, C4, C5, and C6) with stand-ardizing coefficient 0.35, health and environmental sciences (C11 and C12) with 0.39, and pharmaceutical sciences (C7, C8, C9, C10, C13, and C14) with −0.51. Students in the first-term PPE tended to experience successful performance in medical professions by using their pharmaceutical expertise that they had learned. In this study, for the first time, we demonstrated that Japanese students' SECs for pharmaceutical expertise affected successful experiences, leading better outcomes of PPE.

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