Comparing the Efficacy of Fosnetupitant, an NK1 Receptor Antagonist in CDDP-Based Regimens, with That of Fosaprepitant and Aprepitant: A Retrospective Observational Study.

Existing antiemetic therapy against emetic-risk agents across malignancies 24 h post-dose in the acute period in cisplatin (CDDP)-based regimens yields a satisfactory complete response (CR) rate of ≥90%. However, the control rate after 24 h in the delayed period is unsatisfactory. This study compared the efficacy of fosnetupitant (F-NTP), a neurokinin 1 receptor antagonist, with that of fosaprepitant (F-APR) and aprepitant (APR) in the treatment of patients with cancer at high emetic risk due to chemotherapy. In this retrospective case-control study involving patients receiving cisplatin-containing regimens and neurokinin 1 receptor antagonists, patients were divided into three groups based on prophylactic antiemetic therapy: F-NTP, F-APR, and APR. The CR rate was evaluated for each period up to 168 h and further subdivided into acute (0-24 h), delayed (24-120 h), overall (0-120 h), and beyond-delayed (120-168 h) periods. Eighty-eight patients were included in the F-NTP group, 66 in the F-APR group, and 268 in the APR group. The CR rates at 0-168 and 120-168 h after cisplatin administration were significantly higher in the F-NTP group than in the F-APR and APR groups. After adjusting for confounding factors, F-NTP use was an independent factor in the multivariate analysis. Prophylactic antiemetic therapy, including F-NTP, was effective and well-tolerated during the delayed period. The efficacy of F-NTP in managing chemotherapy-induced nausea and vomiting was superior to those of F-APR and APR during the study period.

Case report: High-dose epoprostenol therapy in pediatric patients with pulmonary hypertension and developmental lung disease.

Pulmonary hypertension (PH) with developmental lung disease is a life-threatening disease and accounts for 10%-12% of pediatric PH patients. Administration of specific pulmonary vasodilators to pediatric PH patients has brought about improvement of their long-term prognosis. Intravenous epoprostenol therapy is a gold standard therapy for severe idiopathic pulmonary arterial hypertension (IPAH), but there are few reports demonstrating the efficacy of epoprostenol for pediatric PH patients with developmental lung disease, especially when treating with high doses of epoprostenol. Two cases of pediatric PH patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) and congenital diaphragmatic hernia (CDH) with bronchopulmonary dysplasia (BPD), respectively, treated with epoprostenol above 100 ng/kg/min are presented. In these two cases, severe PH was improved significantly by an aggressive increase of the epoprostenol infusion rate with administration of oral pulmonary vasodilators and appropriate respiratory management, without any significant adverse effects. High-dose epoprostenol therapy may be one of the therapeutic options in pediatric PH patients with developmental lung disease.

Simultaneous inhibition of Chk1 and Bcl-xL induces apoptosis in vitro and represses tumour growth in an in vivo xenograft model.

We previously showed that prexasertib, a checkpoint kinase 1 (Chk1) inhibitor, and navitoclax, a Bcl-2 and Bcl-xL inhibitor, induced a synergistic inhibitory effect on cell proliferation in vitro. Here, we investigated the effect of the simultaneous knockdown of Chk1 and each antiapoptotic protein of the Bcl-2 family (Bcl-2, Bcl-xL, or Mcl-1) with small interfering RNAs on apoptosis in three pancreatic cancer cell lines. Only simultaneous knockdown of Chk1 and Bcl-xL induced significant apoptosis compared with single knockdown in all three cell lines. We evaluated the anti-tumour effects of combined prexasertib and navitoclax treatment in a mouse xenograft model. Treatment to control volume ratios were calculated as 63.2% for prexasertib, 79.4% for navitoclax, and 36.8% for prexasertib and navitoclax. These findings suggest that the simultaneous inhibition of Chk1 and Bcl-xL may be an effective treatment for pancreatic cancer.

Conception by assisted reproductive technology in infants with critical congenital heart disease in Japan.

RESEARCH QUESTION: What is the proportion of infants born as a result of assisted reproductive technology ART across different types of neonatal critical congenital heart disease (CCHD) in a Japanese population? DESIGN: A retrospective analysis of 418 consecutive infants with CCHD that required catheter treatment or surgery within the first 28 days of life or ductal-dependent lesions, in two paediatric centres in Japan, between January 2014 and December 2019. The proportion of ART in infants with each type of CCHD was evaluated. The proportion of ART in infants with univentricular heart defect (UVH) compared with those with biventricular heart defect (BVH) was evaluated. RESULTS: The study group included 229 boys and 189 girls, with a gestational age of 38 ± 2 weeks. Overall, 61 infants (14.6%) were conceived by fertility treatment with 46 (11.0%) conceived by ART. Univentricular heart defect and BVH were identified in 111 infants (26.6%) and 307 infants (73.4%), respectively. The proportion of infants conceived by ART was significantly higher in UVH (16.2%) than in BVH (9.1%) (OR 2.28, 95% CI 1.11 to 4.68, P = 0.025), regardless of maternal age and maternal history of miscarriage. CONCLUSIONS: The proportion of ART in infants with CCHD, especially UVH, was high. These findings could form the basis of a rationale for carrying out fetal echocardiography in fetuses conceived by ART.

[Pressure Compatibility Test of Closed System Drug Transfer Devices for 71 Anticancer Drugs].

Occupational exposure to anticancer drugs may increase the risk of cancer and the risk of miscarriage and stillbirth, and cause other adverse events such as hypersensitivity reactions, skin/mucous reactions, and digestive symptoms. Several studies have investigated the use of closed-system drug-transfer devices (CSTDs) to reduce the environmental pollution by hazardous drugs. However, few reports have verified whether CSTDs contain the hazardous drugs within the vials. The BD PhaSealTM System is a CSTD that is frequently used in Japan. However, the fit of each anti-cancer drug vial has not been investigated. We investigated the fit of 71 major anti-cancer drug vials and protectors released and frequently used in Japan by means of a pressure compatibility test that we developed. The pressure compatibility test involved attaching a three-way stopcock to a Luer lock syringe and attaching an injector in line with the syringe. The pressure tubing was connected to the other side of the three-way stopcock and connected to the pressure inlet of the pressure gauge. The pressure in the anti-cancer drug vial was raised to 100 kPa and connected/disconnected repeatedly. If the pressure fluctuation during the 10th connection was within 6%, it was defined as "no change", and the compatibility of the protector and the vial was evaluated. The median pressure reduction rates at the 10th connection ranged from -1.98% to -4.95%. All drugs surveyed had an error rate within 6%. The BD PhaSealTM Protector was shown to be compatible with the 71 anti-cancer drugs we surveyed.

Development of a simple compatibility inspection method using pressure in a BD PhaSeal™ system and hazardous drug vials.

BACKGROUND: Many reports support the use of closed system drug transfer devices (CSTDs) to protect against exposure to hazardous drugs during their preparation. However, leakage may occur if the CSTD fails to maintain hermeticity when fitted into the vial. Our aims were to devise a measure to prevent HD exposure and to develop a test method to verify CSTD function when a BD PhaSeal™ protector is used in HD preparation. METHODS: We selected the BD PhaSeal™ System, which is the most commonly used CSTD device in Japan. The sealability of the BD PhaSeal™ protector and vial is considered to be due to the hermeticity of the protector and the rubber stopper of the vial. We constructed a protector with a damaged sealing rim and monitored the pressure fluctuation 10 times when the BD PhaSeal™ injector was connected to the pressurized vial. RESULTS: The reduction in pressure of the protector in the group without a damaged sealing rim was 5%, while that in the group with the damaged sealing rim was 84.9%. CONCLUSION: It was suggested that leakage occurred through the gap between the protector and the rubber stopper when using a vial that was not in close contact with the sealing rim. In this study, we developed a test that can be easily used to verify the compatibility of the BD PhaSeal™ protector and a vial in the clinical setting. Thus, when new hazardous drugs are being prepared, these measures can be taken to ensure that the risk of exposure is reduced or eliminated.

Bcl-2/Bcl-xL inhibitor navitoclax increases the antitumor effect of Chk1 inhibitor prexasertib by inducing apoptosis in pancreatic cancer cells via inhibition of Bcl-xL but not Bcl-2.

In our previous study, we showed that prexasertib, a checkpoint kinase 1 (Chk1) inhibitor, enhances the effects of standard drugs for pancreatic cancer, including gemcitabine (GEM), S-1, and the combination of GEM and S-1 (GS). The combination of prexasertib and GS has a strong antitumor effect and induces apoptosis in pancreatic cancer cells by downregulating anti-apoptotic protein Bcl-2. In the present study, we investigated the combined effect of GEM, S-1, and prexasertib with a selective Bcl-2 inhibitor (venetoclax) and a non-selective Bcl-2 inhibitor (navitoclax) in SUIT-2 pancreatic cancer cells. An MTT assay revealed that the combination of prexasertib with navitoclax showed a synergistic effect but the combination with venetoclax did not. Investigation of the pancreatic cancer cell lines SUIT-2, MIA PaCa-2, and BxPC-3 revealed that BxPC-3 also showed a high synergistic effect when combined with prexasertib and navitoclax but not venetoclax. Mechanistic analysis of the combined effect showed that apoptosis was induced. Bcl-2 knockdown with siRNA and prexasertib treatment did not induce apoptosis, whereas Bcl-xL knockdown with siRNA and prexasertib treatment resulted in strong induction of apoptosis. In addition, among the three cell lines, the combined effect of prexasertib and navitoclax resulted in increased apoptotic cell death because the protein expression levels of Bcl-xL and Chk1 were higher. Our results demonstrate that the combination of prexasertib and navitoclax has a strong antitumor effect and induces apoptosis in pancreatic cancer cells by downregulating Bcl-xL. Simultaneous inhibition of Chk1 and Bcl-xL could be a new strategy for treating pancreatic cancer.

Electrocardiographic changes and long-term prognosis of children diagnosed with hypertrophic cardiomyopathy by the school screening program for heart disease in Japan.

BACKGROUND: In Japan, the school screening program for heart disease (SS) has been performed since 1973. However, little has been reported on the electrocardiogram (ECG) changes and long-term prognosis in patients with hypertrophic cardiomyopathy (HCM) detected by the SS. METHODS: All 44 consecutive pediatric HCM patients (10.1 ±â€¯3.0 years old), who had been originally consulted by the SS before the diagnosis of HCM from April 1981 to April 2017, were reviewed retrospectively. RESULTS: At the SS, all patients showed mild or no symptoms. All patients showed ECG abnormalities, and 75 % had a high proposed ECG risk score (≧6). However, 30 % of them had no echocardiogram finding of myocardial hypertrophy. During the follow-up period (14.8 ±â€¯10.0 years), life-threatening events (LTE) occurred in 11 (25 %) patients, and the first LTE occurred during exercise in 8 (18 %). The estimated LTE and heart failure death-free survival rate at 10 years was 64.9 %. The LTE-free survival rate was lower in patients without than in those with myocardial hypertrophy at the SS. CONCLUSIONS: The SS was useful in detecting patients with HCM with mild or no symptoms at the early stage. However, our study indicated that early detection of HCM is not associated with improvement in the prognosis of the patients. Further studies are needed.

Prexasertib increases the sensitivity of pancreatic cancer cells to gemcitabine and S­1.

Our previous study demonstrated that gemcitabine (GEM), S­1, and a combination of GEM and S­1 (GS) induced S­phase arrest and increased the phosphorylation of checkpoint kinase 1 (Chk1), which is a critical mediator of cell survival under impaired DNA replication, in pancreatic cancer cell lines. The aim of the present study was to investigate the combined effect of the Chk1 inhibitor prexasertib and antitumor drugs (GEM and S­1) on pancreatic cancer cell line SUIT­2. Furthermore, we conducted mechanistic analysis of the combined effect. The MTT assay revealed that a combination of prexasertib and GS showed a strong effect. Mechanistic analysis of the combined effect showed effective induction of apoptosis. Furthermore, a combination of prexasertib and GS downregulated the expression of antiapoptotic protein Bcl­2. Chk1 knockdown with small interfering RNA and GS treatment resulted in strong induction of apoptosis. Our results provide evidence to show that the combination of prexasertib and GS has a strong antitumor effect and effectively induces apoptosis in pancreatic cancer cells through downregulation of the antiapoptotic protein Bcl­2. Prexasertib could possibly enhance the effects of standard drugs, including GEM, S­1, and GS, against pancreatic cancer.

[Advanced Pharmaceutical Management Functions in Home Pharmaceutical Care].

Patients who receive home visits by pharmacists show a wide range of diseases.The patients are mainly elderly people with chronic diseases, children with some diseases or disabilities, and cancer patients receiving palliative care.Such patients request various pharmaceutical care at home from pharmacies.Pharmacies are essentially medical facilities and they must receive prescriptions from all patients, but depending on each pharmacy, there are few cases of a pharmacy refusing to receive prescriptions.Pharmacies participating in home pharmaceutical care need to establish a system incorporating 1 ) sufficient number of pharmacists, 2 ) pharmacy aseptic unit, 3 ) stockpiling of medical narcotics, and 4 ) stockpiling of medical supplies.However, because individual pharmacies have different situations, such as the intention of the founder, size of the facility, and experience and regionality of pharmacists, it is impossible for all pharmacies to participate in home pharmaceutical care in the same way.An increasing number of home patients with high dependence on medical care is expected in the future.For these patients, pharmacists need high clinical experiences, and at the same time, the burden on pharmacies to stockpile medicines will increase.Therefore, evaluation of pharmacies for home care patients with high dependence on medical care should be considered as an advanced pharmaceutical management function.

Risk factors for venous irritation in patients receiving vinorelbine: a retrospective study.

BACKGROUND: Vinorelbine is known to be effective in the treatment of non-small cell lung cancer and breast cancer. However, venous irritation is a common side effect. Although there have been some reports on risk factors for venous irritation in patients receiving vinorelbine, the factors evaluated have been limited and the results inconclusive. The aim of this study was to identify risk factors for venous irritation in patients receiving vinorelbine, and factors likely associated with venous irritation, including new factors such as hot compress with a hot towel  for prevention of venous irritation. METHODS: We retrospectively reviewed patients treated with vinorelbine at Kyorin University Hospital, Japan, between March 2013 and December 2016 and divided them into the two groups according to whether or not they had venous irritation. Clinical characteristics were compared between the two groups. RESULTS: Venous irritation occurred in 24 (38.1%) of 63 patients who received vinorelbine. The median number of times vinorelbine was administered before onset of venous irritation was 3 (range 1-14). The group with venous irritation had a significantly lower body surface area than the group without venous irritation (p = 0.035). Low body surface area was also the only significant risk factor for vinorelbine-associated venous irritation in multivariate analysis (adjusted odds ratio 70.42 per 1 m2decrement, 95% confidence interval 1.54-3236.25, p = 0.029). There was no association between the occurrence of venous irritation and the other covariates, such as use of a hot compress, history of diabetes mellitus, or use of a generic formulation of vinorelbine. CONCLUSION: Low body surface area may be a risk factor for venous irritation in patients receiving vinorelbine. Use of hot compress with a hot towel did not prevent venous irritation.

[Role of Pharmacists in Completion of Adjuvant Cisplatin-Vinorelbine Chemotherapy in Japanese Patients with Non-small Cell Lung Cancer].

　Adjuvant cisplatin-vinorelbine chemotherapy has been shown to be effective in patients with completely resected non-small cell lung cancer (NSCLC) in several Phase III trials, but not yet in the Japanese population. Pharmacists are expected to assist patients with completion of adjuvant chemotherapy. The aim of this retrospective study was to evaluate the compliance with and safety of adjuvant cisplatin-vinorelbine chemotherapy in Japanese patients and to evaluate the contribution of pharmacists to completion of treatment. Thirty-four patients with NSCLC who received adjuvant cisplatin-vinorelbine chemotherapy at Kyorin University Hospital between January 2006 and June 2015 were reviewed. The treatment schedule comprised cisplatin 80 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks. Four 3-week cycles were planned. A pharmacist provided guidance to all patients and monitored them for adverse effects thereafter. The pharmacist intervened with advice to doctors as necessary. The 4 cycles were administered in 67.6% of cases. There were no treatment-related deaths. The main grade 3 or 4 toxicities were neutropenia (76.5%) and anorexia (38.2%). The most common reason for discontinuation and dose reduction was anorexia. There were 56 instances of pharmacist intervention. In total, 96.4% of the pharmacist interventions were implemented by doctors, which included administration of an antiemetic on 15 occasions and hot fomentation for prevention of vasculitis on 7 occasions. Adjuvant cisplatin-vinorelbine chemotherapy was tolerated by most patients but was discontinued because of adverse events in some. Pharmacist intervention aids completion of planned chemotherapy and management of treatment-related adverse events.

Joint symptoms associated with anastrozole and letrozole in patients with breast cancer: a retrospective comparative study.

BACKGROUND: Joint symptoms are a common side effect of aromatase inhibitors. However, it is not known if the risk of these symptoms varies between the members of this drug class. The aim of this study was to compare the frequency of joint symptoms associated with anastrozole and that associated with letrozole. METHODS: We retrospectively reviewed patients with breast cancer who were treated with anastrozole or letrozole at Tsukiji Breast Clinic, Japan, between April 2008 and July 2014. Joint symptoms were deemed to include both joint pain and painless joint symptoms. The time to onset of joint symptoms in the anastrozole group was compared with that in the letrozole group using Kaplan-Meier curves and the log-rank test. RESULTS: Of 141 patients identified to have received aromatase inhibitors, 70 had been treated with anastrozole and 71 with letrozole. Joint symptoms occurred in 60.3% of the 141 patients (60.0% in the anastrozole group and 60.6% in the letrozole group; p = 1). Median time to appearance of joint symptoms was 583 days, with no significant difference between the anastrozole and letrozole groups (p = 0.962). There was no significant difference in time to onset of joint pain (p = 0.139); however, time to onset of painless joint symptoms was significantly shorter in the anastrozole group (p = 0.022). The sites at which joint symptoms occurred were similar in the two groups. CONCLUSIONS: The results of this study indicate that there is no difference in the pattern of occurrence of joint symptoms caused by anastrozole and those caused by letrozole. TRIAL REGISTRATION: Trial registration was not required for this study because of its retrospective nature and lack of intervention.

Effect of a combination of S-1 and gemcitabine on cell cycle regulation in pancreatic cancer cell lines.

In a previous study, we showed that a combination of an oral fluoropyrimidine anticancer agent (S-1) and gemcitabine (GEM) had synergistic effects on cell growth and cell cycle arrest in the pancreatic cancer cell line MIA PaCa-2. Therefore, we conducted further mechanistic studies using the pancreatic cancer cell lines MIA PaCa-2 and SUIT-2. The combined effect of S-1 and GEM in SUIT-2 cells was evaluated using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the effects of S-1, GEM and S-1 plus GEM on cell cycle regulation were assessed using flow cytometry. We also examined the expression of several cell cycle regulatory proteins in both MIA PaCa-2 and SUIT-2 cells by western blotting. Classical isobolographic analysis of the MTT assay results showed that the combination of S-1 and GEM had a synergistic effect in SUIT-2 cells, and flow cytometric analysis of the cell cycle showed that the combination of S-1 plus GEM induced S-phase arrest to a greater degree than did either S-1 or GEM alone. Also, the combination of S-1 and GEM resulted in the downregulation of cyclin D1 expression and upregulation of cyclin A, p21 and p27 expression levels. Treatment of MIA PaCa-2 and SUIT-2 cells with a combination of both drugs also led to the increased phosphorylation of checkpoint kinase 1. Combined treatment with S-1 and GEM resulted in more prolonged S-phase arrest than with either treatment alone. This difference is shown to be potentially due to the higher levels of phosphorylated checkpoint kinase 1 in pancreatic cancer cell lines treated with the two agents.

Experimental study of combination therapy with S-1 against pancreatic cancer.

PURPOSE: To determine the most effective combination chemotherapy with S-1 against pancreatic cancer and to clarify the mechanism of synergy between S-1 and the partner drug. METHODS: We tested a combination of S-1 with the following antitumor drugs in an in vitro MTT assay against pancreatic cancer cell line MIA PaCa-2: gemcitabine (GEM), cisplatin (CDDP), irinotecan (CPT-11), mitomycin C, adriamycin, and paclitaxel. The efficacy of S-1, GEM, and a combination of S-1 and GEM was also tested in vivo by administering S-1 (10 mg/kg) orally to nude mice five times a week for 3 weeks, and GEM (100 mg/kg) intravenously every 2-3 days for a total of six times. A treated-to-control ratio (T/C) of relative mean tumor weight values less than 50% was determined to be effective. Furthermore, we investigated the mechanism of the synergistic effect of S-1 and GEM on the cell cycle by flow cytometry, because both S-1 and GEM are known as antimetabolic drugs. To verify cell death induced by a change in the distribution of the cell cycle phases, we investigated apoptosis by sub-G1 analysis and a TUNEL assay. RESULTS: From classical isobolography analysis of the in vitro MTT assay, the combination of S-1 plus GEM was found to be the most effective of the combinations tested. In vivo, T/C (percentage) with the combination of S-1 plus GEM was 48.2%, which was lower than that of S-1 or GEM alone, and the combination enhanced antitumor activity. Cell cycle analysis showed greater cell cycle delay with the combination treatment (S-1 plus GEM) than for each single drug treatment, and apoptotic cells were detected only in treatments including GEM. CONCLUSION: The combination chemotherapy of S-1 and GEM appears to be useful for pancreatic cancer. Both cycle delay by S-1 plus GEM and apoptosis induced by GEM are involved in this synergistic mechanism.