Infusion Reactions in HER2-Positive Gastric Cancer: Switching from Trastuzumab to Its Biosimilar.

This study presents a safety analysis of infusion reactions (IRs) in gastric cancer patients who switched from reference trastuzumab to its biosimilar, trastuzumab-NK, at the Saitama Cancer Center in Japan from April 2018 to March 2022. IRs were identified if patients developed symptoms such as fever, chills, infusion-related reactions, hypersensitivity, rash, pruritus, urticaria, systemic disorders, or immune system disorders on the day of administration or the following day. The incidence of IRs was 14% in the reference trastuzumab group, 33% in the trastuzumab-NK group, and 33% in the switching group. There was no significant difference in IR incidence between the reference trastuzumab and trastuzumab-NK groups (p = 0.235). Among the switching group, only one of the three patients who experienced an IR had a reaction associated with the switch. These findings suggest that the frequency of IRs in the switching group gastric cancer is comparable to the other groups, indicating that switching is a viable treatment option with appropriate management. Additionally, 37 of the 45 patients in the study were male, provides new safety information on switching in gastric cancer for male patients that has not been previously reported.

A double-blind randomized phase II dose-finding study of olanzapine 10 mg or 5 mg for the prophylaxis of emesis induced by highly emetogenic cisplatin-based chemotherapy.

PURPOSE: The aim of this phase II study was to evaluate the efficacy and safety of two doses (10 and 5 mg) of olanzapine in combination with standard antiemetic treatment (aprepitant, palonosetron, and dexamethasone) for patients receiving highly emetogenic chemotherapy (HEC). METHODS: A multi-institutional, double-blind, randomized phase II, dose-finding study of olanzapine was performed in patients with a malignant solid tumor who were receiving HEC with cisplatin (≥ 50 mg/m2). Patients were randomly assigned either olanzapine 10 or 5 mg orally on days 1-4, combined with standard antiemetic treatment. The primary endpoint was a complete response (CR; no emesis and no use of rescue medications) in the delayed phase (24-120 h after the start of cisplatin treatment). RESULTS: 153 patients were randomized to the 10 mg group (n = 76) or the 5 mg group (n = 77). The CR rate in the delayed phase was 77.6% (80% CI: 70.3-83.8, P = 0.01) in the 10 mg group and 85.7% (80% CI: 79.2-90.7, P < 0.001) in the 5 mg group (P value for H 0: complete response rate ≤ 65%). The most common adverse event was somnolence, which had an incidence of 53.3 and 45.5% in the 10 and 5 mg olanzapine groups, respectively. CONCLUSIONS: Both doses of 10 and 5 mg olanzapine provided a significant improvement in delayed emesis. A dose of 5 mg olanzapine was determined as the recommended dose for a further phase III study based on higher CR and lower somnolence rates. CLINICAL TRIAL INFORMATION: UMIN000014214.

Evaluation of the Simple Suspension Method for Oral Anticancer Drugs.

The simple suspension method (SSM) involves administering tablets or capsules using a tube after disintegration and suspension in hot water without crushing or opening the capsule. Particularly, for anticancer drugs, it is an excellent method of administration that reduces the risk of exposure during dispensing. In contrast, information on SSM for individual drugs is insufficient. Anticancer drugs present a therapeutic challenge because their information is limited. We investigated whether SSM is possible with 36 anticancer drugs. Furthermore, we examined the pH of the suspension of these drugs, for which no information on SSM is available. We found that suspension was possible for 24 of the 36 drugs. Furthermore, the pH of the suspension was measured, which provided important information when considering dissolution solutions other than hot water. Little changes in the pH were observed before or after passing through the tube. The results of this study may improve medication adherence in patients with cancer experiencing dysphagia.

Efficacy of Olanzapine in Addition to Standard Triplet Antiemetic Therapy for Cisplatin-Based Chemotherapy: A Secondary Analysis of the J-FORCE Randomized Clinical Trial.

Importance: It is unknown whether olanzapine combined with triplet antemetic therapy is effective for all patients undergoing highly emetogenic chemotherapy. A secondary analysis of randomized clinical trials using olanzapine may provide insight into the effectiveness of olanzapine for chemotherapy-induced nausea and vomiting (CINV), including cisplatin. Objective: To examine the add-on effect of olanzapine according to risk factors for CINV. Design, Setting, and Participants: This preplanned secondary analysis evaluated results of the J-FORCE trial, a large double-blind, placebo-controlled phase 3 randomized clinical trial conducted in Japan from February 9, 2017, to July 18, 2018. Participants were enrolled from 26 participating hospitals across Japan and included patients aged 20 to 75 years who had a malignant tumor and were cisplatin-naive. The efficacy analysis population of the J-FORCE trial was analyzed according to allocation adjustment factors (sex [male or female], age [≥55 years or <55 years], and cisplatin dose [≥70 mg/m2 or <70 mg/m2]) and patient-related risk factors (history of motion sickness, drinking habit [defined as alcoholic drinks consumption in excess of occasional drinking], and history of morning sickness during pregnancy). Statistical analysis was performed from February 18 to April 18, 2020. Interventions: Patients were randomized 1:1 to receive 5 mg of olanzapine or placebo combined with standard triplet antiemetic therapy. Main Outcomes and Measures: The primary end point was complete response (CR, defined as no vomiting and no use of rescue medication) in the delayed phase (24-120 hours after cisplatin-based chemotherapy administration). Secondary end points were CR, complete control, and total control in the acute, delayed, and overall phases for 6 CINV risk factors as well as time to treatment failure. The CR point estimates and 95% CIs of the differences between groups were calculated, and a Mantel-Haenszel test was performed. Results: Of the 705 patients (mean [SD] age, 63.0 [9.2] years; 471 males [66.8%]) included in the efficacy analysis population; 581 patients (82.4%) were 55 years or older, and 526 (74.6%) were treated with a cisplatin dose of 70 mg/m2 or more. Risk difference (RD) for a CR in the delayed phase was significantly greater in the olanzapine group than the placebo group in males (RD, 12.6% [95% CI, 5.0%-20.1%]; P = .001); in females (RD, 14.5% [95% CI, 2.2%-26.3%]; P = .02); in those 55 years or older (RD, 11.1% [95% CI, 3.9%-18.2%]; P = .003) or younger than 55 years (RD, 23.6% [95% CI, 7.3%-38.3%]; P = .005); for a cisplatin dose of 70 mg/m2 or more (RD, 13.5% [95% CI, 5.9%-21.0%]; P < .001); for those without a history of motion sickness (RD, 13.9% [95% CI, 6.9%-20.6%]; P < .001); for those with a drinking habit (RD, 14.9% [95% CI, 6.1%-23.4%]; P = .001) or without a drinking habit (RD, 12.0% [95% CI, 2.5%-21.3%]; P = .01); and for those with a history of morning sickness during pregnancy (RD, 27.2% [9.7%-42.6%]; P = .002). In other subgroups, a delayed CR was higher in the olanzapine group than the placebo group, although not significantly higher. Conclusions and Relevance: Results of this study suggest a benefit of using 5 mg of olanzapine plus triplet antiemetic therapy to counter CINV regardless of the presence or absence of risk factors. Trial Registration: University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000024676.

Impact of air temperature and drug concentration on liquid emission from elastomeric pumps.

BACKGROUND: Elastomeric pumps (EPs) are devices that allow quantitative and continuous drug administration without the need for electronic control, and they are used by being filled with anticancer agents. Although the package inserts of several manufacturers that provide EPs describe the relationship between the flow rate per unit time and temperature, the solution is only saline solution or 5% glucose solution, and data on anticancer drugs have not been published. In this study, we focused on 5-fluorouracil (5-FU), a drug frequently used in cancer chemotherapy, and examined the effect of changes in standard of EPs and temperature on drug emission. METHODS: We evaluated the EP data of patients treated with Baxter Infusor® LV5 and SV2.5 in terms of emission rate, relationship between 5-FU prescription amount and emission rate, and relationship between emission rate and monthly air temperature in LV5 and SV2.5. The number of EPs sampled in the study was N = 5708 (n = 2988 for LV5 and n = 2720 for SV2.5). RESULTS: In LV5, the emission rate varied from 88 to 97% (median 94.0%), whereas in SV2.5, the emission rate was observed as 97 to 98% (median 97.4%). The 5-FU prescription amount and the emission rate were not correlated in LV5 and SV2.5, respectively (LV5; y = - 0.0015x + 97.305, R2 = 0.0226, SV2.5; y = - 0.001x + 100.25, R2 = 0.0466). LV5 showed a higher emission rate in the months with higher air temperature and a lower emission rate in the month with lower air temperature. In addition, LV5 showed a significant reduction in emission rate compared with SV2.5 in all months (P < 0.001). CONCLUSIONS: In this study, we clarified that air temperature is an important factor that affects the drug emission of EPs. Therefore, it is necessary to examine the conditions for total fluid volume suitable for the air temperature in each region and to provide sufficient information to patients.

Effect of different shielding conditions on the stability of Cisplatin.

BACKGROUND: Because cisplatin (CDDP) decreases upon light exposure, it is necessary to prevent such exposure during administration. However, the shielding conditions employed are not uniform. Therefore, in this study, we examined the shielding effects of four shading covers, which are commonly used to ensure the stability of CDDP in clinical settings. METHODS: Four shielding conditions, along with a control, were tested under a 1000-Lux white fluorescent lamp at room temperature: aluminum foil (Al), brown shading cover (BSC), yellow shading cover (YSC), milky-white anti-exposure cover (MAC), and no shading cover (NSC). Under each shielding condition, the relationship between the wavelength and transmittance was monitored in the range of 200-800 nm. CDDP was diluted to three concentration levels: 50, 100, and 250 µg/mL. Furthermore, the amount of remaining CDDP and the pH in the solutions were measured for 120 h. RESULTS: We found that BSC, YSC, and MAC conditions allowed various levels of transmittance; however, Al could not completely transmit light at all wavelengths. Moreover, we showed that the CDDP decreased under MAC and NSC conditions in a time-dependent manner, whereas this decrease was prevented under Al, BSC, and YSC conditions till 120 h. We also demonstrated increases in pH under MAC and NSC conditions in a time-dependent manner, which was prevented under Al, BSC, and YSC conditions till 120 h. Similar results were observed for all three CDDP concentration levels. The results also indicated the approximate relationship between the amount of remaining CDDP and the pH increase. CONCLUSIONS: Considering the opacity of each cover, our results suggest that BSC and YSC are useful and effective for minimizing CDDP degradation in clinical settings. Our results also indicate the alternatives for preparing, storing, and administering CDDP in clinical facilities, making the treatment schedule more flexible. Cumulatively, these findings indicate that the use of the appropriate shading covers, such as BSC or YSC, prevents the decrease in CDDP under fluorescent lighting, potentially contributing to achieving its full therapeutic effect.

Brain-derived neurotrophic factor bound with lecithin derivative showed a markedly enhanced pharmacological potency due to its potent cell membrane affinity followed by prolonged MAPK activation.

We synthesized lecithinized brain-derived neurotrophic factor (lecithinized-BDNF), in which an average of three molecules of a lecithin derivative were bound to recombinant human BDNF. We evaluated its pharmacological activity in C57BL/KsJ-db/db mice, and assessed its targetability and affinity for the nervous system. Subcutaneously administered lecithinized-BDNF markedly reduced the plasma glucose level, food intake, and body weight in C57BL/KsJ-db/db diabetic mice. Its potency was more than 20 times greater than that of unmodified BDNF. We then studied the mechanism for the markedly enhanced pharmacological activity. In vitro cell growth activity of lecithinized-BDNF using the MTT assay was lower than unmodified BDNF, probably due to steric hindrance of the lecithin moieties. While the plasma BDNF level after subcutaneous administration of lecithinized-BDNF was not higher compared with unmodified BDNF. However, higher amount of lecithinized-BDNF accumulated in the spinal cord was observed. Lastly, we found that in vitro binding capacity of lecithinized-BDNF for PC-pAB1 neural cells was much higher than unmodified BDNF. Moreover, lecithinized-BDNF bound to PC-pAB1 cells did not exchange with an excessive amount of unmodified BDNF or an excess of lecithinized-BDNF. PC-pAB1 cells treated with lecithinized-BDNF showed sustained mitogen-activated protein kinase (MAPK, ERK1/2) activation. These data would indicate that the high affinity of lecithinized-BDNF for the target cells, followed by prolonged MAPK activation, would play an important role in its potent pharmacological activity.

Lecithinized brain-derived neurotrophic factor promotes the differentiation of embryonic stem cells in vitro and in vivo.

The addition of lecithin molecules to brain-derived neurotrophic factor (BDNF) has been reported to markedly enhance its pharmacological effect in vivo. In the current study, we show that lecithinized BDNF (PC-BDNF) has a higher affinity than BDNF for neural precursor cells. Although BDNF only slightly increased the expression of the genes for Mash-1, p35, 68 kDa neurofilament, and TrkB receptor, PC-BDNF caused a significant increase in their expression. PC-BDNF also increased the level of neurofilament protein and dramatically increased TrkB mRNA gene expression, which was followed by a sustained activation of the p42/p44 extracellular-regulated kinases. Finally, transplantation of PC-BDNF-treated cells was more effective than BDNF-treated cells at improving impaired motor function caused by spinal cord injury. These findings showed that PC-BDNF has a better potential than BDNF for promoting neural differentiation, partly due to a higher cellular affinity. Furthermore, PC-BDNF-treated cells could be useful for transplantation therapy for central nervous system injuries.