Proposal for Classifying the Emetogenicity of Oral Anticancer Agents with a Focus on PARP Inhibitors: A Prospective, Observational, Multicenter Study (JASCC-CINV 2002).

Background: Olaparib and niraparib (poly adenosine diphosphate [ADP]-ribose polymerase [PARP] inhibitors) have significant antitumor action in patients with ovarian cancer. However, the incidence of nausea and vomiting among patients on these drugs in clinical trials is rather high. There are no guidelines on antiemetic treatment for nausea caused by oral anticancer agents. This study aimed to investigate the incidence of nausea and vomiting caused by PARP inhibitors and the actual situation of antiemetic therapy in patients with gynecologic cancer. Methods: Patients with gynecologic cancer who were scheduled to receive PARP inhibitors were enrolled. Data on PARP inhibitor-induced nausea and vomiting were collected from patient diaries for 21 days. The primary endpoint was the incidence of vomiting during the 21 days after starting olaparib and niraparib. Results: Overall, between January 2020 and March 2023, 134 patients were enrolled. Of the 129 patients who were evaluated, 28 (21.7%) received prophylactic antiemetics for 21 days, and 101 (78.3%) did not. The overall incidence of PARP inhibitor-induced vomiting was 16.3%. The incidence of vomiting in the group that did not receive antiemetic prophylaxis was 13.9%. On dividing the group that did not receive antiemetic prophylaxis into the olaparib and niraparib subgroups, the incidence of vomiting was found to be 18.6% for the olaparib group and 10.3% for the niraparib group. Conclusion: The incidence of emesis without antiemetic prophylaxis among patients on olaparib and niraparib ranged from 10% to 30%. Therefore, olaparib and niraparib can be classified in the low emetogenic risk and prophylactic antiemetic therapy at the time of treatment initiation may be unnecessary.

C-terminal peptide of preproorexin enhances brain-derived neurotrophic factor expression in rat cerebrocortical cells and recognition memory in mice.

During the production of orexin A and B from preproorexin, a common precursor protein, in hypothalamic orexin neurons, C-terminal peptide (herein called preproorexin C-peptide) is concomitantly produced via post-translational processing. The predicted three-dimensional structure of preproorexin C-peptide is similar among mammalian species, suggestive of a conserved function in the mammalian brain. However, C-peptide has long been regarded as a non-functional peptide. We herein examined the effects of rat and/or mouse preproorexin C-peptide on gene expression and cell viability in cultured rat cerebrocortical cells and on memory behavior in C57BL/6J mice. Rat and mouse C-peptides both increased brain-derived neurotrophic factor (Bdnf) mRNA levels. Moreover, C-peptide enhanced high K+-, glutamate-, and BDNF-induced increases in Bdnf mRNA levels without affecting forskolin-induced Bdnf expression. H-89, a protein kinase A inhibitor, blocked C-peptide-induced Bdnf expression, whereas rolipram, a phosphodiesterase inhibitor, enhanced this effect. Intracellular cyclic AMP concentrations were elevated by C-peptide. These results demonstrate that preproorexin C-peptide promoted Bdnf mRNA expression by a cyclic AMP-dependent mechanism. Eleven amino acids at the N terminus of rat preproorexin C-peptide exerted similar effects on Bdnf expression as full-length preproorexin C-peptide. Preproorexin C-peptide also exerted protective effects against CoCl2-induced neuronal cell death. An intracerebroventricular injection of mouse preproorexin C-peptide induced c-fos and Bdnf expression in the cerebral cortex and hippocampus and enhanced novel object recognition memory in mice. Collectively, the present results show that preproorexin C-peptide is a functional substance, at least in some pharmacological and neuronal settings.

Comparison of the incidence of vancomycin-associated nephrotoxicity following the change from trough-guided dosing to AUC-guided doing using trough-only data.

OBJECTIVES: Although use of AUC-guided vancomycin dosing was recommended in the revised 2020 consensus guideline, collection of multiple vancomycin serum samples to calculate AUC may cause clinical complications. AUC calculated from trough-only data (one-point AUC-guided dosing) has not been sufficiently validated. The aim of the present study was to compare the incidence of nephrotoxicity following the change from trough-guided to one-point AUC-guided dosing. METHODS: We conducted a single-centre, prospective cohort study to compare the incidence of nephrotoxicity between a trough-guided dosing group and one-point AUC-guided dosing group. RESULTS: One-point AUC-guided dosing significantly decreased the incidence of acute kidney injury (AKI) compared with trough-guided dosing (2.8% versus 17.4%, P = 0.002). Further, Kaplan-Meier plots for cumulative incidence of the AKI-free rate indicated that the onset of AKI was significantly longer in the one-point AUC-guided dosing group than in trough-guided dosing (HR, 6.5; 95% CI, 1.5-27.4; P = 0.011). Moreover, multivariate Cox proportional hazard analysis indicated that implementation of one-point AUC-guided dosing was a significant protective factor against the incidence of AKI (age-adjusted HR, 0.164; 95% CI, 0.04-0.69; P = 0.014). CONCLUSIONS: Compared with trough concentration-guided dosing, AUC-guided dosing using one-point sampling markedly reduced the incidence of AKI, without additional serum sampling.

Control and Risk Factors of Nausea and Vomiting in Patients With Cervical Cancer Receiving Radiotherapy.

BACKGROUND/AIM: Nausea and vomiting are two of the most distressing adverse events of cancer radiotherapy. The aim of this study was to examine the control rate and risk factors associated with nausea and vomiting in patients with cervical cancer receiving radiotherapy. PATIENTS AND METHODS: This retrospective study examined patients with cervical cancer who received radiotherapy alone or with concomitant cisplatin. Patients who received radiotherapy alone were not administered antiemetic premedication, while patients who received radiotherapy with concomitant weekly cisplatin (40 mg/m2) were administered antiemetic therapy comprising granisetron and dexamethasone. Risk factors for non-complete response (CR) were identified using multivariate logistic regression analysis. RESULTS: Multivariate analysis indicated that younger age and concomitant weekly cisplatin were significant factors associated with non-CR across 5 weeks of treatment in patients who received radiotherapy. The proportion achieving CR among younger patients (<65 years) who received radiotherapy alone or with concomitant cisplatin was significantly lower than that among older patients (≥65 years) (Concomitant cisplatin: 27% vs. 67%, p=0.049; Radiotherapy alone: 62% vs. 91%, p=0.166). However, the proportion of patients achieving CR across 5 weeks of treatment was insufficient in all groups except for those aged ≥ 65 years who received radiotherapy alone. CONCLUSION: Antiemetic prophylaxis should be considered for younger patients with cervical cancer undergoing radiotherapy alone. Further, neurokinin-1 receptor antagonist should be added to 5-hydroxytryptamine type-3 receptor antagonist and dexamethasone as antiemetic prophylactic therapy for patients with cervical cancer undergoing radiotherapy with concomitant weekly doses of 40 mg/m2 cisplatin.

Comparison of single trough-based area under the concentration-time curve versus trough concentration for the incidence of vancomycin-associated nephrotoxicity.

INTRODUCTION: While the revised 2020 consensus guideline recommends the use of area under the concentration-time curve (AUC)-guided vancomycin monitoring, collecting multiple vancomycin serum samples to calculate the AUC may cause clinical complications. The aim of the present retrospective study was to evaluate whether AUC-guided vancomycin monitoring, in which AUC was calculated based on a single trough concentration, is a better predictor of nephrotoxicity than trough-guided monitoring in patients receiving vancomycin therapy. METHODS: A single-center, retrospective cohort study was conducted at the 614-bed Gifu University Hospital in Japan. Patients who received intravenous vancomycin for a documented or suspected infection and had their serum vancomycin trough concentration monitored between October 1, 2016 and September 30, 2020 were enrolled in the present study. RESULTS: Multivariate Cox proportional hazard analysis indicated that AUC (>600 µg•h/mL) was a significant risk factor for the incidence of acute kidney injury (AKI), while trough concentration (≥15 µg/mL) was not. Moreover, the AUC (>600 µg•h/mL) showed higher specificity and similar sensitivity to the trough concentration (≥15 µg/mL). Kaplan-Meier plots of the cumulative incidence of the AKI-free rate in patients indicated that the onset of AKI was significantly longer in patients with AUC ≤600 µg•h/mL than in patients with AUC >600 µg•h/mL (HR, 16.1; 95% CI, 6.3-41.2; p < 0.001). CONCLUSION: AUC based on a single trough concentration was a better predictor of nephrotoxicity than trough concentration.