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.

Intracellular Survival of Biofilm-Forming MRSA OJ-1 by Escaping from the Lysosome and Autophagosome in J774A Cells Cultured in Overdosed Vancomycin.

We investigated the drug-resistant mechanisms of intracellular survival of methicillin-resistant S. aureus (MRSA). Our established MRSA clinical strain, OJ-1, with high biofilm-forming ability, and a macrophage cell line, J774A, were used. After ingestion of OJ-1 by J774A, the cells were incubated for ten days with vancomycin at doses 30 times higher than the minimum inhibitory concentration. The number of phagocytosed intracellular OJ-1 gradually decreased during the study but plateaued after day 7. In J774A cells with intracellular OJ-1, the expression of LysoTracker-positive lysosomes increased until day 5 and then declined from day 7. In contrast, LysoTracker-negative and OJ-1-retaining J774A cells became prominent from day 7, and intracellular OJ-1 also escaped from the autophagosome. Electron microscopy also demonstrated that OJ-1 escaped the phagosomes and was localized in the J774A cytoplasm. At the end of incubation, when vancomycin was withdrawn, OJ-1 started to grow vigorously. The present results indicate that intracellular phagocytosed biofilm-forming MRSA could survive for more than ten days by escaping the lysosomes and autophagosomes in macrophages. Intracellular MRSA may survive in macrophages, and accordingly, they could be resistant to antimicrobial drug treatments. However, the mechanisms their escape from the lysosomes are still unknown. Additional studies will be performed to clarify the lysosome-escaping mechanisms of biofilm-forming MRSA.

The Effects of Silver Sulfadiazine on Methicillin-Resistant Staphylococcus aureus Biofilms.

Methicillin-resistant Staphylococcus aureus (MRSA), the most commonly detected drug-resistant microbe in hospitals, adheres to substrates and forms biofilms that are resistant to immunological responses and antimicrobial drugs. Currently, there is a need to develop alternative approaches for treating infections caused by biofilms to prevent delays in wound healing. Silver has long been used as a disinfectant, which is non-specific and has relatively low cytotoxicity. Silver sulfadiazine (SSD) is a chemical complex clinically used for the prevention of wound infections after injury. However, its effects on biofilms are still unclear. In this study, we aimed to analyze the mechanisms underlying SSD action on biofilms formed by MRSA. The antibacterial effects of SSD were a result of silver ions and not sulfadiazine. Ionized silver from SSD in culture media was lower than that from silver nitrate; however, SSD, rather than silver nitrate, eradicated mature biofilms by bacterial killing. In SSD, sulfadiazine selectively bound to biofilms, and silver ions were then liberated. Consequently, the addition of an ion-chelator reduced the bactericidal effects of SSD on biofilms. These results indicate that SSD is an effective compound for the eradication of biofilms; thus, SSD should be used for the removal of biofilms formed on wounds.

Inhibitory effects of polysorbate 80 on MRSA biofilm formed on different substrates including dermal tissue.

Methicillin-resistant Staphylococcus aureus (MRSA) forms biofilms on necrotic tissues and medical devices, and causes persistent infections. Surfactants act on biofilms, but their mode of action is still unknown. If used in the clinic, cytotoxicity in tissues should be minimized. In this study, we investigated the inhibitory effect of four different surfactants on MRSA biofilm formation, and found that a nonionic surfactant, polysorbate 80 (PS80), was the most suitable. The biofilm inhibitory effects resulted from the inhibition of bacterial adhesion to substrates rather than biofilm disruption, and the effective dose was less cytotoxic for 3T3 fibroblasts. However, the effects were substrate-dependent: positive for plastic, silicon, and dermal tissues, but negative for stainless-steel. These results indicate that PS80 is effective for prevention of biofilms formed by MRSA on tissues and foreign bodies. Therefore, PS80 could be used in medical practice as a washing solution for wounds and/or pretreatment of indwelling catheters.

RARalpha is a regulatory factor for Am-80-induced cell growth inhibition of hematologic malignant cells.

Retinoids are used for treatment of acute promyelocytic leukemia (APL). Am-80, Tamibarotene, binds to retinoic acid receptor alpha (RARalpha) more specifically than all-trans retinoic acid. We studied the tumor cell suppressive effects of Am-80, with respect to cytotoxicity and growth inhibition using eight myeloid and lymphoid malignant cells in culture (HL-60, HL-60R, K-562, Kasumi-1, MEG01, Raji, U266B1, and U937). The effects of Am-80 were examined during 9 days of incubation with 10(-7)-10(-5) M of Am-80 in culture medium, which was changed every 3 days. HL-60 were the only cells sensitive to Am-80-induced cytotoxicity; the latter reached more than 95% after 9 days of incubation, and death was primarily through apoptosis. The total mass of RARalpha in HL-60 was significantly greater (p<0.006) than in ATRA-resistant HL-60 (HL-60R) as well as all of other cells tested. However, in all cells excluding HL-60, Am-80 induced time- and dose-dependent cell growth inhibition without noticeable cytotoxicity. TGF-beta2 was released into the media containing cells incubated with Am-80 for 3 days. A dose-dependent increment of phosphorylation of Smad-2 was also detected. The relative amount of secreted TGF-beta2 correlated with the growth inhibition rates in all cells tested excluding HL-60, and with the total mass of RARalpha in the cells (p=0.0137). Our results indicate that Am-80-induced cell-type non-specific growth inhibition is mediated by TGF-beta2, where the total mass of RARalpha could be an important regulatory factor in hematologic malignant cells.