Study protocol for a double-blind, comparative, randomised 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).

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.

Microglial ASD-related genes are involved in oligodendrocyte differentiation.

Autism spectrum disorders (ASD) are associated with mutations of chromodomain-helicase DNA-binding protein 8 (Chd8) and tuberous sclerosis complex 2 (Tsc2). Although these ASD-related genes are detected in glial cells such as microglia, the effect of Chd8 or Tsc2 deficiency on microglial functions and microglia-mediated brain development remains unclear. In this study, we investigated the role of microglial Chd8 and Tsc2 in cytokine expression, phagocytosis activity, and neuro/gliogenesis from neural stem cells (NSCs) in vitro. Chd8 or Tsc2 knockdown in microglia reduced insulin-like growth factor-1(Igf1) expression under lipopolysaccharide (LPS) stimulation. In addition, phagocytosis activity was inhibited by Tsc2 deficiency, microglia-mediated oligodendrocyte development was inhibited, in particular, the differentiation of oligodendrocyte precursor cells to oligodendrocytes was prevented by Chd8 or Tsc2 deficiency. These results suggest that ASD-related gene expression in microglia is involved in oligodendrocyte differentiation, which may contribute to the white matter pathology relating to ASD.

Case series of elderly patients with scabies topically applied with ivermectin via whole-body bathing.

As a novel method of ivermectin (IVM) administration for the treatment of scabies, we devised a whole-body bathing (WBB), in which patients are immersed in a fluid that contains IVM. A multi-institutional trial for elderly patients with scabies was conducted to investigate the efficacy and safety of IVM-WBB. Seven elderly patients with scabies were enrolled and received IVM-WBB up to four times at 1-week interval. The cure for scabies was defined as the absence of mites in two consecutive microscopic or dermoscopic examinations at weekly intervals and the absence of new skin lesions indicative of scabies. Consequently, the cure rate on day 22, the primary end-point, was 71.4%, and all patients had been cured until day 29. Additionally, neither significant adverse events nor clinically problematic abnormal blood test values were obtained. Furthermore, no IVM was detected in the optional plasma (five cases) collected for IVM measurement after bathing. These results suggest that IVM-WBB was effective to treat scabies, causing no serious adverse events and with a very low internal exposure of IVM.

Efficacy and safety of a combination regimen of phenothrin and ivermectin lotion in patients with head lice in Okinawa, Japan.

In Japan, pyrethroid-resistant head lice have been increasing; however, only 0.4% phenothrin, a pyrethroid drug, is available as an over the counter formulation. In recent years, Sumithrin® Lotion containing 5% phenothrin (PHT) was approved for scabies. In the USA, Sklice® Lotion containing 0.5% ivermectin (IVM) is used for the treatment of pyrethroid-resistant head lice. Therefore, to enhance the treatment of head lice in Japan, we conducted a clinical study to confirm the efficacy and safety of a combination regimen of PHT and IVM (PI regimen). Twelve cases were enrolled and PHT was applied to all patients on day 1. On day 8, five patients (41.7%) were lice free, and PHT was applied again. Notably, seven patients were not lice free and were switched to IVM. The rate of patients who were lice free on the PI regimen, which was the primary end-point, was 75.0% on day 15 and 91.7% on day 22. No adverse events were reported. A genetic analysis of the head lice collected at each visit revealed a kdr mutation in all patients. These results suggest that the PI regimen is safe and effective for the treatment of pyrethroid-resistant head lice in Japan.

[What Is Involved in the Training Program for a Japanese Academic Detailer?]

'Academic Detailing' is an approach to providing doctors with information about medicines based on the latest non-commercial evidence-based data for proper prescription. Overseas, pharmacists have been active as academic detailers. Academic Detailing in Japan, as a new approach to disseminating comparative drug information based on basic pharmaceutical sciences and clinical evidence, will influence clinical decision making by doctors, and contribute to better patient-centered medical care. Pharmacists have been participating in ensuring the proper use of drugs by their patients by entering their homes or wards. However, in the future, it is necessary to take steps to improving pharmaceutical decision making by doctors. Therefore, we are considering the following educational points in the Japanese version of training an academic detailer. "A: We shall compare medicines based on basic pharmaceutical sciences and the latest non-commercial evidence-based data. B: We shall understand the point of using medicines based on the patient's condition. C: We shall choose cost-effective drugs from the viewpoint of pharmacoeconomics. And D: We shall acquire communication skills for effective academic detailing." In the future, this first class of Academic Detailers who facilitate academic detailing in the health care field will be pioneers. They will also participate in research to track and quantify the effects of academic detailing.

Hepatic stellate cells mediate differentiation of dendritic cells from monocytes.

BACKGROUND: We have previously reported that human umbilical cord blood (UCB)-nucleated cells differentiate into hepatocyte-like cells when cultured in a 5-cytokine cocktail medium. We further found that UCB cells rather differentiated into dendritic-shaped cells by coculture with a human stellate cell (HSC) line, LI90. METHODS: Monocytes from UCB and adult peripheral blood were cocultured with LI90 or rat primary HSCs in a cell-culture insert. Monocytes were also cultured with LI90-conditioned medium containing secreted factors, which were analyzed by a cytokine array. RESULTS: In the coculture with LI90, resulting dendritic-shaped cells from monocytes expressed dendritic cell (DC) markers and activated allogeneic T cells, indicating that the dendritic-shaped cells were DCs. LI90 in the cytokine cocktail medium secreted various inflammatory factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Fibroblast growth factor-2 in the cytokine cocktail was responsible for GM-CSF production from LI90 cells and for differentiation of monocytes into DCs in the LI90 coculture. Moreover, the coculture of monocytes with activated HSCs derived from damaged rat liver induced the differentiation of DCs, whereas quiescent HSCs derived from normal liver scarcely induced such a change. CONCLUSION: These results suggest that activated HSCs are involved in differentiation of monocytes into DCs in the liver.

Generation of hybrid hepatocytes by cell fusion from monkey embryoid body cells in the injured mouse liver.

Monkey embryonic stem (ES) cells have characteristics that are similar to human ES cells, and might be useful as a substitute model for preclinical research. When embryoid bodies (EBs) formed from monkey ES cells were cultured, expression of many hepatocyte-related genes including cytochrome P450 (Cyp) 3a and Cyp7a1 was observed. Hepatocytes were immunocytochemically observed using antibodies against albumin (ALB), cytokeratin-8/18, and alpha1-antitrypsin in the developing EBs. The in vitro differentiation potential of monkey ES cells into the hepatic lineage prompted us to examine the transplantability of monkey EB cells. As an initial approach to assess the repopulation potential, we transplanted EB cells into immunodeficient urokinase-type plasminogen activator transgenic mice that undergo liver failure. After transplantation, the hepatocyte colonies expressing monkey ALB were observed in the mouse liver. Fluorescence in-situ hybridization revealed that the repopulating hepatocytes arise from cell fusion between transplanted monkey EB cells and recipient mouse hepatocytes. In contrast, neither cell fusion nor repopulation of hepatocytes was observed in the recipient liver after undifferentiated ES cell transplantation. These results indicate that the differentiated cells in developing monkey EBs, but not contaminating ES cells, generate functional hepatocytes by cell fusion with recipient mouse hepatocytes, and repopulate injured mouse liver.

Enrichment of hepatocytes differentiated from mouse embryonic stem cells as a transplantable source.

BACKGROUND: We previously reported that hepatocytes can be differentiated from embryonic stem (ES) cells by way of embryoid body (EB) formation and are transplantable into the mouse liver. However, the transplantation of EB-derived cells frequently resulted in teratoma formation in the recipient liver. In the present study, we eliminated the tumorigenic cells from EB outgrowths and examined the effects of enriched ES-cell-derived hepatocyte transplantation into an injured liver. METHODS: On day 15 in culture, the EBs were partially disaggregated and subcultured. Hepatocytes in the subcultured cells were examined by the expression of hepatocyte markers. Undifferentiated cells contaminating in the EB-derived cells were eliminated by Percoll discontinuous gradient centrifugation. Furthermore, undifferentiated cells, endothelial cells, and macrophages were eliminated by magnetic cell sorting using platelet/endothelial cell adhesion molecule (PECAM)-1 and Mac-1 antibodies. These enriched ES-cell-derived hepatocytes were then transplanted into the injured mouse liver. RESULTS: Percoll centrifugation and PECAM-1 antibodies eliminated the undifferentiated cells expressing Oct-3/4 from the EB-derived cells. ES-cell-derived hepatocytes showed expression of liver-related genes, synthesis of urea and glycogen, and structural characteristics during subculture. A transplantation study showed that the enriched ES-cell-derived hepatocytes integrated into the injured mouse liver and produced no teratomas. When the ES-cell-derived hepatocytes were transplanted into a CCl4-injured liver, the liver function was subsequently improved. CONCLUSIONS: Functional hepatocytes can be differentiated from mouse ES cells by way of EB formation. The elimination of undifferentiated cells from the EBs provides transplantable cells for liver failure without tumorigenicity.