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Presepsin (P-SEP) is a specific biomarker for sepsis. Monocytes produce P-SEP by phagocytosing neutrophil extracellular traps (NETs). Herein, we investigated whether M1 macrophages (M1 MΦs) are the primary producers of P-SEP after NET phagocytosis. We co-cultured M1 MΦs and NETs from healthy participants, measured P-SEP levels in the culture medium supernatant, and detected P-SEP using western blotting. When NETs were co-cultured with M1 MΦs, the P-SEP level of the culture supernatant was high. Notably, we demonstrated, for the first time, the intracellular kinetics of P-SEP production by M1 MΦs via NET phagocytosis: M1 MΦs produced P-SEP intracellularly 15 min after NET phagocytosis and then released it extracellularly. In a sepsis mouse model, the blood NET ratio and P-SEP levels, detected using ELISA, were significantly increased (p < 0.0001). Intracellular P-SEP analysis via flow cytometry demonstrated that lung, liver, and kidney MΦs produced large amounts of P-SEP. Therefore, we identified these organs as the origin of M1 MΦs that produce P-SEP during sepsis. Our data indicate that the P-SEP level reflects the trend of NETs, suggesting that monitoring P-SEP can be used to both assess NET-induced organ damage in the lungs, liver, and kidneys during sepsis and determine treatment efficacy. [ABSTRACT FROM AUTHOR]

For novel immuno‐oncology therapies, the primary purpose of a dose‐finding trial is to identify an optimal dose (OD), defined as the tolerable dose having adequate efficacy and immune response under the unpredictable dose–outcome (toxicity, efficacy, and immune response) relationships. In addition, the multiple low or moderate‐grade toxicities rather than dose‐limiting toxicities (DLTs) and multiple levels of efficacy should be evaluated differently in dose‐finding to determine true OD for developing novel immuno‐oncology therapies. We proposed a generalized Bayesian optimal interval design for immunotherapy, simultaneously considering efficacy and toxicity grades and immune response outcomes. The proposed design, named gBOIN‐ETI design, is model‐assisted and easy to implement to develop immunotherapy efficiently. The operating characteristics of the gBOIN‐ETI are compared with other dose‐finding trial designs in oncology by simulation across various realistic settings. Our simulations show that the gBOIN‐ETI design could outperform the other available approaches in terms of both the percentage of correct OD selection and the average number of patients allocated to the OD across various realistic trial settings. [ABSTRACT FROM AUTHOR]

With the emergence of molecular targeted agents and immunotherapies in anti-cancer treatment, a concept of optimal biological dose (OBD), accounting for efficacy and toxicity in the framework of dose-finding, has been widely introduced into phase I oncology clinical trials. Various model-assisted designs with dose-escalation rules based jointly on toxicity and efficacy are now available to establish the OBD, where the OBD is generally selected at the end of the trial using all toxicity and efficacy data obtained from the entire cohort. Several measures to select the OBD and multiple methods to estimate the efficacy probability have been developed for the OBD selection, leading to many options in practice; however, their comparative performance is still uncertain, and practitioners need to take special care of which approaches would be the best for their applications. Therefore, we conducted a comprehensive simulation study to demonstrate the operating characteristics of the OBD selection approaches. The simulation study revealed key features of utility functions measuring the toxicity-efficacy trade-off and suggested that the measure used to select the OBD could vary depending on the choice of the dose-escalation procedure. Modelling the efficacy probability might lead to limited gains in OBD selection. [ABSTRACT FROM AUTHOR]

One of the primary objectives of an oncology dose‐finding trial for novel therapies, such as molecular‐targeted agents and immune‐oncology therapies, is to identify an optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. These new therapeutic agents appear more likely to induce multiple low or moderate‐grade toxicities than dose‐limiting toxicities. Besides, for efficacy, evaluating the overall response and long‐term stable disease in solid tumors and considering the difference between complete remission and partial remission in lymphoma are preferable. It is also essential to accelerate early‐stage trials to shorten the entire period of drug development. However, it is often challenging to make real‐time adaptive decisions due to late‐onset outcomes, fast accrual rates, and differences in outcome evaluation periods for efficacy and toxicity. To solve the issues, we propose a time‐to‐event generalized Bayesian optimal interval design to accelerate dose finding, accounting for efficacy and toxicity grades. The new design named "TITE‐gBOIN‐ET" design is model‐assisted and straightforward to implement in actual oncology dose‐finding trials. Simulation studies show that the TITE‐gBOIN‐ET design significantly shortens the trial duration compared with the designs without sequential enrollment while having comparable or higher performance in the percentage of correct OD selection and the average number of patients allocated to the ODs across various realistic settings. [ABSTRACT FROM AUTHOR]

Pegfilgrastim, a pegylated form of granulocyte colony‐stimulating factor, has reduced the risk of developing febrile neutropenia, which is associated with an increase in severe infection and prolonged hospitalization. However, pegfilgrastim administration requires that patients visit hospital following cancer chemotherapy, thus imposing a burden on patients and those around them. An on‐body injector (OBI), which automatically administers pegfilgrastim about 27 hours after chemotherapy, was used in this study. The OBI, which consists of a main pump unit and infusion set, is a drug delivery device designed to be attached to the patient's body, with a timer‐controlled dosing function. This study was conducted in breast cancer patients to evaluate the safety of pegfilgrastim administered subcutaneously via the OBI. The study period consisted of screening and treatment observation periods involving four cycles of neoadjuvant or adjuvant chemotherapy with docetaxel plus cyclophosphamide. One 3.6‐mg pegfilgrastim dose was administered subcutaneously via OBI during each cycle of chemotherapy. The study enrolled 35 patients, and no serious adverse events or febrile neutropenia occurred. Administration of pegfilgrastim was successfully completed at all times when the OBI was attached to the patient, and no safety concerns associated with OBI function arose. For outpatients requiring pegfilgrastim following cancer chemotherapy, the use of an OBI was considered to be a safe option to reduce the need for outpatient visits that restrict their activities of daily living. [ABSTRACT FROM AUTHOR]

Nearly half of the human genome consists of repetitive sequences such as long interspersed nuclear elements. The relationship between these repeating sequences and diseases has remained unclear. Gene trapping is a useful technique for disrupting a gene and expressing a reporter gene by using the promoter activity of the gene. The analysis of trapped genes revealed a new genome element—the chromosome‐specific clustered trap (CSCT) region. For any examined sequence within this region, an equivalent was found using the BLAT of the University of California, Santa Cruz (UCSC) Genome Browser. CSCT13 mapped to chromosome 13 and contained only three genes. To elucidate its in vivo function, the whole CSCT13 region (1.6 Mbp) was deleted using the CRISPR/Cas9 system in mouse embryonic stem cells, and subsequently, a CSCT13 knockout mouse line was established. The rate of homozygotes was significantly lower than expected according to Mendel's laws. In addition, the number of offspring obtained by mating homozygotes was significantly smaller than that obtained by crossing controls. Furthermore, CSCT13 might have an effect on meiotic homologous recombination. This study identifies a transcriptionally active CSCT with an important role in mouse development. [ABSTRACT FROM AUTHOR]

Simultaneous global drug development with multiregional studies is becoming a common strategy for increasing efficiency of the development process. In particular, multiregional dose-finding studies can be informative to identify inter-ethnic difference in dose-response relationships early in development. An application of MCP-Mod to multiregional studies is discussed in this article. We consider sample size allocation to one specific region and provide three methods for demonstrating consistency in the dose-response relationship between the entire population and one specific region: two methods use contrast statistics to show consistency in dose-response signals, and the third method uses the maximum absolute difference between two dose-response curves to show consistency in the dose-response profiles. The proposed methods do not require studies to have sufficient power to detect a truly consistent dose-response relationship in a confirmatory manner, but rather to allow for quantitative design considerations that can ensure such a relationship is observed at the end of the study with acceptable probability. The three methods are illustrated through an anti-anxiety drug example, resulting in a recommended proportion of 20% for subjects in one specific region. The illustration indicates the recommended proportion could vary depending on the total study sample size. [ABSTRACT FROM AUTHOR]

Roxadustat is an oral hypoxia‐inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). Emerging evidence suggests that roxadustat may be beneficial for patients who inadequately respond to erythropoiesis‐stimulating agents (ESAs). This post‐hoc analysis of a Japanese, double‐blind, randomized, phase 3 study in hemodialysis‐dependent CKD patients treated with traditional ESAs assessed the impact of factors associated with ESA hyporesponsiveness on roxadustat and darbepoetin alfa (DA) doses required to maintain target hemoglobin. Endpoints included mean of average doses of roxadustat and DA per administration in the last 6 weeks (AAD/6W) by prior ESA‐resistance index (ERI), iron repletion (transferrin saturation; ferritin), and high‐sensitivity C‐reactive protein (hs‐CRP). Of 415 enrolled patients, 303 were randomized (roxadustat, n = 151; DA, n = 152). Weight‐adjusted AAD/6W increased with increasing ERI for roxadustat (ERI <3.3, 0.89 mg/kg; ERI ≥8.4, 1.51 mg/kg) and DA (ERI <3.3, 0.26 μg/kg; ERI ≥8.4, 0.91 μg/kg); the weight‐adjusted AAD/6W relative to within‐arm mean AAD/6W showed a trend toward increased DA doses for the ERI ≥8.4 category (P =.089). AAD/6W remained stable for roxadustat but increased for DA with decreasing baseline iron repletion markers. The relationship between roxadustat doses and end of treatment (EoT) hs‐CRP was not significant (estimated slope, −0.494; P =.814); a trend toward increased DA doses was observed with increasing EoT hs‐CRP (estimated slope, 2.973; P =.075). Roxadustat doses required to maintain target hemoglobin appear to be less affected by factors that underlie ESA hyporesponsiveness, relative to DA; roxadustat may be beneficial for patients hyporesponsive to ESAs. [ABSTRACT FROM AUTHOR]