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Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies 1-3 . Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity 4,5 , its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (T reg ) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on T reg cells. Accordingly, in mouse models, PI3Kδi decreased the number of T reg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 T reg cells, accompanied by expansion of pathogenic T helper 17 (T H 17) and type 17 CD8 + T (T C 17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity., (© 2022. The Author(s).)

Aims: The aim of this study was to evaluate a population model for epirubicin clearance using internal and external validation techniques., Methods: Jackknife samples were used to identify outliers in the population dataset and individuals influencing covariate selection. Sensitivity analyses were performed in which serum aspartate transaminase (AST) values (a covariate in the population model) or epirubicin concentrations were randomly changed by +/-10%. Cross-validation was performed five times, on each occasion using 80% of the data for model development and 20% to assess the performance of the model. External validation was conducted by assessing the ability of the population model to predict concentrations and clearances in a separate group of 79 patients., Results: Structural parameter estimates from all jackknife samples were within 7.5% of the final population estimates and examination of log likelihood values indicated that the selection of AST in the final model was not due to the presence of outliers. Alteration of AST or epirubicin concentrations by +/-10% had a negligible effect on population parameter estimates and their precision. In the cross-validation analysis, the precision of clearance estimates was better in patients with AST concentrations>150 U l-1. In the external validation, epirubicin concentrations were over-predicted by 81.4% using the population model and clearance values were also poorly predicted (imprecision 43%)., Conclusions: The results of internal validation of population pharmacokinetic models should be interpreted with caution, especially when the dataset is relatively small.

Aims: To develop a limited sampling strategy for estimation of epirubicin clearance., Methods: The data set comprised 1051 concentrations measured in 105 patients with advanced or metastatic breast cancer treated with epirubicin alone. Ten limited sampling designs comprising two or three blood samples were proposed, taken at times identified by D-optimality from population pharmacokinetic parameter estimates. The data set was then truncated to include the sampling times for each of the designs. MAP Bayesian estimates of clearance were generated for each design and compared with clearance estimates obtained using all the data. The limited sampling designs were also validated using a separate data set obtained from 18 patients with either breast cancer or hepatocellular carcinoma. The sensitivity of the best limited sampling designs to sample time recording errors of 0-10% or 10-20% was then assessed using a simulated data set including 200 patients., Results: The optimum sampling times were: end of the injection and 18 min, 40 min, 3 h, 10 h and 48 h after the start of the injection. The best three-sample design included samples at 40 min, 3 h and 48 h and gave unbiased estimates of clearance with an imprecision of 9.1% (95% CI 7.3, 10.5). The best two sample design included samples at 3 and 48 h and gave unbiased estimates of clearance with an imprecision of 12.4% (95% CI 9.6, 14.6). Using the validation data set, these two and three sample designs gave unbiased estimates of clearance with an imprecision of 5.6% (95% CI 3.7, 7.0) and 4.2% (95% CI 2.6, 5.3), respectively. Simulations that included 0-10% or 10-20% errors in the recording of the blood sampling times had negligible effects on the bias and imprecision of clearance estimates., Conclusions: Limited sampling designs have been identified and validated that estimate epirubicin clearance with adequate precision and without bias from two or three blood samples. These designs also allow flexibility in blood sample collection and are robust with regard to sample time recording errors.

We used a nested PCR with Borrelia flagellin gene (flaB) primers and DNA sequencing to determine if Borrelia lonestari was present in Amblyomma americanum ticks removed from military personnel and sent to the Tick-Borne Disease Laboratory of the U.S. Army Center for Health Promotion and Preventive Medicine. In our preliminary investigation, we detected Borrelia sequences in 19 of 510 A. americanum adults and nymphs from Ft. A. P. Hill, Va. During the 2001 tick season, the flaB primers were used to test all A. americanum samples as they were received, and 29 of 2,358 A. americanum samples tested individually or in small pools were positive. PCRs with 2,146 A. americanum samples in 2002 yielded 26 more Borrelia-positive samples. The positive ticks in 2001 and 2002 were from Arkansas, Delaware, Kansas, Kentucky, Maryland, New Jersey, North Carolina, Tennessee, and Virginia. The last positive sample of the 2001 season was a pool of larvae. To further investigate larval infection, we collected and tested questing A. americanum larvae from Aberdeen Proving Ground, Md.; 4 of 33 pools (40 larvae per pool) were positive. Infection of unfed larvae provides evidence of the maintenance of B. lonestari by means of transovarial transmission. Sequence analysis revealed that the amplicons were identical to sequences of the B. lonestari flaB gene in GenBank. Despite the low prevalence of infection, the risk of B. lonestari transmission may be magnified because A. americanum is often abundant and aggressive, and many tick bite victims receive multiple bites.