Evaluating the indotecan-neutropenia relationship in patients with solid tumors by population pharmacokinetic modeling and sigmoidal Emax regressions.

PURPOSE: This study aimed at characterizing indotecan population pharmacokinetics and explore the indotecan-neutropenia relationship in patients with solid tumors. METHODS: Population pharmacokinetics were assessed using nonlinear mixed-effects modeling of concentration data from two first-in-human phase 1 trials evaluating different dosing schedules of indotecan. Covariates were assessed in a stepwise manner. Final model qualification included bootstrap simulation, visual and quantitative predictive checks, and goodness-of-fit. A sigmoidal Emax model was developed to describe the relationship between average concentration and maximum percent neutrophil reduction. Simulations at fixed doses were conducted to determine the mean predicted decrease in neutrophil count for each schedule. RESULTS: 518 concentrations from 41 patients supported a three-compartment pharmacokinetic model. Body weight and body surface area accounted for inter-individual variability of central/peripheral distribution volume and intercompartmental clearance, respectively. Estimated typical population values were CL 2.75 L/h, Q3 46.0 L/h, and V3 37.9 L. The estimated value of Q2 for a typical patient (BSA = 1.96 m2) was 17.3 L/h, while V1 and V2 for a typical patient (WT = 80 kg) was 33.9 L and 132 L. The final sigmoidal Emax model estimated that half-maximal ANC reduction occurs at an average concentration of 1416 µg/L and 1041 µg/L for the daily and weekly regimens, respectively. Simulations of the weekly regimen demonstrated lower percent reduction in ANC compared to the daily regimen at equivalent cumulative fixed doses. CONCLUSION: The final PK model adequately describes indotecan population pharmacokinetics. Fixed dosing may be justified based on covariate analysis and the weekly dosing regimen may have a reduced neutropenic effect.

Impact of an in-person small group surgical skills course for preclinical medical students in an era of increased e-learning.

Objective: The COVID-19 pandemic led to a dramatic decrease in face-to-face teaching. This can particularly impact medical students' skills development. This prompted development of an in-person surgical skills course as guided by the General Medical Council "Outcomes for Graduates" facilitated by tutors with surgical experience. This study aimed to primarily assess participant confidence in surgical skills following the course. Design: This was an interventional study assessing both qualitative and quantitative data collected prior to, during, and post course completion. Data were collected from students via online forms, which included a mixture of "Yes/No" responses, self-assessed confidence levels via Likert scales, and free type questions. Setting: The study assessed feedback for a 5-session surgical skills course delivered at the authors' institution. This is a newly designed course using low-cost materials which was free for all attendees. Participants: Participants were all in the first or second year of medical school. There was capacity for 60 students, and all attendees provided informed consent to participate. Results: A total of 446 students applied for the course with 58 participants in the final study, 31% of whom had prior surgical skills experience. There was a statistically significant increase in student confidence levels following the course for all taught surgical skills (P = .0001). Participants were also more confident that they possessed the skills required for clinical placements (P = .0001) and to work as a junior doctor (P = .01). Thematic qualitative analysis revealed a reliance on third parties for previous surgical experience; this course improved knowledge and skills for future practice. Limitations included session duration and equipment choice. Conclusion: This study demonstrates high demand and student satisfaction from this course, offering a potential framework to improve undergraduate surgical skills teaching. The results presented here have the potential to inform wider curricula development across medical schools in the future. Competencies: Medical knowledge; practice-based learning and Improvement.

The hormonal environment and estrogen receptor signaling alters Chlamydia muridarum infection in vivo.

Genital Chlamydia is the most common bacterial sexually transmitted infection in the United States and worldwide. Previous studies indicate that the progression of chlamydial infection is influenced by various factors, including the female sex hormones estrogen and progesterone. Sex hormone levels naturally fluctuate in women throughout their menstrual cycle. Varying concentrations of estrogen and progesterone may impact the progression of chlamydial infection and the host's immune response to Chlamydia. Estrogen signals through estrogen receptors (ERs), ERα and ERß. These receptors are similar in structure and function, but are differentially expressed in tissues throughout the body, including the genital tract and on cells of the immune system. In this study, we used ovariectomized (OVT) BALB/c mice to investigate the impact of long-term administration of physiologically relevant concentrations of estrogen (E2), progesterone (P4), or a combination of E2/P4 on the progression of and immune response to C. muridarum infection. Additionally, we used ERα and ERß knockout C57/BL6 mice to determine the how ERs affect chlamydial infection and the resulting immune response. Estrogen exposure prevented C. muridarum infection in vaginally infected OVT mice exposed to E2 alone or in combination with P4, while OVT or Sham mice exposed to hormone free, P4 or depo-medroxyprogesterone acetate shed similar amounts of chlamydiae. The hormonal environment also altered T cell recruitment and IFNϵ production the genital tracts of infected OVT and Sham mice on day 10 post infection. The absence of ERα, but not ERß, in ER knockout mouse strains significantly changed the timing of C. muridarum infection. ERαKO mice shed significantly more chlamydiae at day 3 post infection and resolved the infection faster than WT or ERßKO animals. At day 9 post infection, flow cytometry showed that ERαKO mice had more T cells present and targeted RNA sequencing revealed increased expression of CD4 and FOXP3, suggesting that ERαKO mice had increased numbers of regulatory T cells compared to ERßKO and WT mice. Mock and chlamydia-infected ERαKO mice also expressed more IFNϵ early during infection. Overall, the data from these studies indicate that sex hormones and their receptors, particularly ERα and ERß, differentially affect C. muridarum infection in murine models of infection.

Liquid chromatography-mass spectrometry applications for quantification of endogenous sex hormones.

Liquid chromatography, coupled with tandem mass spectrometry, presents a powerful tool for the quantification of the sex steroid hormones 17-ß estradiol, progesterone and testosterone from biological matrices. The importance of accurate quantification with these hormones, even at endogenous levels, has evolved with our understanding of the role these regulators play in human development, fertility and disease risk and manifestation. Routine monitoring of these analytes can be accomplished by immunoassay techniques, which face limitations on specificity and sensitivity, or using gas chromatography-mass spectrometry. LC-MS/MS is growing in capability and acceptance for clinically relevant quantification of sex steroid hormones in biological matrices and is able to overcome many of the limitations of immunoassays. Analyte specificity has improved through the use of novel derivatizing agents, and sensitivity has been refined through the use of high-resolution chromatography and mass spectrometric technology. This review highlights these innovations, among others, in LC-MS/MS steroid hormone analysis captured in the literature over the last decade.