Pharmacokinetics and Concentration-Response of Dupilumab in Patients With Seasonal Allergic Rhinitis.

Patients with moderate to severe allergic rhinitis may benefit from subcutaneous immunotherapy (SCIT), despite the risk of systemic allergic reaction. Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of the type 2 inflammation seen in allergic rhinitis, thereby inhibiting their signaling. In the LIBERTY Grass AID trial (NCT03558997), 16 weeks of treatment with 300 mg of dupilumab every 2 weeks plus timothy grass (TG) SCIT did not reduce TG allergen challenge nasal symptom scores compared with SCIT only but did improve tolerability of SCIT up-titration in patients with a history of grass pollen-induced seasonal allergic rhinitis.

Use of Propensity Scoring and Its Application to Real-World Data: Advantages, Disadvantages, and Methodological Objectives Explained to Researchers Without Using Mathematical Equations.

Real-time data collection of patient health status and medications is sped up with modern electronic devices and technologies. As real-world data provide enormous research opportunities, propensity score (PS) methods have been getting attention due to their theoretical grounds in a nonrandomized study setting. In contrast to randomized clinical trials, observational clinical data obtained from a real-world database may not have balanced distributions of patient characteristics between treatment and control groups at the beginning of the respective study.

Application of Individualized PBPK Modeling of Rate Data to Evaluate the Effect of Hemodialysis on Nonrenal Clearance Pathways.

The aim of this study was to apply individualized, physiologically based pharmacokinetic modeling of CO production rates (iPBPK-R) measured by the erythromycin breath test to characterize the effect of hemodialysis on the function of nonrenal clearance pathways in patients with end-stage renal disease. Twelve patients previously received C-erythromycin intravenously pre- and post-hemodialysis. Serial breath samples were collected after each dose over 2 hours.

Dose Optimization in Kidney Disease: Opportunities for PBPK Modeling and Simulation.

Kidney disease affects pharmacokinetic (PK) profiles of not only renally cleared drugs but also nonrenally cleared drugs. The impact of kidney disease on drug disposition has not been fully elucidated, but describing the extent of such impact is essential for conducting dose optimization in kidney disease. Accurate evaluation of kidney function has been a clinical interest for dose optimization, and more scientists pay attention and conduct research for clarifying the role of drug transporters, metabolic enzymes, and their interplay in drug disposition as kidney disease progresses.

Simultaneous Assessment of Hepatic Transport and Metabolism Pathways with a Single Probe Using Individualized PBPK Modeling of CO Production Rate Data.

Erythromycin is a substrate of cytochrome P4503A4 (CYP3A4) and multiple drug transporters. Although clinical evidence suggests that uptake transport is likely to play a dominant role in erythromycin's disposition, the relative contributions of individual pathways are unclear. Phenotypic evaluation of multiple pathways generally requires a probe drug cocktail.

Trimethylamine -Oxide and Cardiovascular Outcomes in Patients with ESKD Receiving Maintenance Hemodialysis.

Background And Objectives: Trimethylamine -oxide (TMAO), a compound derived from byproducts of intestinal bacteria, has been shown to accelerate atherosclerosis in rodents. To date, there are conflicting data regarding the association of serum TMAO with cardiovascular outcomes in patients with ESKD, a population exhibiting both high serum TMAO and excessive atherosclerosis.

Design, Setting, Participants, & Measurements: We measured baseline serum TMAO concentrations in a subset of participants (=1243) from the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial and conducted analyses evaluating the association between baseline serum TMAO and cardiovascular outcomes.

Metabolic Characterization of Inflammatory Breast Cancer With Baseline FDG-PET/CT: Relationship With Pathologic Response After Neoadjuvant Chemotherapy, Receptor Status, and Tumor Grade.

Background: The aim of this study was to determine if, in inflammatory breast cancer (IBC), baseline metabolic activity (maximum standardized uptake value [SUVmax]) of primary tumor and involved regional lymph nodes (IRLN) are prognostic markers of response after neoadjuvant systemic therapy (NAS).

Patients And Methods: Baseline 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography scans were retrospectively reviewed among 61 women with IBC who received NAS, had mastectomy, and had available pathology reports. Primary tumor and IRLN SUVmax were compared between patients with a pathologic complete response (pCR) versus those with residual disease after NAS.

Minimally invasive esophagectomy: results of a prospective phase II multicenter trial-the eastern cooperative oncology group (E2202) study.

Objective: The primary aim of this trial was to assess the feasibility of minimally invasive esophagectomy (MIE) in a multi-institutional setting.

Background: Esophagectomy is an important, potentially curative treatment for localized esophageal cancer, but is a complex operation. MIE may decrease the morbidity and mortality of resection, and single-institution studies have demonstrated successful outcomes with MIE.

10% Tumor diameter shrinkage on the first follow-up computed tomography predicts clinical outcome in patients with advanced renal cell carcinoma treated with angiogenesis inhibitors: a follow-up validation study.

Vascular endothelial growth factor (VEGF)-targeted agents are standard therapies for metastatic renal cell carcinoma (mRCC), associated with variable tumor shrinkage. Response Evaluation Criteria in Solid Tumors (RECIST) is of limited utility in this setting, and other imaging changes are sought to reliably predict outcome early. We aim to validate 10% tumor shrinkage as the best early indicator of outcome.

Socio-demographic and lifestyle factors for child's physical growth and adiposity rebound of Japanese children: a longitudinal study of the 21st century longitudinal survey in newborns.

Background: It is unknown whether childhood physical development in Asian populations differs from western populations, since no longitudinal analysis has been performed in Asian countries yet. Utilizing the 21st Century Longitudinal Survey in Newborns, we studied the timing of adiposity rebound (AR) among Japanese children and determined whether AR occurs earlier in obese children compared to nonobese children. Furthermore, we identified important demographic, social, and lifestyle factors that affect their physical development.

Intraobserver and interobserver variability in computed tomography size and attenuation measurements in patients with renal cell carcinoma receiving antiangiogenic therapy: implications for alternative response criteria.

Background: Alternative response criteria have been proposed in patients with metastatic renal cell carcinoma (mRCC) who are receiving vascular endothelial growth factor (VEGF)-targeted therapy, including 10% tumor shrinkage as an indicator of response/outcome. However, to the authors' knowledge, intraobserver and interobserver measurement variability have not been defined in this setting. The objective of the current study was to determine intraobserver and interobserver agreement of computed tomography (CT) size and attenuation measurements to establish reproducible response indicators.

Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities.

In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma.

An adaptive two-stage dose-response design method for establishing proof of concept.

We propose an adaptive two-stage dose-response design where a prespecified adaptation rule is used to add and/or drop treatment arms between the stages. We extend the multiple comparison procedures-modeling (MCP-Mod) approach into a two-stage design. In each stage, we use the same set of candidate dose-response models and test for a dose-response relationship or proof of concept (PoC) via model-associated statistics.

A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored.