Risk factors and predictors of immune-related adverse events: implications for patients with non-small cell lung cancer.

INTRODUCTION: Immune checkpoint inhibitors (ICI) are now utilized as a standard of care treatment for multiple cancers, including in both the metastatic setting as well as in earlier stages of disease. The identification of unique immune-related adverse events (irAE) that occur during ICI treatment has led to intense research to identify potential risk factors and biomarkers that may assist in clinical decision making. Although initial studies in ICI were primarily in advanced stage disease, the use of ICI in earlier stages of disease as adjuvant therapies requires a better understanding of patient risk stratification to mitigate or prevent serious irAE. AREAS COVERED: In this review, we set out to describe the current state of research regarding potential risk factors for irAE in patients with non-small cell lung cancer, as well as explore the barriers to understanding irAE. We review data from irAE that occur in large phase 3 trials and prospective studies focusing on irAE, as well as the many retrospective studies that currently form the bulk of our understanding of irAE.

Pharmacokinetics and Tolerability of the Novel Non-immunosuppressive Fingolimod Derivative, OSU-2S, in Dogs and Comparisons with Data in Mice and Rats.

In this study, we characterized the pharmacokinetics of OSU-2S, a fingolimod-derived, non-immunosuppressive phosphatase activator, in mice, rats, and dogs, as well as tolerability and food effects in dogs. Across all species tested, plasma protein binding for OSU-2S was > 99.5%, and metabolic stability and hepatic intrinsic clearance were in the moderate range. OSU-2S did not significantly modulate CYP enzyme activity up until 50 µM, and Caco-2 data suggested low permeability with active efflux at 2 µM. Apparent oral bioavailability in mice was 16% and 69% at 10 and 50 mg/kg, respectively. In rats, bioavailability was 24%, 35%, and 28% at 10, 30, and 100 mg/kg, respectively, while brain/plasma ratio was 36 at 6-h post-dose at 30 mg/kg. In dogs, OSU-2S was well tolerated with oral capsule bioavailability of 27.5%. Plasma OSU-2S exposures increased proportionally over a 2.5-20 mg/kg dose range. After 4 weeks of 3 times weekly, oral administration (20 mg/kg), plasma AUClast (26.1 µM*h), and Cmax (0.899 µM) were nearly 2-fold greater than those after 1 week of dosing, and no food effects were observed. The elimination half-life (29.7 h), clearance (22.9 mL/min/kg), and plasma concentrations of repeated oral doses support a 3-times weekly dosing schedule in dogs. No significant CBC, serum biochemical, or histopathological changes were observed. OSU-2S has favorable oral PK properties similar to fingolimod in rodents and dogs and is well tolerated in healthy animals. This work supports establishing trials of OSU-2S efficacy in dogs with spontaneous tumors to guide its clinical development as a cancer therapeutic for human patients.

The Role of Malnutrition and Muscle Wasting in Advanced Lung Cancer.

PURPOSE OF REVIEW: Malnutrition, cancer cachexia, and sarcopenia often co-occur in patients with advanced cancer and are associated with poorer response to chemotherapy and reduced survival. Here, we evaluate the current literature regarding the role of nutrition and these associated conditions in patients with advanced lung cancer. RECENT FINDINGS: While rates of malnutrition are high, nutritional intervention studies have generally been limited by small sample sizes. Novel strategies such as home-based meal delivery may have promise. While no therapy is approved for cancer cachexia, ghrelin agonists and other targeted therapies have yielded promising data in clinical trials. Recent data also suggest that obesity may improve immunotherapy responsiveness. Malnutrition and associated muscle wasting are clearly negative prognostic markers in advanced lung cancer. Patients with malnutrition should be urgently referred for dietary counseling and guidelines for nutritional support should be followed. Optimal treatment of these syndromes will likely include nutrition and anti-cachexia interventions used in combination.

Registered report: Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs.

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from "Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous 'mRNAs' by Tay and colleagues, published in Cell in 2011 (Tay et al., 2011). The experiments to be replicated are those reported in Figures 3C, 3D, 3G, 3H, 5A and 5B, and in Supplemental Figures 3A and B. Tay and colleagues proposed a new regulatory mechanism based on competing endogenous RNAs (ceRNAs), which regulate target genes by competitive binding of shared microRNAs. They test their model by identifying and confirming ceRNAs that target PTEN. In Figure 3A and B, they report that perturbing expression of putative PTEN ceRNAs affects expression of PTEN. This effect is dependent on functional microRNA machinery (Figure 3G and H), and affects the pathway downstream of PTEN itself (Figures 5A and B). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife.