Immune-Related Adverse Events as Clinical Biomarkers in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

Background

Immune checkpoint inhibitors (ICIs) are an important treatment for metastatic renal cell carcinoma (mRCC). These agents may cause immune-related adverse events (irAEs), and the relationship between irAEs and outcomes is poorly understood. We investigated the association between irAEs and clinical outcomes in patients with mRCC treated with ICIs.

Methods

We performed a retrospective study of 200 patients with mRCC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on irAEs were collected from clinic notes and laboratory values and grades were determined using Common Terminology Criteria in Adverse Events version 5.0. The association with overall survival (OS) and progression-free survival (PFS) was modeled by Cox proportional hazards model. Logistic regression models were used to define odds ratios (ORs) for clinical benefit (CB). Landmark analysis and extended Cox models were used to mitigate lead-time bias by treating irAEs as a time-varying covariate.

Results

Most patients (71.0%) were male, and one-third of patients (33.0%) experienced at least one irAE, most commonly involving the endocrine glands (13.0%), gastrointestinal tract (10.5%), or skin (10.0%). Patients who experienced irAEs had significantly longer OS (hazard ratio [HR], 0.52; p = .013), higher chance of CB (OR, 2.10; p = .023) and showed a trend toward longer PFS (HR, 0.71; p = .065) in multivariate analysis. Patients who had endocrine irAEs, particularly thyroid irAEs, had significantly longer OS and PFS and higher chance of CB. In a 14-week landmark analysis, irAEs were significantly associated with prolonged OS (p = .045). Patients who experienced irAEs had significantly longer median OS (44.5 vs. 18.2 months, p = .005) and PFS (7.5 vs. 3.6 months, p = .003) without landmark compared with patients who did not.

Conclusion

We found that patients with mRCC treated with ICIs who experienced irAEs, particularly thyroid irAEs, had significantly improved clinical outcomes compared with patients who did not have irAEs. This suggests that irAEs may be effective clinical biomarkers in patients with mRCC treated with ICIs. Future prospective studies are warranted to validate these findings.

Implications for Practice

This study found that early onset immune-related adverse events (irAEs) are associated with significantly improved clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs). In this site-specific irAE analysis, endocrine irAEs, particularly thyroid irAEs, were significantly associated with improved clinical outcomes. These results have implications for practicing medical oncologists given the increasing use of ICIs for the treatment of mRCC. Importantly, these results suggest that early irAEs and thyroid irAEs at any time on treatment with ICIs may be clinical biomarkers of clinical outcomes in patients with mRCC treated with ICIs.

     

Molecular Dynamics of Amphiphilic Random Copolymers in the Bulk: A 1H and 19F NMR Relaxometry Study

A set of amphiphilic random copolymers of poly(ethylene glycol) methacrylate (PEGMA) and perfluorohexylethyl acrylate (FA) with different compositions synthesized by atom transfer radical polymerization (ATRP) is investigated by ¹H and ¹⁹F NMR relaxometry. In particular, a thorough investigation of T₁ and T₂ relaxation times at variable temperature and copolymer composition provides the first complete and detailed characterization of the dynamics of both the main chain backbone and the side chains of the PEGMA‐co‐FA copolymers. The results highlight an intramolecular segregation of rigid main chain and mobile side chains, and an additional self‐assembling of the PEGMA and FA side chains into distinct nanodomains, driven by the hydrophobic interactions between FA side chains. The obtainment and observation of nanoscale phase separation in random copolymers is a promising achievement to the aim of controlling self‐assembly in the bulk by suitably modulating copolymers composition, which can open novel avenues to easier fabrications and applications in nanotechnologies.     

A survey of known immune epitopes in the enteroviruses strains associated with acute flaccid myelitis

Enteroviruses are potentially linked to the emergence of Acute Flaccid Myelitis (AFM), a rare but very serious condition that affects the nervous system. AFM has been associated with coxsackievirus A16, enterovirus A71 (EVA71) and enterovirus D68 (EVD68). Little is known about host-pathogen interactions for these viruses, and whether immune responses may have a protective or immunopathological role in disease presentations. Towards addressing this issue, we used the Immune Epitope Database to assess the known inventory of B and T cell epitopes from enteroviruses, focusing on data related to human hosts. The extent of conservation in areas that are targets of B and T cell immune responses were examined. This analysis sheds light on regions of the enterovirus polypeptide that can be probed to induce a specific or cross-reactive B or T cell the immune response to enteroviruses, with a particular focus on coxsackievirus A16, EVA71 and EVD68. In addition, these analyses reveal the current gap-of-knowledge in the T and B cell immune responses that future studies should aim to address.     

Incorporation of magnesium into rat dental enamel and its influence on crystallization

The incorporation of magnesium into the enamel of immature rats was studied by chemical analysis and X-ray diffraction. Magnesium solutions were injected subcutaneously and later intra-orally into growing rats. Increased magnesium was detected in the enamel at the late developmental stage, and a delay in enamel mineralization resulted from increased magnesium uptake. Incisal enamel from the Mg-injected rats had significant line-broadening on X-ray diffraction, characteristic of poorly crystallized enamel.     

Eigenblutspende in der Dysgnathiechirurgie

Aim

To minimize the perioperative risk of transfusion-associated complications, preoperative autologous blood donation is routinely performed in orthognathic surgery. This study critically analyzed the necessity of this procedure with respect to clinical, economic, and juridical issues.

Material and methods

In the Department of Oral and Maxillofacial Surgery, Bonn Medical School, 178 orthognathic surgical procedures were performed from 1994 to 2002. All patients (women, n=101; men, n=77) were informed about the possibility of autologous blood donation. This procedure was carried out in 83%,for single jaw surgery two and for bimaxillary osteotomies three to four units of packed red blood cells were predeposited. Of the patients, 99 underwent monognathic surgery in the lower jaw, 27 patients in the upper jaw, and bimaxillary osteotomy was performed in 52 patients.

Results

The average blood loss for the monognathic procedure in the lower jaw was 756 ml, in the upper jaw 858 ml, and in double jaw surgery 1391 ml. In 13 patients the hemoglobin concentration fell below 7.5 g/dl and 12 patients received their predeposited autologous blood units. A total of 57.7% of all donated autologous blood units were discarded.

Conclusion

Autologous blood donation should be performed from the medical point of view for double jaw surgery and considered in single cases with special risks in monomaxillary osteotomies.