Combination drug regimens for metastatic clear cell renal cell carcinoma

Renal cell carcinomas (RCC) make up about 90% of kidney cancers, of which 80% are of the clear cell subtype. About 20% of patients are already metastatic at the time of diagnosis. Initial treatment is often cytoreductive nephrectomy, but systemic therapy is required for advanced RCC. Single agent targeted therapies are moderately toxic and only somewhat effective, leading to development of immunotherapies and combination therapies. This review identifies limitations of monotherapies for metastatic renal cell carcinoma, discusses recent advances in combination therapies, and highlights therapeutic options under development. The goal behind combining various modalities of systemic therapy is to potentiate a synergistic antitumor effect. However, combining targeted therapies may cause increased toxicity. The initial attempts to create therapeutic combinations based on inhibition of the vascular endothelial growth factor or mammalian target of rapamycin pathways were largely unsuccessful in achieving a profile of increased synergy without increased toxicity. To date, five combination therapies have been approved by the U.S. Food and Drug Administration, with the most recently approved therapies being a combination of checkpoint inhibition plus targeted therapy. Several other combination therapies are under development, including some in the phase 3 stage. The new wave of combination therapies for metastatic RCC has the potential to increase response rates and improve survival outcomes while maintaining tolerable side effect profiles.     

Socioeconomic Disparities in the Presentation of Acute Bacterial Sinusitis Complications in the Pediatric Population

ABSTRACT

Acute bacterial sinusitis is a common disease in the pediatric population that typically resolves without significant complications. Children who do suffer from complications involving the orbit or the brain often experience significant morbidity and potential mortality, typically requiring hospitalization for management. Numerous studies have demonstrated that children from low-income families with public or no insurance are less likely to receive adequate preventative care, are more likely to present with later disease stages, and ultimately endure worse health outcomes. We review the literature to examine if there are socioeconomic disparities in the presentation of complications of acute bacterial sinusitis in the pediatric population.     

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.

     

A circannual rhythm in unstimulated salivary flow rate when the ambient temperature varies by only about 2 degrees C

OBJECTIVE: To determine whether a circannual rhythm in the flow rate of unstimulated whole saliva could be detected in persons living in a region of Sri Lanka where the average monthly temperature is virtually constant throughout the year. DESIGN: Forty-six medical students, 26 male and 20 female, in Peradeniya collected saliva on 12 occasions about once per month from September 19, 2003 to September 28, 2004. A least-squares sine wave of the form: F(t)=M+A x(2 pi t/tau+phi), in which F is the flow rate at time t (in days), M the mesor or rhythm-adjusted mean value, A the amplitude, tau the period (365 days) and phi the phase shift in radians, was fitted to the data. RESULTS: A statistically significant (p<0.05) circannual rhythm in salivary flow rate was detected with the following mean values and 95% confidence intervals: M=0.528 mL/min (0.514-0.543), A=0.0472 mL/min (0.0269--0.0674), phi=1.141 radians (0.704--1.578). The acrophase (peak value of the rhythm) was on October 14 (September 19--November 8). During the study, the average monthly temperature varied between 24.0 and 26.3 degrees C, with the peak temperature in April and minimum in December. CONCLUSION: Even though the monthly ambient temperature variation in Peradeniya was very small, the peak temperatures occurred at the times of the lowest salivary flow rates, suggesting that a small change in ambient temperature (about 2 degrees C) in a warm climate may be sufficient to influence the unstimulated salivary flow rate. In conclusion, for saliva studies, which extend over a prolonged period, it may be important to take into account the circannual rhythm in salivary flow rate.