Objectives: Patients with recurrent and metastatic head and neck cancer (HNC) have limited treatment options. ‘QuadShot’ (QS), a hypofractionated palliative radiotherapy regimen, can provide symptomatic relief and local control and may potentiate the effects of immune checkpoint inhibitors (ICIs). We compared outcomes of QS ± concurrent ICIs in the palliative treatment of HNC. Materials and Methods: We identified patients who received ≥three cycles of QS from 2017 to 2022 and excluded patients without post-treatment clinical evaluation or imaging. Outcomes for patients who received QS alone were compared to those treated with ICI concurrent with QS, defined as receipt of ICI within 4 weeks of QS. Results: Seventy patients were included, of whom 57% received concurrent ICI. Median age was 65.5 years (interquartile range [IQR]: 57.9–77.8), and 50% patients had received prior radiation to a median dose of 66 Gy (IQR: 60–70). Median follow-up was 8.8 months. Local control was significantly higher with concurrent ICIs (12-month: 85% vs. 63%, p = 0.038). Distant control (12-month: 56% vs. 63%, p = 0.629) and median overall survival (9.0 vs. 10.0 months, p = 0.850) were similar between the two groups. On multivariable analysis, concurrent ICI was a significant predictor of local control (HR for local failure: 0.238; 95% CI: 0.073–0.778; p = 0.018). Overall, 23% patients experienced grade 3 toxicities, which was similar between the two groups. Conclusions: The combination of QS with concurrent ICIs was well tolerated and significantly improved local control compared to QS alone. The median OS of 9.4 months compares favorably to historical controls for patients with HNC treated with QS. This approach represents a promising treatment option for patients with HNC unsuited for curative-intent treatment and warrants prospective evaluation.

Urinary tract obstruction (UTO) is a common cause of kidney injury that can result in chronic kidney disease and end-stage renal disease. Heterogeneity in the extent of obstructive renal damage in humans with UTO implies the existence of unknown mechanisms that protect against or accelerate kidney injury. Prior studies show that congenital and acquired UTO initiate a conserved, protective program of renal urothelium remodeling that culminates in expansion of uroplakin (UPK)⁺ cells to promote renal structural integrity. However, the cellular and molecular mechanisms that regulate UPK expression in the renal urothelium are unknown. Peroxisome proliferator-activated receptor γ (PPARγ) drives urothelial differentiation and UPK expression in other tissues but has not been investigated in the renal urothelium. Here we demonstrate that activation of PPARγ in UPK⁺ cells is critical for UTO-induced renal urothelium remodeling. Conditional deletion of Pparg perturbs UPK expression and accelerates parenchymal thinning during UTO, while conditional activation of PPARγ increases UPK expression and results in parenchymal preservation. This study underscores the significance of renal urothelium during UTO and shows that UTO-induced renal urothelial remodeling is achieved through activation of PPARγ. These findings form the foundation for future studies that will determine the therapeutic utility of PPARγ agonists during congenital and acquired UTO.

Urinary tract obstruction (UTO) is a common cause of kidney injury that can result in chronic kidney disease and end-stage renal disease. Heterogeneity in the extent of obstructive renal damage in humans with UTO implies the existence of unknown mechanisms that protect against or accelerate kidney injury. Prior studies show that congenital and acquired UTO initiate a conserved, protective program of renal urothelium remodeling that culminates in expansion of uroplakin (UPK)+ cells to promote renal structural integrity. However, the cellular and molecular mechanisms that regulate UPK expression in the renal urothelium are unknown. Peroxisome proliferator-activated receptor γ (PPARγ) drives urothelial differentiation and UPK expression in other tissues but has not been investigated in the renal urothelium. Here, we demonstrate that activation of PPARγ in UPK+ cells is critical for UTO-induced renal urothelium remodeling. Conditional deletion of PPARγ perturbs UPK expression and accelerates parenchymal thinning during UTO, while conditional activation of PPARγ increases UPK expression and results in parenchymal preservation. This study underscores the significance of renal urothelium during UTO and shows that UTO-induced renal urothelial remodeling is achieved through activation of PPARγ. These findings form the foundation for future studies that will determine the therapeutic utility of PPARγ agonists during congenital and acquired UTO.