Local and Regional Recurrences of Clinically Localized Renal Cell Carcinoma after Nephrectomy: A 15 Year Institutional Experience with Prognostic Features and Oncologic Outcomes.

OBJECTIVE: To evaluate outcomes for patients with local recurrence (LR) of clinically localized renal cell carcinoma (RCC) without concurrent systemic metastasis from our institution, an event that occurs rarely (1%-3%) after surgery. LR may be a harbinger of poor outcomes, and the best management of these patients is unclear. MATERIALS/METHODS: We retrospectively reviewed patients surgically treated for clinically localized RCC (cT1-2N0M0) with subsequent LR (in the partial or radical nephrectomy bed) and/or regional recurrence (RR; in the abdomen distant from the direct site of surgery) without concurrent metastasis from our institutional database (2004-2018). Comparative and survival analyses were performed. RESULTS: Out of 3038 total patients, 1895 had clinically localized RCC, with 30 patients (1.6%) having isolated LR/RR. Median time to recurrence was 26.5 months (IQR:16-35). Of 26 patients treated with local therapy, 14 (53.8%) recurred over a median follow-up time of 29.5 months (IQR:12-45). The 1-year and 2-year secondary recurrence-free survival rates are 60.7% and 49.7%, respectively. Two or more sites of locoregional recurrence significantly predicted secondary recurrence/metastasis after local therapy for local recurrence (hazard ratio: 2.22, P= .04). CONCLUSION: Our results suggest local therapy is appropriate for select patients with LR/RR, with almost 50% of patients undergoing a second local therapy remaining alive with "local cure" and no secondary recurrence. The number of sites of recurrence can be used to better select patients that will benefit from local therapy or systemic/combination therapy. This work provides a framework onto which further studies regarding local therapy and locoregional recurrence of RCC can be performed.

Health-related quality of life and economic burden of vestibular loss in older adults.

Objectives: Vestibular loss is a debilitating condition, and despite its high prevalence in older adults, the quality of life (QoL) burden of vestibular loss in older individuals has not been well-studied. This report quantifies the impact on overall QoL and identifies domains of health most affected. We hypothesize vestibular loss will be associated with impairment in diverse domains of health-related QoL. Study Design: Prospective, case-control study. Methods: A convenience sample of 27 patients age ≥60 years with vestibular physiologic loss was recruited from an academic neurotology clinic. The patients did not have any identifiable cause of their vestibular loss other than aging. The convenience sample was compared to an age-matched cross-sectional sample of the general US population (n = 1266). The main outcome was QoL measured by the Ontario Health Utilities Index Mark III (HUI3). Results: Compared to the general population, patients with vestibular loss had significantly lower overall unadjusted HUI3 scores (-0.32, p < 0.001). Multivariate regression analysis showed vestibular loss was significantly associated with poorer performance in vision (-0.11 p < 0.0001), speech (-0.15, p < 0.0001), dexterity (-0.13, p < 0.0001), and emotion (-0.07, p = 0.0065). Adjusted aggregate HUI3 was also significantly lower for vestibular loss (-0.15, p = 0.0105). These QoL decrements resulted in an average loss of 1.30 Quality-Adjusted Life Years (QALYs). When using a $50,000/QALY willingness-to-pay threshold, vestibular loss was associated with a $64,929 lifetime economic burden per affected older adult, resulting in a total lifetime societal burden of $227 billion for the US population ≥60 years of age. Conclusions: Loss of vestibular function with aging significantly decreases quality of life across multiple domains of well-being. These QoL reductions are responsible for heavy societal economic burdens of vestibular loss, which reveal potential benefits of prompt diagnosis and treatment of this condition. Level of Evidence: 3.

Impact of molecular weight on the intrinsic immunogenic activity of poly(beta amino esters).

Polymeric carriers are ubiquitously studied in vaccine and drug delivery to control the encapsulation, kinetics, and targeting of cargo. Recent research reveals many polymers can cause immunostimulatory and inflammatory responses, even in the absence of other immune signals. However, the extent to which this intrinsic immunogenicity evolves during degradation is understudied. Here we synthesized a small library of poly(beta amino esters) (PBAEs) that exhibit different starting molecular weights (MWs), but with similar and rapid degradation rates. Primary dendritic cells (DCs) treated with free PBAEs, either intact or degraded to form low MW fragments, were not activated. In contrast particles formed from PBAEs at different extents of degradation caused differential expression of classical DC activation markers (for example, CD40, CD80, CD86, MHCII), as well as antigen presentation. During degradation, activation levels changed with changing physicochemical properties (for example, MW, concentration, size, charge). Of note, irrespective of starting MW, immunogenicity peaked when the MW of degrading PBAEs decreased to a range of ∼1500-3000 Da. These findings could help inform design of future carriers that exploit the dynamic interactions with the immune system as materials degrade, leading to carriers that deliver cargo but also help direct the immune responses to vaccine or immunotherapy cargo. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1219-1229, 2017.

Intrinsic immunogenicity of rapidly-degradable polymers evolves during degradation.

Recent studies reveal many biomaterial vaccine carriers are able to activate immunostimulatory pathways, even in the absence of other immune signals. How the changing properties of polymers during biodegradation impact this intrinsic immunogenicity is not well studied, yet this information could contribute to rational design of degradable vaccine carriers that help direct immune response. We use degradable poly(beta-amino esters) (PBAEs) to explore intrinsic immunogenicity as a function of the degree of polymer degradation and polymer form (e.g., soluble, particles). PBAE particles condensed by electrostatic interaction to mimic a common vaccine approach strongly activate dendritic cells, drive antigen presentation, and enhance T cell proliferation in the presence of antigen. Polymer molecular weight strongly influences these effects, with maximum stimulation at short degradation times--corresponding to high molecular weight--and waning levels as degradation continues. In contrast, free polymer is immunologically inert. In mice, PBAE particles increase the numbers and activation state of cells in lymph nodes. Mechanistic studies reveal that this evolving immunogenicity occurs as the physicochemical properties and concentration of particles change during polymer degradation. This work confirms the immunological profile of degradable, synthetic polymers can evolve over time and creates an opportunity to leverage this feature in new vaccines. STATEMENT OF SIGNIFICANCE: Degradable polymers are increasingly important in vaccination, but how the inherent immunogenicity of polymers changes during degradation is poorly understood. Using common rapidly-degradable vaccine carriers, we show that the activation of immune cells--even in the absence of other adjuvants--depends on polymer form (e.g., free, particulate) and the extent of degradation. These changing characteristics alter the physicochemical properties (e.g., charge, size, molecular weight) of polymer particles, driving changes in immunogenicity. Our results are important as many common biomaterials (e.g., PLGA) are now known to exhibit immune activity that alters how vaccines are processed. Thus, the results of this study could contribute to more rational design of biomaterial carriers that also actively direct the properties of responses generated by vaccines.