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Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade.sup.1, this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8.sup.+ T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors. In a retrospective analysis of data from three clinical trials, increased baseline peripheral and tumor IL-8 levels were associated with worse clinical outcomes in patients with metastatic urothelial carcinoma and metastatic renal cell carcinoma treated with anti-PD-L1 therapy., Author(s): Kobe C. Yuen [sup.1] , Li-Fen Liu [sup.1] , Vinita Gupta [sup.1] , Shravan Madireddi [sup.1] , Shilpa Keerthivasan [sup.1] , Congfen Li [sup.1] , Deepali Rishipathak [sup.1] , [...]

Aims: To describe healthcare utilization and cost associated with the short-term and long-term complications of cystectomy among commercially insured bladder cancer patients in the United States.Materials and methods: This retrospective, observational cohort study evaluated adults with bladder cancer receiving a transurethral resection of bladder tumor followed by a partial or radical cystectomy procedure using U.S. administrative claims from the 2005-2015 IBM MarketScan Commercial and Medicare Supplemental databases. Bladder cancer patients were classified into two cohorts: partial cystectomy or radical cystectomy. Cystectomy complications were identified during the cystectomy admission, short-term period, and long-term period. Complication-related utilization and cost outcomes were reported in aggregate during the cystectomy admission and per patient per month (PPPM) during the short-term and long-term follow-up periods.Results: Of 5136 patients who received a cystectomy, 488 (9.5%) received partial cystectomy and 4648 (90.5%) received radical cystectomy. The mean (SD) costs of complications during the cystectomy admission were $11,728 ($43,380) for radical cystectomy and $4657 ($25,668) for partial cystectomy. In the short-term period, PPPM complication-related healthcare costs were $638 [$3793] for partial cystectomy and $2681 [$14,705] for radical cystectomy. In the long-term period, PPPM complication-related healthcare costs were $544 [$2580] for partial cystectomy and $1619 [$7874] for radical cystectomy.Conclusions: Cystectomy-related complications, especially with radical cystectomy, present a substantial financial burden to patients and payers immediately after surgery as well as in the long term. Targeted interventions which improve clinical outcomes but reduce substantial costs associated with cystectomy for bladder cancer are needed. [ABSTRACT FROM AUTHOR]

Background and Purpose: There is widespread geographic variation in healthcare quality, but we often lack clear strategies for improving quality in underserved areas. This study characterized geographic disparities in stroke care quality to assess whether improved access to neurological services has the potential to bridge the care quality gap, particularly in terms of alteplase (rt-PA) administration.Methods: This was a retrospective study using quality performance data from the 2015 Hospital Compare database linked to information on certification status from the Joint Commission and information on local access to neurological services from the Area Health Resources File. We used these data to compare stroke care quality according to geographic area, certification, and neurologist access.Results: Non-metropolitan hospitals performed worse than metropolitan hospitals on all assessed stroke care quality measures. The most prevalent disparity occurred in the use of rt-PA for eligible patients (52.2% versus 82.7%, respectively). Certified stroke centers in every geographic designation provided higher quality of care, whereas large variation was observed among non-certified hospitals. Regression analyses suggested that improvements in hospital certification or access to neurologists were associated with absolute improvements of 44.9% and 21.3%, respectively, in the percentage of patients receiving rt-PA.Conclusions: The large quality gap in stroke care between metropolitan and non-metropolitan areas could be at least partly addressed through improved procedural efforts by stroke center certification increasing the supply of neurological services, (i.e. through training and hiring new neurologists) or by adopting decision support systems such as telemedicine. [ABSTRACT FROM AUTHOR]

Background: The Phase IIIb, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Alteplase in Patients With Mild Stroke: Rapidly Improving Symptoms and Minor Neurologic Deficits (PRISMS) trial will assess r-tPA in ischemic stroke patients who present with mild deficits (i.e. mild stroke). Aims: To assess PRISMS's societal value in clarifying the optimal care for patients with mild ischemic stroke. Methods: A value of information (VOI) decision model was developed to compare the outcomes of mild stroke patients treated vs. not treated with r-tPA. Model inputs were derived from a subset of Third International Stroke Trial patients, a recent meta-analysis of r-tPA trials, expert opinion, and other published sources. VOI analyses were also used to assess the expected US societal value of the PRISMS trial and the expected value of reducing uncertainty in key trial estimates. Results: The expected net societal value of the PRISMS trial was approximately $210 million ($160 m-$260 m), representing a six-fold return on investment. The value of reducing uncertainty in r-tPA efficacy was approximately $150 million ($100 m-$200 m), while reducing uncertainty in r-tPA safety (increased risk for symptomatic intracranial hemorrhage) did not add additional value in comparison. Conclusions: Developing a better understanding of the outcomes of r-tPA treatment in patients with mild ischemic stroke will provide tremendous societal value by clarifying current uncertainty around treatment effectiveness. Enrollment in the PRISMS trial for patients presenting with mild ischemic stroke within 0-3 h of symptom onset should be highly encouraged. [ABSTRACT FROM AUTHOR]

Background: Intravenous recombinant tissue-type plasminogen activator (r-tPA) is an approved treatment for select patients with acute ischemic stroke (AIS). Data indicate r-tPA improves functional outcome three months after AIS compared with placebo. This study models the increase in quality adjusted life years (QALYs) associated with r-tPA compared with similar patients not treated with r-tPA. Methods: Hospital discharge data for AIS and r-tPA were obtained from the Nationwide Inpatient Sample from 1998 to 2011. Discharge location (home, rehabilitation, long-term care, death) was mapped to modified Rankin Scale (mRS) scores based on National Institute of Neurological Disorders and Stroke (NINDS) Study Group Part 1 and 2 clinical studies. The mRS scores were mapped to relative risk of death and QALYs obtained from the literature. The model estimated expected survival and QALYs by age, gender and mRS for patients receiving r-tPA. Life expectancy and QALYs for patients not receiving r-tPA were estimated based on discharge location and mRS for placebo patients in the NINDS study. Results: AIS discharges declined from over 635,000 in 1998 to over 593,000 in 2011. A total of 183,235 patients received r-tPA. Utilization of r-tPA increased from 1% of AIS patients in 1998 to over 4% in 2011. Estimated projections for QALYs gained from utilization of r-tPA to QALYS without r-tPA were just under 240,000 for the 13 years and with no discounting, and just over 165,000 assuming 3% annual discounting. In the most conservative scenario, assuming no difference in proportional discharge status (i.e. patients not treated with r-tPA are discharged in the same manner as rtPA patients), the estimated life years gained are approximately 35,000 and QALYS gained are approximately 90,000. Conclusions: r-tPA for AIS has resulted in estimated gains in quality-adjusted life years due to reduction in disability and improvement in functioning since its introduction in 1998. [ABSTRACT FROM AUTHOR]

Large multicenter acute stroke trials demand a randomization procedure with a high level of treatment allocation randomness, an effective control on overall and within-site imbalances, and a minimized time delay of study treatment caused by the randomization procedure. Driven by the randomization algorithm design of A Study of the Efficacy and Safety of Activase (Alteplase) in Patients with Mild Stroke (PRISMS) (NCT02072226), this paper compares operational and statistical properties of different randomization algorithms in local, central, and step-forward randomization settings. Results show that the step-forward randomization with block urn design provides better performances over others. If the concern on the potential time delay is not serious and a central randomization system is available, the minimization method with an imbalance control threshold and a biased coin probability could be a better choice. [ABSTRACT FROM AUTHOR]

Background Atezolizumab (anti–programmed death-ligand 1) was approved in the USA, Europe, and elsewhere for treatment-naive and platinum-treated locally advanced/metastatic urothelial carcinoma (mUC). Objective To report efficacy and safety from an atezolizumab expanded access study. Design, setting, and participants This single-arm, open-label study enrolled 218 patients at 36 US sites. Key eligibility criteria included progression during/following ≥1 platinum-based chemotherapy for mUC or in perioperative setting (progression within 12 mo) and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2. Intervention Patients received atezolizumab1200 mg intravenously every 3 wk until loss of clinical benefit, unacceptable toxicity, consent withdrawal, decision to discontinue, death, atezolizumab commercial availability, or study closure. Outcome measurements and statistical analysis Key end points reported herein included Response Evaluation Criteria in Solid Tumors v1.1 objective response rate and duration, disease control rate (DCR; response or stable disease), and safety. Results and limitations All patients received prior systemic therapy (68% mUC; 27% adjuvant; and 26% neoadjuvant). At baseline, 57% of 214 treated patients had ECOG PS ≥1, 19% had hemoglobin <10 g/dl, and 25% had liver metastases. Median treatment duration was 9 wk (interquartile range [IQR], 6–12 wk). Median follow-up duration was 2.3 mo (IQR, 1.6–3.4 mo) overall and 2.7 mo (IQR, 2.0–3.5 mo) in patients not known to have died. Seventeen of 114 evaluable patients (15%) had objective responses (16 ongoing at study termination). DCR was 49%. Treatment-related adverse events (mostly fatigue) occurred in 98 of 214 treated patients. Conclusions The benefit/risk profile of atezolizumab was consistent with that observed in previous studies, despite pretreatment and poor prognostic factors. These results suggest a potential role for atezolizumab in a broader patient range than typically eligible for phase 1–3 studies. Patient summary In this expanded access study, atezolizumab was active and tolerable in a range of patients with platinum-treated metastatic urothelial carcinoma. [ABSTRACT FROM AUTHOR]

Integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma (RCC) patients identifies molecular subsets associated with differential clinical outcomes to angiogenesis blockade alone or with a checkpoint inhibitor. Unsupervised transcriptomic analysis reveals seven molecular subsets with distinct angiogenesis, immune, cell-cycle, metabolism, and stromal programs. While sunitinib and atezolizumab + bevacizumab are effective in subsets with high angiogenesis, atezolizumab + bevacizumab improves clinical benefit in tumors with high T-effector and/or cell-cycle transcription. Somatic mutations in PBRM1 and KDM5C associate with high angiogenesis and AMPK/fatty acid oxidation gene expression, while CDKN2A/B and TP53 alterations associate with increased cell-cycle and anabolic metabolism. Sarcomatoid tumors exhibit lower prevalence of PBRM1 mutations and angiogenesis markers, frequent CDKN2A/B alterations, and increased PD-L1 expression. These findings can be applied to molecularly stratify patients, explain improved outcomes of sarcomatoid tumors to checkpoint blockade versus antiangiogenics alone, and develop personalized therapies in RCC and other indications. • Genomics of 823 RCC tumors, including 134 sarcomatoid tumors, reveals 7 subtypes • Subtype specific angiogenesis, immune, metabolic, stromal, and cell-cycle profiles • Differential prevalence of PBRM1 , KDM5C , CDKN2A/2B , and TP53 alterations in subsets • Differential outcomes to VEGF blockade alone or in combination with anti-PD-L1 Motzer et al. perform integrative multi-omics analyses of 823 renal cancer tumors from a randomized clinical trial. A robust molecular classification scheme, based on transcriptional and gene alteration profiles and differential clinical outcomes to VEGF blockade alone or in combination with anti-PD-L1, informs personalized treatment strategies and future therapeutic development in RCC. [ABSTRACT FROM AUTHOR]