The College of Engineering and Applied Sciences & the BTR-A Partnership with Purpose

Published by the Center of the Study of Ethics in Society Western Michigan University

PD-1 as a potential target in cancer therapy

Recently, an improved understanding of the molecular mechanisms governing the host response to tumors has led to the identification of checkpoint signaling pathways involved in limiting the anticancer immune response. One of the most critical checkpoint pathways responsible for mediating tumor-induced immune suppression is the programmed death-1 (PD-1) pathway, normally involved in promoting tolerance and preventing tissue damage in settings of chronic inflammation. Many human solid tumors express PD ligand 1 (PD-L1), and this is often associated with a worse prognosis. Tumor-infiltrating lymphocytes from patients with cancer typically express PD-1 and have impaired antitumor functionality. Proof-of-concept has come from several preclinical studies in which blockade of PD-1 or PD-L1 enhanced T-cell function and tumor cell lysis. Three monoclonal antibodies against PD-1, and one against PD-L1, have reported phase 1 data. All four agents have shown encouraging preliminary activity, and those that have been evaluated in larger patient populations appear to have encouraging safety profiles. Additional data are eagerly awaited. This review summarizes emerging clinical data and potential of PD-1 pathway–targeted antibodies in development. If subsequent investigations confirm the initial results, it is conceivable that agents blocking the PD-1/PD-L1 pathway will prove valuable additions to the growing armamentarium of targeted immunotherapeutic agents. Next-generation immunotherapy agents that target the PD-1 checkpoint pathway are demonstrating antitumor activity and encouraging safety profiles in early clinical trials. Current and future clinical trials will provide new insights, and the evaluation of biomarkers and rational combination therapies is ongoing

Long-Term Use of Nonsteroidal Anti-inflammatory Drugs Decreases the Risk of Cutaneous Melanoma: Results of a United States Case–Control Study

Experimental and observational studies continue to demonstrate conflicting results regarding the role of several commonly used drugs as melanoma chemopreventive agents. This case–control study was designed to assess the associations between cutaneous melanoma (CM) and exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) and statins in current users. A total of 400 CM and 600 eligible age- and gender-matched community-based controls were prospectively recruited and interviewed. We assessed participants’ demographic characteristics, CM risk factors, and current and previous use of medications. Multivariable conditional logistic regression models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between NSAIDs and/or aspirin (ASA), statin exposure, and CM risk. Half of the subjects were men (mean age 60 years). After adjusting for confounders, use of any type of NSAIDs for more than 5 years significantly reduced the risk of melanoma development compared with the low-exposure group (adjusted OR=0.57; 95% CI=0.43–0.77). Subgroup analyses showed that the observed risk reduction was primarily driven by continuous ASA use (>5 years adjusted OR=0.51, 95% CI=0.35–0.75). No significant protective effect was observed with statin exposure (OR=0.97, 95% CI=0.73–1.29). Long-term use of NSAIDs, especially ASA, is associated with a significantly decreased risk of CM development. Clinical intervention studies are warranted to further investigate the potential role of ASA and other NSAIDs as chemopreventive agents for CM.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclu

Concept of Operations for Management by Trajectory

This document describes Management by Trajectory (MBT), a concept for future air traffic management (ATM) in which every flight operates in accordance with a four-dimensional trajectory (4DT) that is negotiated between the airspace user and the Federal Aviation Administration (FAA) to respect the airspace user's goals while complying with National Airspace System (NAS) constraints. In the present-day NAS, the ATM system attempts to predict the trajectory for each flight based on the approved flight plan and scheduled or controlled departure time. However, once the aircraft starts to move, controllers tactically manage the aircraft to implement traffic management restrictions, separate otherwise conflicting aircraft, and address arising NAS constraints. Tactical controller actions are not directly communicated to the automation systems or other stakeholders. Furthermore, the initial trajectory prediction does not anticipate these disruptions or how they will impact the flight. Consequently, and compounded by gaps in required data and models, trajectory predictions are less accurate than possible, which affects Traffic Flow Management (TFM) performance. A cornerstone of the MBT concept is that all air vehicles have, at all times, an assigned 4DT from their current state to their destination. These assigned trajectories consist of trajectory constraints and descriptions. Pilots and air traffic controllers, with the aid of automation, operate the aircraft to comply with the assigned trajectory, unless first negotiating a revision. Equipped aircraft have substantial responsibility for complying with the assigned trajectory without controller intervention. To maximize the operational flexibility available to the airspace user, the assigned trajectory only imposes trajectory constraints as required to achieve the ATM goals of NAS constraint compliance and aircraft separation. Trajectory descriptions are added to the assigned trajectory to ensure sufficient predictability. To further improve trajectory prediction accuracy, airspace users supplement the assigned trajectory by broadcasting intent information and updating it as necessary. Air vehicle intent is a more detailed description of the airspace user's plan for how the flight will fly the assigned trajectory. Air vehicle intent can change freely, without negotiation, as long as it remains in compliance with the assigned trajectory. Aircraft assigned trajectories, air vehicle intent, and predicted trajectories are shared, creating a common view among stakeholders. A NAS Constraint Service gathers and publishes information about all known NAS constraints, enabling airspace users to be informed participants in trajectory negotiation. Trajectory constraints in the assigned trajectory are mapped to NAS constraints to facilitate identifying which aircraft are affected when NAS constraints change. To support efficient trajectory negotiation, all aircraft provide current information about air vehicle capabilities. Assigned trajectories are constructed to satisfy all known NAS constraints, improving trajectory stability and predictability. Uncertainty and disruptions are handled by modifying the assigned trajectory as far in advance as possible. By proactively negotiating changes to the assigned trajectory, rather than relying on controller-selected tactical actions such as vectors to resolve traffic conflicts or implement miles-in-trail restrictions, MBT keeps aircraft on closed trajectories that are fully known to all stakeholders. Since reactive air traffic control actions cannot be predicted in advance, the downstream trajectory cannot be accurately predicted until they happen. Reliable trajectory predictions allow the system to identify needed modifications to trajectories further in advance, where they can be negotiated and communicated as amendments (i.e., additional or altered trajectory constraints) to the assigned trajectory. Decision Support Tools (DSTs) aid controllers in rapidly defining and communicating closed trajectories to the aircraft and support all stakeholders in trajectory negotiation. Anticipated MBT benefit mechanisms include more accurate trajectory predictions, improved ATM performance and robustness to off-nominal conditions, increased flexibility and operational efficiency, reduced impediments to emerging classes of airspace users accessing NAS resources, reduced environmental impacts, and enhanced safety

High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model.</p> <p>Methods</p> <p>Mice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1) Conventional dose (CD) continuous therapy; 2) high dose (HD) intermittent therapy, 3) CD intermittent therapy and 4) HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled (ASL) MRI at day 0, 3, 7 and 10.</p> <p>Results</p> <p>Tumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion.</p> <p>Conclusions</p> <p>A modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.</p

Does Medical Malpractice Law Improve Health Care Quality?

Despite the fundamental role of deterrence in justifying a system of medical malpractice law, surprisingly little evidence has been put forth to date bearing on the relationship between medical liability forces on the one hand and medical errors and health care quality on the other. In this paper, we estimate this relationship using clinically validated measures of health care treatment quality constructed using data from the 1979 to 2005 National Hospital Discharge Surveys and the 1987 to 2008 Behavioral Risk Factor Surveillance System records. Drawing upon traditional, remedy-centric tort reforms — e.g., damage caps — we estimate that the current liability system plays at most a modest role in inducing higher levels of health care quality. We contend that this limited independent role for medical liability may be a reflection upon the structural nature of the present system of liability rules, which largely hold physicians to standards determined according to industry customs. We find evidence suggesting, however, that physician practices may respond more significantly upon a substantive alteration of this system altogether — i.e., upon a change in the clinical standards to which physicians are held in the first instance. The literature to date has largely failed to appreciate the substantive nature of liability rules and may thus be drawing limited inferences based solely on our experiences to date with damage-caps and related reforms

Molecular profiling of melanoma brain metastases compared to primary cutaneous melanoma and to extracranial metastases.

BACKGROUND: Brain metastases are a significant cause of mortality and morbidity for patients with melanoma. We hypothesize that the development of brain metastases may be explained by molecular heterogeneity between primary cutaneous melanoma (PCM) or extracranial (ECM) and brain (MBM) melanoma metastases. MATERIALS AND METHODS: We compared next-generation sequencing, tumor mutational burden (TMB), and immunohistochemical staining for PD-L1 expression, among 132 MBM, 745 PCM, and 1190 ECM. RESULTS: The most common genetic alterations among MBM included: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Four genes were found with higher frequency among MBM compared to PCM or ECM: BRAF (52.4% v 40.4% v 40.9%), SETD2 (11.9% v 1.9% v 3.9%), PBRM1 (7.5% v 1.6% v 2.6%), and DICER1 (4.4% v 0.6% v 0.4%). MBM showed higher TMB ( CONCLUSIONS: Our findings suggest a unique molecular profile for MBM, including higher rates of BRAF mutations, higher TMB and higher PD-L1 expression, and also implicate chromatin remodeling in the pathogenesis of MBM

Phase I/II open-label study of the biologic effects of the interleukin-2 immunocytokine EMD 273063 (hu14.18-IL2) in patients with metastatic malignant melanoma

BACKGROUND: To explore the biological activity of EMD 273063 (hu14.18-IL2), a humanized anti-GD2 monoclonal antibody fused to interleukin-2 (IL2), in patients with unresectable, stage IV cutaneous melanoma as measured by induction of immune activation at the tumor site and in peripheral blood. METHODS: Nine patients were treated with 4 mg/m(2 )per day of EMD 273063 given as a 4-h intravenous infusion on days 1, 2, and 3 every four weeks (one cycle). Peripheral blood was analyzed for T cell and natural killer cell phenotype and frequency, as well as levels of soluble IL2 receptor (sIL2R), IL10, IL6, tumor necrosis factor alpha and neopterin. Biopsies of tumor metastasis were performed prior to therapy and at day 10 of the first 2 cycles to study lymphocyte accumulation by immunohistochemistry. RESULTS: Treatment was generally well tolerated and there were no study drug-related grade 4 adverse events. Grade 3 events were mainly those associated with IL2, most commonly rigors (3 patients) and pyrexia (2 patients). Best response on therapy was stable disease in 2 patients. There were no objective tumor regressions by standard response criteria. Systemic immune activation was demonstrated by increases in serum levels of sIL2R, IL10, and neopterin. There was evidence of increased tumor infiltration by T cells, but not NK cells, in most post-dosing biopsies, suggesting recruitment of immune cells to the tumor site. CONCLUSION: EMD 273063 demonstrated biologic activity with increased immune-related cytokines and intratumoral changes in some patients consistent with the suspected mechanism of action of this immunocytokine

Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naïve patients with advanced non-clear cell renal cell carcinoma (HCRN GU16-260-Cohort B)

Background To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naive patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy.Methods Eligible patients with treatment-naive nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies.Results 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary-1/19 (5%); chromophobe-1/6 (17%); and unclassified-3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of = 5% or not measured, respectively. Median progression-free survival was 4.0 (2.7-4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade >3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death.Conclusions Nivolumab monotherapy has limited activity in treatment-naive nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity