An investigation of the relationship between the systemic inflammatory response, cytokine profile and outcome in patients with renal cancer

Renal cancer is the 14th most common cancer in the UK, but is the most lethal of urological cancers. 40% of patients present with distant metastases, and 30% of patients undergoing a curative nephrectomy will subsequently develop metastases. For localized disease, the mainstay of treatment is radical nephrectomy. For patients with metastatic disease immunotherapy is the current standard of care, though the median survival is only nine months. In Chapter one, the epidemiology, pathology, clinical presentation and treatment of renal cancer are discussed. In the second chapter we have reported the prognostic value of the cumulative Glasgow Prognostic Score (based on the combination of an elevated C-reactive protein and hypoalbuminaemia) in patients with metastatic renal cancer commencing immunotherapy. The Glasgow Prognostic Score was independently associated with cancer specific survival, in addition to the Memorial-Sloan Kettring Cancer Centre Score, with median survivals of 28, 11 and 3 months for patients with GPS of 0, 1 and 2 respectively. The GPS was also superior in predicting outcomes to another commonly used prognostic score, the Metastatic Renal Cancer Comprehensive Prognostic System. In Chapter three we reported the prognostic significance of C-reactive protein, but not hypoalbuminaemia, in addition to the Leibovich score in UISS low and intermediate risk patients undergoing potentially curative nephrectomy. The presence of an elevated C-reactive protein was independently associated with cancer specific survival in addition to the Leibovich score. Both the Leibovich score and C-reactive protein were superior to the SSIGN score in predicting cancer specific survival. In Chapter four we examined the role of circulating cytokines associated with T-lymphocyte subpopulations in patients with renal cancer. In the presence of a systemic inflammatory response, there was an association with increased cytokine concentrations from both T-helper 1 and T-helper 2 responses. However, cytokine concentrations measured using the Luminex technology were variable, and appeared less reliable than those measured using conventional ELISA technology. In Chapter five, a longitudinal study of cytokine concentrations and circulating T-lymphocytes was performed in patients undergoing immunotherapy for metastatic renal cancer. Analysis of C-reactive protein, circulating T-lymphocytes, circulating cytokines was performed prior to commencement of immunotherapy, and after two to four weeks of treatment. Concentrations of C-reactive protein and interleukin-6 did not alter significantly following instigation of immunotherapy, nor did the numbers of circulating T-lymphocyte subsets. However, there was a significant increase in Interleukin-10 concentrations following commencement of immunotherapy. In Chapter 6, we examined the longitudinal relationship between the systemic inflammatory response, and circulating cytokines in patients undergoing nephrectomy. Both interleukin-6 and interleukin-10 concentrations were elevated in patients with evidence of a systemic inflammatory response. However, on multiple regression analysis only interleukin-6 was significantly correlated with C-reactive protein concentrations. Following nephrectomy, the proportion of patients with an elevated C-reactive protein did not change significantly, nor did concentrations of interleukin-6 normalise. In contrast there was a trend towards significance in the elevation of Interleukin-10 concentrations following nephrectomy. It has been previously suggested that the presence of the systemic inflammatory response in patients with renal cancer is due to secretion of pro-inflammatory cytokines by the tumour itself. It appears clear from the investigations carried out during the course of this thesis that the presence of systemic inflammatory response appears unlikely to be solely be determined by the tumour, but may be as a result of a disordered immune response from the host

Identification and cost of adverse events in metastatic breast cancer in taxane and capecitabine based regimens.

PurposeWe sought to compare the economic impact of treatment-related adverse events (AEs) in patients with metastatic breast cancer (mBC) using taxane- or capecitabine-based treatment regimens as either first- or second-line (FL or SL) therapy in the US.MethodsWe used healthcare claims data from the Truven Health Analytics MarketScan® Commercial Databases to conduct a retrospective cohort study comparing the economic impact of AEs amongst taxane- and capecitabine-treated mBC patients in the US. We selected women diagnosed with mBC between 2008-2010 who received a taxane or capecitabine as first- or second-line (FL or SL) chemotherapy. Costs related to hospitalization, outpatient services, emergency department visits, chemotherapy and other medications were tabulated and combined to determine total healthcare costs. The incremental monthly costs associated with the presence of AEs compared to no AEs were estimated using generalized linear models, controlling for age and Charlson Comorbidity Index.ResultsWe identified 15,443 mBC patients meeting inclusion criteria. Adjusted total monthly costs were significantly higher in those who experienced AEs than in those without AEs in both lines of treatment (FL incremental cost: taxanes $1,142, capecitabine$1,817; SL incremental cost: taxanes $1,448, capecitabine$4,437). Total costs increased with the number of AEs and were primarily driven by increased hospitalization amongst those with AEs.ConclusionsAdverse events in taxane- or capecitabine-treated mBC patients are associated with significant increases in costs. Selecting treatment options associated with fewer AEs may reduce costs and improve outcomes in these patients

Soil Fungi Alter Interactions Between the Invader Centaurea Maculosa and North American Natives

Soil microbes may affect the way exotic invasive plants interact with native neighbors. We investigated the effects of soil fungi on interactions between the invasive weed Centaurea maculosa (spotted knapweed) and six species native to the intermountain prairies of the northwestern United States. We also compared the effect of C. maculosa on the composition of the soil microbial community to that of the native species. In the field, fungicide (Benomyl) reduced AM mycorrhizal colonization of C. maculosa roots by \u3e80%. Fungicide did not significantly reduce non-AM fungi. When grown alone, the biomass of C. maculosa was not affected by the fungicide application. However, depending on the combination of native competitor and fungicide, C. maculosa biomass varied from 10-fold decreases to 1.9-fold increases. In untreated soils, C. maculosa grew larger in the presence of Festuca idahoensis or Koeleria cristata than when alone. When fungicide was applied these positive effects of Festuca and Koeleria on C. maculosa did not occur. A third native grass, Pseudoroegneria spicata, had much stronger competitive effects on C. maculosa than Festuca or Koeleria, and fungicide reduced the competitive effects of Pseudoroegneria. Fungicide increased Centaurea biomass when competing with the forb Gallardia aristata. However, fungicide did not affect the way two other forbs; Achillea millefolium and Linum lewisii, interacted with C. maculosa. Rhizosphere microbial communities in the root zones of the three native bunchgrass species differed from that of C. maculosa. However, despite the strong effects of soil fungi in field interactions and differences in microbial community composition, soil biota from different plant rhizospheres did not affect the growth of C. maculosa in the absence of native competitors in greenhouse experiments. Our results suggest that successful invasions by exotic plant species can be affected by complex and often beneficial effects of local soil microbial communities. These effects were not manifest as simple direct effects, but become apparent only when native plants, invasive plants, and soil microbial communities were interacting at the same time

Policy Feedback and the Politics of the Affordable Care Act

There is a large body of literature devoted to how “policies create politics” and how feedback effects from existing policy legacies shape potential reforms in a particular area. Although much of this literature focuses on self‐reinforcing feedback effects that increase support for existing policies over time, Kent Weaver and his colleagues have recently drawn our attention to self‐undermining effects that can gradually weaken support for such policies. The following contribution explores both self‐reinforcing and self‐undermining policy feedback in relationship to the Affordable Care Act, the most important health‐care reform enacted in the United States since the mid‐1960s. More specifically, the paper draws on the concept of policy feedback to reflect on the political fate of the ACA since its adoption in 2010. We argue that, due in part to its sheer complexity and fragmentation, the ACA generates both self‐reinforcing and self‐undermining feedback effects that, depending of the aspect of the legislation at hand, can either facilitate or impede conservative retrenchment and restructuring. Simultaneously, through a discussion of partisan effects that shape Republican behavior in Congress, we acknowledge the limits of policy feedback in the explanation of policy stability and change

Escitalopram in Adolescents with Generalized Anxiety Disorder: A Double-Blind, Randomized, Placebo-Controlled Study

Background: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018. Methods: Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes. Results: Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo. Conclusions: Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing

PURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs

The Dynamics of Functional Brain Networks:Integrated Network States during Cognitive Task Performance

Higher brain function relies upon the ability to flexibly integrate information across specialized communities of brain regions, however it is unclear how this mechanism manifests over time. In this study, we use time-resolved network analysis of functional magnetic resonance imaging data to demonstrate that the human brain traverses between two functional states that maximize either segregation into tight-knit communities or integration across otherwise disparate neural regions. The integrated state enables faster and more accurate performance on a cognitive task, and is associated with dilations in pupil diameter, suggesting that ascending neuromodulatory systems may govern the transition between these alternative modes of brain function. Our data confirm a direct link between cognitive performance and the dynamic reorganization of the network structure of the brain.Comment: 38 pages, 4 figure

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) <= 2 cm: Study Protocol for a Prospective Observational Study

Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN <2 cm of diameter. Several retrospective series demonstrated that a non-operative management is safe and feasible, but no prospective studies are available. Aim of the ASPEN study is to evaluate the optimal management of asymptomatic NF-PanNEN ≤2 cm comparing active surveillance and surgery. Methods: ASPEN is a prospective international observational multicentric cohort study supported by ENETS. The study is registered in ClinicalTrials.gov with the identification code NCT03084770. Based on the incidence of NF-PanNEN the number of expected patients to be enrolled in the ASPEN study is 1,000 during the study period (2017–2022). Primary endpoint is disease/progression-free survival, defined as the time from study enrolment to the first evidence of progression (active surveillance group) or recurrence of disease (surgery group) or death from disease. Inclusion criteria are: age >18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at 68Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies

BACKGROUND. Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment