Patients with persistent or recurrent neutropenic fevers at risk of invasive fungal disease (IFD) are treated empirically with antifungal therapy (AFT). Early treatment using a diagnostic-driven (DD) strategy may reduce clinical and economic burdens. We compared costs and outcomes of both strategies from a UK perspective.
An empirical strategy with conventional amphotericin B deoxycholate (C-AmB), liposomal amphotericin B (L-AmB), or caspofungin was compared with a DD strategy (initiated based on positive ELISA results for galactomannan antigen) and/or positive results for Aspergillus species on polymerase chain reaction assay) using C-AmB, voriconazole, or L-AmB in a decision-analytic model. Rates of IFD incidence, overall mortality, and IFD-related mortality in adults expected to be neutropenic for ≥10 days were obtained. The empirical strategy was assumed to identify 30% of IFD and targeted AFT to improve survival by a hazard ratio of 0.589. AFT-specific adverse events were obtained from a summary of product characteristics. Resource use was obtained, and costs were estimated by using standard UK costing sources. All costs are presented in 2012 British pounds sterling.
Total costs were 32% lower for the DD strategy (£1561.29) versus the empirical strategy (£2301.93) due to a reduced incidence of adverse events and decreased use of AFT. Administration of AFT was reduced by 41% (DD strategy, 74 of 1000; empirical strategy, 125 of 1000), with similar survival rates.
This study suggests that a DD strategy is likely to be cost-saving versus empirical treatment for immunocompromised patients with persistent or recurrent neutropenic fevers.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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Hepatitis C virus (HCV) infection is a worldwide healthcare problem; however, traditional treatment methods have failed to cure all patients, and HCV has developed resistance to new drugs. Systems biology-based analyses could play an important role in the holistic analysis of the impact of HCV on hepatocellular metabolism. Here, we integrated HCV assembly reactions with a genome-scale hepatocyte metabolic model to identify metabolic targets for HCV assembly and metabolic alterations that occur between different HCV progression states (cirrhosis, dysplastic nodule, and early and advanced hepatocellular carcinoma (HCC)) and healthy liver tissue. We found that diacylglycerolipids were essential for HCV assembly. In addition, the metabolism of keratan sulfate and chondroitin sulfate was significantly changed in the cirrhosis stage, whereas the metabolism of acyl-carnitine was significantly changed in the dysplastic nodule and early HCC stages. Our results explained the role of the upregulated expression of BCAT1, PLOD3 and six other methyltransferase genes involved in carnitine biosynthesis and S-adenosylmethionine metabolism in the early and advanced HCC stages. Moreover, GNPAT and BCAP31 expression was upregulated in the early and advanced HCC stages and could lead to increased acyl-CoA consumption. By integrating our results with copy number variation analyses, we observed that GNPAT, PPOX and five of the methyltransferase genes (ASH1L, METTL13, SMYD2, TARBP1 and SMYD3), which are all located on chromosome 1q, had increased copy numbers in the cancer samples relative to the normal samples. Finally, we confirmed our predictions with the results of metabolomics studies and proposed that inhibiting the identified targets has the potential to provide an effective treatment strategy for HCV-associated liver disorders.

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In this paper, we discuss statistical inference for a 2 × 2 table under inverse sampling, where the total number of cases is fixed by design. We demonstrate that the exact unconditional distributions of some relevant statistics differ from the distributions under conventional sampling, where the sample size is fixed by design. This permits us to define a simple unconditional alternative to Fisher’s exact test. We provide an asymptotic argument including simulations to demonstrate that there is little power loss associated with the alternative test when the expected event rates are very small. We then apply the method to design a clinical trial in cataract surgery, where a rare side effect occurs in one in 1000 patients. The objective of the trial is to demonstrate that adjuvant treatment with an antibiotic will reduce this risk to one in 2000. We use an inverse sampling design and demonstrate how to set this up in a sequential manner. Particularly simple stopping rules can be defined when using the unconditional alternative to Fisher’s exact test.
Copyright © 2015 John Wiley & Sons, Ltd.

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Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti-Ang-2-neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti-colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells.

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Telotristat etiprate, a tryptophan hydroxylase inhibitor, was previously evaluated in a Phase II randomized, placebo-controlled clinical trial in patients with carcinoid syndrome (CS) and diarrhea not adequately controlled by octreotide. The objective of the current study was to characterize the symptom experiences of patients participating in that trial.
Consenting patients participated in one-on-one, qualitative interviews focused on eliciting symptoms they had experienced in association with their CS diagnosis and recollection of symptom changes they experienced while participating in the Phase II trial.
Among the 23 patients who participated in the previous 4-week dose-escalation study, 16 were eligible for interviews and 11 participated in the present study. The median time from study completion to the interview was 31 months; 4 of 11 patients were receiving telotristat etiprate in a follow-up, open-label trial at the time of interview. All of the patients (100%) described diarrhea as a symptom of CS, with effects on the emotional, social, and physical aspects of their lives. Improvement in diarrhea during the study was described by 82% of participants, and was very impactful in several patients. Results led to the design and implementation of a larger interview program in Phase III and helped to establish a definition of clinically meaningful change for the clinical development program.
The diarrhea associated with CS can have a large impact on daily lives, and patient interviews can characterize and capture clinically meaningful improvements with treatment. ClinicalTrials.gov Identifier: NCT00853047.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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