Somatic mutations in exons encoding the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are found in human lung adenocarcinomas and are associated with sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib. Nearly 90% of the EGFR mutations are either short, in-frame deletions in exon 19 or point mutations that result in substitution of arginine for leucine at amino acid 858 (L858R). To study further the role of these mutations in the initiation and maintenance of lung cancer, we have developed transgenic mice that express an exon 19 deletion mutant (EGFR ⌬L747-S752 ) or the L858R mutant (EGFR L858R ) in type II pneumocytes under the control of doxycycline. Expression of either EGFR mutant leads to the development of lung adenocarcinomas. Two weeks after induction with doxycycline, mice that express the EGFR L858R allele show diffuse lung cancer highly reminiscent of human bronchioloalveolar carcinoma and later develop interspersed multifocal adenocarcinomas. In contrast, mice expressing EGFR ⌬L747-S752 develop multifocal tumors embedded in normal lung parenchyma with a longer latency. With mice carrying either EGFR allele, withdrawal of doxycycline (to reduce expression of the transgene) or treatment with erlotinib (to inhibit kinase activity) causes rapid tumor regression, as assessed by magnetic resonance imaging and histopathology, demonstrating that mutant EGFR is required for tumor maintenance. These models may be useful for developing improved therapies for patients with lung cancers bearing EGFR mutations.[Keywords: EGFR; lung adenocarcinoma; mice; tyrosine kinase inhibitor] Supplemental material is available at http://www.genesdev.org.

Introduction In registration trials, triple therapy with telaprevir (TVR), pegylated-interferon (IFN), and ribavirin (RBV) achieved sustained virological response (SVR) rates between 64–75%, but the clinical effectiveness and economic burdens of this treatment in real-world practice remain to be determined. Methods Records of 147 patients who initiated TVR-based triple therapy at the Mount Sinai Medical Center (5/2011–12/2011) were reviewed. Direct medical costs for pre-treatment, on-treatment, and post-treatment care were calculated using data from Medicare reimbursement databases, RED Book, and Healthcare Cost and Utilization Project database. Costs are presented in 2012 US dollars. SVR (undetectable HCV RNA 24 weeks after the end-of-treatment) was determined on an intention-to-treat basis. Cost-per-SVR was calculated by dividing the median cost by the SVR rate. Results Median age of the 147 patients was 56 years [interquartile range (IQR) = 51 – 61], 68% were male, 19% were black, 11% had HIV/HCV co-infection, 36% had advanced fibrosis/cirrhosis (FIB-4 scores ≥ 3.25), 44% achieved an SVR. The total cost of care was $11.56 million. Median cost of care was $83,721 per patient (IQR=$66,652– $98,102). The median cost-per-SVR was $189,338 (IQR=$150,735 – $221,860). Total costs were TVR (61%), IFN (24%), RBV (4%), adverse event management (8%), professional fees (2%), and laboratory tests (1%). Conclusions TVR and IFN accounted for 85% of costs. Pharmaceutical prices and the low (44%) SVR rate, in this real-world study, were major contributors to the high cost-per-SVR.

Over half of patients with human immunodeficiency virus (HIV) experience diarrhea that contributes negatively to quality of life and adherence to antiretroviral therapy (ART). Opportunistic infectious agents that cause diarrhea in patients with HIV span the array of protozoa, fungi, viruses, and bacteria. With global use of ART, the incidence of diarrhea because of opportunistic infections has decreased; however, the incidence of noninfectious diarrhea has increased. The etiology of noninfectious diarrhea in patients with HIV is multifactorial and includes ART-associated diarrhea and gastrointestinal damage related to HIV infection (i.e., HIV enteropathy). A basic algorithm for the diagnosis of diarrhea in patients with HIV includes physical examination, a review of medical history, assessment of HIV viral load and CD4+ T cell count, stool microbiologic assessment, and endoscopic evaluation, if needed. For patients with negative diagnostic results, the diagnosis of noninfectious diarrhea may be considered. Pharmacologic options for the treatment of noninfectious diarrhea are primarily supportive; however, the use of many unapproved agents is based on unstudied and anecdotal information. In addition, these agents can be associated with treatment-limiting adverse events (AEs), such as drug–drug interactions with ART regimens, abuse liability, and additional gastrointestinal AEs. Currently, crofelemer, an antisecretory agent, is the only therapy approved in the USA for the symptomatic relief of noninfectious diarrhea in patients with HIV on ART.

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This 386-participant study investigated the structural and psychometric properties of the Spanish version of the Occupational Depression Inventory (ODI). Exploratory structural equation modeling bifactor analysis revealed that the ODI meets the requirements for essential unidimensionality. Measurement invariance held across our sample and the English-and French-speaking samples used in the ODI's initial validation study. Mokken scale analysis indicated that (a) the scalability of the instrument was strong, (b) no violations of monotonicity or local independence were present, and (c) invariant item ordering was sufficiently accurate. The ODI's reliability was optimal. The ODI exhibited both convergent validity and discriminant validity vis-à-vis a job-unrelated measure of depression. Furthermore, occupational depression correlated substantially, and in the expected direction, with objective cognitive performance and 10 widely studied worklife characteristics. This study suggests that the ODI's Spanish version has excellent structural and psychometric properties and can be confidently employed by occupational health specialists.

Cardiac diseases are one of the most common causes of morbidity and mortality following liver transplantation (LT). Prior studies have shown that cardiac diseases affect close to one-third of liver transplant recipients (LTRs) long term and that their incidence has been on the rise. This rise is expected to continue as more patients with advanced age and/or non-alcoholic steatohepatitis undergo LT. In view of the increasing | 2741 AJT IZZY et al.

Background Adding telaprevir to pegylated-interferon and ribavirin increased both response rates and side effects of hepatitis C virus (HCV) treatment. Aims We identified variables associated with severe anemia during telaprevir-based triple therapy. Methods An observational study was performed on 142 HCV-infected patients between June 2011 and March 2012. All subjects completed 12 weeks of telaprevir-based triple therapy or discontinued early due to anemia. Severe anemia was defined by a hemoglobin ≤8.9 g/dL; advanced fibrosis was determined by Fib-4 ≥3.25. Results The 47 (33%) patients who developed severe anemia were similar to those who did not in sex, race, and prior response to dual therapy, but they were more likely to have diabetes (23.4% vs. 6.3%, p<0.01), advanced fibrosis (46.8% vs. 29.5%, p=0.04), and a history of anemia during previous dual therapy (29.7% vs. 11.4%, p=0.02). Patients developing severe anemia were older (59 vs. 56 years, p=0.02), had lower baseline platelet counts (134 vs. 163 x109/L, p=0.04), hemoglobin (14.0 vs. 15.0 g/dL, p<0.01), estimated glomerular filtration rate (79 vs. 90 mL/min/1.73m2, p=0.03), and a higher median ribavirin/weight ratio (14.9 vs. 13.2 mg/kg, p<0.01). In multivariable logistic regression, presence of diabetes (OR=5.61, 95%CI: 1.59–19.72), Fib-4 ≥3.25 (OR=3.09, 95%CI: 1.28–7.46), higher ribavirin/weight ratio (OR=1.31 per mg/kg, 95%CI: 1.13–1.52), and lower baseline hemoglobin (OR=0.57 per g/dL, 95%CI, 0.41–0.80) were independently associated with developing severe anemia. Conclusions Severe anemia occurred in one-third of patients receiving telaprevir-based triple therapy. Risk was greater in patients with diabetes, advanced liver fibrosis, higher ribavirin/weight ratio and lower baseline hemoglobin.

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