The mechanism by which renal cell carcinoma (RCC) colonizes the lung microenvironment during metastasis remains largely unknown. To investigate this process, we grafted human RCC cells with varying lung metastatic potential in mice. Gene expression profiling of the mouse lung stromal compartment revealed a signature enriched for neutrophil-specific functions that was induced preferentially by poorly metastatic cells. Analysis of the gene expression signatures of tumor cell lines showed an inverse correlation between metastatic activity and the levels of a number of chemokines, including CXCL5 and IL8. Enforced depletion of CXCL5 and IL8 in these cell lines enabled us to establish a functional link between lung neutrophil infiltration, secretion of chemokines by cancer cells, and metastatic activity. We further show that human neutrophils display a higher cytotoxic activity against poorly metastatic cells compared to highly metastatic cells. Together, these results support a model in which neutrophils recruited to the lung by tumor-secreted chemokines build an antimetastatic barrier with loss of neutrophil chemokines in tumor cells acting as a critical rate-limiting step during lung metastatic seeding.

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SUMMARY Gastroesophageal reflux and esophageal dysmotility are common in patients with advanced lung disease and are associated with allograft dysfunction after lung transplantation. The effect of transplantation on reflux and esophageal motility is unclear. The aim of this study was to describe the changes in esophageal function occurring after lung transplantation. A retrospective cohort study was performed on lung transplant candidates evaluated at a tertiary care center between 2015 and 2016. A total of 76 patients who underwent lung transplantation had high-resolution manometry and ambulatory pH-metry before and after transplant. Demographic data, esophageal function testing results, and clinical outcomes such as pulmonary function testing were collected and analyzed using appropriate statistical tests and multivariable regression. Of the 76 patients, 59 (78%) received a bilateral transplant. There was a significant increase in esophageal contractility posttransplant, with an increase in median distal contractile integral from 1470 to 2549 mmHg cm s (P < 0.01). There were 19 patients with Jackhammer esophagus posttransplant, including 15 patients with normal motility pretransplant. Nine patients with ineffective or fragmented peristalsis pretransplant had normal manometry posttransplant. Abnormal pH-metry was observed in 35 (46%) patients pretransplant and 29 (38%) patients posttransplant (P = 0.33). Patients with gastroesophageal reflux disease posttransplant had less improvement in pulmonary function at one year, as measured by forced expiratory volume (P = 0.04). These results demonstrate that esophageal contractility increases significantly after lung transplantation, with an associated change in motility classification. In comparison, gastroesophageal reflux does not worsen, but is associated with worse pulmonary function, posttransplant.

Objectives Pegylated-interferon/ribavirin dual therapy for hepatitis C virus (HCV) has a lower sustained virologic response (SVR) rate in HIV/HCV-co-infected patients than in HCV mono-infected patients, but little is known about the relative effectiveness of teleprevir-based triple therapy in the two groups. Methods Data on 33 co-infected and 116 mono-infected patients were analyzed on an intention-to-treat basis. SVR12 was defined as undetectable HCV RNA at week-12 post-end-of-treatment, severe anemia as hemoglobin ≤89 g/L or a drop ≥45 g/L, and advanced fibrosis/cirrhosis as Fib-4 ≥3.25. All co-infected patients had well-controlled HIV. Results The groups were similar in age, gender, percentage with Fib-4 ≥3.25, and HCV viral load, but differed in previous treatment response, with more co-infected patients non responders/treatment intolerant (75.8% vs. 50.0%, <0.01). During treatment, the percentages of patients with undetectable HCV RNA were similar, but, surprisingly, tended to be higher in co-infected patients. SVR12 rates were 60.6% (co-infected) vs. 42.2% (mono-infected), p=0.06. In multivariable analysis, SVR12 was associated with HIV infection (OR: 3.55, p<0.01), African American race (OR: 0.37, p=0.03) and previous treatment response (OR: 0.46, p=0.03). Rates of severe anemia (45.5% vs. 58.6%, p=0.18) were similar in the two groups, but rash (15.2% vs. 34.5%, p=0.03) and rectal symptoms (12.1% vs. 43.1%, p<0.01) were less common in co-infected patients. Conclusions Virologic responses of co- and mono-infected patients did not differ significantly, but tended to be higher in co-infected patients, who had a 60.6% SVR12 rate. Telaprevir-based triple therapy is a promising option for co-infected patients with well-controlled HIV.

Background & Aims Guidelines recommend that patients with Helicobacter pylori (H. pylori)‐associated peptic ulcer disease (PUD) receive H. pylori eradication therapy followed by post‐treatment testing to prove eradication; however, post‐treatment testing rates are suboptimal and barriers to testing are poorly understood. Our aim was to identify factors that predicted receipt of post‐treatment testing. Methods We performed a retrospective cohort study of 152 patients with H. pylori‐associated PUD diagnosed between 2007 and 2015 at a large tertiary medical center in the United States, who received standard eradication therapy and ambulatory follow‐up within one year. The primary outcome of interest was receipt of post‐treatment testing. Logistic regression models compared post‐treatment testing rates in those diagnosed while outpatient vs inpatient, patients with vs without repeat endoscopy, and patients with vs without gastroenterology (GI) clinic follow‐up. Propensity scores controlled for age, sex, race, ulcer location, and symptom persistence. Results Among 152 patients, 67 (44%) patients received post‐treatment testing. There were significant differences in post‐treatment testing rates in those diagnosed as outpatients vs inpatients (57% vs 33%; OR 3.87, P = 0.001) and in patients with vs without GI follow‐up (62% vs 11%; OR 9.85, P < 0.0001). Conclusions The rate of testing for eradication after treatment in patients with H. pylori‐ associated PUD was low. However, this was significantly improved in patients who have GI follow‐up and whose diagnosis was made in the outpatient setting. Our study demonstrates a clear opportunity for quality improvement initiatives.

The human herpes virus 8 (HHV-8)-encoded G protein-coupled chemokine receptor (vGPCR) has been implicated in the pathogenesis of Kaposi's sarcoma (KS), particularly because of its high constitutive signaling activity. Here, we used retroviral transduction to generate vGPCR-expressing 3T3 fibroblasts that are tumorigenic in nude mice, but as expected fail to induce tumors in their immunocompetent counterparts. However, tumor fragments obtained from nude mice grow progressively in immunocompetent BALB/c mice. Unexpectedly, vGPCR-expressing cells established from grafted tumor fragments gave rise to tumors in immunocompetent mice. These tumors exhibit a striking histological resemblance to KS including plump spindle cell morphology, a high degree of vascularization and brisk mitotic activity. High expression of vGPCR was confirmed in the cell lines and tumors using a newly developed vGPCR-specific monoclonal antibody. Finally, short interfering RNA directed at vGPCR abrogated or significantly delayed tumorigenesis in mice, demonstrating that the tumor development is specifically driven by vGPCR. This novel model for vGPCR-mediated oncogenesis will contribute to our understanding of the role of vGPCR in the pathogenesis of HHV-8 and may even be important in identifying critical molecular and epigenetic changes during tumor progression in vivo.

A 22-year-old man presented with 10 years of retrosternal burning and suspected gastroesophageal reflux. Despite taking omeprazole (20 mg once daily) 30 minutes before breakfast, avoiding foods that precipitated symptoms, and sleeping with his head elevated, heartburn and regurgitation while supine continued. He reported intermittent solid-food dysphagia for 2 years but no weight loss (254-lb [115 kg] body weight); physical examination results were unremarkable.Esophagogastroduodenoscopy (EGD) revealed normal esophageal mucosa and normal biopsies. Given his persisting symptoms, an esophageal high-resolution manometry (HRM) study was performed (Table 1; eFigure in the Supplement). Answer B.Perform esophageal (Heller) myotomy and partial fundoplication. Test Characteristicsc Ineffective esophageal peristalsis (DCI<450 mm Hg/s/cm) is subcategorized as either weak (DCI 100-450 mm Hg/s/cm) or failed (DCI<100 mm Hg/s/cm).

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