Citations

We have evaluated the renal blood flow (RBF) response of cirrhotic rats to endothelium-dependent [acetylcholine (ACh)] and -independent [sodium nitroprusside (NP)] vasodilators. In anesthetized rats, ACh dose dependently increased RBF, but the response of the cirrhotic rats (n = 6) was significantly higher than that of the controls (n = 6). NP also increased RBF in a dose-dependent manner, but there were no differences between both groups. NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg i.v.) significantly reduced the responses to ACh in both groups, but those of the cirrhotic rats were still higher than those of the controls. In experiments performed in isolated perfused kidneys, preconstricted with phenylephrine, dose-response curves for ACh and NP were obtained in the presence of indomethacin. Both ACh and NP decreased renal perfusion pressure dose dependently, but only the response of the cirrhotic rats (n = 5) to ACh was significantly higher than that of the controls (n = 5). L-NAME (100 microM) significantly reduced the responses to ACh and increased those of NP and abolished the differences between groups, except at the high dose of ACh. These results demonstrate an elevated endothelium-dependent vasodilator response in the cirrhotic kidney, which is eliminated by combined prostaglandin and nitric oxide (NO) synthesis inhibition and suggest that increased intrarenal activity of NO may be contributing to the renal alterations of liver cirrhosis.

Background The angiographic evaluation of previously coiled aneurysms can be difficult yet remains critical for determining re-treatment. Objective The main objective of this study was to determine the inter-rater reliability for both the Raymond Scale and per cent embolization among a group of neurointerventionalists evaluating previously embolized aneurysms. Methods A panel of 15 neurointerventionalists examined 92 distinct cases of immediate post-coil embolization and 1 year post-embolization angiographs. Each case was presented four times throughout the study, along with alterations in demographics in order to evaluate intra-rater reliability. All respondents were asked to provide the per cent embolization (0–100%) and Raymond Scale grade (1-3) for each aneurysm. Inter-rater reliability was evaluated by computing weighted kappa values (for the Raymond Scale) and intraclass correlation coefficients (ICC) for per cent embolization. Results 10 neurosurgeons and 5 interventional neuroradiologists evaluated 368 simulated cases. The agreement among all readers employing the Raymond Scale was fair (κ=0.35) while concordance in per cent embolization was good (ICC=0.64). Clinicians with fewer than 10 years of experience demonstrated a significantly greater level of agreement than the group with greater than 10 years (κ=0.39 and ICC=0.70 vs κ=0.28 and ICC=0.58). When the same aneurysm was presented multiple times, clinicians demonstrated excellent consistency when assessing per cent embolization (ICC=0.82), but moderate agreement when employing the Raymond classification (κ=0.58). Conclusions Identifying the per cent embolization in previously coiled aneurysms resulted in good inter- and intra-rater agreement, regardless of years of experience. The strong agreement among providers employing per cent embolization may make it a valuable tool for embolization assessment in this patient population.

Abstract Background and aims Benign gastrointestinal (GI) strictures are often refractory to standard endoscopic interventions. Fully covered coaxial lumen-apposing metal stents (LAMS) have emerged as a novel therapy for these strictures. The aim of this study was to evaluate the safety and efficacy of LAMS for refractory GI strictures. Patients and methods A retrospective analysis was performed for patients who underwent LAMS placement for benign luminal strictures in three US centers between January 2014 and December 2016. The primary outcomes were technical success and initial clinical success of LAMS placement. Secondary outcomes were stent migration, rate of re-intervention, and adverse events. Results A total of 49 patients underwent 56 LAMS placement procedures. Previous treatment had failed in 39 patients (79.6 %), and anastomotic strictures were the indication in 77.6 % (38/49), with the most common site being gastrojejunal (34.7 % [17/49]). Technical success was achieved in all procedures and initial clinical success was achieved in 96.4 % of all procedures (54/56). Patient initial clinical success was 95.9 % (47/49). Stent migration occurred in 17.9 % of procedures, and was more likely to occur at sites in the lower GI tract (P = 0.02). The mean stent dwell time was 100.6 days, and the mean follow-up was 169.8 days. Minor adverse events, not requiring hospitalization, occurred in 33.9 % of procedures, including subsequent stricture progression (10.7 %). In cases where LAMS were removed, mean follow-up time was 102.2 days. The re-intervention rate was 75 % at 300 days follow-up after stent removal. Of the LAMS placed at anastomotic strictures, 36.4 % required re-intervention, with approximately two-thirds of these re-interventions requiring placement of a new stent or surgery. Conclusion LAMS placement was successful for the management of refractory GI strictures, with good technical and initial clinical success rates. However, re-intervention rates after LAMS removal were high, and many strictures were not resolved by an extended period of stenting with these coaxial stents. LAMS placement offers additional therapeutic options and in selected cases might be considered a destination therapy for patients with recalcitrant benign strictures.

Abstract Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier function and increases susceptibility to infections. Herein, we hypothesized that somatic mutations together with cigarette smoke create a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from controls (n=33) or cancer cases (n=143), we conducted 16S rRNA gene sequencing (MiSeq), with RNA-seq data from lung cancer cases in The Cancer Genome Atlas (n=1112) serving as the validation cohort. We demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue, indicating a shift in the overall microbial community in lung cancer patients as compared to those without cancer. Lung cancer cases were classified by the relative abundance of two taxa, Variovorax and Streptococcus, with an increase in Variovorax abundance in tumors as compared to non-tumor adjacent paired lung tissue (FDR corrected P=0.013). The species of Variovorax was identified histologically, and also by two additional 16S rRNA strategies (Resphera Insight analysis and PacBio sequencing). A group of taxa were associated with squamous cell carcinoma (SCC), of which Acidovorax were enriched in smokers (P =0.0013). Further, these taxa, including Acidovorax, exhibited higher abundance among the subset of SCC cases with TP53 mutations, an association not seen in adenocarcinomas (AD). Therefore, we observed a microbiome-gene and a microbiome-exposure interaction in SCC lung cancer tissue. Together, these results open the door for future biomarker research that could be used to improve screening and direct mechanistic studies of lung cancer therapy. Citation Format: Leigh Greathouse, James White, Valery Bliskovsky, Ashley Vargas, Eric Polley, Elise Bowman, Mohammed Khan, Ana Robles, Brid Ryan, Amiran Dzutsev, Giorgio Trinchieri, Marbin Pineda, Sven Bilke, Paul Meltzer, Marina Walther-Antonio, Garth Ehrlich, Joshua Mell, Joshua Earl, Sergey Balashov, Archana Bhat, Alex Valm, Clayton Deming, Sean Conlan, Julia Oh, Julie Segre, Curtis Harris. Microbiome-TP53 gene interaction in human lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4925. doi:10.1158/1538-7445.AM2017-4925

Pulmonary vein stenosis (PVS) is a luminal narrowing of extrapulmonary pulmonary veins. In pediatric patients, it arises following repair of congenital heart disease, particularly anomalous pulmonary venous return; in lung disease, especially prematurity; and rarely in isolation. The etiology is unknown and the course often fatal without lung transplantation. We hypothesized that systematic clinicopathologic review of pediatric PVS could provide further pathogenic insight. We included patients who underwent first resection of pulmonary venous tissue for symptomatic PVS at our pediatric referral center from 1995 to 2014. Clinical records and hematoxylin and eosin slides were reviewed. Subsets were immunostained for smooth muscle actin, Ki-67, β-catenin, estrogen receptor, and other markers and analyzed forUSP6gene rearrangement. A total of 97 patients (57% male; median age: 6 mo) were identified. Overall, 59 (61%) had prior congenital heart disease repair, 35 involving pulmonary vein manipulation. Samples included 213 separate anatomic sites (median: 2/patient). Histologically, all showed sparsely cellular intimal expansion composed of haphazardly arranged fibroblasts with slender nuclei in myxoid matrix. This tissue merged with underlying collagen. Most samples had a variably continuous sheath of cardiomyocytes. Ancillary tests supported a reactive fibroblastic proliferation; in particular, fibroblasts showed cytoplasmic β-catenin localization, no estrogen receptor expression, and noUSP6rearrangement. At last follow-up (mean: 2.3 y), 46% of patients had died of disease. Pediatric PVS uniformly consists of a paucicellular fibrointimal proliferation, irrespective of clinical scenario. It may be best conceived of as a form of reactive hyperplasia. As with other forms of vascular remodeling, trauma (iatrogenic or occult) is likely an inciting factor. A comprehensive understanding of the surgical pathology of PVS may further inform therapeutic strategies in this lethal disease.