Citations

Ten ongoing studies designed to test the possibility that extracellular RNAs may serve as biomarkers in human disease are described. These studies, funded by the NIH Common Fund Extracellular RNA Communication Program, examine diverse extracellular body fluids, including plasma, serum, urine and cerebrospinal fluid. The disorders studied include hepatic and gastric cancer, cardiovascular disease, chronic kidney disease, neurodegenerative disease, brain tumours, intracranial haemorrhage, multiple sclerosis and placental disorders. Progress to date and the plans for future studies are outlined.

Summary Objective Epilepsy surgery is the most effective treatment for select patients with drug‐resistant epilepsy. In this article, we aim to provide an accurate understanding of the current epidemiologic characteristics of this intervention, as this knowledge is critical for guiding educational, academic, and resource priorities. Methods We profile the practice of epilepsy surgery between 1991 and 2011 in nine major epilepsy surgery centers in the United States, Germany, and Australia. Clinical, imaging, surgical, and histopathologic data were derived from the surgical databases at various centers. Results Although five of the centers performed their highest number of surgeries for mesial temporal sclerosis ( MTS ) in 1991, and three had their highest number of MTS surgeries in 2001, only one center achieved its peak number of MTS surgeries in 2011. The most productive year for MTS surgeries varied then by center; overall, the nine centers surveyed performed 48% (95% confidence interval [CI] −27.3% to −67.4%) fewer such surgeries in 2011 compared to either 1991 or 2001, whichever was higher. There was a parallel increase in the performance of surgery for nonlesional epilepsy. Further analysis of 5/9 centers showed a yearly increase of 0.6 ± 0.07% in the performance of invasive electroencephalography ( EEG ) without subsequent resections. Overall, although MTS was the main surgical substrate in 1991 and 2001 (proportion of total surgeries in study centers ranging from 33.3% to 70.2%); it occupied only 33.6% of all resections in 2011 in the context of an overall stable total surgical volume. Significance These findings highlight the major aspects of the evolution of epilepsy surgery across the past two decades in a sample of well‐established epilepsy surgery centers, and the critical current challenges of this treatment option in addressing complex epilepsy cases requiring detailed evaluations. Possible causes and implications of these findings are discussed.

Abstract Background & Aims Accumulating evidence indicates that micro RNA s play a role in a number of disease processes including the pathogenesis of liver fibrosis in hepatitis C infection. Our goal is to add to the accruing information regarding micro RNA deregulation in liver fibrosis to increase our understanding of the underlying mechanisms of pathology and progression. Methods We used next generation sequencing to profile all detectable micro RNA s in liver tissue and serum from patients with hepatitis C, stages F1–F4 of fibrosis. Results We found altered expression of several micro RNA s, in particular, miR‐182, miR199a‐5p, miR‐200a‐5p and miR‐183 were found to be significantly upregulated in tissue from liver biopsies of hepatitis C patients with advanced fibrosis, stage F3 and F4, when compared with liver biopsies from patients with early fibrosis, stages F1 and F2. We also found miR‐148‐5p, miR‐1260b, miR‐122‐3p and miR‐378i among the micro RNA s most significantly down‐regulated from early to advanced fibrosis of the liver. We also sequenced the serum micro RNA s; however, we were not able to detect significant changes in circulating micro RNA s associated with fibrosis stage after adjusting for multiple tests. Conclusions Adding measurements of tissue micro RNA s acquired during routine biopsies will continue to increase our knowledge of underlying mechanisms of fibrosis. Our goal is that these data, in combination with studies from other researchers and future long‐term studies, could be used to enhance the staging accuracy of liver biopsies and expand the surveillance of patients at increased risk for cancer and progression to advanced fibrosis.

Minocycline belongs to the family of tetracyclines, which are drugs traditionally approved as antibiotics. Based on preclinical animal cardiac models and clinical neurology trials, this drug has gained special attention as a promising cardiovascular therapeutic agent given its anti-inflammatory, antiapoptotic, antioxidant, and antienzymatic properties. This review focuses on the available evidence for minocycline as a cardioprotective drug, with special attention to mechanisms of action. Ongoing cardiovascular clinical trials are briefly discussed.

Background Surgical site infections (SSIs) result in significant patient morbidity following immediate tissue expander breast reconstruction (ITEBR). This study determined a single institution's 30-day SSI rate and benchmarked it against that among national institutions participating in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). Methods Women who underwent ITEBR with/without acellular dermal matrix (ADM) were identified using the ACS-NSQIP database between 2005 and 2011. Patient characteristics associated with the 30-day SSI rate were determined, and differences in rates between our institution and the national database were assessed. Results 12,163 patients underwent ITEBR, including 263 at our institution. SSIs occurred in 416 (3.4%) patients nationwide excluding our institution, with lower rates observed at our institution (1.9%). Nationwide, SSIs were significantly more common in ITEBR patients with ADM (4.5%) compared to non-ADM patients (3.2%, P=0.005), and this trend was observed at our institution (2.1% vs. 1.6%, P=1.00). A multivariable analysis of all institutions identified age ≥50 years (odds ratio [OR], 1.4; confidence interval [CI], 1.1-1.7), body mass index ≥30 kg/m2 vs. <25 kg/m2 (OR, 3.4; CI, 2.6-4.5), and operative time >4.25 hours (OR, 1.9; CI, 1.5-2.4) as risk factors for SSIs. Our institutional SSI rate was lower than the nationwide rate (OR, 0.4; CI, 0.2-1.1), although this difference was not statistically significant (P=0.07). Conclusions The 30-day SSI rate at our institution in patients who underwent ITEBR was lower than the nation. SSIs occurred more frequently in procedures involving ADM both nationally and at our institution.

Abstract Purpose: To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors. Experimental Design: Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation. Results: Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4–5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (&gt;6 months). Pharmacokinetic analyses showed a biphasic concentration–time profile for PF-05212384 (half-life, 30–37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies. Conclusions: These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies. Clin Cancer Res; 21(8); 1888–95. ©2015 AACR.

Cholangiocarcinoma (CCA) is a lethal hepatobiliary neoplasm originating from the biliary apparatus. In humans, CCA risk factors include hepatobiliary inflammation and fibrosis. The recently identified interleukin (IL)−1 family member, IL‐33, has been shown to be a biliary mitogen which also promotes liver inflammation and fibrosis. Our aim was to generate a mouse model of CCA mimicking the human disease. Ectopic oncogene expression in the biliary tract was accomplished by the Sleeping Beauty transposon transfection system with transduction of constitutively active AKT (myr‐AKT) and Yes‐associated protein. Intrabiliary instillation of the transposon–transposase complex was coupled with lobar bile duct ligation in C57BL/6 mice, followed by administration of IL‐33 for 3 consecutive days. Tumors developed in 72% of the male mice receiving both oncogenes plus IL‐33 by 10 weeks but in only 20% of the male mice transduced with the oncogenes alone. Tumors expressed SOX9 and pancytokeratin (features of CCA) but were negative for HepPar1 (a marker of hepatocellular carcinoma). Substantive overlap with human CCA specimens was revealed by RNA profiling. Not only did IL‐33 induce IL‐6 expression by human cholangiocytes but it likely facilitated tumor development in vivo by an IL‐6–sensitive process as tumor development was significantly attenuated in Il‐6–/– male animals. Furthermore, tumor formation occurred at a similar rate when IL‐6 was substituted for IL‐33 in this model. Conclusion: The transposase‐mediated transduction of constitutively active AKT and Yes‐associated protein in the biliary epithelium coupled with lobar obstruction and IL‐33 administration results in the development of CCA with morphological and biochemical features of the human disease; this model highlights the role of inflammatory cytokines in CCA oncogenesis. (Hepatology 2015;61:1627–1642)

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with increased cardiovascular morbidity and all‐cause mortality. Our aim was to determine the impact of preexisting AF on patients undergoing liver transplantation (LT). A retrospective case‐control study was performed. Records from patients who underwent LT between January 2005 and December 2008 at Mayo Clinic Florida were reviewed. Patients with preexisting AF were identified and matched to patients who did not have a diagnosis of AF. Thirty‐two of 717 LT recipients (4.5%) had AF before LT. These patients were compared to a control group of 63 LT recipients. Pre‐LT left ventricular hypertrophy (P = 0.03), a history of congestive heart failure (P = 0.04), and a history of stroke or transient ischemic attack (P = 0.03) were significantly more prevalent in patients with AF versus controls. Intraoperative adverse cardiac events (P = 0.02) and AF‐related adverse postoperative events (P < 0.001) were more common in the recipients with known AF. Six patients with paroxysmal AF (19%) developed chronic/persistent AF postoperatively. Graft survival and patient survival were similar in the groups. Although patients with AF had a higher incidence of intraoperative cardiac events, a higher cardiovascular morbidity rate, and a complicated postoperative course, this did not affect overall graft and patient survival. Liver Transpl 21:314–320, 2015. © 2014 AASLD.