ROMANA 3: A phase 3 safety extension study of anamorelin in advanced non-small-cell lung cancer (NSCLC) patients with cachexia

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Background: Cancer anorexia-cachexia is a debilitating condition frequently observed in NSCLC patients, characterized by decreased body weight, reduced food intake, and impaired quality of life. Anamorelin, a novel selective ghrelin receptor agonist, has anabolic and appetite-enhancing activities. Patients and methods: ROMANA 3 was a safety extension study of two phase 3, double-blind studies that assessed safety and efficacy of anamorelin in advanced NSCLC patients with cachexia. Patients with preserved Eastern Cooperative Oncology Group ≤ 2 after completing 12 weeks (w) on the ROMANA 1 or ROMANA 2 trials (0-12 weeks) could enroll in ROMANA 3 and continue to receive anamorelin 100 mg or placebo once daily for an additional 12w (12-24 weeks). The primary endpoint of ROMANA 3 was anamorelin safety/tolerability (12-24 weeks). Secondary endpoints included changes in body weight, handgrip strength (HGS), and symptom burden (0-24 weeks). Results: Of the 703 patients who completed ROMANA 1 and ROMANA 2, 513 patients entered ROMANA 3 (anamorelin, N = 345, mean age 62.0 years; placebo, N = 168; mean age 62.2 years). During ROMANA 3, anamorelin and placebo groups had similar incidences of treatment-emergent adverse events (TEAEs; 52.2% versus 55.7%), grade ≥ 3 TEAEs (22.4% versus 21.6%), and serious TEAEs (12.8% versus 12.6%). There were 36 (10.5%) and 23 (13.8%) deaths in the anamorelin and placebo groups, respectively; none were drug-related. Improvements in body weight and anorexia-cachexia symptoms observed in the original trials were consistently maintained over 12-24 weeks. Anamorelin, versus placebo, significantly increased body weight from baseline of original trials at all time points (P < 0.0001) and improved anorexia-cachexia symptoms at weeks 3, 6, 9, 12, and 16 (P < 0.05). No significant improvement in HGS was seen in either group. Conclusion: During the 12-24 weeks ROMANA 3 trial, anamorelin continued to be well tolerated. Over the entire 0-24w treatment period, body weight and symptom burden were improved with anamorelin

Annular pancreas: endoscopic and pancreatographic findings from a tertiary referral ERCP center

Background and Aims Annular pancreas is a congenital anomaly whereby pancreatic tissue encircles the duodenum. Current knowledge of endoscopic findings of annular pancreas is limited to small case series. The aim of this study was to describe the endoscopic and pancreatographic findings of patients with annular pancreas at a large tertiary care ERCP center. Methods This is a retrospective observational study. Our Institutional Review Board–approved, prospectively collected ERCP database was queried for cases of annular pancreas. The electronic medical records were searched for patient and procedure-related data. Results From January 1, 1994, to December 31, 2016, 46 patients with annular pancreas underwent ERCP at our institution. Index ERCP was technically successful in 42 patients (91.3%), and technical success was achieved in all 46 patients (100%) after 2 attempts, when required. A duodenal narrowing or ring was found in most patients (n = 39, 84.8%), yet only 2 (4.3%) had retained gastric contents. Pancreas divisum was found in 21 patients (45.7%), 18 of which were complete divisum. Pancreatobiliary neoplasia was the indication for ERCP in 7 patients (15.2%). Pancreatographic findings consistent with chronic pancreatitis were noted in 15 patients (32.6%) at the index ERCP. Conclusion This is the largest series describing the endoscopic and pancreatographic findings of patients with annular pancreas. We found that 45.7% of patients had concurrent pancreas divisum. Endoscopic therapy was successful in most patients at our institution after 1 ERCP, and in all patients after a second ERCP. Nearly one-third of patients had findings consistent with chronic pancreatitis at the time of index ERCP. It is unclear whether this may be a feature of the natural history of annular pancreas

Computerized Tomography of the Acute Left Upper Quadrant Pain

The purpose of this study was to evaluate the clinical utility of computerized tomography (CT) of the abdomen in the emergent setting of left upper quadrant pain. One hundred patients (average age: 45, range: 19–93 years, female: 57 %, male: 43 %) who presented to the emergency department (ED) and underwent CT scanning of abdomen with the given indication of left upper quadrant pain were included in this study. The results from CT examinations were compared to final diagnoses determined by either ED physician or clinician on a follow-up visit. Sensitivity of CT was 69 % (95 %CI: 52–83 %) for 39 patients who eventually were diagnosed with an acute abdominal abnormality. Twenty-seven patients had an acute abnormal finding on abdominal CT that represented the cause of the patient’s pain (positive predictive value of 100 %, 95 %CI: 87–100 %). Of the remaining 73 patients with negative CT report, 12 were diagnosed clinically (either in the ED or on follow-up visit to specialist) with a pathology that was undetectable on the CT imaging (negative predictive value of 83 %, 95 %CI: 73–91 %). None of the remaining 61 patients with negative CT were found to have pathology by clinical evaluation (specificity of 100 %, 95 %CI: 94–100 %). CT is a useful examination for patients with acute left upper quadrant pain in the emergency department setting with moderate sensitivity and excellent specificity

Nano-oxidation of silicon surfaces: Comparison of noncontact and contact atomic-force microscopy methods

3 pages, 4 figures.Local oxidation lithography by atomic-force microscopy is emerging as a powerful method for nanometer-scale patterning of surfaces. Here, we perform a comparative study of contact and noncontact atomic-force microscopy (AFM) oxidation experiments. The comparison of height and width dependencies on voltage and pulse duration allows establishing noncontact AFM as the optimum local oxidation method. For the same electrical conditions, noncontact AFM oxides exhibit higher aspect ratios (0.04 vs 0.02). The smallness of the liquid meniscus in noncontact AFM oxidation produces smaller oxide widths. We also report a slower oxidation rate in contact AFM oxidation. We explain this result by introducing an effective energy barrier (~0.14 eV) that includes the mechanical work done by the growing oxide against the cantilever (~0.01 eV).This work was financially supported by the Dirección General de Enseñanza Superior e Investigación (PB98-0471) and the European Commission (GR5D-CT- 2000-00349).Peer reviewe

Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms

Deep brain stimulation (DBS) is a promising therapy for patients with refractory depression. However, key questions remain with regard to which brain target(s) should be used for stimulation, and which mechanisms underlie the therapeutic effects. Here, we investigated the effect of DBS, with low- and high-frequency stimulation (LFS, HFS), in different brain regions (ventromedial prefrontal cortex, vmPFC; cingulate cortex, Cg; nucleus accumbens (NAc) core or shell; lateral habenula, LHb; and ventral tegmental area) on a variety of depressive-like behaviors using rat models. In the naive animal study, we found that HFS of the Cg, vmPFC, NAc core and LHb reduced anxiety levels and increased motivation for food. In the chronic unpredictable stress model, there was a robust depressive-like behavioral phenotype. Moreover, vmPFC HFS, in a comparison of all stimulated targets, produced the most profound antidepressant effects with enhanced hedonia, reduced anxiety and decreased forced-swim immobility. In the following set of electrophysiological and histochemical experiments designed to unravel some of the underlying mechanisms, we found that vmPFC HFS evoked a specific modulation of the serotonergic neurons in the dorsal raphe nucleus (DRN), which have long been linked to mood. Finally, using a neuronal mapping approach by means of c-Fos expression, we found that vmPFC HFS modulated a brain circuit linked to the DRN and known to be involved in affect. In conclusion, HFS of the vmPFC produced the most potent antidepressant effects in naive rats and rats subjected to stress by mechanisms also including the DRN.postprin

Dietary and Pharmacologic Manipulations of Host Lipids and Their Interaction with the Gut Microbiome in Non-Human Primates

The gut microbiome influences nutrient processing as well as host physiology. Plasma lipid levels have been associated with the microbiome, although the underlying mechanisms are largely unknown, and the effects of dietary lipids on the gut microbiome in humans are not well-studied. We used a compilation of four studies utilizing non-human primates (Chlorocebus aethiops and Macaca fascicularis) with treatments that manipulated plasma lipid levels using dietary and pharmacological techniques, and characterized the microbiome using 16S rDNA. High-fat diets significantly reduced alpha diversity (Shannon) and the Firmicutes/Bacteroidetes ratio compared to chow diets, even when the diets had different compositions and were applied in different orders. When analyzed for differential abundance using DESeq2, Bulleidia, Clostridium, Ruminococcus, Eubacterium, Coprocacillus, Lachnospira, Blautia, Coprococcus, and Oscillospira were greater in both chow diets while Succinivibrio, Collinsella, Streptococcus, and Lactococcus were greater in both high-fat diets (oleic blend or lard fat source). Dietary cholesterol levels did not affect the microbiome and neither did alterations of plasma lipid levels through treatments of miR-33 antisense oligonucleotide (anti-miR-33), Niemann–Pick C1-Like 1 (NPC1L1) antisense oligonucleotide (ASO), and inducible degrader of LDLR (IDOL) ASO. However, a liver X receptor (LXR) agonist shifted the microbiome and decreased bile acid levels. Fifteen genera increased with the LXR agonist, while seven genera decreased. Pseudomonas increased on the LXR agonist and was negatively correlated to deoxycholic acid, cholic acid, and total bile acids while Ruminococcus was positively correlated with taurolithocholic acid and taurodeoxycholic acid. Seven of the nine bile acids identified in the feces significantly decreased due to the LXR agonist, and total bile acids (nmol/g) was reduced by 62%. These results indicate that plasma lipid levels have, at most, a modest effect on the microbiome, whereas bile acids, derived in part from plasma lipids, are likely responsible for the indirect relationship between lipid levels and the microbiome

Effect of Anesthesia on Microelectrode Recordings During Deep Brain Stimulation Surgery:A Narrative Review

Deep brain stimulation (DBS) is an effective surgical treatment for patients with various neurological and psychiatric disorders. Clinical improvements rely on careful patient selection and accurate electrode placement. A common method for target localization is intraoperative microelectrode recording (MER). To facilitate MER, DBS surgery is traditionally performed under local or regional anesthesia. However, sedation or general anesthesia is sometimes needed for patients who are unable to tolerate the procedure fully awake because of severe motor symptoms, psychological distress, pain, or other forms of discomfort. The effect of anesthetic drugs on MER is controversial but likely depends on the type and dose of a particular anesthetic agent, underlying disease, and surgical target. In this narrative review, we provide an overview of the current literature on the anesthetic drugs most often used for sedation and anesthesia during DBS surgery, with a focus on their effects on MERs

Salivary Glucose Concentration and Excretion in Normal and Diabetic Subjects

The present report aims mainly at a reevaluation of salivary glucose concentration and excretion in unstimulated and mechanically stimulated saliva in both normal and diabetic subjects. In normal subjects, a decrease in saliva glucose concentration, an increase in salivary flow, but an unchanged glucose excretion rate were recorded when comparing stimulated saliva to unstimulated saliva. In diabetic patients, an increase in salivary flow with unchanged salivary glucose concentration and glucose excretion rate were observed under the same experimental conditions. Salivary glucose concentration and excretion were much higher in diabetic patients than in control subjects, whether in unstimulated or stimulated saliva. No significant correlation between glycemia and either glucose concentration or glucose excretion rate was found in the diabetic patients, whether in unstimulated or stimulated saliva. In the latter patients, as compared to control subjects, the relative magnitude of the increase in saliva glucose concentration was comparable, however, to that of blood glucose concentration. The relationship between these two variables was also documented in normal subjects and diabetic patients undergoing an oral glucose tolerance test

Benign Hepatic Nodules Mimicking Hepatocellular Carcinoma in the Setting of Fontan-associated Liver Disease: A Case Report

Fontan procedure, in which systemic circulation is redirected into pulmonary circulation by a baffle, is a palliative surgical strategy for patients born with single ventricle congenital heart disease. Hemodynamic changes secondary to Fontan procedure, also termed as Fontan physiology, result in end-organ damage, especially of the liver. Fontan-associated liver disease (FALD) represents a spectrum of pathologies ranging from mild liver fibrosis to advanced liver cirrhosis and hepatocellular carcinoma (HCC). Hepatic nodules, some of which have been documented as HCC in several case series and reports, are a recognized complicated feature of FALD. Herein, we report a case with benign hepatic nodules mimicking HCC by imaging characteristics, emphasizing the fact that arterially enhancing lesions with delayed washout appearance may reflect benign regenerative or focal nodular hyperplasia-like nodules in patients with Fontan physiology