Roser Ferrer

Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: A randomized double-blind study

BACKGROUND & AIMS Episodic hepatic encephalopathy is frequently precipitated by factors that induce circulatory dysfunction, cause oxidative stress-mediated damage or enhance astrocyte swelling. The administration of albumin could modify these factors and improve the outcome of hepatic encephalopathy. The aim of this study is to assess the efficacy of albumin in a multicenter, prospective, double-blind, controlled trial (ClinicalTrials.gov number, NCT00886925). METHODS Cirrhotic patients with an acute episode of hepatic encephalopathy (grade II-IV) were randomized to receive albumin (1.5g/kg on day 1 and 1.0g/kg on day 3) or isotonic saline, in addition to the usual treatment (laxatives, rifaximin 1200mg per day). The primary end point was the proportion of patients in which encephalopathy was resolved on day 4. The secondary end points included survival, length of hospital stay, and biochemical parameters. RESULTS Fifty-six patients were randomly assigned to albumin (n=26) or saline (n=30) stratified by the severity of HE. Both groups were comparable regarding to demographic data, liver function, and precipitating factors. The percentage of patients without hepatic encephalopathy at day 4 did not differ between both groups (albumin: 57.7% vs. saline: 53.3%; p>0.05). However, significant differences in survival were found at day 90 (albumin: 69.2% vs. saline: 40.0%; p=0.02). CONCLUSIONS Albumin does not improve the resolution of hepatic encephalopathy during hospitalization. However, differences in survival after hospitalization suggest that the development of encephalopathy may identify a subgroup of patients with advanced cirrhosis that may benefit from the administration of albumin.

Surgically induced weight loss by gastric bypass improves non alcoholic fatty liver disease in morbid obese patients

AIM To evaluate the effects of surgical weight loss (Roux-en-Y gastric bypass with a modified Fobi-Capella technique) on non alcoholic fatty liver disease in obese patients. METHODS A group of 26 morbidly obese patients aged 45 ± 2 years and with a body mass index > 40 kg/m(2) who underwent open surgical weight loss operations had paired liver biopsies, the first at surgery and the second after 16 ± 3 mo of weight loss. Biopsies were evaluated and compared in a blinded fashion. The presence of metabolic syndrome, anthropometric and biochemical variables were also assessed at baseline and at the time of the second biopsy. RESULTS Percentage of excess weight loss was 72.1% ± 6.6%. There was a reduction in prevalence of metabolic syndrome from 57.7% (15 patients) to 7.7% (2 patients) (P < 0.001). Any significance difference was observed in aspartate aminotransferase or alanine aminotransferase between pre and postsurgery. There were improvements in steatosis (P < 0.001), lobular (P < 0.001) and portal (P < 0.05) inflammation and fibrosis (P < 0.001) at the second biopsy. There were 25 (96.1%) patients with non alcoholic steatohepatitis (NASH) in their index biopsy and only four (15.3%) of the repeat biopsies fulfilled the criteria for NASH. The persistence of fibrosis (F > 1) was present in five patients at second biopsy. Steatosis and fibrosis at surgery were predictors of significant fibrosis postsurgery. CONCLUSION Restrictive mildly malabsorptive surgery provides significant weight loss, resolution of metabolic syndrome and associated abnormal liver histological features in most obese patients.

Twelve-Month Estrogen Levels in Premenopausal Women With Hormone Receptor–Positive Breast Cancer Receiving Adjuvant Triptorelin Plus Exemestane or Tamoxifen in the Suppression of Ovarian Function Trial (SOFT): The SOFT-EST Substudy

PURPOSE To describe estradiol (E2), estrone (E1), and estrone sulfate (E1S) levels during the first year of monthly triptorelin plus exemestane or tamoxifen and to assess possible suboptimal suppression while receiving exemestane plus triptorelin. PATIENTS AND METHODS Premenopausal patients with early breast cancer on the Suppression of Ovarian Function Trial who selected triptorelin as the ovarian suppression method and were randomly assigned to exemestane plus triptorelin or tamoxifen plus triptorelin were enrolled until the target population of 120 patients was reached. Blood sampling time points were 0, 3, 6, 12, 18, 24, 36, and 48 months. Serum estrogens were measured with a highly sensitive and specific assay. This preplanned 12-month analysis evaluated E2, E1, E1S, follicle-stimulating hormone, and luteinizing hormone levels in all patients and the proportion of patients with E2 levels greater than 2.72 pg/mL at any time point during treatment with exemestane plus triptorelin. RESULTS One hundred sixteen patients (exemestane, n = 86; tamoxifen, n = 30; median age, 44 years; median E2, 51 pg/mL; 55% prior chemotherapy) started triptorelin and had one or more samples drawn. With exemestane plus triptorelin, median reductions from baseline E2, E1, and E1S levels were consistently ≥ 95%, resulting in significantly lower levels than with tamoxifen plus triptorelin at all time points. Among patients on exemestane plus triptorelin, 25%, 24%, and 17% had an E2 level greater than 2.72 pg/mL at 3, 6, and 12 months, respectively. Baseline factors related to on-treatment E2 level greater than 2.72 pg/mL were no prior chemotherapy (P = .06), higher body mass index (P = .05), and lower follicle-stimulating hormone and luteinizing hormone (each P < .01). CONCLUSION During the first year, most patients on exemestane plus triptorelin had E2 levels below the defined threshold of 2.72 pg/mL, consistent with levels reported in postmenopausal patients on aromatase inhibitors, but at each time point, at least 17% of patients had levels greater than the threshold.

Alterations in the Common Pathway of Coagulation During Weight Loss Induced by Gastric Bypass in Severely Obese Patients

The objective of this study was to establish the relationship between the plasminogen activator inhibitor‐1 (PAI‐1), antithrombin‐III (ATIII), fibrinogen, and white blood cell (WBC) levels in severely obese patients. We analyzed various plasma parameters implicated in the intrinsic and extrinsic coagulation pathway from 34 severely obese patients before and 1, 6, and 12 months after gastric bypass. In obese people, ATIII, fibrinogen, and WBC levels were in the upper limit of the normal range, and all were higher and significantly different from nonobese people. After bariatric surgery, the ATIII level continued to be high during the first month and increased until 12 months, while fibrinogen decreased only at that time. PAI‐1 plasma protein and PAI‐1 mRNA levels in liver and adipose tissue show similar profiles and had a strong positive correlation (r = 0.576, P = 0.0003 in liver; r = 0.433, P = 0.0004 in adipose tissue). They were higher in obese patients compared with nonobese control, but tended to recover normal values 1 month after surgery. Thus, the liver and adipose tissue could be an important source of PAI‐1 protein in plasma. Gastric bypass surgery leads to a normalization of the hematological profile and a decrease in PAI‐1 levels, which entails a decrease of risk for thromboembolism in severely obese.

Bariatric surgery in morbidly obese patients improves the atherogenic qualitative properties of the plasma lipoproteins

OBJECTIVE The purpose of this study was to evaluate the effect of weight loss induced in morbidly obese subjects by Roux-en-Y gastric bypass bariatric surgery on the atherogenic features of their plasma lipoproteins. METHODS Twenty-one morbidly obese subjects undergoing bariatric surgery were followed up for up to 1 year after surgery. Plasma and lipoproteins were assayed for chemical composition and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity. Lipoprotein size was assessed by non-denaturing polyacrylamide gradient gel electrophoresis, and oxidised LDL by ELISA. Liver samples were assayed for mRNA abundance of oxidative markers. RESULTS Lipid profile analysis revealed a reduction in the plasma concentrations of cholesterol and triglycerides, which were mainly associated with a significant reduction in the plasma concentration of circulating apoB-containing lipoproteins rather than with changes in their relative chemical composition. All patients displayed a pattern A phenotype of LDL subfractions and a relative increase in the antiatherogenic plasma HDL-2 subfraction (>2-fold; P < 0.001). The switch towards predominantly larger HDL particles was due to an increase in their relative cholesteryl ester content. Excess weight loss also led to a significant decrease in the plasma concentration of oxidised LDL (∼-25%; P < 0.01) and in the total Lp-PLA2 activity. Interestingly, the decrease in plasma Lp-PLA2 was mainly attributed to a decrease in the apoB-containing lipoprotein-bound Lp-PLA2. CONCLUSION Our data indicate that the weight loss induced by bariatric surgery ameliorates the atherogenicity of plasma lipoproteins by reducing the apoB-containing Lp-PLA2 activity and oxidised LDL, as well as increasing the HDL-2 subfraction.

Soluble CD40 ligand in morbidly obese patients: effect of body mass index on recovery to normal levels after gastric bypass surgery.

IMPORTANCE In recent years, the CD40/CD40L system has been implicated in the pathophysiology of severe chronic inflammatory diseases. Recently, obesity has been described as a low chronic inflammatory disease, so this system could also be involved in the inflammatory process. OBJECTIVE To study soluble CD40 ligand (sCD40L) and other factors implicated in coagulation (plasminogen activator inhibitor 1, antithrombin III, and fibrinogen) and inflammation (C-reactive protein) in patients with morbid obesity and different body mass indexes (BMIs) (calculated as weight in kilograms divided by height in meters squared), before and after weight loss induced by bariatric surgery. DESIGN Plasma samples were obtained before and after a bariatric surgery intervention. Several inflammatory markers were then studied (sCD40L, plasminogen activator inhibitor 1, antithrombin III, and C-reactive protein). The values obtained were compared with a control group of nonobese persons. PARTICIPANTS Thirty-four morbidly obese patients undergoing gastric bypass surgery and 22 normal-weight controls matched for age and sex. INTERVENTIONS A Roux-en-Y gastric bypass was performed in morbidly obese patients. MAIN OUTCOME MEASURES Levels of sCD40L, plasminogen activator inhibitor 1, antithrombin III, fibrinogen, and C-reactive protein 12 months after bariatric surgery. RESULTS Obese men showed a tendency for decreased plasma sCD40L levels 1 year after surgery (mean [SEM], 246.5 [70.4] pg/mL before vs 82.2 [23.2] pg/mL after surgery; P < .05), whereas there were not any significant changes in obese women (285.9 [67.5] pg/mL before vs 287.0 [56.9] pg/mL after surgery). Levels of the other markers studied decreased significantly with weight loss in both sexes. However, all other studied markers tend to have higher concentrations in patients with higher BMIs, except for sCD40L, which tended to have lower concentrations in patients with BMIs higher than 55. The decreases with weight loss were lower with higher BMIs for all measurements, except for antithrombin III. CONCLUSIONS AND RELEVANCE Increased BMI, but not sex, influences recovery to normal levels for the markers studied, possibly indicating a worse prognosis.

Behavior of chemiluminescent assays to measure serum testosterone during androgen deprivation therapy.

DOI: 10.1111/iju.13180 PCa guidelines recommend ST measurement during ADT in order to evaluate its efficacy and to diagnose the CR status. Regulatory agencies and PCa guidelines consider 50 ng/dL as the castration level of ST, although some studies suggest that lower levels are associated with better outcomes of the disease. During the 1980s, the FDA established the castration level of ST at 50 ng/dL, based on studies carried out in patients who had undergone surgical castration. This level corresponded to the LLOQ from the RIAs that had been used so far. In 2000, using a recently introduced CLIA, Oefelein et al. redefined the castration level of ST at 20 ng/dL in a group of 35 patients who had undergone surgical castration. The median level of ST was 15 ng/dL and the range 2–30 ng/dL. Surprisingly the level selected by the author corresponded to the 75th percentile of the distribution. In 2007, Morote et al. also using a CLIA declared 32 ng/dL to be “the castrate level of ST with clinical impact” because it represented the lowest level of ST capable of significantly discriminating the progression-free survival of CR in a group of 73 non-metastatic PCa patients subjected to LHRH agonist. Nowadays, CLIAs, which are usually integrated in automated platforms, are widely used in clinical practice to measure ST given that they are sensitive, fast and inexpensive. However CLIAs have a disturbing lack of accuracy and reproducibility, especially at low levels. That is why since 2007 the American Endocrine Society recommends only LC/GC MSMS to measure ST. These methods extract the testosterone in an initial step, avoiding its overdetection caused by contamination mainly with other steroids, and MSMS ensures an accurate and reproducible measurement in a second step. However, direct CLIAs continue to be the most widely used method to determine ST in clinical practice. Because of a recent change of the platforms used in our reference laboratory and the lack of information about the behavior of CLIAs to measure ST in PCa patients undergoing ADT, we carried out a prospective study in order to evaluate two commercial CLIAs. Between July and December 2015, ST measurement was requested in 249 patients with histologically confirmed PCa undergoing continuous LHRH agonist treatment as part of their routine control. Blood collection was carried out between 08.00 and 10.00 hours, and two aliquots of serum were processed in the automated Cobas 8000 (Roche Diagnostics Inc., Indianapolis, IN, USA) (PC8000) and the Advia-Centaur XPi (Siemens, Munich, Germany) (PA-CXPi) platforms, both using CLIA to measure ST directly. The LLOQ were 2.5 and 10 ng/dL, respectively. According to the manufacturers’ information, the intra-assay coefficients of variation ranged between 1.7% and 4.6% in the PC8000, and between 2.3% and 6.2% in PA-CXPi. The mean age of the study group was 74 years (range 48–89 years). ADT was indicated as the primary treatment in 89 patients (35.7%) with metastatic PCa, 118 (47.4%) patients who were treated with radiation therapy and 42 (16.9%) patients having a high risk of dissemination failure after primary treatment of PCa. The average period of LHRH agonist treatment was 19.6 months (range 4–57 months). The study was carried out in accordance with the ethical standards of the Helsinki Declaration II, and written informed consent was obtained. The levels of ST measured in the PC8000 were significantly lower than those measured in the PA-CXPi, P < 0.001, and the correlation between both measurements was only moderate, r = 0.55. The median levels and ranges were 7.8 ng/dL (range <2.5–54.6 ng/dL) and 33.4 ng/dL (range <10–91.6 ng/dL), respectively. The 95th percentiles corresponded to 34.6 and 75.9 ng/dL, respectively. These levels were below 20 ng/dL, between 20 and 50 ng/dL, and above 50 ng/dL in 193 (77.5%), 54 (21.7%) and two (0.8%) cases in the PC8000, and 62 (24.9%), 134 (53.8%) and 53 (21.3%) cases in the PA-CXPi (Fig. 1). The present study highlights the different behavior of direct CLIAs to measure ST in PCa patients undergoing ADT. This fact could compromise the ADT efficacy evaluation as well as the diagnosis of CR. As the automated CLIAs continue to be widely used to determine ST, because LC/GC MSMS technology is not available in most clinical laboratories, a careful selection of the CLIA used to measure ST in PCa patients under ADT is recommended.

Morbidly “Healthy” Obese Are Not Metabolically Healthy but Less Metabolically Imbalanced Than Those with Type 2 Diabetes or Dyslipidemia

BackgroundWe have investigated the differences between metabolically “healthy” morbidly obese patients and those with comorbidities.Materials and MethodsThirty-two morbidly obese patients were divided by the absence (“healthy”: DM−DL−) or presence of comorbidities (dyslipidemic: DM−DL+, or dyslipidemic and with type 2 diabetes: DM+DL+). We have studied various plasma parameters and gene expression adipose tissue, before and after gastric bypass.ResultsThe group DM+DL+ tends to have lower values than the other two groups for anthropometric parameters. Regarding the satiety parameters, only leptin (p = 0.0024) showed a significant increase with comorbidities. Lipid parameters showed significant differences among groups, except for phospholipids and NEFA. For insulin resistance parameters, only glucose (p < 0.0001) was higher in DM+DL+ patients, but not insulin or homeostasis model assessment of insulin resistance (HOMA-IR). The gene expression of adiponectin, insulin receptor (INSR) and glucose receptor-4 (GLUT4), in the subcutaneous fat, decreased in all groups vs. a non-obese control. Interleukin-6 (IL6) and the inhibitor of plasminogen activator type 1 (PAI-1) genes decreased only in DM−DL+ and DM+DL+, but not in “healthy” patients. Leptin increased in all groups vs. the non-obese control. The visceral fat from DM+DL+ patients showed a sharp decrease in adiponectin, GLUT4, IL6 and PAI-1. All parameters mentioned above improved very significantly by surgery, independent of the occurrence of comorbidities.ConclusionsThe morbidly obese “healthy” individual is not really metabolically healthy, but morbidly obese individuals with diabetes and dyslipidemia are more metabolically imbalanced.

Decreased lipases and fatty acid and glycerol transporter could explain reduced fat in diabetic morbidly obese.

The possible differences were investigated in 32 morbidly obese patients depending on whether they were “healthy” or had dyslipidemia and/or type 2 diabetes.

Eficacia del índice de salud prostática para identificar cánceres de próstata agresivos. Una validación institucional

INTRODUCTION New generations of tumor markers used to detect prostate cancer (PCa) should be able to discriminate men with aggressive PCa of those without PCa or nonaggressive tumors. The objective of this study has been to validate Prostate Health Index (PHI) as a marker of aggressive PCa in one academic institution. METHODS PHI was assessed in 357 men scheduled to prostatic biopsy between June of 2013 and July 2014 in one academic institution. Thereafter a subset of 183 men younger than 75 years and total PSA (tPSA) between 3.0 and 10.0 ng/mL, scheduled to it first prostatic biopsy, was retrospectively selected for this study. Twelve cores TRUS guided biopsy, under local anaesthesia, was performed in all cases. Total PSA, free PSA (fPSA), and [-2] proPSA (p2PSA) and prostate volume were determined before the procedure and %fPSA, PSA density (PSAd) and PHI were calculated. Aggressive tumors were considered if any Gleason 4 pattern was found. PHI was compared to %fPSA and PSAd through their ROC curves. Thresholds to detect 90%, 95% of all tumors and 95% and 100% of aggressive tumors were estimated and rates of unnecessary avoided biopsies were calculated and compared. RESULTS The rate of PCa detection was 37.2% (68) and the rate of aggressive tumors was 24.6% (45). The PHI area under the curve was higher than those of %fPSA and PSAd to detect any PCa (0.749 vs 0.606 and 0.668 respectively) or to detect only aggressive tumors (0.786 vs 0.677 and 0.708 respectively), however, significant differences were not found. The avoided biopsy rates to detect 95% of aggressive tumors were 20.2% for PHI, 14.8% for %fPSA, and 23.5% for PSAd. Even more, to detect all aggressive tumors these rates dropped to 4.9% for PHI, 9.3% for %fPSA, and 7.9% for PSAd. CONCLUSIONS PHI seems a good marker to PCa diagnosis. However, PHI was not superior to %fPSA and PSAd to identify at least 95% of aggressive tumors.