Autophagy and nuclear morphometry are associated with histopathologic features in esophageal squamous cell carcinoma.

Less than 15% of patients with esophageal squamous cell carcinoma (ESCC) survive 5 years after diagnosis. A better understanding of the biology of these tumors and the development of clinical biomarkers is needed. Autophagy is a physiological mechanism involved in the turnover of cellular components that plays a key role in cancer. This study evaluated the differential levels of three key regulators of autophagy (SQSTM1, MAP1LC3B, and BECN1) in patients with ESCC, associating autophagy with histopathologic features, including the grade of differentiation, mitotic rate, inflammation score, and the intensity of tumor-infiltrating lymphocytes. Nuclear morphometry of the tumor parenchyma was also assessed, associating it with autophagy and histopathology. All three markers significantly increased in patients with ESCC compared to the control group. Based on the mean expression of each protein in the control group, 57% of patients with ESCC had high levels of all three markers compared to control patients (14%). The most frequent profiles found in ESCC were BECNhigh/MAP1LC3high and BECNhigh/SQSTM1high. According to the TCGA database, we found that the main autophagy genes were upregulated in ESCC. Moreover, high levels of autophagy markers were associated with a poor prognosis. Considering nuclear morphometry, ESCC samples showed a significant reduction in nuclear area, which was strongly negatively correlated with autophagy. Finally, the percentage of normal nuclei was associated with tumor differentiation, while poorly differentiated tumors showed lower SQSTM1 levels. ESCC progression may involve increased autophagy and changes in nuclear structure, associated with clinically relevant histopathological features. KEY MESSAGES: Autophagy markers are co-increased in primary ESCC. Autophagy negatively correlates with nuclear morphometry in ESCC parenchyma. Autophagy and nuclear morphometry are associated with histopathological features. Autophagy is increased in ESCC-TCGA database and associated with poor prognosis.

Predicting dry weight in patients with cirrhotic ascites undergoing large-volume paracentesis.

BACKGROUND & AIMS: Ascites impairs the correct diagnosis and nutritional management in patients with cirrhosis, because the body weight, which is needed for nutritional assessment and calculation of nutritional needs, is overestimated. To adjust the weight in patients with ascites, dietetic guidances indicate substracting 2.2-14 kg or 5-15% of the measured body weight according to the degree of ascites, however, there is a lack of evidence to substantiate these values. The aim of this study was to develop new prediction equations to estimate the dry weight, comparing them with the currently used weight adjustments in patients with refractory cirrhotic ascites. METHODS: Cross-sectional study, that included patients with decompensated cirrhosis undergoing large-volume paracentesis. Patients were submitted to nutritional risk screening, nutritional assessment, and anthropometric measurements that included body weight, abdominal circumference (both measured before and after paracentesis) height, and upper mid-arm circumference. The volume of ascitic fluid drained was also registered. For the predictions of dry weight, linear regression models were performed using as predictor variables: height, pre-paracentesis weight, pre-paracentesis abdominal circumference, or mid-upper arm circumference, and as response variable: post-paracentesis weight. The capacity of these models to predict the post-paracentesis weight was evaluated by comparing it with the currently used predictions through the intraclass correlation coefficient (ICC) and the mean squared error (MSE). RESULTS: Nineteen patients were included, 15 male, and 18 with high nutritional risk and malnutrition. The difference between post-paracentesis weight and pre-paracentesis weight was -5.0 (-3.6 to -9.9) kg, similar to ascitic fluid volume drained. Two equations were developed to predict post-paracentesis weight. ICC values showed that both prediction equations were strongly correlated (r > 0.94) with post-paracentesis weight. Our models also showed lower MSEs (<17.97), compared with the current predictions (MSEs <64.19, when the pre-paracentesis weight is adjusted from absolute values and MSEs <33.24 when adjusted from percentage values), indicating a more accurate prediction. CONCLUSION: The predictive equations from this study may be better options for dry weight estimation in patients with refractory cirrhotic ascites since they showed higher reliability compared to the currently used weight adjustment. External validation in a larger sample is still needed to confirm the clinical applicability of these equations.

High Prevalence of Multidrug Resistant Bacteria in Cirrhotic Patients with Spontaneous Bacterial Peritonitis: Is It Time to Change the Standard Antimicrobial Approach?

Introduction: Spontaneous bacterial peritonitis (SBP) has a deleterious clinical impact in end-stage liver disease, and multidrug resistance has increased, raising concern about effectiveness of traditional antibiotic regimens. Patients and Methods: Single-center retrospective study of ascitic fluid infections in cirrhotic patients. Results: We analyzed medical records related to 2129 culture-positive ascitic fluid and found 183 samples from cirrhotic patients. There were 113 monobacterial SBP cases from 97 cirrhotic patients; 57% of patients were male; hepatitis C and alcohol were the main etiologies for cirrhosis. Multidrug resistant bacteria were isolated in 46.9% of SBP samples, and third-generation cephalosporin and quinolone resistant reached 38.9% and 25.7% of SBP cases. Conclusion: SBP due to multidrug resistant bacteria is a growing problem, and one should consider reported resistance profiles for the decision-making process of empirical first-line treatment prescription.

Bosentan Inducing Autoimmune Hepatitis in a Patient with Idiopathic Pulmonary Arterial Hypertension.

A 41-year-old woman diagnosed with idiopathic pulmonary hypertension presented symptoms despite the use of vasodilators, requiring treatment with bosentan. Previously, the patient had no signs of autoimmunity and had normal liver function. After three years of bosentan use, aminotransferase levels increased, without improvement after bosentan suspension, leading to complementary investigation. The diagnosis of autoimmune hepatitis was confirmed by biopsy, already in the stage of cirrhosis. In conclusion, in case of aminotransferase levels that remain persistently elevated, despite the reduction in doses and/or suspension of bosentan, autoimmune hepatitis must be investigated and treated urgently due to possibly rapid progression to cirrhosis..

Urinary Concentrations of Polycyclic Aromatic Hydrocarbon Metabolites in Maté Drinkers in Rio Grande do Sul, Brazil.

Background: Consumption of maté, an infusion of the herb Ilex paraguariensis (yerba maté), is associated with increased risk of esophageal squamous cell carcinoma (ESCC), but the carcinogenic mechanism is unclear. Commercial brands of yerba maté contain high levels of carcinogenic polycyclic aromatic hydrocarbons (PAHs), which are acquired during the traditional drying process. The purpose of this study was to characterize exposure to PAHs in maté drinkers over a wide range of maté consumption.Methods: We recruited 244 adults who answered a questionnaire and collected a fasting spot urine specimen. We quantified urinary concentrations of seven PAH metabolites and assessed associations between self-reported recent maté consumption and urinary PAH metabolites by multivariate regression.Results: Recent maté consumption showed a significant dose-response association with 6 of 7 PAH metabolites in unadjusted models (Ptrend < 0.05). After adjustment for creatinine and potential confounders, concentrations of 2-naphthol, 1-hydroxyphenanthrene, and the sum of 2- and 3-hydroxyphenanthrene remained significantly associated with recent maté intake. The sum of the urinary concentrations of the phenanthrene metabolites was similar or higher among maté drinkers who did not smoke than among smokers who did not drink matéConclusions: Urinary concentrations of PAH metabolites were significantly associated with self-reported amounts of recent maté intake, and drinking maté increased urinary concentrations of some PAH metabolites as much as smoking cigarettes.Impact: Drinking maté is a source of exposure to potentially carcinogenic PAHs, consistent with the hypothesis that the PAH content of maté may contribute to the increased risk of ESCC in maté drinkers. Cancer Epidemiol Biomarkers Prev; 27(3); 331-7. ©2017 AACR.

Stepwise expression of CDKN2A and RB1 proteins in esophageal mucosa from patients at high risk for squamous cell carcinoma.

Squamous cell carcinoma of the esophagus is a lethal cancer and carries a poor prognosis because of late diagnosis. Identification of molecular markers may aid early diagnosis. We assessed the expression of CDKN2A/RB1 in the esophageal mucosa and its association with the histology. Esophageal biopsies were collected from 38 patients with no esophageal lesion (group 1), from iodine-negative areas of 108 alcoholics/smokers (group 2), and from tumor and nontumor areas in 41 patients with squamous cell carcinoma (group 3). The histologic diagnosis was compared with immunoexpression of CDKN2A/RB1. In group 1, histology showed normal mucosa/mild esophagitis and no expression of CDKN2A/RB1. In groups 2 and 3, the diagnosis was: normal mucosa (38.4%), esophagitis (44.4%), dysplasia and carcinoma in situ (2.8%), and carcinoma (14.3%). The immunoexpression of CDKN2A/RB1 increased in a stepwise manner from the normal mucosa, to esophagitis, dysplasia/carcinoma in situ, and carcinoma (P<0.01). CDKN2A/RB1 was not expressed in the esophageal mucosa of patients without risk factors. p16/pRb expression increased in a stepwise manner, according to the severity of histologic lesions, in biopsies from patients exposed to risk factors or with carcinoma. Esophageal mucosa exposed to risk factors with the expression of those proteins may be at risk for malignant transformation.

Esophageal squamous cell carcinoma - precursor lesions and early diagnosis.

Squamous cell carcinoma of the esophagus (SCCE) carries a poor prognosis due to late diagnosis. Early detection is highly desirable, since surgical and endoscopic resection offers the only possible cure for esophageal cancer. Population screening should be undertaken in high risk areas, and in low or moderate risk areas for people with risk factors (alcoholics, smokers, mate drinkers, history of head and neck cancer, achalasia and lye stricture of the esophagus). Esophageal balloon cytology is an easy and inexpensive sampling technique, but the current methods are insufficient for primary screening due to sampling errors. Conventional endoscopy with biopsy remains the standard procedure for the identification of pre-malignant and early malignant changes in esophageal mucosa and endoscopic detection. It may be enhanced by several techniques such as dye and optic chromoendoscopy, magnifying endoscopy, and optical-based spectroscopic and imaging modalities. Since more than 80% of SCCE deaths occur in developing countries, where expensive techniques such as narrow band imaging (NBI) and autofluorescence imaging are unavailable, the most cost-effective tool for targeting biopsies may be Lugol dye chromoendoscopy, since it is easy, accurate, inexpensive and available worldwide. In ideal conditions, or in developed countries, is it reasonable to think that optimal detection will require a combination of techniques, such as the combination of Lugol's chromoendoscopy and NBI to identify esophageal areas that require further characterization by a high resolution technique. The efficacy and cost-effectiveness will determine whether these modalities will become part of standard endoscopy practice.