Rerouting cardiovascular management following gastric bypass surgery: Dose optimization of carvedilol using population-based analysis.

AIMS: A population-based pharmacokinetic (PK) modeling approach (PopPK) was used to investigate the impact of Roux-en-Y gastric bypass (RYGB) on the PK of (R)- and (S)-carvedilol. We aimed to optimize carvedilol dosing for these patients utilizing a pharmacokinetic/pharmacodynamic (PK/PD) link model. METHODS: PopPK models were developed utilizing data from 52 subjects, including nonobese, obese, and post- RYGB patients who received rac- carvedilol orally. Covariate analysis included anthropometric and laboratory data, history of RYGB surgery, CYP2D6 and CYP3A4 in vivo activity, and relative intestinal abundance of major drug- metabolizing enzymes and transporters. A direct effect inhibitory Emax pharmacodynamic model was linked to the PK model of (S)- carvedilol to simulate the changes in exercise- induced heart rate. RESULTS: A 2-compartmental model with linear elimination and parallel first-order absorptions best described (S)-carvedilol PK. RYGB led to a twofold reduction in relative oral bioavailability compared to nonoperated subjects, along with delayed absorption of both enantiomers. The intestinal ABCC2 mRNA expression increases the time to reach the maximum plasma concentration. The reduced exposure (AUC) of (S)-carvedilol post-RYGB corresponded to a 33% decrease in the predicted area under the effect curve (AUEC) for the 24-hour ß-blocker response. Simulation results suggested that a 50-mg daily dose in post-RYGB patients achieved comparable AUC and AUEC to 25-mg dose in nonoperated subjects. CONCLUSION: Integrated PK/PD modeling indicated that standard dosage regimens for nonoperated subjects do not provide equivalent ß-blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.

Preoperative variables associated with transfusion requirements in orthotopic liver transplantation.

BACKGROUND: Patients with end-stage chronic liver disease (CLD) and submitted to orthotopic liver transplantation (OLT) usually require blood transfusion during the procedure or in the post-operative period due to hemorrhage. Risk factors for transfusion need are not fully known. This study aimed to identify the factors associated with blood components requirements. METHODS: In this retrospective study a total of 166 consecutive patients submitted to OLT with the piggyback technique, between 2001 and 2011, were evaluated for number of blood components transfused during surgical procedure and the four subsequent days (total of 5 days). We evaluated the association between the number of units transfused and clinical variables, such as: Child-Turcotte-Pugh (CTP) and MELD scores, hemoglobin concentration (Hb), INR, serum creatinine, bilirubin and albumin concentrations, and total, hypothermic and normothermic time of graft ischemia. RESULTS: 152 (91.6%) Patients were transfused (median of 24 units of blood components). Risk factors for higher blood transfusion requirements were CTP, INR, Hb and total time of graft ischemia. The group with CTP-A score received less blood components than CTP-B/C (11.5 vs 27; P=0.002). The group with Hb<10 required a higher number of blood units (34.5 vs 23; P=0.003). The group with INR<1.5 received less blood units (20.5 vs 31; P=0.012). The group transplanted with a graft exposed to less than the median of 555 min of ischemia received less transfusion (21 vs 27; P=0.03). MELD score and the other factors were not associated with blood requirements. CONCLUSION: These results demonstrate that CTP, but not MELD score, hemoglobin concentration, INR, and total time of graft ischemia are preoperative variables associated with blood requirements during OLT and in the subsequent days.

The Safety and Cost Analysis of Outpatient Laparoendoscopy in the Treatment of Cholecystocholedocholithiasis: A Retrospective Study.

INTRODUCTION: The advantages of single-stage treatment of cholecystocholedocholithiasis are well established, but the conditions for carrying out treatment on an outpatient basis require a review of concepts and practices of medical corporations. OBJECTIVE: To evaluate the practice of treating cholecystocholedocholithiasis by laparoendoscopy on an outpatient basis with cost analysis. METHOD: A retrospective study was conducted on patients with cholecystocholedocholithiasis treated by combined laparoscopic cholecystectomy and endoscopic choledocholithotomy from January 2015 to January 2019. After collecting data from physical and digital medical records, the patients were divided into two groups-AR (n = 42)-ambulatory regimen and HR (n = 28)-hospitalization regimen-which were compared in terms of demographic, clinical and treatment variables and their results, as well as in terms of costs. RESULTS: The mean age of the AR group was lower than that of the HR group and the physical status of the AR patients was better when assessed according to the American Society of Anesthesiologists (ASA) (p = 0.01). There was no difference between groups regarding the risk of choledocholithiasis (p = 0.99). For the AR group, the length of stay was shorter: 11.29 h × 65.21 h (p = 0.02), as was the incidence of postoperative complications assessed by applying the Clavien-Dindo classification: 3 (7.1%) × 11 (39.2%) (p < 0.01). The total mean costs were higher for the HR group (USD 2489.93) than the AR group (USD 1650.98) (p = 0.02). CONCLUSION: Outpatient treatment of cholecystocholedocholithiasis by laparoendoscopy is safe and viable for most cases, has a lower cost and can support the reorientation of training and practice of hepatobiliary surgeons.

mRNA Expression and Methylation of the RAD51, ATM, ATR, BRCA1, and BRCA2 Genes in Gastric Adenocarcinoma.

Background: Immunohistochemical prognostic significance of the homologous recombination-related proteins RAD51, ATM, BRCA1, and BRCA2 is known in gastric adenocarcinoma, one of the deadliest cancers. Objective and design: This retrospective cohort study aimed to evaluate mRNA expression and promoter methylation of some homologous recombination-related genes in this neoplasm. Methods: We evaluated mRNA expression and methylation of RAD51, ATM, ATR, BRCA1, and BRCA2 in tumor and non-tumor frozen samples from gastrectomy specimens by RT-qPCR and MS-HRM, correlating our results with previous immunohistochemistry data and prognostic features. Results: RAD51, ATR, BRCA1, BRCA2, and ATM mRNA expression was detected in 93.75% (45/48), 93.75% (45/48), 91.67% (44/48), 83.33% (40/48), and 89.58% (43/48) of the tumors; partial or complete methylation, in 94.87% (37/39), 0 (0/42), 97.56% (40/41), 100% (41/41), and 0 (0/40), respectively. Most gene pairs showed significant weak to moderate positive correlations of tumoral mRNA expression with each other: RAD51 with ATR (P = .027), BRCA1 (P < .001), and BRCA2 (P < .001); ATR with BRCA1 (P = .007), and ATM (P = .001); BRCA1 with BRCA2 (P = 0.001). BRCA1 mRNA was reduced in tumors compared with non-neoplastic mucosa (0.345 vs 1.272, P = .015) and, excluding neoadjuvant therapy cases, in T3 to T4 tumors compared with T2 (0.414 vs 0.954, P = .035). Greater tumoral RAD51 mRNA levels correlated with perineural invasion (1.822 vs 0.725, P = .010) and death (1.664 vs 0.929, P = .036), but not with survival time. There was an inverse association between nuclear immunohistochemical positivity for ATR and its mRNA levels (0.487 vs 0.907, P = .032), and no significant correlation for the other markers. Conclusions: Our results suggest RAD51, BRCA1, and BRCA2 methylation as a frequent epigenetic mechanism in gastric cancer, support the hypothesis that reduced BRCA1 expression participates in disease progression, and show an association between RAD51 mRNA and perineural invasion and mortality that may be considered unexpected, considering the former immunohistochemical studies. The lack of correlation between immunohistochemistry and mRNA, and even the inverse association, for ATR, can be seen as indicative of action of post-transcriptional or post-translational regulatory mechanisms, to be better investigated.

Effect of Roux-En-Y Gastric Bypass in the Pharmacokinetics of (R)-Carvedilol and (S)-Carvedilol.

Roux-en-Y gastric bypass is one of the most common surgical treatments for obesity due to the effective long-term weight loss and remission of associated comorbidities. Carvedilol, a third-generation ß-blocker, is prescribed to treat cardiovascular diseases. This drug is a weak base with low and pH-dependent solubility and dissolution and high permeability. As the changes in the gastrointestinal tract anatomy and physiology after roux-en-Y gastric bypass can potentially affect drug pharmacokinetics, this study aimed to assess the effect of roux-en-Y gastric bypass on the pharmacokinetics of carvedilol enantiomers. Nonobese (n = 15, body mass index < 25 kg/m2 ), obese (n = 19, body mass index ≥ 30), and post-roux-en-Y gastric bypass subjects submitted to surgery for at least 6 months (n = 19) were investigated. All subjects were administered a single oral dose of 25-mg racemic carvedilol, and blood was sampled for up to 24 hours. Plasma concentrations of (R)- and (S)-carvedilol were determined by liquid chromatography-tandem mass spectrometry. The maximum plasma concentration (Cmax ) and the area under the plasma concentration-time curve (AUC) of (R)-carvedilol were 2- to 3-fold higher than (S)-carvedilol in all groups. Obese subjects have shown reduced Cmax of (R)- and (S)-carvedilol without changing the AUC. Post-roux-en-Y gastric bypass subjects presented a 3.5-fold reduction in the Cmax of the active (S)-carvedilol and a 1.9 reduction in the AUC from time 0 to infinity compared to nonobese subjects. The time to reach Cmax of (S)-carvedilol increased 2.5-fold in post-roux-en-Y gastric bypass subjects compared to obese or nonobese. Although the ß-blockade response was not assessed, the reduced exposure to carvedilol in subjects post-roux-en-Y gastric bypass may be clinically relevant and require dose adjustment.

Influence of high altitude on the expression of HIF-1 and on the prognosis of Ecuadorian patients with gastric adenocarcinoma.

Since the incidence of gastric adenocarcinoma (GA) is high in populations living at high altitudes, we evaluated the influence of altitude on the expression of HIF-1 and survival of Ecuadorian GA patients. METHOD: 155 GA cases were studied: 56 from coastal (GAC) and 99 from mountainous regions (GAM), and 74 non-GA controls (25 coast and 49 mountain). The expression of HIF-1/HER2 was analyzed by immunohistochemistry. Analyses were performed using Fisher's exact and Breslow-Day tests for homogeneity and Kaplan-Meier curves and restricted median survival time ΔRMST. RESULTS: HIF-1 was overexpressed in normal/inflamed gastric mucosa, especially in mountainous non-GA patients (p = 0.001). There was no difference between GAC and GAM in terms of age/gender, HIF-1/HER2 expression, stage/tumor location. Median survival at 120 months was significantly higher among GAC, with a difference (ΔRMST) of 43.7 months (95% CI 29.5, 57.8) (p < 0.001) and those with positive HIF-1 expression: ΔRMST 26.6 months (95% CI 11.0, 42.1) (p < 0.001). Positive HIF-1 expression was associated with better GAM survival, with ΔRMST 33.6 months (95% CI 14.2, 52.9) (p < 0.001). CONCLUSION: Despite the limitations of this retrospective study, GA patients in the coastal region and those who expressed HIF-1 exhibited a better prognosis, but this factor was associated with better survival only in the mountain region.

Prognostic Value of the Immunohistochemical Expression of RAD51 and BRCA2 in Gastric Adenocarcinoma.

Current scientific literature lacks data on the prognostic value of the expression of RAD51 and BRCA2 in gastric adenocarcinoma. Therefore, we aimed to evaluate those and other homologous recombination-related proteins (ATM, ATR, BRCA1, CHK2, γH2AX, p53) in gastric cancer, assessing their correlation with clinical prognosis. Paraffin-embedded samples were obtained from surgical specimens collected in total or subtotal gastrectomy procedures. Between 2008 and 2017, 121 patients with advanced gastric adenocarcinoma underwent surgical resection and were included in this study. Negativity for nuclear RAD51 correlated with vascular invasion, lymph node metastasis, larger tumor size, and lower overall survival and disease-free survival in univariate analysis. However, nuclear RAD51-negative cases presented better response rates to adjuvant therapy than the positive ones. Nuclear ATR negativity correlated with larger tumor size and a higher histological grade. Positivity for ATM was associated with more prolonged disease-free survival. Positivity for nuclear BRCA2 correlated with lower overall survival and diffuse histological type, whereas its high expression was associated with vascular invasion. Nevertheless, tumors positive for nuclear BRCA2 were more frequently low grade in the intestinal histological type. Our findings indicate that RAD51 and BRCA2 are valuable immunohistochemical prognostic markers in gastric adenocarcinoma.

IS THE NEW PROCORE 20G DOUBLE FORWARD-BEVEL NEEDLE CAPABLE TO OBTAIN BETTER HISTOLOGICAL SAMPLES BY ENDOSCOPIC ULTRASOUND FOR DIAGNOSING SOLID PANCREATIC LESIONS?

BACKGROUND: Fine needle biopsy (FNB) histological samples by endoscopic ultrasound. It is important to obtain representative histological samples of solid biliopancreatic lesions without a clear indication for resection. The role of new needles in such task is yet to be determined. AIM: To compare performance assessment between 20G double fine needle biopsy (FNB) and conventional 22G fine needle aspiration (FNA) needles for endoscopic ultrasound (EUS)-guided biopsy. METHODS: This prospective study examined 20 patients who underwent the random puncture of solid pancreatic lesions with both needles and the analysis of tissue samples by a single pathologist. RESULTS: The ProCore 20G FNB needle provided more adequate tissue samples (16 vs. 9, p=0.039) with better cellularity quantitative scores (11 vs. 5, p=0.002) and larger diameter of the histological sample (1.51±1.3 mm vs. 0.94±0.55 mm, p=0.032) than the 22G needle. The technical success, puncture difficulty, and sample bleeding were similar between groups. The sensitivity, specificity, and diagnostic accuracy were 88.9%, 100%, and 90% and 77.8%, 100%, and 78.9% for the 20G and 22G needles, respectively. CONCLUSIONS: The samples obtained with the ProCore 20G FNB showed better histological parameters; although there was no difference in the diagnostic performance between the two needles, these findings may improve pathologist performance.

Clinical outcomes and costs of the use of fibrin sealant in pancreaticojejunal anastomosis after pancreaticoduodenectomy: a retrospective analysis study.

OBJECTIVES: The benefits of using a fibrin sealant to reinforce the pancreaticojejunal anastomosis are still contentious, a fact that justifies the study of its effects on clinical outcomes and costs of pancreaticoduodenectomy. METHODS: Study of 62 consecutive patients submitted to pancreaticoduodenectomy, divided into two groups of 31 patients each: GWS = group with sealant and GWOS = group without sealant that were compared according to demographic, clinical, laboratory aspects, the incidence of postoperative pancreatic fistula (POPF), according to the definition of the International Study Group on Pancreatic Fistula, updated in 2016, and its postoperative complications categorized according to the Clavien classification, as well as hospital costs evaluated by the absorption costing method (with the exception of those related to medications). RESULTS: The groups were homogeneous and there were no significant differences in the postoperative clinical course or in the indicators of hospital care between them. Hard texture of pancreatic tissue was the only protective factor against the development of POPF (RR = 0.29 (95%CI:0,12-0,68); p = 0.005). Moreover, hospital costs were higher in GWS than in GWOS (p < 0.0001). CONCLUSIONS: The use of fibrin sealant to reinforce pancreaticojejunal anastomosis did not improve the clinical and healthcare outcomes and, in addition, increased hospital costs.

The role of circulating miRNAs and CA19-9 in pancreatic cancer diagnosis.

Diagnosis and treatment of pancreatic ductal adenocarcinoma (PA) remains a challenge in clinical practice. The aim of this study was to assess the role of microRNAs (miRNAs-21, -23a, -100, -107, -181c, -210) in plasma and tissue as possible biomarkers in the diagnosis of PA. Samples of plasma (PAp-n = 13), pancreatic tumors (PAt-n = 18), peritumoral regions (PPT-n = 9) were collected from patients during the surgical procedure. The control group consisted of samples from patients submitted to pancreatic surgery for trauma or cadaveric organs (PC-n = 7) and healthy volunteers donated blood (PCp-n = 6). The expression profile of microRNAs was measured in all groups using RT-PCR, serum CA19-9 levels were determined in PA and PC. In tissue samples, there was a difference in the expression of miRNAs-21, -210 (p < 0.05) across the PAt, PC and PPT groups. The PAp showed overexpression of miRNAs-181c, -210 (p < 0.05) when compared to PCp. The combination of miRNAs-21, -210 tissue expression and serum CA19-9 showed 100% accuracy in the diagnosis of PA, as well as miR-181c expression in the plasma (PApxPCp). The expression of microRNAs in plasma proved to be a promising tool for a noninvasive detection test for PA, as well as further studies will evaluate the utility of microRNAs expression as biomarkers for prognostic and response to therapy in PA.

New photonic technologies for the treatment and diagnosis of hepatic diseases: an overview of the experimental work performed in collaboration, between Physics Institute of São Carlos and Ribeirão Preto Faculty of Medicine of the University of São Paulo.

Recent advances in optical techniques have created a great range of possibilities for diagnosis and therapeutics in liver related diseases. With the uses of efficient light sources like lasers and LEDs (Light Emitting Diodes) it is possible to employ the light-tissue interaction to promote hepatic tissue regeneration after partial hepatectomy, to detect hepatocarcinoma and steatosis by utilizing optical fluorescence, to evaluate the metabolism of the liver during hepatic transplantation as well as to treat liver tumors. We present here an overview of the technique presently in development at the Ribeirâo Preto Faculty of Medicine-USP in cooperation with the Physics Institute of São Carlos-USP. The results obtained so far have been the subject of a list of publications and are here presented as an overview. A new perspective for modern application of optical techniques in different medical practices related to the liver is presented.

Psychological distress in patients listed for liver transplantation.

PURPOSE: To assess the level of depression in patients listed for liver transplantation. METHODS: Sixty-four adult patients, listed for liver transplantation, were submitted to psychological evaluation, including assessment of depression by means of the Beck Depression Inventory. RESULTS: Twenty-two percent of the patients had mild/major depression. The group consisted mainly of male patients aged 47 on average, with a history of alcohol abuse and a Meld (Model for End-Liver Disease) value of 14.5. Patients that had been awaiting liver transplant longer presented less severe liver disease according to the Child-Pugh criteria. CONCLUSION: It is extremely important to assess psychological distress in patients listed for liver transplantation. An interdisciplinary approach is essential to improve the patients' quality of life both in the pre- and post-transplant periods.

Nonalcoholic fatty liver disease and obesity.

PURPOSE: The aim of this review is to update concepts of the nonalcoholic fatty liver disease (NAFLD) and to establish a relationship between this condition and obesity. METHODS: By means of a comprehensive literature review where special attention was devoted to articles published in the last 5 years, NAFLD is discussed in view of new concepts, diagnosis, staging, and treatment. RESULTS: NAFLD is emerging as one of the main causes of chronic liver disease and it is believed to be the hepatic component of the metabolic syndrome, whose central features include obesity, hyperinsulinemia, peripheral insulin resistance, diabetes, dyslipidemia, and hypertension. The surgical treatment of morbid obesity is one of the options available for the treatment of NAFLD. CONCLUSION: Nonalcoholic fatty liver disease is strongly related with obesity.

Liver transplantation: expectation with MELD score for liver allocation in Brazil.

Liver transplantation represents the most effective therapy for patients suffering from chronic end-stage liver disease. Until very recently, in Brazil, liver allocation was based on the Child-Turcotte-Pugh score and the waiting list followed a chronological criterion. In February 2002 the Model for End-stage Liver Disease (MELD) score was adopted for the allocation of donor livers in the US. After that change, an increased number of patients with more severe liver disease was observed, although there was no difference in 1-year patient and graft survival. A reduction in waiting-list mortality was also observed. In Brazil, the MELD score was adopted on May 31st, 2006. Good results are expected regarding the new criterion for allocation.

Hepatitis C: a challenge to hepatologists and to the liver transplantation team.

Hepatitis C is the main cause of cirrhosis and hepatocellular carcinoma and the leading indication of liver transplantation. The aim of this article was to review specific epidemiological, clinical and therapeutic aspects of hepatitis C and their implication for the hepatologists belonging to liver transplantation services. These specific aspects were reviewed in the literature mainly using Medline. Data regarding the epidemiological, clinical and therapeutic aspects of hepatitis C are discussed, with emphasis on their consequences for the liver transplantation team. Hepatitis C is a challenge for hepatologists and for the liver transplantation team. The burden we observe today is the late consequence of infection that occurred in the past. Measures for early recognition of complications of liver disease are recommended. HCV treatment should always be performed before liver transplantation if possible, but if not, HCV recurrence should be recognized and treated early after transplantation.

The effect of laser on remanescent liver tissue after 90% hepatectomy in rats.

PURPOSE: To evaluate the effect of laser beam on reminiscent liver after partial hepatectomy 90%. METHODS: Wistar rats, (N=42), were divided into six groups with seven specimens each. The partial hepatectomy (HP) was performed in all animals through exeresis of approximately 90% of the liver parenchyma. The animals from groups HP and Laser application, HPL24, HPL48 and HPL72 undertook laser irradiation carried out through application (dose of 22.5 J/cm2) in five different sites in the reminiscent liver. The rats were then sacrificed 24, 48 and 72 hours after HP procedure, for the liver regeneration analysis,using the Proliferating Cell Nuclear Antigen (PCNA),and for dosage of serum aminotransferases. RESULTS: Were demonstrated an increase of the serum levels of alanine aminotransferase for the group of 24 hours and a decrease for the group of 72 hours exposed to laser. The index of marked cells had a considerable more improvement for the group of 72 hours exposed in laser compared to other groups. CONCLUSION: Laser did not cause hepatic injuries additional to the partial hepatectomy and perhaps led to a benefit by stimulating the proliferative activity.

Liver disease associated with intestinal failure in the small bowel syndrome.

The introduction of the Total Parenteral Nutrition (TPN) has given rise to a new hope in the treatment of intestinal failure (LF) associated with the Short Bowel Syndrome (SBS). However, together with the TPN and the increase of survival of these patients, new problems and questions have emerged, as well as new therapeutical procedures. Taking into consideration this emerging reality, this paper has the purpose to undertake a review of current concepts and available treatments for patients with IF associated-liver disease. Although TPN provides an increase of survival of patients with intestinal failure, it is a potential source of complication such as: septicemia, hyperglycemia, venous thrombosis and liver disease. There are several hypothesis conceived to explain the liver disease associated to intestinal failure, however the only definite treatment as a potential to reverse the non-cirrhotic liver disease is the small intestine transplantation. Despite indications for intestine transplantation are not entirely defined in literature, the trend is its early indication in high-risk patients, preserving the liver integrity and preventing the eventual need of both liver and intestine transplantations altogether.

Chronic liver disease prevention strategies and liver transplantation.

Chronic liver disease is a considerable burden on society, being one of the three main causes of death in certain regions of Africa and Asia. Liver transplant is the only treatment option for cirrhosis, which is the end stage of many chronic liver diseases. This article reviews the preventable causes of cirrhosis and the preventive strategies which could be implemented in order to avoid the catastrophic consequences of cirrhosis. With small variations around the world, 70 to 80% of the end stage liver diseases are caused by excessive alcohol consumption and by viral hepatitis, both of which are potentially preventable. Excessive alcohol consumption has important public health consequences because of its involvement not only with cirrhosis, but also with motor vehicle accidents, unemployment, domestic violence etc. Among the viral causes, Hepatitis Virus B and C have the greatest impact on public health. Effective vaccine is available for Hepatitis Virus B and must be put in use. While a vaccine for Hepatitis Virus C is awaited, effective preventive strategies should be undertaken to avoid the preventable cases of end stage liver disease.

Impact of blood salvage during liver transplantation on reduction in transfusion requirements.

PURPOSE: The aim of this study was to analyse the changes in transfusion requirements, in patients submitted to orthotopic liver transplantation from cadaveric donors, with the use of intraoperative red blood cell salvage (Cell Saver). METHODS: Data from 41 transplants were analysed. Intraoperative blood loss was calculated from the cell salvage, suction and the swabs. The autologous and heterologous transfusions were recorded The red blood salvage was performed using the Cell Saver 5 System (Haemonetics). For analysis the patients were divided in two groups: one that used the Cell Saver and another that didn't. RESULTS: The median age of the patients was 50 years and the main indication for liver transplantation was cirrhosis (35 cases-85.3%). The median blood loss was 8362+3994 ml (with the Cell Saver) and 10824+7002 ml (without the Cell Saver) and the median transfusion of heterologous packed red blood cells was 9.6+8 units (with the Cell Saver) compared to 22.3+21 units (without the Cell Saver). CONCLUSIONS: The Cells Saver has the potential to reduce the need for heterologous blood transfusion reducing the risks of transmissible diseases.