Cleber Rosito Pinto Kruel

Evaluation of the heme oxygenase-1 expression in esophagitis and esophageal cancer induced by different reflux experimental models and diethylnitrosamine

PURPOSE To study the expression of heme-oxygenase-1 (HO-1), an enzyme induced by oxidative stress, in specimens obtained from an experimental model in rats that evaluated the role of gastric and duodenal reflux in esophageal carcinogenesis. METHODS Esophageal specimens embedded in paraffin obtained from different experimental groups of rats were used for immunohistochemistry analysis of HO-1 expression. The rats had been divided into the following groups and were killed after 22 weeks: (1) cardioplasty to induce acid reflux; (2) esophagoduodenal anastomosis to induce duodenal reflux; (3) no treatment; (4) cardioplasty + diethylnitrosamine (DEN); (5) esophagoduodenal anastomosis + DEN; and (6) DEN. The study sample comprised 3 specimens from each group with the most severe histopathological lesions found on each study branch. RESULTS The expression of HO-1 was seen only in rat specimens submitted to esophagoduodenal anastomosis (Groups 2 and 5), and the analysis of mean fluorescence intensity revealed a significant increase of HO-1 expression (4.8 and 4.6 fold, respectively) when compared with the control group (Group 3) (p<0.05). The main target for HO-1 induction was the inflammatory cells inside the tumor or in subepithelial areas. Rats exposed to gastric reflux had no HO-1 expression. CONCLUSION Reflux esophagitis induced by reflux of duodenal contents, which provoked considerable oxidative stress, may play an important role in esophageal carcinogenesis. Acid reflux did not induce oxidative stress in this experimental model.

Transarterial Embolization for Hepatocellular Carcinoma: A Comparison between Nonspherical PVA and Microspheres.

Transarterial chemoembolization (TACE) and transarterial embolization (TAE) have improved the survival rates of patients with unresectable hepatocellular carcinoma (HCC); however, the optimal TACE/TAE embolic agent has not yet been identified. The aim of this study was to compare the effect of two different embolic agents such as microspheres (ME) and polyvinyl alcohol (PVA) on survival, tumor response, and complications in patients with HCC submitted to transarterial embolization (TAE). Eighty HCC patients who underwent TAE between June 2008 and December 2012 at a single center were retrospectively studied. A total of 48 and 32 patients were treated with PVA and ME, respectively. There were no significant differences in survival (P = 0.679) or tumoral response (P = 0.369) between groups (PVA or ME). Overall survival rates at 12, 18, 24, 36, and 48 months were 97.9, 88.8, 78.9, 53.4, and 21.4% in the PVA-TAE group and 100, 92.9, 76.6, 58.8, and 58% in the ME-TAE group (P = 0.734). Patients submitted to TAE with ME presented postembolization syndrome more frequently when compared with the PVA group (P = 0.02). According to our cohort, the choice of ME or PVA as embolizing agent had no significant impact on overall survival.

Development of clinical celiac disease after pancreatoduodenectomy: a potential complication of major upper abdominal surgery

BackgroundCeliac disease is a gluten-induced disease of global malabsorption. There is a subset of patients with celiac disease who are free of major symptoms but who have typical damage to the intestinal mucosa (silent disease). We present the case of a 50-year-old white woman with no clinical symptoms of celiac disease who developed diarrhea and weight loss 12 weeks after a pancreatoduodenectomy for ampullary cancer.MethodsMicrobiological and biochemical examination of the feces did not provide clues useful to diagnosis, and diarrhea was not affected by pancreatic enzyme replacement or administration of antiperistaltic drugs.Results Review of the pathologic specimen and blood tests were compatible with celiac disease.ConclusionThis clinical scenario illustrates that subclinical celiac disease may be an underdiagnosed cause of malabsorption after major upper gastrointestinal surgery and should be considered in the differential diagnosis of diarrhea after pancreatoduodenectomy.

First Report of Human Pancreas Transplantation Using IGL-1 Preservation Solution: A Case Series.

I Georges Lopez preservation solution (IGL-1) is an extracellular type of preservation solution that has lesser viscosity and lower potassium concentration than the criterion of University of Wisconsin preservation solution (UW). Institute Georges Lopez-1 preservation solution has been used for preservation of human kidney and liver allografts, resulting in transplant outcomes that are similar to those obtained with UW. Although IGL-1 has been used successfully for preservation of human islet cells prior transplantation, and also for experimental pancreas transplantation, no previous report of human pancreas transplantation using IGL-1 was found in the medical literature. From February to October 2015, 5 consecutive simultaneous pancreas and kidney transplants were performed using IGL-1 preservation solution at our institution (Table 1). Procurement operations and pancreas transplantswere performed by a same surgeon (Chedid, M.F.). After cross clamping, 5 L of IGL-1 was infused through deceased donors aorta, and 1 Lwas infused through inferiormesenteric vein. Intravenous

Transarterial Embolization and Percutaneous Ethanol Injection as an Effective Bridge Therapy before Liver Transplantation for Hepatitis C-Related Hepatocellular Carcinoma

Background. Transarterial chemoembolization alone or in association with radiofrequency ablation is an effective bridging strategy for patients with hepatocellular carcinoma awaiting for a liver transplant. However, cost of this therapy may limit its utilization. This study was designed to evaluate the outcomes of a protocol involving transarterial embolization, percutaneous ethanol injection, or both methods for bridging hepatocellular carcinomas prior to liver transplantation. Methods. Retrospective review of all consecutive adult patients who underwent a first liver transplant as a treatment to hepatitis C-related hepatocellular carcinoma at our institution between 2002 and 2012. Primary endpoint was patient survival. Secondary endpoint was complete tumor necrosis. Results. Forty patients were analyzed, age 58 ± 7 years. There were 23 males (57.5%). Thirty-six (90%) out of the total 40 patients were within Milan criteria. Complete necrosis was achieved in 19 patients (47.5%). One-, 3-, and 5-year patient survival were, respectively, 87.5%, 75%, and 69.4%. Univariate analysis did not reveal any variable to impact on overall patient survival. Conclusions. Transarterial embolization, ethanol injection, or the association of both methods followed by liver transplantation comprises effective treatment strategy for hepatitis C-related hepatocellular carcinoma. This strategy should be adopted whenever transarterial chemoembolization and/or radiofrequency ablation are not available options.

ESTIMATING BASAL ENERGY EXPENDITURE IN LIVER TRANSPLANT RECIPIENTS: THE VALUE OF THE HARRIS-BENEDICT EQUATION

ABSTRACT Background: Reliable measurement of basal energy expenditure (BEE) in liver transplant (LT) recipients is necessary for adapting energy requirements, improving nutritional status and preventing weight gain. Indirect calorimetry (IC) is the gold standard for measuring BEE. However, BEE may be estimated through alternative methods, including electrical bioimpedance (BI), Harris-Benedict Equation (HBE), and Mifflin-St. Jeor Equation (MSJ) that carry easier applicability and lower cost. Aim: To determine which of the three alternative methods for BEE estimation (HBE, BI and MSJ) would provide most reliable BEE estimation in LT recipients. Methods: Prospective cross-sectional study including dyslipidemic LT recipients in follow-up at a 735-bed tertiary referral university hospital. Comparisons of BEE measured through IC to BEE estimated through each of the three alternative methods (HBE, BI and MSJ) were performed using Bland-Altman method and Wilcoxon Rank Sum test. Results: Forty-five patients were included, aged 58±10 years. BEE measured using IC was 1664±319 kcal for males, and 1409±221 kcal for females. Average difference between BEE measured by IC (1534±300 kcal) and BI (1584±377 kcal) was +50 kcal (p=0.0384). Average difference between the BEE measured using IC (1534±300 kcal) and MSJ (1479.6±375 kcal) was -55 kcal (p=0.16). Average difference between BEE values measured by IC (1534±300 kcal) and HBE (1521±283 kcal) was -13 kcal (p=0.326). Difference between BEE estimated through IC and HBE was less than 100 kcal for 39 of all 43patients. Conclusions: Among the three alternative methods, HBE was the most reliable for estimating BEE in LT recipients.

HEPATOCELLULAR CARCINOMA: DIAGNOSIS AND OPERATIVE MANAGEMENT

ABSTRACT Introduction: Hepatocellular carcinoma is an aggressive malignant tumor with high lethality. Aim: To review diagnosis and management of hepatocellular carcinoma. Methods: Literature review using web databases Medline/PubMed. Results: Hepatocellular carcinoma is a common complication of hepatic cirrhosis. Chronic viral hepatitis B and C also constitute as risk factors for its development. In patients with cirrhosis, hepatocelular carcinoma usually rises upon malignant transformation of a dysplastic regenerative nodule. Differential diagnosis with other liver tumors is obtained through computed tomography scan with intravenous contrast. Magnetic resonance may be helpful in some instances. The only potentially curative treatment for hepatocellular carcinoma is tumor resection, which may be performed through partial liver resection or liver transplantation. Only 15% of all hepatocellular carcinomas are amenable to operative treatment. Patients with Child C liver cirrhosis are not amenable to partial liver resections. The only curative treatment for hepatocellular carcinomas in patients with Child C cirrhosis is liver transplantation. In most countries, only patients with hepatocellular carcinoma under Milan Criteria are considered candidates to a liver transplant. Conclusion: Hepatocellular carcinoma is potentially curable if discovered in its initial stages. Medical staff should be familiar with strategies for early diagnosis and treatment of hepatocellular carcinoma as a way to decrease mortality associated with this malignant neoplasm.

Wait and transplant for stage 2 hepatocellular carcinoma with deceased-donor liver grafts: how long should we wait?

Deceased-Donor Liver Grafts: How Long Should We Wait? The method which donor organs are allocated to individuals on the waiting list for transplant is an important topic for research and debate. In recent years, there has been growing interest in applying the concept of utilitarianism to the organ allocation system, seeking the maximum survival benefit of the patient population as a whole, rather than that of an individual patient (1). Ideally, exceptions points were created to allow hepatocellular carcinoma (HCC) patients a fair access to the donor pool. However, the current allocation Model for End-stage Liver Disease exception points seem to overestimate the risk disease progression and dropout in HCC patients, and the likelihood of undergoing a liver transplantation still remains higher for HCC candidates in the United States (2). Therefore, an intention-totreat analysis, such as that published in Transplantation by Chan et al. (3), is a promising tool to optimize organ donation in a more fair way. Tumor size has been associated with the risk of metastasis and HCC progression (4). Whether or not the Milan criteria could be extended without increasing waiting list mortality for non-HCC candidates depends on the availability of organs in each specific region. Thus, an optimal selection of the HCC patients for liver transplantation has an upmost importance in regions with a low donation rate. The wait-and-transplant policy proposed by Chan et al. provided almost the same chances of being transplanted for HCC and non-HCC patients, and the survival rates of those who were transplanted were almost the same in both groups (40.4% vs. 37.9%, respectively). However, most of the HCC patients in the waiting list died (n=18) or had to be excluded because of disease progression (7), and at the end of study, only 5 patients remained in conditions of being transplanted. As a matter of a fact, liver transplantation could not be offered in 48.2% (25/52) of the HCC patients. On the other hand, only 26.2% (27/103) of the non-HCC patients died in the waiting list during the same period, so 34.9% (35/103) of the non-HCC patients still had chances of receiving a liver graft when the study was ended. According to the intention-to-treat analysis, all alive and active patients should be considered as having a potential for long-term survival, regardless if they were transplanted or not. Although the outcomes of the patients who were still alive in the waiting list are unpredictable, a significant fraction of them probably will be transplanted in the following months, increasing the transplant patient rate and, consequently, the overall survival in the non-HCC group. We agree that wait-and-transplant policy is an interesting idea to avoid unnecessary liver transplant for patients at great risk of early tumor progression and recurrence, like the HCC candidates beyond the Milan criteria. The scenario of organ shortage increases even more the need to improve patient selection, but it seems to us that a shorter waiting period policy (3 months) could also combine the selection benefits of the 6-month waitand-transplant policy with a lower dropout and mortality rate on the waiting list. Another argument reinforcing this idea is the fact that HCC patients who underwent living donor liver transplantation in the same study also achieved excellent postoperative survival outcomes despite a medium waiting time to transplant of 8.5 days.

Can we go further in translational medicine with silver-standard criteria for early allograft dysfunction?

We read with great interest the article published in Liver Transplantation by Deschenes about the concept of early allograft dysfunction. We also believe that a better understanding of the role of cytokine profiles will lead to improvements in our capacity to define, predict, prevent, and eventually treat early allograft dysfunction. However, translational medicine needs an accurate definition of each particular clinical phenotype to be used as a control because molecular and genomic profiles must be compared against a reliable gold-standard test. Although initial poor graft function has been associated with morbidity and mortality after liver transplantation, there is a lack of agreement about the definition of early allograft dysfunction, and this could explain the variability observed between different series. Recently, Olthoff et al. validated the criteria for graft dysfunction used during the pre–Model for End-Stage Liver Disease era. However, those criteria are based on arbitrarily chosen laboratory cutoffs such as serum aminotransferase, bilirubin levels and international normalized ratio, which may not reflect graft function. Peak aminotransferase levels during the first week after transplantation are responsible for almost half of the diagnoses of early allograft dysfunction. Nevertheless, they reflect the extent of the hepatocellular injury instead of liver function. This concept was reinforced by a recent meta-analysis demonstrating that aspartate aminotransferase levels on postoperative day 1 were significantly higher in patients subjected to total vascular occlusion (Pringle maneuver) versus patients subjected to partial hepatic inflow occlusion. In addition, hyperbilirubinemia and coagulopathy in the early postoperative period (days 1-6) may still reflect the status of the recipient at the time of transplantation rather than the function of the graft. The process of finding an accurate examination for estimating organic function is a challenging task. The evaluation of renal function in the context of endstage liver disease, for example, has some pitfalls because serum creatinine has been shown to overestimate the true glomerular filtration rate as a result of reduced muscle mass, a protein-poor diet, and diminished hepatic biosynthesis of creatine. Thus, whenever a reliable metric is needed, inulin clearance is used as the gold-standard test for evaluating renal function, especially in the context of cirrhosis. According to the current definition of early allograft dysfunction, most patients with graft dysfunction will not die or need retransplantation within 6 months, and this indicates that the actual criteria may lead to a high level of false-positive diagnoses. The lack of an accurate test for detecting early allograft dysfunction may explain why interleukin-6, in contrast to what was demonstrated in experimental models, did not show any hepatoprotective effect in a clinical study. Thus, there is a need to refine the definition of early allograft dysfunction. In our opinion, efforts should be focused on tests that can directly estimate the liver function status (eg, LiMAx) in order to decrease the bench-to-bedside gap and prevent the misinterpretation of molecular profiles.

How to do liver transplantation using renoportal bypass: How to do it

Portal vein (PV) thrombosis is classified in four grades: grade 1, partial PV thrombosis (<50% of the lumen) with or without minimal extension into the superior mesenteric vein (SMV); grade 2, PV thrombosis, >50% occlusion, including total PV occlusion, with or without minimal extension into the SMV; grade 3, PV thrombosis, complete thrombosis of both PV and proximal SMV with open distal SMV; grade 4, PV thrombosis, complete thrombosis of PV and proximal and distal SMV. Clear-cut criteria of choice for the best technique for PV reconstruction during liver transplantation (LT) in the setting of extensive portomesenteric thrombosis have not been established. No prior video documentation of renoportal bypass (RPB) was found in the medical literature or in the internet. The authors hereby illustrate this unusual technique with figures and video documentation (Figs S1–S3, Video S1). The case of a 57-year-old male with hepatitis C virus infection, Child C cirrhosis (Model for End-Stage Liver Disease score 38), grade 4 PV thrombosis is illustrated in this report. Extensive PV thrombosis and a large spontaneous splenorenal shunt had been documented on preoperative computed tomography (CT) angiogram. During surgical exploration, the porta hepatis was dissected in a usual manner and the presence of grade 4 PV thrombosis was confirmed. The hepatic artery and the bile duct were doubly ligated and severed. Dissection of the retro-hepatic inferior vena cava (IVC) with ligation of its tributaries from the liver was performed as a preparation for piggy-back reconstruction. The right hepatic vein was stapled and cut, and the PV was ligated. The middle and left hepatic veins were clamped and severed, and the cirrhotic liver was removed. Kocher manoeuvre and caudal mobilization of the duodenum and the head of the pancreas were performed. The soft tissues next to the anterior wall of the IVC were removed. The left renal vein (LRV) was doubly clamped next to the IVC, cut and sutured. Anastomosis of the middle and left hepatic veins to donor IVC was performed as usual using the piggy-back technique. A RPB was constructed using a segment of donor’s femoral vein as an interposition graft between the LRV and PV of the liver allograft. The venous graft was sewn to the LRV remnant proximally and to the PV of the liver graft distally, both in an end-to-end fashion employing running 6–0 polydioxanone sutures (Fig. 1) (operative time = 480 min; cold ischaemia = 585 min; warm ischemia = 40 min; blood loss = 3.7 L). Daily Doppler ultrasound was performed during the first postoperative week. Post-transplant course of this patient was complicated by transient ascites and renal failure demanding transient dialysis. Patient was discharged home on post-transplant day 47 with normal renal function. He is currently asymptomatic 6 months after LT. CT angiogram reveals a patent RPB. Extensive PV thrombosis is a technical challenge to successful LT. Specifically for grade 3 PVT, whenever PV thromboendovenectomy is not accomplished, placement of an interposition venous graft between recipient SMV and PV of the liver allograft would be the first choice. For grade 4 PVT, utilization of portomesenteric venous system of the recipient usually is not feasible. The same applies to grade 3 PVT in the presence of hypoplasic PV (or a PV with a low flow despite LRV ligation). In these settings, potential options include connecting PV of the liver graft to a collateral vein, construction of a RPB, cavoportal hemitransposition, PV arterialization and multivisceral transplantation. Pre-transplant planning with CT angiogram documenting a large spontaneous splenorenal shunt is necessary for the performance of RPB. As for minimizing cold ischaemia in this setting, standard criteria local donors are preferred. LRV always should be ligated next to IVC. Interposition grafts (donor iliac or femoral veins) are usually necessary. Transient renal failure is a common complication after RPB. Ascites also may occur, usually responding to medical treatment with salt restriction and therapy with diuretics.