Long-term effects of early overnutrition in the heart of male adult rats: role of the renin-angiotensin system.

To analyze the long-term effects of early overfeeding on the heart and coronary circulation, the effect of ischemia-reperfusion (I/R) and the role of the renin-angiotensin system (RAS) was studied in isolated hearts from control and overfed rats during lactation. On the day of birth litters were adjusted to twelve pups per mother (controls) or to three pups per mother (overfed). At 5 months of age, the rats from reduced litters showed higher body weight and body fat than the controls. The hearts from these rats were perfused in a Langendorff system and subjected to 30 min of ischemia followed by 15 min of reperfusion (I/R). The myocardial contractility (dP/dt) and the coronary vasoconstriction to angiotensin II were lower, and the expression of the apoptotic marker was higher, in the hearts from overfed rats compared to controls. I/R reduced the myocardial contractily, the coronary vasoconstriction to angiotensin II and the vasodilatation to bradykinin, and increased the expression of (pro)renin receptor and of apoptotic and antiapoptotic markers, in both experimental groups. I/R also increased the expression of angiotensinogen in control but not in overfed rats. In summary, the results of this study suggest that early overnutrition induces reduced activity of the RAS and impairment of myocardial and coronary function in adult life, due to increased apoptosis. Ischemia-reperfusion produced myocardial and coronary impairment and apoptosis, which may be related to activation of RAS in control but not in overfed rats, and there may be protective mechanisms in both experimental groups.

Effects of coronary ischemia-reperfusion in a rat model of early overnutrition. Role of angiotensin receptors.

BACKGROUND: Obesity during childhood has dramatically increased worldwide in the last decades. Environmental factors acting early in life, including nutrition, play an important role in the pathogenesis of obesity and cardiovascular diseases in adulthood. AIMS: To analyze the effects of early overfeeding on the heart and coronary circulation, the effect of ischemia-reperfusion (I/R) and the role of the renin-angiotensin system (RAS) were studied in isolated hearts from control and overfed rats during lactation. METHODS AND RESULTS: On the day of birth litters were adjusted to twelve pups per mother (control) or to three pups per mother (overfed). At weaning (21 days) the rats were killed and the heart perfused in a Langendorff system and subjected to 30 min of ischemia followed by 15 min of reperfusion. The contractility (left developed intraventricular pressure) was lower in the hearts from overfed rats, and was reduced by I/R in hearts from control but not from overfed rats. I/R also reduced the coronary vasoconstriction to angiotensin II more in hearts from control than from overfed rats, and the vasodilatation to bradykinin similarly in both experimental groups. The expression of both angiotensin AGTRa and AGTR2 receptors was increased in the myocardium of overfed rats, and I/R increased the expression of both receptors in control rats but reduced it in overfed rats. The expression of apoptotic and antiapoptotic markers was increased in hearts of overfed rats compared with control, and further increased by I/R. CONCLUSIONS: These results suggest that both overfeeding and I/R impair cardiac and coronary function due, at least in part, to activation of the angiotensin pathway. However, overfeeding may reduce the impairment of ventricular contractility by I/R.

Coronary response to diadenosine triphosphate after ischemia-reperfusion in the isolated rat heart.

Diadenosine triphosphate (Ap3A) is a vasoactive mediator stored in platelet granules that may be released during coronary ischemia-reperfusion. To study its coronary effects in such circumstances, rat hearts were perfused in a Langendorff preparation and the coronary response to Ap3A (10(-7)-10(-5) mol/L) was recorded. Both at basal coronary resting tone and after precontraction with 11-dideoxy-1a,9a-epoxymethanoprostaglandin F(2)(α) (U46619), Ap3A produced concentration-dependent vasodilation in the heart, which was attenuated following ischemia-reperfusion. Ap3A-induced relaxation was also attenuated in control conditions and after ischemia-reperfusion by the purinergic P2Y antagonist reactive blue 2 (2 × 10(-6) mol/L), the P2Y(1) antagonist MRS 2179 (10(-5) mol/L), the nitric oxide synthesis inhibitor N-omega-nitro-l-arginine methyl ester (l-NAME; 10(-4) mol/L) and the ATP-dependent potassium channel blocker glibenclamide (10(-5) mol/L). These results suggest that Ap3A induces coronary vasodilation, an effect attenuated by ischemia-reperfusion due to the functional impairment of purinergic P2Y receptors and K(ATP) channels, and/or reduced nitric oxide release. This impairment of vasodilation may contribute to the coronary dysregulation that occurs during ischemia-reperfusion.

Influence of approach on outcome in radiofrequency ablation of liver tumors.

In this article some recent data concerning the approach on radiofrequency ablation (RFA) of liver tumors are reviewed. Specifically, several critical statements between surgical and percutaneous approach are raised and discussed: (1) Open approach may lead to a higher complication rate; (2) Temporary occlusion of hepatic inflow during surgical approach may lead to a higher rate of ablation of the liver tumors; (3) Surgical approach may permit better targeting of the tumor to be ablated. (4) Surgical approach may discover additional liver tumors. Finally, several conclusions and recommendations are also addressed.

Management of portal vein thrombosis in liver transplantation: influence on morbidity and mortality.

BACKGROUND: Splanchnic thrombosis is a surgical challenge in liver transplantation (LT). The aim of this study was to analyze our experience in the management of portal vein thrombosis, and its influence on evolution. AIM: The aim of this study was to analyze our experience in the management of portal vein thrombosis, and its influence on evolution. PATIENTS AND METHODS: Between 1999 and 2004, 366 liver transplants were performed in 335 patients. Forty-two patients [12.5%: portal vein thrombosis (PVT) group] had portal thrombosis at the time of LT. We analyzed the technical aspects and compared their evolution with a group of patients without portal thrombosis (n = 293; no-PVT group). Retransplantations were excluded. RESULTS: Of the 42 patients with thrombosis, 18 had partial thrombosis and 16 complete thrombosis [six included the proximal superior mesenteric vein (SMV) and in two the whole splanchnic system]. In 12 cases, usual T-T anastomosis was performed and in 16 cases a thrombectomy was carried out; there were five cases of anastomosis at confluence of the SMV, five cases of anastomosis to a collateral vein, three cases of venous graft, and one case of cavoportal hemitransposition. The operative time was higher in PVT group (417 +/- 103 min vs. 363 +/- 83; p = 0.0005), as RBC transfusion (2.4 +/- 3.1 vs. 1.9 +/- 2.3; p = 0.04), and hospital stay (20.9 +/- 14.9 d vs. 15.1 +/- 10.6; p = 0.002). However, there were no differences in hospital mortality (4% vs. 7.8%; p = 0.98), primary dysfunction (4.8% vs. 7.8%; p = 0.44), or three-yr-actuarial survival (75% vs. 77%; p = 0.95). The incidence of post-transplant thrombosis was higher in the PVT group (15% vs. 2.4%; p = 0.0005). CONCLUSIONS: Portal thrombosis is associated with greater operative complexity and rethrombosis, but has no influence on overall morbidity and mortality.

Liver transplantation across Rh blood group barriers increases the risk of biliary complications.

BACKGROUND: Cold ischemia time and the presence of postoperative hepatic arterial thrombosis have been associated with biliary complications (BC) after liver transplantation. An ABO-incompatible blood group has also been suggested as a factor for predisposal towards BC. However, the influence of Rh nonidentity has not been studied previously. MATERIALS: Three hundred fifty six liver transplants were performed from 1995 to 2000 at our hospital. BC incidence and risk factors were studied in 345 patients. RESULTS: Seventy patients (20%) presented BC after liver transplantation. Bile leakage (24/45%) and stenotic anastomosis (21/30%) were the most frequent complications. Presence of BC in Rh-nonidentical graft-host cases (23/76, 30%) was higher than in Rh-identical grafts (47/269, 17%) (P=0.01). BC was also more frequent in grafts with arterial thrombosis (9/25, 36% vs 60/319, 19%; P=0.03) and grafts with cold ischemia time longer than 430 min (26/174, 15% vs 44/171, 26%; P=0.01). Multivariate logistic regression confirmed that Rh graft-host nonidentical blood groups [RR=2(1.1-3.6); P=0.02], arterial thrombosis [RR=2.6(1.1-6.4); P=0.02] and cold ischemia time longer than 430 min [RR=1.8(1-3.2); P=0.02] were risk factors for presenting BC. CONCLUSION: Liver transplantation using Rh graft-host nonidentical blood groups leads to a greater incidence of BC.

Application of fibrin glue sealant after hepatectomy does not seem justified: results of a randomized study in 300 patients.

OBJECTIVE: To evaluate the efficacy, amount of hemorrhage, biliary leakage, complications, and postoperative evolution after fibrin glue sealant application in patients undergoing liver resection. SUMMARY BACKGROUND DATA: Fibrin sealants have become popular as a means of improving perioperative hemostasis and reducing biliary leakage after liver surgery. However, trials regarding its use in liver surgery remain limited and of poor methodologic quality. PATIENTS AND METHODS: A total of 300 patients undergoing hepatic resection were randomly assigned to fibrin glue application or control groups. Characteristics and debit of drainage and postoperative complications were evaluated. The amount of blood loss, measurements of hematologic parameters liver test, and postoperative evolution (particularly involving biliary fistula and morbidity) was also recorded. RESULTS: Postoperatively, no differences were observed in the amount of transfusion (0.15 +/- 0.66 vs. 0.17 +/- 0.63 PRCU; P = 0.7234) or in the patients that required transfusion (18% vs. 12%; P = 0.2), respectively, for the fibrin glue or control group. There were no differences in overall drainage volumes (1180 +/- 2528 vs. 960 +/- 1253 mL) or in days of postoperative drainage (7.9 +/- 5 vs. 7.1 +/- 4.7). Incidence of biliary fistula was similar in the fibrin glue and control groups, (10% vs. 11%). There were no differences regarding postoperative morbidity between groups (23% vs. 23%; P = 1). CONCLUSIONS: Application of fibrin sealant in the raw surface of the liver does not seem justified. Blood loss, transfusion, incidence of biliary fistula, and outcome are comparable to patients without fibrin glue. Therefore, discontinuation of routine use of fibrin sealant would result in significant cost saving.

Surgical resection of colorectal liver metastases in patients with expanded indications: a single-center experience with 501 patients.

PURPOSE: This study was designed to investigate survival after curative resection of colorectal liver metastases in patients with expanded indications. METHODS: A total of 501 patients had 545 liver resections for metastatic colorectal cancer. There were no predefined criteria for resectability with regard to the number or size of the tumors, locoregional invasion, or extrahepatic disease, except that resection had potential to be complete and macroscopically curative. All patients who had curative hepatic resection were advised to start postoperative adjuvant chemotherapy. RESULTS: A total of 259 patients had expanded indications (52 percent), including 14 with liver metastases >10 cm, 194 with bilateral deposits, 140 with four or more liver metastases, and 73 with extrahepatic disease. The overall actuarial survival rates at one, three, five, and ten years were 88, 67, 45, and 36 percent, respectively, for patients with classic indications and 84, 53, 34, and 24 percent, respectively, for patients with expanded indications (P = 0.0009). In the group of expanded indications, there were more patients who received preoperative than postoperative chemotherapy: 72 (28 percent) vs. 18 (7 percent; P < 0.0001), and 148 (70 percent) vs. 131 (61 percent; P = 0.0466). In a multivariate analysis, four or more liver metastases and extrahepatic disease were independent predictors of poor outcome. Adjuvant chemotherapy significantly improved survival (P = 0.0002). CONCLUSIONS: This study suggested that liver resection should be indicated in patients with expanded indications. The extent of the benefits of preoperative and postoperative chemotherapy needs to be quantitated.

Utility of cell-cycle modulators to predict vascular invasion and recurrence after surgical treatment of hepatocellular carcinoma.

BACKGROUND: The outcome of surgical treatment of hepatocellular carcinoma (HCC) could be improved by applying patient selection criteria based on tumoral aggressiveness. Here we analyzed the prognostic role of the expression of several genes involved in cell-cycle regulation in a group of patients with HCC. METHODS: We retrospectively studied 93 patients (67 transplanted and 26 resections) treated between 1996 and 2000. In micro-thick sections from paraffin-embedded tumoral tissues, the expression of p53, pRb, p16, and cyclin D1 was analyzed. A logistic regression model was used to detect factors related to vascular invasion. A Cox regression model was applied to identify pathologic and molecular factors with the capacity to predict the recurrence of HCC. RESULTS: Only tumor size>3 cm (odds ratio [OR]: 3.4; 95% CI: 1.2-9.9; P=0.019) and pRb expression (OR: 4.1; 95% CI: 1.02-17; P=0.053) were associated with an increased risk of vascular invasion. The regression model applied to the group of transplanted patients showed three factors that were independently related to recurrence: vascular invasion (OR 7.5; 95% CI: 1.1-51.8; P=0.039); pRb expression (OR: 11; 95% CI: 1.2-96.9; P=0.03); and p16 expression (OR: 69.7; 95% CI: 5.1-9448; P=0.001). In the group of resected patients, pRb expression was associated with higher risk of recurrence only in the univariate analysis (P=0.037). The multivariate analysis showed tumor size>3 cm (OR: 57.5; 95% CI: 1.1-51.8; P=0.039) and vascular invasion (OR: 6.1; 95% CI: 1.05-35.3; P=0.044) to be significantly associated with recurrence. CONCLUSIONS: Of the molecular factors studied, only pRb expression was useful as a predictive factor of vascular invasion in patients with HCC, and also of recurrence in transplanted patients with this carcinoma. pRb expression may be relevant to consider when selecting patients for resection and when identifying transplanted patients with a high risk of recurrence.

OncoSurge: a strategy for improving resectability with curative intent in metastatic colorectal cancer.

PURPOSE: Most patients with colorectal liver metastases present to general surgeons and oncologists without a specialist interest in their management. Since treatment strategy is frequently dependent on the response to earlier treatments, our aim was to create a therapeutic decision model identifying appropriate procedure sequences. METHODS: We used the RAND Corporation/University of California, Los Angeles Appropriateness Method (RAM) assessing strategies of resection, local ablation and chemotherapy. After a comprehensive literature review, an expert panel rated appropriateness of each treatment option for a total of 1,872 ratings decisions in 252 cases. A decision model was constructed, consensus measured and results validated using 48 virtual cases, and 34 real cases with known outcomes. RESULTS: Consensus was achieved with overall agreement rates of 93.4 to 99.1%. Absolute resection contraindications included unresectable extrahepatic disease, more than 70% liver involvement, liver failure, and being surgically unfit. Factors not influencing treatment strategy were age, primary tumor stage, timing of metastases detection, past blood transfusion, liver resection type, pre-resection carcinoembryonic antigen (CEA), and previous hepatectomy. Immediate resection was appropriate with adequate radiologically-defined resection margins and no portal adenopathy; other factors included presence of < or = 4 or > 4 metastases and unilobar or bilobar involvement. Resection was appropriate postchemotherapy, independent of tumor response in the case of < or = 4 metastases and unilobar liver involvement. Resection was appropriate only for > 4 metastases or bilobar liver involvement, after tumor shrinkage with chemotherapy. When possible, resection was preferred to local ablation. CONCLUSION: The results were incorporated into a decision matrix, creating a computer program (OncoSurge). This model identifies individual patient resectability, recommending optimal treatment strategies. It may also be used for medical education.

Successful treatment with tenofovir in a child C cirrhotic patient with lamivudine-resistant hepatitis B virus awaiting liver transplantation. Post-transplant results.

Antiviral treatment can be complex in decompensated hepatitis B virus (HBV) cirrhosis because of potential emergence of lamivudine-resistant mutants and worsening liver function, and to multifactorial nephrotoxicity. Negative HBV-DNA status by hybridization before liver transplantation is a favorable prognostic factor. We present the case of a 54-year-old HBV+ liver transplantation candidate who, after testing negative for HBV-DNA, developed YMDD lamivudine-resistant mutants resulting in a deteriorated clinical condition. After 8 months of adefovir plus lamivudine double therapy, only partial response was achieved. Tenofovir was added to this regimen, and an early decline of HBV-DNA was seen at 4 weeks without adverse events. The patient underwent transplantation. At 21-month postoperative follow-up, the patient's outcome was excellent. Post-transplantation HBV prophylaxis, taking into account the prior development of mutants, consists of hepatitis B immunoglobulin plus lamivudine and adefovir. Tenofovir was well tolerated and produced a fast antiviral response, suggesting its potential value in combined antiviral treatment for liver transplantation candidates.

Complete versus selective portal triad clamping for minor liver resections: a prospective randomized trial.

OBJECTIVE: To evaluate the feasibility, safety, efficacy, amount of hemorrhage, postoperative complications, and ischemic injury of selective clamping in patients undergoing minor liver resections. SUMMARY BACKGROUND DATA: Inflow occlusion can reduce blood loss during hepatectomy. However, Pringle maneuver produces ischemic injury to the remaining liver. Selective hemihepatic vascular occlusion technique can reduce the severity of visceral congestion and total liver ischemia. PATIENTS AND METHODS: Eighty patients undergoing minor hepatic resection were randomly assigned to complete clamping (CC) or selective clamping (SC). Hemodynamic parameters, including portal pressure and the hepatic venous pressure gradient (HVPG), were evaluated. The amount of blood loss, measurements of liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), and postoperative evolution were also recorded. RESULTS: No differences were observed in the amount of hemorrhage (671 +/- 533 mL versus 735 +/- 397 mL; P = 0.54) or the patients that required transfusion (10% versus 15%; P = 0.55). There were no differences on postoperative morbidity between groups (38% versus 29%; P = 0.38). Cirrhotic patients with CC had significantly higher ALT (7.7 +/- 4.6 versus 4.5 +/- 2.7 mukat/L, P = 0.01) and AST (10.2 +/- 8.7 versus 4.9 +/- 2.1 mukat/L; P = 0.03) values on the first postoperative day than SC. The multivariate analysis demonstrated that high central venous pressure, HVPG >10 mm Hg, and intraoperative blood loss were independent factors related to morbidity. CONCLUSIONS: Both techniques of clamping are equally effective and feasible for patients with normal liver and undergoing minor hepatectomies. However, in cirrhotic patients selective clamping induces less ischemic injury and should be recommended. Finally, even for minor hepatic resections, central venous pressure, HVPG, and intraoperative blood loss are factors related to morbidity and should be considered.

Biliary complications after liver transplantation: diagnosis with MR cholangiopancreatography.

OBJECTIVE: We sought to evaluate MR cholangiopancreatography (MRCP) as the only imaging procedure used in the diagnosis and management of biliary complications after orthotopic liver transplantation (OLT). CONCLUSION: MRCP is a useful imaging procedure in the assessment of biliary complications after OLT.

Resección quirúrgica de las metástasis hepáticas de carcinoma colorrectal. Tratamiento de las recidivas / Surgical resection of colorectal liver metastases. Treatment of recurrences

Introducción. La cirugía es el mejor tratamiento para las metástasis hepáticas del cáncer colorrectal. Sin embargo, la mitad de los pacientes presentará una recidiva. Objetivos. Analizar la supervivencia del tratamiento quirúrgico de las recidivas tras el seguimiento intencionado de los pacientes operados de metástasis hepáticas del cáncer colorrectal. Material y métodos. Desde 1991 hasta 2002 hemos practicado 394 hepatectomías por metástasis hepáticas del cáncer colorrectal en 368 pacientes. El número, el tamaño y la invasión locorregional no se consideraron criterios de exclusión. En 26 pacientes se llevó a cabo una segunda resección y en 33 se realizó destrucción por radiofrecuencia de las metástasis hepáticas. Treinta enfermos fueron intervenidos de metástasis pulmonares. Resultados. La mortalidad postoperatoria fue del 3 por ciento. La supervivencia actuarial a los 1, 3 y 5 años fue del 89, el 61 y el 40 por ciento, respectivamente. En el análisis multivariante, el valor de antígeno carcinoembrionario preoperatorio mayor de 50 ng/ml, la presencia de 4 o más metástasis hepáticas, la presentación sincrónica, la enfermedad extrahepática y la invasión del margen fueron factores predictivos de mortalidad independientes. La quimioterapia adyuvante mejoró significativamente la supervivencia. La supervivencia a 5 años de los pacientes operados de una recidiva hepática fue del 38 por ciento, mientras que la del tratamiento con radiofrecuencia fue del 48 por ciento a los 3 años. La supervivencia tras la resección de metástasis pulmonares fue del 49 por ciento a los 4 años. Conclusiones. El tratamiento quirúrgico de las metástasis hepáticas del cáncer colorrectal, junto con un seguimiento intencionado y un tratamiento mediante cirugía o radiofrecuencia de las recidivas hepáticas, pulmonares y locorregionales, permite alcanzar una supervivencia excelente a largo plazo (AU)

[Survival and recurrence in the multidisciplinary approach of colorectal cancer]. / Supervivencia y recidiva en el tratamiento multidisciplinario del carcinoma colorrectal.

BACKGROUND AND OBJECTIVE: Colorectal cancer is one of the most frequent causes of death in the general population. Our aim was to analyze our experience in the multidisciplinary approach of colorectal carcinoma during a three year period. PATIENTS AND METHOD: Between January 1996 and December 1998, we studied prospectively 807 patients with colorectal cancer. The epidemiology, treatment and outcome(recurrence and survival) were analyzed. The minimum follow-up was 3 years. RESULTS: There were 598 colon (65.5%) and 279 rectal (34.5%) tumors in all the series. Surgical treatment was elective in 84% and urgent in 16%, and was considered radical in 598 cases (74.1%). Chemotherapy or radiotherapy was administered in 49.6% and 18.3% patients, respectively. The overall 3-year survival was as follows: stage I 97.5%, stage II 90.6%, stage III 75.2%, and stage IV 12.6%. The 3-year free-disease survival was as follows: in colon cancer 97.8% for stage I, 87.3% for stage II, and 71.4% for stage III; and in rectal cancer 96.8% for stage I, 85.1% for stage II, and 75.4% for stage III. During the follow-up 124 patients (20.7%) developed recurrence: local (2.8%), systemic (15.9%) or both (2%). The three-year survival in operated patients with liver metastases was 61.9%. CONCLUSIONS: We have observed adequate survival and recurrence rates which are the result are of systematic protocols established by a multidisciplinary team.

Liver transplantation without steroid induction in HIV-infected patients.

Until recently, human immunodeficiency virus (HIV) infection was considered an absolute contraindication for liver transplantation in Spain. We present the first 4 cases of liver transplantation (LT) carried out in our center in patients infected with HIV and coinfected by the hepatitis C virus (HCV), immunosuppressed with cyclosporine A (CyA) and basiliximab, but without steroids. The 4 patients were male, with a mean age of 38.25 +/- 4.5 years. Mean time of HIV infection was 114 +/- 62.3 months and all patients were receiving highly active antiretroviral therapy (HAART). HCV genotypes of the 4 patients were 4, 1b, 1b, and 1a. Two patients were classified as Child-Turcotte-Pugh C (10 and 11 points), 1 was B (8 points), and the patient with hepatocellular carcinoma was A (5 points). Immunosuppression consisted of basiliximab and monotherapy with CyA. There were no postoperative infections. With a follow-up of 17 +/- 8 months, all patients are alive. There was only 1 acute rejection episode, and this was solved with steroid pulses. Three patients showed HCV recurrence with enzymatic and histological changes and were treated with interferon and ribavirin. One patient had negative HCV-ribonucleic acid after 6 months of treatment. In conclusion, HIV infection should not be considered an absolute contraindication for liver transplantation. The evolution of this type of patients will probably depend on the HCV infection. Immunosuppression without steroids may reduce opportunistic infection.

Mejoría de la morbimortalidad postoperatoria en el trasplante hepático: ¿una asignatura pendiente? / Improvement in postoperative morbidity and mortality in liver transplantation

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