Liver transplantation results for hepatocellular carcinoma in Chile.

UNLABELLED: Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Liver transplantation is the best treatment for HCC; it improves survival, cures cirrhosis, and abolishes local recurrence. We describe the outcomes of patients with HCC who underwent liver transplantation in two liver transplantation centers in Chile. METHODS: This study is a clinical series elaborated from the liver transplantation database of Pontificia Universidad Católica and Clínica Alemana between 1993 and 2009. The survival of patients was calculated using the Kaplan-Meier survival analysis. The significant alpha level was defined as <.05. RESULTS: From 250 liver transplantations performed in this period, 29 were due to HCC. At the end of the study, 25 patients (86%) were alive. The mean recurrence-free survival was 30 months (range 5 months to 8 years). The 5-year survival for patients transplanted for HCC was >80%; however, the 5-year overall survival of patients who exceeded the Milan criteria in the explants was 66%. There was no difference in overall survival between patients transplanted for HCC versus other diagnosis (P = .548). CONCLUSION: This series confirmed that liver transplantation is a good treatment for patients with HCC within the Milan criteria.

Bridge therapy in hepatocellular carcinoma before liver transplantation: the experience of two Chilean centers.

BACKGROUND: Orthotopic liver transplantation (OLT) is currently an established therapy for small, early-stage hepatocellular carcinoma (HCC) within the Milan criteria. Long waiting times due to the shortage of donor organs can result in tumor progression and drop-out from OLT candidacy. Therefore a wide variety of procedures are necessary before OLT. The aim of this retrospective study was to review our experience in relation to bridge therapy prior to OLT for HCC. METHODS: This was a retrospective database review of all of the patient who underwent transplantation in our institutions between January 1993 and June 2009. We analyzed patients with a diagnosis of HCC in the explant. RESULTS: Among 29 patients, including 12 who were diagnosed by the explant and 17 prior to transplantation, 88% underwent bridge therapy during a mean waiting time to OLT of 12 months. Among the 23 procedures, namely 1.5 procedures per patient, included most frequently chemoembolization (48%), alcohol ablation (30%), radiofrequency ablation (13%), and surgery (9%). Thirty-three percent of the explants contained lesions within the Milan criteria. In our series the 5-year survival rate for patients transplanted for HCC was 86%; in the bridge therapy group, it was 73%. CONCLUSIONS: The incidence of patients who underwent bridge therapy (52%) was similar to other reported experiences, but the fulfillment of Milan criteria in the explants was lower. Among the bridge therapy group, the survival was slightly lower, probably because this group displayed more advanced disease.

[Genetic causes of impaired wound healing. Rare differential diagnosis of the non-healing wound]. / Genetische Ursachen schwerer Wundheilungsstörungen. Seltene Differenzialdiagnosen der nicht heilenden Wunde.

Chronic leg ulcers affect about 1% of the German population. The intense search for the underlying cause of impaired wound healing is an essential requirement for successful therapy. The most common causes comprise chronic venous insufficiency (70%), peripheral arterial occlusive disease (10%) and diabetes mellitus. Besides vasculitis, infectious diseases and tumors, genetic diseases may constitute the underlying cause for impaired wound healing. In this review various rare genetic diseases causing chronic wounds like the Klinefelter-Syndrome, immunological diseases including the TAP-deficiency-syndrome and the leukocyte adhesion deficiency-syndromes, red blood cell disorders, thalassemia, thrombotic diseases, progeroid syndromes and inherited connective tissue disorders are presented.

GM-CSF neutralisation suppresses inflammation and protects cartilage in acute streptococcal cell wall arthritis of mice.

OBJECTIVE: The pathogenic involvement of granulocyte-macrophage colony-stimulating factor (GM-CSF) in arthritis has been put forward. We have investigated the therapeutic effect of GM-CSF neutralisation in the streptococcal cell wall (SCW) arthritis model in mice. In this model, the pathogenic contribution of tumour necrosis factor (TNF)alpha is minor and is expressed only on joint swelling, whereas cartilage proteoglycan depletion is independent of this cytokine. METHODS: Acute monarthritis was induced by injection of SCW bacterial extracts to mouse knees. Treatments (mAb 22E9 at 300, 100, 30 microg; or Enbrel 300 microg) were given twice intraperitoneally 2 h before and 3 days after disease induction. Swelling was assessed by (99m)Tc uptake into knees on days 1 and 2. Local cytokine levels were determined in patellae washouts on day one. Proteoglycan loss from cartilage was scored on histological sections at termination on day four. RESULTS: Treatment with anti-GM-CSF mAb 22E9 showed a dose-related efficacy by decreasing swelling that was significant at the 300 and 100 microg doses in comparison to isotype control, and comparable to dexamethasone (5 mg/ml). Proteoglycan loss from cartilage was also significantly reduced by mAb 22E9 300 microg (p=0.001). This reduced proteoglycan loss observed after GM-CSF neutralisation was not seen after TNFalpha-blockade with Enbrel. Similarly, levels of interleukin 1beta in joints were reduced after treatment with 22E9 mAb (p=0.003) but not in mice receiving Enbrel. CONCLUSIONS: Our findings show a pathogenic role for GM-CSF in this arthritis model, support the therapeutic potential of neutralising this cytokine, and may indicate therapeutic activity of an anti-GM-CSF mAb in TNFalpha-independent disease situations.

Early posttransplant lymphoproliferative disease in pediatric liver transplant recipients.

Among 23 pediatric patients who underwent orthotopic liver transplant (OLT), we report two (11 and 26 months old) with posttransplant lymphoproliferative disease (PTLD) that occurred in the early posttransplantation period. They were Epstein-Barr Virus (EBV)-negative and received graft from EBV-positive donors. The surveillance for EBV viremia using serial EBV polymerase chain reaction determinations in the peripheral blood was positive at 10 and 90 days after OLT concomitant with symptoms of primary infection, both patients were treated with gancyclovir. The patients should progression to a Burkitt's and a non-Hodgkin's lymphoma that appeared 3 months posttransplantation. They were treated by withdrawal of immunosuppression and six courses of cyclophosphamide as well as anti-CD20 monoclonal antibody (Rituximab) every 21 days. One patient experienced acute graft rejection, which resolved with steroids and low doses of tacrolimus, she is free of disease at 24 months after the end of treatment. The other patient relapsed with a cerebral lymphoma, receiving aggressive chemotherapy, but died due to sepsis. In conclusion, PTLD occurred among in 2/23 patients who underwent OLT and appeared in the first quarter post OLT. The risk factors associated with early PTLD were primary EBV infection after OLT, young age, and EBV-negative recipient receiving a transplant from an EBV-positive donor. Antiviral treatment alone was inefficient; withdrawal of immunosuppression and courses of Rituximab and cyclophosphamide were well tolerated and controlled PTLD. The risk of graft rejection was increased by withdrawal of immunosuppression. One patient died.

Liver transplantation in Latin America: current status.

The current status of liver transplantation in Latin America is reviewed. For an estimated population of 470 million people, approximately 1100 liver transplantations were performed in 2002, namely, 2.3 liver transplantations per million people per year (pmp). The top transplantation rates were in Argentina 4.5, Brazil 3.9, and Chile 3.6 pmp. In 2001, liver transplantations were not performed in 2 of 10 South American countries nor were liver transplantations performed in 5 of 6 Central American countries. In the Latin American countries performing this procedure, living donor liver transplantation has been performed to palliate the organ shortage for pediatric patients in most of these countries. However, only 3 countries have used the procedure for adult liver transplantation. The lack of adequate financial coverage, education, and organization are the main limiting factors to the development of liver transplantation in Latin America.

Predictive models in cirrhosis: correlation with the final results and costs of liver transplantation in Chile.

Medical scores for predicting survival are essential to stratify patients with end-stage liver disease (ESLD) for prioritization for liver transplantation (OLT). Recently the UNOS has adopted the Mayo Model for End-stage Liver Disease (MELD) score as the basis for liver allocation in the United States. We retrospectively evaluated and assessed the prognostic impact, the length of stay (LOS), and hospital charges for OLT using two severity scores (Child-Turcotte-Pugh [CTP] versus MELD) to stratify cirrhotic patients before OLT. Twenty-six consecutive adult cirrhotic patients (11 women, mean age 46 years) underwent LT between 2000 and 2002. The main causes for transplantation were alcohol and primary biliary cirrhosis. The mean CTP and MELD scores at the moment of listing for OLT were 8.9 and 16.3 points, respectively. The best discriminative values with prognostic impact in terms of outcome and costs of OLT were a Child Pugh score >/=11 points or a MELD score >/=20 points. Patients in these strata showed a significant increase in LOS in the hospital (from a mean of 12 to 22 days) and intensive care stay (from a mean of 4 to 14 days) post-OLT when compared with patients with a lower CTP or MELD score (P <.05). There was also a trend toward higher hospital charges (P =.06). Organ allocation by MELD score will probably adversely affect the LOS and hospital charges of patients being transplanted due to ESLD.

Clinical characterization and survival of adult patients awaiting liver transplantation in Chile.

Liver transplantation has become widely used for patients with decompensated disease. Because of the shortage of donors, each year more patients die on the waiting list. Our aim was to characterize and evaluate the final outcomes of all listed candidates for liver transplantation during a 34-month period. We retrospectively evaluated all adults listed between January 2000 and November 2002. Sixty-three patients (37 women, mean age 45.8 years) were listed: 48 due to chronic liver disease and 15 for a highly urgent transplantation due to acute liver failure. The main etiology of chronic disease was alcoholic (22%) or primary biliary cirrhosis (17%). Of 52 chronic patients, 26 (50%) were transplanted with a mean waiting time of 168 days. Among the others, 8 died (15%) while awaiting transplantation, 3 (5%) were removed from the list, and 15 patients still await transplantation (28%). Among acute liver failure patients, the main etiologies were autoimmune (25%) and medication induced (25%). Of 15 acute patients, 6 (37.5%) have been transplanted at a mean waiting time of 6.8 days with 100% survival posttransplantation. In this cohort, 6 patients (37.5%) died while awaiting liver transplantation, and 4 (25%) survived with medical support. In conclusion, the severity of liver disease and death rate among our waiting list was similar to that observed in developed countries. It seems reasonable to review our current allocation system based on waiting time on the list. We will have to decide whether to transplant sicker patients or those with hepatocarcinoma (as in the United States recently with the MELD system), thereby possibly decreasing the mortality rate on the waiting list at the expense of higher costs and more difficult postoperative care or to just keep our current policy.

Rapid steroid taper and neoral monotherapy in liver transplantation in Chile: a step in the right direction?

UNLABELLED: Diabetes, hypercholesterolemia, hypertension, obesity, osteopenia, and increased risk of viral recurrence are among the complications associated with posttransplant steroid use. Steroid withdrawal or rapid taper has been reported to be safe. The aim of this study was to compare the rejection incidence and severity among patients treated with two different steroid taper strategies. METHODS: This retrospective study included all the adult liver transplant recipients since the program's inception from 1993 to January 2002. The minimum follow-up was 1 year. Exclusions included patients receiving an immunosupressive regimen other than mycophenolate mofetil, steroids, and Neoral, or suffering an autoimmune etiology, or displaying patient or graft survival less than 1 year. The incidence and severity of rejection episodes were compared between the two groups of steroid taper protocols: group A received methylprednisolone (1 g) intraoperatively with a slow taper to 10 mg prednisone per day at 1 year. Group B received methylprednisolone (2 g) intraoperatively followed by a rapid reduction with intention to withdraw by month 4, continuing on Neoral monotherapy. Rejection diagnosis was made on histological bases. RESULTS: One-month and 1-year rejection rates were 47% and 53%, respectively, among the rapid taper group with Neoral monotherapy, which was similar to 60% and 64%, respectively, in the slow taper group. Rejection severity was also comparable between the two groups. CONCLUSIONS: Patients treated with a rapid steroid taper protocol followed by Neoral monotherapy or a slow taper protocol showed similar acute rejection incidences and severities. Their survival rates were also comparable. Further study is necessary to evaluate the impact of rapid steroid taper to prevent the complications of steroid use.

A decade of adult liver transplantation in a single center in Chile.

INTRODUCTION: Since the early days, liver transplantation (OLT) has conquered several barriers worldwide to become a proven therapy. We assessed the evolution of our adult liver transplant program. METHODS: We studied all adult patients who underwent OLT since the inception from November 1993 through May 2003. Donor data, recipient pretransplantation evaluation, surgical technique, results, and costs were examined over our evolution, stratifying 3 groups over time, based on the number of adult OLT per year. RESULTS: Between November 1993 and May 2003, 70 OLT were performed in 64 patients older than 15 years of age. Preoperative Child score, preoperative creatinine level, donor and recipient age, and proportion of emergencies were similar in the 3 groups. Over time, the predominant surgical technique was the piggyback technique (97% of OLT) with a decrease in the use of bypass from 63% to 5% during the last time period. Over the 10 years of our program's existence, warm ischemia time has been reduced to less than 1 hour, whereas cold ischemia time has remained constant at around 5 hours. Biliary and vascular complications decreased over time to around 10%. The mean length of hospital stay (LOS) decreased to 12 days (excluding emergencies). Since inception, our 1-year patient survival rate average is 91%; however, in just the last 3 years of our program (2000 through 2003), the 1-year patient survival rate is 97%. CONCLUSIONS: In summary, our surgical technique has evolved toward piggyback use without veno-venous bypass with a significant decrease in warm ischemia times. As expected, our results have improved over time and our LOS and costs have decreased. Finally, our current results are similar to the best ones reported in the medical literature today.

Trends in mechanical ventilation and immediate extubation after liver transplantation in a single center in Chile.

INTRODUCTION: Some groups have reported early extubation post-liver transplantation in patients with previously defined criteria, in an attempt to shorten the ICU stay and decrease costs. We review our experience with trends in mechanical ventilation and resource utilization. METHODS: We retrospectively reviewed the length of mechanical ventilation, ICU stay, hospital stay, transfusions, and costs of liver transplants performed since the program's inception in 1993 and 2002 including 82 OLT in 71 patients. We also report our experience with immediate postoperative extubation, which we have done from October to December of 2002. We compare different periods: the early days (1993 to 1997), namely, fewer than 10 OLT per year, with the subsequent years assessed individually. RESULTS: There has been a progressive decrease over time in the length of mechanical ventilation, ICU stay, hospital stay, and costs. Since the program's inception actuarial adult patient 1- and 5-year survival rates were 88.7% and 78%, respectively. The 1-year survival rate increased to 97% during the period of 2000 to 2002 (n = 30). From October to the present, we extubated four of seven adult patients who met criteria with none of them requiring reintubation. CONCLUSIONS: We demonstrate improved results, decreased length of mechanical ventilation, ICU, and hospital stay, and costs. The immediate postoperative extubation may be feasible for patients who meet previously defined criteria.

Transcystic cholangiogram access via rubber band with early withdrawal after liver transplantation: a safe technique.

OBJECTIVE: Since different techniques have been described for cholangiogram access after liver transplantation, we compared two different methods for patients with duct-to-duct biliary anastomoses. METHODS: Adult liver transplant patients from program inception in 1993 to May 2003 in whom a duct-to-duct biliary anastomosis with a T-tube choledochostomy were compared with those having a transcystic duct catheter using a rubber band. We excluded 10 patients in which a different technique was used or graft or patient survived less than 21 days. Group A (n = 28,) had a number 10 T-tube exteriorized through the recipient main bile duct; and group B (n = 33) a number 5 Bard ureteral stent tied to the cystic stump with reabsorbable suture and secured with a hemorrhoidal rubber ligature. RESULTS: The biliary complication rate was lower among the transcystic catheter group (9.1%, 3/33) compared to the T-tube group (35.7%, 10/28). Postcatheter withdrawal peritonitis was present in two patients in the T-tube group, one of whom required emergency laparotomy. A satisfactory postoperative cholangiogram was obtained in both groups. The transcystic catheter was withdrawn on average at 29 days, compared to 136 days in the T-tube group. CONCLUSIONS: Both techniques are equally effective in obtaining a satisfactory postoperative cholangiogram. However, the transcystic catheter technique allows a significantly earlier withdrawal with fewer complications compared to the T-tube technique.

IL-2 receptor blockers in liver transplantation: initial experience with daclizumab in Chile.

UNLABELLED: Monoclonal antibodies against the interleukin 2 receptor have been developed in an effort to decrease rejection rates and spare calcineurin inhibitors when renal dysfunction occurs after transplant. While success has been reported in kidney transplantation, its effectiveness in liver transplantation is less clear. METHODS: This prospective nonrandomized study including adult patients was performed between October 2000 and April 2003. Two groups of immunosuppressive regimens were compared: group A received 2 g of methylprednisolone intraoperatively followed by a rapid reduction with intention to withdraw by month 4, continuing on Neoral monotherapy. Cellcept was also given for 2 months in the absence or for up to 4 months in the presence of rejection. Group B received the same immunosuppressive regimen but, in addition, daclizumab 1 to 1.5 mg/kg on day 1 and day 5 posttransplant. Rejection diagnosis is made on histology basis. Protocol biopsies were performed in all the patients on day 7 and if indicated by biochemistry thereafter. RESULTS: Both groups were similar in terms of preoperative CHILD score, serum creatinine, incidence of status I, donor and recipient age and ischemia times. The mean follow-up time was 20 months for Group B (n = 24) and 7 months for Group A (n = 10). The 1-month and 1-year rejection rates are 29.1% and 41% in Group A versus 20% and 30% in group B. Rejection severity was similar between both groups. One-year patient and graft survival rates were 96% and 92% in group A and 100% for both in Group B. CONCLUSIONS: In this series, daclizumab induction therapy seems to display a trend toward a lower rejection rate without increasing infectious complications nor affecting graft survival rates.

[Chronic pancreatitis. A recent national experience with its surgical management]. / Pancreatitis crónica; una experiencia nacional reciente de su manejo quirúrgico.

BACKGROUND: The prevalence of chronic pancreatitis in Chile is not known and there is no local information about the surgical treatment of this disease. AIM: To review retrospectively the results of surgical treatment of chronic pancreatitis. MATERIAL AND METHODS: The charts of 17 patients (12 male), aged 7 to 65 years old, with chronic pancreatitis that were operated in three different Chilean regions, were reviewed. RESULTS: Seven patients had previous endoscopic therapeutic procedures (papillotomy in 4 and stent placing in 3). Seven patients had been subjected to previous biliary surgical procedures. Indications for surgery were severe pain in 14 patients, the suspicion of a pancreatic carcinoma in 4 patients, an infected pseudocyst in one and massive bleeding of multiple pseudo-aneurysms in a pseudocyst in one patient. Twelve patients were subjected to decompressions and 5 to pancreatic resections. There was no operative mortality and one transient pancreatic fistula. After an average follow up of 22 months, pain improved in 94% of cases, pancreatic cancer was diagnosed in one patient and 79% of subjects gained weight. One patient became insulin dependent, one increased his insulin requirements and one had transient steatorrhea, since she could not afford pancreatic enzyme replacement therapy. CONCLUSIONS: The multidisciplinary approach of patients with chronic pancreatitis, with selective use of surgery, may greatly improve their quality of life.

Affinity labelling of frog brain opioid receptors by dynorphin(1-10) chloromethyl ketone.

It has been previously found that chloromethyl ketone derivatives of enkephalins bind irreversibly to the opioid receptors in vitro. Recently a novel affinity reagent, Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Gly chloromethyl ketone (Dynorphin(1-10)-Gly11 chloromethyl ketone, DynCMK) was synthesized, and its binding characteristics to frog (Rana esculenta) brain membranes were evaluated. In competition experiments, the product shows a relatively high affinity for the kappa-opioid binding sites labelled by [3H]ethylketocyclazocine (Ki is approximately equal to 200 nM), whereas its binding to the 1 ([3H]dihydromorphine) and to the delta sites ([3H]D-Ala2-Leu5]enkephalin) is weaker. Preincubation of the frog brain membranes with DynCMK at micromolar concentrations results in a washing-resistant and dose-dependent inhibition of the [3H]ethylketocyclazocine binding sites. Saturation binding analysis of the membranes preincubated with 50 microM DynCMK reveals a significant decrease in the number of specific binding sites for [3H]ethylketocyclazocine compared to the control values. The kappa-preferring binding properties of the compound suggest that it could serve as an affinity label for the kappa-type of opioid receptors.

Synergistic interaction of adenylate cyclase activators and nitric oxide donor SIN-1 on platelet cyclic AMP.

The molecular mechanism of the synergistic platelet inhibition by activators of adenylate cyclase and guanylate cyclase in human platelets was investigated. The adenylate cyclase activators iloprost and prostaglandin E1 and the guanylate cyclase activator 3-morpholino-syndnonimine (SIN-1) dose-dependently inhibited thrombin-induced aggregation of washed human platelets. Furthermore, SIN-1 at a concentration inhibiting platelet aggregation by only 10% shifted the IC50 values of iloprost and prostaglandin E1 by one order of magnitude to the left, indicating a synergistic action of adenylate cyclase and guanylate cyclase activators. Iloprost and prostaglandin E1 dose-dependently elevated platelet cAMP without a significant influence on cGMP. In contrast, the platelet cGMP level was dose-dependently elevated by SIN-1. In addiiton, SIN-1 markedly increased cAMP level induced by low concentrations of adenylate cyclase activators (0.1-0.3 nM iloprost or 10-150 nM prostaglandin E1). In contrast, the rise in cAMP induced by higher adenylate cyclase activator concentrations (3 nM iloprost or 30 microM prostaglandin E1) was significantly reduced in the presence of SIN-1. The same biphasic mode of action of SIN-1 was observed with forskolin, an adenylate cyclase stimulator acting receptor independently, indicating a prostacyclin-receptor independent mechanism. The cAMP elevating effect of SIN-1 in the presence of low prostanoid concentrations was completely abolished by piroximone, a selective inhibitor of phosphodiesterase type III. Therefore, the inhibition of phosphodiesterase III by cGMP seems to be the mechanism for the elevation of cAMP levels by SIN-1 in the presence of low concentration of adenylate cyclase activators in human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)