Cardiac work-up protocol for liver transplant candidates: Experience from a single liver transplant centre

BACKGROUND:

Ischemic cardiac events can cause significant morbidity and mortality postliver transplantation; however, no validated protocols to screen patients before transplantation exist.

OBJECTIVES:

To report the introduction of a noninvasive cardiac screening protocol used at the Liver Unit, University of Calgary (Calgary, Alberta); to determine whether the protocol decreases use of coronary angiograms; and to compare cardiac outcomes using the new protocol with an appropriately matched historical control group.

METHODS:

A new cardiac screening protocol was introduced into the program in 2005, which uses perfusion scintigraphy to screen high-risk cardiac patients, reserving coronary angiograms for abnormal results. Transplanted patients screened using this protocol were compared with matched historical controls. Electronic charts were reviewed for cardiac outcomes intra- and postliver transplantation.

RESULTS:

A total of 396 patients were screened between April 2005 and February 2009. Eighty-two were transplanted by February 2009 and included in the study. Eighty-one patients were successfully matched according to age, sex, cardiac history and presence of diabetes. Twelve of 82 (14.6%) and 11 of 81 (13.6%) in the study and control groups, respectively, underwent coronary angiograms (P=0.85). Coronary artery disease was found in six of 12 (50.0%) study patients and three of 11 (27.3%) control patients who underwent coronary angiography (P=0.27). The mean (± SD) length of the follow-up period was 1.87±0.91 years and 4.45±1.89 years in the study and control groups, respectively. One of 81 in the control group and zero of 82 in the study group experienced an acute coronary syndrome event postoperatively.

CONCLUSIONS:

Coronary events are infrequent in liver transplant recipients. The described protocol is an effective method of coronary artery disease screening before liver transplant but does not reduce the number of cardiac investigations performed.     

The natural history of inflammatory bowel disease and primary sclerosing cholangitis after liver transplantation �C a single-centre experience

OBJECTIVE:

To describe the natural history of primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) after liver transplant, the predictors of PSC and IBD recurrence, and the interaction of these disease processes.

METHODS:

Data regarding patients who received liver transplants for PSC at the University of Alberta Hospital (Edmonton, Alberta) from 1989 to 2006 were retrospectively reviewed. Recurrent PSC (rPSC) was defined by the Mayo Clinic criteria. Cox proportional hazards modelling and Kaplan-Meier statistics were used.

RESULTS:

Fifty-nine patients were studied, with a median follow-up of 68 months. A total of 71.2% of patients were diagnosed with IBD pre-transplant. Clinical IBD severity post-transplant compared with severity pretransplant was unchanged in 67%, worse in 26.5% and improved in 6.1% of patients. Twenty-five per cent of patients developed rPSC post-transplant. The occurrence of at least one episode of acute cellular rejection (hazard ratio 5.7; 95% CI 1.3 to 25.8) and cytomegalovirus mismatch (hazard ratio 4.2; 95% CI 1.1 to 15.4) were found to be significant predictors of rPSC. Although not statistically significant, there was no rPSC in patients without pre- or post-transplant IBD, and in only one patient with a colectomy. Actuarial patient survival rates at one, five and 10 years post-transplant were 97%, 86% and 79%, respectively. Although a significant proportion of patients experienced worsening IBD post-transplantation, the presence or severity of IBD did not influence rPSC or patient survival.

CONCLUSION:

Acute cellular rejection and cytomegalovirus mismatch were both identified as independent predictors of rPSC. The impact of steroids and the ideal immunosuppressive regimen for the control of both IBD and PSC post-transplant requires further examination in prospective studies.     

Influence of apoptosis (BCL2, FAS), cell cycle (CCND1) and growth factor (EGF, EGFR) genetic polymorphisms on survival outcome: an exploratory study in squamous cell esophageal cancer

The study aimed at investigating whether genetic polymorphisms in BCL2, FAS, CCND1, EGF and EGFR genes influence the outcome of patients of esophageal squamous cell cancer treated with radiotherapy, with or without chemotherapy. Sixty nine histologically confirmed, previously untreated, patients with a squamous cell esophageal cancer were inducted into this study. Genotyping of BCL2 (ala43thr), FAS (A-670G), CCND1 (G870A), EGF (+61A/G) and EGFR (G497A) polymorphisms were determined using the polymerase chain reaction followed by restriction fragment length polymorphism methodology. Genotyped data was analyzed using univariate and multivariate logistic regression statistical tests for predicting the survival outcome. Genotypes of BCL2, FAS, CCND1 and EGFR polymorphisms independently did not influence outcome significantly. However, patients with EGF +61AG genotype had median survival of 25.5 months (95% CI = 5.2-45.5), whereas those with EGF +61GG genotype had survival of only 3.7 months (95% CI = 0.0-9.8, p = 0.006). In univariate cox-regression analysis, interaction of genotypes EGF+61GG*radiotherapy tumor dose (< or =50 Gy) and EGF +61GG *upper third tumor location showed high hazard of death, 6.6 (95% CI = 2.0-21.5, p = 0.002) and 26.8 (95% CI = 3.7-194.2, p = 0.001) while EGF+61AG*middle third tumor location had reduced hazard 0.20 (95%CI = 0.06-0.60, p = 0.004). The pilot study suggests that EGF +61AG and +61GG genotypes may predict clinical outcome in esophageal cancer patients treated with radiotherapy with or without chemotherapy. EGF +61AG genotype was associated with improved survival, however +61GG genotype adversely affected the outcome in patients particularly with upper third location of tumor and lower dose (< or =50) of radiotherapy.     

Expression and function of lysophosphatidic acid LPA1 receptor in prostate cancer cells

The bioactive phospholipid lysophosphatidic acid (LPA) promotes cell proliferation, survival, and migration by acting on cognate G protein-coupled receptors named LPA(1), LPA(2), and LPA(3). We profiled gene expression of LPA receptors in androgen-dependent and androgen-insensitive prostate cancer cells and found that LPA(1) gene is differentially expressed in androgen-insensitive and LPA-responsive but not androgen-dependent and LPA-resistant cells. In human prostate specimens, expression of LPA(1) gene was significantly higher in the cancer compared with the benign tissues. The androgen-dependent LNCaP cells do not express LPA(1) and do not proliferate in response to LPA stimulation, implying LPA(1) transduces cell growth signals. Accordingly, stable expression of LPA(1) in LNCaP cells rendered them responsive to LPA-induced cell proliferation and decreased their doubling time in serum. Implantation of LNCaP-LPA(1) cells resulted in increased rate of tumor growth in animals compared with those tumors that developed from the wild-type cells. Growth of LNCaP cells depends on androgen receptor activation, and we show that LPA(1) transduces Galphai-dependent signals to promote nuclear localization of androgen receptor and cell proliferation. In addition, treatment with bicalutamide inhibited LPA-induced cell cycle progression and proliferation of LNCaP-LPA(1) cells. These results suggest the possible utility of LPA(1) as a drug target to interfere with progression of prostate cancer.     

The effect of 1 month of therapy with midodrine,octreotide‐LAR and albumin in refractory ascites: a pilot study

Background: The pathogenesis of refractory ascites (RA) is linked to splanchnic vasodilation. We hypothesized that a combination of midodrine, octreotide long‐acting release (LAR) and albumin would result in increased natriuresis, better control of ascites and an improvement in renal function in patients with RA±Type 2 hepatorenal syndrome. Methods: A prospective pilot study in patients with RA as defined by the International Ascites Club. Consecutive patients received an intramuscular injection of octreotide‐LAR, 50 g of albumin three times per week and midodrine titrated to increase the systolic blood pressure for 1 month. Results: Ten patients with RA were enrolled and eight with complete data to 1 month post‐treatment were included in the analysis. There was no change in renal function but there was a trend towards a reduction in the volume of ascites removed by paracentesis (P=0.08) and a significant reduction in the plasma renin (P=0.01) and aldosterone concentrations (P=0.01). Interestingly, there was a transient worsening in the model for end‐stage liver disease (MELD) score (P=0.01). The deterioration in MELD was completely reversible after discontinuation of therapy. Conclusions: To our knowledge, this is the first study of prolonged midodrine, octreotide and albumin therapy in RA. We observed a significant reduction in the plasma renin and aldosterone concentrations and a trend towards a reduction in the volume of ascites removed by paracentesis without an effect on renal function. The beneficial effects are at the expense of a reversible deterioration in the MELD score. Large controlled trials are needed before this therapy can be routinely recommended.     

Prognostic indicators in hepatocellular carcinoma: a systematic review of 72 studies

Background: Although there are many studies of the predictors of death in hepatocellular carcinoma (HCC), most combine patients with and without cirrhosis and many combine those with compensated and decompensated cirrhosis. Objective: To perform a systematic review of the literature evaluating the predictors of death in patients with cirrhosis and HCC and to evaluate whether the predictors differ between patients with compensated and decompensated cirrhosis. Methods: Inclusion criteria: (i) publication in English, (ii) adult patients, (c) >80% of the patients had cirrhosis, (iv) follow‐up >6 months and (v) multivariable analysis. Quality was based on the accepted quality criteria for prognostic studies. Results: Of the 1106 references obtained, 947 were excluded because they did not meet the inclusion criteria. A total of 23 968 patients were included in 72 studies (median, 177/study); 77% male, median age 64, 55% Child–Pugh class A. The most robust predictors of death were portal vein thrombosis, tumour size, α‐foetoprotein and Child–Pugh class. Sensitivity analysis using only 15 ‘good’ studies and 22 studies in which all patients had cirrhosis yielded the same variables. In the studies including mostly compensated or decompensated patients, the predictors were both liver and tumour related. However, these studies were few and the results were not robust. Conclusions: This systematic review of 72 studies shows that the most robust predictors of death in patients with cirrhosis and HCC are tumour related and liver related. Future prognostic studies should include these predictors and should be performed in specific patient populations to determine whether specific prognostic indicators are more relevant at different stages of cirrhosis.