Georgios Tsoulfas

Survival outcomes in liver transplantation for hepatocellular carcinoma, comparing impact of hepatitis C versus other etiology of cirrhosis

The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide as the most common primary hepatic malignancy. In the US approximately one half of all HCC is related to Hepatitis C virus (HCV) infection. The relationship between the primary disease and HCC recurrence after liver transplantation is unknown. We hypothesized that the primary hepatic disease underlying the development of cirrhosis and HCC would be associated with the risk of recurrent HCC after transplantation. A retrospective review was conducted of all primary liver transplants performed at the University of Rochester Medical Center from May 1995 through June 2004. The pathology reports from the native livers of 727 recipients were examined for the presence of HCC. There were 71 liver transplant recipients with histopathological evidence of HCC. These patients were divided in two groups on the basis of HCV status. Group 1 consisted of 37 patients that were both HCV and HCC positive, and Group 2 consisted of 34 patients that were HCC positive but HCV negative. Patient characteristics were analyzed, as well as number of tumors, tumor size, presence of vascular invasion, lobe involvement, recipient demographics, donor factors, pretransplantation HCC therapy, rejection episodes, and documented HCC recurrence and treatment. There were no statistically significant differences between the 2 groups, with the exception of recipient age and the presence of hepatitis B coinfection. The tumor characteristics of both groups were similar in numbers of tumors, Milan criteria status, vascular invasion, incidental HCC differentiation, and largest tumor size. The HCV positive population had a far lower patient survival rate with patient survival in Group 1 at 1, 3, and 5 years being 81.1%, 57.4%, and 49.3% respectively, compared with 94.1%, 82.8%, and 76.4% in Group 2 (p = 0.049). Tumor‐free survival in Group 1 at 1, 3, and 5 years was 70.3%, 43%, and 36.8% respectively, vs. 88.1%, 73%, and 60.8% in Group 2. In a subgroup analysis, tumor‐free survival was further examined by stratifying the patients on the basis of Milan criteria. Group 1 patients outside of Milan criteria had a statistically lower tumor‐free survival. By contrast, there was no statistical difference in tumor‐free survival in Group 2 patients stratified according to Milan criteria. Cox regression analysis identified HCV and vascular invasion as significant independent predictors of tumor‐free survival. Our results suggest that Milan selection criteria may be too limiting and lose their predictive power when applied to patients without HCV infection. Liver Transpl 13:807–813, 2007.

Minimizing Morbidity of Organ Donation: Analysis of Factors for Perioperative Complications After Living-Donor Nephrectomy in the United States

Background. Expansion of living kidney donation through liberalizing acceptance criteria invites a renewed focus on safety and outcomes. Wide variability exists in reported donor complications, and associated risk factors are ill defined. Use of administrative data can overcome the bias of single-center studies and identify variables associated with untoward events. Methods. The study population consisted of 3074 living kidney donors from 28 centers during 2004 and 2005. Data from a large healthcare registry were used to retrospectively identify the study cohort. Perioperative complications were identified using ICD-9-CM coding and classified according to the Clavien system. Logistic regression models were constructed to identify donor and center factors associated with complications. Results. There were no perioperative deaths. The overall complication rate was 10.6% and major complications defined by Clavien grade ≥3 was 4.2%. The prevalence of tobacco use, obesity, and hypertension, was 7.8%, 2.4%, and 2.3%, respectively. Age >50 (odds ratio [OR]=1.81, 95% confidence interval [95% CI]=1.25–2.61), tobacco use (OR=1.41, 95% CI=1.02–1.94), obesity (OR=1.92, 95% CI=1.06–3.46), and annual center volume ≤50 (OR=2.28, 95% CI=1.68–3.09), were significantly associated with overall morbidity, however only annual center volume ≤50 (OR=2.07, 95% CI=1.27–3.37) was significantly associated with a risk of major complications. Conclusions. The inclusion of donors with tobacco abuse, obesity, and age >50 increases complications; however, the risk of major morbidity is small. Use of administrative data represents an important tool to facilitate the reconciliation of an increased need for organ donors with the concern for donor safety.

The Cumulative Effects of Cold Ischemic Time and Older Donor Age on Liver Graft Survival

INTRODUCTION To provide greater equity among those awaiting a liver transplant, expanded geographic sharing of cadaveric organs has been proposed. A potential unintended consequence could be an increase in cold ischemia time (CIT), which may be deleterious to organs from older donors. This study sought to quantify the relative risk (RR) associated with increased CIT among older donors. METHODS A retrospective study examining 18,787 liver transplants within the United Network for Organ Sharing database from 2002 to 2006 was performed. Cox Regression analysis was used to model the RR of graft loss with respect to increased CIT among older donors (>60 years) relative to younger donors (<60 years), while controlling for multiple donor and recipient characteristics. RESULTS Relative to younger donors with minimal CIT (<6 h), a 73.0% increase in the risk of graft loss was observed for older donors with a CIT between 8 and 10 h, a 56.9% increase for CIT between 10 and 12 h, and a 92.7% increase for a CIT of 12 or more hours. Additionally, the RR of graft loss for older donors with minimal CIT (<6 h) was greater than the RR for younger donors with a CIT between 0 and 12 h. CONCLUSION The additive effects of increased donor age and cold ischemic time greatly impair graft survival. Quantification of the adverse nature of increasing CIT as a potential consequence of wider geographic organ sharing should be considered as allocation policies are modified to improve recipient equity in the face of an aging donor pool.

Surgical treatment for large hepatocellular carcinoma: does size matter?

Despite significant progress in the management of hepatocellular carcinoma (HCC), patients with large HCC (defined as >10 cm) continue to present a significant challenge. The goal of this paper is to review the existing literature regarding large HCC, with emphasis on identifying the issues and challenges involved in approaching these tumours surgically. A computerized search was made of the Medline database from January 1992 to December 2010. The MESH heading ‘large’ or ‘huge’ in combination with the keyword ‘hepatocellular carcinoma’ was used. After excluding further studies that identified ‘large’ HCC as less than 10 cm and/or sequential publications with overlapping patient populations, the search produced a study population of 22 non‐duplicated papers, reporting on a total of 5223 patients with HCC tumours >10 cm. Regarding resection for large HCC, the overall 5‐year survival in these studies ranged from 25% to 45%, with few outliers on both sides, whereas in most studies, the 5‐year disease‐free survival ranged between 15% and 35%, with the only exception being studies with patients with single lesions and no cirrhosis showing disease‐free survival of 41% and 56%, respectively. Risk factors identified included vascular invasion, cirrhosis, high level of alpha‐fetoprotein and the presence of multiple lesions. Finally, liver transplantation, although an attractive concept, did not appear to offer a survival benefit in any of the studies. In conclusion, identifying the risk factors that affect the outcome in patients undergoing surgery for large HCC is critical. The reason is that surgical resection can have excellent outcomes in carefully selected patients.

Pharmacokinetics of mycophenolic acid in liver transplant patients after intravenous and oral administration of mycophenolate mofetil

The bioavailability of mycophenolic acid (MPA) after oral administration of mycophenolate mofetil (MMF) has been reported to be more than 90% in healthy volunteers, and in kidney and thoracic organ transplant patients. Such information is limited in liver transplant (LTx) patients. The present study compares the pharmacokinetics of MPA after intravenous (IV) and oral administrations of MMF in LTx recipients. Pharmacokinetic parameters were calculated using WinNonlin software. A total of 12 deceased donor LTx patients initially received IV MMF and were switched to oral MMF after 2‐7 days (mean, 3.3 ± 1.7) when oral feeds were started. Multiple blood samples were drawn immediately prior to and after IV or oral MMF and the plasma concentration of MPA was measured. The mean peak plasma concentrations and the area under the plasma concentration vs. time curve (AUC) were significantly higher after IV MMF compared to oral MMF (peak plasma concentrations of 10.7 ± 2.1 μg/mL for IV vs. 4.5 ± 2.8 μg/mL for oral; P = 0.0001; and AUC of 28.9 ± 7.1 μg · hr/mL for IV vs. 12.8 ± 4.2 μg · hr/mL for oral; P = 0.0001). The oral bioavailability of MPA was 48.5 ± 18.7%. The systemic clearance, half‐life, and steady state volume of distribution of MPA were 26.9 ± 6 L/hour, 5.5 hours, and 85 liters, respectively. The terminal disposition half‐life was not significantly different between the 2 routes of administration. In conclusion, during the early postoperative period, LTx recipients have MPA exposure with oral MMF of less than half that of IV MMF. Use of IV MMF immediately post‐LTx may provide an immunological advantage. Liver Transpl 13:791–796, 2007.

Stratifying risk of biliary complications in adult living donor liver transplantation by magnetic resonance cholangiography.

Background. Accurate preoperative assessment of biliary anatomy in live donor hepatectomy may be helpful to assess the suitability of a graft and to stratify risk of biliary complications. Methods. A retrospective review of existing data among donor and recipients of 36 living donor transplants was performed to assess role of preoperative magnetic resonance cholangiography (MRC) for defining biliary anatomy and to stratify risk of biliary complications. Results. Thirty-six living liver donors underwent MRC, and subsequently right lobectomy. Intraoperative cholangiography and biliary exploration revealed that 24 donors (66.6%) had conventional and 12 (33.3%) had aberrant biliary anatomy. Intraoperative cholangiography demonstrated a strong correlation with MRC (P=0.001) and intraoperative findings (P=0.001). MRC had specificity and positive predictive value of 100%. The risk of developing biliary complication was 5.9 times higher if the biliary anatomy was of any type other than A (P=0.03, CI 1.06–32.9) after controlling for donor age, recipient age, and type of anastomosis. Conclusion. MRC reliably identified variant biliary anatomy. The preoperative MRC demonstrated congruence with the intraoperative cholangiogram and with the intraoperative findings. MRC is helpful in predicting risk of biliary complications in recipients, and identifies donors who would otherwise be excluded intraoperatively by cholangiography, thus limiting the risk of an unnecessary operation.

Impact of double-j ureteric stent in kidney transplantation: single-center experience.

We retrospectively evaluated the use of double-j stent and the incidence of urological complications in 2 groups of patients who received a kidney transplant. From January 2005 to September 2007 we studied 172 patients receiving kidney transplants, 65 and 107 from living and cadaver donors, respectively. From the 172 patients, a total of 34 were excluded due to ureterostomy or Politano-Leadbetter ureterovesical anastomosis. Another 21 patients were excluded from the study due to graft loss due to acute or hyperacute rejection, cytomegalovirus (CMV) infection, or vascular complication. The remaining patients were divided into 2 groups: group A (44 patients) and B (73 patients) with versus without the use of a double-j-stent, respectively. The 2 groups were comparable in terms of donor and recipient gender, ischemia time, and delayed graft function. We failed to observes significant differences between the 2 groups in mean hospital stay (23 +/- 9 and 19 +/- 9), urinary leak (2.3% and 4.1%), and urinary tract infection (20.4% and 19.2%), among groups A and B, respectively. The only difference observed concerned the gravity of the urinary leak; no surgical intervention was needed among the double-j stent group versus 2 patients demanding ureterovesical reconstruction in the nonstent group. In conclusion, our data suggested that the routine use of a double-j stent for ureterovesical anastomosis neither significantly increased urinary tract infection rates, nor decreased the incidence of urinary leaks, but may decrease the gravity of the latter as evidenced by the need for surgical intervention.

Surgical treatment of hepatic metastases from colorectal cancer

Colorectal carcinoma is one of the most frequent cancers in Western societies with an incidence of around 700 per million people. About half of the patients develop metastases from the primary tumor and liver is the primary metastatic site. Improved survival rates after hepatectomy for metastatic colorectal cancer have been reported in the last few years and these may be the result of a variety of factors, such as advances in systemic chemotherapy, radiographic imaging techniques that permit more accurate determination of the extent and location of the metastatic burden, local ablation methods, and in surgical techniques of hepatic resection. These have led to a more aggressive approach towards liver metastatic disease, resulting in longer survival. The goal of this paper is to review the role of various forms of surgery in the treatment of hepatic metastases from colorectal cancer.

Successful, combined long-term treatment of cerebral aspergillosis in a liver transplant patient.

Invasive aspergillosis has long been recognized as one of the most significant and often fatal opportunistic fungal infections in liver transplant recipients. We report a case of a liver transplant recipient who developed an Aspergillus fumigatus brain abscess that produced significant neurologic symptoms. The patient was managed successfully with a combination of surgery and medical treatment with Voriconazole. To our knowledge, this is the second such case reported in the literature.

Developing an International Combined Applied Surgical Science and Wet Lab Simulation Course as an Undergraduate Teaching Model

Background. Essential Skills in the Management of Surgical Cases (ESMSC) is an international, animal model-based course. It combines interactive lectures with basic ex vivo stations and more advanced wet lab modules, that is, in vivo dissections and Heart Transplant Surgery on a swine model. Materials and Methods. Forty-nine medical students (male, N = 27, female N = 22, and mean age = 23.7 years) from Kings College London (KCL) and Greek Medical Schools attended the course. Participants were assessed with Direct Observation of Procedural Skills (DOPS), as well as Multiple Choice Questions (MCQs). Paired t-test associations were used to evaluate whether there was statistically significant improvement in their performance. Aim. To evaluate the effectiveness of a combined applied surgical science and wet lab simulation course as a teaching model for surgical skills at the undergraduate level. Results. The mean MCQ score was improved by 2.33/32 (P < 0.005). Surgical skills competences, as defined by DOPS scores, were improved in a statically significant manner (P < 0.005 for all paired t-test correlations). Conclusions. ESMSC seems to be an effective teaching model, which improves the understanding of the surgical approach and the basic surgical skills. In vivo models could be used potentially as a step further in the Undergraduate Surgical Education.