M. Gastaca

Management of Hepatocellular Carcinoma Recurrence After Liver Transplantation

UNLABELLED Management of patients with hepatocellular carcinoma (HCC) recurrence after liver transplantation (OLT) is not well established. We conducted a retrospective analysis of our results in the treatment of HCC recurrence after OLT Patients. The 23 HCC recurrences developed after 182 OLT performed for HCC within Milan criteria, had an average follow-up of 60 months. RESULTS The median time to recurrence was 23.4 months. Surgical resection of the recurrence was possible in 11 patients, but an R-0 resection was obtained in 8 patients. Four of these 8 patients developed another recurrence, with 3 succumbing due to tumor recurrence and 1 alive at 12 months with recurrence. The other 4 patients without recurrences, include 3 who are alive at 19, 31, and 86 months and 1 who died at 32.6 months due to hepatitis C recurrence. The 3 patients with palliative resections developed recurrences. Twelve patients were rejected for surgery: 8 were treated symptomatically, 2 with systemic chemotherapy, and 2 with everolimus and sorafenib. This last treatment was also prescribed for 2 patients after R-0 surgery who are alive at 19 and 31 months and for 1 patient after R-1 surgery who is alive at 19 months. Of 15 patients who died, 13 succumbed to HCC recurrence. The average survival from transplantation was 61.7 +/- 37.5 and 48 +/- 34.3 months for patients without and with recurrence, respectively (P < .001). The survival from the recurrence was significantly higher among patients with R-0 surgery: 32.3 +/- 21.5 versus 11.9 +/- 6.9 months (P = .006). CONCLUSIONS HCC recurrence after OLT of patients within Milan criteria was low but had a great impact on survival. Few cases are amenable to R-0 resection, but when possible it was associated with a significantly increased survival, although with an high incidence of a new recurrence. There is a rationale for the use of sorafenib and mammalian target of rapamycin based immunosuppression, which warrants randomized studies.

Intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation: a Spanish matched cohort multicenter study.

Objective:To evaluate the outcome of patients with hepatocellular-cholangiocarcinoma (HCC-CC) or intrahepatic cholangiocarcinoma (I-CC) on pathological examination after liver transplantation for HCC. Background:Information on the outcome of cirrhotic patients undergoing a transplant for HCC and with a diagnosis of HCC-CC or I-CC by pathological study is limited. Methods:Multicenter, retrospective, matched cohort 1:2 study. Study group: 42 patients undergoing a transplant for HCC and with a diagnosis of HCC-CC or I-CC by pathological study; and control group: 84 patients with a diagnosis of HCC. I-CC subgroup: 27 patients compared with 54 controls; HCC-CC subgroup: 15 patients compared with 30 controls. Patients were also divided according to the preoperative tumor size and number: uninodular tumors 2 cm or smaller and multinodular or uninodular tumors 2 cm or larger. Median follow-up: 51 (range, 3–142) months. Results:The 1-, 3-, and 5-year actuarial survival rate differed between the study and control groups (83%, 70%, and 60% vs 99%, 94%, and 89%, respectively; P < 0.001). Differences were found in 1-, 3-, and 5-year actuarial survival rates between the I-CC subgroup and their controls (78%, 66%, and 51% vs 100%, 98%, and 93%; P < 0.001), but no differences were observed between the HCC-CC subgroup and their controls (93%, 78%, and 78% vs 97%, 86%, and 86%; P = 0.9). Patients with uninodular tumors 2 cm or smaller in the study and control groups had similar 1-, 3-, and 5-year survival rate (92%, 83%, 62% vs 100%, 80%, 80%; P = 0.4). In contrast, patients in the study group with multinodular or uninodular tumors larger than 2 cm had worse 1-, 3-, and 5-year survival rates than their controls (80%, 66%, and 61% vs 99%, 96%, and 90%; P < 0.001). Conclusions:Patients with HCC-CC have similar survival to patients undergoing a transplant for HCC. Preoperative diagnosis of HCC-CC should not prompt the exclusion of these patients from transplant option.

“Very Early” Intrahepatic Cholangiocarcinoma in Cirrhotic Patients: Should Liver Transplantation Be Reconsidered in These Patients?

A retrospective cohort multicenter study was conducted to analyze the risk factors for tumor recurrence after liver transplantation (LT) in cirrhotic patients found to have an intrahepatic cholangiocarcinoma (iCCA) on pathology examination. We also aimed to ascertain whether there existed a subgroup of patients with single tumors ≤2 cm (“very early”) in which results after LT can be acceptable. Twenty‐nine patients comprised the study group, eight of whom had a “very early” iCCA (four of them incidentals). The risk of tumor recurrence was significantly associated with larger tumor size as well as larger tumor volume, microscopic vascular invasion and poor degree of differentiation. None of the patients in the “very early” iCCA subgroup presented tumor recurrence compared to 36.4% of those with single tumors >2 cm or multinodular tumors, p = 0.02. The 1‐, 3‐ and 5‐year actuarial survival of those in the “very early” iCCA subgroup was 100%, 73% and 73%, respectively. The present is the first multicenter attempt to ascertain the risk factors for tumor recurrence in cirrhotic patients found to have an iCCA on pathology examination. Cirrhotic patients with iCCA ≤2 cm achieved excellent 5‐year survival, and validation of these findings by other groups may change the current exclusion of such patients from transplant programs.

Liver transplantation for hepatocellular carcinoma in cirrhotic patients

A consecutive series of 88 patients underwent transplantation for hepatocellular carcinoma with cirrhosis over a 7-year period. Liver transplantation was indicated because of the tumor in 75 cases (85.2%); tumor was an incidental finding in 13 cases (14.8%). One patient was retransplanted due to primary nonfunction. The perioperative mortality was 4.5%. Tumor recurrence was observed in seven patients (7.95%) with incidental tumor recurrence in one case. As in patients with known primary liver tumors pretransplant, a thorough follow-up is advisable to establish an early diagnosis of recurrence. The actuarial survival for nonincidental hepatocellular carcinoma at 1, 3, and 5 year was 92%, 77%, and 75%, respectively. The differences in actuarial survival between hepatitis C negative and positive hepatocellular carcinoma were not significant (log-rank test P=.27), though there was a clear improvement in results (94%, 85%, and 78% vs 90%, 71%, and 71%), at 1, 3, and 5 years meaning that HCV infection is an important prognostic factor. Although transplantation for HCC has the advantages of removing the tumor and the cirrhotic liver, it remains a controversial topic. In our experience patients showing lesions less than 5 cm or three or fewer lesions experience an equivalent survival to transplanted patients who do not have cancer.

Survival and Hepatitis C Virus Recurrence After Liver Transplantation in HIV- and Hepatitis C Virus–Coinfected Patients: Experience in a Single Center

INTRODUCTION Posttransplant hepatitis C virus (HCV) recurrence has been shown to negatively impact graft and patient survivals. It has been suggested that HCV recurrence among HIV- and HCV-coinfected transplant recipients is even more aggressive. OBJECTIVE To compare the histological severity and survival of posttransplant HCV recurrence between HIV- and HCV-coinfected and HCV-monoinfected patients. PATIENTS AND METHODS Among 72 adult patients who underwent primary liver transplantation at our institution for HCV-related cirrhosis between October 2001 and April 2007. We excluded one coinfected patient who died on postoperative day 5 leaving 12 HIV- and HCV-coinfected patients for comparison with 59 monoinfected patients. When listed, all coinfected patients fulfilled the criteria of the Spanish Consensus Document for transplantation in HIV patients. Immunosuppression did not differ between the two groups: all were treated with tacrolimus + steroids (slow tapering). Aggressive HCV recurrence was defined as cholestatic hepatitis and/or a fibrosis grade > or =2 during the first posttransplant year. RESULTS Coinfected patients were younger than monoinfected patients: 45 +/- 6 years vs 55 +/- 9 years (P = .0008). There were no differences in Child score, Model for End-stage Liver Disease score, donor age, graft steatosis, ischemia time, HCV pretransplant viral load or genotype between the groups. Significant rejection episodes were also equally distributed (25% vs 14%; P = .38). Seven coinfected patients and 29 monoinfected patients developed aggressive HCV recurrences (58% vs 49%; P = .75). Median follow-up was 924 days. Global survival at 3 years was 80%. Survivals at 1, 2, and 3 years were 83%, 75%, 62% in the coinfected vs 98%, 89%, 84% in the monoinfected patients, respectively (log-rank test = 0.09). CONCLUSIONS The severity of histological recurrence was similar among HIV- and HCV-coinfected and monoinfected HCV liver recipients in the first posttransplant year. Mortality attributed to recurrent HCV was similar in the groups. There were no short-term (3-year) differences in survival between the two groups of patients.

Reducing the incidence of incisional hernia after liver transplantation

Two important issues must be considered when deciding the abdominal incision for a liver transplant (LT): a good access to both liver lobes and a reduced rate of woundrelated morbidity. Historically, two incisions have been recommended for a LT: the classic Mercedes incision [1] and the subcostal bilateral incision [2]. Nevertheless, in recent years, the right subcostal incision with medial extension to xyphoid process (J-shaped incision) has arisen as a good option for liver surgery [3]. The reported frequencies of incisional hernia after LT range from 4.9% to 17.2% and several factors such as older age, acute rejection with steroids treatment, ascites or wound infection seem to be associated [4–7]. In a recent article from UCLA, an incidence of 4.6% of incisional hernia was reported after LT through a Mercedes incision [4]. The authors found that reoperation, pulmonary complications and the male gender were associated risk factors for incisional hernia. Comparing the outcome using the J-shaped incision and the classic Mercedes incision for LT, Heisterkamp et al. [8] found a significantly lower incidence of incisional hernia after the J-shaped incision (7% vs. 24% P = 0.002) with a relaparotomy rate that was not significantly different between the two groups (31% and 45% respectively P = 0.487). From January 1998 to December 2007, we performed 626 consecutive orthotopic liver transplantations. All patients were transplanted using a bilateral subcostal incision that was closed with two layers of running sutures of absorbable monofilament (Maxon 1; Synature, Covidien, Mansfield, USA). Child-Pugh score was A in 141 patients (22.5%), B in 242 (38.7%), and C in 243 (38.8%). Immunosuppression was based on tacrolimus, and steroids from the first post-transplant day (20 mg/day of prednisone). A 3-day course of methylprednisolone was used in 83 patients (13.2%) to treat a moderate or severe acute cellular rejection. Post-transplant relaparotomy was needed in 29 patients (4.6%). No patient was lost to follow-up. An incisional hernia was diagnosed, and subsequently treated in 11 patients, which means an incidence of 1.7%. The Chi-squared test was used to compare our results with the two reports already mentioned [4,8]. Our incidence of incisional hernia was significantly lower with a P value ranging from 0.03 to 0.003 depending on the type of incision, J-shaped or Mercedes. In our opinion, this significantly low incidence of incisional hernia may be explained by several circumstances: (i) the avoidance of Mercedes incision and its relative ischemic area at the trifurcation point, (ii) the low accumulated steroid dose in our patients because of our immunosuppressive protocol and the low rate of steroids-treated acute cellular rejection, and (iii) the significant low incidence of posttransplant relaparotomy (P < 0.001 when compared with the reports previously mentioned [4,8]). According to our results, subcostal bilateral incision may be considered for liver transplantation provided other risk factors for incisional hernia are prevented. Incisions with upward midline extension may be reserved for liver transplants with difficult suprahepatic vein reconstruction, as they allow a vertical access to the suprahepatic vena cava rather than from a caudal view [9].

Human immunodeficiency virus infection does not worsen prognosis of liver transplantation for hepatocellular carcinoma

The impact of human immunodeficiency virus (HIV) infection on patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) is uncertain. This study aimed to assess the outcome of a prospective Spanish nationwide cohort of HIV‐infected patients undergoing LT for HCC (2002‐2014). These patients were matched (age, gender, year of LT, center, and hepatitis C virus (HCV) or hepatitis B virus infection) with non‐HIV‐infected controls (1:3 ratio). Patients with incidental HCC were excluded. Seventy‐four HIV‐infected patients and 222 non‐HIV‐infected patients were included. All patients had cirrhosis, mostly due to HCV infection (92%). HIV‐infected patients were younger (47 versus 51 years) and had undetectable HCV RNA at LT (19% versus 9%) more frequently than non‐HIV‐infected patients. No significant differences were detected between HIV‐infected and non‐HIV‐infected recipients in the radiological characteristics of HCC at enlisting or in the histopathological findings for HCC in the explanted liver. Survival at 1, 3, and 5 years for HIV‐infected versus non‐HIV‐infected patients was 88% versus 90%, 78% versus 78%, and 67% versus 73% (P = 0.779), respectively. HCV infection (hazard ratio = 7.90, 95% confidence interval 1.07‐56.82) and maximum nodule diameter >3 cm in the explanted liver (hazard ratio = 1.72, 95% confidence interval 1.02‐2.89) were independently associated with mortality in the whole series. HCC recurred in 12 HIV‐infected patients (16%) and 32 non‐HIV‐infected patients (14%), with a probability of 4% versus 5% at 1 year, 18% versus 12% at 3 years, and 20% versus 19% at 5 years (P = 0.904). Microscopic vascular invasion (hazard ratio = 3.40, 95% confidence interval 1.34‐8.64) was the only factor independently associated with HCC recurrence. Conclusions: HIV infection had no impact on recurrence of HCC or survival after LT. Our results support the indication of LT in HIV‐infected patients with HCC. (Hepatology 2016;63:488–498)

Incidence and Clinical Relevance of Bacterial Contamination in Preservation Solution for Liver Transplantation

OBJECTIVE Postoperative infection is considered one of the most important causes of morbidity and mortality after liver transplantation. We prospectively studied the incidence and significance of infections in preservation solutions for liver transplantation. MATERIALS AND METHODS From March 2007 to March 2008, we cultured the University of Wisconsin preservation solution for 60 consecutive liver transplantations. Fluid samples were obtained at the beginning and at the end of the back table procedure. Our posttransplant infection prophylactic protocol consisted of ampicillin and cefotaxime for 48 hours. RESULTS Cultures were positive in 59 patients (98.4%). Seventy-five percent of the isolates were superficial saprophytic flora (SSF; Staphylococcus coagulase negative, Streptococcus viridans, and Corynebacterium), nevertheless in 15 cases (25.1%) we isolated high virulence pathogens (Staphylococcus aureus, Klebsiella, Escherichia coli, Enterobacter, and Pseudomonas aeruginosa). There were neither anaerobic nor fungal isolates. Sixteen patients (36%) from the group with SSF developed postoperative fever, including 12 with negative posttransplant cultures, while 4 patients showed positive cultures for various microorganisms distinct from those isolated from the preservation solution. Five patients (30%) with high virulence pathogens in the preservation solution developed posttransplant fever, although no pathogen was isolated. CONCLUSIONS Positive cultures of preservation fluids were observed in 98% of patients, although most of them (75%) were SSF. Microorganisms isolated from posttransplant cultures did not match the ones obtained from the preservation solution. Our results did not support routine culturing of the preservation solution provided that one administrator an adequate posttransplant antibiotic prophylactic regimen.

Biliary Complications in Orthotopic Liver Transplantation Using Choledochocholedochostomy with a T-tube

Despite significant advances in orthotopic liver transplantation (OLT), biliary tract reconstruction is still a major source of complications. Choledochocholedochostomy with a T-tube used to be the standard procedure for biliary reconstruction after OLT. However, many centers currently avoid use of the T-tube because of the high incidence of complications. Our aim was to study the biliary complications occurring at our center when end-to-end choledochocholedochostomy (EE-CC) over a T-tube was used as the standard procedure for biliary reconstruction. A retrospective review was conducted of all patients who underwent liver transplantation from February 1, 1996, to April 30, 2010. Only patients requiring any therapy to treat biliary complications were considered, whereas those with concomitant hepatic artery complications were excluded. The study cohort consisted of 743 patients who had EE-CC with a T-tube. Of these, 73 patients (9.8%) experienced any biliary complication. Anastomotic strictures occurred in 17 patients (2.3%), and non-anastomotic strictures in 2 (0.3%). Fifteen patients with anastomotic strictures were successfully treated by dilatation and stenting. Bile leakage was diagnosed in 39 patients (5.2%). Leakage occurred at the anastomosis in 15 patients (2%), and at the exit site of the T-tube in 24 patients (3.2%). Tube opening was the only treatment used in 30 patients with bile leakage (76.9%). Seven patients experienced leaks after elective T-tube removal (1%). Overall, repeat surgery to manage biliary complications was needed in 9 patients (1.2%). The mortality rate from biliary complications was 0.13%. In conclusion, EE-CC with a T-tube was followed by a low incidence of biliary complications. The complication rate after elective T-tube removal and the repeat surgery rate were extremely low. These results might challenge the current trend to avoid T-tube stenting in OLT.

Liver Retransplantation in HIV‐Infected Patients: A Prospective Cohort Study

Information regarding liver retransplantation in HIV‐infected patients is scant. Data from 14 HIV‐infected patients retransplanted between 2002 and 2011 in Spain (6% retransplantation rate) were analyzed and compared with those from 157 matched HIV‐negative retransplanted patients. In HIV‐infected patients, early (≤30 days) retransplantation was more frequently indicated (57% vs. 29%; p = 0.057), and retransplantation for HCV recurrence was less frequently indicated (7% vs. 37%; p = 0.036). Survival probability after retransplantation in HIV‐positive patients was lower than in HIV‐negative patients, 42% versus 64% at 3 years, although not significantly (p = 0.160). Among HIV‐infected patients, those with undetectable HCV RNA at retransplantation and those with late (>30 days) retransplantation showed better 3‐year survival probability (80% and 67%, respectively), similar to that in their respective HIV‐negative counterparts (72% and 70%). In HIV‐infected and HIV‐negative patients, 3‐year survival probability in those with positive HCV RNA at retransplantation was 22% versus 65% (p = 0.008); in those with early retransplantation, 3‐year survival probability was 25% versus 56% (p = 0.282). HIV infection was controlled with antiretroviral therapy after retransplantation. In conclusion, HIV‐infected patients taken as a whole have unsatisfactory survival after liver retransplantation, although patients with undetectable HCV RNA at retransplantation or undergoing late retransplantation show a more favorable outcome.