Are Current National Review Board Downstaging Protocols for Hepatocellular Carcinoma Too Restrictive?

BACKGROUND: Liver transplantation (LT) is an effective strategy for patients with unresectable hepatocellular carcinoma (HCC). To qualify for standardized LT model for end-stage liver disease exception points, the United Network for Organ Sharing National Liver Review Board (NLRB) requires that the presenting and final HCC tumor burden be within the University of California San Francisco criteria, which were recently expanded (within expanded UCSF [W-eUCSF]). Current NLRB criteria may be too restrictive because it has been shown previously that the initial burden does not predict LT failure when tumors downstage to UCSF. This study aims to assess LT outcomes for HCC initially presenting beyond expanded UCSF (B-eUCSF) criteria in a large multicenter collaboration. STUDY DESIGN: Comparisons of B-eUCSF and W-eUCSF candidates undergoing LT at seven academic institutions between 2001 and 2017 were made from a multi-institutional database. Survival outcomes were compared by Kaplan-Meier and Cox regression analyses. RESULTS: Of 1,846 LT recipients with HCC, 86 (5%) met B-eUCSF criteria at initial presentation, with the remainder meeting W-eUCSF criteria. Despite differences in tumor burden, B-eUCSF candidates achieved comparable 1-, 5- and 10-year overall (89%, 70%, and 55% vs 91%, 74%, and 60%, respectively; p = 0.2) and disease-free (82%, 60%, and 53% vs 89%, 71%, and 59%, respectively; p = 0.07) survival to patients meeting W-eUCSF criteria after LT. Despite increased tumor recurrence in B-eUCSF vs W-eUCSF patients (24% vs 10%, p = 0.0002), post-recurrence survival was similar in both groups (p = 0.69). CONCLUSION: Transplantation for patients initially presenting with HCC B-eUSCF criteria offers a survival advantage similar to those with tumors meeting W-eUCSF criteria at presentation. The current NLRB policy is too stringent, and considerations to expand criteria should be discussed.

Pancreaticoduodenectomy with major vascular resection: a comparison of laparoscopic versus open approaches.

BACKGROUND: Major vascular resection when necessary for margin control during pancreaticoduodenectomy is relatively universal with perioperative and oncological outcomes that are similar to those of patients undergoing a PD without venous involvement. The present study compares total laparoscopic pancreaticoduodenectomy (TLPD) versus open pancreaticoduodenectomy (OPD) with major vascular resection. METHODS: We reviewed data for all patients undergoing TLPD or OPD with vascular resection at Mayo Clinic Rochester, between the dates of July 2007 and July 2013. RESULTS: A total of 31 patients undergoing TLPD and 58 patients undergoing OPD with major vascular resection were identified. Mean operative blood loss was significantly less in the laparoscopic (842 cc) compared to the open group (1,452 cc) (p < 0.001), as was median hospital stay, 6 (4-118) versus 9 (6-73) days, respectively (p = 0.006). There was no significant difference in the total number of complications (lap 35%, open 48%) (p = 0.24) or severe complications (≥III) (lap 6.4%, open 3.4%) (p = 0.51) in the two groups. In-hospital mortality or 30-day mortality was not statistically different between the laparoscopic and open groups, 3.2 and 3.4%, respectively (p = 0.96). Patency of the reconstructed vessels on postoperative imaging was not significantly different between the TLPD (93%) and OPD groups (91%) (p = 0.76). In patients with a diagnosis of adenocarcinoma, there was no significant difference in overall survival between the two groups (p = 0.22). CONCLUSION: The present study clearly demonstrates that not only is TLPD with major vascular resection feasible and safe but that it can achieve results that are similar in morbidity and mortality as well as oncologic outcome compared to patients undergoing OPD with major vascular resection.

Initial management of noncirrhotic splanchnic vein thrombosis: when is anticoagulation enough?

BACKGROUND: The optimal initial treatment of splanchnic vein thrombosis is uncertain. Anticoagulant therapy has been shown to be associated with vessel recanalization and decreased recurrence. Furthermore, information regarding potential predictors of chronic complications is not well understood. METHODS: A retrospective cohort study involving consecutive patients diagnosed with first-episode noncirrhotic splanchnic vein thrombosis referred to the thrombosis clinic of the authors' institution between 2008 and 2011 was conducted. Demographic and clinical information was collected. The response to initial anticoagulant therapy was evaluated by determining radiographic recanalization of vessels and clinical resolution (defined as the absence of ongoing splanchnic vein thrombosis symptoms or complications requiring treatment beyond anticoagulant therapy). RESULTS: Twenty-two patients were included. Anticoagulant therapy alone resulted in vessel recanalization in 41% of patients and 68% achieved clinical resolution. Two patients experienced bleeding events. Factors associated with a lack of clinical resolution included signs of portal hypertension/liver failure on presentation, complete vessel occlusion at diagnosis, presence of a myeloproliferative disorder or JAK2V617F tyrosine kinase mutation and the absence of a local/transient predisposing factor. CONCLUSIONS: Anticoagulant therapy appeared to be an effective initial treatment in patients with splanchnic vein thrombosis. Clinical factors may help to identify patients who are at risk for developing complications thus requiring closer monitoring. These findings were limited by the small sample size and need to be explored in larger prospective studies.

Inferior survival in liver transplant recipients with hepatocellular carcinoma receiving donation after cardiac death liver allografts.

The impact of ischemia/reperfusion injury in the setting of transplantation for hepatocellular carcinoma (HCC) has not been thoroughly investigated. The present study examined data from the Scientific Registry of Transplant Recipients for all recipients of deceased donor liver transplants performed between January 1, 1995 and October 31, 2011. In a multivariate Cox analysis, significant predictors of patient survival included the following: HCC diagnosis (P < 0.01), donation after cardiac death (DCD) allograft (P < 0.001), hepatitis C virus-positive status (P < 0.01), recipient age (P < 0.01), donor age (P < 0.001), Model for End-Stage Liver Disease score (P < 0.001), recipient race, and an alpha-fetoprotein level > 400 ng/mL at the time of transplantation. In order to test whether the decreased survival seen for HCC recipients of DCD grafts was more than would be expected because of the inferior nature of DCD grafts and the diagnosis of HCC, a DCD allograft/HCC diagnosis interaction term was created to look for potentiation of effect. In a multivariate analysis adjusted for all other covariates, this interaction term was statistically significant (P = 0.049) and confirmed that there was potentiation of inferior survival with the use of DCD allografts in recipients with HCC. In conclusion, patient survival and graft survival were inferior for HCC recipients of DCD allografts versus recipients of donation after brain death allografts. This potentiation of effect of inferior survival remained even after adjustments for the inherent inferiority observed in DCD allografts as well as other known risk factors. It is hypothesized that this difference could reflect an increased rate of recurrence of HCC.

Changing donor characteristics in liver transplantation over the last 10 years in Canada.

Liver donor characteristics have a significant impact on graft quality and, in turn, recipient outcomes. In this study, we examined deceased liver donor characteristics and donor risk index (DRI) trends in Canada over the past decade. Data were extracted from the Canadian Organ Replacement Register and Transplant Québec for the decade (2000-2010). Trends in the DRI and donor characteristics, including age, race, height, cause of death (COD), location, cold ischemia time (CIT), and type of donation, were examined. In all, 3746 transplants using deceased liver donors were analyzed. The age of donors, the proportion of black donors, the proportion of cerebrovascular accidents as the COD, and the proportion of donation after cardiac death (DCD) donors all increased over the aforementioned time period. The proportion of transplants classified geographically as local increased, and the CIT for donor livers decreased. Although many of the parameters adversely affecting the DRI increased over the study period, the DRI showed only a slightly significant trend of increasing. The increase in these parameters was counteracted by a decrease in modifiable risk factors such as the CIT and distance traveled. The 5-year recipient survival rate increased from 71.43% (1999-2001) to 75.50% (2005-2007); however, this trend was not significant. Although there was an increase in the use of older and DCD organs, recipient survival was not compromised. In conclusion, demographic trends for liver donors in Canada suggest an increase in the use of higher risk donors. However, the overall graft quality has been not compromised because of a decreasing trend for the CIT and an increase in local transplants. Better coordination and allocation practices in liver transplantation across Canada have minimized the risk of graft failure and resulted in good recipient outcomes.

Endoscopic management of biliary complications following liver transplantation after donation from cardiac death donors.

BACKGROUND: Previous studies have shown a higher incidence of biliary complications following donation after cardiac death (DCD) liver transplantation compared with donation after brain death (DBD) liver transplantation. The endoscopic management of ischemic type biliary strictures in patients who have undergone DCD liver transplants needs to be characterized further. METHODS: A retrospective institutional review of all patients who underwent DCD liver transplant from January 2006 to September 2011 was performed. These patients were compared with all patients who underwent DBD liver transplantation in the same time period. A descriptive analysis of all DCD patients who developed biliary complications and their subsequent endoscopic management was also performed. RESULTS: Of the 36 patients who received DCD liver transplants, 25% developed biliary complications compared with 13% of patients who received DBD liver transplants (P=0.062). All DCD allograft recipients who developed biliary complications became symptomatic within three months of transplantation. Ischemic type biliary strictures in DCD allograft recipients included disseminated biliary strictures in two patients, biliary strictures of the hepatic duct bifurcation in three patients and biliary strictures of the donor common hepatic duct in three patients. CONCLUSIONS: There was a trend toward increasing incidence of total biliary complications in recipients of DCD liver allografts compared with those receiving DBD livers, and the rate of diffuse ischemic cholangiopathy was significantly higher. Focal ischemic type biliary strictures can be treated effectively in DCD liver transplant recipients with favourable results. Diffuse ischemic type biliary strictures in DCD liver transplant recipients ultimately requires retransplantation.

A comparison of survival and pathologic features of non-alcoholic steatohepatitis and hepatitis C virus patients with hepatocellular carcinoma.

AIM: To compare the clinical outcome and pathologic features of non-alcoholic steatohepatitis (NASH) patients with hepatocellular carcinoma (HCC) and hepatitic C virus (HCV) patients with HCC (another group in which HCC is commonly seen) undergoing liver transplantation. METHODS: Patients transplanted for HCV and NASH at our institution from January 2000 to April 2011 were analyzed. All explanted liver histology and pre-transplant liver biopsies were examined by two specialist liver histopathologists. Patient demographics, disease free survival, explant liver characteristics and HCC features (tumour number, cumulative tumour size, vascular invasion and differentiation) were compared between HCV and NASH liver transplant recipients. RESULTS: A total of 102 patients with NASH and 283 patients with HCV were transplanted. The incidence of HCC in NASH transplant recipients was 16.7% (17/102). The incidence of HCC in HCV transplant recipients was 22.6% (64/283). Patients with NASH-HCC were statistically older than HCV-HCC patients (P < 0.001). A significantly higher proportion of HCV-HCC patients had vascular invasion (23.4% vs 6.4%, P = 0.002) and poorly differentiated HCC (4.7% vs 0%, P < 0.001) compared to the NASH-HCC group. A trend of poorer recurrence free survival at 5 years was seen in HCV-HCC patients compared to NASH-HCC who underwent a Liver transplantation (P = 0.11). CONCLUSION: Patients transplanted for NASH-HCC appear to have less aggressive tumour features compared to those with HCV-HCC, which likely in part accounts for their improved recurrence free survival.

Evaluation of the updated definition of early allograft dysfunction in donation after brain death and donation after cardiac death liver allografts.

BACKGROUND: An updated definition of early allograft dysfunction (EAD) was recently validated in a multicenter study of 300 deceased donor liver transplant recipients. This analysis did not differentiate between donation after brain death (DBD) and donation after cardiac death (DCD) allograft recipients. METHODS: We reviewed our prospectively entered database for all DBD (n=377) and DCD (n=38) liver transplantations between January 1, 2006 and October 30, 2011. The incidence of EAD as well as its ability to predict graft failure and survival was compared between DBD and DCD groups. RESULTS: EAD was a valid predictor of both graft and patient survival at six months in DBD allograft recipients, but in DCD allograft recipients there was no significant difference in the rate of graft failure in those with EAD (11.5%) compared with those without EAD (16.7%) (P=0.664) or in the rate of death in recipients with EAD (3.8%) compared with those without EAD (8.3%) (P=0.565). The graft failure rate in the first 6 months in those with international normalized ratio ≥1.6 on day 7 who received a DCD allograft was 37.5% compared with 6.7% for those with international normalized ratio <1.6 on day 7 (P=0.022). CONCLUSIONS: The recently validated definition of EAD is a valid predictor of patient and graft survival in recipients of DBD allografts. On initial assessment, it does not appear to be a useful predictor of patient and graft survival in recipients of DCD allografts, however a study with a larger sample size of DCD allografts is needed to confirm these findings. The high ALT/AST levels in most recipients of DCD livers as well as the predisposition to biliary complications and early cholestasis make these parameters as poor predictors of graft failure. An alternative definition of EAD that gives greater weight to the INR on day 7 may be more relevant in this population.

Reduction of liver ischemia reperfusion injury by silencing of TNF-α gene with shRNA.

BACKGROUND: Tumor necrosis factor-alpha (TNF-α) is a central mediator in the hepatic response to ischemia/reperfusion. Short hairpin RNA (shRNA) has been proven to be an effective means of harnessing the RNA interference pathway in mammalian cells. In the current study, we investigated whether silencing TNF-α gene with shRNA can prevent liver ischemic reperfusion injury (IRI). METHODS: Male BalB/c mice were randomized to TNF-α shRNA, scramble shRNA, or sham operation groups. TNF-α shRNA and scramble shRNA groups were injected 48 h before inducing IRI. IRI was induced via microaneurysm clamps applied to the left hepatic artery and portal vein. Six hours after reperfusion, IRI injury was examined by serum level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), liver histopathology, MPO, and MDA level, as well as by relative quantities of TNF-α mRNA. RESULTS: TNF-α expression induced by ischemia reperfusion in the liver was significantly suppressed after treatment with TNF-α shRNA compared with the group treated with scramble shRNA (P < 0.001). Mice treated with TNF-α shRNA showed lower peak values of AST and ALT than scramble shRNA treated mice (P < 0.001). On histopathologic slides, mice treated with TNF-α shRNA had significantly less ischemia/reperfusion injury based on Suzuki score than the scramble shRNA group, 3.57 ± 2.30 and 8.83 ± 0.98 respectively (P < 0.001), while the sham group was not significantly different from the TNF-alpha shRNA group, 0 ± 0 and 3.57 ± 2.30, respectively (P = 0.075). Liver tissue MDA levels were significantly lower in mice treated with TNF-α shRNA as compared with the group treated with scramble shRNA (P < 0.01). Immunohistochemical staining for MPO was significantly lower in mice treated with TNF-α shRNA compared with the group treated with shRNA (compared with treated with scramble shRNA group.) CONCLUSIONS: Liver IRI can be minimized through gene silencing of TNF-α. This may represent a novel therapy in the setting of transplantation and in other conditions associated with IRI of the liver.

Increased risk of severe recurrence of hepatitis C virus in liver transplant recipients of donation after cardiac death allografts.

BACKGROUND: In hepatitis C virus (HCV) recipients of donation after cardiac death (DCD) grafts, there is suggestion of lower rates of graft survival, indicating that DCD grafts themselves may represent a significant risk factor for severe recurrence of HCV. METHODS: We evaluated all DCD liver transplant recipients from August 2006 to February 2011 at our center. Recipients with HCV who received a DCD graft (group 1, HCV+ DCD, n=17) were compared with non-HCV recipients transplanted with a DCD graft (group 2, HCV- DCD, n=15), and with a matched group of HCV recipients transplanted with a donation after brain death (DBD) graft (group 3, HCV+ DBD, n=42). RESULTS: A trend of poorer graft survival was seen in HCV+ patients who underwent a DCD transplant (group 1) compared with HCV- patients who underwent a DCD transplant (group 2) (P=0.14). Importantly, a statistically significant difference in graft survival was seen in HCV+ patients undergoing DCD transplant (group 1) (73%) as compared with DBD transplant (group 3) (93%)(P=0.01). There was a statistically significant increase in HCV recurrence at 3 months (76% vs. 16%) (P=0.005) and severe HCV recurrence within the first year (47% vs. 10%) in the DCD group (P=0.004). CONCLUSIONS: HCV recurrence is more severe and progresses more rapidly in HCV+ recipients who receive grafts from DCD compared with those who receive grafts from DBD. DCD liver transplantation in HCV+ recipients is associated with a higher rate of graft failure compared with those who receive grafts from DBD. Caution must be taken when using DCD grafts in HCV+ recipients.

The benefit of smart phone usage in liver organ procurement.

A 56-year-old man was on the transplant list with end-stage liver disease secondary to hepatitis C when a donor liver became available at a location 545 km away. The procurement team, consisting of a senior and junior fellow, went on the retrieval, while the staff surgeon remained in the hospital with the recipient. At the time of organ procurement, a suspicious lesion was identified in the left lateral lobe. The transplant fellows took intraoperative pictures of the lesion with a smart phone and sent them to the staff surgeon for advice. A teleconsultation, facilitated by images sent from the smart phone, took place over the next 22 min. The decision was made to proceed with the transplant, as it was felt that the lesion could be resected from the liver allograft. Had the fellows not been able to interact with the staff surgeon in real-time during the surgery, there is a high likelihood that the organ would have been rejected by the staff surgeon due to the unexpected finding. The patient's postoperative course was relatively uneventful with no evidence of infection. The patient was discharged from hospital and continues to do well. We expect that the role of smart phones in remote consultation will continue to expand in future.

Laparoscopic vs open hepatic resection for benign and malignant tumors: An updated meta-analysis.

OBJECTIVE: To compare laparoscopic hepatic resection (LHR) with open hepatic resection (OHR) for benign and malignant tumors. DATA SOURCES: MEDLINE, CENTRAL, and EMBASE databases were searched for relevant studies published between January 1, 1998, and May 1, 2009. STUDY SELECTION: Studies clearly documenting a comparison of LHR with OHR for benign and malignant neoplasms were selected. DATA EXTRACTION: Operative and postoperative measures, resection margins, complications, and survival outcomes were evaluated. Weighted mean differences, relative risks, and hazard ratios (HRs) were calculated using a random-effects model. RESULTS: Twenty-six studies were included in the meta-analysis. The HR of death for malignant tumors was significantly lower in the LHR group compared with the OHR group (HR, 0.64; P = .04). The HR of recurrence for malignant tumors was not significantly different between the 2 groups (HR, 0.79; P = .37). The LHR group had a lower operative blood loss (weighted mean difference, -161 mL; P < .001) and relative risk of total postoperative complications (relative risk, 0.40; P < .001). Duration of hospital stay, days of intravenous narcotic use, and days until oral intake were all significantly lower in the LHR group compared with the OHR group. Operative time between LHR and OHR was not significantly different. CONCLUSIONS: Laparoscopic hepatic resection for malignant tumors is associated with a long-term survival that is at least comparable, if not superior, to OHR with no difference in disease recurrence. The use of LHR for benign and malignant tumors is a safe alternative to OHR with potential operative and postoperative benefits.

Comparison of gastrointestinal complications in on-pump versus off-pump coronary artery bypass grafting.

BACKGROUND: Gastrointestinal (GI) complications following coronary artery bypass grafting (CABG), although infrequent, are associated with significant morbidity and mortality. It has been suggested that systemic inflammatory response plays an important role in these complications. Cardiopulmonary bypass (CPB) is well known to cause increased systemic inflammation, and therefore it has been proposed that performing CABG using an off-pump technique could substantially minimize the risk of GI complications. Prolonged CPB duration has been shown to be an independent predictor of GI complications; however, the effect of avoiding CPB altogether through off-pump procedures has not been thoroughly examined. We sought to compare the incidence of GI complications in patients undergoing on-pump and off-pump CABG. METHODS: We analyzed prospectively entered data on 2451 patients who underwent isolated CABG between January 2000 and October 2004. We compared GI complication rates in 5 predetermined areas (GI bleed, ileus, pancreatitis, ischemic bowel and cholecystitis) among patients who had on-pump CABG with those of patients who had off-pump CABG. We also compared in-hospital mortality due to these complications between the 2 groups. RESULTS: We compared data for a total of 2010 patients in the on-pump group and 441 in the off-pump group. In the on-pump group, 30 (1.49%) patients experienced GI complications compared with 4 (0.91%) in the off-pump group (p = 0.34). Gastrointestinal bleed was the most common complication in the off-pump group. Eight patients in the on-pump group experienced ischemic bowels compared with no patients in the off-pump group. Six patients (0.3%) in the on-pump group died from GI complications, whereas no patients in the off-pump group died from such complications (p = 0.25). CONCLUSION: We found no significant difference in the total number of GI complications between the off-pump and on-pump groups; however, trends could be seen in the types of GI complications that occurred in the 2 groups. Owing to the relatively infrequent occurrence of GI complications, a larger scale study would be beneficial to determine whether the differences observed would be significant.