Liver Transplant vs Liver Resection in patients with Multifocal hepatocellular Carcinoma.

BACKGROUND: The optimal surgical option in patients with Multifocal hepatocellular Carcinoma (MHCC) is an area of active research. The preference varies based on geographic variations and institutional policies. We sought to determine long-term outcomes in patients with MHCC based on surgical treatment - Liver transplant (LT) vs resection (LR). METHODS: We performed a retrospective analysis of NCDB (2004-2015) and identified patients with MHCC within Milan criteria. Patients with αfetoprotein ≥1000 nanograms/milliliter and those who underwent ablation were excluded. The primary outcome measure was long-term survival in patients undergoing LT vs. LR. The secondary aim of our study was to determine clinicodemographic factors associated with the receipt of LT and LR. RESULTS: 1,546 patients were included, of whom 1,211 received LT and 335 underwent LR. Patients who were non-Hispanic White (70.8% vs.54.9% p <0.01), privately insured (53.7% vs. 36.7%, p <0.01), and treated at academic centers (85.4% vs. 71.6%, p<0.01) were more likely to receive an LT. Multivariable Cox analysis revealed LT was associated with improved survival compared to LR ( HR= 0.34, 95% CI= 0.28-0.42). CONCLUSION: We described clinical and sociodemographic differences in LT and LR patients and found LT to be associated with a decreased mortality risk compared to LR. The study's findings should be interpreted in the context of several limitations, including the selection of MHCC criteria within Milan criteria.

Liver Transplantation Outcomes in a U.S. Multicenter Cohort of 789 Patients With Hepatocellular Carcinoma Presenting Beyond Milan Criteria.

BACKGROUND AND AIMS: The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down-staged (DS) with locoregional therapy (LRT). We evaluated post-LT outcomes, predictors of down-staging, and the impact of LRT in patients with beyond-MC HCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002-2013). APPROACH AND RESULTS: Clinicopathologic characteristics, overall survival (OS), recurrence-free survival (RFS), and HCC recurrence (HCC-R) were compared between patients within MC (n = 3,570) and beyond MC (n = 789) who were down-staged (DS, n = 465), treated with LRT and not down-staged (LRT-NoDS, n = 242), or untreated (NoLRT-NoDS, n = 82). Five-year post-LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n = 324; 60.2% and 53.8%; overall P < 0.001). DS patients had superior RFS (60% vs. 54%, P = 0.043) and lower 5-year HCC-R (18% vs. 32%, P < 0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5-year HCC-R of 15.5% in DS/<5 cm and 39.1% in NoDS/>5 cm, P < 0.001). Multivariate predictors of down-staging included alpha-fetoprotein response to LRT, pathologic tumor number and size, and wait time >12 months. LRT-NoDS had greater HCC-R compared with NoLRT-NoDS (34.1% vs. 26.1%, P < 0.001), even after controlling for clinicopathologic variables (hazard ratio [HR] = 2.33, P < 0.001) and inverse probability of treatment-weighted propensity matching (HR = 1.82, P < 0.001). CONCLUSIONS: In LT recipients with HCC presenting beyond MC, successful down-staging is predicted by wait time, alpha-fetoprotein response to LRT, and tumor burden and results in excellent post-LT outcomes, justifying expansion of LT criteria. In LRT-NoDS patients, higher HCC-R compared with NoLRT-NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.

Pathologic Response to Pretransplant Locoregional Therapy is Predictive of Patient Outcome After Liver Transplantation for Hepatocellular Carcinoma: Analysis From the US Multicenter HCC Transplant Consortium.

OBJECTIVE: The aim of the study was to determine the rate, predictors, and impact of complete pathologic response (cPR) to pretransplant locoregional therapy (LRT) in a large, multicenter cohort of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT). BACKGROUND: LRT is used to mitigate waitlist dropout for patients with HCC awaiting LT. Degree of tumor necrosis found on explant has been associated with recurrence and overall survival, but has not been evaluated in a large, multicenter study. METHODS: Comparisons were made among patients receiving pre-LT LRT with (n = 802) and without (n = 2637) cPR from the United States Multicenter HCC Transplant Consortium (UMHTC), and multivariable predictors of cPR were identified using logistic regression. RESULTS: Of 3439 patients, 802 (23%) had cPR on explant. Compared with patients without cPR, cPR patients were younger; had lower Model for End-stage Liver Disease (MELD) scores, AFP levels, and neutrophil-lymphocyte ratios (NLR); were more likely to have tumors within Milan criteria and fewer LRT treatments; and had significantly lower 1-, 3-, and 5-year incidence of post-LT recurrence (1.3%, 3.5%, and 5.2% vs 6.2%, 13.5%, and 16.4%; P < 0.001) and superior overall survival (92%, 84%, and 75% vs 90%, 78%, and 68%; P < 0.001). Multivariable predictors of cPR included age, sex, liver disease diagnosis, MELD, AFP, NLR, radiographic Milan status, and number of LRT treatments (C-statistic 0.67). CONCLUSIONS: For LT recipients with HCC receiving pretransplant LRT, achieving cPR portends significantly lower posttransplant recurrence and superior survival. Factors predicting cPR are identified, which may help prioritize patients and guide LRT strategies to optimize posttransplant cancer outcomes.

Biliary Tract and Primary Liver Tumors: Who, What, and Why?

Biliary tract and primary liver tumors can be divided into intrahepatic and extrahepatic sites. Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma are the most common primary liver malignancies, making up 75% and 15% of cases, respectively. In the United States, there has been an increase in incidence of HCC and cholangiocarcinoma over the last 2 decades, and it is probable that the incidence of both will continue to climb. Gallbladder cancer, however, is the most frequent biliary tract cancer, comprising 80% to 90% of biliary tract cancers worldwide. Underlying epidemiology and cause are discussed.

Impact of Pretransplant Bridging Locoregional Therapy for Patients With Hepatocellular Carcinoma Within Milan Criteria Undergoing Liver Transplantation: Analysis of 3601 Patients From the US Multicenter HCC Transplant Consortium.

OBJECTIVE: To evaluate the effect of pretransplant bridging locoregional therapy (LRT) on hepatocellular carcinoma (HCC) recurrence and survival after liver transplantation (LT) in patients meeting Milan criteria (MC). SUMMARY BACKGROUND DATA: Pre-LT LRT mitigates tumor progression and waitlist dropout in HCC patients within MC, but data on its impact on post-LT recurrence and survival remain limited. METHODS: Recurrence-free survival and post-LT recurrence were compared among 3601 MC patients with and without bridging LRT utilizing competing risk Cox regression in consecutive patients from 20 US centers (2002-2013). RESULTS: Compared with 747 LT recipients not receiving LRT, 2854 receiving LRT had similar 1, 3, and 5-year recurrence-free survival (89%, 77%, 68% vs 85%, 75%, 68%; P = 0.490) and 5-year post-LT recurrence (11.2% vs 10.1%; P = 0.474). Increasing LRT number [3 LRTs: hazard ratio (HR) 2.1, P < 0.001; 4+ LRTs: HR 2.5, P < 0.001), and unfavorable waitlist alphafetoprotein trend significantly predicted post-LT recurrence, whereas LRT modality did not. Treated patients achieving complete pathologic response (cPR) had superior 5-year RFS (72%) and lower post-LT recurrence (HR 0.52, P < 0.001) compared with both untreated patients (69%; P = 0.010; HR 1.0) and treated patients not achieving cPR (67%; P = 0.010; HR 1.31, P = 0.039), who demonstrated increased recurrence compared with untreated patients in multivariate analysis controlling for pretransplant and pathologic factors (HR 1.32, P = 0.044). CONCLUSIONS: Bridging LRT in HCC patients within MC does not improve post-LT survival or HCC recurrence in the majority of patients who fail to achieve cPR. The need for increasing LRT treatments and lack of alphafetoprotein response to LRT independently predict post-LT recurrence, serving as a surrogate for underlying tumor biology which can be utilized for prioritization of HCC LT candidates.

Hepatitis B and Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, and its incidence has been increasing in the last decade largely in parallel to the incidence and duration of exposure to hepatitis B and C. The widespread implementation of hepatitis B vaccine, hepatitis B antivirals, and the introduction of direct antiviral therapies for hepatitis C virus may have a substantial impact in reducing the incidence of HCC. This report reviews the risk factors and underlying mechanisms associated with the development of HCC in hepatitis B, along with advances in the diagnosis, imaging, and management of HCC.

Liver Resection and Transplantation for Patients With Hepatocellular Carcinoma Beyond Milan Criteria.

OBJECTIVES: To assess survival after liver resection and transplantation in patients with hepatocellular carcinoma (HCC) beyond Milan criteria. BACKGROUND: The role of liver resection and transplantation remains controversial for patients with HCC beyond Milan criteria. Resection of advanced tumors and transplantation using extended-criteria are pursued at select high-volume center. METHODS: Patients from 5 liver cancer centers in the United States who had liver resection or transplantation for HCC beyond Milan criteria between 1990 and 2011 were included in the study. Multivariable and propensity-matching analyses estimated the effects of clinical factors and operative selection on survival. RESULTS: Of 608 patients beyond Milan without vascular invasion, 480 (79%) patients underwent resection and 128 (21%) underwent transplantation. Clinicopathologic profiles between resection and transplant patients differed significantly. Hepatitis C and cirrhosis were more prevalent in transplantation group (P < 0.001). Resection patients had larger tumors [median 9 cm, interquartile range (IQR): 6.5-12.9 cm vs. median 4.1, IQR: 3.4-5.3 cm, P < 0.001]; transplant patients were more likely to have multiple tumors (78% vs 28%, P < 0.001).Overall (OS) and disease-free survival (DFS) were both greater after tumor downstaging and transplantation than resection (all P < 0.001). OS did not differ between liver transplant recipients who were not pretreated or pretreated and failed to downstage compared with propensity-matched liver resection patients (P ≥ 0.176); DFS in this propensity matched cohort was greater after liver transplantation (P ≤ 0.017). CONCLUSIONS: Liver resection and transplantation provide curative options for patients with HCC beyond Milan criteria. Further treatment strategies aimed at the efficiency and durability of tumor downstaging and expansion of the role of transplantation among suitable candidates could improve outcomes in patients with large or multifocal HCC.

Venous Thromboembolism Prophylaxis in Liver Surgery.

BACKGROUND: At a recently concluded Americas Hepato-Pancreato-Biliary Association Annual Meeting, a Clinical Practice Guidelines Conference Series was convened with the topic focusing on Venous Thromboembolism (VTE) Prophylaxis in Liver Surgery. The symposium brought together hepatobiliary surgeons from three continents as well as medical experts in hematology and coagulation. METHODS: The content of the discussion included literature reviews, evaluation of multi-institutional VTE outcome data, and examination of practice patterns at multiple high-volume centers. RESULTS: Literature review demonstrated that, within gastrointestinal surgery, liver resection patients are at particularly high-risk for VTE. Recent evidence clearly indicates a direct relationship between the magnitude of hepatectomy and postoperative VTE rates, however, the PT/INR does not accurately reflect the coagulation status of the post-hepatectomy patient. Evaluation of available data and practice patterns regarding the utilization and timing of anticoagulant VTE prophylaxis led to recommendations regarding preoperative and postoperative thromboprophylaxis for liver surgery patients. CONCLUSIONS: This conference was effective in consolidating our knowledge of coagulation abnormalities after liver resection. Based on the expert review of the available data and practice patterns, a number of recommendations were developed.

ECD kidney transplantation outcomes are improved when matching donors to recipients using a novel creatinine clearance match ratio (CCMR).

Improved outcomes have been associated with various methods of size matching between expanded criteria (ECD) donors and recipients. A novel method for improved functional based matching was developed utilizing manipulation of Cockcroft-Gault estimated creatinine clearances for donor and recipient. We hypothesized that optimal clearance-based matches would have superior outcomes for both immediate graft function and long-term graft survival. For the analysis, recipients of ECD kidneys in the Scientific Registry of Transplant Recipients (SRTR) transplanted between October 1, 1987 and August 31, 2011 were included. Univariate and multivariate analyses predicted the hazard ratio of graft failure and the odds ratio of requiring dialysis within the first week. A total of 25,640 ECD kidney transplants were analyzed. On multivariate analysis, higher creatinine clearance match ratio (CCMR) was associated with increased graft failure and odds of requiring dialysis within the first week (comparing highest ratio quintile versus lowest ratio quintile: HR 1.43, p < 0.001; OR 2.08, p < 0.001). This study suggests that ECD kidneys have improved outcomes when the recipient/donor CCMR is optimized.

Kidney clamp, perfuse, re-implant: a useful technique for graft salvage after vascular complications during kidney transplantation.

Although intra-operative vascular complications during renal transplantation are rare, injuries associated with prolonged ischemia may lead to graft threatening early and late complications. This series describes a novel technique for intra-operative repair of vascular complications in five patients over a three-yr period. The method consists of rapid graft nephrectomy and re-preservation of the graft with cold University of Wisconsin solution, which allows for controlled/precise back table repair of the vascular injury without incurring prolonged warm ischemia time. In three cases, the donor renal vein (2) and donor renal artery (1) were damaged and required back table reconstruction. In two cases, the recipient iliac artery needed reconstruction. Three of the five cases used deceased donor iliac vessels from another donor for reconstruction. Two patients required postoperative dialysis for delayed graft function for three to nine d (average six d) and two patients had slow graft function. All grafts were functioning at 17 months (mean) after transplant, with a median serum of 1.61 mg/dL (0.74-3.69). This series demonstrates the effectiveness of kidney clamp, perfuse, resuscitate as an effective intra-operative technique to salvage grafts after vascular injury. Although the grafts may suffer from delayed or slow graft function, excellent long-term function is attainable.

High-dose tigecycline and colistin for successful treatment of disseminated carbapenem-resistant Klebsiella pneumoniae infection in a liver transplant recipient.

Solid organ transplantation (SOT) is a risk factor for the acquisition of carbapenem-resistant Klebsiella pneumoniae. This infection is associated with a high mortality rate given the limited armamentarium of antibiotics for multidrug-resistant organisms along with continued immunosuppression to prevent graft rejection. We report a case of carbapenem-resistant K. pneumoniae pneumonia, bacteraemia and intra-abdominal infection in a newly transplanted liver recipient. The patient was successfully treated with a long course of high-dose tigecycline and colistin, along with surgical drainage. We discuss SOT-relevant epidemiology, therapeutic options and the rationale for our treatment choice.

Liver planning software accurately predicts postoperative liver volume and measures early regeneration.

BACKGROUND: Postoperative or remnant liver volume (RLV) after hepatic resection is a critical predictor of perioperative outcomes. This study investigates whether the accuracy of liver surgical planning software for predicting postoperative RLV and assessing early regeneration. STUDY DESIGN: Patients eligible for hepatic resection were approached for participation in the study from June 2008 to 2010. All patients underwent cross-sectional imaging (CT or MRI) before and early after resection. Planned remnant liver volume (pRLV) (based on the planned resection on the preoperative scan) and postoperative actual remnant liver volume (aRLV) (determined from early postoperative scan) were measured using Scout Liver software (Pathfinder Therapeutics Inc.). Differences between pRLV and aRLV were analyzed, controlling for timing of postoperative imaging. Measured total liver volume (TLV) was compared with standard equations for calculating volume. RESULTS: Sixty-six patients were enrolled in the study from June 2008 to June 2010 at 3 treatment centers. Correlation was found between pRLV and aRLV (r = 0.941; p < 0.001), which improved when timing of postoperative imaging was considered (r = 0.953; p < 0.001). Relative volume deviation from pRLV to aRLV stratified cases according to timing of postoperative imaging showed evidence of measurable regeneration beginning 5 days after surgery, with stabilization at 8 days (p < 0.01). For patients at the upper and lower extremes of liver volumes, TLV was poorly estimated using standard equations (up to 50% in some cases). CONCLUSIONS: Preoperative virtual planning of future liver remnant accurately predicts postoperative volume after hepatic resection. Early postoperative liver regeneration is measureable on imaging beginning at 5 days after surgery. Measuring TLV directly from CT scans rather than calculating based on equations accounts for extremes in TLV.

Evolving role of vascular resection and reconstruction in hepatic surgery for malignancy.

Primary and secondary hepatic malignancies, including hepatocellular cancer, cholangiocarcinoma and metastatic disease from colorectal cancer continue to increase in incidence worldwide, and remain diseases with a high mortality. Liver resection, with negative margins, is associated with improved survival and better quality of life over nonoperative treatment. As liver resection continues to evolve, aggressive centers are increasingly using vascular resection and reconstruction to achieve negative margins and improve outcomes. As these resections become more common, the morbidity and mortality associated with these complex surgical procedures is decreasing. Currently, resections of the portal vein are becoming routine in major liver and pancreatic resections, and experience with hepatic artery, hepatic vein and inferior vena cava resections is increasing. This review paper looks at the current indications, techniques and outcomes for major vascular resection in hepatic malignancy.

Resection of the liver and inferior vena cava for hepatic malignancy.

BACKGROUND: Involvement of the IVC has traditionally been considered a relative contraindication to resection for advanced tumors of the liver. Combined resection of the liver and IVC for malignancy can be performed safely and results in long-term survival in select patients. STUDY DESIGN: Sixty patients undergoing hepatic and IVC resection by the primary author from 1996 to 2012 were reviewed. Median age was 52 years. Resections were carried out for cholangiocarcinoma (n = 26), hepatocellular carcinoma (n = 16), colorectal metastases (n = 13), gastrointestinal stromal tumor (n = 2), hepatoblastoma (n = 2), and squamous cell carcinoma (n = 1). Resections performed included 27 right and 5 left trisegmentectomies and 25 right and 3 left lobectomies, including the caudate lobe. Ex vivo procedures were performed in 6 patients using veno-venous bypass and the other 54 procedures were performed using varying degrees of vascular isolation. In situ cold perfusion of the liver was used in 8 patients. The IVC was reconstructed using a tube graft (n = 38) primarily (n = 8) or with patches (n = 14). RESULTS: There were 5 perioperative deaths (8%). Three patients died of liver failure, 1 patient died of pulmonary hemorrhage, and 1 patient died of massive pulmonary embolism. Nine patients had evidence of postoperative liver failure that resolved with supportive management. Three patients required temporary dialysis. With a median follow-up of 31 months, 14 patients have died of recurrent malignancy between 22 and 44 months, and an additional 4 patients are alive with disease at 16 to 33 months. Actuarial 1- and 5-year survival rates were 89% and 35%, respectively. CONCLUSIONS: Inferior vena cava involvement by malignancy does not obviate liver resection. The procedure's increased risk is balanced by the possible benefits, given the lack of alternative curative approaches.

Treatment outcomes and prognostic factors of intrahepatic cholangiocarcinoma.

The aim of the present study was to determine the treatment outcome and prognostic factors for survival in patients with peripheral intrahepatic cholangiocarcinoma (ICC). A retrospective chart review was performed for patients diagnosed with ICC between 2000 and 2009 at a single institution. We identified a total of 105 patients with ICC. Among them, 63.8% were older than 60 years of age, 50.5% were male and 88.6% were Caucasian. By preoperative imaging approximately half of the patients (50.5%) were surgical candidates and underwent resection. The other half of the patients (49.5%) were unresectable. The unresectable group received chemoradiotherapy (53%) and transarterial chemoembolization (7.7%) as palliative treatments while 23.0% of the patients (12/52) received best supportive care alone. The median survival rates were 16.1 months (13.1­19.2) for the entire cohort, 27.6 months (17.7-37.6) for curative resection, 12.9 months (6.5-19.2) for palliative chemoradiotherapy and 4.9 months (0.4-9.6) for best supportive care (p<0.001). Independent predictors on multivariate analysis were advanced stage at diagnosis and treatment received. In those patients who underwent resection, advanced AJCC stage and presence of microvascular invasion were also independent predictors of poor survival. We concluded that surgery offers the most beneficial curative option and outcome, emphasizing the importance of resectability as a major prognostic factor. The present study also revealed that use of chemoradiotherapy in the adjuvant setting failed to improve survival but its palliative use in those patients with unresectable ICC offered a modest survival advantage over best supportive care. The overriding factors influencing outcome were stage and the presence of microvascular invasion on pathology.

Surgical management trends for cholangiocarcinoma in the USA 1998-2009.

BACKGROUND: Surgical advancements have improved outcomes for cholangiocarcinoma (CCA) patients, but this expertise is not uniformly available. This research examines CCA surgical treatment patterns. METHODS: A retrospective analysis of the U.S. Nationwide Inpatient Sample from 1998-2009 identified CCA patients at high-volume (HV) versus low-volume (LV) hospitals, and teaching versus nonteaching hospitals. We performed multinomial and multivariate logistic regressions to compare differences of surgical treatment between HV vs. LV hospitals, and teaching vs. nonteaching hospitals. Liver resection (LR), pancreaticoduodenectomy, bile duct (BD) resection, and combined liver/BD resection were considered more aggressive therapy than BD stent or bypass. RESULTS: A total of 32,561 patients with CCA were identified. The proportion receiving surgery declined from 36 to 30 %. There was no increase in the proportion of LRs or combined liver/BD resection. Patients at HV or teaching hospitals were more likely to receive surgical treatment [odds ratio (OR), 1.3, p < 0.001; OR, 1.4, p < 0.001]. DISCUSSION: Despite increasing evidence that surgical resection increases survival, the number of patients receiving surgery has decreased. Although combined liver/BD resection has been advocated as standard management for proximal CCA, the practice has not increased. All patients with CCA should be considered for assessment at a HV teaching hospital.