M. Doyle

Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation.

Purpose:To evaluate outcomes of downstaging patients with advanced (American liver tumor study group stage III/IV) hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) to allow eligibility for orthotopic liver transplant (OLT). Methods:From 1999 to 2006, 202 patients with HCC were referred for transplant evaluation. Seventy-six (37.6%) patients with stage III/IV HCC were potential transplant candidates if downstaging was achieved by TACE. OLT was considered based on follow-up imaging findings. The number of patients who were successfully downstaged within the Milan criteria, tumor response using Response Evaluation Criteria in Solid Tumors criteria, findings at explant, and outcomes after transplant were tracked. Results:Eighteen of 76 (23.7%) patients had adequate downstaging to qualify for OLT under the Milan criteria. By Response Evaluation Criteria in Solid Tumors, 27/76 (35.5%) patients had a partial response, 22/76 (29%) had stable disease, and 27/76 (35.5%) had progressive disease. Seventeen of 76 (22.4%) patients who met other qualifications underwent OLT after successful downstaging (13/38 stage III;4/38 stage IV). Explant review demonstrated 28 identifiable tumors in which post-TACE necrosis was greater than 90% in 21 (75%). At a median of 19.6 months (range 3.6–104.7), 16/17 (94.1%) patients who underwent OLT are alive. One patient expired 11 months after OLT secondary to medical comorbidities. One of 17 (6%) OLT patients had recurrent HCC. This patient underwent resection of a pulmonary metastasis and is alive, 63.6 months from OLT. Conclusion:Selected patients with stage III/IV HCC can be downstaged to Milan criteria with TACE. Importantly, patients who are successfully downstaged and transplanted have excellent midterm disease-free and overall survival, similar to stage II HCC.

A review and update of treatment options and controversies in the management of hepatocellular carcinoma

Objective:To review the current management, outline recent advances and address controversies in the management of hepatocellular carcinoma (HCC). Summary of Background data:The treatment of HCC is multidisciplinary involving hepatologists, surgeons, medical oncologists, radiation oncologists, radiologists, interventional radiologists, and other disciplines. Each of these disciplines brings its unique perspective and differing opinions that add to controversies in the management of HCC. Methods:A focused literature review was performed to identify recent studies on the management of HCC and thereby summarize relevant information on the various therapeutic modalities and controversies involved in the treatment of HCC. Results:The main treatment algorithms continue to rely on hepatic resection or transplantation with controversies involving patients harboring early stage disease and borderline hepatic function. The other treatment strategies include locoregional therapies, radiation, and systemic therapy used alone or in combination with other treatment modalities. Recent advances in locoregional therapies, radiation, and systemic therapies have provided better therapeutic options with curative intent potential for some locoregional therapies. Further refinements in combination therapies such as algorithms consisting of locoregional therapies and systemic or radiation therapies are likely to add additional options and improve survival. Conclusions:The management of HCC has witnessed significant strides with advances in existing options and introduction of several new treatment modalities of various combinations. Further refinements in these treatment options combined with enrollment in clinical trials are essential to improve the management and outcomes of patients with HCC.

Morbid obesity in liver transplant recipients adversely affects longterm graft and patient survival in a single-institution analysis

OBJECTIVE The effects of obesity in liver transplantation remain controversial. Earlier institutional data demonstrated no significant difference in postoperative complications or 1-year mortality. This study was conducted to test the hypothesis that obesity alone has minimal effect on longterm graft and overall survival. METHODS A retrospective, single-institution analysis of outcomes in patients submitted to primary adult orthotopic liver transplantation was conducted using data for the period from 1 January 2002 to 31 December 2012. Recipients were divided into six groups by pre-transplant body mass index (BMI), comprising those with BMIs of <18.0 kg/m(2) , 18.0-24.9 kg/m(2) , 25.0-29.9 kg/m(2) , 30.0-35.0 kg/m(2) , 35.1-40.0 kg/m(2) and >40 kg/m(2) , respectively. Pre- and post-transplant parameters were compared. A P-value of <0.05 was considered to indicate statistical significance. Independent predictors of patient and graft survival were determined using multivariate analysis. RESULTS A total of 785 patients met the study inclusion criteria. A BMI of >35 kg/m(2) was associated with non-alcoholic steatohepatitis (NASH) cirrhosis (P < 0.0001), higher Model for End-stage Liver Disease (MELD) score, and longer wait times for transplant (P = 0.002). There were no differences in operative time, intensive care unit or hospital length of stay, or perioperative complications. Graft and patient survival at intervals up to 3 years were similar between groups. Compared with non-obese recipients, recipients with a BMI of >40 kg/m(2) showed significantly reduced 5-year graft (49.0% versus 75.8%; P < 0.02) and patient (51.3% versus 78.8%; P < 0.01) survival. CONCLUSIONS Obesity increasingly impacts outcomes in liver transplantation. Although the present data are limited by the fact that they were sourced from a single institution, they suggest that morbid obesity adversely affects longterm outcomes despite providing similar short-term results. Further analysis is indicated to identify risk factors for poor outcomes in morbidly obese patients.

Short- and long-term outcomes after steatotic liver transplantation.

OBJECTIVE To determine if the use of steatotic grafts adversely affects outcomes in liver transplantation. DESIGN A retrospective review of a prospectively maintained database. SETTING A single center. PATIENTS Four hundred ninety adults who underwent liver transplantation from January 1, 2002, to December 31, 2008, at a single center. Graft biopsies were available in 310 (63.3%) cases. Grafts were classified based on amount of macrovesicular steatosis: 5% or less (n = 222), more than 5% to less than 35% (n = 66), and 35% or more (n = 22). MAIN OUTCOME MEASURES Recipient demographics, Model for End-Stage Liver Disease (MELD) score, patient/graft survival, complications, transfusion rates, and liver function test results. RESULTS One-, 3-, and 5-year patient and graft survivals, respectively, were similar (90.38%, 84.7%, and 74.4%, respectively, P = .3; and 88.7%, 82.5%, and 73.3%, respectively, P = .15). Median follow-up was 25 months. Recipient age, sex, body mass index, laboratory MELD score, and ischemia times were similar among all groups. Packed red blood cell (3 vs 8 U, P < .001), fresh frozen plasma (2 vs 4 U, P = .007), and cryoprecipitate transfusion rates were significantly increased in grafts with 35% or more steatosis. Intensive care unit (5 vs 11 days, P = .02) and hospital (11 vs 21 days, P < .001) stay was also increased in those with grafts with 35% or more steatosis compared with those with 5% or less steatosis. The grafts with 35% or more steatosis had higher transaminase peaks and longer times for bilirubin to normalize (P < .001). CONCLUSIONS Use of carefully selected steatotic grafts was not associated with higher rates of primary nonfunction or poorer outcomes. However, the use of steatotic grafts is associated with increased resource use in the perioperative period.

Using ALPPS to Induce Rapid Liver Hypertrophy in a Patient with Hepatic Fibrosis and Portal Vein Thrombosis

Large or critically located hepatic tumors continue to be a challenge for surgeons as they push to obtain adequate surgical margins and often leave less residual liver behind. While it has been shown that up to 80 % of a healthy liver can be resected, additional challenges exist with the “less than healthy liver” when planning an operative procedure and determining the future liver remnant (FLR) volume. The main goal is to obtain adequate margins while avoiding postoperative liver decompensation and failure. Postoperative liver failure (PLF) has been reported to have a mortality rate as high as 32 % and is often associated with sepsis and multisystem organ failure. It has been shown that patients without liver disease (normal background liver) can recover with an FLR volume of greater than or equal to 25 % without significant postoperative sequelae. However, as we progress down the pathway of liver dysfunction, patients with chronic liver disease but without cirrhosis usually require an FLR of at least 30 %, and those with chronic liver disease with cirrhosis but without portal hypertension require an FLR of at least 40 %.. In the presence of chemotherapy or baseline liver disease, effectively determining the appropriate FLR can be challenging. While cirrhotic patients with tumor burden who meet appropriate criteria (Milan, UCSF, region 4 T3, etc.) are candidates for liver transplantation, those patients who have fibrosis and large tumor burdens or vascular thrombosis are not transplant candidates and therefore need an effective method for resection and prevention of PLF. One proposed method is to induce FLR hypertrophy by taking advantage of the regenerative capacity of the liver. Preoperative portal vein embolization (PVE) diverts portal venous flow from the tumor-bearing segments of the liver while increasing flow to the future liver remnant, resulting in hypertrophy. PVE has been widely adopted and has been shown to contribute 20–35 % hypertrophy in up to 45 days. Although this method often induces hypertrophy, waiting for sufficient growth can be time-consuming and carries the risk of interval disease progression. An ideal method of inducing liver regeneration would exclude all portal venous flow from the tumor-bearing segments of the liver while inducing rapid hypertrophy of the FLR and preventing PLF.

Outcomes Using Grafts from Donors after Cardiac Death

BACKGROUND Previous reports suggest that donation after cardiac death (DCD) liver grafts have increased primary nonfunction (PNF) and cholangiopathy thought to be due to the graft warm ischemia before cold flushing. STUDY DESIGN In this single-center, retrospective study, 866 adult liver transplantations were performed at our institution from January 2005 to August 2014. Forty-nine (5.7%) patients received DCD donor grafts. The 49 DCD graft recipients were compared with all recipients of donation after brain death donor (DBD) grafts and to a donor and recipient age- and size-matched cohort. RESULTS The DCD donors were younger (age 28, range 8 to 60 years) than non-DCD (age 44.3, range 9 to 80 years) (p < 0.0001), with similar recipient age. The mean laboratory Model for End-Stage Liver Disease (MELD) was lower in DCD recipients (18.7 vs 22.2, p = 0.03). Mean cold and warm ischemia times were similar. Median ICU and hospital stay were 2 days and 7.5 days in both groups (p = 0.37). Median follow-ups were 4.0 and 3.4 years, respectively. Long-term outcomes were similar between groups, with similar 1-, 3- and 5-year patient and graft survivals (p = 0.59). Four (8.5%) recipients developed ischemic cholangiopathy (IC) at 2, 3, 6, and 8 months. Primary nonfunction and hepatic artery thrombosis did not occur in any patient in the DCD group. Acute kidney injury was more common with DCD grafts (16.3% of DCD recipients required dialysis vs 4.1% of DBD recipients, p = 0.01). An increased donor age (>40 years) was shown to increase the risk of IC (p = 0.006). CONCLUSIONS Careful selection of DCD donors can provide suitable donors, with results of liver transplantation comparable to those with standard brain dead donors.

Liver Transplantation for Hepatocellular Carcinoma: Long-Term Results Suggest Excellent Outcomes

BACKGROUND Selected 5-year survival results after liver transplantation for hepatocellular carcinoma (HCC) have been reported to be 70%. Our hypothesis was that liver transplantation is effective for long-term cancer control for HCC. STUDY DESIGN A 20-year retrospective review of a prospectively collected database was carried out. Demographic data and patient survival were calculated. RESULTS There were 1,422 liver transplantations performed between January 1990 and April 2011. Of these, 264 had HCC and 157 (59%) were pretreated with transarterial chemoembolization. Recipient age was 55.9 (± 7.9) years and 208 (79%) of patients were male. The underlying disease was hepatitis C virus in 155 (58.7%), hepatitis B virus in 16 (6%), alcohol in 21 (8%), and miscellaneous in the remaining 72 cases. The mean number of tumors was 1.8 (± 1.7) and the mean largest tumor diameter was 2.3 (± 1.3) cm in the explanted liver. One, 5, and 10-year patient survival was 88.5%, 69.1%, and 40.5%, respectively; disease-specific survival was 99.1%, 94.4% and 87.9%; and disease-free survival was 86.0%, 64.6%, and 40.1%. One, 5, and 10-year graft survival was 87.3%, 68.0%, and 41.8%. Nine (3.4%) patients required retransplantation; 75 patients (28.4%) have died, but only 10 of 75 (13.3%) died of recurrent HCC (3.7% of all HCC patients receiving a transplant) and 6 (8%) died of recurrent viral hepatitis. An additional 9 recipients developed recurrence (total HCC recurrence, n = 19 [7%]), 4 of whom died of causes other than HCC. The remaining 5 are disease-free post-treatment (mean 5.5 years after orthotopic liver transplantation). CONCLUSIONS Orthotopic liver transplantation offers an effective treatment strategy for HCC in the setting of cirrhosis, even in the setting of hepatitis C virus. Hepatocellular carcinoma recurrence is uncommon in properly selected patients and disease-specific long-term survival approaches 90%.

Imaging Features of Biphenotypic Primary Liver Carcinoma (Hepatocholangiocarcinoma) and the Potential to Mimic Hepatocellular Carcinoma: LI-RADS Analysis of CT and MRI Features in 61 Cases

OBJECTIVE The purpose of this study was to determine the frequency with which biphenotypic primary liver carcinoma (also called hepatocholangiocarcinoma) may be misclassified as hepatocellular carcinoma (HCC) when only Liver Imaging Reporting and Data System (LI-RADS) major features are used and after consideration of ancillary features. MATERIALS AND METHODS A review of all pathologically proven biphenotypic primary liver carcinomas diagnosed at one institution from 2006 to 2014 was performed. Two subspecialized abdominal imagers independently reviewed cases using LI-RADS version 2014 and assigned major features, ancillary features, and additional findings. The number of lesions meeting imaging criteria for HCC was determined after assessment of major features alone and after the addition of ancillary features. RESULTS Sixty-one patients (30 men, 31 women; mean age, 62 years; range, 22-89 years) with biphenotypic primary liver carcinomas who underwent pretreatment multiphasic contrast-enhanced MRI (48 patients) or CT (13 patients) were included. According to LI-RADS major features alone, 33 (54.1%) lesions met criteria for HCC and therefore might have been misclassified. Thirteen had arterial phase hyperenhancement, washout, and a capsule. Twenty had arterial phase hyperenhancement with either washout (15 lesions) or a capsule (five lesions). After evaluation of ancillary features, 29 of these potential mimics exhibited at least one ancillary feature favoring non-HCC malignancy, possibly leading to appropriate reclassification. Of the four carcinomas that met criteria for HCC by major features and did not have ancillary features favoring non-HCC malignancy, two (3.3% of all tumors) fell within the Milan criteria. CONCLUSION Most biphenotypic primary liver carcinomas have features of non-HCC malignancy and can be correctly categorized as such. Addition of ancillary features to major features may improve diagnostic accuracy over systems in which only major features are used.

Polypoid lesions of the gallbladder: Disease spectrum with pathologic correlation

Gallbladder polyps are seen on as many as 7% of gallbladder ultrasonographic images. The differential diagnosis for a polypoid gallbladder mass is wide and includes pseudotumors, as well as benign and malignant tumors. Tumefactive sludge may be mistaken for a gallbladder polyp. Pseudotumors include cholesterol polyps, adenomyomatosis, and inflammatory polyps, and they occur in that order of frequency. The most common benign and malignant tumors are adenomas and primary adenocarcinoma, respectively. Polyp size, shape, and other ancillary imaging findings, such as a wide base, wall thickening, and coexistent gallstones, are pertinent items to report when gallbladder polyps are discovered. These findings, as well as patient age and risk factors for gallbladder cancer, guide clinical decision making. Symptomatic polyps without other cause for symptoms, an age over 50 years, and the presence of gallstones are generally considered indications for cholecystectomy. Incidentally noted pedunculated polyps smaller than 5 mm generally do not require follow-up. Polyps that are 6-10 mm require follow-up, although neither the frequency nor the length of follow-up has been established. Polyps that are larger than 10 mm are typically excised, although lower size thresholds for cholecystectomy may be considered for patients with increased risk for gallbladder carcinoma, such as patients with primary sclerosing cholangitis.

Surgical Treatment of Hepatocellular Carcinoma in North America: Can Hepatic Resection Still Be Justified?

BACKGROUND The incidence of hepatocellular cancer (HCC) is increasing dramatically worldwide. Optimal management remains undefined, especially for well-compensated cirrhosis and HCC. STUDY DESIGN This retrospective analysis included 5 US liver cancer centers. Patients with surgically treated HCC between 1990 and 2011 were analyzed; demographics, tumor characteristics, and survival rates were included. RESULTS There were 1,765 patients who underwent resection (n = 884, 50.1%) or transplantation (n = 881, 49.9%). Overall, 248 (28.1%) resected patients were transplant eligible (1 tumor <5 cm or 2 to 3 tumors all <3 cm, no major vascular invasion); these were compared with 496 transplant patients, matched based on year of transplantation and tumor status. Overall survivals at 5 and 10 years were significantly improved for transplantation patients (74.3% vs 52.8% and 53.7% vs 21.7% respectively, p < 0.001), with greater differences in disease-free survival (71.8% vs 30.1% at 5 years and 53.4% vs 11.7% at 10 years, p < 0.001). Ninety-seven of the 884 (11%) resected patients were within Milan criteria and had cirrhosis; these were compared with the 496 transplantation patients, with similar results to the overall group. On multivariate analysis, type of surgery was an independent variable affecting all survival outcomes. CONCLUSIONS The increasing incidence of HCC stresses limited resources. Although transplantation results in better long-term survival, limited donor availability precludes widespread application. Hepatic resection will likely remain a standard therapy in selected patients with HCC. In this large series, only about 10% of patients with cirrhosis were transplant-eligible based on tumor status. Although liver transplantation results are significantly improved compared with resection, transplantation is available only for a minority of patients with HCC.