[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma is a leading cause of death in patients with cirrhosis. Management algorithms continually are increasing in sophistication and involve application of single and multimodality treatments, including liver transplantation, hepatic resection, ablation, transarterial chemoembolization, radioembolization, and systemic chemotherapy. These treatments have been shown to increase survival times. As many as 75% of patients with limited-stage disease who are given curative therapies survive 5 years, whereas less than 20% of untreated patients survive 1 year. Treatment can be optimized based on the patient's tumor stage, hepatic reserve, and functional status. However, because of the heterogeneity in presentation among patients, a multidisciplinary approach is required to treat hepatocellular carcinoma, involving hepatologists, surgeons, interventional radiologists, and oncologists. We present each specialist's viewpoint on controversies and advances in the management of hepatocellular carcinoma.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 11/2011; 10(4):354-62. · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The applicability of islet transplantation as treatment for type 1 diabetes is limited by long-term graft dysfunction, immunosuppressive drug toxicity, need for multiple donors, and increased risk of allosensitization. We describe two immunosuppressive regimens based on the costimulation blocker belatacept (BELA) or the antileukocyte functional antigen-1 antibody efalizumab (EFA), which permit long-term islet allograft survival and address some of these concerns.
Ten patients with type 1 diabetes with hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction and maintenance with sirolimus or mycophenolate and BELA (n=5) or EFA (n=5).
All five BELA-treated patients achieved independence after single transplants; one resumed partial insulin use 305 days after transplant but is now independent after a second transplant. All five patients treated with EFA achieved independence after one (3/5) or two (2/5) islet transplants and remained independent while on EFA (392-804 days). After EFA was discontinued because of withdrawal of the drug from the market, two patients resumed intermittent insulin use; the others remain independent. No patient in either group developed significant side effects related to the study drugs, and none have been sensitized to alloantigens. All have stable renal function.
These two novel immunosuppressive regimens are effective, well tolerated, and the first calcineurin inhibitor/steroid-sparing islet protocols resulting in long-term insulin independence. Although EFA is no longer available for clinical use, these early results demonstrate that a regimen using BELA may be an effective alternative to improve graft function and longevity while minimizing renal and β-cell toxicity.
[Show abstract][Hide abstract] ABSTRACT: Hepatocelluar carcinoma (HCC) is the most common primary malignancy of the liver in adults and the third most common cause of cancer death worldwide. The incidence of HCC in the United States is rising steadily because of the prevalence of hepatitis C viral infection and other causes of hepatic cirrhosis. The majority of patients have underlying hepatic dysfunction, which complicates patient management and the search for safe and effective therapies. The Clinical Trials Planning Meeting (CTPM) in HCC was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to identify the key knowledge gaps in HCC and define clinical research priorities. The CTPM structured its review according to current evidence-based treatment modalities in HCC and prioritized the recommendations on the basis of the patient populations representing the greatest unmet medical need.
Journal of Clinical Oncology 09/2010; 28(25):3994-4005. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This opinion piece explores an "ablate and wait" strategy for improving the 5-year recurrence-free outcome of liver transplantation in patients with hepatocellular carcinoma. The Milan criteria delimit by tumor size and number a population of patients who have good survival after liver transplantation. The University of California San Francisco downstaging experience has shown that patients with a tumor burden outside the Milan criteria who undergo tumor ablation and a period of waiting have outcomes that rival those of patients who undergo transplantation within the Milan criteria because the tumor biology is allowed to become apparent by radiological studies during the waiting period. This experience has led to 2 conclusions: first, expansion beyond the Milan criteria should not occur without therapy directed to the tumor followed by a period of waiting to decrease the risk of recurrence, and second, for tumors within the Milan criteria, the same strategy should be considered.
[Show abstract][Hide abstract] ABSTRACT: The applicability of islet transplantation as treatment for type 1 diabetes is limited by renal and islet toxicities of currently available immunosuppressants. We describe a novel immunosuppressive regimen using the antileukocyte functional antigen-1 antibody efalizumab which permits long-term islet allograft survival while reducing the need for corticosteroids and calcineurin inhibitors (CNI). Eight patients with type 1 diabetes and hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction followed by maintenance with efalizumab and sirolimus or mycophenolate. When efalizumab was withdrawn from the market in mid 2009, all patients were transitioned to regimens consisting of mycophenolate and sirolimus or mycophenolate and tacrolimus. All patients achieved insulin independence and four out of eight patients became independent after single-islet transplants. Insulin independent patients had no further hypoglycemic events, hemoglobin A1c levels decreased and renal function remained stable. Efalizumab was well tolerated and no serious adverse events were encountered. Although long-term follow-up is limited by discontinuation of efalizumab and transition to conventional imunnosuppression (including CNI in four cases), these results demonstrate that insulin independence after islet transplantation can be achieved with a CNI and steroid-free regimen. Such an approach may minimize renal and islet toxicity and thus further improve long-term islet allograft survival.
American Journal of Transplantation 08/2010; 10(8):1870-80. · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In 2007, the islet community was notified that the collagenase product most commonly used for human islet isolations contained bovine neural tissue contaminants. To minimize this potential hazard, we adapted our human islet processing procedure to use a GMP-manufactured, bovine neural tissue-free collagenase blend. Here, we describe the factors that we consider most important for achieving reproducible and clinically useable islet isolations using this product.
[Show abstract][Hide abstract] ABSTRACT: Cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) for refractory ascites or recurrent variceal bleeding are at risk for decompensation and death. This study examined whether a new model for end stage liver disease (MELD), which incorporates serum sodium (MELDNa), is a better predictor of death or transplant after TIPS than the original MELD.
One hundred forty-eight consecutive patients undergoing nonemergent TIPS for refractory ascites or recurrent variceal bleeding from 1997 to 2006 at a single center were evaluated retrospectively. Cox model analysis was performed with death or transplant within 6 months as the end point. The models were compared using the Harrell's C index. Recursive partitioning determined the optimal MELDNa cutoff to maximize the risk:benefit ratio of TIPS.
The predictive ability of MELDNa was superior to MELD, particularly in patients with low MELD scores. The C indices (95% confidence interval [CI]) for MELDNa and MELD were 0.65 (95% CI, 0.55-0.71) and 0.58 (95% CI, 0.51-0.67) using a cut-off score of 18, and 0.72 (95% CI, 0.60-0.85) and 0.62 (95% CI, 0.49-0.74) using a cut-off score of 15. Using a MELDNa >15, 22% of patients were reclassified to a higher risk with an event rate of 44% compared with 10% when the score was <or=15.
MELDNa performed better than MELD in predicting death or transplant after non-emergent TIPS, especially in patients with low MELD scores. A MELD score <or=18 can provide a false positive prognosis; a MELDNa score <or=15 provides a more accurate risk prediction.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 06/2009; 7(11):1236-40. · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We previously suggested that in patients with heptocellular carcinoma (HCC), the conventional Milan criteria (T1/T2) for orthotopic liver transplantation (OLT) could be modestly expanded based on pathology (UCSF criteria). The present study was undertaken to prospectively validate the UCSF criteria based on pretransplant imaging. Over a 5-year period, the UCSF criteria were used as selection guidelines for OLT in 168 patients, including 38 patients exceeding Milan but meeting UCSF criteria (T3A). The 1- and 5-year recurrence-free probabilities were 95.9% and 90.9%, and the respective survivals without recurrence were 92.1% and 80.7%. Patients with preoperative T1/T2 HCC had 1- and 5-year recurrence-free probabilities of 95.7% and 90.1%, respectively, versus 96.9% and 93.6%, respectively, for preoperative T3A stage (p = 0.58). Under-staging was observed in 20% of T2 and 29% of T3A HCC (p = 0.26). When explant tumor exceeded UCSF criteria (15%), the 1- and 5-year recurrence-free probabilities were 80.4% and 59.5%, versus 98.6% and 96.7%, respectively, for those within UCSF criteria (p < 0.0001). In conclusion, our results validated the ability of the UCSF criteria to discriminate prognosis after OLT and to serve as selection criteria for OLT, with a similar risk of tumor recurrence and under-staging when compared to the Milan criteria.
American Journal of Transplantation 11/2007; 7(11):2587-96. · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: No prior studies have shown that pre-operative loco-regional therapy for hepatocellular carcinoma (HCC) improves survival following orthotopic liver transplantation (OLT). We performed subgroup analyses according to pathologic HCC stage among 168 patients who underwent OLT to test the hypothesis that pre-operative loco-regional therapy confers a survival advantage in a subgroup at intermediate risk for HCC recurrence. Patients with pathologic T3 HCC meeting the proposed UCSF expanded criteria (single lesion not exceeding 6.5 cm or two to three lesions none > 4.5 cm with total tumor diameter within 8 cm) had a similar 5-year recurrence-free survival as patients with pathologic T2 HCC (88.5% vs. 93.8%; p = 0.56). In the subgroup with pathologic T2 or T3 HCC, the 5-year recurrence-free survival was 93.8% for the 85 patients who received pre-operative loco-regional therapy, versus 80.6% for the other 41 patients without treatment (p = 0.049). The treatment benefit, according to 5-year recurrence-free survival, appeared greater for pathologic T3 (85.9% vs. 51.4%; p = 0.05) than T2 HCC (96.4% versus 87.1%; p = 0.12). In conclusion, although the lack of a randomized controlled design precludes drawing firm conclusions, our results suggest that pre-operative loco-regional therapy may confer a survival benefit after OLT in the subgroup with pathologic T2 and T3 HCC.
American Journal of Transplantation 04/2005; 5(4 Pt 1):795-804. · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our purpose here is to describe our experience with important hemobilia following PTBD and to determine whether left-sided percutaneous transhepatic biliary drainage (PTBD) is associated with an increased incidence of important hemobilia compared to right-sided drainages. We reviewed 346 transhepatic biliary drainages over a four-year period and identified eight patients (2.3%) with important hemobilia requiring transcatheter embolization. The charts and radiographic files of these patients were reviewed. The side of the PTBD (left versus right), and the order of the biliary ductal branch entered (first, second, or third) were recorded. Of the 346 PTBDs, 269 were right-sided and 77 were left-sided. Of the eight cases of important hemobilia requiring transcatheter embolization, four followed right-sided and four followed left-sided PTBD, corresponding to a bleeding incidence of 1.5% (4/269) for right PTBD and 5.2% (4/77) for left PTBD. The higher incidence of hemobilia associated with left-sided PTBD approached, but did not reach the threshold of statistical significance (p = 0.077). In six of the eight patients requiring transcatheter embolization, first or second order biliary branches were accessed by catheter for PTBD. All patients with left-sided bleeding had first or proximal second order branches accessed by biliary drainage catheters. In conclusion, a higher incidence of hemobilia followed left-versus right-sided PTBD in this study, but the increased incidence did not reach statistical significance.
CardioVascular and Interventional Radiology 03/2004; 27(2):137-9. · 2.14 Impact Factor