Living Donors Transplantation and Hepatic Resection


43

Pain Management in Living Liver Donors

Daniela Ladner1, Robert A. Fisher3, Elizabeth A. Pomfret2, Mary Ann Simpson2, Robert S. Brown4, Amna Daud1, Kathryn Waitzman1, John R. Joseph1, Donna Woods1

1Center for Healthcare Studies, Northwestern University Feinberg School of Medicine, Chicago, IL; 2Lahey Clinic, Boston, MA; 3Medical College of Virginia Hospital; Virginia Commonwealth University, Richmond, VA; 4Columbia University Medical Center, New York, NY

BACKGROUND: Living Liver Donation is a highly complex, voluntary surgical procedure associated with pain. However, managing pain after donation is difficult. Pain medications in liver donors (LDs) are not metabolized in the same way as patients with full livers. Furthermore, respiratory complications might occur more readily. Respiratory depression and perceived pain in LDs has not been previously reported. METHOD: Retrospective medical record review (years 2008-2010) of 23 LDs from four large transplant centers participating in the A2ALL Patient Safety System Improvements in Living Donor Liver Transplantation Study (R01DK090129) was conducted by a trained RN reviewer. POD#0-7 pain scores (1-10 scale), pain medications, vitals around pain score, and incidence of respiratory depression requiring intervention were assessed. RESULTS: LDs had mean pain scores of 3.86, 4.52, 4.03, 3.74, 4.81, 4.41, 5.91, and 4.75 on POD #0-7 respectively, however pain scores ranged from 0-10 throughout POD#0-7.The highest reported mean pain scores occurred on POD#6 (5.1). Percentage of pain score assessments > 6 increased on POD#4 (34%), and were highest on POD#6 (48%). All LDs received IV opioids after donation, 56% received IV NSAIDS, 26% received an epidural. PO medications increased from 13% to 100% at discharge. Vitals recorded around the pain scores were correlated (Figure 1). Eight LDs (20%) suffered respiratory complications requiring higher level care (PACU, ICU), respiratory interventions (i. e. re-intubation), reversal agents, and adjustments in ordered pain medications. The centers modified their standard of care to a multi-modal opioid sparing regimen. CONCLUSIONS: LDs experience significant pain after donation according to their subjective pain scores, despite extensive multifaceted pain regimens. Most pain is experienced as IV drugs are switched to PO regimen. Despite close monitoring, a significant portion of patients experience sequelae of over narcotization which presents significant patient safety risks to LDs. Pain management in LDs needs to be improved to ensure safety while providing better pain control with zero tolerance for respiratory events.

image

Disclosures:

Robert S. Brown - Consulting: Salix, Janssen, Vertex; Grant/Research Support: Gilead, Merck, Vertex, AbbVie, Salix, Janssen, BI; Speaking and Teaching: Genentech, Gilead, Merck

The following people have nothing to disclose: Daniela Ladner, Robert A. Fisher, Elizabeth A. Pomfret, Mary Ann Simpson, Amna Daud, Kathryn Waitzman, John R. Joseph, Donna Woods tumors express less CAR protein than normal liver. Conclusions: TCP rescues mice exposed to SFSS after extended liver resections and liver transplantation. Molecular changes induced by CAR activation act on downstream targets of pathways promoting cell cycle progression (Foxm1b) and uncoupling from organ size control (miR375/YAP) to override the regenerative deficits of marginal liver remnants. Reduced CAR expression in tumors suggests a subset of HCCs may not respond to CAR activation, pointing to a patient group amenable to this treatment. Studies in humanized mice and on ex vivo human liver tissue will address the clinical potential of CAR activation by enhancing liver regeneration after extended resections for primarily unresectable liver tumors.

Disclosures:

The following people have nothing to disclose: Christoph Tschuor, Ekaterina Kachaylo, Perparim Limani, Amedeo Columbano, Andrea Schlegel, Jae Hwi Jang, Dimitri A. Raptis, Emmanuel Melloul, Yinghua Tian, Rolf Graf, Bostjan Humar, Pierre A. Clavien

44

Activation of the Constitutive Androstane Receptor (CAR) reverses deficient liver regeneration in the Small-ForSize Syndrome via Foxm1b and miR375/YAP-dependent pathways

Christoph Tschuor1, Ekaterina Kachaylo1, Perparim Limani1, Amedeo Columbano3, Andrea Schlegel1, Jae Hwi Jang2,1, Dimitri A. Raptis1, Emmanuel Melloul4,1, Yinghua Tian1, Rolf Graf1, Bosfjan Humor1, Pierre A. Clavien1

1Swiss Hepafo-Pancreafico-Biliary (HPB) Center, Department of Visceral and Transplant Surgery, University Hospital Zurich, Zurich, Switzerland; 2Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland; 3Department of Toxicology, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy; 4Department of Visceral Surgery, University Hospital Lausanne, Lausanne, Switzerland

Background: Resectability of liver tumors is limited since patients left with marginal liver remnants are at risk for developing the Small-for-Size Syndrome (SFSS). SFSS is characterized by an insufficient recovery due to delayed regeneration. Strategies are needed to overcome regenerative limits, rendering large liver tumors resectable. Activation of the constitutive androstane receptor (CAR), a nuclear receptor expressed in the liver, induces liver hyperplasia. We investigated the potential of the CAR agonist TCPOBOP (TCP) to ameliorate experimental SFSS, thereby enabling extended oncological liver resections. Methods: The effects of TCP on liver regeneration were assessed in four murine models: 68% hepatectomy (Hx) (control), 86% Hx (model of SFSS), 91% Hx (lethal model), and 30% liver transplantation (SFSS transplantation model) in BL6 and CAR-/- mice. Serum bilirubin, ALKP, and albumin served as measures of SFSS-like features. Proliferation-associated molecules, including Foxm1b, p21 and miR375/YAP-dependent pathways were analysed. Functional relevance of the molecules was assessed via siRNA knockdown. Humanized mice and human tissue microarrays (TMA) served for evaluation of the translational potential. Results: Reduced survival in SFSS is associated with deficient regeneration due to deregulation of Foxm1b and YAP/miR375 pathways along with p21 upregulation. TCP markedly improved survival following 86% Hx, 91% Hx and 30% transplantation. Likewise, SFSS-associated features were normalized by TCP, while TCP did not improve survival or liver regeneration in CAR-/- mice. Functional experiments reveal that CAR activation promotes Foxm1b, reversing abnormal induction of p21 and restoring deficiency in liver regeneration. In addition, deregulation of the YAP/miR375 pathway relevant for organ size control is corrected by CAR activation. Human HCC and adenoma TMA's reveal 40% of Purpose tumors express less CAR protein than normal liver. Conclusions: TCP rescues mice exposed to SFSS after extended liver resections and liver transplantation. Molecular changes induced by CAR activation act on downstream targets of pathways promoting cell cycle progression (Foxm1b) and uncoupling from organ size control (miR375/YAP) to override the regenerative deficits of marginal liver remnants. Reduced CAR expression in tumors suggests a subset of HCCs may not respond to CAR activation, pointing to a patient group amenable to this treatment. Studies in humanized mice and on ex vivo human liver tissue will address the clinical potential of CAR activation by enhancing liver regeneration after extended resections for primarily unresectable liver tumors.

Disclosures:

The following people have nothing to disclose: Christoph Tschuor, Ekaterina Kachaylo, Perparim Limani, Amedeo Columbano, Andrea Schlegel, Jae Hwi Jang, Dimitri A. Raptis, Emmanuel Melloul, Yinghua Tian, Rolf

45

Comparison of surgical outcome between minimallyinvasive liver resection and conventional open liver resection for the treatment of hepatocellular carcinoma : a propensity-score matched analysis

Dai Hoon Han, Eun Jung Park, Gi Hong Choi, Jin Sub Choi

Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea

Purpose: This study aimed to analyze operative and survival outcomes of minimally invasive liver resection (MILR) versus conventional open liver resection (COLR) for the treatment of hepatocellular carcinoma (HCC). Moreover, we attempted to reveal the role of the robotic system in MILR (HCC). Methods: From January 1996 to December 2012, 1014 consecutive patients underwent curative liver resection of HCC. Among these patients, 90 patients with MILR were matched to 360 patients with COLR by one-to-four propensity-score matched analysis. A multivariable logistic model based on age, gender, etiology of HCC, tumor size, multiplicity of tumor, the presence or absence of liver cirrhosis and extent of liver resection was used to estimate propensity score. Perioperative surgical outcomes and long-term survival were compared between two groups. Results: The amount of blood loss during operation, transfusion rate and postoperative complication rate were significantly lower in MILR groups. Mean length of hospital stay after operation was significantly shorter in MILR group (8.57 vs. 13.44 days, p<0.001). There were 7 cases of open conversion from MILR and all cases were laparoscopic attempted liver resections. In MILR group, most of major resections were performed with robotic system (n=10, p<0.001). Anatomic liver resections were performed for 15 of 16 patients using robotic system. There was no difference in primary recur site between two groups. The 1-, 2-, 3-year disease-free survival rate of MILR were 84.7%, 66.8%, and 59.6 % respectively, which were comparable to those of COLR (p =0.579). Conclusions: MILR showed better perioperative outcomes with comparable oncologic outcomes for the treatment of HCC. According to the complexity of procedures, the robotic surgery may expand the indication of minimally invasive liver resection in patients with HCC.

Disclosures: The following people have nothing to disclose: Dai Hoon Han, Eun Jung Park, Gi Hong Choi, Jin Sub Choi

46

The impact of nonalcoholic steatohepatitis on the prognosis of patients with hepatocellular carcinoma within the Milan criteria and underwent resection surgery

Chien-Wei Su1,2, Gar-Yang Chau5,3, Jaw-Ching Wu2,4, Hung-Hsu Hung6,2, Hao-Jan Lei5,3, Han-Chieh Lin 1,3, Shou-Dong Lee6,3

1Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 2Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; 3Faculty of Medicine, School of Medicine, National YangMing University, Taipei, Taiwan; 4Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan; 5Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; 6Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan

Background and Aims: Whether or not nonalcoholic steatohepatitis (NASH) on the non-tumor part plays an important role in determining the prognosis of patients with hepatocellular carcinoma (HCC) is still not fully elucidated. This study aimed to compare the outcomes between early-stage HCC patients with and those without NASH after resection surgery. Methods: We enrolled 188 patients who underwent resection surgery for HCC within the Milan criteria. After surgery, fibrosis, steatosis, lobular inflammation, portal inflammation and ballooning on the non-tumor part were assessed comprehensively. The diagnosis and grading of NASH was determined by Brunt score. Factors in terms of overall survival after surgery were analyzed by multivariate analysis. Results: There were 73 (38.8%) patients had NASH with Brunt score ≥1.Patients with NASH had larger body mass index (24.97±3.17 kg/m2 vs. 23.29±3.58 kg/m2, p=0.002), higher fasting glucose levels (115.05±52.34 mg/dL vs. 99.05±34.68 mg/dL, p=0.014), and higher rates of ballooning (75.3% vs. 32.2%, p<0.001) than those without NASH on the non-tumor part. But the viral factors (rates of chronic hepatitis B or chronic hepatitis C), and tumor factors (tumor size, number, venous invasion, cell differentiation) were comparable between these two groups. After a median follow-up of 69.8 months, 73 patients died. The cumulative survival rates at 5 years were 75.8% and 57.3% for patients without NASH and those with Brunt score ≥1, respectively (p=0.007). Multivariate analysis disclosed that age > 65 years (hazard ratio, HR 1.996, 95% confidence interval, CI 1.89-3.349, p=0.009), serum platelet count < 105 /mm3 (HR 2.198, 95% CI 1.274-2.747, p=0.005), indocyanine green retention rate at 15 minutes > 10% (HR 2.038, 95% CI 1.108-3.749, p=0.022), multinodularity (HR 2.400, 95% CI 1.320-4.365, p=0.004), and presence of NASH with Brunt score ≥1(HR 1.774, 95% CI 1.081-2.913, p=0.023) were the independent risk factors associated with poor overall survival after resection surgery. Conclusions: The presence of NASH on the non-tumor part was associated with poor overall survival in HCC patients who were within Milan criteria and underwent resection surgery.

Disclosures:

The following people have nothing to disclose: Chien-Wei Su, Gar-Yang Chau, Jaw-Ching Wu, Hung-Hsu Hung, Hao-Jan Lei, Han-Chieh Lin, Shou-Dong Lee

47

Dual Treatment; A Novel Strategy for Highly-Advanced Hepatocellular carcinoma

Shinichi So, Takumi Fukumoto, Masahiro Kido, Atsushi Takebe, Motofumi Tanaka, Kaori Kuramitsu, Hisoka Kinoshita, Shohei Komatsu, Kenji Fukushima, Takeshi Urade, Yonson Ku

Kobe university, Kobe city, Japan

Introduction The selection criteria for the treatment of highlyadvanced hepatocellular carcinoma (HCC) is still controversial, and its therapeutic efficacy is unsatisfactory. Conversely although survival benefit of surgical resection for these cases have not been reported yet, portal vein (PVTT) or IVC (IVCTT) tumor thrombus is an life-limiting factor and accordingly surgery is selected. We developed a novel strategy for highly-advanced HCC patients; dual treatment. Methods At the first stage, we performed surgical resection including thrombectomy (reduction surgery). Indication criteria for surgery consisted of liver function tests; Child-Pugh score, 15-minute indocyanine retention rate (ICG15), 99mTc-GSA scintigraphy, and Metavir score from liver biopsy obtained before and during the surgery. Additionally the presenting portion of thrombus was carefully analyzed with 3-D CT, MRI, and angiography just prior to the surgery. Within a month we performed percutaneous isolated hepatic perfusion (PIHP) as the second stage for the prevention of recurrence. PIHP is a high-dose regional chemotherapy we developed at our facility. With PIHP, we could administer cytotoxic agents at a dose up to 10 times while reducing the side effect of the agents from the entire body. Indication criteria for PIHP was age 10-70 years, WHO performance status of 2 or less, labolatory data; serum bilirubin 2.5mg/dl or less, ICG15 35% or less, serum aspartate aminotransferase (AST) 300 IU/L or less, platelets 50000/mm3 or more, and no pre-existing heart disease. Results Until December 2009, we treated 75 cases with dual treatment and completed in 64 cases. Among them 21 cases were categorized in vp4 stages. More than 70% patients were performed lobectomy at the first stage. For thrombectomy, we developed back flow perfusion technique; by clamping the portal vein pressure at the front raw, back flow from hepatic vein was maintained at the end side of the PVTT sequentially preventing the clotting of the free-floating thrombus at the time of thrombectomy. Twenty-four (37.5%) patients showed complete response, 22 (34.4%) showed a partial response, 12 (18.8%) showed no response, and 5 (7.8%) showed progressive disease. Response rate was 72%, and survival rate of total/vp4 cases were 75.1/73.7% (1 year), 35.6/35.8% (3 years), and 30.8/35.8% (5 years) respectively. Conclusion Dual treatment could achieve median and long-term prognosis, indicating that this would be a novel strategy for highly-advanced HCC.

Disclosures:

The following people have nothing to disclose: Shinichi So, Takumi Fukumoto, Masahiro Kido, Atsushi Takebe, Motofumi Tanaka, Kaori Kuramitsu, Hisoka Kinoshita, Shohei Komatsu, Kenji Fukushima, Takeshi Urade, Yonson Ku

48

“Small for Size Syndrome” (SFSS) after Living Donor Liver Transplantation (LDLT): It's Not About Size. Report from the Adult to Adult Living Donor Liver Transplantation (A2ALL) Cohort Study

James Pomposelli1, Abhinav Humar2, Talia B. Baker3, David Grant4, Nathan P. Goodrich5, Brenda W. Gillespie6, Robert M. Merion6,5, Igal Kam7, Michael A. Zimmerman7, Benjamin Samtein8, Peter L. Abt9, Chris Freise10, Jean C. Emond8

1Hahey Clinic, Burlington, MA; 2University of Pittsburgh, Pittsburgh, PA; 3Northwestern University, Chicago, IL; 4University of Toronto, Toronto, ON, Canada; 5Arbor Research Collaborative for Health, Ann Arbor, MI; 6University of Michigan, Ann Arbor, MI; 7University of Colorado, Aurora, CO; 8Columbia University, New York, NY; 9University of Pennsylvania, Philadelphia, PA; 10University of California, San Francisco, San Francisco, CA

PURPOSE: Early graft dysfunction (GD) after LDLT has been described as “small for size syndrome” (SFSS) and defined as persistent cholestasis (serum bilirubin >5mg/dL x 3 days) in combination with at least one of: coagulopathy (INR≥2.0 x 3 days), ascites formation (≥1 L/day x 3 days) or encephalopathy (x 3 days) during the first postoperative week. Suspected risk factors for early graft dysfunction or SFSS are low graft weight, graft weight/body weight ratio < 0.8 (GW/BW), and excessive post-reperfusion portal pressure and/or flow. The purpose of this study was to determine the incidence and factors associated with the development of GD after LDLT. METHODS: 198 patients underwent LDLT using 171 right lobe and 27 left lobe grafts at the nine A2ALL centers. Recipient preoperative demographics, operative characteristics including portal pressure and flow data, and postoperative outcomes were collected prospectively. Surgical inflow modulation (hemi-portocaval shunt, splenic artery ligation, splenectomy) was at the discretion of the operating surgeon. Differences in patient characteristics were assessed with chi-square tests and t-tests for categorical and continuous factors, respectively. RESULTS: 71 females and 127 males underwent LDLT. Of these, 22 developed GD (6 female, 16 male). 5 of the 22 recipients (22.7%) that developed Gd had GW/BW ratios < 0.8.Of the 176 recipients without GD, 43 (24.4%) received grafts with GW/BW ratios < 0.8.Operative (30-day) mortality was 3%. The 90-day graft failure rate was 4%. Overall morbidity was 62%. Factors significantly associated with GD included higher preoperative MELD score (17.7 vs 13.9, p=0.002), and reduced post-reperfusion hepatic arterial flow (96 vs. 147 ml/min, p=0.003), reduced portal venous flow (1028 vs. 1490 ml/min, p=0.023) and cardiac output (8.2 vs. 10.1 L/min, p=0.044). Recipient age, sex, graft weight, graft weight to body weight ratio (GW/BW), portal venous pressure, and use of surgical inflow modulation were not associated with the development of GD. Hospital length of stay was not significantly longer in patients with GD (24 vs. 15 days, p=0.21). Operative mortality and graft failure rates were not associated with GD. CONCLUSION: GD, commonly referred to as SFSS, develops independently of GW or GW/BW. Preoperative disease severity and reduction in arterial and portal flow are contributors to GD and may be related to changes in cardiac performance. Subjects with inflow modulation did not have an increased incidence of GD. Additional studies are required to determine is GD can be predicted using clinical parameters and prevented using appropriate intervention.

Disclosures:

The following people have nothing to disclose: James Pomposelli, Abhinav Humar, Talia B. Baker, David Grant, Nathan P. Goodrich, Brenda W. Gillespie, Robert M. Merion, Igal Kam, Michael A. Zimmerman, Benjamin Samstein, Peter L. Abt, Chris Freise, Jean C. Emond

Ancillary