9 Liver Resection for Hepatocellular Carcinoma 125 Several different parenchymal dissection techniques have been developed to min- imize blood loss and expedite hepatic resection. Advances in instrumentation, such as development of the ultrasonic aspirator, the jet cutter, the argon beam coagulator, and saline-linked cautery, have all been purported to improve surgical technique. The ultrasonic dissector is a handheld device that destroys hepatocytes by cavita- tion based on water content and aspirates the liquefied tissue. Vessels and biliary ducts, which contain less water, are preserved allowing for a clear delineation of these structures within the transection plane. Saline-linked cautery (SLC) uses a metal probe to deliver radiofrequency energy conducted through a slow infusion of saline. At our institution, we recently combined saline-linked cautery with ultra- sonic dissection in a standardized fashion (Fig. 9.11). This combination allows a clear delineation of the vascular and biliary anatomy within the transection plane, resulting in a significant decrease in total operative time, blood loss, and need for suture control of intraparenchymal vessels. The primary surgeon dissects the hepatic parenchyma from the patient’s left side utilizing the ultrasonic dissector while the second surgeon operates the SLC from the patient’s right side. Vessels of 3 mm or smaller are coagulated and divided using the SLC device, while those of 3–5 mm in diameter are controlled with titanium clips and divided sharply. Larger vessels and portal triads are sutured with 3-0 silk ties in continuity and divided sharply. This two-surgeon technique resulted in a significant decrease in blood loss and total operative time [66]. The combined technique using the ultrasonic dissec- tor and the SLC has recently been validated by two different groups. Takatsuki Fig. 9.11 Two-surgeon technique for hepatic parenchymal transection. Using the ultrasonic dissection device, the primary surgeon directs the dissection from the patient’s left side. Simultaneously, the secondary surgeon operates the saline-linked cautery device from the patient’s right side. Traction on 4-0 polypropylene stay sutures is used to expose the deepening transection plane (From [66], used with permission) 126 D.Zorzietal. et al. [67] analyzed outcomes in living donor hepatectomy. The authors found a statistically significant lower level of blood loss and donors complications when the two-surgeon technique was used. In a randomized controlled trial, El Moghazy et al. [68] demonstrated a lower blood loss and a faster parenchymal transection time in the group randomized to ultrasonic dissector and saline-linked cautery com- pared to ultrasonic dissector and bipolar cautery in living donor hepatectomy. This is of utmost importance since a faster parenchymal phase may reduce the time of the Pringle maneuver and of ischemic injury of the liver. In addition a recent study reported the level of intraoperative blood loss during resection of HCC to be an independent predictor of overall survival, disease-specific survival, and disease-free survival [69], hence a decreased intraoperative blood loss during HCC resection using the two-surgeon technique may improve oncologic outcome. Drainage Drains have not been shown to be beneficial after hepatic resection for HCC. In a meta-analysis of three randomized controlled trials, the incidence of postoperative biloma was approximately 5% and either equal or even higher in drained patients compared with not drained patients [70]. In one of these trials, which only included patients with chronic liver disease, drainage after resection was an independent pre- dictor of postoperative complications [71]. Drains also failed to detect significant postoperative complications such as bile leak and hemorrhage that needed surgical or radiologic interventions. Outcome After Resection Morbidity and Mortality Improvements in patient selection and surgical technique have resulted in a remark- able decrease in perioperative mortality rates. A large, multicenter review from the 1970s by Foster and Berman reported a perioperative mortality of 21% for major hepatectomy and 58% for patients with cirrhosis [72]. Currently, the mortality rate is approximately 5% with some centers approaching close to zero mortality [22, 29, 73]. Refinements are multifactorial and include surgical technique, anesthesia management, perioperative care, and the establishment of high-volume referral centers specializing in hepatobiliary surgery. Morbidity rates range from 25 to 50% in recent large series [4, 5, 9–11]. In addi- tion to complications associated with all major surgery, posthepatectomy specific complications include right pleural effusion, subphrenic abscess, bleeding, biliary leak/fistula, ascites, and hepatic insufficiency. Blood loss and the need for trans- fusion have clearly been shown to increase morbidity and mortality [74, 75]. In a review of extended hepatectomies for HCC, multivariate analysis identified the Pringle maneuver and blood transfusion as risk factors for morbidity with comorbid 9 Liver Resection for Hepatocellular Carcinoma 127 illness and blood transfusion as independent risk factors for death [11]. The risk of morbidity with Pringle maneuver was primarily for minor complications such as ascites/effusion and mainly in those patients with clamping time exceeding 80 min. Long-Term Outcome During the past two to three decades, survival after hepatic resection has markedly improved over earlier results, likely due to early diagnosis in high-risk patients screened with AFP and ultrasound, improved patient selection, and surgical man- agement. Large series have reported 30–50% 5-year overall survival rates following curative resection [69, 76–78]. The main cause of treatment failure is tumor recurrence. Indeed, cumulative 5-year recurrence rates of 70–100% have been reported after hepatic resection. Recurrence occurs in the liver remnant in about 80–90% [78, 79] of cases, as a result of vascular invasion leading to microsatellite tumors within the liver, i.e., intrahepatic metastases (early recurrence), or second primaries in the remnant liver associated with field effect from hepatitis and cirrhosis (late recurrence). Though surgical resection of intrahepatic tumor recurrence is a demanding proce- dure because of reduced hepatic parenchyma and a more hostile environment, repeat hepatectomy has been proven to be safe and worthwhile [80–85]. About 10–31% of the patients with intrahepatic recurrence can be treated with a second hepatectomy. Utilizing the same selection criteria as for primary resection, three clinicopatho- logic variables were found to be independent prognostic factors: absence of portal invasion at the second resection, single HCC at the primary hepatectomy, and a disease-free interval of at least 1 year after the primary hepatectomy [86]. In a series of 67 patients, the overall 5-year survival after a repeat hepatectomy was 56% – a rate comparable to those reported in many series of initial resection [85]. Aggressive nonsurgical treatment with ethanol injection, radiofrequency ablation, and transar- terial chemoembolization may yield favorable results in patients not suitable for repeat resection. The prognosis after potentially curative therapy depends on tumor-related factors and underlying liver disease. Thus, clinical and pathologic predictors of survival have been extensively investigated. For example, in a stepwise analysis approach on 5,800 patients, the Liver Cancer Study Group of Japan established portal involvement as the predominant prognostic factor, followed by number of tumor nodules, AFP level, tumor size, cirrhosis, age, and surgical curability (as defined by resection margin, stage, and absence of remaining macroscopic tumor) [87]. Resection Prior to Liver Transplantation For those patients whose poor underlying liver function and tumor number or loca- tion preclude traditional hepatic resection, total hepatectomy with orthotopic liver 128 D.Zorzietal. transplantation (OLT) has been advocated. Initial series of OLT for HCC reported poor results, with tumor recurrence in up to 75% of patients. Bismuth et al. were the first to show that in the early era of liver transplantation, the surgical strategy for the treatment of hepatocellular carcinoma in cirrhosis had followed a misconception in selecting patients suffering from advanced, unresectable cancers as transplant candi- dates [88]. Currently, those patients suffering from HCC and cirrhosis with three or less tumor nodules up to 3 cm in maximum diameter or a single tumor not exceeding 5 cm and no signs of vascular invasion are considered for transplantation (Milano criteria) [6]. OLT based on these Milan criteria have been shown to provide very good disease-free survival, so that it is considered to be the optimal treatment of small HCC, especially in patients with underlying chronic liver disease [7, 89]. The evidence that OLT should be the preferred treatment choice for these patients has increased the demand resulting in longer waiting list in the face of a relative shortage of available donors. During long waiting times, some patients suffer progression of disease such that they can never benefit from OLT. Bridge treatments to halt or delay tumor progression during the waiting period for OLT include also liver resection [90–94]. Poon et al. noted that 80% of patients who recur after primary resection for HCC remain eligible for OLT [90]. Thus a new strategy was proposed for patients with preserved liver function and HCC: hepatic resection prior to “salvage” or sec- ondary OLT. The major drawbacks of this concept of primary liver resection prior to transplantation could be the increase technical difficulty during OLT procedure and the risk of impaired posttransplant survival. Belghiti et al. showed that in selected patients with cirrhosis and resectable HCC perioperative and postoperative course of OLT following liver resection did not differ in terms of operative time, blood loss, morbidity and mortality compared to upfront OLT. Also, long-term survival after liver resection prior to OLT was not different compared to upfront OLT [95]. Fibrolamellar Variant of HCC Fibrolamellar carcinoma (FLHCC) is a distinct clinical variant of HCC. This hepatic tumor usually occurs in young patients, most commonly within the second and third decades of life with no gender predominance. There seems to be a preponderance of FLHCC in American Caucasians, with few cases reported in Asian populations. The incidence of FLHCC has been reported at 6–23% of western patients with HCC. Pathologically, FLHCC typically consists of well-circumscribed, large soli- tary lesions with a central scar. Unlike classic HCC, cirrhosis is not a common component of the hepatic disease in patients with FLHCC. In addition, hepatitis infection is uncommon and serum alpha-fetoprotein levels are usually within normal limits. Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) often demonstrate a heterogeneous mass with a central scar that is similar to those seen in cases of focal nodular hyperplasia (FNH). Central calcifications within the mass have been used to distinguish FLHCC from FNH, but this is not specific. Conflicting data exist regarding whether patients with fibrolamellar carcinoma have a better survival when compared to patients with classic HCC. In a series 9 Liver Resection for Hepatocellular Carcinoma 129 published from Memorial Sloan-Kettering Cancer Center, resected patients with FLHCC did not have an improved long-term survival compared to classic HCC, although there were too few patients with FLHCC to make meaningful conclu- sions [96]. These survival data were similar to those published by Nagorney et al. [97] who found no survival advantage for FLHCC over classic HCC without cir- rhosis. They noted, however, a higher resection rate for patients with FLHCC. In contrast, Soreide et al. reported a 56% 5-year survival and a 58% resectability rate for patients with FLHCC [98]. In a large review of the literature, Okuda noted a 95% resectability rate and improved survival for patients with FLHCC as compared to HCC patients [99]. Tumor stage has a profound influence on survival as demon- strated by Hemming et al., with stage II FLHCC patients experiencing extended survival times as compared to patients with stage III disease [100]. Ringe et al. observed the number of hepatic lesions and the presence of nodal disease to be significant variables in predicting survival in resected patients [101]. Survival times are longer in patients with recurrences of FLHCC following resection when com- pared to recurrences of classic HCC. In addition, patients with recurrent FLHCC following resection have been reported to have prolonged survival following re-excision of a local recurrence. Unlike HCC, patients with FLHCC are more likely to have solitary tumors, thus potentially increasing the resection rate. The rate of metastases, both nodal and distant, has been reported up to 30% at the time of diag- nosis. Indeed, the rate of lymph node positivity is quite high in FLHCC, raising the question of en bloc lymphadenectomy at the time of the primary surgery. To date, no one has reported data to adequately answer this question. Patients with unresectable metastatic FLHCC have been reported to have a median survival of 14 months, double that for matched-for-stage HCC patients. Controversy exists as to whether resection or transplantation for FLHCC pro- vides superior survival. One study from the UK noted a 3-year survival of 100% for patients treated with major liver resection versus 76% 3-year survival follow- ing hepatic transplantation for FLHCC (P < 0.025) [102]. These data are similar to data published from Pittsburgh. Pinna et al. [103] documented superior survival for FLHCC patients treated with resection as compared to transplanted patients. Additionally, the survival gap at 5 years was 44%, with 75% of resected patients alive versus 36% of transplant recipients. Further evidence of the apparent superior- ity of hepatic resection compared to transplantation in patients with FLHCC came from Germany, where resected patients had a median survival of 44.5 months versus 28.5 months for transplantation. In a review of the literature on transplantation for HCC, Neuhaus et al. concluded that transplantation is not appropriate for FLHCC without cirrhosis [104]. The potential neoadjuvant role for continuous infusion fluorouracil and subcuta- neous interferon alpha-2b has been suggested based on a phase II trial conducted at the M.D. Anderson Cancer Center [105]. There was a 62.5% response rate follow- ing chemotherapy seen in patients with FLHCC as compared to a 14% response rate in patients with HCC. This suggests that in patients with advanced stage FLHCC, downstaging with chemotherapy should be considered to increase the resectability rate, although further trials are necessary. 130 D.Zorzietal. References 1. Nagasue N, Yukaya H, Hamada T, Hirose S, Kanashima R, Inokuchi K (1984) The natural history of hepatocellular carcinoma. A study of 100 untreated cases. Cancer 54:1461–1465 2. Barbara L, Benzi G, Gaiani S et al (1992) Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology 16:132–137 3. Shuto T, Hirohashi K, Kubo S et al (1998) Changes and results of surgical strategies for hepatocellular carcinoma: results of a 15-year study on 452 consecutive patients. Surg Today 28:1124–1129 4. Zhou XD, Tang ZY, Yang BH et al (2001) Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer 91:1479–1486 5. Takenaka K, Kawahara N, Yamamoto K et al (1996) Results of 280 liver resections for hepatocellular carcinoma. Arch Surg 131:71–76 6. Mazzaferro V, Regalia E, Doci R et al (1996) Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693–699 7. Llovet JM, Bruix J, Fuster J et al (1998) Liver transplantation for small hepatocellular carci- noma: the tumor-node-metastasis classification does not have prognostic power. Hepatology 27:1572–1577 8. Cance WG, Stewart AK, Menck HR (2000) The National Cancer Data Base Report on treatment patterns for hepatocellular carcinomas: improved survival of surgically resected patients, 1985–1996. Cancer 88:912–920 9. Fong Y, Sun RL, Jarnagin W, Blumgart LH (1999) An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 229:790–799 10. Belghiti J, Hiramatsu K, Benoist S, Massault P, Sauvanet A, Farges O (2000) Seven hun- dred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg 191:38–46 11. Wei AC, Tung-Ping Poon R, Fan ST, Wong J (2003) Risk factors for perioperative morbidity and mortality after extended hepatectomy for hepatocellular carcinoma. Br J Surg 90:33–41 12. Pawlik TM, Poon RT, Abdalla EK et al (2005) Critical appraisal of the clinical and patho- logic predictors of survival after resection of large hepatocellular carcinoma. Arch Surg 140:450–457 13. Kosuge T, Makuuchi M, Takayama T, Yamamoto J, Shimada K, Yamasaki S (1993) Long-term results after resection of hepatocellular carcinoma: experience of 480 cases. Hepatogastroenterology 40:328–332 14. Ng KK, Vauthey JN, Pawlik TM et al (2005) Is hepatic resection for large or multinodular hepatocellular carcinoma justified? Results from a multi-institutional database. Ann Surg Oncol 12:364–373 15. Liu CL, Fan ST, Lo CM, Ng IO, Poon RT, Wong J (2003) Hepatic resection for bilobar hepatocellular carcinoma: is it justified? Arch Surg 138:100–104 16. Pawlik TM, Poon RT, Abdalla EK et al (2005) Hepatectomy for hepatocellular carcinoma with major portal or hepatic vein invasion: results of a multicenter study. Surgery 137: 403–410 17. Minagawa M, Makuuchi M, Takayama T, Ohtomo K (2001) Selection criteria for hepatec- tomy in patients with hepatocellular carcinoma and portal vein tumor thrombus. Ann Surg 233:379–384 18. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R (1973) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60:646–649 19. Mansour A, Watson W, Shayani V, Pickleman J (1997) Abdominal operations in patients with cirrhosis: still a major surgical challenge. Surgery 122:730–735 20. Teh SH, Christein J, Donohue J et al (2005) Hepatic resection of hepatocellular carcinoma in patients with cirrhosis: model of end-stage liver disease (MELD) score predicts perioperative mortality. J Gastrointest Surg 9:1207–1215 9 Liver Resection for Hepatocellular Carcinoma 131 21. Belghiti J, Regimbeau JM, Durand F et al (2002) Resection of hepatocellular carcinoma: a European experience on 328 cases. Hepatogastroenterology 49:41–46 22. Makuuchi M, Kosuge T, Takayama T, et al (1993) Surgery for small liver cancers. Semin Surg Oncol 9:298–304 23. Bruix J, Castells A, Bosch J et al (1996) Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 111:1018–1122 24. Eguchi H, Umeshita K, Sakon M et al (2000) Presence of active hepatitis associated with liver cirrhosis is a risk factor for mortality caused by posthepatectomy liver failure. Dig Dis Sci 45:1383–1388 25. Haber MM, West AB, Haber AD, Reuben A (1995) Relationship of aminotransferases to liver histological status in chronic hepatitis C. Am J Gastroenterol 90:1250–1257 26. Healey CJ, Chapman RW, Fleming KA (1995) Liver histology in hepatitis C infection: a comparison between patients with persistently normal or abnormal transaminases. Gut 37:274–278 27. Poon RT, Fan ST, Lo CM, Liu CL, Ng IO, Wong J (2000) Long-term prognosis after resec- tion of hepatocellular carcinoma associated with hepatitis B-related cirrhosis. J Clin Oncol 18:1094–1101 28. Noun R, Jagot P, Farges O, Sauvanet A, Belghiti J (1997) High preoperative serum alanine transferase levels: effect on the risk of liver resection in Child grade A cirrhotic patients. World J Surg 21:390–394 29. Torzilli G, Makuuchi M, Inoue K et al (1999) No-mortality liver resection for hepatocellular carcinoma in cirrhotic and noncirrhotic patients: is there a way? A prospective analysis of our approach. Arch Surg 134:984–992 30. Vauthey JN, Abdalla EK, Doherty DA et al (2002) Body surface area and body weight predict total liver volume in Western adults. Liver Transpl 8:233–240 31. Johnson TN, Tucker GT, Tanner MS, Rostami-Hodjegan A (2005) Changes in liver volume from birth to adulthood: A meta-analysis. Liver Transpl 11:1481–1493 32. Shirabe K, Shimada M, Gion T et al (1999) Postoperative liver failure after major hepatic resection for hepatocellular carcinoma in the modern era with special reference to remnant liver volume. J Am Coll Surg 188:304–309 33. Ribero D, Abdalla E K, Madoff DC, Donadon M, Loyer EM, Vauthey JN (2007) Portal vein embolization before major hepatectomy and its effects on regeneration, resectability and outcome. Br J Surg 94:1386–1394 34. Zorzi D, Laurent A, Pawlik TM, Lauwers GY, Vauthey JN, Abdalla EK (2007) Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 94:274–286 35. Palavecino M, Chun YS, Madoff DC et al (2009) Major hepatic resection for hepatocellular carcinoma with or without portal vein embolization: Perioperative outcome and survival. Surgery 145:399–405 36. Kokudo N, Tada K, Seki M et al (2001) Proliferative activity of intrahepatic colorectal metastases after preoperative hemihepatic portal vein embolization. Hepatology 34:67–72 37. Nagino M, Nimura Y, Kamiya J, Kanai M, Hayakawa N, Yamamoto H (1998) Immediate increase in arterial blood flow in embolized hepatic segments after portal vein embolization: CT demonstration. AJR Am J Roentgenol 171:1037–1039 38. Ogata S, Belghiti J, Farges O, Varma D, Sibert A, Vilgrain V (2006) Sequential arte- rial and portal vein embolizations before right hepatectomy in patients with cirrhosis and hepatocellular carcinoma. Br J Surg 93:1091–1098 39. Aoki T, Imamura H, Hasegawa K et al (2004) Sequential preoperative arterial and portal venous embolizations in patients with hepatocellular carcinoma. Arch Surg 2004;139(7):766–774 40. Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390 132 D.Zorzietal. 41. Leung TW, Patt YZ, Lau WY et al (1999) Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res 5:1676–1681 42. Zorzi D, Abdalla EK, Pawlik TM, Brown TD, Vauthey JN (2006) Subtotal hepatectomy fol- lowing neoadjuvant chemotherapy for a previously unresectable hepatocellular carcinoma. J Hepatobiliary Pancreat Surg 13:347–350 43. Lau WY, Leung TW, Lai BS et al (2001) Preoperative systemic chemoimmunotherapy and sequential resection for unresectable hepatocellular carcinoma. Ann Surg 233:236–241 44. Chang SB, Palavecino M, Wray CJ, Kishi Y, Pisters PW, Vauthey JN (2010) Modified Makuuchi incision for foregut procedures. Arch Surg 145:281–284 45. Kokudo N, Bandai Y, Imanishi H et al (1996) Management of new hepatic nodules detected by intraoperative ultrasonography during hepatic resection for hepatocellular carcinoma. Surgery 119:634–640 46. Takigawa Y, Sugawara Y, Yamamoto J et al (2001) New lesions detected by intraopera- tive ultrasound during liver resection for hepatocellular carcinoma. Ultrasound Med Biol 27:151–156 47. Torzilli G, Makuuchi M (2003) Intraoperative ultrasonography in liver cancer. Surg Oncol Clin N Am 12:91–103 48. Lau WY, Leung KL, Lee TW, Li AK (1993) Ultrasonography during liver resection for hepatocellular carcinoma. Br J Surg 80:493–494 49. Hasegawa K, Kokudo N, Imamura H, et al (2005) Prognostic impact of anatomic resection for hepatocellular carcinoma. Ann Surg 242:252–259 50. Regimbeau JM, Kianmanesh R, Farges O, Dondero F, Sauvanet A, Belghiti J (2002) Extent of liver resection influences the outcome in patients with cirrhosis and small hepatocellular carcinoma. Surgery 131:311–317 51. Poon RT, Fan ST, Ng IO, Wong J (2000) Significance of resection margin in hepatectomy for hepatocellular carcinoma: a critical reappraisal. Ann Surg 231:544–551 52. Jwo SC, Chiu JH, Chau GY, Loong CC, Lui WY (1992) Risk factors linked to tumor recur- rence of human hepatocellular carcinoma after hepatic resection. Hepatology 16:1367–1371 53. Yamamoto J, Kosuge T, Takayama T et al (1996) Recurrence of hepatocellular carcinoma after surgery. Br J Surg 83:1219–1222 54. Cha CH, Ruo L, Fong Y et al (2003) Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation. Ann Surg 238: 315–321 55. Ozawa K (1990) Hepatic function and liver resection. J Gastroenterol Hepatol 5:296–309 56. Liu CL, Fan ST, Lo CM, Tung-Ping Poon R, Wong J (2000) Anterior approach for major right hepatic resection for large hepatocellular carcinoma. Ann Surg 232:25–31 57. Liu CL, Fan ST, Cheung ST, Lo CM, Ng IO, Wong J (2006) Anterior approach versus con- ventional approach right hepatic resection for large hepatocellular carcinoma: a prospective randomized controlled study. Ann Surg 244:194–203 58. Belghiti J, Guevara OA, Noun R, Saldinger PF, Kianmanesh R (2001) Liver hanging maneu- ver: a safe approach to right hepatectomy without liver mobilization. J Am Coll Surg 193:109–111 59. Man K, Fan ST, Ng IO, Lo CM, Liu CL, Wong J (1997) Prospective evaluation of Pringle maneuver in hepatectomy for liver tumors by a randomized study. Ann Surg 226:04–11 60. Belghiti J, Noun R, Malafosse R et al (1999) Continuous versus intermittent portal triad clamping for liver resection: a controlled study. Ann Surg 229:369–375 61. Belghiti J, Noun R, Zante E, Ballet T, Sauvanet A (1996) Portal triad clamping or hepatic vascular exclusion for major liver resection. A controlled study. Ann Surg 224:155–161 62. Torzilli G, Makuuchi M, Midorikawa Y et al (2001) Liver resection without total vas- cular exclusion: hazardous or beneficial? An analysis of our experience. Ann Surg 233: 167–175 63. Johnson M, Mannar R, Wu AV (1998) Correlation between blood loss and inferior vena caval pressure during liver resection. Br J Surg 85:188–190 9 Liver Resection for Hepatocellular Carcinoma 133 64. Rees M, Plant G, Wells J, Bygrave S (1996) One hundred and fifty hepatic resections: evolution of technique towards bloodless surgery. Br J Surg 83:1526–1529 65. Cunningham JD, Fong Y, Shriver C, Melendez J, Marx WL, Blumgart LH (1994) One hun- dred consecutive hepatic resections. Blood loss, transfusion, and operative technique. Arch Surg 129:1050–1056 66. Aloia TA, Zorzi D, Abdalla EK, Vauthey JN (2005) Two-surgeon technique for hepatic parenchymal transection of the noncirrhotic liver using saline-linked cautery and ultrasonic dissection. Ann Surg 242:172–177 67. Takatsuki M, Eguchi S, Yamanouchi K et al (2009) Two-surgeon technique using saline- linked electric cautery and ultrasonic surgical aspirator in living donor hepatectomy: its safety and efficacy. Am J Surg 197, e25–e27 68. El Moghazy WM, Hedaya MS, Kaido T, Egawa H, Uemoto S, Takada Y (2009) Two differ- ent methods for donor hepatic transection: cavitron ultrasonic surgical aspirator with bipolar cautery versus cavitron ultrasonic surgical aspirator with radiofrequency coagulator-A randomized controlled trial. Liver Transpl 15:102–105 69. Katz SC, Shia J, Liau KH et al (2009) Operative blood loss independently predicts recurrence and survival after resection of hepatocellular carcinoma. Ann Surg 249:617–623 70. Petrowsky H, Demartines N, Rousson V, Clavien PA (2004) Evidence-based value of pro- phylactic drainage in gastrointestinal surgery: a systematic review and meta-analyses. Ann Surg 240:1074–1084 71. Liu CL, Fan ST, Lo CM et al (2004) Abdominal drainage after hepatic resection is contraindicated in patients with chronic liver diseases. Ann Surg. 239:194–201 72. Foster JH, Berman MM (1977) Solid Liver Tumors.W. B. Saunders, Philadelphia 73. Jaeck D, Bachellier P, Oussoultzoglou E, Weber JC, Wolf P (2004) Surg.ical resection of hepatocellular carcinoma. Post-operative outcome and long-term results in Europe: an overview. Liver Transpl 10(2 Suppl 1):S58–S63 74. Makuuchi M, Takayama T, Gunven P, Kosuge T, Yamazaki S, Hasegawa H (1989) Restrictive versus liberal blood transfusion policy for hepatectomies in cirrhotic patients. World J Surg. 13:644–648 75. Shimada M, Takenaka K, Fujiwara Y et al (1998) Risk factors linked to postoperative morbidity in patients with hepatocellular carcinoma. Br J Surg. 85:195–198 76. Bismuth H, Majno P, Adam R (1999) Hepatocellular carcinoma: from ethanol injection to liver transplantation. Acta Gastroenterologica Belgica 62:330–341 77. Capussotti L, Borgonovo G, Bouzari H, Smadja C, Grange D, Franco D (1994) Results of major hepatectomy for large primary liver cancer in patients with cirrhosis. Br J Surg. 81:427–431 78. Belghiti J, Panis Y, Farges O, Benhamou JP, Fekete F (1991) Intrahepatic recur- rence after resection of hepatocellular carcinoma complicating cirrhosis. Ann Surg. 214: 114–117 79. Nagasue N, Kohno H, Chang YC et al (1993) Liver resection for hepatocellular carcinoma. Results of 229 consecutive patients during 11 years. Ann Surg. 217:375–384 80. Suenaga M, Sugiura H, Kokuba Y, Uehara S, Kurumiya T (1994) Repeated hepatic resection for recurrent hepatocellular carcinoma in eighteen cases. Surg.ery 115:452–457 81. Kakazu T, Makuuchi M, Kawasaki S et al (1993) Repeat hepatic resection for recurrent hepatocellular carcinoma. Hepatogastroenterology 40:337–341 82. Matsuda Y, Ito T, Oguchi Y, Nakajima K, Izukura T (1993) Rationale of surg.ical management for recurrent hepatocellular carcinoma. Ann Surg. 217:28–34 83. Shimada M, Takenaka K, Taguchi K et al (1998) Prognostic factors after repeat hepatectomy for recurrent hepatocellular carcinoma. Ann Surg. 227:80–85 84. Arii S, Monden K, Niwano M et al (1998) Results of surg.ical treatment for recurrent hepatocellular carcinoma; comparison of outcome among patients with multicentric carcino- genesis, intrahepatic metastasis, and extrahepatic recurrence. J Hepatobiliary Pancreat Surg. 5:86–92 134 D.Zorzietal. 85. Minagawa M, Makuuchi M, Takayama T, Kokudo N (2003) Selection criteria for repeat hepatectomy in patients with recurrent hepatocellular carcinoma. Ann Surg. 238:703–710 86. Shimada K, Sakamoto Y, Esaki M et al (2007) Analysis of prognostic factors affecting survival after initial recurrence and treatment efficacy for recurrence in patients under- going potentially curative hepatectomy for hepatocellular carcinoma. Ann Surg. Oncol 14:2337–2347 87. The Liver Cancer Study Group of Japan (1994) Predictive factors for long-term progno- sis after partial hepatectomy for patients with hepatocellular carcinoma in Japan. Cancer 74:2772–2780 88. Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A (1993) Liver resec- tion versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg. 218: 145–151 89. Jonas S, Herrmann M, Rayes N et al (2001) Survival after liver transplantation for hepa- tocellular carcinoma in cirrhosis according to the underlying liver disease. Transplant Proc 33:3444–3445 90. Poon RT, Fan ST, Lo CM, Liu CL, Wong J (2002) Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg. 235:373–382 91. Fisher RA, Maroney TP, Fulcher AS et al (2002) Hepatocellular carcinoma: strat- egy for optimizing surg.ical resection, transplantation and palliation. Clin Transplant 16 (Suppl 7):52–58 92. Majno PE, Sarasin FP, Mentha G, Hadengue A (2000) Primary liver resection and salvage transplantation or primary liver transplantation in patients with single, small hepatocellular carcinoma and preserved liver function: an outcome-oriented decision analysis. Hepatology 31:899–906 93. Otto G, Heuschen U, Hofmann WJ, Krumm G, Hinz U, Herfarth C (1998) Survival and recurrence after liver transplantation versus liver resection for hepatocellular carcinoma: a retrospective analysis. Ann Surg. 227:424–432 94. Yamamoto J, Iwatsuki S, Kosuge T et al (1999) Should hepatomas be treated with hepatic resection or transplantation? Cancer 86:1151–1158 95. Belghiti J, Cortes A, Abdalla EK et al (2003) Resection prior to liver transplantation for hepatocellular carcinoma. Ann Surg. 238:885–892 96. Vauthey JN, Klimstra D, Franceschi D et al (1995) Factors affecting long-term outcome after hepatic resection for hepatocellular carcinoma. Am J Surg. 169:28–34 97. Nagorney DM, Adson MA, Weiland LH, Knight CD, Jr., Smalley SR, Zinsmeister AR (1985) Fibrolamellar hepatoma. Am J Surg. 149,:113–119 98. Soreide O, Czerniak A, Bradpiece H, Bloom S, Blumgart L (1986). Characteristics of fibro- lamellar hepatocellular carcinoma. A study of nine cases and a review of the literature. Am J Surg. 151:518–523 99. Okuda K (2002) Natural history of hepatocellular carcinoma including fibrolamellar and hepato-cholangiocarcinoma variants. J Gastroenterol Hepatol 17:401–405 100. Hemming AW, Langer B, Sheiner P, Greig PD, Taylor BR (1997) Aggressive surg.ical management of fibrolamellar hepatocellular carcinoma. J Gastrointest Surg. 1:342–346 101. Ringe B, Wittekind C, Weimann A, Tusch G, Pichlmayr R (1992) Results of hepatic resec- tion and transplantation for fibrolamellar carcinoma. Surg. Gynecol Obstet 175:299–305 102. El-Gazzaz G, Wong W, El-Hadary MK et al (2000) Outcome of liver resection and trans- plantation for fibrolamellar hepatocellular carcinoma. Transpl Int 13 (Suppl 1):S406–S409 103. Pinna AD, Iwatsuki S, Lee RG et al (1997) Treatment of fibrolamellar hepatoma with subtotal hepatectomy or transplantation. Hepatology 26(4):877–883 104. Neuhaus P, Jonas S, Bechstein WO (2000) Hepatoma of the liver–resection or transplanta- tion? Langenbecks Arch Surg. 385:171–178 105. Patt YZ, Hassan MM, Lozano RD et al (2003) Phase II trial of systemic continuous flu- orouracil and subcutaneous recombinant interferon Alfa-2b for treatment of hepatocellular carcinoma. J Clin Oncol 21:421–427 . of tumor growth rate and patient survival. Hepatology 16:132–137 3. Shuto T, Hirohashi K, Kubo S et al (1998) Changes and results of surgical strategies for hepatocellular carcinoma: results of. chemotherapy for a previously unresectable hepatocellular carcinoma. J Hepatobiliary Pancreat Surg 13:347–350 43. Lau WY, Leung TW, Lai BS et al (2001) Preoperative systemic chemoimmunotherapy and sequential. with cirrhosis and small hepatocellular carcinoma. Surgery 131:311–317 51. Poon RT, Fan ST, Ng IO, Wong J (2000) Significance of resection margin in hepatectomy for hepatocellular carcinoma: a critical