Retrograde Hepatectomy for Difficultly Resected Liver Cancer: A Report of 244 Cases

Objective To report our experience of retrograde hepatectomy in 244 cases of difficultly resected liver cancer. Methods Large, poor-exposure and inferior vena cava (IVC)-involving liver cancers that were difficult to remove by classical hepatectomy, have been resected successfully by retrograde hepatectomy combined with vascular surgical techniques in 244 patients (group A). Thirty one patients with similar circumstances undergoing classical hepatectomy duing the same period served as controls (group B). Results There were no perioperative mortalities in both groups. The comparison between group A and group B, the estimated intraoperative blood loss was 1290±998 ml versus 2286±1363 ml, post-operative pleural effusions occurred in 26/244 versus 10/31, ascites in 72/244 versus 19/31, moderate to severe jaundice in 14/244 versus 5/31, effusion in the operative area in 17/244 versus 7/31, subphrenic infection in 3/244 versus 1/31, bile leakage in 2/244 versus 1/31, wound infection in 3/244 versus 1/31, respectively. The time until ALT normalizaton in the groups A and B was 13.8±5.1 days and 18.9±8.9 days respectively. The difference between the two groups were statistically significant (P<0.01). Conclusion Retrograde hepatectomy is a safe and effective method for difficultly resected liver cancer. Key words cancer - liver - liver surgery - retrograde

Changes in growth factor and cytokine expression in biliary obstructed rat liver and their relationship with delayed liver regeneration after partial hepatectomy

AIM： To study the effects of obstructive jaundice on liver regeneration after partial hepatectomy. METHODS： Hepatocyte growth factor （HGF）, its receptor, c-Met, vascular endothelial growth factor （VEGF） and transforming growth factor-β1 （TGF-β1） mRNA expression in both liver tissue and isolated liver cells were investigated after biliary obstruction （BO） by quantitative reverse-transcription polymerase chain reaction （RT-PCR） using a LightCycler. Immunohistochemical staining for desmin and e-smooth muscle actin （α-SNA） was also studied. Regenerating liver weight and proliferating cell nuclear antigen （PCNA） labeling index, and growth factor expression were then evaluated after 70% hepatectomy with concomitant internal bUiary drainage in BO rats or sham-operated rats. RESULTS： Hepatic TGF-β1 mRNA levels increased significantly 14 days after BO, and further increased with duration of cholestasis. Meanwhile, HGF and VEGF tended to increase, but was not significant. In cell isolates, TGF-β1 mRNA was found mainly in the hepatic stellate cell （HSC） fraction. Immunohistochemical studies revealed an increased number of HSCs （desmin-positive cells） and activated HSCs （α-SMA-positive cells） in portal areas after BO. In a hepatectomy model, liver regeneration was delayed in BO rats, as compared to sham-operated rats. TGF-β1 mRNA was significantly up-regulated up to 48 h after hepatectomy, and the earlier HGF mRNA peak was lost in BO rats. CONCLUSION： BO induces HSCs proliferation and activation, leading to up-regulation of TGF-β1 mRNA and suppression of HGF mRNA in livers. These altered expression patterns may be strongly involved in delayed liver regeneration after hepatectomy with obstructive jaundice.

Managing injuries of hepatic duct confluence variants after major hepatobiliary surgery:An algorithmic approach

AIM:To investigate injuries of anatomy variants of hepatic duct confluence during hepatobiliary surgery and their impact on morbidity and mortality of these procedures. An algorithmic approach for the management of these injuries is proposed. METHODS:During a 6-year period 234 patients who had undergone major hepatobiliary surgery were retrospectively reviewed in order to study postoperative bile leakage. Diagnostic workup included endoscopic and magnetic retrograde cholangiopancreatography (E/MRCP), scintigraphy and fistulography. RESULTS:Thirty (12.8%) patients who developed postoperative bile leaks were identified. Endoscopic stenting and percutaneous drainage were successful in 23 patients with bile leaks from the liver cut surface. In the rest seven patients with injuries of hepatic duct confluence, biliary variations were recognized and a stepwise therapeutic approach was considered. Conservative management was successful only in 2 patients. Volume of the liver remnant and functional liver reserve as well as local sepsis were used as criteria for either resection of the corresponding liver segment or construction of a biliary-enteric anastomosis. Two deaths occurred in this group of patients with hepatic duct confluence variants (mortality rate 28.5%). CONCLUSION:Management of major biliary fistulaethat are disconnected from the mainstream of the biliary tree and related to injury of variants of the hepatic duct confluence is extremely challenging. These patients have a grave prognosis and an early surgical procedure has to be considered.

Addition of hepatectomy decreases liver recurrence and leads to long survival in hilar cholangiocarcinoma

AIM： To evaluate hepatic recurrence and prognostic factors for survival in patients with surgically resected hilar cholangiocarcinoma in a single institution over the last 13 years. METHODS： From 1994 to 2007, all patients with hilar cholangiocarcinoma referred to a surgical clinic were evaluated. Demographic data, tumor characteristics, and outcome were analyzed retrospectively. Outcome was compared in patients who underwent additional liver resection with resection of the tumor. RESULTS： Of the 69 patients submitted to laparotomy for tumor resection, curative resection （Ro resection） was performed in 40 patients, and palliative resection in 29. Thirty-one patients had only duct resection, and 38 patients had combined duct resection with liver resection including 34 total or part caudate lobes. Curative rates with the combined hepatectomy were significantly improved compared with those without additional hepatectomy （27/38 vs 13/31; X^2 = 5.94, P 〈 0.05）. Concomitant liver resection was associated with a decreased incidence of initial recurrence in liver one year after surgery （11/38 vs 23/31; X^2 = 13.98, P 〈 0.01）. The 3-year survival rate after Ro resection was 30.7% and was 10.5% for palliative resection. R0 resection improved the 3-year survival rate （30.7% vs 10.5%; X^2 = 12.47, P 〈 0.01）.CONCLUSION： Hepatectomy, especially including the caudate lobe combined with bile duct resection should be considered standard treatment to cure hilar cholangiocarcinoma.

Current management strategy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) still remains a considerable challenge for surgeons.Surgery,including liver transplantation,is the most important therapeutic approach for patients with this disease.HCC is frequently diagnosed at advanced stages and has a poor prognosis with a high mortality rate even when surgical resection has been considered potentially curative.This brief report summarizes the current status of the management of this malignancy and includes a short description of new pharmacological approaches in HCC treatment.

Portal vein embolization before major hepatectomy

To discuss the rationale, techniques and the unsolved issues regarding preoperative portal vein embolization (PVE) before major hepatectomy. After a systematic search of Pubmed, we reviewed and retrieved literature related to PVE. Preoperative PVE is an approach that is gaining increasing acceptance in the preoperative treatment of selected patients prior to major hepatic resection. Induction of selective hypertrophy of the nondiseased portion of the liver with PVE in patients with either primary or secondary hepatobiliary, malignancy with small estimated future liver remnants (FLR) may result in fewer complications and shorter hospital stays following resection. Additionally, PVE performed in patients initially considered unsuitable for resection due to lack of sufficient remaining normal parenchyma may add to the pool of candidates for surgical treatment. The results suggest that PVE is recomm-endable in treating the cirrhotic patients before major liver resection.

Des-gamma-carboxy prothrombin as an important prognostic indicator in patients with small hepatocellular carcinoma

AIM:To clarify the effect of a high des-gamma-carboxy prothrombin (DCP) level on the invasiveness and prognosis of small hepatocellular carcinoma. METHODS: Among 142 consecutive patients with known DCP levels, who underwent hepatectomy because of hepatocellular carcinoma, 85 patients met the criteria for small hepatocellular carcinoma, i.e. one ≤ 5 cm sized single tumor or no more than three ≤ 3 cm sized tumors. RESULTS: The overall survival rate of the 142 patients was 92.1% for 1 year, 69.6% for 3 years, and 56.9% for 5 years. Multivariate analysis showed that microscopic vascular invasion (P = 0.03) and serum DCP ≥ 400 mAU/mL (P = 0.02) were independent prognostic factors. In the group of patients who met the criteria for small hepatocellular carcinoma, DCP ≥ 400 mAU/mL was found to be an independent prognostic factor for recurrence-free (P = 0.02) and overall survival (P = 0.0005). In patients who did not meet the criteria, the presence of vascular invasion was an independent factor for recurrence-free (P = 0.02) and overall survivals (P = 0.01). In 75% of patients with small hepatocellular carcinoma and high DCP levels, recurrence occurred extrahepatically. CONCLUSION: For small hepatocellular carcinoma, a high preoperative DCP level appears indicative fortumor recurrence. Because many patients with a high preoperative DCP level develop extrahepatic recurrence, it is necessary to screen the whole body.

A case of asymptomatic intraductal papillary neoplasm of the bile duct without hepatolithiasis

A 65-year-old woman was found to have dilatation of the intrahepatic bile duct in the right anterior segment during a general health. Laboratory data were within normal ranges and no solid mass was detected in her abdominal computer tomography (CT) or nuclear magnetic resonance imaging (MRI). However, endoscopic retrograde cholangiopancreatography (ERCP) demonstrated an obstruction of the right bile duct. Intraoperative cholangiography showed stenosis of the intrahepatic bile duct in the anterior inferior segment (B5) and narrowness of the intrahepatic bile duct in the anterior superior segment (B8), so that we strongly suspected intrahepatic cholangiocarcinoma (ICC). Histologically, surgically resected liver specimens, without tumor mass by macroscopic observation, showed intraductal papillary proliferation with fibrovascular cores and intraductal spreading of carcinoma in situ throughout a considerable area, especially in bile ductules around the peripheral small portal area. Furthermore, the immunohistochemical profile of the tumor (MUC5AC+/CK7+) was compatible with an intraductal papillary neoplasm of the bile duct (IPN-B). Consequently, this case was diagnosed as IPN-B with spreading CIS, stageⅠ(pT1, pN0, P0, H1, M0). We report a case of IPN-B with interesting histopathologicalfindings and emphasize that cholangiography is especially helpful for the diagnosis of bile duct dilatation due to infiltration of carcinoma cells.

Relationship between microvessel count and post-hepatectomy survival in patients with hepatocellular carcinoma

AIM: To elucidate the relationship between the microvessel count (MVC) by CD34 analyzed by immunohistochemical method and prognosis in hepatocellular carcinoma (HCC) patients who underwent hepatectomy based on our preliminary study. METHODS: We examined relationships between MVC and clinicopathological factors in 128 HCC patients. The modifi ed Japan Integrated Staging score (mJIS) was applied to examine subsets of HCC patients. RESULTS: Median MVC was 178/mm^2, which was used as a cut-off value. MVC was not signif icantly associated with any clinicopathologic factors or postoperative recurrent rate. Lower MVC was associated with poor disease-free and overall survivals by univariate analysis (P = 0.039 and P = 0.087, respectively) and lower MVC represented an independent poor prognostic factor in disease-free survival by Cox’s multivariateanalysis (risk ratio, 1.64; P = 0.024), in addition to tumor size, vascular invasion, macroscopic fi nding and hepatic dysfunction. Signifi cant differences in disease-free and overall survivals by MVC were observed in HCC patients with mJIS 2 (P = 0.046 and P = 0.0014, respectively), but not in those with other scores. CONCLUSION: Tumor MVC appears to offer a useful prognostic marker of HCC patient survival, particularly in HCC patients with mJIS 2.

Resection of Giant Hepatic Cavernous Hemangiomas after Dissection of the Third Porta Hepatis

Objective To establish a novel and safe operation technique for the resection of giant hepatic cavernous hemangiomas involving the retro-hepatic vena cava.Methods After ligating the hepatic artery of affected lobe, the short hepatic veins at the third porta hepatis were dissected and ligated individually to separate the tumor from the retrohepatic vena cava, followed by the resection of the tumor under intermittent interruption of the porta hepatis.Results A total of 62 giant hepatic cavernous hemangiomas were successfully resected without hepatic vascular exclusion. Right and caudate lobectomies were done in 27 cases, right hemihepatectomies in 5 cases, right upper segmentectomies in 7 cases, right posterior lobec-tomies in 7 cases, extended left and caudate lobectomies in 10 cases, and caudate lobectomies in 6 cases. The blood transfusion requirement during operation was 1 400 ml on average. All did well postoperatively during a follow up of 4 - 84 months.Conclusion It is safe and feasible to resect giant hepatic cavernous hemangioma following dissection of the third porta hepatis. During operation the key step is dissection of the short hepatic veins.

Perioperative management of primary liver cancer

AIM:To minimize the complications and mortality and improve the survival in primary liver cancer (PLC) patients undergoing hepatic resection. METHODS: We conducted a retrospective analysis of 2143 PLC patients treated from January 1990 to January 2004. The patients were divided into two groups using January 1997 as a cut-off. Small tumor size (< 5 cm), preoperative redox tolerance index (RTI), vascular control method, and postoperative arterial ketone body ratio (AKBR) were used as indicators of surgical outcome. RESULTS: Small tumors had less complications and lower mortality and higher overall survival rate. Use of RTI for selecting patients and types of hepatectomy, reduced complications (21.1% vs 11.0%) and mortality (1.6% vs 0.3%). The half liver vascular occlusion protocol (n = 523) versus the Pringle method (n = 476) showed that the former significantly reduced the postoperative complications (25.8% vs 11.9%) and mortality (2.3% vs 0.6%) respectively, and cut mean hospital stay was 3.5 d. Postoperative AKBR was a reliable indicator of the energy status in survivors. CONCLUSION: RTI is of value in predicting hepatic functional reserve, half liver occlusion could protect the residual liver function, and AKBR measurement is a simple and accurate means of assessing the state of postoperative metabolism. Optimal perioperative management is an important factor for minimizing complications and mortality in patients undergoing hepatic resection.

Vascular endothelial growth factor and angiopoietins regulate sinusoidal regeneration and remodeling after partial hepatectomy in rats

AIM： To study the regulatory mechanisms of sinusoida regeneration after partial hepatectomy. METHODS： We invesldgated the expression of angiopoietin （Ang）-1, Ang-2, Tie-2, and vascular endothelial growth factor （VEGF） in regenerating liver tissue by quantitative reverse-transcription polymerase chain reaction （RT- PCR） using a LightCycler （Roche Diagnostics） and also immunohistochemical staining after 70% hepatectomy in rats. In the next step, we isolated liver cells （hepatocytes, sinusoidal endothelial cell （SEC）, Kupffer cell, and hepatic stellate cells （HSC）） from regenerating liver tissue by in situ collagenase perfusion and counterflow elutriation, to determine potential cellular sources of these angiogenic factors after hepatectomy. Proliferation and apoptosis of SECs were also evaluated by proliferating cell nuclear antigen （PCNA） staining and the terminal deoxynucleotidyl transferase d-uridine triphosphate nick end labeling （TUNEL） assay, respectively. RESULTS： VEGF mRNA expression increased with a peak at 72 h after hepatectomy, decreasing thereafter. The expression of Ang-1 mRNA was present at detectable levels before hepatectomy and increased slowly with a peak at 96 h. Meanwhile, Ang-2 mRNA was hardly detected before hepatectomy, but was remarkably induced at 120 and 144 h. In isolated cells, VEGF mRNA expression was found mainly in the hepatocyte fraction. Meanwhile, mRNA for Ang-1 and Ang-2 was found in the SEC and HSC fractions, but was more prominent in the latter. The PCNA labeling index of SECs increased slowly, reaching a peak at 72 h, whereas apoptotic SECs were detected between 120 h and 144 h. CONCLUSION： Ang-Tie system, together with VEGF, plays a critical role in regulating balance between SEC proliferation and apoptosis during sinusoidal regeneration after hepatectomy. However, the VEGF system plays a more important role in the early phase of sinusoidal regeneration than angiopoietin/Tie system.

Bilateral liver resection for bilateral intrahepatic stones

AIM: To evaluate the shortand long-term outcomes of bilateral liver resection for bilateral intrahepatic stones. METHODS: We reviewed retrospectively 101 consecutive patients with bilateral intrahepatic stones who underwent bilateral liver resection in the past 10 years. The shortand long-term outcomes of the patients were analyzed. The Cox proportional hazards model was used to identify the risk factors related to stone recurrence. RESULTS: There was no surgical mortality in this group of patients. The surgical morbidity was 28.7%. Stone clearance rate after hepatectomy was 84.2% and final clearance rate was 95.0% following postoperative choledochoscopic lithotripsy. The stone recurrence rate was 7.9% and the occurrence of postoperative cholangitis was 6.5% in a median follow-up period of 54 mo. The Cox proportional hazards model indicated that liver resection range, less than the range of stone distribution (P = 0.015, OR = 2.152) was an independent risk factor linked to stone recurrence. CONCLUSION: Bilateral liver resection is safe and its shortand long-term outcomes are satisfactory for bilateral intrahepatic stones.

Efficacy of surgical resection in management of isolated extrahepatic metastases of hepatocellular carcinoma

AIM:To clarify the benefit of surgical excision for patients with extrahepatic metastases of hepatocellular carcinoma(HCC). METHODS:We retrospectively reviewed the medical records of 140 patients with pathologically proven extrahepatic metastases of HCC and evaluated the outcomes of those who had undergone surgical resection(SR)for extrahepatic metastatic lesions.Prognoses made on the basis of extrahepatic metastatic sites were also examined. RESULTS:The survival rates of patients who underwent SR of extrahepatic metastases were significantly better than those of patients who did not receive SR. For the SR group,1-and 3-year survival rates were 24%and 7%,respectively,while for the non-resection group,the survival rates were 8%and 0%,respec- tively(P<0.0001).Survival rates related to metastatic sites were also significantly superior after SR of extrahepatic metastases:median survivals were 32 mo with lung metastasis,10 mo with bone metastasis,6.1 mo with brain metastasis. CONCLUSION:SR can provide survival benefits forpatients with 1 or 2 isolated extrahepatic metastases and who concurrently exhibit good hepatic functional reserve and general performance status as well as successful treatment of intrahepatic HCC.

Insulin promotes sinusoidal endothelial cell proliferation mediated by upregulation of vascular endothelial growth factor in regenerating rat liver after partial hepatectomy

AIM： To determine whether insulin could promote sinusoidal endothelial cell （SEC） proliferation mediated by upregulation of vascular endothelial growth factor （VEGF） in regenerating rat liver after partial hepatectomy （PHx）. METHODS： Adult male Sprague-Dawley rats undergoing 70% PHx were injected with insulin （300 MU/kg） or saline via the tail veins every 8 h after surgery for 7 d and killed at 0, 24, 48, 72, 96, 120, 144, and 168 h after surgery. Proliferation of both hepatocytes and SECs was monitored by evaluating the proliferating cell nuclear antigen （PCNA） labeling index （LI）. The expression of VEGF protein was evaluated by immunohistochemistJv. The mRNA expressions of VEGF and its receptors FIt-1 and FIk-1 were evaluated by semi-quantitative reverse transcription-PCR. RESULTS： Insulin markedly increased the expression of VEGF mRNA between 24 and 120 h after hepatectomy compared to controls. Similarly, insulin significantly increased the expression of Fit-1 between 24 and 96 h. However, insulin had no significant effect on FIk-1. Furthermore, the immunohistochemical staining revealed that expression of VEGF protein increased in the insulin groups. Insulin significantly increased the PCNA LI of hepatocytes and SECs compared to controls. CONCLUSION： Exogenous insulin may promote SEC proliferation with an enhanced expression of VEGF and its receptor Fit-1 in regenerating rat liver after PHx.

Choice between different operative techniques on cavernous hepatic hemangiomas

Objective： To investigate the optimizing of operative techniques on cavernous hepatic hemangioma by comparing the effective of the two approaches （enucleation and hepatectomy）. Methods： From May 1994 to September 2006, fortythree patients underwent the surgical removal of the cavernous hepatic hemangioma were analyzed retrospectJvely. Enucleation was used for 16 cases and hepatectomy for 27 cases. The relative clinical data and operative factors between the two operative techniques were compared. Results： Statistically significant differences in tumor size, location and intraoperative blood lose between the two groups were observed （P 〈 0.05 ）. Although enucleation was associated with less intraoperative bleeding and transfusion requirement but no significant differences in postoperative liver functional parameter, complication and length of hospital stay were observed. Conclusion： With proper choice, enucleation and hepatectomy both are effective treatments for cavernous hepatic hemangiomas.

A special recurrent pattern in small hepatocellular carcinoma after treatment:Bile duct tumor thrombus formation

AIM:To investigate the clinicopathologic features of bile duct tumor thrombus(BDTT) occurrence after treatment of primary small hepatocellular carcinoma(sHCC) .METHODS:A total of 423 patients with primary sHCC admitted to our hospital underwent surgical resection or local ablation.During follow-up,only six patients were hospitalized due to obstructive jaundice,which occurred 5-76 mo after initial treatment.The clinicopathologic features of these six patients were reviewed.RESULTS:Six patients underwent hepatic resection(n=5) or radio-frequency ablation(n=1) due to primary sHCC.Five cases had an R1 resection margin,and one case had an ablative margin less than 5.0 mm.No vascular infiltration,microsatellites or bile duct/canaliculus affection was noted in the initial resected specimens.During the follow-up,imaging studies revealed a macroscopic BDTT extending to the common bile duct in all six patients.Four patients had a concomitant intrahepatic recurrent tumor.Surgical re-resection of intrahepatic recurrent tumors and removal of BDTTs(n=4) ,BDTT removal through choledochotomy(n= 1) ,and conservative treatment(n=1) was performed.Microscopic portal vein invasion was noted in three of the four resected specimens.All six patients died,with a mean survival of 11 mo after BDTT removal or conservative treatment.CONCLUSION:BDTT occurrence is a rare,special recurrent pattern of primary sHCC.Patients with BDTTs extending to the common bile duct usually have an unfavorable prognosis even following aggressive surgery.Insufficient resection or ablative margins against primary sHCC may be a risk factor for BDTT development.