Junichi Shindoh

The intersegmental plane of the liver is not always flat--tricks for anatomical liver resection.

Objective:To investigate the actual three-dimensional (3D) anatomy of the intersegmental plane of the liver to enable safe and precise anatomic resections of the portal territories. Summary of Background Data:Anatomic resection of the liver requires the precise detection of the intersegmental plane. However, we have sometimes encountered a dissociation between conventional understanding of the anatomy of the intersegmental plane and its actual 3D shape. Methods:3D simulations of the livers of 81 healthy donors for living donor liver transplantation were reviewed. Several key angles formed between the plane of each venous trunk and the actual intersegmental plane on 3D simulation images were measured. The relation between these angles and the volume ratio of the liver segments located on both sides of the intersegmental plane were also investigated. Results:The dissociation between the plane of the venous trunks and the actual intersegmental plane was remarkable, especially in the subphrenic region of the right lobe. The volume ratio of segment VIII compared with segment VII was correlated with the degree of cranio-lateral protrusion of segment VIII (r = 0.35, P = 0.001); this finding was attributed to the intricate surface of the right portal scissura. The same tendency was observed in the left portal scissura between the angle and the volume ratio of segment III/II (r = 0.23, P = 0.049), whereas the main portal scissura exhibited a relatively flat surface compared with the other longitudinal scissurae. Conclusions:The intersegmental plane of the liver has an uneven and curved surface, especially in the right and left portal scissurae. The identification and exposure of the landmark vein on the cut surface is an important technique for avoiding disorientation during anatomic liver resection.

Usefulness of contrast-enhanced intraoperative ultrasound using Sonazoid in patients with hepatocellular carcinoma.

Objective:To assess the usefulness of contrast-enhanced intraoperative ultrasound (CE-IOUS) using Sonazoid (gaseous perflubutane) in patients with hepatocellular carcinoma (HCC). Background:Contrast-enhanced intraoperative ultrasound using Sonazoid, a novel ultrasonic contrast agent enabling Kupffer imaging, may enable differentiation of HCC among new focal liver lesions found during fundamental intraoperative ultrasound (fundamental-NFLLs). Methods:Between February 2007 and February 2009, a total of 192 consecutive patients were enrolled. Fundamental intraoperative ultrasound and CE-IOUS were performed successively after laparotomy. The vascularity of 1 representative lesion was examined in harmonic mode for approximately 1 minute after the intravenous injection of Sonazoid (vascular phase). Approximately 15 minutes after the vascular phase, total liver scanning in the harmonic mode was commenced (Kupffer phase). One additional injection of Sonazoid was allowed to examine the vascularity of another lesion, if necessary. A tentative diagnosis of HCC was made when a lesion was either hypervascular during the vascular phase or hypoechoic during the Kupffer phase. A final diagnosis of HCC was made on the basis of the results of a histological examination or dynamic computed tomography findings obtained during the 12-month postoperative period. Results:Seventy-nine fundamental-NFLLs were found in 50 patients (26%), 17 (22%) of which were finally diagnosed as HCC. The sensitivity, specificity, and accuracy of CE-IOUS for differentiating HCC among fundamental-NFLLs were 65%, 94%, and 87%, respectively. Contrast-enhanced intraoperative ultrasound identified 21 additional new hypoechoic lesions in 16 patients, of which 14 lesions (67%) in 11 patients were finally diagnosed as HCC. This prospective study protocol was approved by the institutional review board of the Tokyo University Hospital. An English-language summary of the protocol was submitted (registration ID: UMIN000003046) to the Clinical Trials Registry managed by the University Hospital Medical Information Network in Japan (http://www.umin.ac.jp/ctr/index.htm). Conclusions:With help of CE-IOUS using Sonazoid, more accurate intraoperative staging for HCC can be performed.

Surgical treatment of hepatocellular carcinoma associated with hepatic vein tumor thrombosis

BACKGROUND & AIMS Presence of hepatic vein tumor thrombosis (HVTT) in patients with hepatocellular carcinoma (HCC) is regarded as signaling an extremely poor prognosis. However, little is known about the prognostic impact of surgical treatment for HVTT. METHODS Our database of surgical resection for HCC between October 1994 and December 2011 in a tertiary care Japanese hospital was retrospectively analysed. We statistically compared the patient characteristics and surgical outcomes in HCC patients with tumor thrombosis in a peripheral hepatic vein, including microscopic invasion (pHVTT), tumor thrombosis in a major hepatic vein (mHVTT), and tumor thrombosis of the inferior vena cava (IVCTT). Among 1525 hepatic resections, 153 cases of pHVTT, 21 cases of mHVTT, and 13 cases of IVCTT were identified. RESULTS The median survival time (MST) in the pHVTT and mHVTT groups was 5.27 and 3.95 years, respectively (p=0.77), and the median time to recurrence (TTR) was 1.06 and 0.41 years, respectively (p=0.74). On the other hand, the MST and TTR in the patient group with IVCTT were 1.39 years and 0.25 year respectively; furthermore, the MST of Child-Pugh class B patients was significantly worse (2.39 vs. 0.44 years, p=0.0001). Multivariate analyses revealed IVCTT (risk ratio [RR] 2.54, p=0.024) and R 1/2 resection (RR 2.08, p=0.017) as risk factors for the overall survival. CONCLUSIONS Hepatic resection provided acceptable outcomes in HCC patients with mHVTT or pHVTT when R0 resection was feasible. Resection of HCC may be attempted even in patients with IVCTT, in the presence of good liver function.

Risk factors of post-operative recurrence and adequate surgical approach to improve long-term outcomes of hepatocellular carcinoma.

INTRODUCTION A high recurrence rate of hepatocellular carcinoma (HCC) remains a significant concern. The risk factors for recurrence were analysed and the optimal surgical approaches were investigated. METHODS The subjects comprised 280 consecutive patients with primary solitary HCC measuring ≤5 cm in diameter, who underwent curative resections. Multivariate analysis was conducted to identify the risk factors for post-operative recurrence, and the clinical significance of an anatomic resection was evaluated. RESULTS Multivariate analysis identified HCV infection, a des-gamma-carboxyprothrombin level >100 mAU/ml, underlying cirrhosis, the presence of microvascular invasion, the presence of micrometastases and non-anatomic resection as being significant risk factors for post-operative recurrence. The 5-year recurrence rate was 56.7% in the anatomic resection (AR) group and 74.7% in the non-AR group. The 5-year survival rate was 82.2% in the AR group and 71.9% in the non-AR group. Local recurrence within the same segment was observed in 25% of the patients of the non-AR group. The prognostic superiority of AR was confirmed only in patients with histopathological evidence of microvascular invasion and/or micrometastases, and in patients having a solitary HCC measuring 2 to 5 cm in diameter. CONCLUSIONS Anatomic resection may decrease local recurrence and improve the surgical outcomes in solitary HCC measuring 2 to 5 cm in diameter.

Low Hepatitis C Viral Load Predicts Better Long-Term Outcomes in Patients Undergoing Resection of Hepatocellular Carcinoma Irrespective of Serologic Eradication of Hepatitis C Virus

PURPOSE Hepatitis C virus (HCV) infection has been recognized as a potent risk factor for the postoperative recurrence of hepatocellular carcinoma (HCC). However, little is known about the impact of HCV viral load on surgical outcomes. The study objective was to investigate clinical significance of HCV viral load on long-term outcomes of HCC. PATIENTS AND METHODS Three hundred seventy patients who were classified as Child-Pugh class A and underwent curative liver resections for HCV-related HCC were divided into low and high viral load groups (≤ or > 5.3 log(10)IU/mL) based on the results of a minimum P value approach to predict moderate to severe activity of hepatitis; the clinical outcomes were then compared. RESULTS The 5-year recurrence-free survival rate was 36.1% in the low viral load group and 12.4% in the high viral load group (P < .001). The 5-year overall survival rate was 76.6% in the low viral load group and 57.7% in the high viral load group (P < .001). Multivariate analysis confirmed significant correlation between high viral load and tumor recurrence with a hazard ratio of 1.87 (95% CI, 1.41 to 2.48; P < .001). Subanalysis revealed that the favorable results in the low viral load group were not attributed to whether or not serologic eradication of HCV was obtained both in primary and recurrent lesions. CONCLUSION Low HCV viral load predicts better long-term surgical outcomes in patients with HCC regardless of the serologic eradication of HCV.

Evaluation methods for pretransplant oncologic markers and their prognostic impacts in patient undergoing living donor liver transplantation for hepatocellular carcinoma.

Tumor markers [alpha‐fetoprotein (AFP) or des‐gamma‐carboxyprothrombin (DCP)] and neutrophil/lymphocyte ratio (NLR) reportedly correlate with long‐term outcomes for hepatocellular carcinoma (HCC). However, no standardized method has been established for evaluating the pretransplant data. One hundred and twenty‐four patients who underwent living donor liver transplantation (LDLT) were retrospectively reviewed. The best predictive parameters for tumor recurrence were maximum values for AFP or DCP and 90‐day mean values for NLR, respectively, and multivariate analysis confirmed these values were correlated with tumor recurrence. However, receiver operating characteristic analysis revealed that discriminative powers were sufficient only in maximum AFP [area under the curve (AUC) 0.88, P < 0.001] and maximum DCP (AUC 0.76, P < 0.001), while mean NLR was less predictive (AUC 0.62, P = 0.20). When incorporating AFP and DCP to the Tokyo criteria (≤5 tumors with each tumor ≤5 cm), the presence of at least two of the following factors: (i) beyond the Tokyo criteria, (ii) AFP>250 ng/ml, and (iii) DCP > 450 mAu/ml (>450 ng/ml), was correlated with a worse 5‐year disease‐free survival rate (20.0% vs. 96.8%, P < 0.001) and 5‐year overall survival rate (20.0% vs. 84.0%, P < 0.001). The prognosis of patients undergoing LDLT for HCC strongly relies on maximum AFP or DCP values before transplantation, while the prognostic impact of NLR is limited.

Complete removal of the tumor-bearing portal territory decreases local tumor recurrence and improves disease-specific survival of patients with hepatocellular carcinoma

BACKGROUND & AIMS Anatomic resection (AR) of the tumor-bearing portal territory has been reported to be associated with a decreased recurrence of hepatocellular carcinoma (HCC). However, because of the heterogeneity of the study populations, its oncologic advantage remains controversial. The objective of the present study was to determine the clinical advantage of AR for primary HCC, based on the data from a large prospective cohort treated under a constant surgical policy. METHODS In 209 Child-Pugh class A patients with primary, solitary HCC measuring ⩽5.0cm in diameter, which was resectable either by AR or limited resection (non-AR), the overall survival (OS) and disease-free survival (DFS) were compared with patients in whom complete AR was achieved and those who eventually ended up with non-AR after adjustment for the propensity scores to select AR. Advantages of AR in disease-specific survival and local recurrence were also evaluated by competing-risks regression to clarify the true oncologic impact of AR. RESULTS The AR group showed better DFS than the non-AR group (HR, 0.67; 95% CI, 0.45-0.99; p=0.046), while no significant difference was observed in OS (hazard ratio [HR], 0.82; 95% CI, 0.46-1.48; p=0.511). Competing-risks regression revealed that AR significantly decreases local recurrence (HR, 0.12; 95% CI, 0.05-0.30; p<0.001) and improves disease-specific survival (HR, 0.50; 95% CI, 0.28-0.90; p=0.020), while the other cause of death was highly influenced by patient age (>65years) (HR, 7.51; 95% CI, 2.16-26.04; p=0.002) and not associated with AR. CONCLUSION Complete removal of tumor-bearing portal territory decreases the risk of local recurrence and death from HCC.

The Feasibility of Third or More Repeat Hepatectomy for Recurrent Hepatocellular Carcinoma.

OBJECTIVES To investigate the feasibility and prognostic benefits of third or more hepatectomy (third or more Hx) for recurrent hepatocellular carcinoma. BACKGROUND Second hepatectomy (second Hx) has been accepted as an effective treatment of recurrent hepatocellular carcinoma after first hepatectomy (first Hx). However, the feasibility and efficacy of third or more Hx have not been adequately assessed. METHODS Data were reviewed from 1340 patients with hepatocellular carcinoma who underwent curative hepatectomy. Among them, 941, 289, and 110 underwent first Hx, second Hx, and third or more Hx, respectively. Surgical outcomes and long-term survival were compared among the groups. RESULTS Surgical duration was significantly longer in third or more Hx (median, 6.4 hours) than in second Hx (median, 5.9 hours). Postoperative bile leakage and wound infection were more frequently observed in third or more Hx versus second Hx (12.5% vs 6.2%, [P = 0.04] and 2.9% vs 0.4% [P = 0.03], respectively). Three and 5-year disease-free survival rates were 36.8% and 27.1% in first Hx, 24.4% and 17.9 % in second Hx, and 26.1% and 12.8% in third or more Hx, respectively (P < 0.01 [first Hx vs third Hx], P = 0.95 [second Hx vs third or more Hx]). The 5-year overall survival rates from each resection were similar among the groups (65.3%, 60.5%, 68.2%, respectively). The 5- and 10-year overall survival rates from initial hepatectomy in patients who received third or more Hx were 91.4% and 75.5%, respectively. CONCLUSIONS Third or more Hx is technically demanding in terms of surgical duration and morbidity compared with second Hx. However, aggressive repeat resection offers a survival similar to second Hx, leading to cumulative long-term survival from initial resection.

How can we safely climb the ALPPS

R0 resection with zero mortality is the ultimate goal for hepatobiliary surgeons, especially for the treatment of extensive hepatobiliary malignancies. The safety of liver resection is dependent on the function of the future liver remnant (FLR), and an inadequate FLR volume is related to a significant increase in postoperative mortality and morbidity. Therefore, various criteria for the FLR volume have been proposed to secure the safety of major hepatectomies according to the extent of underlying injury in the liver [1–5]. However, these criteria for FLR volume often cause clinical dilemmas for surgeons in determining the surgical indications for patients with small FLR volumes because the safety of surgery and oncological radicality are, by nature, conflicting factors. In the history of hepatobiliary surgery, there have been two outstanding approaches for the safe management of patients with very small FLR volumes. The first was the development of techniques that manipulate the portal blood flow to induce hypertrophy of the FLR. Initially achieved using portal vein ligation (PVL) [6–8], these techniques have evolved toward percutaneous portal vein embolization (PVE) [9–12]. Increasing evidence has suggested that hypertrophy of the FLR induced by portal flow modulation is associated with an improved safety of major hepatectomies [3, 10, 13]. In addition, dynamic volume parameters, such as the degree of hypertrophy [13] or the kinetic growth rate [14], are also very informative for estimating the histologic quality and functional reserve of the underlying liver. The second noteworthy approach was the ‘‘twostage surgery’’ for the resection of multiple bilobar hepatic lesions. This sequential procedure was initially proposed by surgeons at the Hopital Paul Brousse in Paris, France, with the expectation of allowing interim liver regeneration between the two sequential hepatic resections [15]. An oncological advantage of the two-stage approach has been reported in patients with extensive colorectal liver metastases [16], and this procedure used in conjunction with or without PVE has been adopted by numerous hepatobiliary centers. These two evolutional approaches have expanded the indications for surgery, and many patients with extensive liver tumors have benefited from surgery using these approaches. However, a remaining issue is that these approaches require at least several weeks to complete the entire clearance of the tumor burden within the liver. Some authors have suggested a risk of tumor progression during the waiting time after PVE [17, 18]. Therefore, the time lag between the preoperative intervention and resection can be critical, especially for the treatment of patients with borderline resectable tumors and/or oncologically highly aggressive tumors. A recent notable paper in the field of hepatobiliary surgery was a case series introducing a new surgical procedure known as ‘‘ALPPS’’ (Associating Liver Partition with Portal vein ligation for Staged hepatectomy) that enables the rapid growth of the FLR [19]. The first stage of this procedure includes a right PVL and the in situ splitting of the liver along the umbilical fissure or the main portal fissure. Schnitzbauer et al. [19] reported that a 74 % volume increase was observed in the FLR at a median of 9 days after the first procedure. Immediately after its publication, this article triggered a large number of reactions from all over the world. Although the clinical outcomes demonstrated in this paper were very impressive and all the patients were able to proceed to a right N. Kokudo (&) J. Shindoh Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan e-mail: KOKUDO-2SU@h.u-tokyo.ac.jp

Correlation Between Contrast-Enhanced Intraoperative Ultrasound Using Sonazoid and Histologic Grade of Resected Hepatocellular Carcinoma

OBJECTIVE Our aim was to accurately assess the correlation between findings of contrast-enhanced intraoperative ultrasound using Sonazoid and histologic grade of hepatocellular carcinoma (HCC). SUBJECTS AND METHODS We enrolled 239 consecutive patients who were undergoing surgery for HCC for this study. Because 33 extensively necrotic HCCs were excluded, a total of 374 histologically proven HCCs were detected in all resected specimens and were the study subjects (71 well-differentiated, 239 moderately differentiated, and 64 poorly differentiated HCCs). After a laparotomy and liver mobilization, contrast-enhanced intraoperative ultrasound in the harmonic mode was performed after a Sonazoid injection. The first minute was defined as the vascular phase, in which the vascularity of the 239 HCCs was assessed. After an approximately 15-minute delay, a thorough liver exploration was performed (Kupffer phase). Preoperative dynamic CT was routinely performed, and the findings were assessed for reference. RESULTS The proportion of hypervascular tumors during the vascular phase tended to be lower among well-differentiated than among moderately and poorly differentiated HCCs (66% vs 80%, p = 0.058). The proportion of hypoechoic tumors during the Kupffer phase was significantly lower among well-differentiated than among moderately and poorly differentiated HCCs (54% vs 92%, p < 0.0001). In dynamic CT, the proportions of hypervascular tumors during the early phase and hypodense tumors during the late phase were significantly lower among well-differentiated HCCs than among moderately and poorly differentiated HCCs, respectively (early phase, 51% vs 87%, p < 0.0001; late phase, 59% vs 85%, p < 0.0001). CONCLUSION Contrast-enhanced intraoperative ultrasound using Sonazoid is useful for estimating the histologic grade of HCC.