Hepatic iron overload in the portal tract predicts poor survival in hepatocellular carcinoma after curative resection.

BACKGROUND & AIMS: Hepatic iron overload is associated with liver injury and hepatocarcinogenesis; however, it has not been evaluated in patients with hepatocellular carcinoma (HCC) in Asia. The aim of this study was to clarify the degree and distribution of intrahepatic iron deposition, and their effects on the survival of HCC patients. METHODS: Intrahepatic iron deposition was examined using non-tumorous liver tissues from 204 HCC patients after curative resection, and they were scored by 2 semi-quantitative methods: simplified Scheuer's and modified Deugnier's methods. For the Scheuer's method, iron deposition in hepatocytes and Kupffer cells was separately evaluated, while for the modified Deugnier's method, hepatocyte iron score (HIS), sinusoidal iron score (SIS) and portal iron score (PIS) were systematically evaluated, and the corrected total iron score (cTIS) was calculated by multiplying the sum (TIS) of the HIS, SIS, and PIS by the coefficient. RESULTS: The overall prevalence of hepatic iron was 40.7% with the simplified Scheuer's method and 45.1% with the modified Deugnier's method with a mean cTIS score of 2.46. During a median follow-up of 67 months, the cTIS was not associated with overall survival. However, a positive PIS was significantly associated with a lower 5-year overall survival rate (50.0%) compared with a negative PIS (73.7%, P = .006). In the multivariate analysis, a positive PIS was an independent factor for overall mortality (hazard ratio, 2.310; 95% confidence interval, 1.181-4.517). CONCLUSIONS: Intrahepatic iron deposition was common, and iron overload in the portal tract indicated poor survival in curatively resected HCC patients.

Transforming acidic coiled-coil-containing protein 3 (TACC3) overexpression in hepatocellular carcinomas is associated with "stemness" and epithelial-mesenchymal transition-related marker expression and a poor prognosis.

There is accumulating evidence that hepatocellular carcinomas (HCCs) expressing "stemness"-related markers, e.g., keratin 19 (K19) and epithelial cell adhesion molecule (EpCAM), are associated with aggressive biological behavior. In order to further investigate the molecular characteristics of this subgroup of HCCs, we examined copy number alterations of K19-positive and K19-negative HCCs and found frequent amplifications of the 4p16.3 locus containing the TACC3 gene, which has previously not been described in HCCs. We performed an immunohistochemical analysis of transforming acidic coiled-coil-containing protein 3 (TACC3) expression in HCCs in whole tissue sections and tissue microarrays and examined the clinicopathological characteristics of TACC3-overexpressing HCCs in relation to stemness-related marker (K19, EpCAM) expression, epithelial-mesenchymal transition (EMT)-related proteins, and survival. Cytoplasmic TACC3 protein expression was seen in 7/7 whole tissue sections of K19-positive HCCs, while TACC3 expression was negative or patchy in K19-negative cases. In the tissue microarray cohort, TACC3 was overexpressed in 105/188 (55.9 %) HCCs and was associated with poor differentiation (p = 0.028), major vascular invasion (p = 0.039), higher tumor stages (p = 0.015), younger age (p = 0.003), higher proliferative activity (p < 0.001), and more frequent multipolar mitoses (p < 0.001). TACC3 expression was significantly correlated with K19 (p = 0.010) and EpCAM (p < 0.001) positivity. In addition, TACC3 overexpression was associated with frequent expression of S100A4, uPAR, and ezrin (p < 0.001, all) and loss of E-cadherin expression (p = 0.014), and overall survival was significantly decreased in patients with TACC3-positive HCCs (p = 0.014). In conclusion, TACC3 overexpression was associated with clinicopathological features of aggressiveness, increased EMT-related protein expression, and poor survival, suggesting a potential role for TACC3 as a prognostic biomarker and therapeutic target in HCC.

Determining the extent of cholecystectomy using intraoperative specimen ultrasonography in patients with suspected early gallbladder cancer.

BACKGROUND: Accumulating evidence and guidelines recommend extended cholecystectomy for T1b or greater gallbladder cancers. This study aimed to evaluate the feasibility of intraoperative ultrasonography of a resected gallbladder specimen (specimen US) for the determination of the extent of cholecystectomy. METHODS: We included 45 patients (34 women; median [interquartile range] age, 66 [57-74] years) who underwent specimen US. After simple laparoscopic cholecystectomy, a gallbladder specimen was examined to evaluate the depth of tumor invasion by specimen US and frozen section examination. With the results of those two examinations, the operating surgeon decided whether to perform extended cholecystectomy. The sensitivity and specificity of specimen US and frozen section examination in diagnosing T1b or greater cancer were, respectively, measured using permanent pathology as the reference standard. The surgeons' final decisions were evaluated in the same manner as the intraoperative examinations. RESULTS: Among 22 patients in whom adenocarcinomas were confirmed, 17 patients had T1b or greater cancers. The sensitivity and specificity of specimen US alone were 81 % (95 % CI, 54-96 %) and 85 % (65-96 %), respectively. The sensitivity and specificity of frozen section examination alone were 43 % (10-82 %) and 95 % (75-100 %), respectively. Except one patient in whom extended cholecystectomy was intentionally not performed, 14 out of 16 patients (88 %; 95 % CI, 62-98 %) who were finally confirmed as having T1b or greater cancers underwent extended cholecystectomy by the surgeons' decision based on both specimen US and frozen examination. Out of 28 patients who were finally confirmed as having benign lesions or T1a cancers, 25 (89 %; 72-98 %) underwent simple cholecystectomy. CONCLUSION: Specimen US was feasible to be incorporated in clinical practice. Although the diagnostic accuracy of specimen US alone was moderate, the combined use of specimen US and frozen section examination could help the surgeons make correct decisions on the extent of cholecystectomy.

Peri-Transplant Change in AFP Level: a Useful Predictor of Hepatocellular Carcinoma Recurrence Following Liver Transplantation.

Pretransplant alpha-fetoprotein (AFP) is a useful tumor marker predicting recurrence of hepatocellular carcinoma (HCC). Little is known, however, about the relationship between changes in AFP concentration and prognosis. This study investigated the clinical significance of change in peri-transplant AFP level as a predictor of HCC recurrence. Data from 125 HCC patients with elevated pretransplant AFP level who underwent liver transplantation (LT) between February 2000 and December 2010 were retrospectively reviewed. Patients with AFP normalization within 1 month after LT were classified into the rapid normalization group (n = 97), with all other patients classified into the non-rapid normalization group (n = 28). Tumor recurrence was observed in 17 of the 97 patients (17.5%) with rapid normalization; of these, 11 patients had high AFP levels and six had normal levels at recurrence. In contrast, tumor recurrence was observed in 24 of the 28 patients (85.7%) without rapid normalization, with all 24 having high AFP levels at recurrence. Multivariate analysis showed that non-rapid normalization (harzard ratio [HR], 4.41, P < 0.001), sex (HR, 3.26, P = 0.03), tumor size (HR, 1.15, P = 0.001), and microvascular invasion (HR, 2.65, P = 0.005) were independent risk factors for recurrence. In conclusion, rapid normalization of post-LT AFP level at 1 month is a useful clinical marker for HCC recurrence. Therefore, an adjuvant strategy and/or intensive screening are needed for patients who do not show rapid normalization.

Living donor liver transplantation using a left liver extended to right anterior sector.

In living donor liver transplantations, right liver grafts have been commonly used to meet the metabolic demands of the recipient. However, a small left remnant liver volume sometimes limits its use due to donor safety concerns. Here, we report an innovative living donor hepatectomy using a left liver extended to the right anterior sector (segments 2-5 and 8), which can be considered for donors who are unsuited for right liver donation.

Hepatic venous congestion in living donor grafts in liver transplantation: is there an effect on hepatocellular carcinoma recurrence?

A certain degree of graft congestion in living donor liver transplantation (LDLT) using a right liver graft may be inevitable because of the mismatch between the inflow and outflow structures of the liver. The subsequent inflammatory reaction and rapid regeneration of the graft have been suggested as causes of tumor recurrence. Therefore, we investigated the influence of graft congestion on hepatocellular carcinoma (HCC) recurrence after LDLT. Two hundred eighty-nine LDLT patients for HCC within the University of California San Francisco criteria between November 1999 and February 2012 were investigated. Patients were assigned to groups on the basis of the degree of congestion (≤10% for group A and >10% for group B), which was determined by 3-dimensional reconstruction of posttransplant multidetector helical computed tomography within 2 weeks. Perioperative characteristics, regeneration rates after 6 months, and recurrence rates were compared between the groups, and a multivariate analysis of the influence of congestion on tumor recurrence was subsequently completed. No significant difference in demographics was found. Group B had more elevated peak posttransplant levels of aspartate aminotransferase (296.26 versus 227.53, P = 0.05), alanine aminotransferase (382.91 versus 276.98, P = 0.04), and highly selective C-reactive protein (5.41 versus 3.55, P < 0.001); a higher noncongestive section regeneration rate (25.8% versus 13.6%, P = 0.012); and a higher recurrence rate (30.4% versus 9.7%, P = 0.01) than group A. Graft congestion > 10% [hazard ratio (HR) = 3.10, 95% confidence interval (CI) = 1.15-8.35, P = 0.03], microvascular invasion (HR = 5.43, 95% CI = 2.04-14.44, P < 0.01), and an alpha-fetoprotein level > 200 IU/L (HR = 2.98, 95% CI = 1.10-8.03, P = 0.03) were significantly related to tumor recurrence. Liver congestion may promote the recurrence of HCC after LDLT; therefore, it should be minimized.

Fulminant hepatitis linked to dapsone hypersensitivity syndrome requiring urgent living donor liver transplantation: a case report.

Dapsone is a sulfone-type drug used widely for different infectious, immune, and hypersensitivity disorders as an antibacterial treatment alone or in combination for leprosy and sometimes for infected skin lesions. DHS is a severe idiosyncratic adverse reaction with multi-organ involvement. However, acute necrotic hepatitis requiring an emergent LT is rare. Herein, we report a case of 12-yr-old girl who suffered from fulminant hepatitis and multi-organ failure due to DHS for PPD. She was saved by emergent LDLT. A high index of suspicion and rapid diagnosis are necessary not to miss this potentially lethal but rare disease.

Pediatric split liver transplantation after Fontan procedure in left isomerism combined with biliary atresia: a case report.

LI is a subset of the heterotaxy syndrome and a rare birth defect that involves the heart and other organs. It can be combined with extracardiac abnormalities, especially BA. CHD can be associated with LI in up to 15% of cases, although it is rare in BA. Pediatric LT for a child with ESLD due to BA combined with LI and CHD is a challenging issue for a transplant surgeon. Herein, we report a successful split LT on a three-yr-old boy with LI who survived after a Fontan procedure due to single ventricle, but who suffered from HPS associated with BA.

Optimal tailored screening protocol after living donor liver transplantation for hepatocellular carcinoma.

The indication for hepatocellular carcinoma (HCC) is expanding in living donor liver transplantation (LDLT). Early detection and effective management of recurrence has become an important issue in LDLT for HCC. This study aimed to find an optimal screening protocol in terms of screening interval and screening tools by analyzing recurrence pattern after LDLT for HCC. A total of 205 LDLT patients in two centers from February 1999 to October 2010 was reviewed. Recurrence appeared in 55 cases. Six risk factors for recurrence were identified: preoperative alpha-fetoprotein >400, Edmonson grade 3 or 4, tumor size >7 cm, tumor number ≥7, minimal tumor necrosis in the transarterial chemoembolization group and positive micro-vascular invasion. Four groups with different ranges of index scores showed different recurrence-free survival and median time to recurrence. Group I showed low and late recurrence. Groups II and III showed linearly increased rate of recurrence until 18 months. Group IV showed very early recurrence within 6 months. Across the groups, extra-hepatic recurrence developed in more than 40% of cases and multi-organ recurrence rate was 20%. The screening interval should be different based on the risk of recurrence. Screening should include work-up for extra-hepatic recurrence as well as intra-hepatic recurrence.

Excellent outcome in 238 consecutive living donor liver transplantations using the right liver graft in a large volume single center.

BACKGROUND: Using a right liver (RL) graft improves the outcomes in adult living donor liver transplantation (ALDLT). Here we report the recent excellent outcomes of 238 consecutive RL transplantations in ALDLT. METHODS: Between January 2005 and June 2009, 238 consecutive adult recipients underwent RL transplantation; The middle hepatic vein (MHV) was reconstructed using artificial vascular grafts in 209 cases. Among these study subjects, UNOS status 1 and 2A were 12 (5.0 %) and 20 (8.4 %) patients, and the mean medical MELD score, was 19.9. Hepatitis B virus was the most common original liver disease in 184 patients (77.3 %). Hepatocellular carcinoma was diagnosed in 133 patients (56.3 %), and 102 patients (76.1 %) met the radiologic Milan criteria. The mean graft-versus-recipient weight ratio was 1.14 %. The primary endpoint of this study was the patient and graft survival rate. The mean follow-up period was 32 (0-69) months. RESULTS: The most common major complication was biliary complication (n = 62; 26 %). The 1-, 2-, and 5-year patient survival rates were 96, 95, and 94 %, and the graft survival rates were 99, 99, and 98 %. There were 4 hospital deaths (1.6 %). Eighteen late mortalities were observed after recurrence of hepatocellular carcinoma (HCC, n = 17) and one case of lymphoma recurrence. One case of graft failure 33 months after ALDLT was attributed to cholestatic fibrosing hepatitis B saved by re-ALDLT. On multivariate analysis, no drainage of MHV branches and accompanying HCC beyond Milan criteria were the risk factors for poor patients' survival rate (p < 0.05). CONCLUSIONS: Further technical innovation would be required to overcome biliary complications. The technical innovation using right liver draining MHV branches improved both patient and graft survival outcomes of ALDLT. Despite these advances, selection criteria for HCC are still hurdles, even in RL transplantation.

The effect of donor against recipient one-way HLA mismatch on liver transplantation outcomes from a multicenter registry analysis.

Donor against recipient one-way Human leukocyte antigen (HLA) mismatch (D → R one-way HLA MM) seemed strongly associated with graft-versus-host disease (GVHD). The aim of this study is to investigate the relevance of D → R one-way HLA MM in outcome of liver transplantation (LT). We retrospectively analyzed 2670 patients in Korean Organ Transplantation Registry database between April 2014 and December 2020. The patients were categorized into two groups whether D → R one-way HLA MM or not and evaluated the outcomes of LT between the two groups. 18 patients were found to be D → R one-way HLA MM. The incidence of GVHD (0.3% vs. 22.2%, p < 0.001) and mortality rate (11.6% vs. 38.9%, p = 0.003) was much higher in D → R one-way HLA MM group. D → R one-way HLA MM at 3 loci was seemed to be strongly associated with the incidence of GVHD (OR 163.3, p < 0.001), and found to be the strongest risk factor for patient death (HR 12.75, p < 0.001). Patients with D → R one-way HLA MM at 3 loci showed significantly lower overall survival (p < 0.001) but there were no significant differences in rejection-free survival and death-censored graft survival. D → R one-way HLA MM at 3 loci not only affects the overall survival of LT patients but also the incidence of GVHD.

Face Video Retrieval Based on the Deep CNN With RBF Loss.

This paper presents a novel framework to extract highly compact and discriminative features for face video retrieval tasks using the deep convolutional neural network (CNN). The face video retrieval task is to find the videos containing the face of a specific person from a database with a face image or a face video of the same person as a query. A key challenge is to extract discriminative features with small storage space from face videos with large intra-class variations caused by different angle, illumination, and facial expression. In recent years, the CNN-based binary hashing and metric learning methods showed notable progress in image/video retrieval tasks. However, the existing CNN-based binary hashing and metric learning have limitations in terms of inevitable information loss and storage inefficiency, respectively. To cope with these problems, the proposed framework consists of two parts: first, a novel loss function using a radial basis function kernel (RBF Loss) is introduced to train a neural network to generate compact and discriminative high-level features, and secondly, an optimized quantization using a logistic function (Logistic Quantization) is suggested to convert a real-valued feature to a 1-byte integer with the minimum information loss. Through the face video retrieval experiments on a challenging TV series data set (ICT-TV), it is demonstrated that the proposed framework outperforms the existing state-of-the-art feature extraction methods. Furthermore, the effectiveness of RBF loss was also demonstrated through the image classification and retrieval experiments on the CIFAR-10 and Fashion-MNIST data sets with LeNet-5.

The High-Sensitivity C-Reactive Protein/Albumin Ratio Predicts Long-Term Oncologic Outcomes after Curative Resection for Hepatocellular Carcinoma.

High-sensitivity C-reactive protein (hsCRP) is a prognostic factor for hepatocellular carcinoma (HCC), while albumin is known to be a disease severity index of the malnutrition status in HCC patients. The present study investigated the association between postoperative hsCRP/albumin ratio and both overall survival (OS) and recurrence-free survival (RFS) following HCC surgery. This retrospective observational study examined the medical records of 389 patients who underwent resection for HCC between 2004 and 2013. Postoperative day 0⁻1 hsCRP/albumin ratio was collected, and the optimal postoperative mortality cut-off point was derived using receiver operating characteristics (ROC) analysis. A postoperative hsCRP/albumin ratio increase of 1.0 was associated with a 1.171-fold increase in mortality (hazard ratio (HR): 1.171, 95% confidence interval (CI): 1.072⁻1.278, p < 0.001) and a 1.19-fold increase in recurrence (HR: 1.190, 95% CI: 1.108⁻1.278, p < 0.001). The hsCRP/albumin ratio cut-off point was found to be 0.625 and 0.500. When patients were grouped by this cut-off point, the >0.625 group showed a 2.257-fold increase in mortality (HR: 2.257, 95% CI: 1.470⁻3.466, p < 0.001), and the >0.500 group showed a 1.518-fold increase in recurrence (HR: 1.518, 95% CI: 1.125⁻2.050, p = 0.006).

The Clinicopathological and Prognostic Significance of the Gross Classification of Hepatocellular Carcinoma.

BACKGROUND: We aimed to determine the clinicopathological significance of the gross classification of hepatocellular carcinoma (HCC) according to the Korean Liver Cancer Association (KLCA) guidelines. METHODS: A retrospective analysis was performed on 242 cases of consecutively resected solitary primary HCC between 2003 and 2012 at Seoul National University Bundang Hospital. The gross classification (vaguely nodular [VN], expanding nodular [EN], multinodular confluent [MC], nodular with perinodular extension [NP], and infiltrative [INF]) was reviewed for all cases, and were correlated with various clinicopathological features and the expression status of "stemness"-related (cytokeratin 19 [CK19], epithelial cell adhesion molecule [EpCAM]), and epithelial-mesenchymal transition (EMT)-related (urokinase plasminogen activator receptor [uPAR] and Ezrin) markers. RESULTS: Significant differences were seen in overall survival (p=.015) and disease-free survival (p = .034) according to the gross classification; INF type showed the worst prognosis while VN and EN types were more favorable. When the gross types were simplified into two groups, type 2 HCCs (MC/NP/INF) were more frequently larger and poorly differentiated, and showed more frequent microvascular and portal venous invasion, intratumoral fibrous stroma and higher pT stages compared to type 1 HCCs (EN/VN) (p<.05, all). CK19, EpCAM, uPAR, and ezrin expression was more frequently seen in type 2 HCCs (p<.05, all). Gross classification was an independent predictor of both overall and disease-free survival by multivariate analysis (overall survival: p=.030; hazard ratio, 4.118; 95% confidence interval, 1.142 to 14.844; disease-free survival: p=.016; hazard ratio, 1.617; 95% confidence interval, 1.092 to 2.394). CONCLUSIONS: The gross classification of HCC had significant prognostic value and type 2 HCCs were associated with clinicopathological features of aggressive behavior, increased expression of "stemness"- and EMT-related markers, and decreased survival.

Laparoscopic Anatomical Segment 2 Segmentectomy by the Glissonian Approach.

BACKGROUND: When hepatocellular carcinoma (HCC) was located in segment 2 (S2), segment-oriented hepatectomy was more beneficial than left lateral sectionectomy as this type of anatomical resection preserved the volume of the nontumor-bearing segment. Herein, we presented 2 cases (1 with video) of laparoscopic anatomical S2 segmentectomy by the Glissonian approach. METHODS: The first patient was a 69-year-old woman, who had an incidentally detected liver nodule on abdominal ultrasound for systemic surveillance for her breast cancer. The preoperative liver function was Child-Pugh class A. Abdominal computed tomography showed a 2 cm low attenuating lesion in S2. Contrast magnetic resonance imaging (MRI) showed the same lesion with features more suggestive of HCC. In view of the inconclusive imaging findings, a needle biopsy was performed and it confirmed the diagnosis of HCC. The second patient was a 57-year-old man with hepatitis B and Child-Pugh class B liver cirrhosis. He had an enlarging nonenhancing liver nodule in S2 noted on MRI. Laparoscopic anatomical S2 segmentectomy was performed for these 2 patients. RESULTS: The operative time for the first and second patients was 240 and 185 minutes, respectively. The respective estimated intraoperative blood loss was 50 and 250 mL and no transfusion was necessary. The patients were discharged on the fourth and fifth postoperative day without any complications, respectively. CONCLUSION: This study showed the feasibility of performing a laparoscopic S2 segmentectomy by the Glissonian approach.

Laparoscopic Total Caudate Lobectomy for Hepatocellular Carcinoma.

BACKGROUND: Caudate lobe is located in the deep dorsal area of the liver between the portal triad and the inferior vena cava (IVC). Torrential bleeding can occur from the IVC and short hepatic veins during dissection. Isolated total caudate lobe resection is still rare and technically demanding. We herein present a video on the technical aspect of laparoscopic total caudate lobectomy. METHOD: A 61-year-old woman was admitted for recurrent hepatocellular carcinoma detected on imaging. She had history of multifocal hepatocellular carcinoma in July 2015 and underwent open cholecystectomy, segment 6 and segment 8 tumorectomy. Ten months later, the computed tomography scan and magnetic resonance imaging showed a 1 cm arterial enhancing lesion in segment I (S1) with no other foci of recurrence. Laparoscopic total caudate lobectomy was contemplated. RESULTS: The operative time was 270 minutes. The intraoperative blood loss was 200 mL and blood transfusion was not necessary. The patient was discharged on the fourth postoperative day without any complications. CONCLUSION: This report showed the safety and feasibility of laparoscopic total caudate lobectomy. Nonetheless, it is a technically demanding procedure. It should be performed in carefully selected patients and by experienced hepatobiliary surgeons proficient in laparoscopic liver resection.

Prognostic value of p21-activated kinase 4 in resected pancreatic cancer.

Resectable pancreatic cancer has a high recurrence rate after curative surgery. Biomarkers are needed for distinguishing patients who may benefit from curative resection. In this study, we sought to analyze the prognostic value of p21-activated kinase 1 (PAK1), p21-activated kinase 4 (PAK4), human equilibrative nucleoside transporter 1 (hENT1), and thymidylate synthase (TS) in surgically resected pancreatic ductal adenocarcinomas. A total of 160 pancreatic cancer patients who underwent surgery with curative intent were retrospectively reviewed. Tissue microarrays were constructed and immunohistochemical stains were performed for PAK1, PAK4, hENT1, and TS. The absence of PAK4 expression in pancreatic adenocarcinomas was associated with poorer histologic differentiation (p < 0.001), shorter overall survival [hazard ratio (HR) = 2.86, 95% confidence interval (CI) 1.43-5.71; p = 0.003], and disease-free survival (HR = 2.29, 95% CI: 1.11-4.74; p = 0.025) on univariate analyses. In addition, more frequent venous invasion and lymph node metastases were seen in PAK4-negative tumors although not statistically significant. PAK1, hENT1, and TS expression status did not have significant influences on patient survival. In conclusion, PAK4 of the markers tested in this study may be a potential prognostic biomarker for pancreatic adenocarcinomas.

Post-resection recurrence of hepatocellular carcinoma in cirrhotic patients: Is thrombocytopenia a risk factor for recurrence?

PURPOSE: Liver resection is the main treatment for hepatocellular carcinoma (HCC) patients with sufficient liver reserve. However, the long-term outcomes are dismal because the recurrence rate is high, especially in cirrhotic patients. The role of platelets as a predictive factor for HCC recurrence is still controversial. The aim of this study was to assess the influence of the preoperative platelet count on HCC recurrence after liver resection in patients with liver cirrhosis. STUDY DESIGN: Between 2004 and 2013, 233 HCC patients with pathologically proven liver cirrhosis underwent liver resection and were enrolled in this study. RESULTS: Recurrence occurred in 125 patients (53.6%), predominantly within the remnant liver (100 patients, 42.9%). The 1-, 3-, and 5-year disease-free survival (DFS) rates were 71.4%, 48.1%, and 40.5%, respectively. The predictive factors for DFS were analyzed with Cox's proportional hazard regression model. In the multivariable analysis, the preoperative platelet count (p = 0.021) and pT stage (p = 0.01) were the only significant independent predictors of HCC recurrence. The recurrence rate was clearly stratified by the preoperative platelet count. The optimal cut-off value of 135 × 103/µL on a receiver operating characteristic curve corresponded to the maximum sensitivity and specificity of prediction. The DFS of patients with low preoperative platelet counts was significantly worse than that of patients with high preoperative platelet counts (p = 0.006, log-rank test). CONCLUSIONS: Thrombocytopenia is a significant predictor of HCC recurrence after liver resection in cirrhotic patients. However, the pathophysiological mechanism underlying this finding requires clarification.

Surgery for Intermediate and Advanced Hepatocellular Carcinoma: A Consensus Report from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014).

BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy does not recommended surgery for treating BCLC stage B and C hepatocellular carcinoma (HCC). However, numerous Asia-Pacific institutes still perform surgery for this patient group. This consensus report from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting aimed to share opinions and experiences pertaining to liver resection for intermediate and advanced HCCs and to provide evidence to issue recommendations for surgery in this patient group. SUMMARY: Thirteen experts from five Asia-Pacific regions were invited to the meeting; 10 of them (Japan: 2, Taiwan: 3, South Korea: 2, Hong Kong: 1, and China: 2) voted for the final consensus. The discussion focused on evaluating the preoperative liver functional reserve and surgery for large tumors, multiple tumors, HCCs with vascular invasion, and HCCs with distant metastasis. The feasibility of future prospective randomized trials comparing surgery with transarterial chemoembolization for intermediate HCC and with sorafenib for advanced HCC was also discussed. The Child-Pugh score (9/10 experts) and indocyanine green retention rate at 15 min (8/10) were the most widely accepted methods for evaluating the preoperative liver functional reserve. All (10/10) experts agreed that portal hypertension, tumor size >5 cm, portal venous invasion, hepatic venous invasion, and extrahepatic metastasis are not absolute contraindications for the surgical resection of HCC. Furthermore, 9 of the 10 experts agreed that tumor resection may be performed for patients with >3 tumors. The limitations of surgery are associated with a poor liver functional reserve, incomplete tumor resection, and a high probability of recurrence. KEY MESSAGES: Surgery provides significant survival benefits for Asian-Pacific patients with intermediate and advanced HCCs, particularly when the liver functional reserve is favorable. However, prospective randomized controlled trials are difficult to conduct because of technical and ethical considerations.

SALL4 Expression in Hepatocellular Carcinomas Is Associated with EpCAM-Positivity and a Poor Prognosis.

BACKGROUND: There is increasing interest in hepatocellular carcinomas (HCC) expressing "stemness"-related markers, as they have been associated with aggressive behavior and poor prognosis. In this study, we investigated the usefulness of Sal-like protein 4 (SALL4), a recently proposed candidate marker of "stemness." METHODS: Immunohistochemical stains were performed for SALL4, K19, and epithelial cellular adhesion molecule (EpCAM) on tissue microarrays constructed from 190 surgically resected HCCs, and the results were correlated with the clinicopathological features and patient survival data. RESULTS: Nuclear SALL4 expression was observed in 39/190 HCCs (20.5%), while K19 and EpCAM were expressed in 30 (15.9%) and 92 (48.7%) HCCs, respectively. The nuclear expression was generally weak, punctate or clumped. SALL4 expression was significantly associated with a poor overall survival compared to SALL4-negative HCCs (p = .014) compared to SALL4-negative HCCs. On multivariate analysis adjusted for tumor size, multiplicity, vascular invasion, and pathological tumor stage, SALL4 remained as a significant independent predictor of decreased overall survival (p= .004). SALL4 expression was positively correlated with EpCAM expression (p = .013) but not with K19 expression. HCCs that expressed both SALL4 and EpCAM were associated with significantly decreased overall survival, compared to those cases which were negative for both of these markers (p = .031). CONCLUSIONS: Although SALL4 expression was not significantly correlated with other clinicopathological parameters suggestive of tumor aggressiveness, SALL4 expression was an independent predictor of poor overall survival in human HCCs, and was also positively correlated with EpCAM expression.