Liver Cancer
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Primary liver cancer is a disease in which the cells of liver become cancerous (malignant). Primary liver cancer is different from cancer that has spread from another place in the body to the liver. The liver is found in the upper right side of the abdomen. It is an an important organ which is involved in digesting food and converting it to energy and it also filters and stores blood. Liver cancer is relatively rare, known risk factors for liver cancer are prior hepatitis B or C infections or cirrhosis of the liver. There are two main types of liver cancer in adults: hepatocellular carcinoma and cholangiocarcinoma. Hepatoblastoma is another type of liver cancer which mostly occurs in children. Some types of liver cancer produce abnormaly high levels of alpha-fetoprotein (AFP) which can aid diagnosis.

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Information for Patients and the Public
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Latest Research Publications
Childhood Liver Cancer

Information Patients and the Public (12 links)

Information for Health Professionals / Researchers (13 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Nishiwada S, Ko S, Mukogawa T, et al.
Comparison between percutaneous radiofrequency ablation and surgical hepatectomy focusing on local disease control rate for colorectal liver metastases.
Hepatogastroenterology. 2014 Mar-Apr; 61(130):436-41 [PubMed] Related Publications
BACKGROUND/AIMS: Therapeutic efficacy of radiofrequency ablation (RFA) for colorectal liver metastases (CRLM) was compared with hepatic resection (HR), focusing on local disease control rate as well as risk factors of recurrence and patients survival.
METHODOLOGY: From April 2002 to March 2012, 32 patients underwent RFA and 60 patients underwent HR for CRLM. The rate of local recurrence along the ablated or resected margin was evaluated in these patients.
RESULTS: The local recurrence was seen in 8 patients (13.3%) after HR, and 15 (46.9%) after RFA. Multivariate analysis of all patients revealed that RFA as an initial therapy (P < 0.001), venous invasion liver metastases (P = 0.049) were independent risk factors for local recurrence. Subgroup analysis showed that local recurrence rate after RFA was significantly higher than that after HR in patients with tumors 20 mm or larger (P < 0.001), while there was no significant difference in local recurrence rate between RFA and HR in patients with tumors less than 20 mm (P = 0.676).
CONCLUSIONS: RFA showed a high risk of local recurrence in comparison to HR especially in patients with tumors larger than 20 mm. Indication of RFA should be restricted drastically considering the limitation of efficacy.

Related: Colorectal (Bowel) Cancer

Sakurai K, Sohda T, Ueda S, et al.
Immunohistochemical demonstration of transferrin receptor 1 and 2 in human hepatocellular carcinoma tissue.
Hepatogastroenterology. 2014 Mar-Apr; 61(130):426-30 [PubMed] Related Publications
BACKGROUND/AIMS: Recent studies have confirmed that iron overload is involved not only in liver carcinogenesis, but in its progression. Results in studies using liver cancer cell lines have suggested a relationship between transferrin receptor (TfR) expression and liver carcinogenesis, but TfR expression has not yet been analyzed in human hepatocellular carcinoma (HCC) tissues.
METHODOLOGY: We immunohistochemically assessed the expression of TfR1 and TfR2 in tumor tissues and adjacent non-tumorous liver tissues from 41 HCC patients who underwent partial hepatectomy. We evaluated uptake of iron in hepatocytes and HCC cells using iron staining.
RESULTS: The expression TfR was significantly higher in HCC samples than in adjacent non-tumor tissue (p < 0.001). TfR expression was significantly related to serum alpha-fetoprotein (p < 0.05) and des-gamma carboxy prothrombin (p < 0.05) concentrations. We also found iron deposition in non-tumor tissue from 25 patients, but in only two HCC samples, consistent with findings that hepatocellular iron uptake decreases with liver carcinogenesis.
CONCLUSIONS: We investigated the expression of TfR1 and TfR2 in human HCC tissues by immunohistochemistry, the first report demonstrating TfR2 expression immunohistochemically in human HCC. These results suggest that TfR is expressed in response to iron deficiency during liver carcinogenesis.

Ishikawa T, Kubota T, Abe H, et al.
Percutaneous transhepatic portal vein stent placement can improve prognosis for hepatocellular carcinoma patients with portal vein tumor thrombosis.
Hepatogastroenterology. 2014 Mar-Apr; 61(130):413-6 [PubMed] Related Publications
BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) has an extremely poor prognosis. One reason is that portal hypertension may progress rapidly and intractable gastric/esophageal variceal hemorrhage may occur in PVTT cases. We studied whether a percutaneous transhepatic portal vein stent placement could improve the prognosis for HCC with PVTT.
METHODOLOGY: Five cases of HCC with PVTT where portal hypertension had rapidly progressed were performed portal vein stenting.
RESULTS: All cases had been classified into Child-Pugh class C. Only one of them died of liver failure five months after stent placement, but two of the cases successfully avoided dying of liver failure and the other two cases are still alive with a hepatic functional reserve maintained.
CONCLUSIONS: Although portal vein stent placement for HCC with PVTT is not by itself a therapy for PVTT, portal vein stent placement plays a prominent role in improving hepatic function reserve preventing fatal hepatic failures due to PVTT and gastric/esophageal variceal hemorrhage associated with portal hypertension. This leads to prolonged survival for HCC patients with PVTT. Further prospective trials including the appropriate timing of portal vein stent placement treatment will be needed for larger numbers of HCC patients with PVTT.

Zhang H, Yang R
Resveratrol inhibits VEGF gene expression and proliferation of hepatocarcinoma cells.
Hepatogastroenterology. 2014 Mar-Apr; 61(130):410-2 [PubMed] Related Publications
BACKGROUND/AIMS: Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and growth of a variety of cancer cells. In the paper, we investigated the effects of Resveratrol (Res) on expression ofVEGF gene in human hepatocarcinoma cell cells and cell proliferation.
METHODOLOGY: HepG2 cells were treated with different concentrations of Res (0, 10, 20, 40 micromol/L) and rent time (24, 48, 72h). Cell proliferation was examined by MTT method and the expression of VEGF gene was analyzed by RT-PCR and Western blot.
RESULTS: Res could inhibit expression of VEGF gene, the inhibitory effect of Res increased with the increasing of concentration of Res and treatment time.
CONCLUSIONS: Our results suggest that Res can significantly inhibit the proliferation of HepG2 cells and exerts an anti-tumor effect by repressing the expression of VEGF gene.

Related: VEGFA

Kamiyama T, Tahara M, Nakanishi K, et al.
Long-term outcome of laparoscopic hepatectomy in patients with hepatocellular carcinoma.
Hepatogastroenterology. 2014 Mar-Apr; 61(130):405-9 [PubMed] Related Publications
BACKGROUND/AIMS: The long-term prognosis for patients with hepatocellular carcinoma (HCC) who undergo laparoscopic hepatectomy has not been well compared with that for patients after open hepatectomy.
METHODOLOGY: We analyzed patient survival (PS) and disease-free survival (DFS) of 310 consecutive patients who underwent primary hepatectomy between January 2001 and March 2010. The patients were divided into Group LAP (laparoscopic approach) (n = 24) and Group OPN (with open laparotomy) (n = 286). The median follow-up time was 60.9 months (range, 12.0-123.9 months).
RESULTS: The 5-, and 7-year PS rates of Group LAP were 87.9%, and 87.9%, and those of Group OPN were 82.2% and 69.3%, respectively (P = 0.5638). The 5-, and 7-year DFS rates of Group LAP were 47.1%, and 31.4%, and those of Group OPN were 29.4%, and 24.3%, respectively (P = 0.4594). Laparoscopic hepatectomy in patients of Group LAP resulted in a better outcome of blood loss (P = 0.0314), operative time (P < 0.0001), and hospital stay (P = 0.0008).
CONCLUSIONS: The long-term outcome of laparoscopic hepatectomy for patients with HCC was identified to be comparable to open hepatectomy with regard to PS and DFS. Laparoscopic hepatectomy is a promising therapeutic option for patients with HCC.

Topaloglu S, Ozturk MH
Chemoembolization for neuroendocrine liver metastasis.
Hepatogastroenterology. 2014 Mar-Apr; 61(130):398-404 [PubMed] Related Publications
The liver is the most common site for neuroendocrine tumor metastasis. The characteristic feature of these tumors is related to the secretion of biologically active compounds in large amounts. Systemic chemotherapy has limited success in treating patients with neuroendocrine liver metastasis. Surgical management remains the only potentially curative option for these patients. According to the high incidence of recurrence after surgery, the role of intra-arterial therapy (IATs) in neuroendocrine tumor metastasis has been evolved. This review evaluates the potential role of IATs in the light of current literature.

Søreide K
Acute Budd-Chiari syndrome associated with non-viral cryptogenic hepatocellular carcinoma: revisiting the 'chicken or the egg' theory.
Hepatogastroenterology. 2014 Mar-Apr; 61(130):388-90 [PubMed] Related Publications
Budd-Chiari syndrome is an eponym for "hepatic venous outflow tract obstruction". BCS left untreated has a high mortality rate. Diagnosis can be difficult because of the wide spectrum of presentation of the disease and the varying severity of liver damage. The onset of disease may be insidious, with a chronic, asymptomatic course, or also present on other occasions as an acute, life-threatening condition. In rare instances, BCS is associated with hepatocellular carcinoma (HCC), which may be both a cause and a consequence of BCS. Presented here is a case of acute, rapidly fatal severe BCS associated with HCC. The association between BCS and HCC in 'the chicken or the egg' analogy is revisited.

Li SQ, Lin J, Qi CY, et al.
GPC3 DNA vaccine elicits potent cellular antitumor immunity against HCC in mice.
Hepatogastroenterology. 2014 Mar-Apr; 61(130):278-84 [PubMed] Related Publications
BACKGROUND/AIMS: DNA-based tumor vaccine immunotherapy which elicits exclusively cellular immune response against cancer cells in an antigen-specific fashion has been documented to be an effective treatment for cancers in the past decade. Glypican 3 (GPC3) is especially overexpressed in hepatocellular carcinoma (HCC), but not in benign liver lesions and normal adult tissues, which makes it an ideal tumor antigen designed for HCC immunotherapy.
METHODOLOGY: We constructed a GPC3 cDNA vaccine by using a recombinant plasmid encoding murine GPC3 cDNA for treatment of HCC in a C57BL/6 mouse model. The specificity and effectiveness of anti-tumor immunity were assessed in vitro and in vivo studies.
RESULTS: In vitro studies showed that GPC3 DNA vaccine induced potent specific cytotoxic T lymphoctyes (CTLs) immune response against C57BL/6 homogenous HCC cell line Hepa 1-6 (GPC3+). However, there was no detectable immune response against GPC3-negative SP 2/0 cells and Sk-Hep-1 cells. In vivo study indicated that GPC3 DNA vaccine could significantly suppress homogenous tumor growth and prolong survival time of tumor bearing mice.
CONCLUSIONS: This study demonstrated the first time that the GPC3 DNA vaccine could elicit specific and effective cellular antitumor immunity against GPC3 HCC. This may provide an alternative option for immunotherapy of HCC.

Solarana Ortíz JA, Placencia Gilart JE, Rodríguez Diéguez M, et al.
Primary tumour of the round ligament of the liver: a case presentation.
Pathologica. 2014; 106(1):26-8 [PubMed] Related Publications
A 40-year-old Caucasian female patient presented to the outpatient General Surgery ward in "V. I. Lenin" Teaching Hospital complaining of a recurrent mesogastric pain that had lasted for 3 months. Physical examination showed a palpable mass confined to that area. She was then admitted with diagnosis of an abdominal tumour. Diagnostic work-up revealed that the process involved the round ligament of the liver, which is an exceptional localization, which motivated us to publish this case after surgical treatment by excision, having also taken into account the results of histopathology which revealed a PEComa, confirmed by inmunohistochemistry. After reviewing the available literature, the low incidence of these lesions, as well as the unusual histological variety, makes the present case one of interest.

Falleni M, Bauer D, Opocher E, et al.
A rare case of transmural endometriosis in primary adenocarcinoma of the rectum.
Pathologica. 2014; 106(1):14-5 [PubMed] Related Publications
Intestinal endometriosis of the rectum and sigmoid colon, occurring in up to 34% of pelvic endometriosis, mimics a wide number of conditions that are difficult to differentiate from inflammatory or malignant diseases. Herein we report the first case of transmural endometriosis concomitant with advanced primary rectal adenocarcinoma, presenting with obstructive symptoms. Correct diagnosis based on morphological identification and immunohistochemical characterization of the two entities is crucial for treatment.

Schuld J, Richter S, Kollmar O
The role of cryosurgery in the treatment of colorectal liver metastases: a matched-pair analysis of cryotherapy vs. liver resection.
Hepatogastroenterology. 2014 Jan-Feb; 61(129):192-6 [PubMed] Related Publications
BACKGROUND/AIMS: Although liver resection is the gold standard for patients with colorectal liver metastases (CRLM), only 15-20% of the patients are candidates for surgery. As ablative therapies may extend this low rate of curative option, the aim of the present study was to analyze the impact of cryosurgery (cryo) on survival of patients with CRLM compared to liver resection (Phx).
METHODOLOGY: In a matched-pair analysis, patients undergoing Phx or cryo were compared (n = 39 each). Analysis included pre-, peri-and postoperative data and follow-up for tumor-free and overall survival. Survival was estimated by Kaplan-Meier method.
RESULTS: Out of 124 patients undergoing 143 cryosurgical procedures, 39 patients could be identified undergoing single liver cryo procedure for CRLM with a curative approach. Matching of these patients with a Phx cohort, patients undergoing Phx revealed better overall (20 vs. 46 months) and tumor-free survival (7.8 vs. 33.6 months) than patients with cryo.
CONCLUSIONS: Liver resection is strongly recommended for patients with CRLM compared to cryosurgery.

Related: Colorectal (Bowel) Cancer

Ahn CS, Moon DB, Lee SG, et al.
Survival differences between Milan criteria after down-staging and De novo Milan in living donor liver transplantation for hepatocellular carcinoma.
Hepatogastroenterology. 2014 Jan-Feb; 61(129):187-91 [PubMed] Related Publications
BACKGROUND/AIMS: This study reports our experiences of adult living donor liver transplantation (LDLT) corresponding to downstaging.
METHODOLOGY: Between July 1992 and April 2008, we performed 553 adult LDLTs (35.1%, 553/1575) for HCC. Sixty-five patients was not treated before LDLT and belonged to Milan criteria, classified as De novo Milan group (De novo-M); 22 HCC patients did not meet Milan criteria initially, but subsequently met the criteria after downstaging, classified as artificial Milan group (Artificial-M). The evaluation of downstaging was based on preoperative CT scan and explanted liver biopsy, and excluded the patients having unclear treatment history on analysis.
RESULTS: Artificial-M showed significantly less Child C patients (25%) than De novo-M (64.5%) (0.037). Artificial-M had greater tumor burden than De novo-M in maximal tumor size (2.5 +/- 1.2 versus 2.2 +/- 0.95 cm), sum of tumor diameter (3.4 +/- 1.4 versus 2.4 +/- 1.0 cm), number of nodules (1.8 +/- 0.9 versus 1.2 +/- 0.5), respectively. Five-year cumulative survival was not different between Artificial-M and De novo-M (83.9% versus 93.9%), but 5-year disease free survival were significantly different (71.1% versus 96.5%) (p = 0.0016).
CONCLUSIONS: Five year overall survival rates after LDLT were good in both groups. However, stricter follow-up is necessary in Artificial-M considering greater tumor burden and higher recurrence rate compared to De novo-M.

Elsberger B, Roxburgh CS, Horgan PG
Is there a role for surgical resections of hepatic breast cancer metastases?
Hepatogastroenterology. 2014 Jan-Feb; 61(129):181-6 [PubMed] Related Publications
Breast cancer accounts for over 12,000 deaths in the UK annually; 12% of women develop hepatic metastases receiving systemic therapy as standard treatment. Hepatic resection has been proposed as a potentially curative alternative. Current literature was reviewed and evaluated for hepatic resection on breast cancer liver metastases by conducting a literature search across Ovid Medline, Embase and PubMed. Twenty-one studies were included in the review. All were retrospective, single centre case series. Eighteen studies reported results for ten or more patients. Only three studies reported results for over 50 patients. The time-span for the individual series ranged from 9-20 years. Generally, liver resection for breast cancer liver metastases is a safe procedure with only two post-operative deaths reported. Median time to recurrence was low (10-36 months). Overall 5-year survival ranged from 12-75%. Poorer prognosis correlated with increasing size and number of metastases, extrahepatic spread and short time span from primary surgery to the development of further metastases. Current literature does not establish clearly, who should undergo a hepatic resection for breast cancer metastasis. But it seems that hepatic resection should be considered as a therapeutic option for limited volume liver metastasis in high-risk breast cancer patients. However, prospective cohort studies are required to establish the role of hepatic resection for breast cancer metastasis.

Related: Breast Cancer

Shen WF, Wu L, Dong H, et al.
Hepatic resection for multiple hepatocellular carcinoma less than 5 cm: a prospective comparative study.
Hepatogastroenterology. 2014 Jan-Feb; 61(129):173-80 [PubMed] Related Publications
BACKGROUND/AIMS: Treatment of multiple hepatocellular carcinoma (HCC) remains a critical issue. In addition, the prognosis and prognostic factors of multiple HCC after hepatic resection are rarely prospectively documented.
METHODOLOGY: The clinicopathologic and follow-up data of 81 patients who underwent curative resection of HCC between January 2008 and January 2009 were prospectively collected. Patients were categorized according to the size of the largest tumor: group A (n = 40, two or three HCCs with maximum tumor diameter > 3 cm and < or = 5 cm) and group B (n = 41, two or three HCCs with maximum tumor diameter < or = 3 cm). The two groups were compared for clinicopathologic data and survival results.
RESULTS: The 1-, 2-, 3-, and 4-year survival rates of group A were 75.0%, 58.0%, 50.0%, and 44.0%, respectively, while the survival rates of group B were 93.0%, 80.0%, 66.0%, and 47.0%, respectively. The 1-, 2-, 3-, and 4-year disease-free survival rates of group A were 43.0%, 30.0%, 23.0%, and 15.0%, respectively, comparing to 71.0%, 54.0%, 44.0%, and 36.0% in group B, respectively. The median overall cumulative survival time of group A and group B were 36.0 and 44.5 months, respectively (P = 0.322). The median disease-free survival time of group A was 10.0 months and was significantly shorter than that of group B (30.0 months, P = 0.011).
CONCLUSIONS: Resection may provide comparative survival benefits even for patients with multiple HCCs with maximum tumor diameter > 3 cm and < or = 5 cm.

Lu H, Fan Y, Zhang F, et al.
Fast-track surgery improves postoperative outcomes after hepatectomy.
Hepatogastroenterology. 2014 Jan-Feb; 61(129):168-72 [PubMed] Related Publications
Fast-track (FT) programs have been applied in colorectal surgery for years. But in liver surgery, role of FT programs has not been fully established. So, a perspective study was performed in our center. A total of 297 hepatocellular carcinoma patients were randomized into FT and non-FT (NFT) group (n = 135 and 162, respectively) according to perioperative managements. Operation time, anhepatic phase and intraoperative blood loss were all significantly reduced in FT group; besides, first exhaust time after operation and hospital stay were also shortened significantly. Spearman correlation showed that operation time was positively correlated with four parameters, including the anhepatic phase, the intraoperative blood loss during surgery, the hospital day and the first exhaust time after surgery. The anhepatic phase was also positively correlated with the intraoperative blood loss during surgery. Besides, the hospital day was positively correlated with the intraoperative blood loss during surgery and the first exhaust time after surgery. FT postoperative management was the only predictor of the shorter first exhaust time after operation and the shorter hospital day. No total postoperative complication, readmission and postoperative mortality were observed. Our data indicated that FT programs were safe and effective in hepatectomy.

Marumoto M, Yamasaki T, Marumoto Y, et al.
Systemic gemcitabine combined with hepatic arterial infusion chemotherapy with cisplatin, 5-fluorouracil, and isovorin for the treatment of advanced intrahepatic cholangiocarcinoma: a pilot study.
Hepatogastroenterology. 2014 Jan-Feb; 61(129):162-7 [PubMed] Related Publications
BACKGROUND/AIMS: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis and usually presents as advanced disease. Hepatic arterial infusion chemotherapy (HAIC) is a promising option for advanced hepatocellular carcinoma; however, there have been few reports on the use of HAIC in patients with ICC. In the present study, we investigated the efficacy of treatment with systemic gemcitabine (GEM) combined with HAIC with cisplatin (CDDP), 5-fluorouracil (5-FU), and isovorin in patients with advanced ICC.
METHODOLOGY: Seven patients with advanced ICC, who received systemic GEM combined with HAIC with CDDP, 5-FU, and isovorin were studied.
RESULTS: The response rate after the first chemotherapy cycle was 57.1% (partial response, 4; stable disease, 2; progressive disease, 1). The cumulative survival rates at 1 and 2 years were 85.7% and 28.6%, respectively, and the median survival time was 22.3 months. With regard to grade 3 or 4 adverse reactions, the percentages of patients developing leukopenia, neutropenia, thrombocytopenia, anemia, and anorexia were 28.6%, 28.6%, 42.9%, 14.3%, and 14.3%, respectively. Na treatment-related deaths were encountered.
CONCLUSIONS: Although this is a pilot study, we suggest that systemic GEM combined with HAIC with CDDP, 5-FU, and isovorin, may be a useful therapy for patients with advanced ICC.

Related: Cisplatin Fluorouracil Leucovorin Gemcitabine

Han HS, Ahn KS, Cho JY, et al.
Autologous stem cell transplantation for expansion of remnant liver volume with extensive hepatectomy.
Hepatogastroenterology. 2014 Jan-Feb; 61(129):156-61 [PubMed] Related Publications
BACKGROUND/AIMS: The plasticity of bone marrow stem cells has been confirmed to self-renew and transdifferentiate into hepatocytes. Thus, we performed autologous stem cell transplantation for rapid liver regeneration with extensive hepatectomy in hepatocellular cancer patients.
METHODOLOGY: With informed consent, patients aged 20 to 75 who needed large extensive hepatectomy due to hepatocellular carcinoma were randomly divided into three groups: control, mononuclear cells (MNCs), and CD34+ cells, based on infused cell type. After portal vein embolization (PVE), mobilized MNCs or CD34+ cells were returned to the patient via the portal vein on mobilization day without manipulation. Liver volume, liver function, clinical score and Indocyanine green R15 (ICG-R15) were compared before and after PVE.
RESULTS: Total bilirubin, albumin, and clinical score showed significant improvement (p < 0.05) 1 week post-infusion, with no significant difference between MNC and CD34+ cell groups. Four patients (control, 1; MNC, 1; CD34+, 2) started at over 18% ICG-R15 but can be overturned after PVE. Daily hepatic volume growth (mL/day) was 2.5 for MNC and 4.9 for CD34+ groups, resulting in significant increase over controls (1.1; p < 0.05). We found no correlation between the number of applied CD34+ cells and daily gains in left lateral lobe volume.
CONCLUSIONS: Improvements in liver volume, liver function, clinical score and ICG-R15 suggest that autologous stem cell transplantation is a promising method for liver regeneration.

Related: Stem Cell and Bone Marrow Transplants

Sheng ML, Xu GL, Zhang CH, et al.
Aberrant estrogen receptor alpha expression correlates with hepatocellular carcinoma metastasis and its mechanisms.
Hepatogastroenterology. 2014 Jan-Feb; 61(129):146-50 [PubMed] Related Publications
BACKGROUND/AIMS: Metastasis one of the obstacles before poor prognosis of hepatocellular carcinoma (HCC) is improved. Estrogen receptor alpha (ERalpha) plays an important role in the development and progression of HCC. However, the molecular mechanism of ERalpha in mediating HCC metastasis is still unclear. The aim of the present study was to detect aberrant ERalpha expression in HCC and elucidate its possible mechanisms in HCC metastasis.
METHODOLOGY: We detected expression of ERalpha, phospho-estrogen receptor alpha (p-ERalpha), nuclear factor kappa B (NF-kappaB) p65 and Matrix metalloproteinase-9 (MMP-9) between HCC tissues with portal vein tumor thrombus (PVTT) and those without PVTT by immunohistochemical method. Moreover, the expression of above parameters was also determined in HCC cells of different metastatic potential by using immunocytochemical and reverse transcriptase-polymerase chain reaction (RT-PCR) methods.
RESULTS: The expression of ERalpha and p-ERalpha was lower in HCC with PVTT than those without PVTT. Meanwhile, the expression pattern of above parameters was also similar in HCC cells of different metastatic potential, whereas, the expression of NF-kappaB p65 and MMP-9 was higher in HCC with PVTT than those without PVTT. The expression of NF-kappaB p65 and MMP-9 in HCC cells was also analogous to the tissues.
CONCLUSIONS: These results demonstrated that expression of ERalpha, p-ERalpha, NF-kappaB p65 and MMP-9 correlated with invasion and metastasis in HCC. The mechanism of HCC metastasis may mediate through cross-talk between the NF-KB and ER signaling pathways. Meanwhile, ERa regulated MMP-9 through NF-kappaB indirectly.

Related: MMP9: matrix metallopeptidase 9 ESR1

Imura S, Shimada M, Utsunomiya T, et al.
Clinicopathological characteristics of patients with non-B non-C hepatocellular carcinoma: a special reference to metabolic syndrome.
Hepatogastroenterology. 2014 Jan-Feb; 61(129):129-35 [PubMed] Related Publications
BACKGROUND/AIMS: This study was carried out to clarify the clinicopathological features of hepatocellular carcinoma (HCC) arising in patients without viral infection and to confirm the influence of metabolic syndrome (MS) on characteristics in HCC patients.
METHODOLOGY: Two hundred and thirty-three hepatectomized HCC patients were enrolled. The status of the hepatitis viral infection was defined; non-B non-C (NBNC) (n = 15), negative for HBs-Ag, HBc-Ab or HCV-Ab; HBV (n = 70); HCV (n = 148). We compared clinicopathological features and surgical outcomes among three groups. Additionally, fifty-six HCC patients who were evaluated on coexistence of MS were divided into two groups and analyzed; MS (n = 16) and non-MS (n = 40) groups.
RESULTS: In NBNC-patients, preoperative platelet counts and ICGR15 were significantly better compared to HCV-patients (21.8 x 10(4)/mm3 vs. 11.3 x 10(4)/mm3, 14.0% vs. 19.2%, p <0.05). Body mass index was significantly higher in NBNC-patients (24.9 vs. 22.4, p < 0.05). Overall survival rates were significantly higher in NBNC-patients compared with HBV or HCV-patients (5 y: 87.5% vs. 48.8%, 42.9%, p < 0.05). For NBNC-patients there were significantly more patients in the MS group than in the non-MS group.
CONCLUSIONS: HCC with MS included more NBNC-HCC than HBV or HCV related HCC. Aggressive hepatectomy contributed to the favorable outcome in NBNC-patients because of their better liver function.

Tang YH, Luo Y, Wen TF, et al.
Portal hemodynamics before and after liver resection and its correlation with post-hepatectomy liver failure in patients with Child-Pugh class A: analysis of 151 consecutive cases.
Hepatogastroenterology. 2014 Jan-Feb; 61(129):42-7 [PubMed] Related Publications
BACKGROUND/AIMS: Low portal velocity (PV) was found in cirrhotic patients, which was thought to be a risk factor for post-hepatectomy liver failure (PHLF). This study attempted to find out whether a correlation existed between portal hemodynamics and PHLF.
METHODOLOGY: From December 2010 to December 2012, all consecutive patients with Child-Pugh class A underwent liver resection were included. PV and PF were measured by using Doppler ultrasound preoperatively and on postoperative day 3. Portal hemodynamics change was explored. Univariable and multivariable analysis were used to identify risk factors for PHLF.
RESULTS: PHLF occurred in 25 of 151 patients, and persistent PHLF in 9 patients. Mean portal velocity change (PVmeanC) was significantly different between patients with PHLF and patients without PHLF, but it failed to be identified as independent predictor for PHLF in multivariate analysis, which found alanine aminotransferase (ALT) and Ishak score significantly associated with PHLF, and only ALT significantly associated with persistent PHLF. Subgroup analysis of the 73 cirrhotic patients also showed that none of the portal hemodynamic parameters were independent risk factors for PHLF or persistent PHLF.
CONCLUSIONS: None of the portal hemodynamic parameters could be used to predict PHLF or persistent PHLF.

Ruan L, Wang S, Zhang J, et al.
Doppler perfusion index and contrast-enhanced ultrasound in patients with colorectal cancer liver metastases.
Hepatogastroenterology. 2014 Jan-Feb; 61(129):37-41 [PubMed] Related Publications
BACKGROUND/AIMS: To assess the value of the Doppler perfusion index (DPI) and contrast agent for the detection of liver metastases in patients with colorectal cancer.
METHODOLOGY: DPI was measured in 18 patients with colorectal cancer liver metastases and 18 control subjects. Sixteen patients were underwent contrast-enhanced ultrasonography (CEUS).
RESULTS: patients with liver metastases had significantly greater DPI than control group (0.39 +/- 0.10 vs. 0.19 +/- 0.07, p < 0.05). Sixteen liver metastasis lesions underwent a rapid wash-out of contrast agent during the portal venous phase followed by a complete wash-out of SonoVue during the sinusoidal phase and were differentiated as "fast-in and fast-out" contrast enhancement patter. Another 3 lesions which were not found by baseline ultrasonography were detected to be enhancement defects at sinusoidal phases by CEUS.
CONCLUSIONS: DPI is a sensitive index in detection of colorectal liver metastases; if used combined with contrast agent, much more occult liver metastasis would be detected by ultrasonography.

Related: Colorectal (Bowel) Cancer

Honda Y, Kimura T, Aikata H, et al.
Pilot study of stereotactic body radiation therapy combined with transcatheter arterial chemoembolization for small hepatocellular carcinoma.
Hepatogastroenterology. 2014 Jan-Feb; 61(129):31-6 [PubMed] Related Publications
BACKGROUND/AIMS: We retrospectively evaluated the local tumor control and safety of transcatheter arterial chemoembolization (TACE) followed by stereotactic body radiation therapy (SBRT) for small hepatocellular carcinoma (HCC) in this pilot study.
METHODOLOGY: Twenty-eight patients not for the indication of hepatectomy or ablation procedures were enrolled in this study. Eligible criteria was as followed: i) less than 3 hypervascular HCC nodules, each up to 30 mm in diameter; ii) not suitable for the hepatic resection or ablative therapy; iii) Child-Turcotte-Pugh (CTP) score < or = 7. SBRT was performed within 1-2 months after TACE. Treatment efficacy was evaluated, according to the Response Evaluation Criteria in Cancer of the Liver (RECICL).
RESULTS: The median local tumor control time was not reached. The 1-year cumulative local tumor control rate was 96.3%. The median disease-free survival time was 18 months. The 1- year cumulative overall survival rate was 92.6%. One patient (3.6%) died due to intrahepatic ectopic multiple recurrence and systemic metastasis and one (3.6%) due to cerebral hemorrhage. No patients experienced severe acute hematologic or physical toxicity or radiation induced liver damage.
CONCLUSIONS: Our study demonstrated SBRT combined with TACE is a safe and effective modality of the locoregional therapy for small primary HCC.

Li SX, Tang GS, Zhou DX, et al.
Prognostic significance of cytoskeleton-associated membrane protein 4 and its palmitoyl acyltransferase DHHC2 in hepatocellular carcinoma.
Cancer. 2014; 120(10):1520-31 [PubMed] Related Publications
BACKGROUND: The functions of cytoskeleton-associated membrane protein 4 (CKAP4), one kind of type II transmembrane protein, are associated with the palmitoyl acyltransferase DHHC2. The objective of the current study was to investigate CKAP4/DHHC2 expression and its prognostic significance in patients with hepatocellular carcinoma (HCC).
METHODS: Two independent cohorts of 416 patients with HCC were enrolled. All the patients included had defined clinicopathologic and follow-up data. Using real-time polymerase chain reaction and immunohistochemical assay, CKAP4 and DHHC2 expression were evaluated. The association between CKAP4/DHHC2 expression and HCC-specific disease-free survival and overall survival was analyzed by Kaplan-Meier curves, the log-rank test, and Multivariate Cox regression analyses.
RESULTS: The data documented that CKAP4 expression was much higher in HCC tumor tissues compared with adjacent normal tissues and its expression was significantly correlated with tumor size, intrahepatic metastases, portal venous invasion, and Barcelona Clinic Liver Cancer stage of disease in 2 cohorts of patients. On survival analysis, patients with high CKAP4 expression appeared to have a favorable overall survival and a longer disease-free survival compared with those with low expression. DHHC2 expression was also examined in tissue microarray analysis by immunohistochemistry and the results demonstrated that 87.6% of the cases had low expression of DHHC2. Kaplan-Meier analysis indicated that a high level of DHHC2 expression predicted favorable overall survival and disease-free survival rates in both the training cohort and validation set. Furthermore, the combination of CKAP4 and DHHC2 was found to have a more powerful efficiency in prognosis prediction than either one alone.
CONCLUSIONS: To the best of our knowledge, the current study is the first to demonstrate that the expression of CKAP4 and its palmitoyl acyltransferase DHHC2 correlates with disease progression and metastasis in patients with HCC and may provide prognostic and therapeutic value.

Lupinacci RM, Mello ES, Coelho FF, et al.
Prognostic implication of mucinous histology in resected colorectal cancer liver metastases.
Surgery. 2014; 155(6):1062-8 [PubMed] Related Publications
BACKGROUND: Colorectal mucinous adenocarcinoma (MAC) is a subtype of colorectal adenocarcinoma with prominent mucin production associated with proximal location of tumor, advanced stage at diagnosis, microsatellite instability, and BRAF mutation. The prognostic implication of MAC in colorectal cancer liver metastases (CRCLM) is unknown. The purpose of our study was to determine the frequency and elucidate the prognostic implication of mucinous histology in CRCLM.
METHODS: The medical records of 118 patients who underwent CRCLM resection between 2000 and 2010 were reviewed. Clinicopathologic variables and outcome parameters were examined. Resected specimens were submitted to routine histologic evaluation. Patients were grouped according to the metastasis mucinous content: >50%, MAC; <50%, adenocarcinoma with intermediated mucinous component (AIM); and without any mucinous component, non-MAC (NMA).
RESULTS: Mean follow-up after resection was 37 months. Tumor recurrence was observed in 75% of patients. Overall survival and disease-free survival rates after hepatectomy were 61%, 56%, and 26%, 24% at 3 and 5 years, respectively. Tumors with mucinous component (AIM and MAC) were related to proximal location of the primary tumor and were more frequently observed in females. Multivariate analysis revealed that MAC was an independent negative prognostic factor (hazard ratio, 3.13; 95% CI, 1.30-6.68; P = .011) compared with non-MAC (NMA and AIM).
CONCLUSION: MAC has an adverse prognostic impact compared with NMA, which may influence therapeutic strategy raising an important subject for discussion and future investigation.

Related: Colorectal (Bowel) Cancer

Amarapurkar DN, Dharod M, Gautam S, Patel N
Risk of development of hepatocellular carcinoma in patients with NASH-related cirrhosis.
Trop Gastroenterol. 2013 Jul-Sep; 34(3):159-63 [PubMed] Related Publications
BACKGROUND AND AIMS: The risk of development of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is well established and is being recognized increasingly in non-alcoholic steatohepatitis (NASH)-related cirrhosis. This study aimed to assess the risk of development of HCC in patients with NASH-related cirrhosis.
METHODS: From January 2010 to October 2011, we prospectively enrolled 585 patients with liver cirrhosis (men:women ratio 4.4:1, mean age 50.1 +/- 6.1 years, aetiology HBV 19%, HCV 14.2%, NASH-related 7%, cryptogenic cirrhosis 17.8%, already diagnosed cirrhosis 48.2%, and the remaining were newly diagnosed cases). The cumulative follow-up was for 5.9 +/- 0.5, 6.1 + 0.8 and 6.8 + 1.2 years for HBV, HCV and NASH-related cirrhosis, respectively. Patients with advanced cirrhosis, Child class C and associated comorbid conditions where survival was < 1 year were excluded from the study. The remaining patients were followed up 6-monthly with ultrasound examination and alpha-fetoprotein (AFP) test. Patients suspected of HCC underwent triple-phase computed tomography (CT) scan and liver biopsy was done to confirm the diagnosis.
RESULTS: A total of 54 patients developed HCC, of which 26 had HBV, 14 had HCV, 9 had- cryptogenic and 6 had- NASH-related cirrhosis. The annual rate of development of HCC was 1.5%, 3.6%, 0.6% and 0.46 in HBV, HCV, cryptogenic and NASH-related cirrhosis, respectively.
CONCLUSIONS: The incidence of HCC was highest in HCV and lowest in NASH-related cirrhosis. These figures suggest an intermediate risk of development of HCC when compared to western countries and Japan.

Chan SC
Section 2. Small-for-size liver graft and hepatocellular carcinoma recurrence.
Transplantation. 2014; 97 Suppl 8:S7-S10 [PubMed] Related Publications
Liver transplantation (LT) is the most effective treatment for small and unresectable hepatocellular carcinomas (HCCs). With scarcity of deceased donor livers, living donor LT (LDLT) is the alternative to deceased donor LT (DDLT). Animal studies have suggested that regeneration of the partial liver graft encourages HCC recurrence. Increased recurrence was observed in a few studies. Thus, there is the belief that the use of small-for-size graft carries the potential risk of disease recurrence. Nevertheless, those studies were retrospective, with sample sizes not large enough for conclusions.Living donor LT can be performed when a suitable donor is available. The fast tracking of patients for transplantation without a period of observation is an issue. Meta-analyses, however, showed no significant increase in HCC recurrence after LDLT. Patients listed for DDLT and without suitable living donors have to endure a long wait, during which the aggressiveness of their HCC is observed. Such observation almost guarantees slow disease progression when they get transplanted. Nevertheless, a long wait has the disadvantage of transplanting patients with more advanced tumors, although still within standard criteria. Judicious use of deceased donor grafts is the responsibility of the transplant community.Living donor LT for HCC should only be performed after careful assessment of the recipient and tumor status. Although tumor size and number are references widely adopted in tumor staging, biological staging of tumors using positron emission tomography could provide additional information of tumor behavior. A high level of serum α-fetoprotein also warns against LT because it is predictive of a high HCC recurrence rate.

Lee KW, Yi NJ, Suh KS
Section 5. Further expanding the criteria for HCC in living donor liver transplantation: when not to transplant: SNUH experience.
Transplantation. 2014; 97 Suppl 8:S20-3 [PubMed] Related Publications
Living donor liver transplant (LDLT) is one of the important modalities to treat hepatocellular carcinoma (HCC) in Asian countries. LDLT for HCC consists of >50% of the total LDLT at Seoul National University Hospital (SNUH). Milan or University of California San Francisco (UCSF) criteria were not considered as absolute selection criteria for LDLT at SNUH. We experienced that some patients with beyond Milan criteria have long-term survival after LDLT. On the contrary, LDLT showed poorer outcome than deceased donor LT (DDLT) in patients with within UCSF criteria in our series. There are several reasons for higher recurrence rate in LDLT such as fast-track selection and rapid regeneration in LDLT. Therefore, the feasibility of conventional criteria based on tumor size and number to predict HCC recurrence after LDLT seemed somewhat different from that of DDLT. We identified significant pre-operative biological factors such as AFP, PIVKAII, and PET positivity. Combination of those biological factors predicted HCC recurrence better than conventional criteria based on size and number. All patients with three risk factors showed 100% recurrence. This group should be excluded regardless of Milan criteria.There have been debates in expanding the criteria in LDLT. Some centers still stick on the expanded criteria that are estimated to yield a 5-year survival of approximately 50%. However, there was no completely tailored criterion to predict HCC recurrence exactly. The survival after recurrence was also different from case by case. Furthermore, the introduction of m-TOR inhibitor and targeted agent improved survival after recurrence. Based on these ideas, we experimentally expanded our indication to the far advanced HCC (HCC larger than 10 cm or more than 10 numbers or with macrovascular invasion preoperatively). The patients with far advanced HCC have usually poor prognosis. However, the selected patients with low AFP (<200 ng/ml), 2-year recurrence free survival was 54.5%.In conclusion, we are now expanding the criteria selectively up to patients with macrovascular invasion if there are no other effective treatment options and the expected survival and risk after LT is acceptable in both recipient and donor. The current absolute contraindication for LDLT in SNUH is extrahepatic metastasis.

Related: AFP

Tamura S, Sugawara Y, Kokudo N
Section 4. Further expanding the criteria for HCC in living donor liver transplantation: the Tokyo University experience.
Transplantation. 2014; 97 Suppl 8:S17-20 [PubMed] Related Publications
In Asia, evidence-based guidelines for the management of hepatocellular carcinoma (HCC) have evolved, including the option of liver transplantation. Because of the continuing serious organ shortage, however, living donor liver transplantation (LDLT) remains the mainstream in Japan. Unlike deceased donor transplantation, living donor transplantation is not always limited by the restrictions imposed by the nationwide organ allocation system. The decision for transplantation may depend on institutional or case-by-case considerations, balancing the will of the donor, the operative risk, and the overall survival benefit. Cumulative data from the Japanese national multicenter registry analysis as well as individual center experiences suggest further expanding the criteria for LDLT for HCC from the Milan criteria is feasible with acceptable outcomes.

Sharr WW, Chan SC, Lo CM
Section 3. Current status of downstaging of hepatocellular carcinoma before liver transplantation.
Transplantation. 2014; 97 Suppl 8:S10-7 [PubMed] Related Publications
Liver transplantation (LT) is a well-established option of cure for hepatocellular carcinoma (HCC). Milan criteria is recognized as standard for selection of patients and set the baseline of survival to be achieved. It has been shown that tumor biology including differentiation, vascular invasion, and serum α-fetoprotein (AFP) predict posttransplant recurrence and survival better than morphology. Downstaging by locoregional therapies of HCC before LT, with the response to treatments and progression within observation period, serves as a selection tool rather than modulation of tumor biology. It selects those patients outside standard criteria at presentation but good tumor biology and high chance of good outcome to receive transplantation. The definition of downstaging should be differentiated from neo-adjuvant therapy, and the objectives in surgical and pretransplant candidates also differ.Published studies in this area showed variation in inclusion criteria, downstaging protocol and assessment of successful downstaging. Tumor biology predownstaging and postdownstaging was not incorporated. Posttransplant outcome were not clearly stated with regard to intention-to-treat survival, disease-free survival, and comparison against those originally within criteria. Meta-analysis of these results was impossible. Nevertheless, majority had reasonable protocol and were able to select patients whom likely to have good outcome. At present, there is no evidence that downstaged patients have a poorer prognosis than those presenting within the Milan criteria. Patients with tumors outside Milan criteria should be offered downstaging therapies. Those who are successfully downstaged to within Milan criteria should be eligible to liver transplant as same as those initially fit the criteria. In the last decade, various extended criteria of HCC for LT have been proposed and reported satisfactory survival. That makes downstaging technically unnecessary.To refine and validate the role of downstaging, it needs collaborative and prospective study with significant sample size, adequate preoperative staging, standardized protocol of selection of patients, and approaches to downstaging. Selection criteria should include histopathological data on tumor biology and serum AFP. There should be standardized definition of successful downstaging. Posttransplant disease-free survival should be reported in detail and compared with those who fit the standard criteria initially. A consistent immunosuppressant protocol is important to avoid bias.

Halpern EF
Behind the numbers: inverse probability weighting.
Radiology. 2014; 271(3):625-8 [PubMed] Related Publications
Inverse probability weighting is a propensity score-based technique that can be used to compensate for imbalance in study groups. It is an alternative to regression-based adjustment of the outcomes. It has advantages over matching of cases on the basis of propensity scores when there are more than two groups to compare, when finding matches results in insufficient sample sizes, or when the data are censored. However, it can create artificial imbalance unless it is applied carefully. In this article, an introduction to inverse probability weighting is provided by using the Yang et al study published in this issue of Radiology as an example.

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