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.
Liver cancer explained - symptoms, diagnosis and treatment
Macmillan Cancer Support Video: Liver surgeon Aamir Khan explains primary liver cancer, including possible causes such as alcohol and obesity, symptoms, what tests might be done to diagnose liver cancer, and possible treatments such as surgery, chemotherapy or liver transplant.
PubMed Central search for free-access publications about Liver Cancer MeSH term: Liver Neoplasms US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
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Munene G, Parker RD, Shaheen AA, et al. Disparities in the surgical treatment of colorectal liver metastases. J Natl Med Assoc. 2013; 105(2):128-37 [PubMed] Related Publications
BACKGROUND: Hepatectomy is an accepted standard of care for patients with resectable colorectal liver metastases (CLM). Given that it is unclear whether disparities exist between different patient populations, a population-based analysis was performed to analyze this issue with regards to resection rates and surgical mortality in patients with CLM. METHODS: Using the Nationwide Inpatient Sample, characteristics and outcomes of adult patients with a diagnosis of colorectal cancer and colorectal metastases that subsequently underwent a liver resection during the years 1993-2007 were identified. Multivariate analysis was used to determine the effects of demographic and clinical covariables on resection rates and in-hospital mortality. RESULTS: Incident colorectal and liver metastases were identified in 138,565 patients; 3,528 patients (2.6%) underwent subsequent resection. African American and Hispanic race were associated with lower resection rates compared to Caucasian patients (adjusted OR 0.61 (0.52 - 0.71) and 0.81 (0.68 - 0.96) respectively). Medicaid insurance was associated with decreased resection rates compared to private insurance (AOR 0.47 (0.40 - 0.56)). The overall inpatient mortality rate was 3.1%. Multivariate analysis determined that mortality rate was correlated to both insurance status and geographic region. CONCLUSIONS: The national resection rate is significantly lower than has been reported by most case series. Race and insurance status appear to be correlated to the likelihood of surgical resection. In-hospital mortality is equivalent to the rates reported elsewhere, but is correlated to insurance status and region.
Morris MW, Berch B, Westmoreland T, et al. Resection of a giant hepatic adenoma in an eight-year-old girl. Am Surg. 2013; 79(9):889-90 [PubMed] Related Publications
Hepatic adenomas are benign tumors typically diagnosed in women of reproductive age, however, these tumors occur in the pediatric population although rare. We present the case of a giant hepatic adenoma in an 8-year-old female without established risk factors with progressive abdominal pain, and po intolerance, biliary obstruction, anemia, and fever. Right trisegmentectomy afforded extirpation of the 16 × 14.5 × 8.5 cm mass. The postoperative course was complicated by transient encephalopathy and a bile leak which resolved with appropriate care. The patient is well over 1 year from resection. She demonstrates age appropriate mental and physical function without disease recurrence or complication.
Peungjesada S, Aloia TA, Kaur H, et al. Intrabiliary growth of colorectal liver metastasis: spectrum of imaging findings and implications for surgical management. AJR Am J Roentgenol. 2013; 201(4):W582-9 [PubMed] Related Publications
OBJECTIVE: The propensity for colorectal liver metastasis to invade the biliary tree is increasingly recognized, placing particular emphasis on the risk of postoperative recurrence. This article illustrates the spectrum of imaging findings when colorectal metastasis invades the biliary tree. CONCLUSION: Knowledge of the imaging features of intrabiliary invasion by colorectal liver metastasis improves the quality of preoperative staging and is crucial in an era in which nonanatomic wedge resection and radiofrequency ablation are routinely performed.
Taouli B, Johnson RS, Hajdu CH, et al. Hepatocellular carcinoma: perfusion quantification with dynamic contrast-enhanced MRI. AJR Am J Roentgenol. 2013; 201(4):795-800 [PubMed] Related Publications
OBJECTIVE: The objective of our study was to report our initial experience with dynamic contrast-enhanced MRI (DCE-MRI) for perfusion quantification of hepatocellular carcinoma (HCC) and surrounding liver. SUBJECTS AND METHODS: DCE-MRI of the liver was prospectively performed on 31 patients with HCC (male-female ratio, 26:5; mean age, 61 years; age range, 41-83 years). A dynamic coronal 3D FLASH sequence was performed at 1.5 T before and after injection of gadolinium-based contrast agent with an average temporal resolution of 3.8 seconds. Regions of interest were drawn on the abdominal aorta, portal vein, liver parenchyma, and HCC lesions by two observers in consensus. Time-activity curves were analyzed using a dual-input single-compartment model. The following perfusion parameters were obtained: arterial flow, portal venous flow, arterial fraction, distribution volume, and mean transit time (MTT). RESULTS: Thirty-three HCCs (mean size, 3.9 cm; range, 1.1-12.6 cm) were evaluated in 26 patients. When compared with liver parenchyma, HCC showed significantly higher arterial hepatic blood flow and arterial fraction (p < 0.0001) and significantly lower distribution volume and portal venous hepatic blood flow (p < 0.0001-0.023), with no difference in MTT. Untreated HCCs (n = 16) had a higher arterial fraction and lower portal venous hepatic blood flow value than chemoembolized HCCs (n = 17, p < 0.04). CONCLUSION: DCE-MRI can be used to quantify perfusion metrics of HCC and liver parenchyma and to assess perfusion changes after HCC chemoembolization.
Amin SM, Albrechtsen NW, Forster J, Damjanov I Gangliocytic paraganglioma of duodenum metastatic to lymph nodes and liver and extending into the retropancreatic space. Pathologica. 2013; 105(3):90-3 [PubMed] Related Publications
Gangliocytic paraganglioma (GP) is a rare benign neuroendocrine tumour found most often in the duodenum. To our knowledge, only a dozen cases of possibly malignant duodenal GP with local lymph node metastasis and only one case with liver metastasis have previously been published. Herein, we report an unusual case of GP of the duodenum spreading to the retropancreatic space and metastatic to the liver and lymph nodes. Additionally, the present tumour secreted pancreatic polypeptide (PP) which was detected in the serum during the follow-up period. We suggest that serum PP could be a valuable marker in the diagnosis and follow-up of patients with GP.
Vauthey JN, Zimmitti G, Kopetz SE, et al. RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases. Ann Surg. 2013; 258(4):619-26; discussion 626-7 [PubMed] Related Publications
OBJECTIVE: To determine the impact of RAS mutation status on survival and patterns of recurrence in patients undergoing curative resection of colorectal liver metastases (CLM) after preoperative modern chemotherapy. BACKGROUND: RAS mutation has been reported to be associated with aggressive tumor biology. However, the effect of RAS mutation on survival and patterns of recurrence after resection of CLM remains unclear. METHODS: Somatic mutations were analyzed using mass spectroscopy in 193 patients who underwent single-regimen modern chemotherapy before resection of CLM. The relationship between RAS mutation status and survival outcomes was investigated. RESULTS: Detected somatic mutations included RAS (KRAS/NRAS) in 34 (18%), PIK3CA in 13 (7%), and BRAF in 2 (1%) patients. At a median follow-up of 33 months, 3-year overall survival (OS) rates were 81% in patients with wild-type versus 52.2% in patients with mutant RAS (P = 0.002); 3-year recurrence-free survival (RFS) rates were 33.5% with wild-type versus 13.5% with mutant RAS (P = 0.001). Liver and lung recurrences were observed in 89 and 83 patients, respectively. Patients with RAS mutation had a lower 3-year lung RFS rate (34.6% vs 59.3%, P < 0.001) but not a lower 3-year liver RFS rate (43.8% vs 50.2%, P = 0.181). In multivariate analyses, RAS mutation predicted worse OS [hazard ratio (HR) = 2.3, P = 0.002), overall RFS (HR = 1.9, P = 0.005), and lung RFS (HR = 2.0, P = 0.01), but not liver RFS (P = 0.181). CONCLUSIONS: RAS mutation predicts early lung recurrence and worse survival after curative resection of CLM. This information may be used to individualize systemic and local tumor-directed therapies and follow-up strategies.
Gavert N, Shvab A, Sheffer M, et al. c-Kit is suppressed in human colon cancer tissue and contributes to L1-mediated metastasis. Cancer Res. 2013; 73(18):5754-63 [PubMed] Related Publications
The transmembrane neural cell adhesion receptor L1 is a Wnt/β-catenin target gene expressed in many tumor types. In human colorectal cancer, L1 localizes preferentially to the invasive front of tumors and when overexpressed in colorectal cancer cells, it facilitates their metastasis to the liver. In this study, we investigated genes that are regulated in human colorectal cancer and by the L1-NF-κB pathway that has been implicated in liver metastasis. c-Kit was the most highly suppressed gene in both colorectal cancer tissue and the L1-NF-κB pathway. c-Kit suppression that resulted from L1-mediated signaling relied upon NF-κB, which directly inhibited the transcription of SP1, a major activator of the c-Kit gene promoter. Reconstituting c-Kit expression in L1-transfected cells blocked the biological effects conferred by L1 overexpression in driving motility and liver metastasis. We found that c-Kit expression in colorectal cancer cells is associated with a more pronounced epithelial morphology, along with increased expression of E-cadherin and decreased expression of Slug. Although c-Kit overexpression inhibited the motility and metastasis of L1-expressing colorectal cancer cells, it enhanced colorectal cancer cell proliferation and tumorigenesis, arguing that separate pathways mediate tumorigenicity and metastasis by c-Kit. Our findings provide insights into how colorectal cancer metastasizes to the liver, the most common site of dissemination in this cancer.
Gulubova M, Manolova I, Ananiev J, et al. Relationship of TGF-β1 and Smad7 expression with decreased dendritic cell infiltration in liver gastrointestinal cancer metastasis. APMIS. 2013; 121(10):967-75 [PubMed] Related Publications
Immune responses and their modulation within the liver are critical to the outcome of liver malignancies. In late-stage tumors, secreted TGF-β promotes oncogenic functions and can confer tolerogenicity to some immune cells like DCs. The TGF-β signaling pathway is involved in the control of several biological processes, including immunosurveillance. The aim of the present study was to assess CD1a(+) and CD83(+) DCs and to evaluate the impact of TGF-β pathway on DCs maturation and distribution in the liver metastases from gastric and colorectal tumors. The percentage of CD83(+) DCs in the liver tissue, surrounding metastasis and in the metastasis-free liver was measured by flow cytometry, and TGF-β levels were assessed in the tissue supernatant from the peritumoral liver after mononuclear cell isolation and in the sera of the same patients. CD1a(+) and CD83(+) DCs were observed in the tumor stroma and border. Out of 73 patients, there was cytoplasmic reactivity: of TGF-β1 in 37 (50.7%); of Smad4 in 62 (84.9%); of Smad7 in 46 (63%), and of TGFβRII in 39 (53.4%) of the metastases. The TGF-β1 expression in tumor cell cytoplasm correlated with low CD1a(+) and low CD83(+) DCs infiltration. The tissue levels of TGF-β1, measured by ELISA in the supernatant were significantly increased in metastases than in normal liver. Using a two-color FACS analysis, we found that the percentage of HLA-DR(+) CD83(+) DCs in metastases was significantly decreased as compared with metastasis-free liver tissue. In conclusion, the positive and negative correlations between the mediators from the TGF-β pathway implied the existence of imbalance and suppression of this cytokine activity. The presence of increased TGF-β expression by immunohistochemistry in tumor cells was confirmed by detection of increased TGF-β tissue level in the supernatant from the tissue homogenate. The observation of low numbers of CD1a(+) and CD83(+) DCs in tumor stroma correlated with TGF-β overexpression in tumor cells, a fact that well documents the immunosuppressive role of TGF-β in metastasis development. The increased percentage of CD83(+) DCs in the peritumoral tissue supposes that there could be active recruitment or local differentiation of DCs in the metastasis border, but inside the tumor the immune cells recruitment and activity are suppressed by TGF-β and by other cytokines.
Tam HH, Collins DJ, Brown G, et al. The role of pre-treatment diffusion-weighted MRI in predicting long-term outcome of colorectal liver metastasis. Br J Radiol. 2013; 86(1030):20130281 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
OBJECTIVE: To determine the prognostic value of pre-treatment apparent diffusion coefficient (ADC) of colorectal liver metastases in predicting disease response, progression-free survival (PFS) and overall survival (OS). METHODS: We retrospectively reviewed 102 patients who underwent pre-treatment diffusion-weighted MRI using a breath-hold (b=0, 150, 500) or a free-breathing (b=0, 50, 100, 250, 500, 750) technique. The mean ADC (b=0-500) and mean flow-insensitive ADC (ADChigh) values (breath-hold: b=150 and 500; free-breathing: b=100 and 500) of up to three hepatic lesions were evaluated in each patient. Clinical and laboratory parameters were recorded. Tumour response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria at 12 weeks after treatment. Associations between tumour response, ADC values and clinical/laboratory parameters were examined by one-way analysis of variance. The relationship of ADC with PFS and OS was determined by Kaplan-Meier analysis. RESULTS: 62 patients responded to chemotherapy at 12 weeks. The pre-treatment mean ADC and mean ADChigh were higher in the non-responding group than in the responding group (1.55 vs 1.36, p=0.033; 1.40 vs 1.16, p=0.024). However, the PFS and OS of the two groups of patients stratified by the median of mean ADC values or threshold derived by receiver operating characteristic analysis were not statistically significant. By multivariate Cox regression analysis, patients with ≤2 metastases and response to chemotherapy showed better PFS; white cell count ≤10 and surgical treatment were associated with better OS. CONCLUSION: Colorectal liver metastasis with higher pre-treatment mean ADC and mean ADChigh was associated with poorer response to chemotherapy. However, ADC and ADChigh values did not predict the patient outcome in this study cohort. ADVANCES IN KNOWLEDGE: High mean ADC values of colorectal liver metastases on pre-treatment diffusion-weighted MRI is associated with poorer response to chemotherapy.
Hammer ST, Owens SR Pancreatoblastoma: a rare, adult pancreatic tumor with many faces. Arch Pathol Lab Med. 2013; 137(9):1224-6 [PubMed] Related Publications
Pancreatoblastomas are malignant epithelial neoplasms of the pancreas that are heterogeneous and have variable cellular differentiation, complicating the diagnosis. We report a case of pancreatoblastoma occurring in an adult patient, presenting as a pancreatic head mass with liver metastasis and jaundice. The initial liver biopsy diagnosis was metastatic neuroendocrine carcinoma based on morphology and synaptophysin positivity. At pancreatic resection, the diagnostic features of pancreatoblastoma were recognized. We review the radiologic and pathologic differential diagnosis, histologic heterogeneity, clinical presentation, and associated genetic syndromes for this unusual tumor that can mimic other types of pancreatic neoplasia.
Huang J, Zhang Y, Peng Z, et al. A modified TNM-7 staging system to better predict the survival in patients with hepatocellular carcinoma after hepatectomy. J Cancer Res Clin Oncol. 2013; 139(10):1709-19 [PubMed] Related Publications
OBJECTIVE: To evaluate the accuracy of the 7th edition of the American Joint Committee on Cancer staging system (TNM-7) for patients undergoing hepatectomy for hepatocellular carcinoma (HCC) and to propose a modified TNM system for better prediction of survival. METHODS: Clinico-pathological data for 1,313 patients who underwent hepatectomy as initial treatment for HCC between 2000 and 2008 were retrieved from a prospective database. Overall survival (OS) and disease-free survival (DFS) were analyzed to evaluate the predictive value. RESULTS: The 1-, 3-, 5-year OS and DFS of 1,313 patients were 79.2, 55.4, 45.5 %, and 52.6, 36.1, 31.8 %, respectively. Multivariate analysis revealed that major vascular invasion was the most important prognostic factor for both OS and DFS, along with tumour number and size. Patients with pT1 and pT2 disease had significantly better OS and DFS than those with pT3 disease (P < 0.001). There was no significant difference between pT3a and pT4 (P = 0.552) but patients with pT3b disease had a worse OS and DFS than those with pT4 disease (P = 0.006 and P < 0.001, respectively). A modified TNM system within the existing framework was proposed to combine the current pT3a and pT4 together as the new pT3 and to change pT3b to the new pT4. Analysis showed that this modified system had a better prognostic power than either TNM-6 or TNM-7. CONCLUSION: TNM-7 would seem to be inaccurate for staging advanced HCC. The modified system can improve both the prognostic accuracy and the hazard discrimination of disease to be consistent among subgroups of HCC.
Haruki K, Shiba H, Fujiwara Y, et al. Inhibition of nuclear factor-κB enhances the antitumor effect of tumor necrosis factor-α gene therapy for hepatocellular carcinoma in mice. Surgery. 2013; 154(3):468-78 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is often resistant to chemotherapy. Gene therapy using an adenoviral vector-expressing tumor necrosis factor (TNF)-α is a new therapeutic approach for chemoresistant malignancies. The efficacy of TNF-α, however, is limited, because it leads to the activation of nuclear factor (NF)-κB. We hypothesized that the NF-κB inhibitor nafamostat mesilate would enhance the antitumor effect of adenovirus vector-mediated TNF-α gene therapy for HCC. METHODS: In vitro, we assessed the inhibitory effect of nafamostat mesilate on TNF-α-induced NF-κB activation and enhanced apoptosis in human HCC cell lines (Huh-7 and Hep3B). In vivo, we established a xenograft HCC model in mice by subcutaneous injection of Huh-7 and Hep3B cells. The animals received intraperitoneal (IP) injections of nafamostat mesilate 3 times a week (nafamostat mesilate group), intratumoral (IT) injections of the human TNF-α-expressing adenoviral vector (AxCAhTNF-α) once a week (TNF-α group), IT injections of AxCAhTNF-α once a week, or IP injections of nafamostat mesilate 3 times a week (combination group). RESULTS: In the combination group, TNF-α-induced NF-κB activation was inhibited and TNF-α-induced apoptosis was enhanced in comparison with the other groups both in vitro and in vivo. In the combination group, tumor growth was significantly slower and the apoptotic cell numbers were significantly greater than those of the TNF-α group. CONCLUSION: Inhibition of NF-κB by nafamostat mesilate enhances the antitumor effect of adenoviral vector-mediated TNF-α gene therapy for HCC in mice.
Huang WY, Kao CH, Huang WS, et al. 18F-FDG PET and combined 18F-FDG-contrast CT parameters as predictors of tumor control for hepatocellular carcinoma after stereotactic ablative radiotherapy. J Nucl Med. 2013; 54(10):1710-6 [PubMed] Related Publications
UNLABELLED: The application of stereotactic ablative radiotherapy (SABR) to hepatocellular carcinoma (HCC) is emerging. To identify pretreatment prognostic indicators is crucial for patient selection and optimal individual therapy. The aim of this study was to determine whether (18)F-FDG PET and a combined (18)F-FDG-contrast CT parameter could be useful tools to predict tumor control for patients with HCC treated by SABR. METHODS: We retrospectively identified 31 patients (41 tumors) who underwent (18)F-FDG PET before SABR between November 2007 and September 2011. (18)F-FDG PET parameters were collected as prognostic indicators, including visual PET scale (+/-), maximal standardized uptake value (SUV) of the tumor (T SUV max), ratio of T SUV max to maximal normal-liver SUV, ratio of T SUV max to mean normal-liver SUV, and score combining tumor volume and T SUV max (CT/(18)F-FDG PET score). They underwent SABR with a median dose of 42 Gy (ranging from 30 to 50 Gy) in 4-5 fractions. (18)F-FDG PET parameters and clinical factors were tested as predictors of tumor control and patient survival. RESULTS: The median follow-up time was 18 mo. Among the parameters examined, T SUV max and CT/(18)F-FDG PET score were significantly correlated with tumor control. T SUV max with a cutoff value of 3.2 was the most significant prognostic indicator. The 4-y control rate was 86.2% in tumors with a T SUV max of 3.2 or less but only 37.5% in those with a T SUV max of more than 3.2 (adjusted hazard ratio, 9.40; 95% confidence interval, 1.18-74.76; P = 0.034). CT/(18)F-FDG PET score (≤ 4 vs. >4) was also a significant predictor of tumor control after SABR. Tumors with a CT/(18)F-FDG PET score of more than 4 had a 5.23-fold risk of tumor failure. After adjustment for factors of sex, American Joint Committee on Cancer stage, Cancer of the Liver Italian Program score, and Child-Pugh classification, tumors with a score of more than 4 had a 4.96-fold risk of failure after SABR, compared with tumors with a score of 4 or less. For overall survival, none was statistically significant. CONCLUSION: The use of (18)F FDG PET to predict tumor control is feasible. T SUV max with a cutoff value of 3.2 is the best prognostic indicator. We suggest that (18)F-FDG PET may be a reference for prognostic prediction, patient selection, and radiation dose adjustment for HCC patients treated with SABR.
Chang CH, Lin JW, Wu LC, et al. National antiviral treatment program and the incidence of hepatocellular carcinoma and associated mortality in Taiwan: a preliminary report. Med Care. 2013; 51(10):908-13 [PubMed] Related Publications
BACKGROUND: Taiwan's Bureau of National Health Insurance launched the National Antiviral Treatment Program (NATP) in 2003 to reimburse patients for antiviral drugs and interferons for chronic hepatitis B and C. The objective was to examine the impact of the NATP on the incidence and mortality due to hepatocellular carcinoma (HCC). METHODS: The cumulative numbers of NATP participants were retrieved from the National Health Insurance claims database. The national incidence and mortality rates of HCC were obtained from the Taiwan Cancer Registry in each quarter from 1979 to 2009. An interrupted time-series analysis was applied to test the temporal trend change before and after NATP. RESULTS: From 1979 to 1995, the HCC incidence increased in men and women of all age groups. From 2003 to 2009, 31,155 men and 10,769 women received anti-hepatitis B virus therapy, whereas 13,939 men and 10,721 women received anti-hepatitis C virus therapy. The incidence of HCC reached a plateau and then started to decline in men aged 30-39 (slope change P=0.003), 50-59 (P=0.051), and 60-69 years (P<0.001). A similar trend was noted in women aged 50-59 (P=0.035), 60-69 (P=0.006), and 70-79 years (P=0.052). The HCC mortality rate had been decreasing since 1996 and a further decline was observed after 2004 in men aged 60-69 years and women aged 60-79 years. CONCLUSIONS: There is a strong temporal relationship between NATP and the stabilization of the HCC incidence and related mortality. The cost-effectiveness of the NATP needs further evaluation.
Wang J, Li J, Wang X, et al. Downregulation of microRNA-214 and overexpression of FGFR-1 contribute to hepatocellular carcinoma metastasis. Biochem Biophys Res Commun. 2013; 439(1):47-53 [PubMed] Related Publications
miR-214 is one of the most significantly downregulated microRNAs (miRNAs) in hepatocellular carcinoma (HCC). Fibroblast growth factor receptor 1 (FGFR-1) is a miR-214 target gene implicated in the progression of HCC. However, the roles of miR-214 and FGFR-1 in HCC are not fully understood. Here, we analyzed the expression of miR-214 and FGFR-1 in 65 cases of HCC and paired non-neoplastic tissue specimens using real-time PCR and Western blot (WB), respectively. Our data indicated that miR-214 was downregulated and FGFR-1 was overexpressed in HCC compared to the paired non-neoplastic tissues. The low miR-214 expression was correlated with portal vein invasion (p=0.016) and early recurrence (p=0.045) in HCC patients. Moreover, the low miR-214 expression was correlated with high positive rate of FGFR-1 in HCC cases (p=0.020). Our data further demonstrated that miR-214 overexpression in SK-HEP1 and HepG2 cells downregulated FGFR-1 expression and inhibited liver cancer cell invasion. The Luciferase assay results further demonstrated the targeted regulation of FGFR-1 by miR-214. In conclusion, our data indicate that the downregulation of miR-214 in HCC and the upregulation of its target gene FGFR-1 is associated with HCC progression. Therefore, miR-214 and FGFR-1 are potential prognostic markers and therapeutic targets in HCC.
Uchino K, Fujisawa M, Watanabe T, et al. Oxaliplatin-induced liver injury mimicking metastatic tumor on images: a case report. Jpn J Clin Oncol. 2013; 43(10):1034-8 [PubMed] Related Publications
Oxaliplatin-based chemotherapy is widely used for advanced colorectal cancer treatment, but it occasionally induces liver injury that is characterized histologically by sinusoidal dilatation, hepatic plate atrophy and/or venular obstruction. Most of the patients do not reveal apparent radiological abnormalities, however. Here, we report the case of a 47-year-old man with a radiologically detectable mass-forming oxaliplatin-induced sinusoidal injury that mimicked multiple liver tumors. These mass lesions were found on computed tomography images after the administration of six cycles of folinic acid, fluorouracil and oxaliplatin therapy as adjuvant chemotherapy for Stage III rectal cancer. The patient had to undergo liver resection because imaging studies could not exclude metastases. The histological examination revealed that a resected mass lesion was composed of severe sinusoidal dilatation. Milder dilatation was also seen in the surrounding parenchyma. We diagnosed the patient as having an oxaliplatin-induced sinusoidal injury with severe deviation. As oxaliplatin is a standard agent in colorectal cancer therapy today, all clinicians and pathologists should be aware of such non-neoplastic lesions as one of the rare differential diagnoses of metastatic liver tumor, to prevent overtreatment.
Chi HC, Liao CH, Huang YH, et al. Thyroid hormone receptor inhibits hepatoma cell migration through transcriptional activation of Dickkopf 4. Biochem Biophys Res Commun. 2013; 439(1):60-5 [PubMed] Related Publications
Triiodothyronine (T3) is a potent form of thyroid hormone mediates several physiological processes including cellular growth, development, and differentiation via binding to the nuclear thyroid hormone receptor (TR). Recent studies have demonstrated critical roles of T3/TR in tumor progression. Moreover, long-term hypothyroidism appears to be associated with the incidence of human hepatocellular carcinoma (HCC), independent of other major HCC risk factors. Dickkopf (DKK) 4, a secreted protein that antagonizes the canonical Wnt signaling pathway, is induced by T3 at both mRNA and protein levels in HCC cell lines. However, the mechanism underlying T3-mediated regulation of DKK4 remains unknown. In the present study, the 5' promoter region of DKK4 was serially deleted, and the reporter assay performed to localize the T3 response element (TRE). Consequently, we identified an atypical direct repeat TRE between nucleotides -1645 and -1629 conferring T3 responsiveness to the DKK4 gene. This region was further validated using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA). Stable DKK4 overexpression in SK-Hep-1 cells suppressed cell invasion and metastatic potential, both in vivo andin vitro, via reduction of matrix metalloproteinase-2 (MMP-2) expression. Our findings collectively suggest that DKK4 upregulated by T3/TR antagonizes the Wnt signal pathway to suppress tumor cell progression, thus providing new insights into the molecular mechanism underlying thyroid hormone activity in HCC.
Ikeda H, Harada K, Sato Y, et al. Clinicopathologic significance of combined hepatocellular-cholangiocarcinoma with stem cell subtype components with reference to the expression of putative stem cell markers. Am J Clin Pathol. 2013; 140(3):329-40 [PubMed] Related Publications
OBJECTIVES: To examine the clinicopathologic features of combined hepatocellular-cholangiocarcinoma (HC-CC), which the World Health Organization (WHO) proposed classifying into 2 types, and the expression of delta-like 1 homolog (DLK1), as well as putative stem cell markers, such as NCAM/CD56 and CD133. METHODS: In this study we examined the expression of stem cell markers using immunohistochemistry. RESULTS: Thirty-six cases of combined HC-CC were subclassified into 24 cases, with more than 5% stem cell features (group B) and 12 cases with less than 5% stem cell areas (group A). The postoperative overall survival rate was worse for group B than for group A. DLK1 was frequently expressed in group B cases compared with group A, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma cases. CONCLUSIONS: The 2010 WHO classification seems important for elucidating the pathogenesis of stem cell-related liver cancers.
Data on the risk of hepatocellular carcinoma in interferon-treated patients with chronic hepatitis C participating in placebo-controlled trials of interferon have been published after 3 to 9 years of follow-up. Among patients with chronic hepatitis C and either fibrosis or cirrhosis, interferon greatly reduced the risk of hepatocellular carcinoma after 8 years or more, especially when viral load was below the limit of detection.
Breunig IM, Shaya FT, Hanna N, et al. Transarterial chemoembolization treatment: association between multiple treatments, cumulative expenditures, and survival. Value Health. 2013 Jul-Aug; 16(5):760-8 [PubMed] Related Publications
OBJECTIVES: To examine cumulative survival and Medicaid-paid expenses associated with multiple courses of transarterial chemoembolization (TACE) as primary treatment for hepatocellular carcinoma (HCC). METHODS: Medicare enrollees diagnosed with primary HCC from 2000 to 2007, ever treated with TACE, but not transplant/resection, followed through 2009 by using the Surveillance, Epidemiology and End-Results Program and linked Medicare databases. Cumulative all-cause/HCC-related survival was estimated by using multivariate Cox proportional hazards models stratified by the total number of TACE treatments. Multivariate weighted Cox regressions estimated the average risk of mortality faced with nonproportional hazards. Lin's inverse probability-weighted least squares regression method estimated cumulative Medicare expenditures adjusted for censoring and covariates. RESULTS: Of 1228 patients, 34% were stage 1, 16% stage 2, 19% stage 3, 6% stage 4, and 26% unstaged. About 44% were aged 65 to 75 years, 69% were men, and 72% were Caucasian. Over half (57%) of the patients received one course, 24% two, 11% three, and 8% four courses of TACE. One-course patients incurred an average $74,788 (95% confidence interval [CI] $71,890-$77,686), two-course patients $101,126 (95% CI $94,395-$107,856), three-course patients $111,776 (95% CI $101,931-$121,621), and four-plus-course patients $148,878 (95% CI $136,346-$161,409). One-course patients lived (all-cause) an average 1.86 (95% CI 1.82-1.90), two-course patients 2.09 (95% CI 2.05-2.13), three-course patients 2.81 (95% CI 2.66-2.97), and four-plus-course patients 3.06 (95% CI 2.95-3.18) years after diagnosis. Average risk of all-cause mortality was not significantly different between one/two courses or three/four-plus courses. CONCLUSIONS: Cumulative Medicare expenditures nearly doubled from one-course to four-plus-course patients. On average, four-plus-course patients lived over one more year than did one-course patients. Physician/patient decisions should be balanced with consideration of efficient use of limited resources, but payer's intervention in physician discretion may not be important in this setting.
Takeda S, Liu H, Sasagawa S, et al. HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma. J Clin Invest. 2013; 123(7):3154-65 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
HGF signals through its cognate receptor, MET, to orchestrate diverse biological processes, including cell proliferation, cell fate specification, organogenesis, and epithelial-mesenchymal transition. Mixed-lineage leukemia (MLL), an epigenetic regulator, plays critical roles in cell fate, stem cell, and cell cycle decisions. Here, we describe a role for MLL in the HGF-MET signaling pathway. We found a shared phenotype among Mll(-/-), Hgf(-/-), and Met(-/-) mice with common cranial nerve XII (CNXII) outgrowth and myoblast migration defects. Phenotypic analysis demonstrated that MLL was required for HGF-induced invasion and metastatic growth of hepatocellular carcinoma cell lines. HGF-MET signaling resulted in the accumulation of ETS2, which interacted with MLL to transactivate MMP1 and MMP3. ChIP assays demonstrated that activation of the HGF-MET pathway resulted in increased occupancy of the MLL-ETS2 complex on MMP1 and MMP3 promoters, where MLL trimethylated histone H3 lysine 4 (H3K4), activating transcription. Our results present an epigenetic link between MLL and the HGF-MET signaling pathway, which may suggest new strategies for therapeutic intervention.
Marquardt JU, Thorgeirsson SS Linking MLL and the HGF-MET signaling pathway in liver cancer. J Clin Invest. 2013; 123(7):2780-3 [PubMed] Article available free on PMC after 01/01/2014 Related Publications
Mixed-lineage leukemia (MLL; also known as myeloid/lymphoid), the human homolog of trithorax in Drosophila, is a transcriptional coactivator that plays an essential role during early development and hematopoiesis. Furthermore, MLL is critically involved in the epigenetic regulation of cell cycle, senescence, DNA damage, and stem cell self-renewal. Chromosomal aberrations of MLL in acute leukemias are well documented, but the role of this gene in solid malignancies remains unclear. In this issue of the JCI, Takeda et al. describe a novel epigenetic link between MLL and the HGF-MET signaling pathway conferring invasive and metastatic properties to hepatocellular carcinoma cells.
Shu G, Mi X, Cai J, et al. Brucine, an alkaloid from seeds of Strychnos nux-vomica Linn., represses hepatocellular carcinoma cell migration and metastasis: the role of hypoxia inducible factor 1 pathway. Toxicol Lett. 2013; 222(2):91-101 [PubMed] Related Publications
Brucine is an alkaloid derived from the seeds of Strychnos nux-vomica Linn. which have long been used as a traditional medicine for the treatment of hepatocellular carcinoma (HCC) in China. HCC prognosis can be greatly influenced by metastasis. There has thus far been little research into brucine as a source of anti-metastasis activity against HCC. In this study, we revealed that brucine dramatically repressed HepG2 and SMMC-7721 HCC cell migration with few cytotoxic effects. Hypoxia inducible factor 1 (HIF-1) is a key transcription factor mediating cell migration and invasion. Brucine suppressed HIF-1-dependent luciferase activity in HepG2 cells. The transcriptions of four known HIF-1 target genes involved in HCC metastasis, i.e., fibronectin, matrix metallopeptidase 2, lysyl oxidase, and cathepsin D, were also attenuated after brucine treatment. Experiments in vivo showed that an intraperitoneal injection of 5 and 15 mg/kg of brucine resulted in dose-dependent decreases in the lung metastasis of H22 ascitic hepatoma cells. Moreover, a dosage of brucine at 15 mg/kg exhibited very low toxic effects to tumor-bearing mice. Consistently, brucine downregulated expression levels of HIF-1 responsive genes in vivo. Our current study demonstrated the capacity of brucine in suppressing HCC cell migration in vitro and lung metastasis in vivo. The inhibition of the HIF-1 pathway is implicated in the anti-metastasis activity of brucine.
Zeeneldin AA, Salem SE, Tabashy RH, et al. Transarterial chemoembolization for the treatment of hepatocellular carcinoma: a single center experience including 221 patients. J Egypt Natl Canc Inst. 2013; 25(3):143-50 [PubMed] Related Publications
BACKGROUND: Hepatocelluar carcinoma (HCC) is a major health problem in Egypt as well as in many countries. Transarterial chemoemoblization (TACE) is a treatment modality applicable to locally advanced HCC beyond surgery or ablative therapies and is associated with survival improvements. The aim of this study was to assess the outcomes of TACE in our center over the past four years. METHODS: This is a retrospective cohort study that included 221 patients with locally advanced HCC treated with TACE in a single center between the years 2007 and 2010. The median age was 57 years with male predominance. Liver cirrhosis, viral hepatitis and Bilharziasis were encountered in 64%, 31% and 8% of patients, respectively. Abdominal pain was the most common presenting symptom (67%). Most cases were diagnosed based on radiology (57%) with a TNM stage I or II (73%) and a median AFP value of 150 ng/mL. RESULTS: 221 patients received 440 cycles of TACE with a median of 2 cycles per patient. Cisplatin and doxorubicin (50mg per cycle, each) were the most commonly used drugs. Impaired liver function was the most common toxicity. Liver cell failure occurred in 17% of patients. An objective tumor response was achieved in 44% of cases. The median overall survival (OS) was 16 months (95% CI, 13-19 months) and the median progression free survival (PFS) was 6 months (95% CI, 4.3-7.8 months). Responding patients, Child-Pugh class A and patients receiving standard doses of chemotherapy had a significantly better OS than their counterparts. Only Child-Pugh class A was associated with significantly longer PFS (p < 0.001). CONCLUSION: TACE produces reasonable responses and fair survival rates in locally advanced HCC but with noticeable toxicities. Proper patients' selection and prompt liver support are mandates for improving TACE outcomes.
Ichikawa T, Okada M, Kondo H, et al. Recommended iodine dose for multiphasic contrast-enhanced mutidetector-row computed tomography imaging of liver for assessing hypervascular hepatocellular carcinoma: multicenter prospective study in 77 general hospitals in Japan. Acad Radiol. 2013; 20(9):1130-6 [PubMed] Related Publications
RATIONALE AND OBJECTIVES: To determine the recommended iodine dose of contrast material (CM) for hepatic arterial-dominant phase (HAP) and hepatic parenchymal phase (HPP) imaging to assess hypervascular hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This was a prospective study including 348 patients with hypervascular HCC in 77 hospitals as a postmarketing surveillance to investigate the effects of body weight-tailored dose of CM (300 mgI/mL of iohexol) for hepatic multiphasic contrast-enhanced multidetector-row computed tomography imaging. Informed consent was obtained from all patients who were enrolled. The tumor-to-liver contrast (TLC) of HAP images was assessed qualitatively (QL-TLC) and quantitatively (QT-TLC [HU]; computed tomography [CT] value of tumor-CT value of hepatic parenchyma). Minimal and sufficient QT-TLC were defined as CT values corresponding to the median and 75% of QL-TLC assigned with "good," respectively. The recommended iodine dose was estimated by the relationship between iodine dose (mgI/kg) and QT-TLC. RESULTS: There was a good correlation between QL-TLC and QT-TLC. The recommended iodine dose of CM for HAP imaging was considered to be in the range of 567-647 mgI/kg based on minimal (33.7 HU) and sufficient QT-TLC (40.9 HU). Meanwhile, the recommended dose of CM for HPP imaging was 572 mgI/kg as a dose that gives hepatic enhancement more than 50 HU during HPP imaging. CONCLUSIONS: The recommended iodine dose of CM for HAP and HPP imaging may be different, being 567-647 mgI/kg and 572 mgI/kg, respectively, in assessing hypervascular HCC.
Worku M, Andreson B, Abdurahman Z, et al. A review of a five (5) years experience (Sept. 2004-Aug. 2009) with hepatic resections at Gondar University Hospital (GUH). Ethiop Med J. 2013; 51(1):59-65 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Many patients with benign and malignant hepatobiliary disease have been referred to the surgical outpatient department (OPD) of GUH. Hepatic resection is appropriate treatment for a variety of benign or malignant primary or secondary liver tumors. However, hepatobiliary neoplasms present a surgical management challenge and experience in the effective surgical management of these conditions has been generally lacking in the country. Few patients have been offered resection for liver tumors at GUH. The resections reported here represent the first set of cases from GUH and probably from any other institution in Ethiopia. This review summarizes a five year experience in hepatic resection procedures at GUH. Patients' charts and operating room logbooks, as well as the follow up notes of the senior surgeons were reviewed. Nine tumor resections (major, minor and enucleations) were done. There were two deaths; one from sepsis and the other from an acute cardiopulmonary event. We believe that in carefully selected patients hepatic resection is possible in facilities such as GUH and generally offers the best opportunity for long-term palliation and survival. At laparotomy general abdominal examination is a crucial step and should be routinely undertaken prior to hepatic resection.
Yang T, Zheng ZM, Li XN, et al. MiR-223 modulates multidrug resistance via downregulation of ABCB1 in hepatocellular carcinoma cells. Exp Biol Med (Maywood). 2013; 238(9):1024-32 [PubMed] Related Publications
Multidrug resistance (MDR) has become a major impediment to a successful treatment for liver cancer patients, and one of the common reasons for MDR is the activation of ABCB1 gene, leading to the over-expression of P-glycoprotein (P-gp), which conferred cancer cells be resistant to a broad range of anticancer drugs. MicroRNAs (miRNAs) are a class of short, non-coding RNA moleculars that can regulate gene expression at the post-transcriptional level. In the current study, the aim is to explore whether miRNA participates in the regulation of MDR mediated by ABCB1. We found that the expression of ABCB1 was correlated with the doxorubicin IC50 dose in eight hepatocellular carcinoma (HCC) cell lines: Hep3B, HCC3, LM-6, SMMC7721, Huh-7, SK-Hep-1, HepG2 and BEL-7402. Using the bioinformatics, we discovered that there were several miRNAs that can bind to the 3'UTR of ABCB1 gene. Among these candidate miRNAs, miR-223 was chosen for further study. Then, EGFP reporter assay, real-time PCR and Western blot were performed to verify that miR-223 targeted ABCB1 3'UTR directly, and miR-223 downregulated ABCB1 at both mRNA and protein levels. Finally, we found that the over-expression of miR-223 increased the HCC cell sensitivity to anticancer drugs, and the inhibition of miR-223 had the opposite effect. Importantly, the over-expression or silencing of ABCB1 can rescue the cell response to the anticancer drugs mediated by miR-223 over-expression or inhibition, respectively. In conclusion, our findings indicated that miR-223 played an important role in the regulation of MDR mediated by ABCB1, and it suggests that miR-223 may be considered as a therapeutic biomarker for HCC patients who had MDR problems induced by high expression of ABCB1.
Zhu X, Dai Y, Chen Z, et al. Knockdown of Pokemon protein expression inhibits hepatocellular carcinoma cell proliferation by suppression of AKT activity. Oncol Res. 2013; 20(8):377-81 [PubMed] Related Publications
Overexpression of Pokemon, which is an erythroid myeloid ontogenic factor protein, occurs in different cancers, including hepatocellular carcinoma (HCC). Pokemon is also reported to have an oncogenic activity in various human cancers. This study investigated the effect of Pokemon knockdown on the regulation of HCC growth. POK shRNA suppressed the expression of Pokemon protein in HepG2 cells compared to the negative control vector-transfected HCC cells. Pokemon knockdown also reduced HCC cell viability and enhanced cisplatin-induced apoptosis in HCC cells. AKT activation and the expression of various cell cycle-related genes were inhibited following Pokemon knockdown. These data demonstrate that Pokemon may play a role in HCC progression, suggesting that inhibition of Pokemon expression using Pokemon shRNA should be further evaluated as a novel target for the control of HCC.
Tian F, Liu C, Wu Q, et al. Upregulation of glycoprotein nonmetastatic B by colony-stimulating factor-1 and epithelial cell adhesion molecule in hepatocellular carcinoma cells. Oncol Res. 2013; 20(8):341-50 [PubMed] Related Publications
Considerable effort has been made in elucidating the appropriate biomarkers and the mechanism and functional significance of these biomarkers in hepatocellular carcinoma (HCC). Glycoprotein nonmetastatic B (GPNMB) overexpression occurs in cutaneous melanomas and breast cancer, and it is an attractive candidate for cancer therapy. However, little is known about the expression and regulation of GPNMB in HCC. In this study, we investigated the expression of GPNMB in HCC histochemically and tested the regulation effects of the epithelial cell adhesion molecule (EpCAM) and colony-stimulating factor (CSF-1) on the expression of GPNMB in HCC cells. Our results demonstrated that GPNMB levels were significantly enhanced in HCC compared with adjacent normal liver tissues. In HCC cells, GPNMB expression was regulated by EpCAM and CSF-1 partly through their common downstream product c-myc. Taken together, these results suggest that GPNMB, the expression of which was regulated in HCC cells by the highly coordinated function of various proteins, may be a potential target for HCC therapy.
Occult hepatitis B infection is defined as the presence of HBV DNA in serum and/or the liver tissue without detectable HBsAg with or without anti-HBc or anti-HBs antibodies. In Egypt many studies on occult hepatitis B have been conducted and this infection is well established in various patients groups. This short review sheds light on the occurrence of occult hepatitis B infection among different disease states in Egypt. The coexistence of occult hepatitis B with hepatitis C infection is of particular importance because of its added co-morbidity of liver enzymes elevation, increased severity of liver disease and increased risk of hepatocellular carcinoma. Patients on regular hemodialysis and those exposed to blood transfusion are at high risk of acquiring this form of infection. The highest prevalence of occult hepatitis B virus in Egypt was reported among patients with hepatocellular carcinoma and similar to the scenario for classic hepatitis B infection, genotype D is the most prevalent genotype.