Hepatocellular carcinoma (HCC) arising in non-cirrhotic livers is relatively rare. Compared with HCC arising in cirrhotic livers they have some quirks. HCC in healthy livers are large tumors at diagnosis, and are detected due to the onset of abdominal symptoms, outside of any scheduled monitoring program. In non-cirrhotic patients, HCC has the same appearance as the classic image of cirrhotic HCC substrate. The presence of capsule, extensive intratumoral necrosis and typical behavior in the dynamic study after administration of intravenous contrast are present in most of the non-cirrhotic livers. In the presence of a suspicious lesion of HCC, we must assess the existence of underlying chronic liver disease. Ultrasound, computed tomography, and conventional magnetic resonance are imaging techniques that have a high specificity for the diagnosis of cirrhosis, but exhibit low sensitivity for diagnosis in the early stages of the disease. In recent years, new imaging methods are being developed to assess emerging liver fibrosis. In particular, in patients without chronic liver disease it is imperative to consider the differential diagnosis with other tumors that may settle in healthy livers with similar radiological characteristics as HCC. Therefore, in the presence of a lesion with pathognomonic radiological characteristics of HCC in the absence of cirrhosis, biopsy is required.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the incidence is higher in cirrhosis. Treatment options depend on tumor stage, status of liver function, and the general condition of the patient. Major vascular invasion is a contraindication for liver transplantation. Sorafenib has been found to be useful in association with transarterial chemoembolization as an effective chemotherapeutic agent to prolong survival in inoperable HCCs. Here we describe our experience where sorafenib was used as palliation but later turned out to be a neoadjuvant. Both cases had major portal vein thrombosis and received sorafenib as palliative therapy. After a mean use of 6 months, both patients had marked tumor response and proceeded to have liver transplantations. Both cases are tumor-free at a median follow up of 13 months.
An important limitation for the success of chemotherapy in the treatment of primary liver cancer (hepatocellular carcinoma, hepatoblastoma and cholangiocarcinoma) is the marked efficacy of mechanisms of chemoresistance (MOC). These have been previously classified into five groups depending on whether they result in: a reduced drug uptake or enhanced drug export (MOC-1); poor intracellular activation of prodrugs or higher inactivation of active drugs (MOC-2); changes in the molecular targets that impairs the action of the drug by increasing the activity of the metabolic route to be inhibited or stimulating alternative routes (MOC-3); ability of tumor cells to repair drug-induced modifications in the target molecule, usually DNA (MOC-4); and the activation or inhibition of intracellular signaling pathways that lead to a change in the balance between pro- and anti-apoptotic factors favoring tumor cell survival (MOC-5). Nevertheless, novel information appeared over the last few years has recommended to consider two additional groups, MOC-6 and MOC-7, based on changes in tumor microenvironment, mainly hypoxia and acidity, and epithelial-mesenchymal transition, respectively. These contribute to the defensive armamentaria developed or enhanced in liver cancer cells to resist the pharmacological attack, which accounts for a negligible beneficial effect of commonly used antitumor drugs and only a modest response to novel targeted therapies based on tyrosine kinase inhibitors, such as sorafenib. Therefore, further advances are urgently needed to better understand the molecular and cellular bases of the chemoresistant barrier and help scientists in this field to develop new tools able to overcome cancer cell defenses.
Aim: Oxidative damage of cellular components by free radicals and other reactive oxygen molecules is believed to be associated with the development of degenerative diseases. The aim of the present study was to evaluate the antioxidant capacity and free radical scavenging activity of cape gooseberry juice (CGJ) in diethylnitrosamine-(DENA) and CCl4 (3 mL/kg b.w.)-induced hepatocellular carcinoma (HCC) rats model.
Methods: The rats were divided into 4 groups (6 rats each group). Group 1 (control): the rats of this group did not receive any treatments; group 2 (CGJ): rats were daily administered cape gooseberry juice at a dose of 1 mL/kg b.w.; group 3 (HCC): the rats treated with a single intraperitoneal injection of fresh DENA (200 mg/kg body weight) and received a subcutaneous injection of CCl4 (3 mL/kg/week); group 4: (HCC + CGJ): rats were treated with DENA (200 mg/kg b.w.) and CCl4 (3 mL/kg b.w. per week) in addition to daily administered cape gooseberry juice at a dose of 1 mL/kg b.w.
Results: Treatment with DENA plus CCl4 induced a significant increase in tumor marker level, alpha-fetoprotein level, and liver function enzymes activity as well as elevated levels of malondialdehyde. This suggests oxidative stress accompanied with a significant decrease in antioxidant biomarkers including glutathione, total antioxidant capacity, superoxide dismutase and catalase in the examined tissues. However, the administration of GGJ could reduce these changes to control levels.
Conclusion: CGJ is a promising candidate as a free radical scavenger and antioxidant processor in an HCC rats model. This beneficial effect was achieved by antagonizing free radicals generation and the enhancement of the antioxidant defense mechanisms, resulting in marked improvement of hepatic biomarkers.
Aim: To investigate the correlation of p53 and prohibitin (PHB) expression in the spectrum of hepatitis, cirrhosis, and human hepatocellular carcinoma (HCC).
Methods: Hepatic biopsies from patients with HCC (n = 60), cirrhosis (CIR, n = 30), hepatitis C virus (HCV, n = 30), and normal livers (NL, n = 20) were examined for immunohistochemical expression of RelA/p65, tumor necrosis factor receptor-1 (TNFR1), TNF-related apoptosis-inducing ligand (TRAIL), p53, and PHB. The samples were also analysed by nuclear factor kappa B (NFκB) Southwestern histochemistry and a transferase-mediated dUTP-biotin nick-end labelling assay.
Results: Expression of NFκB and RelA/p65 was detected increasingly from NL to CIR, but had a diminished labelling in the HCC cases (P < 0.05). Expression levels of TNFR1 and TRAIL followed the same pattern (P < 0.05). Apoptosis was increased in HCC, but was progressively reduced from CIR to NL (P < 0.05). p53 and PHB nuclear expressions were amplified in cases of HCC, but diminished in NL, HCV, and CIR (P < 0.05).
Conclusion: These results suggest that in addition to well-understood sequences of proinflammatory events such as TNF-induced NFκB activation and NFκB/TRAIL pathway-mediated apoptosis, development of HCC is also influenced by regulation of p53 and PHB tumour suppressor function. Additional studies are necessary to explain the contradictory mechanisms of the tumour microenvironment observed in the sequence of HCV, CIR, and HCC.
Systemic therapy for hepatocellular carcinoma (HCC) has been disappointing. The only drug approved by Food and Drug Administration recently has been sorafenib. Sorafenib has modest benefits with a low response rate and an improvement in time to progression of only 2-3 months. Multiple randomized trials, which compare the new agent to sorafenib as either first line or second line therapy, have been negative, showing no improved clinical benefit. Recently, in a large phase III randomized trial, regorafenib has shown superiority to placebo as a second line treatment for HCC. However, this drug has multiple side effects and is not well tolerated by many patients. The clinical benefit is also modest. Clearly, new approaches to treat advanced HCC are still needed. There is data showing that HCC is immunogenic and the immune system can be stimulated to attack these cancer cells. This article will briefly review immunotherapy as a promising treatment for HCC.
Aim: Sorafenib is a multi-tyrosine kinase inhibitor and the standard therapy for advanced hepatocellular carcinoma (HCC). This retrospective study aimed to observe the anti-fibrotic effect of sorafenib in patients with advanced HCC.
Methods: Seventeen patients with advanced HCC were recruited. Shear wave velocity (SWV) using acoustic radiation force impulse elastography and non-invasive serum markers for liver fibrosis, such as the aspartate aminotransferase (AST) to alanine aminotransferase ratio (AAR), the AST to platelet ratio index, the fibrosis-4 index and the Lok index, were recorded at the beginning of sorafenib treatment and 3-6 months after sorafenib treatment in 2014-2015.
Results: Nine (52.9%) patients achieved disease control status and 8 had progressive disease after a mean duration of 11.1 months with sorafenib treatment. The mean SWV decreased from 2.37 m/s at the beginning to 1.90 m/s after sorafenib treatment (P < 0.01). This trend was observed in patients with and without liver cirrhosis (from 2.49 to 2.06 m/s, P = 0.06, and from 2.32 to 1.69 m/s, P < 0.05, respectively). Among the non-invasive serum markers, no statistically significant differences were observed except for the AAR in the cirrhotic group.
Conclusion: Sorafenib has potential antif-ibrotic effects in patients with advanced HCC.
Aim: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and liver transplant (LT) prolongs survival. However, 15-20% will experience recurrent HCC, most occurring within 2 years of LT. HCC patients with late recurrences (> 5 years after LT) may have distinctive clinical/biological characteristics.
Methods: A retrospective review was conducted of 88 patients who underwent LT for HCC during 1993-2015, analyzing demographics, clinical factors, explant pathology, and outcome.
Results: Median follow-up was 6.4 years. HCC recurred in 15 (17.0%) patients with mean time to recurrence of 3.96 ± 3.99 years. Five patients reoccurred > 5 years post-LT. All late recurrences involved males in their 50s, recurring at 8.5 years on average. Recurrences occurred in chest wall (2), liver (2), lung (2), bone (1) and pelvis (1), with multifocal involvement in 2 patients. Four patients died within 18 months of late recurrence. The fifth patient is alive after ablation of liver recurrence and treatment with sorafenib and everolimus.
Conclusion: One-third of post-LT patients with recurrent HCC experienced late recurrence. Although the sample size makes it difficult to identify significant risk factors, this study highlights the importance of long-term follow-up and need for biomarkers to identify patients at risk for late recurrences.
Hepatorenal syndrome is not an uncommon life-threatening complication arising from liver cirrhosis. The diagnostic criteria for this syndrome have been revised throughout the years, with recent revisions aimed at improving earlier diagnosis and treatment. Liver transplantation remains the only definitive treatment for hepatorenal syndrome. Due to the scarcity of liver grafts, many patients die waiting. This review focuses on the different strategies to bridge patients to liver transplantation and to improve the postoperative outcome.
It is now widely accepted that lymphoma is a cancer of the lymphatic cells in the immune system and a type of blood cancer that develops when T or B lymphocytes of the white blood cells display uncontrolled proliferation and cellular immortality. Currently, a number of authors have published case reports or case series in which these lesions are defined as primary hepatic lymphoma. This minireview discusses several aspects of the entity of primary hepatic lymphoma, especially the dilemmas in diagnosis.
Aim: Liver transplantation (LT) is the most effective treatment for long-term survival from hepatocellular carcinoma (HCC); however, insufficient donors limit therapy. The authors sought to identify characteristics that predicted long-term survival after non-transplant therapies in patients with small HCC.
Methods: In a database of 1,050 HCC patients, the authors identified those with single HCC ≤ 3.0 cm, who underwent hepatic resection (HR, n = 16), radiofrequency ablation (RFA, n = 55), or LT (n = 23) with 5-year follow-up. Overall survival (OS) and odds-ratios (OR) for survival after HR/RFA were calculated for MELD score, platelet count, creatinine, albumin, AST/platelet ratio index (APRI), international normalized ratio, and bilirubin.
Results: LT patients had 3- and 5-year OS of 82.6% and 73.9% compared to HR/RFA patients with 3- and 5-year OS of 40.8% and 33.8%. The strongest predictors of survival after HR/RFA were MELD < 10 [OR 4.43, 95% confidence interval (CI) 1.85-10.58] and APRI ≤ 0.5 (OR 4.25, 95% CI 1.63-11.08). HR/RFA patients with both MELD < 10 and APRI ≤ 0.5 had 3- and 5-year OS of 77.3% and 72.7%.
Conclusion: Patients with MELD < 10 and APRI ≤ 0.5 who undergo HR/RFA have survival approaching LT. Perhaps patients who meet these criteria can safely undergo non-transplant therapy and donor livers can be allocated to patients with a greater need.
Post-transplantation malignancies are well known complications after liver transplantation. Certain malignancies are more common in pediatric recipients than adults. Inflammatory myofibroblastic tumors (IMTs) are reactive neoplasms with miniscule malignant potential. IMTs are more common after hematopoietic stem cell transplantation. However, there is 1 case reported in the literature after deceased donor liver transplantation. The authors describe a case of IMT after living donor liver transplantation. The patient was a 1-year-old girl who underwent living donor liver transplantation (LDLT) for decompensated cirrhosis secondary to extra hepatic biliary atresia. Six months post LDLT routine ultrasonography revealed multiple solid abdominal masses. Repeated biopsies were inconclusive. Hence surgical excision was carried out. Histopathological examination revealed IMT. Immunohistochemistry was positive for anaplastic-lymphoma kinase activity. Ceritinib, a tyrosine kinase inhibitor, was used as adjuvant chemotherapy for 1 year. At 1.5 years (at the time of writing this paper) of follow-up, the child was disease free on imaging (whole body positron emission tomography-computed tomography). This will be the first case of IMT after LDLT to be reported in the literature.
Liver cancer remains one of the most common human cancers with a high mortality rate. Therapies for hepatocellular carcinoma (HCC) remain ineffective, due to the heterogeneity of HCC with regard to both the etiology and mutation spectrum, as well as its chemotherapy resistant nature; thus surgical resection and liver transplantation remain the gold standard of patient care. The most common etiologies of HCC are extrinsic factors. Humans have multiple defense mechanisms against extrinsic factor-induced carcinogenesis, of which tumor suppressors play crucial roles in preventing normal cells from becoming cancerous. The tumor suppressor p53 is one of the most frequently mutated genes in liver cancer. p53 regulates expression of genes involved in cell cycle progression, cell death, and cellular metabolism to avert tumor development due to carcinogens. This review article mainly summarizes extrinsic factors that induce liver cancer and potentially have etiological association with p53, including aflatoxin B1, vinyl chloride, non-alcoholic fatty liver disease, iron overload, and infection of hepatitis viruses.
Aim: This study aimed to explore the potential of detecting hepatocellular carcinoma (HCC)-associated DNA markers, TP53 249T mutations and aberrant methylation of RASSF1A and GSTP1 genes, for monitoring HCC recurrence. HCC remains a leading cause of death worldwide, with one of the fastest growing incidence rates in the US. While treatment options are available and new ones emerging, there remains a poor prognosis of this disease mostly due to its late diagnosis and high recurrence rate. Although there are no specific guidelines addressing how HCC recurrence should be monitored, recurrence is usually monitored by serum-alpha fetal protein and imaging methods such as magnetic resonance imaging (MRI). However, early detection of recurrent HCC remains limited, particularly at the site of treated lesion.
Methods: Here, the authors followed 10 patients that were treated for a primary HCC, and monitored for months or years later. At these follow-up visits, urine was collected and tested retrospectively for 3 DNA biomarkers that associate with HCC development.
Results: This 10-patient study compared detection of urine DNA markers with MRI for monitoring HCC recurrence. Five patients were confirmed by MRI for recurrence, and all 5 had detectable DNA biomarkers up to 9 months before recurrence confirmation by MRI.
Conclusion: Overall, this suggests that detection of HCC-associated DNA markers in urine could provide a promising tool to complement detection of recurrent HCC by imaging.
Over the past few years, despite improvement in screening and diagnosis of hepatocellular carcinoma (HCC), advanced stage remains the most common presentation at diagnosis, with limited management options, especially options available to patients in limited resource countries. There is currently no effective systemic chemotherapy, targeted, or immunologic therapy for advanced stage HCC. Sorafenib is the only approved front-line molecular-targeted treatment,with slight survival benefit. Regorafenib has recently been approved as second line therapy for HCC after failure of sorafenib. Ongoing research on molecular agents targeting different pathways, combination therapies, and immunotherapy, represent hope for new treatment modalities. This manuscript reviews current treatment, ongoing research, and potential future treatments for advanced HCC.
Aim: Gadobenate dimeglumine (multihance) is a contrast medium which can be used not only as an extracellular contrast agent for dynamic imaging of the liver, but also as a liver specific agent for the acquisition of hepatobiliary-phase images which are more helpful in evaluation of small atypical hepatic focal lesions equal or less than 3 cm. The authors tried to evaluate multihance dynamic magnetic resonance imaging (MRI) as a new modality in early detection of hepatocellular carcinoma (HCC).
Methods: Thirty cirrhotic patients with small hepatic focal lesions (less than 3 cm in diameter), detected by imaging (ultrasound and triphasic computed tomography) were subjected to dynamic MRI with multihance contrast. All patients had a liver biopsy stained with heat shock protein 70, glypican 3, and glutamine synthetase to confirm the diagnosis of HCC.
Results: Eight out of 30 patients (26.6%) with atypical focal lesions proved to have HCC by histology, whereas 7 out of 8 histologically proven HCC patients (87.5%) were shown to have typical criteria on Multihance imaging.
Conclusion: Multihance dynamic MRI is a promising diagnostic modality for detection of early HCC, however, future studies on large numbers of patients are warranted to precisely detect the sensitivity and specificity of this new modality.
Hepatocellular carcinoma (HCC) remains a challenging disease with a high recurrence rate after surgery and there is an imminent need to identify new treatments. Currently, adjuvant therapy like chemotherapeutics arises to counteract the malignant trait escaping from apoptosis of tumors induced by overexpressed anti-apoptotic factors in HCC. Myeloid cell leukaemia-1 (Mcl-1) as an anti-apoptotic member of Bcl-2 is highly expressed in diverse human cancers, which contributes to cancer cell survival and the resistance to diverse chemotherapeutic agents. It is confirmed that Mcl-1 protein expression is quite enhanced in human HCC tissue compared to adjacent non-tumor tissue. Correspondingly, forced Mcl-1 down-regulation leads to prominent apoptosis of HCC cells and a sensitization towards chemotherapeutic drug-induced apoptosis, which indicates Mcl-1 is indeed a crucial regulatory factor of HCC. Hence, this review highlights the function of Mcl-1 on HCC progression, how it is regulated in HCC and the recent anti-hepatoma drug research and development down-regulation of Mcl-1 or targeting on Mcl-1. Meanwhile, the authors discuss Mcl-1 as an essential regulatory factor in HCC can be designed as target for drugs to improve the survival of HCC patients.
Aim: The purpose of this study was to evaluate and compare how hepatocellular carcinoma (HCC) and colorectal metastases respond to LC Bead chemoembolization using doxorubicin and irinotecan.
Methods: The authors report their experience with doxorubicin and irinotecan eluting beads to treat 13 patients with primary HCC and 25 patients with colorectal metastases over a 1-year period at a single community based oncology practice. Within the colorectal cancer group they compared irinotecan eluting beads to doxorubicin eluting beads.
Results: Nine of the 11 (81.8%) doxorubicin treated HCC patients had either complete response or partial response. All of the HCC lesions showed reduction in size and tumor enhancement and 10/11 (91%) HCC patients were alive at 24 months post treatment. Fisher’s exact test revealed that among the 22 with colorectal metastases for whom follow-up data were available, those 11 who were treated with doxorubicin were significantly more likely to demonstrate complete or partial response compared to the 11 in the irinotecan treated group (P < 0.001).
Conclusion: Overall, HCC and colon metastasis patients clearly demonstrated the effectiveness of drug eluting beads with 91% of the HCC patients alive 24 months after treatment.
Aim: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the sixth most common cancer worldwide. The resistance to chemotherapy is a major obstacle in the treatment of HCC, necessitating the discovery of additional agents. There is a growing use of anticancer complementary and alternative medicine worldwide. Therefore, the aim of present study was focused on the confirmation of the suitability and validity of the new markers which would be achieved by demonstrating their significant change and reproducible expression during disease and disease management.
Methods: HepG2 cell line was used to provide a source for HCC cells. The cell cultures were divided into 4 groups: control untreated group, 5-fluorouracil (5-FU) treated group as a standard chemotherapy for HCC (positive control) with the following doses (15.625, 31.2, 62.5, 125, 250 µg/mL), Kochia indica extract treated group with the following concentration (12.5, 25, 50, 100, 200 µg/mL) and the group treated with a combination of 5-FU and Kochia indica in different ratios.
Results: Treatment with Kochia indica extract, 5-FU and the combined treatment showed a significant cytotoxicity to HepG2 cells, with different IC50 values, when compared to the control. Regarding toxic effect, 5-FU showed IC50 = 237.56 µg/mL which is lower cytotoxic in compared to Kochia indica with IC50 =120.5 µg/mL. The results also revealed that tumor cells were more resistant to 5-FU. Alternatively, the co-treatment with Kochia indica extract ameliorated the toxicity induced by 5-FU and enhanced its therapeutic potency, either by synergistic effect of both agents and/or due to its flavonoid components that may enhance the physiological properties of the cell membranes, facilitating 5-FU entrance into tumor cells. This decreased its therapeutic dose to less than 250 µg/mL by combination therapy.
Conclusion: Present findings assume that Kochia indica extract co-therapy can ameliorate the side effects of 5-FU on HepG2 by enhancing its cellular uptake.
Liver fibrosis is the center of diagnosis and management of essentially all chronic liver diseases. While liver biopsy examination still has a role in diagnosis and drug development, it is replaced by non-invasive assessments of liver biopsy in majority of the clinical scenarios. Radiological approaches, namely transient elastography, acoustic radiation force impulse imaging, shear wave elastography, magnetic resonance elastography provide accurate diagnosis of advanced fibrosis and cirrhosis. Serum test formulae based on common laboratory parameters or more specialized parameters including those commercially available panels FibroTest®, FibroMeter® and Enhanced Liver Fibrosis are also available. Combining different modalities may further improve the accuracy. The role of all these non-invasive assessments has been further expanded from diagnostic to prognostic, e.g. risk prediction of hepatocellular carcinoma (HCC) by LSM-HCC score. Treatment of liver fibrosis can be achieved by controlling the underlying diseases, with chronic viral hepatitis as the most established disease model. Currently there are multiple clinical trials evaluating different treatment options to improve fibrosis in patients with non-alcoholic fatty liver disease. Specific anti-fibrotic treatment targets e.g. direct downregulation of hepatic stellate cell, collagen synthesis inhibitors and transforming growth factor-β antagonists have been tested in laboratory and pending further studies in clinical settings.
Aim: The short-term perioperative results of laparoscopic treatment of gallbladder (GB) carcinoma were evaluated to determine whether this technique can be a feasible treatment option.
Methods: Ten patients with fundus/body GB tumors (GBTs) underwent laparoscopic liver resection (LLR) and lymph node dissection. Additionally, 124 patients underwent LLR for liver tumors. These 124 LLRs included 79 partial resections (PRs), 11 left lateral sectionectomies (LLSs), 25 anatomical resections (ARs), and 9 small ARs (SARs). The operation time (OT), intraoperative blood loss (BL), and postoperative length of hospital stay (LOS) were compared between the GBT and various LLR groups.
Results: The median (range) OT in the GBT, PR, LLS, AR, and SAR groups was 298 (186-488), 245 (84-700), 328 (150-682), 458 (224-848), and 352 (274-696) min, respectively. The BL was 109 (10-500), 50 (0/uncountable-3,270), 100 (10-516), 375 (25-3,569), and 705 (35-1,920) mL, respectively. The LOS was 16 (8-105), 15 (5-254), 13 (11-52), 22 (8-44), and 15 (8-44) days, respectively. The OT and BL were significantly different between the GBT and AR groups.
Conclusion: Laparoscopic surgery could be a good treatment option for GBTs suspected to be T1b/T2 GB carcinoma in the GB body/fundus without cystic duct invasion.
Egypt had been vexed by the highest load of chronic hepatitis C in the world. It represents a vast market of the new direct-acting anti-viral drugs (DAAs); effectively treating chronic hepatitis C virus (HCV) infection. Eradication of HCV in Egypt has been challenged by the observed increased diagnosis of hepatocellular carcinoma (HCC) in relation to DAAs therapy. This is the first Egyptian report annotating to a series of sixteen chronic HCV infected cases without a diagnosis of HCC before DAAs therapy and unexpected development of HCC during or after completion of DAAs therapy.
Aim: To investigate the survivals and efficacy of the doxorubicin drug eluting beads transcatheter arterial chemoembolization (TACE) in patients with recurrent hepatocellular carcinoma (HCC) status post orthotopic liver transplantation.
Methods: Consecutive patients with HCC who underwent orthotopic liver transplantation from 2005 to 2012 were reviewed. Patients who developed recurrent HCC after orthotopic liver transplantation and received doxorubicin drug eluting beads TACE therapy were identified and included in the study. Survivals were calculated from the time of 1st doxorubicin drug eluting beads TACE of recurrent HCC. Kaplan Meier estimator with log rank test was used for survival analysis.
Results: Eight patients had recurrent HCC after orthotopic liver transplantation and received doxorubicin drug eluting beads TACE. The overall median survival of these patients was 15.6 months. Two patients had significantly poorer overall median survival from doxorubicin drug eluting beads TACE (3.4 months) and both showed elevated serum alpha-fetoprotein levels (> 400 ng/mL) and extra-hepatic metastases (P = 0.03). Patients with poorly differentiated HCC in explant liver had the poor median overall survival (3.6 months) compared to the patients with well-to-moderately differentiated HCC (21.7 months, P = 0.004).
Conclusion: Doxorubicin drug eluting beads TACE appears to be an effective treatment option for patients with recurrent HCC after orthotopic liver transplantation.
In Hong Kong, surgical resection is the core curative treatment for huge and advanced hepatocellular carcinoma (HCC). For tumors measuring 10 cm or above, major hepatectomy is usually required, but a future liver remnant not large enough will preclude the operation. Hypertrophy of future liver remnant is a way to render more patients operable, and measures include portal vein embolization and associating liver partition and portal vein ligation for staged hepatectomy. For HCC that has invaded a major vessel, en bloc resection with immediate vessel reconstruction is necessary if thrombectomy would not suffice. In case of bilobar involvement, radiofrequency ablation is a useful adjuctive therapy. In the treatment of extrahepatic metastasis, metastasectomy offers a cure to properly selected patients.
Aim: The short and long term outcomes of patients who underwent emergency and interval hepatectomy for ruptured and resectable hepatocellular carcinoma (HCC) were analysed.
Methods: The data of patients with ruptured HCC presenting between April 2004 and October 2015 were analysed. Emergency hepatectomy was defined as hepatectomy within 48 h of the clinico-radiological diagnosis of HCC rupture.
Results: Thirty patients underwent hepatectomy for ruptured HCC. Nine (30%) patients underwent emergency hepatectomy. The median age was 56 and 54 years (P = 0.13) with a similar gender distribution. The mean HCC size (10.5 vs. 8.3 cm, P = 0.17), total blood loss (3,000 vs. 850 mL, P = 0.002) and total units of red blood cell transfusion (1.9 vs. 0.5 units, P = 0.27) were greater in the emergency hepatectomy group. The complication rate was 44% and 38% (P = 0.53), with median length of hospital stay of 10 and 12 days (P = 0.07) in the emergency and interval hepatectomy groups, respectively, and no 30-day mortality in both groups. The median overall survival was 29 and 15.7 months (P = 0.25), with survival rates of 78%, 45%, 0% and 85%, 43% and 5% at 1, 3 and 5 years in the emergency and interval hepatectomy groups, respectively.
Conclusion: Hepatectomy should be considered for ruptured HCC provided the patient could tolerate curative resection.
Hepatocellular carcinoma (HCC) represents the 5th commonest malignancy worldwide. Liver transplantation consist a radical and most efficient treatment for HCC. Tumor recurrence or metastases after liver transplantation is not uncommon. Hereby is presented a case of a patient transplanted for alcoholic liver disease and HCC and presented with bone metastases a few months later. Treatment with sorafenib and everolimus showed full regression of the metastases. In conclusion, the point of this report is to advertise a single case of total regression of bone lesions due to HCC recurrence, with the combination of mammalian target of rapamycin and sorafenib, along with radiation.
Aim: The aim was to assess the clinical impact of direct-acting antiviral treatment in patients with compensated hepatitis C virus-related cirrhosis after one year of follow-up.
Methods: An observational retrospective study was conducted on 129 consecutive patients with compensated cirrhosis treated in 2015, analyzing the evolution of liver function and the development of hepatocellular carcinoma and clinical decompensations.
Results: The median follow-up time was 16 months. Most patients were males (73%), the mean age was 58.1 years and the most frequent genotype was 1b (52.2%). All participants were Child-Pugh A class at the start of the treatment and the median model for end-stage liver disease (MELD) score was 7. Four patients (4.4%) suffered a decompensation: three episodes of ascites and one acute on chronic liver failure. The incidence of de novo hepatocellular carcinoma during the follow-up was 3.6%. Seven patients (7.8%) improved MELD score more than one point and in 11 patients (12.2%) it worsened more than one point. There was a significant improvement in the mean platelets count [P < 0.001, 95% confidence interval (CI): -26,360, -12,096] and in the mean albumin levels (P < 0.001, 95% CI: -322, -130) after treatment.
Conclusion: Direct-acting antiviral treatment is not associated in the short term with a decrease in the development of hepatic decompensation or hepatocellular carcinoma compared to what it was reported for untreated compensated cirrhotic patients. There is an improvement in pre and post-treatment platelet counts and albumin levels showing a probable improvement of the hepatic function.
Aim: The development of hepatocellular carcinoma (HCC) is reduced after interferon based treatment in patients with chronic hepatitis C (CHC). A new therapy using direct-acting antiviral agents (DAA) has been widely applied since 2014 for CHC. The purpose of this study is to investigate the efficacy, safety and development of HCC after DAA treatment.
Methods: The authors enrolled 33 consecutive patients who were treated with DAA for CHC at the hospital between January 2015 and March 2016. The laboratory data were collected at the start and 24 weeks after DAA therapy.
Results: The authors analyzed 33 patients (18 male, 15 female, mean age of 68-year-old). The hepatic C virus genotypes were type 1 (27 patients) and type 2 (6 patients). The number of patients treated with sofosbuvir (SOF) + ledipasvir, daclatasvir + asunaprevir and SOF + ribavirin was 14, 13 and 6, respectively. The sustained virological response (SVR24) rate was 100%. Aspartate aminotransferase, alanine aminotransferase and FIB4-index were significantly decreased after SVR24. Adverse effects were observed in 9 patients (anemia, 5; liver function test disorder, 2; sarcoidosis, 1; pruritus, 1). With regard to HCC development, one elderly patient (3.0%) had multiple HCC recurrence after SVR24.
Conclusion: DAA therapy achieved a high SVR24 rate with a good serological response. However, one patient had multiple HCC recurrence. These findings indicate that careful follow-up may be essential after DAA therapy.
The effectiveness of percutaneous interventional radiology for anastomotic stricture in hepatic vein, portal vein, and biliary tract after living donor liver transplantation (LDLT) is described. As a number of patients with LDLT are infants < 10-year-old in the study, the first treatment option was balloon dilatation, not primary stenting. However, stent placement was performed in patients with recurrent, repeated stenosis.
In China, the death numbers due to primary liver cancer every year account for more than half of this disease burden worldwide. Hepatocellular carcinoma (HCC) represents the major histological type of primary liver cancer. In the Chinese population, at least 85% HCC cases are due to chronic infection with hepatitis B virus (HBV), most of which were acquired in the perinatal period or in early life. As of January 1992, HBV immunization of newborns was introduced to the national Expended Program of Immunization of China. Prior to this program, the Qidong County in China conducted an hepatitis B intervention study, which was a population-based, cluster randomized, controlled trial of HBV vaccination in neonates. The study demonstrated that among young adults < 30 years old, neonatal HBV immunization decreased around 84% risk of HBV-related liver cancer, and 70% risk of mortality due to severe end-stage chronic liver diseases. More than 72% efficacy of neonatal vaccination against chronic HBV infection in adulthood was achieved; however, when catch-up HBV vaccination was given to children at age 10-14 years, the protection efficacy was only 21%. No difference in mortality of HBV-related liver diseases was observed among the young adults < 30 years who received and those who did not receive the catch-up HBV vaccination. These results highlight the crucial importance of HBV vaccination of neonates in reducing the liver cancer risk beginning at birth in highly HBV endemic regions. Due to large numbers of HBV-infected pregnant women with high viremia in China, clinical studies in which antiviral therapy with the nucleot(s)ide analogues was given to HBV-infected pregnant women have provided important evidence that such therapy can reduce the risk of mother-to-child HBV transmission. These clinical data based on cohort studies, randomized clinical trials, and clinical practices in the Chinese population provide important information on prevention of liver cancer, particularly HCC, by preventing chronic HBV infection starting from birth for other populations.
Non-resolving inflammation, which may be maintained by infection, pollution, and metabolic stimulants and their interactions with immunogenetic predisposition, provides a fertile field for cancer development. This is strongly evident in hepatocellular carcinoma. Here, the framework of a hypothesis called Cancer Evo-Dev is presented, based on the advances in hepatitis B virus-induced hepatocarcinogenesis. Several aspects central to this theory are as follows: (1) immune imbalance caused by the interaction of immunogenetic predispositions and hepatitis B virus infection maintains non-resolving inflammation; (2) active inflammation executants promote mutations in viral and host genomes via disbalancing mutagenic forces including cytidine deaminases and mutation-repairing forces including uracil-DNA glycosylases, thus promoting cancer-related somatic mutations and viral mutations; (3) a small percentage of the cells whose somatic mutations alter the survival signalling adapt to the inflammatory microenvironment, de-differentiate via demethylating role of cytidine deaminases, and reversely develop into tumor-initiating cells (TICs); (4) under the cultivation of some factors like POSTN from tumor-infiltrating fibroblasts and M2 macrophages, TICs acquire the stemness, cancer-stem cells obtain distinct metastatic and drug-resistant potentials under the selection pressure from distinct microenvironments; (5) glycolysis persistence in the presence of oxygen provides essential energy for cell survival and the raw material for DNA synthesis. Thus, cancer development is characterized by an evolutionary process of “mutation-selection-adaptation”. The framework of Cancer Evo-Dev can be verified in other cancers. Cancer Evo-Dev lays theoretical foundation for understanding the mechanisms by which inflammation promotes cancer development, and it also plays a role in specific prophylaxis, prediction, and targeted treatment of cancers.
Aim: Sorafenib efficacy and safety in advanced hepatocellular carcinoma (HCC) have been demonstrated in two randomized international clinical trials and in clinical practice studies. Because of poor survival advantage, to identify clinical and biological parameters remains an unmet clinical need.
Methods: Eighty-four patients treated with sorafenib were evaluated for response to therapy and prognostic factors possibly associated with survival.
Results: Median overall survival was 8.5 months. Median duration of therapy was 2.5 months with a median daily dose of 800 mg (IQR 600-800). Dose was adjusted in 52% of patients. Radiological response to therapy showed a significant impact on survival. Child-Pugh score and neoplastic invasion of the portal system were negatively associated with survival. Continuation of sorafenib even at lower dose was positively correlated with survival. The multivariate analysis identified vascular invasion as the only independent variable: median survival of 5.5 months for neoplastic portal vein thrombosis compared to 12 months in the remaining subjects.
Conclusion: A lower sorafenib daily dose is advantageous, even though the reason of this association cannot be explained at present. Neoplastic portal vein thrombosis is strongly associated with dismal survival. Alternative or complementary treatment approaches should be studied in order to improve outcome in this subgroup of patients.
The liver is an essential organ for nutrient and drug metabolism - possessing the remarkable ability to sense environmental and metabolic stimuli and provide an optimally adaptive response. Early growth response 1 (Egr1), an immediate early transcriptional factor which acts as a coordinator of the complex response to stress, is induced during liver injury and controls the expression of a wide range of genes involved in metabolism, cell proliferation, and inflammation. In support of an important role of Egr1 in liver injury and repair, deficiency of Egr1 delays liver regeneration process. The known upstream regulators of Egr1 include, but are not limited to, growth factors (e.g. transforming growth factor β1, platelet-derived growth factor, epidermal growth factor, hepatocyte growth factor), nuclear receptors (e.g. hepatocyte nuclear factor 4α, small heterodimer partner, peroxisome proliferator-activated receptor-γ), and other transcription factors (e.g. Sp1, E2F transcription factor 1). Research efforts using various animal models such as fatty liver, liver injury, and liver fibrosis contribute greatly to the elucidation of Egr1 function in the liver. Hepatocellular carcinoma (HCC) represents the second leading cause of cancer mortality worldwide due to the heterogeneity and the late stage at which cancer is generally diagnosed. Recent studies highlight the involvement of Egr1 in HCC development. The purpose of this review is to summarize current studies pertaining to the role of Egr1 in liver metabolism and liver diseases including liver cancer.
The robotic surgical system was developed to overcome the disadvantages of conventional laparoscopic surgery. The use of robots in liver surgery was not well evaluated. This article aimed at reviewing robotic partial hepatectomy to conventional laparoscopic or open partial hepatectomy in terms of perioperative, oncologic, and healthcare costs for hepatocellular carcinoma (HCC). Studies were identified by searching MEDLINE and PubMed databases for articles from January 2004 to June 2017 using the keywords "laparoscopic hepatectomy", "robotic surgery", "robotic hepatectomy", and "hepatocellular carcinoma". Case reports were not included. The open conversion rate, overall morbidity rate, and mortality rate of robotic partial hepatectomy were reported as 0-14.3%, 0-27%, and 0-3%, respectively. Although little data regarding robotic approach for HCC have been reported, it appears to be better than open approach, particularly blood loss and hospital stay, and similar to conventional laparoscopic approach in terms of short term outcomes. The oncological outcomes were comparable to open or laparoscopic approach. Well-known advantages of the robotic system allow resection of tumor location over posterior and superior segments or major hepatectomy with more ease. The main disadvantage of robotic approach was its high cost. In conclusion, oncological data from homogenous series of HCC after robotic partial hepatectomy was needed. Robotic approach was safe to be an alternative option of minimally invasive hepatectomy for HCC. Its future implementation will depend on the advantages that it can provide over open or conventional laparoscopy approach.
Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) in places where chronic hepatitis B infection is endemic. Oral nucleos(t)ide analog (NA) therapy can reduce the risk of HCC, but cannot completely prevent its development. For HBV-related HCCs, viral inhibition by NAs can preserve or improve liver function, thereby increasing the chance of therapeutic intervention. After surgical resection, NAs can prevent reactivation of HBV, and also reduce the chance of de novo development of HCC in the remnant liver. For those who undergo liver transplantation, NAs are essential to prevent reactivation and graft hepatitis, but is not likely to prevent HCC recurrence, which is due to metastatic disease. The role of NAs for non-curable advanced HCC is less well defined. These include patients undergoing locoregional therapy, chemotherapy, or palliation. Although antiviral therapy can preserve liver function, which may be compromised by HBV, it is unable to prevent disease progression from HCC. At the time of HCC diagnosis, most patients will already be receiving NAs, and these patients should be maintained on therapy. For patients not on antiviral therapy at the time of HCC diagnosis, the decision to commence therapy is often determined by the stage of HCC and life expectancy. Patients undergoing curative therapy, or locoregional therapy/chemotherapy with reasonable life expectancy, should be commenced on antiviral therapy.
Aim: Transforming growth factor (TGF) is overexpressed by tumor cells like other proteins and growth factors. TGF-β1 is then activated in the extracellular compartment but is unable to control cell proliferation because of the absence or low level of TGF-β1 receptors on the plasma membrane of malignant hepatocytes. This potential mechanism might interrupt the autocrine regulation loop of TGF-β1 and its blocking effect on cell proliferation. TGF-β1 is a multifunctional cytokine involved in the regulation of growth and differentiation of both normal and transformed cells. This study aimed to evaluate the association of serum levels of TGF-β1 with disease severity.
Methods: A total of 180 subjects were classified into 6 groups according to Barcelona clinic liver cancer (BCLC) classification, 30 patients each: early (BCLC 0 and A), intermediate (BCLC B), advanced stage (BCLC C), and terminal stage (BCLC D) of hepatocellular carcinoma as well as 1 group of patients with cirrhosis only and 1 control group. Serum levels of TGF-β1 were measured.
Results: Serum levels of TGF-β1 were significantly higher in patients with HCC (1,687.47 ± 1,462.81 pg/mL) than cirrhotics (487.98 ± 344.23 pg/mL, P < 0.001) and controls (250.16 ± 284.61 pg/mL, P < 0.001).
Conclusion: TGF-β1 may have a role in tumor growth and progression.
Worldwide, hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality. In men, it is the fifth most common cancer and seventh most common in women; HCC is the second highest cause of cancer-related death worldwide. It is less prevalent in the USA and Northern Europe and more prevalent in Eastern and South-Eastern Asia. Over 700,000 cases are diagnosed each year - half of which occur in China - and result in roughly the same number of deaths per year. HCC significantly impairs quality of life and is associated with great costs to society. It is estimated that half of the deaths from HCC are associated with hepatitis B virus (HBV). Fortunately, HBV vaccination and antiviral therapy have shown excellent efficacy in decreasing the incidence of HCC. We will discuss the relationship of HBV to HCC, address available treatments for HBV and the impact of treatment on the development of HCC.