BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with multiple etiologies, high incidence, and high mortality. The standard surgical management for patients with HCC consists of locoregional ablation, surgical resection, or liver transplantation, depending on the background state of the liver. Eighty percent of patients initially presenting with HCC are unresectable, either due to the extent of tumor or the level of underlying hepatic dysfunction. While in patients with no evidence of cirrhosis and good hepatic function resection has been the surgical treatment of choice, it is contraindicated in patients with moderate to severe cirrhosis. Liver transplantation is the optimal surgical treatment.
DATA SOURCES: PubMed search of recent articles (from January 2000 to March 2011) was performed looking for relevant articles about hepatocellular carcinoma and its treatment. Additional articles were identified by evaluating references from selected articles.
RESULTS: Here we review criteria for transplantation, the types, indications, and role of locoregional therapy in treating the cancer and in downstaging for possible later transplantation. We also summarize the contribution of immunosuppression and adjuvant chemotherapy in the management and prevention of HCC recurrence. Finally we discuss recent advances in imaging, tumor biology, and genomics as we delineate the remaining challenges for the diagnosis and treatment of this disease.
CONCLUSIONS: Much can be improved in the diagnosis and treatment of HCC. A great challenge will be to improve patient selection to criteria based on tumor biology. Another will be to incorporate systemic agents post-operatively in patients at high risk for recurrence, paying close attention to efficacy and safety. The future direction of the effort in treating HCC will be to stimulate prospective trials, develop molecular imaging of lymphovascular invasion, to improve recipient selection, and to investigate biomarkers of tumor biology.

BACKGROUND: The management of metastatic disease in pancreatic endocrine tumors (PETs) demands a multidisciplinary approach and the cooperation of several medical specialties. The role of surgery is critical, even when a radical excision cannot always be achieved.
DATA SOURCES: A PubMed search of relevant articles published up to February 2011 was performed to identify current information about PET liver metastases regarding diagnosis and management, with an emphasis on surgery.
RESULTS: The early diagnosis of metastases and their accurate localization, most commonly in the liver, is very important. Surgical options include radical excision, and palliative excision to relieve symptoms in case of failure of medical treatment. The goal of the radical excision is to remove the primary tumor bulk and all liver metastases at the same time, but unfortunately it is not feasible in most cases. Palliative excisions include aggressive tumor debulking surgeries in well-differentiated carcinomas, trying to remove at least 90% of the tumor mass, combined with other additional destructive techniques such as hepatic artery embolization or chemoembolization to treat metastases or chemoembolization to relieve symptoms in cases of rapidly growing tumors. The combination of chemoembolization and systemic chemotherapy results in better response and survival rates. Other local destructive techniques include ethanol injection, cryotherapy and radiofrequency ablation.
CONCLUSION: It seems that the current management of PETs can achieve important improvements, even in advanced cases.

BACKGROUND: Living donor liver transplantation (LDLT) is considered to be the alterative choice in light of the great shortage of cadaveric donors. However, the characteristics of the patients who will benefit from LDLT have not been well identified. The aim of this study was to define the pre- and intra-operative factors that may influence patient outcome.
METHODS: The data from 102 LDLT patients who had operations between 2002 and 2009 were collected and analyzed retrospectively. Data were analyzed using uni- and multi-variate analysis according to factors that are known to be associated with outcome in these patients.
RESULTS: Overall, the accurate survival rate of recipients at 1, 3, and 5 years was 84%, 76%, and 70%, respectively. The independent risk factors, preoperative renal dysfunction, intraoperative red blood cell transfusions of greater than 5 units, and female to male match (donor to recipient matching), were identified by Cox regression analysis. The pre-transplant model for end-stage liver disease score and a graft to recipient weight ratio of less than 0.8% were not predictive of outcome. The overall 1-, 3-, and 5-year survival of patients with one or no risk factors and two or more risk factors were 91%, 86%, and 83% and 67%, 56%, and 47%, respectively (P<0.0001).
CONCLUSIONS: In our retrospective study, preoperative renal dysfunction, intraoperative red blood cell transfusions of greater than 5 units, and female to male gender match were independent risk factors for LDLT recipient outcome. Two or more of these risk factors may contribute to poor outcome.

BACKGROUND: The development of collaterals in Budd-Chiari syndrome has been described and these collaterals play an important role in the presentation of this disease. These collaterals are diagnostic and their use in management strategy has never been evaluated. This study aimed to investigate the indications, feasibility and necessity of invasive treatment for patients with Budd-Chiari syndrome and to determine whether such a strategy is necessary for optimal management.
METHODS: Twenty-nine patients who had been treated at our unit were enrolled in this study. Based on physical and biochemical examination, and hemodynamic compensation by collaterals, 18 patients underwent radiological intervention (group A), while the other 11 had no invasive treatment (group B). The related hemodynamic parameters were acquired when percutaneous angiography was performed.
RESULTS: In group A, all patients underwent successfully inferior vena cava (IVC) balloon angioplasty with or without stenting. Four patients also underwent hepatic vein angioplasty. In these patients, the mean IVC pressure before and after treatment was statistically different (29.3±9.2 vs 15.1±4.6 mmHg, P<0.01). The mean IVC pressure was much lower in group B than in group A (12.9±2.4 vs 29.3±9.2 mmHg, P<0.01), but there was no difference from that of the patients after radiological treatment (12.9±2.4 vs 15.1±4.6 mmHg, P>0.05). Median follow-up was 32.3 months (mean 21.3 months; range 3-61 months). In the course of follow-up, the patients in group A survived with good systemic status except for re-stenosis in one patient who underwent re-canalization of the IVC. In group B, 10 patients had good systemic status except one patient who had a meso-caval shunt because of deterioration.
CONCLUSIONS: The rationale of "early diagnosis and early treatment" is not suitable for all patients with Budd-Chiari syndrome. Satisfactory survival can be achieved in some patients without invasive treatment, who are completely compensated by rich collaterals. Nonetheless, a positive treatment procedure should be performed if the patient s situation worsens in the course of regular follow-up.

BACKGROUND: Cholangitis after Roux-en-Y hepaticojejunostomy is usually caused by anastomotic stricture. A small number of cases present without evidence of obstruction and are ascribed to reflux of gastro-intestinal content into the biliary tree above the anastomosis (sump syndrome). Despite prophylactic rotating antibiotic therapy, the cholangitic episode may be severe and life-threatening.
METHODS: From 2001 to 2006, six patients who had undergone an end-to-side hepaticojejunostomy presented to our institution with recurrent episodes of biliary sepsis. Anastomotic stricture was excluded by liver MRI/MRCP and percutaneous transhepatic cholangiogram (PTC). Barium meal showed reflux of contrast into the biliary tree in all patients. Three patients had a short jejunal Roux limb (less than 50 cm) on pre-operative imaging.
RESULTS: Five patients underwent surgery and two of them had two operations. One patient had a Tsuchida antireflux valve and subsequently underwent lengthening of the Roux loop. Three patients had lengthening of the Roux loop; one underwent re-do hepaticojejunostomy and one had concomitant revision of the hepaticojejunostomy and lengthening of the Roux loop. The latter underwent further lengthening of the Roux loop. Three patients are cholangitis-free 6, 36 and 60 months after surgery; two still experience mild episodes of cholangitis.
CONCLUSIONS: An adequate length of the Roux loop is important to prevent reflux. However, Roux loop lengthening to 70 cm or more does not always resolve the problem and cholangitis, although generally less frequent and severe, may recur despite appropriate reconstructive or antireflux surgery. In these cases, life-long rotating antibiotics is the only available measure.

BACKGROUND: Whether a major liver resection is safe has been judged mainly from the patient s hepatic reserve. However, a safe limit for liver resection does not exist yet. This study aimed to construct a new scoring system as a guide to determine a safe limit for liver resection and avoid liver dysfunction after hepatectomy.
METHODS: Eighty-six patients with hepatocellular carcinoma who had undergone hepatectomy in West China Hospital from March 2007 to June 2010 were reviewed. The patients were classified according to the levels of total bilirubin after hepatectomy and the parameters in the perioperative period were compared. Receiver operating characteristic (ROC) analysis was made to assess the liver function compensatory (LFC) value to predict liver dysfunction of the patients after hepatectomy. LFC value is defined as the preoperative KICG value×22.487+standard remnant liver volume (SRLV)×0.020.
RESULTS: Patients were classified into group I (normal group, n=69) and group II (with total bilirubin >85.5 µmol/L for 7 days after hepatectomy, n=17) based on the levels of total bilirubin after hepatectomy. Group II was further divided into two subgroups: recovered subgroup (n=14) and fatal subgroup (n=3). There were no significant differences in preoperative data or intraoperative findings except the indocyanine green test parameters (KICG and ICG R15) and SRLV. ROC analysis showed that the sensitivity and specificity of an LFC value ≤13.01 were 94.1% and 82.6% respectively for predicting liver dysfunction of the patients after hepatectomy.
CONCLUSIONS: The LFC value appears to be a good predictor of postoperative liver dysfunction in patients who undergo hepatectomy for HCC. An expected LFC value of 13.01 seems to be a safe limit for liver resection.

BACKGROUND: Increased liver iron stores may contribute to the progression of liver injury and fibrosis, and are associated with a higher risk of hepatocellular carcinoma development. Pre-transplant symptoms of iron overload in patients with liver cirrhosis are associated with higher risk of infectious and malignant complications in liver transplant recipients. HFE gene mutations may be involved in the pathogenesis of liver iron overload and influence the progression of chronic liver diseases of different origins. This study was designed to determine the prevalence of iron overload in relation to HFE gene mutations among Polish patients with liver cirrhosis.
METHODS: Sixty-one patients with liver cirrhosis included in the study were compared with a control group of 42 consecutive patients subjected to liver biopsy because of chronic liver diseases. Liver function tests and serum iron markers were assessed in both groups. All patients were screened for HFE mutations (C282Y, H63D, S65C). Thirty-six of 61 patients from the study group and all controls had liver biopsy performed with semiquantitative assessment of iron deposits in hepatocytes.
RESULTS: The biochemical markers of iron overload and iron deposits in the liver were detected with a higher frequency (70% and 47% respectively) in patients with liver cirrhosis. There were no differences in the prevalence of all HFE mutations in both groups. In patients with a diagnosis of hepatocellular carcinoma, no significant associations with iron disorders and HFE gene mutations were found.
CONCLUSIONS: Iron disorders were detected in patients with liver cirrhosis frequently but without significant association with HFE gene mutations. Only the homozygous C282Y mutation seems to occur more frequently in the selected population of patients with liver cirrhosis. As elevated biochemical iron indices accompanied liver iron deposits more frequently in liver cirrhosis compared to controls with chronic liver disease, there is a need for more extensive studies searching for the possible influence of non-HFE iron homeostasis regulators and their modulation on the course of chronic liver disease and liver cirrhosis.

BACKGROUND: Fatty liver is a common chronic liver disease worldwide. It is associated with an increasing morbidity in China in recent years. The aim of this study was to analyze the effect of drinking alcohol on the hemoglobin and biochemical values of patients with fatty liver.
METHODS: We investigated the clinical and laboratory data of 669 patients with fatty liver. Of the 669 patients, 166 consumed alcohol more than 60 g per week for at least 2 years, and 503 did not have a history of long-term alcohol consumption. We further analyzed the relationship between alcohol consumption and clinical characteristics of these patients.
RESULTS: The values of aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), and hemoglobin in the long-term consumption group were significantly higher than those in the non long-term consumption group (P<0.05). In the patients without long-term alcohol consumption, the values of GGT and hemoglobin in patients with light alcohol consumption were significantly higher than those in non alcohol consumers (P<0.05).
CONCLUSION: Alcohol consumption is associated with significantly increased values of AST, GGT, and hemoglobin in patients with fatty liver, suggesting their potential roles in hepatic steatosis.

BACKGROUND: Hepatitis C virus (HCV) infection is thought to be chronic and the factors leading to viral clearance or persistence are poorly understood. This study was undertaken to investigate the possibility of a significant relationship between the spontaneous clearance or the persistence of hepatitis C virus (HCV) infection and cytokine and apoptosis gene polymorphisms in Tunisian patients on hemodialysis.
METHODS: Polymorphisms of the genes IL-1 (-889 IL-1α, -511 and +3954 IL-1β, IL-1Ra), IL-18 (-137 and -607), IL-12 (-1188) and Apo1/Fas (-670) were determined by PCR-RFLP, PCR-SSP and PCR-VNTR in 100 healthy blood donors and 100 patients infected with HCV and undergoing hemodialysis. The patients were classified into two groups: G1 consisted of 76 active chronic hepatitis patients (positive for HCV RNA) and G2 consisted of 24 hemodialysed patients who spontaneously eliminated the virus (negative for HCV RNA).
RESULTS: The frequency of genotype association [-137GC/-607CA] IL-18 was higher in G2 (41.7%) than in G1 (15.8%) (P=0.008; OR=0.26; 95% CI, 0.10-0.73). We also found a higher frequency of the AA genotype of the Apo1/Fas gene in G2 (41.6%) than in G1 (17.5%) (P=0.026; OR=3.49; 95% CI, 1.13-10.69). Adjustment for known covariate factors (age, gender and genotype) confirmed these univariate findings and revealed that the genotype association GC-CA of the (-137 and -607) IL-18 gene and the AA genotype of the Apo1/Fas gene were associated with the clearance of HCV (P=0.041 and 0.017, respectively).
CONCLUSION: The two genotypes GC-CA of the (-137 and -607) IL-18 polymorphism and the AA genotype of the Apo1/Fas gene influence the outcome of HCV infection in Tunisian patients on hemodialysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by a multi-cause, multi-stage and multi-focus process of tumor progression. Its prognosis is poor and early diagnosis is of utmost importance. This study was undertaken to investigate the dynamic expression of oncofetal antigen glypican-3 (GPC-3) and GPC-3 mRNA in hepatocarcinogenesis and to explore their early diagnostic value for HCC.
METHODS: A hepatoma model was induced in male Sprague-Dawley rats with 0.05% 2-fluorenylacetamide and confirmed by hematoxylin and eosin staining and gamma-glutamyltransferase (GGT) expression. Total RNA was purified and transcribed into cDNA by reverse transcription. Fragments of the GPC-3 gene were amplified by nested RT-PCR, and confirmed by sequencing. GPC-3 was analyzed by immunohistochemistry, Western blotting or ELISA.
RESULTS: Positive GPC-3 expression showed as brown granule-like staining localized in the cytoplasm. Histological examination of hepatocytes revealed three morphological stages of granule-like degeneration, atypical hyperplasia (precancerous), and cancer formation, with a progressive increase of liver total RNA and GGT expression. The incidence of liver GPC-3 mRNA and GPC-3, and serum GPC-3 was 100%, 100% and 77.8% in the HCC group, 100%, 100%, and 66.7% in the precancerous group, 83.3%, 83.3%, and 38.9% in the degeneration group, and no expression in the liver or blood of the control group, respectively. There was a positive correlation between liver GPC-3 mRNA and total RNA level (r=0.475, P<0.05) or liver GPC-3 (r=1.0, P<0.001) or serum GPC-3 (r= 0.994, P<0.001).
CONCLUSION: Abnormal oncofetal antigen GPC-3 and GPC-3 mRNA expression in hepatocarcinogenesis may be promising molecular markers for early diagnosis of HCC.

BACKGROUND: Hepatitis B virus (HBV) is one of the major pathogens of human liver disease. Studies have shown that HBV X protein (HBx) plays an important role in promoting viral gene expression and replication. In this study we performed a global proteomic profiling to identify the downstream functional proteins of HBx, thereby detecting the mechanisms of action of HBx on virion replication.
METHODS: HBx in the HepG2.2.15 cell line was knocked down by the transfection of small interfering RNA (siRNA). The replication level of HBV was evaluated by microparticle enzyme immunoassay analysis of HBsAg and HBeAg in the culture supernatant, and real-time quantitative PCR analysis of HBV DNA. Two-dimensional electrophoresis combined with MALDI-TOF/TOF was performed to analyze the changes in protein expression profile after treatment with HBx siRNA.
RESULTS: Knockdown of HBx disturbed HBV replication in vitro. HBx target siRNA significantly inhibited the expression of HBsAg, HBeAg and the replication of HBV DNA. Twelve significantly changed proteins (7 upregulated and 5 downregulated) were successfully identified by MALDI-TOF/TOF using proteomics differential expression analysis after the knockdown of HBx. Among these identified proteins, HSP70 was validated by Western blotting.
CONCLUSION: The results of the study indicated the positive effect of HBx on HBV replication, and a group of downstream target proteins of HBx may be responsible for this effect.

BACKGROUND: Many Chinese herbs, especially herbal injections, have been shown to have anti-tumor effects in recent years. However, since most reports focus on the clinical effectiveness of these herbs, their mechanisms of action are not well understood. In this study, we assessed apoptosis in the hepatocellular carcinoma (HCC) cell line HepG2 induced by an injectable extract from the seed of Coix lacryma-jobi (Semen coicis, SC), and monitored the expression of Bcl-2 and caspase-8.
METHODS: Injectable SC was applied to HepG2 cells at different concentrations and the cells were collected 12, 24 and 48 hours later. 5-fluorouracil was used as a positive control group, and fluorescence-activated cell-sorting cytometry was used to measure the apoptosis rate of HepG2 cells and the expression of Bcl-2 and caspase-8 proteins.
RESULTS: SC induced apoptosis in HepG2 cells in a concentration- and time-dependent manner, and the expression of caspase-8 was elevated and prolonged. However, it did not significantly influence the expression of Bcl-2.
CONCLUSION: Injectable SC may induce apoptosis in HCC cells by regulating the expression of caspase-8.

BACKGROUND: The major issue with intraoperative cholangiography (IOC) is whether its diagnostic accuracy for common bile duct (CBD) stones matches that of other diagnostic procedures, and thus, whether it will become a routine diagnostic procedure. The current study aimed to address the main determinants of CBD stone diagnosis in IOC among an Iranian population.
METHODS: In a retrospective review database-based study conducted in Taleghani Hospital in Tehran between 2006 and 2008, baseline data and perioperative information of 2060 patients (male to female ratio 542:1518, mean age 53.7 years) who were candidates for cholecystectomy and underwent concomitant IOC for confirming CBD stones were reviewed. The predictive power of this procedure for diagnosis of abnormal biliary ducts with the focus on biliary stones was determined.
RESULTS: Overall mortality and morbidity following cholecystectomy in the study population were 0.6% and 2.6%, respectively. Both early mortality and morbidity due to cholecystectomy were higher in male than female. The prevalence of CBD stones in IOC was 3.4% (5.2% in male and 2.8% in female, P=0.008). Among those without gallstones, 8.7% had CBD stones and only 3.1% had concomitant gallstones and CBD stones. The main predictors of stone appearance as an abnormal feature of IOC during cholecystectomy were: advanced age (OR=1.022, P=0.001), male gender (OR=1.498, P=0.050), history of abdominal surgery (OR=1.543, P=0.040) and preoperative endoscopic retrograde cholangiopancreatography (OR=5.400, P<0.001).
CONCLUSIONS: IOC is a safe and accurate method for the assessment of bile duct anatomy and stones. Therefore, the routine use of IOC within cholecystectomy seems reasonable and is recommended.

BACKGROUND: In general, the dose requirement and complications of propofol are lower when used in the diluted form than in the undiluted form. The aim of this study was to determine the dose requirement and complications of diluted and undiluted propofol for deep sedation in endoscopic retrograde cholangiopancreatography.
METHODS: Eighty-six patients were randomly assigned to either group D (diluted propofol) or U (undiluted propofol). All patients were sedated with 0.02-0.03 mg/kg midazolam (total dose ≤2 mg for age <70 years and 1 mg for age ≥70) and 0.5-1 µg/kg fentanyl (total dose ≤75 µg for age <70 and ≤50 µg for age ≥70). Patients in group U (42) were sedated with standard undiluted propofol (10 mg/mL). Patients in group D (44) were sedated with diluted propofol (5 mg/mL). All patients in both groups were monitored for the depth of sedation using the Narcotrend system. The primary outcome variable was the total dose of propofol used during the procedure. The secondary outcome variables were complications during and immediately after the procedure, and recovery time.
RESULTS: All endoscopies were completed successfully. Mean propofol doses per body weight and per body weight per hour in groups D and U were 3.0 mg/kg, 6.2 mg/kg per hour and 4.7 mg/kg, 8.0 mg/kg per hour, respectively. The mean dose of propofol, expressed as total dose, dose/kg or dose/kg per hour and the recovery time were not significantly different between the two groups. Sedation-related adverse events during and immediately after the procedure were higher in group U (42.9%) than in group D (18.2%) (P=0.013).
CONCLUSIONS: Propofol requirement and recovery time in the diluted and undiluted propofol groups were comparable. However, the sedation-related hypotension was significantly lower in the diluted group than the undiluted group.

BACKGROUND: The ideal treatment of patients with "borderline resectable pancreatic tumors (BRTs)" needs to be established. Current protocols advise neoadjuvant chemo(radio)therapy, although some patients may appear to have BRT on preoperative imaging and a complete resection may be achieved without the need for vascular resection. The aim of the present study was to identify specific findings on preoperative imaging that could help predict in which patients with BRT a complete resection, with or without vascular resection (VR), could be achieved.
METHODS: Twelve patients with BRTs were identified. Tumor location, maximum degree of circumferential contact (CC), length of contact of the tumor with major vessels (LC), and luminal narrowing of vessels at the point of contact with the tumor (venous deformity, VD) were graded on preoperatively acquired multidetector computed tomography (MDCT) images and then compared with the intraoperative findings and need for VR.
RESULTS: A complete resection (R0) was achieved in 10 patients with 2 having microscopic positive margins (R1) on histopathology at the uncinate margin. Four of the 10 patients required VR (40%). In 3 of the 4 patients whose tumors required VRs, CC was ≥grade III and VD was grade 2. LC did not influence the need for VR.
CONCLUSIONS: It is possible to achieve a complete resection at the first instance in patients found to have BRTs on preoperative imaging. Preoperative MDCT-based grading systems and our proposed criteria may help identify such patients, thus avoiding any delay in curative resections in such patients.

BACKGROUND: Controversy remains over whether the middle hepatic vein should be included in the liver graft in right liver living donor liver transplantation. Congestion in the anterior sector of a right liver graft can cause graft malfunction, which is especially devastating in the case of a graft with marginal size in relation to recipient body size on top of poor pre-transplant recipient status. The case we report here highlighted the importance of the middle hepatic vein in right liver living donor liver transplantation.
METHODS: We illustrated the rectification of outflow obstruction of the middle hepatic vein in the anterior sector of right liver graft caused by technical error during transplantation. The rectification was performed with emergency re-routing using an artificial conduit.
RESULT: Congestion in the anterior sector of the graft improved immediately and the patient s postoperative liver function test results improved gradually.
CONCLUSIONS: The middle hepatic vein is important for effective drainage of the anterior sector of a right liver graft. The re-routing technique described in the report can also be applied to cases in which the middle hepatic vein is injured during hepatectomy requiring immediate reconstruction.

BACKGROUND: The gallbladder is rarely affected by mycobacterium tuberculosis. The diagnosis of gallbladder tuberculosis is often not suspected prior to surgery or biopsy.
METHOD: A young female patient underwent laparoscopic cholecystectomy but presented with a persistently discharging sinus from the port site.
RESULTS: The gallbladder biopsy revealed granulomas typical of chronic granulomatous tuberculosis. The condition of the patient was improved by antitubercular treatment.
CONCLUSIONS: Presentation of gallbladder tuberculosis as a persistent discharging sinus at the port site in a patient who has undergone a laparoscopic cholecystectomy is extremely rare. The diagnosis was reached by histopathology only. The rarity of the presentation prompted us to report the case.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) may arise in any part of the gastrointestinal tract; extra-gastrointestinal locations are extremely rare. Only a few cases of extragastrointestinal stromal tumor arising from the pancreas were reported. None of the reports described a long-term follow-up of the patients.
METHOD: This report describes an interesting and unusual case of GIST arising from the pancreas.
RESULTS: A 74-year-old female presented with a palpable abdominal mass. CT scan showed a large mass 11×8×4 cm originating from the tail of the pancreas. Percutaneous biopsy revealed a GIST predominantly with spindle cells, but some parts also contained epitheloid cells. The patient was treated by distal pancreatic resection with splenectomy. Immunohistochemistry of the tumor showed a staining pattern characteristic of GIST. The patient has achieved a long-term survival of five years and six months without any sign of recurrence of the disease.
CONCLUSION: This is the first reported case of an extra-gastrointestinal stromal tumor arising from the pancreas treated surgically, with a long-term survival.