Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study.

OBJECTIVE: Dysbiosis of the infant gut microbiota may have long-term health consequences. This study aimed to determine the impact of maternal intrapartum antibiotic prophylaxis (IAP) on infant gut microbiota, and to explore whether breastfeeding modifies these effects. DESIGN: Prospective pregnancy cohort of Canadian infants born in 2010-2012: the Canadian Healthy Infant Longitudinal Development (CHILD) Study. SETTING: General community. SAMPLE: Representative sub-sample of 198 healthy term infants from the CHILD Study. METHODS: Maternal IAP exposures and birth method were documented from hospital records and breastfeeding was reported by mothers. Infant gut microbiota was characterised by Illumina 16S rRNA sequencing of faecal samples at 3 and 12 months. MAIN OUTCOME MEASURES: Infant gut microbiota profiles. RESULTS: In this cohort, 21% of mothers received IAP for Group B Streptococcus prophylaxis or pre-labour rupture of membranes; another 23% received IAP for elective or emergency caesarean section (CS). Infant gut microbiota community structures at 3 months differed significantly with all IAP exposures, and differences persisted to 12 months for infants delivered by emergency CS. Taxon-specific composition also differed, with the genera Bacteroides and Parabacteroides under-represented, and Enterococcus and Clostridium over-represented at 3 months following maternal IAP. Microbiota differences were especially evident following IAP with emergency CS, with some changes (increased Clostridiales and decreased Bacteroidaceae) persisting to 12 months, particularly among non-breastfed infants. CONCLUSIONS: Intrapartum antibiotics in caesarean and vaginal delivery are associated with infant gut microbiota dysbiosis, and breastfeeding modifies some of these effects. Further research is warranted to explore the health consequences of these associations. TWEETABLE ABSTRACT: Maternal #antibiotics during childbirth alter the infant gut #microbiome.

Silencing of TLR4 decreases liver tumor burden in a murine model of colorectal metastasis and hepatic steatosis.

BACKGROUND: The relationship between obesity and cancer has become of particular interest due to the rapidly growing prevalence of overweight individuals. Obesity predisposes individuals to the development of hepatic steatosis and is an independent risk factor for several neoplasms. Toll-like receptor 4 (TLR4) is the innate receptor for endotoxin, and steatotic livers are known to be sensitive to endotoxin. TLR4 signaling has been shown to have proneoplastic effects in vitro due to its effect on immune surveillance. Thus far, studies have predominantly focused on the effect of tumor-cell-derived TLR4 without regard to host TLR4 signaling. RESULTS: In the present study we show that steatotic livers have increased expression of TLR4. Obese animals developed higher metastatic tumor burden in the liver than lean controls regardless of the presence or absence of intact host TLR4. After silencing TLR4 expression using RNAi in the mouse colon cancer cell line MC38, there was a significant decrease in metastatic tumor burden within the liver of obese animals. CONCLUSIONS: These findings demonstrate that steatotic livers have increased susceptibility to metastatic tumor growth and that silencing tumor cell TLR4 reduces metastatic tumor burden in steatotic liver.

Impact of maternal pre-pregnancy overweight on infant overweight at 1 year of age: associations and sex-specific differences.

BACKGROUND: Maternal overweight or obesity (OWOB) is linked to gestational diabetes, fetal macrosomia and higher rates of caesarean delivery. OBJECTIVES: The study aims to assess whether maternal pre-pregnancy OWOB is associated with infant overweight in a sex-dependent manner, independent of microbiota-altering variables. METHODS: Weight and length measurements of 955 mother-infant pairs were obtained from the Canadian Healthy Infant Longitudinal Development cohort. Maternal pre-pregnancy weight was defined as follows: normal, overweight (25 ≤ body mass index < 30) and obese (body mass index ≥ 30). Age and sex-adjusted weight-for-length z-scores >97th percentile were classified as infant overweight at age 1 year. Associations between pre-pregnancy and infant overweight were determined by linear and logistic regression, adjusting for covariates. RESULTS: Maternal pre-pregnancy OWOB were associated with infant weight-for-length and overweight risk at 1 year. Except for pre-pregnancy obesity, these associations were not attenuated appreciably after adjustment for birth mode, exclusivity of breastfeeding, exposure to antibiotics and infant sex. Yet only boys born to mothers with obesity were three times more likely to become overweight at age 1 independent of microbiota-altering variables. Pre-pregnancy obesity was associated with weight-for-length in male and female infants. CONCLUSIONS: Maternal pre-pregnancy OWOB increases the risk of infant overweight, and this association is more evident in male infants.

Induction of apoptosis in liver tumors by the monoterpene perillyl alcohol.

The monoterpenes d-limonene and perillyl alcohol (POH) inhibit the growth of mammary tumors. In this investigation we tested whether POH is also effective in reducing liver tumor growth. Diethylnitrosamine was used to induce liver tumors in male Fischer 344 rats. Two weeks after diethylnitrosamine exposure was discontinued, the animals were divided into POH-treated and untreated groups. The mean liver tumor weight for the POH-treated rats after 19 weeks of POH treatment was 10-fold less than that for the untreated animals. POH did not influence tumor cell proliferation but increased the apoptotic index approximately 10-fold. The mRNA levels for the mannose 6-phosphate/insulin-like growth factor II receptor and the transforming growth factor beta type I, II, and III receptors were also significantly increased in the liver tumors from the POH-treated animals when compared to the corresponding receptor mRNA levels in the normal tissue surrounding the tumors and in the tumors of untreated animals. These results demonstrate that POH does not promote the formation of liver tumors, but rather inhibits their growth by enhancing tumor cell loss through apoptosis.

Bile acids in xenogeneic ex-vivo liver perfusion: function of xenoperfused livers and compatibility with human bile salts and porcine livers.

BACKGROUND: In recent years, hepatic support systems using xenogeneic cells have been developed to support patients in fulminant hepatic failure. The extent to which xenogeneic hepatocytes metabolize and excrete human organic anions is unclear. In these studies we examined the ability of the ex vivo porcine liver to clear human bile acids during extracorporeal liver perfusion (ELP). METHODS: Four patients with fulminant hepatic failure underwent extracorporeal liver perfusion with 9 porcine livers. The venovenous circuit was designed as previously described (NEJM,1994,331:234) as were the immunologic features (Transplantation 1994,58:1162). Bile from the porcine liver and serum samples were collected hourly during perfusion. Three bile acids (glycocholic, glycodeoxycholic, taurodeoxycholic acid) were selected as markers for human bile and three (glycohyocholic, glycohyodeoxycholic, and glyco-3alpha-hydroxy-6-oxo-5beta-cholanoic acid) for markers of pig bile. Bile acids from both serum and bile were processed and analyzed through high performance liquid chromatography. The Students' t test was used for statistical analysis. RESULTS: The mean duration of perfusions was 4.1+/-1.5 hr. The mean total bile acid clearance from serum (243+/-44 micromol/h) was similar to the total bile acid biliary excretion (286+/-84 micromol/hr, P = 0.06). After 1 hr of perfusion, bile samples demonstrated a predominance of pig bile salts (65%). After 3 hr of perfusion, human bile acids made up 85% of total biliary bile acids. Pig bile acids appeared in patients' sera after 1 hr of perfusion, and after 3 hr, 35% of serum bile salts were pig-specific. CONCLUSIONS: Porcine livers perfused with human blood can clear the serum of potentially toxic human bile acids and excrete them into bile. Simultaneously, the percentage of pig-specific bile acids in patient serum increases during xenogeneic perfusion for unknown reasons. The relative hepatic uptake of bile acid from serum is similar to bile acid excretion in bile. Further development of systems using porcine livers or hepatocytes is warranted.

Mechanisms of injury in porcine livers perfused with blood of patients with fulminant hepatic failure.

Hyperacute rejection of renal and cardiac xenografts is initiated by the reaction of recipient natural antibodies and complement with endothelial cell antigens of the donor organ. The liver is thought to be less susceptible to this form of rejection; however, the mechanisms underlying its decreased susceptibility are not known. We investigated the organ injury occurring in porcine livers perfused with blood from 4 human subjects with fulminant hepatic failure. Nine porcine livers were perfused via an extracorporeal circuit in order to provide temporary metabolic support. Each porcine liver exhibited metabolic function, and the duration of xenoperfusion ranged from 2 to 5 hr. Histologic examination of the xenoperfused livers revealed focal hepatocellular necrosis, prominent infiltration of neutrophils, and, in 7 of 9 cases, periportal and centrilobular hemorrhage and thrombosis. Immunopathology demonstrated minimal or no human IgM and IgG along the small vessels and sinusoidal surfaces. Trace deposits of human IgM were observed along the luminal surfaces of large blood vessels in most cases. Trace deposits of C3 were noted in 2 of 9 livers; however, C4, iC3b, C5b, properdin, and the membrane attack complex were not detected. Human anti-porcine natural antibody titers decreased less than expected during the perfusions. Serum CH50, C3, and C4 levels were low before each procedure and decreased slightly with perfusion. One patient perfused 2 porcine livers and a human liver. The human liver had focal hepatocellular necrosis, trace deposits of IgM, no deposits of complement, and an infiltrate consisting of neutrophils; however, the neutrophil influx was less than that observed in the xenoperfused livers. To further evaluate the effects of alloperfusion, venovenous bypass was established in 2 pigs and the extracorporeal circuit was utilized to perfuse 2 porcine livers. The alloperfused porcine livers had focal hepatocellular necrosis and a minimal infiltrate of neutrophils. There were no deposits of porcine IgM, IgG, or complement components. In conclusion, although the porcine livers perfused by human blood sustained structural damage, the time course, the absence of immune deposits, and the findings of similar, albeit less severe, lesions in the alloperfused livers suggest that the pathogenesis of tissue injury in the xenoperfused livers differs from that of hyperacute rejection and may be related to the action of recipient neutrophils.

Protective effects of ischemic preconditioning on the cold-preserved liver are tyrosine kinase dependent.

BACKGROUND: Little data exist regarding the use of ischemic preconditioning before sustained hepatic cold storage. We hypothesized that ischemic preconditioning protects hepatic grafts via a tyrosine kinase-dependent pathway. METHODS: Six porcine livers underwent routine harvest (control). Five other livers underwent 15 min of in situ ischemia followed by 15 min of reflow before harvest (ischemic preconditioning). Another five livers were pretreated with a tyrosine kinase inhibitor (genistein) before preconditioning. Upon reperfusion and after 2 hours of cold storage, graft function, graft circulatory impairment, and markers of cellular damage were analyzed. Tissue cytoplasmic extracts were analyzed for tyrosine phosphorylation with Western blot. Significance was determined with t tests. RESULTS: Ischemic-preconditioned grafts demonstrated enhanced bile production, augmented responses to a bile acid challenge, and elevated O2 consumption (P<0.05) compared to controls. Also, preconditioned grafts demonstrated improved hepatic tissue blood flow and decreased hepatic vascular resistance (P<0.005) compared to controls. Endothelial cell preservation (factor VIII immunostain) was improved in preconditioned graft biopsies compared to controls. With genistein pretreatment, all observed improvements returned to control levels. Analysis of cytoplasmic extracts demonstrated an increase in tyrosine phosphorylation before cold ischemia in preconditioned grafts only, but not in control or genistein-pretreated grafts. CONCLUSIONS: The data indicate that ischemic preconditioning protects the liver from sustained cold ischemia and that tyrosine kinases are involved in preconditioning responses.

Venovenous bypass in adult orthotopic liver transplantation: routine or selective use?

BACKGROUND: The role of venovenous bypass (VVB) during orthotopic liver transplantation (OLT) remains controversial. The aims of this study were to evaluate the current role of VVB at all major centers in North America, to examine the results of OLT and complications of VVB between two periods with a strict policy for routine versus selective use of VVB, and to review the literature. STUDY DESIGN: A survey of 50 major liver transplant centers was conducted using mailed questionnaires. A retrospective chart review was performed for 547 OLT patients having transplantation during two distinct periods with a strict policy for routine versus selective use of VVB at the University of Toronto, Canada, and at Duke University Medical Center, Durham, North Carolina. The literature was reviewed with a focus on the benefits and indications for routine versus selective use of VVB. RESULTS: Thirty-eight (76%) of 50 centers responded. Sixteen (42%) of them used VVB routinely, with a reported complication rate of 10-30%. Lymphocele and hematoma were the most common complications, but patients having major vascular injury, air embolism, and death were reported. A recent change to selective use of VVB was reported in 30% of the centers (11 of 38). In the Duke-Toronto series, the complication rates were similar between the two periods, at 13.4% and 18.8%, respectively. The outcome of OLT was not influenced by the policy of routine or selective use of VVB. CONCLUSIONS: There is a trend away from the routine use of VVB during OLT. Intraoperative hemodynamic instability during the hepatectomy and a failed trial of hepatic venous occlusion were the most important criteria for using VVB. We conclude that VVB should be used selectively to avoid associated complications and to decrease operative time and costs.

A critical appraisal of laparoscopic staging in hepatobiliary and pancreatic malignancy.

Prognosis for patients with hepatobiliary and pancreatic cancers is dismal. Surgery is the best therapeutic option for those with tumors which have not yet metastasized. Standard radiologic tests such as computed tomography (CT) scan and trans-abdominal ultrasound are useful in identifying patients for whom an attempt at resection would be futile. Staging laparoscopy with laparoscopic ultrasound allows greater precision in identifying those for whom resection would be helpful with less morbidity than an open exploration. Metastatic disease can be identified more precisely than with radiologic tests and can be characterized by biopsy techniques. Palliative procedures are now being performed laparoscopically with low morbidity and short hospital stays. The use of laparoscopy prior to open exploration for patients with hepatobiliary and pancreatic tumors is advantageous.

PI-3' kinase and NF-kappaB cross-signaling in human pancreatic cancer cells.

Because tumor necrosis factor-alpha (TNF-alpha) and some chemotherapeutic agents activate both apoptosis and NF-kappaB-dependent antiapoptotic genes, they may neutralize their own antitumor effects. The cell-signaling mechanisms for such chemoresistance are not clear but may involve phosphotidylinositol-3' kinase (PI3K). To clarify this we examined whether cross-signaling between PI3K and NF-kappaB enhances the antitumor effect of TNF-alpha in human pancreatic cancer cells. Quiescent pancreatic cancer cells (Panc-1, MiaPaCa-2) with TNF-alpha, Ly294002 (PI3K inhibitor), alone or combined, were restimulated with mitogen (10% fetal calf serum [FCS] to induce cell cycle entry). Proliferation (monotetrazolium), cell cycle progression (ApoBrDU and fluorescence-activated cell sorter analysis), and apoptosis (PARP cleavage; caspase-3 activation) were measured. Akt activation (Akt kinase assay) and IkappaBalpha degradation were determined by Western blot analysis. Translocation of NF-kappaB into the nucleus was examined by EMSA, whereas an NF-kappaB/luciferase reporter gene was used to quantify NF-kappaB-dependent gene expression. Statistical analysis was carried out by means of two-tailed t test (P <0.05). PI3K inhibition significantly enhanced the antiproliferative and proapoptotic effects of TNF-alpha in both cell lines, Ly294002 also blocked TNF-alpha-induced Akt activation but failed to alter cytoplasmic IkappaBalpha degradation or subsequent NF-kappaB nuclear translocation. NF-kappaB-dependent gene expression, however, was ultimately suppressed by Ly294002, suggesting that PI3k-dependent activation of NF-kappaB is IkappaBalpha independent. PI3K inhibition can block NF-kappaB-dependent gene expression regardless of cytoplasmic IkappaBalpha/NF-kappaB activation. Because it also regulates the antitumor effects of TNF-alpha, PI3K may in part determine NF-kappaB-induced chemoresistance in human pancreatic cancer.

Hypoosmotic stress stimulates growth in HepG2 cells via protein kinase B-dependent activation of activator protein-1.

Although hypoosmotic stress-induced cell swelling activates phosphatidylinositol-3-kinase, its impact on the downstream signal protein kinase B and cell growth is unknown. Activator protein-1 is in part phosphatidylinositol-3-kinase dependent, and is important in proliferation. We hypothesized that cell swelling modulates proliferation in HepG2 cells via the protein kinase B-dependent activation of activator protein-1. HepG2 cells pretreated with or without LY294002 were exposed for up to 30 minutes to hypoosmotic medium (160 mOsm/L). Tumor necrosis factor-alpha (1.4 nmol/L) or normoosmolar medium (270 mOsm/L) served as positive and negative controls, respectively. Western immunoblots measured cytoplasmic phosphorylated and total protein kinase B. Electromobility shift assays measured nuclear activator protein-1. Methylene blue assays measured cell proliferation at 24, 48, and 72 hours after stimulation. Hypoosmotic stress phosphorylated protein kinase B by 10 minutes. Subsequently, hypoosmotic exposure stimulated activator protein-1 by 30 minutes. Pulse exposure to hypoosmotic stress potentiated HepG2 proliferation by 72 hours as compared to both negative controls and LY-inhibited cells (n = 4 per group, P = 0.009 and P = 0.004, respectively; P <0.001 analysis of variance. All three activation events were abolished with LY294002 pretreatment. In HepG2 cells, hypoosmotic stress-induced swelling stimulates proliferation via protein kinase B-mediated activation of activator protein-1. These data delineate a possible mechanism linking changes in cell volume to growth in human liver cancer.

Bosentan, an endothelin antagonist, augments hepatic graft function by reducing graft circulatory impairment following ischemia/reperfusion injury.

Endothelin is a potent hepatic vasoconstrictor. We evaluated the role of an endothelin antagonist in hepatic ischemia/reperfusion injury. Bosentan, a novel endothelin receptor antagonist, was infused directly into the portal vein prior to cold ischemia and immediately on reperfusion, in five porcine livers. Five other pigs underwent routine liver harvest and reperfusion without bosentan treatment. Hepatic vascular resistance and liver tissue blood flow, as measured by thermistor flow probes, were determined following reperfusion. Hepatocellular damage was assessed through hepatic venous levels of sorbitol dehydrogenase and lactate dehydrogenase. Endothelial cell damage was determined in sections immuno-stained for factor VIII. Graft function was determined through oxygen consumption, bile production, and response to bile acid challenge. Organs treated with bosentan demonstrated lower vascular resistance and enhanced tissue blood flow (P < 0.05) as compared to untreated organs. Portal vein inflow to hepatic tissue was significantly enhanced (4.4-fold) in the bosentan-treated organs (P < 0.05). No difference was observed in hepatocellular damage. Pathology scores for factor VIII immunohistochemical staining were 2.3-fold higher in the bosentan-treated livers as compared to untreated livers (P < 0.05). The bosentan-treated livers also demonstrated enhanced oxygen consumption, increased bile production, and augmented biliary response to a bile acid challenge (P < 0.05). These results indicate that administration of bosentan before and after ischemia/reperfusion reduces hepatic circulatory disturbances, diminishes endothelial cell damage, and augments hepatic graft function.

Alterations in intrahepatic hemodynamics of the harvested porcine liver.

Hemodynamic properties of a donor liver, during initial reperfusion, are associated with the degree of graft preservation injury and have been proposed to correlate with subsequent markers of liver function. In the present study, hepatic hemodynamics, that is, portal venous pressure, hepatic vascular resistance, and compliance (vascular distensibility), were characterized (1) in situ before porcine livers were manipulated, (2) after these same livers were isolated and perfused within a bypass circuit, and (3) on reperfusion after 2 hours of cold ischemia. Hepatic vascular resistance was determined in each of these three states from the portal vein pressure response to differing hepatic blood flows. In addition, the response of the same livers to norepinephrine and nitroprusside was evaluated in each condition. In the in situ and isolated perfused liver, portal venous pressure increased only modestly despite doubling of hepatic flows. After cold ischemia, the pressure response to higher flows was significantly greater and much less of a reduction in hepatic vascular resistance was noted than in studies prior to cold ischemia. Unlike livers prior to cold ischemia, the pressure response to norepinephrine was attenuated following cold ischemia. The response to nitroprusside, however, remained intact reducing the portal pressure to that of in situ livers. Therefore the portal hypertension that follows cold ischemia appears to be largely provoked by the preservation injury and not by surgical manipulation or the bypass circuit. This increment in portal pressure is responsive to a nitric oxide donor.

Complications of laparoscopic cholecystectomy.

Laparoscopic cholecystectomy is a safe and effective treatment of cholelithiasis in experienced hands. Mortality is rare. The Southern Surgeons Club data and several other recent large series indicate that major complications occur in less than 3% of patients. The most significant common complication is injury to the bile duct, for which the greatest risk factor is inexperience. Major biliary injury usually requires reoperations. Roux-en-Y hepaticojejunostomies, often multiple, are usually necessary for repair. The popularity of this technique continues, and further efforts should be focused on elimination of the learning curve for major biliary injury. If injuries do occur, they should be recognized early, and patients should be referred to centers experienced in their treatment.

Down-regulation of transforming growth factor beta receptor type I, II, and III during liver regeneration.

BACKGROUND: After partial hepatectomy (PH), it has been shown that hepatocytes are resistant to the mitoinhibitory effects of transforming growth factor beta (TGF-beta). Three types of TGF-beta receptors have been characterized in mammals. MATERIALS AND METHODS: In this study, changes in the protein and mRNA expression of TGF-beta types I, II, and III receptors relative to DNA synthesis were studied as a function of time after PH in the rat. RESULTS: There was a significant decrease in the protein and mRNA for all three receptor subtypes immediately after PH. All three receptors reached a nadir at 24 hours after PH, which correlated to the time of peak DNA synthesis. The type II receptor recovered to preoperative levels by 120 hours after PH, whereas the types I and III receptors remained at 60% of prehepatectomy levels. Sham-operated rats did not experience a significant drop in receptor protein or mRNA levels. CONCLUSIONS: This decrease in TGF-beta type II receptor expression may account for the reduction in the sensitivity of hepatocytes to TGF-beta after PH. Furthermore, the TGF-beta receptors appear to represent a class of immediate-early genes that are negatively, rather than positively, regulated after PH.

Laparoscopic staging and tumor ablation for hepatocellular carcinoma in Child C cirrhotics evaluated for orthotopic liver transplantation.

BACKGROUND: Surgical resection and liver transplantation remain the only treatments that offer cure for hepatoma, but are limited to those with early stage disease. Prelisting radiological staging is not always definitive. In this study, we sought to delineate the role of laparoscopy for clarification of staging in advanced cirrhotic patients when radiological assessment during evaluation for orthotopic liver transplants (OLTx) is equivocal. METHODS: Over a 3-year period, 18 patients with advanced liver insufficiency being evaluated for OLTx listing underwent laparoscopic staging when the following criteria were met: (1) lesion(s) with indeterminate size/borders, (2) an indeterminate number of lesions, or (3) lesion(s) and alpha-fero protein (AFP) less than 100 ng/ml. Patients underwent exploratory laparoscopy and laparoscopic ultrasound with biopsy, with or without ablation of lesion(s). RESULTS: Laparoscopic staging was initiated in 18 patients; four of the first six patients were converted to open procedures. Twelve patients were restaged as a result of the procedure: six down-staged and six up-staged. Stage changes were based on laparoscopic visualization of advanced disease in two, ultrasonographic clarification of tumor size/number in seven, and biopsy in three. Twelve of the 14 laparoscopic procedures included laparoscopic radiofrequency ablation while one received ethanol ablation. One patient required 2 units of red blood cells. One patient died on postoperative day 7 because of gastrointestinal bleeding. Four of the six down-staged patients underwent liver transplant, and pathological staging of the explants agreed with laparoscopic staging in all cases. CONCLUSION: Laparoscopic staging for HCC in advanced cirrhosis can clearly characterize tumor burden when preoperative radiological assessment is equivocal.

Potentially curative treatment in patients with hepatocellular cancer--results from the liver cancer research network.

BACKGROUND: The extent to which potentially curative therapies are used in patients with hepatocellular cancer (HCC) and their related outcomes are unknown in the US. AIM: To determine the rate and outcomes of potentially curative treatment in patients with HCC. METHODS: Eleven US centers followed patients with HCC between 2001 and 2007. We determined rates of liver transplantation, surgical resection, or tumour ablation during follow-up, examined differences in adjusted survival of patients receiving these treatments, and determined the factors associated with receipt of potentially curative treatment. RESULTS: Of the 267 patients, 76 (28%) patients had early HCC, defined as Child A or B cirrhosis, with a solitary HCC or ≤ 3 nodules, each ≤ 3 cm. Of these, 53 (69.7%) received curative treatment. Thirty six percent of patients with non-early HCC received curative treatment. Compared to patients with non-early HCC who did not receive curative treatment, patients with early HCC and curative treatment had the best survival [hazard ratio, HR = 0.19 (95% CI, 0.08-0.42)] followed by patients with advanced HCC who received curative treatment [HR = 0.37 (95% CI, 0.22-0.64)]. Baseline performance status was significantly associated with receipt of curative treatment as well as survival after adjusting for demographics, clinical characteristics, and HCC stage. CONCLUSIONS: In this multicenter database, most of the patients with early HCC received potentially curative treatment. However, only 28% of patients had early HCC. One-third of patients with non-early HCC also underwent curative therapy. Potentially curative treatment improved survival and this effect was seen in patients with early as well as non-early HCC.