Metastatic tumor antigen in hepatocellular carcinoma: golden roads toward personalized medicine.

Hepatocellular carcinoma (HCC), a prototype of hypervascular tumors, is one of the most common malignancies in the world, especially hyperendemic in the Far East where chronic hepatitis B virus (HBV) infection is highly prevalent. It is characterized by the clinical feature of a poor prognosis or a high mortality due to its already far advanced stages at diagnosis. It is so multifactorial that hepatocarcinogenesis cannot be explained by a single molecular mechanism. To date, a number of pathways have been known to contribute to the development, growth, angiogenesis, and even metastasis of HCC. Among the various factors, metastatic tumor antigens (MTAs) or metastasis-associated proteins have been vigorously investigated as an intriguing target in the field of hepatocarcinogenesis. According to recent studies including ours, MTAs are not only involved in the HCC development and growth (molecular carcinogenesis), but also closely associated with the post-operative recurrence and a poor prognosis or a worse response to post-operative anti-cancer therapy (clinical significance). Herein, we review MTAs in light of their essential structure, functions, and molecular mechanism in hepatocarcinogenesis. We will also focus in detail on the interaction between hepatitis B x protein (HBx) of HBV and MTA in order to clarify the HBV-associated HCC development. Finally, we will discuss the prognostic significance and clinical application of MTA in HCC. We believe that this review will help clinicians to understand the meaning and use of the detection of MTA in order to more effectively manage their HCC patients.

Tumor Necrosis Factor-Alpha Gene Polymorphism Associated With Development of Hepatitis B Virus-associated Hepatocellular Carcinoma.

GOAL AND BACKGROUND: Host genetic diversity may play roles in development of HCC. This study was conducted to validate the effects of tumor necrosis factor-alpha (TNF-α) gene polymorphism on development of hepatocellular carcinoma (HCC) in patients chronically infected with hepatitis B virus (HBV). STUDY: The study cohort comprised 224 patients with HBV-associated HCC and 206 with HBV-associated liver cirrhosis (LC). Using chromosomal DNA, TNF-α promoter gene polymorphisms were determined at 3 common single-nucleotide polymorphism (SNP) sites (TNF-α-1031 T>C, TNF-α-857 C>T, and TNF-α-308 G>A) using a single base extension method. The genotype distributions were compared between the 2 groups. All the HBV-associated LC patients were followed up regularly every 6 to 12 months for surveillance of HCC development. RESULTS: In the cross-sectional analysis, the frequency of TNF-α-857 T allele was much higher in patients with HCC compared with those with LC (42% vs. 31%, P<0.01). Of 206 HBV-associated LC patients, 12 (5.8%) developed HCC during the median follow-up period of 36 months. The cumulative occurrence rates of HCC were significantly higher in patients with TNF-α-857 T allele than those withTNF-α-857 C/C genotype (1-, 3-, and 5-y rates: 2.9%, 12.8%, and 20.7% vs. 0%, 3.1%, and 5.3%, respectively; P=0.013). However, the other genetic polymorphisms of TNF-α promoter gene did not affect the development of HCC. In multivariate analysis, TNF-α-857 T allele was a significant predictor of HCC development (hazard ratio 6.29, P=0.01). CONCLUSION: Our data suggest that TNF-α-857 T allele is closely associated with development of HCC in HBV-associated LC patients.

Safety and efficacy of adjuvant pegylated interferon therapy for metastatic tumor antigen 1-positive hepatocellular carcinoma.

BACKGROUND: Metastatic tumor antigen 1 (MTA1) overexpression is closely associated with postoperative recurrence of hepatocellular carcinoma (HCC). It has been suggested that pegylated interferon (Peg-IFN) can prevent the occurrence of HCC in patients who have chronic viral hepatitis. In this study, the authors examined whether postoperative adjuvant Peg-IFN therapy can reduce the recurrence of MTA1-positive HCC after curative surgical resection. METHODS: In this case-control study, 93 patients with MTA1-positive HCC who underwent curative surgical resection were prospectively enrolled. The median patient age was 53 years (range, 27-78); there were 65 men and 28 women; the etiology was hepatitis B virus (HBV) in 77 patients, hepatitis C virus (HCV) in 6 patients, and non-HBV/non-HCV in 10 patients; 31 patients received Peg-IFN (Peg-INTRON) subcutaneously at a dose of 50 µg per week for 12 months (the Peg-IFN group); and the remaining 62 patients were followed only and did not receive any adjuvant therapies (control group). Patients were followed every 1 to 3 months for a median of 24 months. RESULTS: HCC recurred postoperatively in 26 of 93 patients (28%), and 9 patients (10%) died during follow-up. The overall cumulative recurrence rates were significantly lower in the Peg-IFN group than in the control group (7% and 14% vs. 24% and 34% at 1 year and 2 years, respectively; P < .05). In addition, the 1-year and 2-year cumulative survival rates were higher in the Peg-IFN group compared with the control group (100% vs. 93% and 100% vs. 87%, respectively; P < .05). In multivariate analysis, the receipt of adjuvant Peg-IFN therapy, in addition to having a lower Cancer of the Liver Italian Program score and being a woman, was an independent, favorable factor for a lower risk of postoperative recurrence. CONCLUSIONS: The current data indicate that adjuvant Peg-IFN therapy may reduce the recurrence of HCC in patients who have MTA1-positive HCC after curative surgical resection.

Factors predisposing metastatic tumor antigen 1 overexpression in hepatitis B virus associated hepatocellular carcinoma.

BACKGROUND/AIM: Overexpression of metastatic tumor antigen-1 (MTA-1) is suggested to be associated with frequent postoperative recurrence and poor survival of hepatocellular carcinoma (HCC) patients. In this study, we intended to determine clinical factors predisposing the overexpression of MTA-1 in patients with hepatitis B virus (HBV)-associated HCC and also examine whether MTA-1 overexpression affects the survival periods of these patients treated with curative surgical resection. METHODS: A total of 303 patients with HBV-associated HCC who underwent curative surgical resection were subjected. The expressions of MTA-1 in HCC and surrounding non-tumor liver tissues were evaluated using the immunohistochemical method. The clinical, radiological and histological characteristics of the patients were analyzed in relation to the expression of MTA-1 to find predisposing factors of MTA-1 overexpression. RESULTS: MTA-1 was overexpressed in 104 HCC tissues (34.3 %) and none of the surrounding non-tumor tissues. Clinically, MTA-1 overexpression was significantly associated with younger age, female gender, higher serum alpha-fetoprotein level, and Child-Turcotte-Pugh class A. Also, portal vein thrombosis, microvascular invasion, capsular invasion and poorly histological differentiation were associated with overexpression of MTA-1. The cumulative survival rates were significantly lower in patients with MTA-1 overexpression compared with those in the MTA-1 negative group (P = 0.03). In addition to the overexpression of MTA-1, the presence of microvascular or capsular invasion was a significant factor determining the poor survival of the patients with HBV-associated HCC after curative resection. CONCLUSIONS: MTA-1 is overexpressed in patients with HBV-associated HCC of invasive nature. MTA-1 overexpression is associated with shorter survival periods of patients with HBV-associated HCC after curative resection.

Retreatment of Chronic Hepatitis C Failed to Daclatasvir Plus Asunaprevir by Other Direct-acting Antivirals.

The pegylated interferon plus ribavirin combination therapy has been used as the primary treatment for chronic hepatitis C (CHC) but fails to produce a sustained viral response (SVR) in many patients. In recent years, the treatment of CHC has been rapidly changing because of the introduction of direct-acting antivirals (DAAs), which have a high cure rate. However, retreatment of patients after failure of the first DAA therapy is difficult. We report two rare cases of CHC that showed acquired SVR with other DAA combinations after failure to daclatasvir and asunaprevir.

Successful Medical Treatment for Peritonitis Resulting from a Large Pyogenic Liver Abscess Rupture.

The rupture of a pyogenic liver abscess (PLA) with peritonitis is a rare occurrence but a surgical emergency with a high mortality rate in the case of gas-forming PLA. Rare cases of ruptured PLA that recovered completely with only medical treatment have been reported. This paper reports a case of a large PLA rupture with peritonitis. In this case, surgical intervention was too risky because of the patient's age and poor general condition. The patient recovered fully with appropriate antibiotic therapy and sufficient percutaneous drainage. Therefore, medical treatment may be considered an alternative option in cases of a ruptured large PLA with peritonitis if surgical intervention is too risky.

[The difference of clinicopathologic features according to leptin expression in colorectal adenoma].

BACKGROUND/AIMS: Colorectal adenoma and cancer are known to be associated with obesity. Leptin, an adipocyte-derived hormone that plays a crucial role in obesity has been suggested as a growth factor in colon cancer. However, the association between adenoma and leptin remains controversial. We evaluated the leptin expression in human colorectal adenoma and its correlation to clinicopathologic factors. METHODS: Leptin expression was assessed by immunohistochemistry in 91 samples of colorectal adenoma larger than 5 mm, which were removed by endoscopic polypectomy. All patients underwent colonoscopy for cancer screening at Seoul Paik Hospital from 2007 to 2008 and we only included the patients less than 50 years of age. Leptin expression and its relationship with clinicopathologic features were analyzed. RESULTS: Eighty samples were available for the interpretation of leptin expression and showed positive in 42 (52.5%) cases and negative in 38 (47.5%) cases. As body mass index (BMI) increased based on World Health Organization (WHO) classification the positivity of leptin expression also increased (ptrend=0.02). In leptin positive group, the correlation of leptin expression with adenoma size and histological showed positive tendency without statistical significance. CONCLUSIONS: Leptin expression of colorectal adenoma was associated with BMI. The question of whether leptin contributes to colorectal adenoma development is unresolved and will require additional studies.

Chronic Non-granulomatous ulcerative jejunoileitis assessed by wireless capsule endoscopy.

Chronic non-granulomatous jejunoileitis is a rare disease characterized by malabsorption, abdominal pain, and diarrhea that causes shallow ulcers in the small bowel. The etiology of chronic non-granulomatous jejunolieitis remains unknown. A 69-year-old man complained of abdominal pain and lower extremity edema. A 99m-Tc albumin scan showed increased radioactivity at the left upper quadrant, suggesting protein-losing enteropathy. A small bowel follow-through did not disclose any lesions. Wireless capsule endoscopy revealed several small bowel ulcers and strictures. A jejunoileal segmentectomy with end-to-end anastomosis was performed, and the histologic examination revealed non-granulomatous ulcers with focal villous atrophy. Ruling out all other possible diagnoses, we diagnosed our patient with chronic non-granulomatous ulcerative jejunoileitis. Postoperatively, the patient's abdominal pain and lower extremity edema improved, and the serum albumin normalized. This is the first case of chronic non-granulomatous ulcerative jejunoileitis localized by wireless capsule endoscopy and treated successfully with segment resection.

[The usefulness of endoscopic ultrasonography in the diagnosis of choledocholithiasis without common bile duct dilatation].

BACKGROUND/AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) is the most accurate modality in diagnosis of choledocholithiasis. However, it carries some complications. Endoscopic ultrasonography (EUS) is less invasive than ERCP and used for the diagnosis of choledocholithiasis. Recent studies showed that a usefulness of EUS for the diagnosis of small choledocholithiasis without common bile duct (CBD) dilatation. For such a reason, ERCP is being replaced by EUS in the diagnosis of bile duct stones. The aim of this study was to investigate the accuracy of EUS for the diagnosis of choledocholithiasis without CBD dilatation. METHODS: A total of 66 patients with suspected choledocholithiasis without CBD dilatation were enrolled. EUS were performed in all cases within 48 hours after computed tomography (CT) or ultrasonography (US). Final diagnosis was obtained by ERCP or clinical course (minimum 6 months follow-up). We analyzed the accuracy of US, CT, and EUS, respectively. RESULTS: CT and US were performed in 51 and 15 cases, respectively. CBD stones were detected in 23 (35%) patients by ERCP. EUS showed 100% sensitivity, 95% specificity, 92% positive predictive value, and 100% negative predictive value for identifying CBD stones. CT or US showed 26%, 93%, 67%, and 70%, respectively. There were no EUS-related complications. CONCLUSIONS: EUS was more effective than CT or US and as accurate as ERCP for the diagnosis of small choledocholithiasis without CBD dilatation. Thus, EUS may help to avoid unnecessary diagnostic ERCP and its complication.

[The incidence and clinical features of Clostridium difficile infection; single center study].

BACKGROUND/AIMS: Clostridium difficile is the predominant cause of nosocomial diarrhea. Recently, the incidence of Clostridium difficile infection (CDI) increases in Europe and North America. A retrospective study was performed to evaluate the change of incidence and clinical features of CDI in Korea. METHODS: From January 2003 to December 2008, inpatients diagnosed with CDI in Seoul Paik hospital were enrolled. The diagnosis of CDI was made when patients complained diarrhea with any positive results in C. difficile toxin assay, stool culture, or endoscopy. The incidence, recurrence rate, and clinical features were compared between early period (2003-2005) and late period (2006-2008). RESULTS: The incidence of CDI was 21.73 cases per 10,000 admitted patients in early period group, and significantly increased to 71.71 cases per 10,000 admitted patients in late period group (p < 0.01). The hospital stay duration at the time of CDI diagnosis was shorter in late period group. Cephalosporin had the highest ratio as the causative antibiotics of CDI. However, there was no difference in recurrence rate between early and late period groups. Recurrence associated clinical factor was serum albumin level. CONCLUSIONS: The incidence of CDI showed increasing tendency during recent 6 years. The awareness of increasing disease burden is the first step in control of CDI.

Visceral Artery Pseudoaneurysm Rupture after Endoscopic Retrograde Cholangiopancreatography.

A visceral artery pseudoaneurysm after ERCP is a rare adverse event that is potentially life-threatening. Most cases reported previously originated from the peripancreatic arteries, including the splenic artery, gastroduodenal artery, or pancreaticoduodenal artery. The mechanism of the occurrence of visceral artery pseudoaneurysms after ERCP has not been elucidated until now. Recently, a pseudoaneurysm rupture originating from the superior mesenteric artery after ERCP was observed in a patient without a history of pancreatitis. This paper reports this case with a review of the relevant literature.

Rare Clinical and Radiologic Case of Cholangiocarcinoma Mimicking Pyogenic Abscess, Hepatic Echinococcal Cysts, and Metastases.

Cholangiocarcinoma is a biliary carcinoma with a wide spectrum of imaging, histological, and clinical features. In immunocompromised patients, pyogenic abscesses are relatively common and an echinococcal hepatic cysts are very rare. The authors experienced a very rare case of cholangiocarcinoma showing multiple hypodense masses with wall enhancement mimicking pyogenic liver abscess, echinococcal hepatic cyst, and cystic metastases. An 83-year-old man, complaining of fatigue and poor oral intake, presented to our outpatient clinic. Abdominal computed tomography (CT) revealed multiple, variable-sized hypodense masses with peripheral rim enhancement throughout the liver. Dynamic liver magnetic resonance images also showed findings similar to those of a CT scan. We performed ultrasound-guided biopsy of the mass which revealed cholangiocarcinoma.

Lack of association between genotypes and subtypes of HCV and occurrence of hepatocellular carcinoma in Egypt.

The distribution of hepatitis C virus (HCV) genotypes was evaluated in individuals with hepatocellular carcinoma (HCC) and cirrhosis in Egypt. A total of 206 patients sero-positive for HCV-RNA among 400 surveyed individuals (186 with HCC, 100 with cirrhosis, and 114 healthy volunteers) were analyzed for HCV genotype. Of 206 patients, 129 had HCC, 65 had cirrhosis without HCC, and 12 were healthy volunteers. Phylogenetic analysis of sequence showed that of 206 samples, 186 contained HCV genotype 4 (90.3%), while 20 had HCV genotype 1 (9.7%). Among subjects with genotype 4, subtype 4a was predominant (79%), other subtypes included 4d, 4m, 4n, and 4o. Among those with HCV genotype 1, 15 had subtype 1g and five subtype 1a. Although subtype 4a was noted slightly more frequently in HCC (76%) compared to cirrhosis (66%) and controls (50%), there was no statistically significant difference between these three groups (P = 0.08). In conclusion, HCV genotype 4 predominates in Egypt. There was no association between subtypes of genotype 4 and the development of HCC.

Metastatic tumor antigen 1 is closely associated with frequent postoperative recurrence and poor survival in patients with hepatocellular carcinoma.

Metastatic tumor antigen 1 (MTA1) is known to play a role in angiogenic processes as a stabilizer of hypoxia-inducible factor 1-alpha (HIF1-alpha). In this study, we examined whether overexpression of MTA1 affects the recurrence of hepatocellular carcinoma (HCC) after surgical resection and the survival of the patients. A total of 506 HCC patients who underwent hepatic resection were included in the study. They were followed up for a median of 43 months (range, 1-96 months) after hepatectomy. MTA1 expression levels were determined by the proportion of immunopositive cells (none, all negative; +, <50%; ++, >50%). The relationships between MTA1 expression and the HCC histological features, the appearance of recurrent HCC after surgical resection, and the survival of the patients were examined. Eighty-eight cases (17%) of the HCCs were positive for MTA1, although the surrounding liver tissues were all negative for MTA1; 62 cases were + and 26 cases were ++. Increased MTA1 expression levels in HCC were correlated with larger tumors (P = 0.04), perinodal extension (P = 0.03), and microvascular invasion (P = 0.008). Histological differentiation had marginal significance (P = 0.056). However, there was no association between MTA1 expression and age, sex, Child-Pugh class, and capsule invasion of HCC. Interestingly, MTA1 expression levels were significantly greater in hepatitis B virus (HBV)-associated HCC compared with hepatitis C virus (HCV)-associated HCC (P = 0.017). The cumulative recurrence rates of MTA1-positive HCCs were markedly greater than those of MTA1-negative HCCs (P < 0.0001). The cumulative survival rates of patients with MTA1-positive HCCs were significantly shorter than those of patients with MTA1-negative HCCs (P < 0.0001). In conclusion, our data indicate that MTA1 is closely associated with microvascular invasion, frequent postoperative recurrence, and poor survival of HCC patients, especially in those with HBV-associated HCC.

Antifibrogenic effects of tamoxifen in a rat model of periportal hepatic fibrosis.

BACKGROUNDS/AIMS: It has been reported that tamoxifen may affect hepatoma cell growth in vitro by suppressing transforming growth factor beta-1 (TGF-beta1) expression, suggesting that tamoxifen might also retard fibrogenesis. Thus, we examined whether tamoxifen might suppress TGF-beta1 expression and consequently inhibit the process of hepatic fibrosis in vivo. METHODS: To induce periportal hepatic fibrosis, 50 male adult Sprague-Dawley rats were injected with 0.62 mmol/kg of allyl alcohol, intraperitoneally, twice a week for 8 weeks. Hepatic fibrosis scores, intrahepatic collagen levels and plasma TGF-beta1 expression levels were evaluated in three groups of 10 rats orally administered tamoxifen at 1, 5 and 10 mg/kg, respectively, and in 20 controls. Messenger RNAs (mRNAs) encoding TGF-beta1 and TGF-beta receptors in liver tissue were semiquantified using reverse transcriptase polymerase chain reaction. RESULTS: Hepatic fibrosis scores decreased progressively as the dose of tamoxifen increased, resulting in a significant change in rats treated with tamoxifen at 10 mg/kg compared with controls (P=0.018). Intrahepatic collagen content was significantly less in the group treated with tamoxifen at 10 mg/kg compared with the control (P=0.045). Plasma TGF-beta1 levels were also significantly lower in rats treated with tamoxifen at 10 mg/kg compared with controls (P=0.007). All three concentrations of tamoxifen tested decreased the expression levels of hepatic TGF-beta1 mRNA and type I TGF-beta receptor (TGF-beta RI) mRNA to similar extents. CONCLUSIONS: Tamoxifen seems to inhibit the process of hepatic fibrosis dose-dependently by suppressing the transcription of TGF-beta1 and TGF-beta RI in an experimental model of periportal hepatic fibrosis.

Overexpression of metastasis-associated protein 2 is associated with hepatocellular carcinoma size and differentiation.

BACKGROUND AND AIM: Metastasis is a multistep event in which neoplastic cells detach from the tumor, migrate, disseminate, extravasate, and eventually proliferate at the secondary distant sites. Hepatocellular carcinoma (HCC) is characterized by hypervascularity and frequent metastasis. Recently, metastasis-associated proteins were identified and named metastatic tumor antigens (MTA) 1, 2, and 3. They have been found to be contained in the nucleosome remodeling and histone deacetylase complex. MTA2 has been reported to interact with p53 and inhibit p53-mediated cell growth arrest and apoptosis by deacetylation. Although it has been reported that the expression of MTA1 is related to tumor progression and metastasis, it is still unclear how MTA2 is involved in HCC. In this study, we found that the overexpression of MTA2 is associated with HCC size and differentiation after hepatectomy. METHODS: The expression of MTA2 was examined in 506 human HCC samples that underwent hepatic resection using tissue microarray. The expression of MTA2 was classified into 0, 1, 2, and 3, based on immunoreactivity. RESULTS: The expression of MTA2 was predominantly localized to the nucleus. MTA2 was detected in 487 (96.2%) of the 506 human HCC samples. Notably, the MTA2 expression level strongly increased depending on the size and differentiation of HCC. CONCLUSIONS: These findings indicate a tight correlation between the MTA2 expression level and HCC size and differentiation. Therefore, MTA2 might be a predictor of aggressive phenotypes and a possible target molecule for anticancer drug design in human HCC.

Trichuris trichiura infection diagnosed by colonoscopy: case reports and review of literature.

Trichuris trichiura, commonly referred to as a whipworm, has a worldwide distribution, particularly among countries with warm, humid climates. In Korea, trichuriasis was a highly prevalent soil-transmitted helminthiasis until the 1970s. However, the nationwide prevalence decreased to 0.02% in 2004 as a result of national control activities and improvement in the socioeconomic status of Koreans. Most infected individuals have no distinct symptoms, if lightly infected. The diagnosis is typically confirmed by detection of T. trichiura eggs on examination of a stool sample; few reports have described detection of the parasite during colonoscopy. Recently, we managed 4 patients with trichuriasis who were diagnosed by detection of the parasite on colonoscopy, and we reviewed the literature on the colonoscopic diagnosis of T. trichiura in Korea. We suggest that colonoscopy might be a useful diagnostic tool, especially when infected by only a few male worms with no eggs in the stool.

Synchronous Primary Leiomyosarcoma in the Thoracic Vertebra and the Liver.

This is a case report of simultaneous primary leiomyosarcomas in the spine and liver. A 64-year-old woman presented to the Seoul Paik Hospital with epigastric discomfort and constipation that she had experienced for two months. A physical examination revealed severe tenderness around the thoraco-lumbar junction. Esophagogastroduodenoscopy showed an ulceroinfiltrative lesion on the gastric angle. An abdominopelvic CT scan revealed two low attenuated lesions in the S4 and S8 regions of the liver, as well as a soft tissue mass at the T10 vertebra. Percutaneous ultrasonography-guided needle biopsy of the hepatic nodules revealed a leiomyosarcoma. The tumor at the T10 vertebra was removed to avoid spinal cord compression. The histology of this tumor was compatible with that of leiomyosarcoma. The potential primary sites for leiomyosarcoma, including the lung, thyroid, breast, kidney, genitourinary organs, and gastrointestinal tract, were subsequently investigated. No detectable abnormal findings that would suggest the origin of the tumor were found. Synchronous primary leiomyosarcomas in the spine and liver are quite rare and have a poor prognosis.

Mycobacterium ulcerans infection as a cause of chronic diarrhea in an AIDS patient: a case report.

Chronic diarrhea is one of the most frequent gastro-intestinal manifestations in acquired immunodeficiency syndrome (AIDS). Protozoa and nontuberculous mycobacteria (NTM) are opportunistic pathogens that can easily infect these patients. Among the NTM, Mycobacterium avium complex (MAC) is the most frequently observed pathogen in HIV-infected patients. However, NTMs other than MAC have not been reported as a gastrointestinal pathogen as yet. We present a case of chronic diarrhea in an AIDS patient in whom Mycobacterium ulcerans and cryptosporidium co-infection is evidenced from colonic tissue.