Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells

BACKGROUND/AIMS: Silibinin, the main component of silymarin, is used as a hepatoprotectant and exhibits anticancer effects against various cancer cells. This study evaluated the effects of a combination of silibinin with either gefitinib or sorafenib on hepatocellular carcinoma (HCC) cells. METHODS: Several different human HCC cell lines were used to test the growth-inhibiting effects and cell toxicity of silibinin both alone and in combination with either gefitinib or sorafenib. The cell viability and growth inhibition were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and a colony-forming assay. Furthermore, changes in epidermal growth factor receptor (EGFR)-related signals were evaluated by Western blot analysis. RESULTS: Gefitinib, sorafenib, and silibinin individually exhibited dose-dependent antiproliferative effects on HCC cells. Combined treatment with silibinin enhanced the gefitinib-induced growth-inhibiting effects in some HCC cell lines. The combination effect of gefitinib and silibinin was synergistic in the SNU761 cell line, but was only additive in the Huh-BAT cell line. The combination effect may be attributable to inhibition of EGFR-dependent Akt signaling. Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin. CONCLUSIONS: Combined treatment with silibinin enhanced the growth-inhibiting effects of both gefitinib and sorafenib. Therefore, the combination of silibinin with either sorafenib or gefitinib could be a useful treatment approach for HCC in the future.

Allopurinol-induced DRESS syndrome mimicking biliary obstruction

An 84-year-old man was admitted to our hospital with fever, jaundice, and itching. He had been diagnosed previously with chronic renal failure and diabetes, and had been taking allopurinol medication for 2 months. A physical examination revealed that he had a fever (38.8degrees C), jaundice, and a generalized maculopapular rash. Azotemia, eosinophilia, atypical lymphocytosis, elevation of liver enzymes, and hyperbilirubinemia were detected by blood analysis. Magnetic resonance cholangiography revealed multiple cysts similar to choledochal cysts in the liver along the biliary tree. Obstructive jaundice was suspected clinically, and so an endoscopic ultrasound examination was performed, which ruled out a diagnosis of obstructive jaundice. The patient was diagnosed with DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome due to allopurinol. Allopurinol treatment was stopped and steroid treatment was started. The patient died from cardiac arrest on day 15 following admission.

A Multicenter Phase II Trial of Gemcitabine Plus Oxaliplatin in Unresectable Gallbladder Cancer

BACKGROUND/AIMS: No standard chemotherapy has been established for advanced gallbladder cancer. The authors studied the activity and tolerability of a gemcitabine and oxaliplatin (GEMOX) combination in unresectable gallbladder cancer (GBC). METHODS: Adult patients with pathologically confirmed unresectable GBC were prospectively recruited at three centers. No patient had received prior chemotherapy or radiotherapy. Patients received cycles of gemcitabine at 1,000 mg/m2 on day 1, followed by oxaliplatin at 100 mg/m2 on day 2, every 2 weeks. The primary study endpoint was time to progression. RESULTS: Forty patients with unresectable GBC were enrolled. The median age was 60 years (range, 38 to 79 years). All patients showed good performance status. Of the 33 analyzable patients, 12 achieved partial response (36%), 17 stable disease (52%), and four progressive disease (12%). No patient achieved a complete response. The tumor control rate was 88%. At a median follow-up of 6.8 months, the median time to progression was 5.3 months (95% confidence interval [CI], 3.7 to 6.9), and median overall survival was 6.8 months (95% CI, 6.1 to 7.5). Nine of the 40 patients (23%) experienced at least a grade-3 adverse event, but no patient experienced a grade-4 adverse event. CONCLUSIONS: GEMOX combination therapy is a feasible option and is well tolerated in unresectable GBC.

A Case of Cholangiocarcinoma with Brain and Leptomeningeal Carcinomatosis / 대한내과학회지

Cholangiocarcinoma is a malignant disease originating from the epithelium of the biliary tract, and its prognosis is dismal due to distant metastasis in its early stages. The most common metastatic sites are the intra-abdominal organs, lymph nodes, and lungs. A patient was diagnosed with intrahepatic cholangiocarcinoma and underwent surgical resection. During the follow-up period, metastases were detected at the remnant liver and both lung fields. Eleven months after resection, the patient complained of severe headache. An approximately 5-cm cystic mass was found at the left occipital lobe of the cerebrum, and metastatic malignant cells were present on cerebrospinal fluid cytology. The patient underwent whole-brain radiotherapy. We herein report a rare case of cholangiocarcinoma with cystic brain metastasis together with a review of the relevant literature.

Focal-Type Autoimmune Pancreatitis Mimicking Cholangiocarcinoma / 대한내과학회지

Autoimmune pancreatitis (AIP) is a rare pancreatic disorder of autoimmune etiology. It has characteristic clinical features, such as pancreatic parenchymal swelling and irregular narrowing of the main pancreatic duct due to plasma cell infiltration. It occurs mostly in Far East Asia. Although it generally involves whole pancreatic parenchyma, some cases demonstrate focal involvement of the pancreas or adjacent organs, which are often mistaken for cancer. We report a case of AIP that was confused with cholangiocarcinoma of the distal common bile duct (CBD). The patient experienced sudden development of jaundice with vague abdominal discomfort. Abdominal computed tomography revealed a well-enhanced lesion, and positron emission tomography showed high standard uptake value at the distal CBD, indicating malignant disease. However, pathological examination by surgical excision indicated focal-type AIP. This is believed to be the first case of focal-type AIP mimicking cholangiocarcinoma.

Pancreatic Endocrine Tumors: Clinical Manifestations and Predictive Factors Associated with Survival / 대한소화기학회지

BACKGROUND/AIMS: Since pancreatic endocrine tumors (PET) are rare and heterogeneous diseases, their survival and prognosis are not well known. Due to recent advances in CT/MRI technology, incidentalomas of the pancreas are detected with increasing frequency. This study presents results of clinical manifestations of PET and predictive factors associated with survival. METHODS: From year 1990 through 2006, medical records of 98 patients (56 men, 42 women) who were diagnosed as PET pathologically at Seoul National University Hospital were reviewed retrospectively. RESULTS: Ages ranged from 17 to 76 years (mean 51.6+/-1.3 years) with a mean follow-up of 3.6+/-0.4 years (range 0-10.1 years). Overall 5-year survival rate was 68.1%, and 5-year survival rate of the patients who had distant metastases at initial diagnosis was 43.9%. Functioning tumors [hazard ratio (HR) 0.229, 95% confidence interval (CI) 0.056-0.943, p=0.041] and lymph node or liver metastases (HR 5.537, 95% CI 2.106-14.555, p<0.001) were the significant prognostic factors associated with survival rate. However, tumor size and pathology showed no significant association with survival. CONCLUSIONS: Because small and pathologically benign nature do not predict good prognosis in PET, aggressive treatment such as curative resection would be considered initially even in the case of incidental PET.

NK/T cell lymphoma developed during the follow up period of Kimura's disease / 대한내과학회지

Kimura's disease is a rare chronic inflammatory disease of the lymphoid organs and this presents as painless nodules in the head and neck area. It occurs endemically in the Far East Asia and sporadically in the West. Its exact etiology is unknown and it has no potential to transform into malignant disease. However, it is often confused with malignant disease such as malignant lymphoma. We report a case of NK/T cell lymphoma patient who had Kimura's disease in the right thigh 3 years ago. She then suffered from sudden dyspnea. Radiological studies revealed multiple small nodules scattered in both lung fields. NK/T cell lymphoma was diagnosed by open lung biopsy. In addition, Epstein-Barr virus (EBV) was detected in the previous site of Kimura's disease and lung nodule by molecular pathologic examination. To the best of our knowledge, this is the first case of NK/T cell lymphoma complicating Kimura's disease with coexisting chronic EBV infection.

The Diagnostic Accuracy of Endoscopic Ultrasonography for the Preoperative Staging of Gastric Cancer: the Risk of Overstaging and Understaging / 대한소화기내시경학회지

BACKGROUND/AIMS: The preoperative staging of gastric cancer facilitates the planning of therapy. Preoperative endoscopic ultrasonography is a useful procedure for the staging of gastric cancer, but sometimes there can be problems with overstaging and understaging. METHODS: Endoscopic ultrasonography was performed preoperatively on 171 patients with gastric cancer. The results of endoscopic ultrasonography were compared with the postoperative histological staging. RESULTS: The overall accuracy of endoscopic ultrasonography for the determination of the T stage was 65.5%, the overall accuracy was 74.4%, 51.7% and 38.9% for determining the T1, T2 and T3 staging, respectively. Endoscopic ultrasonography had an accuracy of 67.3% for determining the absence of lymph node metastasis. In univariate analysis, the diagnostic accuracy was lower for infiltrative type and gastric cancer with microinvasion significantly. Multivariate analysis showed overstaging occurred for gastric cancers with concomitant ulcer, inflammation or submucosal fibrosis (p=0.004) and that understaging occurred for gastric cancers with infiltrative type or microinvasion (p=0.029, p<0.001). CONCLUSIONS: Endoscopic ultrasonography is a valuable diagnostic tool for most gastric cancers with some exceptions due to the overstaging and understaging. Gastric cancers with concomitant ulcer, inflammation or submucosal fibrosis may contribute to overstaging. By contrast, gastric cancers with infiltrative type or microinvasion may result in understaging.

A Case of Exophytic Squamous Cell Carcinoma of the Stomach / 대한소화기내시경학회지

Squamous cell carcinoma of the stomach has been reported to occur at a younger age and have a worse prognosis than gastric adenocarcinoma. Even though squamous cell carcinoma of the stomach has several different clinical characteristics, it is difficult to distinguish it from gastric adenocarcinoma by radiological or endoscopical methods without a histopathological confirmation. Primary squamous cell carcinoma of the stomach is a rare type of cancer. To date, only six cases have been reported in Korea. Gastric cancer seldom grows exophytically and there are no reports of squamous cell carcinoma of the stomach with exophytic growth in Korea. We report a case of pure squamous cell gastric cancer with exophytic growth with a brief review of the relevant literature.

Risk Factors for Upper Gastrointestinal Rebleeding in Critically Ill Patients / 대한소화기내시경학회지

BACKGROUND/AIMS: To determine the incidence and risk factors associated with rebleeding after upper gastrointestinal bleeding (UGIB) in critically ill patients. METHODS: This study retrospectively reviewed the medical records of 60 patients undergoing bedside esophagogastroduodenoscopy between April 2000 and February 2004 for UGIB that developed whilst in the intensive care unit (ICU). RESULTS: Eight out of 60 patients died within 7 days, and an additional 7 patients died within 30 days after the initial bleeding. Two of these 15 patients (13.3%), died from GI bleeding. The 7-day and 30-day rebleeding rates were 34.6% (18/52 patients), and 51.1% (23/45 patients), respectively. Multiple logistic regression using the significant variables revealed, anemia (Hb or =3 units) to be significant independent risk factor for 30-day rebleeding. CONCLUSIONS: The rebleeding rates in the ICU setting were as high as 34.6% at 7 days and 51.1% at 30 days. This suggests that the underlying conditions of the critically ill patients affect the rebleeding rate more than the endoscopic features. Therefore, adequate general ICU care including the prevention and correction of hypoxia, anemia, and hypoalbuminemia, and minimizing blood loss can reduce the risk of rebleeding after UGIB in an ICU setting.

Surgical Treatment of 3 cases of Takayasu Arteritis with Renovascular Hypertension

Renovascular hypertension secondary to renal artery vascular disease is the most common form of surgically correctable hypertension. The common causes of renovascular hypertension are atherosclerosis, fibromuscular dysplasia, and Takayasu arteritis. Takayasu arteritis is a chronic nonspecific arteritis of unkown cause that is relatively prevalant in young female subjects. It has been well known that the pathologic feature of the disease consist predominantly of occulsive changes in the aorta and the origin of its major branches. The most important pathogenetic mechanism of hypertension seems to be through renal artery stenosis. We have experimented three hypertensive patients with Takayasu arteritis experienced. Basic diagnosis was established by angiographic study. This article presents surgical treatment methods of Takayasu arteritis with renovascular hypertension and brief review of literatures.

Cancer of the Colorectum: Analysis of Prognosis

To evaluate the several clinicopathological factors and the expression of P-glycoprotein that influence the survival rate of the patients with colorectal cancer, 168 patients with colonic adenocarcinoma, who were operated in Wonkwang University Hospital from January, 1982 to July 1992 were reviewed. The staging of the tumors were performed according to Astler Coller modification of Dukes classification of colon carcinoma. Immunohistochemical staining for P-glycoprotein test was performed with the specimen of Dukes B2 and C of patient who were received postoperative chemotherapy(ACNU+5FU intravenously or oral 5FU) and/or immunotherapy(PSK or OK-432) over 4 months. P-glycoprotein positive was defined when the tumor cells more than 20% showed red dot in the cytoplasm. Statistical analyses were carried out using SPSS for windows and cumulative survival rate was calculated using the Kaplan-Meier method. 1) Age: under 60 years(n=76) 80.2%, over 60 years(n=61) 72.8%(P>0.05). 2) Sex: male (n=67) 83.2%, female(n=70) 70.7%(P>0.05). 3) The duration of symptoms: under 3 months(n=67) 74.9%, over 3 months(n=70) 79.0% (P>0.05). 4) The location of tumor: left colon(n=45) 85.7%, right colon(n=33) 75.5%, rectum(n=59) 71.7%(P>0.05). 5) The histologic types: well differentiated(n=116) 77.0%, poor differentiated(n=21) 76.2%(P>0.05%). 6) Lymph node metastasis: negative nodes(n=98) 82.7%, positive nodes(n=39) 62.2%(P0.05). 8) Chemotherapy +/- Immunotherapy: In stsge B2, receiving group(n=47) 82.6%, not receiving group(n=17) 74.3%(P>0.05). In stage C, receiving group(n=27) 65.8%, not receiving group (n=11) 53%(P>0.05). 9) P-glycoprotein: In stage B2 and C1, positive expression(n=15) 66.7%, negative expression (n=26) 84.6%(P>0.05). Multivariate analysis indicated that the positive lymph node was independendently correlated with survival. We think that the prognosis of colonic adenocarcinoma are related with lymph node metastasis and the further prospective study are needed for evaluation of the relationship between the prognosis and p-glycoprotein expression.

Clinical analysis of periampullary cancer / 한국간담췌외과학회지

BACKGROUND: Periampullary cancer is referred to malignant tumor that occurs in pancreatic head, distal common bile duct, ampulla of Vater and duodenum according to anatomical position and poor prognosio he clinical symptoms, diagnosis and treatments are identical to positional characteristics. Since 1935, after Whipple originally described the removal of periampullary tumors, both the surgical method and the outcome associated with it have changed extensively. The mortality and morbidity rates associated with the procedure as performed today have decreased. (Objective) The authors evaluated the incidence, resectability and the clinical outcome of periampullary cancer. PATIENTS AND METHODS: We performed the clinical analysis retrospectively on 124 cases of periampullary cancer in the Department of Surgery and Internal medicine, School of Medicine, Wonkwang University from Oct. 1986 to July 1996. RESULTS: There were 77 men and 47 women and the male to female ratio was 1.64:1. The prevalent ages were in the 7th decade (44.4%), and 8th decade (27.4%). Fifty-four pancreatic head carcinomas(43.4%), 40 distal common bile duct carcinomas(32.3%), 28 Ampulla of Vater carcinomas( 22.6%), and 2 carcinomas of the periampullary duodenum(1.6%) were found. The major clinical symptoms and signs were abdominal pain (71%), jaundice (60.5%), and weight loss(33.1%). Resectability of pancreatic head cancer, distal common bile duct cancer, and ampulla of Vater cancer were 44.4%, 72.5%, and 85.7%, respectively. The mean resectability rate was 63.7%. The resection was performed in 60 cases ; Pylorus-preserving pancreaticoduodenectomy (29 cases), Whipple's operation (28 cases), total pancreatectomy (3 cases). The palliative procedure was performed in 14 cases ; gastrojejunostomy (6 cases), choledochotomy with T-tube drainage (5 cases), explolaparotomy with biopsy (4 cases). Postoperative mortality in resection surgery was 8.3%. Postoperative complication in resection surgery was 36.7%. The major causes of postoperative complications were wound complication( 16.7%) and respiratory complication(5.0%). The 1- year and 3-year survival rates after the resection were 47.1% and 22.0%, but those of nonresection group were 15.4% and 0%. The survival rate of resection group was significantly better than that of nonresection group (p<0.05). In the nonresection group, the 1-year survival rate in conservative treatment group including interventional procedure was 8.7% and 0% in palliative surgery group. Survival of nonoperable group was significantly better than that of palliative surgery group (p<0.05). According to anatomical tumor site, the 1-year and 3-year survival rates of pancreatic head cancer were 23.1%, 11.8%, and those of distal common bile duct cancer were 34.2%, 6.5%, and Ampulla of vater cancer 63.0%, 27.0%, respectively. SUMMARY: The pancreas head is the most common site of periampullary cancer. Survival of resection group and conservative treatment group is better than that of nonresection group and palliative surgery group, respectively.