Nerve/Glial Antigen 2: A Novel Target for Anti-Tumor Therapy in Colorectal Cancer.

BACKGROUND/AIMS: To identify cell surface markers selectively expressed by tumor cells and tumor vasculature is the current goal for tumor therapy. One such marker is nerve/glial antigen 2 (NG2), which is a transmembrane glycoprotein. We aimed to investigate the expression of NG2 in colorectal cancer (CRC) and its association with clinicopathological parameters. METHODS: Immunohistochemical staining of NG2, vascular endothelial growth factor, and CD34 in 65 patients diagnosed with CRC over a 5-year period was performed. NG2 expression in both tumor cells and tumor vasculature was scored according to the German Reactive Scoring System. The association between NG2 and patient and tumor characteristics was analyzed. RESULTS: NG2 was expressed by tumor cells in 56.9%, tumor vasculature in 43%, and simultaneously by both in 27.6% of the cases. Tumor cell NG2 was more common in elderly patients (p = 0.023) and vascular NG2 was associated with better tumor differentiation (p = 0.035). Notably, vascular NG2 was expressed in half of the patients with left colon cancer, although it was not expressed in a majority of those with right colon cancer (50.9 vs. 17.7%, p = 0.041). CONCLUSION: Both tumor cell and vascular NG2 expression were shown to be present in a significant number of patients with CRC and this makes NG2 a double target for anti-tumor therapies. Such therapies might be more effective for elderly patients with well-differentiated left colon cancer.

Recent advances in endoscopic management of gastric neoplasms.

The development and clinical application of new diagnostic endoscopic technologies such as endoscopic ultrasonography with biopsy, magnification endoscopy, and narrow-band imaging, more recently supplemented by artificial intelligence, have enabled wider recognition and detection of various gastric neoplasms including early gastric cancer (EGC) and subepithelial tumors, such as gastrointestinal stromal tumors and neuroendocrine tumors. Over the last decade, the evolution of novel advanced therapeutic endoscopic techniques, such as endoscopic mucosal resection, endoscopic submucosal dissection, endoscopic full-thickness resection, and submucosal tunneling endoscopic resection, along with the advent of a broad array of endoscopic accessories, has provided a promising and yet less invasive strategy for treating gastric neoplasms with the advantage of a reduced need for gastric surgery. Thus, the management algorithms of various gastric tumors in a defined subset of the patient population at low risk of lymph node metastasis and amenable to endoscopic resection, may require revision considering upcoming data given the high success rate of en bloc resection by experienced endoscopists. Moreover, endoscopic surveillance protocols for precancerous gastric lesions will continue to be refined by systematic reviews and meta-analyses of further research. However, the lack of familiarity with subtle endoscopic changes associated with EGC, as well as longer procedural time, evolving resection techniques and tools, a steep learning curve of such high-risk procedures, and lack of coding are issues that do not appeal to many gastroenterologists in the field. This review summarizes recent advances in the endoscopic management of gastric neoplasms, with special emphasis on diagnostic and therapeutic methods and their future prospects.

Ectopic opening of the common bile duct and duodenal stenosis: an overlooked association.

BACKGROUND: Ectopic opening of the common bile duct into the duodenal bulb (EO-CBD-DB) is a rare disease that may be complicated by duodenal ulcer, deformity, stenosis and biliary stones. The aim of this study is to report clinical presentations, endoscopic diagnosis and treatment of this entity as well as to investigate its association with duodenal stenosis. METHODS: Gastroduodenoscopic findings and radiological imaging were evaluated for ectopic papilla and duodenal stenosis. Diagnostic methods, endoscopic procedures and long-term outcomes of the endoscopic treatment were presented. RESULTS: EO-CBD-DB was found in 74 (77.1%) of the 96 patients with duodenal deformity/stenosis (79 male, 17 female, mean age: 58.5, range: 30-87 years). The papilla with normal appearance was retracted to the bulb in 11 while it was at its usual location in the remaining 11. The history of biliodigestive surgery was more common in patients with EO-CBD-DB who were frequently presented with the common bile duct stone-related symptoms than the other patients. Thirteen (17.6%) of the patients with EO-CBD-DB were referred to surgery. Endoscopic treatment was completed in 60 (81.1%) patients after an average of 1.7 (range: 1-6) procedures. These patients were on follow-up for 24.8 (range: 2-46) months. Endoscopic intervention was required in 12 (20%) of them because of recurrent biliary problems. Treatment of the patient who had stricture due to biliary injury during laparoscopic cholecystectomy is still continued. CONCLUSIONS: The presence of EO-CBD-DB should be considered particularly in middle-aged male patients who have duodenal deformity/stenosis. Endoscopic treatment is feasible in these patients. The long-term outcomes of endoscopic therapy need to be compared with surgical treatment.

Endoscopic retrograde cholangiography by double balloon enteroscopy in patients with Roux-en-Y hepaticojejunostomy.

BACKGROUND: In patients with Roux-en-Y hepaticojejunostomy (HJ), endoscopic retrograde cholangiography (ERC) cannot usually be achieved since the anastomosis is not reachable via standard duodenoscope. In this study, we report our experience with ERC using double balloon enteroscope (DBE) (DBE-ERC) in patients with HJ. METHODS: The DBE-ERC procedures performed since the index case done dated May 3, 2006 have been overviewed. RESULTS: Fourteen patients underwent the procedure. DBE-ERC was successful in all but one patient, for whom the anastomosis could not be reached (success rate to reach anastomosis: 92.9%). The remaining 13 patients (7 female, 6 male; age 28-61 years, mean 45.3 years) had 20 sessions of DBE-ERC. The cannulation of the bile duct was achieved in all patients. The procedures, such as sphincteroplasty, dilatation, stone extraction and stent placement, were performed. Therapeutic procedures were all successful, except for in a single patient, who had the common bile duct filled with multiple stones and was referred for surgery. Three patients who had anastomotic stenosis treated by stenting are symptom free on follow-up at 3, 9 and 12 months, respectively, after stent removal. Retroperitoneal air was detected in a patient following stricturoplasty, but recovery was attained with medical treatment alone. Mean duration of the procedures was 75 +/- 62 min. CONCLUSION: DBE-ERCP enables us to perform ERC in a group of patients for whom it was impossible previously. Further experience is needed to evaluate its therapeutic efficacy compared with alternative methods.

Serum eosinophilic cationic protein is correlated with food impaction and endoscopic severity in eosinophilic esophagitis.

BACKGROUND/AIMS: The aim of the present study was to analyze the diagnostic accuracy of serum eosinophilic cationic protein (ECP) for eosinophilic esophagitis (EoE) and the correlation of ECP with clinical, histopathological, laboratory, and endoscopic features of EoE. MATERIALS AND METHODS: Fifteen patients with EoE and 14 healthy controls were included in the study. Demographic parameters were recorded. EoE Endoscopic Reference Score (EREFS) was calculated according to endoscopic features, and esophageal biopsies were obtained by a single experienced endoscopist in a patient group. Serum ECP levels (µg/mL), absolute eosinophil count (U/mm3), and maximum peak of eosinophils/high-power field in esophageal biopsies were analyzed. RESULTS: The median age of all participants was 33.0 (min-max: 18-46) years. There were 27 (93.1%) male patients. Serum ECP level was significantly higher in patients with EoE than in healthy volunteers (20.4 vs. 8.8, p<0.0001). According to the receiver operating characteristic (ROC) curve analysis, ECP had 80% sensitivity and 92.8% specificity to diagnose EoE with a cut-off value of 13.9 µg/mL (area under the ROC curve 0.895; p<0.0001; 95% CI: 0.725-0.978). EREFS (p<0.0001) and the presence of food impaction (p=0.04) were significantly correlated with ECP. CONCLUSION: Serum ECP is an accurate non-invasive biomarker for EoE with high specificity and sensitivity. In addition, ECP is strongly correlated with EREFS and the symptom of food impaction.

Hyperhomocysteinemia due to pernicious anemia leading to pulmonary thromboembolism in a heterozygous mutation carrier.

Pulmonary thromboembolism is a life-threatening condition resulting mostly from lower extremity deep-vein or pelvic-vein thrombosis. A 46-year-old woman was admitted to hospital with pain on the right side of the chest and hemoptysis. On laboratory analysis, D-dimer level was elevated. Computed tomographic pulmonary angiography revealed intravascular filling defects due to thrombi in right lower lobe pulmonary segmental arteries. Screening for thrombophilic states was normal except for heterozygous mutations of both prothrombin and methylene tetrahydrofolate reductase (MTHFR 677) genes. Homocysteine level was high, and vitamin B12 level and serum ferritin level were reduced. Serum antiparietal antibody was positive, and therefore, pernicious anemia was diagnosed along with iron-deficiency anemia. After the diagnoses were established, enoxaparin followed by warfarin was started in addition to oral vitamin B12, pyridoxine, thiamine, folic acid, and ferroglycine sulfate supplementation. At the end of 8 weeks of the replacement therapy, vitamin B12, folate, and homocysteine levels and red cell volume were found to be normal, with complete resolution of the thrombus confirmed by repeat computed tomographic pulmonary angiography. We conclude that hyperhomocysteinemia due to vitamin B12 deficiency associated with pernicious anemia might have decreased the threshold for thrombosis. In addition, the presence of heterozygous prothrombin and methylene tetrahydrofolate reductase mutations might serve as synergistic cofactors triggering pulmonary thromboembolism.

Anomalous opening of the common bile duct into the duodenal bulb: endoscopic treatment.

BACKGROUND: Anomalous biliary opening especially the presence of the ampulla of Vater in the duodenal bulb is a very rare phenomenon. We report clinical implications, laboratory and ERCP findings and also therapeutic approaches in 53 cases. METHODS: The data were collected from the records of 12.158 ERCP. The diagnosis was established as an anomalous opening of the common bile duct (CBD) into the duodenal bulb when there is an orifice observed in the bulb with the absence of a papillary structure at its normal localization and when the CBD is visualized by cholangiography through this orifice without evidence of any other opening. RESULTS: A total of 53 cases were recruited. There was an obvious male preponderance (M/F: 49/4). Demographic data and ERCP findings were available for all, but clinical characteristics and laboratory findings could be obtained from 39 patients with full records. Thirty-seven of 39 cases had abdominal pain (95%) and 23 of them (59%) had cholangitis as well. Elevated AP and GGT were found in 97.4% (52/53). History of cholecystectomy was present in 64% of the cases, recurrent cholangitis in 26% and duodenal ulcer in 45%. Normal papilla was not observed in any of the patients and a cleft-like opening was evident instead. The CBD was hook shaped at the distal part that opens to the duodenal bulb. Pancreatic duct (PD) was opening separately into the bulb in all the cases when it was possible to visualize. Dilated CBD in ERCP was evident in 94% and the CBD stone was demonstrated in 51%. PD was dilated in four of 12 (33%) cases. None of them has a history of pancreatitis. Endoscopically, Papillary Balloon Dilatation instead of Sphincterotomy carried out in 19 of 27 patients (70%) with choledocholithiazis. Remaining eight patients had undergone surgery (30%). Clinical symptoms were resolved with medical treatment in 16(32%) patients with dilated CBD but no stone. Perforation and bleeding were occurred only in two patients, which stones extracted with sphincterotomy (each complication in 1 patient). CONCLUSION: The opening of the CBD into the duodenal bulb is a rare event that may be associated with biliary and gastric/duodenal diseases. To date, surgical treatment has been preferred. In our experience, sphincterotomy has a high risk since it may lead to bleeding and perforation by virtue of the fact that a true papillary structure is absent. However, we performed balloon dilatation of the orifice successfully without any serious complication and suggest this as a safe therapeutic modality.

HIV and liver diseases: recent clinical advances.

Because the life expectancy of patients infected with HIV has been prolonged, liver diseases have assumed far greater importance as a cause of morbidity and mortality in these patients. Given the shared risks of transmission, patients who have HIV often are coinfected with hepatotrophic viruses such as hepatitis C and hepatitis B. Further, antiretroviral therapy (ART) used by patients who have HIV is often hepatotoxic, contributing to liver damage. With increasing immunosuppression caused by AIDS, patients who have HIV have to deal with these issues and the increased risk of infection with opportunistic viral, fungal, bacterial, and protozoal pathogens. In addition, steatosis and lipodystrophy now are recognized more commonly in patients who have HIV, particularly in the setting of ART. Thus, understanding of liver diseases in the setting of HIV infection becomes an important focus in caring these individuals. There have been numerous advances in the treatment of liver disease in patients who have HIV, particularly in treating viral hepatitis C and B. This article reviews various liver manifestations in patients who have HIV and the recent advances in diagnostic and therapeutic options.

Early repeat endoscopic retrograde cholangiopancreatography: predictive factors and interventions required.

BACKGROUND/AIMS: Early repeat endoscopic retrograde cholangiopancreatography may be required due to various conditions in patients who underwent planned endoscopic retrograde cholangiopancreatography. We aimed to assess the factors leading to early repeat endoscopic retrograde cholangiopancreatography and to determine the patients who need closer follow-up. MATERIALS AND METHODS: A total of 691 patients with a mean age of 60.3±16.4 years who had naive papilla on endoscopic retrograde cholangiopancreatography were involved in the study. The patients who required repeat endoscopic retrograde cholangiopancreatography were identified. Presentations, predictive factors, treatment modalities, and outcomes of the patients were investigated. RESULTS: Early repeat endoscopic retrograde cholangiopancreatography was needed in 19 (2.7%) patients. The most common presentation was cholangitis in 10 (52.6%) and unresolved jaundice in 4 (21.1%). Multivariate analysis identified biliary stricture (p=0.024), stricture at the hilus (p=0.005) and unilateral drainage in the presence of hilar stricture (p=0.017) as the independent risk factors for early repeat endoscopic retrograde cholangiopancreatography. Stent migration or dysfunction was the most common underlying cause. Therapeutic interventions were nasobiliary drainage in 13, stent exchange in 4 and stone removal in 2. Additionally, percutaneous drainage in 4 patients, drainage of abscess in 2 patients and percutaneous drainage of gallbladder in 1 patient were performed. Three patients died due to their underlying illness. CONCLUSIONS: Unilateral stenting especially in hilar strictures is a predictive factor for early repeat endoscopic retrograde cholangiopancreatography with high mortality. These patients should be under close follow-up.

Serum retinol-binding protein 4 in patients with nonalcoholic fatty liver disease: does it have a significant impact on pathogenesis?

OBJECTIVES: Conflicting data have been reported in the literature about the role of retinol-binding protein 4 (RBP4) in insulin sensitivity, type 2 diabetes, and obesity in humans. It is of interest whether serum RBP4 is associated with various features of nonalcoholic fatty liver disease (NAFLD). METHODS: Serum RBP4, adiponectin, leptin, and resistin were measured by enzyme-linked immunosorbent assay in 76 nondiabetic NAFLD patients, 55 of whom had elevated alanine aminotransferase (ALT). Thirty-four of 55 underwent a liver biopsy. Fasting insulin, liver and lipid panels were analyzed and ultrasound score, body mass index, and homeostasis model assessment for insulin resistance were recorded for each patient. Twenty-four healthy individuals served as controls. RESULTS: Serum RBP4 levels were not different between the steatosis group and controls as well as between the groups with high and normal ALT. Serum adiponectin was significantly lower and resistin was higher (P<0.001) in steatosis group compared with controls. RBP4 and resistin were negatively correlated, whereas leptin and resistin were correlated positively in patients with high ALT. At multivariate analysis, homeostasis model assessment for insulin resistance [odds ratio (OR): 10.71; 95% confidence interval (95% CI): 1.40-81.74], leptin (OR: 22.14; 95% CI: 2.40-204.12), resistin (OR: 6.29; 95% CI: 0.94-41.91), ALT (OR: 1.205; 95% CI: 1.05-1.39), and aspartate aminotransferase (OR: 0.846; 95% CI: 0.72-0.99) were independent variables associated with steatosis. Serum leptin, adiponectin, resistin, gamma-glutamyl transferase, and cholesterol were associated with histological activity by multivariate linear regression. CONCLUSION: Serum RBP4 is not a predictive factor in NAFLD irrespective of ALT. Low adiponectin, elevated resistin, and leptin were significantly associated with necroinflammation.

Endoscopic therapy of hepatic hydatid cyst disease in preoperative and postoperative settings.

The most common and serious complication of hepatic hydatid cyst disease is the communication between the cyst and the biliary tree. The diagnosis and treatment of this condition poses various difficulties. Data from patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) for hydatid cysts communicating with the bile ducts either in the preoperative or postoperative setting over a 2-year period have been analyzed. In the preoperative group (n=41), jaundice (n=18), biliary colic (n=11), and cholangitis (n=10) were the most common presentations. On the other hand, the most common indication for ERCP in the postoperative group (n=69) was biliocutaneous leaks (n=60) and cholangitis (n=9). All but 2 patients in the preoperative group were treated by endoscopic sphincterotomy and/or extraction of hydatid cyst remnants followed by the placement of nasobiliary drainage catheter for the patients who had filling defects on cholangiogram. Subsequently, these patients were referred for surgery. ERCP was a definitive treatment for the remaining 2 patients. Endotherapy was successful for the patients who developed leak or had cyst remnants following surgery, whereas long-term biliary stenting was required for those who developed bile duct stenosis. There was no ERCP-associated complication, except mild pancreatitis in a single patient and self-limited hemorrhage in 2 patients. ERCP is an efficacious and safe method for the diagnosis and management of biliary complications associated with hydatid cyst disease.

Recurrent hepatic sarcoidosis post-liver transplantation manifesting with severe hypercalcemia: a case report and review of the literature.

Sarcoidosis is a systemic granulomatous disease primarily involving the lungs, lymph nodes, skin, eyes and nervous system; liver involvement is asymptomatic in most cases. However, once the patient develops clinical symptoms liver disease is usually progressive and may necessitate orthotopic liver transplantation. There are a few reports of asymptomatic recurrent sarcoidosis developing within the liver allograft. We report a case of early recurrence of sarcoidosis in the liver allograft diagnosed on biopsy in a patient who presented with severe hypercalcemia, kidney dysfunction, and increase in size of abdominal lymph nodes. The liver chemistry tests were within normal limits. The patient responded well to steroid treatment by normalizing serum calcium and creatinine levels and reducing lymph node size. To date, there has been no report in the literature of symptomatic recurrence of hepatic sarcoidosis following orthotopic liver transplantation.

Mutations of the HFE gene among Turkish hereditary hemochromatosis patients.

Since the discovery of the HFE gene, C282Y and H63D mutations have been reported as significantly correlated with clinically manifested hereditary hemochromatosis (HH). As the other genes involved in iron metabolism have been described, non-HFE cases of HH have been identified. Since in the general Turkish population, the C282Y mutation is not found and the H63D mutation is of high frequency, we aimed to determine mutations in the HFE genes in our patients with HH. The HFE gene of the five patients with HH were sequenced. C282Y mutation was absent, and all HH patients were heterozygote for H63D mutation. No other mutation was found in HFE gene by sequencing. Although the higher allele frequency of the H63D mutation in Turkish HH patients than in the general population implies a role of the H63D mutation in iron overload, there is a strong possibility that Turkish HH patients have non-HFE hemochromatosis.

Detection of mutant p53 in hepatocellular cancer from Turkey and its correlation with clinicopathologic parameters.

The samples of hepatocellular carcinoma from Turkey, a country with a high prevalence of hepatitis B virus and hepatitis C virus, but low dietary exposure to aflatoxin B1, were examined in order to detect the frequency of mutant p53 and its association with clinical and pathological data. Fifty-two samples of hepatocellular cancer from the patients who were diagnosed in our clinic were included in this study. The mutant p53 protein was searched for by specific enzyme-linked immunosorbent assay. Of 52 patients with hepatocellular carcinoma, 26 (50%) had the mutant p53. The incidence of p53 mutation in hepatocellular cancer patients with chronic liver disease due to hepatitis B virus infection was significantly higher than in those with chronic liver disease due to alcohol, indicating that not alcohol but hepatitis B virus, in fact induces the mutations in p53 gene. In addition, it has been shown that the p53 mutation was significantly associated with the diameter of tumor nodule and the degree of cellular differentiation in hepatocellular cancer. The p53 mutation rate found in our study is concordant for a geography where hepatitis B virus and hepatitis C virus are common. Hepatitis B virus and possibly hepatitis C virus, but not alcohol, should be responsible, to a degree, for the mutational change in p53 protein in hepatocellular cancer patients with chronic liver disease. The p53 mutation is a late event in hepatocarcinogenesis because it is related with cellular differentiation and tumor diameter. The specific ELISA can be a useful screening test in future studies to select the patients for gene therapy using wild-type p53.