Omer Yerci

Ursodeoxycholic Acid and Atorvastatin in the Treatment of Nonalcoholic Steatohepatitis

BACKGROUND/AIMS Nonalcoholic steatohepatitis (NASH) is a serious disorder with the potential to gradually progress to cirrhosis. It is generally associated with obesity, diabetes and hyperlipidemia. Currently, there is no established therapy for NASH. The aim of the present study was to evaluate the effectiveness of atorvastatin and ursodeoxycholic acid (UDCA) in the treatment of NASH. METHODS This prospective study included 44 adult patients (24 men, 20 women) with a mean age of 48.90+/-7.69 years and mean body mass index (BMI) of 29.40+/-3.82. Ten patients had a history of diabetes. Serological markers for viral hepatitis were negative in all patients and there was no history of alcohol or drug abuse. Patients who had autoimmune hepatitis were excluded from the study. Liver biopsy was performed before therapy to confirm the diagnosis. Among NASH patients, 17 normolipidemic cases received UDCA 13 to 15 mg/kg/day (group 1), while hyperlipidemic cases (n=27) received atorvastatin 10 mg/day (group 2) for six months. The BMI, serum lipids, liver function tests and liver density, assessed by computerized tomography, were evaluated before and after the treatment period. The BMI, serum aminotransferase levels, histological parameters (steatosis, inflammation, fibrosis scores) and liver densities were not statistically different between the groups at the beginning of therapy. RESULTS The BMI, serum glucose, and triglyceride levels did not change in either group after the treatment period. In group 1, serum alanine aminotransferase (ALT) and gamma-glutamyl-transferase (GGT) levels reduced significantly, and in group 2, serum cholesterol, aspartate aminotransferase, ALT, alkaline phosphatase and GGT levels reduced significantly. Liver densities increased only in group 2, probably as a result of diminishing fat content of liver. The normalization of transaminases was also more prevalent in group 2. Liver steatosis was closely correlated with liver density, but inflammation and fibrosis were not. CONCLUSIONS The use of atorvastatin in NASH patients with hyperlipidemia was found to be both effective and safe. The benefit of statin and UDCA therapy in normolipidemic patients with NASH requires confirmation with further placebo-controlled trials.

The bone marrow aspirate and biopsy in the diagnosis of unsuspected nonhematologic malignancy: a clinical study of 19 cases.

BackgroundAlthough bone marrow metastases can be found commonly in some malignant tumors, diagnosing a nonhematologic malignancy from marrow is not a usual event.MethodsTo underscore the value of bone marrow aspiration and biopsy as a short cut in establishing a diagnosis for disseminated tumors, we reviewed 19 patients with nonhematologic malignancies who initially had diagnosis from bone marrow.ResultsThe main indications for bone marrow examination were microangiopathic hemolytic anemia (MAHA), leukoerythroblastosis (LEB) and unexplained cytopenias. Bone marrow aspiration was not diagnostic due to dry tap or inadequate material in 6 cases. Biopsy results were parallel to the cytological ones in all cases except one; however a meticulous second examination of the biopsy confirmed the cytologic diagnosis in this patient too. The most common histologic subtype was adenocarcinoma, and after all the clinical and laboratory evaluations, the primary focus was disclosed definitively in ten patients (5 stomach, 3 prostate, 1 lung, 1 muscle) and probably in four patients (3 gastrointestinal tract, 1 lung). All work up failed in five patients and these cases were classified as tumor of unknown origin (TUO).ConclusionOur series showed that anemia, thrombocytopenia, elevated red cell distribution width (RDW) and hypoproteinemia formed a uniform tetrad in patients with disseminated tumors that were diagnosed via bone marrow examination. The prognosis of patients was very poor and survivals were only a few days or weeks (except for 4 patients whose survivals were longer). We concluded that MAHA, LEB and unexplained cytopenias are strong indicators of the necessity of bone marrow examination. Because of the very short survival of many patients, all investigational procedures should be judged in view of their rationality, and should be focused on treatable primary tumors.

The Relationship between c-erbB-2 Oncogene Expression and Clinicopathological Factors in Gastric Cancer

Gastric carcinoma is one of the most common carcinomas and a leading cause of death from cancer in Turkey. The relationship between clinicopathological features of the disease and oncogenes is under investigation. In this retrospective study we investigated the relationships between expression of c-erbB-2 oncoprotein and grade, stage and pathological characteristics of the tumour, and prognosis. Formalin-fixed, paraffin-embedded tissue sections were prepared from gastrectomy specimens from 55 patients with gastric carcinoma. The tissue sections were stained immunohistochemically to reveal c-erbB-2 protein. Six (10%) of the tumours stained positively for c-erbB-2 protein. There was no statistically significant association (P > 0.5) between c-erbB-2 staining and tumour grade, stage or pathological characteristics (necrosis, lymph-node infiltration), or between staining and prognosis. The results suggest that overexpression of c-erb-B-2 protein is not related to the pathological characteristics of the tumour in gastric carcinoma and is not an important prognostic indicator.

Analysis of prognostic and immunohistochemical factors in gastrointestinal stromal tumors with malignant potential

The aim of this study was to analyze 37 patients with malignant primary gastrointestinal stromal tumors and to compare the findings and their therapeutic implications with those previously reported. The medical records of 37 patients who were diagnosed and operated on between January 1996 and December 2002 were retrospectively reviewed. The patients’ age, tumor size, type of surgery, histologic type, mitotic counts, presence of necrosis, Ki-67 proliferative index, National Institutes of Health 2001 consensus classification, immunohistochemical staining, and recurrence were examined to analyze factors affecting survival. Overall actuarial survival for all patients was 46%. When analyzed by type of resection, the complete resection group (R0 resection) had a mean overall survival of 48.2 +- 6.18 months compared with the patients with incomplete resection (R1-R2) who survived a mean of 10.8 +- 3.2 months (P = 0.00). Univariate analysis showed development of recurrence (P = 0.00), tumor size of 8 cm or greater (P = 0.05), Ki-67 proliferative index greater than 0.82 (P = 0.0448), desmin staining (P = 0.0076), age younger than 49 years (P = 0.0009), and incomplete resection (P = 0.00) to be significantly correlated with a poor survival. In multivariate analysis, desmin staining (P = 0.031), tumor size (P = 0.033), age (P = 0.01), recurrence (P = 0.038), and R0 resection (P = 0.02) were significant independent prognostic factors. We recommend that more careful preoperative and more frequent postoperative follow-up examinations be performed for patients with large tumors, age of younger than 49 years, and Ki-67 proliferative index greater than 0.82.

The expression of fragile sites in lymphocytes of patients with rectum cancer and their first-degree relatives.

Fragile sites are non-staining gaps and breaks in specific points of chromosomes. These sites also include acentric fragments, triradial figures and several rearrangements. Although this issue has been controversial recently, they may be related to structural chromosomal rearrangement in some neoplasms. In this study, the expression of fragile sites induced by aphidicolin (Apc), 5-bromodeoxyuridine (BrdU) and caffeine was investigated on prometaphase chromosomes obtained from the peripheral blood lymphocytes of 36 patients with rectum cancer, 30 first-degree relatives and 30 normal healthy controls. The results of the structural chromosome aberrations determined in patients and their first-degree relatives were significantly higher than those in control subjects (P<0.001). We determined aphidicolin type common fragile sites (1p36, 1p31, 1p21, 1q21, 1q25, 1q44, 2p24, 2q21, 2q33, 2q37, 3p14, 5q21, 5q33, 13q13, 14q24, 16q23 and 18q21). When the rates of sites such as 1p21, 1q25, 2q33, 3p14, 5q21 and 14q24 in patients and in their first-degree relatives were compared with the control group, the difference was statistically significant. Our results indicated an increased genetic instability in patients with rectum cancer and their first-degree relatives. Therefore, the increase of fragile site expression may be an important marker showing genetic predisposition to rectum cancer.

A Comparison of Three Fibrinolytic Agents in Prevention of Intra-Abdominal Adhesions

Abstract Purpose: Three different drugs affecting the coagulation process at various stages were studied for their effectiveness in preventing intra-peritoneal adhesion formation in rats. Material and Methods: Forty female Wistar-Albino rats divided into four groups based on the drugs administered during the experimental laparotomy and caecal abrasion: the control group-no drug administered, the intra-peritoneal tissue plasminogen activator (TPA) group, the subcutaneous fondaparinux sodium (FS) group and the intra-peritoneal activated drotrecogin alfa (ADA) group. After two weeks, intra-peritoneal adhesions were macroscopically and microscopically scored. Results: The macroscopic scores of the three groups were similar but all lower than the control group (p = 0.002). Inflammation (p = 0.023) and fibrosis (p = 0.019) scores were lower in just the ADA group when compared to the control group. Conclusions: All three agents were effective in preventing adhesions when compared to the control group. Nevertheless, ADA seemed the most effective except when considering clinical applicability, in which case FS seemed to offer the greatest advantage.

High expression of multidrug resistance-1 (MDR-1) and its relationship with multiple prognostic factors in gastric carcinomas in patients in Turkey.

Drug resistance remains a major problem in the treatment of gastric cancer. In Turkey, gastric carcinoma is the second most common cancer and, because the rate of early diagnosis is low, chemotherapy plays an important role in the treatment of the disease. We aimed to investigate expression of the multidrug resistance-1 gene (MDR-1) and its relationship with multiple prognostic factors in gastric cancers. Between 1996 and 1998, a total of 55 patients (37 men and 19 women; median age 55 years) were studied. Sections from specimens of gastric carcinomas were immunohistochemically stained to detect P-glycoprotein (which is associated with MDR-1 expression). We found MDR-1 expression in 48 (87%) of the patients. None of the multiple prognostic factors, including histological type of tumour, correlated with expression of MDR-1. Patients who had low MDR-1 expression had better survival. We conclude that the expression of MDR-1 in gastric cancer is high in Turkey, and this may be related to poor prognosis.

Expression of p53 protein and prognosis in gastric carcinoma

A study was carried out to assess whether p53 expression is related to tumour type, grade or pathological characteristics, or to prognosis, in gastric cancer. Immunohistochemical studies were performed to detect p53 protein in sections from 55 consecutive gastrectomy or partial gastrectomy specimens. Tumours were classified for T-stage, histopathological grade and pathological characteristics. Immunohistochemical staining detected p53 protein in 11 (19%) of the 55 specimens. There was no statistically significant difference between patients with p53 positively staining tumours and patients with p53 negatively staining tumours with regard to tumour grade, stage or pathological characteristics (lymph-node infiltration, depth of invasion, necrosis, or necrosis of vessels). Survival time was statistically significantly lower in patients with positively staining tumours (mean survival times 12.0 and 23.4 months, respectively). These results suggest that expression of p53 protein is related to poor prognosis in gastric carcinoma.

Analysis of mismatch repair gene mutations in Turkish HNPCC patients

Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) is caused by the inheritance of a mutant allele of a DNA mismatch repair gene. We aimed to investigate types and frequencies of mismatch repair (MMR) gene mutations in Turkish patients with HNPCC and to identify specific biomarkers for early diagnosis of their non-symptomatic kindred’s. The molecular characteristics of 28 Turkish colorectal cancer patients at high-risk for HNPCC were investigated by analysis of microsatellite instability (MSI), immunohistochemistry and methylation-specific PCR in order to select tumors for mutation analysis. Ten cases (35.7%) were classified as MSI (+). Lack of expression of the main MMR proteins was observed in MSI (+) tumors. Hypermethylation of the MLH1 promoter region was observed in one tumor. Nine Lynch syndrome cases showed novel germ-line alterations of the MMR gene: two frame-shifts (MLH1 c.1843dupC and MLH1 c.1743delG) and three missense mutations (MLH1 c.293G>C, MLH1 c.954_955delinsTA and MSH2 c.2210G>A). Unclassified variants were evaluated as likely to be pathogenic by using the in-silico analyses. In addition, the MSH2 c.2210G>A alteration could be considered as a founder mutation for the Turkish population due to its identification in five different Lynch syndrome families and absence in control group. The present study adds new information about MMR gene mutation types and their role in Lynch syndrome. This is the first detailed research on Turkish Lynch syndrome families.

The Expression Frequency of Common Fragile Sites and Genetic Predisposition to Colon Cancer

The expression frequency of common fragile sites induced by aphidicolin (Apc), bromodeoxyuridine (BrdU), and caffeine was evaluated on prometaphase chromosomes obtained from the peripheral blood lymphocytes of 32 patients with colon cancer, 30 of their clinically healthy family members and 30 age-matched normal controls. The proportion of damaged cells (P < 0.001), the mean number of chromosomal aberrations and the expression frequencies of fragile sites were significantly higher in the patient and relative groups compared to the control group. Our findings show an increased genetic instability in patients with colon cancer and their first-degree relatives. In addition, common fragile sites can be used as a suitable marker for determining genetic predisposition to cancer.