Comparison of protracted infusion 5-fluorouracil and capecitabine in adjuvant chemoradiotherapy for rectal cancer.

BACKGROUND/AIMS: 5-Fluorouracil-based chemoradiotherapy is the most widely used treatment modality in the adjuvant treatment of rectal cancer. Capecitabine represents a valuable alternative to 5-Fluorouracil in this situation. METHODOLOGY: Patients with stage II and stage III rectal adenocarcinoma, who were included in this analysis, received adjuvant chemoradiotherapy consisting of external-beam radiotherapy (50.4-54Gy) either with 5-Fluorouracil at a median dose of 300 mg/m2/day by protracted venous infusion for 5 days a week, or capecitabine at a median dose of 1650 mg/m2/day for 5 days a week after surgery. The data concerning the toxicity and the efficacy of the treatments were compared in patients treated with 5-Fluorouracil- and capecitabine-based chemoradiotherapy. RESULTS: Forty-three patients received 5-Fluorouracil, and 24 patients received capecitabine during adjuvant radiotherapy. Although there were no differences between the groups in terms of toxicity rates, distant metastasis-free survival, disease-free survival, and overall survival rates; a trend for improved loco-regional recurrence-free survival rate was observed in the capecitabine arm (p = 0.063). CONCLUSIONS: Capecitabine is at least as effective as 5-Fluorouracil in the postoperative treatment of rectal adenocarcinoma. Considering the trend for improved loco-regional recurrence-free survival rate in the capecitabine arm, it seems that the drug exerts better synergy with radiotherapy in this situation.

The relationship between MIB-1 proliferative activity and mitotic index in gastrointestinal stromal tumors.

BACKGROUND/AIMS: Gastrointestinal stromal tumors (GIST) are mesenchymal tumors originating from the gastrointestinal canal wall. Although a number of studies are performed concerning prognostic factors, no indicators of recurrence or metastasis could be established. In this study we assessed the prognostic value of MIB-1 proliferative index (PI) in GIST, and whether there was a relationship to any other clinicopathological findings. METHODOLOGY: In the study 37 patients with GIST diagnosis were included. The cases were classified as low, intermediate, and high risk groups according to tumor size and mitotic activity. The average PI of 10% in high risk group was set as the cut-off value. RESULTS: Of all the cases, those with a MIB-1 PI over the cut-off value had a significantly shorter survival (Log-rank test, p < 0.05). Likewise cases with small bowel tumors with a MIB-1 PI over the cut-off value had a significantly shorter survival (Log-rank test, p < 0.05). A statistically significant negative correlation was found between presence of necrosis and survival using McPearson correlation test (p < 0.01). CONCLUSIONS: MIB-1 PI and presence of necrosis are possible indicators of prognosis especially in GIST cases of the small bowel.

Periampullary carcinomas.

BACKGROUND/AIMS: The purpose of this study was to determine predictors of survival after resection for periampullary neoplasms. METHODOLOGY: In this study, we reevaluated our 17 cases of this type tumor which we had reported as periampullar site tumors, in advanced stages with undetermined localization, in our pathology department of the Uludag University faculty of medicine. RESULTS: Six of our cases were female, and 11 were male with a mean age of 60.6 years (range 31-77). Their main complaints were loss of weight, anorexia, jaundice and fatigue. Physical and endoscopic examination of these patients revealed periampullary mass and Whipple operations were performed on all of them. Histopathologic examinations of these tumors revealed adenocarcinoma in 15, small cell (neuroendocrin) carcinoma in two. All were in the advanced stages. Eight of them were alive and free of disease after 1.5- to 20-month follow-ups, while ten died because of disease. CONCLUSIONS: Periampullary carcinoma is a problem with increasing clinical significance. Tumor size, tumor type and differentiation, lymph node status appears to be prognostic markers.

Preoperative chemoradiotherapy in patients with locally advanced rectal cancer.

BACKGROUND/AIMS: To determine the percentage of responders and the resectability rate for patients with locally advanced carcinoma of the rectum treated by infusional 5-fluorouracil chemotherapy and pelvic radiation. METHODOLOGY: Twenty-four patients with a diagnosis of locally advanced unresectable rectal cancer received preoperative 5-fluorouracil by intravenous infusion at the dose of 250-300mg/m2/day concurrent with pelvic radiation (median 50.4 Gy/28 fractions). Surgery was performed with a mean delay of 15 days after completion of irradiation and included 11 abdominoperineal resections and five anal sphincter-preserving procedures. RESULTS: The median follow-up was 22 months. Complete histological response occurred in 6%, and tumor down-staging in 58% of cases. There was a significant difference in the rate of local control based on the distance of the tumor from the anal verge (>5.4cm; p=0.046). Our results have suggested the importance of the total dose on the local control (p=0.061). Higher local failure rate has been observed with prolonged treatment time (p=0.018). With metastasis-free survival as the endpoint, only stage (p=0.027) was a statistically significant prognostic factor. CONCLUSIONS: The favorable influence of higher doses of preoperative radiotherapy on pathologic stage has been observed. Even after preoperative radiotherapy, postoperative staging remained a prognostic factor.

Postoperative concomitant chemoradiotherapy in locally advanced rectal cancer.

BACKGROUND/AIMS: To gain maximal effectiveness while decreasing toxicity by giving 5-fluorouracil for 45 minutes starting just within 5 minutes after the completion of radiotherapy thrice weekly. METHODOLOGY: Thirty-eight patients with locally advanced rectal cancer were enrolled in the study. Ranges of total radiation doses were between 50.4 Gy and 61.2 Gy with a median of 59.4 Gy with fraction size of 1.8 Gy five times weekly. 5-fluorouracil was administered thrice weekly with the dose of 250-300mg/m2/day concomitantly with radiation therapy. RESULTS: Median follow-up time was 30 months. Administration of chemotherapy concomitant with radiotherapy (p=0.089), AJCC stage III (p=0.079), Duke's stage C (p=0.079), presence of lymph node involvement (p=0.079) and presence of local recurrence (p=0.066) appeared to be effecting distant metastasis although differences did not reach statistically significance. Mean overall survival was 46 months in patients without any distant metastasis (SD: 3.28; 95% CI: 39.46 and 52.31) while it was 35 months in patients with distant metastasis (SD: 5.71; 95% CI: 23.52 and 45.90, p=0.016). CONCLUSIONS: Our results have provided further evidence of the ability of postoperative chemoradiotherapy to delay and prevent local recurrence and metastasis of rectal cancer.

Epidemiological aspects of endemic upper gastrointestinal cancers in eastern Turkey.

BACKGROUND/AIMS: The aim of our study was to present the epidemiological aspects of endemic upper gastrointestinal (esophageal and gastric) cancers in the Van region of Eastern Turkey. METHODOLOGY: The patients were diagnosed by esophagogastroscopy, biopsy and histopathological analysis. The control group consisted of 73 healthy subjects. Epidemiological characteristics (age, sex, dietary habits, educational status, life style) were evaluated by questionnaires. Helicobacter pylori infection was diagnosed in nontumoral gastric mucosal biopsy specimens by Giemsa staining. RESULTS: 298 esophageal Ca and 384 gastric Ca patients were diagnosed in seven years (1994-2001). Most of the patients (90%) were of rural origin. Endoscopic prevalence rate of upper gastrointestinal (UGI) Ca was the highest (1 Ca per 7 esophagogastroscopy) in the Van region compared to other parts of Turkey. Esophageal Ca were 1.5 times more common in females whereas gastric Ca were 1.6 times more common in males. Ninety per cent of esophageal cancers were epidermoid and the remaining 10% were adenocarcinomas. Ninety-seven per cent of gastric Ca were adenocarcinomas. Helicobacter pylori infection was not significantly increased in gastric Ca patients compared to controls. CONCLUSIONS: Low educational and socioeconomic status, consumption of smoked, salted, hot, fatty foods, overdrinking hot tea and well water, cigarette smoking, poor intake of fresh fruits and vegetables and poor hygienic conditions were probable culprit factors.

Fas antigen (CD95) expression and apoptosis in hepatocytes of patients with chronic viral hepatitis.

BACKGROUND: Apoptosis may be defined as programmed cell death. It is involved in the normal development and homeostasis of tissues in multicellular organisms. An increased or decreased rate of apoptosis may lead to a range of diseases. Fas antigen is a cell-surface receptor that induces apoptotic pathways when treated with Fas ligand or anti-Fas antibody. There is increasing evidence that apoptosis plays an important role in the immunopathogenesis of chronic viral hepatitis, in which the Fas antigen-Fas ligand pathway is particularly involved. METHODS: Fas antigen expression and apoptosis (apoptotic index) were assayed using flow cytometry in the hepatocytes of 27 patients with chronic viral hepatitis. Histopathological activity, scored by Knodell's histological activity index, other histopathological parameters, serum transaminase values and patient age were then compared with apoptotic index and Fas antigen expression. RESULTS: Apoptosis and Fas antigen expression in hepatocytes were correlated closely with histological activity (grade) of chronic viral hepatitis, but there were no correlations with histological stage, patient age or serum transaminase levels. CONCLUSION: Apoptosis and its triggering molecule, Fas antigen, induce mechanisms that appear to be associated with the pathogenesis of chronic viral hepatitis.

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.

Alcohol and esophageal cancer, is there an exaggerated accusation?

Difficulty in its early diagnosis, fast progression and high mortality makes esophageal carcinoma one of the most important fatal diseases in the world. Its unequal geographic distribution gives a hint to clinicians and epidemiologists an impression that this disease is definitely related to environmental factors. Deficiencies in essential vitamins and other substances in diet have been blamed for many years. Tobacco and alcohol were also found guilty for a long time. But a great majority of people in high-risk areas are Moslem and teetotalers. Therefore some other factors as nitrosamines, which were found to enhance the risk of esophageal carcinoma, should be also emphasized in the etiology of the disease. Nitrosamines are most likely acting as the promoters in the carcinogenesis of esophagus. It is difficult to explain the importance of alcohol in high-risk areas where most of the people are teetotalers.

Risk factors for esophageal cancer in eastern Anatolia.

BACKGROUND/AIMS: Epidemiologic studies implicate dietary factors in risk of esophageal cancer, particularly in high-incidence areas of the world. In this case-control study, 44 patients with esophageal cancer and 100 healthy controls were interviewed in the Gastroenterology Department of Teaching Hospital, School of Medicine, Atatürk University, Erzurum, Turkey. Eastern Anatolia where the study was conducted remains at a crossroads where this particular disease is endemic. METHODOLOGY: Questionnaire included education, level of income, residence, alcohol and tobacco consumption, eating and drinking habits. The data obtained from the patients were compared to those of control cases and analyzed using multiple logistic regression, chi 2 and Student's t test. RESULTS: The patients' economic level was lower than that of controls. There was no association between esophageal cancer and tobacco and alcohol consumption in this region. While fruit and vegetable consumption showed a significantly inverse association with esophageal cancer. Salt and polyunsaturated fat consumption as well as drinking habit of hot tea regionally known as kitlama were positively associated with esophageal cancer. CONCLUSIONS: Etiology of esophageal cancer shows slight differences in Eastern Anatolia, where esophageal cancer is more prevalent than other parts of the country, from that of other parts of the world. Drinking of hot tea 'kitlama' and low fruit diet are the most common risk factors.

Therapeutic effect of oral recombinant human granulocyte macrophage-colony stimulating factor in radiotherapy-induced esophagitis.

BACKGROUND/AIMS: Radiation-induced esophagitis is one of the most important early side effects of irradiation of chest, and head and neck malignancies. This condition often leads to interruption of radiotherapy for several days. An effective treatment for reducing the incidence and severity of this complication has not yet been found. We aimed to investigate the therapeutic effect of rhGM-CSF on radiation-induced esophagitis in the patients with chest or head and neck malignancies. METHODOLOGY: Ninety-seven patients with chest or head and neck malignancies who had not previously received radiation therapy, were treated with radiotherapy, concurrent or sequential chemoradiotherapy. Forty-eight patients who had grade 1, 2 or 3 esophagitis symptoms according to Radiation Therapy Oncology Group radiation morbidity score, underwent upper gastrointestinal endoscopy. In the patients with grade 3 esophagitis (according to Kuwahata's scoring system) rhGM-CSF was administered for 5-10 consecutive days as an oral solution. RESULTS: Endoscopic examinations showed grade 3 esophagitis in 26 of these patients according to Kuwahata's score. Twenty-five patients with grade 3 esophagitis were given rhGM-CSF therapy. Radiotherapy was continued in 23 patients. After the rhGM-CSF therapy, esophagitis had regressed from grade 3 to grade 0 in 10 (43%), from grade 3 to grade 1 in 8 (35%), and from grade 3 to grade 2 in 3 patients (12%). Two patients (9%) did not respond to rhGM-CSF therapy. Twenty-one patients (91%) completed planned radiotherapy without interruption. CONCLUSIONS: In patients with radiation-induced esophagitis, ulcerated esophageal mucosa healed with local granulocyte macrophage-colony stimulating factor administration in median 8 days without radiotherapy interruption.

Evaluation of the effects of Helicobacter pylori eradication therapy on gastric antral epithelial hyperproliferation: a prospective six-month follow-up study.

BACKGROUND/AIMS: H. pylori-induced hyperproliferation of the gastric epithelium may have a critical role in gastric carcinogenesis. H. pylori-related hyperproliferation and reversibility of hyperproliferation after eradication therapy is still controversial. Therefore, we have evaluated the effects of H. pylori and its eradication on gastric antral epithelial proliferation. METHODOLOGY: A total of 32 H. pylori-positive and 22 H. pylori-negative subjects were enrolled into the study. Triple eradication therapy was given to the H. pylori-positive group. Upper endoscopy was repeated one month after the therapy and six months later, antral biopsy specimens were taken in each endoscopy. Biopsy specimens from H. pylori-negative subject were taken at the beginning of the study and sixth months later also. RESULTS: Proliferative index was 40.2% in H. pylori-positive state; it regressed to 27.6% after eradication and six months later the proliferative index was 30.7%. H. pylori-negative group's proliferative index was 25.5% initially and six months later it was 25.6%. The difference between the H. pylori-positive and -negative group was statistically significant (p<0.0001). The difference between H. pylori-positive group's values at the beginning of the study and one month after the eradication was significant (p<0.0001). In addition, the difference between H. pylori-positive group's initial values and those six months after eradication was also significant (p<0.0001). CONCLUSIONS: H. pylori increased the gastric epithelial proliferation and after the eradication therapy proliferative index decreased to control values. H. pylori and the related factors inducing gastric antral hyperproliferation may have an important role in H. pylori-related gastric malignancies.

A retrospective study demonstrating properties of nonvariceal upper gastrointestinal bleeding in Turkey.

BACKGROUND/AIMS: Helicobacter pylori infection, non-steroidal anti-inflammatory drugs and peptic ulcer are considered as the major factors for upper gastrointestinal system bleeding. The objective of the study was to determine the sociodemographic and etiologic factors, management and outcome of patients with non-variceal upper gastrointestinal system bleeding in Turkey. METHODS: Patients who admitted to hospitals with upper gastrointestinal system bleeding and in whom upper gastrointestinal endoscopy was performed were enrolled in this retrospective study. The detailed data of medical history, comorbid diseases, medications, admission to intensive care units, Helicobacter pylori infection, blood transfusion, upper gastrointestinal endoscopy, and treatment outcome were documented. RESULTS: The most frequent causes of bleeding (%) were duodenal ulcer (49.4), gastric ulcer (22.8), erosion (9.6), and cancer (2.2) among 1,711 lesions in endoscopic appearances of 1,339 patients from six centers. Seven hundred and four patients were evaluated for Helicobacter pylori infection and the test was positive in 45.6% of those patients. Comorbid diseases were present in 59.2% of the patients. The percentage of patients using acetylsalicylic acid and/or other non-steroidal anti-inflammatory drug was 54.3%. Bleeding was stopped with medical therapy in 66.9%. Only 3.7% of the patients underwent emergency surgery, and a 1.1% mortality rate was determined. CONCLUSIONS: Patients with upper gastrointestinal system bleeding were significantly older, more likely to be male, and more likely to use non-steroidal anti-inflammatory drugs. Though most of the patients were using gastro-protective agents, duodenal and gastric ulcers were the contributing factors in more than 70% of the upper gastrointestinal bleeding. The extensive use of non-steroidal anti-inflammatory drug is a hazardous health issue considering the use of these drugs in half of the patients.

Prevalence patterns of gastric cancers in Turkey: model of a developing country with high occurrence of Helicobacter pylori.

AIM: In developed countries, there has been a recent increase in the prevalence of adenocarcinoma of the esophagus and cardia, along with a decrease in distal gastric cancers. Little is known regarding the prevalence of these diseases in developing countries. The aim of the present study was to evaluate changes in the prevalence of gastric adenocarcinomas in Turkey as a function of anatomic location. METHODS: Data were retrospectively collected from 16 centers from January 1990 to December 2000. Owing to the exclusion criteria, a total of 4065 cases of tumors of the stomach and distal esophagus were included. Tumors localized to the body, the antrum and pyloric channel were considered distal cancers. Helicobacter pylori (H. pylori) was also detected. RESULTS: Patients' mean age was 60.7 +/- 9 years, with a male : female ratio of 68:32. The ratio of distal/proximal adenocarcinoma was 2,1 [corrected] for the western part of Turkey and 3,8 [corrected] for the eastern part of the country (P < 0.0001), and this did not change during the 11 years. H. pylori was detected significantly less in the west compared to the east for distal tumors (65.7 vs 38.7%, respectively, P = 0.02). CONCLUSION: In Turkey, a developing country with a high H. pylori prevalence, contrary to the state of developed countries, the ratio of distal versus proximal gastric adenocarcinomas has not changed. Geographical distribution should be taken into the account in projecting the changing patterns of gastric cancers.