Expression of Fas (CD95/APO-1) and Fas ligand (FasL) in experimentally-induced acute pancreatitis.

INTRODUCTION: Acinar cell death is a crucial event in acute pancreatitis (AP) and may occur either by apoptosis or necrosis. The aim of this study was to investigate the expression of the apoptosis associated proteins Fas and FasL in experimentally induced severe AP. METHODS: AP was induced in 30 rats by injecting 0.2 ml of 4.5% sodium taurocholate solution into the biliopancreatic duct. Sham operated animals (n = 30) and 10 normal controls were used for comparisons. Animals were killed at 6, 12, 24, 48, 72 hr and 1 week after operation (five animals at each time point) and both serum and pancreatic tissue were obtained. The severity of AP was graded by morphological evaluation and by measuring serum amylase levels. Acinar cell apoptosis was detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. Tissue expressions of Fas and FasL were evaluated by immunohistochemistry. RESULTS: Sodium taurocholate injection resulted in severe acute necrotizing pancreatitis as early as six hr after taurocholate infusion with gradually increasing severity and a peak at 72 hr, and a significant increase of serum amylase at 6 and 12 hr. Apoptotic acinar cells were observed between 48 and 72 hr. The expression of both Fas and FasL in pancreatic tissue was induced in comparison with normal controls. Fas expression in AP was higher and statistically significant at 24 hr whereas FasL expression was consistently lower with a statistical significance observed at 12 hr when compared to sham-operated animals suggesting Fas upregulation and FasL downregulation in this model of AP. CONCLUSIONS: Induction and sequential changes in the expressions of Fas and FasL occur during taurocholate induced severe AP in rats and their temporal modulation might associate with acinar cell death by apoptosis.

Primary squamous cell carcinoma of the ampulla of Vater.

CONTEXT: Squamous carcinoma of the ampulla of Vater is a very rare tumor with only three cases been reported so far. CASE REPORT: Here, we report the case of a 68-year-old man who presented with painless obstructive jaundice, general fatigue, loss of appetite and weight loss. Laboratory tests revealed hypochromic anemia. Total and direct bilirubin, alkaline phosphatase, liver enzymes, carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) were all elevated. Abdominal ultrasonography and computed tomography showed a distended gallbladder, dilatation of the intra- and extra-hepatic bile ducts and enlargement of the pancreatic head. Endoscopic retrograde cholangiopancreatography revealed a bulging papilla with infiltrative growth at the ampulla of Vater but endoscopic biopsies were inconclusive. The patient was treated with classical Whipple's pancreaticoduodenectomy. Histopathological examination showed a moderately differentiated squamous cell carcinoma. Multiple serial sectioning of the tumor specimen failed to detect an adenomatous component. Regional lymph nodes and resection margins were free of tumor and the disease was classified as stage IIA (T3N0M0) according to the TNM system. Adjuvant treatment was not given. Despite curative resection, multiple liver metastases developed after four months and the patient succumbed to progressive hepatic failure 5 months after the operation. CONCLUSION: Primary pure squamous cell carcinoma of the ampulla of Vater is a very rare histological type of carcinoma. Clinical characteristics and optimal treatment are obscure. Primary surgical treatment with curative intent should be performed although this type of carcinoma associates with dismal prognosis.

Spontaneous colo-umbilical fistula complicating diverticulitis of the sigmoid colon.

Colocutaneous fistula caused by diverticulitis is relatively uncommon with colo-umbilical fistulas being even rarer. We herein report a rare case of a spontaneous colo-umbilical fistula due to diverticulitis of the sigmoid colon. The fistula developed from a diverticulum of the sigmoid colon that discharged through the umbilicus after two episodes of acute diverticulitis. The condition was successfully treated by resectional surgery.

Common bile duct obstruction secondary to a periampullary diverticulum.

Periampullary duodenal diverticula are not uncommon and are usually asymptomatic although complications may occasionally occur. Here, we report the case of a 72-year-old woman who presented with painless obstructive jaundice. Laboratory tests showed abnormally elevated serum concentrations of total and direct bilirubin, of alkaline phosphatase, of γ-glutamyl transpeptidase, and of aspartate and alanine aminotransferases. Serum concentrations of the tumor markers carbohydrate antigen 19-9 and carcinoembryonic antigen were normal. Abdominal ultrasonography showed dilatation of the common bile duct (CBD), but no gallstones were found either in the gallbladder or in the CBD. The gallbladder wall was normal. Computed tomography failed to detect the cause of CBD obstruction. Magnetic resonance imaging and magnetic resonance cholangiopancreatography revealed a periampullary diverticulum measuring 2 cm in diameter and compressing the CBD. The pancreatic duct was normal. Hypotonic duodenography demonstrated a periampullary diverticulum with a filling defect corresponding to the papilla. CBD compression by the diverticulum was considered as the cause of jaundice. The patient was successfully treated by surgical excision of the diverticulum. In conclusion, the presence of a periampullary diverticulum should be considered in elderly patients presenting with obstructive jaundice in the absence of CBD gallstones or of a tumor mass. Non-interventional imaging studies should be preferred for diagnosis of this condition, and surgical or endoscopic interventions should be used judiciously for the effective and safe treatment of these patients.

Tissue expression of the proteins fas and fas ligand in colorectal cancer and liver metastases.

BACKGROUND AND AIM: Our purpose is to study the clinical significance of Fas/FasL expression in colon cancer and liver metastases (LM). MATERIAL AND METHODS: The expression of Fas/FasL in 68 patients with colon cancer was examined immunohistochemically and correlated to the clinicopathological features of the tumors. RESULTS: High expression of FasL, was observed in stage D and in LM (p=0.024). Fas expression was reduced in stage D tumors and in LM, when compared to earlier stages of disease (p=0.024). LM had also shown a decreased expression of Fas (p=0.016). Tumors with low FasL expression upregulate more often their Fas expression (p = 0.028). No correlation could be established regarding the patients survival. CONCLUSIONS: Low expression of Fas and high expression of FasL are more often in colon tumor stage D and in liver metastasis; these imply tumor aggression, resistance against apoptosis, and could be held as negative prognostic factors.

Synchronous breast and rectal cancers in a man.

Breast cancer in men is relatively rare and its coexistence with other primary non-breast cancers exceptional. Here, we report the case of a 50-year-old man who presented with symptoms of rectal adenocarcinoma and in whom a synchronous, asymptomatic cancer of the left breast was found incidentally at physical examination.

Synchronous carcinoma of the ampulla of vater and colon cancer.

Carcinoma of the papilla of Vater is a relatively rare tumor and its coexistence with other primary sporadic cancers is very exceptional. Here we report the case of a 76-year-old man who presented with painless obstructive jaundice, pathologically elevated liver function tests and increased serum levels of carbohydrate antigen 19-9 and carcinoembryonic antigen. Endoscopic retrograde cholangiography revealed a large polypoid mass in the ampulla of Vater. A large tumor in the ascending colon was also incidentally detected by abdominal computed tomography. Endoscopic biopsies from both lesions showed adenocarcinomas. Metastases to the liver and to the hepatoduodenal ligament and hepatic artery lymph nodes were found during surgery. Right colectomy and a biliary bypass were performed. Histological analysis showed an ampullary adenocarcinoma with metastases to regional lymph nodes and the liver and a colonic adenocarcinoma with local invasion into the pericolic fat. Treatment with gemcitabine plus cisplatin was suggested postoperatively. The association of sporadic ampullary and colonic adenocarcinomas and the mutually increased risk of developing either a synchronous or a metachronous tumor following each other should be considered in patients with primary ampullary or colorectal cancer during the preoperative evaluation and postoperative follow-up of these patients.

Ischemic colitis of the left colon in a diabetic patient.

Diabetes mellitus may affect the gastrointestinal tract possibly as a result of autonomic neuropathy. Here we present a 68-year-old male with non-insulin-dependent diabetes mellitus who presented with prolonged watery diarrhea and in whom imaging studies demonstrated ischemic colitis of the left colon. Resection of the affected colon resulted in sustained disappearance of symptoms.

Cutaneous metastasis at a surgical drain site after gastric cancer resection.

Cutaneous metastasis from intra-abdominal malignant solid tumours such as gastric adenocarcinoma is very rare. Here, we report the case of a 76-year-old male patient with a T4N2M0, poorly differentiated, signet-ring cell gastric carcinoma, who underwent potentially curative resection of the tumour and developed cutaneous metastasis at the site of the surgical drain 4 months after the operation while he was on chemotherapy. The lesion involved the skin and the subcutaneous fat only. A CT scan revealed local recurrence at the resection bed but no distant metastases. The patient died 1 month later. It is concluded that the development of cutaneous metastasis after gastric carcinoma resection indicates tumour recurrence or disseminated disease and is associated with poor prognosis.

Neuropeptide urocortin 1 and its receptors are expressed in the human liver.

The corticotropin-releasing hormone (CRH) system, consisting of CRH, urocortins (Ucns), their receptors CRH(1) and CRH(2), and CRH-binding protein, holds the principal role in mediating the response to stress stimuli. Besides their expression in the brain, CRH neuropeptides and receptors have been found in multiple peripheral sites. We investigated the expression of the CRH system in the human liver, using RT-PCR and immunohistochemistry. Ucn 1 gene transcripts were amplified in all the human liver biopsies examined. Ucn 1 immunoreactivity was localized in hepatocytes. CRH(1) and CRH(2(alpha)) receptor gene expression was also found, and receptor protein had a similar distribution to Ucn 1. Finally, Ucn 1 and CRH receptor expression was demonstrated in hepatic biopsies from a variety of liver pathologies, including primary or metastatic liver carcinoma and cirrhosis. We conclude that the CRH system is expressed by human liver under normal and pathological conditions, Ucn 1 being the major ligand. Further study is required to unfold the biological role of these effectors in liver physiology and pathogenesis, as they may act in an autocrine manner through activation of the CRH receptors expressed locally.

Human leptin induces angiogenesis in vivo.

Leptin is an adipocyte-produced peptide, which plays a crucial role in the regulation of body weight. There is also evidence that leptin stimulates endothelial cell proliferation and the formation of capillary-like tubes in vitro. The disc angiogenesis system was used to measure the angiogenic effect of leptin in vivo. Discs containing 25, 50, 100 and 250ng/ml of leptin were implanted subcutaneously in Wistar rats, removed after a growth period of 7 and 14 days, and compared with spontaneous growth controls and with positive controls containing equivalent doses of vascular endothelial growth factor (VEGF). Discs were examined morphologically for stroma and vessel development and by immunohistochemistry for quantitative evaluation of angiogenesis. The specificity of the angiogenic effect of leptin was tested by blocking leptin with a polyclonal anti-leptin antibody. Leptin induced a significant level of angiogenesis in a dose-dependent manner both at 7 and 14 days, with a peak at the dose of 100ng/ml. The angiogenic activity of leptin was completely abolished by the anti-leptin neutralizing antibody. VEGF also induced significant dose-dependent angiogenesis at the same time points with a peak observed at a concentration of 100ng/ml. The angiogenic response to leptin was significantly higher at 7 days compared with VEGF but not at the 14-day time point. In conclusion, leptin has a specific angiogenic effect in vivo, which is dose- and time-dependent in a concentration range of 25-250ng/ml. This effect is equivalent to the angiogenic effect of VEGF but is evident earlier compared with VEGF.

The contribution of acute cholecystitis, obesity, and previous abdominal surgery on the outcome of laparoscopic cholecystectomy.

The aim of this study was to evaluate the impact of acute cholecystitis (AC), obesity, and previous abdominal surgery on laparoscopic cholecystectomy (LC) outcomes. Records of 1940 patients undergoing LC in 1992 and 2004 were reviewed in order to assess the independent and joint effects of the above risk factors on conversion, morbidity, operation time, and hospital stay. In multivariate regression analysis, adjusting for sex and age, AC alone and in combination with obesity or previous abdominal surgery increased the risk of conversion and complications and was associated with prolonged operation time and hospital stay compared with the patients without any of the risk factors (reference group). The independent and joint effects of obesity and previous abdominal surgery were significant only on operation time. On the contrary, previous upper abdominal surgery alone and in combination with AC was associated with 3- and 17-fold relative odds of conversion, respectively. The combined presence of AC, obesity, and previous abdominal surgery yielded an odds ratio for conversion of 7.5 and for complications of 10.7, as well as a longer operation time and hospital stay. The presence of previous upper abdominal surgery with AC and obesity had a substantial effect on conversion, with an odds ratio of 87.1 compared with the reference group. LC is safe in patients with AC, previous abdominal surgery, or obesity. However, the presence of inflammation alone or in combination with obesity and/or previous (especially upper) abdominal surgery is the main factor that influences the adverse outcomes of LC.

Adhesion molecules as targets for the treatment of neoplastic diseases.

The quest for therapeutic specificity is implicit in all branches of medicine. In cancer treatment, cytotoxic agents, such as chemotherapy and radiotherapy, comprise the current therapeutic modality. Unfortunately, when used against most solid malignancies, their therapeutic indices are relatively low due to the significant damage they inflict on normal tissues. Furthermore, cure rates have remained essentially static over the last two decades. Specificity in killing neoplastic cells, while sparing healthy ones is therefore the only alternative approach, with several molecules qualifying as candidates for targeting therapy. Reduction of cell-cell and cell-matrix adhesion are, early tumorigenesis events also implicated in the invasive and metastatic process. The fact that abnormal adhesive marker expression is a feature commonly shared by most malignancies, along with its tendency to occur as both an early and late event in neoplastic development, makes these molecules potential candidates for antineoplastic targeted therapies. This review presents the perspectives of specific anti-adhesion molecule targeting as a possible therapeutic approach in neoplastic diseases.

Serum leptin levels and their response during laparoscopic and open cholecystectomy.

We compared serum leptin responses during and after laparoscopic and open cholecystectomy, and assessed their correlation with the responses of inflammatory cytokines. Serum levels of leptin, interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured by an enzyme-linked immunoassay in 31 patients who underwent laparoscopic cholecystectomy and in 24 patients who underwent open cholecystectomy. Serum samples were obtained preoperatively, at 10 and 30 min after the commencement of surgery, and at 6 and 24 h after the operation. The cumulative responses of leptin, IL-1alpha, IL-6 and TNF-alpha to surgery were calculated and the associations between them were evaluated. Serum leptin levels were significantly increased at 24 h after both procedures. The serum leptin concentration at this time point and the cumulative leptin response were significantly lower after laparoscopic cholecystectomy than after open cholecystectomy. Changes in serum IL-1alpha, TNF-alpha and IL-6 concentrations showed similar kinetics in both groups, with postoperative IL-6 levels being consistently lower in the laparoscopic cholecystectomy group. Cumulative IL-6 and TNF-alpha responses were significantly lower after laparoscopic cholecystectomy than after open cholecystectomy. The cumulative responses of leptin, IL-1alpha and IL-6 correlated significantly with each other. Leptin may be involved in the systemic inflammatory response to surgical injury, and the postoperative leptin elevation and cumulative leptin response are significantly lower after laparoscopic cholecystectomy than after open cholecystectomy.