[Somatostatin receptors expression (SSTR1-SSTR5) in pheochromocytomas]. / Ekspresja receptorów somatostatynowych (SSTR1-sSTR5) w guzach chromochlonnych.

Confirmation of somatostatin receptors (SSTR) expression in neuroendocrine tumours has changed their modern diagnosis and therapy, and starts to influence the approach to pheochromocytomas. In vitro studies have revealed the SSTR expression in pheochromocytomas, particularly subtype 2A and 3. They also have indicated that their confinement to cell membranes is essential for successful diagnostics with the use of somatostatin analogues. Scintigraphy with radiolabeled somatostatin analogues is nowadays an approved complementary method of pheochromocytoma localization, particularly the malignant ones. Cell culture studies have indicated that the commercially available somatostatin analogues are able to control tumour growth and secretion. Unfortunately these results have not been confirmed by clinical studies. It seems that the analogues with the broader affinity to sstr may be a good therapeutic option for pheochromocytoma patients. Promising results of radiotherapy with labeled analogues have been recently announced.

Gastric solid glomus tumor and multiple glomangiomyomas of the large bowel with intravascular spread, multifocal perivascular proliferations and liver involvement.

The authors present a case of multiple glomus tumors (GTs) of the gastrointestinal tract, representing the type of a gastric glomus tumor proper and large bowel glomangiomyomas with myopericytoma-like features, observed in a 46-year old female, with multifocal perivascular proliferations of primitive cells and hepatic involvement. Histologically, the multilobular gastric tumor and hepatic lesions corresponded to a typical glomus tumor, while the tumor situated in the transverse colon, up to 7 cm in diameter, presented as a glomangiomyoma infiltrative (with myopericytoma-like foci), and satellite tumors in the large bowel mucosa, 0.5-0.7 cm in diameter, represented small glomangiomyomas. In addition, the patient demonstrated two types of concomitant vascular lesions: 1/ intravascular spread in the form of neoplastic plugs that obliterated the lumen of medium-size veins, and 2/ microscopic perivascular proliferation of primitive, small cells seen in the vicinity of the main tumor and in the adjacent adipose tissue. The patient has been ill for 2.5 years; she has been subjected to a partial colectomy with a resection of the small intestinal loop, greater omentum and the right ovary, followed by chemotherapy. At present, she is stable, and the infiltration--especially in the epigastric region--has decreased. The picture may confirm the theory that multiple GTs develop in association with multifocal proliferation of perivascular stem cells, as well as that their ability to penetrate into the lumen of large vessels gives origin to satellite tumors, which are not necessarily metastatic. It seems that at present, the group of perivascular SMA+ tumors may include infantile-type myofibromatosis in adults, myopericytoma, glomangio(myo)pericytoma, glomangiomyoma, glomus tumor proper, and glomangioma. Most likely, also some tumors previously classified as hemangiopericytomas belong to this group. The distinctive feature present in at least some of the above listed perivascular tumors is their synchronous or metachronous growth in a particular region and their ability to occupy intravascular space as nodules or solid bands, which in turn may give origin to satellite tumors. Multifocal lesions associated with a short survival in a given patient will obviously support the presence of metastatic disease. In the remaining cases, determination whether the patient has metastatic disease requires deep consideration and caution, also while deciding on treatment to be employed.

Blood serum levels of proinflammatory cytokines in patients with different degrees of biliary pancreatitis.

BACKGROUND: Proinflammatory cytokines play a fundamental role in the local and systemic inflammatory responses in the initial stages of acute biliary pancreatitis (ABP) and in the development of severe forms of the disease. OBJECTIVES: The aim of the present study was to assess the systemic release of proinflammatory cytokines and to characterize differences between patients with mild ABP (MABP) and severe ABP (SABP). PATIENTS AND METHODS: In the current study, 54 patients with MABP were compared with 14 patients with SABP. Serum levels of tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8 and IL-12p40 were measured every second day after admission for one week. RESULTS: The tumour necrosis factor-alpha level was similar in all days of analysis in patients with MABP but was lower compared with SABP patients. The level of IL-1beta was higher at admission in patients with MABP. The level of IL-6 peaked on admission day in both groups, but in patients with SABP, the obtained values were higher. The level of IL-8 on admission day was slightly higher in patients with MABP and systematically decreased when measured on the following days (the third, fifth and seventh days of the study). An increased level of IL-8 during the third, fifth and seventh days of the investigation was seen in SABP patients. The level of IL-12p40 was slightly higher in patients with MABP on the day of admission. CONCLUSIONS: The levels of some proinflammatory cytokines are higher in patients with SABP than in patients with MABP. The most consistent difference between the two groups was that the levels of IL-6 were significantly higher in patients with SABP throughout the study. Serum concentration of IL-6 may be helpful as a marker of severity and outcome of ABP.

Effects of cyclooxygenase-2 inhibition on serum and tumor gastrins and expression of apoptosis-related proteins in colorectal cancer.

The objective of the present study was to determine the influence of cyclooxygenase-2 (COX-2) inhibition by Celecoxib (CLX) in humans with distal colorectal adenocarcinoma (CRC) on serum and tumor levels of progastrin and gastrin and serum levels of proinflammatory cytokines (IL-8, TNF-alpha). In addition, the effects of this CLX treatment on tumor and adjacent mucosa expression of gastrin, its receptors (CCK2), and COX-1 and COX-2, as well as protein expression of the active form of nuclear factor kappa B (NFkappa B) and the apoptotic-related proteins Bcl-2 and survivin, have been examined. Ten distal CRC patients were examined twice, once before and then after 14-day treatment with CLX (200 mg bid). Large biopsy samples were taken from the tumor and intact mucosa 10 cm above the tumor. For comparison, 20 age- and sex-matched healthy controls were enrolled and treated with CLX as CRC patients. Serum levels of IL-8 and TNF-alpha were measured by enzyme-linked immunosorbent assay, and serum levels of amidated gastrins and progastrin, by specific radioimmunoassay. The gene or protein expressions of progastrin, gastrin, CCK2, COX-1, COX-2, Bcl-2, and survivin as well as NFkappa B were determined by RT-PCR or Western blot in biopsy samples of tumor and intact mucosa of CRC patients. Serum IL-8 and TNF-alpha values were severalfold higher in CRC patients than in controls. The increase in serum proinflammatory cytokines was accompanied by increased expression of the active form of NFkappa B. Serum progastrin levels were also found to be significantly higher in CRC than in controls. Treatment of CRC with CLX resulted in a significant decrease in serum levels of progastrin and this was accompanied by an increment in tumor expression of COX-2 with a concomitant reduction in gastrin, Bcl-2, survivin, and NFkappa B expression. We conclude that (1) distal CRC patients show significantly higher serum progastrin levels than matched healthy controls, confirming that this hormone may be implicated in rectal carcinogenesis; (2) CRC patients exhibit significantly higher serum levels of IL-8 and TNF-alpha than healthy controls, probably reflecting more widespread inflammatory reaction in the colonic mucosa in CRC; (3) gastrin, COX-2, Bcl-2, survivin, and NFkappa B were overexpressed in CRC tumor compared to intact mucosa, but treatment with CLX significantly reduced serum levels of progastrin and IL-8 and TNF-alpha, which could mediate the up-regulation of COX-2 in CRC; and (4) CLX also enhanced expression of COX-2, while inhibiting the expression of gastrin, Bcl-2, survivin, and NFkappa B, suggesting that COX-2 inhibition might be useful in chemoprevention against CRC, possibly due to suppression of the antiapoptotic proteins and reduction in progastrin-induced and NFkappa B-promoted tumor growth.

Gastrointestinal stromal tumors. A multicenter experience.

The report presents 200 cases of gastrointestinal stromal tumors (GIST). The material originated from six diagnostic centers in Poland and was reclassified according to the current criteria. Among lesions other than GISTs, 14 were identified as smooth muscle tumors and seven as neural tumors. GISTs were located in the stomach (51-63.3% of the investigated series), small intestine (27.4-33.8%), colon (approximately 4.5%), abdominal cavity, i.e. in the peritoneum and omentum (6%), and in the retroperitoneal space (2.5%). A slight predominance of women was noted (53-56%). The age of the patients ranged between 14 and 93 years of life, with the mean age of 62.4 years. Individuals younger than 45 years of age accounted for 10% of the group. In ten patients (five of them less than 45 years of life), multiple tumors were detected, their number ranging from two to less than 20; these individuals constituted 5% of the entire series. Moderately and highly aggressive tumors predominated. In the series, when multiple tumors were excluded, a total of 24 epithelioid GISTs (12%) were observed; of this number, 13 were situated in the stomach, six--in the small intestine, two--in the abdominal cavity and another two in the retroperitoneal space. Synchronic tumors observed in patients with GISTs were seen in seven patients, including an adenocarcinoma of the colon, two adenocarcinomas of the stomach, a carcinoid tumor of the small intestine, a pheochromocytoma of the retroperitoneal space, an anaplastic lymphoma and a disseminated squamous cell carcinoma. In immunohistochemical reactions (CD117, CD34, SMA, S-100, DES), attention was focused on the immunoreactivity of small GISTs, below 2 cm in size, and of multiple tumors. Immunohistochemical reactions were equally differentiated as to their presence and intensity in small tumors and in highly aggressive lesions above 5-10 cm in size. In multiple GISTs, immunohistochemical tests strongly indicated the heterogeneity of neoplastic cells, which, nevertheless, showed no consistent association with the location of the tumor, its aggressiveness, cellular structure or a tendency to form multiple foci.

Multifocal atrophic gastritis: pathogenesis and therapeutic implications.

OBJECTIVE: This study, carried out on 51 patients with multifocal atrophic gastritis (MAG) and 92 age and sex-matched dyspeptic controls, was designed to examine both exocrine (gastric acid) and endocrine (gastrin) gastric secretion before and after therapeutic intervention including Helicobacter pylori eradication and vitamin C treatment. METHODS: Fasting and gastrin-releasing peptide-induced gastric acid secretion, serum levels of gastrin and proinflammatory (IL-1beta, IL-8, TNF-alpha) as well as gastric mucosal gene expression of ornithine decarboxylase (ODC), cyclooxygenase 2 (COX-2) and growth factors (epidermal growth factor and transforming growth factor alpha) were determined before and after the eradication of Helicobacter pylori and therapy with large doses (1 g/d) of vitamin C for 3 months. RESULTS: The H. pylori eradication, assessed by C-urea breath test, and vitamin C therapy failed to reverse the histological atrophy of the gastric mucosa but improved significantly the functional status of the atrophied mucosa, especially its exocrine and endocrine secretory activities, attenuated the expression of premalignant markers such as ODC and COX-2, raised the production of growth factors and diminished the release of proinflammatory cytokines. CONCLUSIONS: These results indicate that MAG may be considered as an environmental disease of the gastric mucosa, whose functional status can be improved by the eradication of H. pylori combined with antioxidant therapy with large doses of vitamin C.

Biomarkers in various types of atrophic gastritis and their diagnostic usefulness.

Atrophic gastritis has been shown to involve either the oxyntic gland area, resulting in hypergastrinemia and hypopepsinogenemia I, the antral gland area, causing hypogastrinemia without change in serum pepsinogen I (diffuse antral gastritis; DAG), or the entire gastric mucosa (multifocal atrophic gastritis; MAG), resulting in both hypogastrinemia and hypopepsinogenemia I; and rare atrophic gastritis limited to the oxyntic gland area, with antibodies against oxyntic cells and/or intrinsic factor (autoimmune metaplastic atrophic gastritis; AMAG). This study was performed on 126 patients with various forms of gastritis and on 126 age- and gender-matched controls, who were subjected to endoscopy with biopsy, H. pylori testing (13C-UBT, serology), assays for serum gastrin and pepsinogen I, and testing for basal and pentagastrin-induced gastric acid secretion. The following groups of patients were examined: group I (N = 22), with AMAG; group II (N = 53), with DAG; group III (N = 51), with MAG; and group IV (N = 126), age- and gender-matched controls without gastritis. The following changes were found. In group I very high serum gastrin and very low pepsinogen I were observed, and all patients were achlorhydric and H. pylori negative. In group II, with low serum gastrin and normal pepsinogenemia and gastric chlorhydria, all patients were H. pylori positive. In group III, with lower serum gastrin and lower pepsinogen I levels and reduced chlorhydria, all patients were also H. pylori positive. And all group IV controls, with normal serum gastrin and pepsinogen I and normal gastric acid secretion without antral or fundic gastritis, were H. pylori negative. We conclude that measurements of serum gastrin and pepsinogen I and gastric acid secretion as well as testing for H. pylori infection may be useful in noninvasive diagnosis of various types of atrophic gastritis and in identification of patients with premalignant gastritis and a high risk of gastric cancerogenesis.

Helicobacter pylori and nonsteroidal anti-inflammatory drugs in perforations and bleeding of peptic ulcers.

BACKGROUND: This study was designed to assess the relative contribution of H pylori (Hp) infection and NSAID in the pathogenesis of perforation and bleeding of peptic ulcer (PU). MATERIAL/METHODS: Total of 91 PU perforations and 135 active bleeding were examined during last 5 years. At the same time, 1384 age- and gender-matched PU patients without such complications were examined. Furthermore, the effects of various concentrations of aspirin on the growth of Hp isolated from antral mucosa of these PU were examined in vitro. RESULTS: The average rates of Hp prevalence in PU patients with perforation or bleeding in NSAID intake were, respectively, only 50% and 62% as compared to 70.7 and 74% in PU patients non-using NSAID. The Hp prevalence in perforated and bleeding PU at all ages, particularly those at age of 60 years or higher, were significantly lower compared to that found below this age, while no such difference in Hp infection rate was seen in PU not using NSAID. In vitro studies on CagA and VacA positive Hp subjected to culture medium containing aspirin showed a dose dependent reduction in bacterial growth with complete bacteria killing occurring at 500 microg/ml of aspirin. CONCLUSIONS: The Hp prevalence, especially in older PU patients using NSAID, is significantly lower in perforated and bleeding PU compared to that in non-complicated PU, and this could be explained by direct suppression of Hp by NSAID used by these patients.

[Minimally invasive techniques in the treatment of acute biliary pancreatitis]. / Ostre zólciowe zapalenie trzustki leczone technikami maloinwazyjnymi.

43 cases of consecutive bilary acute pancreatitis were treated by early endoscopic sphincterotomy and laparoscopic cholecystectomy within first 48 hours after admission. The basic cause of disturbance of bile outflow was microlithiasis. Course of the disease was monitored by level of proinflammatory interleukins in the blood serum of analysed patients. Marked decrease of their level after endoscopic sphincterotomy was observed. This decrease was progressed after laparoscopic cholecystectomy followed by continuos closed lavage of abdominal cavity. Our results indicated that minimally invasive techniques should be done in the early stage of mild and moderate cases of acute biliary pancreatitis.

Evaluation of NF2 and NF1 tumor suppressor genes in distinctive gastrointestinal nerve sheath tumors traditionally diagnosed as benign schwannomas: s study of 20 cases.

A significant percentage of conventional schwannomas, whether sporadic or associated with neurofibromatosis 2 (NF2), show loss of heterozygosity (LOH) at NF2 and/or NF2 inactivating mutations. Similarly, a significant percentage of neurofibromas show LOH at NF1 and/or NF1 inactivating mutations. There are no molecular genetic data on gastrointestinal (GI) nerve sheath tumors traditionally diagnosed as benign schwannomas, rare neoplasms possibly derived from the schwannian elements dispersed between the smooth muscle fibers. In this study, we analyzed 1 esophageal, 16 gastric, 1 small intestinal, and 2 colonic tumors of such type. Histologically, all were spindle cell neoplasms positive for S-100 protein, vimentin, and glial fibrillary acidic protein, and negative for smooth muscle markers, KIT, CD34, neurofilament proteins, and HMB45. Focal or extensive lymphoid cuffs, often containing germinal centers, were present in most cases. None of the patients had NF2 or NF1. Chromosomes 22 and 17, particularly NF2 and NF1 loci, were analyzed for LOH in all GI tumors and for comparative purposes in 10 conventional schwannomas. LOH on 22q was seen in 40% of conventional schwannomas but in only 5% (1 of 20) of GI schwannomas. PCR amplification followed by direct sequencing of PCR products failed to identify mutations in NF2 coding sequences (exons 1-15) in 13 cases, including a case with LOH on 22q. Losses on 17q involving NF1 were seen in both GI and conventional schwannomas in 50% and 33% of analyzed tumors, respectively. LOH at NF1 might be one of the genetic features seen in peripheral nerve sheath tumors from different locations and should be interpreted with caution. However, lack of NF2 alterations strongly supports the hypothesis that GI schwannomas represent a morphologically and genetically distinct group of peripheral nerve sheath tumors that are different from conventional schwannomas.

Gene expression of ornithine decarboxylase, cyclooxygenase-2, and gastrin in atrophic gastric mucosa infected with Helicobacter pylori before and after eradication therapy.

H. pylori (Hp) -induced atrophic gastritis is a well-known risk factor for the development of gastric cancer. Whether Hp eradication can prevent or retard the progress of atrophy and metaplasia has been the topic of numerous studies but the subject remains controversial. Recently, the increased expression of ornithine decarboxylase (ODC), gastrin and cyclooxygenase (COX)-2 has been shown to be increased in premalignant lesions in gastric mucosa and to play an essential role in the malignant transformation. The aim of the study is to assess the effect of eradication therapy on atrophic gastritis and analyze the gene expression for ODC, COX-2 and gastrin in gastric mucosa after succesful eradication in patients with atrophic gastritis. Twenty patients with chronic atrophic gastritis including both corpus and antrum of the stomach were included in this study. Four antral mucosal biopsy specimens were obtained from antrum and four from corpus. The histopathologic evaluation of gastritis was based on Sydney classification of gastritis. All patients were Hp positive based on the [13C] urea breath test (UBT) and the presence of anti-Hp IgG and anti-CagA-antibodies detected by ELISA. The patients were then eradicated with triple therapy consiting of omeprazol (2 x 20 mg), amoxycillin (2 x 1 g) and clarithromycin (2 x 500 mg) for seven days and vitamin C 1 g/day for three months. In gastric mucosal samples obtained from the antrum and corpus before and after eradication, the mRNA expression for ODC, COX-2, and gastrin was assessed by reverse-transcription polymerase chain reaction (RT-PCR). In all patients the gastric secretory analysis was performed by measuring gastric acid output and serum gastrin levels. After triple therapy the successful eradication assessed by UBT was observed in 95% of patients. In 45% of patients the infection with CagA-positive Hp strain was observed. Three months after eradication a significant reduction in the gastric activity (neutrophilic infiltrate) and severity (mononuclear infiltrate) of gastritis was observed. The atrophy score improved in both antrum and corpus after eradication. The expression of COX-2 and ODC was significantly up-regulated in the gastric mucosa of patients with atrophic gastritis and significantly reduced after eradication therapy. In all successfully eradicated patients with atrophic gastritis a significant increase in gastric acid secretion and decrease in serum gastrin were observed. We conclude that: (1) Hp eradication leads to the decrease in ODC and COX-2 gene expression in the gastric mucosa, and this may be relevant for the prevention of the Hp-associated gastric carcinogenesis; and (2) gastric atrophy ameliorates upon successful Hp eradication therapy.

Case presentation of gastrinoma combined with gastric carcinoid with the longest survival record -- Zollinger-Ellison syndrome: pathophysiology, diagnosis and therapy.

BACKGROUND: Zollinger-Ellison syndrome is a very rare disease caused by tumor with gastrin producing cells accompanied by hypergastrinemia leading to gastric hypersecretion and peptic ulcers and their complications. CASE STUDY: Female case of gastrinoma (Zollinger-Ellison syndrome; Z-E) with a record of 38 yrs of survival. Acute gastro-duodenal ulcers started at 28 yr of age and Z-E was diagnosed by using gastrin assays. Basal and maximal acid outputs and ratio of basal/maximal outputs were away over normal limits. Because of ulcer recurrence and complications, patient was subjected to several gastric surgeries but refused total gastrectomy. She was also treated with many H2-receptor (R) antagonists and proton-pump inhibitors (PPI), each new drug being initially highly effective but then showing declining efficacy except when PPI, lansoprazole was used. The gastrin level rose in the course of disease from initial high value of 2000 pg/mL to the extreme 4500 ng/mL at present. During the last 2 yrs, metastasis mainly to liver developed and they were successfully treated by synthetic octapeptide derivative of somatostatin and, as a result, metastatis partly reduced and plasma gastrin drasticly decreased. Biopsy taken from liver metastasis showed the presence of typical gastrinoma cells with gastrin and chromogranin, while that from oxyntic mucosa revealed the ECL-cell hyperplasia with carcinoid tumors and unexpected gastric atrophy. CONCLUSIONS: This phenomenal case described in this article might be the new proven evidence needed by gastroenterologists to overturn the traditional treatment using total gastrectomy as a treatment of choice to the partial gastrectomy combined with proton pump inhibitors.