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Microsatellite instability (MSI) in tumors results in an accumulation of mutations in (target) genes. Previous studies suggest that the profile of target genes differs according to tumor type. This paper describes the first genome-wide search for target genes for mismatch repair-deficient endometrial cancers. Genes expressed in normal endometrium containing coding repeats were analyzed for mutations in tumors. We identified 44 possible genes of which seven are highly mutated (>15%). Some candidates were also found mutated in colorectal and gastric tumors. The most frequently mutated gene, NRIP1 encoding nuclear receptor-interacting protein 1, was silenced in an endometrial tumor cell line and expression microarray experiments were performed. Silencing of NRIP1 was associated with differences in the expression of several genes in the estrogen-receptor network. Furthermore, an enrichment of genes related to cell cycle (regulation) and replication was observed. We present a new profile of target genes, some of them tissue specific, whereas others seem to play a more general role in MSI tumors. The high-mutation frequency combined with the expression data suggest, for the first time, an involvement of NRIP1 in endometrial cancer development.

The effect of different radiation qualities on (i) 53BP1 (p53 Binding Protein 1) and p-ATM (phosphorylated ataxia telangiectasia mutated) foci induction, and (ii) on the kinetics of foci disappearance was analysed.Normal human skin fibroblasts were exposed to 240 kV broad-field X-rays or targeted with individually counted helium ((3)He) particles or protons ((1)H) from a Charged Particle Microbeam. Anti-p-ATM and anti-53BP1 antibodies were used for foci visualisation via immunocytochemistry.1 Gy of X-rays yielded approximately 33 53BP1-positive foci/cell. The ratio between the number of delivered particles and yielded tracks was found to be 1:1 and 3:1 after targeted (3)He and (1)H irradiation, respectively. It was determined that approximately 50% of radiation-induced damage was repaired as measured by loss of foci during the first 2, 6, and 10 hours following X-ray, protons, and (3)He irradiation, respectively.There was significant radiation quality dependence for 53BP1- and p-ATM-positive foci induction observed. Foci disappearance was radiation dose-independent in the samples irradiated with X-rays. Our results confirm that kinetics of foci disappearance depends on radiation quality, even when individual ions are targeted to cells.

Exposure of the gastric mucosa to aspirin results in exfoliation of the surface epithelium and deep mucosal necrosis. We assessed the changes in the mucosal microvessels during aspirin-induced injury and arachidonic acid protection of the gastric mucosa using transmission electron microscopy. Male Spra-gue-Dawley rats received intragastric pretreatment with either solubilizer (control) or detergent solubi-lized arachidonic acid (148 mg kg-1). One hour later 1-ml suspension of 200 mg kg-1 body weight acidified aspirin was administered intragastrically. The ultra-structure of mucosal microvasculature was assessed at 15 min and 4 h after aspirin administration both qualitatively and quantitatively by determining the number of necrotic or damaged capillaries in standardized mucosal sections. In addition, mucosal specimens were immunostained with a specific antiserum against vimentin, an endothelial marker, and fluorescence intensity was measured with a Nikon FX microscopic photometric system. In control rats, aspirin produced significant damage to both superficial and deeper microvessels consisting of: rupture of capillary walls, necrosis of endothelial cells, damage to endothelial organelles, deposition of fibrin and adherence of platelets to damaged endothelium. Vimentin fluorescence was reduced three-fold. Microvascular injury preceded the development of deep necrotic lesions. Microvascular damage and deep mucosal necrosis were significantly reduced by arachidonic acid pretreatment. We conclude that gastric mucosal microvessels are the major target for aspirin-induced injury and arachidonic acid protection.

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms driven by oncogenic, mutational activation of KIT or platelet-derived growth factor receptor alpha (PDGFRA). GIST-specific KIT or PDGFRA mutations have been linked to tumor location, tumor cell morphology and clinical behavior. The purpose of this study was to evaluate the clinicopathologic profile of GISTs that have KIT exon 13 or exon 17 mutations. Through the collaboration of several GIST research groups, we gathered 54 cases from the pre-imatinib era that had such primary mutations. From our observations and those in the literature, we estimate that the frequency of these mutations is no higher than 1-2%. Almost all (32 of 33, 97%) of the KIT exon 13 mutations were the 1945A>G substitution leading to Lys642Glu. A majority (15 of 21, 71.4%) of the KIT exon 17 mutations were the 2487T>A substitution leading to Asn822Lys. Demographic and clinicopathologic data were available for 26 and 14 KIT exon 13 and exon 17 mutant GISTs, respectively. Median age and male to female ratio were similar to ones reported in other GIST studies. Small intestinal tumors were two times more frequent than gastric ones among KIT exon 17 mutants. Also, intestinal tumors were slightly overrepresented among KIT exon 13 mutants when compared with population-based studies. The majority of KIT exon 13 or exon 17 mutants had a spindle-cell morphology and only a few had epithelioid features. Tumor size varied from 1.2 to 25 cm and average mitotic rates were 9.5 and 4.2 for KIT exon 13 and exon 17 mutants, respectively. Gastric KIT exon 13 mutant GISTs tend to be slightly larger and more aggressive than gastric GISTs in average, whereas the behavior of small intestinal GISTs with KIT exon 13 mutations does not differ from other small intestinal GISTs. The latter is also true for all KIT exon 17 mutant GISTs.

Summary Aim Craniofacial resection provides multidirectional approaches to remove nasal and paranasal tumours that involve the skull base. Vital structures, such as the dura, brain, and blood vessels, can be protected or resected and reconstructed safely. An en bloc excision of the tumour can be accomplished. The purpose of this study was to analyse oncological and functional results of craniofacial resection in our series of patients. Material and methods The medical records of 40 consecutive patients who had undergone craniofacial resection for tumours of the nasal cavity, paranasal sinuses, and adjacent areas were reviewed. The extent of disease, treatment results (the length of disease-free survival), complications, and prognoses were analysed. Results Lesions were malignant in 7 patients and benign in the remaining 33. All the patients had dural or intradural involvement. There was no operative death, and the rate of surgical morbidity was 20%. Craniofacial resection is the only surgical approach with acceptable rate of complications in selected patients with tumour comprising the anterior and medial cranial base, nasal cavity, paranasal sinuses, nasopharynx and orbits. Heroic resections are modern surgical procedures challenging both for ENT surgeons and neurosurgeons. The result is satisfactory when they are performed by a multi-specialist team.

Hypermethylation of the CDH1 promoter region seems to be the most common epigenetic mechanism in this gene silencing in gastric cancer. In this study, CDH1 promoter hypermethylation was observed in 54.8% (46/84) of the analyzed sporadic gastric carcinomas. We introduce a new relation: clustering of Goseki grading into 3 grade was determined by CDH1 promoter hypermethylation. The percentage of methylation in Goseki III cancers was significantly higher (83%) when compared with other grades; the lowest proportion was detected in IV (36%) and II (38%) groups, whereas grade I demonstrated typical percentage of promoter hypermethylation. A novel polymorphism R732R in exon 14 of the CDH1 gene was detected by mutational analysis. Additionally, all cases with the MSI-high phenotype revealed CDH1 promoter hypermethylation. In MSI-low and MSS gastric cancers, this percentage was lower, reaching 71% and 41%, respectively. Moreover, the methylation status was correlated with the LOH phenotype. We detected CDH1 promoter hypermethylation in all EBV-positive gastric cancers (5/5), whereas methylation in the EBV-negative group occurred in 58% of cases. We also report that "methylated" tumors were slightly larger than "nonmethylated," whereas the second group revealed a higher probability of longer patient survival, though these relationships were not statistically significant. These results suggest that downregulation of E-cadherin, caused by promoter hypermethylation, in sporadic gastric carcinomas may be associated with a worse prognosis and specific tumor phenotype.

This study examined the clonality of B- and T-cells by PCR in 83 patients with Philadelphia-negative myeloproliferative disorders (Ph-MPD), to investigate its clinical and morphological correlates. Clonal lymphocytic populations were found in 23% of patients (T: n = 20, B: n = 3), with no frequency differences between ET, CIMF and PV. At the presentation, patients with clonal bands were older (58.1+/-13.8 vs 47.5+/-14.6, p = 0.0039), but did not differ in other clinical parameters. After the median follow-up of 21 months they were less likely to be asymptomatic (11.8% vs 41.1%, p = 0.029). The T-cell clonality was the strongest predictor of the symptomatic last follow-up by discriminant function analysis, surpassing the patient's age. This surprising negative prognostic impact of lymphocyte clonality in Ph-MPD may result from this phenomenon to be a better measure of the 'hematopoietic biologic age' than the metrical age itself.

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.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.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.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.

Mutational activation of KIT or PDGFRA is considered an early step in pathogenesis of gastrointestinal stromal tumors (GISTs); however, other nonrandom genetic changes have also been identified. At least three common regions of deletions on chromosome 22q, which may harbor putative tumor suppressor genes, have been defined. However, mapping of these regions has been inconsistent. It has also been speculated that GI autonomous nerve tumors (GANTs), GISTs with ultrastructural features suggestive of autonomic nerve differentiation, are characterized by a specific deletion involving 22q13 cytogenetic region. This study was undertaken to evaluate loss of heterozygosity (LOH) on chromosome 22q in 50 GISTs, including 10 GANTs. Four tumors were incidental minimal lesions

Candida albicans frequently inhabits the gastrointestinal tract of humans leading to gastrointestinal candidiasis, especially following suppression of gastric acidity, but studies on the relation between this fungal infection and gastric pathology are limited due to lack of convenient animal models resembling Candida infection in humans. MATERIAL AND METHODS. We compared the effects of C. albicans and vehicle inoculation on gastric secretion and healing of gastric ulcers induced by acetic acid in rats treated with 1) ranitidine (30 mg kg(-1) day(-1) s.c.) and 2) aspirin (ASA) (60 mg kg(-1) day(-1) i.g.) with or without probiotic bacteria Lactobacillus acidophillus. At day 0 and at 4, 15 and 25 days after ulcer induction, the ulcer area, the gastric blood flow (GBF), the quantitative gastric cultures of Candida and the expression of mRNAs for pro-inflammatory cytokines IL-1beta and TNF-alpha and growth factors EGF and TGFalpha were assessed in the gastric mucosa.Gastric acid output was reduced by over 40% soon after Candida inoculation and this effect persisted during all time intervals tested. The area of ulcers in control rats significantly decreased at day 15 and the ulcers disappeared almost completely after 25 days of their induction. In contrast, the ulcers were present until day 25 in Candida-inoculated rats followed by a fall in GBF and a rise in plasma gastrin levels, these effects being significantly attenuated by the co-treatment with Lactobacillus. Candidiasis was accompanied by up-regulation of mRNA for IL-1beta, TNF-alpha, EGF and TGFalpha and a significant increment in plasma IL-1beta and TNF-alpha levels.1) Persistent colonization with Candida could be achieved in rats treated with antisecretory agents or non-steroidal anti-inflammatory drugs (NSAIDs) such as ASA; 2) candidiasis reduces gastric acid secretion, while delaying ulcer healing possibly due to the impairment in GBF in the ulcer area and enhanced expression and release of IL-1beta and TNFalpha and 3) probiotic therapy could be useful in the treatment against the deleterious action of fungal infection on the healing of pre-existing gastric ulcers.

Melatonin, an antioxidant, protects the pancreas against acute inflammation but, although this indole is released mainly at night, no study has been undertaken to determine circadian changes of plasma melatonin levels and the severity of acute pancreatitis. The aims of this study were: (a) to compare the severity of caerulein-induced pancreatitis (CIP) produced in the rat during the day and at the night, and (b) to assess the changes of plasma melatonin level and the activity of an antioxidative enzyme; superoxide dismutase (SOD), in the pancreas subjected to CIP during the day time and at night without or with administration of exogenous melatonin or its precursor; l-tryptophan. Rats were kept in 12 hr light/dark cycle. CIP was induced by subcutaneous infusion of caerulein (5 μg/kg/hr for 5 hr). Melatonin (5 or 25 mg/kg) or l-tryptophan (50 or 250 mg/kg) was given intraperitoneally 30 min prior to the start of CIP. CIP induced during the day time was confirmed by histological examination and manifested by pancreatic edema, and rises of amylase and lipase plasma activities (by 400 and 500%, respectively), whereas pancreatic SOD, pancreatic blood flow (PBF) and oxygen consumption by pancreatic tissue (VO2) were decreased by 70, 40 and 45%, respectively, as compared with the appropriate controls. All morphological and biochemical parameters of CIP induced at night were significantly less severe, compared with those recorded during the light phase. Plasma melatonin immunoreactivity was significantly higher during the night, than during the day, especially following administration of melatonin or its precursor, which reversed all manifestations of CIP. In conclusion, a circadian rhythm modulates the severity of CIP with a decrease of pancreatitis severity during the night compared with that at the day time and this may be due to the increased plasma level of melatonin and higher activity of SOD in the pancreas.

A new high-throughput tissue-arraying technique, now frequently used in tumor pathology, requires standardization of methods of DNA analysis, previously applied in full histological sections. The main objectives of this study were to evaluate DNA ploidy status and DNA ploidy-related parameters using the CAS200 image analyzer in malignant melanoma tissue microarrays and to compare them with full histological sections. Comparison of DNA ploidy-related parameters, including percentage of diploid cells, percentage of aneuploid cells between 2c and 4c, percentage of tetraploid cells, percentage of aneuploid cells between 4c and 8c, percentage of octaploid cells, percentage of 16-ploid cells, and 5c exceeding rate, did not reveal any significant differences between malignant melanoma tissue microarrays and full sections. The DNA ploidy status according to Auer differed in 1 out of 59 cases investigated. Our study demonstrated that it is possible to evaluate DNA ploidy status and DNA ploidy-related parameters in tissue microarrays, which is of practical relevance to tumor pathology.

Ku70 and Ku80 proteins are responsible for the repair of DNA double-strand breaks and function as a regulatory subunit of the DNA-dependent protein kinase. In this study we analyzed expression of both genes in malignant melanoma tissue arrays applying in situ hybridization probes produced by our research group and using immunohistochemical analysis. Expression of both genes was down-regulated as melanoma progressed. In situ hybridization demonstrated more Ku70- and Ku80-positive cells than immunohistochemical methods, but the correlation between the two methods was highly significant (P

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express KIT and show gain-of-function KIT mutations. Most of these mutations affect the KIT juxtamembrane domain, but other KIT domains are mutated at a lower frequency. In this study, frequency of GCC TAT insertion mutation (1530ins6) in KIT exon 9 (extracellular domain) and its possible clinicopathologic significance was investigated. Screening of 520 GISTs identified 26 cases with 1530ins6 KIT mutation and confirmed the previously reported low frequency of this type of KIT mutation among GISTs of different locations. Of the 26 tumors with 1530ins6 KIT mutation studied, 21 originated from the small intestine, 1 from the colon, and 3 from the rectum. In 1 case, primary small intestinal versus colonic localization could not be clearly established because of intra-abdominal dissemination. No distinctive morphological features were identified for the cohort of tumors defined by 1530ins6 KIT mutations. Most of the tumors showed predominant spindle cell morphology, and a few cases had epithelioid or pleomorphic histological features. Following previously published criteria based on tumor size and mitotic rate, 22 of 26 (85%) tumors were classified as malignant or potentially malignant, and 4 (15%) were classified as probably benign. A malignant clinical course was documented in 18 of 19 tumors from the malignant category. The survival times of 11 patients who died of disseminated GISTs ranged from 1 month to 105 months (median survival time, 26 months). In contrast, 2 of 4 GISTs assigned as probably benign tumors with follow-up information had long disease-free survival. GISTs carrying 1530ins6 occur exclusively in the intestinal location, and a great majority of these tumors follow a malignant course.

In various organs, including heart, kidneys, brain, liver and stomach, preconditioning by brief exposure to ischemia protects the organ against damage evoked by subsequent severe ischemia. This study has been undertaken to check whether two brief ischemic periods protect the pancreas against severe ischemia/reperfusion-induced pancreatitis and, if so, what is the role of sensory and vagal nerves in this phenomenon. In male Wistar rats, the ischemic preconditioning of the pancreas was performed by clamping of celiac artery (2 x 5 min with 5 min interval). Thirty minutes after preconditioning or sham operation, the ischemia/reperfusion-induced pancreatitis was evoked by clamping of inferior splenic artery for 30 min using microvascular clips, followed by 1 h reperfusion. Sensory nerves ablation was induced 10 days before final experiments by capsaicin. Truncal vagotomy was performed 1 week before the experiment. Exposure to regular 30-min pancreatic ischemia followed by 1 h reperfusion led to the development of acute hemorrhagic pancreatitis. Ischemic preconditioning, applied prior to induction of pancreatitis, caused the reduction in plasma lipase, plasma interleukin-1beta and histological signs of pancreatic damage, as well as attenuated the reduction in pancreatic blood flow and DNA synthesis. Ablation of sensory nerves by capsaicin caused an aggravation of ischemia/reperfusion-induced pancreatic damage and attenuated a protective effect of ischemic preconditioning. Noxious effect of sensory nerves ablation on the pancreas was accompanied by the reduction in pancreatic blood flow and an increase in plasma interleukin-1beta. Similar but less pronounced deleterious effect on the pancreas was observed after vagotomy. We conclude that: (1) pancreatic ischemic preconditioning reduces the severity of ischemia/reperfusion-induced pancreatitis; (2) this effect seems to be related, at least in part, to the improvement of pancreatic blood flow and the reduction in the release of proinflammatory interleukin-1beta; (3) sensory and vagal nerves are involved in protective effect of ischemic preconditioning against pancreatic damage.

Background and aims. Colorectal carcinomas demonstrating low-level microsatellite instability (MSI-L) may form a distinct group differing both from high-level MSI (MSI-H) and microsatellite-stable (MSS) tumors. Materials and methods. In a retrospective series of 172 colorectal carcinomas the microsatellite status was examined based on DNA extracted from archival blocks. Three groups – MSS (n=100), MSI-L (n=37), MSI-H (n=35) – were compared with respect to clinical data, stage, histology, and immunoexpression of Ki-67, and P53. Results. Compared to MSS and MSI-H carcinomas the MSI-L tumors were exceptionally rarely right-sided, and demonstrated the lowest proliferation fraction. There was a trend for less frequent high-grade histology, more frequent intermediate P53 expression, and prominent mucinous histology. Conclusion. Features of MSI-L colorectal carcinomas are not necessarily located between their MSS and MSI-H counterparts. The MSI-L category may contain a group of tumors belonging to a distinct carcinogenetic pathway.

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 × 20 mg), amoxycillin (2 × 1 g) and clarithromycin (2 × 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. (2) gastric atrophy ameliorates upon successful Hp eradication therapy.

Melatonin, a pineal secretory product, synthesized from l-tryptophan, has received increased attention because of its antioxidative and immunomodulatory properties. It has been detected in the gut and shown to protect the gastric mucosa, and liver from acute damage, but the role of melatonin in the protection of the pancreas against acute inflammation is not clear. The aim of this study was to investigate the effects of melatonin and its precursor, l-tryptophan, on caerulein-induced pancreatitis (CIP) and on ischemia/reperfusion (I/R)-provoked pancreatitis in rats. CIP was induced by subcutaneous infusion of caerulein to the rats (25 microg/kg). I/R was induced by clamping of the inferior splenic artery for 30 min followed by 2 hr of reperfusion. Melatonin (10, 25 or 50 mg/hr) or l-tryptophan (50, 100 or 250 mg/kg) was given as a bolus intraperitoneal (i.p.) injection 30 min prior to the onset of pancreatitis. CIP and I/R were confirmed by histologic examination and manifested by typical pancreatic edema, by an increase of plasma levels of amylase (by 500% in CIP and by 40% in I/R) and the pro-inflammatory tumor necrosis factor alpha (TNFalpha) (by 500%). Lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), were increased several fold in the pancreas CIP and I/R, whereas pancreatic blood flow (PBF) was significantly reduced in these animals. Pretreatment of rats subjected to CIP or to I/R with melatonin (25 or 50 mg/kg i.p.) or l-tryptophan (100 or 250 mg/kg i.p.) significantly reduced pancreatic edema, plasma levels of amylase and TNFalpha and diminished pancreatic MDA + 4-HNE contents, while enhancing PBF, pancreatic integrity and plasma levels of the anti-inflammatory interleukin 10 (IL-10). This was accompanied by a marked and dose-dependent rise of plasma melatonin immunoreactivity. Gene expression of N-acetyl transferase, an enzyme involved in melatonin biosynthesis, was detected in the pancreas of normal rats and was significantly enhanced in the rats with CIP. We conclude that exogenous melatonin, and that produced from l-tryptophan, attenuates pancreatic damage induced by CIP or by I/R and this effect may be attributable to the reduction in lipid peroxidation and TNFalpha release combined with an increase of plasma anti-inflammatory IL-10 in rats with acute pancreatitis.

Background and aims: We previously reported that the sole clinicopathological parameters of carcinomas diagnosed in a single institution in 1975 differed from those in patients diagnosed in 1995. The findings might be compatible with the loss of importance of the microsatellite instability of the carcinogenic pathway. Materials and methods: We examined the microsatellite status and selected immunomarkers (Ki-67, p53, BAX) in the archival material from 1975 (n=76) and 1995 (n=105). Results and conclusion: The distribution of tumors showing no microsatellite instability, low microsatellite instability, and high microsatellite instability in the 2-yearly cohorts was similar (1975: 55.6%, 22.2%, 22.2%; 1995: 60.2%, 20.4%, 19.4%, respectively). The percentage of carcinomas showing microsatellite instability at the APC locus differed significantly (1975: 37.5%; 1995: 21.4%). The typical clinicopathological parameters of carcinomas exhibiting high microsatellite instability were largely shared by the carcinomas demonstrating instability at the APC locus. The carcinomas resected in 1995 more frequently demonstrated high expression of an antiapoptotic protein BAX and a different distribution of their Ki-67 proliferation fraction. The evolution of colorectal carcinoma in Poland also involves qualitative changes, including its genetic background.

The aim of the study was to evaluate the potential of human breast cancer tissue to secrete growth hormone (GH), insulin-like growth factor I (IGF-I) and prolactin in response to 10(-7) M progesterone stimulation. Explants were divided according to estrogen receptor (ER)/progesterone receptor (PR) phenotype (ER(-)PR(-); ER(+)PR(-); ER(+)PR(+); ER(-)PR(+)). Our results show distinct differences in cultured breast cancer tissue responses to progesterone stimulation with regard to secretion of proliferative agents such as GH, IGF-I and prolactin. All but ER(-)PR(-) breast cancer cell types responded in vitro to progesterone stimulation with an increase in local GH secretion, while in non-malignant tissue progesterone induced local GH secretion only in PR(+) cells. Moreover, only in PR(+) cells did progesterone stimulate local IGF-I and prolactin secretion, in both malignant and non-malignant tissue. This study provides evidence for the first time that in PR(+) breast cancer tissue, progesterone may increase GH, prolactin and IGF-I secretion in both malignant and surrounding non-malignant tissue. These hormones may act as local growth factors that stimulate the proliferation of mammary tumors.

Lipopolysaccharides (LPS), the component of the cell wall of gram-negative bacteria, have been implicated in the pathogenesis of acute pancreatitis, but the mechanism of their action on the pancreas has not been fully explored. The aim of this study was to investigate the effects of various doses of LPS on the integrity of intact pancreas and that involved in acute caerulein-induced pancreatitis (CIP) in the rat and to compare these effects with those of nitric oxide (NO) donor, S-nitrose-acetylpenicillamine (SNAP). The expression of constitutive NO synthase (cNOS) and inducible NO synthase (iNOS) mRNA was also examined in the isolated pancreatic acini obtained from the inflamed pancreas of rats treated with LPS. CIP was produced by subcutaneous (s.c.) infusion of caerulein (5 μg/kg·h for 5 h) to conscious rats. Bolus injections of various doses of LPS (0.1, 1, 10, 20 or 40 mg/kg) or SNAP (1.5, 3 or 6 mg/kg) were made intraperitoneally (i.p.) either alone or 30 min prior to s.c. infusion of caerulein to induce CIP. Infusion of caerulein produced acute pancreatitis confirmed by histological examination and manifested by an increase of pancreatic mass (by about 200%). Blood levels of amylase and lipase were augmented by 400 and 800% respectively, whereas the pancreatic blood flow (PBF) was decreased by 50% in rats with CIP. Injection of low doses of LPS (0.1–1 mg/kg i.p.) or SNAP (1.5–3 mg/kg i.p.) 30 min prior to caerulein infusion reversed the harmful effects of pancreatic overstimulation with caerulein and reduced significantly the histological manifestations of CIP such as edema, neutrophil infiltration and vacuolization of the acinar cells. These protective effects of low doses of LPS pretreatment on the pancreas were completely antagonized by the suppression of the activity of NO synthase (NOS) with NG-nitro-L-arginine (L-NNA) applied (20 mg/kg i.p.) 15 min prior to the LPS injection. Combination of L-arginine (100 mg/kg i.p.), a substrate for NOS, with L-NNA given prior to low doses of LPS, restored the LPS-induced protection of the pancreas in rats with CIP. In contrast, higher doses of LPS (20–40 mg/kg i.p.) or SNAP (6 mg/kg i.p.), which produced a significant fall of the PBF, did not protect the pancreas against CIP. Administration of various doses of LPS to rats with CIP resulted in significant and dose-dependent stimulation of NO biosynthesis in the isolated acini obtained from the pancreas of these animals. LPS enhanced the expression of both cNOS and iNOS in the pancreatic acini obtained from rats subjected to CIP. The signal for cNOS mRNA was detected in all samples, reaching peak at the protective dose of LPS (1 mg/kg i.p.), while iNOS was overexpressed only at the highest doses of LPS that failed to exhibit the protective activity. We conclude that the pretreatment with low doses of LPS protects the pancreas against the damage provoked by CIP and this effect could be attributed, at least in part, to the activation of L-arginine-NO system in the pancreas.

Background: Experiments were aimed to test the cross-reactivity of immune Th1 cells that mediate contact hypersensitivity (CHS) or inflammatory bowel disease (IBD) to TNP in the mouse. Methods: CBA/J mice were immunized either epicutaneously or intrarectally with TNP and after appropriate time intervals were challenged with antigen in a crossed manner. The CHS reaction was measured by the ear swelling test. IBD was quantified by increase of colon weight and myeloperoxidase level. Both reactions were confirmed histologically. In passive-transfer experiments, mesenteric lymph node cells of animals sensitized intrarectally and peripheral lymph node and spleen cells of mice immunized epicutaneously were used. In some experiments, before being immunized mice were made either unresponsive to the TNP hapten by induction of suppressor T cells, or resistant to suppression after induction of upregulatory T cells. Results: Irrespective of the mode of sensitization upon appropriate challenge with antigen all mice developed a good CHS reaction as well as significant IBD. This cross-reactivity could be passively transferred by immune cells. In mice in which antigen-specific down- or upregulatory cells were induced before sensitization both CHS and IBD to TNP were modulated accordingly. Conclusion: TNP hapten deposited on skin or on mucosal surfaces induces effector cells that recognize antigen independent of its tissue localization, and produce a local inflammatory reaction. TNP-specific up- and downregulatory cells, shown before to regulate the CHS reaction, similarly modulate the generation and development of hapten-induced IBD.

Over past three decades in Poland we have seen a steady increase in the incidence of colorectal cancer. It is unclear whether this phenomenon is associated with changes in biology of the disease. In the present study we compared basic clinical data and pathological features of colorectal carcinomas submitted as resection specimens to a single institution in 1975 (n=76) and 1995 (n=106). We found a significant increase in sigmoid tumors (15.8% in 1975, 34.9% in 1995, P=0.0028), a decline in the frequency of mucinous carcinomas (22.4% in 1975, 7.5% in 1995, P=0.0041), and reversed distribution of low- and high-grade tumors (more high-grade than low-grade carcinomas in 1975, the opposite in 1995). We observed trends toward more pronounced peritumoral desmoplastic response, less prominent chronic peritumoral inflammatory infiltrate, and more frequent perineural invasion. The 1995 patients were on average significantly older at surgery (59 years in 1975, 64 years in 1995, P=0.02) and had smaller tumors (max. diameter=5.49 cm in 1975, 4.27 cm in 1995, P=0.0018). There were no differences in distribution of tumor stage, patient's sex, type of infiltrating margin formed by carcinomas, relative amount formed by the solid tumor component, invasion of veins and lymphatics, or presence of an adenoma contiguous with a carcinoma. Differences between 1975 and 1995 cases observed in our material probably reflect the changing biology of colorectal carcinoma in Poland. Mucinous, high-grade, proximal tumors, surrounded by prominent chronic inflammatory infiltrate, diagnosed in relatively younger subjects are associated with familial and sporadic cancers due to widespread genomic instability (replication error positive or RER(+) phenotype). We conclude that in Poland the APC/K-ras/p-53 carcinogenesis pathway is becoming even more important than the carcinogenesis characterized by RER(+) tumors. This study is a starting point for further investigations aimed at confirming this hypothesis.

Synthesis and localization of inducible nitric oxide synthase mRNA (iNOS-mRNA) and iNOS protein in the cultures of human monocytes (Mφ) and colon carcinoma cell line (DeTa) that resulted in nitric oxide (NO) synthesis has been studied. The iNOS-mRNA was observed around the sixth hour of culture and peaked at the twelfth hour. The iNOS-mRNA, as determined by the in situ hybridization and iNOS protein, as detected by staining with specific anti-iNOS monoclonal antibodies, were observed preferentially in the cytoplasm of some Mφ, but not in cancer cells. Mφ cultured alone did not show detectable iNOS-mRNA expression and iNOS protein. Mφ sorted out from tumor cells after 8hof co-culture expressed iNOS protein and iNOS-mRNA, which were not detected in Mφ without previous contact with cancer cells. Prevention of NO synthesis by (L-N5-1-iminoethyl)-ornithine (L-NIO) partly inhibited Mφ cytotoxic activity against DeTa (NO-inducing cancer cell line) but not against the human pancreatic cancer (HPC-4) cell line that does not induce NO production in Mφ. This suggests that Mφ cytotoxic activity, at least in some cases, may be NO dependent. These observations provide further evidence that Mφ can be directly stimulated by cancer cells for de novo production of NO and suggest that iNOS occurring in the tumor-infiltrating macrophages may arise as a result of their interactions with tumor cells. However, because only some tumor cells are able to induce NO production in a small proportion of Mφ, its role in the anti-tumor response of the host is probably limited. J. Leukoc. Biol. 65: 597–604; 1999.

Background : Helicobacter pylori infection in humans is a major risk factor for peptic ulcer, but studies on the relation between H. pylori infection and gastric pathology are limited due to a deficiency of convenient animal models resembling this infection in humans. Methods : We studied the effects of inoculation of conventional BALB/c mice with CagA and VacA positive (type I) H. pylori or CagA and VacA negative H. pylori (type II) strains on gastric secretion and healing of chronic acetic acid-induced ulcers in mouse stomachs. The ulcer area, gastric blood flow, plasma interleukin (IL)-1β and IL-12, as well as plasma gastrin and gastric luminal somatostatin were determined. Gastric mucosal biopsy samples were also taken for assessment of the presence of viable H. pylori using a rapid urease test, H. pylori-culture and the RT-PCR analysis of the signal for H. pylori CagA. Results : Gastric acid and pepsin secretion was reduced by over 50% immediately after H. pylori inoculation and accompanied by a significant increment in plasma gastrin and fall in gastric luminal somatostatin content observed over all test days, particularly in mice infected with type I H. pylori. The area of ulcers in vehicle-treated controls decreased significantly starting from day 2 after ulcer induction and then continued to decline for a further 14 days to heal almost completely after 28 days. In contrast, the ulcers were present until day 28 in all mice infected with type I or type II H. pylori strains, being significantly larger, especially with type I H. pylori infection. The gastric blood flow at the ulcer margin and ulcer crater in vehicle-treated mice gradually increased with decreasing ulcer size, after 14 and 28 days reaching a value which was not significantly different from that in vehicle-administered mice. In contrast, the gastric blood flow in type I H. pylori and, to a lesser extent, in type II H. pylori infected mice was significantly lower than in vehicle controls, both at the margin and at the crater of ulcers at all tested days. Histological changes such as oedema or congestion of surface epithelium were found after 7 days whereas mucosal inflammatory infiltration appeared after 14 days with a further increase after 28 days, especially in type I H. pylori and to a lesser extent in type II H. pylori infected mice. Plasma IL-1β and IL-12 were significantly elevated at all tested days of ulcer healing and their increments were significantly higher in type I than in type II H. pylori infection. Conclusions : Conventional mice with gastric ulcers can be successfully infected by both toxigenic and nontoxigenic H. pylori strains, and this infection causes an immediate suppression of gastric secretion and markedly delays the healing of ulcers due to the fall in mucosal microcirculation in the ulcer region, cytokine release and an impairment in the gastrin–somatostatin link that appears to be independent of gastritis and more pronounced with infection of toxigenic than nontoxigenic strains.

The increasing frequency and poor prognosis in pancreatic cancer prompt us to search for morphological lesions being a substrate for its development. Studies of autopsy and surgically resected material as well as recent molecular studies have proved that one of the possible pathways of pancreatic neoplasia is the intraepithelial proliferation – dysplasia – cancer sequence. In the present paper we studied the proliferative activity (Ki‐67 index) in pancreatic intraepithelial proliferative lesions and its correlation with geometric features of cell nuclei as signs of increasing dysplasia. The studies were carried out in a group of 35 patients operated on for pancreatic cancer, chronic pancreatitis and other conditions not associated with the pancreas. We used immunohistochemical methods and basic morphometric parameters. The results of our studies indicate that the cell proliferative activity depends both on the type of epithelial proliferation and underlying pancreatic disease. The values of Ki‐67 index are significantly different in low‐grade proliferation (flat and papillary hyperplasia) and high‐grade proliferation (atypical papillary hyperplasia and carcinomain situ). A set of karyometric features correlates with Ki‐67 index but there is no single feature which would have a diagnostic value.

Objective: Cholecystokinin (CCK) is able to protect gastric mucosa against acute injury in experimental animals but little is known about the role of this hormone in maintaining mucosal integrity in humans. This double-blind, placebo controlled study was performed in 16 healthy volunteers. It describes the effects of CCK-8 infused intravenously (i.v.) at physiological doses and endogenous CCK released by intraduodenal (i.d.) oleate on gastric mucosal damage, as brought about by ethanol without or with pretreatment with loxiglumide, a selective CCK-A receptor antagonist. Methods: CCK-8 was infused i.v. 30 min before and throughout the study or i.d. oleate was instilled through a separate duodenal tube. Thirty minutes after the start of i.v. infusion of CCK or i.d. oleate instillation, 100 ml of 50% ethanol spray was applied to the gastric mucosa using an endoscope. Gastroscopy was performed and mucosal lesions were quantified using modified Lanza score. Gastric biopsies were taken from oxyntic mucosa for histological evaluation and gastric content was aspirated for radioimmunoassay of somatostatin. Results: In placebo-treated subjects ethanol caused endoscopic damage, with an average score of 2.8 ± 0.2. Histologically, a widespread disruption of surface epithelium and deep hemorrhagic necrotic lesions were observed. Pretreatment with CCK or i.d. oleate markedly reduced the endoscopic lesion score to 0.7 ± 0.1 and 0.3 ± 0.1, respectively, and in both cases this reduction was accompanied by a significant rise in plasma CCK. Histologically, surface epithelium was still disrupted but deep necrotic lesions were absent. Gastric content collected before and after CCK or oleate showed a several-fold increase of luminally released somatostatin. Conclusions: Pretreatment with loxiglumide abolished the protective effects of i.v. CCK-8 and i.d. oleate on mucosal lesions induced by ethanol and prevented the rise in intragastric somatostatin, but failed to affect the increments in plasma CCK. Endogenous CCK plays a physiological role in the maintenance of mucosal integrity. This occurs through activation of CCK-A receptors and is associated with an increased gastric luminal release of somatostatin.

Background: Recent studies indicate that eradication of Helicobacter pylori might prevent peptic ulcer formation in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). On the other hand, gastric adaptation after repeated exposures to aspirin (ASA) is well documented but the influence of H. pylori on this process remains to be elucidated. Aim: To compare gastric damage and adaptation following repeated exposures to ASA in a group of patients with H. pylori infection, before and after eradication of the bacterium, and in H. pylori-negative controls. Methods: Eight healthy volunteers without H. pylori infection and eight patients with duodenal ulcer (DU) history and H. pylori infection before and after H. pylori eradication were given ASA 2 g/day for a period of 14 days. Mucosal damage was evaluated by endoscopy and histology of biopsy samples. Gastric microbleeding, DNA synthesis in the gastric mucosa and mucosal expression, as well as luminal content of transforming growth factor-α (TGFα) were determined on days 0, 3, 7 and 14 of the ASA course. Results: In all patients aspirin-induced gastric damage reached a maximum on day 3. In H. pylori-positive patients, this damage was maintained at a similar level up to day 14, whereas in H. pylori-negative controls and H. pylori-eradicated patients this damage significantly lessened on day 14 and was accompanied by elevated DNA synthesis as well as increased mucosal expression and luminal release of TGFα. Conclusions: H. pylori-positive DU patients do not adapt to continued administration of ASA but eradication of the bacterium restores adaptation. This phenomenon deserves further clinical evaluation.

Overexpression of transforming growth factors (TGF) in acute pancreatitis (AP) suggested that these substances play an important role in pancreatic repair and remodeling but the contribution of epidermal growth factor (EGF), that is well known to promote cell growth and regeneration, has not been investigated. The aim of this study was to compare the gene and immunohistochemical expression of EGF and TGF-β1, cell proliferation, and biochemical parameters in AP induced by infusion of a supramaximal dose of caerulein in rats. The rats were sacrificed at 0, 12, 24, 48, 72 h, 5 and 10 days after the termination of caerulein infusion. Pancreatic tissue DNA synthesis, cell proliferation, histological and immunohistochemical assessments and plasma amylase were estimated following induction of AP. The mRNA expression for EGF and TGF-β1 was evaluated by reverse transcription-polymerase chain reaction. During 10 days of the study after induction of AP a gradual normalization of biochemical and histological parameters was observed. DNA synthesis and cell proliferation which were significantly decreased at 0 and 24 h, increased significantly at 48 and 72 h, and then gradually decreased reaching at day 10 the values similar to those of vehicle-treated control rats. In these control rats the EGF mRNA or immunohistochemical expression was not detected, while the TGF-β1 expression was weak. After induction of AP, the mRNA and immunohistochemical expression of EGF showed an increase during the initial 5 days, while those of TGF-β1 showed a marked increase between 0 and 48 h and then again at day 10. We confirm that: (1) the expression of TGF-β1 during AP is biphasic with an initial increase probably related to pancreatic damage and inhibition of cell proliferation and with the later phase of increase accompanied by the stimulation of the synthesis of extracellular matrix components and (2) AP is accompanied by an induction of synthesis of EGF that occurs in the initial phase of AP, probably limiting the extent of AP, and enhancing the stimulation of the pancreatic repair and regeneration.

This study was designed to determine the efficacy of L -arginine in healing of gastric ulcers induced by acetic acid and to assess the role of nitric oxide (NO), prostaglandins, gast

Thirty-three common naevi, 26 dysplastic naevi, 58 primary melanomas of facial skin, 24 oral melanomas, 32 lymph nodes and 12 distant melanoma metastases were stained using Feulgen method to evaluate the ploidy status by image analysis GAS-200 system. Eight percent of common naevi, 22% of dysplastic naevi, 43% of facial melanomas, 65% of oral melanomas, 40% of lymph nodes with melanoma metastases and 66% of distant melanoma metastases were classified as aneuploid. In facial melanomas the percentage of aneuploid cases increased with Clark level. Survival time of patients was significantly shorter for aneuploid cases as compared to euploid ones (p

We examined the susceptibility of mucous cells isolated from gastric mucosa of portal hypertensive rats to ethanol injury. In addition, we assessed their response to protective action of prostaglandin against ethanol injury in vitro. Ethanol significantly decreased cell viability in calcium-containing medium. The injury of mucous cells isolated from portal hypertensive rats was more extensive than those isolated from sham-operated rats. Ethanol-induced cell injury was reduced similarly in both groups by pretreatment with 16,16-dimethyl prostaglandin E2. These results suggest that mucous cells isolated from portal hypertensive gastric mucosa are more susceptible to ethanol injury and this susceptibility is dependent on extracellular calcium. The cells from portal hypertensive gastric mucosa retain, however, sensitivity to protective action of 16,16-dimethyl prostaglandin E2.

The study was designed to determine the gastroprotective and ulcer healing efficacy of basic transforming growth factor (bFGF) and to assess whether this peptide contributes to the action of sucralfate on the rat stomach. Application of human recombinant bFGF (1-100 micrograms/kg/hour subcutaneously) failed to affect the formation of acute gastric lesions induced by 100% ethanol and acidified aspirin but reduced the stress induced by gastric lesions. Sucralfate (100-200 mg/kg given orally) protected gastric mucosa against the ethanol, aspirin, and stress induced acute gastric lesions but the addition of bFGF (100 micrograms/kg subcutaneously or intragastrically) failed to affect sucralfate induced protection against ethanol or aspirin but increased that against stress. Administration of bFGF (3-300 micrograms/kg/day) by an intragastric or an intraperitoneal route or sucralfate (400 mg/kg/day) orally to rats with acetic acid induced gastric ulcers, enhanced the healing rate of these ulcers during seven day treatment in a dose dependent manner. This was accompanied by a pronounced increase in the number of capillaries and myofibroblasts and in DNA synthesis and DNA and RNA concentrations in the granulation tissue in the ulcer area. [125I]bFGF (1 microCi) applied subcutaneously or intragastrically accumulated in two to threefold higher amounts in the ulcer area than in the intact mucosa, particularly in rats treated with sucralfate. Concurrent treatment with indomethacin (2 mg/kg intraperitoneally) delayed ulcer healing and reduced the binding of labelled bFGF to the ulcer area, angiogenesis, and DNA synthesis by sucralfate. Addition of [125I]bFGF to sucralfate at various pHs resulted in the coprecipitation of bFGF by sucralfate in a pH dependent manner from about 10% at pH 7.0 to 90% at pH 1.5. Thus bFGF shows little protective activity and is not essential for gastroprotection afforded by sucralfate but plays an important part in healing of gastric ulcers possibly due to its growth promoting and angiogenic actions.

Solitary bone cyst is rarely situated in facial bones.We discuss clinical view, results of radiological examinations and differential histopathological diagnostics of cases.We present 3 cases of patients: 51 year old man with cyst in frontal sinus; 29 year old man and 46 year old woman--both with changes in bones of the orbit. In all the cases results of histopathological examinations were similar. Cystic-shape pieces of vascularizated connective tissue were observed. Multiple cracks filled with cholesterol, macrophages with hemosiderin and occasionally multinuclear cells were noticed.Solitary bone cyst may be located in the periorbital bone, especially frontal. Excellent laryngological, optic and cosmetic results are results of the surgery. Suspicious of the solitary bone cyst is possible due to MR or CT imaging, but final diagnosis must be confirm by histological examination.

To examine the effects of prostaglandin on bile acid-mediated intestinal vascular injury, male rats were given 50 mg/kg of fluorescein isothiocyanate (FITC)-stained dextran 70 or 25 mg/kg of Evans Blue intravenously. Before intestinal injury with 45-minute perfusion of 5 mmol/L chenodeoxycholic acid, rats received 16,16-dimethyl prostaglandin E2 (5 micrograms/kg intravenously or 0.5 micrograms/mL or in the perfusate for 15 minutes or vehicle). FITC-dextran clearance from the blood to the intestinal lumen and tissue Evans Blue content were used as measures of intestinal vascular injury. Morphological mucosal injury was assessed by transmission electron microscopy and quantitative histological analysis. Chenodeoxycholic acid perfusion caused villous denudation and shortening of and ultrastructural damage to villous venules. Functional vascular injury was evidenced by a 10-fold increase in the rate of FITC-dextran blood-to-lumen clearance and a 3-4-fold increase in tissue Evans Blue content. Pretreatment with either intravenous or intraluminal 16,16-dimethyl prostaglandin E2 reduced FITC-dextran clearance by 70%-80% and tissue Evans Blue content by 50%. However, only luminal prostaglandin reduced superficial mucosal morphological injury, possibly because of differences in the local concentrations of 16,16-dimethyl prostaglandin E2 or chenodeoxycholic acid or because of superficial mucosal protection and injury being, at least in part, independent of mucosal microvascular injury and protection.

To analyze relationships between nuclear features of papillary renal cell carcinoma (PapRCC) subtypes.The material for the study consisted of 53 cases, of which 29 were type 1, 17 type 2 and 7 intermediate. At least 100 nuclei per case were segmented from images of 4',6-diamidino-2-phenylindole-stained slides. The geometric and texture features were extracted and used for analysis.In analysis of variance, it was shown that both individual cases and tumor types differ in the majority of the parameters. On nonsupervised expectation-maximization clustering, it was possible to classify the nuclei into separate categories, but PapRCC classes were not reproduced. The neural network classified the nuclei with sensitivity0.6 and specificity0.75. Analyzing the results for individual cases, the nuclei of type 1 cases were properly classified in 74-91%, nuclei of type 2 cases in 58-80% and nuclei of intermediate cases in 53-70%.Our findings show that PapRCC subtypes are distinct enough to be reproduced by image analysis.

Epidermal growth factor (EGF) is a mitogenic polypeptide that inhibits gastric acid secretion, protects the gastric mucosa against acute injury, and accelerates ulcer healing. In the present study we demonstrated immunohistochemically, using two different techniques, localization of EGF receptors in normal rat gastric oxyntic mucosa: in proliferative zone cells and in some parietal cells. It is likely that these cells represent the major targets for the EGF [and transforming growth factor alpha (TGF-alpha) which shares a common receptor with EGF] actions, stimulating cell proliferation and inhibiting acid secretion.

Mucinous tubular and spindle cell carcinoma (MTSCC) of the kidney is a rare, recently described entity. The authors present three new cases. The histological picture was that of classic MTSCC, with alternating small tubules located in a mucin-containing stroma, and spindle cell areas composed of bland, monomorphic cells. On immunohistochemistry, the tumors were positive for epithelial markers, including CK7 and CK18, vimentin, CD15, AMACR, and neuroendocrine markers, such as NSE and CD57. On FISH analysis we found losses on chromosomes 1 and 8, and gains of chromosomes 7 and 17. This is the first report of this rare entity in Polish medical literature.

The detection of isolated (circulating or disseminated) tumour cells (ITC) in patients with cancer requires very sensitive methods, as such cells are very rare. In the present study, the method that combines the negative isolation of CD45- leukocytes from the blood and bone marrow of patients with gastric cancer by flow cytometry, followed by the positive isolation of single cytokeratin-positive (CK+) cells by a Laser Capture Microdissection System for the determination of MAGE-1, -2 mRNA expression was used to detect ITC. This study shows that this method is highly sensitive as it allows to determine beta-actin-mRNA expression in a single CK+ cell. Using > or =5 CK+ cells as a cut-off level, the MAGE-1 mRNA expression was detected in 100% of CK+ cells in the peripheral blood and in 75% of bone marrow samples of patients with gastric cancer. The MAGE-2 mRNA expression was observed in 40 and 58% of samples, respectively. Furthermore, an analysis of primary tumours and locoreginal lymph nodes with respect to the mRNA expression of the two genes showed that MAGE-1 mRNA expression was detected in 88% of the primary tumours and in 67% of the lymph node samples, whereas the MAGE-2 mRNA expression was observed in 72 and 67% of the cases, respectively. Thus, the method described here allows the precise and sensitive determination of tumour-associated gene expression in single ITC present in the blood and bone marrow of patients with gastric cancer.

Craniofacial resection provides multidirectional approaches to remove nasal and paranasal tumours that involve the skull base. Vital structures, such as the dura, brain, and blood vessels, can be protected or resected and reconstructed safely. An en bloc excision of the tumour can be accomplished. The purpose of this study was to analyse oncological and functional results of craniofacial resection in our series of patients.The medical records of 40 consecutive patients who had undergone craniofacial resection for tumours of the nasal cavity, paranasal sinuses, and adjacent areas were reviewed. The extent of disease, treatment results (the length of disease-free survival), complications, and prognoses were analysed.Lesions were malignant in 7 patients and benign in the remaining 33. All the patients had dural or intradural involvement. There was no operative death, and the rate of surgical morbidity was 20%. Craniofacial resection is the only surgical approach with acceptable rate of complications in selected patients with tumour comprising the anterior and medial cranial base, nasal cavity, paranasal sinuses, nasopharynx and orbits. Heroic resections are modern surgical procedures challenging both for ENT surgeons and neurosurgeons. The result is satisfactory when they are performed by a multi-specialist team.

In a previous study we found that 16,16-dimethyl prostaglandin E2 protects the small intestine against chenodeoxycholic acid injury in the rat. One possible explanation for prostaglandin's protective action may be that prostaglandin-induced villus contraction accelerates mucosal restitution. This hypothesis was tested in rats by perfusing intestinal segments in vivo in a single-pass fashion with 0.125-0.5 micrograms/L of 16,16-dimethyl prostaglandin E2. These studies showed a dose-dependent, reversible contraction of intestinal villi and crypts. To test the effect of this contraction on mucosal restitution, standardized intestinal injury was produced in indomethacin-pretreated rats perfused in vivo with 5 mmol/L chenodeoxycholic acid. The rats were then perfused with bile acid-free buffer containing either 0.5 microgram/mL of 16,16-dimethyl prostaglandin E2 or vehicle. This study showed that despite decreasing villus height after bile acid injury, 16,16-dimethyl prostaglandin E2 did not significantly affect the rate of morphologic (assessed by villus denudation) or functional (assessed by mannitol and water absorption) restitution of the injured intestinal mucosa. Thus, although 16,16-dimethyl prostaglandin E2 causes villus contraction, this effect does not result in more rapid restitution of the injured intestinal mucosa and is not a likely mechanism for prostaglandin-mediated protection of the intestinal mucosa.

In Poland, data on the incidence and mortality associated with malignancies are collected by the National Cancer Register (NCR). The Register is based on the International Classification of Diseases (ICD-10), which does not allow for assessing the incidence of lymphatic neoplasms classified according to the WHO classification system enforced since 2001. Under the National Program of Combating Neoplastic Diseases that focuses on detection and diagnosing malignant lymphomas in Poland in order to record and precisely classify lymphatic neoplasms, in 2006, the Haematopathological Section of the Polish Society of Pathologists, acting in collaboration with the Polish Lymphoma Study Group, initiated a nationwide register of lymphatic malignancies, a continuation of the Register of Lymphomas for the Province of Małopolska. The register not only renders epidemiological data more specific, but also allows for a comprehensive quality control.

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.