Abstract: AIMS AND BACKGROUND: Colorectal cancer is the second most common cause of cancer-related death in Europe and the United States. Several studies have evaluated the immune response to colorectal cancer, with contradictory results. Some studies showed that lymphocyte infiltration in colorectal cancer seemed to be an important prognostic parameter, a finding not confirmed by other studies. Several studies showed the gamma-delta T-cell receptor repertoire of intestinal adenocarcinoma. In this study, we hypothesize that the presence of T cells with the T-cell receptor gamma complex may play a particular role in carcinogenesis and tumor progression. METHODS: A total of 58 patients with colon adenocarcinoma was included in the analysis. We used the TNM staging system to grade colon cancer. RESULTS: Thirty samples (52.6%) revealed a polyclonal rearrangement of T-cell receptor gamma. In the NO cases, only 5 samples revealed a T-cell receptor gamma molecular assessment; in N1/N2 cases, 25 revealed a T-cell receptor gamma molecular assessment. CONCLUSIONS: The results showed statistical significance between the presence of T-cell receptor gamma and N1/N2 stage lymph nodes (P = 0.001).

Abstract: Gastric cancer remains a major health problem despite its decline in incidence in Western countries. Although radical surgery represents the primary curative option for gastric cancer patients, most of them relapse and die due to their disease despite an R0 resection. At present the routine use of postoperative adjuvant therapy to reduce disease recurrence is still considered an investigational approach. Out of a total of 275 patients (stage IB through IV M0 AJCC/UICC) who underwent surgery for gastric cancer at our Surgery Unit between 1993 and 2001, 156 were eligible for adjuvant chemotherapy, of whom only 52 accepted to undergo this treatment. This group of patients was retrospectively compared with a control group (1:2) and overall survival was assessed using hazard ratio and Kaplan-Meier estimates. Five-year survival was 40% in the chemotherapy group and 37.8% in the group which underwent surgery alone. Indeed, chemotherapy did not reduce the risk of death (HR 0.87, 95% CI = 0.57-1.34, p=0.54). Serosal involvement and the invasion of more than 6 lymph nodes were the main independent prognostic factors identified by multivariate analysis. The current study did not show a clear advantage of chemotherapy over surgery alone. However, our results can help to define strategies for future clinical trials with the use of new regimens based on more effective and less toxic drugs.

Abstract: OBJECTIVE: Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and internal organs. Although the esophagus is the most frequently affected part of the gastrointestinal tract, all other segments can be involved. The present study was undertaken to evaluate the fibrotic process and the expression of fibrogenic cytokines in the gastric wall of SSc patients with gastroesophageal involvement. METHODS: Full-thickness surgical and endoscopic gastric biopsy samples were obtained from 14 SSc patients and 10 controls. Tissue sections were either stained with Masson's trichrome or by immunohistochemistry and analyzed for the expression of types I, III, and IV collagen, alpha-smooth muscle actin (alpha-SMA), transforming growth factor beta (TGFbeta), connective tissue growth factor (CTGF), and endothelin 1 (ET-1). RESULTS: In the gastric wall of SSc patients, Masson's trichrome staining and immunohistochemistry for types I and III collagen revealed a high amount of collagen in the lamina propria that increased toward the muscularis mucosae. In addition, muscle layers showed features of atrophy, with wide areas of focal fibrosis surrounding smooth muscle cells. Type IV collagen was present around glands and small vessels, suggesting a thickening of the basal lamina. The expression of the fibrogenic cytokines TGFbeta and CTGF, ET-1, and the myofibroblast marker alpha-SMA was stronger in SSc patients than in controls. CONCLUSION: A pronounced deposition of collagen, the presence of myofibroblasts, and increased expression of several profibrotic factors are important hallmarks in the stomach of patients with SSc. The fibrotic involvement of the gastric wall may account for muscle atrophy leading to stomach hypomotility in SSc.

Abstract: In many pathologic circumstances, quantitative mRNA expression levels are important for evaluation of possible genome mutations. The development of real-time polymerase chain reaction (RT-PCR) technology has facilitated the realization of nucleic acid quantification. Potentially, quantitative PCR offers a number of advantages over traditional methods because it permits the use of small amounts of genetic material. In the present study, we optimize a RNA purification technique on specimens that are formalin-fixed, paraffin-embedded and we examine prolonged formalin fixation effects on quantitative RT-PCR analysis. We compared RNA levels with 70 colic mucosa samples using the cyclooxygenase 2 gene as marker. The difference in amplification successes between formalin-fixed tissues and formalin-fixed, paraffin-embedded tissues was not statistically significant. Moreover, we compared the expression of formalin-fixed samples with the expression of each fresh tissue. Wilcoxon Mann-Whitney test shows that only the difference in the expression levels of 1- or 3-hour formalin-fixed samples is not statistically significant with respect to other fixation times. We found that the mRNA can be reliably extracted from formalin fixed, paraffin-embedded tissue sections but that prolonged formalin fixation produces different results in quantitative RT-PCR. It can be related to difference in RNA sequences length and the generation of secondary structures that are more susceptible to the prolonged formalin fixation. We suppose that the paraffin do not influence the RNA extraction yield because there are no statistical significant differences between amplification success of formalin-fixed tissues and paraffin-embedded tissues. Therefore, in relative expression quantization, we confirm that it is appropriate to use specimens with same protocols and time for formalin fixation.

Abstract: BACKGROUND: Occlusive complication is a common event in the colo-rectal cancer (20-30% of cases). Operative mortality and 5 yrs survival of not occlusive cancer vs occlusive cancer is 11% vs 23% and 45% vs 25% rispectively. In occlusive cancer the level of parietal infiltration affects considerably the local and peritoneal recurrence. 50% of all patients underwent a surgical re-operation for colo-rectal cancer have peritoneal neoplastic implant. AIM: The resolution of occlusive complication in immediate or delayed urgency with decompressive derivation, it allows to perform an integrated treatment of choice that it could guarantee the oncological radical procedure. RATIONALE-METHODS: The intraperitoneal hyperthermic chemotherapy (IPHC) combined with radical or cytoriductive surgery performs its action through sinergistic effects of high dosage and concentration of drugs and hyperthermia. These agents perform a cell killing with a direct contact against micro and/or macroscopic neoplastic residue. EXPECTED RESULTS: In radical surgery with curative intent, the association with IPHC ("preventive" adjuvant) has got as objective the distruction of microscopic local or peritoneal metastasis. In occlusive cancer with synchronous or metachronous peritoneal carcinomatosis, the performance of the cytoreductive surgery with IPHC ("therapeutic" adjuvant) is the only treatment that improves the survival and the quality of remainig life. CONCLUSIONS: The clinical results reported by many Istitutions indicates that the 2-5 yrs survivals are 45-60% and 20-30% rispectively. These data lead us to believe that an optimal eradication of micro and/or macroscopic peritoneal spreading could be optained also in occlusive colo-rectal cancer.

Abstract: The homeobox (HOX) genes are a large family of regulator genes involved in the control of developmental processes and cell differentiation. The HOX genes encode transcription factors, and an increasing number of studies have shown that these genes may be implicated in the growth and the progression of many types of tumours. The present study investigated the expression of the HOX and integrin genes and their relationships in gastric carcinoma. We analyzed the RNA expression of 13 HOX genes from HOXA, C and D clusters and alphaV, alpha5 and alpha8 integrin genes in 24 gastric cancer samples by quantitative real-time PCR. The results showed that the HOXA2 gene and the alpha8 integrin gene had a lower expression in tumour samples than in normal gastric mucosas. The comparison between the HOX and integrin genes showed that HOXA2 and alphaV integrin expression presented the same trend in 83% of the samples. Moreover, in cancer samples that expressed the HOXD11 gene, the expression of alphaV integrin was lower with respect to normal mucosas. The different roles of HOX and integrin genes in gastric carcinoma remain to be fully elucidated. These findings suggest that the HOX genes may play a critical role in the genesis, maintenance and diffusion of gastric carcinoma.

Abstract: Colon cancer is the most frequent neoplasia of the intestine. This pathology is the third highest cause of death from cancer with 430,000 deaths globally per year. Estrogen has also been implicated in the development and progression of colon cancer. Also sex-specific differences have been suggested to be involved in the process. Previous studies have shown estrogen beta receptor to be the dominant receptor type in normal colonic tissue and its down-regulation along with the progression of colorectal cancer. The presence of estrogen receptors and products of estrogen-related genes in the colon suggests that estrogens have direct effects on the colonic tissue. However, the specific effect of estrogens on a normal colon and the role in the colon carcinogenesis are far from clear. The aim of this study is to analyze by real-time polymerase chain reaction, the relative quantitative expression of the estrogens beta, beta1, beta2, and beta5 receptors in colon adenocarcinomas and to compare this expression with the respective in normal tissues. Moreover, we evaluate a possible correlation between estrogen's receptor expressions and disease stages. Normal tissues show estrogen beta receptor expression greater than pathologic tissues and the estrogen beta receptors result as most expressed in the lower disease stages.

Abstract: BACKGROUND: DNA ploidy and S-phase fraction (SPF) measured by DNA flow cytometry (FC) have been previously shown to correlate with several clinicopathological variables in several types of tumours. PATIENTS AND METHODS: DNA FC was performed on multiple frozen tumour samples obtained from 115 patients undergoing curative surgery for gastric cancer (GC). The findings were prospectively tested for correlation with traditional clinicopathological indicators of prognosis. RESULTS: Overall, 20 tumours (17.4%) were diploid, 46 (40.0%) monoclonal and 49 (42.6%) multiclonal. Excluding 4 patients who died within 1 month of surgery, high SPF (>9.6%) was detected in 55 patients (49.6%) and was found to be significantly associated with vascular invasion and multiclonality (p=0.02). An association of borderline statistical significance emerged with macroscopic type (p=0.06) and pN and pM status (p=0.07). Multivariate regression analysis did not show a significant effect of SPF (p=0.11) or DNA ploidy (p=0.28) on 7-year survival. CONCLUSION: Aneuploidy appears to be a prognostic factor of low penetrance, whereas SPF is a more promising parameter of tumour aggressiveness in patients with GC.

Abstract: The L-PAM-ILP procedures under true hyperthermal regime (41.5-41.8 degrees C) require both close control of the physical parameters of the treatment (temperatures profiles and time duration, artero-venous pressure, perfusate flow rate) and medical rationale (drug, dosage, fractioning, timing). All the above essential procedures must be supported by rigorous methodology, reliable operation of the medical devices and apparatus and real-time monitoring of the treatment parameters. Real-time monitoring is essential for proper trimming and modulation of the parameters during treatment. This paper delineates the technical improvements that we have implemented for drug leakage monitoring and control in the systemic circulation aimed at improving the therapeutic efficacy and at reducing the occurrence of unexpected complications.

Abstract: OBJECTIVES: Consumption of alcoholic beverages reduces the risk of coronary artery disease (CAD), and epidemiological studies have shown that ethanol per se is protective. However, the mechanism by which ethanol exerts protection is not fully known. Ethanol can stimulate neuropeptide-containing primary sensory neurons via the activation of transient receptor potential vanilloid 1 (TRPV1). Here, we have studied whether ethanol-mediated TRPV1 activation causes the release of calcitonin gene-related peptide (CGRP) that, via dilatation of coronary arteries and other mechanisms, may protect the heart from CAD. METHODS AND RESULTS: Ethanol caused a marked relaxation of small-sized porcine isolated coronary (0.008-2.37%, w/v) and human isolated gastro-epiploic (0.0008-2.37%, w/v) arteries in vitro, an effect that was abolished by capsaicin-desensitization, the TRPV1 antagonist capsazepine, and the CGRP receptor antagonist, CGRP(8-37). In guinea-pig isolated and perfused hearts, ethanol (0.079-0.79%, w/v) increased baseline coronary flow in a concentration-dependent manner: 0.237% ethanol doubled baseline coronary flow. This effect was also abolished by capsaicin-desensitization, capsazepine, and CGRP((8-37)). Finally, the ethanol-induced increase in CGRP release from guinea-pig isolated and perfused hearts and from slices of porcine coronary arteries was abolished by capsaicin-desensitization and by capsazepine. Similar functional and neurochemical results were obtained in all preparations with capsaicin. CONCLUSIONS: Ethanol, at low concentrations not dissimilar from those found in blood following low to moderate consumption of alcoholic beverages, releases CGRP within coronary arteries via stimulation of TRPV1 on perivascular sensory nerve terminals. Ethanol-induced release of CGRP may contribute to the reduction in the risk of CAD associated with alcohol consumption by various mechanisms, including the increase in coronary flow and arterial dilatation.

Abstract: The focus of this study was to use differential protein expression to investigate operative pathways in early stages of human colon cancer. Colorectal cancer represents an ideal model system to study the development and progression of human tumors, and the proteomic approach avoids overlooking posttranslational modifications not detected by microarray analyses and the limited correlation between transcript and protein levels. Colon cancer samples, confined to the intestinal wall, were analyzed by expression proteomics and compared with matched samples from normal colon tissue. Samples were processed by two-dimensional gel electrophoresis, and spots differentially expressed and consistent across all patients were identified by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry analyses and by Western blot analyses. After differentially expressed proteins and their metabolic pathways were analyzed, the following main conclusions were achieved for tumor tissue: 1) a shift from beta-oxidation, as the main source of energy, to anaerobic glycolysis was observed owed to the alteration of nuclear- versus mitochondrial-encoded proteins and other proteins related to fatty acid and carbohydrate metabolism; 2) lower capacity for Na(+) and K(+) cycling; and 3) operativity of the apoptosis pathway, especially the mitochondrial one. This study of the human colon cancer proteome represents a step toward a better understanding of the metabolomics of colon cancer at early stages confined to the intestinal wall.

Abstract: AIMS: To report clinical outcomes of a large series of cases with advanced thyroid cancer. STUDY DESIGN: Three hundred and eighty-five patients at the UICC stages III and IV were selected for the study with thyroid cancer. RESULTS: Papillary carcinoma and sclerosing carcinoma have better survival than the Hürthle cell and insular types. Lymphatic metastasis does not appear to worsen the prognosis. All the tumour forms offer the chance of long survival. CONCLUSIONS: Surgical treatment is the primary treatment of thyroid carcinoma. The combined treatments of surgery, metabolic beam therapy, suppressive hormone therapy, radiotherapy and chemotherapy cure a high percentage of patients with the tumour at an advanced stage.

Abstract: Children have limited venous access possibilities; therefore, when long-term therapy is necessary, it is better to place a catheter in a central vein. The Port catheter, totally implanted, is less exposed to the risk of infection and permits a normal life. However, there is the possibility of the displacement or fragmentation of the catheter that can be diagnosed initially only by clinical symptoms and later by a chest X-ray. We report a case of disconnection between the Port catheter and the reservoir resulting in catheter migration to the left pulmonary artery.

Abstract: Cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LOX) are key enzymes involved in arachidonic acid metabolism. Their products, prostaglandins and leukotrienes, are involved in colorectal tumor development. We aimed at evaluating whether combined blocking of the COX-2 and 5-LOX pathways might have additive antitumor effects in colorectal cancer. The expression/activity of COX-2 and 5-LOX were assessed in 24 human colorectal cancer specimens. The effects of the COX-2 inhibitor celecoxib and the 5-LOX inhibitor MK886 on prostaglandin E(2) and cysteinyl leukotriene production, tumor cell proliferation, cell apoptosis, and Bcl-2/Bax expression were evaluated in the Caco-2 and HT29 colon cancer cells. We also investigated the effect of the enzymatic inhibition on mitochondrial membrane depolarization, one of the most important mechanisms involved in ceramide-induced apoptosis. Up-regulation of the COX-2 and 5-LOX pathways was found in the tumor tissue in comparison with normal colon mucosa. Inhibition of either COX-2 or 5-LOX alone resulted in activation of the other pathway in colon cancer cells. Combined treatment with 10 micromol/L celecoxib and MK886 could prevent this activation and had additive effects on inhibiting tumor cell proliferation, inducing cell apoptosis, decreasing Bcl-2 expression, increasing Bax expression, and determining mitochondrial depolarization in comparison with treatment with either inhibitor alone. The administration of the ceramide synthase inhibitor fumonisin B1 could prevent some of these antineoplastic effects. In conclusion, our study showed that inhibition of 5-LOX by MK886 could augment the antitumor activity of celecoxib in human colorectal cancer.

Abstract: Ion channels regulate a broad range of cellular activities. Alteration in ion channel function has been reported in different human pathologies, such as cardiac, neuromuscular, autoimmune diseases, and cancer. We investigated the expression of hERG1 K+ channels in the human upper gastrointestinal tract, focusing our attention on the lower esophagus. In particular, we analyzed by both Reverse transcription and polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) endoscopic samples obtained from normal subjects, from patients suffering from gastroesophageal reflux, associated or not with esophagitis, and from patients affected by Barrett's esophagus (BE), that is, intestinal metaplasia. None of the normal samples, nor those from patients with gastro-esophageal reflux symptoms and reflux esophagitis expressed the hERG1 protein. On the other hand, 69% of patients with BE expressed hERG1. Since BE is a preneoplastic lesion, dysplasias (Ds) and adenocarcinomas (ADKs) arising on a previously diagnosed BE were also analyzed, and all the samples showed a high expression of the hERG1 protein. The surveillance of patients with BE showed that 89% of those who later developed ADKs displayed hERG1 expression. Data here reported, support the hypothesis that hERG1 expression marks an early step of the progression of normality to cancer in the human esophagus through a metaplastic and dysplastic stage.

Abstract: We studied the expression of several homeobox genes of the HOX family in the adult human intestinal mucosa. HOX genes are regulatory genes homologous to the homeotic genes controlling the body plan of the fruit fly Drosophila melanogaster. The HOX genes are distributed in four homologous HOX loci termed HOX-A, B, C and D, located on four different chromosomes. They have been found to be expressed in many embryonic tissues and axial structures like the central nervous system, the spine and in selected adult cells. The expression of 39 HOX genes belonging to HOX-A, B, C and D was studied by in situ hybridization on specimens of mucosa from normal adult colon. All the genes studied were shown to be expressed in these tissues, but the genes belonging to the four loci showed different localization within the colonic mucosa: HOX-A genes are expressed in undifferentiated proliferating cells at the base of the crypts, HOX-C genes in differentiated cells at the apex of the crypts and HOX-B and HOX-D genes are weakly expressed along the entire crypt length. Expression of some of these genes was also studied in differentiating CaCo-2 cells and tumoral tissues. In particular, in colonic adenocarcinomatous cells, some HOX-A genes appear to be abundantly expressed confirming the presence of these gene products in normal.

Abstract: Vanilloid receptor type 1 (TRPV1) is expressed in a capsaicin-sensitive and peptide-containing sub-population of primary sensory nerves that in the rat stomach seems involved in regulation of chlorhydropeptic secretion and gastroprotection. Our aim was to identify which cell types express TRPV1 in the human stomach in order to gain a better insight in the role of this receptor in the regulation of HCl secretion. Immunohistochemistry, by using three different commercially available anti-capsaicin antibodies, in situ hybridisation and Western blot analysis were performed on fragments surgically obtained from the gastric body on the large curvature. TRPV1 labelling was found in the parietal cells at the level of intra-cytoplasmatic granules matching mitochondrial features and distribution. Immunolabelled neurons and nerve fibres were also seen, the latter numerous in the submucosa and mucosa and often ending close to the parietal cells. TRPV1 presence was confirmed by Western blot analysis and in situ hybridisation. TRPV1 presence in nerve structures and parietal cells suggests the possibility of a combined effect of both neuronal and epithelial TRPV1 on chlorhydropeptic secretion. The presumed TRPV1 mitochondrial location inside parietal cells is in favour of the existence of a local pathway of auto-regulation of HCl secretion. Therefore, TRPV1 might modulate chlorhydropeptic secretion in the human stomach through more complex pathways than previously thought.

Abstract: Interstitial cells of Cajal (ICC) are distributed throughout the gastrointestinal muscle coat with a region-specific location, and are considered to be pace-maker and/or mediators of neurotransmission. Little is known about their shape, size, distribution and relationships with excitatory and inhibitory nerves in human stomach. With this aim, we labeled the ICC, using c-Kit immunohistochemistry, followed by a quantitative analysis to evaluate the distribution and area occupied by these cells in the circular and longitudinal muscle layers and at the myenteric plexus level in the human fundus, corpus and antrum. Furthermore, by NADPH-d histochemistry and substance P (SP) immunohistochemistry, we labeled and quantified nitric oxide (NO)-producing and SP-containing nerves and evidenced their relationships with the ICC in these three gastric regions. In the fundus, the ICC appeared as bipolar cells and in the corpus and antrum they mainly appeared as multipolar cells, with highly ramified processes. The networks formed by ICC differed in the three gastric regions. The ICC number was significantly higher and cell area smaller in the fundus compared to the corpus and antrum. The area occupied by the ICC was significantly higher at the myenteric plexus level compared with circular and longitudinal muscle layers. Everywhere, NADPH-d-positive nerves were more numerous than SP-positive ones. Both kinds of fibers were closely apposed to the ICC in the corpus and antrum. In conclusion, in the human stomach, the ICC have region-specific shape, size and distribution and in the corpus and antrum have close contact with both inhibitory and excitatory nerves. Presumably, as suggested for laboratory mammals, these differences are in relationship with the motor activities peculiar to each gastric area.

Abstract: The Authors describe a case of spontaneous migration in the right jugular vein of a central venous catheter tip, properly positioned in the right atrium through the right subclavian vein two days before.

Abstract: To investigate the potential involvement of the nitric oxide (NO) pathway in colorectal carcinogenesis, we correlated the expression and the activity of inducible nitric oxide synthase (iNOS) with the degree of tumor angiogenesis in human colorectal cancer. Tumor samples and adjacent normal mucosa were obtained from 46 surgical specimens. Immunohistochemical expression of iNOS, vascular endothelial growth factor (VEGF), and CD31 was analyzed on paraffin-embedded tissue sections. iNOS activity and cyclic GMP levels were assessed by specific biochemical assays. iNOS protein expression was determined by Western blot analysis. iNOS and VEGF mRNA levels were evaluated using Northern blot analysis. Both iNOS and VEGF expressions correlated significantly with intratumor microvessel density (r(s) = 0.31, P = 0.02 and r(s) = 0.67, P < 0.0001, respectively). A significant correlation was also found between iNOS and VEGF expression (P = 0.001). iNOS activity and cyclic GMP production were significantly higher in the cancer specimens than in the normal mucosa (P < 0.0001 and P < 0.0001, respectively), as well as in metastatic tumors than in nonmetastatic ones (P = 0.002 and P = 0.04, respectively). Western and Northern blot analyses confirmed the up-regulation of the iNOS protein and gene in the tumor specimens as compared with normal mucosa. NO seems to play a role in colorectal cancer growth by promoting tumor angiogenesis.

Abstract: BACKGROUND: The test and treat strategy for Helicobacter pylori infection has raised some concern since young gastric cancer patients may have no alarm symptoms. In this study the frequency of alarm symptoms was assessed in a series of young gastric cancer patients, as well as the impact of absence of alarm symptoms on delay in diagnosis and stage of gastric cancer at diagnosis and survival. METHODS: A retrospective study was carried out on 92 gastric cancer patients < or = 45 years of age identified from databases in four hospitals between January 1985 and December 2001. Characteristics analysed included duration and features of dyspeptic symptoms, presence of alarm symptoms, time interval from the onset of symptoms to diagnosis, pTNM stage and survival. RESULTS: Of the 92 patients, 54 (58.7%) presented uncomplicated dyspepsia and 38 (41.3%) alarm symptoms. In those with uncomplicated dyspepsia, epigastric pain was the most common complaint (64.1%) followed by vomiting (30.4%), heartburn and nausea. Weight loss was the most common alarm symptom (30.4%), followed by anorexia (10.9%), dysphagia or anaemia (7.6%). The mean delay from first symptoms to final diagnosis was 16.8 +/- 13.9 weeks in patients with alarm symptoms and 29.3 +/- 39.9 weeks in patients without alarm symptoms (P:ns). Patients without alarm symptoms showed significantly less aggressive gastric cancer compared to patients with alarm symptoms in relation to TNM stage and survival (cumulative 5-year survival rate: 76% versus 49% P: 0.01). The survival rate, at 5 years, of patients without alarm symptoms, and with a history of dyspepsia of more than 24 weeks, was higher than that in patients with early diagnosis (93.4% versus 66.5%: P: 0.05). CONCLUSIONS: A large proportion of young gastric cancer patients present without alarm symptoms. Despite the delay in diagnosis, these patients have a better outcome than those with alarm symptoms. Thus the delay in diagnosis of patients without alarm symptoms does not affect survival.

Abstract: BACKGROUND: Intratumoral microvessel density (MVD) could be used as a prognostic factor in colorectal cancer. We retrospectively analyzed the value of microvessel count in predicting the clinical outcome of stage I and II (Dukes A and B) rectal cancer patients. METHODS: Eighty-four patients who had undergone curative resection of lymph node-negative rectal cancer were included. Tumor type and differentiation, the depth of local invasion, venous invasion, the character of the invasive margin, and the degree of lymphocytic infiltration were evaluated for each tumor specimen. Immunohistochemical staining for the CD31 endothelial antigen was performed to highlight the microvessels. RESULTS: The median value of MVD was 45 microvessels. Low MVD (microvessels < or = 45) was observed in 41 patients (48.8%), and high MVD (>45) was found in 43 (51.2%). The presence of conspicuous lymphocytic infiltration was significantly associated with increased vessel density. With uni- and multivariate survival analysis MVD did not show any prognostic significance. The character of the invasive margin was the only parameter with independent prognostic value. CONCLUSIONS: MVD does not seem to provide any additional prognostic information when compared with standard histopathological parameters in lymph node-negative rectal cancer. It is likely that the strong association between MVD and the presence of conspicuous lymphocytic infiltration may interfere with its predictive value.

Abstract: Lymph node involvement is the most important prognostic factor for patients who have undergone radical surgery for colorectal carcinoma. An accurate examination of the surgical specimens is mandatory for the correct assessment of the lymph node status of the tumor. The risk of understaging is particularly high for patients with tumors classified as Dukes B (TNM stage II). The aim of this study was to determine if a specified minimum number of lymph nodes examined per surgical specimen could have any effect on the prognosis of patients who had undergone radical surgery for Dukes B colorectal cancer. Between 1988 and 1995 a total of 140 patients underwent radical resection of Dukes B colorectal cancer by the same surgeon (C.C.). The relation between clinicopathologic variables and survival was estimated using the Kaplan-Meier method. The Cox proportional hazard regression model was used to identify the variables that can independently influence survival. A median of 12 lymph nodes (range 3-38) was examined per tumor specimen. The 5-year survival rate of Dukes B patients who had had eight or fewer lymph nodes examined after surgery was 54.9%, whereas the survival rate for those who had had nine or more lymph nodes examined was 79.9% (p < 0.001). Cox regression analysis identified the number of lymph nodes as the only independent prognostic factor (p = 0.01). Seventy patients with one to four metastatic lymph nodes (Dukes C patients) who had been operated on during the same period were included in the survival analysis for comparison. The 5-year survival rate of the Dukes B patients with eight or fewer lymph nodes examined was similar to that of the 70 Dukes C patients (54.9% and 51.8%, respectively). Examination of eight or fewer lymph nodes in Dukes B colorectal patients may be considered a high risk factor for missing positive lymph nodes in the surgical specimens. Our results suggest that harvesting and examining a minimum of nine lymph nodes per surgical specimen may be sufficient for reliable staging of lymph node-negative tumors.

Abstract:

Abstract: Helicobacter pylori affects gastric secretion. This functional effect might have a morphometric counterpart. Therefore, the gastric cell secretory compartment was morphometrically assessed in different pathophysiologic conditions related to Helicobacter pylori infection. Nineteen Helicobacter pylori-positive nonduodenal ulcer subjects, 15 omeprazole chronically treated subjects, and 19 duodenal ulcer patients were studied against 19 controls. Somatostatin, gastrin, enterochromaffin-like, and parietal cell density was assessed in gastric biopsies. No differences in any cell type density were found between Helicobacter pylori-positive nonduodenal ulcer subjects and controls. On the contrary, differences were significant when comparing omeprazole and duodenal ulcer patients to controls (higher density of gastrin, enterochromaffin-like, and parietal cells, lower density of somatostatin cells). In duodenal ulcer a reversion to control values followed Helicobacter pylori eradication and ulcer healing. A direct linear correlation between enterochromaffin-like, gastrin, and parietal cell density was demonstrated. An almost complete map of mucosal cells involved in gastric secretion is provided by this study. The cell density pattern, identical to the omeprazole group, points to an impaired feedback control of secretion in duodenal ulcer. The reversion to control values after Helicobacter pylori eradication and ulcer healing demonstrates the pathogenetic role of Helicobacter pylori-host interaction in these changes.

Abstract: BACKGROUND & AIMS: Recent studies have shown that cyclooxygenase (COX)-2 and its products, prostaglandins (PGs), may be involved in colorectal carcinogenesis. The aim of this study was to determine whether COX-2 expression and PGE(2) production correlate with microvessel density, vascular endothelial growth factor (VEGF) expression, and tumor metastasis in human colorectal cancer. METHODS: Tumor samples and adjacent normal mucosa were obtained from 31 surgical specimens. Immunohistochemical expression of COX-2, VEGF, and CD31 was analyzed on paraffin-embedded tissue sections. COX-2 and COX-1 proteins were determined by Western blot analysis. COX-2 and VEGF messenger RNA expressions were evaluated using Northern blot analysis. PGE(2) production was determined by specific radioimmunoassay. RESULTS: The immunohistochemical expressions of both COX-2 and VEGF were significantly correlated with microvessel density (P = 0.02 and P = 0.002, respectively). A significant correlation was found between COX-2 and VEGF expression (P = 0.004). Western analysis confirmed the up-regulation of COX-2 protein expression. COX-2 and VEGF genes were overexpressed in tumor specimens as compared with normal mucosa. PGE(2) levels were significantly higher in metastatic tumors than in nonmetastatic ones (P = 0.03). CONCLUSIONS: COX-2 is related to tumor angiogenesis in colorectal cancer. It is likely that VEGF is one of the most important mediators of the COX-2 angiogenic pathway.

Abstract: BACKGROUND AND OBJECTIVES: There is a great deal of controversy regarding the definition, classification, and staging of cardiac adenocarcinoma (CA). Recently, a shift from distal to proximal lesions has been documented in gastric cancer. We have stratified our cases of gastric cancer as CA, distal gastric cancer (DGC), and stump cancer (SC). METHODS: Between 1986 and 1998, 450 patients with gastric cancer were operated on at our institute. The resectability rate was 81.6%. Of 367 patients, 48 were CA, 298 DGC, and 21 SC. These 3 groups were compared in terms of clinicopathologic factors and survival rates. RESULTS: CA was significantly higher in male patients and showed a prevalence of the Lauren intestinal type. Regarding staging parameters, CA showed a higher rate of T3 tumors and of resection line involvement. Five-year survival rates were 23. 2% for CA, 45.0% for DGC, and 17.4% for SC. CONCLUSIONS: A possible cause of the poor outcome of CA is presentation at a more advanced stage. CA was similar to SC as far as epidemiology, pathologic factors, and survival rates.

Abstract: BACKGROUND AND OBJECTIVES: The relationship between the number of lymph nodes examined and the outcome in patients with node-negative (N(-)) gastric cancer was studied. We compared N(-) patients to those with nodal involvement (N(+)) to identify clinicopathologic characteristics of N(-) gastric cancer. Finally, we evaluated outcome indicators in this group of patients. METHODS: Of 367 patients, 130 (35.4%) were N(-). These patients were stratified according to the main prognostic variables, to assess differences with N(+) cases. A statistical analysis using the Cox model was performed to estimate outcome indicators. RESULTS: N(-) gastric carcinomas were significantly different from N(+) cases in terms of tumor depth and site, TNM stage, grading, residual disease, and vessel involvement. The overall 5-year survival rate was 72%. It was 82% in those patients with more than 15 nodes retrieved and 59% in the others. Serosal involvement, residual disease, and poor differentiation were independent prognostic factors. CONCLUSIONS: The clinicopathologic factors and outcome of N(-) cases were similar to those of early gastric cancer. At least 15 examined nodes appears to be necessary to define a case as N(-). The prognostic value of D2 lymphadenectomy in N(-) patients suggests a biologic role of micrometastases.

Abstract: Invasive bile determination is very useful in the diagnosis of many gastric pathologies. At the moment, this measurement is performed with Bilitec 2000, an optical fiber sensor, that is based on absorption by bilirubin. Nevertheless, erroneous evaluations are possible, due to the different configurations which the bilirubin molecule can adopt. The optical behavior of human samples of pure bile and bile+gastric juice has been examined using an optical fiber spectrophotometer and two suitably modified Bilitec 2000 units. A protocol has been established for the treatment of biological fluids, in order to make it possible to study the behavior of their optical properties as a function of pH and concentration without causing any alteration in the samples. The analysis of pH dependence evidenced the presence of different calibration curves at different pH values: the self-aggregation of the bilirubin molecules observed in pure bile samples was almost totally absent in the gastric samples. Measurements carried out on Bilitec 2000 showed that the most appropriate wavelength for bilirubin detection in the stomach should be 470 nm.

Abstract: The ability of the 'alkaline' components of reflux to cause harm in vivo is still open to debate, although these components have been shown in vitro to be capable of damaging the mucosa. The precipitation of bile acids and lysolecithin that occurs at low pH values is the main reason for questioning in vivo mucosal damage. This study was undertaken to determine the composition of gastric aspirates at different original pH values and the degree of solubility of the alkaline components when pH modifications are artificially induced. The samples for chemical analysis were collected from indwelling nasogastric tubes after surgical procedures that did not involve the upper gastrointestinal tract. Bile acid and lysolecithin concentrations were assessed by means of dedicated methods. Thirty-five samples were available for bile acid evaluation and 27 for lysolecithin evaluation. Bile acid and lysolecithin assessments were repeated after pH adjustment at 2, 3.5, 5.5 and 7. For easier assessment of the results, three ranges of the original pH were selected (pH < 2, 2 < or = pH < 5, pH > or = 5). For each pH range, results were pooled together and compared with those in the other pH ranges. Bile acid concentrations were 113+/-48, 339+/-90 and 900+/-303 (mean +/- s.e.m. micromol/L), respectively, in the three groups selected on account of the different original pH values. Differences were significant (p < 0.001). Both taurine- and glycine-conjugated bile acids were represented even at pH < 2. No major differences were observed in bile acid concentration with the artificially induced pH variations. Lysolecithin concentrations were 5.99+/-3.27, 30.80+/-8.43 and 108.37+/-22.17 (mean +/- SEM microg/ml), respectively, in the three groups selected on account of the different original pH ranges. Differences were significant (p < 0.001). No significant differences in lysolecithin concentration were detected with the artificially induced pH variations. In conclusion, both bile acids and lysolecithin are naturally represented in the gastric environment even at very low pH values, although their concentrations decrease on lowering of the naturally occurring pH. Given the concentration variability of bile acids and lysolecithin, further studies are needed to assess the minimal concentration capable of mucosal damage in vivo.

Abstract: BACKGROUND/AIMS: The study aims to evaluate the pH and the presence of bile in the denervated whole stomach pulled up to the neck after subtotal esophagectomy. METHODOLOGY: The pH and the presence of bile in the gastric cavity were monitored by combined 24-hour pH and bilimetry in 16 patients having their whole stomach as an esophageal substitute (i.e., 8 with and 8 without a gastric drainage procedure) and in 25 healthy control subjects. The percentage of time during which pH was < 2 as well as the percentage of time during which bile absorbance was > 0.25 for the total, upright, and supine periods of recording were considered for each subject studied. Seven patients underwent a gastroscopy with biopsies. RESULTS: Intragastric acidity was normal in 50% of patients while it was reduced in the other 50%. Ten of the 16 patients (62.5%), i.e., 4 with (50%) and 6 without (75%) a drainage procedure, had excessive exposure of the gastric mucosa to bile. No significant correlation was found between the existence of a high intraluminal pH profile and excessive bile exposure (p = 0.9163). Bile exposure was significantly higher in whole stomach patients than in controls in both the upright and supine positions, irrespective of the existence or absence of a drainage procedure (p ranging from 0.0272-0.0001). Bile exposure in the supine position tended to be longer in patients without than in those with a drainage procedure (p = 0.0929). Helicobacter pylori-negative chemical gastritis was present in 3 of the 7 patients who underwent a gastroscopy, all 3 having excessive bile exposure and no food retention in the transplant lumen. CONCLUSIONS: Gastric denervation and transposition up to the neck increased exposure of the gastric mucosa to bile, irrespective of the patient's position and of the presence of a gastric drainage procedure. The absence of gastric drainage procedure tends to ensure exposure to bile prolongeLow gastric acidity, if present, is due to a reduction in acid secretion rather than to a buffering effect from duodenal juice having refluxed. Gastritis is more likely to be related to excessive exposure of the gastric mucosa to bile than to food retention.

Abstract: Bilitec 2000 is a new device which spectrophotometrically detects the presence of bilirubin in the refluxate. It is, up to date, the only method able to monitor for 24 hours the exposure time of esophageal and/or gastric mucosa to bilirubin-containing reflux. From the technical point of view, a particularly relevant aspect is the necessity of associating pH and Bilitec monitorings. The reason why is that, even in the stomach where Bilitec itself is adequate for assessing the exposure time to duodenogastric reflux, the damaging capability of the different components of reflux strictly depends upon pH. The most correct position inside the stomach for gastric monitoring is the 5 cm-below-the-LES-distal-border-position. The diet needs to be standardized in order to avoid false positive results due to the ingestion of foods with absorption close to bilirubin absorption. Ranges of normality will soon be available from a collaborative European Study. At variance with the indications for esophageal monitoring which are wide (the same as for pH-monitoring), indications for gastric Bilitec monitoring are represented only by severe dyspeptic symptoms possibly related to duodenogastric reflux. An antrum-confined C gastritis in the absence of history of consumption of gastro-lesive drugs strongly suggests the possibility of duodenogastric reflux. In this case, Bilitec monitoring can provide further evidence by measuring the time of exposure of the gastric mucosa to reflux.

Abstract: BACKGROUND: The role of excessive duodenogastric reflux (DRG) in the genesis of gastric symptoms in patients primarily referred for both gastroesophageal reflux (GER) symptoms and esophagitis is poorly understood. METHODS: The study is based on the clinical, endoscopic, histologic, and 24-hour gastric data from the Bilitec optoelectronic device (Prodotec, Florence, Italy, licensed by Synectics Medical, Stockholm, Sweden) from 49 patients having both typical GER symptoms and gastric symptoms suggestive of excessive DGR (i.e., epigastric pain, nausea, or bilious vomiting) in the absence of previous esophageal or gastric surgery (group 1). Helicobacter pylori organisms were searched for on antral biopsy specimens with use of the Giemsa method. The percentages of total, upright, and supine time during which absorbance exceeded various thresholds through all the working range of the Bilitec device were calculated. Bilitec data from group 1 were compared with those from 16 patients with endoscopic esophagitis and GER symptoms only (group 2) and 25 healthy subjects (group 3). RESULTS: The prevalence of an abnormal Bilitec test result in group 1 increased from 27% (13/49) at the 0.25 absorbance threshold to 36% (18/49) at thresholds ranging from 0.40 to 0.60 and to 41% (20/49) when multiple thresholds ranging from 0.25 to 0.60 were considered. In group 2 one patient had an abnormal Bilitec test result at the 0.25 to 0.30 threshold, whereas the other 15 patients had a normal test result. H pylori antral infection was present in 14 group 1 patients. None of these had an abnormal Bilitec test result, whereas the test was positive in 40% of the H pylori-negative patients without endoscopic gastritis and in 70% of H pylori-negative patients with endoscopic gastritis (P = .001). CONCLUSIONS: Twenty-four-hour intragastric bile monitoring provides the clinician with unequivocal evidence of excessive DGR in 41% of patients with an intact stomach having endoscopic esophagitis, GER symptoms, and gastric symptoms suggestive of DGR. The most dependable data are obtained when absorbance thresholds higher than 0.40 are considered. H pylori antral infection and excessive DGR at 24-hour intragastric bile monitoring are mutually exclusive.

Abstract: Duodenogastric reflux (DGR) is suspected to be an aetiological factor in the pathogenesis of foregut disease. The 'Bilitec' bile probe allows continuous detection of bilirubin, based on spectrophotochemical properties. We aimed to describe duodenogastric bile reflux in healthy, normal volunteers in a Western European population, as a basis for the future study of DGR in disease. An international multicentre study was established. DGR was measured using 24 h ambulatory bile and pH monitoring in the proximal stomach, in 43 normal volunteers from the third to the seventh decades. Subjects adhered to a standard protocol. The total test period, supine and upright components, were analysed. The 90th percentile values for absorbance thresholds of 0.14, 0.25, 0.3, 0.4 and 0.5 were 40.5%, 20.9%, 19.6%, 11.6% and 4.6% of the total time respectively. There was a wide range of absorbance within each threshold. Supine DGR was greater than upright, and associated with an alkaline tide. The upright phase was further subdivided into upright fasting, prandial and post prandial phases, and ranges for these periods are also described. No relationship between age, weight, or body mass index and duodenogastric reflux was seen. The results of this study form a range which allows further investigation into the contribution of duodenogastric bile reflux in the pathogenesis of foregut disease.

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Abstract: Neuron density and distribution of the NADPH-diaphorase positive neurons were studied in the fundus, corpus and antrum of adult human stomach using cresyl violet staining and NADPH-diaphorase histochemistry. The submucous plexus contained significantly less neurons than the myenteric plexus. Submucous NADPH-d positive neurons were mostly located in ganglia close to the circular muscle layer. Myenteric NADPH-d positive neurons represented 50-60% of the neurons in all the three regions; their density, however, was significantly lower in the fundus. NADPH-d positive fibers formed a rich plexus in the innermost portion of the circular muscle layer of the corpus.

Abstract: PURPOSE: The clinical significance and prognostic value of the histopathologic parameters used in both the Dukes and Jass classifications were evaluated to select those with an independent effect on survival after radical surgery for colorectal cancer. METHODS: The depth of local spread (limited to the bowel wall or extended beyond it), the number of metastatic lymph nodes (none, 1-4, more than 4), the character of the invasive margin (pushing or infiltrating), and the presence or absence of conspicuous peritumoral lymphocytic infiltration were assessed in 235 patients who had undergone radical resection for colorectal cancer. The influence of these variables on survival was studied by univariate and multivariate analysis. RESULTS: No significant difference in survival was found between patients with conspicuous peritumoral infiltrate and those without it; moreover, multivariate analysis failed to show any independent prognostic value for either lymphocytic infiltration or depth of local invasion. However, the character of the invasive margin and the number of metastatic lymph nodes were identified as the only variables with any independent importance on survival. Based on these data, a new prognostic model may be proposed; it uses the character of the infiltrative margin as a discriminating factor among patients within the lymph node-negative (Dukes A and B stages) and lymph node-positive (Dukes C1 and C2 subsets) groups. A good prognosis for Dukes A, B, and C1 patients was associated with pushing tumors; C1 and C2 patients with infiltrating tumors had a poor prognosis. On the whole, the new prognostic model has allowed for the placement of 59.6 percent of our patients into groups that provide a confident prognosis. The clinical outcome of Dukes A and B patients with infiltrating tumors is still uncertain. CONCLUSIONS: The character of the invasive margin is an important prognostic factor in colorectal cancer. The association of this parameter with the traditional Dukes classification may provide additional useful prognostic information and aid in the selection of those patients who could most benefit from adjuvant therapy.

Abstract: The antioxidants, 2-tert.-butyl-4-methoxyphenol (BHA) and its oxidative peroxidation product 2,2'-dihydroxy-3,3'-di-tert.-butyl-5,5'-dimethoxybiphenyl (di-BHA), 3,5-di-tert.-butyl-4-hydroxytoluene (BHT) and propyl gallate, were measured in plasma and tissue homogenates by HPLC and electrochemical detection, with a sensitivity down to 0.2 (BHA), 0.1 (di-BHA), 0.4 (BHT) and 1 (propyl gallate) ng ml(-1) of plasma or tissue homogenate. The data demonstrate that in man, at the current level of exposure to dietary antioxidants, significant amounts of BHA, BHT and propyl gallate are accumulated in the omentum. Furthermore, they provide the first evidence that the peroxidase-catalysed oxidation of BHA is operative in man.

Abstract: OBJECTIVES: A "gastrin link" has been suggested to explain the statistically relevant association between Helicobacter pylori and duodenal ulcer. Given the well known, although not entirely clarified, relationships between gastrin and histamine, the purpose of this study was to assess whether gastric mucosal histamine pathways and, more specifically, histamine-storing cells are involved in the Helicobacter pylori-duodenal ulcer route. METHODS: Fasting serum gastrin, gastric mucosal histamine content, and mucosal density of both enterochromaffin-like cells and mast cells were compared in 11 H. pylori-positive, non-duodenal ulcer subjects, in 16 duodenal ulcer patients (all H. pylori positive), and in 11 H. pylori-negative control subjects. RESULTS: Fasting serum gastrin concentration and mucosal histamine content were significantly higher in the duodenal ulcer group than in controls, whereas H. pylori-positive, non-ulcer subjects had values that were intermediate between those of the other two groups. Enterochromaffin-like cell density was significantly greater in duodenal ulcer patients than in the other groups. CONCLUSIONS: These results demonstrate the involvement of histamine pathways in H. pylori infection and duodenal ulcer. The most original finding in this study was that enterochromaffin-like cell density is three times greater in duodenal ulcer patients than in H. pylori-positive, non-ulcer subjects. This could explain the previous report of an exaggerated acid response to gastrin in duodenal ulcer patients when compared with H. pylori-positive, non-ulcer subjects and thus provide further insight into the pathogenesis of ulcers.

Abstract: OBJECTIVES: Helicobacter pylori infection is recognized as a risk factor for gastric adenocarcinoma. "Mitogenesis increases mutagenesis," so the effects of H. pylori infection on the gastric mucosal proliferative compartment have been investigated. METHODS: In 25 H. pylori-positive and 19 H. pylori-negative subjects, epithelial cell proliferative activity and the pattern of the proliferative compartment were separately evaluated in relation to both the different type of mucosa (antrum and corpus) and the H. pylori positivity/negativity after 3H-thymidine labeling. RESULTS: Both mucosal cell kinetics and the pattern of the proliferative compartment in the antrum appeared different from those of the corpus. Comparing H. pylori-positive and H. pylori-negative subjects, differences were detected only in the total number of cells in the antrum, whereas all of the cell kinetics parameters, except the labeling index, were greater in the corpus of the former group. A superficialization of the proliferative compartment was shown in H. pylori-positive subjects. Changes were more evident in subjects with more severe gastritis but were also present in H. pylori-positive subjects without corpus gastritis. CONCLUSIONS: These results show that H. pylori infection is associated with modifications in the proliferative compartment of the gastric mucosa. Both infection per se and chronic gastritis seem to be relevant for such changes.

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Abstract: Columnar epithelial metaplasia of the distal esophagus (i.e. barrett's esophagus) is an acquired condition showing a prevalence of 4%. It is probably due to abnormal reparative processes of the esophageal squamous epithelium after gastroesophageal reflux damage. "Mixed" (both acid and biliary) reflux seems more relevant for the pathogenesis of Barrett's esophagus than acid reflux alone, as shown by recent studies with Bilitec 2000. Its diagnosis is not easy for the "cardiac", "fundic" or "indeterminate" types of columnar metaplasia and needs a close cooperation between the endoscopist and the pathologist. On the contrary, it is less difficult for the "distinctive" type of metaplasia. Barrett's esophagus surveillance represents a major challenge in the perspective of its malignant degeneration (adenocarcinoma risk 350 times greater than in the general population). Therapy of Barrett's esophagus includes drugs and surgical treatment. Among the drugs proton pump inhibitors such as Omeprazole seem, at the moment, the most effective for reflux control, as well as the Nissen-Rossetti operation seems the most widely accepted among the anti-reflux surgical procedures. The novelty concerning Barrett's esophagus therapy is represented by laser photoablation associated with proton pump inhibiting therapy. But the experience with this treatment is still at a preliminary stage. For Barrett's esophagus with severe dysplasia and/or adenocarcinoma and/or squamous cell carcinoma esophagectomy is needed with a different extent and approach, according to the extent of Barrett's esophagus and to the stage and site of the neoplastic changes.

Abstract: Gastric mucosal histamine content, enterochromaffin-like cell density, and mast cell density were studied in 13 subjects under omeprazole therapy, 13 partially gastrectomized subjects with a Billroth II reconstruction, 10 partially gastrectomized subjects with a Roux-en-Y reconstruction, and 9 control subjects. Histamine content was significantly greater both in the subjects with higher gastrinemic levels (omeprazole-treated subjects) and those with more abundant enterogastric reflux (Billroth II subjects) than in controls. Enterochromaffin-like cell density was significantly greater in the omeprazole subjects than in each of the other groups. Mast cell density was significantly greater in Billroth II subjects than in controls. Serum gastrin levels, mucosal histamine content, and enterochromaffin-like cell density were positively correlated. Gastrin was not correlated to mast cell density. These results support the existence of different control pathways for enterochromaffin-like and mast cells. Moreover, they suggest that enterochromaffin-like cells and mast cells are involved in the regulation of gastric secretion and in gastric mucosal injury-repair mechanisms, respectively, due to histamine release.

Abstract: In the present study we have experimentally addressed the effects of Helicobacter pylori on the bile acid capability of histamine release. Bile acids alone were confirmed to be able to induce in vitro histamine release from rat serosal and mucosal mast cells. On the contrary, no significant histamine release was obtained when incubating any Helicobacter pylori preparations alone with mast cells. However, histamine release induced by bile acids was significantly enhanced, without any significant increase in lactate dehydrogenase activity, when whole washed or formalin-killed bacterial cells or crude cell walls were incubated with mast cells in the presence of cholic (0.3 mM), deoxycholic (0.3 mM), or lithocholic (0.3 mM) acids, chenodeoxycholylglycine (0.3 mM), and deoxycholyltaurine (3 mM). The electron microscopic features of mast cells incubated with Helicobacter pylori were consistent with an exocytotic secretion. The release of histamine induced by 0.3 mM deoxycholic acid in the presence of Helicobacter pylori was inhibited by the preincubation of the cells with dimaprit (an H2 agonist) and potentiated by the H2 antagonist, ranitidine. The current results suggest a link between human Helicobacter pylori infection and histamine release and a possible involvement of gastric mucosal mast cells in the pathogenesis of Helicobacter pylori-associated gastritis.

Abstract: The efficacy and tolerability of nimesulide and naproxen were compared in a randomised double-blind study of patients with pain and inflammation after haemorrhoidectomy. Both drugs appeared similarly effective in reducing pain and oedema and no adverse reaction was detected. These data extend the information on the anti-inflammatory and analgesic efficacy of nimesulide in the postoperative setting.

Abstract: Helicobacter pylori seems to be involved in the etiology of peptic ulcer and chronic gastritis. Histamine is fundamental in gastric secretion modulation, and some features of H. pylori-associated gastritis (edema, vasodilatation, inflammatory cell infiltration) are typical of the histamine-mediated response. This in vitro study has been undertaken as a preliminary step, in order to find a possible link between H. pylori and histamine release. H. pylori isolated from gastric biopsies has been tested as whole washed bacterium, whole formalin-killed bacterium, and crude cell wall preparation with serosal mast cells obtained by density gradient centrifugation or elutriation from peritoneal and pleural washings of male Wistar albino rats. Histamine release was assayed fluorimetrically. No significant histamine release was obtained by testing the various bacterial preparations alone with mast cells. On the contrary, whole washed cells, whole formalin-killed cells and crude cell walls from H. pylori have been found to potentiate compound 48/80 or calcium ionophore A23187-induced histamine release. Crude cell walls showed the highest activity, whereas filtered supernatants from broth cultures constantly appeared inactive. The enhancement in histamine release differed between the different strains. The present in vitro study, which shows the potentiating effect of H. pylori on histamine release, may prove interesting; however, at present, clinical implications cannot be inferred and further studies as well as in vivo demonstrations are needed.

Abstract: BACKGROUND: Experimental studies in the dog and the rat have shown histamine involvement in reflux-related gastric mucosal injury. However, no definite demonstrations of a link between reflux-related gastric mucosal injury and mast cell mediators exist in humans. METHODS: The relationships between reflux, gastric mucosal histamine content, and gastric histology were assessed in partially gastrectomized subjects presumptively with high (11 Billroth II subjects) and low reflux levels (9 total biliary diversion subjects), respectively. Findings were compared with those in a control group consisting of 8 endoscopically and histologically proven normal subjects. RESULTS: Bile acid quantity and concentration in the gastric aspirates were significantly greater in Billroth II subjects than in total biliary diversion subjects. Significantly higher cumulative scores for foveolar hyperplasia, mucosal edema, capillary dilatation and congestion, and smooth muscle fibers in the lamina propria were found in Billroth II subjects than in total biliary diversion subjects. Mucosal histamine content as well as mast cell density and degranulation differed significantly between Billroth II and the other two groups. CONCLUSIONS: These results represent the first demonstration in humans of an association between mast cell mediators and chemical gastric mucosal injury.

Abstract: The study deals with the analysis of proliferative activity in colon carcinomas and adjacent normal appearing mucosa, evaluated with in vitro 3H-Thymidine and autoradiography. In the colonic mucosa no significant differences in 3H-Thymidine Labelling Index (TLI) were observed in relation to the distance of the sample from the neoplasia. The distribution of S-phase cells along the crypt length is low at the bottom, increases rapidly with a maximum within the lower 25% and decreases in the highest positions. When the proliferative activity is increased there is the possibility of expanding the proliferative compartment towards the luminal region of the crypt. The division of the crypt into 5 parts makes it possible to identify 2 different patterns: the first with a very high TLI in the lower fifth, then a sharp decrease and without labelled cells in the highest parts; the second with labelled cells present also in the luminal fifth. These 2 aspects are characteristic of specimens with the lowest and the highest TLI values respectively. The analysis of TLI in colo-rectal cancers shows that cell kinetics parameters are not related to clinical and histopathological features such as sex, age, Dukes and TNM stages and grade of differentiation.

Abstract: A new technique for the long-term ambulatory detection of enterogastric and nonacid gastroesophageal reflux has been conceived, developed, and validated. It is based on the use of a fiberoptic sensor that utilizes the optical properties of bile. In vitro studies have shown good precision, good stability, sensitivity of 2.5 mumol/liter bilirubin concentration, as well as a useful working range of 2.5-100 mumol/liter bilirubin concentration. In vivo studies have been performed in 29 subjects. Simultaneous gastric aspirations have allowed a comparison of fiberoptic system measurements both with spectrophotometric analysis and bile acid concentrations of corresponding gastric juice samples. Linear correlations were shown between fiberoptic assessment and both spectrophotometric and bile acid concentration findings (P < 0.01). Simultaneous assessment of reflux with the fiberoptic system and cholescintigraphy has shown a 92.9% concordance as regards the presence or absence of reflux. Present results imply that the fiberoptic system is an important tool for the understanding of the clinical relevance of enterogastric and nonacid gastroesophageal reflux.

Abstract: The relationships between gastric pH and Helicobacter pylori infection were studied in 37 consecutive subjects affected with nonulcer dyspepsia. Each underwent esophagogastroduodenoscopy with multiple gastric biopsies for both H. pylori and histologic assessment, and 24-hr antral pH monitoring. H. pylori was harbored by 59.5% of the subjects with whole gastric spread of infection in all but one patient. Histologic gastritis was shown in 70.3% of the subjects. H. pylori was strongly associated with gastritis, both antral nonatrophic and multifocal atrophic. The ranges of 24-hr pH values were 1.3-6.9 in the H. pylori-positive and 1.2-6.8 in the H. pylori-negative group. Differences in pH values between the two groups were not significant. Moreover, the mean percent time duration of pH above 2, 4, and 6 did not significantly differ between the two groups. Therefore, this study has shown that chronic H. pylori infection is not related to luminal gastric pH.

Abstract: Foveolar hyperplastic changes have been recently considered to be the most distinctive histological finding after partial gastrectomy, and their relationship with bile reflux has been proven. The present study was undertaken to establish whether an increase in 3H-thymidine uptake--which is an expression of increased gastric mucosal proliferative activity--might correspond to these hyperplastic changes. Histology and thymidine uptake values were assessed and compared in nineteen rats operated upon either by means of a Polya gastrectomy (11), or with a Roux-en-Y biliary diversion (8). Thymidine uptake values and the extent of gastric hyperplastic changes were greater in the Polya than in the Roux-en-Y group. Moreover, a significant correlation was found between thymidine uptake values and the extent of hyperplastic changes. The relationship between hyperplastic changes and post-gastrectomy increased mucosal proliferative activity would thus seem to have been demonstrated. Since bile acids have been shown to stimulate cell proliferation in ileal and colonic mucosa, a rôle for bile reflux can be hypothesized for the increased cell proliferation activity in the gastric stump.

Abstract: Thirty-four randomized, partially gastrectomized subjects (12 with a Billroth II, 11 with a Billroth I, and 11 with a total biliary diversion reconstruction) were studied in order to assess the relationships between bile reflux, gastric histology, and cell proliferation kinetics. Bile acid quantity and concentration in the gastric aspirates progressively decreased from Billroth II to Billroth I to total biliary diversion (after which reflux was almost absent). Perianastomotic mucosa in Billroth II subjects showed the greatest degree of foveolar hyperplasia, and this decreased markedly with increasing distance from the anastomosis. Hyperplastic changes were less evident in Billroth I, and virtually absent in total biliary diversion subjects. The overall foveolar hyperplasia-like behavior of cell kinetic parameters (total pit cell number, labeled pit cell number, and labeling index) was shown. Moreover, subjects with mean bile acid concentration greater than 150 mumol/L had both a greater prevalence of foveolar hyperplasia and greater values of cell kinetic parameters than those with mean bile acid concentration less than or equal to 150 mumol/L. A superficialization of the proliferative compartment was also evident in the former group. These results show a close relationship between postgastrectomy bile reflux, foveolar hyperplasia, and cell kinetic parameters. Histologic and cell kinetic findings are probably the expression of gastric adaptation to chronic bile reflux exposure. Moreover, the type and entity of cell kinetic involvement and its relationship to foveolar hyperplasia and reflux may suggest new "tools" in post-gastrectomy surveillance and help to clarify patterns of gastric carcinogenesis.

Abstract: Foveolar hyperplastic changes have been recently considered to be the most distinctive histological findings following partial gastrectomy, and their relationship to bile reflux has been proven. The present study was undertaken in order to determine whether an increase in 3H-thymidine uptake, which is an expression of increased gastric mucosal proliferative activity, might correspond to these hyperplastic changes. Histology and thymidine uptake values were assessed and compared in nineteen rats operated upon either with a Polya gastrectomy (11) or with a Roux-en-Y biliary diversion (8). Thymidine uptake values and the extent of gastric hyperplastic changes were greater in the Polya than in the Roux-en-Y group. Moreover, a significant correlation was found between thymidine uptake values and the extent of hyperplastic changes. Therefore, the relationship between hyperplastic changes and increased mucosal proliferative activity post-gastrectomy would seem to have been proven. Since bile acids have been shown to be able to stimulate cell proliferation in ileal and colonic mucosa, a role for bile reflux in the increased cell proliferation activity in the gastric stump can be hypothesized.

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Abstract: Twenty-four patients with Raynaud's phenomenon, without ARA criteria for classification, were examined, after clinical history, by means of esophageal manometry, combined gastric and esophageal pH-monitoring, endoscopy. The results showed in these patients a high incidence of esophageal motor abnormalities (66.6%), of gastroesophageal reflux (50%), and of duodenogastric reflux (45.8%).

Abstract: Short- and long-term results of B-I and B-II reconstructions were compared in order to assess which anastomosis is to be recommended after partial gastrectomy for gastric ulcer. All the patients (287) electively operated for gastric ulcer 10-20 years ago were considered for the study. Operative mortality did not significantly differ, while duration of post-operative time before discharge and post-operative morbidity were significantly lower after B-I. Long-term percentage probability of survival was higher after B-I than after B-II (87.0 and 63.7 after 19 years, respectively), while quality of life was similar in the two groups. In the 64 subjects (26 B-I and 38 B-II) who underwent the study protocol, fasting bile reflux appeared more abundant and bile acid concentration greater after B-II than after B-I. While bacteria and nitrite concentrations did not differ in the two groups, bile acid pattern differed in a greater deoxycholic acid percentage concentration in the B-II group. In spite of an increased deoxycholic acid concentration and therefore a probably more lithogenic bile, gallstones were shown in 23.11% and 39.41% of the B-I and the B-II subjects, respectively, without significant differences. In conclusion, when partial gastrectomy is indicated for gastric ulcer, B-I reconstruction seems preferable to B-II because of its lower post-operative mobility, less evident entero-gastric reflux and histological consequences, less evident bile acid pattern changes from normal, and an apparently longer life-expectancy after discharge.

Abstract: Twelve partially gastrectomized subjects who have consecutively undergone total biliary diversion for severe bilious vomiting were studied before and after operation in order to assess the effects of surgery on gastric histology and enterogastric reflux. Before and six months after operation, the following protocol was performed: (1) blood examinations including serum basal gastrin; (2) endoscopy with multiple gastric biopsies; and (3) quantitation of bile acids in the gastric aspirate. Of the preoperative symptoms, bilious vomiting and heartburn completely disappeared postoperatively in all the subjects. Fasting bile reflux was significantly reduced (bile reflux was annulled in six and considerably lowered in the remaining six subjects), and erythema of the gastric mucosa completely disappeared in all the subjects after diversion. Among histological findings, while a significant regression of foveolar hyperplasia was found both in the perianastomotic area and in the body of gastric remnant, none of the other aspects identifiable in postgastrectomy gastric mucosa (chronic gastritis changes included) were affected by diversion. These results show that biliary diversion is effective in correcting reflux, bilious vomiting, erythema, and foveolar hyperplasia of the gastric mucosa and confirm the suggested relationship between bile reflux and gastric foveolar hyperplasia.

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Abstract: Forty-four randomized, partially gastrectomized subjects were studied to assess whether gastric histologic findings after partial gastrectomy were related to reflux. Gastric biopsy specimens (12) were taken at different distances from the anastomosis. Histologic findings were as follows: (a) hyperplastic changes of the foveolar epithelium and (b) loss of the chief and parietal gland cells with atrophy of gastric glands (chronic atrophic gastritis). Hyperplastic changes typical of the perianastomotic area gradually decreased with increasing distance from the anastomosis. Hyperplastic changes showed a greater prevalence in Billroth II than in Billroth I subjects (100% vs. 29.4%). No significant association was found between histologic findings and symptoms. Hourly bile acid quantity (fasting bile reflux) and concentration were determined in the gastric aspirates. Bile reflux was greater after Billroth II than after Billroth I (fasting bile reflux median values: 30.5 vs. 0.18 mumol/h, respectively). The same was true for bile acid concentration (mean bile acid concentration median values: 624.9 vs. 17.5 mumol/L, respectively). Moreover, Billroth I subjects with hyperplasia had a greater quantity and concentration of reflux than those without hyperplasia (fasting bile reflux and mean bile acid concentration median values: 2.6 vs. 0.8 mumol/h and 4.7 vs. 2.7 mumol/L, respectively). These findings show that bile reflux is correlated with hyperplastic changes of the foveolar epithelium, but prevalence and severity of atrophic gastritis were not related to reflux. Therefore, although we failed to show any relationship between chronic atrophic gastritis and reflux, foveolar hyperplasia was shown to be reflux related.

Abstract: A case of a variety of Ehlers-Danlos syndrome (EDS) type IV presenting with haematemesis and melaena and symptoms of gastro-esophageal reflux is described. At referral, the manometric esophageal findings similar to scleroderma and the abundant gastroesophageal reflux seemed noteworthy. 3 years after surgery, bleeding and reflux symptoms appeared, perfectly cured by a total biliary diversion operation. The reported case suggests that patients with EDS type IV especially when presenting with haematemesis and melaena should be investigated for reflux, since bleeding might be due to the action of reflux on the fragile-walled vessels of such patients.

Abstract: Biopsies of duodenal and ileal mucosa from patients with familial polyposis coli were studied. Areas of atypia were identified in the duodenum of six patients and in the ileum of three patients. Grade I atypia was characterized by crowding and elongation of cells and nuclei, a slight reduction in the number of goblet cells and the presence of a brush border; grade II atypia was further characterized by pseudo- or pluristratification of cells, a marked reduction in the number of goblet cells and the absence of a brush border. In areas of atypia, columnar cells often contained PAS-positive apical granules, which were diastase-resistant and unstained by alcian blue at any pH; the brush border, even where recognizable in haematoxylin-eosin and PAS-stained sections, was unreactive histochemically for alkaline phosphatase. Goblet cells were few in areas of atypia, but those present were regularly stained by PAS and alcian blue pH 2.6. Apical granules, similar in their histochemical characteristics to those observed in columnar cells in areas of atypia, were also found in otherwise normal mucosal areas, even in some patients with no overt areas of atypia in the biopsies studied. These granules have been interpreted as an abnormality, possibly preceding the onset of atypia. Hyperplasia of goblet cells, secreting mucins with the same staining pattern as in normal intestine, was found in some patients, either adjacent to areas of atypia or independent of them. Intervening columnar cells had a normal morphology, alkaline phosphatase-reactive brush borders and no sign of mucus secretion. This goblet cell hyperplasia has been interpreted as a reactive, nonspecific alteration of the mucosa.

Abstract: One hundred and ten partially-gastrectomized patients were studied in order to assess prevalence of symptoms, entero-gastric reflux, endoscopic erythematous changes and histological gastritis and to explore some aspects of the pathogenesis of gastritis syndrome. Prevalence of symptoms (37.2% of the patients) was lower than prevalence of reflux (86.9% and 72.9% of patients with fasting bile reflux or scintigraphic assessment, respectively) endoscopic hyperaemia (72.7% of patients) and remnant chronic gastritis (88.3% of patients). Histological appearance in the perianastomotic area was mostly identifiable as hyperplastic-regenerative. While histological findings, gastric pH, bacteria and nitrite concentration and patients' age were reciprocally correlated, symptoms, endoscopic changes, remnant chronic gastritis and gastric environmental changes were not more severe in patients with more abundant enterogastric reflux. Therefore, as far as the methods for reflux assessment used in the present study are concerned, postgastrectomy findings (symptoms, extent of erythematous changes, severity of remnant chronic gastritis) are not related to reflux. These results suggest that the term "alkaline reflux gastritis syndrome", at this stage of knowledge, should be used with caution.

Abstract: Endoscopy and biopsy of the upper gastrointestinal tract and terminal ileum were performed in 24 patients with familial polyposis or Gardner's syndrome in order to further define the incidence of extracolonic adenomatous polyps. Polyps, usually multiple and small in size, were detected in the gastric fundus (12.5 percent), antrum (29.1 percent), duodenum (66.6 percent), and terminal ileum (41.7 percent). Histology showed hyperplasia of the fundic glands and cystic dilatation in the polyps of gastric fundus, and adenomas in several cases of antral (three patients) or duodenal polyps (14 patients). Polyps of the terminal ileum were either adenomas (five patients) or lymphoid aggregates. Patients with stigmata of Gardner's syndrome, desmoids or mesenteric fibromatosis presented a major incidence of adenomas in the duodenum, but not in other parts of the digestive tract investigated. Subsequent checkup after an average of 33 months in ten patients revealed an increase of lesions only in the duodenum in two patients. These findings confirm that adenomatous polyps are not limited to the colon and rectum, as previously believed, but can affect the whole gastrointestinal tract. Periodic surveillance of mucosa seems to be indicated, especially for the duodenum, since degeneration of adenomas into carcinoma is possible.

Abstract: One hundred and fifteen partially-gastrectomized patients were submitted to combined gastric and esophageal pH-monitoring with the aim of studying non-acid gastroesophageal reflux (GER). Since the detection of non-acid GER seems to be linked to the possibility of detecting entero-gastric reflux, only those patients (61) in whom entero-gastric reflux could be evaluated were considered. 37.7% of the patients showed non-acid GER according to the personal definition of such a reflux (any sudden esophageal pH change of 0.5 or more with earlier or simultaneous entero-gastric reflux). On the contrary, with De Meester and coworkers' criteria, only 21.3% of the patients were considered alkaline refluxers. Slight symptoms and slight endoscopical/histological changes were present in 20-30% of both non-refluxers and refluxers (whichever method of GER evaluation was considered). Therefore, correlations between GER and symptoms, endoscopical changes and manometric findings seemed poor using either method of GER evaluation. However, since the theoretical basis of combined gastric and esophageal pH-monitoring seems correct and the application of new techniques and the development of the parameters of "normality" can hopefully increase our understanding, the routine use of gastric and esophageal pH-monitoring should not be abandoned.

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Abstract: In a series of 39 subjects previous results for serum folate levels were confirmed while intraglobular folate did not differ from those in a control group. To verify the hypothesis that SASP administration could be responsible for serum folate deficiency three different sub-groups were considered. 11 patients had never taken SASP (sub-group I), 16 patients had taken SASP in the past but the treatment had been withheld at least 2 months before (sub-group II), 12 patients were still taking the drug at the time of the study (sub-group III). Differences in serum folate levels between each one of the three sub-groups and the control group were significant. The same was not true for the differences between each one of the three sub-groups and the other. These findings seem to confirm that SASP treatment is not the major cause of serum folate deficiency, but a multifactorial pathogenesis might account for it.

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Abstract: A series of 60 patients were operated on, in our hospital, for Crohn's disease over a ten-year period. Three main groups of patients were distinguished according to the kind of intestinal involvement at surgery; those with the classical disease (involvement of the terminal ileum), those with Crohn's ileocolitis and those with Crohn's colitis. Operations, in which all the affected bowel with a free margin of at least 15 cm on each side of the lesions was resected, were considered "radical" surgical procedures. All patients who underwent surgery for the classical disease were treated radically and 54.4% of those affected with Crohn's ileocolitis underwent radical surgery. From our data early surgery seems to have an important effect upon radicality. In the follow-up study, mortality, percentage recurrence, quality of life and biochemical findings were separately assessed and evaluated for each group of subjects. Only radically operated subjects were evaluated for recurrence. The percentage recurrence was 12.9% in the classical disease group (mean postoperative follow-up time: 44.2 months), 27.3% in Crohn's ileocolitis group (mean follow-up time: 21.1 months), 0% in Crohn's colitis group (mean follow-up time: 61.5 months). Over-all operative mortality was 0%.

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Abstract: The structure of human terminal ileum mucosa was studied both after total colectomy and conventional ileostomy and after total colectomy and ileo-rectal anastomosis. Villous height, gland depth, number of mitoses, relative density of goblet cells and types of mucins secreted were microscopically evaluated in ileal biopsy specimens from 24 patients a minimum 6 months after surgery. Subtotal villous atrophy with glandular hypertrophy was demonstrated after both surgical procedures. The degree of villous atrophy and glandular hypertrophy was not dependent either on the disease for which surgery was performed, nor on the duration of the post-surgical period. Villous atrophy and glandular hypertrophy appeared greater in ileo-rectal anastomosis specimens than in those from ileostomy. Goblet cell density did not seem to be affected by total colectomy. After surgery no changes in the types of mucins secreted were shown by the histochemical techniques employed. This light microscopical study did not provide any evidence of increase ileal absorptive surface after total colectomy.

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Abstract: The present work was performed in order to examine the rectoanal reflex in healthy subject. Our findings suggest that the fecal continence is sustained by both the anal sphincters. The maximal anal pressure at rest is governed by activity of the internal sphincter while the external anal sphincter promptly contracts when the rectum is distended.

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