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PubMed2003

Circadian fluctuations of melatonin, tumor necrosis factor-alpha and its soluble receptors in the circulation of patients with advanced gastrointestinal cancer.

The objective of the study was to investigate the dynamic changes of melatonin (MLT), tumor necrosis factor alpha (TNFalpha), soluble TNFalpha receptors ( type I and type II) in serum of advanced cancer patients during 24 hours. The examined group consisted of 42 patients suffering from advanced gastrointestinal neoplasms (colorectal, gastric and pancreatic cancer). Blood samples were collected 6 times a day (8 a.m., 2 p.m., 6 p.m., 10 p.m., 2 a.m., and again 8 a.m.) as well as in healthy controls. Serum levels of TNFalpha and both its receptors were measured using ELISA type and the radioimmunoassay method was used to assess MLT levels. The circadian rhythm of MLT was altered because MLT reached its peak level at 8.50 a.m. with 5 hours delay in respect to average peak time in healthy humans. The presence of circadian rhythm of TNFalpha was proved (acrophase-1.40 a.m.), and no diurnal rhythm of soluble TNF receptors was observed. The concentration of soluble type I (p-55) receptor was distinctly lower than soluble type II (p-75). The peak of soluble type I receptor value appeared at 10.00 p.m. while the type II receptor reached its minimum level at the same time. Although there was no statistical correlation between the receptor concentrations, the shapes of both curves remained inversely proportional. The present results may suggest the presence of complex self-regulation mechanisms between the neuroendocrine system and the cytokine network in advanced gastrointestinal cancer patients.

Adult↗
PubMed1990

Gastrointestinal laser endoscopy--future horizons.

The laser, especially the neodymium:yttrium-aluminum-garnet device, has been a dominant influence on the development of gastrointestinal therapeutic endoscopy. More than 2,000 such procedures were performed in the first 5 years of experience with laser endoscopy at the Mayo Clinic. The major areas for future development are (1) the control of acute and chronic gastrointestinal bleeding, (2) the palliation of malignant gastrointestinal neoplasms, and (3) the management of benign and malignant obstructive lesions of the biliary tract. Refinements in laser devices, delivery systems, and techniques such as photodynamic therapy will be needed to achieve more selective tissue destruction. Improvements in the new adjunctive endoscopic methods of electronic (video) endoscopy and ultrasonography may enhance evolving laser applications by more accurately identifying diseased tissues and guiding their destruction.

Endoscopy↗
PubMed2005

Guanylyl cyclase C is a marker of intestinal metaplasia, dysplasia, and adenocarcinoma of the gastrointestinal tract.

Gastrointestinal (GI) tumors continue to be major causes of cancer-related mortality, in part, reflecting metastases that escape detection by histopathology. Moreover, although approximately 10% of carcinomas arise from unknown locations, these tumors frequently originate in the GI tract. Guanylyl cyclase C (GC-C) is a receptor selectively expressed by intestinal epithelial cells whose persistent expression by colorectal carcinomas and ectopic expression by adenocarcinomas of the upper GI tract suggest its use as a marker for GI malignancies. Here, expression of GC-C protein, identified by immunohistochemistry, was examined in tissues and tumors arising from the human GI tract. Guanylyl cyclase C protein was expressed by epithelial cells from the duodenum to the rectum, but not by those in normal esophagus and stomach. Expression was retained in tubular adenomas, inflammatory bowel disease, premalignant lesions, and in primary and metastatic adenocarcinomas from the colon, including metastases to lymph nodes and liver. Moreover, GC-C was ectopically expressed in all cases of dysplasia and adenocarcinomas arising from intestinal metaplasia in esophagus and stomach. Thus, GC-C appears to be an immunohistochemical marker for identifying adenocarcinomas of unknown origin, metastases in patients undergoing staging for GI adenocarcinomas, and intestinal metaplasia, dysplasia, and tumors arising therein in the upper GI tract.

Adenocarcinoma↗
PubMed2005

Morphological imaging in the localization of neuroendocrine gastroenteropancreatic tumors found by somatostatin receptor scintigraphy.

PURPOSE: To evaluate the necessity of morphological images (MI) in reading somatostatin receptor scintigraphy (SRS) in patients with suspected neuroendocrine gastroenteropancreatic (GEP) tumors. MATERIAL AND METHODS: A Japanese multicenter clinical trial of SRS was conducted in 40 patients with suspected GEP tumors. Three experienced radiologists interpreted the images in three separate sessions in a blinded manner (1: SRS images alone, 2: MI alone, 3: SRS and MI analyzed simultaneously), and the reading results of each session were compared. In addition, the diagnostic abilities of SRS, MI and SRS alone and simultaneous SRS and MI readings were compared for patients where final diagnosis was obtained. RESULTS: SRS detected more suspected lesions (positive or inconclusive uptake) than morphological images did (51 vs 27 lesions), but included many physiological uptakes detected as positive or inconclusive uptakes. Combined reading of SRS and morphological images helped to correctly recognize these physiological uptakes, and also helped in determining the anatomical localization of the abnormal uptakes. Combined reading of SRS and morphological images gave the highest diagnostic impact. CONCLUSION: The sensitivity of SRS with regard to GEP is high. However the specificity is very low. Morphologic imaging is necessary for the exclusion of physiological uptake and correct anatomic location of an abnormal tracer uptake. The combined reading of SRS and morphologic imaging studies gives the highest diagnostic impact.

Adenocarcinoma↗
PubMed1989

Non-surgical management of liver metastases.

The liver represents the most common site of visceral metastasis for primary gastrointestinal neoplasms, but it is also a common site of metastasis for extra-abdominal tumours including breast cancer, lung cancer as well as other cancers. Metastatic liver disease is often the cause of death for cancer patients. Metastatic liver disease is a heterogenous entity depending upon histologic type, site of primary tumour and other extrahepatic involvement. Surgical resection is feasible only in highly selected patients with no extrahepatic metastasis. The nonsurgical modalities of management of liver metastases include radiotherapy, chemotherapy, biologicals or a combination of these modalities. Hepatic irradiation can produce satisfactory palliation but has dose limiting toxicity of radiation hepatitis. The systemic chemotherapy of liver metastases has evolved over the past decades from single agent systemic treatment to regional infusion chemotherapy. The drugs employed in treatment depend on the site of primary tumour. 5-fluorouracil remains the mainstay of chemotherapy in most gastrointestinal cancers. Recent technological advances in drug delivery system and genetic engineering have given new vistas to nonsurgical management of liver metastases. Ambulatory or implantable pumps have enabled drugs to be delivered by continuous infusion via an implantable vascular access system. Monoclonal antibodies conjugated to toxins or radioisotopes offer exciting prospects for targeted therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

[Gastrointesinal stromal tumors--clinical and morphological aspects].

Gastrointestinal Stromal Tumors (GISTs) are uncommon mesenchimal tumors that usually arise in the wall of the gastrointestinal tract. Although heterogenous in morphology, GISTs represent a group of tumors probably originating from the intestinal pacemaker cell, interstitial cell of Cajal. The tumour cell phenotype can be established only when histomorphology is coupled with immunostaining. They account for approximately 0.1% to 3% of all gastrointestinal neoplasms. GISTs arise anywhere along the GI tract, from the oesophagus to the rectum. Most tumors (70%) occur in the stomach and about 20-30% occur in the small intestine. A small percentage of GISTs arise elsewhere in the GI tract, omentum, or retroperitoneum. We describe four GISTs arising in stomach, small intestine, omentum and colon with their clinical and morphological presentation.

Aged↗
PubMed1998

Gastrin and the enterochromaffin-like cell: an acid update.

Gastrin is synthesized and secreted mostly in a heptadecapeptide form from neurocrine G cells located in the antrum. The biologically active sequence of the molecule is a C-terminal pentapeptide, which has been conserved across many species. Transcriptional regulation of gastrin mRNA synthesis is positively regulated by transforming growth factor-alpha (TGF-alpha) and inhibited by somatostatin (SST). The inactive precursor form is converted to the active molecule by several post-translation processing steps which include cleavage, C-terminal amidation, glycosylation, phosphorylation and sulfation. Aberrations in processing steps generate incompletely processed forms, particularly glycosylated progastrin, which may act as autocrine growth factors for gastrointestinal neoplasms. Gastrin release is stimulated by luminal aromatic amino acids and inhibited by a decrease in luminal pH. Other gastrin agonists include beta-adrenergic agents, acetylcholine, gastrin-releasing peptide (bombesin), TGF-alpha, and possibly the gastric pathogen, Helicobacter pylori. The principal peptide inhibitor of gastrin release is SST. The major physiological roles of gastrin include stimulation of acid secretion, regulation of mucosal cell lineage and mucosal cell proliferation. The fundic enterochromaffin-like (ECL) cell is the principal cellular transducer of the gastrin-acid signal. Activation of its gastrin/CCKB receptor results in histamine synthesis and release with consequent activation of the fundic parietal cell H2 receptor. An increase in luminal pH caused by acid inhibitory pharmacotherapy agents (particularly proton pump inhibitors) results in hypergastrinemia and ECL cell hyperplasia. Gastric carcinoids however appear occur in patients with multiple endocrine neoplasia type I syndrome, suggesting that an associated genomic defect is necessary. Gastrin is thus both a potent gastrointestinal trophic and histamine secretory agent. As a hormone it is a paradigm in the elucidation of both cellular secretory and growth factor induced cell proliferation.

Enterochromaffin-like Cells↗
PubMed1977

Gastric cancer: current status of treatment.

While carcinomas of the stomach is decreasing in incidence in the Dnited States, it is still a major cause of cancer death. But gastric neoplasms are not decreasing in some other geographic areas. According to some studies, 30% of all cancer in the U.S.S.R. originates in the stomach. The rate of gastric neoplasms is greatest in Japan, and over 54% of all cancer in the male population arises in the stomach. The peak age for development of stomach cancer is between 70 and 80 years; over 60% of all stomach cancer is diagnosed in patients between the ages of 60 and 70, while more than 10% is found in those over 80. The main hope for cure at this time rests with surgical treatment. However, despite increased use of surgery, the 5-year survival rate of approximately 13% for patients diagnosed during 1955-59 has not improved to any degree since that time. The major drugs commonly used to treat gastric cancer are 5-fluorouracil (5-FU) and mitomycin C. Controversy still exists concerning the optimum method for administering 5-FU, the most frequently used drug in the United States. The standard loading-course method was attended by a high risk of severe toxicity and drug-related deaths. Several variations of the loading course have evolved. Currently, the Mayo Clinic group uses a 5-day course of 13.5 mg 5-FU/kg repeated every 5 weeks, with therapy interrupted if stomatitis or diarrhea develops; with this regimen the drug-related mortality rate was reported to be less than 1%. Studies have shown that 5-FU plus radiotherapy can enhance survival in patients with locally unresectable diseases. The overall objective with 5-FU is 20-25% with an average of 4-5 months' duration of response. Despite the many patients treated with 5-FU, rarely has a systematic analysis been done of factors such as age, sex, disease-free interval, histologic grade of the tumor, or sites or metastases, which might predispose to a favourable or unfavorable response. In Japan the most commonly used drug for treatment of gastric cancer is mitomycin C, the second most frequently used drug in the United States. The overall objective response rate with mitomycin C is between 20 and 30%, with the higher response rates being reported in the Japanese data. The average duration of response ranges from 1 to 3 months. The nitrosoureas [1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1,3-cis(2-chloroethyl)-1-nitrosourea (CCNU), and methyl CCNU (MeCCNU)] have shown some evidence of activity against gastric cancer. BCNU has yielded an objective response rate of 18% (6/33) and an average duration of response of 4.5 months in gastric cancer patients, most of whom had no prior therapy. Adriamycin recently has been shown to have some antitumor activity, with an approximate response rate of 25%. Combination approaches have been more successful in stomach cancer than in any other gastrointestinal neoplasm. The Japanese have reported higher response rates with a combination of 5-FU, mitomycin C, and cytosine arabinoside...

Adenocarcinoma↗
PubMed1978

Villous tumors of the stomach and small bowel.

Villous tumors of the stomach and small bowel are premalignant lesions with focal adenocarcinomatous change as high as 72%. They are frequently multiple and associated with other gastrointestinal neoplasms. Thirty percent of those in the stomach are associated with an independent gastric carcinoma. Villous tumors have morphological features that facilitate specific roentgenographic diagnosis. Endoscopic biopsy may confirm the diagnosis but may give false-negative results for malignant neoplasms and therefore should not delay treatment. After diagnosis, surgical resection is mandatory and subsequent radiological-endoscopic follow-up is essential.

Adenocarcinoma↗
PubMed1996

The detection of disseminated tumor cells in bone marrow from colorectal-cancer patients by a cytokeratin-20-specific nested reverse-transcriptase-polymerase-chain reaction is related to the stage of disease.

The dissemination of cancer cells is a prerequisite in the development of micrometastases and solid metastases. Our previous examinations of these cells were based on immunocytological staining of tumor-associated antigens and cytokeratins. We have now developed a highly sensitive and specific detection method based on a nested reverse-transcriptase-polymerase-chain reaction (RT-PCR) of cytokeratin-20 (CK-20) mRNA. Using this method, we examined the bone marrow of 57 patients with colorectal cancer and detected increasing numbers of CK-20-positive samples, depending on the UICC stage. Some 35% of all bone-marrow samples tested positive for CK-20: none were found in colorectal cancer stage 1, 24% were in stage II, 31% in stage III and 71% in stage IV. Investigation of bone-marrow specimens of patients with pancreatic cancer showed that 4 out of 11 patients were positive for CK-20 mRNA. To confirm that sample positivity for CK-20 expression was due to disseminated tumor cells, we examined bone marrow from a control group (n = 16) without apparent carcinoma. In this group, 15 out of 16 donors were CK-20-negative, while one donor with familial adenomatous polyposis showed a CK-20-specific signal.

Base Sequence↗
PubMed1997

Use of multiple primary cancers to indicate associations between smoking and cancer incidence: an analysis of 500,000 cancer cases diagnosed in Norway during 1953-93.

The occurrence of multiple primary cancers is relatively rare, but may provide indications of common or opposite risk factors for different types of cancer. In the present study, the occurrence of multiple primary cancers was used to indicate possible associations between smoking and the incidence of cancers other than those generally accepted as smoking-associated. All cancer cases in persons above the age of 30, registered at the population-based Cancer Registry of Norway (1953-1993), were used in the analysis. For each type of cancer, the observed occurrence of smoking-associated cancers in the patients was compared with the expected occurrence if the patients had the same risk as the general population. Similar comparisons were made for the occurrence of other cancers in patients with a smoking-associated cancer. The results were presented as standardized incidence ratio (SIR), the ratio of the observed and the expected numbers of cases. The results indicated that uterine cervical cancer may share some important risk factor(s) with the cancers generally accepted as smoking-associated. This is in accordance with the literature, where an association between smoking and uterine cervical cancer has been found consistently. In addition, the results for liver cancer and leukemia indicated that these types of cancer also share some risk factor(s) with the smoking-associated cancers.

Adult↗
PubMed1997

Somatostatin receptor subtypes sst1, sst2, sst3 and sst5 expression in human pituitary, gastroentero-pancreatic and mammary tumors: comparison of mRNA analysis with receptor autoradiography.

Using in situ hybridization techniques with selective oligoprobes, the gene expression of sst1, sst2, sst3 and sst5 was studied in a series of 32 human pituitary adenomas, 28 breast tumors and 21 endocrine gastroentero-pancreatic tumors, shown to express somatostatin receptors to variable extents. In most of these tumors the sst2 receptor subtype was abundantly expressed, even though a significant number of pituitary adenomas, breast and gastroentero-pancreatic tumors expressed sst1 and/or sst3 as well. A very high incidence of the sst5 subtype was found in growth hormone-producing pituitary adenomas and, to a lesser extent, in inactive pituitary adenomas, whereas breast tumors seldom expressed sst5; gastroentero-pancreatic tumors showed all possible combinations of sst expression, with, however, a predominance of sst2 and sst1. Overall, the presence of sst2 mRNA and/or sst5 mRNA generally correlated with the presence of octreotide binding sites. A lack of octreotide binding sites corresponded with a lack of sst2 mRNA. Several tumors exhibiting a low number of octreotide binding sites had no measurable sst2 mRNA, despite abundance of beta-actin mRNA, suggesting in these cases a very low abundance of sst mRNAs or a too low sensitivity of the in situ hybridization methodology. In all other cases, the method allowed precise localization of the respective mRNAs on the tumor tissue, notably in breast tumors with non-homogeneous receptor distribution. Tumors without measurable amounts of somatostatin receptors had no detectable sst mRNA. Our results indicate a highly variable abundance of the various sst mRNAs in individual somatostatin receptor-containing tumors.

Autoradiography↗
PubMed1997

Case-control study of cancer risk in tetraethyl lead manufacturing.

A case-control study was conducted to investigate the relative risk of cancer detection among Du Pont employees who worked in a tetraethyl lead (TEL) manufacturing area. The study's objective was to determine whether the employees' risk of developing or dying from cancer was associated with occupational exposure to TEL. All malignant neoplasms detected in the active and pensioned employee population during the period 1956-1987 were studied. TEL exposure was estimated by the following measures: ever employed in the TEL area, years of employment in TEL, TEL exposure rank, and the TEL cumulative exposure index. TEL manufacturing exposed employees to both organic and inorganic lead compounds. Because the underlying data did not permit the exposure assessment to distinguish between organic and inorganic lead, the TEL exposure measures reflect exposure to the TEL manufacturing process itself. The effects of latency, cigarette smoking habits, and exposures to other known or suspected carcinogens at the plant were also assessed. A strong association was observed between exposure to the TEL manufacturing process and rectal cancer (the odds ratio was 3.7 with 90% confidence limits of 1.3-10.2 for the analysis of ever/never exposed to TEL). An exposure-response relationship was noted with a fourfold elevation in the odds ratio at the high-very high cumulative exposure level. These patterns were even more pronounced after assuming a 10 year latency. Similar results were obtained for cancers of the sigmoid colon. These findings suggest that exposure to the TEL manufacturing process may have played a causal role in the colorectal cancer experience at the plant. This position is supported by the graded exposure-response relationships, the consistency of the results across exposure measures, the specificity of the health outcome (i.e., colorectal cancer), and the strength of the association. However, the evidence for causality is not compelling. This is the first report of an association between TEL manufacturing and colorectal cancer, and the evidence is compatible with a wide range of causal (i.e., indirect vs. direct acting; initiating vs. promoting) and noncausal (i.e., statistical and methodological bias; coincidence) interpretations.

Aged↗
PubMed2000

Metallothionein in human gastrointestinal cancer.

Metallothionein (MT) is a small thiol-rich metalloprotein with antioxidant properties, involved in tumour pathophysiology and therapy resistance. In order to assess the contribution of MT in gastrointestinal carcinogenesis, this study examined both the MT content by radioimmunoassay and the MT localization by immunohistochemistry in pairs of neoplastic and normal-appearing human gastrointestinal tissues. In addition, the relationship between MT expression and major clinicopathological parameters was assessed. The MT concentration of gastric carcinomas and of colorectal adenomas, carcinomas, and liver metastases was found to be significantly lower than that of corresponding normal-appearing tissue. A relatively high MT content, however, was found to be associated with the villous character of colorectal adenomas and with the Dukes' stage of colorectal carcinomas, indicating a relationship between MT level and malignant potential. Immunohistochemical evaluation showed a fairly good correlation with these quantitative data. MT was found to be expressed at a low level and in a patchy pattern in the gastrointestinal neoplastic and metastatic tissues, whereas in normal-appearing gastrointestinal mucosa MT was uniformly distributed in the cytoplasm and/or nucleus of apical cells. Although in the gastric cancer patients no association was found between the MT concentration and the clinicopathological parameters, the strong MT expression in areas with intestinal metaplasia, known to have neoplastic potential, further points to a relationship between this antioxidant metalloprotein and the malignant character of cells. Gastrointestinal neoplasms are apparently accompanied by a low level and decreased expression of MT, but those with a relatively high level seem to have an increased malignant potential. Further studies will be required to determine the clinical relevance of these observations.

Adenocarcinoma↗
PubMed1978

Radiographic evaluation of metastatic melanoma.

Malignant melanoma can potentially involve any organ system in the body once it metastasizes beyond the regional lymph nodes. A survey of the radiographic and associated clinical manifestations of metastatic melanoma is presented. The findings from 74 autopsies of patients who died of metastatic melanoma are included.

Adult↗
PubMed1979

5 FU infusion with mitomycin-C vs. 5 FU infusion with methyl-CCNU in the treatment of advanced upper gastrointestinal cancer: a Southwest Oncology Group Study.

A randomized trial was conducted by the Southwest Oncology Group (SWOG) in advanced carcinoma of the stomach and pancreas. Patients were assigned to receive monthly 5-fluorouracil 96-hour continuous infusions with either bolus mitomycin-C or oral methyl-CCNU. Mitomycin-C and methyl-CCNU were administered every eight weeks. The 5 FU-mitomycin combination produced a 14% and 22% response rate in disseminated stomach and pancreatic carcinoma, respectively. The combination of infusion 5 FU and methyl-CCNU achieved responses in 9% and 5% of stomach and pancreatic tumors, respectively. There was no significant difference in survival between limbs for either tumor. Median survival in gastric carcinoma on the 5 FU-mitomycin regimen was 25 weeks vs. 18 weeks on the 5 FU-METHYL-CCNU arm. In pancreatic carcinoma median survival on the mitomycin limb was 19 weeks as compared to 17 weeks on the methyl-CCNU program. Leukopenia was greater for the first course on the mitomycin limb. Regression analysis demonstrated that performance status was the most important pretreatment characteristic for predicting survival in both tumors. Neither 5 FU infusion combination appears to significantly alter the dismal prognosis of advanced upper gastrointestinal neoplasms.

Antineoplastic Agents↗