[Biliary fistula (postoperative, spontaneous)].
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Biliary Fistula↗
Biomedical subjects
M Mai
Publications and source records attributed to M Mai.
Analysis of chromosome 17p13 (p53 locus) alterations in gastric carcinoma cells by dual-color fluorescence in situ hybridization.
Chromosome 17 and p53 gene locus alterations were determined on 67 gastric carcinomas by dual-color fluorescence in situ hybridization, using probes for centromere 17 and the 17p13.1 (p53 locus). The results were compared with loss of heterozygosity (LOH) at 17p13.3, direct sequencing of exons 5 to 9 of p53, and nuclear overexpression of p53 protein. Deletion of p53 was found in 26 of 67 tumors (39%). All 26 also showed LOH at 17p13.3, frequently overexpressed p53 protein, and had polysomy 17. The functional loss of p53 gene in these tumors, 85% of which were of intestinal type, appears to be caused by both deletion of 17p13.1 and missense mutation of the remaining allele. There were 9 tumors that had neither deletion nor LOH but had a large proportion of cancer cells that overexpressed p53 election. Despite evidence of LOH, there was no p53 deletion in 11 tumors. Finally, 21 tumors, mostly of diffuse type, showed neither deletions, LOH, nor p53 overexpression. Our data suggest that in gastric cancer, deletion of 17p is principally responsible for the allelic loss at the p53 gene and that analysis of deletions by the dual-color fluorescence in situ hybridization is a sensitive and useful approach to clarify chromosomal aberrations.
Carcinoma↗
Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer.
Angiogenesis is essential for tumor growth and metastasis and depends on the production of angiogenic factors by host and/or tumor cells. The role of angiogenesis and angiogenic factor expression in intestinal- and diffuse-type gastric cancer are undefined. Archival specimens of 51 intestinal-type and 38 diffuse-type human gastric carcinomas were examined for tumor vessel counts, angiogenic factor expression, and the presence or absence of angiogenic factor receptors on tumor endothelium using antibodies against vascular endothelial growth factor (VEGF) and its receptors (KDR and flt-1), basic fibroblast growth factor (bFGF) and its receptors (bek and flg), and factor VIII (endothelial cells). Vessel count and VEGF and bFGF expression were higher in intestinal-type than in diffuse-type gastric cancers (P = 0.01, P < 0.001, and P < 0.001, respectively). Similarly, vessel count and VEGF expression were higher in patients with liver metastasis than in patients with peritoneal dissemination (P = 0.003 and P = 0.01, respectively). Vessel count correlated with VEGF expression and the presence of endothelial KDR in intestinal-type gastric cancer (P = 0.003 and P = 0.02, respectively) but not diffuse-type gastric cancer. Vessel count, VEGF expression, and presence of endothelial KDR increased with increasing stage of disease in intestinal-type gastric cancer but not diffuse-type gastric cancer. The expression of bFGF and its receptors did not correlate with vessel count in either cancer type. These findings suggest that the pattern of metastasis in intestinal-type gastric cancer is angiogenesis dependent. The correlation of VEGF expression and its endothelial receptor with vessel count and stage of disease suggests that VEGF is at least one of the factors responsible for the induction of angiogenesis in intestinal-type gastric cancer.
Adult↗
Expression of membrane-type matrix metalloproteinase in human gastric carcinomas.
We have examined the implications of membrane-type matrix metalloproteinase (MT-MMP) for activation of the zymogen of MMP-2 (proMMP-2) in human gastric carcinoma. Northern blot analysis demonstrated exclusive expression of MT-MMP in the carcinoma tissues. Immunohistochemically, MT-MMP was colocalized in the carcinoma cells in almost all MMP-2-positive cases (13 of 14 cases). Gelatin zymography of the culture media showed a correlation of the proMMP-2 activation with MT-MMP expression in the carcinoma cells. A microdissection study indicated that proMMP-2 activation is caused only in the carcinoma cell nests that express MT-MMP but not in the normal gastric mucosa. These results are the first demonstration of the MT-MMP-assisted activation of proMMP-2 in the human gastric carcinoma.
Carcinoma↗
Factors influencing growth rate of recurrent stomach cancers as determined by analysis of serum carcinoembryonic antigen.
BACKGROUND: Although there are many reports regarding the growth rate of human tumors, those discussing stomach cancer are rare due to the difficulty in evaluating the growth rate of stomach cancer. Stomach cancers grow with either a large central depression or through severe invasion. Metastatic sites of stomach cancer, however, grow expandingly, as with pulmonary tumors. METHODS: The reported doubling time estimate, based on the serum level of carcinoembryonic antigen (CEA), agreed with the actual tumor doubling time investigated in 112 previously untreated patients with recurrent gastric cancers. The influencing factors of the CEA doubling time were studied clinicopathologically, and a possible correlation between postoperative survival and the CEA doubling time was noted. RESULTS: The CEA doubling time ranged from 12 to 105 days, with a mean of 37.5 +/- 20.5 days (mean +/- standard deviation) and a median of 32 days. The CEA doubling time did not differ significantly between sexes or between patients of varying ages. However, the CEA doubling time was significantly shorter in patients with papillary adenocarcinoma than in those with well or moderately differentiated tubular adenocarcinoma. The CEA doubling time of patients with poorly differentiated adenocarcinoma was divided into two groups--a shorter one and a longer one. The doubling time was also significantly shorter in patients with liver metastasis than in those with lymph node metastasis or peritoneal dissemination. Furthermore, among patients who did not receive any chemotherapy, a significant correlation was observed between the CEA doubling time and postoperative survival time. Most treated patients survived longer than untreated patients. CONCLUSION: The influencing factors on growth rates in recurrent stomach cancers were histologic type and metastatic sites. This growth rate plays an important role in determining the degree of biologic malignancy and may be influenced by some chemotherapeutic regimens.
Adenocarcinoma↗
Mutant K-ras in apparently normal mucosa of colorectal cancer patients. Its potential as a biomarker of colorectal tumorigenesis.
BACKGROUND: The best way to reduce the incidence of colorectal cancer mortality would be to prevent this cancer. However, none of the biomarkers proposed can accurately identify persons at increased risk of colorectal cancer or those at low risk. As a possible genetic biomarker, K-ras mutations, which are frequently found in colorectal cancers, were analyzed in apparently normal colorectal mucosa. METHODS: Nonneoplastic mucosa and tumor tissues were collected at surgery from 70 patients with colorectal cancer: one sample each from 50 patients (group A) and multiple samples from the other 20 patients (group B). Mutant K-ras codon 12 was analyzed by the enriched polymerase chain reaction (EPCR), by which one mutant can be detected among 10(3) to 10(4) normal alleles. RESULTS: Only with the aid of EPCR was mutant K-ras detected in nonneoplastic mucosa of nine patients (18%) in Group A and five patients (25%) in Group B. This increased incidence could be attributed to the multiple tissue sampling. The presence of mutant K-ras in nonneoplastic mucosae was not consistently correlated with that in the tumors. These findings suggest that the mutant K-ras identified in nonneoplastic mucosa actually represents de novo mutations, which may be initiated by different etiologic factors and at different times. CONCLUSION: Mutant K-ras detected in apparently normal mucosa should be a useful biomarker for identifying persons at higher risk of colorectal cancer. Our study also emphasizes the need for improving the method for sample collection to achieve true representation of the colorectal mucosa.
Adenocarcinoma↗
Molecular analysis of the cytokine network involved in cachexia in colon 26 adenocarcinoma-bearing mice.
Two clones, one cachexigenic (clone 20) and the other noncachexigenic (clone 5), from a murine colon adenocarcinoma, colon 26 cells, were used to analyze the involvement of immune reactions as well as the cytokine network in cachexia. Clone 20 induced cachexia in nude and SCID mice as well as in normal BALB/c mice, suggesting that lymphocytes played little, if any, role in the process. Both clones failed to express mRNA of interleukin (IL) 1 alpha, IL-1 beta, IL-6, and tumor necrosis factor alpha in vitro with or without the coculture of NIH3T3 cells or spleen cells. However, IL-6 mRNA was selectively detected at the tumor site of clone 20 but not at that of clone 5-bearing mice. In contrast, tumor necrosis factor alpha mRNA was detected at tumor sites and in spleens of only clone 5-bearing mice, suggesting a potential role of IL-6, but not tumor necrosis factor alpha, in inducing cachexia. Anti-IL-6 antibody partially reversed the weight loss induced by clone 20, whereas the continuous infusion of IL-6 failed to cause weight loss, despite being associated with an elevation of a serum acute phase protein. These results suggest that IL-6 is necessary but not sufficient for the induction of cachexia. Both clones expressed IL-6 mRNA in the presence of IL-1 in vitro, and mice bearing either clone expressed IL-1 beta mRNA at the tumor site. Moreover, IL-1 receptor antagonist (IL-1Ra) mRNA was detected at the tumor site of clone 5-bearing mice but not at that of clone 20-bearing mice, suggesting that IL-1Ra might block IL-1 activity to reduce IL-6 production in clone 5-bearing mice. However, the transfection of clone 20 with IL-1Ra cDNA failed to abolish its capacity to produce IL-6 and to cause cachexia. Collectively, additional factor(s) besides IL-1Ra and IL-1 beta may control IL-6 and some other cachexigenic factor production, thereby causing cachexia in this model.
Adenocarcinoma↗
Preparation of specific antibodies against murine IL-1ra and the establishment of IL-1ra as an endogenous regulator of bacteria-induced fulminant hepatitis in mice.
Blocking monoclonal antibodies (mAbs) specific to mouse interleukin-1 receptor antagonist (IL-1ra) were prepared by immunizing Armenian hamsters with recombinant mouse IL-1ra. A sensitive and specific ELISA against mouse IL-1ra was also established. In Propionibacterium acnes-induced liver injury, P. acnes induced transient increase of serum tumor necrosis factor-alpha levels but not those of IL-1ra, IL-1, and IL-6. However, subsequent lipopolysaccharide (LPS) challenge induced the increase of serum levels of all these cytokines and the peak serum IL-1ra level was more than 20 times as high as serum IL-1 levels. Immunohistochemical analysis demonstrated that IL-1ra was predominantly produced by hepatocytes during the course of the priming phase by P. acnes and eliciting phase by LPS challenge. Furthermore, the administration of a mAb to mouse IL-1ra exacerbates the liver injury induced by P. acnes and sublethal dose of LPS, suggesting a protective role of endogenous IL-1ra in this liver injury model.
Animals↗
Expression of angiotensin-converting enzyme in renovascular hypertensive rat kidney.
We hypothesized that the gene expression of angiotensinogen, angiotensin-converting enzyme, and angiotensin II type 1 receptor, in addition to renin, is increased in kidneys after renal artery stenosis. Two-kidney, one clip renovascular hypertension was initiated in Sprague-Dawley rats by clipping of the left renal artery; control rats were sham operated. Blood pressure was not changed for the first 2 days after clipping but was elevated on day 4 (mean arterial pressure, 104 +/- 4 versus 87 +/- 2 mm Hg in sham-operated control rats, P < .002) and increased further during the next 24 days. Rats were killed 2, 4, 7, 14, and 28 days after clipping or sham operation, and poly(A)(+)-purified renal cortical RNA was analyzed by Northern blotting. Autoradiographs were quantitated by densitometry and normalized for the expression of a housekeeping gene. Renin expression was increased in the clipped kidney (by 149% on day 2) and decreased in the nonclipped kidney (by 82% on day 2), compared with kidneys of control rats. Expression of the angiotensin-converting enzyme was increased in clipped kidneys from the first day after clipping (158%) and throughout the experiment (66% on day 28), but was unchanged or slightly decreased in nonclipped kidneys. Angiotensinogen mRNA showed little change. Angiotensin II type 1 receptor expression was decreased in nonclipped kidneys but unchanged during the first 7 days in clipped kidneys. Our results show that components of the renin-angiotensin system other than renin are also differentially expressed in clipped kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
[New concepts on precancerous lesions of the stomach].
As for precancerous lesion of the stomach detail analysis of endoscopic follow-up cases and histopathological investigations brought some new informations on its carcinogenesis. In this paper recent several reports were introduced and discussed on new opinion of precancerous conditions such as adenoma, intestinal metaplasia, gastric ulcer, remnant stomach and H. pylori. Gastric adenoma was considered to be neoplastic because of high incidence of carcinoma in situ. The stomach coexisted with adenoma showed high percentage of new arising tumor in same stomach and therefore, we can say that these are thought to be high risk group for well differentiated adenocarcinoma. Concerning the relation between intestinal metaplasia and gastric cancer we have never obtained final conclusion. However, it is likely that incomplete type of intestinal metaplasia appeared to be coexistent with gastric cancer, especially intestinal type carcinoma, which was thought to be paracancerous lesions. Recent advance of molecular biology has indicated new knowledge on gastric carcinogenesis, suggestive of multistep pathways. According to their reports, genomic instanbility appeared frequently in gastric adenoma and intestinal metaplasia as well as gastric carcinoma. Gastric carcinogenesis for ulcer, remnant stomach and H. pylori was also discussed. In near future the mechanism of gastric carcinogenesis is expected to be solved from view point of genetic events.
Humans↗
Infrequent K-ras activation in superficial-type (flat) colorectal adenomas and adenocarcinomas.
Clinicopathological evidence is accumulating that a superficial-type (flat) colorectal tumor is a distinct neoplastic entity. To clarify the genetic characteristics of this tumor, we investigated the K-ras gene mutations and morphological features of 43 tumors of this type. A mutation of the K-ras codon 12 was detected in only 5 (16%) of 31 adenomas and 2 (17%) of 12 adenocarcinomas. The presence or absence of this mutation was not correlated with the tumor size or stage or with histopathological findings. None of these tumors had a mutation in codon 13 or exon 2, including codon 61. This low incidence of K-ras mutations (16%) suggests that superficial-type colorectal tumors are etiologically distinct from ordinary colorectal polypoid tumors and that there may be an alternative pathway of colorectal tumorigenesis.
Adenocarcinoma↗
Expression of type-IV collagenases in human tumor cell lines that can form liver colonies in chick embryos.
Chick embryo has been used as a model system for evaluating the metastatic potential of tumor cells. We have previously demonstrated that expression of the tissue inhibitor of matrix metalloproteinase-I (TIMP-I) gene can suppress liver colonization of tumor cels in chick embryo, probably by inhibiting the activity of matrix metalloproteinases (MMP) produced by tumor cells. In an attempt to identify MMP associated with liver colonization, we examined 24 human tumor cell lines for their potential to form metastatic colonies in chick-embryo liver after the cells had been inoculated into the chorioallantoic membrane (CAM) vein. We compared the results with the mRNA expression of MMP (MMP-I, MMP-2, MMP-3, MMP-9) studied previously. Three of 8 cell lines from mesenchymal tumors (fibrosarcoma HT1080, osteosarcomas SK-ES and MNNG/HOS) and 2 of 16 cell lines from epithelial tumors (gastric carcinoma KKLS and bladder carcinoma T24) proliferated in the livers. MMP-2 and MMP-9 were the enzymes whose transcripts were more frequently expressed in these 5 metastatic cell lines (MMP-1; 2/5, MMP-2; 4/5, MMP-3; 0/5, MMP-9; 3/5), but other cell lines that did not form liver colonies expressed the transcripts at lower frequency (MMP-2; 7/19, MMP-9; 3/19). Although either or both MMP-2 and MMP-9 transcripts were expressed in 4 of the 5 metastatic cell lines, they were undetectable in T24 cells. However, induced expression of both enzymes was detected by immunostaining in the T24 cells colonized in the liver. Thus, type-IV collagenases expressed by tumor cells may play a role in facilitating colonization in chick embryos.
Animals↗
Renal cell carcinoma producing alpha-fetoprotein (AFP) with a unique lectins-affinity profile.
Renal cell carcinoma (RCC) producing alpha-fetoprotein (AFP) is a rare entity and merely 7 cases have been reported so far. The present case, a 71-year-old woman, showed a high serum AFP level of 204 ng/ml. The RCC of the autopsied right kidney consisted mainly of spindle-shaped or bizarre sarcomatous tumor cells. AFP was immunolocalized only in the concomitant clear cell component. Concanavalin A (Con A)-nonadsorption rate of serum AFP was 42%, which was an intermediate value between those of yolk sac tumors and metastatic liver carcinomas. Lens culinalis agglutinin (LCA)-affinity study of the patient's AFP showed an unknown peak X, which was eluted between the known peaks 2 and 3. These results suggest a certain structural alteration in carbohydrate moieties of the AFP derived from this RCC. A review of the clinicopathologic features of 8 patients with AFP-producing RCC was made to understand the pathophysiology of AFP-producing neoplasms.
Aged↗
Superficial-type adenomas and adenocarcinomas of the colon and rectum: a comparative morphological study.
BACKGROUND/AIMS: It has been uncertain whether colorectal carcinomas preferentially arise on preexisting adenomas or de novo. However, from a morphological viewpoint, it seems unlikely that pedunculated or exophytic malignant polyps progress to the deeply ulcerated advanced carcinomas usually found clinically. METHODS: The morphological features of 26 nonpolypoid, superficial-type colorectal tumors (17 adenomas and 9 adenocarcinomas) were compared to clarify the developmental route of colorectal carcinomas. RESULTS: The adenomas and adenocarcinomas were very similar in size and gross appearance; however, examination of the surface appearances of unsectioned tumors by dissecting microscopy was helpful for distinguishing the two. Histologically, no adenomatous tissue was found in any case of superficial-type adenocarcinoma. Five of the nine adenocarcinomas, even including those of small size, invaded the submucosal layer, and two showed lymph node metastasis. CONCLUSIONS: These findings suggest that superficial-type adenocarcinomas show rapid growth and aggressive behavior. We suggest that this type of carcinoma may not progress by the adenoma-to-carcinoma pathway but that it may arise from a very small superficial-type adenoma.
Adenocarcinoma↗
[Surgical treatment and adjuvant therapy of patients with neoplasms].
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Combined Modality Therapy↗
[Neoadjuvant chemotherapy for far-advanced gastric carcinoma].
Far-advanced gastric carcinoma of the stomach remains a lethal disease, showing a particularly poor prognosis in the patients with linitis plastica type. Considering the high potential for biological malignancies, we attempted preoperative induction (neoadjuvant) chemotherapy against far-advanced cancer associated with distant metastases. Anticancer drugs used in this study were FAM or sequential MTX/5-FU. Neoadjuvant chemotherapy was carried out on 24 patients prior to surgery. The response to chemotherapy showed shrinking of massive nodal involvement in 50% (5/10) and complete disappearance of malignant ascites in 87.5% (7/8). The morphological improvement of primary gastric lesions was obtained in 9 out of 24 cases (37.5%). In 15 cases (68.2%) total gastrectomy was done with extended lymph node dissection. In one of 9 cases showing marked improvement, no viable cancer cells were seen in whole stomach associated with multiple foci of granulomatous lesions of regional nodes after 3 cycles of MTX/5-FU. Disease-free survival of neoadjuvant group showed a significant prolongation of its median survival of 14 months, compared to that of 4-6 months in the surgery alone group. Our result leads to the conclusion that the patients whose tumor was effectively destroyed by neoadjuvant chemotherapy had a good prognosis.
Adult↗
Tissue inhibitor of metalloproteinase 1 is a negative regulator of the metastatic ability of a human gastric cancer cell line, KKLS, in the chick embryo.
Tissue inhibitors of metalloproteinases (TIMPs) are the negative regulators of matrix metalloproteinases that degrade extracellular matrix. We examined the regulatory role of TIMP-1 in the metastatic activity of human gastric cancer cell lines in chick embryos because unregulated matrix metalloproteinase activities are believed to be essential during metastatic processes. One of the nine cell lines examined, KKLS cells, formed metastatic colonies in the chick livers. These cells expressed undetectable levels of TIMP-1, and this was not inducible by 12-O-tetradecanoylphorbol 13-acetate. Derivatives of KKLS cells with different levels of TIMP-1 expression were prepared by transfection of the human TIMP-1 complementary DNA controlled by a simian virus 40 early promoter. Metastatic abilities were suppressed by almost 70% in the transfectants expressing high levels of TIMP-1. In contrast, no suppression was observed in the control transfectants or in cells expressing the transfected TIMP-1 gene at low levels. These data indicate that a reduced expression of TIMP-1 in KKLS cells is responsible for their consequent metastatic potential. Moreover, it suggests that matrix metalloproteinase enzymatic activities are a prerequisite for metastatic activity in this experimental model system.
Animals↗
Vascular conversion of angiotensin I in stroke-prone spontaneously hypertensive and Wistar-Kyoto rats.
OBJECTIVE: Linkage studies have shown that the gene locus for angiotensin converting enzyme (ACE) is associated with the expression of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). We tested the hypothesis that the conversion of angiotensin I (Ang I) to angiotensin II (Ang II) in blood vessels is elevated in SHRSP. DESIGN: We measured the conversion rate of Ang I to Ang II during one pass through an isolated resistance vessel bed. We used the same substrains of SHRSP and Wistar-Kyoto control rats (WKY) that had been employed in the earlier linkage studies. METHODS: Isolated hindquarters from young and adult (10- to 12- and 36- to 38-week-old) rats were perfused with an artificial medium and then infused with Ang I at 0.5 and 2 pmol/ml. Ang I and II were measured with high-performance liquid chromatography and radioimmunoassay in hindquarter effluent and in blank control channels. Conversion and extraction rates were calculated from angiotensin levels in hindquarter and blank perfusion channels, respectively. RESULTS: The conversion rates of Ang I to Ang II did not differ between SHRSP and WKY in young or in adult rats. Captopril completely abolished the formation of Ang II in all groups of rats. During infusion at the higher dose of Ang I, the extraction of Ang I was significantly decreased in SHRSP compared with WKY. CONCLUSIONS: Our results are consistent with the notion that the metabolism of angiotensin is decreased in spontaneously hypertensive rats. However, we found no support for the hypothesis that vascular ACE is responsible for high blood pressure in SHRSP. These findings suggest that other genes close to the ACE locus or the hyperexpression of the enzyme in other areas may contribute to hypertension in these rats.
Aging↗