[Precancerous lesions and early cancers of the digestive tract].
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Digestive System Neoplasms↗
Biomedical subjects
J F Flejou
Publications and source records attributed to J F Flejou.
Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X-chromosome inactivation.
Focal nodular hyperplasia (FNH) of the liver is a benign tumor commonly considered as a reactive disorder related to a pre-existing vascular malformation. However, the pathogenesis of this lesion has been recently discussed. To determine whether FNH is a polyclonal or a clonal lesion, we investigated the inactivation pattern of the X chromosome, using molecular genetic analysis of the DNA methylation pattern at a polymorphic site on the human androgen receptor gene (HUMARA). Fifteen FNH were studied, and results were compared with those obtained from 7 hepatic adenomas (HA) and 2 hepatocellular carcinomas (HCC). DNA was extracted from both lesional and nonlesional livers, fixed, and paraffin-embedded. To assess the methylation pattern, we used a quantitative fluorescent polymerase chain reaction (PCR) procedure that allows for the accurate measurement of the peak intensities of each allele. Three patients were noninformative because they were homozygous at the HUMARA locus. According to the threshold for monoclonality established by a titration curve, all FNH showed a random pattern of X-chromosome inactivation consistent with a polyclonal lesion. In contrast, all but 1 hepatic adenoma and all hepatocellular carcinomas were clonal, as shown by the nonrandom pattern of X-chromosome inactivation observed in these cases. In conclusion, these results suggest that FNH should be considered as a reactive disorder rather than as a tumoral proliferation. Discordant results recently observed in the literature could be at least in part explained by methodological differences in the PCR procedure.
Adenoma↗
[Results of the surgical treatment of cancer of the cardia].
OBJECTIVES: In the curative treatment of the adenocarcinoma of the cardia (AC), the extent of the esogastrectomy and the need for lymph node dissection are still debated. The palliative treatment of AC is now currently non-surgical. The aim of this study was (a): to assess early results of palliative surgery; and (b) to evaluate the results of curative resection with reference to the influence of the extent of gastrectomy and lymph node dissection on early results and long-term survival. Methods. From 1979 to 1989, 179 patients (mean age = 60 +/- 12 years) with AC had 45 palliative resections (mean age = 56 +/- 15) and 134 curative resections (mean age = 61 +/- 12). Thirty-eight proximal subtotal esogastrectomy (PSOG) and 7 total esogastrectomy (TOG) were palliative; 72 PSOG and 62 TOG extended to the spleen were curative and associated with lymphadenectomy. RESULTS: The operative mortality rate was 8.9% regardless of the palliative or curative intent of resection. After palliative resection, the mortality rate was 2.6% (1/38) after PSOG and 42.9% (3/7) after OGT = (p = 0.01); the median survival was 8 months. After curative resection, the mortality rate was 12.5% (9/72) after PSOG and 4.8% (3/62) after extended TOG (p = 0.2); actuarial 5-year survival rate was 42% after PSOG and 39% after extended TOG. CONCLUSIONS: These results suggests that: (a) palliative PSOG for AC can be performed with a low mortality; and (b) resection with extensive lymphadenectomy allows substantial survival regardless of the extent of gastrectomy.
Actuarial Analysis↗
Fibrolamellar carcinoma of the liver: composition of the extracellular matrix and expression of cell-matrix and cell-cell adhesion molecules.
We have analyzed the composition of the tumor stroma and the expression of cell-matrix and cell-cell adhesion molecules in 11 cases of fibrolamellar carcinoma of the liver (FLC), in comparison with 34 cases of hepatocellular carcinoma and 8 cases of focal nodular hyperplasia. Fibrolamellar carcinoma was characterized by the presence of large amounts of tenascin in tumor stroma and by the scarce expression of basement membrane components at the contact of neoplastic clusters. Like normal hepatocytes, neoplastic cells constantly expressed the alpha1 integrin chain, lacked the beta4 integrin chain, and coexpressed E-cadherin and the hepatocyte N-related cadherin. Abnormalities in the expression of cell adhesion molecules, including altered cadherin expression, alphaV integrin chain induction, and CD44 expression, were detected in the majority of cases. The composition of the tumor stroma and the pattern of expression of cell adhesion molecules in fibrolamellar carcinoma were reminiscent of those observed in grade III and grade IV hepatocellular carcinomas. Our results therefore show that, despite its slow local growth and good prognosis, fibrolamellar carcinoma expresses many characteristics usually associated with clinically aggressive malignancies. Further studies are needed to identify the factors responsible for the apparent dissociation between clinical behavior and biological characteristics in this tumor.
Adult↗
Expression of cadherins and alpha-catenin in primary epithelial tumors of the liver.
BACKGROUND & AIMS: Cadherins and their associated molecules, such as alpha-catenin, have been shown recently to play a pivotal role in epithelial carcinogenesis. METHODS: The expression of E-cadherin, N-cadherin, and alpha-catenin in 10 normal samples, 28 focal nodular hyperplasias, 9 liver cell adenomas, 65 hepatocellular carcinomas, and 9 cholangiocarcinomas was studied by immunohistochemistry and Western blotting. RESULTS: In the normal liver, hepatocytes expressed E-cadherin and a 129-kilodalton cadherin identified by the anti-N-cadherin antibody GC4. The expression level of alpha-catenin was low. Bile duct cells expressed only E-cadherin and showed high levels of alpha-catenin. The expression of cadherins and alpha-catenin was preserved in focal nodular hyperplasia. In liver cell adenomas, cadherins and alpha-catenin were heterogeneously expressed. In hepatocellular carcinomas, cadherin and alpha-catenin expression was frequently reduced or absent. Alterations in cadherin expression correlated with large tumor size, low grade of histological differentiation, and occurrence of capsular and vascular invasion. In cholangiocarcinomas, neoplastic cells inconstantly expressed E-cadherin and alpha-catenin. CONCLUSIONS: Alterations of cadherin and alpha-catenin expression are frequent in liver cell adenomas and primary liver carcinomas. Their incidence in hepatocellular carcinomas is of prognostic significance.
Adenoma, Liver Cell↗
PML nuclear bodies are general targets for inflammation and cell proliferation.
Acute promyelocytic leukemia is associated with a t(15;17) translocation that generates a fusion product between PML and the retinoic acid receptor alpha. Recently, PML was shown to concentrate within subnuclear domains, referred to as nuclear bodies, that are disorganized in acute promyelocytic leukemia cells. This observation provided the first evidence that alteration of a nuclear structure may play a role in human pathogenesis. In an attempt to clarify the role of PML and, more generally, of the associated nuclear bodies, we used immunohistochemistry to explore the expression of PML in normal, inflammatory, and neoplastic human tissues. With the exception of endothelial cells and macrophages that contain a high amount of PML protein, a weak speckled labeling pattern was observed in the nucleus of all cell types analyzed. By contrast to normal tissues, the level of PML expression was considerably enhanced in inflammatory tissues, predominantly around the mononuclear cell infiltrate, as well as during either normal or pathological proliferative states, in particular in tumoral pathology. Surprisingly, in most hepatocellular carcinoma, a cytoplasmic delocalization of PML was observed. Finally, the number of PML nuclear bodies increased up to twice their normal value as quiescent cultured cells were stimulated to grow upon serum addition. Altogether these results strongly suggest that the PML-associated nuclear bodies are implicated both in the inflammatory process and in cell growth control.
Adenocarcinoma↗
Preoperative cyst fluid analysis is useful for the differential diagnosis of cystic lesions of the pancreas.
BACKGROUND/AIMS: It has been suggested that activity of pancreatic enzymes and concentrations of tumoral markers in cyst fluid may help to distinguish pseudocyst, serous, and mucinous cystadenomas. The aim of this study was to prospectively assess the reliability of preoperative biochemical and tumor marker analysis in cyst fluids obtained by fine-needle aspiration for pathological diagnosis. METHODS: Cyst fluid was obtained preoperatively by fine-needle aspiration, and biochemical and tumoral marker values were measured. The diagnosis of cystic tumors (7 serous cystadenomas and 12 mucinous tumors) was established by surgical specimen analysis. Thirty-one pancreatic pseudocysts complicating well-documented chronic pancreatitis were also studied. RESULTS: Carbohydrate antigen 19.9 levels of > 50,000 U/mL had a 75% sensitivity and a 90% specificity for distinguishing mucinous tumors from other cystic lesions. Carcinoembryonic antigen levels of < 5 ng/mL had a 100% sensitivity and an 86% specificity for distinguishing serous cystadenomas from other cystic lesions. Amylase levels of > 5000 U/mL had a 94% sensitivity and a 74% specificity for distinguishing pseudocysts from other cystic lesions. CONCLUSIONS: High carbohydrate antigen 19.9, low carcinoembryonic antigen, and high amylase levels in cyst fluid are very indicative of mucinous tumors, serous cystadenomas, and pseudocysts, respectively.
Amylases↗
Absence of human papillomavirus DNA detected by polymerase chain reaction in French patients with esophageal carcinoma.
BACKGROUND & AIMS: Recent studies have suggested that esophageal human papillomavirus infection could be a risk factor for esophageal squamous cell carcinoma. The aim of this study was to evaluate the prevalence of human papillomavirus DNA sequences in the esophagus of French patients with esophageal squamous cell carcinoma. METHODS: Multiplex polymerase chain reactions with consensus primers directed to the L1 gene or specific primers for human papillomavirus types 6, 11, 16, 18, 31, and 33 directed to E6 gene (40 cycles followed by restriction mapping of the amplified products) were used to determine the presence of human papillomavirus DNA sequences in esophageal squamous cell carcinoma (n = 75), normal adjacent mucosa (n = 49), and metastatic lymphadenopathies (n = 5). As an internal control, a target located in the embryonic myosin heavy-chain gene was used in each reaction. RESULTS: Human papillomavirus DNA sequences could not be detected in any of the tumoral samples, the normal adjacent mucosa, or the metastatic lymphadenopathies. CONCLUSIONS: Human papillomavirus seems not to be implicated in esophageal carcinogenesis, at least in French patients, because the viral genomes are not associated with esophageal squamous cell carcinomas.
Adult↗
Focal nodular hyperplasia of the liver: composition of the extracellular matrix and expression of cell-cell and cell-matrix adhesion molecules.
We studied by immunohistochemistry 25 cases of focal nodular hyperplasia (FNH) to evaluate the composition of the extracellular matrix and the expression and distribution of endothelial cell-cell adhesion molecules and integrin receptors. The extracellular matrix of FNH retained the overall organization of that of normal liver. The matrix of central scars resembled that of portal tracts. The main difference was the presence of large vitronectin deposits, which might indicate the existence of local hemodynamic disturbances. The matrix lining the sinusoid-like vessels running in the hyperplastic parenchyma retained characteristic features of the normal perisinusoidal matrix, such as the presence of tenascin. In the zone surrounding the central scars, it contained large amounts of laminin, von Willebrand factor, and thrombospondin, suggesting the development of perisinusoidal fibrosis. Laminin deposition was accompanied by the induction of cell-cell adhesion molecules on adjacent endothelial cells and by the up-regulation of specific integrin receptors on both hepatocytes and sinusoidal endothelial cells. In conclusion, our study: (1) reinforces the hypothesis that FNH is merely a hyperplastic response of liver parenchyma to local vascular abnormalities, and (2) shows that the lesions of perisinusoidal fibrosis associated with FNH are accompanied by the induction of integrin receptors on hepatocytes and sinusoidal endothelial cells.
Adult↗
Structure and expression of the cyclin A gene in human primary liver cancer. Correlation with flow cytometric parameters.
BACKGROUND/AIMS: The cyclin A gene plays an important role in both the S and G2-M phases of the cell cycle, and has been identified at a site of hepatitis B virus DNA integration in a human liver cancer. We analyzed tumorous and non-tumorous samples from patients with primary liver cancer to determine whether a) the cyclin A gene is rearranged in liver tumors and b) the cyclin A transcript level correlates with the percentage of proliferating cells. METHODS: Samples from 43 patients were analyzed by Southern blot. Cyclin A RNA accumulation was evaluated in 18 cases by slot blot and correlated with the percentage of cells in S plus G2-M phases defined by flow cytometry. RESULTS: No rearrangement of the cyclin A gene was found in tumorous compared to non-tumorous tissue. A very strong positive correlation was found between the cyclin A RNA level and the cumulative percentage of cells in S plus G2-M phases (r = 0.99; p < 0.0001). CONCLUSIONS: This in vivo study shows that the expression of cyclin A RNA correlates with the percentage of proliferating cells in primary liver cancer. Thus, cyclin A is a new potential liver tumor cell proliferation index.
Blotting, Southern↗
[Diagnosis of cystadenomas and cystadenocarcinomas of the pancreas. Study of 35 cases].
OBJECTIVES: The aims of this study were to assess the circumstances of diagnosis and accuracy of imaging procedures in patients with cystic pancreatic tumours. METHODS: Thirty-five consecutive patients with cystic pancreatic tumours (serous cystadenomas: n = 19, mucinous cystadenomas: n = 9, cystadenocarcinomas: n = 7) were studied from 1988 to 1993. Respective diagnostic values of ultrasonography, endoscopic ultrasonography, CT scan and analysis of cyst fluid were evaluated. RESULTS: The circumstances of diagnosis were abdominal pain (74%), weight loss (23%), jaundice (8%), abdominal mass (6%), asymptomatic (6%). Initial diagnosis of cystadenoma was correctly made by ultrasonography, CT scan and endoscopic ultrasonography in 63%, 77% and 84%, and the type of cystadenoma was correctly diagnosed in 20%, 51% and 55%. A pseudocyst was falsely diagnosed in 28%, 12% and 3%, respectively. After blind review of CT scans and endoscopic ultrasonography records, the type of cystadenoma was correctly diagnosed in 82% by both procedures. Cytological examination of cyst fluid of 18 cystic tumours gave correct diagnosis in 10 cases with sufficient material. A low CEA (P < 0.002), Ca 19.9 (P < 0.003) and absence of mucins (P < 0.002) in cyst fluid was evocative of serous cystadenoma. CONCLUSIONS: Abdominal pain was the main circumstance of diagnosis in cases of pancreatic cystadenomas. The type of cystadenoma was correctly diagnosed in 82% by CT scan and endoscopic ultrasonography. Cytological examination, tumoural marker and mucin levels in cyst fluid were helpful for an accurate diagnosis of cystic tumours.
Adult↗
[Variety of pancreatic lesions observed in von Hippel-Lindau disease. Apropos of 8 cases].
Von Hippel-Lindau's disease is a rare genetic disease, with an autosomal dominant mode of inheritance, characterised by the development of several tumours, such as haemangioblastoma of the central nervous system and retina, renal cysts or carcinoma and pheochromocytoma. Several pancreatic lesions, mainly represented by multiple cysts, are also encountered. We report here 8 cases of pancreatic involvement in patients affected with von Hippel-Lindau's disease. It consisted of multiple cysts (3 cases), serous cystadenoma (2 cases), endocrine tumour (1 case), haemangioblastoma (1 case) and ductal adenocarcinoma (1 case). Diagnosis of a rare lesion of the pancreas (multiple cysts, serous cystadenoma or vascularized tumour) in a young patient may lead to search the other lesions of von Hippel-Lindau's disease and to undergo a familial inquiry in order to propose a multidisciplinary approach for patients affected by the disease.
Adenocarcinoma↗
Mechanism of the abnormal vitamin K-dependent gamma-carboxylation process in human hepatocellular carcinomas.
BACKGROUND: An important marker for hepatocellular carcinoma is the presence of des-gamma-carboxy (abnormal) prothrombin. However, the molecular basis for the reduced carboxylation of prothrombin is unknown. METHODS: Two groups of patients were defined according to the absence (Group I, n = 7) or presence (Group II, n = 8) of des-gamma-carboxy prothrombin. The enzymatic activity of gamma-carboxylase and the total microsomal prothrombin concentration were determined in all tumors. The kinetic parameters for the synthetic peptide Phe-Leu-Glu-Glu-Leu (FLEEL) were measured in eight tumors. The gamma-carboxylase mRNA expression was evaluated by Northern blot analysis in 12 of 15 tumors. In addition, the total vitamin K content (K1, K1 epoxide, and menaquinones 4-10) in 10 tumors was investigated by high performance liquid chromatography. RESULTS: Concentrations of menaquinones 4-10 were normal in the nontumorous part of the liver but significantly decreased (P = 0.02) in all the tumors (Groups I and II). This decrease was more severe in Group II (P = 0.02). The tumors in Group I had normal or increased gamma-carboxylase activity and increased mRNA expression (P < 0.02) as compared with their nontumorous counterparts. The tumors in Group II were heterogeneous. Five tumors displayed low gamma-carboxylase activity, associated with low mRNA expression in two, whereas two others had high gamma-carboxylase activity and mRNA expression. The concentration of FLEEL at half-maximal velocity was normal in all the tumors examined (Groups I and II), and a relation was found between the level of expression of gamma-carboxylase and the maximal velocity for FLEEL carboxylation in the tumors in Group II (r = 0.98; P < 0.01). The microsomal content of normal prothrombin was within normal limits in all tumors (Groups I and II). CONCLUSIONS: Tumor vitamin K content has a critical role in the synthesis of des-gamma-carboxy prothrombin. Furthermore, the gamma-carboxylase defect, which is observed in some secreting tumors, is the result of the defective gene expression of a normal enzyme and not the consequence of the presence of a competitive inhibitor. It is possible that a 75% reduction in gamma-carboxylase gene expression could take a part in the secretion of des-gamma-carboxy prothrombin, but this mechanism is not predominant.
Biomarkers↗
Associated primary esophageal and lung carcinoma: a study of 39 patients.
From 1979 to 1992, of 1,294 patients with esophageal squamous cell carcinoma, 39 patients (3.2%) (38 male patients, 1 female patient; mean age, 58 years) had associated primary lung carcinoma. Criteria for the diagnosis of primary lung carcinoma were: (1) non-squamous cell carcinoma tumors, (2) tumors existing before the esophageal squamous cell carcinoma, and (3) solitary squamous cell carcinoma presenting with endobronchial involvement. The two tumors were observed synchronously in 22 patients (56%) and metachronously in 17, with a mean tumor-free interval of 46 months (range, 18 to 77 months). In patients with synchronous disease, 10 underwent nonoperative treatment or a palliative surgical procedure, and 12 (55%) underwent a curative operation. In patients with metachronous disease, a curative operation was performed in all for the first tumor and in 9 (53%) for the second tumor. The overall postoperative mortality rate was 15%. Two patients (10%) died after the curative operation. None of the patients died who underwent curative esophagectomy combined with lobectomy. For the patients with synchronous disease, the 5-year survival rate was 11% in those who underwent a curative operation, and the longest survival in those who received palliative treatment was 18 months. For the patients with metachronous disease, the 5-year survival rates from the date of the diagnosis of the second tumor were 17% for those who had a curative operation and 11% for those who received palliative treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Actuarial Analysis↗
Microscopic colitis: a "transatlantic" unifying concept.
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Colitis↗
Endothelial cell heterogeneity in the normal human liver acinus: in situ immunohistochemical demonstration.
While a certain degree of structural and functional intra-lobular heterogeneity of sinusoidal endothelial cells has been observed in rodents, little information is available about the zonal characteristics of sinusoidal endothelial cells in the human liver acinus. We have therefore examined the intra-acinar distribution of a panel of endothelial markers in the normal human liver, including: (a) structural markers of continuous and sinusoidal endothelia (PECAM-1, CD-34 protein, VE-cadherin, 1F10 antigen), (b) functional markers specific for sinusoidal endothelial cells, as previously determined in the laboratory (CD4 protein, the lipopolysaccharide-binding protein receptor (CD 14), aminopeptidase N, ICAM-1, receptors II and III for the Fc fragment of immunoglobulins G), (c) endothelial cell-matrix adhesion proteins and leukocyte-endothelial cell adhesion molecules. We observed a heterogeneous distribution for: (a) the 1F10 antigen, whose distribution in the human liver acinus was restricted to vessels situated along the axis of acinar zone 1, (b) the lipopolysaccharide-binding protein receptor and the receptor III for the Fc fragment of IgG, not expressed or only barely expressed in acinar zone 1. The distribution of the other markers tested did not display significant intra-lobular variation. Our in situ results suggest the existence of a degree of zonal heterogeneity in the structural and functional characteristics of sinusoidal endothelial cells in the human liver acinus. This might contribute to the constitution of distinct microenvironments within the human liver parenchyma.
Adult↗
Late pancreatic metastasis from renal cell carcinoma.
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Carcinoma, Renal Cell↗
Parenchymal innervation of normal and cirrhotic human liver: a light and electron microscopic study using monoclonal antibodies against the neural cell-adhesion molecule.
Hepatic innervation participates in the control of sinusoidal blood flow and in the regulation of certain metabolic functions of the liver. The study of the distribution of hepatic nerves has been hampered by the lack of adequate markers. We therefore tested the value of the neural cell-adhesion molecule (NCAM) as a probe for the study of parenchymal nerves in the normal and cirrhotic human liver. Four antibodies against various epitopes of NCAM were tested by light and electron microscopic immunohistochemistry: Leu19, ERIC-1, VC1.1, and HNK-1. Their reactivity was compared with that of antibodies against the following neural cell markers: S100 protein, neurofilaments, and neuron-specific enolase (NSE). The tissue reactivity of anti-NCAM antibodies was variable, suggesting a microheterogeneity of the NCAM molecule in the normal liver. Clones Leu19 and ERIC-1 proved to be the most sensitive of the anti-NCAM antibodies. Their sensitivity was superior to that of the antibodies directed against the other neural cell markers tested. In the normal liver, both Leu19 and ERIC-1 demonstrated a heterogeneous distribution of nerve fibers inside the hepatic lobule. Intralobular nerve fibers predominated in Zone 1. This might contribute to the constitution of distinct zonal microenvironments inside the hepatic lobule. In cirrhosis, no nerve fiber was detected inside parenchymal nodules; no nerve plexus was visible at the contact of proliferating neoductules. These alterations might contribute to the pathogenesis of the hemodynamic and metabolic disorders observed in cirrhosis.
Antibodies, Monoclonal↗