Biomedical subjects
S Prévot
Publications and source records attributed to S Prévot.
Vegf, Vegf-B, Vegf-C and their receptors KDR, FLT-1 and FLT-4 during the neoplastic progression of human colonic mucosa.
Because the crucial role of angiogenesis has been demonstrated in tumor growth and metastasis, the present study was undertaken to characterize the relative expression of vascular endothelial growth factors VEGF (vascular endothelial growth factor), VEGF-B, VEGF-C, and their receptors KDR (kinase insert domain-containing receptor), FLT-1 (fms-like tyrosine kinase), and FLT-4 in human colonic cancers, in relation to the Astler-Coller pathological classification, and to prognosis. VEGF and VEGF-B gene expression was quantified by Northern blot in 72 tumor samples matched with control tissues. VEGF gene expression was 1.4 times higher in adenocarcinomas than in control tissues (p = 0.02), but did not increase further between Astler-Coller tumor stages A and D, and did not correlate with disease recurrence for patients at stages B2 or C. In adenomas, VEGF mRNA levels were not significantly different from those in the paired control colonic mucosa. The expression pattern of VEGF isoforms, mainly identified by RT-PCR (reverse-transcriptase-coupled polymerase chain reaction) as VEGF121 and VEGF165 and to a lesser extent VEGF189, was comparable in tumor and control tissues. VEGF-B mRNA levels were unchanged during the neoplastic progression of colonic mucosa. In contrast to KDR and FLT-4, the expression of VEGF-C and FLT-1 genes increased in some pathological tissues. These results provide evidence that the early and sustained increase in VEGF transcripts and the expression of multiple angiogenic factors and receptors contribute to the development of colon cancer, and thus constitute a putative target for anti-angiogenic drug therapy.
[Pseudotumoral abdominal granuloma concomitant with immune reconstitution after antiretroviral treatment].
BACKGROUND: Use of powerful multiple-drug antiretroviral regimens can significantly raise CD4+ counts restoring immune function, but in certain cases, leading to inflammatory reactions. CASE REPORT: An HIV-infected patient developed a mycobacteriosis of the digestive tract when his CD4 count fell below 5/mm3. He was given antimycobacterial treatment in combination with an effective triple antiretroviral regimen. At two years, the clinical situation was controlled with persistent optimal response (CD4 = 338/mm3 HIV-RNA < 500 copies/ml); the antimycobacterial regimen was discontinued. One year later the patient still had a CD4+ count above 500/mm3 but developed a voluminous mesenteric mass invaded by a CD68+ histiocyte proliferation. No causal agent could be identified. The clinical course was favorable after reintroducing antimycobacterial treatment combined with short-term corticosteroid therapy. DISCUSSION: Reconstitution of the immune system after long-term use of the new antiretroviral therapies raises the question of whether anti-infectious prophylaxis should be maintained. However, possible reactions to earlier pathogens after restoration of specific immunity would warrant secondary prophylaxis even in patients responding to powerful antiretroviral combinations.
A high voltage electrical burn of lung parenchyma.
High voltage electrical trauma may cause severe visceral injuries. We report a case of direct electrical injury to the lung parenchyma, without evidence of any thoracic wall contact injury, in an electrician who sustained a 20 kV-electrical shock while working in a substation cubicle. The diagnosis of a true electrical burn of the left lower lobe was suggested early on by imaging and then confirmed by surgical exploration, histological findings and the significant improvement of the patient's condition following resection of the infarcted lobe. All possible causes of bronchial and pulmonary pathologies in such a context were ruled out. The fatal outcome of two previous similar cases and the generally high mortality of any electrical visceral injury support early surgical management as the only rational life-saving treatment. Current pathophysiological knowledge substantiates the theory of an isolated visceral injury located far away from the contact wounds. However, the pathogenesis of such severe injuries is not entirely understood.
Benign schwannoma of the digestive tract: a clinicopathologic and immunohistochemical study of five cases, including a case of esophageal tumor.
We report five cases of schwannomas of the digestive tract. The patients were two men and three women, whose ages ranged from 56 to 74 years. Three cases arose in the stomach, one in the ascending colon, and one in the esophagus; the latter was a hitherto unreported location for this tumor. The schwannomas ranged from 2 to 11 cm in diameter. They were well circumscribed but not encapsulated, with interlacing bundles of spindle cells, nuclear atypia and no mitosis, interspersed with collagenous strands. Inflammatory cells were scattered throughout the tumors and a peripheral cuff of lymphoid aggregates was observed in all cases. Intracellular periodic acid-Schiff (PAS)-positive crystalloids were found in three cases; no skeinoid fibers were seen. A diffuse and intense positivity for vimentin and S-100 protein was detected in all five cases together with a variable and sometimes focal positivity for glial fibrillary acidic protein and neuron-specific enolase. None of the tumors showed expression of CD34 or the smooth muscle antigens tested. The four cases with a sufficient follow-up had a favorable outcome without any recurrence or metastasis. The morphologic and immunohistochemical features of digestive schwannomas were compared with those of other gastrointestinal stromal tumors. Schwannomas have many differences. Digestive schwannomas can be readily recognized on histologic and immunohistochemical examination. They are spindle cell tumors without epithelioid features, with a peripheral cuff of lymphoid tissue. Specific intracellular needle-shaped PAS-positive crystalloids are found in some cases, whereas skeinoid fibers are not. These tumors always express S-100 protein in a diffuse and strong manner, and they express glial fibrillary acidic protein but not express CD34. Digestive schwannomas usually are gastric tumors and have never been reported in the small bowel. They pursue a benign course and are far rarer than gastrointestinal autonomic nerve tumors.
[Tumoral angiogenesis: physiopathology, prognostic value and therapeutic perspectives].
INTRODUCTION: Angiogenesis activation plays a crucial role in tumoral growth and metastases dissemination. This review summarizes and analyzes current knowledge on molecular mechanisms related to angiogenesis and the prognostic value of its effectors. It also focuses on the therapeutical relevance of various drugs that might inhibit angiogenesic processes. CURRENT KNOWLEDGE AND KEY POINTS: Tumor angiogenesis involves complex interactions between tumoral, stromal, endothelial cells, fibroblasts and the extracellular matrix. Normal and malignant angiogenesis depends on the balance of proangiogenic and antiangiogenic factors. Endothelial cells are activated by growth factors, such as Vascular Endothelial Growth Factor (VEGF), and proliferate; they release proteases able to induce degradation of the basement membrane and extracellular matrix, and undergo migration and tubulogenesis. Angiostatin and endostatin are two powerful inhibitors of angiogenesis in experimental models. Assessment of intratumoral microvessel density and quantification of angiogenic factors, including VEGF, are of prognostic value in most cancers, particularly in breast cancer. However, the use of these prognosis markers in clinical practice is still controversial due to the lack of prospective studies and to technical limits inherent to the scoring and standardization of immunohistochemical methods. FUTURE PROSPECTS AND PROJECTS: Better understanding of the molecular basis of angiogenesis allows the development of new therapeutical strategies. Biochemical targets of antiangiogenic therapy are: the interaction between angiogenic factors and their receptors; the interaction of endothelial cells with the extracellular matrix; and intracellular signaling pathways. Angiogenesis inhibitors may not cause tumor regression, but inhibit cellular growth and produce "disease dormancy". Extensive phase I to III clinical trials involving antiangiogenesis therapy are in progress.
Overexpression of stromelysin-3, BM-40/SPARC, and MET genes in human esophageal carcinoma: implications for prognosis.
Molecular markers can improve staging and predict aggressive clinical behavior in esophageal cancer, thus helping to define appropriate therapeutic protocols and to identify patients who will benefit from surgery. We therefore characterized, by Northern blot and/or immunohistochemistry, the relative expression of three effectors involved in the invasion, angiogenesis, and dissemination of tumor cells in esophageal cancer versus nontumoral mucosae: (a) stromelysin-3 (ST3), a member of the metalloproteinase family; (b) basement membrane 40/secreted protein acidic and rich in cysteine (BM-40/SPARC), an extracellular matrix-associated protein involved in angiogenesis; and (c) the hepatocyte growth factor receptor MET, which triggers the scattering of epithelial cells. Results were analyzed in relation to clinicopathological parameters (cpTNE) including tumor size (T), lymph node status (N), periesophageal tissue invasion (E), disease recurrence, and overall survival. The ST3, BM-40/SPARC, and MET genes were found to be overexpressed in tumor samples compared to control mucosa. BM-40/SPARC and MET mRNA levels were not linked to any one of the cpTNE, indicating that this overexpression occurs at an early stage of neoplastic progression. In contrast, ST3 expression, identified by immunohistochemistry in fibroblastic cells surrounding neoplastic islets, correlated with tumor size and periesophageal tissue invasion. Of the 36 patients studied, those with high ST3 levels had shorter disease-free survival than those with low levels, but there was no relationship between the cpTNE and disease recurrence or survival. Our study demonstrates that ST3, BM-40/SPARC, and MET are involved in different steps of esophageal carcinogenesis and that ST3 overexpression is a marker of aggressive clinical behavior. We conclude that in esophageal cancer, ST3 might help to assess survival and the risk of recurrence after surgical resection.
Overexpression of p53 mRNA in colorectal cancer and its relationship to p53 gene mutation.
We analysed the frequency of p53 mRNA overexpression in a series of 109 primary colorectal carcinomas and its association with p53 gene mutation, which has been correlated with short survival. Sixty-nine of the 109 cases (63%) demonstrated p53 mRNA overexpression, without any correlation with stage or site of disease. Comparison with p53 gene mutation indicated that, besides cases in which p53 gene mutation and p53 mRNA overexpression were either both present (40 cases) or both absent (36 cases), there were also cases in which p53 mRNA was overexpressed in the absence of any mutation (29 cases) and those with a mutant gene in which the mRNA was not overexpressed (four cases). Moreover, the mutant p53 tumours exhibited an increase of p53 mRNA expression, which was significantly higher in tumours expressing the mutated allele alone than in tumours expressing both wild- and mutated-type alleles. These data (1) show that p53 mRNA overexpression is a frequent event in colorectal tumours and is not predictive of the status of the gene, i.e. whether or not a mutation is present; (2) provide further evidence that p53 protein overexpression does not only result from an increase in the half-life of mutated p53 and suggest that inactivation of the p53 function in colorectal cancers involves at least two distinct mechanisms, including p53 overexpression and/or mutation; and (3) suggest that p53 mRNA overexpression is an early event, since it is not correlated with Dukes stage.
Lymphomas associated with HIV infection.
Lymphomagenesis in HIV positive patients is a complex phenomenon not yet completely understood (Karp and Broder, 1992). The great majority of NHL are of the B cell type. Burkitt lymphoma seems to develop early during the evolution of HIV infection in patients with a CD4 count above 200/microliter. MYC is rearranged in the majority of the cases. EBV latent infection is observed in 30-45%. EBV status is characterized by a negativity for EBNA2 and LMP1 The main sites of the tumour are the lymph node and the bone marrow. Diffuse large cell lymphomas, mostly represented by immunoblastic lymphomas with plasmacytoid differentiation and by centroblastic lymphomas rich in immunoblasts, are a late event in HIV infection, in patients with a low CD4 count (often below 50/microliter). The prognosis is worse than in Burkitt and Burkitt like lymphoma. MYC is rearranged in about 30-40% of the cases, whereas more than 70% are EBV positive. EBV status is characterized by a positivity for both EBNA2 and LMP1. B type ALC lymphomas are more frequently associated with EBV than in the general population and exhibit the same EBV status as diffuse large cell lymphomas. HD occurs at any stage of HIV infection. The majority of patients are in clinical stage III or IV at the time of diagnosis, and HIV associated HD shows a more aggressive course than non-HIV HD. Many cases remain difficult to classify; instead, the immunophenotype of neoplastic cells is similar to that in HD occurring in the general population. Histiocytes and epithelioid cells are even more numerous than T lymphocytes, and the CD4:CD8 ratio is low. Neoplastic cells are EBV positive in most or all cases, although they are consistently HIV negative by in situ hybridization. Lymphomagenesis seems to be very complex, with multiple agents acting together or successively. EBV, other viruses, rearrangement of various genes and production of cytokines all seem to have major roles in addition to immune deficiency.
[Primary leiomyosarcoma of bone: a clinico-pathologic and immunohistochemical study of 3 cases].
Primary leiomyosarcoma of bone is rare. Herein we describe 3 cases with immunohistochemical study. All 3 cases were positive for smooth muscle actin and/or desmin. None was positive for cytokeratin. Differential diagnosis includes metastatic spindle cell carcinoma, other sarcoma (fibrosarcoma, malignant fibrous histiocytoma) and metastatic extra-osseous leiomyosarcoma, mostly from uterus or digestive tract.
Solitary fibrous tumor of the adrenal gland.
Solitary fibrous tumors are rare neoplasms, most commonly involving the pleura, recently described in various other locations. We report a solitary fibrous tumor of the right adrenal gland in a 42-year-old woman, discovered incidentally during abdominopelvic ultrasonographic examination. Pathologic and immunohistologic features of the tumor were identical to those of other solitary fibrous tumors. Three-quarters of this unencapsulated infiltrating tumoral mass presented foci of hemorrhage and were made of small, round, epithelioid-like cells that expressed the CD34 antigen more weakly than do the typical spindle cells usually observed in solitary fibrous tumors. Despite hemorrhage and poor limitation, the tumor behaved in a innocuous manner; the mass remaining unchanged for more than 5 years before the patient agreed to surgical intervention, which was recommended because of a sudden enlargement of the mass.
Detection of Epstein Barr virus in an hepatic leiomyomatous neoplasm in an adult human immunodeficiency virus 1-infected patient.
We report the first case of a human immunodeficiency virus (HIV)-related primary hepatic leiomyoma in an adult patient. The diagnosis was made at autopsy and confirmed by immunohistochemistry. Epstein Barr virus (EBV) was identified in tumour cells by in situ hybridization. Review of the literature revealed 13 cases of visceral myogenic tumours occurring in acquired immunodeficiency syndrome children, and only 2 cases in adults. One was a spinal epidural leiomyoma, the other multiple smooth muscle tumours of the colon and adrenal gland. This is the first report of EBV in smooth muscle neoplastic cells in an HIV-infected adult patient.
Primary non Hodgkin's malignant lymphoma of the vagina. Report of 3 cases with review of the literature.
Twenty cases of primary non-Hodgkin's malignant lymphoma (ML) of the vagina were studied: the 17 cases reported in the literature, and 3 further cases observed at the Hôtel-Dieu Hospital in Paris over the last 10 years. The mean age of the women was 49 years. The most frequent complaint was vaginal bleeding, only a few patients presented an ulcerated mass. No evidence of ML was seen on any of the cervico-vaginal cytologic smears. Diagnosis was made on the vaginal biopsy. According to the Kiel classification, 8 of these ML were of low malignancy and 12 of high malignancy. Apart from one of our cases, which was an angiocentric pleomorphic T ML with predominance of medium-sized cells, they were all B ML. According to the Ann Arbor staging system for extra-nodal ML, 12 of these ML were stage IE, 2 were stage IIE and 2 other stage IVE. Eight patients died, 6 of ML less than 17 months after diagnosis, 2 much later of diseases unrelated to ML. The mean follow-up period of patients who survived, free of disease, was 75 months. The surgical treatment has to be limited, associated with polychemotherapy and completed by local radiotherapy.
Epithelial tumors of the ovary: CT findings and correlation with US.
One hundred thirty patients with 170 epithelial ovarian tumors were prospectively studied with computed tomography (CT) before surgery. Ultrasound (US) was performed in 108 patients with 138 tumors. At pathologic examination, 78 tumors (46%) were benign, 14 (8%) borderline, and 78 (46%) malignant. CT results were compared with surgical and pathologic findings in all patients. CT enabled detection of 148 of 170 tumors (87%), and US enabled detection of 118 of 138 tumors (86%). Benign serous cystadenomas (n = 42) were correctly characterized with a sensitivity of 69% at CT and 70% at US. Benign mucinous cystadenomas (n = 21) were correctly characterized with a sensitivity of 62% at CT and 50% at US. Malignancy was suggested in nine of 14 patients (64%) with borderline tumors at CT and in five of 14 (36%) at US. The overall accuracy of characterization of benign versus malignant tumors (including borderline tumors) was 94% with CT and 80% with US. In the 108 patients studied with both CT and US, the sensitivity of CT was significantly superior to that of US (P less than .03), whereas there was no significant difference in specificity (P = .125).
[Primary non-Hodgkin's malignant lymphoma of the breast. Anatomopathologic diagnosis of 14 cases].
Fourteen primary non-Hodgkin's malignant lymphoma (ML) of the breast observed between 1985 and 1989 were reviewed. Using the Ann Arbor staging system, 5 of these ML were at clinical stage IE, 2 at stage IIE, and only one was at clinical stage IVE (the ML involved both breasts of a young woman after her third post-partum and she died quickly), staging was not available in 6 cases. At the time of physical examination, the diagnosis of ML was not suspected. When possible, it was done or-suspected before surgery, studying fine needle aspiration cytology (4 cases) or drill biopsy (2 cases). Cytological examination was also useful to make the difference between primary large cells T ML and granulocytic sarcomas which sometimes occur before the acute myeloid leukemia and/or the blast crisis of a myeloproliferative disorder. According to the Kiel histopathological classification (updated in 1988), 78.5% of these ML were of great malignancy, more than half of them being polymorphous centroblastic B ML. Only one of them was an angiocentric pleomorphic T lymphoma of great malignancy. None of the ML of low malignancy, all of the follicular type, was a MALT (Mucosa Associated Lymphoid Tissue) ML, as described by Isaacson. Intra-epithelial lymphocytes were observed in 6 of the ML of great malignancy; but in 2 cases, they were T lymphocytes and these lympho-epithelial lesions could not be interpreted as an argument for the MALT nature of these ML. None of our cases were associated with a ML from another MALT site.
Autoimmune serum containing an antibody against a 94 kDa nucleolar protein.
Little information exists on how various nucleolar proteins function in ribosome biogenesis. Of special interest is that group of nucleolar proteins which are not incorporated into mature ribosomes because they are candidates for a role in the regulation of ribosome construction. Non-ribosomal nucleolar proteins can be analyzed using autoimmune sera from scleroderma patients which often contain antinucleolar antibodies. One such serum, designated ScBr, is shown by indirect immunofluorescence to react specifically with nucleoli in cells of 3 different mammalian species, indicating that the antigen is at least partly conserved evolutionarily. It is not RNase-sensitive, but is completely eliminated after incubation with pronase and 2 M NaCl. Immuno-electron microscopy was carried out on Lowicryl ultrathin sections to localize the antigen. The labeling was observed over both the granular and the dense fibrillar component but not the fibrillar centers, indicating that the antigen is associated with ribosomal RNA transcription sites and ribosome assembly into precursor particles. In addition, the antibody was localized to small nucleoplasmic entities, termed dense nuclear bodies. This could indicate a relationship between nucleoli and dense nuclear bodies. By immunoprecipitation, only a single protein of 94 kDa molecular weight was revealed. By immunoblotting, the band at 94 kDa was found to be the only positive band for high ScBr dilutions. Observation of the behavior of the antigen during mitosis revealed that it became dispersed into the cytoplasm after breakdown of the nuclear envelope, lining most of the chromosomes rather than remaining associated with the NOR-chromosomes. The antigen appeared to be restored to nucleoli only in late telophase; phase-dense prenucleolar bodies of early telophase cells did not show positive staining for the antigen. During actinomycin-D RNA synthesis inhibition as well as in non-stimulated lymphocytes the positive staining is greatly decreased. These results were consistent with a role for the 94 kDa nucleolar protein in the process of preribosome assembly.