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Biomedical subjects

V A Memoli

Publications and source records attributed to V A Memoli.

At least 19 recordsLinked to original sources
PubMed1992

Immunohistochemical staining for transforming growth factor beta 1 associates with disease progression in human breast cancer.

The transforming growth factor beta s (TGF-beta) comprise a family of M(r) 25,000 pluripotent growth factors which have been implicated in the development and progression of human breast cancer. Conflicting data suggest that TGF-beta has the potential to either inhibit or promote the progression of mammary neoplasia. We therefore examined a pathological library of malignant breast biopsy specimens to determine the prevalence and distribution of immunoreactivity with antibodies specific for the three mammalian isoforms of TGF-beta (beta 1, beta 2, and beta 3). We found that intense staining for TGF-beta 1 was positively associated with rate of disease progression, and that this was independent of age, stage, nodal status, or estrogen receptor status (P = 0.009).

Adult↗
PubMed1992

Pathways of coagulation activation in situ in rheumatoid synovial tissue.

Immunohistochemical techniques were applied to rheumatoid synovium in order to detect components of coagulation and fibrinolysis pathways within these tissues. These techniques revealed an intact coagulation pathway and plasminogen activator inhibitor-2 associated with macrophage-like cells that were present throughout these tissues, especially in subsurface areas. Cell-associated thrombin generation appeared to account for conversion of abundant fibrinogen to fibrin. Occasional macrophage-like cells also stained for urokinase but tissue-type plasminogen activator and plasminogen activator inhibitor-1 were restricted to vascular endothelium. Intense synovial fibrin deposition (with the limited evidence for associated fibrinolysis) may contribute to local inflammation and explain certain clinical features of rheumatoid arthritis. These findings suggest novel treatment hypotheses for this disease.

Arthritis, Rheumatoid↗
PubMed1992

Pathways of coagulation/fibrinolysis activation in malignancy.

Recent progress in elucidating the complex and heterogeneous interactions between malignancy and coagulation or fibrinolysis reactions in humans has clarified the pathogenesis of disseminated intravascular coagulation that occurs with malignancy and has revealed evidence for two distinct pathways of growth regulation based on production by tumor cells of initiators of thrombin formation versus plasminogen activators. We have proposed a preliminary classification of tumors (see Table 2) based on these interactions. Type I tumors are those in which the tumor cells are associated with an intact coagulation pathway that leads to thrombin formation at the tumor periphery but in which the tumor cells lack u-PA. Examples of tumors in this category include SCCL, malignant melanoma, and renal cell carcinoma. Type II tumors are those in which the tumor cells express u-PA but lack an associated coagulation pathway leading to thrombin formation. Examples of type II tumors include prostate cancer, colon cancer, breast cancer, and N-SCLC. Type III tumors are those that express neither of these pathways, or exhibit some other pattern of interaction. Obviously, this formulation must be regarded as hypothetical. However, this concept fits with the limited data available to date from clinical trials. More importantly, this hypothesis can be tested further by means of intervention aimed at interrupting pathways relevant to specific tumor types. Characterization of additional tumor types by the methods described should permit amplification of this classification of tumors and other patterns of interaction may be defined. Exploration of the coagulation-cancer interaction holds considerable promise for gaining new understanding of both the coagulation mechanism and tumor biology. Most intriguing is the prospect that imaginative approaches to cancer treatment may be devised that are not only relatively nontoxic and low cost, but also effective.

Animals↗
PubMed1992

Fibrinogen deposition and macrophage-associated fibrin formation in malignant and nonmalignant lymphoid tissue.

Nonmalignant lymphoid tissue and tissue from patients with nodular sclerosis, Hodgkin's disease, and large cell lymphocytic lymphoma was examined by immunohistochemical techniques for the occurrence in situ of components of coagulation and fibrinolysis reaction pathways. Staining for material interpreted as fibrinogen was observed in abundance in both malignant and reactive lymphoid tissue. Fibrin also occurred to a variable extent but focally in all tissues. Components of coagulation pathways, including tissue factor, factor VII, factor X, and factor XIII ("a" subunit), were restricted to tissue macrophages. Double-labeling techniques revealed fibrin in direct apposition to tissue macrophages. We conclude that fibrinogen and fibrin occur in both benign and malignant lymphoid tissue and that the transformation of fibrinogen to fibrin is attributable to macrophage-initiated thrombin formation. We postulate that both systemic and local hypercoagulability associated with these disorders may be attributable to macrophage activation resulting in expression of procoagulant activity.

Adolescent↗
PubMed1991

Coexisting macrophage-associated fibrin formation and tumor cell urokinase in squamous cell and adenocarcinoma of the lung tissues.

Mechanisms of coagulation activation in situ were studied by means of immunohistochemical techniques applied to surgically resected primary adenocarcinomas and squamous cell carcinomas of the lung. Findings in these two histologic types were similar. Double-labeling techniques using macrophage-specific antibody together with antibody to either tissue factor, factor VII, factor X, or factor V revealed coincident staining for each of these coagulation factors on tumor-associated macrophages. Staining of tumor cells for these factors was rare and inconsistent. Both macrophages and fibroblasts in the tumor connective tissue stained for the a subunit of factor XIII. Fibrinogen was abundant throughout the tumor connective tissue, but staining for fibrin and D-dimer cross-linked sites of fibrin was restricted to areas adjacent to macrophages, indicating that thrombin was generated in association with tumor macrophages but not with tumor cells. By contrast, tumor cells stained diffusely for urokinase-type plasminogen activator and focally for thrombomodulin. These findings contrast with those reported previously for small cell carcinoma of the lung and suggest that coagulation activation in adenocarcinoma and squamous cell carcinoma of the lung may occur indirectly through activation of certain host cells such as macrophages. By contrast, tumor cell plasminogen activator may mediate certain aspects of the malignant phenotype in these tumor types.

Adenocarcinoma↗
PubMed1991

Flow cytometric DNA content analysis in neuroendocrine carcinoma of the lung. Correlation with survival and histologic subtype.

The DNA content of 53 primary and locally metastatic pulmonary neuroendocrine carcinomas was retrospectively determined by flow cytometric analysis of nuclei released from paraffin-embedded tissues and compared with histologic subtypes and clinical survival. Forty-one percent (9 of 22) of tumors classified as well-differentiated neuroendocrine carcinoma (WDNC) were aneuploid. In contrast, 85% (17 of 20) of small cell neuroendocrine carcinoma (SCNC), and 73% (8 of 11) of intermediate cell neuroendocrine carcinoma (ICNC) were aneuploid. DNA content was not a significant independent predictor of patient survival within each histologic subtype (P greater than 0.05 for all subtypes). Yet, when all cases were examined as a single group, diploid cases showed better clinical survival than cases with DNA aneuploidy (P less than 0.02). However, the survival advantage for diploid DNA content did not quite achieve statistical significance when only cases of limited stage disease were analyzed (0.10 greater than P greater than 0.05). Histologic subtype was also a prognostic indicator, with WDNC cases showing a significantly longer survival than either SCNC (P less than 0.05) or ICNC (P less than 0.02), for those cases with limited-stage disease. These results indicate information on clinical staging and the histologic subtype are important parameters to compare with DNA content analysis in determining independent prognostic factors in neuroendocrine or small cell carcinoma of the lung.

Adult↗
PubMed1991

Cellular localization of activated factor X by Xa-specific probes.

A probe, recombinant antistasin, that reacts specifically with the activated form of factor X (Xa) was used in immunohistochemical procedures to detect cellular sites of Xa generation within intact tissues. Factor Xa was detected on tumor cells in small cell carcinoma of the lung, renal cell carcinoma, and malignant melanoma. Tumor-associated macrophages (but not tumor cells) expressed Xa in adenocarcinoma and squamous cell carcinoma of the lung, and Hodgkin's disease. Factor Xa in these locations corresponded to evidence reported previously for an intact coagulation pathway and thrombin formation associated with these tumor cells and macrophages. By contrast, only rare connective tissue cells stained for Xa in breast and colon cancer, tumor types shown previously to lack an intratumoral coagulation pathway and thrombin generation, and in normal liver, lung, breast, kidney, and placental tissues. Hepatocytes did not stain. These results suggest that such probes may be useful for studying the activation state of cell-associated factor X in situ within intact tissues.

Factor Xa↗
PubMed1991

Reactivity of anti-CD15 monoclonal antibody PM-81 with breast cancer and elimination of breast cancer cells from human bone marrow by PM-81 and immunomagnetic beads.

The CD15 carbohydrate antigen, lacto-N-fucopentaose III is expressed on a variety of human cancer cells including acute myeloid leukemia, small cell carcinoma of the lung, and colorectal carcinomas. We have found that cells from breast cancer cell lines and patient-derived tissue are strongly CD15 positive, as seen by binding to the PM-81 monoclonal antibody. In this report we show that monoclonal antibody PM-81 and immunomagnetic beads can remove breast cancer cells from bone marrow and thus be used as "purging" agents for autologous bone marrow transplantation. PM-81 and immunomagnetic beads removed up to 3 log of SK-BR-3 and MCF7 breast carcinoma cell line cells while minimally affecting normal hematopoietic progenitor cells. This technique may be useful for purging marrow for autologous bone marrow transplantation in breast cancer.

Antibodies, Monoclonal↗
PubMed1991

Fibrin formation on vessel walls in hyperplastic and malignant prostate tissue.

To explore mechanisms of coagulation activation in adenocarcinoma of the prostate, the occurrence and distribution of components of coagulation and fibrinolysis pathways in situ were studied by means of immunohistochemical techniques applied to frozen sections of fresh malignant and benign hyperplastic prostatic tissue obtained at transurethral resection. Fibrinogen was distributed throughout the perivascular and tumor connective tissue in both malignant and benign disease but was not present in adjacent areas of normal prostate. Antibodies specific for fibrin and D-dimer crosslink sites stained vascular endothelium focally in both malignant and benign tissues. Both neoplastic cells and benign hyperplastic glandular epithelial cells stained weakly and in a patchy distribution for tissue factor and focally for low-molecular-weight urokinase-type plasminogen activator. Focal staining of vascular endothelium was also observed for tissue plasminogen activator and plasmin-antiplasmin complex neoantigen. By contrast, no tissue staining was observed for factor VII, factor X, factor XIII "a" subunit, high-molecular-weight urokinase-type plasminogen activator, plasminogen activator inhibitors 1 to 3, protein C, and protein S. Thus, the similarity in findings between benign hyperplastic and neoplastic prostate tissue, the lack of either an intact tumor cell-associated coagulation pathway or fibrin formation, and the presence of fibrin on vascular endothelium are consistent with the concept that coagulation activation in prostatic cancer may not be due to a direct effect of the tumor cells on the clotting mechanism. Rather, such activation may be induced by a soluble tumor product that activates procoagulant activity on certain host (for example, vascular endothelial) cells. These findings, together with the lack of effect of warfarin anticoagulation on the clinical course of patients with prostatic cancer, contrast with findings in certain other tumor types and suggest that coagulation activation may not contribute to progression of adenocarcinoma of the prostate.

Antibodies, Monoclonal↗
PubMed1991

Fibrinogen deposition without thrombin generation in primary human breast cancer tissue.

The occurrence and distribution of components of coagulation pathways in situ were determined using immunohistochemical techniques applied to 10 cases of primary carcinoma of the breast, normal breast tissue obtained from two patients undergoing reductive mammoplasty, and three patients with benign breast tumors. Tumor cells stained for factor X and thrombomodulin but not for tissue factor, factor V, factor VII, or factor XIII. Rare nonneoplastic duct epithelial cells stained for thrombomodulin, but these tissues did not otherwise stain for any of these antigens. Macrophages within the tumor stroma stained for tissue factor, factor VII, and factor XIII but not for factor V or factor X. These features of macrophages were the same in malignant and nonmalignant breast tissue. Fibrinogen was present in abundance throughout the connective tissue in breast cancer but not in nonmalignant tissues. By contrast, no staining was observed using fibrin-specific antibodies. These results suggest that an intact coagulation pathway does not exist in breast cancer tissue and that thrombin capable of transforming fibrinogen to fibrin is not generated in significant amounts in this tumor type. While fibrin is not a feature of the connective tissue stroma in breast cancer, it is conceivable that the abundant fibrinogen present in the tumor connective tissue (and factor XIII present in connective tissue macrophages) might contribute to the structural integrity of breast tumor tissues.

Breast Neoplasms↗
PubMed1991

Occurrence of components of fibrinolysis pathways in situ in neoplastic and nonneoplastic human breast tissue.

The occurrence and distribution of components of fibrinolysis pathways were determined using immunohistochemical techniques applied to 10 cases of primary carcinoma of the breast, normal breast tissue obtained from two patients undergoing reductive mammoplasty, and three cases of benign breast tumors. Tumor cells stained for urokinase- and tissue-type plasminogen activators, plasminogen activation inhibitor-1, plasminogen, and plasmin-antiplasmin complex neoantigen. The tumor connective tissue stained for fibrinogen and its D fragment plasmin digestion product. By contrast, only occasional nonneoplastic duct epithelial cells stained for urokinase- and tissue-type plasminogen activators and there was little or no staining for the other antigens tested. These results are consistent with the existence of local amplification of expression of enzymatically active plasminogen activators, and particularly of urokinase-type plasminogen activator, in situ in primary breast cancer tissue. These features distinguish malignant from benign breast tissue and may modulate neoplastic progression through an effect on tumor cell proliferation, invasion, and metastatic dissemination.

Breast↗
PubMed1991

Hemorrhagic myelolipoma of adrenal gland after blunt trauma.

A case of adrenal myelolipoma is reported in a patient in whom symptoms of hematuria and flank pain developed after the patient had sustained blunt trauma. Adrenal myelolipomas are usually found incidentally at autopsy. However, the symptomatic presentation of this patient was probably caused by traumatic intratumor hemorrhage. The etiology and pathogenesis of these tumors are discussed in relation to their occasional symptomatic presentation and to their differential diagnosis.

Accidental Falls↗
PubMed1990

Reevaluation of pulmonary neoplasms resected as small cell carcinomas. Significance of distinguishing between well-differentiated and small cell neuroendocrine carcinomas.

The clinicopathologic features of 50 cases of surgically resected small cell carcinoma were reevaluated (doubly blinded). Two pulmonary carcinomas were excluded because neuroendocrine features could not be demonstrated; two additional cases also were excluded because the tumors grossly invaded the chest wall and their pulmonary origin was not substantiated. Thirty-four tumors were confirmed to be small cell neuroendocrine carcinoma (SCNC). Only seven of 11 (64%) patients with T1N0,T2N0 tumors survived more than 1 year; one of 11 (9%) patients survived more than 2 years. In 12 cases, the diagnosis was changed to well-differentiated neuroendocrine carcinoma (WDNC). Of these, nine of nine (100%) patients with T1N0,T2N0 tumors survived more than 1 year; six of eight (75%) patients survived more than 2 years. These observations strongly indicate that a significant number of long-term survivors with the diagnosis of small cell carcinoma may, in fact, have a distinctly less aggressive type of pulmonary neuroendocrine carcinoma. It was concluded that the distinction between small cell and well-differentiated types of neuroendocrine carcinomas has significant prognostic and therapeutic implications.

Adult↗
PubMed1990

Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung.

Components of coagulation and fibrinolysis reactions were identified in situ by immunohistochemical staining in fresh frozen sections of small cell carcinoma of the lung tissue. Tumor cells stained positively for tissue factor, a protein that is capable of activating the extrinsic pathway of coagulation (the components of which have been seen within small cell carcinoma of the lung [SCCL] tissue), and for proteins C and S antigens. Fibrin was seen in a focal distribution at the host-tumor interface, indicating that thrombin had acted upon the fibrinogen found throughout the tumor stroma. Staining with a neoepitope-specific antibody, which does not discriminate between fibrinogen fragment D and fibrin fragment D-dimer, was similar to that of the fibrin antibody. High molecular weight urokinase-type and tissue-type plasminogen activators were seen in vascular endothelium, but neither existed within the tumor. Low molecular weight urokinase was found in rare isolated foci of tumor cells primarily adjacent to areas of necrosis. Plasminogen activator inhibitor-3 occurred in tumor cell cytoplasmic blebs and in necrotic tumor cells, but plasminogen activator inhibitors 1 and 2 were not seen. Our data suggest a mechanism for thrombin generation and fibrin formation within SCCL tissues that could support cell proliferation, stroma formation, and preservation. These features could be conductive to perpetuation of this tumor and conceivably could form the basis of the beneficial effects of antithrombotic therapy seen in SCCL.

Blood Coagulation↗
PubMed1990

Malignant melanoma. Interaction with coagulation and fibrinolysis pathways in situ.

Immunohistochemical techniques applied to fresh frozen sections of metastatic malignant melanoma tissue revealed abundant fibrinogen (or fibrin I) in perivascular areas throughout the tumor connective tissue stroma. Fibrin was readily detected in a focal distribution in the connective tissue around nodules of viable tumor. Staining for D-dimer of cross-linked fibrin (using an antibody that cross-reacted with fragment D of fibrinogen) coincided with staining for fibrin. Diffuse staining of tumor cell bodies was observed for Factor X, and Factor XIII ("a" subunit) was detected in scattered areas of connective tissue throughout the tumors. Factor VII was not detected, and only rare tumor cells stained for tissue factor. These results support the concept that a tumor cell-associated, thrombin-generating pathway exists in situ in malignant melanoma tissue that includes Factor X but neither tissue factor nor Factor VII. By contrast, tumor cell staining was observed rarely for urokinase and to a variable extent for tissue plasminogen activator.

Antibodies, Monoclonal↗
PubMed1990

Hyperplasia and tumors of the islets of Langerhans in mice bearing an elastase I-SV40 T-antigen fusion gene.

Transgenic mice bearing a fusion gene consisting of rat elastase I 5' flanking DNA fused to the early-coding (T-antigen) region of the SV40 genome (ELSV mice) develop carcinomas of the acinar cells of the exocrine pancreas. Histopathological examination of pancreatic tissue from 79 such animals revealed that, in addition to acinar cell neoplasms, ELSV mice develop two distinct lesions of the islets of Langerhans. By the age of 26 weeks, 36% of the mice had developed insulinomas. Starting at 8 weeks of age, the mice also developed D (somatostatin)-cell hyperplasia, which began at the periphery of the islets but which in advanced cases resulted in nearly complete replacement of other islet cell types by D-cells. By 26 weeks of age, 85% of the mice examined demonstrated the D-cell abnormality. Both the insulinomas and D-cell lesions were negative by immunohistochemistry for T-antigen, which was, however, demonstrated in acinar cell neoplasms using a monoclonal antibody against a C-terminal T-antigen epitope. Insulinomas have been described in other SV40 transgenic mice, particularly when the SV40 enhancer is not included in the transgene, suggesting that the presence of native SV40 enhancer may ordinarily suppress the expression of T-antigen in pancreatic beta-cells. The somatostatin-cell lesion is unique to the ELSV model; it may be neoplastic or represent a response to the growth and neoplastic changes occurring simultaneously in the exocrine pancreas.

Adenoma, Islet Cell↗