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J F Simpson

Publications and source records attributed to J F Simpson.

At least 91 records · Page 5Linked to original sources
PubMed1991

Pathology of preinvasive and excellent-prognosis breast cancer.

Recent advances in breast cancer treatment have made recognition of different prognostic groups mandatory. In addition, further experience with screening-detected lesions has resulted in definition of new associations. Therapeutic approaches to these frequently microscopic lesions are currently the source of much debate. This article reviews recent studies of excellent-prognosis carcinomas, as well as premalignant and other histologically defined lesions that indicate an increased risk for development or recurrence of carcinoma. Advances in fine-needle aspiration and in hormone receptor assays are also reviewed.

Biopsy, Needle↗
PubMed1991

Role of pulmonary inflammation in altered airway responsiveness in three sheep models of acute lung injury.

Pulmonary inflammation may contribute to increased airway responsiveness in experimental models of acute lung injury. Infusions of endotoxin, phorbol myristate acetate (PMA), or zymosan-activated plasma (ZAP) all result in the accumulation of polymorphonuclear leukocytes (PMNs) in the lung and alterations in lung mechanics. These three interventions have strikingly different effects on airway responses to aerosol histamine: ZAP does not increase airway responsiveness, whereas endotoxin causes a greater increase in airway responsiveness than does PMA. The present histologic study examines the question of whether the pattern and severity of PMN and mast cell accumulation in large- and medium-sized airways and lung periphery could contribute to the differences in airway responsiveness to histamine. Minimally instrumented sheep were given either an infusion of endotoxin (0.5 microgram/kg over 20 min), a bolus injection of PMA (5 micrograms/kg), or repetitive boluses of autologous ZAP (5 ml). Four and a half hours later, the animals were killed, and the left lung was removed and fixed in the distended state. Three levels of the left lung were examined by light microscopy: the large hilar bronchus, a medium-sized bronchus, and peripheral lung. The number of PMNs and mast cells in the airway wall were expressed as cells/mm length of airway circumference and in the lung periphery as cells/100 alveolar profiles. Both endotoxin and PMA caused a significant 2- to 3-fold increase in number of PMNs/mm of large airway circumference, the majority of PMNs being in the blood vessels of the lamina propria and submucosa; ZAP caused only minimal PMN accumulation in the blood vessels of the submucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

CA 72-4 radioimmunoassay in the diagnosis of malignant effusions. Comparison of various tumor markers.

We evaluated the utility of the CA 72-4, CEA, CA 125, CA 19-9 and CA 15-3 radioimmunoassays for the detection of tumor-associated antigens (TAAs) in effusions of malignant vs. benign origin. Fluids were obtained from 51 patients with adenocarcinomas, 27 with non-epithelial malignancies, and 68 with benign disorders. The CA 72-4 radioimmunoassay (cut-off value 8.5 U/ml) detected the TAG-72 antigen in 51% of adenocarcinoma patients' effusions, while only 1 of 68 benign specimens had an elevated TAG-72 level. Similarly, CEA levels above 5 ng/ml were found in 55% of the fluids from patients with adenocarcinoma and 3.2% of effusions from patients with benign disease. CA 19-9 (cut-off value 37 U/ml) exhibited a lower degree of sensitivity, with positive values in 23.5% of the effusions due to adenocarcinomas and in 4.5% of the effusions due to benign disease. At a cut-off value of 29 U/ml, CA 15-3 was positive in 49% of fluids from patients with adenocarcinoma and in 3.0% of the benign fluids. The CA 125 RIA failed to show any specificity using the established cut-off value of 35 U/ml, with approximately 80% of all the effusions giving positive results. The specificity of the assay was increased by using a cut-off value of 3000 U/ml, but with a substantial loss in sensitivity (23.5%). Using a combination of the CA 72-4 and CEA RIAs the sensitivity for malignant effusions was increased to 73.5%. No additional improvement in the overall sensitivity was observed when using the CA 72-4 assay in combination with assays for the other markers, except in the case of 1 effusion. We conclude that the CA 72-4 RIA, possibly in combination with other assays such as CEA, may be useful in distinguishing between adenocarcinomatous and benign effusions.

Adenocarcinoma↗
PubMed1990

Serological mapping of the TAG-72 tumor-associated antigen using 19 distinct monoclonal antibodies.

Monoclonal antibody (MAb) B72.3 has been shown to be of potential utility in the management of human carcinoma via its use in (a) the targeting of carcinoma lesions in colorectal and ovarian cancer patients, (b) immunohistochemical analyses of biopsies and effusions, and (c) serum assays to help define the presence of carcinoma. The B72.3-reactive antigen, designated tumor-associated glycoprotein 72 (TAG-72), has been characterized as a high molecular weight glycoprotein with the properties of a mucin. We report here the utilization of MAb B72.3 and 18 second generation MAbs (generated using purified TAG-72 obtained from a colon carcinoma xenograft as immunogen) to construct a serological map of the TAG-72 molecule. The generation and initial characterization of 10 of the second generation MAbs have been described previously; in addition, eight previously unreported MAbs were used. All 19 MAbs produced immune precipitate lines against purified TAG-72 in double immunodiffusion, indicating that each epitope recognized by a single MAb is present at least twice on the TAG-72 molecule. Immunodepletion analyses utilizing 11 of the anti-TAG-72 MAbs indicated that each recognizes the same molecule or population of molecules. Nineteen competition radioimmunoassays were developed and 19 purified competitor immunoglobulins were used in each assay. The patterns of cross-competition indicated the presence of a complex array of tumor-associated epitopes on the TAG-72 molecule. Some of the MAbs recognized epitopes that were structurally or spatially related to one another, but none appeared to recognize identical epitopes. The spectrum of inhibitory reactivities of these MAbs for TAG-72 binding varied from extremely restricted to more broad inhibition. The serological mapping studies reported here provide information as to the range and nature of the epitopes expressed on the TAG-72 molecule, help form the basis for selecting alternative anti-TAG-72 MAbs for use in potential clinical applications, and further define the nature of this oncofetal antigen.

Antibodies, Monoclonal↗
PubMed1990

Advantage of dose fractionation in monoclonal antibody-targeted radioimmunotherapy.

Monoclonal antibody (MAb) B72.3 IgG was radiolabeled with 131I and administered to female athymic NCr-nu mice bearing the LS-174T human colon adenocarcinoma xenograft to determine if fractionation of MAb dose had any advantage in tumor therapy. In the LS-174T xenograft, only approximately 30%-60% of tumor cells express the B72.3-reactive TAG-72 antigen. The LS-174T xenograft was used to reflect the heterogeneity of the TAG-72 antigen often seen in biopsy specimens from patients. In contrast to a single 600-muCi dose of 131I-B72.3 IgG where 60% of the animals died from toxic effects, two 300-muCi doses of 131I-B72.3 IgG (total of 600 muCi) reduced or eliminated tumor growth in 90% of mice, with only 10% of the animals dying from toxic effects. Dose fractionation even permitted escalation of the dose to three doses (each 1 wk apart) of 300 muCi of 131I-B72.3 IgG (for a total of 900 muCi), resulting in even more extensive tumor reduction or elimination and minimal toxic effects. The use of an isotype-matched control MAb revealed a nonspecific component to tumor growth retardation, but the use of the specific B72.3 IgG demonstrated a much greater therapeutic effect. Tumors that had escaped MAb therapy were analyzed for expression of the B72.3-reactive TAG-72 antigen with the use of the immunoperoxidase method; they were shown to have the same antigenic phenotype as the untreated tumors. We verified tumor elimination by killing the test animals after a 7-week observation period and performing histologic examination of tumor sites. We also monitored toxic effects by histologic examination of numerous organs, including bone marrow. These studies thus demonstrate the advantage of dose fractionation of a radiolabeled MAb for tumor therapy. We anticipate that the concept of dose fractionation can be practically applied in radioimmunotherapeutic clinical trials with the development and use of recombinant-chimeric MAbs and modified constructs.

Animals↗
PubMed1990

Enhanced tumor binding using immunohistochemical analyses by second generation anti-tumor-associated glycoprotein 72 monoclonal antibodies versus monoclonal antibody B72.3 in human tissue.

Monoclonal antibody (MAb) B72.3 was generated using a membrane-enriched fraction of a human mammary carcinoma biopsy. It has demonstrated reactivity to the majority of human adenocarcinomas including colorectal, gastric, pancreatic, ovarian, endometrial, mammary, and nonsmall cell lung cancer as well as weak or nondetectable reactivity to the majority of normal adult tissues, with the exception of secretory endometrium. Radiolabeled B72.3 has demonstrated MAb localization of carcinoma in approximately 70% of several hundred colorectal and ovarian carcinoma patients. The B72.3-reactive antigen, tumor-associated glycoprotein 72, has been purified from a human colon cancer xenograft and used as an immunogen to generate second generation MAbs. Twenty-eight of these MAbs, designated CC (colon cancer), were shown to be reactive with tumor-associated glycoprotein 72; direct-binding radioimmunoassays, Western blotting, live cell surface binding assays, liquid competition radioimmunoassays, and affinity constant measurements distinguished CC MAbs from each other and from B72.3. Two of these MAbs, CC49 and CC112, were selected for further immunohistochemical characterization. These MAbs were tested here against a spectrum of normal, benign, and malignant human adult tissues using the avidin-biotin-peroxidase technique, and their reactivity was compared with B72.3. Both CC MAbs were more reactive than B72.3 against a range of tumors. Extensive testing with MAbs CC49 and B72.3 using serial tissue sections demonstrated that both MAbs reacted similarly to most normal adult tissues with MAb CC49 reacting stronger to inflammatory colonic tissue. In 35 of 48 (72%) carcinoma biopsies of the gastrointestinal tract, ovary, breast, and lung in which one of the MAbs reacted to at least 20% of the cells, CC49 reacted to a greater percentage of carcinoma cells and/or tumor-associated mucin than B72.3. The reciprocal was observed in only 2% of the carcinomas. This study thus provides evidence that these second generation anti-tumor-associated glycoprotein MAbs may be more efficient than B72.3 in the further study of human carcinoma cell populations and in the diagnostic and therapeutic procedures presently being pursued with MAb B72.3.

Adenocarcinoma↗
PubMed1990

The application of monoclonal antibodies in the cytologic evaluation of tumors.

The focus of this review has been the application of MAbs as adjuncts in the interpretation of cytology specimens. It is evident that most if not all of the MAbs studied thus far are neither completely tumor-specific nor -sensitive; however, when used to address a directed clinical question, they may be "operationally specific." More important, there continues to be no current substitute for the understanding and practice of sound diagnostic cytopathologic principles. Ultimately, the application of MAbs resides in the importance of tumor-associated antigen expression and phenotyping of tumors with therapeutic and prognostic implications.

Antibodies, Monoclonal↗
PubMed1989

Serologic mapping and biochemical characterization of the carcinoembryonic antigen epitopes using fourteen distinct monoclonal antibodies.

A series of 14 monoclonal anti-carcinoembryonic antigen (CEA, Mr 180,000) antibodies (MAbs) that show a strong degree of selective reactivity for human colon carcinomas versus normal adult tissues were used to construct a serological map of the CEA molecule. The MAbs were generated using extracts of colon carcinomas as immunogen and are thus given a COL designation. None of the 14 COL-MAbs tested were reactive with purified non-specific cross-reacting antigen (NCA, Mr 55,000) from normal lung, although some showed reactivity to human granulocytes. All the COL-MAbs tested were reactive with normal fecal antigen-2 (NFA-2, Mr 170,000); however, many of the COL-MAbs demonstrated a higher affinity constant to CEA than to NFA-2. Cross-competition radioimmunoassays classified the 14 COL-MAbs into 5 groups. The chemical nature of the COL-binding domains was tested using chemically or enzymatically treated CEA; all reacted with periodate-treated CEA and deglycosylated CEA, indicating that the COL-reactive epitopes appear to be of a proteinaceous nature. Heat treatment, reduction, alkylation, pepsin digestion or pronase treatment of CEA, however, gave differential results with respect to COL binding. Antibody titration experiments were carried out to define differential reactivities to colorectal carcinoma versus NCA-containing granulocyte extracts; these results were compared with results obtained using several anti-CEA MAbs that have been used in clinical trials. Granulocyte binding and biochemical studies showed that the COL MAbs may distinguish as many as 7 to 10 CEA epitopes.

Animals↗
PubMed1989

A monoclonal antibody (D612) with selective reactivity for malignant and normal gastro-intestinal epithelium.

We describe the generation and characterization of a monoclonal antibody (MAb), designated D612, with selective reactivity for malignant and normal gastro-intestinal epithelium. MAb D612, a murine IgG2a, was generated using a membrane-enriched fraction of a human colon carcinoma biopsy as immunogen. Employing radioimmunoassays (RIAs) of biopsy extracts to a range of normal and neoplastic tissues, and both immunofluorescence and immunoperoxidase assays on frozen sections of a range of normal and neoplastic tissues, we have shown that MAb D612 binds to 82% of colorectal carcinomas tested (n = 67) and to normal gastro-intestinal epithelium, but does not bind similarly to either neoplastic or normal tissues from a wide range of other sites. Western blotting has shown MAb D612 to react with a high-molecular-weight antigen. Live cell RIAs and FACS analyses demonstrate the reactive epitope to be present on the surface of colon carcinoma cells. Immunohistochemical studies have shown intense membrane staining of colon adenocarcinomas with MAb D612; the vast majority of both primary and metastatic colon adenocarcinomas from a variety of sites were positive with many lesions showing homogeneous staining of virtually all cells present. Using human effector cells, we also showed that MAb D612 mediates antibody-dependent cell-mediated cytotoxicity (ADCC) of human colon carcinoma cells; this activity was enhanced in the presence of interleukin (IL-2). Radiolabelled D612-purified IgG selectively binds a human colon carcinoma xenograft in situ. The pattern of membrane-associated staining, the molecular weight of the reactive antigen, the IgG2a isotype, the ability to mediate ADCC in the presence of IL-2, and the immunohistochemical and RIA studies demonstrating highly restricted reactivity to malignant and normal gastro-intestinal tissue, all distinguish MAb D612 from other MAbs thus far described.

Adenocarcinoma↗
PubMed1989

Selective interferon-induced enhancement of tumor-associated antigens on a spectrum of freshly isolated human adenocarcinoma cells.

Freshly isolated cells from patients with pleural or peritoneal effusions cytologically diagnosed as adenocarcinoma (n = 43), malignant nonepithelial neoplasms (n = 10), and benign (n = 8) were analyzed for expression of constitutive levels of the tumor antigens TAG-72 [recognized by monoclonal antibody (MAb) B72.3] and carcinoembryonic antigen (CEA) (recognized by MAb COL-4) as well as the class I and class II major histocompatibility (MHC) antigens, and the ability of human interferons (Hu-IFNs) to enhance cell surface expression of those antigens as measured by MAb binding. Both type I and type II IFNs enhanced the expression of TAG-72 and CEA and altered the level of expression of the MHC antigens. Comparative studies of three different Hu-IFNs (IFN-alpha A, IFN-beta ser, and IFN-gamma) revealed that IFN-gamma was the most potent in augmenting either B72.3 or COL-4 binding. Unlike the IFN-gamma -mediated induction of the class II human leukocyte antigens, the change in tumor antigen expression consisted of enhanced constitutive antigen expression; de novo induction of either TAG-72 or CEA could not be achieved by either type I or type II IFN. Of 43 effusions isolated from different adenocarcinoma patients, 42 (97.7%) expressed either CEA or TAG-72, and treatment with Hu-IFN increased the level of expression of either antigen in 36 of 42 samples (85.7%). These studies demonstrate the augmentation of tumor-associated antigens on human carcinoma cells isolated from serous effusions by Hu-IFNs which may be used to enhance the targeting of conjugated MAbs to human carcinoma lesions.

Adenocarcinoma↗
PubMed1988

Generation and characterization of B72.3 second generation monoclonal antibodies reactive with the tumor-associated glycoprotein 72 antigen.

Monoclonal antibody (MAb) B72.3 was generated using a membrane-enriched fraction of a human mammary carcinoma biopsy. It has demonstrated reactivity to the majority of human adenocarcinomas including colorectal, gastric, pancreatic, ovarian, endometrial, mammary, and non-small cell lung cancer and no or weak reactivity to normal adult tissues, with the exception of secretory endometrium. The B72.3-reactive antigen, termed tumor-associated glycoprotein (TAG)-72, has been purified and used as an immunogen to generate B72.3 second generation MAbs. Since the source of purified TAG-72 was a human colon cancer (CC) xenograft, these MAbs have been given a CC designation. Twenty-eight CC MAbs, all immunoglobulin Gs, have been generated and shown to be reactive with TAG-72 and via both radioimmunoassay and immunohistochemical analyses show differential reactivity to carcinoma versus normal adult tissue biopsies. Nine CC MAbs (CC11, 15, 29, 30, 40, 46, 49, 83, and 92) were selected for further characterization. As a result of analyses using direct-binding radioimmunoassay to a range of human carcinomas, Western blotting, live cell surface binding assays, five liquid competition radioimmunoassays, and Ka measurements, all nine CC MAbs could be distinguished from each other and from B72.3. The Ka of B72.3 was determined to be 2.54 X 10(9) M-1; all the CC MAbs demonstrated higher KaS with MAbs CC92, 49, and 83 having KaS of 14.26, 16.18, and 27.72 X 10(9) M-1, respectively. These studies thus demonstrate that one or more of the anti-TAG-72 CC MAbs may be more efficient than B72.3, or useful in combination with B72.3, toward the further study of human carcinoma cell population and the diagnostic and therapeutic procedures presently utilizing MAb B72.3.

Animals↗
PubMed1987

Complementation of anti-CEA and anti-TAG-72 monoclonal antibodies in reactivity to human gastric adenocarcinomas.

Monoclonal antibody (MAb) B72.3 and MAb COL-4 are reactive with the high-molecular-weight (Mr greater than 10(6] tumor-associated glycoprotein (TAG)-72, and the Mr 180,000 carcino-embryonic antigen (CEA), respectively. Antibody competition radioimmunoassays (RIAs) using 125I-MAb B72.3 or 125I-COL-4 have demonstrated that each MAb also recognizes a distinct antigenic determinant. Solid-phase RIAs using MAbs B72.3 and COL-4, however, demonstrated similar reactivity for each MAb with gastric carcinomas versus normal gastric mucosa. Tissue sections from all of 17 gastric adenocarcinomas also reacted with both MAb B72.3 and MAb COL-4 when immunoperoxidase techniques were used. Double-staining techniques using both MAbs on the same section were performed on formalin-fixed, paraffin-embedded gastric tissue sections using the combination of avidin-biotin peroxidase complex and avidin-biotin alkaline phosphatase complex immunohistochemical methods. The double-staining technique revealed that some carcinoma cells react with MAb B72.3, some react with MAb COL-4, and others react with both MAbs. This technique has demonstrated that more carcinoma cells can be detected by both MAbs as compared to the number of stomach carcinoma cells shown to be reactive with either one or the other MAb. These studies thus define the rationale for the use of combinations of MAbs which recognize different tumor-associated antigens as immunological adjuncts for detection and perhaps therapy of gastric carcinoma.

Adenocarcinoma↗
PubMed1987

Applications of immunocytochemistry to clinical cytology.

This article reviews the recent studies reporting the applications of immunocytochemistry to diagnostic problems in clinical cytology. A series of studies with monoclonal antibody (MAb) B72.3 is discussed in detail. MAb B72.3, reactive with a high molecular weight, glycoprotein, tumor-associated antigen, designated TAG-72, has been shown previously to be reactive with formalin-fixed, paraffin-embedded tissue sections of adenocarcinomas of the ovary, colon, and breast, but not a variety of normal adult tissues. It has demonstrated utility as an immunocytochemical adjunct to diagnose carcinoma in cell block and cytocentrifuge preparations of human serous effusions, with selective reactivity for tumor cells (particularly adenocarcinoma) over reactive mesothelium. Using the avidin-biotin complex (ABC) method of immunoperoxidase staining and formalin-fixed, paraffin-embedded cell suspensions, MAb B72.3 detected tumor cells in effusions from the majority of patients with adenocarcinoma of the breast. No reactivity was demonstrated in any cell type in benign effusions. In contrast, MAb B72.3 showed no reactivity to leukemic or lymphomatous effusions, or to mesothelial cells from malignant effusions. MAb B72.3 also detected tumor cells in effusion specimens from most of the patients with "non-small cell" carcinoma of the lung and with carcinoma of the ovary. MAb B72.3 was also used with fine-needle aspiration biopsies (FNABs) and corresponding surgically excised tumors to determine cellular reactivity. Positive staining with MAb B72.3 was observed in needle aspirates of the great majority of "non-small cell" carcinomas of the lung, adenocarcinomas of the breast, adenocarcinomas of the colon, and carcinomas from other body sites. In contrast, small cell carcinomas of the lung, malignant melanomas, lymphomas, sarcomas, and glial tumors stained negatively with the antibody. Most benign lesions from the breast, lung, pancreas, parotid, and thyroid also showed no staining. In many patients, tumor-bearing tissue had also been resected and was available for comparative examination with MAb B723. In more than 90% of these patients, the staining patterns of tumor cells in the aspirates were found to be predictive of the patterns of antibody reactivity in the comparable surgically resected tumors. From these studies it is concluded that MAb B72.3 defines a tumor-associated antigen that is expressed in neoplastic cells versus benign cells, is most selectively expressed in carcinomas, and may be used as a novel adjunct for the diagnosis of neoplasms in effusions and in FNABs.

Animals↗
PubMed1982

Isolation of large numbers of fully viable human neutrophils: a preparative technique using percoll density gradient centrifugation.

Techniques were developed for the isolation of human neutrophils from large volumes of human blood. This preparative procedure avoids exposure to Ficoll/Hypaque and offers a low cost alternative to centrifugal elutriation. First, leukocyte-enriched suspensions were obtained by treating buffy coats with 2% dextran. The leukocyte suspensions were then fractionated on three steps Percoll density gradients. The gradients were designed to carry large numbers of cells while maintaining resolution of the cell peaks. As a result, at least 320 X 10(6) leukocytes could be processed on a single 12 ml gradient. Extensive testing of the procedure showed that the purity of the neutrophil band was 96.5 +/- 3.16% (n = 50). The band contained 82.4 +/- 14.6% (n = 39) of the neutrophils applied to the gradient. Viability assays (bacterial killing, chemotaxis) demonstrated that neutrophils isolated on Percoll gradients were just as active as those harvested by centrifugal elutriation. Recovery data are presented and compared to the results obtained by others.

Blood Bactericidal Activity↗
PubMed1971

Listeria monocytogenes meningitis: an opportunistic infection.

Meningitis caused by L. monocytogenes is discussed from the standpoints of clinical presentation and course, underlying illness, and altered host resistance. The `opportunistic' nature of the infection is emphasized, and case histories of patients with diseases which may specifically alter host resistance in such a fashion as to render the patient susceptible to this organism, or who are receiving drugs which may have the same result, are presented. The critical role of host macrophages, and the alteration of this role by Hodgkin's disease, leukaemia, and cytotoxic drug therapy are emphasized.

Adolescent↗