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T M Grogan

Publications and source records attributed to T M Grogan.

At least 91 records · Page 5Linked to original sources
PubMed1990

Effects of interleukin-4 on the in vitro growth of human lymphoid and plasma cell neoplasms.

Recombinant human interleukin-4 (rhIL-4) has pleiotropic biologic effects including stimulation of normal B-cell growth. We investigated the effects of rhIL-4 on the in vitro growth of 35 fresh human lymphoid and plasma cell malignancies. Inhibition of growth was seen in 52% and 60% of multiple myeloma and lymphoma specimens, respectively. Growth was stimulated relative to control in 8.6% (3 of 35) of the tumors tested. Immunophenotyping showed that tumors displaying growth stimulation expressed surface markers associated with a poor clinical prognosis. Our findings support the clinical evaluation of rhIL-4 as a therapeutic agent in selected patients with lymphoid and plasma cell neoplasms.

Antigens, Neoplasm↗
PubMed1990

Immunobiologic factors predictive of clinical outcome in diffuse large-cell lymphoma.

The prognostic importance of immunobiologic factors in diffuse large-cell lymphoma (DLCL) is studied in 105 consecutive DLCL patients. Multivariate results using the Cox proportional hazards model clearly indicate that the Ki-67 index (P = .002), a marker of cell proliferation activity, and the presence or absence of human leukocyte antigen-DR (HLA-DR) (P = .007) are strong predictors of survival even in the presence of established clinical factors of stage (P = .015) and symptoms (P = .050). Using these four variables, prognostic groups were formed identifying patient groups with varying degrees of risk. The group of patients with three or four risk factors present at the time of diagnosis had a median survival of 4 months compared with a median survival of 59 months for the group with no risk factors. Similarly, prognostic groups for disease-free survival (DFS) were constructed based on the proportional hazards model that involved B versus T phenotype (P = .035) and HLA-DR (P = .054). Median DFS for the patient group with one or two risk factors present was 11 months compared with 43 months with no risk factors present. This study suggests immunobiologic parameters are important predictors of clinical outcome in DLCL patients and are of value in identifying subgroups of patients who have not responded to currently available therapy. The practical significance of this study is to identify parameters that may suggest specific changes in therapy of patient subgroups.

Aged↗
PubMed1990

T-cell antigen-positive multiple myeloma.

We report the simultaneous expression of T-cell antigens on the myeloma cells from six patients with multiple myeloma (MM). These six patients come from a total population of 215 samples (115 direct samples, clinical incidence of 5.2%) of plasmacytic malignancies immunotyped at the University of Arizona. Four patients expressed T helper antigen (Leu 3, CD4), one expressed T-cell antigen receptor (Leu 4, CD3), and one expressed E-rosette antigen receptor (Leu 5, CD2). The presenting clinical features, histology, and plasma cell morphology showed no differences from multiple myeloma patients who did not express T-cell antigen. However, although the survival duration ranged from 5 to 93 mo overall, survival from demonstration of T antigen expression was very short, (2 to 7+ mo), with five of six (80%) patients dying less than or equal to 5 mo after study. The reason for T antigen expression is unknown. It may indicate that myeloma can arise from a normally minor subpopulation of B cells involved with immunoregulation; conversely, it could be a coincidental aberrancy associated with malignant change in the plasma cells.

Adult↗
PubMed1990

Tumor-infiltrating T-lymphocytes in B-cell diffuse large cell lymphoma related to disease course.

Recent data from studies of experimental murine tumors and certain human tumors (primarily melanoma) suggest that tumor-infiltrating T-lymphocytes (T-cell TILs) represent a highly potent and specific host antitumor response. We conducted an immunohistochemical analysis of the T-cell TIL subpopulations in frozen tissue sections taken from 82 consecutive B-cell diffuse large cell lymphoma (DLCL) patients. Initially, we analyzed the relationship in these patients between relapse-free survival (RFS) and their T-cell TIL characteristics. Nineteen patients had a low percentage (less than 6% of Leu-2+ (suppressor/cytotoxic) T-cell TILs, and 63 patients had a high percentage (greater than 6%) of Leu-2+ TILs. We found that a low percentage of Leu-2+ TILs correlated with a reduction in RFS: at 20 mo follow-up, all 19 low Leu-2+ patients had relapsed, whereas 70% of the 63 high Leu-2+ patients remained relapse-free (P = 0.008). No significant correlations appeared between patients' T-cell TIL subsets and overall survival. The percentage of newly diagnosed tumors with low counts of Leu-4+ (pan-T) TILs was marginally greater among interleukin-2 (IL-2) receptor-positive tumors than among IL-2 receptor-negative tumors (50 versus 28%, P = 0.098), which suggests that specific phenotypic characteristics of B-cell DLCL may modulate the host T-cell TIL response. Our results indicate that the host's T-cell TIL response in B-cell DLCL can be quantitated from frozen tissue sections and that this response may be related to disease course. Further related TIL studies may lead to new immunorestorative therapeutic approaches for patients with deficient or aberrant cytotoxic T-lymphocyte host responses.

Adolescent↗
PubMed1989

Prediction of doxorubicin resistance in vitro in myeloma, lymphoma, and breast cancer by P-glycoprotein staining.

Prior studies have shown that the P-glycoprotein is a cell membrane efflux pump that is quantitatively increased in expression in multidrug-resistant tumor cell lines. In this study, fresh tumor tissues from patients with multiple myeloma, malignant lymphoma, or metastatic breast cancer were studied immunohistochemically for P-glycoprotein expression and for in vitro sensitivity to doxorubicin. Twenty-six patients who were either previously untreated or in relapse after chemotherapy had tumor specimens submitted that could be evaluated in both assays. The testing was done independently and blindly in separate laboratories instead of our being provided relevant clinical data on the patients. Tumor cells from 12 of the 26 patients (46%) stained positively for P-glycoprotein. Fifteen of the 26 specimens (58%) exhibited drug resistance in vitro. Although only three (21%) of the 14 P-glycoprotein-negative tumors exhibited in vitro resistance to doxorubicin, all 12 fresh tumors that stained positively for P-glycoprotein were resistant to doxorubicin. The difference in frequency of intrinsic doxorubicin resistance between P-glycoprotein-negative and -positive tumors was highly significant (P less than .001). Similar trends were observed in each of the individual tumor categories and were statistically significant in myeloma and breast cancer. Four of the biopsy specimens that stained positively for P-glycoprotein and exhibited doxorubicin resistance were from patients who had not received prior cytotoxic chemotherapy. Similar conclusions were reached when results of drug sensitivity tests were ranked in relation to the median infective dose rather than by criteria based on correlations with clinical drug resistance. Our findings indicate that positive staining for P-glycoprotein associated with multidrug resistance predicts intrinsic cellular resistance of human cancers to doxorubicin. We anticipate that immunohistochemical staining for P-glycoprotein will prove useful in clinical oncology.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Myelomonocytic myeloma cell line (LB 84-1).

A human cell line (LB 84-1) has been established from the bone marrow of a patient with Bence-Jones myeloma. Coexpression of plasma cell (Leu[CD38]) and myelomonocytic antigens (Leu MI[CD15], Leu M5 [CD11c], MY7 [CD13] plus butyrate and chloracetate esterase) proved to be an unusual but sustained feature of this cell line. The plasma cell phenotype with multinuclearity was retained. Shared major chromosomal abnormalities (del [5] [p14], t[5;?] [q35;?], del [6] [q21], and del 7[q32]) between the direct and cell line karyotypes affirmed the LB 84-1 cell as being derived from the original patient myeloma clone. The mechanisms potentially responsible for the aberrant coexpressed phenotype are discussed. This myelomonocytic myeloma cell line will hopefully prove to be a valuable tool for the study of the genotypic and phenotypic evolution of human myeloma.

Antigens, Differentiation, Myelomonocytic↗
PubMed1989

Immunohistochemical detection and quantitation of P-glycoprotein in multiple drug-resistant human myeloma cells: association with level of drug resistance and drug accumulation.

Using several multiple drug-resistant human myeloma cell lines as standards, we developed an immunohistochemical staining technique and means of quantitating P-glycoprotein in individual myeloma cells. The level of staining intensity for P-glycoprotein in individual myeloma cells was quantitated by measuring the average optical density of each cell with a microscopic computerized cell analysis system. Using this system, we observed that the level of P-glycoprotein for individual cells within a cell population of known drug sensitivity was very homogeneous (coefficient of variation less than or equal to 13%). Analysis of cell lines with gradually increasing levels of multidrug resistance (8226/S, 8226/Dox6 and 8226/Dox40) demonstrated a close association between the level of resistance to doxorubicin, defined by the mean lethal dose (D0) and the amount of P-glycoprotein on individual cells determined by the optical density (r = 0.82, P less than 0.0005). Intracellular doxorubicin (DOX) accumulation in the individual cell lines was inversely related to the level of drug resistance expressed as D0. P-glycoprotein was also detected in the marrow-derived myeloma cells of patients with drug refractory disease using immunohistochemical staining. The amount of P-glycoprotein in the cells of one patient was directly compared to the amount found in the simultaneously stained standard cell lines (8226/Dox6 and 8226/Dox40) by comparing the optical densities for individual cells. Using this immunohistochemical technique to detect and quantitate P-glycoprotein in patient myeloma cells and comparing it to standard multidrug resistant myeloma cell lines may be of value in determining the contribution of P-glycoprotein to clinical drug resistance in patients with multiple myeloma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Myelomonocytic antigen positive multiple myeloma.

In a four year span, between 1983 and 1987, 215 bone marrow and cell culture samples from 125 myeloma patients were immunotyped and coexpression of myelomonocytic and plasma cell antigens occurred in 16 (13%). We employed both immunohistochemical and flow cytometry methods including coplots and double labelling. Three types of myeloma cases were found: (1) those with isolated myeloid antigen coexpression, usually Leu M1 or esterase (BE, CE) positive (11 cases); (2) those with multiple myeloid antigens (Leu M1, M3, M5, MY7, BE, CE) (four cases); and (3) one case beginning as 1 and ending as 2. Isolated myeloid antigen expression was generally associated with typical features of myeloma with survival close to the anticipated median (33 months), while multiple myeloid antigen expression was associated with more aggressive disease and shorter survival duration (median survival 16 months). The latter subgroup also had other poor prognostic factors including high labelling index and common acute lymphoblastic leukemia antigen (CALLA) positivity. Other features found overall were frequent abnormal karyotypes (seven of 12 abnormal) and coexpressed IgA (eight of 16); all IgA+ cases also coexpressed Leu M1. We conclude that there is an unusual and unexpected predilection for coexpression of myelomonocytic antigens in myeloma cells. The reasons are not immediately obvious. Whether the coexpression indicates that myeloma cells truly have latent multilineage potential or just aberrantly coexpress other hematopoietic antigens as a manifestation of malignancy remains to be explained. However, a cell line established from the bone marrow of one patient is a valuable scientific tool allowing detailed analysis of these questions.

Antigens, Differentiation, Myelomonocytic↗
PubMed1989

The use of intravenous ribavirin to treat influenza virus-associated acute myocarditis.

We studied three patients with influenza virus-associated fulminant myocarditis; one was infected by type B and the others by type A influenza virus. In one patient, dissemination of type A (H1N1) virus to the myocardium was demonstrated, and viremia complicated the clinical course despite the use of oral amantadine HCl and ribavirin aerosol. All patients were treated with iv ribavirin, two initially and the third after viremia was detected during hyperacute rejection of a cardiac transplant. No significant adverse effects could be directly attributed to therapy, and viral shedding abruptly terminated coincident with its use; however, both patients treated shortly after onset of myocarditis died. The third required support by an artificial heart, and died 8 mo later. Immunotyping of myocardial tissues in two cases revealed an initial predominance of T helper cells. Serial endomyocardial biopsies available from one of these demonstrated a subsequent marked decrease in the T helper cell population as inflammation and necrosis subsided during and following therapy.

Acute Disease↗
PubMed1989

Drug-resistance in multiple myeloma and non-Hodgkin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy.

The B-cell neoplasms, multiple myeloma and non-Hodgkin's lymphoma, frequently become drug resistant, despite initial responses to chemotherapeutic drugs. Tumor cells from eight patients with clinically drug-refractory disease were evaluated by immuno-histochemical staining for monoclonal immunoglobulin (Ig) expression, nuclear proliferation antigen, P-glycoprotein (P-gly) expression, and other cellular antigens. P-gly was detected on tumor cells from six of eight patients with drug-resistant disease. Of the six patients with P-gly-positive tumors, five patients had advanced multiple myeloma and one had a drug-refractory non-Hodgkin's lymphoma. Cellular RNA analysis confirmed the over-expression of P-gly. In an effort to overcome drug resistance, a pilot study evaluated possible verapamil enhancement of chemotherapy in these eight patients. All patients had developed progressive disease while receiving a regimen containing vincristine and doxorubicin, and seven of eight patients had previously received continuous infusion vincristine and doxorubicin plus oral dexamethasone (VAD). At the time of progressive disease, continuous infusion verapamil was added to the VAD regimen. Three of the eight patients who were refractory to vincristine and doxorubicin alone responded when verapamil was added to VAD. The three patients who responded had P-gly-positive tumors. Verapamil increased the intracellular accumulation of doxorubicin and vincristine in vitro for both a P-gly-positive myeloma cell line and tumor cells from two patients with end-stage myeloma which over-expressed P-gly. The dose-limiting side effect associated with the addition of verapamil to chemotherapy was temporary impairment of cardiac function, manifest as hypotension and cardiac arrhythmia. We conclude that P-gly expression occurs in drug-refractory B-cell neoplasms and may contribute to the development of clinical drug resistance. However, other factors, such as the proliferative activity of the tumor, may also play a role in determining response to chemotherapy. The administration of verapamil along with VAD chemotherapy may partially circumvent drug resistance in patients whose tumors over-express P-gly.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Immunophenotyping to detect and characterize acute lymphocytic leukemia in testicular biopsies.

This study establishes the utility of immunophenotyping testicular biopsy specimens in patients with acute lymphoid leukemia. The value of immunophenotyping in detecting or excluding leukemic testicular infiltration is demonstrated in six children with acute lymphocytic leukemia. A panel of monoclonal antibodies was employed on snap-frozen testicular biopsies, allowing both detection and immunologic characterization of four neoplastic lymphocytic infiltrates. Two samples were proven both histologically and phenotypically negative for leukemic infiltration. One of the four leukemic cases was clinically silent and might have escaped detection except for phenotyping. One leukemic infiltrate was also suspected to possess a multidrug-resistant phenotype (p-glycoprotein +); the latter possibility was excluded by an absence of reactivity with anti-p-glycoprotein monoclonal antibody. Thus, three clinically useful applications are demonstrated: (1) confirmation of testicular leukemic relapse, gaining assertion in histologically uncertain cases; (2) exclusion of clinically suspected disease relevant to cessation of therapy, and (3) detection/exclusion of drug-resistant phenotypes. Unexpectedly, we found expression of plasma cell-associated antigen in testicular germ cells, which may prove to be diagnostically useful in the future evaluation of germ cell tumors.

Antibodies, Monoclonal↗
PubMed1989

Ultrastructural morphometry distinguishes Burkitt's-like lymphomas from neuroendocrine neoplasms: useful criteria applied to the evaluation of a poorly differentiated neuroendocrine neoplasm of the nasal cavity masquerading as Burkitt's-like lymphoma.

The present study describes the potential usefulness of ultrastructural morphometry in diagnosis. Ultrastructural morphometric criteria were applied to the evaluation of a poorly differentiated neuroendocrine neoplasm of the nasal cavity that was initially thought to be a Burkitt's-like lymphoma (BLL). Although the nasal lesion in question failed to stain with over 50 cell lineage-relevant antibodies, it did stain for vimentin (an intermediate filament protein) and Ki-67 (a nuclear antigen associated with cell proliferation). Routine electron microscopy revealed a primitive neoplasm with abundant cytoplasmic lipid droplets and sparse dense granules with no intercellular junctions. Treatment options, which included extensive facial surgery, prompted more study. Tissue processed for the uranaffin reaction revealed sparse uranaffin-positive granules indicating the presence of true neurosecretory granules. An ultrastructural morphometric analysis of the neoplastic nuclei of this patient placed the tumor outside the morphometric domains for BLLs (18 cases) and neuroblastomas (11 cases) and within the morphometric domain of neuroendocrine carcinomas (9 cases). A greater mean standard deviation (P less than 0.05) and mean coefficient of variation (P less than 0.02) of nuclear perimeter in the neuroendocrine (NE) group related to the BLL group indicated greater nuclear pleomorphism within the NE group as illustrated in bivariate graphic displays. The possible origin of the neoplasm within the nasal mucosa is discussed.

Burkitt Lymphoma↗
PubMed1988

Lennert's lymphoma. A clinicopathologic study with emphasis on phenotype and its relationship to survival.

In this report we describe the results of a clinical and immunohistochemical analysis of 11 consecutive patients with the specific clinicopathologic entity of Lennert's lymphoma (non-Hodgkin's malignant lymphoma with a multifocal epithelioid histiocytic reaction [MLEH]) evaluated at the Arizona Cancer Center. Detailed immunophenotyping of ten patients showed that seven patients (73%) had an activated "novel" T-cell phenotype, indicative of peripheral T cell lymphoma (PTL). Additionally, six of these seven PTL patients had T-helper (Leu-3) antigen expression to the exclusion of T-suppressor (Leu-2) expression. Three patients, in complete contrast, had a B-cell lymphoma with monoclonal immunoglobulin expression. The B-cell MLEH were morphologically indistinguishable from T-cell MLEH. Clinically, the initial diagnosis proved difficult; ten of the 11 patients were initially misdiagnosed, most often as another lymphoid disorder or as granulomatous disease (mean delay of 10 months in diagnosis from onset of symptoms). The median survival of all patients was 20 months (1 to 45+ months) with two apparent subgroups: those who had rapid progression of disease with a median survival of 5 months, all of T-cell phenotype; and a small group whose median survival has not yet been reached, all of B-cell phenotype. Our results suggest that the immunophenotype, B-cell versus T-cell, may be a major predictor of survival, with B-cell MLEH patients having a longer survival than those of T-cell type.

Adult↗
PubMed1988

Chest radiographic abnormalities in Lennert's lymphoma.

In reviewing the medical records of ten patients with Lennert's lymphoma, we found chest radiographic abnormalities in five cases. Two cases had hilar and mediastinal adenopathy without associated parenchymal or pleural disease, and three cases had isolated pulmonary parenchymal abnormalities. In one patient, both the chest radiograph and the histologic findings, obtained by open lung biopsy, mimicked miliary granulomatous disease. This article emphasizes the need to be alert to this aggressive T-cell neoplasm, since its clinical course differs significantly from some of the diseases it tends to imitate. By being aware of the entity and by using thorough pathologic and immunopathologic techniques, difficult cases of Lennert's lymphoma can be successfully diagnosed.

Aged↗
PubMed1988

HLA-DR (Ia) immune phenotype predicts outcome for patients with diffuse large cell lymphoma.

The clinical utility for establishing the immune phenotype in patients with non-Hodgkin's lymphoma is controversial. To help resolve this dilemma, we studied 104 consecutive patients with diffuse large cell lymphoma, the most common subtype of potentially curable non-Hodgkin's lymphomas. The presence or absence of the human class II histocompatibility antigen was determined using the monoclonal antibody anti-HLA-DR (Ia), and the results correlated with pretreatment clinical features and survival. We found that eight HLA-DR negative patients had similar pretreatment clinical characteristics compared with 96 HLA-DR positive patients, but HLA-DR negative patients had a significantly shorter survival duration compared with HLA-DR positive patients (P = 0.003 log-rank). The median survival of the HLA-DR negative patients was 0.5 years compared to 2.8 yr for the HLA-DR positive patients. No HLA-DR negative patient survived beyond 1.5 yr. A multi-variate analysis, adjusting for prognostic factors of known clinical significance, confirmed the importance of HLA-DR as a prognostic factor (P = 0.016). We conclude that determining the presence of HLA-DR is a relatively simple pretreatment study that identifies a small but important group of patients who are not curable using currently available combination chemotherapy.

Aged↗
PubMed1988

A comprehensive immunotopographic map of human thymus.

We have achieved a comprehensive immunotopographic mapping of human thymus by using a large battery of monoclonal antibodies and the methodological refinement of comparative serial tissue section immunohistochemistry, allowing analysis of multiple phenotypes in the same tissue site. Previous immunohistochemical studies of thymus have concentrated on the majority T-cell and epithelial cell populations. Besides demonstrating the complexity of T-cell antigenic expression (e.g., simultaneous cortical expression of Leu 2, Leu 3, CALLA, Tdt, and Leu 6), we delineate surprisingly complex B-cell zones (e.g., septal B-follicles with DRC+C3d+ dendritic cells and zonal maturation of B-cells). Whereas septal B-follicles were found in 25% of cases, medullary B-cells were universally present as a substantial minority component. This expanded immunotopographic knowledge of the complex T-, B-, epithelial, and reticulum cell neighborhoods suggests that the thymus is an organ capable of a broad repertoire of immunological responses, not limited to T-cell development.

Adolescent↗
PubMed1988

The aberrancy of immunophenotype and immunoglobulin status as indicators of prognosis in B cell diffuse large cell lymphoma.

To assess the prognostic significance of the immunophenotype in diffuse large cell lymphoma (DLCL), 105 DLCL patients were studied between 1978 and 1987 using a panel of 40 monoclonal antibodies applied to frozen tissue. Eighty-three patients were found to have B cell phenotypes, and 20 patients had T cell phenotypes. Focusing on markers relevant to clinical outcome among B cell LCL showed that lack of expression of the pan B antigens Leu14 and Leu16 were correlated with decreased survival (Leu14, P = 0.01; Leu16, P = 0.06; log-rank). HLA-DR activity also showed that lack of expression of this antigen correlated with poor survival (P = 0.004, log-rank). Kappa light chain immunoglobulin lack of expression showed predictive value for decreased survival as well (P = 0.005, log-rank). Multivariate analyses of known clinically important variables and the immune phenotypes confirm that the loss of HLA-DR and B cell aberrancy are independent factors predicting a poor clinical outcome. Losing some B activation/kappa antigens appears to be a broad biologic phenomenon linking surface antigen lack of expression with decreased survival. This suggests that aberrancy of immunophenotype and immunoglobulin status are key predictors of survival in B-LCL.

Antigens, Surface↗