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F I Preffer

Publications and source records attributed to F I Preffer.

At least 37 records · Page 2Linked to original sources
PubMed1994

Flow cytometric analysis of DNA ploidy, percent S-phase fraction, and total proliferative fraction as prognostic indicators of local control and survival following radiation therapy for prostate carcinoma.

PURPOSE: Treatment recommendations for localized prostate cancer may be improved by the identification of tumor factors prognostic for local control and survival. In this retrospective study, flow cytometric deoxyribonucleic acid (DNA) ploidy analysis and cell cycle analysis were performed on paraffin-embedded biopsy material to determine if additional prognostic factors could be identified in patients treated with radiation therapy. METHODS AND MATERIALS: Seventy patients with T1-4NxM0 tumors were identified in whom the primary treatment had been radical radiation therapy with no prior or concurrent endocrine therapy and in whom sufficient prostatic tissue was available for flow cytometric analysis. There were 40 diploid, 26 aneuploid, and 4 multiploid cases. Aneuploid and multiploid cases were combined for analysis. Cell cycle data were obtained on all diploid and 10 aneuploid cases. RESULTS: The histologic differentiation of the tumor (well or moderate vs. poor) was an independent predictor of overall survival and disease-free survival (p = 0.05 and 0.01, respectively). Local control was worse in the poorly differentiated patients, although this was not statistically significant in a multivariate analysis (p = 0.08). Neither T-stage, deoxyribonucleic acid ploidy (diploid vs. nondiploid), percent S-phase fraction, nor total proliferative fraction (S-phase fraction + G2M) significantly predicted for any of these endpoints. Within the diploid and well or moderately differentiated subgroup (n = 25), S-phase (< 4.2 vs. > or = 4.2) was a significant predictor of local control (100% vs. 51%, p = 0.03). A comparable distinction could be made using total proliferative fraction (< 10% vs. > or = 10%) with local control rates of 100% vs. 56% (p = 0.05). Among the poorly differentiated tumors, no similarly favorable subgroup was identified. CONCLUSIONS: This retrospective and multivariate analysis identifies both histology and percent S-phase or total proliferative fraction as predictors of local control following irradiation, and confirms that histology, but not DNA ploidy, is significant for overall survival. If these previously unreported findings are confirmed by prospective studies, S-phase should be added to histology as a parameter in the evaluation of clinical trials.

Cell Division↗
PubMed1994

A comparative study of flow cytometry and histopathologic findings in thyroid follicular carcinomas and adenomas.

As a possible diagnostic aid in the often difficult histopathologic distinction of thyroid follicular carcinomas from adenomas based on invasion most flow cytometry studies have indicated a higher aneuploidy incidence in carcinomas. However, these reports often are difficult to analyze mainly due to nonuniformity of pathologic diagnostic criteria. The present study compares the flow cytometry results of 65 follicular tumors with pathologic findings based on the World Health Organization's specific diagnostic and staging criteria. Aneuploidy was significantly higher in the 28 cancers than in the 27 hypercellular (fetal and embryonal) adenomas (57% v 22%; P = .02). There was a high percentage of aneuploidy (75%; nine of 12 cases) in the widely invasive follicular carcinomas, compared with 40% (six of 15 cases) in the minimally invasive carcinomas, 22% (six of 27 cases) in the hypercellular adenomas, and 10% (one of 10 cases) in the normofollicular or macrofollicular adenomas. However, aneuploidy was not significantly different between the most difficult differential histopathologic diagnoses of minimally invasive follicular carcinoma (40%; six of 15 cases) and hypercellular adenoma (22%; six of 27 cases) (P = .12). Other data included relatively high frequencies of aneuploidy in hypercellular adenomas (29%; six of 21 cases) and diploid status of carcinomas (36%; 12 of 33 cases). In summary, although the overall findings show a trend toward increasing aneuploidy from well-differentiated and hypercellular adenomas to minimally and widely invasive follicular carcinomas, the aneuploidy data are inconsistent and indicative of its nonspecificity and limited diagnostic usefulness.

Adenocarcinoma, Follicular↗
PubMed1993

The AgNOR technique, PCNA immunohistochemistry, and DNA ploidy in the evaluation of choroid plexus biopsy specimens.

The histologic distinctions between normal choroid plexus and choroid plexus papilloma and between choroid plexus papilloma and choroid plexus carcinoma are sometimes difficult. The authors performed the silver nucleolar organizer region (AgNOR) technique, immunohistochemistry for proliferating cell nuclear antigen (PCNA), and DNA ploidy analysis by flow cytometry on 9 samples of normal choroid plexus, 8 papillomas, and 13 carcinomas to evaluate whether these techniques can aid in these differential diagnoses. Significant differences were found in the mean AgNOR count between normal choroid plexus (1.35 +/- 0.11) and choroid plexus papillomas (2.42 +/- 0.81) (P < 0.001), but not between choroid plexus papillomas and carcinomas. In the normal choroid plexus, AgNORs were smooth and round; in the papillomas and carcinomas, however, they varied in size and shape. Compound AgNORs were commonly present in the tumors but were essentially absent in controls. Antibody to PCNA did not stain normal choroid plexus cells (except for focal staining in one sample of normal choroid plexus adjacent to a carcinoma) but stained many papilloma and carcinoma cells. DNA ploidy analysis demonstrated aneuploidy in some papillomas and carcinomas but could not be used for the distinction of normal choroid plexus from papillomas. These results suggested that the AgNOR technique and PCNA immunohistochemistry could be used to distinguish normal choroid plexus from choroid plexus papilloma in small, diagnostically difficult biopsy specimens.

Antigens, Neoplasm↗
PubMed1993

A phase I trial of immunosuppression with anti-ICAM-1 (CD54) mAb in renal allograft recipients.

Several adhesion molecules contribute to the interaction between T cells and antigen presenting cells or target cells. Leukocyte function-associated molecule-1 (LFA-1[CD11a/CD18]) and intercellular adhesion molecule-1 (ICAM-1 [CD54]) are one such critical adhesive receptor-counter-receptor combination. The importance of ICAM-1 dependent adhesion in the rejection response was initially demonstrated in cynomolgus renal allograft recipients treated with the anti-ICAM-1 murine monoclonal antibody BIRR1. BIRR1 also appeared to limit ischemic damage in these animals. A Phase I clinical trial has subsequently been completed in 18 patients who received cadaver donor renal allografts at high risk for delayed graft function (prolonged preservation time, highly-sensitized recipient). An adequate BIRR1 serum level was associated with significantly less delayed graft function (P < .01) and rejection (P < .01). In 1-hr biopsies, mouse IgG was detected along the endothelium of the vessels and glomeruli in the graft. There were no instances of primary non-function (PNF), and current allograft survival (followup: 16-30 months) in these "high-risk" mAb-treated patients is 78%. There were 3 instances of PNF and a graft survival rate of 56% in the recipients of the contralateral kidney allografts treated with conventional immunosuppression. No significant "first-dose" effect was associated with BIRR1 administration. These results establish a dosing schedule and the clinical safety of BIRR1. They also suggest that inhibition of leukocyte adhesion by mAb therapy may be useful in controlling allograft rejection and possibly in limiting reperfusion injury. Thus, these observations support the clinical importance of accessory molecules in T cell function. We hypothesize that anti-CD54 mAb acts by blocking leukocyte adhesion to the endothelium, thereby interfering with sensitization or target cell interaction.

Adolescent↗
PubMed1992

Deoxyribonucleic acid flow cytometry in invasive bladder carcinoma: a possible predictor for successful bladder preservation following transurethral surgery and chemotherapy-radiotherapy.

Tumor deoxyribonucleic acid (DNA) ploidy was evaluated as an objective parameter that may correlate better with the responsiveness of bladder cancer to chemotherapy plus radiotherapy than do clinical features or histopathological subtypes. A total of 40 patients with localized muscle-invading bladder cancer (clinical stages T2 to T4) underwent prospective treatment on a potential bladder preserving protocol. Tumors of 37 of the 40 patients were analyzed by DNA flow cytometry of multiple paraffin embedded specimens. Transurethral resection, neoadjuvant chemotherapy and 40 Gy. radiotherapy plus cisplatin were followed by urological reevaluation of the tumor (a complete response required a negative biopsy and a negative urine cytology study). A total of 7 noncomplete response patients underwent immediate radical cystectomy whereas the full bladder sparing treatment (radiotherapy to 64.80 Gy. plus cisplatin) was given to 23 complete response patients and 7 noncomplete response patients who were unsuited for surgery. Of the tumors 22 (59%) were purely aneuploid and 10 (27%) were purely diploid. Five tumors contained aneuploid and diploid patterns in different tumor specimens (partly diploid). Current status with a 30-month median followup in surviving patients includes an 82% overall survival rate in the aneuploid group versus 47% in the diploid/partly diploid group. Of all the patients 68% are free of invasive tumor: 82% in the aneuploid group versus 47% in the diploid/partly diploid group. By multivariate analysis pure aneuploidy was significantly (p = 0.05) correlated with freedom from invasive tumor in the bladder (either as persistence or as recurrence) and approached significance (p = 0.08) in correlation with overall patient survival. A longer observation time will be required to confirm this unexpectedly good outcome for patients with pure aneuploid tumors. We hypothesize that pretreatment DNA ploidy status may become a clinically useful prognostic factor in selecting patients for successful treatment with transurethral surgery and neoadjuvant chemotherapy plus radiotherapy.

Clinical Protocols↗
PubMed1992

Identification of müllerian inhibiting substance specific binding in human cell lines.

The receptor for Müllerian Inhibiting Substance (MIS), a gonadal glycoprotein hormone, has not been previously identified. Plasma membranes from MIS-sensitive human tumor cell lines (HTB-111, endometrial carcinoma; and A-431, vulvar squamous carcinoma) were detergent extracted and incubated with 125I-labeled MIS anti-idiotypic antibody, or radioiodinated human recombinant MIS (125I rhMIS), with and without unlabeled competitors. 125I anti-idiotypic MIS antibody bound to HTB-111 membrane extracts was displaceable by unlabeled anti-idiotypic antibody, but not by anti-isotypic antibody prior to cross-linking. Specific binding of the anti-idiotypic MIS antibody to endometrial carcinoma cells was verified using fluorescence activated cell analysis and fluoresceinated antibody. Furthermore, unlabeled anti-idiotypic MIS antibody competed for 125I rhMIS binding to A-431 vulvar carcinoma membranes. The labeled anti-idiotypic MIS antibody binding complex could be separated from 32P labeled EGF receptor in the A-431 membranes, indicating that EGF, a natural inhibitor of MIS activity, and MIS itself bind to different receptors. These studies demonstrate a specific, displaceable binder for MIS in the plasmalemmae of two human tumor lines. Purification of this cell surface receptor protein will be greatly aided by using the MIS anti-idiotypic antibody.

Anti-Mullerian Hormone↗
PubMed1992

The effects of OKT4A monoclonal antibody on cellular immunity of nonhuman primate renal allograft recipients.

Significant differences in cellular responses were found among allograft recipients treated with various OKT4A mAb protocols. Recipients of multiple infusion low-dose and 2-bolus OKT4A immunosuppressive regimens regularly showed potent donor-specific cytotoxic CD8+ and CD4+ intragraft T cells and donor-reactive PBMC in MLC tests. In contrast, PBMC isolated from recipients of high-dose OKT4A therapy generally showed very weak or no response to donor-antigens during the later posttransplant periods. Furthermore, an absence of IL2-responsive intragraft cells was found to correlate with stable graft function in these recipients. We conclude that OKT4A mAb, in high doses, can block allosensitization and induce donor-specific nonresponsiveness in vivo. An OKT4A-based therapy, therefore, may have the potential of inducing long-lasting donor-specific immunosuppression, or even tolerance.

Animals↗
PubMed1992

Occurrence of melanoma in "dysplastic" nevus spilus: report of case and analysis by flow cytometry.

We report a case of melanoma arising in a large nevus spilus. On histologic examination, the nevus spilus had diagnostic features of melanocytic dysplasia. Further characterization by flow cytometry showed DNA-aneuploidy within the melanoma as well as in one of the darker pigmented papules within the nevus spilus. The significance of this finding and a review of melanomas originating in nevi spili are presented.

Adult↗
PubMed1991

Most human pulmonary infiltrating lymphocytes display the surface immune phenotype and functional responses of sensitized T cells.

Pulmonary infiltrating lymphocytes (PIL) isolated directly from human lung were examined for their surface immune phenotype by monoclonal antibody staining and cytofluorimetry. In order to purify PIL, resected lungs were enzymatically digested with collagenase and DNase and subjected to density centrifugation and nylon-wool column separation. In some cases, CD4+ lymphocytes were further purified with alpha CD8 and complement. The majority of pulmonary lymphocytes were CD2+ (87 +/- 1%) and CD3+ (73 +/- 4%). Virtually all of the CD3+ PIL were Ti alpha beta+. Greater than 90% of both CD4+ or CD8+ PIL were CD45RO+ and CD45RA-, consistent with prior antigen sensitization in vivo. A subset of CD4+ PIL (34 +/- 4%) expressed Leu8, the human congener of the murine MEL-14 lymphocyte homing receptor, whereas most homologous CD4+ peripheral blood lymphocytes were Leu8+ (75 +/- 8; P less than 0.01). HLA-DR surface antigens were expressed by 45 +/- 5% of CD4+ PIL versus 9 +/- 1% of CD4+ peripheral blood lymphocytes (P less than 0.001). There was no significant difference in the percentage of low-affinity interleukin-2 (IL-2) receptor-positive CD4+ lymphocytes in lung and blood (9 +/- 3% versus 13 +/- 2%). Analysis of the DNA synthetic cell cycle showed that approximately 5% of blood CD4+ lymphocytes and approximately 25% of CD4+ PIL were in S/G2/M. Compared to homologous blood T cells, purified PIL displayed enhanced proliferative responses to IL-2 and diminished responses to the lectin phytohemagglutinin. Lectin-stimulated PIL showed greater secretion of interferon-gamma and IL-2 than did blood lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Laboratory monitoring of therapy with OKT3 and other murine monoclonal antibodies.

The first monoclonal antibody (MAb) approved by the Food and Drug Administration (FDA) for therapeutic use, OKT3, is now a standard treatment for organ allograft rejection. This article reviews the interpretation of laboratory tests used to manage patients treated with MAb. Emphasis is placed on OKT3, with which the experience is also the greatest, although comparisons with other MAbs in clinical trials is also discussed.

Animals↗
PubMed1990

In vivo effects of monoclonal antibody to ICAM-1 (CD54) in nonhuman primates with renal allografts.

These studies test whether allograft rejection can be blocked by interference with leukocyte adhesion, using a murine IgG2a mAb (R6.5) reactive with monkey ICAM-1 (CD54). In 16 Cynomolgus renal allograft recipients, R6.5 was administered prophylactically as the sole immunosuppressive agent for 12 days (0.01 to 2 mg/kg/day). Survival in 14 recipients with technically successful grafts was significantly prolonged (24.2 +/- 2.4 vs 9.2 +/- 0.6 days for controls; p less than 0.001). Intercellular adhesion molecule-1 (CD54) (ICAM-1) was expressed on vascular endothelium in the kidney and other organs in the monkey in a pattern similar to that in humans. During cellular rejection in controls, ICAM-1 expression increased on endothelial cells, infiltrating mononuclear leukocytes and tubular cells. Biopsies during R6.5 administration showed decreased T cell infiltration (CD2, CD8, CD4) compared with controls and decreased arterial endothelial inflammation. No changes occurred in circulating T cells, aside from variable coating with mIgG. In six of eight other recipients R6.5 administration (0.5 to 2 mg/kg/day for 10 days) reversed preexisting rejection that resulted from taper of Cyclosporine to subtherapeutic levels. Responding grafts showed decreased edema and hemorrhage but no consistent change in the infiltrate. At 1 h after the first dose, mouse IgG deposited primarily on the graft vascular endothelium without any change in the inflammatory infiltrate. Mouse IgG also deposited on the endothelium of normal organs without eliciting an inflammatory response and was cleared from the endothelium within 4 days. Inasmuch as the principal site of binding was the vascular endothelium, we hypothesize that the antibody blocks adhesion to graft ICAM-1 molecules on the vessels. Anti-ICAM-1 also binds to recipient cells and may interfere with Ag presentation and/or T cell interactions. Whatever the mechanism(s), these studies indicate that an anti-ICAM-1 antibody inhibits T cell mediated injury in vivo, and that ICAM-1 is a critical molecule in the pathogenesis of allograft rejection.

Animals↗
PubMed1990

Prolonged survival of nonhuman primate renal allograft recipients treated only with anti-CD4 monoclonal antibody.

The immunosuppressive efficacy of the monoclonal antibody OKT4A reactive with human and monkey CD4 cells was evaluated in cynomolgus renal allograft recipients. Low-dose (0.1 to 0.3 mg/kg/day) intact monoclonal antibodies (10 recipients) or F(ab')2 fragments (two recipients) were administered for 12 days. High-dose OKT4A (10 mg/kg) was administered on the day of transplantation as the only suppression in five animals. Four control animals received either no therapy or a monoclonal antibody nonreactive with monkey cells (OKT3). Maximum survival of the control animals and those treated with F(ab')2 was 11 days. Mean survival in the recipients of low-dose OKT4A was 25.4 +/- 4.3 days and in the group receiving high-dose OKT4A it was 39 +/- 6.4 days. All OKT4A-treated animals showed "coating" and CD4 modulation without depletion of circulating T cells. No modulation occurred in the F(ab')2-treated recipients. Serial allograft biopsy specimens showed reduced lymphocyte infiltration that was nearly complete in recipients of high-dose OKT4A. Biopsy-derived donor-reactive cytotoxic T-cell lines were generated regularly from recipients of low-dose, but not high-dose, OKT4A during periods of stable function. All animals treated with monoclonal antibodies developed an immunoglobulin G antimurine humoral response. Thus OKT4A is a potent immunosuppressive agent administered even as a single bolus, and depletion of CD4 cells is not required to suppress rejection. Anti-CD4 monoclonal antibodies may prove useful in patients, perhaps requiring only a limited number of higher-dose injections in the peritransplant period.

Animals↗
PubMed1989

Identification of pre-T cells in human peripheral blood. Extrathymic differentiation of CD7+CD3- cells into CD3+ gamma/delta+ or alpha/beta+ T cells.

CD7+CD3- cells purified (greater than 99.99%) by FACS from the peripheral blood of healthy adults include precursors for mature T cells that have the capacity to differentiate into TCR-1+ or TCR-2+ CD3+ cells. Extrathymic differentiation was demonstrable from all eight healthy donors in the presence of a high concentration of IL-2, mitogenic levels of PHA, and irradiated blood mononuclear feeder cells, after a lag of approximately 40 d in vitro. The extrathymic T (ET) cells were predominantly TCR-1+, although TCR-2+ cells were also derived. ET TCR-1+ cells were CD4-CD8-, CD4-CD8DIM+, and CD4+CD8-, and were distinguished from natural T TCR-2+ cells by a variety of cell surface markers. The ET cells had phenotypes generally displayed by normal mature T cells, although the CD5DIM+ on ET cells was more typical of thymocytes. Acquisition of CD3 on purified CD7+CD3- cells was not due to antigenic modulation or growth of contaminants, and ET cells could be demonstrated at the clonal level. Studies in athymic mice and bone marrow recipients support the view that extrathymic maturation does occur in vivo. Whether the CD7+CD3- cell population was unexposed to the thymus, or exposed but not processed, is unknown. In any case, unusual or "forbidden" autoreactive specificities are predicted since ET cells differentiate without thymic selection of the TCR.

Antigens, CD7↗
PubMed1989

Tumour-infiltrating lymphocytes and interleukin-2 in treatment of advanced cancer.

Tumour-infiltrating lymphocytes (TIL) were isolated and expanded from small tumour biopsy samples of twenty-eight patients (thirteen with malignant melanoma, seven with renal cell carcinoma, and eight with non-small-cell lung cancer). The patients were treated with autologous expanded TIL (about 10(10)) and continuous infusions of recombinant human interleukin-2(1-3 x 10(6) U/m2 per 24 h). 29% of the patients with renal cell cancer and 23% of those with melanoma achieved objective tumour responses lasting 3-14 months. Toxic side-effects were limited, and no patient required intensive-care monitoring. Adoptive immunotherapy with TIL and interleukin-2 may be an effective systemic approach to the treatment of some patients with malignant melanoma and renal cell carcinoma.

Carcinoma, Renal Cell↗
PubMed1989

Adoptive immunotherapy with IL-2 results in the loss of delayed-type hypersensitivity responses and the development of immediate hypersensitivity to recall antigens.

Skin testing represents a direct method of assessing immune responses in vivo. Twenty-six patients with metastatic cancer of the lung, kidney, or melanoma were treated with adoptive transfers of autologous tumor-infiltrating or blood lymphocytes and continuous infusions of interleukin-2 (IL-2). Prior to therapy, cutaneous anergy to recall antigens was observed in 19 patients (73%), whereas 6 (27%) displayed normal delayed-type hypersensitivity (DTH) responses. When tested again at the end of therapy, DTH responses could not be elicited in any of the patients. Proliferative responses to skin test antigens, lectins, and IL-2 diminished progressively during therapy but returned to baseline values at 1 month. Unexpectedly, 14 of these patients (53%) developed immediate skin test responses to candida antigens and 5 (19%) to mumps antigens. These immediate responses were characterized by local erythema and induration that developed within minutes of injecting antigen. Biopsies displayed marked dermal edema and infiltration by eosinophils. Although serum IgE levels were not increased, immediate reactivity could be transferred by a heat-sensitive serum factor. The implications of this novel response are uncertain, and its development did not correlate directly with the anti-tumor effects of therapy. We conclude that adoptive immunotherapy with IL-2 produces a reduction in cutaneous DTH and diminished responses to mitogens while simultaneously promoting cutaneous allergy. We hypothesize that this may reflect diminished IL-2 production by antigen-specific helper T cells and that other lymphokines may promote these immediate hypersensitivity responses.

Antigens, Fungal↗