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D Berd

Publications and source records attributed to D Berd.

At least 55 records · Page 3Linked to original sources
PubMed1992

Effective combination chemo/hormonal therapy for malignant melanoma: experience with three consecutive trials.

Our experience with the combination of dacarbazine, carmustine, cisplatin with and without tamoxifen is reported. In our initial study, with all 4 drugs, we had an overall response rate of 50% with a complete response rate of 15%. Due to a high incidence of deep venous thrombosis and the lack of effectiveness of tamoxifen as a single agent, we deleted tamoxifen from the regimen and treated another 20 patients. Surprisingly, the response rate decreased to 10%. We then re-incorporated tamoxifen into the regimen and treated 25 additional patients. In this third group of patients we experienced an objective response rate of 52% with a complete response rate of 8%. Overall, 65 patients have been treated: 45 with and 20 without tamoxifen. Twenty-three (51%) patients treated with tamoxifen have responded, with 5 (11%) patients achieving a complete response. Only 2 (10%) patients treated without tamoxifen have responded. Despite the improvement in the response rate, a corresponding increase in survival has not been seen. Patients treated with tamoxifen had a mean survival of 10.8 (SD 13.6) months compared with a mean survival of 9.8 (SD 7.3) months for those treated without tamoxifen. The absence of survival advantage for the tamoxifen-treated patients may be due to early failure in the central nervous system. In 48% of the responding tamoxifen-treated patients, the first site of failure was the central nervous system, while systemic disease was still responding.

Adult↗
PubMed1991

Growth and metastasis of fresh human melanoma tissue in mice with severe combined immunodeficiency.

Cryopreserved cell suspensions of freshly excised melanoma metastases from nine patients were injected s.c. into C.B-17 severe combined immunodeficiency (SCID) mice. All 9 tumors grew as s.c. masses and six of nine were successfully transplanted into other SCID mice. Transplant inocula as low as 5 x 10(5) cells resulted in 100% tumor incidence. Moreover, seven of nine tumors metastasized, five from the original s.c. implants and two from transplanted s.c. tumors. Metastases were detected mainly in the lungs but also were found in abdominal viscera (liver, spleen, and pancreas) and thoracic lymph nodes. Flow cytometric analysis showed that expression of a panel of melanoma antigens, melanoma-associated proteoglycan, ganglioside GD3, and ganglioside GD2, was maintained with SCID passage. The original tumor inocula contained a variable percentage of tumor-associated lymphocytes (1-76%). Flow cytometry analysis indicated that these were mainly CD3+ T-cells. However, there was no correlation between the percentage of tumor-associated lymphocytes and the time required for development of a palpable tumor after s.c. injection or the ability to metastasize. These results demonstrate the growth and spontaneous metastasis of fresh human melanoma in SCID mice and suggest that this model could be important for therapeutic and basic biological studies.

Animals↗
PubMed1991

Immunization with haptenized, autologous tumor cells induces inflammation of human melanoma metastases.

Twenty-four patients with metastatic melanoma were treated with a novel form of active immunotherapy, autologous tumor cell vaccine conjugated to the hapten, dinitrophenyl. This approach is based on the idea, well established in animal systems, that presentation of tumor antigens in the context of a strongly immunogenic hapten augments the development of immunity to those antigens. After being sensitized to dinitrophenyl, patients were given injections of dinitrophenyl-vaccine every 28 days following pretreatment with low dose cyclophosphamide. The vaccine induced a striking inflammatory response in superficial metastases in 14 of 24 patients, consisting of erythema, swelling, warmth, and tenderness over tumor masses. Immunohistochemistry and flow cytometric analysis of biopsy specimens showed marked infiltration with lymphocytes, the majority of which were CD8+, HLA-DR+ T-cells. These observations suggest that a T-cell-mediated immune response against melanoma-associated antigens was facilitated by the "helper" effect of the anti-hapten response.

Antibodies, Monoclonal↗
PubMed1990

A randomized study of methanol-extraction residue of bacille Calmette-Guerin as postsurgical adjuvant therapy of uveal melanoma.

A randomized controlled clinical trial of methanol-extracted residue of bacille Calmette-Guerin adjuvant treatment of posterior uveal melanoma was undertaken. Of 113 patients, 34 patients received adjuvant immunotherapy and 79 patients received no treatment. No difference in survival was observed between the adjuvant-treated group and the control group of patients. This study found that the size of the tumor was a highly significant risk factor for death caused by metastasis of uveal melanomas. The standard deviation of the nucleolar area of the neoplastic cells was a significant risk factor, even though patients with tumors composed of Callender's spindle-type cells were not included in the study.

Adjuvants, Immunologic↗
PubMed1990

"Autoregulation" of human neutrophil activation in vitro: regulation of phorbol myristate acetate-induced neutrophil activation by cell density.

Phorbol myristate acetate (PMA, 10(-7) M) activation of adherent neutrophils (PMNs) led to a markedly attenuated release of superoxide anion (O2-) per cell when PMNs were activated at high density (2.85 fmol O2-/PMN at 2 million in 0.1 ml) in comparison with cells activated at low cell density (12.0 fmol O2-/PMN at 250,000 in 0.1 ml). This "autoregulatory" phenomenon was not due to a defect in the superoxide anion assay employed, to a differential adherence of neutrophils at high vs. low density, or to substrate (cytochrome c) or cell stimulus (PMA) limitation. It was associated with an inhibition of apparent NADPH oxidase activity and a leftward shift (toward a lower level of activation) in the activation profile of PMNs (as determined by FACS analysis using PMNs preloaded with 2'7'-dichlorofluorescin diacetate in which H2O2 production results in the production of the fluorescent product 2'7'-dichlorofluorescein intracellularly). Other aspects of the neutrophil activation response including arachidonic acid mobilization, phospholipid metabolism, and perhaps phosphatidylinositol turnover were also attenuated when PMNs were activated at high cell density. Studies with cells in solution, cells treated with cycloheximide, and cells treated with 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid suggest that PMN contact with a surface, neutrophil protein synthesis, and an increased surface expression of the heterodimer CD11b/CD18 on PMNs all were not required for autoregulation. Finally, morphometric and morphologic examination of PMNs activated at low vs. high density revealed histologic and structural correlates associated with the attenuated PMN activation response of cells triggered at high cell density. We conclude that multiple structural and functional aspects of the PMN activation response are modulated by cell density and suggest that this property is important both in the physiologic control of neutrophil activation and in the design of in vitro assays of the neutrophil activation response.

Arachidonic Acid↗
PubMed1990

Treatment of metastatic melanoma with an autologous tumor-cell vaccine: clinical and immunologic results in 64 patients.

We treated 64 patients with metastatic melanoma using a melanoma vaccine preceded by low-dose cyclophosphamide (CY), and monitored immunologic effects and antitumor activity. On day 0, the patients were given CY 300 mg/m2 intravenously. Three days later, they were injected intradermally with vaccine consisting of 10 to 25 x 10(6) autologous, enzymatically dissociated, cryopreserved, irradiated (25 Gy) tumor cells mixed with bacillus Calmette-Guérin (BCG). This treatment sequence was repeated every 28 days. Of 40 assessable patients with measurable metastases, five had responses, four complete and one partial, with a median duration of 10 months (7 to 84+ months). In six additional patients, we observed an antitumor response that seems to be peculiar to this vaccine therapy: the regression of metastatic lesions that appeared after the immunotherapy was begun. Delayed-type hypersensitivity (DTH) to autologous, mechanically dissociated melanoma cells that had not been exposed to extraneous antigens, such as enzymes or fetal calf serum, increased significantly following immunotherapy (day 0 v day 49, P less than .001; day 0 v day 161, P less than .001; day 0 v day 217, P = .021). Antitumor responses to the vaccine were strongly associated with DTH, as indicated by three observations: (1) eight of 10 patients who exhibited tumor regression had positive DTH, (2) in postsurgical adjuvant patients, there was a highly significant linear relationship (P less than .001) between the intensity of DTH to autologous melanoma cells and the time to recurrence of tumor, and (3) nine patients who developed DTH to the autologous melanoma cells in their original vaccine developed new metastases that failed to elicit DTH or elicited a much smaller response. In three cases, we were able to excise regressing tumors for histologic examination; such tumors were characterized by an intense infiltration of lymphocytes. This demonstration that an immune response to melanoma-associated antigens can be elicited in cancer-bearing patients provides some basis for optimism about the prospects for developing active immunotherapy that has practical therapeutic value.

Adult↗
PubMed1990

Time to recurrence varies inversely with thickness in clinical stage 1 cutaneous melanoma.

The thickness of a tumor has been identified as the principal prognostic factor in cutaneous malignant melanoma. However, time to recurrence has not conclusively been related to thickness. A retrospective study of 216 patients with a primary cutaneous malignant melanoma that recurred was conducted to clarify this relationship and investigate possible independent relationships between age at diagnosis and sex of patients to time to recurrence. The results of analysis of linear regression revealed an inverse linear relationship between thickness and time to recurrence (p less than 0.001). Patients more than 50 years of age at the time of diagnosis were shown to relapse sooner than those less than 50 years of age (p = 0.014). Sex was not a significant factor in predicting time to recurrence (p greater than 0.10). These results suggest that thickness of tumor provides an indication of time to recurrence in those patients destined to recur and stress the need for long term surveillance in patients with a history of malignant melanoma because of the possibility of late relapse even with thin lesions.

Female↗
PubMed1989

Depletion of T-cells with the CD4+CD45R+ phenotype in lymphocytes that infiltrate subcutaneous metastases of human melanoma.

We studied the phenotypes of lymphocytes extracted from 22 specimens of human melanoma, 11 s.c. metastases and 11 lymph node metastases, by two-color flow cytometry. Lymphocytes extracted from s.c. metastases were characterized by a significantly reduced ratio of CD4+ to CD8+ T-cells, as compared with peripheral blood lymphocytes from the same patients. Ten of 11 tumor-infiltrating lymphocytes from s.c. metastases, but only 1 of 11 peripheral blood lymphocytes, had a CD4/CD8 ratio of less than 1.0. This alteration was not observed for lymphocytes obtained from nodal metastases. Furthermore, almost all of the CD4+ T-cells in s.c. metastases expressed the antigen CD29w and were negative for the complementary antigen CD45R. In contrast, the CD29w/CD45R ratio of tumor-infiltrating lymphocytes from lymph node metastases was similar to that of matched peripheral blood lymphocytes. Thus tumor-infiltrating lymphocytes from s.c. metastases have the phenotype associated with true helper or antigen-committed T-cells, which could reflect their sensitization to tumor antigens, while tumor-infiltrating lymphocytes from lymph node metastases may represent merely an expanded residua of lymph node lymphocytes. Since tumor-infiltrating lymphocytes expanded in vitro are being tested as therapy for patients with advanced cancer, these observations may have important therapeutic implications.

Antigens, CD↗
PubMed1989

Flow cytometric determination of the frequency and heterogeneity of expression of human melanoma-associated antigens.

We used flow cytometry to measure the expression of human melanoma antigens on cell suspensions dissociated from metastatic masses. The objective was to study the heterogeneity between tumor samples from different patients and between different tumors excised from a single patient. Fifty-three metastases excised from 34 melanoma patients were analyzed with a panel of nine murine monoclonal antibodies (MOABs). Melanoma cells were stained by an indirect fluorescent method and analyzed on a Coulter EPICS C flow cytometer after gating to exclude tumor-infiltrating leukocytes and dead cells. The most consistently and most strongly expressed antigen was the high-molecular-weight proteoglycan (detected by the MOAB 9.2.27), which was expressed on 95% of the melanoma specimens and by a high proportion of cells within each specimen (mean +/- SE, 79.2 +/- 5.5). However, strong expression of this antigen was limited to melanoma cells that had been dissociated mechanically and was markedly diminished by exposure to collagenase. Culture of collagenase-dissociated tumor cells for 24 to 48 h resulted in reexpression of the antigen. The expression of other melanoma-associated antigens was not affected by collagenase treatment, but for these antigens there was more variability between cells from an individual tumor and between tumors from different patients. The percentage of enzyme-dissociated tumors considered positive for MOAB binding (defined as at least 10% of cells positive) and the mean +/- SE of the percentage of positive cells within a tumor were as follows: MOAB ME-9-61 (antigen, p97) = 84% + (41.2 +/- 5.4%); MOAB ME-20.4 (antigen, nerve growth factor receptor) = 40% + (18.7 +/- 5.1%); MOAB ME-24 (antigen, ganglioside GD3) = 84% + (50.8 +/- 4.8%); MOAB ME-311 (antigen, ganglioside 9-O-acetyl-GD3) = 76% + (42.5 +/- 5.1%); MOAB ME-361 (antigen, mainly ganglioside GD2) = 3% + (1.9 +/- 0.8%); MOAB 3F8 (antigen, ganglioside GD2) = 36% (10.5 +/- 3.8%); MOAB 14G2a (antigen, ganglioside GD2) = 86% + (46.0 +/- 6.7%); MOAB L243 (antigen, HLA-DR) = 56% + (22.5 +/- 5.5%). In 19 cases, we were able to compare the antigenic profiles of two tumors excised from the same patient at different times. Analysis by nonindependent t test showed no significant differences in MOAB binding between the paired tumors. Moreover, linear regression analysis indicated that there was a linear relationship, with a slope approximately = 1, between the percentage of positive cells in Tumor 1 versus Tumor 2.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1989

The importance of tamoxifen to a cisplatin-containing regimen in the treatment of metastatic melanoma.

The combination of dacarbazine (DTIC, 220 mg/m2) and cisplatin (DDP, 25 mg/m2) IV daily for 3 days every 3 weeks, carmustine (BCNU, 150 mg/m2) IV every 6 weeks, and tamoxifen (TAM, 10 mg orally twice daily) produced a 50% objective response rate in patients with metastatic melanoma. Associated with this treatment, there was a high incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE). In an effort to reduce this toxicity, this regimen minus TAM was studied, and the results are reported. Twenty of twenty patients are evaluable for response and toxicity. There was one complete response (CR) lasting 5+ months and one partial response (PR) lasting 4+ months for an overall response rate of 10% (95% confidence limits, 1.23% to 31.70%). Two patients exhibited a mixed response and three patients developed disease stabilization lasting 4 to 10 months. Toxicity was similar to the original study except that no patients developed DVT or PE. This statistically significant (Fisher's exact test [two-tail] P = 0.008) decrease in the response rate by comparison with that achieved with the TAM-containing regimen may signal an essential role of TAM in this regimen. TAM may be acting in synergy with cisplatin through its calcium channel-blocking properties. TAM should be included as described in the initial reports, and the patients should be carefully observed for vascular complications.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Fc-receptor for mouse IgG1 (Fc gamma RII) and antibody-mediated cell clearance in patients treated with Leu2a antibody.

A pilot study was performed to explore the clinical potential of Leu2a antibody in reversing acute renal allograft rejection. Anti-Leu2a, a murine IgG1 monoclonal antibody (mIgG1 mAb), is specific for the CD8 molecule that is expressed in high density on class I reactive T cells. Of the 6 recipients treated with anti-Leu2a, two responded with a complete reversal of rejection with long-term allograft function maintained for over a year. In two other recipients, acute rejection was initially reversed, but later rejection episodes resulted in allograft failure at 2-3 months posttreatment. Rejection in the two other recipients showed no response to Leu2a mAb treatment. Specific depletion of peripheral blood CD8+ cells occurred in four of the six recipients. Even in this small series, it was evident that cell clearance was neither necessary nor sufficient for reversal of rejection. However, a complete correspondence between cell clearance and the ability of the recipients' mononuclear cells to undergo mitogenic response to the mIgG1 anti-CD3 (Leu4) mAb in vitro was noted. Binding of IgG1 mAb to the Fc-receptor (Fc gamma RII/CD32) expressed on blood monocytes is known to be essential for the T cell mitogenic response to soluble mIgG1 CD3 mAb in vitro. Our data suggest that binding to Fc gamma RII may be an essential step in the process of mIgG1 Leu2a mAb-mediated cell clearance in vivo.

Animals↗
PubMed1989

Flow cytometric evaluation of bronchoscopic washings and lavage fluid for DNA aneuploidy as an adjunct in the diagnosis of lung cancer and tumors metastatic to the lung.

The presence of DNA aneuploidy (deviation from an exact multiple of the diploid amount of DNA) has been used to aid in the diagnoses of several malignancies. We undertook this study to determine if the addition of flow cytometric analysis (FCA) of bronchial washings and lavage specimens for the presence of DNA aneuploidy would increase the yield from bronchoscopy in the diagnosis of lung cancer and other tumors metastatic to the lung. Fifty-nine patients with a variety of both benign (33) and malignant (26) pulmonary disorders had specimens divided and submitted for both FCA and routine cytologic examination. The presence of an "obviously visible" second, aneuploid peak on the DNA histograms proved to be highly specific for the presence of malignancy, but lacked sensitivity. It was concluded that FCA is a promising technique for increasing the diagnostic yield from bronchoscopy at no increased risk to the patient. However, further studies are needed prior to its routine clinical application.

Aneuploidy↗
PubMed1988

Effect of low dose cyclophosphamide on the immune system of cancer patients: depletion of CD4+, 2H4+ suppressor-inducer T-cells.

We studied peripheral blood lymphocytes (PBL) from 42 patients with metastatic melanoma undergoing treatment with cyclophosphamide (CY) plus melanoma vaccine to determine whether CY immunopotentiation could be related to depletion of T-cells that function as inducers of suppression. Every 28 days, the patients were given CY, 300 mg/m2 i.v., followed 3 days later by the intradermal injection of autologous, irradiated melanoma cells mixed with Bacillus Calmette-Guérin. PBL were separated by density gradient centrifugation and cryopreserved until needed for testing. They were stained with monoclonal antibodies directly conjugated to fluorescein isothiocyanate or phycoerythrin and analyzed by two-color flow cytometry. At no time after the initiation of CY plus vaccine were there any significant changes in the percentages of helper-inducer T-cells (CD4+), suppressor-cytotoxic T-cells (CD8+), or the subpopulation of CD8+ cells expressing Leu 15, a marker for suppressor cells. Treatment of melanoma patients with CY plus vaccine resulted in a progressive fall in the proportion of CD4+ T-cells expressing the 2H4 (CD45) antigen, which identifies inducers of suppression. The reduction of CD4+, 2H4+ T-cells did not become apparent until day 28 after the first dose of CY and reached statistical significance only on days 49 (21 days after the second dose) and 105 (21 days after the fourth dose) (mean changes +/- SE: day 49, -5.4 +/- 1.4%, P less than 0.01; day 105, -9.1 +/- 2.2%, P less than 0.01; t test for nonindependent samples). In contrast, the proportion of CD4+ T-cells expressing the antigen 4B4 (CDw29), which are true helper cells, increased slightly, although not significantly, following the institution of CY plus vaccine (mean changes: day 49, +2.9 +/- 2.1%; day 105, +3.6 +/- 2.4%). Similar results were obtained when absolute numbers of circulating cells, rather than percentages, were analyzed. Thus the number of CD4+, 2H4+ T-cells fell from a mean of 395,000/ml on day 0 to 309,000/ml on day 49 (P less than 0.01) to 256,000/ml on day 105 (P less than 0.05). The absolute number of CD4+, 4B4+ cells remained unchanged at the same time points. These changes were not due to progression of metastatic disease, since a comparison of patients with progressive metastases with those who were rendered disease free by surgery showed no significant differences in the reduction of the percentage of CD4+, 2H4+ T-cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1988

Active immunotherapy of human melanoma exploiting the immunopotentiating effects of cyclophosphamide.

Malignant tumors may escape rejection by the immune system because they induce a state of immunological tolerance mediated by tumor antigen-specific suppressor T cells. In animal systems, cyclophosphamide can reverse the tolerance and thereby facilitate immunologically mediated tumor destruction. We have applied these concepts to the immunotherapy of human malignant melanoma. Forty-three patients with metastatic disease were treated with a whole cell vaccine 3 days after intravenous administration of cyclophosphamide, 300 mg/m2. The vaccine consisted of cryopreserved, irradiated autologous melanoma cells, obtained from metastatic masses by dissociation with collagenase and DNAse, mixed with bacillus Calmette-Guerin (BCG) and injected intradermally. The cyclophosphamide (CY) + vaccine combination was repeated every 28 days. Delayed-type hypersensitivity (DTH) was tested by injecting 1 x 10(6) melanoma cells intradermally and measuring the diameter of induration at 48 h. Most patients had minimal pretreatment DTH responses to melanoma cells (mean +/- SE, mm = 2.4 +/- 0.5). After two vaccine treatments, the responses increased significantly (mean increase +/- SE = 12.1 +/- 1.6 p less than .001) and that level of response was maintained after 4, 6, and 8 treatments. The patients were also skin-tested with a mixture of the enzymes used to dissociate the tumors. No patients exhibited DTH to collagenase + DNAse prior to vaccine injection, but every patient developed DTH to the mixture following two treatments (mean, mm = 26.4 +/- 3.9). Although extracting viable cells from tumor tissue without the use of enzymes proved difficult, we were able to test DTH to mechanically dissociated tumor cells in 23 patients. After two vaccine treatments, there was a significant increase in DTH to enzyme-free autologous melanoma cells (mean DTH +/- SE, mm: 5.4 +/- 1.0, p less than .01). Whereas 5 of 23 patients had positive DTH responses (5 mm induration or greater) before treatment, 11 of 23 were positive after two treatments. Further significant increases in DTH enzyme-free cells were observed after 6 and 8 treatments. Thus, it appears that patients receiving CY + vaccine developed DTH to tumor-associated antigens as well as to residual collagenase and DNAse on the cell surface. Thirty-three patients could be evaluated for antitumor effects of cyclophosphamide + vaccine. There were 3 complete remissions, 1 partial remission, and 2 minor responses. Two complete responders remain alive and free of disease after 57 and 12 months, respectively, and the third died after 39 months. The partial remission consisted of 75% regression of a pulmonary metastasis.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1987

Effect of low dose cyclophosphamide on the immune system of cancer patients: reduction of T-suppressor function without depletion of the CD8+ subset.

Low dose cyclophosphamide (CY) can augment the development of delayed-type hypersensitivity to primary antigens in patients with advanced cancer. In this paper, we have considered the hypothesis that the immunopotentiation is related to reduction of T-suppressor activity. Peripheral blood lymphocytes were collected and cryopreserved from 45 patients with metastatic malignancy before and then 3, 7, and 19 days after administration of CY, 300 mg/m2 i.v. The peripheral blood lymphocytes were tested for generation of concanavalin A-inducible suppressor activity, proliferative response to phytohemagglutinin, and phenotype using monoclonal antibodies to CD4 and CD8. Concanavalin A-inducible suppression was significantly reduced by day 3 and declined progressively through day 19. The mean percentage changes in suppression were: day 3, -23.4 +/- 6.8 (SE) (P less than 0.01); day 7, -33.1 +/- 14.3 (P = 0.052); day 19, -43.1 +/- 10.7 (P less than 0.01). In contrast, CY caused no significant changes in phytohemagglutinin proliferation (mean percentage changes: day 3, -4.7 +/- 6.1; day 7, -15.6 +/- 7.5; day 19, -5.5 +/- 8.1), indicating that the reduction in concanavalin A-inducible suppression was not merely a reflection of a general reduction in peripheral blood lymphocyte function. The total number of circulating lymphocytes was not affected by low dose CY. Moreover, flow cytometric analysis showed no significant changes in the percentage of circulating CD8+ or CD4+ T-cells or in the CD4/CD8 ratio at any time point after CY. Thus, administration of low dose CY to these patients caused impairment of nonspecific T-suppressor function without selective depletion of the CD8+ subset that is generally associated with that function. Several immunoregulatory models that are consistent with these observations are discussed.

Adult↗