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D L Morton

Publications and source records attributed to D L Morton.

At least 127 records · Page 7Linked to original sources
PubMed1994

Both VH and VL regions contribute to the antigenicity of anti-idiotypic antibody that mimics melanoma associated ganglioside GM3.

Previously we developed a murine monoclonal anti-idiotype (anti-id) antibody (4C10) that mimics the melanoma-associated ganglioside antigen GM3, that is, it carries the internal image of GM3. 4C10 was made against the human monoclonal antibody (HuMAb) L612, which reacts with several types of human cancer cells, including melanoma and breast cancer. To reduce mouse components of 4C10, the constant region was replaced by a human constant domain to form the murine/human chimeric anti-id antibody TVE-1. In the present study, we sought to determine which chain (VH or VL) of the anti-id is responsible for the antigenicity of GM3. The TVE-1 VH and VL expression vectors were simultaneously transfected with either the VH or VL expression vector of a murine-human chimeric IgG antidansyl haptenic antibody, resulting in the construction of three different combinations of VH and VL chimeric antibodies. These IgG molecules were produced from the transfectomas, and their reactivity to HuMAb L612 was tested. Neither of the IgG proteins that had cross-combined the VH-VL pair showed positive results, suggesting that both heavy and light chains are required to express the antigenicity. The in vivo antigenicity of this chimeric anti-id was confirmed by skin tests in melanoma patients receiving active specific immunotherapy.

Animals↗
PubMed1994

Lymphatic mapping and sentinel lymphadenectomy for breast cancer.

OBJECTIVE: The authors report the feasibility and accuracy of intraoperative lymphatic mapping with sentinel lymphadenectomy in patients with breast cancer. SUMMARY BACKGROUND DATA: Axillary lymph node dissection (ALND) for breast cancer generally is accepted for its staging and prognostic value, but the extent of dissection remains controversial. Blind lymph node sampling or level I dissection may miss some nodal metastases, but ALND may result in lymphedema. In melanoma, intraoperative lymph node mapping with sentinel lymphadenectomy is an effective and minimally invasive alternative to ALND for identifying nodes containing metastases. METHODS: One hundred seventy-four mapping procedures were performed using a vital dye injected at the primary breast cancer site. Axillary lymphatics were identified and followed to the first ("sentinel") node, which was selectively excised before ALND. RESULTS: Sentinel nodes were identified in 114 of 174 (65.5%) procedures and accurately predicted axillary nodal status in 109 of 114 (95.6%) cases. There was a definite learning curve, and all false-negative sentinel nodes occurred in the first part of the study; sentinel nodes identified in the last 87 procedures were 100% predictive. In 16 of 42 (38.0%) clinically negative/pathologically positive axillae, the sentinel node was the only tumor-involved lymph node identified. The anatomic location of the sentinel node was examined in the 54 most recent procedures; ten cases had only level II nodal metastases that could have been missed by sampling or low (level I) axillary dissection. CONCLUSIONS: This experience indicates that intraoperative lymphatic mapping can accurately identify the sentinel node--i.e., the axillary lymph node most likely to contain breast cancer metastases--in some patients. The technique could enhance staging accuracy and, with further refinements and experience, might alter the role of ALND.

Adult↗
PubMed1994

Prognostic value of a 90kD subunit containing glycoprotein tumor-associated antigen specific immune complexes in lung cancer patients.

An ELISA to detect a glycoprotein TAA-specific immune complexe (IC) has been developed utilizing a murine monoclonal antibody, AD1-40F4, that recognizes a 90kD subunit of the antigen. In this study we determined the applicability of the assay to assess the presence of the glycoprotein TAA-IC in lung cancer patients. The incidence of glycoprotein TAA-IC was 63% (33/89), significantly higher (p < 0.05) than normal controls (3.2%; 8/250). Comparative analyses of pre- and post-operative sera of non-small cell lung cancer patients revealed that in 30% (20/66) of patients, the ELISA value for the marker did not become negative, i.e., decrease below the cut-off level (0.410 ODnm) after surgical resection of the tumor. It is postulated that these patients either had extensive disease or microscopic metastases that were not resectable. Evaluation of post-operative glycoprotein TAA-IC results in relation to disease recurrence revealed a significant association between the presence of the antigen in serum and disease recurrence. There did not appear to be any association between the glycoprotein TAA-IC and the other conventional marker, CEA; however, using more than one marker increases the incidence of detection of the disease.

Adolescent↗
PubMed1993

Molecular cloning of a human monoclonal antibody reactive to ganglioside GM3 antigen on human cancers.

In this study we report the characterization of a human monoclonal antibody (HuMab), L612, that reacts with ganglioside GM3 and has therapeutic application for the treatment of human neoplasms, particularly melanoma. A permanent IgM-secreting Epstein-Barr virus-transformed B-cell line L612 was established. L612 HuMab bound specifically to neoplastic cell lines in culture and in tissue biopsy specimens such as melanoma, colon, breast, and lung cancer. The antibody did not bind to normal cells or biopsy tissue. HuMab L612 showed the highest reactivity to melanoma cells, particularly to those with high concentrations of GM3. Immunostaining on high-performance thin-layer chromatography plates demonstrated that L612 HuMab bound to GM3 purified from melanoma cells. Removal of the sialic acid from GM3 abolished antibody binding. HuMab L612 also reacted to GM4 purified from egg yolk, indicating that it recognizes an NeuAc alpha 2-3 galactose antigen determinant. HuMab L612 heavy and light chains were sequenced and determined to belong to the mu heavy chain variable subgroup III and kappa chain variable subgroup IV families, respectively. The studies indicate that the L612 HuMab has significant therapeutic potential for a wide variety of human cancers.

Adenocarcinoma↗
PubMed1993

A preclinical model to assess the antigenicity of an HLA-A2 melanoma cell vaccine.

BACKGROUND: The authors have demonstrated that immunization with melanoma whole-cell vaccine (MCV) augments T-cell responses to melanoma and that cytotoxic T-cells (CTL) recognize allogeneic melanoma-bearing shared HLA-A antigens. A preclinical model was developed to assess CTL activation in vitro using melanoma lines as stimulators. HLA-A2 expression is predominant in melanoma patients and plays a role in HLA class I restricted CTL killing of melanomas. The authors hypothesized that a MCV consisting of allogeneic HLA-A2 melanomas may be as good as autologous melanoma MCV for HLA-A2 patients. METHODS: CTL were generated from peripheral blood lymphocytes of patients with HLA-A2 melanoma by stimulation with autologous melanoma, allogeneic melanoma (HLA-A2 or non-HLA-A2), or allogeneic MCV (mixed HLA-A2 and non-HLA-A2 melanomas). RESULTS: HLA-A2 MCV and autologous melanoma were similar and significantly better stimulators than the others. Specificity also was supported by CTL killing and mixed lymphocyte tumor reaction assays. CONCLUSIONS: These studies provide important information for the studying immunization of patients with HLA-A2 melanoma with an allogeneic HLA-A2 MCV in a Phase I clinical trial.

Antigens, Neoplasm↗
PubMed1993

Multivariate analysis of the relationship between survival and the microstage of primary melanoma by Clark level and Breslow thickness.

BACKGROUND: The American Joint Committee on Cancer (AJCC) uses both Breslow thickness and Clark level in its staging system for malignant melanoma. Stage I corresponds to Breslow thicknesses less than 1.5 mm and Clark levels II and III. Stage II corresponds to Breslow thicknesses of at least 1.5 mm and Clark levels IV and V. However, most investigators have found Clark level to be of no prognostic significance once Breslow thickness has been taken into consideration by multivariate analysis. METHODS: The authors examined the prognostic significance of Clark level by studying patients in the large database of the John Wayne Cancer Institute. Among 5575 patients with melanoma seen during the past 20 years, complete data on microstaging by both Clark and Breslow methods were available for 3323 patients. The 5-year survival rates were as follows: Clark II, 95%; III, 81%; IV, 68%; V, 47%. The Breslow thicknesses were as follows: < 0.75 mm, 95%; 0.75-1.49 mm, 85%; 1.5-3.99 mm, 66%; > or = 4.0 mm, 46%. RESULTS: By univariate analysis, both Clark level and Breslow thickness were highly significant prognostic indicators (P < 0.0001). By multivariate analysis, Breslow thickness remained significant (P < 0.0001). However, even when Breslow thickness was included in the model, Clark level also remained highly significant (P < 0.0015). CONCLUSIONS: Decisions regarding therapy for patients with clinical Stage I melanoma should consider both Clark level and Breslow thickness of the primary lesion. When there is a discordance between the two methods of microstaging, the AJCC stage should be amended to reflect the least favorable of the two prognostic indicators.

Humans↗
PubMed1993

Transfection of interleukin 2 gene into human melanoma cells augments cellular immune response.

A preclinical model was used to determine if transfection of the interleukin 2 (IL-2) gene into human melanoma cells would augment the response of autologous and allogeneic peripheral blood lymphocytes (PBLs) from melanoma patients. IL-2 gene was transfected into three human melanoma cell lines; secretion of IL-2 from stable transfected cells was confirmed by enzyme-linked immunosorbent assay. The PBL response to these melanoma cells was then examined in a mixed-lymphocyte tumor reaction using PBLs from eight melanoma patients. The PBL response to autologous (P < 0.01) or human leukocyte antigen A cross-reactive (P < 0.05) transfected melanoma cells was significantly higher than it was to nontransfected melanoma cells. These data suggest that IL-2 gene transfection may be an important strategic approach to enhancing specific immune responses induced by a polyvalent melanoma cell vaccine.

Base Sequence↗
PubMed1993

Malignant melanoma. Effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later.

OBJECTIVES: We evaluated recurrence and survival for 68 patients with malignant melanoma who participated in a 6-week structured psychiatric group intervention 5 to 6 years earlier, shortly after their diagnosis and initial surgical treatment. We also explored the role of several factors as possible predictors of outcome. DESIGN: This was a randomized controlled experimental study. The Cox proportion hazards regression model was used to quantify the relationship between treatment and the outcomes adjusted by the covariates (age, sex, Breslow depth, tumor site, baseline Profile of Mood States Total Mood Disturbance, baseline active-behavioral coping, baseline natural killer cell activity, and treatment [ie, group intervention]). The stepwise procedure was used for covariate selection. RESULTS: For control patients, there was a trend for recurrence (13/34) and a statistically significant greater rate of death (10/34) than for experimental patients (7/34 and 3/34, respectively). We found that being male and having a greater Breslow depth predicted greater recurrence and poorer survival. Analysis of multiple covariates found that only Breslow depth and treatment (ie, group intervention) were significant. Adjusting for Breslow depth, treatment effect remained significant. Finally, baseline affective distress and baseline coping were significant psychobehavioral predictors for recurrence and survival. Surprisingly, higher levels of baseline distress as well as baseline coping and enhancement of active-behavioral coping over time were predictive of lower rates of recurrence and death. CONCLUSION: Psychiatric interventions that enhance effective coping and reduce affective distress appear to have beneficial effects on survival but are not proposed as an alternative or independent treatment for cancer or any other illness or disease. However, the exact nature of this relationship warrants further investigation.

Adaptation, Psychological↗
PubMed1993

A protein fraction from aged garlic extract enhances cytotoxicity and proliferation of human lymphocytes mediated by interleukin-2 and concanavalin A.

Fraction 4 (F4), a protein fraction isolated from aged garlic extract, enhanced cytotoxicity of human peripheral blood lymphocytes (PBL) against both natural-killer (NK)-sensitive K562 and NK-resistant M14 cell lines. Although F4 treatment alone increased cytotoxicity, the effect was more remarkable when F4 was administered together with suboptimal doses of interleukin-2 (IL-2); combination treatment of 5 micrograms/ml F4 plus 10 U/ml IL-2 for 72 h generated lymphokine-activated killer activity equivalent to that produced by 100 U/ml IL-2 alone against M14. F4 enhanced IL-2-induced proliferation and IL-2 receptor (Tac) expression of PBL without significant increase of IL-2 production. The enhancement of cytotoxicity both by F4 alone and by F4 plus IL-2 was abolished by anti-IL-2 antibody. F4 also enhanced concanavalin-A(ConA)-induced proliferation of PBL. Radiolabeled-ConA binding assays revealed that F4 treatment greatly augmented the affinity and slightly increased the number of ConA binding sites in PBL. F4 also enhanced ConA-induced IL-2 receptor (Tac) expression and IL-2 production of PBL. Anti- IL-2 antibody inhibited the effect of F4 on ConA-induced proliferation. These data suggest that IL-2 is involved in augmentative effects of F4. Our results indicate that F4 is a very efficient immunopotentiator and may be used for immunotherapy.

Concanavalin A↗
PubMed1993

Interleukin-4 plus tumor necrosis factor alpha augments the antigenicity of melanoma cells.

Immune cytokines are important regulators of the immune response to neoplastic cells. We previously reported that interleukin 4 (IL-4) and either tumor necrosis factor alpha (TNF) or interferon gamma (IFN) synergistically inhibit melanoma cell growth and induce cell differentiation. In the present study we used various combinations of IL-4, IFN and TNF to enhance the antigenicity of melanoma cells. IL-4 plus TNF significantly increased the ability of melanoma cells to stimulate cytotoxic T cells (CTL) and act as targets of these CTL; IL-4 plus IFN was somewhat less effective, while TNF plus IFN was not as effective. IL-4 plus TNF also increased the expression of HLA class I and HLA-DR antigens on melanoma cells. The CTL lines examined in this study were CD3+CD4+ and oligoclonal. These preclinical results suggest that the immune response to melanoma whole-cell vaccines might be enhanced by pretreating vaccine cells with IL-4 plus TNF.

Antigens, CD↗
PubMed1993

Aberrant expression of gangliosides in human renal cell carcinomas.

Aberrant and elevated ganglioside expression has been observed in neoplasms, and has been shown to be an important marker of tumor progression. We therefore studied the gangliosides of renal cell carcinoma (RCC) by analyzing gangliosides from 18 RCC biopsies, 10 RCC lines and 5 normal kidney biopsies. A comparison of tumor with normal tissue revealed a significant difference in individual ganglioside expression in which the former consistently expressed eight major gangliosides, GM3, GM2, GM1, GD3, GD1A, GD2, GD1B and GT1B, according to the nomenclature of Svennerholm. There was a notable significant mean increase in the expression of GM2, GM1 and GD1A and a significant decrease in the expression of GD3 in tumor tissue compared with normal kidney tissue. Compared with tumor biopsy tissue, RCC cell lines showed a significant decrease in the expression of GM3, but a significant increase in GM2, GM1 and GD2. There was a marked increase in a pathway gangliosides (GM2, GM1, and GD1a) in RCC biopsies and cell lines compared with normal kidney. These studies indicating that RCC have markedly aberrant ganglioside expression similar to neural origin tumors may relate to the activation of a ganglioside pathway enzymes. Gangliosides expressed on RCC tumors may be important markers of tumor progression and target antigens for immunotherapy.

Biomarkers, Tumor↗
PubMed1993

Growth inhibition and modulation of cell markers of melanoma by S-allyl cysteine.

A sulfur-containing amino acid compound, S-allyl cysteine (SAC), derived from garlic extract inhibited proliferation of nine human and murine melanoma cell line in a dose-dependent manner (1.2-10 mM) assessed by a [3H]thymidine incorporation assay. Three control human lymphoblastoid cell lines were not inhibited by SAC concentrations < 5 mM. Four human melanoma cell lines in a soft-agar assay also showed dose-dependent inhibition of colony formation by SAC. Melanin content was increased up to 95% compared to the same untreated cell lines in these four human melanoma and two B16 murine melanoma sublines. Expression of cell surface gangliosides, cellular-differentiation and transformation markers, decreased after SAC treatment. Significant morphological changes including 'flattening and/or dendritic-like elongations' were also observed. Thus SAC inhibited cellular growth and proliferation and modulated major cell differentiation markers of melanoma.

Animals↗
PubMed1993

Intraoperative lymphatic mapping and selective cervical lymphadenectomy for early-stage melanomas of the head and neck.

PURPOSE: We developed intraoperative lymphatic mapping with selective lymphadenectomy (SLND) to identify micrometastatic spread of cutaneous melanoma to regional lymph nodes. This study was undertaken to assess the sensitivity and specificity of our technique in patients with clinical stage I (CS-I) melanoma of the head or neck. PATIENTS AND METHODS: Seventy-two CS-I melanoma patients underwent intraoperative lymphatic mapping of primary cutaneous melanomas located on the head, neck, or upper chest/back draining to the neck. Key (sentinel) cervical lymph nodes in the regional lymphatic drainage basin were identified, selectively excised during SLND, and examined for microscopic evidence of tumor cells. If these sentinel nodes were tumor-negative, the surgery was concluded; if the sentinel nodes were tumor-positive, all nodes in the drainage basin were removed during en bloc lymphadenectomy (LND). RESULTS: Intraoperative lymphatic mapping identified sentinel nodes in 90% of the regional drainage basins. Fifteen percent of these nodes were tumor-positive, indicating the need for LND. There were no false-negative sentinel nodes, and extended follow-up showed no local nodal recurrences in patients whose sentinel-node histology did not indicate the need for LND. CONCLUSION: Intraoperative lymphatic mapping and SLND is a minimally invasive and highly accurate screening technique for determining which patients with CS-I head and neck melanomas have subclinical node metastases and therefore might benefit from cervical LND.

Adolescent↗
PubMed1993

The role of surgery in the treatment of nonregionally recurrent melanoma.

BACKGROUND: Between 1971 and 1989, 144 patients underwent 183 surgical procedures for resection of nonregional metastatic melanoma. METHODS: Thirty-six patients with subcutaneous or nodal metastases, 46 patients with pulmonary metastases, 17 patients with brain metastases, 19 with gastrointestinal metastases, and 26 patients with miscellaneous sites of metastatic involvement underwent resection. RESULTS: The overall 5- and 10-year actuarial survival rates were 20% and 14%, respectively. A single postoperative death occurred in a patient operated on for palliative treatment of gastrointestinal metastases. CONCLUSIONS: Cox regression analysis suggests that patients with a solitary metastasis confined to the subcutaneous, nonregional lymph nodes or lung are most likely to benefit from aggressive surgical intervention. Surgical intervention represents a potentially important modality in the management of selected patients with nonregional metastatic melanoma.

Adolescent↗
PubMed1992

Variations in the ganglioside profile of uveal melanoma correlate with cytologic heterogeneity.

Gangliosides may play an important role in the proliferation and spread of human malignant melanoma. Because the frequency of metastases in uveal and cutaneous melanoma differs, it is possible that they may express different gangliosides. We analyzed the ganglioside profiles of primary uveal melanoma in 14 cases and of cutaneous melanoma metastasis in 19 cases. In cutaneous melanoma, GM3 ranged from 4.2% to 74.6% and GD3 from 22.1% to 91.8% of total lipid-bound sialic acid. GM2 (found in 13 of 19 cases, ranging from 0.5% to 11.7%), GD2 (11/19, 0.5%-22.0%) and 9-O-acetyl-GD3 (13/19, 0.5%-12.6%) were also frequently observed. By contrast, in 11 cases of uveal melanoma, GM3 was > 90%, GD3 was < 10%, GM2 was < 1.1%; neither GD2 nor 9-O-acetyl-GD3 were detected. The ganglioside profiles of these uveal melanomas were virtually identical to those of normal melanocytes obtained from foreskins. Histological examination of these 11 biopsies showed a monomorphous cell composition, but neither infiltration of lymphocytes or melanophages nor cell necrosis was observed. In 3 other cases, GD3 was increased to 19.5%-46.0%. Histological examination of these 3 biopsy specimens showed at least 2 populations of tumor cells that were separable based on morphological grounds, and mononuclear inflammatory cells interspersed among the tumor cells. An increase in GD3 appears to be related to tumor polyclonality and infiltration of the tumor by lymphocytes and macrophages. These results suggest that ganglioside expression of uveal melanoma is associated with host immune responses to the tumor. Furthermore, the low metastatic capacity of uveal melanoma, in contrast to the high metastatic rate of cutaneous melanoma, may be a result of its differentiated ganglioside expression, which is strikingly similar to that of normal melanocytes.

Gangliosides↗