Disseminated melanoma--is there a new standard therapy?
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
D Guerry
Publications and source records attributed to D Guerry.
Loco-regional nodal relapse in melanoma.
Two-hundred and seven patients without evidence of disease following lymph node dissection (LND) were stratified into three groups: Group A, lymph node relapse within the site of prior LND; Group B, lymph node relapse in a different, but regional, lymph node group; Group C, no lymph node relapse. Decreased survival was noted in both Groups A and B versus Group C. Prognostic factors were identified as: (i) axial or subungal/volar (subvolar) location and the number of positive lymph nodes at initial LND for nodal relapse within the same lymph node group; (ii) male gender, axial/subvolar location, and the number of histologically positive lymph nodes at initial LND for nodal relapse in a different, but regional lymph node group; (iii) relapse within the initial LND site for a decreased survival. Six of 10 patients with both axial/subvolar primaries and four or more positive lymph nodes developed a relapse within the dissection site post-LND. These prognostic factors describe a subset of patients who would be candidates for postoperative adjuvant local/regional and systemic therapy trials.
Adolescent↗
Characterization of tenascin secreted by human melanoma cells.
Tenascin is a large glycoprotein of the extracellular matrix. It shows a site-restricted expression during embryogenesis and can be found in adult tissues during wound healing and tumorigenesis. Because of the potential involvement of tenascin in adhesion and invasion during metastasis, the study of the interactions of tumor cells with tenascin is of considerable interest. Using five anti-melanoma monoclonal antibodies to four different epitopes of human tenascin, we found that most melanoma cells secrete tenascin in vitro constitutively. Transforming growth factor beta 1 in the medium increased secretion in tenascin-producing cells. Tenascin was present in sera of melanoma patients, with significantly elevated levels in patients with advanced melanomas as compared to patients with low tumor burden or to normal donors. Normal and malignant melanocytes did not attach to tenascin as substrate within 1 to 2 h and tenascin could also inhibit fibronectin-dependent adhesion. These results indicate that tenascin may play a critical role in cell-substrate interactions of melanoma cells.
Antibodies, Monoclonal↗
Survival and quality of life among patients receiving unproven as compared with conventional cancer therapy.
BACKGROUND: Cancer treatments without proved efficacy have achieved new levels of popularity, particularly among well-educated patients. The value of these therapies is vigorously debated. METHODS: We compared the length of survival and quality of life in patients who received treatment at a prominent unorthodox cancer clinic in addition to conventional treatment and in matched control patients from an academic cancer center who received only conventional treatment. All the patients had documented extensive malignant disease associated with a predicted median survival time of less than one year. The study sample consisted of 78 pairs of patients matched according to sex, race, age, diagnosis, and time from the diagnosis of metastatic or recurrent disease, who were enrolled over a period of 3 1/2 years. Periodic follow-up (approximately every two months) continued until death. RESULTS: There was no difference between the two patient groups in length of survival. Median survival for both groups was 15 months (P = 0.22; relative risk, 1.23; 95 percent confidence interval, 0.88 to 1.72). Quality-of-life scores were consistently better among conventionally treated patients from enrollment on. CONCLUSIONS: For this sample of patients with extensive disease and for this particular unorthodox treatment regimen, conventional and unorthodox treatments produced similar results.
Adult↗
Dysplastic nevi as risk markers of sporadic (nonfamilial) melanoma. A case-control study.
The melanoma risk associated with dysplastic nevi outside the context of familial melanoma was studied by the case-control method. One hundred five newly diagnosed incident melanoma cases with negative family histories for familial melanoma and 181 controls (frequency matched for race, age, and sex) were studied by personal interview and cutaneous examination. The prevalence of dysplastic nevi was 41 (39%) of 105 in the cases and 13 (7%) of 181 in the controls. The odds ratio for dysplastic nevi by multiple logistic regression analysis simultaneously correcting for age, sex, eye color, hair color, actinic damage, freckles, and total number of nondysplastic nevi was 6.8 (95% confidence interval, 2.7, 16.9). This study supports the significance of dysplastic nevi as markers of increased risk for nonfamilial melanoma.
Case-Control Studies↗
Screening and surveillance of patients at high risk for malignant melanoma result in detection of earlier disease.
Screening, surveillance, and educational programs have been recommended for members of hereditary melanoma kindreds with dysplastic nevi, who are at very high risk for melanoma. For melanomas detected in a surveillance program offered to 555 such persons, the average thickness was 0.52 mm for 28 surveillance incident melanomas, 0.55 mm for 64 nonsurveillance incident melanomas, and 1.44 mm for 48 index lesions (p less than 0.001). The proportion of cases with level I or II invasion was 60.8%, 58.3%, and 36.2% respectively (p = 0.002). The nonsurveillance incident melanomas were diagnosed before entry into the surveillance program, but these patients were presumably aware of the earlier occurrence of two index melanomas in their families. These findings are consistent with a favorable effect of surveillance and education in a high-risk population and suggest that patient factors as well as physician factors may contribute to early diagnosis.
Dysplastic Nevus Syndrome↗
Model predicting survival in stage I melanoma based on tumor progression.
We used the lesional steps in tumor progression and multivariable logistic regression to develop a prognostic model for primary, clinical stage I cutaneous melanoma. This model is 89% accurate in predicting survival. Using histologic criteria, we assigned melanomas to tumor progression steps by ascertaining their particular growth phase. These phases were the in situ and invasive radial growth phase and the vertical growth phase (the focal formation of a dermal tumor nodule or dermal tumor plaque within the radial growth phase or such dermal growth without an evident radial growth phase). After a minimum follow-up of 100.6 months and a median follow-up of 150.2 months, 122 invasive radial-growth-phase tumors were found to be without metastases. Eight-year survival among the 264 patients whose tumors had entered the vertical growth phase was 71.2%. Survival prediction in these patients was enhanced by the use of a multivariable logistic regression model. Twenty-three attributes were tested for entry into this model. Six had independently predictive prognostic information: (a) mitotic rate per square millimeter, (b) tumor-infiltrating lymphocytes, (c) tumor thickness, (d) anatomic site of primary melanoma, (e) sex of the patient, and (f) histologic regression. When mitotic rate per square millimeter, tumor-infiltrating lymphocytes, primary site, sex, and histologic regression are added to a logistic regression model containing tumor thickness alone, they are independent predictors of 8-year survival (P less than .0005).
Female↗
Levels of disialogangliosides in sera of melanoma patients monitored by sensitive thin-layer chromatography and immunostaining.
Levels of GD2, GD3, and 9-O-acetyl GD3 were monitored in sera of patients with melanoma and healthy adults with two monoclonal antibodies that specifically detect these gangliosides. By direct measurement of radioactivity in the immunolabeled chromatogram, GD2 could be detected in normal sera at 2 ng/mL. Serum levels of GD2 and GD3 were increased approximately sixfold and fivefold, respectively, in patients with disseminated melanoma, compared with those of healthy adults. The acetylated derivative of GD3, which is highly specific for melanoma cells, was not detected in serum. This sensitive assay allows the quantitation of tumor-associated gangliosides that are circulating in sera of melanoma patients.
Adult↗
Defective antigen presentation by human melanoma cell lines cultured from advanced, but not biologically early, disease.
The present studies were undertaken to characterize Ag presentation by cultured human melanoma cell lines. Cell lines established from "biologically early" lesions of malignant melanoma were able to present the soluble Ag tetanus toxoid (TT) to autologous and HLA-DR-matched allogeneic, TT-immune T cell clones. Proliferation of T cell clones in response to Ag presented by primary melanoma peaked on day 2 of culture with Ag. Ag presentation was blocked by pretreatment of TT-pulsed and fixed melanoma cells with mAb against HLA-DR, but not HLA-DQ, HLA-DP, or HLA-ABC. Ag processing and presentation were inhibited by treating the melanoma cells with ammonium chloride. In parallel with previous findings from this laboratory demonstrating the inability of cell lines cultured from "advanced" primary or metastatic melanoma to induce autologous T cell proliferation, such cell lines also failed to present this exogenous Ag despite the presence of cell-surface HLA-class II molecules. Thus, in contrast to the finding in biologically early melanoma, none of the multiple TT-immune, T cell clones from autologous patients or HLA-DR matched donors was able to respond to TT presented by melanoma cells cultured from advanced disease. Co-incubation studies revealed that metastatic melanoma cells did not secrete inhibitory substances during the APC assay, however, they were able to process TT, rendering it "immunogenic" in the presence of fixed, autologous non-T cells. When fixed, autologous melanoma cells were assayed for their ability to present processed Ag; fixed cells of early but not advanced disease were able to present Ag in this setting, indicating that the presenting limb becomes flawed in the evolution of the metastatic phenotype. Finally, studies of chloroquine inhibition of the capacity of melanoma cells derived from early primary disease to stimulate autologous peripheral blood T cells suggest that such cells process and present tumor-associated Ag in the same fashion as the "model" Ag TT.
Ammonium Chloride↗
Production of interleukin 1 activity by cultured human melanoma cells.
A panel of melanoma cell lines derived from 7 primary and 20 metastatic lesions was tested for the production of interleukin 1 (IL-1) in standard mouse thymocyte costimulation assays. Constitutively produced IL-1 activity was found in the conditioned media of 4 of 7 primary and 5 of 20 metastatic melanoma cell lines tested. Four of 9 cell lines secreting IL-1 were also shown to contain cell-associated activity in their lysates. Melanoma-conditioned media were, however, unable to support the growth of CTLL, an interleukin 2-dependent cell line. The secreted IL-1 activity was significantly inhibited by antibodies to recombinant IL-1 alpha (3 of 3 lines), but not antibody to recombinant IL-1 beta. When conditioned medium from one cell line was fractionated on a Superose 12 column by fast protein liquid chromatography, a major peak of activity eluted at Mr 22,500-27,500. The presence of 2.2-kilobase mRNA hybridizing a probe for IL-1 alpha and 1.6-kilobase mRNA hybridizing a probe for IL-1 beta was detected by Northern blot in 3 of 4 secreting cell lines but not in a nonsecreting line. Taken together, these results suggest that cultured melanoma cells produce the cytokine IL-1 alpha, although the relationship between melanoma IL-1 and monocyte IL-1 is unclear. The production of IL-1 by melanoma cells is of interest because of its potential roles in the biology of melanoma through direct effects on tumor growth or through indirect effects on adjacent stromal and endothelial cells and infiltrating lymphoid cells.
Antibodies, Monoclonal↗
Patient and physician delay in melanoma diagnosis.
The sequence of events leading ultimately to the diagnosis and treatment of malignant melanoma was investigated. We conducted interviews with 275 patients and the physicians whom they had consulted regarding their suspicious lesions before their eventual referral to a melanoma center. An average of 1 year elapsed from the time that patients first noticed a new or changed lesion and the date of diagnosis. Major components of delay were attributable to both patients and physicians. An average of 6 months elapsed between patients' recognition of a new or changed lesion and their realization that the lesion was suspicious. For 21% of cases, at least 2 months elapsed between physicians' observation of lesions and a definitive diagnosis of malignant melanoma, and 13% were diagnosed a minimum of 4 months following a visit to the physician. Patients routinely cannot distinguish between melanomas and moles. Physicians do not always diagnose melanoma accurately or act promptly in response to suspicious lesions. We have yet to take adequate advantage of the unique opportunity for early detection and cure in this readily visible, rapidly increasing malignancy.
Adult↗
Interferon-gamma regulates the T cell response to precursor nevi and biologically early melanoma.
To examine the potential regulatory role of interferon-gamma in the cellular immune response to melanoma and its precursor lesions, we have tested the capacity of this lymphokine to enhance HLA class II antigen-dependent T lymphocyte blastogenesis, its in vitro production by autologous T cells stimulated by melanoma, and its presence in melanocytic lesions in situ. Cell lines derived from a dysplastic nevus, a radial growth phase primary tumor, a vertical growth phase primary, and metastatic lesions were induced by recombinant interferon-gamma to express increased amounts of HLA class II antigens. Such cells were then examined in radioimmunoassay for expression of HLA-DR antigens and in co-culture for their ability to stimulate proliferation of autologous T cells. Interferon-gamma treatment of melanocytic cells increased their expression of HLA-DR antigens threefold to sixfold. In parallel with these findings, co-culture of T cells with interferon-treated cells of a dysplastic nevus and a radial phase melanoma led to augmented T cell incorporation of tritiated thymidine, and this stimulation was inhibited with a monoclonal antibody to HLA-DR antigens. Despite augmented expression of HLA class II antigens (HLA-DR, -DQ, and -DP), vertical growth phase and metastatic melanoma cells failed to stimulate autologous T cells. When T cells were co-cultured with stimulating melanoma cells, culture supernatants contained significantly increased amounts of interferon-gamma (12 U/ml) in comparison with supernatants of T cells alone (4 U/ml). No interferon was detectable in cultures of melanoma cells alone. To link these in vitro phenomena to in situ events, we used murine monoclonal antibodies to interferon-gamma, the interleukin 2 receptor, and HLA-DR antigens in an immunoperoxidase system to detect interferon production and lymphocyte activation in frozen sections of lesions representative of melanocytic tumor progression. In these studies, precursor dysplastic nevi and radial phase melanomas contained the highest numbers of activated lymphocytes and stained positively for interferon-gamma. These results suggest that interferon-gamma plays a central role in the regulation of the cellular immune response to melanoma. It is produced by T cells, likely activated by tumor antigens seen in the context of HLA class II antigens. In turn, interferon-gamma production enhances expression of HLA class II antigens by melanoma and precursor cells, and such enhancement is associated with additional T cell activation in a positive feed-back loop.
Antigens, Neoplasm↗
Phase II evaluation of dibromodulcitol and actinomycin D, hydroxyurea, and cyclophosphamide in previously untreated patients with malignant melanoma.
In this Eastern Cooperative Oncology Group (ECOG) phase II study, dibromodulcitol (DBD) and a combination of actinomycin D, hydroxyurea, and cyclophosphamide (AHC) were compared with methyl-CCNU, the current ECOG standard, in patients who had received no prior chemotherapy for disseminated malignant melanoma. The response rates were 6% (3/50) for AHC, 9% (3/34) for DBD, and 14% (7/49) for methyl-CCNU. Median survival times were 4, 5, and 6 months, respectively. Neither regimen appears to offer any advantage over methyl-CCNU as front-line therapy for patients with disseminated melanoma.
Adolescent↗
WR-2721 and high-dose cisplatin: an active combination in the treatment of metastatic melanoma.
Cisplatin, alone or in combination with other chemotherapeutic agents, is relatively inactive against metastatic melanoma. Prior trials have demonstrated partial response (PR) rates of less than 10% with cisplatin alone. WR-2721 is an organic thiophosphate compound, which in the animal model, selectively protects normal tissues against the toxicity of cisplatin chemotherapy. During the course of a phase I trial of WR-2721 and cisplatin, objective PRs were noted in patients with far advanced metastatic melanoma. These observations led us to perform a phase II trial of WR-2721 and cisplatin. Thirty-six patients received 128 courses of WR-2721 before cisplatin (60 to 150 mg/m2). All patients had progressive disease before treatment. Objective PRs were observed in 19 of 36 evaluable patients (53%). Three additional patients had minor responses (MRs). PRs occurred in 53% of patients with prior chemotherapy (ten of 19). Sites of responding metastases were subcutaneous disease (15 of 19 patients), lymph nodes (16 of 21 patients), lung (four of ten patients), and liver (eight of 17 patients). The median duration of response was 4 months, with a mean of 4.5 months (range, 1 to 8 months). Transient nephrotoxicity was observed in less than 5% of courses. In all cases, renal function returned to normal within 1 to 2 weeks. Hematologic toxicity was mild and infrequent. Nine patients developed peripheral neuropathy following a median cisplatin dose of 670 mg/m2. Twenty patients experienced mild clinical hearing loss. These data suggest that WR-2721 may potentiate the antitumor activity of cisplatin in metastatic melanoma.
Adult↗
Human cutaneous nevi transplanted onto nude mice: a model for the study of the lesional steps in tumor progression.
Normal human cutaneous nevi were transplanted to the skin of nude mice and some of the grafts were treated topically with 7,12-dimethylbenz[a]anthracene (DMBA, 1.6 mumol weekly). Histologically proven human skin was present in 22 grafts. In the 9 untreated control grafts, the tendency of nevic cells to form nests and the number of nevomelanocytes decreased with time; the melanocytic cells showed no signs of hypertrophy or atypia. In most of the 14 specimens treated with DMBA, the nevomelanocytes showed distinct signs of hypertrophy. The cells were enlarged and often dendritic and were filled with melanin granules for which the transfer to keratinocytes appeared to be blocked. The nevomelanocytes of 4 of the 9 specimens treated with DMBA for greater than or equal to 82 days (9-16 DMBA applications), showed atypical enlarged nuclei with mitotic figures. Since atypia is one criterion for identifying precursors of transformed cells, the model of human nevi grafted onto nude mouse skin may be useful for studying the various steps involved in the progression of benign melanocytic nevi to malignant melanoma.
9,10-Dimethyl-1,2-benzanthracene↗
The role of lymph node dissection for clinical stage I malignant melanoma of intermediate thickness (1.51-3.99 mm).
The survival times of patients who had an elective regional lymph node dissection was compared with that of those who did not undergo the procedure in a database of 72 patients with clinical Stage I melanoma of intermediate thickness (1.51-3.99 mm). All of the patients had been followed for 5 years or longer or until death. No significant differences were found in other reported prognostic factors, suggesting that the two groups were comparable. By multivariate analysis, a low mitotic rate, intermediate patient age, and the presence of an infiltrative lymphocytic response were found to be associated with favorable survival. There did not appear to be any association of elective regional lymph node dissection with survival; and it was concluded that such therapy should not be regarded as "standard" for clinical Stage I melanoma of intermediate thickness.
Actuarial Analysis↗
Acquired precursors of cutaneous malignant melanoma. The familial dysplastic nevus syndrome.
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Adolescent↗
Recombinant gamma-interferon induces changes in expression and shedding of antigens associated with normal human melanocytes, nevus cells, and primary and metastatic melanoma cells.
Recombinant gamma-interferon (rIFN-gamma) induced or augmented the expression of HLA-DR class II antigens on melanocytes isolated from newborn foreskin, from congenital, common acquired, and dysplastic nevi, and from primary and metastatic melanoma. The stimulatory effect of rIFN-gamma on HLA-DR antigen expression was suppressed by the addition of the phorbol ester TPA or its analog PDBu to the culture medium. Whereas rIFN-gamma did not significantly alter the expression of melanoma-associated, non-class II antigens on melanoma cells, there was a marked decrease in the expression of antigens associated with nevus cells. In addition, rIFN-gamma stimulated shedding of antigens. Increased antigen shedding was most apparent for an intracytoplasmic melanoma-associated protein of 80kd, followed by the ganglioside GD2 and by an alkali labile ganglioside. The simultaneous stimulation of class II antigen expression and shedding of melanoma-associated antigens as well as suppression of nevus-associated antigen expression could play an important role in the host immune response to premalignant and malignant melanocytic lesions.
Antigens, Neoplasm↗