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H F Seigler

Publications and source records attributed to H F Seigler.

At least 55 records · Page 3Linked to original sources
PubMed1994

Transduction of human melanoma cells with interleukin-2 gene reduces tumorigenicity and enhances host antitumor immunity: a nude mouse model.

Human melanoma tumor cells were genetically modified in vitro by transferring the interleukin-2 (IL-2) gene via a retroviral vector into established or fresh tumor cells. In addition, human melanoma cells were transduced in vivo by the direct injection of the IL-2/retroviral vector into melanoma xenografts in nude mice. The gene-modified melanoma cells expressed the IL-2 cytokine gene and secreted biologically active IL-2. Transduction of melanoma cells with the IL-2 gene did not affect the antigenic profile of the cells, but caused a strong abrogation of their tumorigenicity. One million parental cells formed subcutaneous tumors in nude mice. In contrast, various doses of up to 20 x 10(6) IL-2-transduced cells failed to form tumor in the mice. Coinjection of IL-2-producing cells with parental cells inhibited tumor formation even when highly tumorigenic doses of parental cells were used. Histochemical analysis of the injection sites of IL-2-modified cells showed an influx of host immune cells, predominantly macrophages, as early as the third day after inoculation. Neutrophils, mast cells, and eosinophils were also seen in the inflammatory exudate. Eventually, transduced cells showed signs of degeneration and necrosis and ultimately died in 4 weeks. Macrophages were seen in parental tumor sites only during the first few days after injection, and then parental tumors exhibited fast, progressive growth. The study suggests that melanoma cells transduced with the IL-2 cytokine gene may provide an effective vaccine for melanoma patients, whereas the in vivo transduction of tumors with cytokine genes is feasible and may represent a novel approach for the immunotherapy of cancer patients.

Animals↗
PubMed1994

Malignant melanoma in children.

BACKGROUND: Cutaneous melanoma is an uncommon malignancy in children and for this reason, there is little information available regarding the timing and patterns of recurrence in children with this disease. This study reviews the experience at a single institution (Duke University Melanoma Clinic) in treating children with malignant melanoma. METHODS: Eighty-five patients < or = 18 years of age with malignant melanoma have been treated. All but three patients were over the age of 10; 73% of them were > 14. As for adults, treatment consisted of wide local excision of all primary lesions with primary closure or split-thickness skin graft, as needed. In addition, 22 patients underwent dissection of regional lymph nodes. Patients whose tumors had aggressive pathologic characteristics were treated with an adjuvant immunotherapy protocol. Patients with recurrence at distant sites were offered combination chemotherapy. RESULTS: Patients and pathologic characteristics of sex, race, primary site, histologic type, tumor thickness, and Clark level were similar to those observed in adults. Actuarial survival rates (79% versus 77% at 5 years) of the pediatric and adult Stage I melanoma patients were also not significantly different. Children had a greater incidence of recurrence after initial treatment, although recurrence tended to happen after a longer disease-free interval than for adults. Half of the 79 children who were first seen with Stage I disease have suffered a relapse, but more than one-third were disease free for > or = 5 years after initial treatment. Of the 18 patients who were disease free for > or = 7 years, 12 (67%) ultimately had recurrent disease, including five patients who had recurrences > 13 years after initial diagnosis. CONCLUSIONS: The early age at which malignant melanoma may occur and the significant potential for very late recurrence mandate that pediatricians and other primary care physicians consider the diagnosis of melanoma even in young patients with new skin lesions and that patients treated for melanoma be carefully followed for a lifetime.

Adolescent↗
PubMed1994

Surgical management of regional lymph nodes in patients with melanoma. Experience with 4682 patients.

OBJECTIVE: The purpose of this study was to evaluate a large number of patients with cutaneous melanoma who had or who were at risk for lymph node metastases to contribute to the understanding of the behavior of and appropriate management of draining nodes. A major goal of the study was to reassess the clinical impact of elective lymph node dissections (ELND) in a large patient population. SUMMARY BACKGROUND DATA: Large retrospective studies suggest that ELND may improve the prognosis of patients with intermediate thickness melanomas; however, that improvement has not been observed in two randomized prospective controlled trials. METHODS: The charts of 4682 patients treated at a single institution for localized or regional disease were reviewed individually. The median follow-up was 4.7 years, with 814 patients followed more than 10 years. The data were tabulated and evaluated with the aid of a computer data base system. RESULTS: Among patients with nodal metastases, 10% of nodal metastases were to contralateral nodes, and 6% were to nodal basins that would not be predicted by classic models of lymphatic drainage; in 13% of patients, nodal metastases occurred to greater than one nodal basin (3% of the entire study group). For all thickness ranges, the incidence of nodal metastases was comparable to the incidence of distant metastases; intermediate-thickness lesions had no relative predilection for nodal metastases. At the initial evaluation, regional nodal basins were clinically negative in 3550 patients, of whom 911 (25.7%) underwent ELND. Stratified into five thickness groups (< 0.76 mm, 0.76 to 1.5 mm, 1.5 to 2.5 mm, 2.5 to 4 mm, and > 4 mm), pathologically positive nodes were identified in 0%, 5%, 16%, 24%, and 36%, respectively (16% overall). Among the 911 patients who underwent ELND, 214 (23%) had nodal metastases, 143 at the time of ELND and 71 at a later date. Of these 71 patients, 31 (44%) had nodal metastases in a previously dissected nodal basin, and 40 (56%) had them in basins not previously dissected. The survival of patients with clinically negative nodes treated with and without ELND were compared. The two groups were well matched for major prognostic factors. Stratified by Breslow thickness and primary site, no significant improvement in survival was observed with ELND. CONCLUSIONS: Because of the significant incidence of metastases to contralateral and atypical nodal basins, lymphoscintigraphy may be justified for the preoperative evaluation of patients for ELND. However, the therapeutic value of ELND is questionable as a result of (1) the finding that the risk of nodal metastases is not relatively more common than is that of distant metastases among patients with intermediate-thickness melanomas, (2) the fact that only 16% of ELND were positive, (3) the finding that ELND may not prevent recurrent nodal disease in the dissected basin, and (4) the absence of any apparent impact on survival among patients who underwent ELND.

Female↗
PubMed1994

Melanoma of the foot.

We performed a prospective study of the results of treatment of primary cutaneous melanoma of the foot in 282 patients to determine if there were any factors that could predict survival. These patients were part of a group of 1018 patients who had primary cutaneous melanoma affecting the lower extremity. We found that 184 (65 per cent) of the 282 patients had a tumor that extended into the reticular dermis or subcutaneous tissue (a Level-IV or V lesion according to the system of Clark et al.). Sixty-three patients (22 per cent) had evidence of local, regional, or distant metastatic disease at the time of presentation. Location of the melanoma on the plantar aspect of the foot was found to be an independent variable that was associated with a poorer rate of survival (56 per cent at five years and 46 per cent at ten years) compared with a dorsally located melanoma (80 per cent at five years and 67 per cent at ten years). Subungual lesions were associated with an extremely low rate of survival (17 per cent at ten years); however, because of the small number of subungual lesions that were followed, the difference in survival between the patients who had a plantar lesion and those who had a subungual lesion was not significant (p = 0.52). Variables, in order of decreasing importance, that had independent prognostic significance for survival of patients who had a melanoma of the foot were the clinical stage of the lesion at the time of presentation (p < 0.001) and the age of the patient (p < 0.03), as determined by multivariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Transduction of human melanoma cells with the gamma interferon gene enhances cellular immunity.

Human tumor cells transduced with the gamma interferon (gamma IFN) gene are currently used in specific active immunotherapy protocols to enhance the antitumor immune responses of cancer patients. This in vitro study was undertaken to examine the initial events in the cellular immune response that may occur following the administration of the gamma IFN-transduced cell vaccine. Human melanoma tumor cell lines were transduced with a MoMLV-based retroviral vector carrying the human gamma IFN gene. The transduced cells expressed the cytokine gene, secreted biologically active gamma IFN, and exhibited enhanced expression of MHC class I and class II (HLA-DR), and ICAM-1 surface antigens. The gamma IFN-transduced and corresponding parental melanoma cells were used for the induction of short-term lymphocyte cultures. Peripheral blood lymphocytes or lymph node cells from 20 melanoma patients were stimulated for 5 to 15 days with autologous or MHC class I-matched allogeneic parental or gamma IFN-transduced melanoma cells. Seven of the 20 lymphocyte cultures showed substantial increases in lytic activity following stimulation with the transduced melanoma cells in comparison to control lymphocyte cultures stimulated with unmodified parental melanoma. The cytolytic activity stimulated with gamma IFN-modified melanomas was mediated partly by MHC-restricted cytotoxic T lymphocytes and partly by NK cells. Lymphocyte cultures that displayed increases in cytotoxicity after stimulation with the gamma IFN-transduced melanoma cells also exhibited enhanced expression or induction of one or more of the following lymphokines: IL-4, IL-1 alpha, IL-1 beta, gamma IFN, and TNF-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, Neoplasm↗
PubMed1993

Skin melanoma. Cured fraction and survival time as functions of thickness, site, histologic type, age, and sex.

BACKGROUND: Previously, nonparametric or semiparametric methods have been used to determine the relationship of various prognostic covariates with survival of skin cancer. Unfortunately, these methods do not readily distinguish between factors that modulate cure and those that modulate survival time among uncured patients. METHODS: The multivariate lognormal model can be used to detect the association of cured fraction and median survival time with specific prognostic covariates. This model was applied to survival data from 2004 patients with skin melanoma using the following prognostic covariates: thickness, site, and histologic type of the tumor and sex and age of the patient. RESULTS: This analysis revealed that a low cured fraction was associated with thick lesions and location other than trunk or extremity, whereas a short median survival time was associated with thick lesions and tumor located on the trunk. Advanced age was highly associated only with short median survival time. CONCLUSION: The lognormal survival model offers insight into the biology of skin melanoma by distinguishing the roles played by likelihood of cure and survival time. The differential associations of various covariates with these two parameters suggest that biologic mechanisms that govern cure are not identical to those that govern survival time.

Age Factors↗
PubMed1993

Randomized trial of high-dose chemotherapy with autologous bone marrow support as adjuvant therapy for high-risk, multi-node-positive malignant melanoma.

BACKGROUND: Chemotherapy adjuvant to surgery in metastatic melanoma has been evaluated in only a few prospective randomized trials. In the treatment of metastatic melanoma, dacarbazine has response rates of 15%-25% and in several studies, when combined with other alkylating agents, has yielded even higher response rates. Among the highest response rates are those achieved by using high-dose chemotherapy regimens combined with autologous bone marrow support (transplantation). PURPOSE: We conducted a prospective randomized clinical trial to test the efficacy of high-dose alkylating agents in combination with autologous bone marrow support given as adjuvant therapy for high-risk stage II (World Health Organization) melanoma. METHODS: Thirty-nine patients with metastases involving five or more lymph nodes were randomly assigned to one of two treatment arms within 8 weeks of lymphadenectomy: immediate treatment or observation only. The immediate-treatment arm consisted of 19 patients who, immediately after random assignment, received high-dose chemotherapy with alkylating agents, followed 3 days later by reinfusion of autologous bone marrow. The observation arm consisted of 20 patients who were observed until relapse (confirmed by biopsy) and were then treated with the identical high-dose alkylating agent chemotherapy followed by reinfusion of autologous bone marrow. Bone marrow was harvested from the patients under general anesthesia 1-2 weeks prior to chemotherapy and was cryopreserved. Chemotherapy consisted of intravenous administration of cyclophosphamide (1875 mg/m2 as a 1-hour infusion daily for 3 days), cisplatin (55 mg/m2 per day by continuous infusion over the same 72-hour period), and carmustine (BCNU) (600 mg/m2) given immediately after cisplatin on the 4th day as a 2-hour infusion. The total doses of the three drugs were 5625, 165, and 600 mg/m2, respectively. All patients received medical evaluations every 6-12 weeks over the study period. Kaplan-Meier estimates were used to determine the time to disease progression on the basis of intent to treat. RESULTS: There was no statistically significant difference in overall survival or in time to disease progression between the two treatment arms. However, the median time to progression was 16 weeks in the observation arm and 35 weeks in the immediate-treatment arm. CONCLUSIONS: Immediate adjuvant high-dose chemotherapy with alkylating agents followed by autologous bone marrow support more than doubled the time to disease progression compared with observation alone, though the difference was not statistically significant. No differences in overall survival were noted.

Adult↗
PubMed1993

Cell surface reactive human monoclonal antibody directed to human melanoma-associated gangliosides.

An IgM human monoclonal antibody (human MAb) was generated by fusing lymph node cells isolated from a surgical specimen of malignant melanoma with the heteromyeloma cell line SHMD-33. The antibody, designated 7c11.e8, reacted with surface antigens on human melanoma cells as shown by live cell immunofluorescence and absorption assays. The MAb 7c11.e8 reacted with DSI, SPG, GM4, GM3 and GD3 in enzyme-linked immunosorbent assays (ELISA), and did not react with GD2, GM1, GM2, GD1a, GD1b, GT1b and a number of neutral glycosphingolipids. The main binding epitope for the MAb was, therefore, the terminal N-acetylneuraminic acid 2-3 Gal linked by a beta 1-1 bond to the ceramide, or a beta 1-4 bond to glucose or glucosamine. As shown by immunohistochemical assays, 7c11.e8 antigen was expressed on all melanoma tumour tissues, and on a few samples of colon carcinoma, normal colon, skin, spinal cord, kidney and liver. However, other normal organs such as breast, lung, small intestine, stomach and lymph nodes did not react with the MAb. In the presence of human serum the antibody initiated a strong lysis of melanoma tumour cells in complement-dependent cellular cytotoxicity (CDCC) assays. This study demonstrates that it is possible to isolate human monoclonal antibodies directed to cell surface antigens using viable cell assays in the screening protocol. The preferential binding of 7c11.e8 to melanoma tissues and the reactivity with two of the major melanoma gangliosides (GM3 and GD3) suggest that 7c11.e8 may provide a useful reagent for diagnosis and therapy of malignant melanoma.

Antibodies, Monoclonal↗
PubMed1993

Lentigo maligna melanoma of the head and neck.

Historically, lentigo maligna melanoma has been considered a "favorable" histological type of melanoma, and treatment by wide local excision was considered curative. A retrospective multivariate analysis of 143 head and neck patients with stage I lentigo maligna melanoma was performed from a database of 1067 head and neck patients followed at Duke Medical Center. Fifty-six percent of all lentigo maligna melanomas presented with lesions deeper than 0.76 mm, and 8% presented with stage II or III disease. Recurrent disease occurred in 45% of stage I patients, with a 5-year disease-free interval of 6 years and a median survival time of 10 years. Multivariate analysis demonstrated no significant difference in disease-free interval or survival by histological subtype. The data suggest that treatment should be based on tumor thickness and not histologic subtype.

Adult↗
PubMed1993

Multiple primary melanoma: incidence and risk factors in 283 patients.

To identify patients with melanoma at risk for a second primary lesion and to assess the prognostic relevance of multiple primary lesions, 7816 patients treated for malignant melanoma have been reviewed. Two to nine primary lesions were identified in 283 patients (3.6%): two lesions were identified in 82% of these 283 patients, three lesions in 11%, and four lesions in 3%. Sixty-four percent were metachronous. Among patients with melanoma, the 10-year actuarial risk of a second primary lesion was 5%; a third of that risk was expressed within 3 months of the initial diagnosis plus a subsequent risk of 0.38% per year. Risk factors for multiple primary lesions were family history of melanoma, thin primaries, male sex, Celtic complexion, and a history of another cancer. Patients with a family history of melanoma had a 14% risk of a second primary lesion during the first 10 years after diagnosis. By univariate and multivariate analyses, there was no survival disadvantage for patients with multiple primary lesions. After median follow-ups of 3.7 and 4.8 years, respectively, 51.7% and 50.5% of the groups with single and multiple primaries were disease free. Mortality rates were 31% and 25%, respectively. It is appropriate to base therapeutic decisions and prognostic evaluations on the specific risk factors of each individual lesion. Identification of patients at high risk for multiple primary lesions may permit early diagnosis and improved outcomes.

Actuarial Analysis↗
PubMed1993

Survival of patients with carcinoma of the esophagus treated with combined-modality therapy.

Since 1985, 229 cases of carcinoma of the esophagus have been considered for entry into a protocol with the use of preoperative chemotherapy and radiation therapy followed by surgical intervention as the primary element of treatment. One hundred sixty-five patients (93 with adenocarcinoma and 72 with squamous cell carcinoma) had esophagogastrectomy. The 5-year survival of the protocol patients who underwent resection was 25% for both groups--squamous cell carcinoma and adenocarcinoma. Of the protocol patients with squamous cell carcinoma who underwent resection, 40% had a sterilized specimen, whereas of those with adenocarcinoma, 20% had a sterilized specimen. If the patient had a sterilized specimen, the 5-year survival was approximately 60% for adenocarcinoma and 40% for squamous cell carcinoma. Those patients with adenocarcinoma and Barrett's esophagus had a 5-year survival of 55%. Of the patients who underwent only esophagectomy and esophagogastrectomy and had not been entered into the protocol, none lived beyond 3 years. The operative mortality rate for those who had esophagogastrectomy was 5%. Sixty-four patients completed the radiation therapy and chemotherapy but did not undergo surgical procedures because of progressive disease or refusal. Of those patients who completed chemotherapy and radiation therapy without surgical intervention, 5-year survival was 18% in patients with squamous cell carcinoma, whereas no patients with adenocarcinoma survived beyond 3 years. The finding of a sterilized specimen after esophagectomy is a favorable prognostic factor in patients with adenocarcinoma or squamous cell carcinoma. The finding that patients with Barrett's esophagus and adenocarcinoma have an improved chance for survival is perhaps related to an earlier diagnosis. It is clear that some patients with squamous cell carcinoma who did not undergo surgical procedures did have a sterilized specimen, because the survival in this group approached 20% at 5 years.

Adenocarcinoma↗
PubMed1992

The annual risk of melanoma progression. Implications for the concept of cure.

BACKGROUND: Melanoma may remain clinically dormant for years, and patients may have distant metastatic disease decades after the initial diagnosis is made. Because of this potential for late recurrence, the concept of "cure" for melanoma is not particularly meaningful. METHODS: To understand better the risks of future disease as a function of time elapsed after diagnosis, the clinical course of melanoma was reviewed in 5838 patients. Using conditional probability methods, the risk of recurrent disease and the risk of death were determined for 1-year and 5-year intervals during the first 15 years of follow-up. RESULTS: The estimated 5-year risk of recurrence declined from 44% at the time of diagnosis to 21% after 6 years. The 5-year risk of mortality decreased from 26% after 1 year to 16% after 9 years. Among patients with recurrent or metastatic disease, the annual risk of mortality was approximately 20% per year for 3 years; thereafter, the risk declined markedly. Among patients with thick primary lesions, the greatest risk was during the first few years after diagnosis, but in patients with thin lesions, the risk was distributed evenly over 15 years and did not decrease with time. CONCLUSIONS: Conditional probability methods permit estimation of future risks to address questions frequently asked by patients with cancer who want to know when they can be considered cured of cancer or when the risk of recurrent disease has decreased. These data on the future risk of recurrent disease and mortality can give a patient meaningful information on which to base life decisions.

Female↗
PubMed1992

Human melanoma-mediated inhibition of autologous CD4+ helper tumor-infiltrating lymphocyte growth in vitro.

Tumor-infiltrating lymphocytes (TIL) were isolated from a human melanoma metastatic to the abdomen. The TIL were 99% CD3+ and 99% CD4+ and CD8-. They were dependent on interleukin-2 (IL-2) for growth, as measured in a thymidine uptake assay, and were not cytotoxic to autologous or allogeneic melanoma or K562. When co-cultured with irradiated autologous tumor cells, or tumor cell supernatants, the TIL not only did not respond, but the IL-2-dependent growth was inhibited significantly. Inhibition occurred during the first 24 hours of co-culture and persisted as long as the tumor was present. After being washed free of inhibitory tumor cells, the TIL again were able to grow in the presence of IL-2, indicating that the inhibition was not caused by irreversible toxicity mediated by the tumor. Addition of excess IL-2 did not reverse the inhibitory effect, but addition of indomethacin, an inhibitor of cyclooxygenase and prostaglandin synthesis, partially blocked the inhibition. These data show melanoma-mediated inhibition of induction and expansion of human T-cells in vitro, which may reflect one of the mechanisms of inhibition of cellular responses in vivo. These results stress the need to examine the techniques for optimal in vitro expansion of tumor-specific TIL or cytotoxic T-cells for adoptive immunotherapy.

Biological Factors↗
PubMed1992

Human xenograft-nude mouse model of adoptive immunotherapy with human melanoma-specific cytotoxic T-cells.

We investigated the efficacy of human melanoma-specific cytotoxic T-cells (CTLs) in treating experimental human melanoma metastases in a nude mouse model of adoptive immunotherapy. Hepatic metastases were generated by the intrasplenic injection of 1.5 x 10(6) human melanoma cells. Animals were then randomized to receive saline, interleukin-2 only, or CTLs and interleukin-2. CTLs were effective when administered 3 or 7 days after generation of hepatic metastases, with 96 and 88% of animals disease-free, respectively, when examined at one month. Interleukin-2 alone was not effective. In addition, CTLs were effective when as few as 2.5 x 10(6) T-cells were adoptively transferred. Only 33% of the animals were tumor-free when CTLs were administered on day 10, and CTLs were not effective when given at day 14. Human CTLs that were not cytotoxic for the tumor line used in vivo, when tested in a 51Cr assay, were also not effective in the model of immunotherapy. This suggests that the tumor-specific CTLs maintain their specificity in vivo, and eliminates a nonspecific inflammation directed against the human CTLs as a possible cause of the antitumor effect. These studies lay the foundation for clinical trials of CTLs in the adoptive immunotherapy of patients with metastatic melanoma.

Animals↗
PubMed1992

Relationship between disease-free interval and survival in patients with recurrent melanoma.

A total of 2468 patients with recurrent melanoma were subdivided on the basis of disease-free interval: group 1 had recurrences within 1 year (n = 810), group 2 at years 1 to 3 (n = 1001), group 3 at years 3 to 5 (n = 363), group 4 at years 5 to 10 (n = 329), and group 5 after 10 years (n = 145). Ten-year survivals were 21%, 23%, 25%, 28%, and 35%, respectively. Patients who had recurrences within 1 year had a decreased median survival compared with those who had later recurrences, although the differences were not clinically significant (only 6 to 8 months). Survival was improved for the few patients who had recurrences longer than 10 years from diagnosis. However, for the majority of patients, who had recurrences between 1 and 10 years, the disease-free interval did not predict subsequent survival. The data support the hypothesis that malignant cells can exist in a state of relative quiescence for extended periods. Once disease reactivation occurs, however, the subsequent survival is relatively predictable and is independent of the initial period of tumor dormancy.

Actuarial Analysis↗