Biomedical subjects

H F Seigler

Publications and source records attributed to H F Seigler.

At least 73 records · Page 4Linked to original sources

PubMed1992

Inhibition of the growth of human melanoma metastases in nude mice by melanoma-specific murine monoclonal antibody.

The administration of anti-melanoma murine monoclonal antibody (MAB) 16.C8 (IgG2a) to nude mice bearing established human melanoma lung or liver metastases resulted in a significant inhibition of tumour growth. A total dose of 2 mg of affinity purified 16.C8 caused complete inhibition of tumour growth in 89 and 100% of animals in the liver and lung model, respectively. In contrast, a significant tumour growth was found in most control animals which received an irrelevant IgG2a MAB or 2% human serum albumin in Hanks Balanced Salt Solution (HBSS). The MAB was most effective when treatment was started on day 1 or 4 following tumour inoculation. When the 16.C8 MAB treatment was delayed 7 or 14 days, 33 and 67% of 16.C8 treated animals, respectively, developed tumours. The MAB-mediated anti-tumour activity appeared to be dose dependent, and the effect of a suboptimal dose was potentiated by the concomitant administration of recombinant interleukin 2 (rIL-2). Recombinant IL-2 alone in a similar dose did not elicit comparable anti-tumour activity. Moreover, the MAB 16.C8 inhibited tumour growth in irradiated animals which may suggest the involvement of host-radioresistant cellular elements in the 16.C8 antibody-mediated anti-tumour activities in nude mice. These results suggest that MAB 16.C8 alone or combined with rIL-2 may prove useful in the immunotherapy of metastatic melanoma.

Animals↗

PubMed1992

Recurrent malignant melanoma: the identification of prognostic factors to predict survival.

The prognostic factors for stage 1, 2 melanoma have been elucidated. Tumor thickness, ulceration of the primary melanoma, and perhaps, primary site may be used to predict the percentage of patients with regional nodal disease or systemic metastases and the prognosis of patients who have only cutaneous disease at diagnosis. Very little is known about prognosis once there is a recurrence. A retrospective, computer-aided chart review identified 4,185 patients registered at the Duke University Melanoma Database who had stage 1, 2 disease at diagnosis. During a mean follow-up period of 7 years, 35.9% experienced a recurrence. Local regional recurrences explained 62.5% to 85.5% of the recurrences. Even after elective node dissections, local regional recurrences explained most relapses (58.1%). Sixty-five percent of the recurrences occurred within the first 3 years of of follow-up. There was a pronounced difference in 5-year survival in those patients who suffered a recurrence sometime during their clinical course compared with those who never relapsed (p = 0.00001, for trunk primary melanoma). Patients with local or regional recurrence have a better prognosis than patients who relapse systemically, with 5-year survivals from the time of recurrence of 55% for a patient with a local recurrence, 51% for a patient with a regional nodal recurrence, and 20% for a patient with a systemic recurrence. A multivariate regression analysis identified thickness, ulceration of the primary melanoma, and age and location of the primary melanoma on the extremity as variables that predicted prognosis. The only factors concerning the recurrent state that added prognostic information was the disease-free interval and the presence of systemic metastases as the initial recurrence.

Adolescent↗

PubMed1992

Therapeutic and prognostic considerations of head and neck melanoma.

Therapeutic considerations are discussed based on recurrence and survival statistics of 900 patients treated at Duke University Medical Center (Durham, NC). Approximately one-third of all patients developed recurrence. Factors affecting recurrence include tumor thickness, presence of positive regional nodes at diagnosis, and advanced Clark level. Patients with more than one adverse index had even higher rates of recurrence than with one alone. The 5-year survival of all patients after recurrence was 32%. Therapeutic decisions should include considerations that relate to patients' recurrence patterns and survival curves.

Academic Medical Centers↗

PubMed1992

Anorectal melanoma: clinical characteristics and the role of abdominoperineal resection.

Twenty-four patients with primary anorectal melanoma diagnosed since 1974 have been retrospectively studied. The most common presenting symptom was rectal bleeding, typically misdiagnosed as hemorrhoids. Progressive disease most commonly presented as a large pelvic mass, diffuse bilateral pulmonary nodules, or diffuse liver metastases. Twenty-one patients (88%) died of their disease; none survived more than 6 years. Among the patients who have died of their disease, mean survival was 2.2 years. Among assessable stage I patients initially managed with abdominoperineal resection (APR), 50% developed recurrent local regional disease (mean disease-free interval = 23 months), compared with 100% of those managed with more limited surgery (mean disease-free interval = 16 months). Even after APR, however, distant metastases were common, and there was no prolongation of survival for patients treated with APR. Primary melanoma of the anorectum has a high metastatic potential and carries a grave prognosis. APR appears to have some effect in controlling local and regional disease, but prolongation of survival will depend both on earlier diagnosis and on development of more successful therapeutic approaches.

Academic Medical Centers↗

PubMed1992

"Thin" malignant melanoma: risk factors and clinical management.

Thin melanomas can metastasize and can be lethal. Six hundred eighty-one patients with melanomas less than 0.76 mm thick have been evaluated, and are reviewed in this study and discussed in the context of a literature review. Among those referred without metastatic disease (583 patients), 4.8% metastasized after a mean follow-up of 3.6 years. Among those referred with metastatic disease (98 patients), mortality was 35% after a mean follow-up of 5.9 years. Male patients (p less than 0.04) and patients with axial primary lesions (p less than 0.05) had increased risk of metastasis. Severe histological regression was present in 40% of primary lesions that metastasized and only 17% of similar lesions that did not (p less than 0.001). Increased age was associated with increased local skin metastases, but not with increased nodal or distant metastases. A prognostic model was designed that identifies a low-risk population with an actuarial risk of metastasis at 10 years that is less than 3%. High-risk patients have an actuarial risk of metastasis of 11% at 5 years and 22% at 10 years (p = 0.0084). Identifying high-risk and low-risk patients with thin melanomas may improve guidelines for the application of adjuvant therapies to this population. New approaches to this problem include use of molecular biology techniques, immunohistochemistry, and varied methods of histological sectioning.

Academic Medical Centers↗

PubMed1992

Malignant melanoma and pregnancy.

Among 100 patients diagnosed with melanoma during pregnancy and followed a mean of 6.8 years, when compared with a nonpregnant female population, there was a significantly shorter disease-free interval for the pregnant group. Median disease-free intervals were 5.8 and 11.9 years, respectively. The time to development of lymph node metastases was shorter in the pregnant patients (p = 0.015). Nodal metastases developed in 48% of the pregnant patients and only 26% of the nonpregnant patients, at 10 years. Multivariate analysis demonstrated that pregnancy at diagnosis was significantly associated with the development of metastatic disease (p = 0.008), when controlling for tumor site, thickness, and Clark level. Pregnancy, however, was not a risk factor for patient mortality. The literature continues to be split on the role of pregnancy in melanoma; however, most recent series show no difference in survival. Multiple studies have failed to show significant effects of female hormones on melanoma cells or on the incidence or progression of melanoma.

Academic Medical Centers↗

PubMed1992

Immunotherapy for malignant melanoma with a tumor cell vaccine.

Specific active immunotherapy for melanoma has been administered to several thousand patients since 1972, using an irradiated whole-cell preparation. A humoral response to vaccination can be demonstrated in a large percentage of patients. This response increases while immunizations are continued and decreases after cessation of therapy. The vaccinations are well tolerated; however, the therapeutic impact of this whole-cell vaccine awaits a randomized trial for definitive evaluation.

Academic Medical Centers↗

PubMed1992

Prospects for cellular immunotherapy for metastatic melanoma.

Systemic therapy for metastatic malignant melanoma has been disappointing. The search for alternate therapeutic methods includes investigation of the interaction between melanoma and the human immune system. A cellular immune response to melanoma has been documented in vitro and in vivo. In most patients with disseminated disease, however, immune T cells fail to eradicate the tumor. While this phenomenon is poorly understood, the occasional occurrence of spontaneous regression provides some indication that the immune response may, in fact, be capable of eradicating established tumor in vivo. Current efforts to augment and to direct the immune response to melanoma include investigation of specific and nonspecific adoptive immunotherapy. Specific therapy includes the generation of tumor-activated specific killer cells from peripheral blood, draining nodes, or metastatic tumor deposits. An increasing understanding of antigen recognition and improved methodology for T-cell culture are contributing toward the application of cellular immunotherapy to patients with melanoma.

Animals↗

PubMed1992

Thin malignant melanomas of the head and neck.

Historically, Breslow classified thin melanomas as invasive lesions less than 0.76 mm in depth with rare instances of recurrence and mortality. From 1970 to 1990, 87 patients with thin head and neck melanoma were treated at Duke Medical Center. A computer-aided retrospective analysis was performed. Recurrence occurred in 30% of these patients; however, of the 66 patients seen at this institution prior to recurrence, only 8% recurred. Recurrence significantly shortened survival. Compared to an overall 84% 5-year survival, there was less than a 50% 5-year survival after recurrence. For thin melanomas, thickness did not affect survival. There was no difference in survival between thin melanomas and those ranging from 0.76 to 1.5 mm. A multivariate analysis was performed. The data suggest that thin melanomas of the head and neck may recur at a higher rate than previously reported and in addition, that they can be lethal.

Adult↗

PubMed1992

Analysis of 945 cases of pulmonary metastatic melanoma.

From 1970 to 1990, 7564 patients with melanoma were seen at Duke University Cancer Center. Complete follow-up data were available in all patients. The estimated probability of a pulmonary metastasis developing 5, 10, or 20 years after initial diagnosis was 0.13, 0.19, and 0.30, respectively. Pulmonary metastases were documented in 945 patients (12%), these having 1-, 3-, and 5-year survival rates of 30%, 9%, and 4%, respectively. The methods of diagnosis were chest radiograph (n = 544), computed tomography (n = 157), transthoracic needle biopsy (n = 121), bronchoscopy (n = 14), thoracotomy (n = 112), and autopsy (n = 7). Evidence of advanced pulmonic spread included bilateral disease in 543 and more than two nodules in 595. Univariate predictors for early formation of pulmonary metastases (p less than 0.001) were male sex, black race, increased primary thickness (millimeters), higher Clark's level, nodular or acral lentiginous histology, location on trunk or head and neck, and regional lymph nodes positive for metastasis. Multivariate predictors of improved survival (p less than 0.001) in order of importance were complete resection of pulmonary disease, longer time for formation of metastases, treatment with chemotherapy, one or two pulmonary nodules, lymph nodes negative for metastasis lymph nodes (p less than 0.005), and histologic type (p less than 0.04). Additionally, survival in patients with one nodule and resection (n = 84) was better than in those with similar disease and no resection (n = 142 months, p less than 0.001). These data comprise the largest series to date and emphasize the importance of long-term follow-up, as well as supporting the selective use of resection for isolated pulmonary metastases, increasing the 5-year survival rate from 4% to 20%.

Adult↗

PubMed1992

Generation of human IgG, IgA, and IgM anti-melanoma monoclonal antibodies utilizing lymphocytes of an actively immunized melanoma patient.

Active specific immunotherapy with irradiated allogeneic melanoma cells has been shown to enhance the humoral immune response in melanoma patients. An increased titer of melanoma-binding antibodies was demonstrated in sera of immunized patients. Lymph node cells and splenocytes isolated from an actively immunized melanoma patient were fused with the human-murine heteromyeloma cell lines SHMD-33, SPM4-0, and SBC-H20. A group of human anti-melanoma monoclonal antibodies (MABs) were generated from the SHMD-33 fusion. Isolated MABs (one IgG2, one IgA, and two IgM) have been stable in cultures for more than 12 months and have produced human immunoglobulins at 0.2-0.9 Ug/ml/day. As shown by solid phase radioimmunoassays, the MABs react with autologous tumor cells and allogeneic melanoma tumors, including the cell line that was used for immunotherapy. In immunocytochemical assays, all four MABs react with a number of melanoma tumor cell lines. The IgG2 and IgA MABs stained preferentially melanoma tumor cells. In contrast, the IgM MABs cross-reacted with a broad panel of tumor cells from colon, prostate, pancreas, lung, and other human tumors. The MABs appear to be directed to intracellular rather than membrane-associated antigens as shown by immunofluorescence assays on live and permeabilized cells. The IgG2 antibody recognizes a 70 kDa antigen in melanoma cell lysates by Western immunoblotting. The target antigens for the other MABs have not yet been defined. Stability in culture and strong binding to melanoma tumor cells provide the basis for evaluating the potential of these human MABs. The IgG2 MAB, in particular, may prove useful for diagnostic and therapeutic applications in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

MHC-restricted recognition of autologous melanoma by tumor-specific cytotoxic T cells. Evidence for restriction by a dominant HLA-A allele.

Autologous melanoma-specific CTL recognize a common tumor-associated Ag (TAA) in the context of HLA class I antigens. We have demonstrated that HLA-A2 can be a restricting Ag and, in T cell lines homozygous for HLA-A2, that CTL can be generated by stimulation with HLA-A2 allogeneic melanomas. In the current study, we have investigated T cell lines from patients who are heterozygous at HLA-A region locus, to determine the relative importance of each A-region allele in this MHC-restricted recognition of tumor. We have shown that HLA-A1 can be a restricting Ag, and that allogeneic melanomas expressing HLA-A1 can substitute for the autologous tumor in the generation of HLA-A1-restricted CTL. However, when T cell lines express both HLA-A1 and HLA-A2, the HLA-A2 allele governed restriction of the melanoma TAA. Three autologous-stimulated HLA-A1, A2 CTL lines all demonstrated restriction by the HLA-A2 allele, when examined in cytotoxicity assays, cold-competition assays, and proliferation assays. There was no evidence of restriction by the second HLA-allele, HLA-A1. Although the autologous-stimulated CTL use a single A-region allele for tumor recognition, the autologous HLA-A1, A2 tumors are lysed by both HLA-A1-restricted and HLA-A2-restricted CTL. The dominance of restricting alleles was further demonstrated when HLA-matched allogeneic melanomas were used as the stimulating tumor to generate tumor-specific CTL. Stimulation of the heterozygous (HLA-A1, A2) lymphocytes with HLA-A2-matched allogeneic melanomas resulted in CTL specific for the autologous tumor, and restricted by the HLA-A2 Ag. However, stimulation with an HLA-A1-matched allogeneic melanoma failed to induce tumor-specific CTL restricted by the HLA-A1 Ag. The data suggest there is a dominance of HLA-A region Ag at the level of the T cell, such that only one is restricting in the recognition of the autologous melanoma. At the level of the tumor, however, the TAA is expressed in the context of both HLA-A region alleles. We can generate specific CTL from lymph node cells or PBL and HLA-A region matched allogeneic melanomas; however, because most patients are heterozygous at the HLA-A region locus, an understanding of the dominant restricting alleles must be obtained so that an appropriately matched allogeneic melanoma can be selected.

Alleles↗

PubMed1991

Treatment of human melanoma hepatic metastases in nude mice with human cytotoxic T lymphocytes.

We investigated the effects of human melanoma-specific cytotoxic T lymphocytes in treating experimental human melanoma hepatic metastases in a nude mouse model of adoptive immunotherapy. Hepatic metastases were generated by intrasplenic injection of 1.5 x 10(6) human melanoma cells. Three days after injection, animals received salt solution and interleukin 2 or interleukin 2 and cytotoxic T lymphocytes. Twenty-four of 25 control animals had developed multiple tumor nodules in the liver; 11 of 13 animals receiving only interleukin 2 also had significant tumor burdens. In striking contrast, 17 of 18 animals receiving cytotoxic T lymphocytes and interleukin 2 had no gross or histologic evidence of tumors. The remaining animal had a 2-mm nodule. Human tumor-specific cytotoxic T lymphocytes are effective in vivo in a model of adoptive immunotherapy and may prove useful in adoptive immunotherapy of humans with metastatic melanoma.

Animals↗

PubMed1991

Malignant melanoma in black Americans. A trend toward improved survival.

A search of patients seen at the Duke University Melanoma Clinic (Durham, NC) identified 79 black patients. Five- and 10-year survival was 35% and 26%, respectively. Patients presenting in the recent decade had less advanced disease, resulting in an improved 5-year survival of 49%. Five-year survival for white patients was 74%. Black patients had more negative prognostic indicators when compared with white patients. In a multivariate analysis, however, race was not a prognostic indicator, suggesting melanoma is not inherently more aggressive in black patients. The trend during the past decade has been for black patients to present with less advanced disease, with improved survival. This may be related to better appreciation of the disease by patients and physicians alike. Continued emphasis on education and early diagnosis may result in further improvement for black patients with melanoma.

Actuarial Analysis↗

PubMed1991

Role of surgical intervention in the management of intestinal metastases from malignant melanoma.

Malignant melanoma is the most common metastatic lesion of the intestine. Surgical consultation is often sought when bowel metastases become symptomatic. To determine the role of surgical intervention in such cases, a database of 6,000 melanoma patients was examined, and a subset of 102 patients with small intestinal or colonic metastases were identified premortem. Common presenting features included abdominal pain with or without acute symptoms (29% of patients), obstruction or intussusception (27%), and bleeding (26%). The presence of metastatic lesions was confirmed by surgical exploration in 80% of patients, endoscopic procedures in 11%, and percutaneous biopsy in 5%. Cure was achieved in 36 patients by resection, which resulted in the removal of all demonstrable disease. The subsequent mean length of survival in this group was 31 +/- 5.2 months. Forty-two patients underwent palliative enteric bypass or debulking procedures, and 24 patients received either chemotherapy alone or symptomatic treatment. The average length of survival in these latter groups was 9.6 +/- 15.9 and 9.6 +/- 3.6 months, respectively, both of which were significantly less than the duration of survival in the complete resection group (p less than 0.05). Small or large bowel resection for bleeding or obstruction and enteric bypass for obstruction provided symptomatic relief in 92% of patients thus treated. There was no operative mortality in the series. An aggressive search for resectable disease in patients with symptoms secondary to intestinal metastases from malignant melanoma should be performed. Surgical intervention may then allow the palliation of pain, obstruction, and bleeding. Survival can be significantly prolonged if it is possible to remove all demonstrable disease.

Adult↗

PubMed1991

DNA ploidy of malignant melanoma determined by image cytometry of fresh frozen and paraffin-embedded tissue.

Image analysis of DNA content was performed from single nuclei of melanoma monolayer imprints made from fresh frozen tissue of 14 patients with primary malignant melanoma and 16 patients with local recurrences at the incision site and local or distant metastases. This procedure requires fewer cells and is an advantage when the quantity of tumor available is limited, especially in thin low Breslow depth cutaneous melanomas. Image analysis allowed reproducible measurement of DNA ploidy from 100 cells. The frequency of aneuploidy was similar in primary and metastatic melanomas. Three of 3 patients with euploid primary melanomas showed no evidence of recurrences or metastases, though one died of unrelated disease with short follow-up. The 4 patients with primary melanoma who developed metastases had aneuploid primaries; two of these patients died of metastatic disease. Three of 4 patients with euploid metastatic tumors were free of disease at last follow-up, and 1 patient died with stable disease. Nine of 12 patients with aneuploid tumors died of metastatic disease. The frequency of DNA ploidy in the present image analysis study correlated with previous flow cytometry studies. In 9 patients with primary tumors with a Breslow depth greater than 0.75 mm, the DNA content was also determined in nuclei obtained from formalin-fixed paraffin-embedded tissue. The frequency of aneuploidy was higher in fresh tissue (7 of 9) as compared with paraffin-embedded tissue of the same cases (4 of 9).

Aneuploidy↗

PubMed1991

Cell binding and tumor inhibiting functions of a new antihuman melanoma murine monoclonal antibody.

Murine, antihuman melanoma cell monoclonal antibody (mAb) 16.C8 was generated by fusing the murine myeloma cell line P3X63/Ag8.653 with splenocytes from a nude mouse bearing a human melanoma xenograft, after reconstitution with splenocytes from syngeneic immunocompetent BALB/c mice. The antibody reacted strongly with fresh human melanoma cells and exhibited preferential reactivity with established human melanoma and neuroectodermal tumor cell lines. Electrophoresis and Western blotting experiments indicated that 16.C8 is directed against a sialoglycoprotein antigen with a molecular weight of 110-120 kDa. mAb 16.C8 mediated lysis of melanoma cells in vitro in antibody-dependent cellular cytotoxicity assays using human mononuclear effector cells isolated from normal volunteers or malignant melanoma patients. In addition, the administration of mAb 16.C8 to nude mice bearing established human melanoma lung and liver metastases resulted in significant inhibition of tumor growth as shown by gross and histologic examination. In contrast, animals treated with Hanks' balanced salt solution or nonspecific immunoglobulin exhibited a large tumor burden. These results suggest that mAb 16.C8 may be of value in treatment of metastatic melanoma in humans.

Animals↗

PubMed1991

The role of resection in the management of melanoma metastatic to the adrenal gland.

Melanoma metastatic to the adrenal gland diagnosed before death was exceedingly rare before the development of computed tomographic (CT) scanning. The records of 28 patients with melanoma metastatic to the adrenal gland seen since 1975 were reviewed. Eighteen patients were men and 10 were women. Twenty-three patients had unilateral disease. Four patients were diagnosed only at autopsy, leaving 24 for analysis of treatment and survival. Twenty-one patients had received specific active immunotherapy, four had received chemotherapy (dacarbazine, lomustin, bleomycin, and vincristine), and three had received both before the diagnosis of their adrenal disease. Adrenal metastases were diagnosed by CT scanning in 14 patients with symptoms, 10 (91%) of whom had pain. Ten patients were diagnosed by CT before entry into a chemotherapy protocol. Of eight patients who underwent resection of all known disease, five underwent unilateral adrenalectomy, two underwent unilateral adrenalectomy and bowel resection, and one underwent bilateral adrenalectomy. Two patients underwent partial resection of large unilateral tumors. Fourteen patients with adrenal metastases and disease elsewhere were initiated or continued with chemotherapy or were treated symptomatically. Mean survival in the group that underwent resection for cure was 59 months (3 to 112 months), whereas survival in the group with unresectable tumors was 15 months (1.5 to 132 months). Four of eight patients who underwent resection for cure lived more than 5 years after detection of adrenal metastasis, whereas in only one of 14 patients with unresectable tumors was the same true. Patients with metastatic melanoma localized to one or both adrenal glands may benefit from early detection and surgical intervention.

Adrenal Gland Neoplasms↗