Biomedical subjects

C L Slingluff

Publications and source records attributed to C L Slingluff.

At least 55 records · Page 3Linked to original sources

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↗

PubMed1990

Generation of human autologous melanoma-specific cytotoxic T-cells using HLA-A2-matched allogeneic melanomas.

Autologous tumor-specific cytotoxic T-lymphocytes (CTLs), generated by repeated stimulation with autologous melanoma and expanded in interleukin 2, are major histocompatibility complex restricted. These CTLs recognize a common tumor-associated antigen in the presence of HLA class I determinants, suggesting that allogeneic melanomas which express the restricting HLA-A region antigen could substitute for the autologous tumor in the generation of CTLs. This was investigated in the HLA-A2 system. Four T-cell lines were established by stimulation of lymphocytes with either autologous tumor or an HLA-A2-matched allogeneic melanoma. Allogeneic stimulated CTLs specifically lysed the autologous tumor and demonstrated an identical pattern of HLA-A2 restriction, when compared to the autologous stimulated CTLs. Lysis by the allogeneic stimulated CTLs was blocked by a monoclonal antibody to HLA class I antigens; lysis was also inhibited by both autologous tumor or HLA-A2 allogeneic melanomas when evaluated in cold target competition studies. The allogeneic stimulated CTLs proliferated in response to both autologous tumor and HLA-A2 melanomas, but not in response to HLA-A2 nonmelanomas. By phenotypic analysis these CTLs were CD3+ and predominantly CD8+ cells. We conclude that autologous tumor-specific CTLs can be generated using HLA-A region-matched allogeneic melanomas for stimulation. Since established, HLA-typed melanoma tumor lines can be used in the absence of autologous tumor; this procedure can be applied clinically to a broad patient population and may prove useful in the adoptive immunotherapy of melanoma.

Autoimmunity↗

PubMed1990

Inhibition of the growth of human melanoma xenografts in nude mice by human tumor-specific cytotoxic T-cells.

Melanoma-specific T-cells (CTLs) are specifically cytotoxic for autologous tumor, when assayed in vitro. To examine their effectiveness in vivo, we tested the ability of these human T-cells to inhibit growth of human melanoma xenografts by using a Winn assay. Nude mice receiving specific CTLs (n = 10) demonstrated a dramatic inhibition of tumor growth. All treated mice were tumor-free at day 50 and nine remained tumor-free at day 65, vs. control mice (n = 10) with average tumor volumes of 321 mm3 and 808 mm3, respectively. To control for the possibility that a non-specific response to the human T-cells could inhibit tumor growth, an additional group received allospecific CTLs. There was no inhibition of tumor growth in this group (n = 8), with the average tumor volume of 2,768 mm3 at day 40 vs. 1,882 mm3 in the control group (n = 10). We conclude that these tumor-specific CTLs can inhibit tumor growth in vivo and may prove useful in the adoptive immunotherapy of melanoma.

Animals↗

PubMed1990

Acral melanoma: a review of 185 patients with identification of prognostic variables.

One hundred eight-five patients with acral melanoma treated since 1972 were reviewed. These included 53 subungual lesions, 123 plantar lesions, and 9 palmar lesions. Eighty percent presented with stage I disease. Mean age was 57 years. Males outnumbered females 1.1:1. Seventeen percent (17%) were blacks. Actuarial 10-year survival was 58% for stage I patients and 35% for stage II patients. Univariate Cox regression analyses identified 5 prognostic variables affecting survival: stage at diagnosis (P less than 0.001), race (P less than 0.001), ulceration (P = 0.012), Clark's level (P = 0.014), and thickness of the primary lesion (P = 0.013). Factors unrelated to survival included sex of the patient, site (volar vs. subungual), histology, and treatment with amputation. Multivariate analysis for patients with stage I lesions identified race (P = 0.001) and ulceration (P = 0.018) as significant variables, with thickness approaching significance (P = 0.094). In an additional series of 71 patients with melanomas arising from extremity sites near the junction of glabrous and non-glabrous skin, survival was significantly poorer for those arising from glabrous skin (P = 0.024), and reflects a higher incidence of metastatic disease at diagnosis. Specific active immunotherapy was the principal adjuvant used for these patients, and survival was comparable to that reported with regional perfusion therapy. Acral melanoma a) has a strong racial predilection, b) carries a grave prognosis, and c) arises from glabrous skin. It is a clinical entity distinct from other extremity melanomas. Surgical management with either wide excision or amputation is appropriate for the primary lesion.

Adolescent↗

PubMed1990

Malignant melanoma arising during pregnancy. A study of 100 patients.

Melanoma is often diagnosed in young adults, a significant proportion of whom are women of child-bearing age. The prognosis of women diagnosed with melanoma during a pregnancy continues to be debated. One hundred patients, ages 19 to 40 years, have been identified who were pregnant at the time of diagnosis of their melanoma. All were treated with local excision. Sixteen per cent underwent elective lymph node dissections. Immunotherapy was administered to 83% of patients. Mean follow-up was 6.8 years from the date of diagnosis. The patients were compared to an age-matched group of 86 women who were not pregnant at the time of diagnosis. Overall mortality during the follow-up period was 25% in the pregnant group and 23% in the control group. Among the pregnant group, there was an increased incidence of lymph node metastases during the follow-up period (39% versus 26%, p = 0.053). Among stage I patients, there was a significantly shorter DFI for the pregnant group (p = 0.039), with 50% of pregnant patients and 67% of control patients free of disease at 10 years. Similarly, among stage 1 patients, the time to development of lymph node metastases was shorter in the pregnant group (p = 0.021). 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. Patients who developed melanoma during pregnancy did not, however, have a significant decrease in survival.

Adult↗

PubMed1990

Toxic shock syndrome after inguinal hernia repair. Report of a case with patient survival.

A 40-year-old man developed fulminant multisystem failure several days after elective repair of an inguinal hernia. Toxic shock syndrome (TSS) was diagnosed. There was, however, no evidence of wound infection at the time of multisystem failure. Only later in his hospital course did the wound drain. Staphylococcus aureus was cultured from the wound and was the presumed etiologic agent in the patient's life-threatening illness. The patient recovered fully with supportive care, antibiotics, and surgical debridement of the inguinal hernia site. This case is discussed in the context of existing literature on the toxic shock syndrome. The site of infection is typically nonsuppurative, but the systemic manifestations are typically life threatening. The responsible organism is commonly believed to be a strain of S. aureus that expresses a toxin (TSS toxin-1) that effects multisystem failure, but which also diminishes the local inflammatory response and explains the benign appearance of the wound. Although this is a rare clinical entity, elective surgical procedures complicated by fatal TSS have been reported. Surgeons should understand this disease and the management necessary to avert mortality.

Adult↗

PubMed1990

Anorectal melanoma: clinical characteristics and results of surgical management in twenty-four patients.

Twenty-four patients with primary anorectal melanoma diagnosed since 1974 have been studied retrospectively. There was a predominance of women (2.4:1): Mean age was 64 years. The most common initial symptom was rectal bleeding, typically misdiagnosed as hemorrhoids. Seventeen patients had stage I cancer when first seen, four had stage II, and three had distant disease. Progressive disease most commonly started as a large pelvic mass, diffuse bilateral pulmonary nodules, or diffuse liver metastases. Twenty patients (83%) died of the disease; none survived more than 6 years. Among the patients who died of the disease, median survival was 1.9 years. Median survival for patients with stage I disease (29 months) was longer than that for patients with stage II disease (11 months; p less than 0.05) or stage III disease (9 months). Twelve patients were treated initially with abdominoperineal resection (APR), and three additional patients underwent APR to manage recurrent local or regional disease that developed later in the clinical course. Among evaluable patients with stage I disease initially managed with APR, 50% developed recurrent local-regional disease (mean disease-free interval, 23 months), compared with 100% of those who underwent 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 on both earlier diagnosis and development of more successful therapeutic approaches.

Anus Neoplasms↗

PubMed1990

Implications of leukoregulin to autologous tumor-specific human T-cell populations.

Interactions between the cellular and humoral compartments of the human immune system are well documented. Leukoregulin (LR) is a hormone with the ability to upregulate the natural killer (NK) phenomenon by increasing target cell sensitivity to NK lymphocyte cytotoxicity. In the present report, the interactions between LR and human cytotoxic T-lymphocytes (CTLs) are described. Two cultured T-cell populations are specifically cytotoxic for autologous human melanoma and fail to lyse allogeneic melanoma, K562, or autologous peripheral blood lymphocytes (PBLs) in 4 h chromium release assays. Pretreating allogeneic melanoma or K562 with LR resulted in 19-67% lysis at an effector:target (E:T) ratio of 5:1, while no more than 10% lysis was observed without LR. Autologous PBLs were also subject to lysis when pretreated with LR (50% at an E:T of 40:1 with LR, and 2% without LR). The observed effect was dose-related and was most effectively inhibited by autologous cold targets, but persisted in the presence of antibody to human lymphocyte antigen class I antigens (w6/32). Lysis of autologous melanoma was not increased by pretreatment with LR. LR appears to mediate lysis of melanoma, NK targets, and normal PBLs by tumor specific CTLs. The effect is dose-related and non-major histocompatibility complex-restricted. The data do not support a significant role for LR in the normal physiology of human CTLs, but the striking effects in vitro may prove to be experimentally or therapeutically useful.

Antibodies, Monoclonal↗

PubMed1989

The role of HLA class I antigens in recognition of melanoma cells by tumor-specific cytotoxic T lymphocytes. Evidence for shared tumor antigens.

CTL lines were established in vitro by stimulating patient lymphocytes with autologous melanoma cells in the presence of IL-2. Resulting CTL lines lysed autologous melanoma and failed to lyse several allogeneic melanomas or K562. The mechanism of target cell recognition by autologous tumor-specific CTL was evaluated in this system, using several CTL lines: DT6, DT105, DT141, DT166, DT169, and DT179. Autologous melanoma lysis was inhibited by W6/32, mAb directed against HLA class I Ag, but not by L243, mAb directed against HLA class II Ag. CTL from DT6, DT141, DT166, DT169, and DT179 lysed fresh and cultured allogeneic melanomas, which shared the HLA-A2 Ag, but failed to lyse allogeneic melanomas, which shared B-region or C-region Ag, or shared no HLA class I Ag. CTL from DM141 lysed DM93, which shared A2 and Bw6, but failed to lyse DM105, which shared only Bw6. DM105 CTL failed to lyse allogeneic melanomas that shared HLA-A1, or that shared B or C region Ag, but they did lyse allogeneic melanoma DM49, which expressed an A region Ag that either was A10 or was serologically cross-reactive with A10. A T cell leukemia line, three EBV transformed B cell lines, and a pancreatic cancer line, all of which expressed HLA-A2, were not lysed by DM6 or DM179 CTL. Furthermore, HLA-matched nonmelanomas failed to inhibit autologous tumor lysis in cold target inhibition assays, whereas an HLA-A2+ allogeneic melanoma, DM93, inhibited autologous tumor lysis as effectively as the autologous tumor itself. HLA-A2, and possibly other HLA-A-region Ag, appear to function in HLA-restricted recognition of shared melanoma associated Ag by CTL.

Antibodies, Monoclonal↗

PubMed1989

Melanoma-specific cytotoxic T cells generated from peripheral blood lymphocytes. Implications of a renewable source of precursors for adoptive cellular immunotherapy.

Cytotoxic T lymphocytes (CTL) specific for autologous human melanoma have been generated in vitro from peripheral blood lymphocytes (PBL) of five patients with resectable stage II malignant melanoma. The PBL were cultured with 5u/ml recombinant IL-2 and were repeatedly stimulated with irradiated fresh or cultured autologous tumor cells. Cytotoxicity was determined by four-hour chromium release assays. Specific cytotoxicity developed in 30 to 40 days, after three or four stimulations with tumor. The PBL-derived CTL are CD3+ and are mixed for CD4+ and CD8+ phenotypes. They lysed autologous melanoma and failed to lyse allogeneic melanoma, K562, or autologous lymphocytes. The lysis of autologous tumor was maintained for more than 4 months. The cells proliferated in response to autologous, but not allogeneic melanoma cells, in a dose-dependent manner. Lysis of the autologous tumor target was inhibited with w6/32, a monoclonal antibody to HLA Class I antigens. It is concluded that PBL may serve as a plentiful and renewable source of precursor cells for the generation of autologous tumor-specific CTL, which may be useful in specific adoptive cellular immunotherapy of melanoma.

Antibodies, Monoclonal↗

PubMed1988

Human cytotoxic T cells specific for autologous melanoma cells: successful generation from lymph node cells in seven consecutive cases.

Human T-cell populations specifically cytotoxic for autologous melanoma cells have been successfully generated from lymph node cells obtained from seven consecutive patients. The lymph node cells were stimulated in vitro with autologous irradiated melanoma cells; stimulation was repeated every 10-15 days at a tumor cell-to-lymphocyte ratio of approximately 1:20. Cytotoxic activity was assessed by a 4-hour 51Cr release assay. Mean lysis of autologous tumor cells was 47% at an effector-to-target cell ratio of 20:1, while mean lyses of the human myeloid leukemia cell line K562, allogeneic melanoma cells, and an osteosarcoma cell were 20%, 13%, and 11%, respectively. There was no lysis of autologous fibroblasts, fresh lymphocytes, or phytohemagglutinin-stimulated blasts. Three grades of specificity developed sequentially. In grade I, lysis of autologous tumor cells exceeded lysis of allogeneic tumor cells but did not exceed lysis of K562 cells. In grade II, lysis of autologous tumor cells exceeded lysis of K562 cells and all allogeneic tumor cells tested. In grade III, potent lysis of autologous tumor cells (greater than 40%) exceeded lysis of K562 cells and of all allogeneic tumor cells tested. All seven lymphocyte populations reached or exceeded grade I. Six reached or exceeded grade II. Two progressed to grade III. The generated cells were T cells, as determined by phenotypic analysis with flow cytometry. CD4+ cells and CD8+ cells accounted for 83%-100% of the cells. CD8+ T cells were separated from CD4+ T cells by panning with OKT8 and OKT4 antibodies. The resulting CD8-enriched and CD4-enriched populations were compared as effectors in cytotoxicity assays. The results suggest that the cell responsible for lysis of autologous tumor cells is CD8+. The methods used in this study have repeatedly resulted in the successful generation of cytotoxic T lymphocytes specifically cytotoxic for autologous melanoma cells; it is suggested that these cells have potential application for adoptive immunotherapy of melanoma.

Antigens, Surface↗

PubMed1988

Autologous lymph node cell-derived tumor-specific cytotoxic T-cells for use in adoptive immunotherapy of human melanoma.

The in vitro development of tumor-specific cytotoxic T-cells from draining and tumor-involved lymph nodes obtained from melanoma patients were examined. Fresh draining or tumor-involved lymph node cells (LNC) demonstrate no significant cytotoxic activity against a variety of tumor targets including autologous melanoma. Natural killer cell (NK) activity is very low or absent in all of these specimens. Culture of the cells with irradiated autologous tumor and expansion in recombinant interleukin 2 (rIL-2) results in strong cytotoxicity for autologous tumor cells. The cultured cells are T-cells of mixed CD4 and CD8 phenotypes. Following restimulation with autologous tumor, these lines are capable of becoming specifically cytotoxic for autologous tumor as tested in direct killing and in cold target inhibition studies. The LNC yield from fresh specimens ranges from 1 X 10(7) to more than 1 X 10(9) cells averaging 5 X 10(8) cells. After the cells are cultured, we can achieve up to a 60-fold or more increase in cell numbers, that demonstrate strong cytotoxicity for melanomas. The potential for adoptive immunotherapy using such specifically sensitized cytotoxic T-cells of mixed phenotypes is discussed.

Cell Line↗

PubMed1988

Stage II malignant melanoma: presentation of a prognostic model and an assessment of specific active immunotherapy in 1,273 patients.

The ability to redefine risk factors and to predict prognosis in patients with malignant melanoma at the time they manifest nodal metastasis can be a benefit to the patient emotionally and to the physician therapeutically. A retrospective review of 1,273 patients with stage II malignant melanoma was performed at our institution. The most significant prognostic factors in a simultaneous hazard Cox multivariate analysis, predicting melanoma-related mortality among stage II patients, were the number of positive nodes (P less than 0.0001), age (P = 0.0004), site of the primary lesion (P = 0.0036), disease-free interval (P = 0.016), thickness of the primary lesion (P = 0.017), and sex of the patient (P = 0.0616). We have developed a model for predicting survival of stage II patients, designed for use in the clinic setting. Its application in a computer system makes it accessible and understandable. The most favorable risk group (18% of the population) has actuarial 5- and 10-year survival rates of 58% and 49%, respectively, from the time of the nodal metastasis. The least favorable risk group (7% of the population) has 5- and 10-year survival rates of 15% and 10%, respectively. There are three intermediate risk groups. All groups differ prognostically (P less than 0.04). The principal adjuvant therapy offered to these patients was specific active immunotherapy, which appears to have a 10-20% survival benefit in stage II patients with greater than one positive node, when compared with institutional controls. The apparent survival benefit of the immunotherapy supports continued clinical investigation of its therapeutic potential.

Actuarial Analysis↗

PubMed1988

Lethal "thin" malignant melanoma. Identifying patients at risk.

Thin melanomas can metastasize and be lethal. The purpose of this review was to identify negative risk factors in patients with melanomas less than 0.76 mm thick. Six hundred and eighty-one (681) such patients are reviewed in this study. Of those referred without metastatic disease (583 patients), metastases developed in 4.8% after a mean followup of 3.6 years. Of those referred with metastatic disease (98 patients), mortality was 35% after a mean followup of 5.9 years. Male patients (p less than 0.04) and patients with axial primaries (p less than 0.05) were at an increased risk of metastasis. Severe histologic regression was present in 40% of the primary lesions that metastasized and in 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, using two clinical risk factors (axial primary site and male sex) and two histologic risk factors (Clark's Level IV and severe histologic regression). The prognostic model identified a low-risk population--women with extremity primaries--with an actuarial risk of metastasis at 10 years that was less than 3%. Patients with either (1) both clinical risk factors or (2) one clinical risk factor and one histologic risk factor were identified as high-risk patients. Their actuarial risk of metastasis was 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.

Adult↗

PubMed1987

Human T cells specifically activated against autologous malignant melanoma.

Lymphocytes from ten patients with melanoma were specifically stimulated in vitro with autologous melanoma cells and expanded in interleukin 2. Significant lysis of autologous melanoma cells was demonstrated in T cells derived from six of these patients. The mean percent of lysis of autologous tumor cells at an effector-target ratio of 20:1 was 46% among these six patients. The T cells derived from two patients developed specificity in lysing autologous melanoma cells. In both cases, specificity was enhanced by the in vitro stimulation with autologous tumor cells. Restimulation with autologous melanoma cells was associated with increasing specificity over time. Whether derived from peripheral blood lymphocytes or from lymph node cells, T cells from one patient lysed fresh autologous melanoma cells more potently than K562, allogeneic melanoma cells, and nonmelanoma cells. On day 38, at an effector-target ratio of 10:1, cell lysis of K562, an osteosarcoma, a pancreatic cancer, and three allogeneic melanomas was 3%, 4%, 7%, 8%, 7%, and 2%, respectively, while lysis of autologous melanoma cells was 47%. Specificity was maintained beyond day 60. The T cells could be expanded over 50-fold within one month.

Cell Separation↗