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H F Seigler

Publications and source records attributed to H F Seigler.

At least 37 records · Page 2Linked to original sources
PubMed1998

Human dendritic cells, pulsed with either melanoma tumor cell lysates or the gp100 peptide(280-288), induce pairs of T-cell cultures with similar phenotype and lytic activity.

Dendritic cells (DCs) pulsed with unfractionated tumor cell lysates or defined tumor peptides provide potent vaccines which elicit strong antitumor immunity. In this study, we generated DCs from the 2-h adherent progenitor cells obtained from the peripheral blood of melanoma patients. These DCs were able to capture biotinylated melanoma tumor cell lysates. We examined the efficacy of immunogens composed of DCs loaded either with the melanoma peptide gp100 [amino acids 280-288 (DC/gp100)] or with lysates from melanoma tumor cells (DC/lysates) in inducing cytotoxic T-cells from autologous PBLs of HLA-A2 melanoma patients. After four to five weekly stimulations of bulk PBLs with DC/gp100 or DC/lysates, the cultures were enriched with CD3+ T-cells and exhibited one of three phenotypic and functional patterns: (1) Predominant expression of CD8+ and MHC class I-restricted CTLs which displayed strong lytic activity against melanoma cells and T2 cells loaded with the gp100 peptide, (2) mixed CD4+/CD8+ phenotype and weak lytic activity, or (3) nonlytic and predominantly CD4+ cultures. Interestingly, T-cell cultures from each patient exhibited similar phenotypes and lytic activities whether the stimulant was DC/gp100 or DC/cell lysates. Our study demonstrates that DCs pulsed with soluble melanoma peptides or cell lysates are capable of inducing CD8+ CTLs from autologous PBLs of some, but not all, melanoma patients. The function and phenotype of the generated T-cell cultures are governed by DCs since both antigens (the gp100 peptide and melanoma lysates), when presented by a given DC preparation, induced similar T-cell cultures. In summary, it may be difficult to predict the nature of the cellular responses elicited by DC/tumor antigen vaccines from patient to patient.

Antigens, Neoplasm↗
PubMed1998

Vaccination with dendritic cells inhibits the growth of hepatic metastases in B6 mice.

Dendritic cells (DC) are specialized antigen-presenting cells that can activate naive and mature T-cells, induce cellular immunity, and stimulate strong antitumor reactions in vivo. This study was undertaken to examine the function of DC vaccines in suppressing the growth of hepatic metastases in C57BL/6 mice. Experimental mice received two i.v. doses of 1 x 10(6) bone marrow-derived DC, either unpulsed or pulsed with MCA-106 fibrosarcoma cell lysates, on days -14 and -7. Controls were injected with HBSS. Hepatic metastases were established on day 0 through intrasplenic injections of 1 x 10(5) MCA-106 tumor cells. Animals were sacrificed on day 21 and their livers were excised to assess tumor burden. Splenocytes from DC-treated groups were cytotoxic against MCA-106 cells, but not against the L929 and CT26 (syngeneic fibroblast and colon tumor, respectively) cell lines. All control mice developed grossly evident hepatic metastases, while 62 and 44% of the mice receiving MCA-106 cell lysate-pulsed DC and unpulsed DC vaccines, respectively, were completely free of tumor. Mean hepatic mass for the controls, including tumor, was almost double that for treated animals. Antibody depletion of either CD4+ or CD8+ lymphocytes abrogated the protective effect of the vaccine. This study demonstrates that immunization with DC confers cellular immunity, with both CD4+ and CD8+ T-cells playing a significant role, and impedes the subsequent establishment and growth of hepatic metastases in mice. The antitumor capabilities of DC justify their use in immunotherapeutic vaccines against human cancers.

Animals↗
PubMed1998

Reporting fine-needle aspirates of breast: a survey of preferences among surgeons.

BACKGROUND: The optimal format for reporting results of breast fine-needle aspiration cytology is controversial, with some experts favoring a five-category system and others recommending a four-category format. METHODS: A survey of 200 surgeons was performed to determine their preference for a four- or five-category report format. They were also questioned concerning the number of patients per year in whom they diagnosed breast cancer, if they used fine-needle aspiration cytology (FNAC) regularly, and why they favored one category over the other. RESULTS: Eighty-five complete responses were received. Fifty-eight percent of these surgeons (49) routinely used FNAC for the diagnosis of breast nodules. There was no strong preference for either report format. Twenty-four of 49 routine users of FNAC favored a four-category format, and another four had no preference. CONCLUSION: Surgeons who routinely used FNAC in the diagnosis of breast disease do not have a preference for the five-category probabilistic system.

Biopsy, Needle↗
PubMed1998

Malignant melanoma of the mucous membranes: a review of 119 cases.

BACKGROUND: Melanomas arising from the mucous membranes lining the respiratory, digestive, and genitourinary tracts are rare. Women are more commonly affected than are men, mainly because there is no male counterpart for vulvovaginal lesions. The mainstay of therapy is surgery, with little current use of adjuvant modalities in primary therapy. These lesions usually are advanced at initial presentation; consequently, the prognosis is poor, with 5-year survivals well below 50% in most series. METHODS: One hundred and nineteen patients with primary mucosal melanoma were reviewed. They represented 1.1% of the 10,393 melanoma patients seen at Duke University between 1970 and 1995. All data were obtained from the patients' clinic charts and computerized databases. RESULTS: There were 43 tumors arising from the head and neck region, 46 from the urogenital tract, and 30 from the anorectum. A female predominance was observed, with a female-to-male ratio of 2.7:1. All but five of the patients underwent resection with curative intent. Regional or distant metastases, or both, were encountered in 36 patients at the time of presentation. In patients with head and neck and urogenital tumors, local recurrences accounted for most of the treatment failures, whereas systemic recurrences were more common with tumors arising in the anorectum. The age and gender of the patient, anatomic site of origin of the tumor, clinical stage at initial presentation, and ulceration of the primary all clearly affected prognosis. Overall, the probabilities of being alive 1, 5, and 10 years after diagnosis were 80%, 29%, and 15%, respectively. CONCLUSIONS: Widely accepted classification systems are needed so that results from separate institutions can be compared adequately. Multi-institutional trials could help in delineating standardized therapeutic protocols and in establishing the potential roles of emerging modalities in the treatment of this subtype of melanoma.

Adult↗
PubMed1998

Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma.

UNLABELLED: Brain metastases are a common and devastating complication in patients with malignant melanoma. Therapeutic options for these patients are limited, and the prognosis is usually poor. OBJECT: A retrospective review of 6953 patients with melanoma treated at a single institution was undertaken to identify demographic factors associated with the development of clinically significant brain metastases in 702 of these patients and to determine the factors influencing the prognosis of this population to permit more informed recommendations regarding surgical therapy. METHODS: Factors found to be associated with the development of brain metastases included male gender, primary lesions located on mucosal surfaces or on the skin of the trunk or head and neck, thick or ulcerated primary lesions, and histological findings of acral lentiginous or nodular lesions. The overall median survival time of all patients with brain metastases was 113.2 days, and these metastases contributed to the death of 94.5% of the patients in this group. Patients with primary lesions located in the head or neck region had a significantly shorter survival time relative to other patients with brain metastases, whereas patients with a single brain metastasis, patients without lung or multiple other visceral metastases, and patients whose initial presentation with melanoma included a brain metastasis had a significantly better prognosis. The small group of patients who survived for more than 3 years was characterized by the presence of a surgically treated, single brain metastasis in the absence of other visceral metastatic disease. CONCLUSIONS: Although most patients with brain metastases resulting from melanoma have a dismal prognosis, some who are likely to survive for longer periods can be identified. In these patients surgical resection can significantly prolong meaningful survival. The decision to recommend surgery should be based primarily on the resectability of the brain metastases and on the status and number of other organs with metastatic lesions.

Adult↗
PubMed1998

Mucosal melanoma of the female genitalia: a clinicopathologic study of forty-three cases at Duke University Medical Center.

BACKGROUND: Mucosal melanoma of the female genitalia is a rare neoplasm. Only nine reports reviewing more than 40 patients have been published on this subject in the past 30 years. These lesions arise from melanocytes, which can be found within the mucosa lining the female genital tract. Surgical resection is the mainstay of therapy, with little use for other modalities except in palliative roles. The overall prognosis is poor, with reported 5-year survival rates usually below 50%. METHODS: Forty-three patients with primary mucosal melanoma of the female genitalia seen at the Duke University Medical Center Melanoma Clinic during a 25-year period were studied retrospectively. Specific information was obtained from the patients' clinic charts and computerized databases. RESULTS: Thirty vulvar, nine vaginal, and four cervical lesions were identified. The median age at diagnosis was 61.4 years. At initial presentation, two thirds of the patients had localized disease only. Tumor ulceration and thickness of the primary lesion had a measurable impact on prognosis, whereas the presence of regional metastases at presentation did not. All but one patient underwent resection with curative intent. The performance of radical operations did not improve outcome among patients with vulvar melanoma. Many of the treatment failures were the result of local recurrences, hinting at the need to improve local control. Despite therapy, the overall corrected 5-year survival rate was 54%. CONCLUSIONS: Prospective multicenter trials for patients with vulvovaginal melanoma could be helpful in establishing uniform, standardized surgical protocols and delineating the applicability of new modalities and therapies, such as lymphoscintigraphy with sentinel node biopsy and high-dose interferon.

Adult↗
PubMed1997

A Phase I clinical trial of immunotherapy with interferon-gamma gene-modified autologous melanoma cells: monitoring the humoral immune response.

BACKGROUND: Tumor cells transduced with cytokine genes provide immunogenic vaccines for cancer immunotherapy. METHODS: A Phase I clinical trial was conducted for the specific active immunization of melanoma patients with interferon-gamma (IFN-gamma) gene-modified autologous melanoma tumor cells. Short term melanoma cultures were transduced retrovirally with the gene for human IFN-gamma. The genetically modified melanoma cells secreted biologically active IFN-gamma and showed enhanced expression of major histocompatibility complex class I and class II surface antigens. These cells were inactivated by irradiation (50 gray) and were cryopreserved for the vaccine. Twenty melanoma patients were enrolled in this clinical trial. The immunizations were administered in escalating doses once every 2 weeks for 3 months. The first and second injections consisted of 2 million cells, followed by 6 million for the third and fourth injections, and then 18 million for the fifth and sixth injections. The humoral immune responses of the patients were assessed by enzyme-linked immunoadsorbent assay, radioimmunoassay, and radioimmunoprecipitation. RESULTS: Thirteen of the 20 patients completed the immunization protocol. Eight of these 13 patients showed a humoral immunoglobulin (Ig)G response against autologous and allogeneic melanoma cells. The other five patients either had no detectable antimelanoma antibodies or showed a weak IgG response that did not rise significantly above the preimmune level. All the sera contained low or undetectable levels of antimelanoma IgM antibodies. The IgG response increased progressively in titer during the course of immunization. The positive sera showed preferentially strong binding to melanoma cell lines and some cross-reactivity to nonmelanoma tumors. A 75-80 kD antigen on melanoma cells was immunoprecipitated by postimmune sera of 3 of the responding patients. Preimmune sera from these three patients and sera from other patients immunized with a standard nontransduced melanoma cell vaccine failed to precipitate this antigen. Two patients with significant increases in serum IgG had clinical tumor regression, and two additional patients with low serum IgG response had transient shrinkage of nodular disease during therapy. CONCLUSIONS: These data suggest that gene therapy with IFN-gamma-transduced melanoma cells is safe and worthy of further investigation in patients with less advanced stage malignant melanoma. The ability to monitor changes in the humoral responses of the immunized patients has been demonstrated.

Cancer Vaccines↗
PubMed1997

Immunotherapeutic potential of tumor antigen-pulsed and unpulsed dendritic cells generated from murine bone marrow.

Dendritic cells (DC) are highly efficient antigen-presenting cells able to capture, process, and present antigens to naive and primed T-cells. In this study, we have investigated the ability of DC, derived from murine bone marrow and pulsed with tumor cell extracts, to induce regression of preexisting tumors. In an experimental model of B16 melanoma in B6 mice, a significant reduction in metastatic nodules in the lungs was observed in tumor-bearing animals treated with either DC alone or DC pulsed with tumor extracts. Kinetic studies demonstrate that the efficacy of these tumor vaccines is inversely related to tumor burden. In this model, tumor-specific cytotoxic T-cells (CTL) could also be induced in vitro from spleen cells derived from tumor-bearing animals treated with DC pulsed with tumor extracts. Untreated mice had no CTL. Furthermore, DC alone elicited tumor-specific CTL responses in tumor-bearing mice, but not in naive mice. Immune cell depletion experiments show that the therapeutic effects of DC are primarily mediated by CD8+ T-cells, while CD4+ T-cells and NK cells are involved in DC-mediated antitumor immunity to a limited extent. These results illustrate the potential use of DC and DC pulsed with tumor extracts as potent therapeutic reagents for cancer and provide a rationale for using DC in vivo to eliminate disseminated tumors or residual tumor deposits following surgery.

Animals↗
PubMed1997

Generation of primary tumor-specific cytotoxic T lymphocytes from autologous and human lymphocyte antigen class I-matched allogeneic peripheral blood lymphocytes by B7 gene-modified melanoma cells.

Expression of B7.1 costimulatory molecules on tumor cells has been shown to elicit antitumor immunity in mice. In the present study, we have developed a human B7.1 retroviral vector system to effectively transduce human melanoma cell lines and investigated the potential role of B7.1 in the generation of tumor-specific CTLs from peripheral blood lymphocytes (PBLs) in vitro. We have demonstrated that B7.1-modified melanoma cells are able to induce primary CTL activity from autologous, human lymphocyte antigen (HLA) class I-matched allogeneic PBLs and purified CD8+ T cells in the absence of exogenous cytokines. CTLs generated by B7.1 are tumor specific and HLA class I restricted, and CD8+ T cells are primarily responsible for this specific cytotoxicity. Furthermore, CTLs generated from HLA class I-matched PBLs by B7.1 are cytolytic to tumor cells autologous to the stimulated PBLs. These data suggest that B7.1-modified tumor cells can be used as a potent tumor vaccine for both autologous and HLA class I-matched allogeneic patients.

Animals↗
PubMed1997

Primary malignant melanoma of the esophagus.

A 48-year-old woman presented with a 6-month history of dysphagia, often associated with retrosternal chest pain. Upper endoscopy revealed an unusual pigmented lesion within the middle portion of the esophagus, and multiple biopsies were obtained. The histopathology and immunohistochemical profile of the tissue specimens were diagnostic of malignant melanoma. A thorough clinical and radiographic evaluation was performed, providing no additional findings or alternative primary source. Of approximately 11,500 melanoma patients entered in the Duke University melanoma database since 1970, this represents the only case of primary esophageal melanoma. The case is described and a review of the literature is presented.

Endosonography↗
PubMed1996

Recognition and lysis of human melanoma by a CD3+, CD4+, CD8- T-cell clone restricted by HLA-A2.

The in vitro cytotoxic response to human melanoma is characterized by CD3+ CD8+ T-cells which recognize shared peptide antigens presented in the context of HLA class-I-encoded gene products. We report here studies of a CD3+, CD4+, CD8-, HLA-A2-restricted, melanoma-specific cytotoxic T-cell clone derived by limiting dilution from a T-cell line induced in PBLs from a melanoma patient following in vitro stimulation with an HLA-A2-matched melanoma cell line. The CD4+ cytotoxic T-cell clone is lytic only for melanomas which share the HLA-A2 allele, and the cytotoxicity is blocked by antibody to the T-cell receptor and by antibody to HLA class I. The clone proliferates only following stimulation with HLA-A2-matched melanoma tumor cells. The data suggest that cytotoxic CD4+ T-cells may play a significant role in immunity to melanoma, and HLA class-I-restricted recognition of melanoma may not necessarily require the CD8 molecule on the lytic T-cell.

CD3 Complex↗
PubMed1996

Effect of irradiation on cytokine production, MHC antigen expression, and vaccine potential of interleukin-2 and interferon-gamma gene-modified melanoma cells.

Recent studies have shown that tumor cells transduced with interleukin-2 (IL-2) or interferon-gamma (IFN-gamma) genes stimulated a potent and specific antitumor immunity in experimental animals. For use as a human vaccine, tumor cells must be inactivated by irradiation to ensure the arrest of their growth. This study was undertaken to examine the effects of irradiation (10,000 rad) on the growth characteristics and vaccine potential of IL-2 and IFN-gamma-modified human melanomas and B16 murine melanoma. Irradiation caused cessation of cell growth and gradual reduction of cell number. Irradiated melanoma cells displayed 1.5 to 10-fold increases in the surface expression of MHC class I and/or class II antigens. The increases in MHC antigens persisted for 7-14 days postirradiation and then declined thereafter. Furthermore, IL-2- and IFN-gamma-transduced melanoma cells showed enhanced expression of the cytokine mRNA and increased cytokine secretion after irradiation. The effect of irradiation on the vaccine potential of the transduced cells was examined in C57BL/ 6 mice by prophylactic immunization and immunotherapy, and in nude mice by mixed transplantation assays. The irradiated, cytokine-transduced B16 cell vaccine was as or more effective than the unirradiated vaccine. These irradiated vaccines protected the animals against a challenging tumorigenic dose of B16 parental cells and suppressed the growth of 4-day-established B16 lung metastases. The ability of the irradiated IL-2-transduced human melanomas to inhibit the growth of admixed parental melanoma cells was retained but was less efficacious than unirradiated cells. The results suggest that irradiation does not abrogate the vaccine potential of IL-2- and IFN-gamma-transduced melanomas. These findings have implications for designing specific active immunotherapy protocols utilizing cytokine gene-modified tumor cells.

Animals↗
PubMed1996

Immunological memory induced by genetically transduced tumor cells.

BACKGROUND: Recent studies have demonstrated the usefulness of gene-modified tumor cells for immunotherapy. Using the tumorigenic murine fibrosarcoma, MCA 106, we investigated the effects of localized interferon-gamma (IFNg) secretion on tumorigenicity and on long-term memory. METHODS: The murine IFNg (MuIFNg) gene was introduced into tumor cells. High and low IFNg-secreting clones were isolated. C57BL/6 mice were injected subcutaneously (s.c.) with either parental (P), high or low IFNg-secreting (H- or L-IFNg) cells, and tumor growth was assessed weekly. Spleens were harvested on different days postinjection (p.i.) to assess in vitro cytolytic activity. In parallel, tissues from injection sites were stained with macrophage-, CD4-, and CD8-detecting antibodies. Mice were injected s.c. with H-IFNg MCA106 tumor. After 150 days the animals were rechallenged s.c. with MCA106P in one leg and with irrelevant syngeneic tumor in the other. RESULTS: Both P- and L-IFNg cells had similar growth, whereas the H-IFNg cells never grew. Only splenocytes from the H-IFNg animals showed in vitro CTL activity persisting until day 30 p.i. Histological data revealed a macrophage and CD4+ infiltrate much earlier in the H-IFNg group compared with the P group. Only the irrelevant, syngeneic tumor grew in animals previously injected with H-IFNg cells, whereas both P and irrelevant syngeneic tumors grew in controls. CONCLUSIONS: Transduction of MCA106 cells with the MuIFNg gene diminished in vivo tumorigenicity in proportion to the amount of IFNg secreted. Immunization with H-IFNg cells elicited a host response characterized by macrophages and CD4+ cells. Long-term tumor-specific memory was seen after immunization with H-IFNg cells.

Animals↗
PubMed1995

Metastatic melanoma to the spine. Demographics, risk factors, and prognosis in 114 patients.

STUDY DESIGN: One-hundred-fourteen patients with metastatic melanoma of the spine were retrospectively reviewed. OBJECTIVE: The goal was to define the demographics, risk factors, and prognosis for this population. SUMMARY OF BACKGROUND DATA: The incidence of melanoma is increasing faster than any other cancer. Therefore, orthopedic and neurologic surgeons will be increasingly confronted by patients with spinal metastases from melanoma. However, the demographics, risk factors, and prognosis remain unclear. METHODS: From 7010 consecutive patients with melanoma, 114 were identified with clinically or radiographically evident spinal metastases. A comparison was made between these patients and the remainder of the population with melanoma seen at our institution using contingency table analysis with statistical significance determined by a chi-squared test. Survival data were represented by Kaplan-Meier curves, and log-rank testing was used for statistical comparisons. RESULTS: Risk factors associated with the development of these metastases included primary lesions that were ulcerated, deeper than 0.76 mm, or of Clark level II, or located on the trunk or mucosal surfaces. The median survival time for all patients was 86 days, but this was reduced in patients with more than one metastatic site in addition to the spine. CONCLUSION: The prognosis for most patients with spinal metastases from melanoma is dismal. However, patients with metastatic disease limited to the spine and one other organ may survive for a relatively prolonged time and may be candidates for surgical intervention directed toward symptomatic relief.

Adult↗
PubMed1995

Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum.

OBJECTIVE: In this study, the impact of preoperative chemotherapy and radiation on the histopathology of a subgroup of patients with rectal adenocarcinoma was examined. As well, survival, disease-free survival and pelvic recurrence rates were examined, and compared with a concurrent control group. SUMMARY BACKGROUND DATA: The optimal treatment of large rectal carcinomas remains controversial; current therapy usually involves abdominoperineal resection plus postoperative chemoradiation; the combination can be associated with significant postoperative morbidity. In spite of these measures, local recurrences and distant metastases continue as serious problems. METHODS: Fluorouracil, cisplatin, and 4500 cGy were administered preoperatively over a 5-week period, before definitive surgical resection in 43 patients. In this group of patients, all 43 had biopsy-proven lesions > 3 cm (median diameter), involving the entire rectal wall (as determined by sigmoidoscopy and computed tomography scan), with no evidence of extrapelvic disease. The patients ranged from 31 to 81 years of age (median 61 years), with a male:female ratio of 3:1. A concurrent control group consisting of 56 patients (median: 62 years, male:female ration of 3:2) with T2 and T3 lesions was used to compare survival, disease-free survival, and pelvic recurrence rates. RESULTS: The preoperative chemoradiation therapy was well tolerated, with no major complications. All patients underwent repeat sigmoidoscopy before surgery; none of the lesions progressed while patients underwent therapy, and 22 (51%) were determined to have complete clinical response. At the time of resection, 21 patients (49%) had gross disease, 9 (22%) patients had only residual microscopic disease, and 11 (27%) had sterile specimens. Of the 30 patients with evidence of residual disease, 4 had positive lymph nodes. In follow-up, 39 of the 43 remain alive (median follow-up = 25 months), and only 1 of the 11 patients with complete histologic response developed recurrent disease. Six of the 32 patients with residual disease (2 with positive nodes) have developed metastatic disease in follow-up (median time to diagnosis 10 months, range 3-15 months). Three of these patients with metastases have died (median survival after diagnosis of metastases = 36 months). Local recurrence was seen in only 2 of 43 patients (< 5%). Cox-Mantel analysis of Kaplan-Meier distributions demonstrated increased survival (p = 0.017), increased disease-free survival (p = 0.046), and decreased pelvic recurrence (p = 0.031) for protocol versus control patients. CONCLUSIONS: This therapeutic regimen has provided enhanced local control and decreased metastases. Furthermore, the marked degree of tumor downstaging, as seen by a 27% incidence of sterile pathologic specimens and a low rate of positive lymph nodes in this group with initially advanced lesions, strongly suggest that less radical surgery and sphincter preservation may be used with increasing frequency.

Adenocarcinoma↗
PubMed1994

Elevation of topoisomerase I messenger RNA, protein, and catalytic activity in human tumors: demonstration of tumor-type specificity and implications for cancer chemotherapy.

Topoisomerase I has been identified as an intracellular target of camptothecin, a plant alkaloid with anticancer activity. Various lines of evidence suggest that the sensitivity of cells to this drug is directly related to the topoisomerase I content. In humans, the levels of topoisomerase I have been shown to be elevated in colorectal tumors, compared to normal colon mucosa. The aim of our study was to determine whether (a) topoisomerase I levels are elevated in other solid tumors, (b) the elevated enzyme is catalytically active in these tumors, and (c) the increase in topoisomerase I levels in colorectal tumors is a result of increased transcription or translation. Topoisomerase I levels were quantitated in crude extracts from colorectal, prostate, and kidney tumors and their matched normal counterparts by Western blotting and by direct determination of catalytic activity, and mRNA levels were determined by Northern blotting. By Western blotting, colorectal tumors showed 5-35-fold increases in topoisomerase I levels, compared to their normal colon mucosa. In the case of prostate tumors, the increase was 2-10-fold, compared with benign hyperplastic prostate tissue from the same patients. However, no difference was observed in topoisomerase I levels in kidney tumors, compared to their normal counterparts. The catalytic activity of topoisomerase I was determined by a quantitative 32P-transfer assay in crude homogenates, without isolating nuclei. Colorectal and prostate tumors exhibited 11-40- and 4-26-fold increases, respectively, in catalytic activity. However, kidney tumors did not show any alteration in catalytic activity, compared to their normal matched samples. Thus, for all three tumor types there was a good correlation between enzyme levels and catalytic activity. Finally, colorectal tumors were analyzed for steady state mRNA levels. A 2-33-fold increase in mRNA levels was found in colorectal tumors, compared to normal colon mucosa. These results suggest that alterations in topoisomerase I expression in humans are tumor type specific and that the increase in topoisomerase I levels results from either increased transcription of the topoisomerase I gene or increased mRNA stability.

Amino Acid Sequence↗
PubMed1994

Survival superiority of females with melanoma. A multivariate analysis of 6383 patients exploring the significance of gender in prognostic outcome.

OBJECTIVE: To evaluate the effects of gender on prognostic outcome of patients with melanoma. DESIGN: Retrospective cohort study, including 20 years of follow-up. SETTING: Duke University Melanoma Clinic, Durham, NC, a referral center for patients with melanoma. PATIENTS: Patients with melanoma (N = 6383), consisting of 45% females and 55% males, obtained from a referred sample. Eligibility requirements were nonocular melanomas and white race. MAIN OUTCOME MEASURES: Time to metastases and survival. RESULTS: Females with melanoma demonstrated a superior prognostic outcome over males, with a 34% survival advantage and a 28% disease-free advantage. When each of the variables of age, site, Clark's level, histologic type, and tumor thickness was explored for possible influences on prognostic outcome, female survival advantage persisted, although modified by independent variables. The greatest influence came from the variables of site, Clark's level, and Breslow's thickness. Age, specifically in premenopausal vs postmenopausal age groups, was not significant in altering females' prognostic advantage. A multivariate analysis combining the effects of all the variables resulted in females still maintaining a 22% survival advantage and a 17% disease-free advantage. CONCLUSIONS: Females with melanoma have a significant prognostic advantage over their male counterparts that cannot be fully explained by influences from the variables of age, site, Clark's level, histology, and Breslow's thickness. This superior prognostic outcome does not appear to be associated with menstrual status. Evidence does suggest that the protective factor for females occurs at the level of metastases.

Adult↗