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National Cancer Institute®
Ultima Vez Modificado: 1 de abril del 2002
UI - 11686036
AU - Benson C; Gore ME
TI - Melanoma.
SO - Cancer Chemother Biol Response Modif 2001;19():629-38
AD - Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK.
UI - 11776490
AU - Zogakis TG; Bartlett DL; Libutti SK; Liewehr DJ; Steinberg SM; Fraker
TI - DL; Alexander HR Factors affecting survival after complete response to isolated limb perfusion in patients with in-transit melanoma.
SO - Ann Surg Oncol 2001 Dec;8(10):771-8
AD - Surgery Branch and the Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
BACKGROUND: Isolated limb perfusion (ILP) results in complete response (CR) rates of 60% to 90% in patients with regionally advanced melanoma. Survival after a CR may be influenced by various factors, particularly out-of-field disease in iliac lymph nodes (ILN) identified during lower-extremity ILP. We examined clinical and pathological parameters, including ILN status and outcome, for patients with in-transit melanoma (16 men and 34 women; median age, 57 years) with stage IIIA or IIIAB melanoma had a CR to a 90-minute hyperthermic iliac ILP with melphalan (10 mg/L limb volume, n = 20) or melphalan and tumor necrosis factor (4-6 mg+/-200 microg interferon; n = 30). Clinical and pathological parameters were analyzed by univariate and Cox proportional hazards models to determine which were associated with survival or in-field recurrence. RESULTS: The median in-field recurrence-free survival in the cohort of 50 patients after a CR to ILP was 1.4 years, and the actuarial 5-year in-field recurrence-free survival was 30%. By univariate analysis, there was a trend for improved outcome with female sex and stage IIIA (vs. IIIAB) at initial diagnosis was associated with improved survival after a CR to ILP (P = .056 and .012, respectively). Eleven (22%) of 50 patients had positive ILNs identified and resected at ILP. The probability of overall in-field recurrence was 70% after 4 years, and there was no difference between those with or without positive ILNs; median time to in-field recurrence was 13 and 19 months, respectively (P = .62). Similarly, overall survival was not influenced by positive ILN status (median [months]: +ILN, 69 vs. -ILN, 58; P = .68). Of note, Cox models identified that the risk of death was significantly greater in those with a history of prior systemic therapy (hazard ratio: 2.67 [95% confidence interval, 1.17-6.11]; P = .02) and those with an in-transit lesion size > or =1.4 cm2 (hazard ratio, 3.12 [95% confidence interval, 1.30-7.5]; P = .011). When these two variables were combined, there was a highly significant association with shortened survival (P = .002 by log-rank test). CONCLUSIONS: These data indicate that for patients undergoing ILP and in whom positive ILNs are found and resected, ILP is justified. In addition, patients who have a CR after ILP and have a history of prior treatment or larger lesions should be considered for adjuvant systemic therapy.
UI - 11783968
AU - Bishop JA; Corrie PG; Evans J; Gore ME; Hall PN; Kirkham N; Roberts DL;
TI - Anstey AV; Barlow RJ; Cox NH; Melanoma Study Group; British Association of Dermatologists UK guidelines for the management of cutaneous melanoma.
SO - Br J Plast Surg 2002 Jan;55(1):46-54
AD - Genetic Epidemiology Division, ICRF Clinical Centre, St James's University Hospital, Leeds, UK.
These guidelines for management of cutaneous melanoma present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation. To reflect the collaborative process for the UK, they are subject to dual publication in the British Journal of Dermatology and the British Journal of Plastic Surgery. Copyright 2002 The British Association of Plastic Surgeons and the British Association of Dermatologists.
UI - 11862432
AU - Quto b SS; Ng CE
TI - Comparison of apoptotic, necrotic and clonogenic cell death and inhibition of cell growth following camptothecin and X-radiation treatment in a human melanoma and a human fibroblast cell line.
SO - Cancer Chemother Pharmacol 2002 Feb;49(2):167-75
AD - Ottawa Regional Cancer Centre, Ottawa, ON, K1H 1C4, Canada.
PURPOSE: We evaluated apoptotic, necrotic and clonogenic cell death and inhibition of cell growth in a human melanoma cell line (Sk-Mel-3) and a normal human fibroblast cell line (AG1522) following treatment with camptothecin (CPT) or with concurrent CPT and X-radiation. MATERIALS AND METHODS: Apoptotic and necrotic cell death was determined morphologically by dual-staining (propidium iodide, acridine orange). Inhibition of cell growth was determined from the number of cells remaining in the culture dish following treatment. RESULTS: In Sk-Mel-3 cells: (a) after treatment with CPT alone, both apoptotic and necrotic cell death increased significantly ( P<0.05) relative to untreated controls; (b) after concurrent CPT and radiation treatment, however, only the increase in necrotic cell death was significant ( P<0.05) relative to cells receiving radiation alone; and (c) all assays of cellular effects/cytotoxicities were consistent in showing that CPT, given alone or with radiation, led to a substantial increase in cell kill. In contrast, in AG1522 cells: (a) there were no significant increases in apoptotic or necrotic cell death following either CPT alone or concurrent CPT and radiation; and (b) the clonogenic assay measured substantially higher cytotoxicities than the other assays. CONCLUSIONS: Necrotic cell death was more important than apoptotic cell death during concurrent CPT and radiation treatment in Sk-Mel-3 cells, but not in AG1522 cells.
UI - 11900232
AU - Gibbs P; Anderson C; Pearlman N; LaClaire S; Becker M; Gatlin K;
TI - O'Driscoll M; Stephens J; Gonzalez R A phase II study of neoadjuvant biochemotherapy for stage III melanoma.
SO - Cancer 2002 Jan 15;94(2):470-6
AD - Oncology Department, Royal Melbourne Hospital, Parkville, Victoria, Australia.
BACKGROUND: Phase II studies of biochemotherapy (combining interleukin-2, interferon-alpha, and multiagent chemotherapy) have reported high response rates and a significant number of durable complete responses in patients with metastatic melanoma. METHODS: A pilot Phase II study was performed to explore the safety and activity of neoadjuvant biochemotherapy in patients with Stage III melanoma. median age of the patients was 46 years (range, 19-70 years). Two cycles of biochemotherapy were administered prior to and after complete lymph node dissection. Each cycle was comprised of cisplatin, 20 mg/m2 intravenously (i.v.), on Days 1-4; vinblastine, 1.6 mg/m2 i.v., on Days 1-4; dacarbazine, 800 mg/m2 i.v., on Day 1; interleukin-2, 9 x 10(6) IU/m2/day i.v. over 24 hours, on Days 1-4; and interferon-alpha, 5 x 10(6) IU/m2/day subcutaneously, on Days 1-5, every 3 weeks. Twelve patients did not have measurable disease. All patients were evaluable for toxicity and survival. RESULTS: Clinical responses were observed in 14 of 36 patients (38.9%) with measurable disease, including 13 partial responses (36.1%) and 1 complete response (2.8%). Complete pathologic responses were noted in 4 patients (11.1%). Toxicity, although severe, was manageable and typically short-lived. There were no treatment-related deaths reported. At a median follow-up of 31 months, 38 of the 48 patients (79.2%) were alive and 31 patients (64.6%) remained free of disease progression. CONCLUSIONS: Neoadjuvant biochemotherapy appears to have promising activity in patients with Stage III melanoma. A larger multicenter study currently is underway to explore this approach further.
UI - 11902528
AU - Nathan PD; Eisen TG
TI - The biological treatment of renal-cell carcinoma and melanoma.
SO - Lancet Oncol 2002 Feb;3(2):89-96
AD - Medical Oncology at the Royal Free Hospital, London, UK.
Biological therapies are claiming a place in the routine management of some solid tumours. In this review we focus on the biological treatment of melanoma and renal-cell carcinoma, identifying the background to current practice and areas of promise that may be in routine clinical use in the near future. Melanomas and renal-cell carcinomas are particularly resistant to chemotherapy and radiotherapy and are characterised by the host immune response to the tumours. For this reason there has been particular interest in the biological therapy of these diseases. Biological therapies differ from chemotherapeutic approaches in their mechanism of action, time to response, and side-effect profiles. Although biological treatment has a long history, it is only with recent advances in immunology and molecular biology that progress has been made. In the next few years investigators expect to build on their research experience with biotherapeutic agents to provide tangible benefits for patients.
UI - 11870174
AU - Kilbridge KL; Cole BF; Kirkwood JM; Haluska FG; Atkins MA; Ruckdeschel
TI - JC; Sock DE; Nease RF Jr; Weeks JC Quality-of-life-adjusted survival analysis of high-dose adjuvant interferon alpha-2b for high-risk melanoma patients using intergroup clinical trial data.
SO - J Clin Oncol 2002 Mar 1;20(5):1311-8
AD - Department of Health Evaluation Sciences, University of Virginia Health System, Charlottesville, VA 22908-0821, USA. email@example.com
PURPOSE: High-dose adjuvant interferon alpha-2b (IFN alpha 2b) for high-risk melanoma is a 1-year regimen that improves relapse-free and overall survival but has significant toxicity. A quality-of-life--adjusted survival (QAS) analysis analysis of two cooperative group phase III trials, E1684 and E1690/S9111/C9190, was performed, incorporating patient values (utilities) for the toxicity of IFN alpha 2b treatment and melanoma recurrence. PATIENTS AND METHODS: Quality-Adjusted Time Without Symptoms or Toxicity methodology was used with melanoma patient utilities and trial data to estimate the effect of IFN alpha 2b on QAS. The increase or decrease in QAS that patients could expect from treatment was estimated based on their utilities. Eleven utility predictor questions were tested to identify patients with utilities that result in decreased QAS. RESULTS: Using E1684 data, IFN alpha 2b would result in an increase in QAS for all sets of patient utilities. This benefit was significant (P <.05) for 16% of patients. Using E1690/S9111/C9190 data, 77% of patients would experience a benefit in QAS from IFN alpha 2b and 23% would experience a decrease in QAS; neither of these effects was statistically significant. Using utility predictors and the E1690/S9111/C9190 analysis, a decision rule was formulated that helps identify patients in whom IFN alpha 2b may detract from QAS. CONCLUSION: Most patients experienced improvement in QAS in both trials, but this benefit was statistically significant in only 16% of patients in E1684. Change in QAS depends more on the utility for IFN alpha 2b toxicity than on the utility for melanoma recurrence. Cancer patients probably have higher utilities for IFN alpha 2b toxicity than members of the general population and will tend to favor IFN alpha 2b treatment as a result.
UI - 11888868
AU - Lindner P; Doubrovsky A; Kam PC; Thompson JF
TI - Prognostic factors after isolated limb infusion with cytotoxic agents for melanoma.
SO - Ann Surg Oncol 2002 Mar;9(2):127-36
AD - Sydney Melanoma Unit, Royal Prince Alfred Hospital, USA.
BACKGROUND: Isolated limb perfusion (ILP) with cytotoxic agents is a remarkably effective but complex technique used to treat locally recurrent and metastatic melanoma confined to a limb. Isolated limb infusion (ILI), essentially a low-flow ILP performed without oxygenation via percutaneous catheters, has been developed as a simpler alternative. METHODS: The outcome in 135 patients treated by ILI was reviewed. RESULTS: The overall response rate in the treated limb was 85% (complete response [CR] rate 41%, partial response rate 44%). Median response duration response was 16 months (24 months for patients with CR). Median patient survival was 34 months. In those with a CR, the median survival was 42 months. CR rate and survival time decreased with increasing disease stage. Patients aged >70 years had a better overall response than younger patients. On multivariate analysis, factors associated with an improved outcome were a lower stage of disease, a final limb temperature >37.8 degrees C, and a tourniquet time >40 minutes. CONCLUSIONS: The frequency and duration of responses after ILI were comparable to those achieved by conventional ILP. The ILI technique is particularly useful for older patients who might not be considered suitable for conventional ILP.
UI - 11567700
AU - Cascinelli N; Belli F; MacKie RM; Santinami M; Bufalino R; Morabito A
TI - Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial.
SO - Lancet 2001 Sep 15;358(9285):866-9
AD - National Cancer Institute, Via G Venezian 1, 20133, Milan, Italy. firstname.lastname@example.org
BACKGROUND: Less than half of patients with melanoma that has spread to local draining regional lymph nodes (stage III melanoma) live with no disease for 5 years or longer after surgery. We aimed to see whether interferon alpha-2a increased survival prospects in these patients. METHODS: 444 patients from 23 centres in the WHO Melanoma Programme had complete lymphadenectomy for pathologically proven regional nodal spread of melanoma and were randomly assigned to receive either 3 MU subcutaneously of recombinant interferon alpha-2a three times a week for 3 years, or to observation alone after surgery. Patients were stratified by centre, nodes with macroscopic or microscopic melanoma, number of affected nodes, and nodal metastatic spread. Treatment was continued for 3 years or until first sign of relapse. FINDINGS: 424 patients entered the study. 5-year disease-free survival of those who had surgery plus interferon alpha-2a was 27.5% (95% CI 21.7-33.6); for those who received surgery alone, survival was 28.4% (22.5-34.6) (p=0.50). Neither Kaplan-Meier cumulative survival rates, nor multivariate analysis of survival, showed a difference between those who had surgery and interferon alpha-2a (35%, 95% CI 29-42) and those who had surgery alone (37%, 31-44). INTERPRETATION: Patients with melanoma that has spread to the local draining regional lymph nodes tolerate well 3 MU of interferon alpha-2a given subcutaneously three times a week for 3 years, but this treatment does not improve either disease-free or overall survival.
UI - 11919239
AU - Lens MB; Dawes M
TI - Interferon alfa therapy for malignant melanoma: a systematic review of randomized controlled trials.
SO - J Clin Oncol 2002 Apr 1;20(7):1818-25
AD - Center for Evidence-Based Medicine, University of Oxford, Oxford, United Kingdom. email@example.com
PURPOSE: No standard systemic adjuvant therapy has been proven to increase overall survival in melanoma patients. The effect of interferon alfa (IFNalpha) as a single agent or in combination has been widely explored in clinical trials. The purpose of this study was to assess the benefit of IFNalpha therapy in malignant melanoma. METHODS: We performed a systematic review of randomized controlled trials comparing regimens with or without IFNalpha adjuvant therapy in melanoma patients. We assessed the effect of IFNalpha therapy on overall survival (OS), disease-free survival (DFS), melanoma recurrences, and toxicity. The quality of each trial was systematically evaluated. RESULTS: Nine randomized controlled trials (RCTs) of IFNalpha therapy in melanoma patients were identified. Eight were published and one was unpublished. Eight trials comprising 3,178 patients fulfilled our inclusion criteria and were analyzed. Quality assessment scores ranged from 22 to 71, with a mean score of 55.4 (95% confidence interval, 53.8 to 57.0). For OS, only one trial reported a statistically significant benefit for IFNalpha, but our analysis did not confirm it. Two trials reported statistically significant benefit in DFS for the patients treated with IFNalpha, but our analysis confirmed it in only one trial. There was a wide clinical heterogeneity between included trials, making meta-analysis inappropriate. CONCLUSION: In our review, results from included RCTs demonstrated no clear benefit of IFNalpha therapy on OS in melanoma patients. A large RCT is required to answer whether a full regimen of IFNalpha therapy is effective and to identify the subgroups of patients who might benefit from IFNalpha treatment.
UI - 11891956
AU - Patel SG; Prasad ML; Escrig M; Singh B; Shaha AR; Kraus DH; Boyle JO;
TI - Huvos AG; Busam K; Shah JP Primary mucosal malignant melanoma of the head and neck.
SO - Head Neck 2002 Mar;24(3):247-57
AD - Head and Neck Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. firstname.lastname@example.org
INTRODUCTION: The relative rarity of mucosal melanomas of the head and neck (MMHN) has made analysis of treatment approaches difficult. Advances in diagnostic techniques and treatment interventions have had obvious impact on outcomes in cutaneous melanoma, but the effects on outcome in MMHN remain undefined. This study aims to assess the outcome and identify clinical and histologic prognostic indicators in a recent cohort of patients with MMHN treated at a single institution. METHODS: The clinical records of 59 patients with the diagnosis of MMHN treated at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1978 and 1998 were retrospectively reviewed. Pathologic material on each of these patients was prospectively reviewed by at least two pathologists (MP, KB, or AH) for confirmation of diagnosis and assessment of histologic variables. Survival was calculated by the Kaplan-Meier method. Clinical (patient demographics, tumor characteristics, and treatment) and histologic data (tumor thickness, melanosis, melanoma in situ, vascular invasion, and multifocality) were analyzed for impact on outcome by both univariate and multivariate analyses. RESULTS: Thirty-five patients (59%) had sinonasal tumors (SNMM), whereas 24 (41%) had oral (ORMM) tumors. Forty-seven patients (79.6%) were staged as stage I, 8 (13.6%) as stage II, and 4 (6.8%) were classified as stage III. Regional lymphatic metastases at presentation were more frequent in ORMM compared with SNMM (25% vs 6%, p =.05). Surgery was used in all patients. Adjuvant radiation therapy was used more frequently in the SNMM group compared with the ORMM group (40% vs 17%, p =.04). The rates of local failure for ORMM and SNMM were 51% and 50%, nodal failure rates were 42% and 20%, and distant failure rates were 67% and 40%, respectively (p = NS). With a median follow-up of 20 months, the 5-year disease-specific survival rate was 44% (40% for ORMM vs 47% for SNMM, p = NS). Significant prognostic factors for disease-specific survival on univariate analysis included advanced clinical stage at presentation, tumor thickness greater than 5 mm, presence of vascular invasion, and development of nodal and distant metastases. On multivariate analysis, however, regional nodal failure lost significance. CONCLUSIONS: Clinical stage at presentation, tumor thickness greater than 5 mm, vascular invasion on histologic studies, and development of distant failure are the only independent predictors of outcome in MMHN. Copyright 2002 Wiley Periodicals, Inc.
UI - 11920589
AU - Jager E; Hohn H; Necker A; Forster R; Karbach J; Freitag K; Neukirch C;
TI - Castelli C; Salter RD; Knuth A; Maeurer MJ Peptide-specific CD8+ T-cell evolution in vivo: response to peptide vaccination with Melan-A/MART-1.
SO - Int J Cancer 2002 Mar 20;98(3):376-88
AD - Medizinische Klinik II, Hamatologie-Onkologie, Krankenhaus Nordwest, Frankfurt, Germany.
Monitoring of CD8+ T-cell responses in cancer patients during peptide vaccination is essential to provide useful surrogate markers and to demonstrate vaccine efficacy. We have longitudinally followed CD8+ T-cell responses in 3 melanoma patients who were immunized with peptides derived from Melan-A/MART-1. Recombinant HLA-A2 tetramers loaded with the naturally presented Melan-A/MART-1 nonamer peptide (AAGIGILTV) and the Melan-A/MART-1 analog (ELAGIGILTV) were used in combination with phenotypical analysis for different T-cell subsets including naive T cells, effector T cells, "true memory" T cells and "memory effector" T cells, based on CD45RA/RO and CCR7-expression. At least in a single patient, T cells binding to the AAGIGILTV epitope were detected in naive, precursor (CD45RA+/CCR7+) CD8+ T cells, and CD8+ T cells binding to the analog ELAGIGILTV peptide were identified in the terminally differentiated (CD45RA+/CCR7-) T-cell subset. Molecular and functional analysis of tetramer-binding T cells revealed that the T-cell receptor (TCR) repertoire was oligo/polyclonal in AAGIGILTV-reactive T cells, but different and restricted to a few TCR clonotypes in ELAGIGILTV-reactive T cells prior to vaccination. The TCR repertoire reactive with Melan-A/MART-1 peptide epitopes was broadened during vaccination and exhibited a different profile of cytokine release after specific stimulation: tetramer-binding T cells from 2/3 patients secreted granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon-gamma but not interleukin-2 (IL-2) in response to Melan-A/MART-1 peptides. In the third patient, tetramer-binding T cells secreted IL-2 exclusively. Our results show that T-cell responses to peptide vaccination consist of different T-cell subsets associated with different effector functions. Complementary analysis for TCR CDR3 and cytokine profiles may be useful to define the most effective CD8+ T-cell population induced by peptide vaccination. Copyright 2002 Wiley-Liss, Inc.
UI - 11920592
AU - Scheibenbogen C; Sun Y; Keilholz U; Song M; Stevanovic S; Asemissen AM;
TI - Nagorsen D; Thiel E; Rammensee HG; Schadendorf D Identification of known and novel immunogenic T-cell epitopes from tumor antigens recognized by peripheral blood T cells from patients responding to IL-2-based treatment.
SO - Int J Cancer 2002 Mar 20;98(3):409-14
AD - Medizinische Klinik III, Hematology, Oncology and Transfusion Medicine, Universitaetsklinikum Benjamin Franklin, Freie Universitat Berlin, Berlin, Germany. email@example.com
In previous studies CD8+ T cells specific for melanocyte antigens have been frequently found in melanoma patients responding to interleukin-2 (IL-2)-based therapies. In our study we analyzed the suitability of using circulating T cells from melanoma patients with clinical response after IL-2-based therapy to identify novel T-cell epitopes from defined tumor antigens. Using unstimulated peripheral blood mononuclear cells and the interferon-gamma (IFN-gamma) ELISPOT assay, we studied CD8(+) T-cell responses against 5 peptides from the tumor antigen tyrosinase (Tyr) selected by epitope prediction using an HLA-A1-binding computer algorithm. T cells specifically secreting IFN-gamma in response to 3 of these 5 peptides, namely, Tyr (454-463), Tyr (146-156) and Tyr (243-251), could be detected in 4 of 4 HLA-A1-positive patients with clinical response. In contrast, no T-cell responses against these peptides were seen in 6 HLA-A1-positive melanoma patients with progressive disease and in 8 healthy subjects. We could generate specific cytotoxic T lymphocytes (CTL) against Tyr (454-463) using peptide-pulsed autologous dendritic cells as antigen-presenting cells. The induced CTLs efficiently killed melanoma cells that express HLA-A1 and tyrosinase. The peptides Tyr (146-156) and Tyr (243-251) had recently been identified as CTL epitopes by other groups. Further ex vivo characterization of the T cells reactive against the novel epitope Tyr (454-463) in 1 patient by multicolor flow cytometry showed specific CD3+/CD8+/IFN-gamma+ T cells with frequencies of up to 0.41% of the CD3+/CD8+ T-cell population. Most of this T-cell population also expressed granzyme B. Our data confirm that in patients with tumor regressions induced by immunotherapy or chemoimmunotherapy circulating T cells reactive with tyrosinase epitopes can frequently be detected. Peripheral blood T cells from such patients are a valuable source for screening peptides selected by epitope prediction This strategy facilitates the rapid identification of immunogenic T-cell epitopes that are probable targets of immune-mediated tumor rejection. Copyright 2002 Wiley-Liss, Inc.
UI - 11896110
AU - Ridolfi R; Chiarion-Sileni V; Guida M; Romanini A; Labianca R; Freschi
TI - A; Lo Re G; Nortilli R; Brugnara S; Vitali P; Nanni O; Italian Melanoma Intergroup Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial.
SO - J Clin Oncol 2002 Mar 15;20(6):1600-7
AD - Department of Medical Oncology, Pierantoni Hospital, Forli.
PURPOSE: Phase II and III studies have shown that the addition of interleukin-2 (IL-2) and interferon alpha-2b (IFN alpha-2b) in multiagent chemotherapy (CT) for advanced melanoma increases overall response (OR), albeit without clear evidence of an improvement in overall survival (OS). Treatment with high-dose IL-2 can cause severe toxicity and is normally administered in an inpatient setting. We conducted a multicenter prospective randomized clinical trial in outpatients with metastatic melanoma to compare CT with biochemotherapy (bioCT) using immunomodulant doses of IL-2 and IFN alpha-2b. PATIENTS AND METHODS: One hundred seventy-six eligible patients with advanced melanoma were randomized to receive CT (cisplatin and dacarbazine with or without carmustine every 21 days) or bioCT comprising the same CT regimen followed by low-dose subcutaneous IL-2 for 8 days and IFN alpha-2b three times a week, both for six cycles. RESULTS: At a median follow-up of 18 (CT) and 16 (bioCT) months, median OS was 9.5 versus 11.0 months (P =.51), respectively. In the 89 CT-arm patients, 18 ORs (20.2%) (three complete responders [CRs] and 15 partial responders [PRs]) were observed according to World Health Organization criteria. In the 87 bioCT-arm patients, 22 ORs (25.3%) (three CRs and 19 PRs) (P =.70) were recorded. Treatment-related toxicity was fairly similar in both arms. CONCLUSION: The addition of low-dose immunotherapy did not produce a statistically significant advantage in OS, time to progression, or OR. However, the 11-month median OS in the bioCT arm does not differ greatly from the best results with high-dose IL-2-containing regimens reported in the literature. Furthermore, our treatment schedule was carried out on outpatients and had an acceptable level of toxicity.
UI - 11719634
AU - Cohen L; de Moor C; Devine D; Baum A; Amato RJ
TI - Endocrine levels at the start of treatment are associated with subsequent psychological adjustment in cancer patients with metastatic disease.
SO - Psychosom Med 2001 Nov-Dec;63(6):951-8
AD - Department of Behavioral Science, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. firstname.lastname@example.org
OBJECTIVE: This study examined the association between hormonal profiles at the start of cancer treatment and subsequent psychological symptomatology. METHODS: Twenty-seven patients with metastatic renal cell carcinoma and 18 patients with metastatic melanoma completed three assessments during the course of treatment: at the start of treatment (baseline), at the end of treatment (3 weeks after baseline), and at a follow-up appointment 1 month later. Cortisol, norepinephrine, and epinephrine levels were measured at baseline using 15-hour urine samples. At each assessment, patients completed the Impact of Event Scale (IES) and the Brief Symptom Inventory (BSI). RESULTS: Patients reported moderate levels of distress throughout treatment as measured by the IES and BSI. Norepinephrine levels at the start of treatment were positively associated with IES total scores at the end of treatment and at follow-up, and cortisol levels were positively associated with IES total scores at follow-up after adjusting for baseline IES and overall distress scores. Norepinephrine levels were also positively associated with depression scores at follow-up, and cortisol levels were positively associated with depression scores at the end of treatment and at follow-up after adjusting for baseline depression and overall distress scores. CONCLUSIONS: Hormonal profiles at the start of cancer treatment are associated with subsequent psychological adjustment.
UI - 11773161
AU - Agarwala SS; Glaspy J; O'Day SJ; Mitchell M; Gutheil J; Whitman E;
TI - Gonzalez R; Hersh E; Feun L; Belt R; Meyskens F; Hellstrand K; Wood D; Kirkwood JM; Gehlsen KR; Naredi P Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma.
SO - J Clin Oncol 2002 Jan 1;20(1):125-33
AD - Melanoma Center, University of Pittsburgh Cancer Institute, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA. email@example.com
PURPOSE: Reactive oxidative species (ROS) produced by phagocytic cells have been ascribed a role in the localized suppression of lymphocyte function within malignant tumors. Histamine has been shown to inhibit ROS formation and possibly synergize with cytokines to permit activation of natural killer cells and T cells. This study was designed to determine whether the addition of histamine to a subcutaneous (SC) regimen of interleukin-2 (IL-2) would improve the survival of metastatic melanoma patients. PATIENTS AND METHODS: A phase III, multicenter, randomized, parallel group study comparing IL-2 plus histamine with IL-2 alone was conducted in 305 patients with advanced metastatic melanoma. Patients were randomized to IL-2 (9 MIU/m(2) bid SC on days 1 to 2 of weeks 1 and 3, and 2 MIU/m(2) bid SC on days 1 to 5 of weeks 2 and 4) with or without histamine (1.0 mg bid SC days 1 to 5, weeks 1 to 4). The primary end point, survival, was prospectively applied to all randomized patients (intent-to-treat-overall population, ITT-OA) and all patients having liver metastases at randomization (ITT-LM population). Secondary end points included safety of the combined treatment, time to disease progression, and response rate. RESULTS: Combined treatment with histamine plus IL-2 significantly improved overall survival in the ITT-LM population (P =.004) and showed a trend for improved survival in the ITT population (P =.125). Grade 3 and 4 adverse events were comparable in the two arms. CONCLUSION: Use of histamine as an adjunct to IL-2 is safe, well tolerated, and associated with a statistically significant prolongation of survival compared with IL-2 alone in metastatic melanoma patients with liver involvement. Further trials to confirm and understand the role of histamine in this combination treatment are underway.
UI - 11912825
AU - Robinson JK
TI - Early detection and treatment of melanoma: update 2000.
SO - Dermatol Nurs 2000 Dec;12(6):397-402, 441-2
AD - Loyola University Chicago, Maywood, IL, USA.
Risk factors for the development of melanoma, early detection, biopsy technique, and treatment recommendations are discussed. Survival depends upon the stage at the time of diagnosis; thus, early detection of thin melanoma limited to the skin's surface enhances survival.
UI - 11926952
AU - Lens MB; Dawes M; Goodacre T; Newton-Bishop JA
TI - Elective lymph node dissection in patients with melanoma: systematic review and meta-analysis of randomized controlled trials.
SO - Arch Surg 2002 Apr;137(4):458-61
AD - Centre for Evidence-Based Medicine, University of Oxford Nuffield Department of Clinical Medicine, the Oxford Radcliffe National Health Service Trust, Oxford OX3 9DU, England. firstname.lastname@example.org
HYPOTHESIS: Elective lymph node dissection does not improve survival in patients with melanoma without clinically detectable lymph node metastases. OBJECTIVE: To determine whether elective lymph node dissection in patients with melanoma without clinically detectable regional metastases decreases overall mortality. DESIGN: Systematic review and meta-analysis of randomized controlled trials comparing elective lymph node dissection with delayed lymphadenectomy at the time of clinical recurrence. SETTING: Randomized controlled trials available participants. INTERVENTION: Elective lymph node dissection compared with delayed lymphadenectomy or no lymphadenectomy in patients with melanoma without clinically detectable regional metastases. MAIN OUTCOME MEASURE: Overall mortality in treatment groups as compared with control groups at the end of a 5-year follow-up period. RESULTS: Three randomized controlled trials met the inclusion criteria. The pooled odds ratio for overall mortality for the 3 trials was 0.86 (95% confidence interval, 0.68-1.09). Results are statistically nonsignificant, but they have potential clinical significance. CONCLUSIONS: This systematic review of randomized controlled trials comparing elective lymph node dissection with surgery delayed until the time of clinical recurrence shows no significant overall survival benefit for patients undergoing elective lymph node dissection. Trials included in this review, however, contain significant bias. The question is not answered for all patients, and the results do not exclude the possibility that some subgroups may benefit from elective lymph node dissection. Further research is required.
UI - 11917943
AU - Jelic S; Babovic N; Stamatovic L; Kreacic M; Matkovic S; Popov I
TI - Vinblastin-carboplatin for metastatic cutaneous melanoma as first-line chemotherapy and in dacarbazine failures: a single-center study.
SO - Med Oncol 2001;18(3):189-95
AD - Institute for Oncology and Radiology of Serbia, Department of Medical Oncology, Belgrade, Yugoslavia. email@example.com
First-line treatments of metastatic melanoma are usually decarbazine (DTIC) and/or alpha-interferon based, with response rates in the range of at most 20-30%. In this study, initiated, in fact, by a temporary DTIC shortage in the country, we have assessed the efficacy and toxicity of a vinblastine-carboplatin regimen for metastatic melanoma. The regimen was subsequently applied in two cohorts of patients: a chemotherapy-naive one and in DTIC failures (because the regimen was claimed non-cross-resistant). The regimen contained 6 mg/m2 vinblastine on d 1 and 450 mg/m2 carboplatin on d 1 for 3 wk. In the chemotherapy-naive cohort, 50 patients were included, 29 males and 21 females, median age 54 yr (range: 33-68), performance status 0+1 for 26 patients and 2+3 for 24 patients. Forty-eight patients were evaluable for activity. The response was the following: complete response (CR), 1/48 (2%); partial response (PR), 13/48 (27%); stable disease (SD), 20/48 (42%); progressive disease (PD), 14/48 (29%). The overall response rate was 14/48 (29%). The median response duration was 7 mo (range: 3-14); the median time to progression was 4 mo (range: 2-14). Toxicity included granulocytopenia and thrombocytopenia grade IV in 3/50 patients and nausea grade II in 8/50 patients. In the DTIC-failures cohort, 58 patients were included, 38 males and 20 females, median age 51 yr (range: 20-65), performance status 0+1 for 25 patients and 2+3 for 33 patients. All 58 patients were evaluable for activity. The response was the following: CR 3/58 (5%), PR 4/58 (7%), SD 10/58 (17%), PD 41/58 (71%). The overall response rate was 7/58 (12%). The median response duration was 11 mo (range: 3-24); the median time to progression was 4 mo (range: 2-24). Toxicities included granulocytopenia grade IV in 4/58 patients and nausea grade II in 4/58 patients. Thus, despite the fact that the regimen achieved a response rate comparable to DTIC in a first-line setting, the lack of cross-resistance did not prevent it from being of limited activity in DTIC failures, although, even in this group, several long-lasting responses and stabilizations were noted.
UI - 11903242
AU - Barlow RJ; White CR; Swanson NA
TI - Mohs' micrographic surgery using frozen sections alone may be unsuitable for detecting single atypical melanocytes at the margins of melanoma in situ.
SO - Br J Dermatol 2002 Feb;146(2):290-4
AD - Department of Dermatology, Oregon Health Sciences University, Portland, OR, USA. firstname.lastname@example.org
BACKGROUND: It remains questionable whether micrographic surgery with frozen sections is an appropriate technique for excision of melanoma in situ (MIS) of the lentigo maligna type. Advocates of the technique have interpreted MIS as being histologically defined by nests and contiguous atypical melanocytes on the basal layer. Others, however, have viewed the periphery of MIS as consisting of scattered single atypical melanocytes, a finding that may be difficult or impossible to establish on frozen sections. OBJECTIVES: To examine the reliability of micrographic surgery using frozen sections interpreted by an experienced Mohs' surgeon, in the excision of MIS. METHODS: From a total of 154 specimens, frozen sections from the 50 specimens with margins that were considered difficult to interpret were thawed, sent for routine processing and then examined 'blind' by a dermatopathologist. RESULTS: Using the dermatopathologist's report on paraffin-embedded sections as a reference point, the sensitivity and specificity of frozen sections were calculated to be 59% and 81%, respectively. CONCLUSIONS: Using these histological criteria, micrographic surgery with frozen sections alone is unreliable in the excision of MIS.
UI - 11920783
AU - Kroon BB; Noorda EM; Vrouenraets BC; Nieweg OE
TI - Isolated limb perfusion for melanoma.
SO - J Surg Oncol 2002 Apr;79(4):252-5
AD - The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. email@example.com
UI - 11894998
AU - Willemsen R A; Debets R; Hart E; Hoogenboom H R; Bolhuis R L; Chames P
TI - A phage display selected fab fragment with MHC class I-restricted specificity for MAGE-A1 allows for retargeting of primary human T lymphocytes.
SO - Gene Ther 2001 Nov;8(21):1601-8
AD - Department of Clinical and Tumor Immunology, Academic Hospital Rotterdam/Daniel den Hoed Cancer Center, The Netherlands.
The clinical benefit of adoptive transfer of MHC-restricted cytotoxic T lymphocytes(CTL) for the treatment of cancer is hampered by the low success rate to generate antitumor CTLs. To bypass the need for tumor-specific CTL, we developed a strategy that allows for grafting of human T lymphocytes with MHC-restricted antigen specificity using in vitro selected human Fab fragments fused to the Fc(epsilon)RI-gamma signaling molecule. Retroviral introduction of a Fab-based chimeric receptor specific for MAGE-A1/HLA-A1 into primary human T lymphocytes resulted in binding of relevant peptide/MHC complexes. Transduced T lymphocytes responded to native MAGE-A1/HLA-A1POS target cells by specific cytokine production and cytolysis. Therefore, peptide/MHC-specific Fab fragments represent new alternatives to TCR to confer human T lymphocytes with tumor specificity, which provides a promising rationale for developing immunogene therapies.
UI - 11839253
AU - Hamilton S; Odili J; Gundogdu O; Wilson GD; Kupsch JM
TI - Improved production by domain inversion of single-chain Fv antibody fragment against high molecular weight proteoglycan for the radioimmunotargeting of melanoma.
SO - Hybrid Hybridomics 2001;20(5-6):351-60
AD - RAFT Institute of Plastic Surgery and Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, UK.
Melanoma is among the few cancers with rising incidence. Currently there is no effective treatment for metastatic disease, but improved detection of melanoma has the potential to benefit the management of patients with early disease. Radioimmunodection by imaging with single-chain Fv (scFv) antibody fragments is one such emerging diagnostic method. However, the amount of scFv that can be produced at a scale suitable for use in patients is limiting. We have previously shown that the bacterial expression of a scFv derived from a monoclonal antibody (MAb) specific for melanoma-associated proteoglycan can be increased by light chain shuffling. In this report we show that a further increase in expression yield can be obtained by reversing the usual V(H)-V(L) orientation of scFvs to V(L)-V(H). Such seemingly minor changes have previously been reported to have unexpected effects on the in vitro and in vivo binding properties of recombinant antibodies. Our results show that reversal of the V domain orientation of the scFv improves expression by 150% without an adverse effect on melanoma binding in vitro and tumor targeting in vivo. Therefore, our results show that alteration of V domain orientation can improve the production yield of clinically useful antibody fragments. When used in combination with other antibody engineering approaches for increased antibody production changing the domain orientation is a simple strategy to achieve significant improvements in the production of scFvs for tumor radioimmunodetection for patient studies.
UI - 11331315
AU - Kirkwood JM; Ibrahim JG; Sosman JA; Sondak VK; Agarwala SS; Ernstoff MS;
TI - Rao U High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801.
SO - J Clin Oncol 2001 May 1;19(9):2370-80
AD - Division of Hematology-Oncology and Department of Pathology, Department of Medicine, University of Pittsburgh Cancer Institute Melanoma Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2582, USA. firstname.lastname@example.org
PURPOSE: Vaccine alternatives to high-dose interferon alfa-2b therapy (HDI), the current standard adjuvant therapy for high-risk melanoma, are of interest because of toxicity associated with HDI. The GM2 ganglioside is a well-defined melanoma antigen, and anti-GM2 antibodies have been associated with improved prognosis. We conducted a prospective, randomized, intergroup trial to evaluate the efficacy of HDI for 1 year versus vaccination with GM2 conjugated to keyhole limpet hemocyanin and administered with QS-21 (GMK) for 96 weeks (weekly x 4 then every 12 weeks x 8). PATIENTS AND METHODS: Eligible patients had resected stage IIB/III melanoma. Patients were stratified by sex and number of positive nodes. Primary end points were relapse-free survival (RFS) and overall survival (OS). RESULTS: Eight hundred eighty patients were randomized (440 per treatment group); 774 patients were eligible for efficacy analysis. The trial was closed after interim analysis indicated inferiority of GMK compared with HDI. For eligible patients, HDI provided a statistically significant RFS benefit (hazard ratio [HR] = 1.47, P = .0015) and OS benefit (HR = 1.52, P = .009) for GMK versus HDI. Similar benefit was observed in the intent-to-treat analysis (RFS HR = 1.49; OS HR = 1.38). HDI was associated with a treatment benefit in all subsets of patients with zero to > or = four positive nodes, but the greatest benefit was observed in the node-negative subset (RFS HR = 2.07; OS HR = 2.71 [eligible population]). Antibody responses to GM2 (ie, titers > or = 1:80) at days 29, 85, 365, and 720 were associated with a trend toward improved RFS and OS (P2 = .068 at day 29). CONCLUSION: This trial demonstrated a significant treatment benefit of HDI versus GMK in terms of RFS and OS in melanoma patients at high risk of recurrence.
UI - 11956264
AU - Eton O; Legha SS; Bedikian AY; Lee JJ; Buzaid AC; Hodges C; Ring SE;
TI - Papadopoulos NE; Plager C; East MJ; Zhan F; Benjamin RS Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial.
SO - J Clin Oncol 2002 Apr 15;20(8):2045-52
AD - Department Melanoma/Sarcoma, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. email@example.com
PURPOSE: The addition of cytokines to chemotherapy has produced encouraging results in advanced melanoma. In this phase III trial, we compared the effects of chemotherapy (cisplatin, vinblastine, and dacarbazine [CVD]) with those of sequential biochemotherapy consisting of CVD plus interleukin-2 and interferon alfa-2b. PATIENTS AND METHODS: Metastatic melanoma patients who had not previously received chemotherapy were stratified by prognostic factors and given chemotherapy or biochemotherapy. CVD consisted of dacarbazine (days 1 and 22) and cisplatin and vinblastine (days 1 to 4 and 22 to 25). Biochemotherapy involved CVD with vinblastine reduced 25% plus interleukin-2 by 24-hour continuous infusion (on days 5 to 8, 17 to 20, and 26 to 29) and interferon alfa-2b by subcutaneous injection (on days 5 to 9, 17 to 21, and 26 to 30). Response was assessed every 6 weeks. RESULTS: Among 190 patients enrolled, 91 were assessable for biochemotherapy and 92 for chemotherapy. Ten percent of the patients were alive a median of 52 months from start of therapy. Response rates were 48% for biochemotherapy and 25% for chemotherapy (P =.001); six patients given biochemotherapy and two given chemotherapy had complete responses. Median time to progression (TTP) was 4.9 months for biochemotherapy and 2.4 months for chemotherapy (P =.008); median survival was 11.9 and 9.2 months, respectively (P =.06). The influence of treatment on TTP and survival was confirmed in multivariate analyses with other prognostic factors not included in the original stratification. Biochemotherapy produced substantially more constitutional, hemodynamic, and myelosuppressive toxic effects. CONCLUSION: Cytokines substantially augment the antitumor activity of chemotherapy at the expense of considerable toxicity in patients with metastatic melanoma.
UI - 11956265
AU - Rao UN; Ibrahim J; Flaherty LE; Richards J; Kirkwood JM
TI - Implications of microscopic satellites of the primary and extracapsular lymph node spread in patients with high-risk melanoma: pathologic corollary of Eastern Cooperative Oncology Group Trial E1690.
SO - J Clin Oncol 2002 Apr 15;20(8):2053-7
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