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NCI CANCERLIT^® Search: Therapy of Melanoma - September 2002

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National Cancer Institute^®
Ultima Vez Modificado: 1 de septiembre del 2002

Angiogenic and immune parameters during recombinant interferon-alpha2b adjuvant treatment in patients with melanoma.
Surgical techniques of melanoma and sentinel node biopsy.
Mohs micrographically controlled surgery and the treatment of malignant melanoma.
European approach to adjuvant treatment of intermediate- and high-risk malignant melanoma.
Adjuvant therapy for patients with high-risk malignant melanoma.
Isolated limb perfusion in locally advanced cutaneous melanoma.
Interleukin-2 and histamine dihydrochloride in metastatic melanoma.
Cisplatin and dacarbazine with or without subcutaneous interleukin-2 and interferon alfa-2b in advanced melanoma outpatients.
Plasma protein binding, lipoprotein distribution and uptake of free and lipid-associated BCL-2 antisense oligodeoxynucleotides (G3139) in human
Enhanced humoral immune response correlates with improved disease-free and overall survival in American Joint Committee on Cancer stage II
Expression of multidrug resistance genes MVP, MDR1, and MRP1 determined sequentially before, during, and after hyperthermic isolated limb
Temozolomide plus thalidomide in patients with advanced melanoma: results of a dose-finding trial.
Primary malignant mucosal melanoma of the head and neck region: pooled analysis of 60 published cases from India and review of literature.
[Malignant skin melanoma]
A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft
The bisphosphonate pamidronate induces apoptosis in human melanoma cells in vitro.
Therapy of melanoma with allogeneic melanoma lysates alone or with interferon-alfa.
Nevus, redux.
Interview with professor Bin Kroon.
Prognostic factors for survival and factors associated with long-term remission in patients with advanced melanoma receiving cytokine-based
Phase II trial of carbetimer in metastatic melanoma.
Value of neck dissection in the treatment of patients with intermediate-thickness cutaneous malignant melanoma of the head and
Considerations in the surgical treatment of malignant melanoma.
The time from diagnostic excision biopsy to wide local excision for primary cutaneous malignant melanoma may not affect patient survival.
Sentinel node biopsy site used as full thickness skin graft donor for cutaneous melanoma.
Immunomodulatory effects of high-dose and low-dose interferon alpha2b in patients with high-risk resected melanoma: the E2690 laboratory
How does interferon work? Does it even matter?
Detection of P-glycoprotein in the Golgi apparatus of drug-untreated human melanoma cells.
Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy.
Acceptability and tolerance of a low tyrosine and phenylalanine diet in patients with advanced cancer -- a pilot study.
[The shadow rule and appropriate sun behavior]
[Role of sentinel node biopsy in the management of melanoma]
[Safety margins in the excision of primary malignant melanoma. Proposals based on controlled clinical trials]
[Comment on the contribution by A. Hauschild et al.: "Safety margins in excision of primary malignant melanoma"]
Quantitative real-time RT-PCR as a method for monitoring T lymphocyte reactivity to full-length tyrosinase protein in vaccinated melanoma
Novel oncolytic adenoviruses targeted to melanoma: specific viral replication and cytolysis by expression of E1A mutants from the
Relative biological effectiveness of boron ions on human melanoma cells.
Malignant melanoma.
Vaccination for malignant melanoma: recent developments.
Royal College of Radiologists Annual Undergraduate Essay Prize. Melanoma: the new smallpox? Can vaccines be used to treat melanoma?
Mohs micrographic surgery for melanoma: a case series, a comparative study of immunostains, an informative case report, and a unique mapping
[What is the role of sunscreens in the prevention of melanoma?]
[Dermatology, melanoma]
[Recommendations for the management of melanoma]
Adjuvant irradiation for axillary metastases from malignant melanoma.
A phase II trial of pyrazine diazohydroxide in patients with disseminated malignant melanoma and no prior chemotherapy--Southwest
Current concepts in the management of patients with melanoma.
A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with
Mobilization of dendritic cell precursors in patients with cancer by flt3 ligand allows the generation of higher yields of cultured dendritic

1
UI - 11417749
AU - Dreau D; Foster M; Hogg M; Swiggett J; Holder WD; White RL
TI - Angiogenic and immune parameters during recombinant interferon-alpha2b adjuvant treatment in patients with melanoma.
SO - Oncol Res 2000;12(5):241-51
AD - Department of General Surgery Research, Carolinas Medical Center, Charlotte, NC 28203, USA. ddreau@carolinas.org
As an adjuvant therapy for patients with high risk of recurrent melanoma, high-dose interferon (IFN)-alpha2b therapy has been shown to have some efficacy. We examined 22 patients with resected melanoma who were treated with repeated injections of recombinant IFN-alpha2b during the treatment. Both angiogenic and immune parameters were measured. White blood cells (WBCs) and lymphocyte numbers, lymphocyte subpopulations, serum concentrations of IFN-alpha and anti-IFN-alpha antibodies, and the serum vascular endothelial growth factor (VEGF), interleukin (IL)-8, and basis fibroblast growth factor (bFGF) concentrations were determined over time in resected, recurrence-free patients with American Joint Committee on Cancer (AJCC) stage III melanoma with one or less (LN+ < or = 1, n = 7) or more than one (LN+ > 1, n = 8) lymph nodes involved, and AJCC stage IV resected disease (n = 7). Follow-up and recurrence-free intervals were longer in stage III (LN+ < or = 1) patients compared with stage IV patients (P < 0.05). The number of WBCs and lymphocytes decreased during the treatment for all patient groups (P < 0.001). In addition, percentages of CD8 and CD20 were higher in stage IV patients than in stage III (LN+ > 1) and stage III (LN+ < or = 1) patients at the beginning of therapy (P < 0.05). A significant increase in the percentage of CD20+ cells, mostly B lymphocytes, was observed in the stage III (LN+ > 1) and stage III (LN+ < or = 1) patients over time but not in stage IV patients (P < 0.001). Low IL-8 and bFGF concentrations at the beginning of therapy were associated with significantly longer recurrence-free survival (P < 0.05). These results warrant a larger trial to determine if the differences observed in patients before treatment can provide prognostic markers in patients receiving IFN-alpha2b therapy.

2
UI - 12170435
AU - Testori A; Mozzillo N
TI - Surgical techniques of melanoma and sentinel node biopsy.
SO - Semin Oncol 2002 Aug;29(4):328-35
AD - Melanoma Unit, European Institute of Oncology, Milan, Italy.
The adequacy of surgical treatment of melanoma patients is the most important milestone in the natural history of the disease, once the diagnosis has been confirmed. Surgery plays a fundamental role in the initial stages of the disease, ie, to remove the primary lesion and to excise accurately the locoregional metastases. On the contrary, the impact of a surgical indication to treat distant metastases has never been confirmed in a prospective study; thus, there are no standard guidelines and it represents a decision to be discussed with each individual patient. Copyright 2002, Elsevier Science (USA). All rights reserved.

3
UI - 12170436
AU - Nagi C; O'Grady TC; Izadpanah A
TI - Mohs micrographically controlled surgery and the treatment of malignant melanoma.
SO - Semin Oncol 2002 Aug;29(4):336-40
AD - Division of Dermatology, University of California, San Diego, School of Medicine, San Diego, CA, USA.
Mohs micrographic surgery is a technique that offers surgeons and pathologists a means to examine the entire surgical margins of excised cutaneous malignancies in a more complete manner than conventional methods. Initially developed to treat nonmelanoma skin cancers, its use has been expanded to include histologic margin evaluation for treatment of malignant melanoma. Clinical studies demonstrate equivalent or better 5-year survival rates with Mohs surgery compared to conventional wide local excision. For surgical treatment of melanoma, it offers unique advantages for lesions requiring tissue conservation and accurate margin determination, particularly in anatomic sites where cosmetic and functional concerns are of importance (head and neck, hands, and feet), and for large or ill-defined lesions such as lentigo maligna or lentigo maligna melanoma. Copyright 2002, Elsevier Science (USA). All rights reserved.

4
UI - 12170441
AU - Eggermont AM; Gore M
TI - European approach to adjuvant treatment of intermediate- and high-risk malignant melanoma.
SO - Semin Oncol 2002 Aug;29(4):382-8
AD - Department of Surgical Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Adjuvant therapies for patients with melanoma at high risk of relapse whether local, such as excision margins, elective regional lymph node dissection (ELND), and prophylactic isolated limb perfusion (ILP), or systemic, such as chemotherapy, immunotherapy, immunochemotherapy, or vaccination therapy, have little or no impact on survival when evaluated in randomized trials. The European approach to the treatment of each stage of malignant melanoma is characterized by thoughtful caution with particular attention being paid to the avoidance of unwarranted mutilation or toxicity because phase 3 studies have failed to demonstrate unequivocal benefits for a more aggressive approach. In Europe, there is no standard adjuvant systemic therapy; high-dose interferon (IFN) is used sporadically in individual patients by some physicians, but there is little enthusiasm for adopting this regimen as the standard of care because of its high toxicity profile and the lack of a clear beneficial impact on long-term survival. Less toxic lower-dose maintenance IFN regimens, antiangiogenic agents, and vaccine therapies are currently being explored. Copyright 2002, Elsevier Science (USA). All rights reserved.

5
UI - 12170442
AU - McClay EF
TI - Adjuvant therapy for patients with high-risk malignant melanoma.
SO - Semin Oncol 2002 Aug;29(4):389-99
AD - San Diego Cancer Research Institute, and San Diego Melanoma Research Program, Vista, CA, USA.
The role of adjuvant therapy in the treatment of patients with high-risk malignant melanoma remains an area of intense investigation. The initial enthusiasm for high-dose interferon has been tempered by the results of more recent studies that allow for conflicting interpretations. Vaccine therapy trials have failed to clearly demonstrate a survival benefit, although several trials are currently ongoing. Recent studies of the role of chemotherapy suggest there may be combinations that have a survival benefit which deserve further study. This article will address patient selection and staging workup, and review options for treatment. Copyright 2002, Elsevier Science (USA). All rights reserved.

6
UI - 12170443
AU - Rossi CR; Foletto M; Pilati P; Mocellin S; Lise M
TI - Isolated limb perfusion in locally advanced cutaneous melanoma.
SO - Semin Oncol 2002 Aug;29(4):400-9
AD - Department of Surgical and Oncological Sciences Clinica Chirurgica II, University of Padova, Padova, Italy.
Isolated limb perfusion (ILP) is a well-established locoregional procedure to deliver high doses of cytostatics to an extremity with multiple in-transit lesions from cutaneous melanoma, with minimal systemic and mild local toxicity. This approach is quite sophisticated and requires accurate monitoring of systemic leakage and of the temperature of the affected limb in order to avoid major systemic and local side effects. Mephalan (L-PAM) is considered the reference drug, although complete responses are reported in only about 50% of patients. Since the early 1990s, tumor necrosis factor-alpha (TNF-alpha) was administered with melphalan in ILP aiming to improve the therapeutic index of this procedure. However, despite the impressive results reported, its role still remains controversial, seemingly confined to large tumor bulk. Fotemustine ILP was proposed as a less toxic alternative to L-PAM, after the results of a pilot experience claiming similar response rates with less local toxicity. A formal phase 1-2 study is now underway to confirm these findings. More straightforward procedures, such as isolated limb infusion, are appealing, as they seem capable of achieving good response rates, are easily repeatable, and are less costly. Larger series are required to validate such results. As potential agents to be delivered through ILP, new vasoactive drugs and agents with new mechanisms of action that interplay with chemotherapy, as well as virus-mediated gene therapy, are being developed. Copyright 2002, Elsevier Science (USA). All rights reserved.

7
UI - 12177116
AU - Agarwala SS; Hellstrand K; Naredi P
TI - Interleukin-2 and histamine dihydrochloride in metastatic melanoma.
SO - J Clin Oncol 2002 Aug 15;20(16):3558-9

8
UI - 12177119
AU - Koduri J; Baumann MA
TI - Cisplatin and dacarbazine with or without subcutaneous interleukin-2 and interferon alfa-2b in advanced melanoma outpatients.
SO - J Clin Oncol 2002 Aug 15;20(16):3560; discussion 3560-1

9
UI - 12086721
AU - Wasan EK; Waterhouse D; Sivak O; Bally MB; Klasa RJ; Wasan KM
TI - Plasma protein binding, lipoprotein distribution and uptake of free and lipid-associated BCL-2 antisense oligodeoxynucleotides (G3139) in human melanoma cells.
SO - Int J Pharm 2002 Jul 8;241(1):57-64
AD - Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada V6T 1Z3. kwasan@interchange.ubc.ca
The objectives of this study were to determine the protein binding and lipoprotein distribution of G3139 and G3139 lipoplexes following incubation in human plasma, assess complement activation of, and the effect of pre-incubation of G3139 and G3139 lipoplexes in human plasma on in vitro cellular uptake of G3139. Effect of concentration and time on incorporation of free and lipid associated (lipoplexes) [3H]Bcl-2 AO (25-600 ng/ml) into normolipidemic human plasma lipoproteins was determined by density gradient ultracentrifugation after incubation at 37 degrees C for 5, 30, 60 and 120 min. Protein binding in the lipoprotein deficient fractions (LPDP) was determined by equilibrium dialysis. Complement interaction was determined by ELISA after exposure of human plasma to AO+/- liposomes prepared in serial dilution. In vitro uptake of G3139 and G3139 lipoplexes into human melanoma cells was assessed qualitatively by fluorescence microscopy after 4-h exposure to G3139 (free or as lipoplexes) with or without pre-incubation of G3139 in normal human plasma. Analysis of Bcl-2 AO-lipoprotein interaction over time and concentration indicated no significant movement of the compound within the different lipoprotein and LPDP fractions. Majority of drug was recovered within LPDP fraction, and more than 85% of drug recovered within LPDP fraction was protein bound. No significant activation of complement was noted for either free AO or lipoplexes. Pre-incubation of free AO or AO-lipoplexes in human plasma resulted in a greater cellular uptake of AO-lipoplexes compared with plasma free controls. These findings suggest that the majority of [3H]Bcl-2 AO is plasma protein bound with little lipoprotein association and no significant movement between different lipoprotein and LPDP fractions. Plasma protein binding other than lipoprotein binding may be responsible for the difference in cellular uptake of free AO vs. cationic lipoplexes.

10
UI - 12149297
AU - DiFronzo LA; Gupta RK; Essner R; Foshag LJ; O'Day SJ; Wanek LA; Stern
TI - SL; Morton DL Enhanced humoral immune response correlates with improved disease-free and overall survival in American Joint Committee on Cancer stage II melanoma patients receiving adjuvant polyvalent vaccine.
SO - J Clin Oncol 2002 Aug 1;20(15):3242-8
AD - Sonya Valley Ghidossi Vaccine Laboratory, Roy E. Coats Research Laboratories, John Wayne Cancer Institute at Saint John's Health Center, 2200 Santa Monica Boulevard, Santa Monica, CA 90404, USA.
PURPOSE: Although the improved overall survival (OS) of patients who receive Canvaxin (CancerVax Corp, Carlsbad, CA) polyvalent vaccine (PV) immunotherapy for metastatic melanoma has been correlated with cellular and humoral immune responses, the mechanisms of vaccine immunotherapy for early-stage melanoma are unclear. Specific immune responses to tumor-associated antigens might correlate with disease-free survival (DFS) and OS in patients receiving adjuvant PV therapy for primary melanoma. PATIENTS AND METHODS: Eighty-three patients received PV plus bacille Calmette-Guerin after wide excision of American Joint Committee on Cancer stage II melanoma. Humoral and cellular responses during the first 12 weeks of adjuvant immunotherapy were assessed by serum antibody titers to a tumor-associated 90-kd glycoprotein antigen (TA90) expressed by PV, and by delayed-type hypersensitivity (DTH) skin testing with PV (PV-DTH). RESULTS: At a median follow-up period of 46.6 months (range, 10.7 to 93.6 months), an increased PV-DTH response seemed to be associated with improved 5-year DFS (54% v 20%) and 5-year OS (75% v 60%), but the correlations were not statistically significant. Anti-TA90 immunoglobulin (Ig) M levels > or = 1:800 were significantly correlated with improved 5-year DFS and improved 5-year OS, and multivariate analysis identified anti-TA90 IgM as an independent prognostic factor for OS and DFS. CONCLUSION: These findings suggest that an increased IgM response in patients receiving PV therapy for stage II melanoma is associated with decreased recurrence and improved survival.

11
UI - 12149303
AU - Stein U; Jurchott K; Schlafke M; Hohenberger P
TI - Expression of multidrug resistance genes MVP, MDR1, and MRP1 determined sequentially before, during, and after hyperthermic isolated limb perfusion of soft tissue sarcoma and melanoma patients.
SO - J Clin Oncol 2002 Aug 1;20(15):3282-92
AD - Division of Surgery and Surgical Oncology, Charite, Humboldt University, Campus Berlin-Buch, Robert Rossle Hospital and Tumor Institute, Robert-Rossle-Strasse 10, 13092 Berlin, Germany. ustein@mdc-berlin.de
PURPOSE: Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor alpha and melphalan is a highly effective treatment for advanced soft tissue sarcoma (STS) and locoregional metastatic malignant melanoma. Multidrug resistance (MDR)-associated genes are known to be inducible by heat and drugs; expression levels of the major vault protein (MVP), MDR1, and MDR-associated protein 1 (MRP1) were determined sequentially before, during, and after ILP of patients. PATIENTS AND METHODS: Twenty-one STS or malignant melanoma patients were treated by ILP. Tumor tissue temperatures were recorded continuously and ranged from 33.4 degrees C initially to peak values of 40.4 degrees C during ILP. Serial true-cut biopsy specimens from tumor tissues were routinely microdissected. Expression analyses for MDR genes were performed by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry. RESULTS: In 83% of the patients, MVP expression was induced during hyperthermic ILP. MVP-mRNA inductions often paralleled the increase in temperature during ILP. Increased MVP protein expressions either were observed simultaneously with the MVP-mRNA induction or were delayed until after the induction at the transcriptional level. Inductions of MDR1 and MRP1 were observed in only 13% and 27% of the specimens analyzed. Temperatures and drugs applied preferentially led to an induction of MVP and were not sufficient to induce MDR1 and MRP1 in the majority of tumors. CONCLUSION: This study is the first to analyze the expression of MDR-associated genes sequentially during ILP of patients and demonstrates that treatment might lead to increased levels of MVP, whereas enhanced levels of MDR1 and MRP1 remain rare events.

12
UI - 12039921
AU - Hwu WJ; Krown SE; Panageas KS; Menell JH; Chapman PB; Livingston PO;
TI - Williams LJ; Quinn CJ; Houghton AN Temozolomide plus thalidomide in patients with advanced melanoma: results of a dose-finding trial.
SO - J Clin Oncol 2002 Jun 1;20(11):2610-5
AD - Departments of Medicine, Epidemiology and Biostatistics, and Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. hwuw@mskcc.org
PURPOSE: To establish a safe and tolerated regimen of an oral cytotoxic agent, temozolomide, and a cytostatic agent, thalidomide, in patients with unresectable stage III or IV malignant melanoma. PATIENTS AND METHODS: Patients with unresectable stage III or IV melanoma without brain metastases were entered successively onto four treatment cohorts: level 1, temozolomide 50 mg/m(2)/d for 6 weeks followed by a 4-week break; levels 2, 3, and 4, temozolomide 75 mg/m(2)/d for 6 weeks followed, respectively, by breaks of 4, 3, and 2 weeks. Thalidomide was started at 200 mg/d, and escalated to a maximum dose of 400 mg/d. Safety was assessed at weeks 2 and 4 and every 4 weeks thereafter; tumor response was evaluated every 8 to 10 weeks. RESULTS: Twelve patients were enrolled, three on each cohort. Therapy was generally well tolerated on all of the treatment schedules. Thalidomide at a dose of 400 mg/d was well tolerated in patients younger than 70, and 200 mg/d was well tolerated in older patients. The most common adverse events were grade 2 or 3 constipation and neuropathy, which were attributed to thalidomide. Five major responses (one complete, four partial) were documented, all at dose levels 2 to 4. Three of the five responding patients were in the over-70 age group. The median duration of response was 6 months (range, 4 to 17+ months), and the median overall survival was 12.3 months (range, 4 to 19+ months). CONCLUSION: The combination of temozolomide and thalidomide was well tolerated and had antitumor activity in patients with advanced melanoma, including elderly patients over 70 years old.

13
UI - 11917203
AU - Pandey M; Mathew A; Iype EM; Sebastian P; Abraham EK; Nair KM
TI - Primary malignant mucosal melanoma of the head and neck region: pooled analysis of 60 published cases from India and review of literature.
SO - Eur J Cancer Prev 2002 Feb;11(1):3-10
AD - Department of Surgical Oncology, Regional Cencer Centre, Medical College PO, Trivandrum, Kerala, 695 011, India. manojpandey@vsnl.com
Malignant melanoma arising in the head and neck mucosa is a rare entity with incidence ranging from 2% to 10%. Because of the lack of data, the biological behaviour of these lesions still remains unpredictable and outcome dismal. We carried out a literature review for cases of mucosal melanoma of the head and neck reported from India and performed a pooled analysis on the available data. A total of 60 cases of head and neck melanomas were reported, of which 46 were in men. Palate and alveolus were the commonest sites. A total of 29 (48.3%) patients had regional node metastasis at presentation while five (12%) had distant metastasis. Three-year overall survival of 27.7% was observed. However, the disease-free survival rates at 3, 5 and 6 years were 39.4%, 39.4% and 13.1%, respectively. Metastasis at presentation and use of adjuvant radiotherapy were found to be the only significant predictors of survival. Malignant mucosal melanoma has aggressive biological behaviour and poor outcome. Radical surgery and adjuvant radiotherapy may provide a better local control and may help in improving survival.

14
UI - 12082854
AU - Drzewiecki KT; von der Maase H
TI - [Malignant skin melanoma]
SO - Ugeskr Laeger 2002 Jun 3;164(23):3031-5
AD - Plastik- og brandsarsafdelingen, H:S Rigshospitalet, DK-2100 Kobenhavn o.

15
UI - 12072074
AU - Farshad A; Burg G; Panizzon R; Dummer R
TI - A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays.
SO - Br J Dermatol 2002 Jun;146(6):1042-6
AD - Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, CH-8091 Zurich, Switzerland.
BACKGROUND: Lentigo maligna (LM) and lentigo maligna melanoma (LMM) are the most common melanocytic neoplasms on sun-exposed skin of elderly patients. OBJECTIVES: To perform a retrospective study of 150 patients with LM and LMM treated with radiotherapy using Grenz or soft X-rays. METHODS: The information recorded and analysed included gender, age, diagnosis, size of the lesion, localization, X-ray treatment, recurrence rate, other skin malignancies and non-dermatological neoplasms. RESULTS: The 150 patients comprised 78 women and 72 men (mean age 70 years). Ninety-three patients had LM, 54 had LMM and three had both neoplasms. Ninety per cent of lesions were located on the face. Treatment was with Grenz rays in 96 patients with LM and 11 with LMM (70%) and with soft X-rays in 46 patients with LMM (30%). Three patients were treated using both modalities. One hundred and one patients were followed up for at least 2 years after radiotherapy (mean 8 years). The mean time to recurrence was 45.6 months, and the recurrence rate was 7% (seven of 101). Other skin malignancies were observed in 65 of 150 patients, including basal cell carcinoma in 23 (35%) and actinic keratosis in 20 (31%). Four patients developed internal cancers. CONCLUSIONS: The study showed that radiotherapy of LM and LMM was curative. In particular, radiotherapy proved to be an excellent treatment for elderly patients. Owing to the high incidence of other skin cancers, LM patients need careful follow-up.

16
UI - 12177810
AU - Riebeling C; Forsea AM; Raisova M; Orfanos CE; Geilen CC
TI - The bisphosphonate pamidronate induces apoptosis in human melanoma cells in vitro.
SO - Br J Cancer 2002 Jul 29;87(3):366-71
AD - Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Fabeckstr. 60-62, 14 195-Berlin, Germany.
Pamidronate belongs to the class of nitrogen-containing bisphosphonates that are potent inhibitors of bone resorption frequently used for the treatment of osteoporosis and cancer-induced osteolysis. The inhibition of osteoclasts' growth has been suggested as the main mechanism of the inhibitory effect of pamidronate on bone metastases. Recent findings indicated that bisphosphonates also have a direct apoptotic effect on other types of tumour cells. Nitrogen-containing bisphosphonates were shown to inhibit farnesyl diphosphate synthase, thus blocking the synthesis of higher isoprenoids. By this mechanism they inactivate monomeric G-proteins of the Ras and Rho families for which prenylation is a functional requirement. On the background of the known key role of G-proteins in tumorigenesis, we investigated a possible beneficial use of pamidronate in the treatment of malignant melanoma. Our results indicate that pamidronate inhibits the cell growth and induces apoptosis in human melanoma cells in vitro. Susceptibility to pamidronate did not correlate to CD95 ligand sensitivity or p53 mutational status. Furthermore it is interesting to note that overexpression of bcl-2 did not abolish pamidronate-induced apoptosis. These data suggests that pamidronate has a direct anti-tumour effect on malignant melanoma cells, independently of the Bax/Bcl-2 level. Copyright 2002 Cancer Research UK

17
UI - 12197233
AU - Mitchell MS; Darrah D; Stevenson L
TI - Therapy of melanoma with allogeneic melanoma lysates alone or with interferon-alfa.
SO - Cancer Invest 2002;20(5-6):759-68
AD - Hudson-Webber Cancer Research Center, Karmanos Cancer Institute, 110 East Warren Avenue, Suite 740, Detroit, MI 48201, USA.

18
UI - 11801787
AU - LeBoit PE
TI - Nevus, redux.
SO - Am J Dermatopathol 2001 Oct;23(5):491-3
AD - Department of Pathology, University of California, San Francisco, California 94115, USA. philipl@itsa.ucsf.edu

19
UI - 12199197
AU - Kroon B
TI - Interview with professor Bin Kroon.
SO - Eur J Cancer 2002 Jul;38(11):1425

20
UI - 12110497
AU - Keilholz U; Martus P; Punt CJ; Kruit W; Mooser G; Schadendorf D; Lienard
TI - D; Dummer R; Koller J; Voit C; Eggermont AM Prognostic factors for survival and factors associated with long-term remission in patients with advanced melanoma receiving cytokine-based treatments: second analysis of a randomised EORTC Melanoma Group trial comparing interferon-alpha2a (IFNalpha) and interleukin 2 (IL-2) with or without cisplatin.
SO - Eur J Cancer 2002 Jul;38(11):1501-11
AD - Medizinische Klinik III, UKBF, Free University Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. keilholz@ukbf.fu-berlin.de
The aim of this study was to define prognostic factors for survival, and especially for long-term survival in a mature data-set of patients with stage IV melanoma treated within a randomised trial of cytokine-based protocols. Long-term follow-up data on patients enrolled into a European Organization for Research and Treatment of Cancer (EORTC) trial comparing interferon-alpha (IFNalpha) plus interleukin-2 (IL-2) with or without cisplatin were collected. Univariate and multivariate Cox regression analyses were performed to define prognostic factors for survival. The characteristics of patients alive at 2 and 5 years after randomisation were compared with the entire cohort using the chi(2) test. The minimum potential follow-up of the 131 evaluable patients was 5 years. 18 patients (14%) were alive 2 years after randomisation, and 11 (8%) 5 years after randomisation. Pretreatment performance status (PS), serum lactate dehydrogenase (LDH) and tumour mass were significant predictors for survival, whereas site of metastases and number of sites were non-significant. PS and LDH were the only independent prognostic factors. All except 1 patient alive at 2 and 5 years had a pretreatment PS of 100%, and only three long-term survivors had elevated pretreatment LDH. There was no association between the site of metastases and long-term survival. Response to treatment was a major predictor for long-term survival, whereas addition of cisplatin did not impact upon overall survival probability or on long-term survival. The probability of long-term survival in stage IV melanoma patients after IL-2-based treatments is governed by pretreatment PS, serum LDH and response to treatment. Site of metastases, the basis for the M-subcategories of the new AJCC staging system, was not informative in this study.

21
UI - 8262738
AU - Quan WD Jr; Mitchell MS
TI - Phase II trial of carbetimer in metastatic melanoma.
SO - Invest New Drugs 1993 May-Aug;11(2-3):231-3
AD - USC/Norris Comprehensive Cancer Center, Los Angeles.
A phase II study of the synthetic polyelectrolyte Carbetimer 6500 mg/m2 i.v. daily for five days every 21-day cycle was conducted in patients with metastatic melanoma. No responses were seen in 18 evaluable patients. Two patients had stable disease for five months. Toxicity was generally manageable and included mild hyperphosphatemia, mild proteinuria, fatigue, pain at the injection site, and nausea. Carbetimer is inactive in metastatic melanoma at this dose and schedule.

22
UI - 9932599
AU - Myers JN
TI - Value of neck dissection in the treatment of patients with intermediate-thickness cutaneous malignant melanoma of the head and neck.
SO - Arch Otolaryngol Head Neck Surg 1999 Jan;125(1):110-5
AD - Department of Surgery, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. jmyers@notes.mdacc.tmc.edu

23
UI - 9932601
AU - Fisher SR
TI - Considerations in the surgical treatment of malignant melanoma.
SO - Arch Otolaryngol Head Neck Surg 1999 Jan;125(1):116-7

24
UI - 12100184
AU - McKenna DB; Lee RJ; Prescott RJ; Doherty VR
TI - The time from diagnostic excision biopsy to wide local excision for primary cutaneous malignant melanoma may not affect patient survival.
SO - Br J Dermatol 2002 Jul;147(1):48-54
AD - Department of Dermatology, Royal Infirmary of Edinburgh, Scotland, UK. dermotbmckenna@hotmail.com
BACKGROUND: The surgical management of primary cutaneous malignant melanoma usually involves an excision biopsy of the suspected lesion followed by wide local excision. No study has addressed whether a delay between these two surgical procedures influences patient outcome. OBJECTIVES: To determine if the surgical interval (SI) between the diagnostic excision biopsy and wide local excision for primary cutaneous malignant melanoma affects recurrence or survival outcome. METHODS: A cohort of 986 patients who had a diagnostic excision biopsy followed by wide local excision was identified from those registered on a specialist database that records the clinicopathological features, surgical treatment and follow-up information of all patients with malignant melanoma in Scotland. The cohort was divided into five arbitrary groups determined by the length of the SI as follows:< or =14 days, 15-28 days, 29-42 days, 43-91 days and > or = 92 days. Overall survival, disease-free survival and recurrence-free interval between the groups were compared univariately and multivariately. RESULTS: The mean age at excision biopsy was 47.4 years and the median period of follow-up was 5 years (range 27 days to 20.7 years). The median SI was 30 days (range 1-468 days). The SI was: (i)< or =14 days for 130 (13%); (ii) 15-28 days for 320 (33%); (iii) 29-42 days for 262 (27%); (iv) 43-91 days for 251 (25%); and (v) > or = 92 days for 23 (2%) patients. The latter group was older, had thinner melanomas, a higher percentage of lesions on the head and neck, fewer superficial spreading malignant melanomas and ulceration present less often compared with patients treated earlier. Univariately, there was no significant difference in overall survival (P = 0.60) or disease-free survival (P = 0.24) between the groups. Although there was a statistically significant difference in the percentage of recurrence-free patients between the groups (P = 0.011), the better recurrence-free rates occurred in the 29-42 and 43-91 day groups. After adjusting for age, sex, tumour thickness, site, histology, ulceration and mitotic activity using Cox's proportional hazards model, there was no statistically significant difference in overall survival, disease-free survival and recurrence-free percentages between the surgical groups (P = 0.88, P = 0.44 and P = 0.084, respectively). CONCLUSIONS: There was no evidence that survival outcome or recurrence was related to the time interval between the diagnostic excision biopsy and wide local excision of melanoma.

25
UI - 12169366
AU - Dresel A; Kuhn JA; McCarty TM
TI - Sentinel node biopsy site used as full thickness skin graft donor for cutaneous melanoma.
SO - Am J Surg 2002 Aug;184(2):176-8
AD - Baylor University Medical Center, Department of Surgery, Dallas, TX 75246, USA.
BACKGROUND: Wound defects after wide local excision (WLE) for cutaneous melanoma can occasionally require the use of skin grafts for closure. Harvesting the skin graft can result in an additional wound. METHODS: The increasing use of sentinel lymph node (SLN) biopsy in cutaneous melanoma at our institution has facilitated the development of an alternative technique for obtaining donor skin. The proposed method utilizes the skin overlying the SLN as the skin graft donor site. Sixteen patients underwent WLE of intermediate to thick melanomas with SLN biopsy and full thickness skin graft harvested from the SLN biopsy site. RESULTS: After a median follow-up of 12 months, there were no graft failures. There were 2 partial graft losses. There were no wound complications. There were no melanoma recurrences. CONCLUSIONS: In cases where primary closure is not technically feasible or cosmetically favorable, the use of the SLN incision site as a skin graft donor provides the surgeon with an effective repair and spares the patient an additional skin graft donor site defect.

26
UI - 12209697
AU - Kirkwood JM; Richards T; Zarour HM; Sosman J; Ernstoff M; Whiteside TL;
TI - Ibrahim J; Blum R; Wieand S; Mascari R Immunomodulatory effects of high-dose and low-dose interferon alpha2b in patients with high-risk resected melanoma: the E2690 laboratory corollary of intergroup adjuvant trial E1690.
SO - Cancer 2002 Sep 1;95(5):1101-12
AD - Department of Medicine, University of Pittsburgh, Pennsylvania, USA. jmk@jimmy.harvard.edu
BACKGROUND: The clinical antitumor activity of recombinant interferon alpha2b (IFNalpha2b) has been well documented in patients with advanced and high-risk melanoma; however, its mechanism of action remains conjectural. Trial E2690 evaluated the immunomodulatory effects of IFNalpha2b in vivo during treatment at high doses (the HDI arm; n = 51 patients) and at low doses (the LDI arm; n = 54 patients) in relation to standard observation (OBS; n = 43 patients). METHODS: This study evaluated peripheral blood lymphocytes (PBLs) for phenotypic markers and cytotoxic functions at 1 month, 3 months, and 12 months in the HDI arm, the LDI arm, and the OBS arm and examined correlations between changes observed in PBLs or in tumors with regard to treatment dosage and disease outcome. Tumor biopsy samples were studied for response to IFNalpha2b at a range of concentrations in vitro. RESULTS: Baseline blood phenotypic and functional assays did not predict disease outcome; however, modulation of these immunologic assays by IFNalpha2b treatment was observed and was associated with IFNalpha2b dosage. Tumor cell class II major histocompatibility antigen expression (human leukocyte/lymphocyte antigen DR) and adhesion molecule expression (ICAM-1) were modulated by exposure to IFNalpha2b in a dose dependent manner. Blood natural killer (NK) cell function, T-cell function, and subset distribution were modulated early by patients in the HDI arm and later by patients in the LDI arm. None of the variables tested in these studies predicted recurrence free survival. The numbers of patients studied were smaller than may be needed to detect potentially clinically significant changes. CONCLUSIONS: These data demonstrate changes in immunologic parameters associated with IFNalpha2b treatment and dosage that may account for some of the differences in the clinical efficacy of this modality. The current results also suggest the need for further study of newer molecular intermediates of IFNalpha2b and T-cell response to specific antigens of melanoma. Copyright 2002 American Cancer Society.

27
UI - 12209676
AU - Sondak VK
TI - How does interferon work? Does it even matter?
SO - Cancer 2002 Sep 1;95(5):947-9

28
UI - 9506534
AU - Molinari A; Calcabrini A; Meschini S; Stringaro A; Del Bufalo D;
TI - Cianfriglia M; Arancia G Detection of P-glycoprotein in the Golgi apparatus of drug-untreated human melanoma cells.
SO - Int J Cancer 1998 Mar 16;75(6):885-93
AD - Laboratorio di Ultrastrutture, Istituto Superiore di Sanita, Rome, Italy.
The intracellular location of the MDR1 gene product, known as P-glycoprotein (P-gp), has been detected by flow cytometry in 3 stabilized human melanoma cell lines which had never undergone cytotoxic drug treatment and did not express P-gp on the plasma membrane. In addition, MDR1 mRNA expression was revealed by RT-PCR in the same cell lines. Immunofluorescence microscopy, performed by using the same 2 monoclonal antibodies (MM4.17 and MRK-16) as employed in the flow-cytometric analysis, revealed the presence of P-gp intracytoplasmically, in a well-defined perinuclear region. Double immunofluorescence labelling and immunoelectron microscopy strongly suggested the location of the transporter molecule in the Golgi apparatus. The same observations have been obtained on a primary culture from a metastasis of human melanoma. Analysis of the expression of another membrane transport protein, the multidrug-resistance-related protein (MRP1), showed that it was present in the cytoplasm of all the melanoma cell lines examined. MRP1 also showed Golgi-like localization. The study by laser scanning confocal microscopy on the intracellular localization of the anti-tumoral agent doxorubicin (DOX) during the drug-uptake and -efflux phases, indicated the Golgi apparatus as a preferential accumulation site for the anthracyclinic antibiotic. P-gp function modulators (verapamil and cyclosporin A) were able to modify DOX intracytoplasmic distribution and to increase drug intracellular concentration and cytotoxic effect in melanoma cells. On the contrary, MRP1 modulators (probenecid and genistein) did not significantly influence either DOX efflux and distribution or the sensitivity of melanoma cells to the cytotoxic drug.

29
UI - 12202672
AU - Kirkwood JM; Bender C; Agarwala S; Tarhini A; Shipe-Spotloe J; Smelko B;
TI - Donnelly S; Stover L Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy.
SO - J Clin Oncol 2002 Sep 1;20(17):3703-18
AD - University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. jmk@jimmy.harvard.edu
PURPOSE: The toxicity associated with adjuvant high-dose interferon-alfa-2b therapy (HDI) for high-risk melanoma can lead to premature discontinuation. It is important to understand the expected adverse events and their underlying mechanisms and to anticipate and aggressively manage toxicity during treatment in order to ensure that patients receive the maximum therapeutic benefit. METHODS: The toxicity profile of HDI was reviewed by examining data from the United States cooperative group trials. Available published data related to the potential mechanisms responsible for the observed adverse events are discussed, and comprehensive recommendations for managing side effects are presented. RESULTS: The HDI regimen is associated with acute constitutional symptoms, chronic fatigue, myelosuppression, elevated liver enzyme levels, and neurologic symptoms. The majority of patients tolerate 1 year of therapy with an understanding of the anticipated toxicities in conjunction with appropriate dose modifications and supportive care. Ongoing monitoring for liver dysfunction and hematologic toxicity is critical to ensure safety. Many of the toxicities associated with interferon-alfa (IFN-alpha) seem to be the result of endogenous cytokines and their effects on the neuroendocrine system. Recent data have also demonstrated that IFN-alpha suppresses the activity of specific CYP450 isoenzymes and that this correlates with discrete toxicities. Pharmacologic interventions are under study for fatigue and depression. An increased understanding of the mechanisms of IFN-alpha-associated toxicity will lead to more rational and effective supportive care and improved quality of life. CONCLUSION: Continued research in this area should lead to improvements in the safety and tolerability of adjuvant therapy for melanoma.

30
UI - 12028515
AU - Harvie MN; Campbell IT; Howell A; Thatcher N
TI - Acceptability and tolerance of a low tyrosine and phenylalanine diet in patients with advanced cancer -- a pilot study.
SO - J Hum Nutr Diet 2002 Jun;15(3):193-202
AD - University Department of Medical Oncology, South Manchester University Hospitals NHS Trust, Manchester, UK. m_harvie@fs1.with.man.ac.uk
BACKGROUND: Low phenylalanine (phe) and tyrosine (tyr) diets limit tumour growth in animal models and may offer a novel cancer therapy. We studied the efficacy and acceptability of a low phe and tyr diet in patients with advanced cancer. METHODS: Patients with advanced metastatic melanoma (n=22) and metastatic breast cancer (n=15) were invited to follow a low phe and tyr diet (10 mg kg-1 phe and tyr per day) for 1 month. In those individuals who followed the diet for 1 month, we attempted to establish the effects on nutritional status (body weight, fat free mass, percentage body fat, serum albumin), immune cell function (white cell count, lymphocytes and neutrophils), plasma levels of phe-tyr and tryptophan and quality of life (Hospital Anxiety and Depression score). RESULTS: Only three of the 22 patients with metastatic melanoma and three of the 15 patients with metastatic breast cancer agreed to start the diet. All patients experienced problems and side-effects and increases in anxiety and depression. There were declines in weight, with loss of fat and fat free mass but slight increases in white cell counts and neutrophils. CONCLUSIONS: Low phe and tyr diets do not appear to be a viable treatment option for patients with advanced cancer.

31
UI - 12107949
AU - Lorentzen HF; Weismann K
TI - [The shadow rule and appropriate sun behavior]
SO - Ugeskr Laeger 2002 Jun 17;164(25):3346-50
AD - Dermatologisk afdeling D42, H:S Bispebjerg Hospitalet, DK-2400 Kobenhavn NV.
INTRODUCTION: Sun lotions have not been effective in preventing the alarming increase in the incidence of melanoma, possibly, because of incorrect use, lack of protection from UVA and increased exposure times caused by reduced penetration of erythemogenic UVB. Seeking shade prevents deleterious effects from the sun's ultraviolet rays. MATERIAL AND METHODS: We examined the association between UV intensity and the ratio of shadow length to object height. A linear model fitted the data (R = 0.95). With an astronomical navigation equation for the calculation of altitude of the sun and substituting altitude with UV intensity we developed a model predicting the UV load from the point of observation, the time of the year (declination) and the time of day (hour angle). Accumulated UV doses can be calculated by integration. RESULTS: When the shadow to object ratio is 0.5, skin types I and II will experience erythema after a few minutes, when the ratio is 1 erythema appears after 20-30 minutes, and when the ratio is 2 erythema appears after about one hour. In the Mediterranean, accumulated UV exposure from sunrise to sunset in late summer will be 30-50 times the minimal erythema dose (skin types I + II) of which more than 60% is in the interval where the shadow is shorter than its object. DISCUSSION: The shadow rule (short shadows--seek shade) is simple and universal and children can be taught it. A rule of thumb is: when shadows are shorter than objects throwing them, avoid direct sunlight, when shadow and object are of equal length restrict sun exposure to half an hour, and when shadows are twice the length of objects an hour in the sun is permissible.

32
UI - 12143158
AU - Sales F; Bourgeois P; Verdebout JM
TI - [Role of sentinel node biopsy in the management of melanoma]
SO - Rev Med Brux 2002 Jun;23(3):A176-9
AD - Service de Chirurgie, Institut J. Bordet, U.L.B.

33
UI - 11757453
AU - Hauschild A; Eiling S; Lischner S; Haacke TC; Christophers E
TI - [Safety margins in the excision of primary malignant melanoma. Proposals based on controlled clinical trials]
SO - Hautarzt 2001 Nov;52(11):1003-10
AD - Universitats-Hautklinik Kiel. ahauschild@dermatology.uni-kiel.de
Excisional biopsy is recommended as the procedure of choice whenever there is suspicion of malignant melanoma. Incisional biopsies are only rarely indicated. For nearly seventy years the debate about the optimum resection safety margin around the primary tumor was influenced by historical case reports and paradigms. Recently, controlled clinical studies have provided new insights. Accumulating evidence over the last two decades shows that narrower surgical margins influence neither the rate of satellites or in-transit-metastases nor the occurrence of advanced metastatic disease. Local recurrence is rare (approx. 0.1%) when primary tumors are thin and is seen more often (approx. 10%) in primary tumors of greater thickness (> 4 mm). Analysis of the overall survival in randomized trials shows equal prognosis for malignant melanoma for narrow and wide resection margins. Due to these findings in-toto excisional biopsy for in-situ melanoma, a resection margin of 1 cm for thin primary tumors (< 1 cm tumor thickness) and a resection margin of 1 to 2 cm for primary tumors greater than 1 mm appears sufficient. With these recommendations, primary closure of wounds will be possible in nearly all cases, reducing surgical costs and morbidity. This article should serve as a basis of discussion for the proposed revision of the current guidelines of the German Dermatologic Society (DDG) on the primary surgical care of melanoma patients.

34
UI - 12053699
AU - Mohrle M; Breuninger H
TI - [Comment on the contribution by A. Hauschild et al.: "Safety margins in excision of primary malignant melanoma"]
SO - Hautarzt 2002 Apr;53(4):291-2

35
UI - 12133625
AU - Housseau F; Lindsey KR; Oberholtzer SD; Gonzales MI; Boutin P; Moorthy
TI - AK; Shankara S; Roberts BL; Topalian SL Quantitative real-time RT-PCR as a method for monitoring T lymphocyte reactivity to full

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