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Latest Research on Melanoma
     
Crit Rev Oncol Hematol. 2008 Feb 7 [Epub ahead of print]
Dendritic cell vaccines in melanoma: From promise to proof?
Lesterhuis WJ, Aarntzen EH, De Vries IJ, Schuurhuis DH, Figdor CG, Adema GJ, Punt CJ.
Department of Medical Oncology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

Dendritic cells (DC) are the directors of the immune system, capable of inducing tumour antigen-specific T- and B-cell responses. As such, they are currently applied in clinical studies in cancer patients. Early small clinical trials showed promising results, with frequent induction of anti-cancer immune reactivity and clinical responses. In recent years, additional trials have been carried out in melanoma patients, and although immunological responses are often reported, objective clinical responses remain anecdotal with objective response rates not exceeding 5-10%. Thus, DC vaccination research has now entered a stage in between 'proof of principle' and 'proof of efficacy' trials. Crucial questions to answer at this moment are why the clinical responses remain scarce and what can be done to improve the efficacy of vaccination. The answers to these questions probably lie in the preparation and administration of the DC vaccines. Predominantly, cytokine-matured DC are used in clinical studies, while from preclinical studies it is evident that DC that are activated by pathogen-associated molecules are much more potent T cell activators. For sake of easy accessibility monocyte-derived DC are often used, but are these cells also the most potent type of DC? Other yet unsettled issues include the optimal antigen-loading strategy and route of administration. In addition, trials are needed to investigate the value of manipulating tolerizing mechanisms, such as depletion of regulatory T cells or blockade of the inhibitory T cell molecule CTLA-4. These issues need to be addressed in well-designed comparative clinical studies with biological endpoints in order to determine the optimal vaccine characteristics. DC vaccination can then be put to the ultimate test of randomized clinical trials. Here, we review the immunobiology of DC with emphasis on the different aspects that are most relevant for the induction of anti-tumour responses in vivo. The different
variables in preparing and administering DC vaccines are discussed in this context and the immunological and clinical results of studies with DC vaccines in melanoma patients are summarized.

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Dermatol Surg. 2008 Feb 6 [Epub ahead of print]
Mohs Micrographic Surgery is Accurate 95.1% of the Time for Melanoma In Situ: A Prospective Study of 167 Cases.
Bene NI, Healy C, Coldiron BM.
The Skin Cancer Center, Cincinnati, Ohio, USA.

BACKGROUND Mohs micrographic surgery (MMS) represents a promising option for treatment of melanoma in situ (MIS). However, interpretation of melanocytic lesions by fresh frozen sections may be difficult. OBJECTIVE The objective of this study was to determine if margins called clear by MMS were clear by subsequent paraffin-embedded sections and to compare cure rate with available data for MMS and standard excision. MATERIALS AND METHODS A total of 167 patients with MIS, including 116 patients with MIS in sun-exposed skin of lentigo maligna (LM) type, were treated by MMS with subsequent evaluation of the final margin with paraffin-embedded sections that were cut en face, over a period of 12 years. A total of 143 patients were available for follow-up from 6 months to 12 years (mean, 50 months; median 48 months; 594.5 patient-years), and 109 patients were available for follow-up from 2 to 12 years (mean, 63 months; median, 60 months; 569 patient-years). RESULTS The clearance rate by MMS technique using frozen sections was 94.1% for MIS non-LM type, 95.7% for MIS LM type, and 95.1% for both. The cure rate was 97.8% for MIS non-LM type, 99.0% for MIS LM type, and 98.6% for both for mean follow-up of 50 months and 97.4% for MIS non-LM type, 98.6% for MIS LM type, and 98.2% for both for mean follow-up of 63 months. CONCLUSION MMS is a viable option for treatment of MIS that may increase cure rate and reduce the size of the defect especially in cosmetically and functionally sensitive areas.

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Cancer. 2008 Feb 7 [Epub ahead of print]
Adjuvant radiotherapy for cutaneous melanoma.
Mendenhall WM, Amdur RJ, Grobmyer SR, George TJ Jr, Werning JW, Hochwald SN, Mendenhall NP.
Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, Florida.

The purpose of the current study was to discuss the efficacy of adjuvant radiotherapy (RT) in the treatment of melanoma by reviewing the pertinent literature. The risk of locoregional recurrence after surgery alone for locally advanced melanoma is relatively high. The likelihood of a positive sentinel lymph node biopsy (SLNB) exceeds 20% for melanomas >2 mm thick and approximately >/=20% of those patients with positive SLNB will be found to have residual positive lymph nodes on completion lymph node dissection. Patients with positive regional lymph nodes have an approximately >/=20% risk of regional recurrence after surgery alone, particularly if multiple lymph nodes are involved and/or extracapsular extension is present. Postoperative adjuvant RT results in locoregional control rates of 85% to 90% or higher in high-risk patients with a modest risk of complications. The impact of adjuvant RT on survival is likely minimal. Cancer 2008. (c) 2008 American Cancer Society.

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J Clin Oncol. 2008 Feb 1;26(4):535-41.
Improved survival after lymphadenectomy for nodal metastasis from an unknown primary melanoma.
Lee CC, Faries MB, Wanek LA, Morton DL.
Roy E. Coats Research Laboratories, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA 90404, USA.

PURPOSE: No primary lesion is identified in 10% to 20% of patients presenting with palpable evidence of regional metastatic melanoma. Because the prognostic significance of unknown primary melanoma (MUP) is unclear, we compared clinical outcomes of patients with MUP and known primary melanoma (MKP) with regional nodal metastases. PATIENTS AND METHODS: We reviewed our 13,000-patient prospective melanoma database (1971 through 2005) to identify patients managed with regional lymphadenectomy for palpable nodal metastases from MUP or MKP. Multivariate analysis identified prognostic factors significant for survival. MUP and MKP were then matched by significant covariates. Overall survival (OS) was estimated by Kaplan-Meier method and compared by log-rank analysis. Results: Multivariate analysis of data from 1,571 study patients identified four significant covariates associated with worse prognosis: age >or= 60 years (hazard ratio [HR] = 1.294; P = .0017), male sex (HR = 1.335; P = .0004), nodal tumor burden >or= one (HR = 1.256; P < .0001), and known primary (HR = 1.507; 95% CI, 1.220 to 1.862; P = .0001). Five-year OS was significantly higher for 262 patients with MUP than for 1,309 patients with MKP (55% +/- 6% v 44% +/- 3%; P = .0021). Computerized matching of MUP and MKP by four significant covariates (age, sex, nodal tumor burden, and decade of diagnosis) yielded 221 matched pairs. Median and 5-year OS rates were 165 months and 58% +/- 7%, respectively, for MUP as compared with 34 months and 40% +/- 7%, respectively, for MKP (P = .0006). CONCLUSION: Lymphadenectomy is effective for nodal metastasis from MUP. The significantly better postoperative survival for MUP versus MKP suggests a strong endogenous immune response against the primary melanoma. Immunologic studies to identify cell-mediated and antibody components of this response may lead to new approaches for determining melanoma prognosis and treatment.

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Melanoma Res. 2008 Feb;18(1):16-21.
Postoperative morbidity of lymph node excision for cutaneous melanoma-sentinel lymphonodectomy versus complete regional lymph node dissection.
Kretschmer L, Thoms KM, Peeters S, Haenssle H, Bertsch HP, Emmert S.
aDepartment of Dermatology, Georg August University of Göttingen, Göttingen bDermatologic Clinic Krefeld, Krefeld, Germany.

For patients with melanoma metastasis to a sentinel lymph node, subsequent complete regional lymph node dissection (CLND) is currently regarded to be the surgical standard. This approach, however, has not been confirmed by controlled studies, so that surgical morbidity is of primary importance. Using clinical examination and a questionnaire, we determined morbidity in 315 patients with axillary or inguinal lymph node excision on whom 275 sentinel lymphonodectomies (SLNEs) and 90 CLNDs were performed. The overall incidence of at least one complication following SLNE was 13.8%. The short-term complication rate was 11.3% (allergic reaction to blue dye 0%, wound breakdown 0%, haematoma 2.5%, wound infection 3.6%, seroma 6.9%). The incidence of long-term complications was 4.1% (persistent tattoo 0.4%, functional deficit 0.4%, nerve dysfunction/pain 0.7% or swelling 2.5%). All complications were mild. Significantly, the complication rate was not higher for patients aged 70 years or older. After CLND, the overall complication rate was significantly higher (65.5%, P<0.000001). The incidence of short-term complications was 50% (haematoma 0%, wound breakdown 6.7%, wound infection 24.7% or seroma 34.8%). The incidence of long-term complications was also 50% (nerve dysfunction/pain 8.9%, functional deficit 16.8%, swelling 37.1%). Overall, inguinal lymph node excision was burdened by a higher complication rate (P=0.015). Age and sex did not influence postoperative morbidity. No deaths linked to either procedure were noted. Complication rates after SLNE are low and most complications are minor and short-lasting. In contrast, CLND has been demonstrated to be a major and potentially morbid surgical procedure. This highlights the importance of testing the therapeutic value that CLND adds to the sentinel lymph node procedure.

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Cancer Treat Rev. 2008 Jan 26 [Epub ahead of print]
Targeted therapy for uveal melanoma.
Triozzi PL, Eng C, Singh AD.
Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH, United States.

Uveal melanoma is the most common primary intra-ocular malignancy in adults. Overall mortality rate remains high because of the development of metastatic disease, which is highly resistant to systemic therapy. Improved understanding of the molecular pathogenesis of cancers has led to a new generation of therapeutic agents that interfere with a specific pathway critical in tumor development or progression. Although no specific genes have been linked to the pathogenesis of uveal melanoma, which differs from that of cutaneous melanoma, progress has been made in identifying potential targets involved in uveal melanoma apoptosis, proliferation, invasion, metastasis, and angiogenesis. This review focuses on the prospects for improving the systemic therapy of uveal melanoma using molecularly targeted agents that are currently in clinical use as well as agents being tested in clinical trials. Preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases. Modifiers of adhesion molecules, matrix metalloproteinase, and angiogenic factors also have demonstrated potential benefit. Clinical trials of some of these approaches have been initiated in patients with metastatic uveal melanoma as well as in the adjuvant setting after primary therapy.

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Ann Oncol. 2008 Jan 4 [Epub ahead of print]
Temozolomide plus pegylated interferon alfa-2b as first-line treatment for stage IV melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology Group (DeCOG).
Spieth K, Kaufmann R, Dummer R, Garbe C, Becker JC, Hauschild A, Tilgen W, Ugurel S, Beyeler M, Bröcker EB, Kaehler KC, Pföhler C, Gille J, Leiter U, Schadendorf D.
Department of Dermatology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.

BACKGROUND: Combination of temozolomide (TMZ) with nonpegylated interferon alfa is associated with increased efficacy in terms of response rates compared with monotherapy. A multicenter phase II study was carried out to assess the activity and toxicity of TMZ plus pegylated interferon alfa-2b (peg-IFNalpha-2b), hypothesizing improved efficacy due to modified pharmacokinetic properties of the novel interferon (IFN) formulation. PATIENTS AND METHODS: In all, 124 patients with stage IV melanoma without prior chemotherapy and no cerebral metastases were treated with 100 mug peg-IFNalpha-2b s.c. per week and oral TMZ 200 mg/m(2) (days 1-5, every 28 days). Primary study end point was objective response, and secondary end points were overall and progression-free survival (PFS) and safety. RESULTS: In all, 116 patients were assessable for response: 2 (1.7%) had a complete response and 19 (16.4%) a partial response (overall response rate 18.1%). Of total, 25.0% achieved disease stabilization and 56.9% progressed. Overall survival was 9.4 months; PFS was 2.8 months. Grade 3/4 thrombocytopenia occurred in 20.7% and grade 3/4 leukopenia in 23.3%. CONCLUSIONS: The efficacy of TMZ plus peg-IFNalpha-2b in this large phase II study is moderate and comparable to published results of the combination of TMZ with non-peg-IFN. Likewise, the safety profile of peg-IFNalpha-2b seems to be similar to non-peg-IFN when combined with TMZ.

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J Clin Oncol. 2008 Jan 1;26(1):66-75.
Survival for patients with invasive cutaneous melanoma among ethnic groups: the effects of socioeconomic status and treatment.
Zell JA, Cinar P, Mobasher M, Ziogas A, Meyskens FL Jr, Anton-Culver H.
Division of Hematology/Oncology, Department of Internal Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine 92697, USA. jzell@uci.edu

PURPOSE: Although uncommon, melanoma is associated with poor survival characteristics among African Americans and Hispanics compared with non-Hispanic whites (NHWs). Low socioeconomic status (SES) is also associated with poor survival among patients with melanoma, but it is not known whether this is because of SES itself or because of treatment disparities. We set out to determine this by using the large, population-based California Cancer Registry (CCR) database as a model. PATIENTS AND METHODS: We conducted a case-only analysis of CCR data (1993 to 2003), including a descriptive analysis of relevant clinical variables and SES. The SES variable used has been derived from principle component analysis of census block-level CCR data that was linked to census data to address seven indicators of SES. Univariate analyses of overall survival (OS) were conducted using the Kaplan-Meier method. Multivariate survival analyses were performed using Cox proportional hazard ratios (HRs). RESULTS: A total of 39,049 incident patient cases of cutaneous melanoma, including 36,694 in NHWs; 127 in African Americans; 1,996 in Hispanics; and 262 in Asian-Americans, were analyzed. Higher SES was associated with an early stage at presentation (P < .0001), with treatment with surgery (P = .0005), and with prolonged survival (P < .0001). After adjustments for age, sex, histology, American Joint Committee on Cancer stage, anatomic site, treatment, and SES, a statistically significant increased risk of death was observed for African Americans compared with NHWs (HR, 1.60; 95% CI, 1.17 to 2.18); no survival differences were noted for Asians or Hispanics compared with NHWs in the adjusted analysis. CONCLUSION: Low SES independently predicts poor outcome among patients with cutaneous melanoma. However, the poor OS observed for African American patients with melanoma is not explained by differences in treatment or SES.

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J Clin Oncol. 2007 Dec 1;25(34):5426-34.
Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients.
Ives NJ, Stowe RL, Lorigan P, Wheatley K.
Birmingham Clinical Trials Unit, Division of Medical Sciences, Robert Aitken Institute, University of Birmingham, Edgbaston, Birmingham, United Kingdom. n.j.ives@bham.ac.uk

PURPOSE: To assess the effect of adding interferon-alpha (IFN) +/- interleukin-2 (IL-2) to chemotherapy in patients with metastatic melanoma. METHODS A published data meta-analysis of trials of biochemotherapy versus chemotherapy in patients with metastatic melanoma was undertaken. End points evaluated were rates of partial response (PR), complete response (CR) and overall (partial + complete) response (OR); response duration; progression-free survival; overall survival (OS); and toxicity. The only subgroup analysis performed was by type of immunotherapy, with trials divided according to whether IFN only or IFN and IL-2 were administered in the biochemotherapy arm. RESULTS: Eighteen randomized trials were identified: 11 trials of chemotherapy +/- IFN and seven trials of chemotherapy +/- IFN and IL-2. More than 2,600 patients were entered onto the trials, with 555 responses and 2,039 deaths. There was a clear benefit for biochemotherapy for PR (odds ratio = 0.66; 95% CI, 0.53 to 0.82; P = .0001), CR (odds ratio = 0.50; 95% CI, 0.35 to 0.73; P = .0003) and OR (odds ratio = 0.59; 95% CI, 0.49 to 0.72; P < .00001). For OR, these benefits were significant for both the IFN (odds ratio = 0.60; 95% CI, 0.46 to 0.79; P = .0002) and IFN + IL-2 (odds ratio = 0.58; 95% CI, 0.44 to 0.77; P = .0001) subgroups. In contrast, there was no benefit overall in OS (odds ratio = 0.99; 95% CI, 0.91 to 1.08; P = .9), but there was evidence of heterogeneity of treatment effect between the individual trials (P = .006). CONCLUSION: This meta-analysis provides a comprehensive summary of all the data currently available, and shows that although biochemotherapy clearly improves response rates, this does not appear to translate into a survival benefit.

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Melanoma Res. 2007 Dec;17(6):393-399.
Evidence and interdisciplinary consense-based German guidelines: diagnosis and surveillance of melanoma.
Garbe C, Hauschild A, Volkenandt M, Schadendorf D, Stolz W, Reinhold U, Kortmann RD, Kettelhack C, Frerich B, Keilholz U, Dummer R, Sebastian G, Tilgen W, Schuler G, Mackensen A, Kaufmann R.
University Department of Dermatology, Tübingen, and others.

Melanoma is a malignant tumor that arises from melanocytic cells and primarily involves the skin. The most important exogenous etiological factor is exposure to ultraviolet irradiation. Diagnosis of melanoma is based primarily on its clinical features, and the A-B-C-D rule is useful in identifying pigmented lesions, which are suspicious for melanoma (Asymmetry, Border irregular, Color inhomogeneous and Diameter more than 5 mm). Dermoscopy is very helpful in clarifying the differential diagnosis of pigmented lesions. About 90% of melanomas are diagnosed as primary tumors without any evidence for metastasis. The tumor-specific 10-year survival for all such tumors is about 75-85%. The most important prognostic factors for primary melanoma without metastases are vertical tumor thickness (Breslow depth) as measured on the histological specimen, presence of histopathologically recognized ulceration, invasion level (Clark level) and identification of micrometastases in the regional lymph nodes via sentinel lymph node biopsy. The current tumor node metastasis classification for the staging of primary melanoma is based on these factors. Melanomas can metastasize either by the lymphatic or by the hematogenous route. About two-thirds of metastases are originally confined to the drainage area of regional lymph nodes. A regional metastasis can appear as satellite metastases up to 2 cm from the primary tumor, as intransit metastases in the skin between the site of the primary tumor and the first lymph node and as regional lymph node metastases. In the stage of regional metastasis, the differentiation between micrometastasis and macrometastasis and the number of lymph nodes involved are crucial. As soon as distant metastasis develops, prognosis depends on the site of the metastasis and on the lactate dehydrogenase levels in the blood. The frequency and extent of follow-up examinations is based on the initial tumor parameters. In thin primary melanomas up to 1-mm tumor thickness, clinical examinations at 6-month intervals are sufficient and in thicker primary melanomas, at 3-month intervals. Lymph node sonography as well as determination of the tumor marker protein S100beta are recommended. Additionally, in the stage of regional metastasis, whole body imaging should be performed every 6 months; in the stage of distant metastasis, surveillance has to be scheduled individually.

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Melanoma Res. 2007 Dec;17(6):360-364.
Targeted combined anti-inflammatory and angiostatic therapy in advanced melanoma: a randomized phase II trial.
Reichle A, Vogt T, Coras B, Terheyden P, Neuber K, Trefzer U, Schultz E, Berand A, Bröcker EB, Landthaler M, Andreesen R.
Departments of aHematology/Oncology bDermatology, University Hospital Regensburg, Regensburg cDepartment of Dermatology, University Hospital Würzburg, Würzburg dDepartment of Dermatology, University Hospital Hamburg, Hamburg eDepartment of Dermatology, University Hospital Erlangen, Erlangen fDepartment of Dermatology, University Hospital Berlin, Berlin, Germany.

An angiostatic approach was used to assess the impact of anti-inflammatory therapy in combination with metronomic low-dose chemotherapy. A randomized multi-institutional phase II trial was designed to select metronomic chemotherapy (arm A: trofosfamide 50 mg orally three times daily, day 1+) or combined anti-inflammatory/angiostatic treatment (arm B: trofosfamide as above mentioned plus rofecoxib 25 mg orally, day 1+, and pioglitazone 60 mg orally, day 1+) for further evaluation. A total of 76 patients, mostly (>60%) refractory to at least one previous chemotherapy with maximum tolerated doses, and progression of metastatic melanoma were included. The estimated progression-free survival (PFS) rates at one year were 0% for metronomic chemotherapy (A), but 9% for additional anti-inflammatory therapy (B). Vice versa the hazard ratio for the intent-to-treat analysis of A versus B was 1.9 (P=0.008). By Cox analysis, the impact of anti-inflammatory therapy on PFS achieved significance (P=0.016) as well as C-reactive protein response on overall survival (P=0.045). WHO grade 3 (no grade 4) toxicities were reported in arm A/B in 19 and 28%, respectively. In conclusion, control of tumour-associated inflammatory processes (C-reactive protein response) is associated with longer PFS than achieved with metronomic chemotherapy alone in metastatic melanoma.

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J Dtsch Dermatol Ges. 2007 Nov 26 [Epub ahead of print]
Never perform laser treatment of skin tumors with clinical "EFG" criteria.
Giacomel J, Zalaudek I, Mordente I, Nicolino R, Argenziano G.
Mends St Medical Centre, South Perth, Western Australia, Australia.

Laser treatment is a common procedure for the treatment of cosmetically troubling skin lesions but has the limitation that histopathologic diagnosis is usually not obtained prior to treatment. Laser treatment of melanomas with benign clinical features may delay or make more difficult the correct diagnosis of such tumors. A helpful tool to identify clinically innocent appearing melanomas is the "EFG" rule, summarizing the common clinical features as "elevated, firm skin lesions showing continuous growth". We report a 42-year-old woman who presented with a recurrent and metastatic melanoma after laser treatment of a tumor which was apparently clinically innocent and highlight the clinical features of such benign-looking melanomas.

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Plast Reconstr Surg. 2007 Nov;120(6):1533-9.
A face lift approach for sentinel node biopsy in head and neck melanoma patients.
Venturi ML, Davison SP.
Department of Plastic Surgery, Georgetown University Medical Center, Washington, DC, USA.

BACKGROUND: Management of head and neck melanoma has changed dramatically with the use of sentinel node biopsy for staging. Nodal dissection may now be delayed or deferred based on the results of the sentinel node biopsy. The authors suggest using a face lift incision to access the nodal basins for sentinel node biopsy in head and neck melanoma. METHODS: A face lift incision was used successfully for sentinel node biopsy in 21 patients. The diagnosis of melanoma, histologic subtype, and depth of penetration were established by biopsy with permanent sections. All patients underwent lymphoscintigraphy on the morning of their surgery. If the scan showed multiple nodes at various levels of the neck or parotid, the patient was selected for a face lift incision for biopsy. RESULTS: The study comprised 14 men and seven women between the ages of 26 and 82 years (mean age, 55 years). The sites of melanoma included the temple in six patients, cheek in five, neck in four, and ear and scalp in two patients each. The average Clark's level and Breslow depth were 3.67 and 1.76 mm, respectively. The average number of basins involved was 2.14; the average number of nodes was 3.33, with an average of 1.56 nodes per basin. Follow-up ranged from 2 to 53 months (average, 26 months). Only two patients had sentinel nodes that were positive for metastatic melanoma. One complication, a transient paresis of the right marginal mandibular nerve, was observed. CONCLUSIONS: Using a face lift incision for sentinel node biopsy in head and neck melanoma is a safe, reliable technique. It provides excellent access to multiple nodal basins, well-concealed incisions, wide exposure for delayed therapeutic nodal dissection, and local and regional flap options for reconstructing the excision site.

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Cancer Chemother Pharmacol. 2007 Nov 17 [Epub ahead of print]
Safety and anti-tumor activity of sorafenib (Nexavar((R))) in combination with other anti-cancer agents: a review of clinical trials.
Takimoto CH, Awada A.
South Texas Accelerated Research Therapeutics (START), 4319 Medical Drive, Suite 205, San Antonio, TX, 78229, USA, takimoto@start.stoh.com.

PURPOSE: Sorafenib (Nexavar((R))) is an oral multi-kinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. Sorafenib has demonstrated preclinical and clinical activity against several tumor types, as a monotherapy and in combination with other anti-cancer agents. METHODS: This review summarizes the safety, pharmacokinetics, and anti-tumor activity of sorafenib combined with other targeted agents or cytotoxics from a series of Phase I/II trials in approximately 600 patients with advanced solid tumors. RESULTS: Sorafenib in combination with other agents was generally well tolerated, and most adverse events were mild to moderate in severity. Frequent drug-related toxicities were dermatologic, gastrointestinal, or constitutional. Most trials supported sorafenib 400 mg bid as the recommended dose for combination. Sorafenib generally had little effect on the pharmacokinetics of coadministered agents and vice versa. Preliminary anti-tumor activity was observed; overall disease control rates (partial response plus stable disease) ranged from 33 to 92%. Particularly promising activity was observed in patients with melanoma, hepatocellular carcinoma, and non-small-cell lung cancer receiving sorafenib plus paclitaxel/carboplatin, doxorubicin, and gefitinib, respectively. CONCLUSIONS: Sorafenib demonstrated a good safety profile and encouraging anti-tumor effects when coadministered with other agents in patients with advanced solid tumors.

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J Am Acad Dermatol. 2007 Oct 26 [Epub ahead of print]
Staged excision for lentigo maligna and lentigo maligna melanoma: A retrospective analysis of 117 cases.
Hazan C, Dusza SW, Delgado R, Busam KJ, Halpern AC, Nehal KS.
From the Departments of Dermatology.

BACKGROUND: Complete surgical excision for lentigo maligna (LM) and LM melanoma (LMM) in the head and neck region may be challenging because of potential significant subclinical extension. OBJECTIVE: We sought to review clinical and histologic features of LM and LMM and determine surgical margin necessary for complete excision. METHODS: We conducted a retrospective study of 117 LM and LMM cases treated with a staged margin-controlled excision technique with rush paraffin-embedded sections. RESULTS: The mean total surgical margin required for excision of LM was 7.1 mm and was 10.3 mm for LMM. Of the tumors diagnosed as LM on initial biopsy specimen, 16% were found to have unsuspected invasion. Total surgical margin was associated with initial clinical lesion diameter. LIMITATIONS: Retrospective and single-institution experience are limitations. CONCLUSION: This study corroborates that the standard excision margins for LM and LMM are often inadequate and occult invasive melanoma occurs in LM. An excision technique with permanent sections using a team of dermatopathology and surgery that carefully examines the central tumor and the surgical margins is reliable for the treatment of LM and LMM.

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Ann Surg Oncol. 2007 Aug 7; [Epub ahead of print]
Stage-IV Melanoma and Pulmonary Metastases: Factors Predictive of Survival.
Neuman HB, Patel A, Hanlon C, Wolchok JD, Houghton AN, Coit DG.
Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Room H1221, New York, New York, 10021, USA, coitd@mskcc.org.

BACKGROUND: We reviewed a contemporary, single-institution experience to evaluate the natural history of stage-IV melanoma metastatic to the lung and identify factors predictive of survival. METHODS: A search of our prospective database was performed to identify patients with stage-IV melanoma and pulmonary metastases as the initial disease site; only patients seen at our institution prior to developing stage-IV disease and in whom treatment response was available were included. Patients' demographic, clinical, and treatment variables were recorded. Cox regression was used to identify factors independently predictive of survival. RESULTS: The study cohort was comprised of 122 patients. Median survival was 14 months (5-year survival of 8%). Clinical factors at time of diagnosis of stage IV independently predictive of survival were a solitary pulmonary metastasis (HR 2.7, CI 1.6-4.4, P<0.0005) and absence of extra-pulmonary disease (HR 1.9, CI 1.2-3.1, P = 0.01). Among treatmen
t factors, only metastasectomy was independently predictive of survival (HR 0.42, CI 0.21-0.87, P = 0.02). Of the patients, 26 (21%) underwent metastasectomy, with a median survival of 40 months compared with 13 months in patients not selected for surgical treatment. Of these 26, 23 (88%) experienced recurrence at a median of 5 months after the procedure. No survival difference was seen between responders and non-responders to systemic therapy (P = 0.55). CONCLUSIONS: In stage-IV melanoma with pulmonary metastases, a solitary metastasis and absence of extra-pulmonary disease are predictive of survival. While these factors are often present in patients selected for pulmonary metastasectomy, this independently predicts survival. However, response to systemic therapy does not correlate with a survival difference.

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Ann Surg Oncol. 2007 Aug 1; [Epub ahead of print]
Pelvic Lymph Node Dissection Is Beneficial in Subsets of Patients with Node-positive Melanoma.
Badgwell B, Xing Y, Gershenwald JE, Lee JE, Mansfield PF, Ross MI, Cormier JN.
Department of Surgical Oncology, Unit 444, The University of Texas M. D. Anderson Cancer Center, 1400 Holcombe Boulevard, P.O. Box 301402, Houston, Texas, 77030-1402, USA, jcormier@mdanderson.org.

BACKGROUND: The benefits of deep pelvic lymph node dissection (DLND) for patients with node-positive melanoma continue to be debated. The objective of our analysis was to identify factors associated with involvement of pelvic nodes and to determine survival outcomes following DLND. METHODS: We retrospectively reviewed the records of 804 patients who had undergone any type of lymph node dissection between 1990 and 2001. Logistic regression was performed to identify factors associated with tumor metastasis to pelvic nodes. Associations between clinicopathological factors and survival outcomes were estimated using the Cox proportional hazards model. RESULTS: Of the 804 patients, 235 underwent superficial lymph node dissection (SLND) and 97 underwent combined SLND and DLND (combined LND). Age >/=50 years, number of positive superficial nodes, and positive radiological imaging findings were found to be predictors of metastasis to deep nodes. With a median follow-up of 7.5 years, 5-year overall survival (OS) was 42% for patients with positive deep nodes and 51% for those with negative deep nodes (P = 0.11). OS in patients with melanoma that metastasized to three or fewer deep pelvic lymph nodes is comparable to that in patients with no deep nodal involvement. Multivariate analysis identified number of positive deep nodes, male gender, and extra-capsular extension as independent adverse prognostic factors for OS. CONCLUSIONS: These relatively favorable survival outcomes support current surgical practice and the classification of metastatic pelvic nodal disease as stage-III rather than stage-IV (distant) disease.

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Obstet Gynecol. 2007 Aug;110(2):296-301.
Vulvar Melanoma: A Multivariable Analysis of 644 Patients.
Sugiyama VE, Chan JK, Shin JY, Berek JS, Osann K, Kapp DS.
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine, University of California, San Francisco Comprehensive Cancer Center, San Francisco, California; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Department of Radiation Oncology, Stanford University School of Medicine, Stanford Cancer Center, Stanford, California; and Division of Hematology/Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, Orange, California.

OBJECTIVES: To determine the prognostic factors associated with the survival of vulvar melanoma patients. METHODS: Data were obtained from the Surveillance Epidemiology and End Results database from 1973 to 2003. Kaplan-Meier survival curves and Cox regression models were used for analysis. RESULTS: Of the 644 vulvar melanoma patients, the median age was 68 years. Of these 572 women were white, 28 were Hispanic, 18 were African-American, and 14 were Asian. A total of 302 had localized disease, 168 had regional disease, and 28 had distant disease. Of the participants who underwent surgical resection, 171 (26.6%) had conservative surgery, 164 (25.5%) had radical excision, and 241 (37.5%) had unspecified surgical resections. One hundred seventy-nine (27.8%) had lymph node resections, and 33 patients had concurrent radiation therapy. Nodal metastases were identified in 58 (9%) of the participants. The 5-year disease-specific survival rates for those with localized, regional, and
distant disease were 75.5%, 38.7%, and 22.1%, respectively (P<.001). Women aged 68 years or younger had a better survival rate than older patients (72.0% compared with 47.7%; P<.001). Those with 0, 1, and 2 or more positive lymph nodes had survival rates of 68.3%, 29%, and 19.5%, respectively (P<.001). In a multivariable analysis, younger age, localized disease, and negative lymph nodes were independent prognostic factors for improved survival. CONCLUSION: Age, stage, and lymph node involvement were significant factors for survival in vulvar melanoma. LEVEL OF EVIDENCE: III.

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Melanoma Res. 2007 Aug;17(4):225-31.
A pilot study of low-dose thalidomide and interferon alpha-2b in patients with metastatic melanoma who failed prior treatment.
Solti M, Berd D, Mastrangelo MJ, Sato T.
aDivision of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania bNorthwest Cancer Specialists, Vancouver, Washington, USA.

Melanoma is a hypervascular tumor and angiogenesis plays a critical role in the development/progression of metastases. As various pathways are involved in tumor angiogenesis, a combination of agents with different antiangiogenesis activities is a reasonable approach. To determine the efficacy and toxicity of combination treatment with low-dose thalidomide and low-dose interferon (IFN) in patients with stage IV melanoma who failed prior treatment(s), fifteen patients with metastatic melanoma (nine cutaneous, six uveal) received oral thalidomide (200 mg daily) with subcutaneous interferon (IFN)-alpha2b (3 MIU, 3x/week). Stabilization or regression of metastases (as evidenced by computed tomographic measurement) was the primary endpoint of the study. Patients were evaluated monthly for toxicity and every 2 months for clinical response. At a median follow-up of 22.8 months (range, 12-32 months), one patient with metastatic cutaneous melanoma achieved partial response, three patie
nts achieved stable disease (one uveal, two cutaneous), nine patients progressed, and two were not evaluable. The time to progression was 6 months for the patient with partial response, and 2, 5.5+ and 11 months for three patients with stable disease. The estimated median overall survival was 4.7 months (confidence interval, 2.2-9.9 months; range, 0.9-31.5 months), and median progression-free survival was 1.8 months (confidence interval, 1.5-3.0 months; range, 0.5-14 months). Grade 3 toxicities related to treatment included neutropenia (n=5), elevation of transaminases (n=2), and neuropathy (n=1). No treatment-related deaths were experienced. Thalidomide+IFN is a safe and tolerable palliative treatment for previously treated stage IV melanoma.

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Vaccine. 2007 Jul 5; [Epub ahead of print]
Vaccine therapy for melanoma: Current status and future directions.
Terando AM, Faries MB, Morton DL.
John Wayne Cancer Institute at Saint John's Health Center, 2200 Santa Monica Boulevard, Santa Monica, CA 90404, United States.

A vaccine is typically defined as any preparation used as a preventive inoculation to confer immunity against a specific disease. Vaccines for infectious diseases are highly effective, acting by inducing antigen-specific immunity that prevents subsequent infection. Unfortunately, the success of vaccines in infectious diseases has not been mirrored in oncology. This failure is the result of several challenges facing cancer vaccines, including the conceptual shift from disease prevention to disease treatment, tumor-induced immunosuppression and other mechanisms of immune escape, the similarity between tumor antigens and self antigens to which the patient is tolerant, unfavorable effector-to-target ratios in patients with established tumors, and financial and regulatory issues. Despite this, cancer remains a promising target for vaccine therapy. Melanoma in particular is known for its inherent immunogenicity on the basis of many anecdotal reports of spontaneous immune-based tumo
r regression, and thus has been the focus of immunotherapeutic approaches. Rare but significant vaccine-induced clinical regression of melanoma has spurred intensive investigations to augment vaccine efficacy. This review explores the many vaccine strategies that have been clinically tested for the treatment of melanoma and considers future approaches of cancer immunotherapy.

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Cancer. 2007 Jul 10; [Epub ahead of print]
Biochemotherapy of metastatic melanoma in patients with or without recently diagnosed brain metastases.
Majer M, Jensen RL, Shrieve DC, Watson GA, Wang M, Leachman SA, Boucher KM, Samlowski WE.
Multidisciplinary Melanoma Program, Huntsman Cancer Institute, Salt Lake City, Utah.

BACKGROUND.: Brain metastases are an alarming complication of advanced melanoma, frequently contributing to patient demise. The authors performed a retrospective analysis to determine whether the treatment of metastatic melanoma with biochemotherapy would result in similar outcomes if brain metastases were first controlled with aggressive, central nervous system (CNS)-directed treatment. METHODS.: Seventy melanoma patients were treated with biochemotherapy for metastatic melanoma between 1999 and 2005. Of these, 20 patients had recently diagnosed brain metastases, whereas 50 did not. Brain metastases (if present) were treated with stereotactic radiosurgery >/=28 days prior to systemic therapy. All patients were treated with biochemotherapy consisting of either dacarbazine or temozolomide in combination with a 96-hour continuous intravenous infusion of interleukin-2 and subcutaneous interferon-alpha-2B. The primary endpoint was survival from the time of the initial diagnosis o
f metastatic disease. RESULTS.: Median survival from the time of the diagnosis of metastatic melanoma was 15.8 months for patients with brain metastases and 11.1 months for those without CNS involvement (P = .26 by the log-rank test; P = .075 by the Gehan Wilcoxon test). Dacarbazine-based and temozolomide-based regimens appeared similar with regard to their effect on overall survival and CNS disease progression. A plateau in further brain recurrences was observed in patients who survived for > 20 months. CONCLUSIONS.: Data from the current study suggest that the outcome of biochemotherapy is comparable in patients with and those without brain metastases, if brain metastases are controlled with multidisciplinary treatment. Prolonged survival can be achieved in approximately 15% of patients, regardless of whether or not brain metastases are present. Cancer 2007. (c) 2007 American Cancer Society.

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Cancer Biother Radiopharm. 2007 Jun;22(3):309-21.
Patient-specific vaccines derived from autologous tumor cell lines as active specific immunotherapy: results of exploratory phase I/II trials in patients with metastatic melanoma.
Dillman RO, DePriest C, DeLeon C, Barth NM, Schwartzberg LS, Beutel LD, Schiltz PM, Nayak SK.
Hoag Cancer Center, Newport Beach, CA 92658, USA. rdillman@hoaghospital.org

Seventy-four (74) patients with metastatic melanoma were treated with patient-specific vaccines derived from autologous tumor cell lines. Cryopreserved irradiated tumor cells were injected weekly for 3 weeks, then monthly for 5 months. At a median follow up >6 years, the median event-free survival (EFS) was 4.5 months, with 13 patients alive and progression free 6-12 years later. Median overall survival (OS) was 20.5 months, with 29% 5-year OS. Tumor response rate was 9% among the 35 patients with evaluable disease who received at least 3 injections. Better survival was observed for patients who had minimal rather than clinically evident metastatic disease at the time vaccine therapy was initiated (5-yr OS 47% vs. 13%; p < 0.0001), received granulocyte-macrophage colony-stimulating factor and/or interferon gamma as an adjuvant (5-yr EFS 26% vs. 0%; p < 0.0001) or received an average of <7 million cells for each of the first 3 injections, compared to those who received 7-11.9
million or >12 million cells per injection (5-yr EFS OS 35% vs. 24%; p = 0.041 and p = 0.034). There was a trend toward better EFS for those who had a positive delayed type hypersensitivity (DTH) reaction to an intradermal injection of 1 million irradiated tumor cells at baseline, or converted to positive after 3 injections, compared to those whose DTH remained negative (5-yr EFS 39% vs. 18%; p = 0.159). This treatment approach is feasible, produces minimal toxicity, and is associated with longterm survival in a significant proportion of patients.

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J Drugs Dermatol. 2007 Apr;6(4):374-8.
Cytokine therapy in advanced melanoma.
Kalaaji AN.
Department of Dermatology, Mayo Clinic, Rochester, MN 55905, USA.

Patients with melanoma considered at high risk for recurrence or regional metastases often have to choose between adjuvant interferon therapy or enrolling in a clinical trial. High-dose interleukin-2 therapy has had limited success in producing durable responses in stage IV melanoma; this success has been offset by marked toxicity. High-dose interferon alpha therapy has consistently shown disease-free survival benefit in clinical trials but has marked toxicity. The overall survival benefit has been inconsistent and controversial. Treatment with granulocyte macrophage colony-stimulating factor has shown promise in early studies. Various cytokines have had some success in treating advanced stage melanoma but with marked toxicity. Cytokine therapy that is well-tolerated and consistently provides an overall survival benefit for high-risk melanoma patients has not been achieved. Cytokines will continue to have a role in therapy for advanced-stage melanoma, most likely in combination with other immunomodulatory therapy. The challenge is finding the right doses, frequency, combinations, and duration of treatment.

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Eur J Gynaecol Oncol. 2007;28(3):220-4.
Management of vulvar melanoma and review of the literature.
Suwandinata FS, Bohle RM, Omwandho CA, Tinneberg HR, Gruessner SE.
Department of Obstetrics and Gynecology, Justus-Liebig-University of Giessen, Giessen, Germany.

BACKGROUND: Vulvar melanoma represents a rare group of malignancies and is the second most common vulvar malignancy. Treatment options range from local excision of the tumor and sentinel lymph node dissection to radical resection involving en bloc vulvectomy and inguinofemoral lymphanedectomy. Vulvar melanomas have an overall poor prognosis, and there is lack of consensus in the published literature regarding treatment options. OBJECTIVE: To discuss the management of vulvar melanomas through review of the actual literature. METHODS: Identification of studies through computerized searches (January 2006) was conducted using MEDLINE (1966 to present), the Cochrane Central Register of Controlled Trials, the National Research Register and the Medical Research Council's Clinical Trials Register. The medical subject headings and text words used were: vulvar melanoma, malignant, management, case report, and therapy. The literature review was done over the past 36 years. RESULT: Results of these primary retrospective series have shown no improvement in the overall recovery or disease survival rates. CONCLUSION: Patients with malignant melanoma are often diagnosed at 70 years of age with multiple comorbidities. Less radical surgery presents a more realistic option for many patients without decreasing their survival rates. Surgery is still the gold standard of treatment and offers the best available treatment for controlling and potential curing of malignant melanomas. However, the whole concept of therapy should be tailored to meet the specific needs of individual patients.

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Ann Surg. 2007 Apr;245(4):591-596.
Long-term Results of Hyperthermic, Isolated Limb Perfusion for Melanoma: A Reflection of Tumor Biology.
Sanki A, Kam PC, Thompson JF.
>From the *Sydney Melanoma Unit, Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia; daggerDepartment of Anesthetics, University of Sydney, Royal Prince Alfred Hospital, Sydney, NSW, Australia; and double daggerDiscipline of Surgery, University of Sydney, Sydney, NSW, Australia.

PURPOSE:: To review the long-term duration of limb tumor complete remission (CR) and patient survival following therapeutic hyperthermic isolated limb perfusion (ILP) with cytotoxic drugs for melanoma. METHODS:: A retrospective case series of 124 ILPs performed in 111 patients. RESULTS:: There were 120 assessable ILPs. Patient staging (M.D. Anderson system) was stage II 11.7%, stage IIIA 44.2%, stage IIIAB 33.3%, and stage IV 10.8%. CR was initially attained after 83 ILPs (69.2%) and partial remission (PR) after 19 ILPs (15.8%). Limb CR was maintained in 28 (33.7%) of the 83 cases. Disease recurred in the perfused limb after an initial CR in the remaining 55 cases (median time to recurrence, 11 months); in 19 of these cases, the limb was disease-free at last follow-up after further locoregional treatment. A long-term CR was achieved, with or without further treatment, in 47 (56.6%) of the 83 cases in which an initial CR had occurred (mean follow-up, 97 months; median, 65 months). There was no significant difference in long-term local remission for stage IIIA and IIIAB patients. Five-year survival for those who had a partial or no response to ILP was 7%. Ten-year survival for those who had a long-term CR was 49%. CONCLUSIONS:: ILP, with or without further locoregional treatment, achieved long-term control of recurrent and metastatic limb disease in 56.6% of cases in which an initial CR was achieved. A complete response to ILP was a positive prognostic indicator for survival, probably reflecting more favorable tumor biology in this subset of patients.

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J Eur Acad Dermatol Venereol. 2007 Apr;21(4):439-51.
Photodynamic therapy: update 2006 Part 2: Clinical results.
Calzavara-Pinton P, Venturini M, Sala R.
Department of Dermatology, Azienda Ospedaliera Spedali Civili and University of Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy.

In several randomized, controlled studies, the application of a standard preparation containing methyl-aminolevulinate (MAL; Metvix(R), Galderma, F), followed by red light irradiation proved effective and well tolerated in the treatment of actinic keratosis and basal cell carcinoma, and has now been approved for clinical use in European countries. A brand name aminolevulinic acid (ALA) solution (Levulan Kerastick(R), Dusa Pharmaceuticals Inc., Wilmington, MA) plus blue light exposure has been approved for the treatment of actinic keratosis in the USA. Randomized and controlled studies have shown that MAL as well as ALA are also effective in the treatment of Bowen's disease. In addition, a large and growing number of open studies or case reports have evaluated its use in the treatment of a broad range of other neoplastic, inflammatory and infectious skin diseases. However, efficacy and definite advantages over standard therapies remain to be clarified because the experimental design of these studies was often poor, the number of enrolled patients was generally low, and the follow-up was shorter than 12 months. However, these studies have suggested a few possible clinical applications worthy of further investigation. A growing number of laboratory and clinical findings suggest that several new synthetic sensitizers, besides ALA and MAL, may be helpful in the treatment of non-melanoma skin cancers, melanoma metastasis, and selected inflammatory and infective skin diseases. These compounds are deliverable intravenously, have short half-lives both in the blood and skin, and are highly efficient. However, they are as of yet not approved for clinical use.

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Am J Surg. 2007 Apr;193(4):493-7.
Surgical management of melanoma of the gallbladder: a report of 13 cases and review of the literature.
Katz SC, Bowne WB, Wolchok JD, Busam KJ, Jaques DP, Coit DG.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

BACKGROUND: Melanoma has the potential to spread to virtually any organ, including the gallbladder. The role of intervention in this rare entity must be based on a thorough appreciation of the underlying disease biology. METHODS: We present a review of all patients treated for gallbladder melanoma at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1991 and 2003. RESULTS: The study group consisted of 13 patients with melanoma metastatic to the gallbladder. The median survival was 12 months following the diagnosis, and only 1 patient survived more than 42 months. Factors associated with improved outcome included symptomatic metastases and metastatic disease confined to the gallbladder (P < .05). Cholecystectomy led to the resolution of right upper quadrant pain in all patients for the duration of their survival. CONCLUSIONS: In patients with melanoma metastatic to the gallbladder, overall survival is determined more by the biology of the disease than treatment. In the presence of symptoms, cholecystectomy is often effective palliation in carefully selected patients.

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Otol Neurotol. 2007 Mar 23; [Epub ahead of print]
CPA Melanoma: Diagnosis and Management.
Brackmann DE, Doherty JK.
House Clinic, Los Angeles, California, U.S.A.

OBJECTIVE:: Melanoma rarely invades the cerebellopontine angle (CPA) and can evade accurate diagnosis, which may alter management decisions. Diagnosis may be facilitated via careful history, magnetic resonance imaging (MRI) findings, and cerebrospinal fluid (CSF) analysis. STUDY DESIGN:: Retrospective case review. SETTING:: Tertiary referral center. PATIENTS:: Thirteen internal auditory canal/CPA lesions in eight patients who presented with CPA syndrome and who had a pathological diagnosis consistent with malignant melanoma. There were four bilateral and four unilateral lesions. Six of eight patients had a history of melanoma. One was apparently primary CPA lesion, whereas all others were metastatic. INTERVENTION(S):: T1- and T2-weighted precontrast and postcontrast gadolinium-enhanced MRI were obtained, including fat suppression and fluid-attenuated inversion recovery sequence images in two patients; lumbar puncture with CSF centrifugation and cytological analysis confirmed the diagnosis in two patients. Translabyrinthine craniotomy was performed for tumor extirpation in five patients. MAIN OUTCOME MEASURE(S):: Symptoms at presentation, MRI findings, presence of malignant cells in CSF, tumor progression, intraoperative findings, response to treatment, time interval from initial diagnosis of melanoma elsewhere, and survival. RESULTS:: Seven of eight patients had history and/or MRI findings suggestive of malignancy in the internal auditory canal and/or CPA, and diagnosis was confirmed via CSF analysis in two patients. In one patient, diagnosis was made at surgery. CONCLUSION:: Internal auditory canal melanoma portends a grim prognosis, can occur up to 17 years after initial melanoma diagnosis/treatment, and can be detected with appropriate MRI sequences, especially enhanced fluid-attenuated inversion recovery images. In disseminated cases, diagnosis can be confirmed with lumbar puncture demonstrating malignant cells. Management includes tumor resection when melanoma seems to be solitary and malignant cells are not present in CSF. Intrathecal chemotherapy and radiation are recommended for dissemination, although the survival rate is still poor.

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Mayo Clin Proc. 2007 Mar;82(3):364-80.
Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis.
Markovic SN, Erickson LA, Rao RD, Weenig RH, Pockaj BA, Bardia A, Vachon CM, Schild SE, McWilliams RR, Hand JL, Laman SD, Kottschade LA, Maples WJ, Pittelkow MR, Pulido JS, Cameron JD, Creagan ET; Melanoma Study Group of the Mayo Clinic Cancer Center.
Division of Hematology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA.

Malignant melanoma is an aggressive, therapy-resistant malignancy of melanocytes. The incidence of melanoma has been steadily increasing worldwide, resulting in an increasing public health problem. Exposure to solar UV radiation, fair skin, dysplastic nevi syndrome, and a family history of melanoma are major risk factors for melanoma development. The interactions between genetic and environmental risk factors that promote melanomagenesis are currently the subject of ongoing research. Avoidance of UV radiation and surveillance of high-risk patients have the potential to reduce the population burden of melanoma. Biopsies of the primary tumor and sampling of draining lymph nodes are required for optimal diagnosis and staging. Several clinically relevant pathologic subtypes have been identified and need to be recognized. Therapy for early disease is predominantly surgical, with a minor benefit noted with the use of adjuvant therapy. Management of systemic melanoma is a challenge because of a paucity of active treatment modalities. In the first part of this 2-part review, we discuss epidemiology, risk factors, screening, prevention, and diagnosis of malignant melanoma. Part 2 (which will appear in the April 2007 issue) will review melanoma staging, prognosis, and treatment.

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Cancer. 2007 Mar 9; [Epub ahead of print]
Multimodality treatment of melanoma brain metastases incorporating stereotactic radiosurgery (SRS).
Samlowski WE, Watson GA, Wang M, Rao G, Klimo P Jr, Boucher K, Shrieve DC, Jensen RL.
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

BACKGROUND.: Brain metastases are a frequent complication in advanced melanoma. A 3.6 to 4.1-month median survival has been reported after treatment with whole brain radiotherapy. We performed a retrospective analysis of our institutional experience of multimodality treatment utilizing linear accelerator (Linac)-based stereotactic radiosurgery (SRS). METHODS.: Forty-four melanoma patients with brain metastases underwent 66 SRS treatments for 156 metastatic foci between 1999 and 2004. Patients were treated with initial SRS if </=5 brain metastases were present. All patients had Karnofsky Performance Status (KPS) >/=70, but 37 patients had active systemic metastases (Recursive Partition Analysis Class 2). Survival was calculated from the time of diagnosis of brain metastases. Minimum follow-up was 1 year after SRS. The potential role of prognostic factors on survival was evaluated including age, sex, interval from initial diagnosis to brain metastases, surgical resection, addition of whole brain radiotherapy (WBRT), number of initial metastases treated, and number of SRS treatments using Cox univariate analysis. RESULTS.: The median survival of melanoma patients with brain metastases was 11.1 months (95% confidence interval [CI]: 8.2-14.9 months) from diagnosis. One-year and 2-year survivals were 47.7% and 17.7%, respectively. There was no apparent effect of age or sex. Surgery or multiple stereotactic radiotherapy treatments were associated with prolonged survival. Addition of WBRT to maintain control of brain metastases in a subset of patients did not improve survival. CONCLUSIONS.: Our results suggest that aggressive treatment of patients with up to 5 melanoma brain metastases including SRS appears to prolong survival. Subsequent chemotherapy or immunotherapy after SRS may have contributed to the observed outcome. Cancer 2007. (c) 2007 American Cancer Society.

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J Am Acad Dermatol. 2007 Mar 7; [Epub ahead of print]
Primary mucosal melanoma.
Patrick RJ, Fenske NA, Messina JL.
From the Department of Dermatology, University of South Florida College of Medicine.

Primary mucosal melanomas are rare, biologically aggressive neoplasms. The distribution of head and neck, female genital tract, anal/rectal, and urinary tract sites is 55.4%, 18.0%, 23.8%, and 2.8%, respectively. The median age at presentation is the seventh decade, and women are given the diagnosis more frequently than men. Unfortunately, most afflicted individuals harbor micrometastatic disease and experience a course characterized by multiple local recurrences before the clinical development of distant disease. Approximately a third of patients have nodal involvement at presentation, and the overall 5-year survival is only 25%. Despite aggressive surgical resection and a multitude of adjuvant treatments, the prognosis remains grave. Early detection, which is difficult because of the occult anatomic locations in which these tumors occur, allows the best hope for cure.

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Cutis. 2007 Feb;79(2):149-52.
Lentigo maligna (melanoma in situ) treated with imiquimod cream 5%: 12 case reports.
Spenny ML, Walford J, Werchniak AE, Beltrani V, Brennick JB, Storm CA, Perry AE, Chapman MS.
Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, USA.

Lentigo maligna (LM) is an in situ variant of melanoma. Although LM has the potential for invasion, it often has a greatly protracted radial growth phase and may remain indolent for years. The current standard of care is surgical excision, but this often results in substantial morbidity; thus, nonsurgical approaches continue to be investigated. Imiquimod cream 5% is an immunomodulatory agent that previously has been reported to successfully eradicate LM. We evaluated the treatment course of topical imiquimod in 12 patients with LM. Data from patients with biopsy-proven LM were collected retrospectively, reviewed, and summarized. Patients ranged in age from 54 to 83 years. Most patients chose imiquimod cream as their initial form of treatment; however, other patients had a history of LM recurrence after excision or had positive histologic margins at the time of excision. Initial application regimens varied from 2 to 7 times weekly. The average duration of treatment was 15.7 weeks but ranged from 7 to 44 weeks. Results of posttreatment biopsies of the most clinically suspicious areas in 6 patients showed histologic clearance; 2 patients demonstrated single atypical melanocytes and 4 patients demonstrated clinical clearance without histologic confirmation. These findings suggest that imiquimod cream 5% may be an effective alternative treatment for LM.

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J Drugs Dermatol. 2007 Jan;6(1):10-6.
Skin cancer in individuals of African, Asian, Latin-American, and American-Indian descent: differences in incidence, clinical presentation, and survival compared to Caucasians.
Byrd-Miles K, Toombs EL, Peck GL.
Department of Dermatology, Washington Hospital Center, Washington, DC 20010, USA. katinamilesmd@msn.com

Skin cancer most commonly affects Caucasians and rarely affects individuals of African, Asian, Latin-American, and American-Indian descent. Although skin cancer is rare in these groups, the diagnosis may be associated with significant morbidity and mortality. Many factors may account for this discrepancy. Skin cancers in these groups may have atypical presentations. Melanoma usually involves areas not exposed to the sun, including palmoplantar skin and mucosal surfaces with the acral lentiginous melanoma being the most common histologic subtype. Basal cell carcinomas may involve sun-exposed areas such as the head and neck, while squamous cell carcinomas tend to involve unexposed areas in these groups. Because of the low index of suspicion in both the medical community and the ethnic groups, diagnosis is often delayed resulting in an advanced presentation and a worse prognosis.
  

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