Melanoma: Gershenwald JE

Andtbacka RH, Gershenwald JE. · Department of Surgery, University of Utah, Salt Lake City, Utah, USA. · J Natl Compr Canc Netw. · Pubmed #19401063 No free full text.

Abstract: Sentinel lymph node (SLN) biopsy has emerged over the past 2 decades as a rational approach for staging regional lymph nodes in patients with clinically node-negative melanoma (stage I and II disease). Large multi-institutional studies have confirmed that when performed by experienced surgeons, it is an accurate, reliable technique for identifying occult regional nodal disease, and that SLN status is the most important prognostic factor in patients with stage I and II melanoma. However, the incidence of occult regional nodal metastasis in patients with thin melanoma (<or= 1.0 mm; approximately 70% of patients with newly diagnosed melanoma) is low, and whether to perform SLN biopsy in these patients remains controversial. Several predictors of SLN metastasis in patients with thin melanoma have been suggested, but none widely accepted. This article reviews current literature on these predictors in patients with thin melanoma. Although the ability to draw conclusions was limited by the size and design of the available studies, the authors tentatively conclude that SLN biopsy can be considered for patients with melanomas 0.75 mm or larger, those with T1b melanomas (i.e., <or= 1.0 mm; Clark level IV/V and/or ulcerated), and those with thin melanomas with an increased tumor mitotic rate (especially >or= 1 mitosis/mm2). Including younger age (e.g., <or= 40 years) in the decision also seems reasonable, particularly if the primary tumor is associated with a high tumor mitotic rate. Tumor regression does not seem to be associated with an increased risk for SLN metastasis. Firm conclusions on the predictive value of vertical growth phase, absence of tumor-infiltrating lymphocytes, or male gender were not possible, particularly if used as a sole criterion for offering this procedure. SLN biopsy should be discussed with all patients with newly diagnosed thin melanoma.

Choi EA, Gershenwald JE. · Department of Surgical Oncology, Unit 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. · Surg Oncol Clin N Am. · Pubmed #17560520 No free full text.

Abstract: The incidence of malignant cutaneous melanoma is rising. Imaging studies represent a major component of the staging work-up and follow-up of melanoma patients and are used to facilitate preoperative planning and intraoperative management. Study benefits are not clear, and evidence does not support any particular protocol for their use. The National Comprehensive Cancer Network's updated guidelines for use of imaging studies in melanoma patients represent a consensus based on lower level evidence, including clinical experience. The utility of individual imaging studies in melanoma patients depends on disease stage. Chest radiography, CT, MRI, lymphoscintigraphy, ultrasonography, PET, and PET/CT have specific roles in patient evaluation. Clinicians must use available evidence to guide decisions regarding which imaging modalities are appropriate for a given indication.

Aloia TA, Gershenwald JE. · University of Texas M. D. Anderson Cancer Center Houston, Texas, USA. · Curr Probl Surg. · Pubmed #16099230 No free full text.

This publication has no abstract.

Balch CM, Soong SJ, Atkins MB, Buzaid AC, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF. · American Society of Clinical Oncology, Alexandria, VA, USA. · CA Cancer J Clin. · Pubmed #15195788 links to  free full text

Abstract: A completely revised staging system for cutaneous melanoma was implemented in 2003. The changes were validated with a prognostic factors analysis involving 17,600 melanoma patients from prospective databases. This major collaborative study of predicting melanoma outcome was conducted specifically for this project, and the results were used to finalize the criteria for this evidence-based staging system. In fact, this was the largest prognostic factors analysis of prospectively followed melanoma patients ever conducted. Important results that shaped the staging criteria involved both the tumor-node-metastasis (TNM) criteria and stage grouping for all four stages of melanoma. Major changes in the staging include: (1) melanoma thickness and ulceration are the dominant predictors of survival in patients with localized melanoma (Stages I and II); deeper level of invasion (ie, IV and V) was independently associated with reduced survival only in patients with thin or T1 melanomas. (2) The number of metastatic lymph nodes and the tumor burden were the most dominant predictors of survival in patients with Stage III melanoma; patients with metastatic nodes detected by palpation had a shorter survival compared with patients whose nodal metastases were first detected by sentinel node excision of clinically occult or "microscopic" metastases. (3) The site of distant metastases (nonvisceral versus lung versus all other visceral metastatic sites) and the presence of elevated serum lactate dehydrogenase (LDH) were the dominant predictors of outcome in patients with Stage IV or distant metastases. (4) An upstaging was implemented for all patients with Stage I, II, and III disease when a primary melanoma is ulcerated by histopathological criteria. (5) Satellite metastases around a primary melanoma and in-transit metastases were merged into a single staging entity that is grouped into Stage III disease. (6) A new convention was implemented for defining clinical and pathological staging so as to take into account the new staging information gained from lymphatic mapping and sentinel node biopsy.

Rousseau DL, Gershenwald JE. · Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. · Semin Oncol. · Pubmed #15190500 No free full text.

Abstract: In 2002, the American Joint Committee on Cancer (AJCC) revised the staging system for cutaneous melanoma on the basis of a survival analysis of important melanoma prognostic factors. Features of the revised system include new strata for primary tumor thickness, incorporation of primary tumor ulceration as an important staging criterion in both the tumor (T) and node (N) classifications, revision of the N classification to reflect the prognostic significance of regional nodal tumor burden, and new categories for distant metastatic disease. These changes reflect evolving insight into melanoma arising from the results of numerous clinical investigations and database analyses. One of the most important recent changes in melanoma care is the establishment of lymphatic mapping and sentinel lymph node (SLN) biopsy as a highly accurate and minimally morbid technique for pathologic regional nodal staging. In this article, the salient features of the revised melanoma staging system are examined, with specific attention paid to its use in this era of lymphatic mapping and SLN biopsy.

Pawlik TM, Ross MI, Gershenwald JE. · Department of Surgical Oncology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA. · Ann Surg Oncol. · Pubmed #15070595 No free full text.

This publication has no abstract.

Gershenwald JE, Bar-Eli M. · Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. · Cancer Biol Ther. · Pubmed #14764994 links to  free full text

This publication has no abstract.

Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF. · Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Semin Surg Oncol. · Pubmed #12923915 No free full text.

Abstract: The American Joint Committee on Cancer (AJCC) implemented major revisions of the melanoma TNM and stage grouping criteria in the recently published 6th edition of the Staging Manual. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include: 1) melanoma thickness and ulceration but not level of invasion to be used in the T classification, 2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of microscopic vs. macroscopic nodal metastases to be used in the N classification, 3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase (LDH) to be used in the M classification, 4) an upstaging of all patients with Stage I, II, and III disease when a primary melanoma is ulcerated, 5) a merging of satellite metastases around a primary melanoma and in transit metastases into a single staging entity that is grouped into Stage III disease, and 6) a new convention for defining clinical and pathological staging so as to take into account the new staging information gained from intraoperative lymphatic mapping and sentinel node biopsy.

Balch CM, Sober AJ, Soong SJ, Gershenwald JE, Anonymous00010. · Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Semin Cutan Med Surg. · Pubmed #12773013 No free full text.

Abstract: The new melanoma staging system from The American Joint Committee on Cancer (AJCC) is described. This major revision includes new criteria for staging the primary tumor (T), metastatic nodes (N) and distant metastases (M) as well as stage groupings. These criteria more accurately reflect those prognostic features of the primary and metastatic melanoma that correlate with survival outcome. Physicians managing melanoma should use this staging system in their clinical practice and in the conduct of melanoma clinical trials.

Bedrosian I, Gershenwald JE. · Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. · Surg Clin North Am. · Pubmed #12744615 No free full text.

Abstract: Over the past 30 years, several important surgery clinical trials examining the issues of excision margins, ELND, and regional therapy have given rise to the current practice guidelines for the care of melanoma patients. The development of the SLN selective lymphadenectomy concept and the increasing use of molecular staging techniques have presented new challenges in this field. Clinical trials have been initiated to address these latest issues. In the next decade, these trials should help guide the integration of the new technologies into the surgical management of melanoma.

Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF. · Johns Hopkins Medical Institutions, Baltimore, MD, USA. · J Clin Oncol. · Pubmed #11504745 No free full text.

Abstract: PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. CONCLUSION: This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.

McMasters KM, Reintgen DS, Ross MI, Gershenwald JE, Edwards MJ, Sober A, Fenske N, Glass F, Balch CM, Coit DG. · Department of Surgery, University of Louisville, James Graham Brown Cancer Center, KY 40202, USA. · J Clin Oncol. · Pubmed #11387357 No free full text.

Abstract: Although sentinel lymph node (SLN) biopsy for melanoma has been adopted throughout the United States and abroad as a standard method of determining the pathologic status of the regional lymph nodes, some controversy still exists regarding the validity and utility of this procedure. SLN biopsy is a minimally invasive procedure, performed on an outpatient basis at the time of wide local excision of the melanoma, with little morbidity. Numerous studies have documented the accuracy of this procedure for identifying nodal metastases. There are four major reasons to perform SLN biopsy. First, SLN biopsy improves the accuracy of staging and provides valuable prognostic information for patients and physicians to guide subsequent treatment decisions. Second, SLN biopsy facilitates early therapeutic lymph node dissection for those patients with nodal metastases. Third, SLN biopsy identifies patients who are candidates for adjuvant therapy with interferon alfa-2b. Fourth, SLN biopsy identifies homogeneous patient populations for entry onto clinical trials of novel adjuvant therapy agents. Overall, the benefit of accurate nodal staging obtained by SLN biopsy far outweighs the risks and has important implications for patient management.

Gershenwald JE, Buzaid AC, Ross MI. · Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. · Clin Lab Med. · Pubmed #11221515 No free full text.

Abstract: Although a standardized and uniformly accepted cancer staging system is an essential and fundamental requirement to enable meaningful comparisons across patient populations, the sometimes capricious biologic behavior of melanoma makes developing such a staging system particularly difficult. Since the earliest well-documented attempts at classifying patients with cutaneous melanoma were described more than 50 years ago, the identification of increasingly powerful prognostic factors has led to sequential modifications of the cutaneous melanoma staging system. The current AJCC staging system is based on relatively well-established prognostic factors; however, several recent reports have identified additional prognostic factors not included in the current system, and other studies support the re-evaluation of some of the currently employed staging criteria. Some of the more controversial areas include the relevance of level of invasion versus tumor thickness, optimal cutoffs for tumor thickness, importance of ulceration, the grouping of satellites with in-transit metastases, the inclusion of microsatellites and local recurrences as a separate staging criterion, the replacement of size of nodal mass with number of positive nodes, the importance of nodal metastases in more than one nodal basin, and the prognostic significance of distant metastases. Future modifications of the staging system are anticipated to better incorporate these observations. Stage-specific staging recommendations for the patient with melanoma provide the clinician with a framework to most efficiently assess extent of disease in an era of cost-conscious clinical practice. In the asymptomatic patient with primary melanoma (stage I or II), we recommend a chest roentgenogram and evaluation of alkaline phosphatase and LDH levels; extensive radiologic evaluations are not indicated, because the rate of detection in this population is extremely low. Additional staging information should also be obtained by the technique of lymphatic mapping and sentinel lymphadenectomy. For patients with local-regional disease (stage III, satellites, and local recurrence), a selective approach to imaging studies is warranted. For this patient population, we recommend complete blood count, liver function tests including alkaline phosphatase and LDH, a chest roentgenogram, and a CT scan of the abdomen. Although the yield of these tests, particularly CT of the abdomen, in detecting distant metastases in asymptomatic patients is low, they may identify false-positive abnormalities and provide an important baseline for future studies in this high-risk population. For patients with disease below the waist or in the head and neck region, we recommend CT of the pelvis and CT of the neck, respectively. Additional studies should be done only if clinically indicated. Finally, patients with known systemic disease (stage IV) should be more comprehensively evaluated, because the likelihood of detecting asymptomatic metastases is higher. Accordingly, in addition to the work-up outlined previously for stage III patients, we also perform a CT scan of the chest and MR imaging of the brain; other studies (e.g., bone scan, gastrointestinal series) are performed on the basis of symptoms.

Gershenwald JE, Fischer D, Buzaid AC. · Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, USA. · Clin Plast Surg. · Pubmed #10941558 No free full text.

Abstract: The identification of increasingly powerful prognostic factors has led to sequential modifications of the cutaneous melanoma staging system. Changes in the staging system are anticipated as more refined prognostic factors are identified. This article provides an overview of the system, including a brief history and an introduction to recent advances in staging of patients with primary melanoma (i.e., sentinel lymphadenectomy). Practical recommendations for a stage-specific workup for the patient, which are especially important given the need for quality care in an increasingly cost-conscious environment, are provided.

Kim KB, Eton O, Davis DW, Frazier ML, McConkey DJ, Diwan AH, Papadopoulos NE, Bedikian AY, Camacho LH, Ross MI, Cormier JN, Gershenwald JE, Lee JE, Mansfield PF, Billings LA, Ng CS, Charnsangavej C, Bar-Eli M, Johnson MM, Murgo AJ, Prieto VG. · Department of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. · Br J Cancer. · Pubmed #18728664 No free full text.

Abstract: Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

McMasters KM, Noyes RD, Reintgen DS, Goydos JS, Beitsch PD, Davidson BS, Sussman JJ, Gershenwald JE, Ross MI, Anonymous00130. · The Department of Surgery, University of Louisville, James Graham Brown Cancer Center and Center for Advanced Surgical Technologies (CAST), Louisville, Kentucky 40202, USA. · J Surg Oncol. · Pubmed #15221928 No free full text.

Abstract: The Sunbelt Melanoma Trial is an ongoing multicenter prospective randomized trial that involves 79 centers and over 3600 patients from across the United States and Canada. This is one of the first large randomized studies to incorporate molecular staging using reverse transcriptase polymerase chain reaction (RT-PCR). While the results related to the primary endpoints of the study are not yet available, several analyses have shed light on many aspects of sentinel lymph node (SLN) biopsy and melanoma prognostic factors. In particular, we have developed a practical definition of sentinel nodes based on the degree of radioactivity. We have established the low rate of postoperative complications associated with SLN biopsy as compared to complete lymph node dissection. We have identified factors that predict the presence of SLN metastases. In contrast, we have been unable to identify factors that indicate a low risk of non-sentinel node metastases in patients with a positive sentinel node, suggesting that completion lymphadenectomy is appropriate for such patients. We have further established the value of identifying interval or in-transit sentinel nodes, which can be the only site of nodal metastasis. We have evaluated the particular challenges associated with SLN biopsy of head and neck melanomas, have evaluated the patterns of early recurrence, and have identified an interesting correlation between increasing patient age and a number of prognostic factors. Future analyses will evaluate the benefit of early therapeutic lymphadenectomy and early institution of adjuvant interferon alfa-2b therapy, as well as the validity of molecular staging.

Gershenwald JE, Thompson W, Mansfield PF, Lee JE, Colome MI, Tseng CH, Lee JJ, Balch CM, Reintgen DS, Ross MI. · Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. · J Clin Oncol. · Pubmed #10071292 No free full text.

Abstract: PURPOSE: To compare the effect of pathologic sentinel lymph node (SLN) status with that of other known prognostic factors on recurrence and survival in patients with stage I or II cutaneous melanoma. PATIENTS AND METHODS: We reviewed the records of 612 patients with primary cutaneous melanoma who underwent lymphatic mapping and SLN biopsy between January 1991 and May 1995 to determine the effects of tumor thickness, ulceration, Clark level, location, sex, and SLN pathologic status on disease-free and disease-specific survival. RESULTS: In the 580 patients in whom lymphatic mapping and SLN biopsy were successful, the SLN was positive by conventional histology in 85 patients (15%) but negative in 495 patients (85%). SLN status was the most significant prognostic factor with respect to disease-free and disease-specific survival by univariate and multiple covariate analyses. Although tumor thickness and ulceration influenced survival in SLN-negative patients, they provided no additional prognostic information in SLN-positive patients. CONCLUSION: Lymphatic mapping and SLN biopsy is highly accurate in staging nodal basins at risk for regional metastases in primary melanoma patients and identifies those who may benefit from earlier lymphadenectomy. Furthermore, pathologic status of the SLN in these patients with clinically negative nodes is the most important prognostic factor for recurrence. The information from SLN biopsy is particularly helpful in establishing stratification criteria for future adjuvant trials.

Tellez CS, Shen L, Estécio MR, Jelinek J, Gershenwald JE, Issa JP. · Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. · Melanoma Res. · Pubmed #19441164 No free full text.

Abstract: A better understanding of key molecular changes during the pathogenesis of melanoma could impact strategies to reduce mortality from this cancer. Two epigenetic events involved in the pathogenesis of cancer are hypermethylation of tumor-suppressor gene promoters associated with transcriptional repression and hypomethylation associated with gene reexpression and genomic instability. We analyzed 16 melanoma cell lines for aberrant hypermethylation of 15 cancer-linked genes (ER alpha, MGMT, RAR beta 2, RIL, RASSF1A, PAX7, PGR beta, PAX2, NKX2-3, OLIG2, HAND1, ECAD, CDH13, MLH1, and p16) and hypomethylation of two genes (MAGEA1, maspin) and two repetitive sequences (LINE-1 and Alu) using pyrosequencing. We observed hypermethylation of ER alpha in 50% of the cell lines, MGMT (50%), RAR beta 2 (44%), RIL (88%), RASSF1A (69%), PAX7 (31%), PGR beta (56%), PAX2 (38%), NKX2-3 (63%), OLIG2 (63%), HAND1 (63%), ECAD (88%), CDH13 (44%), MLH1 (0%), and p16 (6%). In human melanoma cell lines, hypomethylation of MAGEA1 (44%), maspin (25%), LINE-1 (75%), and Alu (13%) is frequently observed. We analyzed a panel of cell lines for BRAF V600E and NRAS codon 61 mutations. In melanoma cell lines, the BRAF and NRAS mutations had no association with aberrant methylation. We found that the cumulative aberrant hypermethylation of the gene promoters was correlated with the level of global DNA methylation. We conclude that aberrant hypermethylation, is frequent in melanoma cell lines, directly correlated with global DNA methylation, and independent of BRAF and NRAS mutations.

Kim KB, Legha SS, Gonzalez R, Anderson CM, Johnson MM, Liu P, Papadopoulos NE, Eton O, Plager C, Buzaid AC, Prieto VG, Hwu WJ, Frost AM, Alvarado G, Hwu P, Ross MI, Gershenwald JE, Lee JE, Mansfield PF, Benjamin RS, Bedikian AY. · Department of Melanoma Medical Oncology, M. D. Anderson Cancer Center, The University of Texas, Houston 77030, Texas, USA. · Melanoma Res. · Pubmed #19430405 No free full text.

Abstract: The objective of this study was to compare the clinical benefit of biochemotherapy and interferon-alpha-2b (IFN) as adjuvant therapy. Biochemotherapy has higher response rates than other regimens in patients with metastatic melanoma. We conducted a randomized phase III study comparing the clinical benefit of biochemotherapy and IFN as adjuvant therapy. Patients who had undergone lymphadenectomy for melanoma metastatic to regional lymph nodes were randomly assigned to either biochemotherapy or IFN, and IFN patients were further randomized to either high-dose IFN (HDI) or intermediate-dose IFN (IDI). The primary end point was relapse-free survival (RFS); the secondary end point was overall survival (OS). The planned enrollment was 200 patients, the number required to have 80% power to detect, at a significance level of 5%, an improvement in median RFS from 18 to 36 months and an improvement in median OS from 40 to 80 months between the IFN and biochemotherapy groups. A futility analysis was performed because of slow accrual. One hundred and thirty-eight patients were enrolled - 71 in the biochemotherapy group, 34 in the HDI subgroup, and 33 in the IDI subgroup. No significant differences in median RFS or OS between the HDI and IDI subgroups were observed. With a median follow-up of 49.3 months, neither the biochemotherapy nor IFN group had reached median RFS or OS, and there were no significant differences in estimated median RFS or OS (P=0.86 and 0.45, respectively) between the two groups. Biochemotherapy is not more effective than IFN as adjuvant therapy for melanoma. These findings support early termination of this trial.

Balch CM, Morton DL, Gershenwald JE, McMasters KM, Nieweg OE, Powell B, Ross MI, Sondak VK, Thompson JF. · Departments of Surgery, Oncology, and Dermatology, Johns Hopkins Medical Center, Baltimore, Maryland, USA. · J Am Acad Dermatol. · Pubmed #19389531 No free full text.

Abstract: An international panel was convened by the organizing committee of the International Sentinel Node (SN) Society (ISNS) at their meeting in Sydney, Australia, on February 21, 2008, to address questions about SN biopsy (SNB) for melanoma. The panelists subsequently wrote this consensus statement, based on their interpretation of current evidence, as a guide to clinical treatment of patients with clinically localized melanoma. The panel comprised a cross section of expert melanoma surgeons who have contributed data and leadership to investigations of SNB.

Xing Y, Badgwell BD, Ross MI, Gershenwald JE, Lee JE, Mansfield PF, Lucci A, Cormier JN. · Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA. · Cancer. · Pubmed #19309746 No free full text.

Abstract: BACKGROUND: The objectives of this analysis were to compare various measures associated with lymph node (LN) dissection and to identify threshold values associated with disease-specific survival (DSS) outcomes in patients with melanoma. METHODS: Patients with lymph node-positive melanoma who underwent therapeutic LN dissection of the neck, axilla, and inguinal region were identified from the SEER database (1988-2005). We performed Cox multivariate analyses to determine the impact of the total number of LNs removed, number of negative LNs removed, and LN ratio on DSS. Multivariate cut-point analyses were conducted for each anatomic region to identify the threshold values associated with the largest improvement in DSS. RESULTS: The LN ratio was significantly associated with DSS for all LN regions. The LN ratio thresholds resulting in the greatest difference in 5-year DSS were .07, .13, and .18 for neck, axillary, and inguinal regions, respectively, corresponding to 15, 8, and 6 LNs removed per positive lymph node. After adjustment for other clinicopathologic factors, the hazard ratios (HRs) were .53 (95% confidence interval [CI], .40 to .71) in the neck, .52 (95% CI, .42 to .65) in the axillary, and .47 (95% CI, .36 to .61) in the inguinal regions for patients who met the LN ratio threshold. CONCLUSIONS: Among the prognostic factors examined, LN ratio was the best indicator of the extent of LN dissection, regardless of anatomic nodal region. These data provide evidence-based guidelines for defining adequate LN dissections in melanoma patients.

Staquicini FI, Tandle A, Libutti SK, Sun J, Zigler M, Bar-Eli M, Aliperti F, Pérez EC, Gershenwald JE, Mariano M, Pasqualini R, Arap W, Lopes JD. · The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. · Cancer Res. · Pubmed #18922915 No free full text.

Abstract: Host immunity affects tumor metastasis but the corresponding cellular and molecular mechanisms are not entirely clear. Here, we show that a subset of B lymphocytes (termed B-1 population), but not other lymphocytes, has prometastatic effects on melanoma cells in vivo through a direct heterotypic cell-cell interaction. In the classic B16 mouse melanoma model, one mechanism underlying this phenomenon is a specific up-regulation and subsequent homophilic interaction mediated by the cell surface glycoprotein MUC18 (also known as melanoma cell adhesion molecule). Presence of B-1 lymphocytes in a panel of tumor samples from melanoma patients directly correlates with MUC18 expression in melanoma cells, indicating that the same protein interaction exists in humans. These results suggest a new but as yet unrecognized functional role for host B-1 lymphocytes in tumor metastasis and establish a biochemical basis for such observations. Our findings support the counterintuitive central hypothesis in which a primitive layer of the immune system actually contributes to tumor progression and metastasis in a mouse model and in melanoma patients. Given that monoclonal antibodies against MUC18 are in preclinical development but the reason for their antitumor activity is not well understood, these translational results are relevant in the setting of human melanoma and perhaps of other cancers.

Davies MA, Stemke-Hale K, Tellez C, Calderone TL, Deng W, Prieto VG, Lazar AJ, Gershenwald JE, Mills GB. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. · Br J Cancer. · Pubmed #18813315 No free full text.

Abstract: Recently, a rare activating mutation of AKT1 (E17K) has been reported in breast, ovarian, and colorectal cancers. However, analogous activating mutations in AKT2 or AKT3 have not been identified in any cancer lineage. To determine the prevalence of AKT E17K mutations in melanoma, the most aggressive form of skin cancer, we analysed 137 human melanoma specimens and 65 human melanoma cell lines for the previously described activating mutation of AKT1, and for analogous mutations in AKT2 and AKT3. We identified a single AKT1 E17K mutation. Remarkably, a previously unidentified AKT3 E17K mutation was detected in two melanomas (from one patient) as well as two cell lines. The AKT3 E17K mutation results in activation of AKT when expressed in human melanoma cells. This represents the first report of AKT mutations in melanoma, and the initial identification of an AKT3 mutation in any human cancer lineage. We have also identified the first known human cell lines with naturally occurring AKT E17K mutations.

Beadle BM, Guadagnolo BA, Ballo MT, Lee JE, Gershenwald JE, Cormier JN, Mansfield PF, Ross MI, Zagars GK. · Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. · Int J Radiat Oncol Biol Phys. · Pubmed #18774657 No free full text.

Abstract: PURPOSE: To compare treatment-related outcomes and toxicity for patients with axillary lymph node metastases from malignant melanoma treated with postoperative radiation therapy (RT) to either the axilla only or both the axilla and supraclavicular fossa (extended field [EF]). METHODS AND MATERIALS: The medical records of 200 consecutive patients treated with postoperative RT for axillary lymph node metastases from malignant melanoma were retrospectively reviewed. All patients received postoperative hypofractionated RT for high-risk features; 95 patients (48%) received RT to the axilla only and 105 patients (52%) to the EF. RESULTS: At a median follow-up of 59 months, 111 patients (56%) had sustained relapse, and 99 patients (50%) had died. The 5-year overall survival, disease-free survival, and distant metastasis-free survival rates were 51%, 43%, and 46%, respectively. The 5-year axillary control rate was 88%. There was no difference in axillary control rates on the basis of the treated field (89% for axilla only vs. 86% for EF; p = 0.4). Forty-seven patients (24%) developed treatment-related complications. On both univariate and multivariate analyses, only treatment with EF irradiation was significantly associated with increased treatment-related complications. CONCLUSIONS: Adjuvant hypofractionated RT to the axilla only for metastatic malignant melanoma with high-risk features is an effective method to control axillary disease. Limiting the radiation field to the axilla only produced equivalent axillary control rates to EF and resulted in lower treatment-related complication rates.

Gershenwald JE, Andtbacka RH, Prieto VG, Johnson MM, Diwan AH, Lee JE, Mansfield PF, Cormier JN, Schacherer CW, Ross MI. · Department of Surgical Oncology, Division of Quantitative Sciences, Unit 444, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. · J Clin Oncol. · Pubmed #18606982 No free full text.

Abstract: PURPOSE: We and others have demonstrated that additional positive lymph nodes (LNs) are identified in only 8% to 33% of patients with melanoma who have positive sentinel LNs (SLNs) and undergo complete therapeutic LN dissection (cTLND). We sought to determine predictors of additional regional LN involvement in patients with positive SLNs. PATIENTS AND METHODS: Patients with clinically node-negative melanoma who underwent SLN biopsy (1991 to 2003) and had positive SLNs were identified. Clinicopathologic factors, including extent of microscopic disease within SLNs, were evaluated as potential predictors of positive non-SLNs. RESULTS: Overall, 359 (16.3%) of the 2,203 patients identified had a positive SLN. Positive non-SLNs were identified in 48 (14.0%) of the 343 patients with positive SLNs who underwent cTLND. On univariate analysis, several measures of SLN microscopic tumor burden, one versus three or more SLNs harvested, tumor thickness more than 2 mm, age older than 50 years, and Clark level higher than III were predictive of positive non-SLNs; primary tumor ulceration and number of positive SLNs had no apparent impact. On multivariable logistic regression analysis, measures of SLN microscopic tumor burden were the most significant independent predictors of positive non-SLNs; tumor thickness more than 2 mm and number of SLNs harvested also predicted additional disease. A model was developed that stratified patients according to their risk for non-SLN involvement. CONCLUSION: In melanoma patients with positive SLNs, SLN tumor burden, primary tumor thickness, and number of SLNs harvested may be useful in identifying a group at low risk for positive non-SLNs and be spared the potential morbidity of a cTLND.