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.
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.
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).
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.
Background
This phase III study was undertaken to evaluate the efficacy of an allogeneic whole-cell vaccine (Canvaxin™) plus bacillus Calmette-Guerin (BCG) after complete resection of stage IV ...melanoma.
Methods
After complete resection of ≤5 distant metastases, patients were randomly assigned to BCG+Canvaxin (BCG/Cv) or BCG+placebo (BCG/Pl). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and immune response measured by skin test (ClinicalTrials.gov identifier: NCT00052156).
Results
Beginning in May 1998, 496 patients were randomized. In April 2005, the Data Safety Monitoring Board recommended stopping enrollment due to a low probability of efficacy. At that time, median OS and 5-year OS rate were 38.6 months and 44.9%, respectively, for BCG/Pl versus 31.4 months and 39.6% in the BCG/Cv group (hazard ratio (HR), 1.18;
p
= 0.250). Follow-up was extended at several trial sites through March 2010. Median OS and 5-year and 10-year survival was 39.1 months, 43.3 and 33.3%, respectively, for BCG/Pl versus 34.9 months, 42.5 and 36.4%, in the BCG/Cv group (HR 1.053;
p
= 0.696). Median DFS, 5- and 10-year DFS were 7.6 months, 23.8 and 21.7%, respectively, for BCG/Pl versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG/Cv group (HR 0.882;
p
= 0.260). Positive DTH skin testing correlated with increased survival.
Discussion
In this, the largest study of postsurgical adjuvant therapy for stage IV melanoma reported to date, BCG/Cv did not improve outcomes over BCG/placebo. Favorable long-term survival among study patients suggests that metastasectomy should be considered for selected patients with stage IV melanoma.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose: The availability of a variety of immune response modifiers creates an opportunity for improved efficacy of immunotherapy,
but it also leads to uncertainty in how to combine agents and how to ...assess those combinations. We sought to assess the effect
of the addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) to vaccination with a melanoma vaccine.
Experimental Design: Ninety-seven patients with resected melanoma (stage II-IV) were enrolled, stratified by stage, and randomized to receive
a cellular melanoma vaccine with or without GM-CSF. The primary endpoint was delayed-type hypersensitivity (DTH) response
to melanoma cells. Antibody responses, peripheral leukocyte counts, and survival were also examined.
Results: The GM-CSF arm showed enhanced antibody responses with an increase in IgM titer against the TA90 antigen and increased TA90
immune complexes. This arm also had diminished antimelanoma cell delayed-type hypersensitivity response. Peripheral blood
leukocyte profiles showed increases in eosinophils and basophils with decreased monocytes in the GM-CSF arm. These immune
changes were accompanied by an increase in early melanoma deaths and a trend toward worse survival with GM-CSF.
Conclusion: These data suggest that GM-CSF is not helpful as an immune adjuvant in this dose and schedule and raise concern that it may
be harmful. Based on the discordant findings of an immune endpoint and clinical outcome, the use of such surrogate endpoints
in selecting treatments for further evaluation must be done with a great deal of caution. (Clin Cancer Res 2009;15(22):7029–35)
To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC).
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.
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.
This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.
Toll-like receptors (TLR) have been shown to be expressed on various types of cancers; however, their functional activity
is not known. We examined TLR profiles of human melanoma cells and showed ...that TLR2, TLR3, and TLR4 were found to be highly
expressed. By PCR array analysis, specific stimulation of TLR2, TLR3, and TLR4 on melanoma cells showed significant activation
of the adaptor protein MyD88, as well as downstream signal transduction factors nuclear factor-κB and inflammatory response–related
factors. Specific ligand activation of TLR2, TLR3, and TLR4 was shown to induce cell migration. Peripheral blood lymphocytes
and melanoma purified RNA was shown to activate TLR3 on melanoma cells. These studies show expression and functional activity
of specific TLRs on melanoma cells and as potential therapeutic targets to control tumor progression. Mol Cancer Ther 2008;7(11):3642–53
Aberrations in the methylation status of noncoding genomic repeat DNA sequences and specific gene promoter region are important epigenetic events in melanoma progression. Promoter methylation status ...in long interspersed nucleotide element-1 (LINE-1) and absent in melanoma-1 (AIM1;6q21) associated with melanoma progression and disease outcome was assessed. LINE-1 and AIM1 methylation status was assessed in paraffin-embedded archival tissue (PEAT; n=133) and in melanoma patients’ serum (n=56). LINE-1 U-Index (hypomethylation) and AIM1 were analyzed in microdissected melanoma PEAT sections. The LINE-1 U-Index of melanoma (n=100) was significantly higher than that of normal skin (n=14) and nevi (n=12; P=0.0004). LINE-1 U-Index level was elevated with increasing American Joint Committee on Cancer (AJCC) stage (P<0.0001). AIM1 promoter hypermethylation was found in higher frequency (P=0.005) in metastatic melanoma (65%) than in primary melanomas (38%). When analyzed, high LINE-1 U-Index and/or AIM1 methylation in melanomas were associated with disease-free survival (DFS) and overall survival (OS) in stage I/II patients (P=0.017 and 0.027, respectively). In multivariate analysis, melanoma AIM1 methylation status was a significant prognostic factor of OS (P=0.032). Furthermore, serum unmethylated LINE-1 was at higher levels in both stage III (n=20) and stage IV (n=36) patients compared with healthy donors (n=14; P=0.022). Circulating methylated AIM1 was detected in patients’ serum and was predictive of OS in stage IV patients (P=0.009). LINE-1 hypomethylation and AIM1 hypermethylation have prognostic utility in both melanoma patients’ tumors and serum.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Melanoma brain metastasis (MBM) is frequent and has a very poor prognosis with no current predictive factors or therapeutic molecular targets. Our study unravels the molecular alterations of ...cell‐surface glycoprotein CD44 variants during melanoma progression to MBM. High expression of CD44 splicing variant 6 (CD44v6) in primary melanoma (PRM) and regional lymph node metastases from AJCC Stage IIIC patients significantly predicts MBM development. The expression of CD44v6 also enhances the migration of MBM cells by hyaluronic acid and hepatocyte growth factor exposure. Additionally, CD44v6‐positive MBM migration is reduced by blocking with a CD44v6‐specific monoclonal antibody or knocking down CD44v6 by siRNA. ESRP1 and ESRP2 splicing factors correlate with CD44v6 expression in PRM, and ESRP1 knockdown significantly decreases CD44v6 expression. However, an epigenetic silencing of ESRP1 is observed in metastatic melanoma, specifically in MBM. In advanced melanomas, CD44v6 expression correlates with PTBP1 and U2AF2 splicing factors, and PTBP1 knockdown significantly decreases CD44v6 expression. Overall, these findings open a new avenue for understanding the high affinity of melanoma to progress to MBM, suggesting CD44v6 as a potential MBM‐specific factor with theranostic utility for stratifying patients.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Sentinel node biopsy and standard of care for melanoma Balch, Charles M., MD; Morton, Donald L., MD; Gershenwald, Jeffrey E., MD ...
Journal of the American Academy of Dermatology,
05/2009, Volume:
60, Issue:
5
Journal Article
Peer reviewed
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.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Circulating tumor cells (CTC) have been found in patients with metastatic melanoma and are associated with advanced melanoma stage and poor patient outcome. We hypothesize that CTC harbor genomic ...changes critical in the development of distant systemic metastasis. Here, we present the first genome-wide copy-number aberration (CNA) and loss of heterozygosity (LOH)-based characterization of melanoma CTC.
CTC were isolated from peripheral blood monocytes of 13 melanoma patients with regional metastasis stage IIIB/C using antibodies against melanoma-associated cell surface gangliosides.
We characterized 251 CNA in CTC. Comparative analysis demonstrated >90% concordance in single-nucleotide polymorphism profiles between paired CTC and tumor metastases. In particular, there were notable recurring CNA across patients. In exploratory studies, the presence of several top CTC-associated CNA was verified in distant metastasis (stage IV) from 27 patients, suggesting that certain genomic changes are propagated from regional metastasis to CTC and to distant systemic metastases. Lastly, an exploratory biomarker panel derived from 5 CTC-associated CNA CSMD2 (CUB and Sushi multiple domains 2), 1p35.1; CNTNAP5 (contactin associated protein-like 5), 2q14.3; NRDE2 (NRDE-2, necessary for RNA interference, domain containing), 14q32.11; ADAM6 (ADAM metallopeptidase domain 6, pseudogene), 14q32.33; and TRPM2 (transient receptor potential cation channel, subfamily m, member 2), 21q22.3 conferred prognostic utility for melanoma recurrence hazard ratio (HR), 1.14; CI, 1.00-1.44; P = 0.0471 and death (HR, 2.86; CI, 1.23-14.42; P = 0.0014) in 35 patients with stage IIIB/C melanoma, with a 5-year disease-free survival of 13% vs 69% (P = 0.0006) and overall survival of 28% vs 94% between high-risk and low-risk groups defined by the biomarker panel, respectively.
This study provides the first detailed CNA-based profile of melanoma CTC and illustrates how CTC may be used as a novel approach for identification of systemic metastasis.
PDF
