Distant Melanoma Metastases Research Articles

The Molecular Evolution of Melanoma Distant Metastases

The evolution of primary melanoma to lymph node and distant metastasis is incompletely understood. We examined the genomic diversity in melanoma progression in matched primary melanomas, lymph node and distant metastases from 17 patients. Fluorescence in situ hybridization (FISH) analysis revealed cancer cell fractions with monotonic copy number alterations (CNAs), including PHIP gain and PTEN loss, in the metastatic cascade. By contrast, the cancer cell fraction with CNAs for BPTF and MITF was reduced in lymph node metastases but increased in distant metastases. Separately, the cancer cell fraction with NCOA3 CNA was comparable in primary tumors and lymph nodes yet increased in distant metastases. These results suggest enrichment of the PI3K and MITF pathways in the transition through the metastatic cascade. By contrast, next-generation sequencing analysis did not identify a consistent pattern of changes in variant allele frequency (VAF) while revealing several intriguing findings, including decreased VAF in distant metastases and distinct drivers in lymph node versus distant metastases. These results provide evidence that distant melanoma metastasis does not always emanate from lymph node metastasis. These results enhance our understanding of clonal patterns of melanoma metastasis, with possible implications for targeted therapy and metastasis competency.

876P An observational retrospective study on microsatellite instability (MSI) in metastatic melanoma

Microsatellite instability (MSI) has been reported in skin melanoma and is thought to be a progression dependent phenomenon seen predominantly on metastases. However, a paucity of data is available about frequency, predictive and prognostic value of MSI in melanoma, in particular using the pentaplex panel of markers approved for colon cancer. Primary aim of this study was to provide a descriptive analysis of the presence of MSI in distant melanoma metastases, regardless of BRAF status and type of first-line treatment.

Metastatic melanoma of the gallbladder in a patient with acute cholecystitis: a case report and review of the literature

Melanoma is an aggressive type of cancer that has significant metastatic potential. Most commonly, distant melanoma metastases are identified in the lung, liver and brain. Metastatic melanoma of the gallbladder is extremely rare and is usually associated with widespread gastrointestinal deposits which purports a poor prognosis. Whilst an uncommon site of melanoma metastases, it accounts for 50% of all tumour metastases to the gallbladder. There are a small number of case reports and case series that describe different manifestations of melanoma metastases to the gallbladder. We report the case of a patient who presented with acute cholecystitis on a background of cholelithiasis and underwent a laparoscopic cholecystectomy with histopathology identifying gallbladder metastasis from malignant melanoma.

Abstract 85: Metastasizing melanoma cells exhibit increased dependence on the pentose phosphate pathway to manage oxidative stress

Abstract To study distant metastasis we developed a patient-derived xenograft (PDX) assay in which melanoma cells from patients spontaneously metastasize in NOD/SCID IL2Rγnull (NSG) mice in a manner that correlates with metastatic behavior in patients (Sci Transl Med 4:159). Using this assay, we discovered that distant melanoma metastasis is limited by oxidative stress (Nature 527:186). Reactive Oxygen Species (ROS) increase dramatically in melanoma cells as they metastasize through the blood. The rare cells that survive undergo reversible metabolic changes that confer oxidative stress resistance. We found that metastatic melanomas had significant increases in metabolites from the pentose phosphate pathway as compared to primary cutaneous melanomas. Metabolites in the oxidative branch of the pentose phosphate pathway, downstream of the NADPH-regenerating enzyme Glucose-6-Phosphate Dehydrogenase (G6PD), were the most dramatically increased in metastatic nodules. We hypothesized that metastasizing melanoma cells increase their dependence on the pentose phosphate pathway in order to manage oxidative stress. We used CRISPR gene editing to create loss-of-function mutations in G6PD in patient-derived melanomas. When transplanted into NSG mice, the tumors formed by G6PD mutant melanomas showed significantly reduced oxidative pentose phosphate pathway activity, increased ROS levels, decreased NADPH/NADP ratios, and reduced metastatic potential as compared to parental control melanomas. Our results demonstrate that metastasizing melanoma cells exhibit increased dependence upon the pentose phosphate pathway as compared to primary cutaneous tumors. Untargeted metabolomics revealed that G6PD mutant melanomas exhibit increased glutamine utilization, perhaps to compensate for increased oxidative stress. Citation Format: Arin B. Aurora, VIshal Khivansara, Ashley Leach, Misty Martin-Sandoval, Thomas Mathews, Sean J. Morrison. Metastasizing melanoma cells exhibit increased dependence on the pentose phosphate pathway to manage oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 85.

Laparoscopic-assisted distal gastrectomy and central pancreatectomy for gastric and perigastric lymph node metastases and pancreatic invasion from melanoma: a case report

BackgroundIn melanoma, completely resectable metastases are surgically resected to expect to prolong relapse-free survival and overall survival. However, distant metastases of melanoma are rarely indicated for surgery because multiple metastases are often observed at diagnosis. We report a case of a man in his 50s who underwent laparoscopic-assisted distal gastrectomy and central pancreatectomy for gastric metastases, lymph node metastases, and pancreatic invasion that could be completely resected.Case presentationA 50-year-old man was diagnosed with malignant melanoma of the left parietal region. After diagnosis, tumor resection and left cervical lymph node dissection were performed, and interferon-β treatment was added as adjuvant therapy. Seventeen months after adjuvant therapy, metastasis of stomach and abdominal lymph nodes from melanoma was diagnosed. And the pancreatic invasion of lymph nodes was suspected. Laparoscopic-assisted distal gastrectomy and the central pancreatectomy were performed because pancreatic invasion of melanoma was intraoperatively found. After 9 months of relapse-free survival, abdominal recurrence was observed. Nivolumab and ipilimumab were administered, and recurrent lesions are currently controlled. The patient has survived more than 3 years since metastasis resection.ConclusionIn conclusion, laparoscopic-assisted distal gastrectomy and the central pancreatectomy were performed for gastric and perigastric lymph node metastases and pancreatic invasion due to malignant melanoma, and the negative surgical margin was achieved. Although patient selection is required, the central pancreatectomy was a good indication for maintaining exocrine and endocrine function. The development of immune checkpoint inhibitors and molecular-targeted agents may increase gastrointestinal surgery for metastatic melanoma in the future.

Surgery for Metastatic Melanoma: an Evolving Concept.

This review describes the evolving role of surgery in stage III and IV melanoma. Surgery has been the first option to cure melanoma patients at initial diagnosis of metastatic spread: a complete surgical excision of the disease either in stage III or IV has been the gold standard for decades. A positive sentinel node biopsy (SNB) has been followed by a complete lymph node dissection (CLND) since the early stages of modern surgical oncology. However, since two randomized trials have indicated that a CLND does not improve survival in patients with a positive SNB, a CLND is no longer considered mandatory. A therapeutic lymph node dissection (TLND) is still offered to patients with macroscopic nodal disease and in highly selected cases, patients with distant melanoma metastases can be treated surgically as well. Also the availability of adjuvant, and in the future possibly neoadjuvant, systemic therapy have shifted the landscape to less extensive surgery in metastatic melanoma. With the development of new systemic options, surgery in metastatic melanoma has become more and more part of a multidisciplinary treatment: surgical indications are moving from previous standards to a new role.

SOX9 is a dose-dependent metastatic fate determinant in melanoma

BackgroundIn this research, we aimed to resolve contradictory results whether SOX9 plays a positive or negative role in melanoma progression and determine whether SOX9 and its closely related member SOX10 share the same or distinct targets in mediating their functions in melanoma.MethodsImmunofluorescence, TCGA database and qPCR were used to analyze the correlation between the expression patterns and levels of SOX9, SOX10 and NEDD9 in melanoma patient samples. AlamarBlue, transwell invasion and colony formation assays in melanoma cell lines were conducted to investigate the epistatic relationship between SOX10 and NEDD9, as well as the effects of graded SOX9 expression levels. Lung metastasis was determined by tail vein injection assay. Live cell imaging was conducted to monitor dynamics of melanoma migratory behavior. RHOA and RAC1 activation assays measured the activity of Rho GTPases.ResultsHigh SOX9 expression was predominantly detected in patients with distant melanoma metastases whereas SOX10 was present in the different stages of melanoma. Both SOX9 and SOX10 exhibited distinct but overlapping expression patterns with metastatic marker NEDD9. Accordingly, SOX10 was required for NEDD9 expression, which partly mediated its oncogenic functions in melanoma cells. Compensatory upregulation of SOX9 expression in SOX10-inhibited melanoma cells reduced growth and migratory capacity, partly due to elevated expression of cyclin-dependent kinase inhibitor p21 and lack of NEDD9 induction. Conversely, opposite phenomenon was observed when SOX9 expression was further elevated to a range of high SOX9 expression levels in metastatic melanoma specimens, and that high levels of SOX9 can restore melanoma progression in the absence of SOX10 both in vitro and in vivo. In addition, overexpression of SOX9 can also promote invasiveness of the parental melanoma cells by modulating the expression of various matrix metalloproteinases. SOX10 or high SOX9 expression regulates melanoma mesenchymal migration through the NEDD9-mediated focal adhesion dynamics and Rho GTPase signaling.ConclusionsThese results unravel NEDD9 as a common target for SOX10 or high SOX9 to partly mediate their oncogenic events, and most importantly, reconcile previous discrepancies that suboptimal level of SOX9 expression is anti-metastatic whereas high level of SOX9 is metastatic in a heterogeneous population of melanoma.

Expression and clinical significance of S100 family genes in patients with melanoma.

Genes in the S100 family are abnormally expressed in a variety of tumor cells and are associated with clinical pathology, but their prognostic value in melanoma patients has not yet been fully elucidated. In this study, we extracted and profiled S100 family mRNA expression data and corresponding clinical data from the Gene Expression Omnibus database to analyze how expression of these genes correlates with clinical pathology. Compared with normal skin, S100A1, S100A13, and S100B were expressed at significantly higher levels in melanoma samples. S100A2, S100A7, S100A8, S100A9, S100A10, S100A11, and S100P were all highly expressed in primary melanoma samples but were expressed at low levels in metastatic melanoma, and all of these genes were strongly correlated with each other (P<0.001). We found the expression of these S100 family genes to be significantly correlated with both lymphatic and distant melanoma metastasis, as well as with American Joint Committee on Cancer grade but not with Clark’s grade, age, or sex. This suggests that expression of these genes may be related to the degree of tumor invasion. Although further validation through basic and clinical trials is needed, our results suggest that the S100 family genes have the potential to play an important role in the diagnosis of melanoma. S100 expression may be related to tumor invasion and may facilitate the early diagnosis of melanoma, allowing for a more accurate prognosis. Targeted S100 therapies are also potentially viable strategies in the context of melanoma.

THE PLACE OF SURGERY IN MODERN TREATMENT OF SKIN MELANOMA

Recent breakthroughs in the treatment of melanoma are associated with the systemic therapy by drugs of new classes, however, the place of surgery remains to be the main in the management of both localized and widespread melanoma. In this literature review, there are systematized the modern concepts of local excision of the primary tumor, the value of biopsy of sentinel lymph node and possibilities of surgical treatment of distant metastases of melanoma.

The role of surgery in the treatment of distant metastases of skin melanomar

The choice of tactics in the treatment of one of the most common types of cancer skin- melanomy- is currently an urgent task facing the cancer community. High activity of local growth and regional metastasis of melanoma, its capacity for dissemination and multiple distant metastases make this task extremely important factor, largely determining the course and outcome of disease. Metastatic melanoma skin requires complex treatment, one of whose components is the surgical method. This article analyzes the use of surgical treatment of distant metastases of melanoma, depending on the location, quantity and rate of growth, the nature and effectiveness of previous treatment, the patient’s general condition. The authors have shown the prospects of application of surgical treatment in the radical treatment of patients with distant metastases of melanoma, the effectiveness of this method in the palliative treatment of metastatic melanoma and important role in the treatment of distant metastases of melanoma in combination with other treatments.

Métastases cutanées d’un mélanome sur un territoire de radiothérapie au niveau du sein : traitement par vémurafénib et chirurgie d’exérèse large

This article describes the unique case of a female patient who presented distant melanoma metastasis on the breast while having irradiation therapy for breast cancer. This happened eight months after the initial treatment for a melanoma of the back (under the right scapula). Furthermore, this case report demonstrates the efficiency of Vemurafenib® as a treatment for late stage melanomas. The patient was a 47-year-old female that had a superficial spreading melanoma under the right scapula (Breslow 1.02mm) that was treated with 2cm skin excision and sentinel lymph node sampling that was negative. The melanoma was positive for the BRAF600E mutation. One month after this incident, the patient developed breast cancer that was treated with conservative surgery and radiotherapy. Three months after the end of the irradiation treatment, she developed multiple melanoma metastasis on the skin of the breast. Our multidisciplinary team decided to initiate a treatment with vemurafenib. The patient showed an excellent response, so the surgical team completed the treatment with a radical mastectomy and immediate reconstruction with a pedicled latissimus dorsi flap. The histologic report of the mastectomy specimen showed no sign of melanocytic proliferation, that demonstrates the efficacy of vemurafenib. The patient showed no relapse after two years of follow-up. The speed of development and location of cutaneous metastases in this case brought us to think about the effects of radiation therapy on the skin. Radiation therapy causes acute complications (radiodermatitis) by cellular and molecular mechanisms. Moreover, depressed immunity is found after irradiation. Association of these mecanisms could explain the appearance of these metastases in irradiation field. The efficiency of vemurafenib found in our case is consistent with what is described in literature, especially with the improvement in median overall survival. This case demonstrates a unique case of distant melanoma metastasis on the irradiation field of a breast cancer. It also demonstrates the efficacy of vemurafenib as well as the efficacy of a radical complementary surgical treatment in these patients.

Serum S100B, Lactate Dehydrogenase and Brain Metastasis Are Prognostic Factors in Patients with Distant Melanoma Metastasis and Systemic Therapy

BackgroundPrognostic factors of melanoma with distant metastasis and systemic treatment are only poorly established. This study aimed to analyse the impact of S100B, lactate dehydrogenase (LDH) and the type of treatment on survival in advanced patients receiving systemic treatment.Patients and MethodsWe analysed overall survival of 499 patients from the university department of dermatology in Tuebingen, Germany, with unresectable melanoma at the time point of initiation of first-line systemic therapy. Only patients who started treatment between the years 2000 and 2010 were included. Disease-specific survival was calculated by bivariate Kaplan Meier survival probabilities and multivariate Cox hazard regression analysis.ResultsIn univariate analysis LDH, S100B, the site of distant metastasis (soft tissue vs. lung vs. other visceral), the presence of brain metastases and the type of treatment (monochemotherapy, polychemotherapy, immunotherapy or biochemotherapy) were associated with overall survival (all p<0.001). In multivariate analysis LDH (Hazard ratio [HR] 1.6 [1.3–2.1]; p<0.001), S100B (HR 1.6 [1.2–2.1]; p<0.001) and the presence of brain metastases (HR 1.5 [1.1–1.9]; p = 0.009), but not the type of treatment had significant independent impact. Among those factors normal S100B was the best indicator of long-term survival, which was 12.3% after 5 years for this subgroup.ConclusionSerum S100B is a prognostic marker predicting survival at the time of initiation of first-line treatment in unresectable melanoma patients. Compared to the other independent factors LDH and the presence of brain metastases it is most appropriate to predict long-term survival and requires further prospective investigation in patients treated with new and more potent drugs in metastatic melanoma.

Abstract C11: Molecular mechanism driving BMI1-induced melanoma metastasis

Abstract Malignant melanoma is one of the most aggressive human cancers, with a high potential for lethal metastasis and therapeutic resistance. The epigenetic chromatin regulator Bmi1 acts as a key component of the Polycomb Repressor Complex 1 (PRC1) and is a known oncogene. Various studies shown that BMI1 is highly expressed in many human hematopoietic malignancies and in different solid tumor types including prostate, breast, ovarian, colon, brain and lung cancer. Importantly, high Bmi1 expression is an excellent predictor of both metastatic progression and poor therapeutic response. Bmi1's role in tumor onset has been assessed using germline mutant mice showing that Bmi1 ablation efficiently suppress tumor development. This impaired tumorigenicity correlates with an impairment of the self-renewal and proliferative properties of tumor initiating cells, mainly due to Bmi1's repressive activity on the Ink4a/Arf tumor suppressor locus. Nevertheless, this function does not explain why Bmi1 is frequently upregulated in tumors nor Bmi1's role in tumor progression. To evaluate Bmi1's contribution to melanoma progression, we upregulated Bmi1 in two different melanoma cell lines, a murine metastatic cell line and a poorly metastatic human cell line. We found that Bmi1 overexpression activates or increases invasive behavior of both cell lines, without enhancing their proliferative capacity. This finding allowed us to dissect Bmi1's oncogenic activity at later stages of tumorigenesis, in the absence of Bmi1's deregulation of cell proliferation. Our data show that Bmi1 significantly enhances in vitro cell movement and modulates adhesion. Bmi1 also protects cells from apoptosis induced by different stimuli and increases lung metastasis formation in vivo. To characterize Bmi1-induced changes in gene expression, we have performed comparative deep sequencing of total RNA libraries generated from Bmi1 or GFP overexpressing cells. Gene ontology analysis revealed enrichment in cancer-relevant pathways that seem to be controlled by Bmi1, including cell movement, cell death and survival, tissue development and cell morphology. In particular, Bmi1 expression modulates the gene regulatory programs associated with EMT, TGFβ and the non-canonical Wnt pathways. We have identified a new Bmi1 target gene, poorly characterized, that seems to be responsible for Bmi1-induced melanoma progression. These data determine a causal role for Bmi1 in melanoma cell migration and establishment of distant melanoma metastasis. Citation Format: Roberta Ferretti, Jacqueline A. Lees. Molecular mechanism driving BMI1-induced melanoma metastasis. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C11.

Long-term cure after complete resection and adjuvant immunotherapy for distant melanoma metastases.

8534 Background: In phase II trials, postoperative therapy with Canvaxin allogeneic melanoma cell vaccine plus Bacillus Calmette-Guerin (BCG) improved the survival of patients with stage IV melanoma. A multicenter, phase III placebo-controlled study was undertaken to investigate the vaccine’s efficacy. Methods: After complete resection of melanoma involving up to 5 distant sites, patients were randomized to treatment with BCG plus Canvaxin (BCG-Canvaxin) or BCG plus placebo (BCG-placebo). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS) and skin test responsiveness to the study agent. Results: Between May 1998 and April 2005, 496 patients were randomized. In April 2005, entry to the study was terminated due to low probability of demonstrating treatment differences. However, 256 patients from sites enrolled in a follow-up study were monitored until March 2010. Median OS and 5-year and 10-year rates of OS were 39.1 months, 43.3% and 33.3%, respectively, in the BCG-placebo group, versus 34.9 months, 42.5% and 36.4%, respectively, in the BCG-Canvaxin group (hazard ratio, 1.053; 95% confidence interval, 0.81 to 1.36; p=0.6964). Median DFS, 5-year DFS, and 10-year DFS were 7.6 months, 23.8% and 21.7%, respectively, for the BCG-placebo group, versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG-Canvaxin group (hazard ratio, 0.882; 95% confidence interval, 0.708 to 1.097; p=0.2595). Positive skin test results correlated with improved survival. Conclusions: BCG-Canvaxin was not superior to BCG-placebo, but the highly favorable long-term survival for combined groups indicates that complete metastasectomy should be considered as initial therapy for patients with resectable stage IV melanoma (ClinicalTrials.gov identifier: NCT00052156).

Functional T Cells Targeting NY-ESO-1 or Melan-A Are Predictive for Survival of Patients With Distant Melanoma Metastasis

To analyze the prognostic relevance of circulating T cells responding to NY-ESO-1, Melan-A, MAGE-3, and survivin in patients with melanoma with distant metastasis. We examined 84 patients with follow-up after analysis (cohort A), 18 long-term survivors with an extraordinarily favorable course of disease before analysis (> 24 months survival after first occurrence of distant metastases; cohort B), and 14 healthy controls. Circulating antigen-reactive T cells were characterized by intracellular cytokine staining after in vitro stimulation. In cohort A patients, the presence of T cells responding to peptides from NY-ESO-1, Melan-A, or MAGE-3 and the M category according to the American Joint Committee on Cancer classification were significantly associated with survival. T cells responding to NY-ESO-1 and Melan-A (hazard ratios, 0.29 and 0.18, respectively) remained independent prognostic factors in Cox regression analysis and were superior to the M category in predicting outcome. Median survival of patients possessing T cells responding to NY-ESO-1, Melan-A, or both was 21 months, compared with 6 months for all others. NY-ESO-1-responsive T cells were detected in 70% of cohort A patients surviving > 18 months and in 50% of cohort B patients. Melan-A responses were found in 42% and 47% of patients in cohorts A and B, respectively. In contrast, the proportion was only 22% for NY-ESO-1 and 23% for Melan-A in those who died within 6 months. The presence of circulating T cells responding to Melan-A or NY-ESO-1 had strong independent prognostic impact on survival in advanced melanoma. Our findings support the therapeutic relevance of Melan-A and NY-ESO-1 as targets for immunotherapy.

Expression of MAGE-C1/CT7 and MAGE-C2/CT10 Predicts Lymph Node Metastasis in Melanoma Patients

MAGE-C1/CT7 and MAGE-C2/CT10 are members of the large MAGE family of cancer-testis (CT) antigens. CT antigens are promising targets for immunotherapy in cancer because their expression is restricted to cancer and germ line cells and a proportion of cancer patients presents with immune responses against CT antigens, which clearly demonstrates their immunogenicity. This study investigates the expression of MAGE-C1/CT7 and MAGE-C2/CT10 in primary and metastatic melanoma. Immunohistochemical staining of tissue microarrays that consisted of 59 primary malignant melanomas of the skin, 163 lymph node and distant melanoma metastases and 68 melanoma cell lines was performed. We found MAGE-C1/CT7 expression in 15 out of 50 (24%) primary melanomas and 15 out of 50 (24%) cell lines, whereas MAGE-C2/CT10 was detected in 17 out of 51 (33%) primary melanomas and 14 out of 68 (17%) cell lines. MAGE-C1/CT7 and MAGE-C2/CT10 were both detected in 40% of melanoma metastases. Patients with MAGE-C1/CT7 or MAGE-C2/CT10 positive primary melanoma had significantly more lymph node metastases (p = 0.005 and p<0.001, resp.). Prediction of lymph node metastasis by MAGE-C1/CT7 and MAGE-C2/CT10 was independent of tumor cell proliferation rate (Ki67 labeling index) in a multivariate analysis (p = 0.01). Our results suggest that the expression of MAGE-C1/CT7 and MAGE-C2/CT10 in primary melanoma is a potent predictor of sentinel lymph node metastasis.

Symptomatische Herzmetastase

Symptomatic cardiac melanoma metastases are very rare. A 76-year-old woman was admitted because of dyspnea and intrathoracic pain 8 years after surgery of a superficial spreading melanoma and 4 years after resection of in-transit metastases. MRI and echocardiography disclosed an intracavitary right atrial mass. Histologically a cardiac melanoma metastasis was found. Unspecific cardiac symptoms in a patient with elevated risk for distant metastases of melanoma should be further investigated to discover cardiac metastasis early.

Promoter Hypermethylation of the O6-Methylguanine DNA Methyltransferase Gene and Microsatellite Instability in Metastatic Melanoma

Tumor spread to distant organs is the most serious consequence of melanoma, as only 10-20% of stage IV patients respond to current chemotherapies. Tumor sensitivity to alkylating agents is affected by the activity of cellular DNA repair proteins, such as O(6)-methylguanine DNA methyltransferase (MGMT) and the DNA mismatch repair proteins. Chemosensitivity may be enhanced by reduced MGMT activity, but the frequency of MGMT promoter silencing through hypermethylation is unknown in distant melanoma metastases. The frequency and significance of microsatellite instability (MSI) in metastatic melanoma is also unclear, and it has been suggested that MSI frequency increases during the metastatic process. We undertook an analysis of 84 melanoma metastases from 47 patients. MGMT methylation was detected using methylation-specific PCR in 26 of the 84 metastases (31%), but there was discordance between individual metastases from the same patient. Therefore, as a result of this variation, MGMT methylation may have only limited value as a predictor of chemosensitivity. High MSI involving mononucleotide repeat markers was not found. Low MSI was detected in five of 50 metastases (10%) and only one of the five metastases also had MGMT methylation. These results demonstrate that in contrast to some previous reports, these tumors have a low frequency of MSI.

Surgical therapy for distant metastases of malignant melanoma.

Manifestation of distant metastases in melanoma patients commonly indicates a poor prognosis. The aim of the current study was to examine the role of surgical treatment in these patients. Data from 444 patients with distant melanoma metastases were gathered prospectively from January 1978 through December 1997. Characteristics of the primary tumor, time until the first occurrence of distant metastases, frequency and site of distant metastases, surgical therapy, and survival were evaluated by univariate and multivariate analyses. Histology, Breslow thickness, Clark level, and pT and pN categories (UICC 1997) significantly influenced the median interval from initial diagnosis to manifestation of distant metastases. The most common single localization was the lung (n = 83), followed by distant lymph node (n = 79), and skin metastases (n = 51). One hundred seventy-four patients received surgical treatment (39%) and 111 (25%) patients received surgical treatment with curative resection (R0, UICC 1997), most frequently in distant lymph node or skin metastases (57% and 59%, respectively). Median survival time and 2-year survival rate for all patients were 7 months and 15.8%, respectively, 17 months and 36.1% following curative resection, 6 months and 12.7% after incomplete resection (n = 63) (P < 0.0001). Conservatively treated patients survived for a median of only 4 months with a 2-year survival of 8.1%. Multivariate survival analysis showed localization of the primary tumor (head/neck/trunk vs. extremities), the number of involved sites, and surgical therapy to be independent prognostic factors. Surgical therapy of distant metastases was most beneficial when complete removal of metastatic tissue was achieved. Selection of patients for surgical excision should be determined by individual patient indications.

Does endogenous immune response determine the outcome of surgical therapy for metastatic melanoma?

Although the presence of tumor cells in the blood of patients with metastatic melanoma suggests widely disseminated disease, many of these patients enjoy prolonged survival or cure after surgical resection. Our previous study of adjuvant vaccine therapy after complete resection of metastatic melanoma revealed a strong correlation between postoperative survival and elevated antibody titers to a 90-kDa tumor-associated antigen (TA90) expressed by melanoma cells of the vaccine. We hypothesized a similar correlation between postoperative survival and endogenous anti-TA90 antibody titers induced by the patient's melanoma in the absence of postoperative adjuvant immunotherapy. From 1970 to 1996, 64 patients underwent complete resection of distant melanoma metastases and did not receive postoperative adjuvant immunotherapy. Serum collected within 4 months after surgery was tested in a coded and blinded fashion for anti-TA90 IgG and IgM by enzyme-linked immunosorbent assay, and for total IgG and IgM (controls) by radial immunodiffusion. Median follow-up for the study population was 19 months (range, 3-147 months). There was no significant correlation between anti-TA90 IgG titer and total IgG level (P = .4785), or between anti-TA90 IgM and total IgM (P = .0989). Univariate analysis showed that postoperative anti-TA90 IgM titer as a continuous variable was significantly associated with overall survival (OS); i.e., the higher the anti-TA90 IgM titer, the longer the OS. Using an established cutoff titer of 800, median OS was 42 months for patients with high anti-TA90 IgM titers (n = 28) vs. 9 months for patients with low titers (n = 36) (P = .0001). There was no significant correlation between total IgG/IgM and survival (P = .4107 and .4044, respectively). Multivariate analysis identified anti-TA90 IgM as the most significant independent variable influencing OS after complete resection of distant melanoma metastases (P = .0001). We conclude that the endogenous immune response to metastatic melanoma determines the outcome after surgical therapy. Enhancement of this specific immune response may prolong the survival of patients with distant melanoma metastases.