A synopsis of serum biomarkers in cutaneous melanoma patients.

Many serum biomarkers have been evaluated in melanoma but their clinical significance remains a matter of debate. In this paper, a review of the serum biomarkers for melanoma will be detailed and will be discussed from the point of view of their practical usefulness. The expression of biomarkers can be detected intracellularly or on the cell membrane of melanoma cells or noncancer cells in association with the melanoma. Some of these molecules can then be released extracellularly and be found in body fluids such as the serum. Actually, with the emergence of new targeted therapies for cancer and the increasing range of therapeutic options, the challenge for the clinician is to assess the unique risk/response ratio and the prognosis for each patient. New serum biomarkers of melanoma progression and metastatic disease are still awaited in order to provide efficient rationale for followup and treatment choices. LDH as well as S100B levels have been correlated with poor prognosis in AJCC stage III/IV melanoma patients. However, the poor sensitivity and specificity of those markers and many other molecules are serious limitations for their routine use in both early (AJCC stage I and II) and advanced stages of melanoma (AJCC stage III and IV). Microarray technology and proteomic research will surely provide new candidates in the near future allowing more accurate definition of the individual prognosis and prediction of the therapeutic outcome and select patients for early adjuvant strategies.

Cell migration-the role of integrin glycosylation.

BACKGROUND: Cell migration is an essential process in organ homeostasis, in inflammation, and also in metastasis, the main cause of death from cancer. The extracellular matrix (ECM) serves as the molecular scaffold for cell adhesion and migration; in the first phase of migration, adhesion of cells to the ECM is critical. Engagement of integrin receptors with ECM ligands gives rise to the formation of complex multiprotein structures which link the ECM to the cytoplasmic actin skeleton. Both ECM proteins and the adhesion receptors are glycoproteins, and it is well accepted that N-glycans modulate their conformation and activity, thereby affecting cell-ECM interactions. Likely targets for glycosylation are the integrins, whose ability to form functional dimers depends upon the presence of N-linked oligosaccharides. Cell migratory behavior may depend on the level of expression of adhesion proteins, and their N-glycosylation that affect receptor-ligand binding. SCOPE OF REVIEW: The mechanism underlying the effect of integrin glycosylation on migration is still unknown, but results gained from integrins with artificial or mutated N-glycosylation sites provide evidence that integrin function can be regulated by changes in glycosylation. GENERAL SIGNIFICANCE: A better understanding of the molecular mechanism of cell migration processes could lead to novel diagnostic and therapeutic approaches and applications. For this, the proteins and oligosaccharides involved in these events need to be characterized.

Evaluation of the prognostic significance of serum galectin-3 in American Joint Committee on Cancer stage III and stage IV melanoma patients.

Galectin-3 (Gal-3) is a member of the beta-galactoside-binding lectins family and has been implicated in angiogenesis, tumor invasion, and metastatic process in vitro and in vivo. As we showed recently that advanced melanoma patients presented high serum level of Gal-3, we investigated the association of this protein with the outcome of melanoma patients. Whether this protein could be a biomarker has not been assessed, and we compared the prognostic value of serum Gal-3 in multivariate analysis with lactate dehydrogenase, C-reactive protein and S100B. We conclude that Gal-3 could be of prognostic value in melanoma patients; more precisely, this protein has a strong independent prognostic signification with a cut-off value of 10 ng/ml. After these data, we believe that serum Gal-3 measurement can have an important role in the follow-up and management of advanced American Joint Commission on Cancer stage III and stage IV melanoma patients. Further studies will uncover whether Gal-3 will be able to open new therapeutic perspectives.

The post-thrombotic syndrome - a condition to prevent.

The incidence of the post-thrombotic syndrome (PTS) is increasing along with the incidence of deep vein thrombosis (DVT). The overall frequency of PTS ranges from 20 percent to 50 percent of DVT patients; severe PTS, which includes leg ulcers, occurs in a quarter of cases. Because of its severity and chronicity, PTS is associated with great morbidity and cost. Its diagnosis is primarily based on the presence of typical symptoms and signs, but objective evidence of venous valvular reflux can help to confirm the diagnosis. Because therapeutic options for PTS are extremely limited and results are often disappointing, prevention, recognition of clinical signs or complications, and early treatment remain the keys to reducing its morbidity. The prevention of DVT recurrence by anticoagulation and use of graduated compression stockings is likely to reduce the risk of PTS. There is no proven role for thrombolysis in preventing PTS.

Management of Merkel tumours: an evidence-based review.

(1) Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer of neuroendocrine origin generally seen in patients over 50 years of age. It has a high propensity for recurrence post-treatment; 5-year overall survival rates range from 23% to 80%. (2) The rarity of MCC means that there is a lack of prospective controlled trials in these patients. Patients are generally treated with surgery as a first-line therapy, supplemented with adjuvant radiotherapy and chemotherapy if required. (3) The use of adjuvant therapies in MCC remains controversial. Data from case series and meta-analyses of case series suggest that the addition of radiotherapy to surgery in patients with MCC can confer significant benefits with regard to reducing local and regional recurrence rates and prolonging disease-free survival. Generally, the current literature tends not to support the use of chemotherapy in these patients. (4) Stage-specific treatment regimens have been outlined involving various combinations of surgery, radiation and chemotherapy for International Union Against Cancer (UICC) stage I to III disease, while the emphasis of treatment in patients with UICC stage IV disease is on palliative care with or without radio- or chemotherapy. There is a need for more structured clinical research to better illuminate the most effective treatments for this disease.

A therapeutic approach to perianal extramammary Paget's disease: topical imiquimod can be useful to prevent or defer surgery.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare skin disease which can be limited to the epidermis and can sometimes also be associated with underlying carcinomas. At clinical examination, lesions are well-defined eczematous areas and have been described typically in the anogenital region. Surgery is the cornerstone treatment. CASE REPORT: In this report the case of a 66-year-old patient presenting with a long-lasting EMPD of perianal region without deep gastrointestinal neoplasia is described. Because of the extension of the lesion, surgery should have led to abdominoperineal amputation, but the patient rejected this option. Three months of daily application of topical imiquimod was prescribed as an alternative treatment. Biopsy-confirmed complete regression could be observed thereafter, and no recurrence has been noted during a 12-month follow-up. CONCLUSIONS: This successful treatment of a perianal-located EMPD by topical imiquimod warrants further investigations.

Novel treatment strategies for malignant melanoma: a new beginning?

Malignant melanoma is one of the most common cancer types among the Caucasian population. While the prognosis is excellent for patients diagnosed at an early stage and treated by adequate surgery, unresectable or advanced metastatic diseases shrink the overall survival at 5 years dramatically to less than 10%. For disseminated malignant melanoma, the appropriate systemic medical treatment is still controversial. Fortunately, progress in the molecular biology and in the understanding of pathogenesis has been made recently and should in the near future translate into molecular-based therapeutic strategies. In this review, we briefly describe the status of current treatment strategies and existing standards for malignant melanoma. We will focus on the new and emerging compounds including recent developments of targeted therapy such as antiangiogenic and immunomodulatory drugs, Bcl-2 antisense therapy, raf kinase inhibitors, heat shock protein modulators, anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 monoclonal antibody and finally PARP and proteasome inhibitors.

Significance of cell kinetic parameters in the prognosis of malignant melanoma: a review.

Malignant melanoma has been extensively studied concerning methods of predicting progression and clinical outcome. The maximum tumor thickness as measured by Breslow's method is the cornerstone prognostic criterion, but despite this, evolution of the disease in some patients remains unpredictable, confirming that new reliable prognostic factors are awaited. Cell kinetic evaluation has been shown to be a useful tool for assessing the prognosis of breast and gastrointestinal cancer patients. Indeed, in these fields, the mitotic index and MIB-1 expression index, which are indirect estimates of the growth fraction of tumor cell population, are commonly shown to correlate with tumor grade and patient survival and presented as prognostic factors. In melanoma, results of cell kinetic investigations are conflicting: some studies have established a link between high proliferative activity and a bad prognosis, whereas other reports suggest the opposite. The aim of this review is to discuss these findings.

Salivary gland carcinomas, paranasal sinus cancers and melanoma of the head and neck: an update about rare but challenging tumors.

PURPOSE OF REVIEW: This is a review about recent clinical developments in rare cancers of the head and neck. RECENT FINDINGS: Progress in molecular biology techniques has allowed the identification of new prognostic factors, and potential molecular-targeted therapies. This is of importance since chemotherapy continues to play a role but is still limited in this group of malignancies. New techniques of irradiation such as intensity-modulated radiotherapy and three-dimensional conformal radiotherapy appear to improve the locoregional control of these tumors. Surgery continues to be the cornerstone of treatment, with a growing interest in the technique of sentinel lymph node biopsy. SUMMARY: As salivary gland carcinomas, paranasal sinus cancers and melanoma of the head and neck are rare malignancies, these tumors must be treated in specialized anticancer centers with access to the latest surgical and irradiation techniques. Moreover, clinical studies with translational research are needed to identify strong prognostic and predictive factors, and effective molecular-targeted therapies.

A new dendritic cell vaccine generated with interleukin-3 and interferon-beta induces CD8+ T cell responses against NA17-A2 tumor peptide in melanoma patients.

Dendritic cells derived from monocytes cultured in the presence of type I interferon were found to induce efficient T cell responses against tumor antigens in vitro. We vaccinated eight stage III or IV melanoma patients with dendritic cells generated with interferon-beta and interleukin-3, activated by poly I: C, and pulsed with the tumor-specific antigen NA17.A2. This dendritic cell vaccine was well-tolerated with only minor and transient flu-like symptoms and inflammatory reactions at the injection sites. In most patients, isotopic imaging documented dendritic cells (DC) migration from the intradermal injection site to the draining lymph nodes. Finally, mixed lymphocyte-peptide culture under limiting dilution conditions followed by tetramer labeling indicated that three out of eight patients mounted a CD8 T cell response against the NA17.A2 antigenic peptide. We conclude that DC generated in type I-IFN represent an interesting alternative to DC generated in IL-4 and GM-CSF for cancer immunotherapy.

Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate.

The aim of the present phase I/II study was to evaluate the safety, immune responses and clinical activity of a vaccine based on autologous dendritic cells (DC) loaded with an allogeneic tumor cell lysate in advanced melanoma patients. DC derived from monocytes were generated in serum-free medium containing GM-CSF and IL-13 according to Good Manufacturing Practices. Fifteen patients with metastatic melanoma (stage III or IV) received four subcutaneous, intradermal, and intranodal vaccinations of both DC loaded with tumor cell lysate and DC loaded with hepatitis B surface protein (HBs) and/or tetanus toxoid (TT). No grade 3 or 4 adverse events related to the vaccination were observed. Enhanced immunity to the allogeneic tumor cell lysate and to TAA-derived peptides were documented, as well as immune responses to HBs/TT antigens. Four out of nine patients who received the full treatment survived for more than 20 months. Two patients showed signs of clinical response and received 3 additional doses of vaccine: one patient showed regression of in-transit metastases leading to complete remission. Eighteen months later, the patient was still free of disease. The second patient experienced stabilization of lung metastases for approximately 10 months. Overall, our results show that vaccination with DC loaded with an allogeneic melanoma cell lysate was feasible in large-scale and well-tolerated in this group of advanced melanoma patients. Immune responses to tumor-related antigens documented in some treated patients support further investigations to optimize the vaccine formulation.

Expression of galectin-3 in primary and metastatic melanoma: immunohistochemical studies on human lesions and nude mice xenograft tumors.

Galectins are a large family of proteins which bind galactoside-containing glycans. Their role in cancer seems to be important since members of the family may mediate cell adhesion and modulate cell growth. Galectin-3 (Gal-3) is expressed in the nucleus, in the cytoplasm and on the cell surface, and can also be secreted into the extracellular matrix. A series of experimental and clinical data have been reported which indicate that Gal-3 may play a putative role in carcinogenesis, cancer progression and the process of metastasis. To study the possible correlation between Gal-3 expression and malignant potential in primary melanoma lesions, we conducted an immunohistochemical study with monoclonal anti-Gal-3 antibody in a series of primary and metastatic melanoma lesions as well as benign skin pigmented lesions. We also developed a xenograft melanoma model in nude mice with two melanoma cell lines (ATCC G-361 and ATCC HT-144) and assessed staining with the Gal-3 antibody in the xenografts and the metastases. The expression of anti-Gal-3 staining was determined semiquantitatively. The expression of Gal-3 was higher in thin primary melanoma lesions than in benign pigmented skin lesions or metastases and seemed to correlate inversely with the aggressiveness as estimated by the Breslow index which is recognized as the main prognostic factor in melanoma. We propose Gal-3 expression in melanoma as a diagnostic and/or a prognostic parameter and suggest that further studies of such a role for Gal-3 are warranted.

Multifaceted role of galectin-3 on human glioblastoma cell motility.

Astrocytic tumors' aggressiveness results from an imbalance between cell proliferation and cell death favoring growth, but also from the propensity of tumor cells to detach from the primary tumor site, migrate, and invade the surrounding parenchyma. Astrocytic tumor progression is known to be associated with an increased expression of galectin-3. We investigated in cell culture how galectin-3 expression affects astrocytoma cell motility. Galectin-3 deficient cells were obtained by stable transfection of the U373 glioblastoma cell line with a specific expression antisense plasmid. Cultured galectin-3 deficient glioblastoma cells showed increased motility potential on laminin and modifications in the cytoskeleton reorganization. In addition, c-DNA microarrays and quantitative immunofluorescence analysis showed that galectin-3 deficient U373 cells have an increased expression of integrins-alpha6 and -beta1, proteins known to be implicated in the regulation of cell adhesion.

Interferon alpha as adjuvant postsurgical treatment of melanoma: a meta-analysis.

BACKGROUND: The literature on the benefit of alpha-interferon (IFN-alpha) as adjuvant postsurgical treatment of melanoma reports discordant results. OBJECTIVE: With the published data so far, we performed a meta-analysis in order to evaluate the effect of IFN-alpha on the relapse rate (RR) and the overall survival (OS). METHODS: Published randomised trials were identified by Medline search. Stage IV melanoma was not considered. RESULTS: Nine published studies were included, with a total of 2,880 patients. Both the per protocol and the intention-to-treat analysis show that IFN-alpha significantly decreased the RR (OR = 0.74; 95% CI = 0.64-0.86). Subgroup analyses show that, for all stages, high and low doses decreased the RR (OR = 0.71, 95% CI = 0.54-0.92, and OR = 0.76, 95% CI = 0.63-0.91, respectively). No difference has been evidenced on OS. CONCLUSIONS: High and low doses of IFN-alpha significantly decrease the RR, but the OS does not seem to be improved.