Course Of Melanoma Research Articles

Is oestrogen an important player in melanoma progression?

The oestrogen-dependent regulation of cell behaviour is realised by stimulation of specific oestrogen receptors. The classical oestrogen receptors ERα and ERβ are transcription factors, and they modulate expression of hormonally regulated genes, while the third one, GPER, is thought to be responsible for the observed rapid, non-genomic cellular response. Oestrogen dependency is attributed to a number of cancers, including breast, ovarian and endometrial cancer; however, there is still growing evidence that melanoma should also be cited as a hormonally dependent tumour. This comes from the observations of gender-related differences in melanoma progression and reports concerning the history of the malignant course of melanomas during pregnancy. Although, the observations of oestrogen regulation of melanoma progression are controversial, the effect of oestrogen should not be neglected, as the skin possesses its own hormonal microenvironment. This aspect of melanoma progression should be taken under careful consideration as it may offer new therapeutic possibilities.

Cutaneous melanoma in patients treated with tumour necrosis factor inhibitors: a retrospective series of 15 patients

Several case reports suggested that tumour necrosis factor-α (TNF) inhibitors might increase the incidence and/or alter the natural course of melanoma towards a more aggressive behaviour. Our objective was to point if history of melanoma in patients exposed to TNF inhibitors could present with a particular pattern at diagnosis or during follow-up. We performed a retrospective multicentre study settled in the West part of France to collect and analyse all cases of patients with melanoma who received anti-TNF therapy. Fifteen cases were included. First, 10 patients (mean age: 55.6years; sex ratio: 1) had a melanoma diagnosed after TNF inhibitors initiation. The mean duration between initiation of treatment and melanoma was 48.7months. Two patients died of metastatic disease. Second, four patients had a past history of melanoma before anti-TNF therapy (mean duration of treatment: 10.8months). None experienced a progression of melanoma disease. Last, one woman had a past history of melanoma before and then developed a second melanoma when exposed to biotherapy. Our case series does not reveal a distinct profile of melanoma in the patients exposed to TNF inhibitors. Additional prospective trials including larger number of patient are needed to demonstrate the possible link between biological therapy with TNF inhibitors and development of melanoma.

Lecithin retinol acyltransferase as a potential prognostic marker for malignant melanoma

Metabolism inside cells differs between cancer and normal cells. Because disturbance of vitamin A metabolism might be important, we investigated expression of the enzymes lecithin retinol acyltransferase (LRAT) and RPE65 by immunohistochemistry in melanoma metastases and melanocytic nevi. Semiquantitative evaluation of this expression revealed downregulated expression of RPE65 in malignant melanoma compared with benign melanocytic nevi (P<0.001). In contrast, expression of LRAT was not significantly different (P=0.339). High LRAT expression in melanoma metastases was inversely correlated with patient survival; Kaplan-Meier analysis revealed earlier melanoma-related death (P=0.003). Expression of LRAT might, therefore, be a prognostic marker of the clinical course of melanoma.

“Unsteady Gait”: An Uncommon Presentation and Course of Malignant Melanoma in Terminal Ileum—A Case Report and Review of Literature

Malignant melanoma within the gastrointestinal tract is an uncommon neoplasm that is usually metastatic in origin, with primary melanomas being relatively uncommon. Embryologically melanocytes normally exist in the esophagus, stomach, small bowel, and anorectum and this theory supports the primary melanoma of the gastrointestinal tract that has been confirmed for lesions occurring through several published reports. However, most patients with brain metastases from malignant melanoma are diagnosed after treatment for known extracranial metastases and have poor outcomes. Our case is unique in that we discuss an unusual case of 69-year-old female patient presented with unsteady gait as the first symptom of disease and where the presumed primary lesion later was found in the terminal ileum on colonoscopy. Treatment consisted of surgical removal of the terminal ileal lesion with chemotherapy, whole-brain radiotherapy, and cyberknife radiosurgical procedure. Patient was in remission for more than 14 months and later succumbed to disease. Despite the advances in therapeutic options, prognosis for patients with melanoma brain metastases remains poor with a median survival time of six months after diagnosis.

Sex-dependent liver colonization of human melanoma in SCID mice—role of host defense mechanisms

The possibility that endocrine factors may influence the clinical course of malignant melanoma is suggested by the superior survival data of women. In preclinical models we observed a higher rate of colony formation by human melanoma cells in male compared to female SCID mice, but only in the case of the liver and not in other organs. The gender difference could be seen at an early phase of colony formation. On the other hand, in our human melanoma cell lines we failed to detect steroid receptor protein expression, and treatment with sex hormones did not considerably influence their in vitro behavior. Investigating the possible contribution of host cells to the observed gender difference, we performed in vivo blocking experiments applying pretreatment of the animals with Kupffer cell inhibitor gadolinium chloride and the NK cell inhibitor anti-asialo GM1 antibody. While Kupffer cell blockade enhanced melanoma liver colonization equally in the two sexes, a more prominent increase was observed in female than in male mice in the case of NK cell inhibition. Further supporting the importance of NK cells in the lower liver colonization efficiency of melanoma cells in females, gender difference in colony formation was lost in NSG mice lacking NK activity. Although in humans no organ selectivity of gender difference in melanoma progression has been observed according to data in the literature, our results possibly indicate a contribution of natural host defense mechanisms to gender difference in survival of patients with melanoma or other tumor types as well.

Pregnancy Promotes Melanoma Metastasis through Enhanced Lymphangiogenesis

The relationships of pregnancy and melanoma have been debatable. Our aim was to assess the influence of gestation on the course of melanoma in a classic murine model of tumor progression and in women. B16 mouse melanoma cells were injected in nonpregnant or pregnant mice on day 5 of gestation. Animals were evaluated for tumor progression, metastases, and survival. Tumor sections were analyzed for lymphatic and blood vessel number and relative surface and expression of angiogenic growth factors. Finally, primary melanomas from pregnant and nonpregnant women, matched for age and tumor thickness, were also considered. Tumor growth, metastasis, and mortality were increased in B16-injected pregnant mice. Tumors displayed an increase in intratumoral lymphangiogenesis during gestation. This increased lymphatic angiogenesis was not observed in normal skin during gestation, showing its specificity to the tumor. An analysis of melanoma from pregnant and matched nonpregnant women showed a similar increase in lymphatic vessels. Tumors from pregnant mice had increased expression of vascular endothelial growth factor A at the RNA and protein levels. The increased vascular endothelial growth factor A production by melanoma cells could be reproduced in culture using pregnant mouse serum. In conclusion, pregnancy results in increased lymphangiogenesis and subsequent metastasis. Caution should be applied in the management of patients with advanced-stage melanoma during gestation.

ERCC5 p.Asp1104His and ERCC2 p.Lys751Gln Polymorphisms Are Independent Prognostic Factors for the Clinical Course of Melanoma

Genetic variants in DNA repair enzymes contribute to the susceptibility to cutaneous melanoma; consequently, we analyzed whether common nonsynonymous single-nucleotide polymorphisms in DNA repair enzyme genes might also influence the course of disease. To this end, we determined eight polymorphisms of seven different DNA repair enzymes in 742 patients with cutaneous melanoma, and correlated these with overall survival. Univariate Cox proportional hazards model analyses revealed that ERCC5 (XPG) 1104 His/His was significantly associated with impaired survival. Indeed, the univariate hazard ratio (HR) was 2.8 times higher for patients with ERCC5 1104 His/His (P<0.001) compared with ERCC5 1104 Asp/Asp. Accordingly, the 5-year survival rate was 55% (95% confidence interval 43-71) for patients with ERCC5 1104 His/His, whereas 82% (95% confidence interval 78-86) of patients with ERCC5 1104 Asp/Asp were still alive at this time. Importantly, adjusted Cox regression analysis not only confirmed ERCC5 1104 His/His as an independent prognostic factor (multivariate HR=4.5; P<0.001), but also revealed the significant impact of ERCC2 (XPD) 751 Gln/Gln on prognosis, with a 2.2-fold increased HR compared with ERCC2 751 Lys/Lys (P=0.009). Thus, ERCC5 codon 1104 and ERCC2 codon 751 polymorphisms are independent prognostic factors in patients with cutaneous melanoma.

Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study

BackgroundThe clinical features and the prognostic relevance of vitiligo lesions in melanoma patients are still controversial. This prospective observational study was designed to characterise the clinical features of melanoma-associated vitiligo, to analyse the association with other autoimmune manifestations and to ascertain whether the development of vitiligo lesions carries a prognostic relevance on the clinical course of melanoma. Materials and methodsA total of 2954 consecutive patients have been included; multivariate analyses of distant metastasis-free survival (DMFS) and overall survival (OS) were carried out to ascertain the independent prognostic role of vitiligo as a time-dependent covariate. ResultsVitiligo was demonstrated in 83 of 2954 melanoma patients (2.8%). A significantly higher percentage of autoimmune diseases was demonstrated in vitiligo patients (7 of 83) with respect to patients without vitiligo (80 of 2871) (P=0.004). Multivariate analyses selected the time-dependent covariate vitiligo as the favourable independent prognostic variable associated to a longer DMFS in stage III and a higher OS in both stage III and stage IV. ConclusionMelanoma-associated vitiligo should be considered as a distinct clinical entity, separate from vitiligo vulgaris, and identifies a subgroup of patients characterised by a high prevalence of immune-mediated diseases and by a favourable prognosis.

Prospective monitoring of adjuvant treatment in high-risk melanoma patients: lactate dehydrogenase and protein S-100B as indicators of relapse

At present there is no international consensus on laboratory testing during the follow-up of melanoma patients. We carried out a prospective monitoring study on the usefulness of lactate dehydrogenase (LDH) and protein S-100B assessment in high-risk melanoma patients. Ninety-seven patients treated within prospective randomized trials on the adjuvant treatment of melanoma received quarterly clinical visits and blood examinations. During the median observation period of 30 months disease progression was observed in 52 of 97 patients (53.1%). The clinical course of melanoma was correlated to elevated LDH and S-100B serum concentrations. The comparative analysis revealed that (i) neither LDH nor S-100B were indicators of in-transit metastases, (ii) clinically apparent lymph nodes were rarely detected because of elevated S-100B (29.4%) or LDH (11.8%) only, and (iii) the S-100B assessment was superior to LDH in the identification of early distant metastasis (53.8 vs. 23.1%; P=0.008). The rate of false-positive (elevated) LDH-serum levels and S-100B-serum levels in clinically disease-free melanoma patients did not differ significantly (S-100B 1.9% vs. LDH 1.6%). Our data indicate that only protein S-100B might be used as a highly specific and relatively sensitive marker of early distant metastasis. Both markers, LDH and S-100B, are not able to identify loco-regional metastases with a low tumor load in high-risk melanoma patients.

Protein microarray for the analysis of human melanoma biomarkers

The clinical course of malignant melanoma is notoriously variable. Current staging criteria allow assignment to risk categories but do not permit accurate assessment of prognosis. The simultaneous detection of biomarkers reflecting disease stage and likelihood of progression is therefore urgently needed for treatment decisions.Herein we describe the development of a protein microarray platform for the parallel analysis of five melanoma serum biomarker proteins: S100B, VEGF-A, CRP, IL-6 and IL-10. The platform utilizes ARChip Epoxy as a solid support for the covalent immobilization of antibodies using contact printing. Tests are based on sandwich immunoassays with streptavidin–biotin chemistry and fluorescence detection. Using CRP as a model marker optimization of the system in respect to printing buffer, antigen probe concentration (1mg/mL), assay binding buffer and incubation time (120min) is outlined. High reproducibility (CV<20%), weak cross-reactivity (<0.5% for IL-10) and low limit of detection (1.88×10−4mg/L) were achieved. Fit of a four-parameter logistic quantification model to standard curves of the five on-chip assays shows excellent coefficients of determination (R2≥0.966). Achieved sensitivities are perfectly comparable to classical ELISA kits and obtained working ranges allow discrimination between normal and literature-reported elevated serum levels of melanoma markers.

Progression of malignant melanoma is associated with reduced 25‐hydroxyvitamin D serum levels

Solar UV‐exposure, particularly intensive short‐time and recreational sun exposure, is considered to be the major etiologic factor for melanoma. But on the other hand 90% of all requisite vitamin D has to be formed in the skin through the action of the sun – a serious problem due to the fact that new scientific findings convincingly demonstrate vitamin D deficiency to be associated with a variety of severe diseases including various types of cancer (e.g. colon, prostate and breast cancer). According to recent reports sun exposure is associated with a relatively favorable prognosis and increased survival rate in various malignancies, including malignant melanoma. It has been speculated that these findings were related to UV exposure‐induced relatively high serum levels of vitamin D which may lead to a more favorable course of melanoma. To prove this hypothesis the present study aimed to correlate the serum level of 25‐hydroxyvitamin D (which represents the readily measurable ‘storage’ precursor form of vitamin D) with tumor thickness at time of diagnosis and course of disease in patients with melanoma. The study population consisted of 212 patients with histologically proven cutaneous melanomas of different stages: stage I (n = 50); stage II (n = 20); stage III (n = 20); stage IV (n = 122). Basal 25‐hydroxyvitamin D levels were analyzed (DiaSorin LIAISON 25‐OH Vitamin D‐Assay) in those patients and compared with a control group (n = 80). Additionally, each participant was requested to fill out a questionnaire about the history of sun exposure. Interestingly, basal 25‐hydroxyvitamin D levels were lower in melanoma patients as compared to the control group, although this difference was statistically not significant. Moreover, progression of malignant melanoma was associated with statistically significantly reduced 25‐hydroxyvitamin D serum levels. In conclusion, our findings add to the growing body of evidence that 25‐hydroxyvitamin D serum levels may be of importance for pathogenesis and progression of malignant melanoma.

Short German guidelines: Malignant melanoma

Malignant melanoma is a malignant tu-mor which arises from melanocytic cellsand primarily involves the skin. For thebalance of these guidelines, the termsmalignant melanoma and melanoma willbe used interchangeably, because thereare no benign melanomas. Melanomascan also arise in the eye (conjunctiva anduvea), meninges and on various mucosalsurfaces. While melanomas are usuallyheavily pigmented, there are also amela-notic tumors. Even small tumors have atendency towards metastasis and thus arelatively unfavorable prognosis. Melan-omas account for 90% of the deaths as-sociated with cutaneous tumors. The incidence of melanoma is increasingworldwide in white populations, especi-ally where fair-skinned peoples receiveexcessive sun exposure. In central Europethe incidence is 10 – 12 / 100,000yearly; in the USA, 10-25 / 100,000yearly; and in Australia the highest inci-dence, 50-60 / 100,000 yearly. In indivi-duals with more pigmentation (Asians,Africans) melanomas are uncommonand almost always found on either acralor mucosal surface. Individuals withlarge numbers of melanocytic nevi andthose with melanoma precursors (dyspla-stic nevi, congenital nevi) are at greaterrisk. The inheritance of melanoma is po-lygenic; 5-10% of melanomas appear inmelanoma-prone families. In addition tothese genetic and constitutional factors,the most important exogenous factor isexposure to UV irradiation. The relativeroles of toxic substances, medicationsand hormones (pregnancy, oral contra-ceptives) are controversial. The immunestatus of the patient plays a major role indetermining the course of melanoma, asnumerous examples of spontaneous re-gression or of rapid progression in im-munosuppressed individuals bear testi-mony.A number of different types of melano-mas can be identified clinically and hi-stologically. Some tumors either repre-sent mixed forms or are not classifiable.Examples of special forms are amelanoticmelanomas, mucosal melanomas, andother extracutaneous melanomas, whichtogether account for about 5% of allmelanomas.

Influence of therapy on the antioxidant status in patients with melanoma

Some anticancer drugs can result in increased production of reactive oxygen species (ROS). Alkylating agents are the most frequently used drugs in chemotherapeutic regimens for the treatment of malignant melanoma. It is known that triazenes exhibit in vivo activity by alkylation of nucleic acids and proteins, but there is no data about ROS formation during oxidative metabolism. Single agents of most interest for treatment of malignant melanomas include 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (DTIC) and nitrosoureas such as 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), but complete response to these drugs is rare. The present study aimed to determine whether an oxidative stress occurs during the clinical course of melanoma and the influence of therapy on the antioxidant status of patients with melanoma. For this purpose, we investigated plasma concentrations of MDA as indices of the levels of lipid peroxidation products. In addition, we studied the activities of the antioxidant enzymes superoxide dismutases (SOD) and catalase (CAT) in patients with melanoma before any treatment, after surgical removal of melanoma, and after chemotherapy with DTIC or in combination with CCNU of the operated patients. Twenty one patients with melanoma were studied. Patients were operated prior to chemotherapy. After recovery for 10-20 days postoperatively, they were studied again for MDA, SOD and CAT activity. The patients were divided into two groups according to the chemotherapy (3-7 treatment cycles): with DTIC-given orally daily for 5 days, every 3 weeks as a single 2200 mg/kg dose and with the combination-DTIC (the same dose) + CCNU-administered orally at a dosage of 120 mg/m(2) once every 40 days in accordance with protocols, approved by the Bulgarian Ministry of Health. The total amount of lipid peroxidation products in plasma was assayed. Plasma levels of MDA and CAT activity were significantly higher, and erythrocyte SOD activity significantly lower, in patients with melanoma, than in control healthy volunteers (P < 0.0001). Ten to twenty days after surgery, oxidative stress decreased but levels of MDA increased as a result of therapy. Important sources of increased ROS production may be the monocytes, phagocytosis of tumour cells and the cancer tissues. Plasma MDA in patients treated with DTIC + CCNU were significantly higher (P < 0.001), but erythrocyte SOD statistically lower (P < 0.00001), compared with patients treated with DTIC only. However, a combination of DTIC + CCNU did not attenuate oxidative stress, or reduced antioxidant status. Patients treated with this combination are at bigger risk of oxidative injury. Therefore, this disturbance might be due to augmented generation of toxic ROS, possibly from the metabolism of CCNU. Increased oxidative stress follows an imbalance in antioxidant defence in non-treated patients with melanoma. The impaired antioxidant system favours accumulation of ROS, which may promote the cancer process. After complete removal of melanoma tissues, oxidative stress decreased. The antioxidant status of melanoma patients operated on was influenced by the different chemotherapeutic regimens used and may play an important role in the response. Patients on DTIC + CCNU are at higher risk of oxidative injury. This drug combination probably exerts its toxic activity by ROS, which could be products of the metabolism of CCNU.

Comparison of the prognostic value of matrix metalloproteinases 2 and 9 in cutaneous melanoma

Previously, gelatinases matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to be involved in melanoma invasion and progression. Also, overexpression of MMP-2 has been suggested to be linked to hematogenous metastasis in melanoma. This study was conducted to study the prognostic value of MMP-2 and MMP-9 in human melanoma. The expression of MMP-2 and MMP-9 immunoreactive protein was evaluated in 157 cases of primary melanomas. An immunohistochemical analysis using specific monoclonal antibodies for MMP-2 and MMP-9 on paraffin-embedded tissues was performed, and the immunostaining results were compared with the clinical course of melanoma. Overexpression of MMP-2 (>20% of malignant cells positive) was an independent prognostic marker for melanoma related death, with odds ratio of 2.6 (95% confidence interval, 1.32-5.07). The 10-year disease-specific survival rate was only 51% in patients with overexpression of MMP-2 protein compared with 79% in patients with a primary melanoma with low expression for MMP-2 (P = .001). Interestingly, male patients with a melanoma with overexpression of MMP-2 showed a 10-year disease-specific survival of only 41% compared with 77% in other male patients (P = .003). It is notable that the immunoreactive protein for MMP-9 in primary melanoma was not found to be of any prognostic importance. In the future, MMP-2 could be acknowledged as a new prognostic factor in melanoma. MMP-9, on the other hand, was not associated with the clinical course of melanoma. Based on the current data, MMP-2 could be evaluated as an inclusion factor for adjuvant studies especially in male melanoma patients.

The Prognostic Role of Blood Lymphocyte Subset Distribution in Patients With Resected High-risk Primary or Regionally Metastatic Melanoma

The aim of this study was to investigate whether the profile of peripheral blood lymphocyte subsets of patients with high-risk malignant melanoma is associated with prognosis. Blood samples were systematically obtained from 31 patients with high-risk melanoma eligible for the Nordic Melanoma Cooperative Group adjuvant interferon study. The frequencies of peripheral blood lymphocyte subsets were monitored by flow cytometry using CD3, CD4, CD8, CD56, and CD69 monoclonal antibodies. Patients with low proportions of CD3+CD4+CD69+ cells and of CD3+CD56+ cells before treatment had an improved disease-free survival compared to those with high proportions [77.7 vs. 16.8 mo, hazard ratio (HR) 0.25, confidence interval (CI) 0.09-0.71, P=0.005 and 77.2 vs. 16.0 mo, HR: 0.25, CI 0.086-0.73, P=0.001, respectively]. Low pretreatment levels of these cell populations also correlated with a better overall survival (79.2 vs. 22.6 mo, HR: 0.17, CI 0.05-0.52, P=0.0005 and 78.2 vs. 21.4 mo, HR: 0.2, CI 0.07-0.59, P=0.001, respectively). In the multivariate analysis both the pretreatment proportion of CD3+CD4+CD69+ cells (P=0.01, HR: 0.21, CI 0.07-0.67) and CD3+CD56+ cells (P=0.01, HR: 0.22, CI 0.062-0.65) were independent prognostic factors for overall survival. Our data show that both the proportions of CD3+CD4+CD69+ cells and of CD3+CD56+ cells seem to have a prognostic potential in the natural course of melanoma. These results need to be confirmed in larger studies.

The polymorphisms of interleukin-10 gene influence the prognosis of patients with advanced melanoma

The interleukin-10 gene ( IL-10) is polymorphic. The genotypes result in inter-individual differences in IL-10 production, which may play a role in the pathophysiology and the clinical course of melanoma and other cancers. We analyzed the frequency of the ATA haplotype formed by the alleles at –1082 (G/A), –819 (C/T), and –592 (C/A) at the promoter region of the IL-10 gene in patients with melanoma ( n = 108) and healthy subjects ( n = 393). We also studied the long-term prognostic significance of the ATA haplotype carriage. There were significantly more ATA carriers in melanoma patients compared with control subjects (44 vs. 33%, respectively, P = 0.03). In the patients who presented with localized disease, the haplotype carriage was not significantly associated with recurrence rate, disease-free survival, or overall survival. In the patients who presented with or developed advanced disease ( n = 36), the ATA haplotype carriage [HR 0.47, 95% confidence interval (CI) 0.22–1.01, P = 0.05] was found statistically significant when adjusted by metastatic sites (HR 4.63, 95% CI 1.88–11.44, P = 0.0009) in multivariate analysis for survival. ATA haplotype carriage appears to increase the susceptibility to melanoma. This is not a significant prognostic factor in localized melanoma, but in advanced disease, it implies longer survival.

The CDKN2a common variants: 148 Ala/Thr and 500 C/G in 3' UTR, and their association with clinical course of melanoma.

Changes in CDKN2a gene are known to be linked with sporadic melanoma and hereditary predisposition to this cancer. In the Polish population mutations in the coding region of the CDKN2a gene are rather rare, therefore the attention has been focused on polymorphisms and alterations in uncoding regions such as 3' UTR. The aim of this study was to analyze two common polymorphisms, Ala148Thr and 500 C/G, and correlate them with the clinical course of melanoma. DNA from 285 patients was analyzed and found polymorphisms were correlated with the clinical parameters employing statistical methods. The obtained results allow us to conclude: (i) survival times of 500 C/G carriers vs. cumulating proportion surviving was not statistically significant; (ii) CDKN2a polymorphism 500 C/G correlated with Ala148Thr; (iii) no correlation was observed between the 500 C/G polymorphism and age of diagnosis, localization of primary melanoma and survival time; (iv) we did not find correlation between 500 C/G and type of cancer in the family; (v) changes in the CDKN2a gene were not found in patients with second cancer.

Prognostic factors in melanoma

Summary Background There are clinical and pathological factors associated with the clinical course of melanoma. These parameters allow us to predict survival times and establish a course of treatment. Aim The aim of the study was to assess the significance of immunohistochemical markers in the progression of melanoma, and relate these findings to the influence of clinical and histological factors on survival time. Materials/Methods In this study, archival histological material obtained from 50 melanoma patients operated on in the Great Poland Cancer Centre between 1990–1995 was analysed. Using immunohistochemistry we detected the presence of markers known to be important in the diagnosis of melanoma, including: HMB-45, PCNA, Ki-67, MMP-2, CD44 and nm23. Following this, univariate logistic regression was performed and clinical, histopathological and immunohistochemical data of statistical significance were correlated with survival time using the Cox nonparametric proportional hazard regression model. Results The results suggested that the most important prognostic factors correlating with survival time were: the presence of nm23 antigen (p = 0.0342) and the thickness of the melanoma, as measured by the Breslow method in mm (p = 0.0191). According to the univariate analysis there were correlations between patient death or survival and the histological type, Superficial Spreading Melanoma Malignum (SSMM) (p = 0.0187), regional lymphatic metastases (p = 0.0030) and positive Ki-67 results (p = 0.0282). Conclusions Taken together, our results allowed us to conclude (a) that there was a correlation between survival time and nm23 antigen expression and the thickness of melanoma, as measured by the Breslow method in mm, (b) that there were correlations between patient survival or death and the histological type of Superficial Spreading Melanoma Malignum, regional lymphatic metastases and positive Ki-67, (c) that other parameters (age, gender, anatomical location of the melanoma, the presence of ulceration, lymphatic infiltration, the existence of satellites, and positive PCNA and MMP-2) showed no significant influence on survival.

Molecular Staging in Stage II and III Melanoma Patients and Its Effect on Long-Term Survival

To assess the prognostic value of serial reverse transcriptase polymerase chain reaction (RT-PCR) -based measurements of tyrosinase mRNA in peripheral blood of stage II and III melanoma patients. During routine follow-up of American Joint Committee on Cancer stage II and III melanoma patients, serial testing for tyrosinase transcripts in peripheral blood was performed by RT-PCR. The PCR results were compared with the clinical data collected during the follow-up. Over a period of 3 years, 111 patients (78 stage II and 33 stage III patients) were enrolled, and tyrosinase determinations were carried out. The 6-year disease-specific survival probability was 97% for patients always showing negative RT-PCR results and 67% for patients who tested positive at least once. In a Cox proportional hazards model, the prognostic value of sex, age, site of primary tumor, histologic subtype, stage, Breslow's tumor thickness, Clark level, and the time-dependent variable PCR result was assessed. Patients with a positive RT-PCR test had a distinctly higher risk of dying from melanoma, with a hazard ratio of 12.6 (95% CI, 3.4 to 46.3; P < .001). Our study shows a strong association between PCR and disease-specific survival time. Detection of tyrosinase mRNA in peripheral blood may be of similar importance for the clinical course of melanoma as the detection of micrometastatic disease in the sentinel lymph node. Whether a combination of these two factors leads to a better definition of the prognosis of melanoma patients is under investigation in current studies.

Corticosteroid Treatment for Melanoma-Associated Retinopathy

Visual disturbance in the course of melanoma is rare. Specific localized metastases and drug toxic effects are frequently the cause. Recognition of a retinopathy raises several questions when the diagnosis of melanoma-associated retinopathy (MAR) can be confirmed. Descriptions of such patients in dermatologic literature are rare and deserve attention because therapeutic decisions are mandatory. A 70-year-old woman had a first melanoma in 1985 and a second primary melanoma in 1994. Axillary lymph node involvement occurred in November 2000, leading to surgery and chemotherapy. In December 2001, she had sudden bilateral visual loss, with shimmering blobs of color and flickering photopsias. Computed tomography and cerebral magnetic resonance imaging ruled out localized tumor on the eyes or optic nerves or evolution of disease. Ophthalmologic examination revealed a bilateral posterior uveitis, with hyalitis and progressive destruction of retinal pigment. The electrophysiologic data confirmed the diagnosis of MAR. Symptoms improved after systemic corticosteroid therapy, with no relapse after tapering doses despite worsening of melanoma. As a rare paraneoplastic visual syndrome possibly leading to blindness, MAR is characterized by bipolar cell involvement without photoreceptor cell impairment. Also, MAR is linked to the presence of autoantibodies directed against melanoma antigens that cross-react with the rod bipolar cells of the retina. Corticosteroid therapy is rarely beneficial. Our case of MAR is noteworthy because it involved a woman, was associated with an uveitis, and improved with corticosteroid therapy.