Effect of intravenous immunoglobulin administration on erythrocyte and leucocyte parameters.

BACKGROUND: Intravenous immunoglobulins (IVIG) are an attractive therapeutic tool for therapy of toxic epidermal necrolysis and severe forms of certain autoimmune diseases, including dermatomyositis, autoimmune blistering diseases, systemic vasculitis and lupus erythematodes. OBJECTIVES: Prompted by a case of IVIG-associated haemolytic anaemia, the effects of IVIG administrations on haematological parameters in patients with dermatological conditions were investigated. METHODS: Erythrocyte and leucocyte parameters were retrospectively analysed in 16 patients who had received IVIG at doses from 1 to 3 g/kg bodyweight (n = 35 cycles). The influence of IVIG on leucocyte survival was determined in vitro. RESULTS: Decreased absolute erythrocyte numbers, haemoglobin and haematocrit levels and a case of haemolytic anaemia were linked to transfusion of high-, but not low-dose IVIG. In contrast, leucopenia post-IVIG occurred in the vast majority of the recipients, unrelated to the administered IVIG amounts. In vitro investigations revealed a dose-dependent impairment of cell survival by IVIG in the neutrophil and monocyte, but not in the lymphocyte subpopulations. In several IVIG preparations, substantial amounts of blood group anti-A/anti-B antibodies were detected which could have accounted for the observed changes in the haematological parameters in our study cohort. CONCLUSIONS: IVIG products should be administered strictly according to indications. Commercially available IVIG products can contain blood group-specific antibodies that may induce haemolysis in some recipients. Monitoring of blood counts during applied IVIG therapy, especially when high doses are administered, is recommended.

Adjuvant treatment with pegylated interferon α-2a versus low-dose interferon α-2a in patients with high-risk melanoma: a randomized phase III DeCOG trial.

BACKGROUND: Adjuvant treatment with interferon (IFN)-α-2a improved disease-free survival (DFS) and showed a trend for improving overall survival (OS) in melanoma. This trial was designed to examine whether PEG-IFN is superior to IFN with regard to distant metastasis-free survival (DMFS), DFS and OS. PATIENTS AND METHODS: In this multicenter, open-label, prospective randomized phase III trial, patients with resected cutaneous melanoma stage IIA(T3a)-IIIB (AJCC 2002) were randomized to receive PEG-IFN (180 µg subcutaneously 1×/week; 24 months) or IFN α-2a (3MIU subcutaneously 3×/week; 24 months). Randomization was stratified for stage, number of metastatic nodes, age and previous IFN treatment. The primary end point was DMFS; secondary end points were OS, DFS, quality of life (QoL) and tolerability. RESULTS: A total of 909 patients were enrolled (451 PEG-IFN versus 458 IFN). Neither 5-year DMFS [PEG-IFN 61.0% versus IFN 67.3%; hazard ratio (HR) 1.16, P = 0.21] nor 5-year OS (PEG-IFN 73.2% versus IFN 75.2%; HR 1.05, P = 0.70) nor 5-year DFS (PEG-IFN 57.3% versus IFN 60.9%; HR 1.09, P = 0.40) showed significant differences. Subgroup analyses in patients ± ulcerated primaries and of different tumor stages did not find differences in DMFS, OS or DFS between the treatment groups. One hundred and eighteen patients (26.2%) in the PEG-IFN and 61 patients (13.3%) in the IFN population did not receive the full dosage and length of treatment due to adverse events (P < 0.001). Leukopenia and elevation of liver enzymes were more common in the PEG-IFN arm (56% versus 23.5% LCP; 19.1% versus 9.4% AST; 33.0% versus 16.5% ALT). QoL was identical for nearly all domains. CONCLUSION: PEG-IFN did not improve the outcome over IFN. A higher percentage of patients under PEG-IFN discontinued treatment due to toxicity. CLINICAL TRIALSGOV IDENTIFIER: NCT00204529.

Impact of oncogenic BRAF mutations and p16 expression on the growth rate of early melanomas and naevi in vivo.

BACKGROUND: It is important to know what drives and arrests melanocytic growth in vivo but observations linking oncogenic mutations to growth rates of melanocytic neoplasms in vivo are sparse. OBJECTIVES: To clarify the relationship between BRAF(V) (600E) mutations and p16 expression and the growth rate of melanocytic neoplasms in vivo. METHODS: We measured the growth rate of 54 melanocytic lesions (26 melanomas, 28 naevi) in vivo with digital dermatoscopy and correlated it with BRAF(V) (600E) and p16 expression, and with dermatoscopic and histological patterns. RESULTS: Melanomas grew faster than naevi (mean 2·7 vs. 0·8 mm(2) /year; P < 0·001) and the growth rate was faster in lesions with more nests (> 25% nests: 2·0 mm(2) /year vs. < 25% nests: 1·0 mm(2) /year; P = 0·036). Melanomas with the BRAF(V) (600E) mutation grew significantly faster than melanomas without the mutation (mean 3·36 vs. 1·60 mm(2) /year, P = 0·018). This effect of the BRAF(V) (600E) mutation on the growth rate was not observed in melanocytic naevi (mean 1·01 vs. 0·47 mm(2) /year, P = 0·274). Histopathologically, extensive nesting, larger nests and larger cell sizes were more common in melanocytic neoplasms with the BRAF(V) (600E) mutation than in those without the mutation. Melanomas expressing p16 had a slower growth rate than melanomas without p16 expression (2·27 vs. 4·34 mm(2) /year, P = 0·047). This effect was not observed in naevi (0·81 vs. 0·68 mm(2) /year, P = 0·836). CONCLUSIONS: The expression of BRAF(V) (600E) and the loss of p16 accelerate the growth rate of early melanomas in vivo but not in melanocytic naevi. In comparison to melanocytic proliferations that lack the mutation, the epidermal melanocytes in lesions that harbour BRAF(V) (600E) mutations are larger and more frequently arranged in large nests.

Characterization of patients at high risk of melanoma in Austria.

BACKGROUND: Risk of melanoma is determined by genetic and exogenous factors. Only a few studies have included both characteristics in a comprehensive multivariable analysis. OBJECTIVES: To find determinants of patients at high risk of melanoma in Austria, including phenotype, genotype and lifestyle characteristics in comprehensive analyses. METHODS: In total, 1668 patients with melanoma from the M3 case-control study were studied. Overall, 567 participants were sequenced for CDKN2A, 232 for CDK4, 123 for MITF encoding the variant E318K and 964 for MC1R. RESULTS: Patients with melanoma with a positive family history (n = 190, 11·6%), multiple primary melanomas (n = 261, 15·7%) and younger age (< 50 years, n = 675, 40·5%) were defined as being at high risk. All other patients with melanoma were defined as the reference group. We found significant differences between those two groups and between the high-risk subgroups (positive family history, multiple primary melanomas and younger age). Pigmentation phenotype was associated with the high-risk group in general (childhood freckling, odds ratio 1·46, P = 0·007; blond/reddish hair colour, odds ratio 1·43, P = 0·011). Patients with a positive family history and patients with early-onset disease were similar regarding both their phenotypic characteristics and external factors. Established high-risk mutations in CDKN2A were found in cases with a positive family history (n = 12) or multiple melanomas (n = 2). Moreover, we found three patients carrying the MITF p.E318K variant, two with a CDK4 variant and seven with nonsynonymous MC1R variants with undescribed biological significance, of which four were predicted as damaging. CONCLUSIONS: Austrian patients could represent a reservoir for novel genetic variants. Further investigation of populations in Central and Eastern Europe might reveal more novel and disease-relevant variants.

Actinic damage on the back is significantly determined by MC1R variants and previous sun exposure compared with other body sites in a multivariate analysis.

BACKGROUND: Only recently, site-dependent associations of actinic damage with melanoma were identified in our study population. OBJECTIVES: To elucidate the diverse aetiologies for actinic damage at different body sites. METHODS: We performed multivariate logistic regression analyses to identify independent risk factors for actinic damage on the face, hands and the back in 2112 participants of central European origin. RESULTS: For actinic damage on the face, age was the only risk factor that remained consistently significant in a multivariate analysis, whereas actinic damage on the back was predominantly associated with number of sunburns, freckles in childhood, holiday weeks and male sex. Moreover, we identified a particular significance of MC1R variants and dorsal actinic skin damage. CONCLUSIONS: The particular effect of MC1R variants and sun exposure during recreational time on dorsal actinic damage indicates that actinic damage on the back is more informative regarding susceptibility to sunlight and past sun exposure associated with melanoma risk.

Guidelines on the use of extracorporeal photopheresis.

BACKGROUND: After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. MATERIALS AND METHODS: In order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. RESULTS AND CONCLUSION: These guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

Pretherapeutic laboratory findings, extent of metastasis and choice of treatment as prognostic markers in ocular melanoma- a single centre experience.

BACKGROUND: Uveal melanoma is the most common intraocular neoplasm with a high tendency to metastasize predominantly to the liver. Prognostic parameters for progression and overall survival are not well defined. The aim of this study was to assess the value of pretherapeutic serum levels of C-reactive protein (CRP), lactate dehydrogenase, albumin and fibrinogen in patients with uveal melanoma and to evaluate their significance as prognostic parameters for survival. METHODS: Forty-nine patients with metastatic uveal melanoma treated between 2000 and 2010 were retrospectively analysed. The potential influence of levels of CRP, lactate dehydrogenase, fibrinogen and albumin as well as other commonly known prognostic variables on progression-free and overall survival were investigated. RESULTS: Patients' age and treatment with systemic chemotherapy were the only variables to show significant influences on progression-free and overall survival in a univariate analysis. Multivariate analysis confirmed the influence of these variables on progression-free survival, presence of metastasis, pretherapeutic CRP levels and treatment with systemic chemotherapy were associated with overall survival. CONCLUSION: In this patient cohort elevated pretherapeutic CRP and extent of metastasis are independent prognostic factors for decreased overall survival, whereas treatment with systemic chemotherapy showed a significant association with improved overall survival.

bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice.

Malignant melanoma is a prime example of cancers that respond poorly to various treatment modalities including chemotherapy. A number of chemotherapeutic agents have been shown recently to act by inducing apoptosis, a type of cell death antagonized by the bcl-2 gene. Human melanoma expresses Bcl-2 in up to 90% of all cases. In the present study we demonstrate that bcl-2 antisense oligonucleotide treatment improves the chemosensitivity of human melanoma grown in severe combined immunodeficient (SCID) mice. Our findings suggest that reduction of Bcl-2 in melanoma, and possibly also in a variety of other tumors, may be a novel and rational approach to improve chemosensitivity and treatment outcome.

Dermal infiltrates of cutaneous T-cell lymphomas with epidermotropism but not other cutaneous lymphomas are abundant with langerin⁺ dendritic cells.

BACKGROUND: The Langerhans cell (LC) hypothesis suggests that cutaneous T-cell lymphomas (CTCL) are diseases of chronic T-cell stimulation by LC-mediated antigen presentation. OBJECTIVE: To investigate a broad panel of CTCL and cutaneous B-cell lymphomas (CBCL) for the spatial association of langerin(+) dendritic cells (DC) with T and B cells in the skin, respectively. METHODS: Fifty-five specimens of CTCL and 10 of CBCL were double-stained with monoclonal antibodies against langerin and CD3 or CD20, respectively, and evaluated by confocal laser scan microscopy. RESULTS: Dermal infiltrates in mycosis fungoides (n = 38), primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (n = 3) and primary cutaneous peripheral T-cell lymphoma, unspecified (n = 3) were characterized by a high frequency of dermal langerin(+) DCs. These cells were exclusively present in the malignant infiltrates. No direct co-localization of CD3 and langerin could be resolved. Dermal langerin(+) cells were detected only in one of six primary cutaneous anaplastic large cell lymphomas (C-ALCL), characterized by epidermotropism. In other C-ALCL cases (five of six), in lymphomatoid papulosis (n = 3), subcutaneous panniculitis-like T-cell lymphoma (n = 2), and all variants of CBCL no dermal langerin(+) DCs could be found. CONCLUSIONS: Langerin(+) DCs are abundant in the dermal infiltrates of T-cell lymphomas with specific involvement of the epidermis. This might indicate that immature LC and neoplastic T cells interact and gives rise to further studies to characterize the phenotype of the langerin(+) cell population described here and its role in the pathology of CTCL.

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study.

BACKGROUND: This phase II study evaluated the safety and activity of ipilimumab, a fully human mAb that blocks cytotoxic T-lymphocyte antigen-4, in patients with advanced melanoma. PATIENTS AND METHODS: Patients with previously treated, unresectable stage III/stage IV melanoma received 10 mg/kg ipilimumab every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. The primary end point was best overall response rate (BORR) using modified World Health Organization (WHO) criteria. We also carried out an exploratory analysis of proposed immune-related response criteria (irRC). RESULTS: BORR was 5.8% with a disease control rate (DCR) of 27% (N = 155). One- and 2-year survival rates (95% confidence interval) were 47.2% (39.5% to 55.1%) and 32.8% (25.4% to 40.5%), respectively, with a median overall survival of 10.2 months (7.6-16.3). Of 43 patients with disease progression by modified WHO criteria, 12 had disease control by irRC (8% of all treated patients), resulting in a total DCR of 35%. Adverse events (AEs) were largely immune related, occurring mainly in the skin and gastrointestinal tract, with 19% grade 3 and 3.2% grade 4. Immune-related AEs were manageable and generally reversible with corticosteroids. CONCLUSION: Ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population.

A virosomal formulated Her-2/neu multi-peptide vaccine induces Her-2/neu-specific immune responses in patients with metastatic breast cancer: a phase I study.

We have previously shown in mice that vaccination with three Her-2-peptides representing B-cell epitopes of the extracellular domain of Her-2/neu induces Her-2/neu-specific IgG antibodies with strong anti-tumor activity in vitro and in vivo. We have now finalized a phase I clinical trial with an anti-Her-2/neu vaccine-construct of immunopotentiating reconstituted influenza virosomes with the three peptides in patients with metastatic breast cancer (MBC). Ten MBC patients with low protein overexpression of Her-2/neu of MBC (+ or ++ upon immunohistochemistry, FISH negative) and positive hormone receptor status were enrolled in a single center phase I study. The virosomal formulated vaccine, consisting of 10 microg/peptide, was intramuscularly applied three times on days 1, 28, and 56. The primary endpoint of the study, which lasted 12 weeks, was safety, the secondary endpoint immunogenicity. Local erythema at the injection site was the only vaccine-related side effect occurring in four patients. In 8 of 10 patients an increase in peptide-specific antibody titer measured by ELISA was found. Importantly, the induced antibodies were also directed against the native Her-2/neu protein. Cellular immune responses, as measured by in vitro production of IL-2, IFN-c, and TNF-a of PBMCs showed a marked increase after vaccination in the majority of vaccinees. Notably, the number of CD4+CD25+Foxp3+T regulatory cells, which were significantly increased compared to healthy controls prior to vaccination, was markedly reduced following vaccination. In all, the immunological responses after vaccination indicated that the patients in stage IV of disease were immunocompetent and susceptible to vaccination. The Her-2/neu multipeptide vaccine was safe, well tolerated and effective in overcoming immunological tolerance to Her-2/neu. The induction of anti-Her-2-specific antibodies could result in clinical benefit comparable to passive anti-Her-2 antibody therapy.

Suppression of mTOR complex 2-dependent AKT phosphorylation in melanoma cells by combined treatment with rapamycin and LY294002.

BACKGROUND: Inhibition of mTOR complex 1 (mTORC1) with rapamycin leads to phosphorylation of AKT in some cancer cells, with unknown biological consequences. The role of this phosphorylation in melanoma is unknown, although preliminary clinical data indicate poor activity of rapalogues in melanoma. OBJECTIVES: We aimed at elucidating the role of AKT phosphorylation after mTORC1 inhibition in melanoma cells. METHODS: Western blotting, apoptosis assays, cell cycle analyses and viability assays were performed to analyse the effects of rapamycin and LY294002 treatment on melanoma cells. For suppression of mTOR complex 2 (mTORC2) an siRNA directed against rictor was used. RESULTS: Rapamycin showed limited effects on cell viability but resulted in strong and lasting AKT phosphorylation in melanoma cells. Combined PI3K/mTOR inhibition with LY294002 had pronounced effects on viability but also led to increased AKT phosphorylation after prolonged treatment. In contrast, combination of rapamycin plus LY294002 suppressed AKT phosphorylation. Suppression of AKT phosphorylation did not correlate with decreases in cell viability. Inhibition of mTORC2 led to reduced levels of phosphorylated AKT. CONCLUSIONS: mTORC1 inhibition with rapamycin and with LY294002 can lead to AKT phosphorylation in melanoma cells via mTORC2. Combination of rapamycin and LY294002 suppresses AKT phosphorylation but without significant effect on treatment efficacy.

Prognostic relevance of hypoxia inducible factor-1alpha expression in patients with melanoma.

Overexpression of hypoxia inducible factor (HIF)-1alpha has been found in several human cancers and is thought to correlate with aggressive disease and poor response. A retrospective analysis was carried out on 89 patients with primary cutaneous melanoma. HIF-1alpha expression was assessed by immunohistochemistry in formalin-fixed, paraffin wax-embedded tumour sections. Overall survival (OS) and disease-free survival (DFS) were determined using univariate and multivariate analyses. Of the 89 patients, 78 (87.6%) expressed HIF-1alpha, and the remaining 11 patients (12.4%) did not. HIF-1alpha expression correlated with age (P = 0.002), but not with the main predictive factors in melanoma. Survival analysis disclosed no difference between the groups for OS and DFS. In multivariate analysis, only Breslow Index and ulceration were significantly associated with poor OS. Our results indicate that HIF-1alpha overexpression is present in most primary melanomas, but is not associated with clinicopathological variables, patient prognosis or survival.

Jun and Fos family protein expression in human breast cancer: correlation of protein expression and clinicopathological parameters.

OBJECTIVES: The activator protein-1 (AP-1) is a dimeric transcription factor formed by members of the Jun and Fos protein family. AP-1 plays a role in a variety of physiological functions including cell proliferation and differentiation, although both c-Jun and c-Fos have also been implicated in oncogenic transformation and tumor progression. To further elucidate the role of AP-1 in breast cancer, we have investigated the expression of the AP-1 proteins c-Jun, JunB, JunD, phosphorylated c-Jun, c-Fos, Fral, Fra2 and the tumor supressor protein p53. METHODS: Protein expression was evaluated on a breast cancer tissue microarray with 58 lymph node positive or negative breast cancer specimens, 29 corresponding lymph node metastases, and 11 tissue samples from surrounding tumor-free tissue, each cored as triplicate. Jun and Fos protein family expression was evaluated by immunohistochemistry and was correlated with clinicopathological parameters. RESULTS: High expression levels were observed for c-Jun, JunD, c-Fos and Fra2, whereas JunB and Fral exhibited lower staining. c-Jun protein expression was correlated to Fral staining (p = 0.007, Kendall's Tau) and Fral was further associated with c-Fos (p < 0.001), JunD (p = 0.001) and Fra2 (p = 0.011) expression. JunD expression correlated with c-Fos (p < 0.001), JunB (p = 0.035) and c-Jun (p = 0.05). Activated c-Jun correlated with c-Fos expression (p = 0.041). JunB was negatively correlated to tumor stage, (p = 0.093, corr coeff. = -0.293, Spearman's correlation) but was significantly increased in nodal negative tumors (p = 0.004, Mann Whitney test). In addition, increased Fral expression showed a trend towards an increased overall survival (p = 0.077, RR = 0.534, Cox regression). CONCLUSION: Our results suggest an important role for JunB and Fral in the biological behavior of malignant breast tumors.

T-cell receptor repertoire of lymphocytes infiltrating cutaneous melanoma is predominated by V alpha specificities present in T-cells of normal human skin.

Lymphocytes infiltrating solid tumors can be propagated in vitro with interleukin 2 and are then capable, as CD8+ cytotoxic T-cells, of specific lysis of autologous tumor targets in a class I-restricted manner. Since the specificity of these cells is determined by their T-cell receptor (TCR) configuration, the aim of this study was to delineate the TCR V alpha repertoire of tumor-infiltrating lymphocytes within 24 melanoma specimens and to compare these data with the TCR expression pattern of unaffected peritumoral and normal human skin. While lymphocytes within all skin specimens tested expressed a substantial, albeit limited, heterogeneity of V alpha specificities with an average number of 9.0 different V alpha gene segments, the V alpha repertoire within cutaneous melanoma lesions was significantly more restricted (mean of V alpha expression, 3.86; P < 0.001) with a predominance of only 3 V alpha families (V alpha 13, V alpha 15, and V alpha 16), all of which were also found to be expressed within normal skin. Collectively, the fact that the TCR V alpha repertoire in melanoma is skewed toward the predominance of only a few V alpha regions may be indicative of a limited number of melanoma-associated antigenic determinants being involved in the anti-tumor immune response.

Activated N-ras contributes to the chemoresistance of human melanoma in severe combined immunodeficiency (SCID) mice by blocking apoptosis.

Activation of the N-ras gene by point mutations occurs in about 15 % of all human melanomas. Using recently established melanoma severe combined immunodeficiency-human mouse xenotransplantation models, here we further investigate the biological significance of these mutations. We demonstrate that activated N-ras significantly contributes to the chemoresistance of human melanoma both in vitro and in vivo by blocking apoptosis. Overexpression of wild-type N-ras had no such effects. With antisense oligonucleotides and farnesyltransferase inhibitors, tools capable of blocking Ras function on the therapeutic horizon, our observation that activated N-ras is not a bystander but a factor worth targeting to improve therapeutic outcome in melanoma gains additional importance.

A genetically engineered influenza A virus with ras-dependent oncolytic properties.

The NS1 protein of influenza virus is a virulence factor that counteracts the PKR-mediated antiviral response by the host. As a consequence, influenza NS1 gene knockout virus delNS1 (an influenza A virus lacking the NS1 open reading frame) fails to replicate in normal cells but produces infectious particles in PKR-deficient cells. Because it is known that oncogenic ras induces an inhibitor of PKR, we addressed the question of whether the delNS1 virus selectively replicates in cells expressing oncogenic ras. We show that upon transfection and expression of oncogenic N-ras, cells become permissive for productive delNS1 virus replication, suggesting that the delNS1 virus has specific oncolytic properties. Viral growth in the oncogenic ras-transfected cells is associated with a reduction of PKR activation during infection. Moreover, treatment of s.c. established N-ras-expressing melanomas in severe combined immunodeficiency mice with the delNS1 virus revealed that this virus has tumor-ablative potentials. The delNS1 virus does not replicate in nonmalignant cell lines such as melanocytes, keratinocytes, or endothelial cells. The apathogenic nature of the delNS1 virus combined with the selective replication properties of this virus in oncogenic ras-expressing cells renders this virus an attractive candidate for the therapy of tumors with an activated ras-signaling pathway.

Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group.

PURPOSE: Patients with primary cutaneous melanoma with a Breslow thickness > or = 1.5 mm have only a 30% to 70% probability of survival after surgery, and no adjuvant therapy has so far improved this outcome. Since interferon alfa-2a (IFNalpha2a) exhibits antitumor activity in metastatic melanoma, we investigated whether adjuvant IFNalpha2a diminishes the occurrence of metastases and thus prolongs disease-free survival in melanoma patients after excision of the primary tumor. PATIENTS AND METHODS: In a prospective randomized study, 311 melanoma patients with a Breslow thickness > or = 1.5 mm were assigned to either adjuvant IFNalpha2a treatment (n = 154) or observation (n = 157) after excision of the primary tumor. IFNalpha2a was given daily at a dose of 3 mIU subcutaneously (s.c.) for 3 weeks (induction phase), after which a dose of 3 mIU s.c. three times per week was given over 1 year (maintenance phase). RESULTS: Prolonged disease-free survival was observed in patients treated with IFNalpha2a versus those who underwent surgery alone. This difference was significant (P = .02) for all patients enrolled onto the study (intention-to-treat analysis) at a mean observation time of 41 months. Subgroup analysis showed that Breslow tumor thickness had no influence on treatment results in the groups of patients investigated. CONCLUSION: Adjuvant IFNalpha2a treatment diminishes the occurrence of metastases and thus prolongs disease-free survival in resected primary stage II cutaneous melanoma patients.

Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.

PURPOSE: To compare fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and to assess safety and quality of life in patients with disseminated cutaneous melanoma. PATIENTS AND METHODS: Patients received either intravenous fotemustine 100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4 weeks (two cycles). Nonprogressive patients received a maintenance treatment every 4 weeks (fotemustine 100 mg/m2 or DTIC 250 mg/m2 for 5 days). RESULTS: Two hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n=229; 15.2% v 6.8%; P=.043) and in full analysis set (n=221) (15.5% v 7.2%; P=.053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P=.059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P=.067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms. CONCLUSION: ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favor of fotemustine in terms of overall survival and time to BM was evidenced.

Farnesylthiosalicylic acid inhibits the growth of human Merkel cell carcinoma in SCID mice.

Merkel cell carcinoma (MCC) is a neuroendocrine malignancy showing poor response to a variety of therapeutic strategies. We evaluated the antitumor activity of S-trans, trans-farnesylthiosalicylic acid (FTS), a new inhibitor of Ras signal transduction, in a newly established SCID mouse xenotransplantation model for human MCC (seven animals per group). FTS injected intraperitoneally at 5 mg/kg per day for 2 weeks up-regulated the tumor suppressor p53 and induced tumor cell apoptosis in established MCCs growing subcutaneously in SCID mice. These effects led to a statistically significant inhibition of MCC growth (P<0.002). The mean tumor weights following FTS or control treatment were 0.32+/-0.15 g and 1.08+/-0.29 g, respectively. There was no evidence of FTS related toxicity at the effective dose used. Our findings stress the notion that FTS may qualify as a novel and rational treatment approach for MCC and possibly for other tumors that rely on tyrosine kinase signaling.