Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma.

PURPOSE: Some phase II studies have suggested that the combination of interferons (IFNs) with dacarbazine (DTIC) in the treatment of malignant melanoma (MM) increases the antitumor activity of DTIC alone. In an attempt to confirm this hypothesis, a randomized study was performed with the further intent of observing whether low doses of recombinant interferon alfa-2a (rIFN alpha 2a) could be as effective as intermediate doses. PATIENTS AND METHODS: Two hundred sixty-six patients were randomized onto three different treatment arms: DTIC 800 mg/m2 intravenously (IV) days 1 and 21; DTIC plus rIFN alpha 2a 9 mIU intramuscularly (IM) daily; and DTIC plus rIFN alpha 2a 3 mIU IM three times per week. Major prognostic factors were well balanced among the three arms. Chemotherapy was administered for a maximum of eight cycles. After 6 months of therapy, rIFN alpha 2a was continued until disease progression at 3 mIU three times per week in responding patients who had received the combined treatment. RESULTS: The percentage of objective responses did not differ among the three groups (20%, 28%, and 23%, respectively), although a significant prolongation of response duration was observed when rIFN alpha 2a was added to DTIC (2.6 v 8.4 v 5.5 months, respectively). However, this improvement in response duration did not translate into an amelioration of overall survival. The addition of rIFN alpha 2a led to the onset of flu-like syndrome, but in no case was it necessary to withdraw the treatment program and no toxic deaths or life-threatening toxicities were reported. CONCLUSION: In this study, rIFN alpha 2a significantly prolonged response duration, whereas no effects on response rate and survival were observed; rIFN alpha 2a 3 mIU appeared to be equally effective and better tolerated than 9 mIU.

Diagnostic and referral accuracy of family doctors in melanoma screening: effect of a short formal training.

Little is known about ability of family doctors in the diagnosis and management (decision as to dermatologic referral) of pigmented skin lesions. We sought to evaluate the impact of a short formal training on diagnostic and referral accuracy of family doctors in melanoma screening. A formal 4-h training session was given to a sample of 41 practising family doctors working in the Florence health district, Tuscany, Italy. Before and after the course, a diagnostic test with a series of clinical images of pigmented skin lesions including four invasive melanomas (mean thickness, 1.5 mm; range, 0.8-2.2) was performed (open intervention study). Although only 46.8% of observations yielded a correct melanoma diagnosis at baseline, 96.1% of melanoma observations were correctly associated with intention to refer the lesion to dermatologist. After training, the percentage of correct melanoma diagnosis significantly increased (76.2%, P=0.01) while no further improvement was found as to sensitivity of referral (94.8%, P=0.58). Compared to baseline, post-training evaluation showed a significant reduction of benign lesions sent to dermatologist: the percentage lowered from 52.1 to 35.8% (P=0.0014) for melanocytic nevi and from 38.6 to 17.5% (P<0.001) for benign non-melanocytic lesions (pigmented seborrheic keratoses, dermatofibromas, and vascular lesions). Grouping these two diagnostic categories, the overall specificity in dermatology referral increased from 55.0% at baseline to 73.1% after training (P<0.001). In conclusion, attendance at a 4-h formal training session was able to increase the specificity of family doctors as to dermatologist referral of suspicious lesions (less false-positive referral of benign lesions) without significant loss in sensitivity concerning melanoma.

Ki67 antigen expression correlates with tumor progression and HLA-DR antigen expression in melanocytic lesions.

Advanced steps of tumor progression are generally characterized by an increased growth fraction within the neoplastic cell population. The presence of a relevant growth fraction is also related to widely accepted prognostic parameters in some human malignancies. Our aims were to evaluate the presence of a growth fraction with Ki67 monoclonal antibody (MoAb), and to correlate it with tumor progression and HLA-DR antigen expression in 88 melanocytic lesions. The lesions were 19 acquired melanocytic nevi, 58 primary melanomas [divided into 26 superficial spreading melanomas (SSM), 24 superficial spreading melanomas with nodular areas (SS + NM), and five nodular melanomas (NM)], and 11 metastases from malignant melanomas. Ki67 MoAb stained 16%, 19%, 71%, 100%, and 82% of nevi, SSM, SS + NM, NM, and metastases, respectively. Among primary melanomas, Ki67 MoAb stained 12%, 28%, 50%, and 70% of tumors less than 0.75, 0.75-1.49, 1.5-2.9, and greater than or equal to 3 mm thick, respectively. A concordant reactivity pattern for Ki67 and HLA-DR antigens was found in 72% of lesions (p less than 0.0001). We have shown that a representative growth fraction (ie, Ki67 reactivity) is present in melanocytic lesions only in advanced steps of tumor progression and correlates with HLA-DR antigen expression. Despite the different biologic values of Ki67 and HLA-DR antigens, we suggest the joint evaluation of both antigens as a useful marker of aggressive behavior in melanoma.

Skin melanoma in Italy: a population-based study on survival and prognostic factors.

Survival and prognostic factors of invasive cutaneous melanoma patients diagnosed in the province of Florence, Italy, were studied using a regression analysis of relative survival rates. The case series consisted of 428 patients reported by the Tuscany Cancer Registry between 1985 and 1989. The effect of gender, age, anatomical site, histological type and microstaging parameters upon relative survival were evaluated using an extension of the Cox proportional hazard model. Five-year relative survival was 70%; 8-year relative survival, referring to a subset of patients, was 67%. In univariate analysis, the following variables were significantly associated with better prognosis: female gender, age younger than 60 years, superficial spreading melanoma (SSM) compared with nodular melanoma (NM), location on the limbs, a thinner lesion according to Breslow, a shallower Clark level. Females had a clear-cut prognostic advantage over males in each category of the variables considered above. After simultaneous adjustment for all other variables, three factors continued to show an independent prognostic effect: age, gender and microstaging parameters (Breslow thickness and Clark level, separately fitted in the model). In the multivariate analysis, the prognostic advantage of females over males was specifically seen for lesions located on the trunk and for both SSM and NM histotype.

BCA-1, A B-cell chemoattractant signal, is constantly expressed in cutaneous lymphoproliferative B-cell disorders.

We analysed the immunophenotypic and molecular expression of BCA-1 (B-cell-specific chemokine) and CXCR5 (BCA-1 receptor) in normal skin and different cutaneous lymphoproliferative disorders (cutaneous T-cell lymphoma (CTCL); cutaneous B-cell lymphoma (CBCL); cutaneous B-cell pseudolymphoma (PCBCL)), with the aim of investigating their possible involvement in the pathogenesis of cutaneous B-cell disorders. BCA-1 and CXCR5 were constantly expressed in CBCL and PCBCL, but not in normal skin and CTCL. BCA-1 and CXCR5 were constantly coexpressed by CD22+ B-cells, while CD35+ follicular dendritic cells coexpressed BCA-1 in PCBCL cells only. In low grade CBCL, as compared with high grade CBCL, the intensity of CXCR5 expression on neoplastic CD22+ cells was lower than that of BCA-1. The image analysis of reverse transcriptase-polymerase chain reaction (RT-PCR) products showed a significant quantitative difference between PCBCL/low grade CBCL and high grade CBCL. The above findings, although only observed in a small series of patients, are in keeping with findings in MALT gastric and gastric MALT lymphomas, adding further evidence of the close similarities between CBCL and MALT lymphomas.

Immunophenotypical markers, ultrastructure and chemosensitivity profile of metastatic melanoma cells.

The survival of patients affected by cutaneous melanoma has improved dramatically in the last 10 years, because of earlier diagnosis. Despite this, the therapeutic results obtained in metastatic melanoma (MM) are very disappointing due to its poor responsiveness to cytotoxic agents. In this type of solid tumor, tumor chemosensitivity assays have been suggested to be an important tool to predict clinical responsiveness to therapy. Metastatic melanoma cells (MMCs) were obtained from subcutaneous melanoma metastases of five patients and cultured for several consecutive passages. An immunofluorescence and an electron microscopic study were performed in order to establish the ultrastructural and physiopathological features of MMCs. A sulphorodamine-B test was used to measure in vitro sensitivity of MMCs to temozolomide, cisplatin, vindesine, taxol and interpheron alpha-2a. Following a 72 h exposure, maximum activity was obtained with vindesine (median inhibitory concentration, IC(50), 0.23 nM) and taxol (median IC(50) 0.31 nM). Cisplatin median IC(50) values were higher (4.6 microM) than taxol and vindesine, but still in the range of clinically achievable plasma concentrations. Temozolomide inhibited cell proliferation only at very high concentrations (median IC(50) 228 microM). No significant cell growth inhibitory effects (

Current treatment guidelines for topical corticosteroids.

The effectiveness of a topical corticosteroid is related to various factors which should be considered when planning treatment. The most relevant factor is the potency of the drug. Another important factor is the absorption through the skin, which is influenced by marked regional variations in percutaneous penetration, hydration and the degree of inflammation present, types of dressings, the solubility of the drug and the age of the patient. Multiple daily applications do not lead to better or faster resolution of the disease. Intermittent therapy with treatment-free intervals, when the vehicle alone is applied, can be as effective as continuous treatment. The choice of a topical corticosteroid depends not only on the severity or activity of the disease, but also on the age of the subject, the body site affected and the extent of the surface area to be treated. In addition, the choice of vehicle depends on the type of lesion and on the body region afflicted. Combinations of a corticosteroid with other agents can be useful, but they are recommended in only a few specific indications. Treatment guidelines for topical corticosteroids must therefore take into account a number of factors which will influence the clinician's ultimate decision in providing care for the patient with steroid-responsive dermatoses.

Topical corticosteroids. Which drug and when?

A number of factors have to be taken into account when dealing with the treatment of skin diseases with topical corticosteroids, including disease type and phase, potency of the drug, safety, site to be treated, age of the patient, and drug formulation. Concerning the specific indications for topical corticosteroid treatment, we can distinguish skin diseases in which: (a) topical corticosteroids are the treatment of choice; (b) topical corticosteroids are useful as alternative and/or adjuvant treatment; (c) the proposed use of topical corticosteroids has to be confirmed as useful; and (d) topical corticosteroids can be used as a symptomatic treatment. Within these groups, the treatment schedule has to be adjusted according to the above mentioned general factors.

Topical corticosteroids and unwanted local effects. Improving the benefit/risk ratio.

The main goal of pharmacological research in the field of topical corticosteroids (TCs) is to dissociate efficacy and adverse effects as much as possible. The optimal use of TCs, i.e. the careful evaluation of the benefit/risk ratio, depends on: (i) the chemical structure of the TC; (ii) the type of vehicle; (iii) the mode of application; and (iv) the features of the skin to be treated. The recent availability of TCs characterised by a good dissociation between efficacy and adverse effects makes the classic and widely used classification system of TCs based upon potency out of date. Indeed, TCs with increasing potency have been characterised up to now, as a rule, by an increasing risk of adverse effects. Therefore, a classification system taking into major account the benefit/risk ratio seems particularly needed for clinical use in dermatology.

Epidemiology of atypical melanocytic naevi: an analytical study in a Mediterranean population.

Atypical naevi are markers for increased risk of malignant melanoma, providing additional information about melanoma risk beyond that given by common melanocytic naevi. Little is known about the epidemiology of atypical naevi (AN), and available data are limited to predominantly fair-skinned populations. By using a case-control study that included 705 subjects with atypical naevi and 1,782 controls, we have analysed the aetiology of AN in a Mediterranean population, paying particular attention to the role of sunburn. After adjusting for age, sex and years of formal education, the presence of atypical naevi was significantly related to frequent sunburn before the age of 20 (odds ratio, OR, = 1.8; 95% CI, 1.3-2.5). Although less evident, this relationship was maintained by also taking into account the sun sensitivity, expressed as phototype, as a cofounder (OR = 1.5; 95% CI, 1.0-2.0). Concerning phenotypical features, an increased risk of having atypical naevi was found for all the parameters included in so-called 'fair complexion', i.e. blue eyes, blond or red hair, fair skin, phototype I-II, and a tendency to freckle. The greatest difference between subjects with and without atypical naevi related to the number of common melanocytic naevi: more than 30 common naevi were found in 41.5% of cases, but only in 9% of controls (OR = 8.0; 95% CI, 6.3-10.3). Overall, the six variables entered in the multivariate model that best predicted the risk of atypical naevi, were: young age, male sex, high educational level, presence of a large number of common naevi, phototype I-II, and a history of painful sunburn. In conclusion, the variables predicting the risk of developing atypical naevi in Mediterranean people are identical to those observed in predominantly fair-skinned populations. The aetiologic role of sunlight has been pointed out and shows a statistically significant relationship between frequent sunburn and the development of atypical naevi also after controlling for the subject's phototype.

Cutaneous melanoma in the Florentine area, Italy: incidence, survival and mortality between 1985 and 1994.

In recent decades, the increase in incidence of melanoma (MM) and the consequent mortality pointed to the concept of a 'melanoma epidemic'. More recently, the mortality has been slowly declining in many countries. This study is aimed at evaluating the incidence, mortality and survival in the Florentine area of Italy, using registry-based information. Between 1985 and 1994, 997 cases were notified with a survival of 713 patients (1985-92) and 316 deaths. Age-adjusted incidence, mortality rates and 95% confidence interval were calculated by period, gender and Breslow thickness. The relative survival rates were calculated and the effects of prognostic factors were evaluated using multivariate analysis. The incidence of MM increased during this period. This result referred only to 'thin melanomas', while the incidence rate for melanomas thicker than 1.00 mm remained unchanged both in young and old individuals. The mortality rate remained stable. The 5-year survival rate increased between 1985 and 1992. The inclusion of Breslow thickness in the multivariate model caused a reduction of the period effect. In conclusion, a changing pattern of MM epidemiology is being observed, with increase of 'thin' forms and a tendency for mortality to decline. The increasing awareness of population about MM prevention may partially explain these findings.

Squamous cell carcinoma arising in vulval lichen sclerosus: a longitudinal cohort study.

Histological changes of lichen sclerosus (LS)--a chronic inflammatory disease--are frequently found in association with squamous cell carcinoma (SCC) of the vulva, suggesting that women with this disorder are at increased risk. However, follow-up studies have been less convincing, showing that the vast majority of these patients do not go on to develop cancer. In this study, a series of 211 women affected by histologically demonstrated vulval LS were treated with topical therapy (testosterone, clobetasol) and followed prospectively by repetitive vulval examination. Three patients developed SCC of the vulva (two invasive, one in situ) at the sites affected by LS during an average follow-up period of 1 year and 8 months. Compared with the reference population, the number of cases of invasive SCC detected significantly exceeded the number estimated to occur in a comparable age-matched group. The standardized incidence rate of vulval SCC in the LS cohort was 317 (95% CI 35.7-1146.2). Cumulative risk was 14.8% (0.06% in the general female population), with a relative risk of 246.6. In conclusion, these data support the view that LS is a precursor of SCC, although characterized by slight tendency to evolve to carcinoma. Medical treatment of LS, although useful in the control of severity of disease, did not seem to be able to prevent the evolution to malignancy.

Modern diagnosis of cutaneous lymphoma.

The issue of primary cutaneous lymphoma (CL) has been greatly influenced by the increasing knowledge about lymphoid cell biology, the widespread use of sensitive and specific immunological and molecular markers, and the careful correlation among clinical, histological and immunomolecular features. This latter is the key element of the classification of CL proposed by the EORTC Cutaneous Lymphoma Study Group in 1997, which categorizes distinct clinicopathological entities with prognostic and therapeutic relevance. With few exceptions, no reliable diagnosis and subtyping of CL can be made without the aid of immunohistochemistry and/or molecular analysis. On the other hand, the acritical use of immunological and molecular markers can be misleading if not combined properly with a correct clinical and histological evaluation. For this reason, a step-by-step diagnosis and staging protocol is exceedingly important. Finally, great caution should be used in the interpretation of lymphoid cell infiltrates of the skin which show a monoclonal rearrangement in the absence of reliable clinical and/or pathological evidence of neoplasia.

Adhesion molecule profile and malignancy of melanocytic lesions.

The ability of melanoma cells to metastasize is largely dependent upon cell surface molecules that mediate cell-matrix and cell-cell interactions. Our aim was to investigate the expression of such molecules (adhesion molecules) on tissue sections of a series of melanocytic lesions in different stages of tumour progression. Four common naevi, four congenital naevi, four dysplastic naevi, three Spitz naevi, 20 primary melanomas and 15 metastatic melanomas were tested with an alkaline phosphatase/anti-alkaline phosphatase technique and a panel of monoclonal antibodies directed toward different alpha subunits of VLA receptors, beta 1, VNR-alpha and beta 3 subunit, and CD44 hyaluronate receptor. Only metastatic melanomas expressed the alpha 4 subunit, and only thick primary melanomas and metastases expressed the beta 3 subunit. The alpha 6/beta 1 chain was expressed at significantly higher levels on benign lesions, and a trend towards increased expression of alpha 2 and alpha 3 subunits was found in malignant versus benign lesions. Our results show that the pattern of integrin expression changes in melanocytic lesions along with malignant transformation.

Spatial association of melanocytic naevus and melanoma.

A series of 233 consecutive primary cutaneous melanomas was histologically and clinically studied. Histologically, 53 melanomas (22.7%) were associated with naevus cells. Such a high degree of association suggests that melanocytic naevus may be a precursor of a large number of melanomas. Analysing the cases according to Clark's levels and Breslow's index, a decrease in the naevus-melanoma association was seen with tumour progression, suggesting that advanced tumours may overgrow pre-existing nevus cells, appearing as de novo melanomas. The comparison between histological and clinical data suggest some interpretations of the natural history of melanoma.

Non-invasive analysis of melanoma thickness by means of dermoscopy: a retrospective study.

Epiluminescence microscopy (ELM), or dermatoscopy, is a non-invasive technique for the diagnosis of cutaneous melanoma that may play a role in the non-invasive, preoperative assessment of melanoma thickness. This study investigated the correlation between the frequency of appearance of some standard ELM criteria and the histological thickness of melanomas. In addition, the possible role of the total dermoscopic score (TDS) according to ABCD rule of dermoscopy as a predictor of melanoma thickness was analysed. The dermoscopic images of 84 cutaneous melanomas were retrospectively investigated to evaluate the presence of 10 standard ELM criteria, and for each lesion the TDS was established (with observers blinded as to the tumour thickness). A statistically significant association was found between the presence of an irregular pigment network and melanomas with a Breslow index equal to or lower than 0.75 mm (positive predictive value of 68%); in contrast, radial streaming, atypical vascular pattern and grey-blue areas were associated with melanomas > 0.75 mm (positive predictive values of 77%, 65% and 70%, respectively). Of the melanomas thinner than 0.76 mm, 82% showed a TDS lower than 6.80 (optimized cut-off point), while 79% of melanomas thicker than 0.75 mm had a TDS higher than 6.80 (chi2 = 30.815, P < 0.001); the positive predictive value of a TDS > 6.80 in the detection of lesions thicker than 0.75 mm was 79%. In conclusion, a statistically significant correlation does exist between some dermoscopic features and melanoma thickness. Both the mostly used dermoscopic methods (standard ELM pattern analysis and the ABCD rule of dermatoscopy) may provide useful information in the non-invasive assessment of melanoma thickness. However, their diagnostic performance is far from 100%; further studies are needed to investigate whether the combination of dermoscopy with other non-invasive approaches (e.g. sonometry) may result in an overall improvement in the diagnostic performance.

Incidence of cutaneous melanoma in the centre of Italy: anatomic site distribution, histologic types and thickness of tumour invasion in a registry-based study.

The majority of epidemiological data on cutaneous melanoma (CM) derives from studies carried out in a predominantly fair-skinned population. On the contrary, little is known of the epidemiological figures (including incidence data) in mediterranean populations. The aim of this study was to investigate the incidence rates of CM in a geographically-defined area of the centre of Italy, with particular attention to anatomic site distribution, histologic types and thickness of tumour invasion. After revision of the data base of the Tuscany Cancer Registry concerning the period 1985 to 1987, 282 incident cases of invasive CM (135 males, 147 females) were found in a resident population of 1,174,121 inhabitants. The mean annual age-standardized rates were 6.7/100,000 for males and 7.0/100,000 for females. Site-specific incidence rates showed an almost three-fold higher incidence of CM of the trunk in males than females (3.7/100,000 vs 1.4/100,000). Conversely, a four-fold higher incidence in females than in males was observed for the lesions of lower limb (2.1/100,000 vs 0.5/100,000). A statistically significant difference of incidence rates was also observed for the thigh (females 1.1/100,000, males 0.2/100,000), a normally sun-exposed area. Concerning histologic types of CM, the incidence of the nodular type was higher in males than in females (1.8/100,000 vs 1.3/100,000), even if the difference was not statistically significant in any class of age.(ABSTRACT TRUNCATED AT 250 WORDS)

In situ expression of transforming growth factor beta is associated with melanoma progression and correlates with Ki67, HLA-DR and beta 3 integrin expression.

Transforming growth factor-beta (TGF beta), which is secreted by cultured melanoma cells constitutively, inhibits the proliferation of normal melanocytes and of most melanoma cells in vitro, but some melanoma cells from advanced stages of the disease develop resistance to TGF beta-dependent growth inhibition, without developing any change in TGF beta cell surface binding. In vitro TGF beta also downregulates the expression of HLA-DR molecules on melanoma cells, and upregulates the expression of the beta 3 integrin subunit on some cell lines. Immunohistochemical analysis of 53 melanocytic lesions (12 naevi, 30 primary melanomas and 11 metastases) revealed a trend of increasing expression of TGF beta and TGF beta receptor type III with tumour progression, and a significantly higher expression of both TGF beta (P < 0.0001) and the receptor (P < 0.05) in metastatic and thick (> 1 mm) primary melanomas compared with thin (< 1 mm) primary melanomas. The expression of TGF beta correlated with expression of a marker of proliferation, Ki67, and with HLA-DR and beta 3 integrin subunit expression. Coexpression of the four molecules was observed in all metastases and in most thick primary melanomas. These findings argue against an inhibitory effect of TGF beta on cell proliferation or HLA-DR antigen expression in melanoma, and suggest the upregulation of the beta 3 subunit. TGF beta protein appears to be a biological marker of melanoma progression in situ.

Macrophage--T-lymphocyte interaction in lichen planus. An electron microscopic and immunocytochemical study.

Papular lichen planus lesions from 12 patients were studied by a double-step immunocytochemical method to detect T-lymphocytes. Semithin sections were studied by light microscopy and ultrathin sections examined by electron microscopy. In the dermal infiltrate, many T-lymphocytes appeared closely juxtaposed to macrophages or Langerhans cells, frequently arranged in a rosette-like pattern. In the epidermis, T-lymphocytes were juxtaposed to macrophages or Langerhans cells and to degenerated keratinocytes. The close relationship between T-lymphocytes, macrophages or Langerhans cells and degenerated keratinocytes supports the hypothesis that lichen planus is immunological in nature: T-lymphocytes, after interacting with macrophages or Langerhans cells, become cytotoxic for keratinocytes.

Phase II study of interferon alpha-2a and dacarbazine in advanced melanoma.

Based on the report of some activity of combination therapy with dacarbazine (DTIC) and interferon alpha-2a (rIFN alpha-2a) in disseminated melanoma, we conducted a phase II study to determine the feasibility and efficacy in a large series of patients. DTIC was administered in 79 patients at the dose of 800 mg/m2 every 3 weeks and rIFN alpha-2a was given daily at the dose of 9 X 10(6) IU for the first 10 weeks and three times a week thereafter. Among the 75 evaluable patients, 25% achieved an objective response, with 8% complete and 17% partial remissions. The regression occurred within a mean time of 1.9 +/- 1.03 months from starting therapy and the mean duration of response was 8.2 +/- 4.2 months. The major side effects were vomiting, anorexia, fever, fatigue, and myalgia. There was one death related to sepsis after myelosuppression. In the other patients bone marrow and liver toxicities were not remarkable. Our data reveal that a combination regimen of rIFN alpha-2a with a cytotoxic agent has some therapeutic activity in the management of advanced malignant melanoma.