Prior immunisation of patients with malignant melanoma with vaccinia or BCG is associated with better survival. An European Organization for Research and Treatment of Cancer cohort study on 542 patients.

There is increasing evidence that infections and vaccinations play an important role in the normal maturation of the immune system. It was therefore of interest to determine whether these immune events also affect the prognosis of melanoma patients. A cohort study of 542 melanoma patients in six European countries and Israel was conducted. Patients were followed up for a mean of 5 years and overall survival was recorded. Biometric evaluations included Kaplan-Meier estimates of survival over time and Hazard Ratios (HRs), taking into account all known prognostic factors. During the follow-up between 1993 and 2002, 182 of the 542 patients (34%) died. Survival curves, related to Breslow's thickness as the most important prognostic marker, were in accordance with those observed in previous studies where the cause of death was known to be due to disseminated melanoma. In a separate analysis of patients, vaccinated with vaccinia or Bacille Calmette-Guerin (BCG), HRs and the corresponding 95% Confidence Intervals (CIs) were 0.52 (0.34-0.79) and 0.69 (0.49-0.98), respectively. Joint analyses yielded HRs (and 95% CIs) of 0.55 (0.34-0.89) for patients vaccinated with vaccinia, 0.75 (0.30-1.86) with BCG, and 0.41 (0.25-0.69) with both vaccines. In contrast, infectious diseases occurring before the excision of the tumour had little, or, at the most, a minor influence on the outcome of the melanoma patients. These data reveal, for the first time, that vaccination with vaccinia in early life significantly prolongs the survival of patients with a malignant tumour after initial surgical management. BCG vaccination seems to have a similar, although weaker, effect. The underlying immune mechanisms involved remain to be determined.

Long-term adjuvant therapy of high-risk malignant melanoma with interferon alpha 2b.

Fifty-three high-risk melanoma patients in stage I and 15 patients in stage II were treated after standard surgical intervention with adjuvant therapy with recombinant interferon alpha-2b (rIFN alpha 2b) therapy for a total period of 20 months. Concomitant patients (stage I, n = 82; stage II, n = 33) with identical stages and prognostic factors without adjuvant therapy were used to evaluate the efficacy of rIFN alpha 2b therapy. No difference in 5-year relapse incidence and overall survival rates could be detected. However, it appears that patients of both stage I and stage II benefit from long-term adjuvant rIFN alpha 2b therapy, because during the treatment period (20 months), the incidence of relapses was lower in comparison to controls. After stopping treatment the incidence of relapse is equal in treated and control groups. According to the results of our study, we suggest using continuous low-dose rIFN alpha 2b therapy for adjuvant treatment of malignant melanoma.

Impact of vaccinations and infectious diseases on the risk of melanoma--evaluation of an EORTC case-control study.

A significant correlation between a reduced risk of melanoma and BCG and vaccinia vaccination in early childhood or infectious diseases later in life has already been reported from the FEBrile Infections and Melanoma (FEBIM) multicentre case-control study. This correlation is further evaluated in this study based on 603 incident cases of malignant melanoma and 627 population controls in six European countries and Israel by means of a joint analysis of the influence of vaccinations and infectious diseases. In addition, the previously unconsidered impact of influenza vaccinations is evaluated for the whole study population. The strong effects of the frequently given BCG and vaccinia vaccinations in early childhood, as well as of uncommon previous severe infectious diseases, were apparently not cumulative. With the Odds Ratio (OR) being set at 1 in the absence of vaccinations and infectious diseases, the OR dropped to 0.37 (95% Confidence Interval (CI): 0.10-1.42) when subjects had experienced one or more severe infectious diseases, associated with a fever of > 38.5 degrees C, and had not been vaccinated with BCG or vaccinia. The OR was 0.29 (CI: 0.15-0.57) in those who had had a severe infectious disease and were vaccinated with either BCG or vaccinia and 0.33 (CI: 0.17-0.65) for those with 1 or more severe infectious diseases and who had received both vaccinations. We conclude that both vaccinations as well as previous episodes of having a severe infectious disease induced the same protective mechanism with regards to the risk of melanoma. Because of a 'masking effect' by the vaccinia vaccination, the protective effect of the BCG vaccination and of certain infectious diseases against cancer has remained undetected. The vaccinations contributed more to the protection of the population than a previous episode of having an infectious disease. In view of the termination of vaccinations with vaccinia in all countries and of BCG in many of them, these findings call for a re-evaluation of vaccination strategies.

Topical cyproterone acetate treatment in women with acne: a placebo-controlled trial.

OBJECTIVE: To evaluate the clinical and hormonal response of topically applied cyproterone acetate, oral cyproterone acetate, and placebo lotion in women with acne. DESIGN: Placebo-controlled, randomized study. SETTING: Patients were recruited from the Institute of Endocrine Cosmetics, Vienna, Austria. PATIENTS: Forty women with acne. INTERVENTIONS: Treatment with oral medication consisting of 0.035 mg of ethinyl estradiol and 2 mg of cyproterone acetate (n=12), 20 mg of topical cyproterone acetate lotion (n=12), and placebo lotion (n=16) was offered. Patients were assessed monthly for 3 months. MAIN OUTCOME MEASURES: Clinical grading according to acne severity and lesion counts as well as determinations of serum cyproterone acetate concentrations. RESULTS: After 3 months of therapy with topical cyproterone acetate, the decrease of mean facial acne grade from 1.57 to 0.67 was significantly better (P<.05) compared with placebo (which showed a change from 1.57 to 1.25), but not compared with oral medication (1.56 to 0.75) (P>.05). Lesion counts also decreased from 35.9 to 9.1 in the topical cyproterone acetate group compared with oral medication (45.4 to 15.5) (P>.05) and placebo (38.2 to 23.1) (P<.05). After topical cyproterone acetate treatment, serum cyproterone acetate concentrations were 10 times lower than those found after oral cyproterone acetate intake. CONCLUSIONS: The therapeutic effect of topically applied cyproterone acetate for acne treatment was clearly demonstrated. Topically applied sexual steroids in combination with liposomes are as effective as oral antiandrogen medication in acne treatment, while reducing the risk of adverse effects and avoiding high serum cyproterone acetate concentrations.

Infections and melanoma risk: results of a multicentre EORTC case-control study. European Organization for Research and Treatment of Cancer.

Immune function plays a prominent role in the defence against cutaneous malignant melanoma and the increased risk of melanoma development during immunosuppression. Since the immune system is challenged beyond its routine activity by an infection, the effect of previous infectious diseases on the risk of melanoma may also be crucial. In a European Organization for Research and Treatment of Cancer (EORTC) case-control study performed in six European countries and Israel, we compared the history of severe infections in 603 melanoma patients with that in 627 population controls. We calculated adjusted odds ratios (ORs) to estimate the effect of infectious diseases on melanoma risk. The ORs for melanoma risk were below 1 for nearly all types of infections (except two) if body temperature was not taken into consideration, and for all infections with a body temperature above 38.5 degrees C. In the latter category significantly lowered ORs were found for pulmonary tuberculosis (0.16; 95% confidence interval [CI] 0.01-0.98), Staphylococcus aureus infections (0.54; 95% CI 0.31-0.94), sepsis (0.23; 95% CI 0.06-0.70), influenza and related infections (0.65; 95% CI 0.48-0.86) and pneumonia (0.45; 95% CI 0.27-0.73). Analysis of the cumulative influence revealed a consistent pattern of results pointing to a reduction in melanoma risk with increasing numbers of recorded infections and fever height. This apparent dose-response relationship suggests a causal association. Speculations on the underlying mechanism include a Shwartzman-like phenomenon when melanoma formation precedes the infection and/or an infection-related Th1-cell activation preventing the establishment of the tumour.

Antibody formation against human collagen and C1q in response to a bovine collagen implant.

The humoral immune response to commercially available bovine collagen implants (Zyderm, Zyplast) is characterized in a 45-year-old female patient. Circulating anti-collagen antibodies were detected after eight injections of Zyderm and after two injections of Zyplast given during a period of 3 years. The specificity of these antibodies for bovine and human collagens as well as for the collagen-like region of C1q (a subcomponent of the first component of complement), was investigated by affinity chromatography. Serum levels of anti-collagen and anti-C1q antibodies were measured using ELISA. High levels of antibodies to bovine collagens, showing a strong cross-reactivity with human collagen type III were detected in the patient's serum. Only weak cross-reactivity with human collagen type I and IV and no reactivity with type II were observed. In addition, these antibodies specifically cross-reacted with the collagen-like region of C1q. The antibody levels decreased continuously and disappeared 1 year after cessation of treatment. These results demonstrate for the first time the formation of autoantibodies upon treatment with a bovine collagen implant. Although antibodies to collagens and C1q have been found in various autoimmune diseases, neither adverse reactions to the bovine collagen implant nor any other clinical symptoms were observed in association with the described antibody response.

UVA- and UVB-induced changes in hairless mouse skin collagen.

UVA- and UVB-induced alterations in dermal collagen were investigated in a murine animal model. Groups of hairless mice were exposed to UVA and UVB for 28 weeks at a dose of 60 J/cm2 three times weekly and 0.06 J/cm2 three times weekly, respectively. Untreated animals were used as controls. Every 4 weeks dorsal skin was examined for quantitative and qualitative changes in dermal collagen. Neither UVA nor UVB caused a significant alteration in total skin collagen content. However, after UVA treatment the ability of skin collagen to be digested by pepsin decreased dramatically (up to 65% of skin collagen remained insoluble after 4 months), whereas exposure to UVB had no significant effect. Furthermore a shift in the ratio of alpha 1(I,III) chains to alpha 2(I) chains was detected after UVA exposure. The amount of type V collagen in mouse skin, as determined by a sensitive ELISA method, was markedly decreased after UVA treatment, but not after UVB treatment.

[Diagnostic value of ultrasound in malignant melanoma]. / Der diagnostische Stellenwert des Ultraschalls beim malignen Melanom.

High-resolution real-time sonography enables visualisation of the morphology of the cutis and of cutaneous tumours. Evaluation of 26 malignant melanomas showed that there is a high degree of correlation between the sonographically measured values of maximal tumour thickness with those determined postoperatively by histometry. As malignant melanomas have very few internal echos, they can be easily differentiated from benign tumours. High-resolution sonography is thus the only diagnostic imaging method which helps to evaluate preoperatively malignant melanomas.

[DTIC in malignant melanoma: a perspective (author's transl)]. / Dacarbazin (DTIC) in der Behandlung des malignen Melanoms: Ubersicht derzeit vorliegender erster Behandlungsergebnisse.

Effective therapy of malignant melanoma is still problematic. A variety of chemotherapeutic agents has proved to be ineffective in this tumour. The most extensively used chemotherapeutic agent for treatment of melanoma is DTIC (dimethyl-triaceno-imidazol-carboxamide). The objective response rate in monotherapy schedules has been reported to be up to 25%. Combination therapy with other cytostatic agents did not improve the results of DTIC alone. Experimental studies and clinical investigations have demonstrated that chemotherapy can be combined successfully with immunotherapy by potentiating the effect of tumour elimination. A review of the clinical studies with DTIC in malignant melanoma is presented.

[Dysplastic nevus syndrome]. / Das dysplastische Nävussyndrom.

The dysplastic nevus (DN) was first described by Clark in 1976. It was subsequently recognized to be a precursor of melanoma. Dysplastic nevi present with typical clinical and histological criteria. The dysplastic nevus syndrome (DNS) can be considered when at least two other family members have been shown to have multiple dysplastic nevi. From our own experience of over 2000 non-selected patients with melanoma only 60 (3%) were shown to have the DNS. In these 60 we could prove direct genetic penetration even though no HLA phenotype preference could be seen. Evaluation of the biological activity of the DN in cell cultures, as well as T-lymphocyte analysis in the neighborhood of the DN have shown signs of incipient malignant transformation of the DN. The practical implications of these findings and observations are discussed.

[Immunology and therapy of malignant melanoma (author's transl)]. / Immunologie und Therapie des malignen Melanoms.

Immunological investigations in malignant melanoma have demonstrated the important role of immunological defence mechanisms in the control of tumour growth and tumour spread. On the basis of the different test systems for investigation of immunecompetence and tumourspecific immunity it was possible to demonstrate that patients with melanoma, especially of clinical stages II and III, have a weak, sometimes an anergic immune reaction against their own tumour. The information obtained from in vitro and in vivo studies in human on tumour immunity formed the rational basis for immunotherapy in malignant melanoma. Increasing evidence suggests that active non-specific immunotherapy and, especially, active specific immune-stimulation with inactivated melanoma cells can delay the appearance of distant metastases and result in an improved survival rate for patients with involved regional lymph nodes. At present the use of involved chemotherapy is mostly confined to patients with disseminated malignant melanoma. The most extensively used chemotherapeutic agent for treatment of melanoma is the DTIC (dimethyl-triaceno-imidazole-carboxamide). The objective response rate with this monotherapy has been reported to be up to 25%. Nitrosoureas (BCNU, CCNU, MECCNU) have also been widely used and have brought clinical responses similar to DTIC. Experimental studies in animal models and investigation in human have demonstrated that chemotherapy can be combined successfully with immunotherapy with a potential additive, perhaps synergistic, effect.

[Local immunotherapy. Alternative therapy for malignant cutaneous lesions (demonstration on 30 patients with malignant melanoma) (author's transl)]. / Lokale Immunotherapie. Eine Alternativbehandlung bei Hautmetastasen (Demonstration and 30 Melanomfällen).

Experimental data in animal models and clinical experience with a systemic immunotherapeutic approach in patients with tumours were the determining factors in the decision to test the local effect of this form of therapy on primary and secondary malignant lesion of the skin. The antitumour effect of local immunotherapy seems to be based on the induction of a cell-mediated immune challenge reaction in close contact with the malignant neoplasm. A trial of local immunotherapy was undertaken in 30 patients with melanoma with local recurrence of the primary tumour or multiple metastases involving the skin. The therapeutic indications and clinical response are discussed.

[Prognosis in primary malignant melanoma based on histological assessment (a comparative study between two groups with different length of survival)]. / Zur histologischen Prognosestellung beim primären melanom (Vergleichsstudie zweier Kollektive mit verschiedenem Krankheitsverlauf)

In this retrospective study, sixty patients with primary malignant melanoma running a highly variable course (long- and short-term survivors) were reviewed histologically. In contrast to reports by other workers, a constant histological reaction pattern was selected, whereas the host reaction was the variable factor studied. In the majority of long-term survivors the tumour was surrounded by a dense lympho-histiocytic infiltrate, which was minimal or even absent in patients with a short-term survival rate. In the patients with long-term survival the peritumour connective tissue was definitely increased, whereas in the group in which the disease ran a short course there was destruction of peritumour connective tissue. The importance of these findings as an additional parameter for histological prognosis is discussed.

[Immunotherapy of malignant melanoma (active specific and non-specific immune stimulation) (author's transl)]. / Immunotherapie beim malignen Melanom (Aktive spezifische und akute unspezifische Immunstimulierung)

A prospective study was carried out on patients with stage I to III malignant melanoma. Following tumour resection these patients were treated with membrane extracts of autologous tumor tissue and BCG (Pasteur) or BCG alone by intradermal injections weekly for a minimum period of 6 months. They were followed up immunologically by delayed cutaneous hypersensitivity reactions: skin tests with recall antigens, PHA, with autologous tumour membrane extracts and challenge to 2-4-dinitrochlorobenzene (DNCB). The lymphocytic reactivity was assessed in vitro by means of the direct lymphocytic migration inhibition assay, purified tuberculin and autologous or allogoneic tumour extracts being used as antigens; the lymphocytic blastogenic response to PHA was also investigated. This study, which includes the data of 50 patients, demonstrates that it is possible to increase tumour--specific and general immune reactivity by this form of treatment.

[Mollusca contagiosa--review and critical evaluation of a new form of therapy (author's transl)]. / Mollusca contagiosa. Ubersicht und kritische Betrachtung einer neuen Behandlungsmethode

The present state of knowledge of the clinical features and therapy of molluscum contagiosum is reviewed. Treatment with retinoic acid, applied topically, is evaluated on the basis of 15 cases. In the majority of patients the lesions cleared up within an average of 8.9 days. This therapy is contraindicated only in patients with a disposition to develop eczema. This form of therapy appears to be superior to all those in common use up to the present date, especially in children with multiple or recurrent lesions.

[The increase in skin melanomas in Austria (1926-1980)]. / Zur Zunahme der Hautmelanome in Osterreich (1926 bis 1980).

This statistical study demonstrates the increase in incidence of cutaneous malignant melanoma in Austria over the time period 1926 to 1980 and the changing pattern of tumour localization. The results of this study are discussed with reference to aetiology, especially of sunlight as a causative factor.

[Treatment of metastatic malignant melanoma (author's transl)]. / Klinische Erfahrungen mit DTIC beim metastasierenden Melanom.

24 patients with metastatic malignant melanoma were treated with DTIC applied alone or in combination with other cytotoxic agents (Oncovin, Bleomycin, Adriblastin). Treatment resulted in objective improvement (3 patients), subjective improvement (2 patients), stable state (5 patients). The other patients showed further progression of their disease.