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.

Survival probabilities and hazard functions of malignant melanoma in Germany 1972-1996, an analysis of 10433 patients. Evolution of gender differences and malignancy.

The evaluation of the impact of prevention activities on the course of survival in conjunction with the individual hazard rate of dying is described using data from a follow-up study of 10433 melanoma patients during three observation periods (1972-1980, 1981-1988, 1989-1996). Kaplan-Meier survival curves combined with hazard functions were calculated. At all observation periods, survival of men was lower compared with women and their maximum dying risk was earlier (70 versus 100 months after removal of the primary tumour). In 1989-1996, differences in the survival rates were approximately halved compared with those for 1972-1980 or 1981-1988, respectively. This improvement was predominantly seen in young men. There was a lower survival rate of men compared with women with identical thickness categories. The maximum dying risk for those men with tumours >4 mm peaked at approximately 60 months, the other thickness categories showing a lower and later maximum; in women, the maximum dying risk for tumours >4 mm was also seen at approximately 60 months, but less pronounced. Over time, the influence of Breslow thickness on the survival rates remained constant in women; in men, with the exception of thick tumours, there was a trend towards a better survival. Melanoma awareness campaigns conducted in Germany since the late 1980s have resulted in a trend towards a remarkable increase of thin tumours in recent years, whereas the number of new cases with thick tumours has remained constant.

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.

Immunohistochemical panels for differentiating epithelial malignant mesothelioma from lung adenocarcinoma: a study with logistic regression analysis.

Immunohistochemistry provides an important indicator for differential diagnosis between pleural malignant mesothelioma and lung adenocarcinoma, which have complex therapeutic and medicolegal implications. To pinpoint a reliable, restricted panel of markers, the authors evaluated the efficacy of select commercial antibodies in a series of patients with confirmed clinicopathologic diagnosis of mesothelioma or lung adenocarcinoma with the aid of multiple logistic classification tables. Specimens of 46 mesotheliomas and 20 lung adenocarcinomas were examined with calretinin, thrombomodulin, cytokeratins (CKs) 5/6, and high-molecular weight CKs (indicators of mesothelioma), alongside MOC 31, Ber-EP4, and carcinoembryonic antigen (CEA; indicators of lung adenocarcinoma). Of the mesotheliomas, 40 of 46 (87%) were positive with calretinin, 29 of 46 (63%) with thrombomodulin, 40 of 46 (87%) with CKs 5/6, and 41 of 46 (89%) with high-weight CKs; five of 46 mesotheliomas (11%) were focally reactive with MOC 31, four of 46 (9%) with Ber-EP4, and two of 46 (4%) with CEA. Of the lung adenocarcinomas, 18 of 20 (90%) were positive with MOC 31, 20 of 20 (100%) with Ber-EP4, and 17 of 20 (85%) with CEA; and two of 20 (10%) were focally reactive with calretinin, one of 20 (5%) with thrombomodulin, none of 20 (0%) with CKs 5/6, and five of 20 (25%) with high-weight CKs. Multiple logistic modeling indicated two batteries of three antibodies permitting more than 98% overall accuracy: Ber-EP4 plus CKs 5/6 plus calretinin, and Ber-EP4 plus CKs 5/6 plus CEA.

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.

Fungal colonization of the paranasal sinuses.

Fungal infection of the paranasal sinuses occur in four primary types: acute invasive (1), chronic invasive (2), chronic fungus ball (3) and allergic fungal sinusitis (4). The first and second form can be fatal and is often found in immunosuppressed patients. The present paper concerns a group of immunocompetent patients with non-invasive chronic sinusitis caused by moulds. Over the period from 1994 to 1998, 132 tissue samples from the paranasal sinuses obtained by endoscopic operation from 117 patients was examined for mycotic infections. The mycological examination was carried out if granulomatous and crumbly material was seen in the sinus by endoscopy (91 times maxillary sinus, 23 times ethmoid sinus, 11 times frontal sinus, 7 times sphenoid sinus). Out of 117 patients 29 were positive (24,9%). From 132 surgical specimens fungi were proved in 34 times (25,7%). The following fungal species were isolated: Aspergillus fumigatus 17 times, other Aspergillus spp 6 times, Alternaria alternate 2, Penicillium rugulosum 1, and moulds without differentiation 5 times. In the histological examination an invasive mycelial growth in the mucous membrane or in the bones was never observable. Our findings represented a commensal colonization of the paranasal sinuses, but not a mycosis. The colonization is evidently assisted by a chronic hyperthrophic sinusitis with increased mucus production which impedes the mucociliary clearance. For immunosuppressed patients, however, this situation causes a danger of invasion with fatal consequences.

A multicenter, open-label study of the efficacy and safety of ciclopirox nail lacquer solution 8% for the treatment of onychomycosis in patients with diabetes.

This multicenter, open-label, uncontrolled, noncomparative, observational, postmarketing study assessed the efficacy and safety of ciclopirox nail lacquer solution 8% in 3666 patients for the treatment of onychomycosis. Results of an analysis in a subset of 215 (5.9%) patients with diabetes are summarized here. Patients applied ciclopirox nail lacquer once daily to affected toenails and fingernails for 6 months. Efficacy parameters included the decrease from baseline of the affected area of the nail. Physicians rated the level of onychomycosis at 3 months and the efficacy of ciclopirox nail lacquer at 6 months. Treatment with ciclopirox nail lacquer reduced the mean affected nail area from 64.3% at baseline to 41.2% at 3 months and 25.7% at 6 months. At 3 months, physicians rated onychomycosis as improved in 88.7% of patients. unchanged in 9.8%, and worse in 1.5%. The efficacy of ciclopirox nail lacquer was good in 62.0% of patients, satisfactory in 23.9%, and unsatisfactory in 14.1%. Adverse events were mild to moderate, with no serious events reported. Ciclopirox nail lacquer is safe and effective for the topical treatment of onychomycosis in patients with diabetes and produced results similar to those observed in the general population.

[Diagnosis, differential diagnosis and therapy of onychomycosis]. / Diagnose, Differentialdiagnose und Therapie der Onychomykose.

Onychomycosis is a common infectious disease. The diagnosis always requires proof of the presence of fungi by culture. Nail psoriasis and onychodystrophy of another origin are clinically very similar to onychomycosis. There is a choice of topical and systemic antimycotics available for treatment. The modern antimycotic nail lacquars are well suited for the treatment of distal onychomycosis. If more than 2/3 of the nail plate and/or the nail matrix are infected, the treatment must be systemic. There is a choice of griseofulvin, terbinafine and itraconazole.

[Candida infections in infancy and early childhood]. / Candida-Infektionen im Säuglings- und Kleinkindesalter.

Candida infections in infancy can manifest themselves as skin, mucosal or systemic candidiasis. Eighty to nintey percent of all candida infections in this age group are caused by Candida albicans. Whereas in neonates, infections mostly occur sub partu, in older children predisposing underlying diseases get an increasing etiological importance. The diagnosis is based on microscopic and cultural detection of yeast as well as on the course of the titers of Candida antigen and antibodies. For topical antifungal treatment of skin and mucosa infections, different preparations of the polyenes nystatin and amphotericin B have been proven to be most effective. In systemic candidiasis the combination of amphotericin B and 5-flucytosin is the treatment of choice. In view of the potential severe side effects of this combination therapy, fluconazol as a sole treatment represents an effective alternative. Prophylaxis against Candida infections comprises sticking to hygienic regimes, mycological surveillance of risk groups and oral application of antimycotics.

Dermatomycological guidelines: 10 years of experience in Germany.

Since the mid-1990s of the last century, dermatomycological guidelines have been prepared and published in Germany. This has been achieved by a group of experts encompassing leading representatives of Deutschsprachige Mykologische Gesellschaft, Deutsche Dermatologische Gesellschaft as well as Berufsverband Deutscher Dermatologen. Preparation of guidelines is based on a defined procedure. The first draft is prepared by one to three experts and then forwarded to all members of the working group for further discussion and improvement. This can be by way of either conventional mail or electronic mail. All aspects turning up in the process are reflected by the head of the working group and these aspects are used to prepare another version, which is again distributed to all members of the working group. Following up to three or four pertinent rounds of optimisation, a final version based on general consensus will be available at the end. All guidelines are subject to adaptation in a period of 3-5 years at the latest or if needed even earlier.

Onychomycosis.

The guideline on onychomycosis, as passed by the responsible German medical societies, is presented in the present study.

Tinea capitis: ringworm of the scalp.

The guideline tinea capitis, as passed by three German medical societies, is presented in the present study.

[Epidemiology, clinic and treatment of dermatomycoses caused by zoophilic dermatophytes] . / Epidemiologie, Klinik und Therapie von Dermatomykosen durch zoophile Dermatophyten.

In the last 50 years the spectrum of agents of dermatophytoses changed. The change is remarkable especially in the case of zoophilic dermatophytes. Microsporum canis has displaced Trichophyton verrucosum. In the period from 1966 to 1970 2822 dermatophytoses were registered as occupational dermatoses in the former German Democratic Republic. In the following years the number of these diseases was continuously reduced, between 1981 and 1985 down to 995 cases. This reduction is predominantly the result of active immunoprophylaxis by means of inactivated, hydrolized vaccines, mainly by the Soviet live vaccine LTF-130. The scientific basis of this vaccination was established by Kielstein and co-workers. The treatment of Microsporum canis infection of the scalp requires the administration of systemically acting antimycotics over a long period (6-8 weeks).

[The change of dermatophyte spectrum in dermatomycoses]. / Zur Veränderung des Dermatophytenspektrums bei dermatologisch relevanten Erkrankungen.

The spectrum of dermatophytes out of mycotic skin lesions had changed in last 70 years. Before the Second World War in Germany Microsporum audouinii and Epidermophyton floccosum held the first position, since the fifties of last century Trichophyton rubrum is the most frequently isolated dermatophyte accounting for 80-90% of the strains, followed by T. mentagrophytes. This development is typical for Central and North Europe and is connected with the increase in the incidence of tinea pedis. In contrast to this, in Southern Europe and in Arab countries zoophilic dermatophytes, such as M. canis and T. verrucosum, are the most frequently isolated dermatophytes. An analysis of the frequency and distribution of tinea pedis in different occupations and the route of infection is also reported. The epidemiologic findings are contrary to the assumption that patients are genetically predisposed to T. rubrum infection in a dominant autosomal pattern.

[Modern antimycotics. What the treating physician needs to know]. / Moderne Antimykotika. Was der behandelnde Arzt darüber wissen sollte.

The treatment of dermatophytoses is a complex process influenced by the properties of the antimycotic and the causative agent as well as by patient-related factors. Both the minimal inhibition concentration and the drug concentration in the infected tissue influence treatment success. Dermatophytes can be present as arthrospores in the skin, nails or hair. Non-proliferating dermatophytes (arthrospores) are less susceptible to antimycotics than proliferating ones, particularly to antibiotics which act through the inhibition of fungal ergosterol synthesis. Non-proliferating dermatophytes do not synthesize ergosterol, a essential component of fugal cell membranes. Also, dermatophytes accumulating in hollow spaces mostly in the nail plate, cannot be reached by antimycotics. The concentration of terbinafine and itraconazole is very high in sebum. This is of importance in the treatment of dermatophytoses localized to in the stratum corneum and in or around the hair. Preadolescent children do not have functioning sebaceous glands; this explains the difficulties in the treatment of pediatric tinea capitis.

[Mycophobia--a new disease?]. / Mykophobie--eine neue Krankheit?

In the recent 18 months we analysed 13 patients with so-called therapy-resistant intestinal candidosis. Symptoms like flatulence, digestive trouble, intestinal inefficiency, arthralgia, heart trouble, etc., were declared. From four patients Candida albicans and in further three patients C. parapsilosis, C. lusitaniae, Trichosporon cutaneum, and Geotrichum candidum could be isolated. Serological tests were normal. In none of the 13 patients a mycosis which needed therapy was proven. Eight patients had signs of a depression or neurosis. In all 13 patients the occasional or repeated isolation of yeasts from faeces or the oral cavity was falsely interpreted as a fungal infection and thus became the inductor of a phobia.

[Limits of brief treatment of onychomycoses]. / Grenzen der Kurzzeitbehandlung von Onychomykosen.

New antifungals for oral therapy have improved the chances of healing onychomycoses. Nevertheless, in daily practice the failure rate is 20-30% both with itraconazole and terbinafine. In our investigations for the fungicidal effects of terbinafine, we could show that the same strain of Trichophyton rubrum or T. mentagrophytes in the rest period needs 1000 times higher concentration of terbinafine (2.0 to 0.002 microgram/ml) for complete fungal killing as in the growth phase. Thus resting fungi in the nail are not harmed, and if the concentration of terbinafine is lower than the MIC for the fungi, they can cause a relapse. Itraconazole is a fungistatic agent. Its concentration in the nail plate must be higher than the MIC for the causative fungi for a long time-10 to 12 months. The usual short-term treatment of onychomycosis over 3 months can be insufficient in individual cases such as patients with disorders, e.g. circulatory disorders or slowed nail growth.

[Candida in dermatology]. / Candida in der Dermatologie.

Regarding Candida in dermatology, two pathogenetic pathways must be taken into account: 1. on infection of the skin 2. immunological reactions with skin alterations as a result of Candida infection or colonization in the mouth and/or intestine. Case reports describe typical situations of napkin dermatitis, intertriginous candidosis, the intrauterine Candida infection of the foetus, Candida granuloma, Candida folliculitis and Candida paronychia. In the second part results of investigations of patients suffering from psoriasis, atopic dermatitis and urticaria are presented. There were no differences in the colonization with Candida albicans and in the level of Candida antibody titres between patients and a healthy control group.

[Comparative examinations of the effect of general and local anesthesia upon the T-lymphocytes in melanoma operations (author's transl)]. / Vergleichende Untersuchungen zum Einfluss der Narkose und der Lokalanästhesie auf die T-Lymphozyten bei Melanomoperationen.

We examined the number of T-Lymphocytes in 14 malignant melanoma patients using the sheep erythrocyte rosette test and the PHA stimulation test. These investigations were carried out before the operation under general anesthesia was performed as well as 1, 7, 14, 21, and 28 days after the operation. 16 patients with various large surface skin operations in local anesthesia served as a control group. Among them there were also 5 malignant melanoma cases. The tests preoperatively accomplished yielded normal results (T-lymphocytes 65.7 +/- 2.95%, PHA stimulation 79.01 +/- 1.69%) for all 19 melanoma patients. 24 hours after the operation the average portion of T-lymphocytes decreased in relation to the whole lymphocytes and reached only the level of 53.8 +/- 7.8%. After 7 days it amounted to 57.5 +/- 8.5%, after 14 days to 59.5 +/- 7.8%, after 21 days to 62.3 +/- 5.4% and after 28 days to 62.8 +/- 6.1%. The PHA stimulation was significantly diminished only after 24 hours, but not longer after 7 days. A correlation between the diminution of T-lymphocytes observed 14 and more days after the operation and the duration of the general anesthesia may be suggested in single cases. -- Patients operated under local anesthesia showed after 2 and 24 hours a significant diminution of T-lymphocytes. After 7 days the values had returned to normal levels (66.7 +/- 5.9%).