High- and intermediate-risk susceptibility variants in melanoma families from the Mediterranean area: A multicentre cohort from the MelaNostrum Consortium.

BACKGROUND: Most of large epidemiological studies on melanoma susceptibility have been conducted on fair skinned individuals (US, Australia and Northern Europe), while Southern European populations, characterized by high UV exposure and dark-skinned individuals, are underrepresented. OBJECTIVES: We report a comprehensive pooled analysis of established high- and intermediate-penetrance genetic variants and clinical characteristics of Mediterranean melanoma families from the MelaNostrum Consortium. METHODS: Pooled epidemiological, clinical and genetic (CDKN2A, CDK4, ACD, BAP1, POT1, TERT, and TERF2IP and MC1R genes) retrospective data of melanoma families, collected within the MelaNostrum Consortium in Greece, Italy and Spain, were analysed. Univariate methods and multivariate logistic regression models were used to evaluate the association of variants with characteristics of families and of affected and unaffected family members. Subgroup analysis was performed for each country. RESULTS: We included 839 families (1365 affected members and 2123 unaffected individuals). Pathogenic/likely pathogenic CDKN2A variants were identified in 13.8% of families. The strongest predictors of melanoma were ≥2 multiple primary melanoma cases (OR 8.1; 95% CI 3.3-19.7), >3 affected members (OR 2.6; 95% CI 1.3-5.2) and occurrence of pancreatic cancer (OR 4.8; 95% CI 2.4-9.4) in the family (AUC 0.76, 95% CI 0.71-0.82). We observed low frequency variants in POT1 (3.8%), TERF2IP (2.5%), ACD (0.8%) and BAP1 (0.3%). MC1R common variants (≥2 variants and ≥2 RHC variants) were associated with melanoma risk (OR 1.4; 95% CI 1.0-2.0 and OR 4.3; 95% CI 1.2-14.6, respectively). CONCLUSIONS: Variants in known high-penetrance genes explain nearly 20% of melanoma familial aggregation in Mediterranean areas. CDKN2A melanoma predictors were identified with potential clinical relevance for cancer risk assessment.

Therapeutic combination of radiofrequency surgical dissection and oral acitretin in the management of perianal Buschke-Lowenstein tumour: a case report.

Giant condyloma acuminatum (GCA), or Buschke-Löwenstein tumour (BLT), is a rare large tumour of the anogenital area. It is caused by human papillomavirus genotypes 6 and 11, and it is characterized by aggressive local invasion and frequent recurrences after treatment. Treatment of choice is radical excision, although chemotherapy and radiation are also used in special cases. We report a case of a young man with anogenital GCA, presenting with a large perianal mass and pain during defaecation. The patient was treated by surgical removal of almost the entirety of the mass, using radiofrequency surgical dissection. The concurrent use of oral acitretin for the treatment of erythrodermic psoriasis led to elimination of the remaining disease. The patient remains free of disease 26 months after the end of treatment.

Comprehensive mutational analysis of CDKN2A and CDK4 in Greek patients with cutaneous melanoma.

BACKGROUND: The penetrance of CDKN2A mutations is subject to geographical and latitudinal variation and is presumably dictated by ultraviolet radiation exposure and possibly other co-inherited genetic factors. The frequency of mutations increases with the number of family members affected and the number of primary tumours, and also fluctuates with geography. To date, little is known about the prevalence of CDKN2A mutations in patients with melanoma from Greece. OBJECTIVE: To characterize the frequency of CDKN2A and CDK4 mutations in a hospital-based population of Greek patients with melanoma. METHODS: Three hundred and four consecutive single primary melanoma (SPM), nine familial melanoma (FM) and seven multiple primary melanoma cases (MPM) were assessed for sequence variants in exons 1α, 1ß and 2 of CDKN2A and exon 2 of CDK4. RESULTS: Germline CDKN2A mutations were detected in 10 of 304 SPM (3·3%), in four of seven MPM (57%) and in two of nine FM (22%) cases. The most common mutation was a Northern European allele (p16 p.R24P) detected in eight individuals. Five previously unreported CDKN2A variants were also identified: -34G>C, c.41_43delins20bp, c.301G>C (p.G101R), c.301G>A (p.G101E) and c.296_297insGACC. We also describe the first report of a CDK4 p.R24H substitution in a Greek family. CONCLUSIONS: The Greek population appears to harbour a higher prevalence of the CDKN2A mutation than other reported cohorts. This supports the notion that genetic susceptibility may play a stronger influence in a country with a relatively low incidence of melanoma. Furthermore, the identification of Northern European alleles suggests that gene migration may be responsible, in part, for the observed cases in Greece.

Atopic patients with genital warts have a more protracted clinical course and a greater probability of recurrences.

The factors predicting an unfavourable response of genital warts to treatment have not been determined. The disease characteristics were recorded for 390 patients with genital warts and treated by cryotherapy. The time to achieve clearance was recorded. A personal and family history of asthma, hay fever or eczema, as well as a personal history of common warts and number of recurrences was obtained by telephone four to five years after the clinical visits. In multiple regression analysis, the number of lesions (P < 0.001), extent of the disease (P = 0.003) and personal history of atopy (P = 0.001) were found to influence the time until response to treatment. Similar results were obtained for family history of atopy. The number of sexual partners (P = 0.007), extent of the disease (P = 0.009) and personal history of atopy (P < 0.001) were the main factors influencing the probability of recurrence in multiple logistic regression. The results for family history of atopy were again similar. The study concludes that atopy is a major factor influencing the time frame of the therapeutic response and the probability of recurrence in patients with genital warts.

Infliximab for the treatment of psoriasis in Greece: 4 years of clinical experience at a single centre.

BACKGROUND: Infliximab, a chimeric monoclonal antibody, has been shown to be effective for moderate to severe psoriasis. Clinical experience with long-term infliximab therapy for psoriasis is accumulating, and it is therefore important to share our experience with its use in real-life clinical practice. OBJECTIVES: To report our experience with infliximab (Remicade; Schering Plough, Kenilworth, NJ, U.S.A.) for the treatment of moderate to severe plaque psoriasis (and/or arthritis) from a single clinic in Greece. PATIENTS AND METHODS: Between August 2004 and March 2008, 62 patients presenting to our clinic with moderate to severe psoriasis were treated with infliximab. Disease phenotype, clinical course, disease severity and adverse events were assessed throughout the treatment period. RESULTS: Infliximab resulted in a reduction of median Psoriasis Area and Severity Index (PASI) of 70% at week 6 and 84.4% at week 14. Nineteen patients who have completed 1 year on infliximab treatment experienced sustained efficacy with a median PASI improvement of 92.16% and a Physician's Global Assessment (PGA) of 'clear' or 'almost clear', while nine patients have reached approximately 20 months of continuous therapy. All patients with psoriatic arthritis showed marked improvement in their clinical symptoms following the first infusion. Eight patients (12.9%) experienced adverse events that required discontinuation of treatment. There were no statistically significant differences in PASI and Dermatology Life Quality Index (DLQI) scores between patients with arthritis and those with only skin lesions, or between those who received methotrexate, either from the beginning or during infliximab therapy, and those who did not receive methotrexate at all. Selected patients of interest are discussed. CONCLUSIONS: The above data confirm previous reports that treatment with infliximab is an efficacious and safe option for patients with moderate to severe plaque psoriasis (and/or arthritis). Long-term follow-up, continued pharmacovigilance, and controlled comparative studies will be required to fully evaluate its use in the treatment of psoriasis.

Melanoma/skin cancer screening in a Mediterranean country: results of the Euromelanoma Screening Day Campaign in Greece.

BACKGROUND: Since the year 2000 a melanoma/skin cancer screening campaign has been organized annually in Greece in the context of the Euromelanoma Screening Day Campaign. OBJECTIVES: We aimed to analyse the characteristics of the screened population, to recognize relevant risk factors and to identify the cases of histologically confirmed malignant melanoma (MM) in individuals with suspicious skin lesions. METHODS: An analysis of the completed screening forms from the years 2000-2004 was performed with respect to relevant demographic, epidemiological and clinical data. RESULTS: A total of 9723 individuals were screened, most of whom where below the age of 50 years (71%), female (59%), and of skin phototype II and III (76%). Sunburn during childhood was reported in 47% of participants, while 5% of the screened population had a personal or family history of melanoma. On clinical examination, 14.4% had actinic keratoses, 31.2% had dysplastic nevi, while 6.4% carried a presumptive diagnosis of non-melanoma skin cancer. In the 2003-2004 screening campaign, 19 out of the 171 clinically suspicious lesions were histologically proven to be MM, the majority of which (58%) were 'thin' melanomas (Breslow's thickness of

p53 codon 72 Pro homozygosity increases the risk of cutaneous melanoma in individuals with dark skin complexion and among noncarriers of melanocortin 1 receptor red hair variants.

BACKGROUND: p53 has a common polymorphism at amino acid 72, encoding either arginine or proline. p53Arg and p53Pro exhibit differences in various biological activities, such as cell-cycle arrest and induction of apoptosis. Numerous epidemiological studies have examined the role of this polymorphism in several human malignancies, including cutaneous cancers, with contradictory results. OBJECTIVES: To investigate the germline frequency of p53 codon 72 polymorphism in malignant melanoma in a Mediterranean population, and to examine possible associations with various clinicopathological factors. METHODS: In this hospital-based case-control study we used allele-specific polymerase chain reaction for p53 codon 72 genotyping in blood specimens from 107 Greek patients with sporadic cutaneous melanoma and 145 healthy controls. RESULTS: After adjustment for age, sex and phototype the Pro/Pro genotype was associated with increased risk for cutaneous melanoma compared with the Arg/Arg genotype (adjusted odds ratio, OR 3.17, 95% confidence interval, CI 1.03-9.78). This correlation was more pronounced in subjects with phototypes III or IV (adjusted OR 9.56, 95% CI 1.56-58.46), dark skin (adjusted OR 10.96, 95% CI 1.64-73.28), dark eyes (adjusted OR 8.86, 95% CI 1.69-46.52) and dark hair (adjusted OR 3.17, 95% CI 1.01-9.95), and among noncarriers of melanocortin 1 receptor gene (MC1R) red hair polymorphisms (adjusted OR 2.99, 95% CI 1.02-8.78). CONCLUSIONS: p53 codon 72 Pro/Pro genotype could be a risk factor for the development of melanoma in the Greek population, especially in subgroups with darker skin pigmentation, as well as among noncarriers of the MC1R red hair polymorphic variants.

In vivo fluorescence kinetics and photodynamic therapy in condylomata acuminata.

BACKGROUND: Topical application of 5-aminolaevulinic acid (ALA) to condylomata acuminata leads to accumulation of protoporphyrin IX (PpIX); therefore ALA-induced photodynamic therapy (ALA-PDT) appears to be a potential treatment. OBJECTIVES: To investigate in vivo the PpIX fluorescence time course after topical application of ALA in order to determine the optimal time for irradiation, and to assess the efficacy of subsequently performed ALA-PDT. METHODS: Fluorescence kinetics was studied in 12 male patients with condylomata acuminata. Confirmation of diagnosis was established with conventional histology and polymerase chain reaction. Lesions were treated with 20% ALA and irradiated at the optimal time with a dose of 70 J cm-2 or 100 J cm-2 light. An additional session with 100 J cm-2 was administered 1 week later to lesions that persisted. RESULTS: The in vivo study of fluorescence kinetics indicated that the optimal time for irradiation varied among patients from 6 to 11 h. The overall cure rate was 72.9%, 12 months after treatment. CONCLUSIONS: Topical ALA-PDT is a potentially effective treatment for condylomata acuminata.

Ochratoxin A concentrations in Greek domestic wines and dried vine fruits.

A survey for the presence of ochratoxin A (OTA) was conducted from 1995 to 1999 on 268 locally produced commercial wines, and on 81 samples of domestic dried vine fruits (currants and sultanas) collected between 1998 and 2000 from sites of primary storage and processing. The OTA concentration in red dry wines (n = 104, median = 0.09 microgram l(-1)) was not significantly different from that for white (n = 118, median = 0.06 microgram l(-1)) and rosé (n = 20, median = 0.08 microgram l(-1)) wines. Eighteen samples of dessert wines (sweet, semi-sweet, semi-dry) and eight samples of retsina wine showed larger OTA concentrations with medians of 0.33 and 0.27 microgram l(-1), respectively. Our data indicate that the geographic region of origin influences OTA contamination for the red dry wines. In fact, a trend of increasing OTA contamination was observed for red wines from northern to southern Greece. Regarding the OTA levels in dried vine fruits, sultanas (n = 27, median = 0.6 microgram kg(-1)) were less contaminated than currants (n = 54, median = 1.3 microgram kg(-1)). Also, sultanas produced in 2000 and currants produced in 1999 showed the lowest incidence of OTA contamination, with medians of 0.3 and 0.9 microgram kg(-1), respectively.

In vivo detection of human papilloma virus-induced lesions of anogenital area after application of acetic acid: a novel and accurate approach to a trivial method.

Human papilloma virus infection is increasing at an alarming rate. The ability of the virus to establish a subclinical infection and its association with malignancy of the lower genital tract make the statistics even more worrisome. Topical application of acetic acid solution provokes temporal alterations of the light-scattering properties of human papilloma virus-induced lesions of anogenital area. For the in vivo study of the phenomenon, an imaging system has been employed, which performs time-lapse imaging and enables the calculation and display of the kinetics of the provoked alterations in any point within the examined area. Confirmation of diagnosis has been established with conventional histology and polymerase chain reaction. It has been shown that the method provides early detection and staging of skin alteration or transformation due to human papilloma virus infection and enables mapping of the infected area.

Fractionated carboplatin radiosensitization: a phase I dose-escalation study.

Carboplatin is one of the most common drugs used for radiochemotherapy of cancer. However, the best way to combine the drug with fractionated radiotherapy has not been established. In the present study the authors investigated which maximum tolerated daily bolus dose of carboplatin would allow safe radiopotentiation for 10 consecutive radiotherapy days, the scheme being repeated twice during the 6 weeks that a conventional radiotherapy scheme lasts. Seventy-two patients with lung or pelvis malignancies were included in a dose escalation study. Twenty-four patients comprised the first baseline cohort and were treated with radiotherapy alone. The daily dose of carboplatin was escalated starting from 38 mg/m2 daily (for 10 days) and increasing by 7 mg/m2 per day. Six patients were to be included in each cohort. All 12 patients treated at the 38 mg/m2 and 45 mg/m2 dose level completed two cycles of 10-day carboplatin treatment with no grade III-IV toxicity. Granulocyte colony-stimulating factor effectively averted the incidence of neutropenia and allowed the administration of the second carboplatin 10-day cycle in five of six patients at the 52 mg/m2 daily dose level. Platelet grade III-IV toxicity was observed in all 12 patients (six supported with granulocyte colony-stimulating factor and six with granulocyte colony-stimulating factor and recombinant human erythropoietin) treated at the 59 mg/m2 daily dose level and none of them received the second cycle of chemotherapy. Twelve patients were treated at the same dose level using amifostine 500 mg before carboplatin infusion. Two patients interrupted chemotherapy because of severe nausea and vomiting. Nine of 10 who accomplished the 10-day treatment had platelet levels more than 90,000/microl on day 28 and completed the second 10-day cycle without severe toxicity. Acute radiation toxicity did not increase in the carboplatin cohorts. In this study the authors established a high-dose fractionated carboplatin schedule that can be safely administered during radical radiotherapy.