Which medical disciplines diagnose and treat melanoma in Europe in 2019? A survey of experts from melanoma centres in 27 European countries.

BACKGROUND AND OBJECTIVES: The incidence of melanoma is increasing. This places significant burden on societies to provide efficient cancer care. The European Cancer Organisation recently published the essential requirements for quality melanoma care. The present study is aimed for the first time to roughly estimate the extent to which these requirements have been met in Europe. MATERIALS AND METHODS: A web-based survey of experts from melanoma centres in 27 European countries was conducted from 1 February to 1 August 2019. Data on diagnostic techniques, surgical and medical treatment, organization of cancer care and education were collected and correlated with national health and economic indicators and mortality-to-incidence ratio (MIR) as a surrogate for survival. Univariate linear regression analysis was performed to evaluate the correlations. SPSS software was used. Statistical significance was set at P < 0.05. RESULTS: The MIR was lower in countries with a high health expenditure per capita and with a higher numbers of general practitioners (GPs) and surgeons (SURG) per million inhabitants. In these countries, GPs and dermatologists (DER) were involved in melanoma detection; high percentage of DER used dermatoscopy and were involved in the follow-up of all melanoma stages; both medical oncologists (ONC) and dermato-oncologists administered systemic treatments; and patients had better access to sentinel lymph node biopsy and were treated within multidisciplinary tumour boards. CONCLUSION: Based on these first estimates, the greater involvement of GPs in melanoma detection; the greater involvement of highly trained DER in dermatoscopy, dermatosurgery, follow-up and the systemic treatment of melanoma; and the provision of ongoing dermato-oncology training for pathologists, SURG, DER and ONC are necessary to provide an optimal melanoma care pathway. A comprehensive analysis of the melanoma care pathway based on clinical melanoma registries will be needed to more accurately evaluate these first insights.

Low-dose daily aspirin reduces topical minoxidil efficacy in androgenetic alopecia patients.

Topical minoxidil is the only US FDA approved OTC drug for the treatment of androgenetic alopecia (AGA). Minoxidil is a pro-drug converted into its active form, minoxidil sulfate, by the sulfotransferase enzymes in the outer root sheath of hair follicles. Previously, we demonstrated that sulfotransferase activity in hair follicles predicts response to topical minoxidil in the treatment of AGA. In the human liver, sulfotransferase activity is significantly inhibited by salicylic acid. Low-dose OTC aspirin (75-81 mg), a derivative of salicylic acid, is used by millions of people daily for the prevention of coronary heart disease and cancer. It is not known whether oral aspirin inhibits sulfotransferase activity in hair follicles, potentially affecting minoxidil response in AGA patients. In the present study, we determined the follicular sulfotransferase enzymatic activity following 14 days of oral aspirin administration. In our cohort of 24 subjects, 50% were initially predicted to be responders to minoxidil. However, following 14 days of aspirin administration, only 27% of the subjects were predicted to respond to topical minoxidil. To the best of our knowledge, this is the first study to report the effect of low-dose daily aspirin use on the efficacy of topical minoxidil.

Mechanism of action of minoxidil in the treatment of androgenetic alopecia is likely mediated by mitochondrial adenosine triphosphate synthase-induced stem cell differentiation.

Topical minoxidil is the only topical drug approved by the US Food and Drug Administration (FDA) for the treatment of androgenetic alopecia. However, the exact mechanism by which minoxidil stimulates anagen phase and promotes hair growth is not fully understood. In the late telegen phase of the hair follicle growth cycle, stem cells located in the bulge region differentiate and re-enter anagen phase, a period of growth lasting 2-6 years. In androgenetic alopecia, the anagen phase is shortened and a progressive miniaturization of hair follicles occurs, eventually leading to hair loss. Several studies have demonstrated that minoxidil increases the amount of intracellular Ca2+, which has been shown to up-regulate the enzyme adenosine triphosphate (ATP) synthase. A recent study demonstrated that ATP synthase, independent of its role in ATP synthesis, promotes stem cell differentiation. As such, we propose that minoxidil induced Ca2+ influx can increase stem cell differentiation and may be a key factor in the mechanism by which minoxidil facilitates hair growth. Based on our theory, we provide a roadmap for the development of a new class of drugs for the treatment of androgenetic alopecia.

[PSYCHODERMATOLOGY].

Psychodermatologic disorders are conditions involving an interaction between the mind and the skin. Correlation between psychiatric and dermatological disorders is a highly complex relation considering etiology, diagnostic procedures and treatment. There are three major groups of psychodermatological disorders: psychosomatic (psychophysiologic) disorders, primary psychiatric disorders and secondary psychiatric disorders. Psychosomatic disorders are dermatological diseases which can be exacerbated or worsened by emotional stress, but are not caused directly by stress. Emotional stress can exacerbate many chronic dermatoses like urticaria, eczema, psoriasis, acne, seborrheic dermatitis, atopic dermatitis, alopecia areata, psychogenic purpura, rosacea, atypical pain syndromes and hyperhidrosis. The treatment of patients with the resistant chronic dermatosis can be difficult when stress is not recognized as a provoking factor. Primary psychiatric disorders are psychiatric conditions which induce development of various skin changes, e.g trichotillomania, factitial dermatitis, neurotic excoriations, delusions of parasitosis and dysmorphophobia. They include psychiatric disorders with anxiety, compulsive- opsessive and depressive symptoms and pathologic delusional ideas or hallucinations regarding the skin. Secondary psychiatric disorders appear as a result of a certain disfiguring skin disease that induces psychologic suffering such as loss of self-confidence, anxiety and social phobia. This category includes diseases like psoriasis, chronic eczema, various ichthyosiform syndromes, rhinophyma, multiple neurofibromas, severe acne, and other cosmetically disfiguring cutaneous lesions. The therapeutic approach of psychodermatological disorders should be multidisciplinary including primary care physicians, dermatologist, psychiatrist and psychologist. It is very important to educate dermatologists in the diagnostic procedures and therapy of psychiatric disorders which sometimes coexist with the skin disease. Majority of psychodermatological disorders can be treated with cognitive-bihevioral psychotherapy, psychotherapeutic stress-and-anxiety-management techniques and psychotropic drugs. Psychopharmacologic treatment includes anxiolytics, antidepressants, antipsychotics and mood stabilizer.

Surgical and histologic pitfalls in the management of lentigo maligna melanoma.

Lentigo maligna melanoma (LMM) is a malignancy with increasing incidence, accounting for about 4% to 15% of all melanomas. Lentigo maligna (LM) is LMM in situ, usually presenting an irregular tan colored or brownish pigmented macular lesion persisting for years on chronically sun-exposed skin. Left untreated, LM may evolve into invasive form of LMM. Histologic evaluation of LM/LMM can be difficult due to widespread atypical melanocytes that are present in the area chronically sun damaged skin. It has been shown that chronically sun-damaged non-lesional skin can display some atypical features even in the absence of a melanocytic neoplasm. It is important for dermatopathologists to be aware of these findings so that such features are interpreted appropriately when making a histological assessment that may ultimately influence therapy and outcome. LMM is characterized by significant subclinical lesion extension which makes the treatment another challenge. Nowadays, a variety of therapeutic options are available in the treatment of LMM. Surgery remains the mainstay of LMM therapy, however the treatment of LM remains controversial subject in the literature. Non-surgical treatment modalities for LM include: destructive procedures such radiotherapy, cryotherapy, curettage, laser, electro-destruction and immunotherapy with the topical application of 5% imiquimod cream. These treatment options should be considered for a subset of patients with LM, especially in elderly patients with extensive or unresectable disease in difficult areas on the face or, as a second-line therapy if surgery is contraindicated. Surgical options include simple excision and margin-control techniques such as staged excision and Mohs micrographic surgery.In this article, authors are reviewing the latest diagnostic and therapeutic advances in the management of LMM.

Sun behaviour patterns and perception of illness among melanoma patients.

BACKGROUND: Melanoma is one of the most aggressive skin tumours for which the major risk factor is ultraviolet radiation. Sun protection is extremely important, especially for melanoma patients who, once diagnosed with melanoma, have 500 times greater chance of developing another melanoma than the general population. OBJECTIVE: In this study, we examined the perception of melanoma and attitudes towards sun protection among melanoma patients and compared their results with the patients suffering from other dermatological disorders. METHODS: In total, 240 participants were included in the study: 120 patients suffering from melanoma and 120 participants in the control group. The Sun Behaviour Patterns Questionnaire and the Brief Illness Perceptions Questionnaire were used in this study to assess sun behaviours and perception of melanoma. RESULTS: Melanoma patients have negative attitude towards sunbathing: 57% avoid sunbathing and 27% spend time in the sun only during swimming, otherwise seeking shade, whereas participants in the control group have more positive attitude towards sunbathing. Results indicate very short time of using sunscreen protection during the year and very small number of people using adequate SPF value, in both melanoma and control group. CONCLUSION: Participants in control group perceive melanoma as a more serious illness than patients who think that melanoma has mild symptoms, is easy to cure and control, has moderate consequences and lasts relatively long. Both melanoma patients and participants in the control group show relatively good sun behaviour patterns and slightly negative attitudes towards sun protection.

The Euromelanoma skin cancer prevention campaign in Europe: characteristics and results of 2009 and 2010.

BACKGROUND: Euromelanoma is a skin cancer education and prevention campaign that started in 1999 in Belgium as 'Melanoma day'. Since 2000, it is active in a large and growing number of European countries under the name Euromelanoma. OBJECTIVE: To evaluate results of Euromelanoma in 2009 and 2010 in 20 countries, describing characteristics of screenees, rates of clinically suspicious lesions for skin cancer and detection rates of melanomas. METHODS: Euromelanoma questionnaires were used by 20 countries providing their data in a standardized database (Belgium, Croatia, Cyprus, Czech Republic, FYRO Macedonia, Germany, Greece, Hungary, Italy, Lithuania, Luxembourg, Malta, Moldavia, Portugal, Serbia, Slovenia, Spain, Sweden, Switzerland and Ukraine). RESULTS: In total, 59,858 subjects were screened in 20 countries. Most screenees were female (64%), median ages were 43 (female) and 46 (male) and 33% had phototype I or II. The suspicion rates ranged from 1.1% to 19.4% for melanoma (average 2.8%), from 0.0% to 10.7% for basal cell carcinoma (average 3.1%) and from 0.0% to 1.8% for squamous cell carcinoma (average 0.4%). The overall positive predictive value of countries where (estimation of) positive predictive value could be determined was 13.0%, melanoma detection rates varied from 0.1% to 1.9%. Dermoscopy was used in 78% of examinations with clinically suspected melanoma; full body skin examination was performed in 72% of the screenees. CONCLUSION: Although the population screened during Euromelanoma was relatively young, high rates of clinically suspected melanoma were found. The efficacy of Euromelanoma could be improved by targeting high-risk populations and by better use of dermoscopy and full body skin examination.

Prognostic value of galectin-3 in primary cutaneous melanoma.

BACKGROUND: Galectin-3, one of the ß-galactoside-binding lectins, has been suggested as a marker of disease progression in melanoma patients because of its overexpression observed in recent studies. However, prognostic value of galectin-3 in primary cutaneous melanoma (PCM) has not been clearly defined. OBJECTIVES: The aim of the study was to analyse whether the intensity of galectin-3 expression can predict survival in patients with PMC. METHODS: Galectin-3 expression was evaluated using immunohistochemistry in 104 PCM samples, including 71 (68.2%) superficial spreading (SSM) and 33 (31.8%) nodular melanomas (NM). RESULTS: Significant difference of galectin-3 expression between SSM and NM was determined (P < 0.001). Increased galectin-3 expression was positively correlated with tumour thickness (P < 0.001), Clark (P < 0.001) and Breslow (P < 0.001) stage, mitotic rate (P < 0.001), presence of tumour ulceration (P < 0.001), lymphatic invasion (P = 0.018), positive sentinel lymph node (P < 0.022) and distant metastases (P < 0.001). Kaplan-Meier analysis showed an association between increased galectin-3 expression and reduced recurrence-free survival (RFS) (P = 0.001) and reduced disease-specific survival (DSS) (P = 0.015). In Cox proportional hazards regression analysis, significant predictors of reduced RFS were positive sentinel lymph node (P = 0.025) and lymphovascular invasion (P = 0.021), whereas predictors of DSS were tumour thickness (P = 0.012), lymphovascular invasion (P = 0.047), Clark stage (P = 0.029) and location of tumour on upper extremities (P = 0.024). CONCLUSIONS: Our results support the potential role of galectin-3 in PCM development, progression and metastasis. Moreover, galectin-3 could serve as an additional prognostic marker that might help in further stratifying the risk of disease progression and metastasis in patients with PMC.

Technique and survival after laparoscopically assisted right hemicolectomy.

BACKGROUND: The role of laparoscopic colon resection in the management of colon cancer is still controversial. In this article, the surgical strategy and techniques are described, with further consideration of the oncologically relevant aspects. METHODS: Between March 1993 and July 2003, we performed laparoscopic right hemicolectomy in 56 patients with right colon carcinoma. Average age was 74.5 years (range, 17-92). We performed a standardized surgical procedure that included mobilization from the vascularized mesenteric bridges with a window technique, transection of the ileocolic lymphovascular pedicle, and lateral and proximal mobilization of the ileocecum, ascending colon, right flexure, and proximale transversum. After enlargement of one of the trocar incisions the exteriorized colon was resected and an extracorporeal anastomosis was performed in the standard manner. RESULTS: There were no conversions to open. The mean operating time was 119 +/- 38 min, the mean length of resected colon was 27.8 +/- 4.48 cm, and the average width of the clear margins was 6.8 +/- 5.3 cm. One patient died. Lymph nodes were positive in 21 patients. The 5-year survival rate in the 48 patients who were operated on with curative intent was 75%. We have had two local recurrences. The overall 5-year mortality-free fraction was 63%. Cox multivariate analysis showed that the mortality-prognostic factors were tumor stage and length of resected colon, whereas Kaplan-Meier analysis showed that the mortality-prognostic factors were positive lymph nodes and tumor stage. CONCLUSIONS: Our results show that laparoscopic right hemicolectomy for colon cancer can be performed safely. Complications and recurrence rates are comparable to those for left-sided laparoscopic and open procedures. Therefore, we recommend this procedure as the method of choice. Laparoscopically treated patients with stage II and stage III disease have almost the same cumulative rate of survival.

Mal de Meleda: genetic haplotype analysis and clinicopathological findings in cases originating from the island of Mljet (Meleda), Croatia.

BACKGROUND: Mal de Meleda (keratoderma palmoplantaris transgrediens) is an autosomal recessive disorder, first described on the island of Mljet (Meleda), Croatia. The candidate region for the gene responsible for this disorder was found on the chromosome 8qter, and the responsible mutations have recently been identified in 12 Algerian and 7 Croatian families. OBJECTIVES: To fully characterize all 12 living cases originating from the original setting of the disease, the island of Mljet, in the light of new findings and using modern diagnostic technology. PATIENTS AND METHODS: Twelve patients and 37 family members were identified over the period 1998-1999, interviewed and examined. RESULTS: The reconstruction of 8 genealogies suggests a common ancestry of all cases but one. The clinical presentation and pathologic findings of these cases are described in detail and are consistent with previous reports. Symptoms and signs were found to be milder in non-manual workers who had applied continuous symptomatic treatment. Blood samples were taken from 8 cases and 16 close relatives for genetic studies. These confirmed a shared haplotype in all cases, but in none of 17 unaffected control individuals, near the marker D8S1751 on chromosome 8. CONCLUSIONS: This review characterizes mal de Meleda in its original setting and shows that the sporadic cases found in the regions of medieval trade routes of the Republic of Dubrovnik (Middle East and Northern Africa) carry the same mutation as the patients from Mljet Island, Croatia.

Increased incidence of colorectal cancer in the split-dalmatia county: epidemiological study.

AIM: To investigate the incidence of colorectal cancer in the Split-Dalmatia County in the 1981-1998 period, and compare it with the incidence in the Republic of Croatia. METHODS: The data were obtained using case records and registries of all hospitals and Public Health Institute in the County and the Croatian Cancer Registry. Age-standardized incidence per 100,000 was calculated from the number of patients with colorectal cancer and the number of inhabitants. RESULTS: There were 2,454 new cases of colorectal cancer (1,383 men and 1,071 women) in the Split-Dalmatia County in 1981-1998. Colon cancer was diagnosed in 55% of the cases. Age-standardized incidence rates for colorectal carcinoma per 100,000 population were 11.4 (men 14.8, women 9.0) in 1981, and 63.5 (men 93.1, women 42.5) in 1998. The total incidence increased from 16.1 (colon cancer 7.9, rectal cancer 8.2) in 1981-1985 period to 52.8 (colon cancer 30.5, rectal cancer 22.3) in 1994-1998 period, or approximately 3.3 times. The colorectal cancer incidence rate in the Split-Dalmatia County increased from 16.2 in 1985 to 46.4 in 1995, and in whole Croatia from 32.4 in 1985 to 37.8 in 1995. CONCLUSION: There was a great increase in the reported incidence of colorectal cancer in the Split-Dalmatia County in the 1981-1998 period. The relative increase of incidence in the colorectal cancer was much greater in the Split-Dalmatia County than in Croatia as a whole. These changes call for preventive and screening measures for colorectal carcinoma.

Variable expression of Gorlin syndrome may reflect complexity of the signalling pathway.

Nevoid Basal Cell Carcinoma Syndrome (NBCCS) or Gorlin syndrome is an autosomal dominant disorder characterized by cancer predisposition and multiple developmental defects. Syndrome related disorders have been attributed to alterations of PTCH gene, which plays an important role in Shh signalling pathway. Unresolved complexities of the pathway impede understanding of mechanisms through which PTCH alterations lead to variable phenotype expression in Gorlin syndrome patients, while the role of chromosomal instability is not yet clear. To increase our understanding of NBCCS, every manifestation of the syndrome and associated genetic damage should be seriously considered. Therefore, several atypical NBCCS cases are presented in this paper.

Involvement of patched (PTCH) gene in Gorlin syndrome and related disorders: three family cases.

AIM: To find genetic alterations in PTC or other genes of the Shh/PTCH pathway in tumorous and non- tumorous samples from three families and to correlate them with the varying expression of disorders in presented nevoid basal cell carcinoma syndrome (NBCCS) phenotypes. METHOD: DNA was extracted from archival paraffin-embedded tissues, tumor tissue or peripheral blood leukocytes, and the loss of heterozygosity (LOH) and single strand conformational polymorphism analysis was performed using PCR with primers for polymorphic 9q22.3 markers (D9S196, D9S287, D9S180, D9S127); PTCH exons 3, 6, 8, 13, 15, 16; and smo (smoothened) exon 1. G-banding tecnique was used for cytogenetic analysis of the peripheral blood lymphocytes. RESULTS: We found a LOH for PTCH in several cases and variability in smo in one case. In one case NBCCS could reasonably be ascribed to hemizygous PTCH inactivation, while in other two families this typical correlation between the syndrome phenotype and the observed genetic alterations could not been established. CONCLUSIONS: Further analysis of relatively sparse cases of NBCCS is needed before the symptoms of the syndrome could be convincingly explained by genetic alterations in the Shh/PTCH signalling pathway.