Distribution of high-risk α-genus human papillomavirus genotypes impacts cutaneous neoplasms.

BACKGROUND: High-risk α-genus human papillomaviruses (α-HPVs) are linked to cervical and genital carcinomas; however, their correlation with cutaneous squamous cell carcinoma (cuSCC) or premalignant skin lesions remains controversial. OBJECTIVE: We evaluated the contribution of high-risk α-HPV to the occurrence of cuSCC, Bowen's disease and actinic keratosis (AK), and the distribution of high-risk α-HPV genotypes in these cutaneous tumours. METHODS: HPV genotypes were determined using a commercial PCR-based microarray on skin tissue samples collected from 76 [38 young (<60 years) and 38 elderly (>60 years)] cuSCC, 34 Bowen's disease, 48 AK patients and 10 young controls. Associations between α-HPV prevalence and relevant risk factors were analysed. RESULTS: High-risk α-HPV was more frequently detected in cuSCC patients (57.9%) than in the patients with Bowen's disease (38.2%), AK (0.0%) and control patients (10.0%). The high-risk α-HPV prevalence was higher in young than in elderly cuSCC patients (65.8% vs. 50.0%, P = 0.031). The most common HPV type was 16, present in 90.9% of all HPV-carrying cuSCC patients. Multiple infections with different high-risk α-HPV types were found in 20.5% of HPV-related cuSCC, whereas only single infection with type 16 was found in Bowen's disease. Although sun exposure is known as a major risk factor for cuSCC, high-risk α-HPVs were more frequently found in non-exposed sites rather than in sun-exposed sites of cuSCC. CONCLUSION: Multiple infections, as well as single infection with high-risk α-HPV may link to cuSCC. In spite of the involvement of high-risk α-HPV at high levels in cuSCC and Bowen's disease, no high-risk α-HPV was detected in AK patients, suggesting that Bowen's disease rather than AK might be involved in the development of HPV-related cuSCC as a precursor.

Cryosurgery combined with topical interventions for actinic keratosis: a systematic review and meta-analysis.

BACKGROUND: Actinic keratoses (AKs) are early in situ carcinomas of the skin caused by cumulative sun exposure. Cryosurgery is an easy and practicable lesion-directed approach for treatment of isolated lesions. OBJECTIVES: To investigate whether an upfront combination of cryosurgery with a topical intervention is superior to cryosurgery alone for treatment of AK. METHODS: We performed a systematic literature search in MEDLINE, Embase and CENTRAL and hand searched pertinent trial registers for eligible randomized controlled trials until 17 July 2018. Results from individual studies were pooled using a random effects model. The risk of bias was estimated with the Cochrane Risk of Bias Tool and the quality of evidence of the outcomes with the GRADE approach. RESULTS: Out of 1758 records initially identified, nine studies with a total sample size of 1644 patients were included. Cryosurgery in combination with a topical approach showed significantly higher participant complete clearance rates than monotherapy [risk ratio (RR) 1·74, 95% confidence interval (CI) 1·25-2·43, I2 = 73%, eight studies]. The participant partial clearance rate was not statistically different (RR 1·64, 95% CI 0·88-3·03, I2 = 77%, three studies). The number of patients who completed the study protocol and did not withdraw due to adverse events was equal in both groups (RR 0·98, 95% CI 0·95-1·01, I2 = 75%, seven studies). The studies were estimated to have high risk for selective reporting bias. CONCLUSIONS: Our results suggest the superiority of a combination regimen for AK clearance, with equal tolerability. This study highlights the importance of a field-directed approach in patients with multiple AKs or field cancerization.

[Stable disease or complete response? : A critical evaluation of the radiologic response to immune checkpoint blockade in advanced melanoma]. / Stabile Erkrankung oder vollständiges Ansprechen? : Evaluation der radiologischen Interpretation des Therapieansprechens auf Immune-Checkpoint-Blockade im metastasierten malignen Melanom.

BACKGROUND: Rating the response of melanoma to immune checkpoint blockade (ICB) by conventional CT proves to be difficult, since response patterns and kinetics differ from the classical responses seen with other therapies. Hence, immune-related response criteria were developed. However, they are mainly based on the alteration of the diameter of lesions over time but do not include metabolic activity. OBJECTIVE: The aim of this study was to search for additional criteria to improve the interpretation of the radiologic images of patients with metastatic melanoma after ICB. MATERIALS AND METHODS: We retrospectively analysed 7 patients with metastatic melanoma over a period of 13-41 months after treatment with ICB using contrast enhanced CT scans from the neck region to the lower abdomen and compared the results in the follow ups with 18F-FDG PET/CT. RESULTS: Metastatic lesions in 5 of 7 patients rated as stable disease (SD) in CT staging showed no metabolic activity in 18F-FDG PET/CT. The size of these lesions did not increase or show metabolic activity in the further follow-up, even after discontinuation of ICB. In contrast, tumor lesions in the other 2 patients rated as SD in CT staging showed metabolic activity in 18F-FDG PET/CT. These tumor lesions expanded significantly in the further course of the disease. CONCLUSION: In addition to the size of a tumor lesion, its metabolic activity adds important information regarding treatment response. Thus, we propose that the metabolic activity assessed with 18F-FDG-PET/CT should be included in the immune response criteria. No FDG uptake in a lesion should be rated as inactive tumor rather than SD and further treatment may not be required.

The impact of sentinel node dissection on disease-free and overall tumour-specific survival in melanoma patients: a single centre group-matched analysis of 1192 patients.

BACKGROUND: Sentinel lymph node dissection (SLND) is considered a standard staging procedure providing important prognostic information on melanoma patients. It remains a matter of debate, whether SLND and hence, removal of potential lymph node micrometastasis will alter survival outcome. OBJECTIVE: The aim of this group-matched analysis was to compare survival data of a large cohort of melanoma patients who were treated by wide local excision only (WLE) and nodal observation (WLE group) to a group of patients treated with WLE plus SLND group to investigate the potential therapeutic benefit of SLND in the treatment of patients with melanoma. METHODS AND MATERIALS: A total of 596 consecutive patients who had undergone WLE plus SLND between 1996 and 2003 were assessed. As a historical control group 596 patients treated with WLE and nodal observation but without SLND between 1986 and 1995 were selected. The groups were matched according to sex, age, Breslow tumour thickness and localization of primary tumour. The adjuvant treatment and follow-up examinations were performed according to protocols of the German Dermatologic Cooperative Oncology Group (DeCOG) and applicable study protocols that our clinic participated in; and hence, subject to change over time. RESULTS: Kaplan-Meier testing revealed significant differences in survival in favour of the SLND group. Mean overall tumour-specific survival (OS) was 102.7 months in the SLND group vs. 97.0 months in the WLE group respectively (P-value: 0.024). Disease-free survival (log-rank test: 0.003) and time to lymph node progression (P-value: <0.01) also differed significantly between the two groups. CONCLUSION: SLND is not only an important diagnostic procedure, but might also be of therapeutic benefit in terms of disease-free and overall tumour-specific survival of melanoma patients.

Pathogenesis and clinical presentation of rosacea as a key for a symptom-oriented therapy.

Rosacea is a common chronic inflammatory skin disorder that typically occurs in adults and affects the face. Synonyms of rosacea include "acne rosacea", "couperose" and "facial erythrosis", in German also "Kupferfinne" and "Rotfinne". The disorder is characterised by a chronic and flaring course and is caused by a genetically predisposed, multifactorial process. A higher incidence is seen in people with fair skin and a positive family history. The characteristic rosacea symptoms manifest primarily, but not exclusively centrofacially, with forehead, nose, chin and cheeks significantly affected. Based on the various main symptoms a classification of the individual clinical pictures can be performed. However, a classification often does not reflect the clinical reality, since the various symptoms commonly coexist. The present review provides an introduction on pathogenesis and clinical manifestations of rosacea and prefers a symptom-oriented therapy approach.

Rosazea-Management: Update über allgemeine Maßnahmen und topische Therapieoptionen.

Obwohl bislang für die Rosazea keine kurative Therapie besteht, können verschiedene Optionen zur Behandlung der Symptome und zur Vorbeugung von Exazerbationen empfohlen werden. Neben Selbsthilfemaßnahme wie der Vermeidung von Triggerfaktoren und einer geeigneten Hautpflege sollte das Rosazea-Management bei Patienten mit erythematöser und leichter bis schwerer papulopustulöser Rosazea die Anwendung topischer Präparate als First-Line-Therapie umfassen. Da Überlappungen der charakteristischen Rosazea-Symptome im klinischen Alltag die Regel sind, sollte die medikamentöse Therapie auf die individuellen Symptome zugeschnitten werden; auch eine Kombinationstherapie kann erforderlich sein. Zu den für die Behandlung der Hauptsymptome der Rosazea zugelassenen Wirkstoffen gehören Brimonidin gegen das Erythem sowie Ivermectin, Metronidazol oder Azelainsäure gegen entzündliche Läsionen. Ihre Wirksamkeit wurde in zahlreichen validen, gut kontrollierten Studien belegt. Darüber hinaus existieren verschiedene nicht zugelassene topische Behandlungsmöglichkeiten, deren Wirksamkeit und Sicherheit noch in größeren, kontrollierten Studien zu untersuchen ist.

State of the art: systemic rosacea management.

Based on numerous trials, oral tetracyclines and most commonly their second-generation derivative doxycycline have become the main pillar in systemic rosacea treatment. However, the only preparation that has been approved so far in this setting is 40 mg doxycycline in an anti-inflammatory dosage and with a modified release formulation. With the introduction of this once-daily, non-antibiotic dosing of doxycycline, oral therapy is more commonly prescribed as first-line treatment in moderate to severe papulopustular rosacea. In addition, topical and oral strategies are often used in combination due to the more substantial improvements compared to monotherapy. Although several other non-approved oral agents like macrolides, isotretinoin, and carvedilol have been evaluated for systemic treatment and showed promising results, yet the experience with these drugs in rosacea is limited, and thus they should be reserved for special situations.

Aktueller Stand der systemischen Rosazea-Therapie.

Basierend auf den Daten zahlreicher Studien sind orale Tetracycline - und hier insbesondere Doxycyclin als Tetracyclin der zweiten Generation - die Grundpfeiler der systemischen Rosazea-Therapie. Bisher ist dafür jedoch nur Doxycyclin 40 mg in antientzündlicher Dosierung mit veränderter Wirkstofffreisetzung zugelassen. Seit Einführung der Therapie mit Doxycyclin einmal täglich in nicht antibiotischer Dosierung wird die orale Therapie häufiger als Erstbehandlung bei mittelschwerer bis schwerer papulopustulöser Rosazea verschrieben. Oft wird diese Behandlung aufgrund der besseren Wirksamkeit im Vergleich zur Monotherapie auch mit einer topischen Behandlung kombiniert. Obwohl in der Systemtherapie weitere, nicht zugelassene Wirkstoffe wie Makrolide, Isotretinoin und Carvedilol mit viel versprechenden Ergebnissen untersucht wurden, ist die vorliegende Erfahrung bisher begrenzt, so dass diese Substanzen speziellen Situationen vorbehalten bleiben sollten.

Pathogenese und Klinik der Rosazea als Schlüssel für eine symptomorientierte Therapie.

Rosazea ist eine häufige chronisch-entzündliche Hauterkrankung, die typischerweise bei Erwachsenen vorkommt und das Gesicht betrifft. Synonyme der Rosazea sind Acne rosacea, Kupferfinne, Rotfinne, Couperose und Rosacea. Die Erkrankung ist durch einen chronischen und schubartigen Verlauf gekennzeichnet und wird durch ein genetisch prädisponiertes, multifaktorielles Geschehen bedingt. Ein vermehrtes Auftreten wird bei hellem Hauttyp und positiver Familienanamnese verzeichnet. Die charakteristischen Rosazea-Symptome manifestieren sich vorwiegend, aber nicht ausschließlich zentrofazial, wobei Stirn, Nase, Kinn und die Wangen maßgeblich betroffen sind. Dabei werden unterschiedliche Hauptsymptome voneinander unterschieden, anhand derer eine Klassifikation der verschiedenen klinischen Bilder vorgenommen werden kann. Eine Klassifizierung wird oftmals jedoch nicht der klinischen Realität gerecht, da die verschiedenen Symptome häufig gemeinsam auftreten. Diese Übersichtarbeit führt in die Pathogenese und Klinik der Rosazea ein und plädiert für einen symptomorientierten Therapieansatz.

Rosacea Management: Update on general measures and topical treatment options.

Although there is presently no cure for rosacea, there are several recommended treatment options available to control many of the symptoms and to prevent them from getting worse. In addition to self-help measures like avoidance of trigger factors and proper skin care, rosacea management should include topical medications as one of the first-line choices for patients with erythematous and mild to severe papulopustular rosacea. Since mixed forms of characteristic rosacea symptoms are more common, medical treatment must be symptom-tailored for each individual case and will often involve a combination therapy. Approved topical agents for the major symptoms of rosacea encompass brimonidine for erythema and ivermectin, metronidazole or azelaic acid for inflammatory lesions, all of which have shown their efficacy in numerous valid, well-controlled trials. In addition, there are several other, not approved topical treatments which are possible options that require further validation in larger well-controlled studies.

Morphologic features of basal cell carcinoma using the en-face mode in frequency domain optical coherence tomography.

BACKGROUND: Optical coherence tomography (OCT) has become a valuable non-invasive tool in the in vivo diagnosis of non-melanoma skin cancer, especially of basal cell carcinoma (BCC). Due to an updated software-supported algorithm, a new en-face mode - similar to the horizontal en-face mode in high-definition OCT and reflectance confocal microscopy - surface-parallel imaging is possible which, in combination with the established slice mode of frequency domain (FD-)OCT, may offer additional information in the diagnosis of BCC. OBJECTIVES: To define characteristic morphologic features of BCC using the new en-face mode in addition to the conventional cross-sectional imaging mode for three-dimensional imaging of BCC in FD-OCT. METHODS: A total of 33 BCC were examined preoperatively by imaging in en-face mode as well as cross-sectional mode in FD-OCT. Characteristic features were evaluated and correlated with histopathology findings. RESULTS: Features established in the cross-sectional imaging mode as well as additional features were present in the en-face mode of FD-OCT: lobulated structures (100%), dark peritumoral rim (75%), bright peritumoral stroma (96%), branching vessels (90%), compressed fibrous bundles between lobulated nests ('star shaped') (78%), and intranodular small bright dots (51%). These features were also evaluated according to the histopathological subtype. In the en-face mode, the lobulated structures with compressed fibrous bundles of the BCC were more distinct than in the slice mode. CONCLUSION: FD-OCT with a new depiction for horizontal and vertical imaging modes offers additional information in the diagnosis of BCC, especially in nodular BCC, and enhances the possibility of the evaluation of morphologic tumour features.

The invisible basal cell carcinoma: how reflectance confocal microscopy improves the diagnostic accuracy of clinically unclear facial macules and papules.

Difficult to diagnose and early non-melanoma skin cancer lesions are frequently seen in daily clinical practice. Besides precancerous lesions such as actinic keratosis, basal cell carcinomas (BCCs) score the highest frequency in skin tumors. While infiltrative and nodular BCCs require a surgical treatment with a significant impact on the patients' quality of life, early and superficial BCCs might benefit from numerous conservative treatments, such as topical immune-modulators or photodynamic therapy. Dermoscopy has shown a high sensitivity and specificity in the diagnosis of early BCCs, and non-invasive imaging techniques like reflectance confocal microscopy (RCM) have proven to be helpful. The aim of our study was to investigate the importance of RCM in the diagnosis of BCCs with indistinct clinical and dermoscopic features. We retrospectively examined 27 histologically proven BCCs in which diagnosis was not possible based on naked eye examination; we separately reviewed clinical, dermoscopic, and confocal microscopy features and evaluated the lesions meeting the common diagnostic criteria for BCCs, and our diagnostic confidence. All lesions were clinically unclear, with no characteristic features suggestive for BCC; dermoscopy showed in most cases unspecific teleangiectasias (74 %) and micro-erosions (52 %). Confocal microscopy revealed in most of the cases the presence of specific criteria: peripheral palisading of the nuclei (89 %), clefting (70 %), stromal reaction (70 %), dark silhouettes (70 %), inflammatory particles (70 %), and tumor islands (67 %). In the absence of significant diagnostic clinical signs and with unclear dermoscopic features, specific confocal patterns were present in most of the lesions and enabled a correct diagnosis. In the absence of significant clinical features of BCC and in the case of uncertain dermoscopy, striking confocal features are detectable and easy to recognize in most cases. Confocal microscopy can therefore be instrumentful in the diagnosis of the so-called invisible BCCs.

Atypical discrete papular lichen myxedematosus associated with monoclonal gammopathy: report of four cases and review of the literature.

BACKGROUND: Discrete papular lichen myxedematosus (DPLM) is a rare form of localized lichen myxedematosus that presents with skin involvement only and without systemic involvement. OBJECT: To describe our experience with atypical cases of DPLM associated with monoclonal gammopathy. METHODS: Data were collected from patients with clinicopathological evidence of DPLM associated with monoclonal gammopathy who presented to the Department of Dermatology of two tertiary university-affiliated medical centres from 2000 to 2015 and were followed prospectively. RESULTS: The sample included four patients (three males) with a mean age of 58 years. No clinicopathological differences from typical cases of DPLM were observed, except for the presence of monoclonal gammopathy. The patients were followed up for a mean of 34 months (6-72 months) and no progression to scleromyxedema, multiple myeloma or systemic involvement was observed. No therapy was applied, except for topical tacrolimus or steroids, and the eruptions remained stable. CONCLUSION: Our experience indicates an excellent prognosis of DPLM even for atypical cases in spite of the presence of monoclonal gammopathy.

Maintenance of remission following successful treatment of papulopustular rosacea with ivermectin 1% cream vs. metronidazole 0.75% cream: 36-week extension of the ATTRACT randomized study.

BACKGROUND: There are a limited number of approved treatments for papulopustular rosacea (PPR) and remission is difficult to maintain after successful treatment. OBJECTIVES: To investigate remission over a 36-week extension period in patients with moderate to severe PPR successfully treated with 16 weeks' treatment with ivermectin 1% cream once daily (QD) or metronidazole 0.75% cream twice daily (BID) in a randomized, parallel-group Phase III study. METHODS: Treatment was discontinued in patients initially successfully treated [Investigator's Global Assessment (IGA) score of 0 or 1] with ivermectin 1% cream QD (n = 399) or metronidazole 0.75% cream BID (n = 365; Part A) and patients were followed every 4 weeks for up to 36 weeks (Part B). Treatment with the same study treatment as used in Part A was only re-initiated if patients relapsed (IGA ≥ 2). Efficacy assessments were: time to first relapse; relapse rate; and number of days free of treatment. Safety assessments included incidence of adverse events and local cutaneous signs and symptoms. RESULTS: The median time to first relapse was significantly longer (115 days vs. 85 days) and relapse rates at the end of the study period significantly lower (62.7% vs. 68.4%) for patients initially successfully treated with ivermectin 1% compared with metronidazole 0.75%; Kaplan-Meier plot demonstrated a statistically significant difference between the two arms (P = 0.0365). The median number of days free of treatment was higher for ivermectin compared with metronidazole (196 days vs. 169.5 days; P = 0.026). The percentage of patients who experienced a related adverse event was equally low in both groups. CONCLUSION: The results of this relapse study showed that an initial successful treatment with ivermectin 1% cream QD significantly extended remission of rosacea compared with initial treatment with metronidazole 0.75% cream BID following treatment cessation.