Human Papillomavirus 42 Drives Digital Papillary Adenocarcinoma and Elicits a Germ Cell-like Program Conserved in HPV-Positive Cancers.

The skin is exposed to viral pathogens, but whether they contribute to the oncogenesis of skin cancers has not been systematically explored. Here we investigated 19 skin tumor types by analyzing off-target reads from commonly available next-generation sequencing data for viral pathogens. We identified human papillomavirus 42 (HPV42) in 96% (n = 45/47) of digital papillary adenocarcinoma (DPA), an aggressive cancer occurring on the fingers and toes. We show that HPV42, so far considered a nononcogenic, "low-risk" HPV, recapitulates the molecular hallmarks of oncogenic, "high-risk" HPVs. Using machine learning, we find that HPV-driven transformation elicits a germ cell-like transcriptional program conserved throughout all HPV-driven cancers (DPA, cervical carcinoma, and head and neck cancer). We further show that this germ cell-like transcriptional program, even when reduced to the top two genes (CDKN2A and SYCP2), serves as a fingerprint of oncogenic HPVs with implications for early detection, diagnosis, and therapy of all HPV-driven cancers. SIGNIFICANCE: We identify HPV42 as a uniform driver of DPA and add a new member to the short list of tumorigenic viruses in humans. We discover that all oncogenic HPVs evoke a germ cell-like transcriptional program with important implications for detecting, diagnosing, and treating all HPV-driven cancers. See related commentary by Starrett et al., p. 17. This article is highlighted in the In This Issue feature, p. 1.

Dermal lipofibromatosis-like neural tumor.

BACKGROUND: Lipofibromatosis-like neural tumor (LPF-NT) is a rare soft tissue typically occurring in the subcutis, characterized by a cellular proliferation of CD34- and S100-protein positive spindle-shaped tumor cells with an infiltrative growth pattern. OBJECTIVE: To describe five cases arising mainly in the dermis in order to expand their morphologic spectrum. METHODS: H&E slides were reviewed, and all cases were stained for CD34, SOX10, S100, ALK, and NTRK1 and some of them with additional staining. RESULTS: Patients were three males and two females with a mean age of 44.8 years (14-68 years). Histopathologically, all cases were characterized by a dense dermal infiltration by monomorphous, mildly atypical, plump to spindle-shaped tumor cells, staining diffusely positive for CD34, S100, and NTRK1 but were negative for S100, EMA, NKIC3, MNF116, SMA, ALK, and desmin. LIMITATIONS: Limited clinical information. CONCLUSION: LPL-NT can be located mainly in the dermis. Sixty percent of our cases showed typical areas of LPL-NT intermingled with more plump cells like the ones in fibrous hamartoma of infancy. We recommend a panel of CD34, S100, and NTRK1 antibodies not only in subcutaneous spindle cell neoplasms but also in the ones predominantly involving the dermis in order to make an accurate diagnosis.

Topical Cyclosporine in Oral Lichen Planus-A Series of 21 Open-Label, Biphasic, Single-Patient Observations.

Topical cyclosporine (CSA) has been reported as an alternative treatment in steroid-refractory oral lichen planus (OLP), but evidence is limited and conflicting. An N-of-1 trial setting could be appropriate to evaluate interindividual differences in treatment response. We studied a series of 21 open-label, biphasic single-patient observations. Patients (15 women, 6 men) with OLP recalcitrant to topical steroids received four weeks of CSA mouth rinse (200 mg/twice daily) followed by four weeks of drug withdrawal. Pain (visual analogue scale (VAS) score), disease extent (physicians' global assessment (PGA) score) and quality of life (Dermatology Life Quality Index (DLQI) score,) were assessed at baseline (T0), after four weeks of treatment (T1) and after another four weeks without treatment (T2). Median age was 58 years (interquartile range/IQR = 52-67) and median disease duration was 18 months (IQR = 12-44). Median baseline VAS score decreased significantly at T1 (p = 0.0003) and increased at T2 (p = 0.032) (T0 = 5 (IQR = 3-6.5); T1 = 2 (IQR = 0.5-3.4); T2 = 3 (IQR = 2-4.8)). Similarly, median baseline PGA score decreased significantly at T1 (p = 0.001) and increased at T2 (p = 0.007) (T0 = 2 (IQR = 1.3-2.5); T1 = 1 (IQR = 1-2); T2 = 2 (IQR = 1-2)). Median baseline DLQI score also decreased significantly at T1 (p =.027) but did not change at T2 (p = 0.5) (T0 = 2.5 (IQR = 1-5.8); T1 = 1 (IQR = 0-3); T2 = 1 (IQR = 1-4)). CSA responders (n = 16) had significantly higher median baseline VAS scores (5.2 (IQR = 5-6.5)) than nonresponders (n =5) (2 (IQR = 2-3.5) (p = 0.02). In our study, pain, disease extent and quality of life of patients with OLP improved significantly during therapy with low-dose CSA mouth rinse and exacerbated after drug withdrawal. Remarkably, patients with high initial VAS scores seemed to profit most.

Psoriasis is associated with fissured tongue but not geographic tongue: a prospective, cross-sectional, case-control study.

BACKGROUND AND OBJECTIVES: It has been postulated that psoriasis is associated with tongue lesions and geographic tongue might be "oral psoriasis". However, reports are inconclusive, prevalence rates vary and data for Europe are sparse. In this prospective case-control study we investigated the point-prevalence of tongue conditions in an Austrian cohort. PATIENTS AND METHODS: Psoriasis patients and healthy volunteers were assessed regarding tongue and skin lesions, age, sex, smoking habits, allergies, onset of psoriasis, PASI scores and anti-psoriatic treatment. RESULTS: We included 173 psoriasis patients, 58 women, 115 men (median age: 50 [37-60] years), and 173 volunteers, 79 women, 94 men (median age: 54 [43-64] years). Overall, 95 subjects had allergies, 64 psoriasis patients and 50 volunteers were smokers. Median age at onset of psoriasis was 26 (12-40) years, the median PASI score was 2 (0-4.1), most patients received ustekinumab (n = 47). Fissured tongue was significantly associated with psoriasis (25 [14.4 %] psoriasis patients, 13 [7.5 %] volunteers; P = 0.04). Geographic tongue was present in four individuals of each group (2.3%) and associated with smoking (P = 0.01) but not with psoriasis. CONCLUSIONS: Overall, we found a low point-prevalence of tongue lesions in this Austrian cohort. Psoriasis was associated with fissured tongue but not with geographic tongue. Thus, we cannot corroborate the hypothesis that geographic tongue is an oral manifestation of psoriasis.

The role of wide local excision for the treatment of severe hidradenitis suppurativa (Hurley grade III): Retrospective analysis of 74 patients.

BACKGROUND: Effective medical treatment for patients with severe hidradenitis suppurativa (HS) is limited. OBJECTIVES: We sought to measure the impact of wide local excision on quality of life in HS Hurley grade III patients and to examine the rate of postoperative complications, disease recurrences, and satisfaction with the cosmetic results. METHODS: Seventy-four patients were enrolled. Outcome measures included Dermatology Life Quality Index responses, disease duration, recurrence, previous therapies, postoperative complications, and satisfaction with cosmetic results. RESULTS: Most patients had inguinogenital/gluteal disease (68.9%, P < .001). Involvement of both the axillary and the inguinogenital/gluteal areas were pronounced in male patients (P = .018). None of the patients was treated with tumor necrosis factor-α inhibitors. Most patients (71.6%) had a disease history of >5 years at the time of presentation and multiple unsuccessful attempts with systemic and local therapeutic interventions. Wide local excision improved Dermatology Life Quality Index scores from initially 27.89 to 5.31 after surgery (P < .001), independent of localization (P = .195). Forty-seven percent of patients had postoperative complications, most frequently pain and scarring. The vast majority of patients (70.3%) were satisfied with the cosmetic results. LIMITATIONS: The retrospective nature of the study was a limitation. CONCLUSIONS: Wide local excision significantly improves the quality of life of HS patients. Local recurrence rates are low, and satisfaction with the cosmetic results is high.

Etanercept, Adalimumab und Ustekinumab bei Psoriasis: Analyse von 209 Behandlungsreihen in Österreich.

HINTERGRUND UND ZIELE: Biologika werden häufig zur Behandlung der Psoriasis eingesetzt und wurden in zahlreichen klinischen Studien getestet. Allerdings können sich Wirkungen und Nebenwirkungen (AEs) bei "real-world"-Patienten unterscheiden, da diese keiner solch strengen Auswahl und Überwachung unterzogen werden. Wir haben Therapieadhärenz ("Medikamenten-Überlebenszeit"), Wirksamkeit und AEs (Qualität, Zeitpunkt des Auftretens) bei "real-world"-Psoriasis-Patienten, die mit Etanercept, Adalimumab oder Ustekinumab behandelt wurden, untersucht. PATIENTEN UND METHODEN: Retrospektive Datenanalyse (1. Januar 2004 bis 30. Juni 2015) an Patienten, die an einer Psoriasis-Klinik in einem österreichischen Krankenhaus behandelt wurden. Alle Patienten, die mindestens eine Dosis von Etanercept, Adalimumab oder Ustekinumab erhalten hatten, wurden in die Analyse einbezogen. Wir analysierten Demographie, Therapieadhärenz, den Psoriasis Area and Severity Index (PASI) sowie Qualität und Zeitpunkt des Auftretens von AEs. ERGEBNISSE: In 209 Behandlungsreihen variierte die geschätzte mittlere Therapieadhärenz zwischen den verschiedenen Behandlungen: 21 Monate (SE: 6,9) für Etanercept, 61 Monate (SE: 9,4) für Adalimumab und 65 Monate (SE 1,4) für Ustekinumab. Männliches Geschlecht und Vorbehandlung mit einem Biologikum waren positive Prädiktoren für längere Therapie mit Adalimumab. Wir fanden keinen signifikanten Unterschied in der am PASI gemessenen Arzneimittelwirksamkeit. SCHLUSSFOLGERUNGEN: Die meisten AEs treten während des ersten Jahres der Behandlung auf. Adalimumab und Ustekinumab zeichnen sich im Vergleich zu Etanercept durch eine längere Therapieadhärenz aus.

Etanercept, adalimumab, and ustekinumab in psoriasis: analysis of 209 treatment series in Austria.

BACKGROUND AND OBJECTIVES: Widely used in the treatment of psoriasis, biologics have been tested in numerous clinical trials. However, drug efficacies and adverse events (AEs) may differ in 'real-world' patients as they do not undergo as rigorous selection and monitoring. Our objective was to examine drug survival, efficacy, and AEs (quality, time of onset) in 'real-world' psoriasis patients treated with etanercept, adalimumab, and ustekinumab. PATIENTS AND METHODS: Retrospective data analysis (Jan 1, 2004 to Jun 30, 2015) of patients treated at a psoriasis clinic in an Austrian hospital. All patients who had received at least one dose of etanercept, adalimumab, or ustekinumab were included in the analysis. We analyzed: demographics, drug survival, Psoriasis Area and Severity Index (PASI), as well as quality and time of onset of AEs. RESULTS: In 209 treatment series, the estimated median drug survival varied among the various treatments: 21 months (SE: 6.9) for etanercept, 61 months (SE: 9.4) for adalimumab, and 65 months (SE 1.4) for ustekinumab. Male gender and pretreatment with a biologic were positive predictors of longer drug survival in adalimumab. We found no significant difference in drug efficacy as determined by PASI. CONCLUSIONS: Most AEs occur during the first year of treatment. Adalimumab and ustekinumab are marked by longer drug survival compared to etanercept.

Searching for the Chokehold of NRAS Mutant Melanoma.

Up to 18% of melanomas harbor mutations in the neuroblastoma rat-sarcoma homolog (NRAS). Yet, decades of research aimed to interfere with oncogenic RAS signaling have been largely disappointing and have not resulted in meaningful clinical outputs. Recent advances in disease modeling, structural biology, and an improved understanding of RAS cycling as well as RAS signaling networks have renewed hope for developing strategies to selectively block hyperactive RAS function. This review discusses direct and indirect blocking of activated RAS with a focus on current and potential future therapeutic approaches for NRAS mutant melanoma.

Acyl protein thioesterase 1 and 2 (APT-1, APT-2) inhibitors palmostatin B, ML348 and ML349 have different effects on NRAS mutant melanoma cells.

Oncogenic NRAS mutations are frequent in melanoma and lead to increased downstream signaling and uncontrolled cell proliferation. Since the direct inhibition of NRAS is not possible yet, modulators of NRAS posttranslational modifications have become an area of interest. Specifically, interfering with NRAS posttranslational palmitoylation/depalmitoylation cycle could disturb proper NRAS localization, and therefore decrease cell proliferation and downstream signaling. Here, we investigate the expression and function of NRAS depalmitoylating acyl protein thioesterases 1 and 2 (APT-1, APT-2) in a panel of NRAS mutant melanoma cells. First, we show that all melanoma cell lines examined express APT-1 and APT-2. Next, we show that siRNA mediated APT-1 and APT-2 knock down and that the specific APT-1 and -2 inhibitors ML348 and ML349 have no biologically significant effects in NRAS mutant melanoma cells. Finally, we test the dual APT-1 and APT-2 inhibitor palmostatin B and conclude that palmostatin B has effects on NRAS downstream signaling and cell viability in NRAS mutant melanoma cells, offering an interesting starting point for future studies.

The burden of malignant melanoma--lessons to be learned from Austria.

AIM OF STUDY: Incidence rates of melanoma, generated by cancer registries (CRs), are susceptible to reporting inconsistencies due to increasing decentralisation of diagnosis. We therefore independently assessed the burden of melanoma in Austria. METHODS: We collected histopathological reports on melanoma of all patients diagnosed in Austria in 2011. Demographic and clinical characteristics, histopathological tumour stages were assessed. Their regional distributions and incidence rates were analysed and compared with data of national and international CRs. RESULTS: A total of 5246 patients were diagnosed with 1951 in-situ and 3295 invasive melanomas in Austria in 2011 (population 8.4 million). Age, sex and anatomic distribution corresponded to findings in other European countries, however, the incidence of 25/100,000 (world age-standardised rate) for invasive melanomas was two-fold higher than published by the Austrian CR (12/100,000). Varying frequencies in diagnosing thin melanomas (≤1 mm; n = 4415) accounted exclusively for significant regional disparities, while advanced tumours (>1 mm; n = 761) were evenly distributed. Western Austria showed the highest rates (36/100,000). Patients from eastern Austria whose melanomas were diagnosed in laboratories in western Austria (n = 76) showed significantly higher proportions of in-situ lesions (n = 43; 57%) compared to those whose tumours were diagnosed in eastern Austria (n = 4014; in-situ = 1369; 34%) (p < 0.0001). CONCLUSIONS: In Austria, the melanoma burden and its potential socio-economic implications are significantly underestimated. Similarities of incidences indicate this could affect other European countries with well-established CRs and compromise international comparability of data. Austrian regional disparities suggest overdiagnosis of thin melanomas due to the variability of pathologists' thresholds for the diagnosis of early stage tumours.

Phrynoderma and acquired acrodermatitis enteropathica in breastfeeding women after bariatric surgery.

BACKGROUND AND OBJECTIVES: Women who have undergone bariatric surgery are susceptible to nutritional deficiencies in subsequent pregnancies. We highlight the importance of dermatologists in the early recognition of cutaneous signs of malnutrition occurring in this specific clinical setting. PATIENTS AND METHODS: We compare clinical characteristics of two young women with dermatological signs of combined post-gestational nutritional deficiencies following Roux-en-Y gastric bypass surgery. RESULTS: Patient 1 exhibited follicular papules on the extremities, perianal eczema, perlèche, alopecia, and depigmentation of hair. Patient 2 showed erythematous plaques in genitoanal and acral areas, perlèche, diffuse alopecia, and depigmentation of hair. Based on clinical and histopathological findings, decreased vitamin A (patient 1) and zinc levels (patient 2), we diagnosed phrynoderma and acquired acrodermatitis enteropathica, respectively. Comparison of the two patients revealed that both (i) were lacking follow-up after gastric bypass surgery, (ii) developed skin lesions as primary symptoms with (iii) mixed clinical manifestations due to combined deficiencies, and (iv) experienced initial symptoms during lactation suggesting a causal relationship. CONCLUSIONS: Our observations highlight the potentially increased risk of women to develop post-gestational dermatological manifestations of malnutrition following bariatric surgery. The awareness of dermatologists with respect to this emerging, susceptible patient group may help avert damage to mother and child.

Effect of personality traits on the oral health-related quality of life in patients with oral mucosal disease.

OBJECTIVES: The aim of this study was to assess the relationship between oral health-related quality of life, the nature of mucosal disease, and personality traits. METHODS: One hundred forty-nine patients seeking care for oral mucosal disease were recruited in this cross-sectional study conducted at the University Clinic of Dentistry in Vienna from June to December 2013. All participants agreed in answering two questionnaires: the Oral Health Impact Profile German version (OHIP-G), which assessed the perceived limitations of oral health-related quality of life and the Neuroticism Extraversion Openness Five-Factor Inventory (NEO-FFI), which evaluated five personality domains. A multiple linear regression was applied to examine the potential influence on OHIP scores. RESULTS: Bullous/erosive mucosal diseases and oral lichen planus patients (n = 73, 49% of total) reported the highest impact on oral health-related quality of life (OHIP total score 49.3 ± 35.7, p = 0.02). A highly significant influence of neuroticism, as a personality trait, was observed on oral health-related quality of life (p = 0.001). Women had significantly more restrictions (OHIP score 45.3 ± 32.2) compared to men (32.6 ± 30.1, p = 0.009). CONCLUSIONS: Psychosocial factors such as personality traits, especially neuroticism, are significantly associated with quality of life ratings in patients with mucosal disease. CLINICAL RELEVANCE: Since mucosal diseases impact patient's daily living and quality of life while affected by their psychological profiles, this should be considered when formulating a therapeutic approach.

Efficacy of intravenous immunoglobulins in livedoid vasculopathy: long-term follow-up of 11 patients.

BACKGROUND: Evidence for the efficacy of various therapies of livedoid vasculopathy (LV) is limited. OBJECTIVE: We sought to determine efficacy and tolerability of 2 g/kg of intravenous immunoglobulins (IVIG) every 4 weeks in patients with LV. METHODS: This was a long-term follow-up study of 11 patients with LV treated with 2 g/kg of IVIG assessing the clinical characteristics, disease course, and quality of life. RESULTS: The treatment regimen led to complete remission of ulcerations and pain in 17 of 29 disease episodes (59%) after 3 cycles and in 25 of 29 episodes (86%) after 6 cycles. Two disease episodes showed remission after 7 and 8 cycles, resulting in a total number of remissions of 27 (93%). Subscore analysis showed resolution of pain in 80% after 2 IVIG cycles. Disease severity and quality of life were significantly improved after 6 cycles. Median duration of remissions was 26.7 months after initial and 7.5 months after subsequent disease episodes. LIMITATIONS: This was a retrospective study that did not include the comparison of IVIG efficacy and its impact on quality of life with treatment options. CONCLUSIONS: In our patients with LV, high-dose IVIG led to fast and complete resolution of pain and ulcerations and to substantial improvement in quality of life.