European e-Delphi process to define expert consensus on electrochemotherapy treatment indications, procedural aspects, and quality indicators in melanoma.

BACKGROUND: Skin metastases are an important co-morbidity in melanoma. Despite broad adoption, electrochemotherapy implementation is hindered by a lack of treatment indications, uncertainty regarding procedural aspects, and the absence of quality indicators. An expert consensus may harmonize the approach among centres and facilitate comparison with other therapies. METHODS: An interdisciplinary panel was recruited for a three-round e-Delphi survey. A literature-based 113-item questionnaire was proposed to 160 professionals from 53 European centres. Participants rated each item for relevance and degree of agreement on a five-point Likert scale, and received anonymous controlled feedback to allow revision. The items that reached concordant agreement in two successive iterations were included in the final consensus list. In the third round, quality indicator benchmarks were defined using a real-time Delphi method. RESULTS: The initial working group included 122 respondents, of whom 100 (82 per cent) completed the first round, thus qualifying for inclusion in the expert panel (49 surgeons, 29 dermatologists, 15 medical oncologists, three radiotherapists, two nurse specialists, two clinician scientists). The completion rate was 97 per cent (97 of 100) and 93 per cent (90 of 97) in the second and third rounds respectively. The final consensus list included 54 statements with benchmarks (treatment indications, (37); procedural aspects, (1); quality indicators, (16)). CONCLUSION: An expert panel achieved consensus on the use of electrochemotherapy in melanoma, with a core set of statements providing general direction to electrochemotherapy users to refine indications, align clinical practices, and promote quality assurance programmes and local audits. The residual controversial topics set future research priorities to improve patient care.

Electrochemotherapy is an effective locoregional therapy for skin metastases from melanoma, a problem faced by almost half of patients with metastatic disease. The lack of comparative studies and the heterogeneity of its clinical application among centres make it challenging to support consistent, evidence-based recommendations. To address this unmet need, a three-round online survey was conducted to establish a consensus on treatment indications, standard operating procedures, and quality indicators. In the survey, a panel of 100 European melanoma experts agreed on 56 statements that can be used to improve patient selection, homogenize treatment application, and monitor outcomes.

Identification of Biomarkers and Critical Evaluation of Biomarker Validation in Hidradenitis Suppurativa: A Systematic Review.

IMPORTANCE: The identification and validation of biomarkers in hidradenitis suppurativa (HS) has potential to improve the understanding and management of this chronic, burdensome disease. OBJECTIVE: To systematically identify all known HS biomarkers, categorize them by biomarker type, and critically evaluate their validity according to established criteria. EVIDENCE REVIEW: Eligibility criteria for this review (PROSPERO Registration 230830) included randomized clinical trials, uncontrolled clinical trials, cohort studies, case-control studies, and other observational studies with no restrictions of patient age, sex, race or ethnicity, or language of publication up until December 31, 2020. All articles were categorized into biomarker type, defined using the US Food and Drug Administration Biomarkers, Endpoints, and other Tools (BEST) glossary. Assessment of each identified biomarker was undertaken in line with the US Food and Drug Administration and European Medicines Agency guidelines for the validation of proposed biomarkers. Assessment of the strength of overall data regarding individual biomarkers was undertaken using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. FINDINGS: A total of 3953 nonduplicate articles were screened, of which 1429 articles were retrieved based on the include/exclusion criteria applied. After full-text screen and data extraction, 106 articles were included in this review. The evidence of strength of 6 categories of biomarkers (susceptibility/risk, diagnostic, monitoring, predictive, prognostic, and pharmacodynamic/response biomarkers) was assessed using GRADE criteria. A total of 48 biomarkers were identified with a minimum GRADE rating of moderate. Only 1 diagnostic (serum IL-2R), 1 monitoring (dermal Doppler vascularity), and 2 predictive biomarkers (epithelialized tunnels and positive family history of HS) achieved a GRADE rating of high. None of the identified biomarkers had sufficient clinical validity to be recommended for routine use in the clinical setting. CONCLUSIONS AND RELEVANCE: Major barriers to the identification, validation, and introduction of routine biomarkers in the management of HS include lack of independent biomarker validation studies (especially assumption-free "omics"-based techniques); insufficient assessment of collinearity between identified or proposed biomarkers; and a lack of routine integration of biomarkers into the structure of clinical trials. International consensus among researchers, clinicians, and pharmaceutical stakeholders is required to standardize goals and methods and encourage biomarker integration into future HS clinical trials. This systematic review presents a number of priorities for near-term future research to overcome such barriers and limitations of biomarkers in HS.

[Psychiatric comorbidities in hidradenitis suppurativa/acne inversa]. / Psychiatrische Komorbidität bei Hidradenitis suppurativa/Acne inversa.

BACKGROUND: The findings of most studies suggest that depression and anxiety disorders are the most common psychiatric comorbidities in patients with hidradenitis suppurativa/acne inversa (HS/AI). METHODS: In a prospective study, 51 patients with HS/AI were further examined for psychiatric comorbidity using a standardized interview and questionnaires. RESULTS: In psychiatric examination, 29.4% of HS/AI patients had additional mental symptoms, mainly manifested as depressive disorder. The HS/AI patients were rather young and female, and they showed a high incidence of nicotine and alcohol use, and a positive family history of paternal alcohol dependence. In addition, HS/AI patients experienced more severe psychosocial impairments in the form of lack of partnership and lower school attainment. CONCLUSIONS: Acne inversa is a severe chronic inflammatory skin disease that, like other inflammatory dermatoses, is associated with mental comorbidity and psychosocial impairments. Since especially young patients are affected, a psychiatric-psychotherapeutic cotreatment should be considered already at an early stage.

Wound Care With a Porcine Extracellular Matrix After Surgical Treatment of Rhinophyma.

BACKGROUND: Rhinophyma surgery is commonly associated with prolonged wound healing and the need for multiple wound dressings. OBJECTIVES: To evaluate clinical outcome with a porcine extracellular matrix (ECM) after shave excision of rhinophyma compared with common wound care procedure. MATERIALS AND METHODS: Retrospective analysis of patients with common dressings (CD) compared with patients with additional ECM (OASIS) application. Clinical findings were assessed prior to treatment and at follow-up visit using the Patient and Observer Scar Assessment Scale (POSAS), Vancouver Scar Scale (VSS), and Rhinophyma Severity Index (RHISI). RESULTS: Overall, 28 patients (67.5 ±9.0 years) with a mean wound area of 33.9 (±8.5) cm² were included. After a mean follow-up period of 132 (±73) days, scales of POSAS, VSS, and RHISI showed significant (P< .0001) reductions of 47.0% (±11.1), 56.0% (±12.0), and 62.3% (±14.3), respectively. Subgroup analysis showed no significant differences of aforementioned parameters between the ECM group (n= 17) and CD group (n= 11). In contrast, the number of dressing changes were significantly (P< .006) less in the ECM group (1.4 ±0.8) compared with CD group (4.1 ±2.6). The ECM group showed a significant (P< .017) shorter time to re-epithelization (10.5 ±1.7 days) than the CD group (13.1 ±2.2 days). CONCLUSIONS: The application of porcine ECM is practicable and reduces the number of dressing changes and time to re-epithelization clearly. Crusts are scaling off spontaneously without any aggressive action needed. Our findings indicate that ECM application is a promising approach for rhinophyma wound care.

Dicer Sequencing, Whole Genome Methylation Profiling, mRNA and smallRNA Sequencing Analysis in Basal Cell Carcinoma.

BACKGROUND/AIMS: Perturbations in the expression of microRNAs (miRNAs) and their maturing machinery components such as Dicer have been previously described for basal cell carcinoma (BCC). However, the mutational status of Dicer in BCC is unclear. Further, the sclerodermiform subtype of BCC (sBCC) has not been previously investigated regarding its methylation profile or its smallRNA expression profile via RNA sequencing. We conducted this study to investigate the mutational status of Dicer in BCC. METHODS: Dicer sequencing was performed on the Illumina MiSeq System in a total of 16 BCC samples (8 nodular BCCs, 8 sBCCs) and mapped against the human reference genome (i.e., hg19). Dicer sequencing was performed in all 16 BCC samples. We performed whole genome methylation profiling with Infinium MethylationEPIC BeadChips as well as mRNA and smallRNA sequencing in 5 sBCCs with the Illumina NextSeq500 next-generation sequencing system. RESULTS: Compared to the wildtype Dicer sequence, we found 5 to 7 variants per sBCC sample including insertion, deletion, and multiple nucleotide variants. Global methylation profiles were highly similar between groups. mRNA sequencing revealed S100A9, KRT14, KRT10, S100A8, S100A7, COX1, KRT1, COX3, and smallRNA sequencing analysis miR-21, miR-99a, miR26-a-2, let-7f, let-7g, let-7i, miR-100, and miR-205 were the most strongly expressed in sBCCs. CONCLUSION: We identified a variety of Dicer mutations that could play a role in aberrant miRNA expression in BCC. The noted RNA sequences should be further evaluated in functional studies to explore their potential pathogenetic role in sBCC.

Reduced ten-eleven translocation and isocitrate dehydrogenase expression in inflammatory hidradenitis suppurativa lesions.

BACKGROUND: As environmental factors appear to predispose patients to hidradenitis suppurativa (HS), studying epigenetic modifications is of interest to further understand the pathogenesis of HS. OBJECTIVES: To study the expression of DNA hydroxymethylation regulators, namely the ten-eleven translocation (TET) and isocitrate dehydrogenase (IDH) family, in the skin of HS patients. MATERIALS & METHODS: Twenty patients with HS and 12 healthy subjects were recruited. We analysed the expression of TET1, TET2, TET3, IDH1, IDH2, IDH3a, and IDH3b in lesional and perilesional HS tissue as well as tissue from healthy controls by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). In addition, immunohistochemistry was performed for TET1, TET2, and TET3. RESULTS: RT-PCR analysis showed that mRNA of all the studied genes was significantly under-expressed in lesional HS skin compared to healthy skin. IDH1 and IDH2 mRNA expression was also significantly lower in perilesional HS skin compared to healthy skin, and TET3 mRNA expression was significantly lower in lesional HS skin compared to perilesional HS skin. RT-PCR analysis for TET1, TET2, and TET3 mRNA expression was confirmed by immunohistochemical analysis. Correlation analysis revealed a significant positive correlation between TET and IDH gene expression in perilesional and lesional HS skin. CONCLUSIONS: Our results suggest that epigenetic changes occur in HS tissue and that aberrant expression of the DNA hydroxymethylation regulators may play a role in the pathogenesis of HS. As epigenetic modifications are reversible, further research into the cause of these aberrant expression patterns is warranted in order to develop possible novel therapeutic approaches.

Argon plasma coagulation of actinic keratoses imaged by optical coherence tomography: An in vivo study indicating a possible lesion-directed treatment.

Actinic keratoses (AKs) can progress into invasive squamous cell carcinoma and thus may become a life threatening disease. Argon plasma coagulation (APC) might complement the therapeutic armamentarium in particular for AK lesions. However, there is no data on APC-induced micromorphological changes following the treatment of AKs. We aimed to determine in vivo APC-induced effects on the epidermis and dermoepidermal junction (DEJ) zone in AK lesions. We performed APC in 108 AKs using the spray mode with a power setting of 15 W and a flow rate of 2.0 L/min. Before and after the intervention, optical coherence tomography (OCT) was performed. After APC, 74.2% (46/62) lesions presented with clearly demarcated DEJ and without any epidermal tissue left, 25.8% (16/62) of treated lesions showed residual epidermal tissue left. In 19.4% (12/62), parts of the DEJ and in 6.5% (4/62), the entire DEJ could not be discriminated. The χ2 test showed a significant (P = 0.0025) association between the presence of hyperkeratosis prior to APC and intact DEJ after APC. In conclusion, APC as shown by OCT is a well controllable treatment modality for AKs causing only limited damage to dermal tissue. Further studies are needed to evaluate clinical outcome as well as recurrence rates.

A Novel Severity Assessment Scoring System for Hidradenitis Suppurativa.

Importance: The variation in both clinical appearance and responses to diverse treatment options emphasize the importance of an accurate, clinically relevant, yet easy-to-use scoring system in hidradenitis suppurativa. Objective: To propose and provide validation data for the newly designed Severity Assessment of Hidradenitis Suppurativa score. Design, Setting, and Participants: We prospectively assessed disease severity using Hurley staging and the modified Hidradenitis Suppurativa Score in 355 patients referred to Ruhr-University Bochum Department of Dermatology between March 2016 and June 2017. We also assessed disease severity via the Severity Assessment of Hidradenitis Suppurativa score. Main Outcomes and Measures: Evaluation and assessment of convergent validity and responsiveness to treatment of the Severity Assessment of Hidradenitis Suppurativa score. Results: Eighty-eight of the 355 patients (134 [37.7%] men and 221 [62.3%] women with a median [IQR] age of 40 [30-49] years) were classified as Hurley stage I, 221 were Hurley stage II, and 46 were Hurley stage III, with an overall median modified Hidradenitis Suppurativa Score of 31 (interquartile range [IQR], 19.3-53). The median total Severity Assessment of Hidradenitis Suppurativa score was 6 (IQR, 4-9), significantly different among the 3 Hurley groups. The median SAHS score for patients in Hurley stage I was 5 (IQR, 3-6), 6 (IQR, 5-9) for patients in Hurley stage II, and 9 (IQR, 7-12) for patients in Hurley stage III (P < .001, Kruskal-Wallis test). Correlation analysis showed a significant correlation between the modified Hidradenitis Suppurativa Score and the Severity Assessment of Hidradenitis Suppurativa score (r = 0.79, P < .001). Disease severity assessment before and after 3 months of conservative systemic treatment showed a significant correlation between the Severity Assessment of Hidradenitis Suppurativa score and modified Hidradenitis Suppurativa Score. Both the mHSS (P = .001) and the SAHS score (P < .001) significantly differed between the baseline visit (median mHSS, 33 [IQR, 24-52]; median SAHS score, 6 [IQR, 5-9]) and the 3-month visit (median mHSS, 28 [IQR, 15-43.5]; median SAHS score, 5 [IQR, 4-6.3]). The 2 patient-reported items demonstrated excellent test-retest reliability with intraclass correlation coefficient values greater than 0.8. Conclusions and Relevance: Our validation data demonstrated that the Severity Assessment of Hidradenitis Suppurativa score is a disease severity instrument that significantly correlates with Hurley staging and the modified Hidradenitis Suppurativa Score, and is responsive enough to measure treatment outcome.

Altered Global 5-Hydroxymethylation Status in Hidradenitis Suppurativa: Support for an Epigenetic Background.

BACKGROUND: The pathogenesis of hidradenitis suppurativa (HS), with its complex inflammatory network, is still elusive. Imbalances in DNA methylation can lead to genome destabilization and have been assumed to play a role in inflammatory diseases. Global DNA methylation and hydroxymethylation have not been studied in HS yet. OBJECTIVE: We conducted this study to investigate the global DNA methylation and hydroxymethylation status in lesional and perilesional HS skin compared to healthy controls. METHODS: Immunohistochemical analysis was performed for 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in 30 lesional and 30 corresponding healthy-appearing perilesional HS tissue samples. We included 30 healthy subjects as an interindividual control group. RESULTS: 5-hmC levels were significantly lower in healthy-appearing perilesional (p < 0.0001) and lesional HS skin (p < 0.0001) when compared to healthy controls. There was no significant difference between lesional HS skin and perilesional HS skin regarding 5-hmC levels (p = 0.6654). In contrast to 5-hmC, 5-mC staining showed no significant changes between the 3 groups. Univariate analysis revealed no significant association between patients' characteristics, disease severity, and the levels of 5-mC and 5-hmC. CONCLUSION: Our findings indicate that imbalances in DNA hydroxymethylation may play a role in the pathogenesis of HS rather than DNA methylation. Further studies are warranted to investigate the significance of DNA hydroxymethylation and the regulating enzymes in HS in order to advance our knowledge of the inflammatory network in this disease.

Hidradenitis suppurativa gains increasing interest on World Wide Web: a source for patient information?

BACKGROUND: Gathering health information from Internet websites is increasingly utilized by patients. No data exist about hidradenitis suppurativa (HS)-related online health information. Thus, we aimed to study the quality, popularity, readability, and timeliness of the most frequented websites on HS. METHODS: Google Trends was used to evaluate the public interest in HS. An Internet search on Google was performed for the terms "hidradenitis suppurativa," "acne inversa," and "Verneuil's disease." Readability scores, HONcode quality certification, Alexa popularity rank, and content were assessed. RESULTS: Google search queries on HS have steadily risen in the last 10 years. The website analysis revealed 39 unique websites, which were difficult to read. Ten websites (26%) had HONcode quality certification, and the median (IQR) Alexa popularity rank was 48871 (2333-361275). Thirteen websites (33%) yielded disease-specific photos with a median rating between "quite useful" and "uncertain." A therapy option with adalimumab was mentioned on 11 websites (28%). CONCLUSIONS: In addition to an increasing interest, we found a broad variation in the quality, readability, popularity, and timeliness of content on HS-related websites. Improvement of the quality and readability of HS-related websites is desirable to potentially raise disease awareness and contribute to an earlier presentation of patients suffering with undiagnosed HS.

Expression of oncogenic miR-17-92 and tumor suppressive miR-143-145 clusters in basal cell carcinoma and cutaneous squamous cell carcinoma.

BACKGROUND: A variety of cancers are associated with the expression of the oncogenic miR-17-92 cluster (Oncomir-1) and tumor suppressor miR-143-5p/miR-145-5p. Epidermal skin cancer has not been investigated for the expression of miR-17-92 and miR-143-145 clusters, despite being extensively studied regarding global microRNA profiles. The goal of this study was to investigate the expression and possible correlation of expression of miR17-92 and miR-143-145 cluster members in epidermal skin cancer. METHODS: We evaluated punch biopsies from patients with cutaneous squamous cell carcinoma (cSCC, n=15) and basal cell carcinoma (BCC, n=16), along with control specimens from non-lesional epidermal skin (n=16). Expression levels of the miR17-92 cluster (including miR-17-5p, miR-17-3p, miR-18a-3p, miR-18a-5p, miR-19a-3p, miR-19a-5p, miR-19b-3p, miR-19b-1-5p, miR-20a-3p, miR-20a-5p, miR-92a-3p, and miR-92a-5p) and the tumor-suppressive cluster miR-143-145 (including miR-143-5p and miR-145-5p) were detected by quantitative real-time reverse transcriptase polymerase chain reaction. RESULTS: We noted a highly significant increased expression of the miR-17-92 members miR-17-5p, miR-18a-5p, miR19a-3p, and miR-19b-3p and tumor suppressor miR-143-5p (p<0.01) in cSCC. miR-145-5p had a significantly decreased expression (p<0.05) for in BCC. A correlation analysis revealed multiple correlating miRNA-pairs within and between the investigated clusters. CONCLUSION: This study marks the first evidence for the participation of members of the miR-17-92 cluster in cSCC and miR-143-145 cluster in BCC.

Combination of oral zinc gluconate and topical triclosan: An anti-inflammatory treatment modality for initial hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is often a therapeutic challenge with relapses and chronicity which can severely impact patients' quality of life. OBJECTIVE: To evaluate the efficacy of anti-inflammatory oral zinc gluconate, 90mg/day, combined with topical triclosan, 2% twice daily. METHODS: We retrospectively evaluated the medical records of HS patients in our HS Center of the Department of Dermatology, Venereology, and Allergology, Ruhr-University Bochum, regarding change of disease severity and quality of life. Secondary outcome measures were the number of nodules and fistulas, the number of boils or flair-ups, and the intensity of pain. RESULTS: Sixty-six patients in Hurley stage I and II were included. After 3 months of combination therapy, the modified HS Score and the Dermatology Life Quality Index improved significantly (p<0.0001 and p=0.0386, respectively). The number of inflammatory nodules, new boils or flare-ups, and erythema scores decreased significantly. Fistula count and the visual analogue scale score showed no significant difference. Side-effects (mostly abdominal pain and nausea) were reported by 12 (22.2%) patients. CONCLUSION: The combination therapy of zinc gluconate and topical triclosan can be considered as an anti-inflammatory treatment for HS patients in Hurley stage I and initial Hurley stage II.

Microbial Profile and Antimicrobial Susceptibility of Bacteria Found in Inflammatory Hidradenitis Suppurativa Lesions.

BACKGROUND: The role of bacterial colonization in hidradenitis suppurativa (HS) lesions is poorly understood. To date, data on the related microbial profile and especially on bacterial resistance rates are scarce. METHODS: The results of bacterial cultures and susceptibility patterns of the isolated microorganisms obtained from deep portions of HS lesions from patients who underwent surgery at our HS Centre between 2010 and 2015 were retrospectively evaluated. RESULTS: Analyses of 113 bacterial samples from 113 HS patients revealed bacterial growth in 95 samples (84.1%). Polymicrobial growth was found in 51 samples (45.1%). Coagulase-negative staphylococci and Staphylococcus aureus were the most commonly isolated bacteria, followed by Proteus mirabilis and Escherichia coli. Data on susceptibility testing were available for 68 samples, which yielded 129 isolates. The isolated strains were primarily resistant to penicillin G, followed by erythromycin, clindamycin and ampicillin. The highest effectiveness against isolates was observed for fosfomycin, imipenem, fluoroquinolones (moxifloxacin, ciprofloxacin, levofloxacin), and cotrimoxazole. CONCLUSIONS: Our findings on bacterial species and their topographical distribution revealed that the microbial flora in HS lesions reflects commensal flora of the skin. Due to the susceptibility rate and immunomodulatory and anti-inflammatory properties, cotrimoxazole may represent an alternative antibiotic agent and should be considered for therapy in HS patients.