Haptoglobin is an independent marker for disease severity and risk for metabolic complications in hidradenitis suppurativa: A prospective study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease that is highly correlated with obesity. Haptoglobin serum levels have recently been recognized as an important biomarker linking obesity with chronic inflammation. OBJECTIVE: To compare haptoglobin with previously proposed serum biomarkers for the determination of disease severity in HS patients. For this purpose, disease severity of HS patients was determined by a panel of clinical scores as well as several risk factors, such as weight and smoking habits. METHODS: A prospective, diagnostic accuracy study was performed at the International Centre for Hidradenitis suppurativa/Acne inversa Bochum (ICH). The study included a total of 263 patients, including 131 who had a confirmed diagnosis of HS in Hurley I (n = 16), II (n = 56) and III (n = 59) HS, and 132 healthy controls. The main outcome was to identify serological inflammatory markers for HS disease severity [severe (III) vs. moderate/mild (II/I)] as assessed by Hurley classification. RESULTS: The serum levels of acute phase proteins haptoglobin and CRP, as well as the number of neutrophils in peripheral blood, number of monocytes, the systemic immune-inflammation index and the pan-immune-inflammatory value correlated with disease severity according to established clinical scores (mHSS, SAHS, Hurley, DLQI). HS patients had significantly higher haptologlobin levels compared to healthy controls. Logistic regression analysis revealed haptoglobin as the only independent marker predicting severe HS. CONCLUSION: In this prospective study, we discovered that the serum levels of the acute phase protein haptoglobin levels serve as an independent marker of disease severity in HS. While this presents the first study in the context of HS. Thus, the present data not only yield a highly promising serum marker to be further validated.

Long-term efficacy, safety and tolerability of secukinumab in children and adolescents with severe chronic plaque psoriasis: Two-year results from a Phase III double-blind, randomized controlled trial.

BACKGROUND: Secukinumab has previously demonstrated sustained efficacy and favourable safety for up to 52 weeks in paediatric patients (children and adolescents aged 6 to <18 years) with severe chronic plaque psoriasis (NCT02471144). OBJECTIVE: To investigate the long-term (104 weeks) efficacy and safety of secukinumab. METHODS: After 52 weeks, patients continued to receive secukinumab low dose (LD [75/150 mg]) or high dose (HD [75/150/300 mg]). Patients on etanercept (0.8 mg/kg) until Week 52 entered follow-up. Data for patients receiving secukinumab LD from the beginning and those switching to secukinumab LD from placebo ('Any secukinumab' LD) and patients receiving secukinumab HD from the beginning and those switching to secukinumab HD from placebo ('Any secukinumab' HD) are presented. ASSESSMENTS: Psoriasis Area and Severity Index (PASI) score, PASI (75/90/100) responses, Investigator's Global Assessment modified 2011 (IGA mod 2011) 0/1 response, Children's Dermatology Life Quality Index (CDLQI) score and CDLQI 0/1 response up to Week 104, and, safety up to Week 104 for all patients and up to 4 years for some patients (~320 patient-years [PY] of treatment). RESULTS: Secukinumab-treated patients showed sustained PASI 75/90/100 and IGA mod 2011 0/1 responses up to Week 104. Throughout the second year of treatment, efficacy was similar for the 'Any secukinumab' LD and HD groups for PASI 75 and IGA mod 2011 0/1 responses. PASI 90/100 responses were mostly comparable between the dose groups up to Week 88, but higher in the 'Any secukinumab' HD than the 'Any secukinumab' LD group at Week 104. Patients achieved a sustained CDLQI 0/1 response that was similar between the 'Any secukinumab' LD (61.1%) and HD (65.0%) groups. Safety data were consistent with the established safety profile of secukinumab. CONCLUSION: Secukinumab demonstrated sustained long-term efficacy (up to 2 years) and a favourable safety profile (~320 PY of treatment) in paediatric patients with severe chronic plaque psoriasis.

Prompt response of advanced cutaneous squamous cell carcinoma to cemiplimab in a kidney transplant patient receiving treatment with everolimus.

The safety and efficacy of immune checkpoint inhibitors in solid organ transplant recipients (SOTR) are unclear, as SOTR are usually excluded from clinical investigations due to their high risk for irreversible allograft rejection. We observed a kidney transplant patient with metastatic cutaneous squamous cell carcinoma who experienced complete response under anti-tumour therapy using cemiplimab and prevention of transplant rejection by fixed dose everolimus.

Comparison of mutation profiles in primary melanomas and corresponding nodal naevi using next-generation sequencing.

BACKGROUND: Nodal naevi (NN) represent aggregates of melanocytes within peripheral lymph nodes. NN are relatively often found in patients with malignant melanoma (MM), and may mimic metastatic disease. AIM: To study mutation profiles in MM and NN to find out whether NN descend from a primary MM. METHODS: Next-generation sequencing was performed on formalin-fixed paraffin-embedded tissue of 26 pairs of primary MM and corresponding NN detected by sentinel lymph node biopsy, and 29 MM-characteristic genes were investigated. RESULTS: In this study, 90% of mutations were detected exclusively in either MM or NN, but not both, in the same patient; the percentage of identical NN and MM mutations in the same individual was only 10%. The most frequently discovered shared mutations were a C>G substitution in the CDKN2A gene and in-frame deletion in ARID1A. Oncogenic driver mutations were frequently observed in MM but only rarely in NN. About three-quarters of mutations in both MM and NN were characterized by C>T or G>A substitutions. The detected rate of ultraviolet (UV)-related C>T base changes was comparably high in both primary MM (35%) and NN (32%). CONCLUSIONS: Based on our data, it seems that NN descend from previously UV-exposed BRAF wildtype cutaneous melanocytes, rather than from primary MM or arrested progenitor cells.

Aggressive cutaneous squamous cell carcinoma in a hydroxyurea- and ruxolitinib-pretreated patient with polycythaemia vera.

Hydroxyurea and ruxolitinib are frequently used to treat myeloproliferative disorders, including polycythaemia vera, and chronic treatment is associated with many cutaneous adverse effects such as the development of aggressive non-melanoma skin cancer (NMSC). We report an 85-year-old man with a history of hydroxyurea- and ruxolitinib-treated polycythaemia vera who was referred for the management of progressively growing tumours on his scalp. Histopathology of the largest scalp lesion revealed a partly desmoplastic cutaneous squamous carcinoma with perineural invasion. Initial imaging revealed metastatic disease in cervical lymph nodes, bones and lungs. The scalp lesions were successfully treated with bleomycin-based electrochemotherapy. Under initial systemic therapy using four cycles of cetuximab, metastatic disease progressed. Following the approval by the health insurance, compassionate use of pembrolizumab monotherapy was initiated. After three cycles of pembrolizumab, however, metastatic disease further progressed and the patient finally died from global respiratory insufficiency. The present case exemplifies the cutaneous adverse effects of long-term hydroxyurea and ruxolitinib therapy, frequently resulting in highly aggressive NMSCs that are usually not responsive to systemic treatments even such as immune checkpoint inhibitors.

Complete blood collection-based systemic inflammation biomarkers for patients with hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a relatively common chronic inflammatory condition of intertriginous skin. In recent years, the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR) and platelet/neutrophil ratio (PLR) have been shown to be indicators of systemic inflammation correlating with severity of inflammatory conditions. OBJECTIVES: We aimed to analyse for the first time the systemic inflammation biomarkers also including the pan-immune-inflammation value (PIV) and the systemic immune-inflammation index (SII) in HS patients and controls. METHODS: This study retrospectively investigated clinical and laboratory data of 142 patients with HS. Moreover, a sex-age-matched healthy control group was included. The severity of HS was routinely assessed by the Hurley staging, the mHSS and the SAHS score. All inflammation-based biomarkers were calculated from absolute values of complete blood counts. Receiver-operating characteristics analyses, including the Youden index, were performed in order to determine optimal cut-off values and test performance. RESULTS: Whereas PIV and SII were significantly higher in HS patients, PLR, MLR and PNR were significantly lower in HS patients when compared to controls. Almost all inflammation-based biomarkers significantly correlated with disease severity. However, PIV was the only test that was significantly associated with HS severity as indicated by a Youden index of 0.56 (associated criterion: 756.4; AUC: 0.79, P < 0.0001). CONCLUSIONS: Although all systemic inflammation-based biomarkers investigated are more or less associated with HS severity, the PIV appears to have the best performance in this regard. It may be employed in adjunction with the clinical scores for treatment decision making or clinical trial assessments.

Management of immune-related adverse events in anti-PD-1-treated patients with advanced cutaneous squamous cell carcinoma.

Immune checkpoint inhibitors (ICI) have shown very promising results in the management of patients with inoperable or metastatic cutaneous squamous cell carcinoma (cSCC). However, ICI can cause a range of immune-related adverse events (irAEs) affecting a multitude of organs including skin, gastrointestinal tract, endocrine system, heart, lung, kidneys and the nervous system. In principle, clinical management irAEs does not change significantly with respect to the kind of cancer treated with ICI. However, advanced cSCC typically occurs in a clinically challenging patient population typically presenting with advanced age and/or significant comorbidities such as immunosuppression due to haematological malignancies and their respective treatment. Moreover, many patients with advanced cSCC are organ transplant patients taking immunosuppressants. As a consequence use of ICI per se and management of ICI-induced irAEs generates more complexity and difficulties in patients with cSCC compared to other entities. Here, we provide a brief review on the management of anti-programmed cell death protein 1-induced irAEs in patients with cSCC focusing on the characteristic clinical challenges present in this population.

Development of thoracic sarcoid reactions associated with complete response to anti-PD-1 therapy in a patient with advanced cutaneous squamous cell carcinoma.

In patients with advanced cutaneous squamous cell carcinoma (cSCC), positive efficacy data were reported for anti-PD-1 antibodies. However, anti-PD-1 treatment is associated with a wide range of immune-related adverse events (irAEs). Here, we report on a 78-year-old woman with a huge cSCC on the right cheek spanning from the temporal to the cervical region with evidence for infiltration of the parotid gland, right masseter muscle and right auditory canal. Ultrasound revealed cervical, submandibular and supraclavicular lymph node metastases on patient's right side. On the basis of a medical hardship application, treatment with pembrolizumab was initiated. After two applications, a dramatic regression of the tumour was observed. At this point, the patient was switched to cemiplimab, which, in the meantime, had become available in Germany. After 3 months on cemiplimab, the tumour-related ulcer on the right cheek showed almost complete regression and all previously affected lymph nodes displayed no evidence for malignancy. Thoracic computed tomography (CT) scans revealed enlarged mediastinal and bilateral hilar lymph nodes assessed as primarily reactive. Three months later, however, mediastinal and bilateral hilar lymph nodes further increased in size, accompanied by radiological alterations of the lung parenchyma. Lymph node biopsies revealed sarcoid reactions (SRs) including fibrotic non-caseating epitheloid cell granulomas surrounded by lymphocytes. Since the patient did not display any clinical symptoms, cemiplimab treatment was continued following a 4-week break. Three months later, CT showed significant regression of the described enlarged lymph nodes and parenchymal lung changes. Twenty months after anti-PD-1 treatment, the patient was still in complete remission. In conclusion, we describe, for the first time, the case of a patient with advanced cSCC who developed disseminated thoracic SRs which were associated with dramatic regression of tumour masses. Thus, as with other irAEs, development of SRs might be indicative of an anti-tumour response to anti-PD-1 therapy.

Cutaneous findings following COVID-19 vaccination: review of world literature and own experience.

There is growing evidence that not only the novel coronavirus disease (COVID-19) but also the COVID-19 vaccines can cause a variety of skin reactions. In this review article, we provide a brief overview on cutaneous findings that have been observed since the emerging mass COVID-19 vaccination campaigns all over the world. Unspecific injection-site reactions very early occurring after the vaccination are most frequent. Type I hypersensitivity reactions (e.g. urticaria, angio-oedema and anaphylaxis) likely due to allergy to ingredients may rarely occur but can be severe. Type IV hypersensitivity reactions may be observed, including delayed large local skin lesions ("COVID arm"), inflammatory reactions in dermal filler or previous radiation sites or even old BCG scars, and more commonly morbilliform and erythema multiforme-like rashes. Autoimmune-mediated skin findings after COVID-19 vaccination include leucocytoclastic vasculitis, lupus erythematosus and immune thrombocytopenia. Functional angiopathies (chilblain-like lesions, erythromelalgia) may also be observed. Pityriasis rosea-like rashes and reactivation of herpes zoster have also been reported after COVID-19 vaccination. In conclusion, there are numerous cutaneous reaction patterns that may occur following COVID-19 vaccination, whereby many of these skin findings are of immunological/autoimmunological nature. Importantly, molecular mimicry exists between SARS-CoV-2 (e.g. the spike-protein sequences used to design the vaccines) and human components and may thus explain some COVID-19 pathologies as well as adverse skin reactions to COVID-19 vaccinations.

Efficacy and safety of fumaric acid esters in young patients aged 10-17 years with moderate-to-severe plaque psoriasis: a randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Apart from biologics, no systemic drugs are approved in Europe for children with moderate-to-severe psoriasis. Retrospective observational studies have shown promising results for fumaric acid esters (FAE) in this setting. OBJECTIVES: To show superiority of FAE over placebo in terms of treatment response after 20 weeks in children and adolescents aged 10-17 years. METHODS: In a multicentre, randomized, double-blind, placebo-controlled phase IIIb study, patients aged 10-17 years with moderate-to-severe plaque psoriasis requiring systemic therapy were randomized 2 : 1 to receive FAE (n = 91) or placebo (n = 43) over 20 weeks, followed by an open-label FAE treatment phase. The coprimary endpoints were ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and Physician's Global Assessment (PGA) score of 0 or 1 (clear or almost clear) at week 20. The study was registered with EudraCT number 2012-000035-82. RESULTS: At week 20, 55% [95% confidence interval (CI) 0·44-0·65] of FAE-treated patients achieved a PASI 75 response vs. 19% (95% CI 0·08-0·33) in the placebo group (absolute difference 36%, 95% CI 0·20-0·53; P < 0·001). In total, 42% (95% CI 0·32-0·53) in the FAE group vs. 7% (95% CI 0·01-0·19) in the placebo group achieved a PGA score of 0 or 1 at week 20 (absolute difference 35%, 95% CI 0·21-0·49; P < 0·001). During the double-blind period, drug-related adverse events occurred more frequently in patients receiving FAE compared with placebo (76% vs. 47%). Gastrointestinal disorders were the most common adverse events. CONCLUSIONS: FAE administered over a period of 20 weeks demonstrated a better response than placebo; the difference was statistically significant and clinically meaningful. Application up to 40 weeks was generally well tolerated. However, further studies are required.

NOD2 signalling in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is associated with dysregulated immune responses including altered expression of cytokines, chemokines, and antimicrobial peptides and proteins (AMPs). AIMS: To evaluate the expression of nucleotide-binding oligomerization domain-containing (NOD)2 and related factors in HS skin samples and keratinocyte cultures. METHODS: We performed real-time PCR for NOD2, receptor-interacting serine/threonine-protein kinase (RIP)2, cyclic amine resistance locus (CARL), skin-derived antileukoproteinase (SKALP)/elafin, human ß-defensin (hBD)2, LL37, psoriasin and RNAse7 in lesional and nonlesional skin of 19 patients with HS and in keratinocyte cultures [unstimulated, muramyl dipeptide (MDP)-stimulated or Pam2CSK4 (Pam2)-stimulated] from and nonlesional skin. RESULTS: We observed significantly elevated mRNA expression for NOD2 (P < 0.01), hBD2 (P = 0.02), RNase7 (P < 0.001), psoriasin (P < 0.01) and SKALP/elafin (P = 0.02) in lesional compared with nonlesional skin. We found a significant correlation between NOD2 mRNA and hBD2 (r = 46; P = 0.04), psoriasin (r = 0.67; P < 0.01) and SKALP/elafin (r = 0.65; P < 0.01). In unstimulated, Pam2-stimulated and MDP-stimulated normal keratinocytes, NOD2, RIP2, CARL and SKALP/elafin expression significantly (P < 0.05) increased from 6 to 48 h, whereas in unstimulated, Pam2-stimulated and MDP-stimulated HS keratinocytes, RIP2, CARL and SKALP/elafin expression significantly (P < 0.05) declined from 6 to 48 h. mRNA expression of NOD2 (unstimulated, Pam2-stimulated, MDP-stimulated), CARL (unstimulated, Pam2-stimulated, MDP-stimulated) and SKALP/elafin (unstimulated, Pam2-stimulated) at 6 h was significantly increased in HS compared with normal keratinocytes. CONCLUSION: We have shown for the first time that NOD2 signalling is activated in HS and might contribute to the pathogenesis via induction of AMPs and activation of other pathways such as nuclear factor κB signalling.

Expression of Hedgehog signalling molecules in microcystic adnexal carcinoma.

BACKGROUND: Microcystic adnexal carcinoma (MAC) is a rare skin neoplasm that has not been characterized on a molecular basis. AIM: To assess expression profiles of Hedgehog (HH) signalling molecules in MAC and control tumours. METHODS: Immunohistochemistry was performed for Sonic Hedgehog (SHH), Indian Hedgehog (IHH), Patched 1 (PTCH1) and Smoothened (SMO) on patient MAC tissue (n = 26) and control tumour tissue, including syringoma (SyG; n = 11), trichoepithelioma (TE; n = 11) and basal cell carcinoma (BCC; n = 12) tissues. RESULTS: Patched 1 and SMO immunoreactivity was significantly higher in BCC than in SyG, TE or MAC (P < 0.001 and P < 0.03, respectively). The highest IHH expression was observed in BCC and TE compared with SyG and MAC (P < 0.04). Notably, the highest SHH protein expression was observed in SyG compared with MAC, TE and even BCC (P < 0.001). In patients with MAC, SMO immunoreactivity significantly (r = 0.51; P < 0.01) correlated with PTCH1 expression. Further correlation studies did not show significant associations between the HH expression markers assessed (P > 0.05). CONCLUSION: Our results indicate that alterations of the HH signalling are unlikely to play a major role in the pathogenesis of MAC, which is in contrast to the morphologically similar BCC and TE. Our observation provides additional information to the limited molecular pathology knowledge on this rare tumour.

Increased expression profile of NCSTN, Notch and PI3K/AKT3 in hidradenitis suppurativa.

BACKGROUND: In a small number of kindreds with familial hidradenitis suppurativa (HS) different mutations of NCSTN (nicastrin) have been identified. Blocking of NCSTN leads to impairment of the Notch and PI3K/AKT signalling pathway, which is assumed to play a pathogenic role in HS. However, very limited data are available concerning expression levels of these pathway components in HS skin. OBJECTIVES: To analyse the mRNA and protein expression of NCSTN, Notch1-3, PIK3R3 and AKT3 in HS. METHODS: Skin samples from healthy controls, lesional and perilesional skin of HS patients with and without a positive family history were analysed by quantitative real-time RT-PCR and immunohistochemistry. Univariate statistical analyses were conducted regarding association between expression levels and patient's characteristics. RESULTS: Expression levels of all investigated genes showed significantly higher levels in lesional HS skin compared with healthy controls. Univariate analysis showed no association between a positive family history and mRNA expression levels. Perilesional HS skin of patients with mild disease severity (Hurley I) showed significant higher mRNA expression levels of the investigated pathway components compared to moderate (Hurley II) and severe disease (Hurley III). CONCLUSION: We found no evidence for diminished expression levels of the Notch signalling. In contrast, the NCSTN, Notch and PI3K/AKT signalling components are overexpressed in HS. Future research is needed to investigate a possible pathogenetic role or to reveal a coactivation of these overexpressed components during inflammatory response in HS.

Decline of programmed death-1-positive circulating T regulatory cells predicts more favourable clinical outcome of patients with melanoma under immune checkpoint blockade.

BACKGROUND: The role of T regulatory lymphocytes (Tregs) and their immunosuppressive mechanisms in the context of programmed death (PD)-1 blockade is not completely understood. OBJECTIVES: To assess the impact of PD-1-blocking antibody treatment on Treg subpopulations in the blood. METHODS: We studied circulating Treg subpopulations in patients with melanoma under nivolumab or pembrolizumab treatment using flow cytometry and correlated these findings with clinical outcomes. RESULTS: These analyses revealed that the frequency of CD4+  CD25++  CD127-  PD-1+ lymphocytes (PD-1+ Tregs) significantly decreased after the first cycle of immunotherapy (23% vs. 8·6%, P = 0·043). Compared with patients who did not show a significant decline of PD-1+ Tregs after the first treatment, those who did had better clinical outcomes with respect to progression-free survival (PFS, P = 0·022) and melanoma-specific death (MSD, P = 0·0038). Multivariate analysis confirmed that a significant decline of PD-1+ Tregs in peripheral blood after the first treatment cycle is a significant predictor of more favourable PFS and MSD (P = 0·04 and 0·017, respectively). Interestingly, the occurrence of immune-related adverse events was also an independent predictor for decreased risk of MSD (P = 0·047; odds ratio 0·064, 95% confidence interval 0·0042-0·97). CONCLUSIONS: We provide preliminary evidence that circulating PD-1+ Tregs rapidly decline after the initiation of treatment with PD-1-blocking antibodies, which is associated with reduced risk of melanoma progression and MSD. Patients showing no decrease of these PD-1+ Tregs in peripheral blood are characterized by an impaired response to immune checkpoint blockade and worse outcome. What's already known about this topic? Programmed death (PD)-1-blocking antibodies are highly effective in melanoma treatment. However, more than half of patients do not benefit from this therapy and to date it is difficult to predict which patients will respond to it. What does this study add? PD-1-blocking antibody therapy rapidly results in a decline of circulating PD-1+ T regulatory cells (Tregs). What is the translational message? Patients showing a decrease of PD-1+ Tregs appear to have better clinical outcome under PD-1 treatment.

Does very early timing of lymph node surgery after resection of the primary tumour improve the clinical outcome of patients with melanoma?

BACKGROUND: In patients with cutaneous melanoma (CM), the time span between resection of the primary tumour and sentinel lymph node biopsy (SLNB) as well as the subsequent interval between SLNB and complete lymph node dissection (CLND) varies greatly. AIM: To determine whether very early timing of SLNB after resection of the primary tumour, or timing of CLND after SLNB affect the clinical outcome of patients with CM, compared with longer time intervals. METHODS: We compared the time spans between complete resection of the primary tumour and SLNB, and the interval between SLNB and CLND in a cohort of 896 patients with melanoma who had undergone SLNB. An interval between primary resection and SLNB or between SLNB and CLND of up to 7 days was classified as very early (VE-SLNB and VE-CLND, respectively). This time span was compared with intervals of > 7 days. Univariate and multivariate statistics were performed. RESULTS: VE-SLNB was significantly associated with the presence of micrometastases. However, this was probably due to tumour thickness being significantly higher in patients with VE-SLNB compared with patients with later SLNB. Importantly, VE-SLNB was not significantly associated with disease relapse and VE-CLND was not associated with melanoma-specific death. CONCLUSIONS: VE-SLNB and VE-CLND neither improved nor worsened the clinical outcome of patients. Thus, timing of SLNB and CLND has no influence on the overall clinical outcome of patients with melanoma. Our findings support the rational planning of lymph node surgery after resection of the primary tumour and provide help for effective patient counselling.

Frequency of circulating subpopulations of T-regulatory cells in patients with hidradenitis suppurativa.

BACKGROUND: Decreased number of T-regulatory cells (Tregs) and/or their loss of function potentially lead to uncontrolled immune-mediated inflammatory responses. There are only few data available on Tregs in hidradenitis suppurativa (HS) - a disease in which it has been suggested that host immune factors and an overactive immune system of the follicular epithelium play a pathogenetic role. OBJECTIVES: To analyse frequencies of Tregs subpopulations in blood of HS patients in comparison with a healthy control group. MATERIALS & METHODS: Blood samples obtained from HS patients and healthy controls were evaluated by flow cytometry and enzyme-linked immunosorbent assay. RESULTS: The frequency of natural Tregs among CD4+ T lymphocytes were significantly reduced in the HS group compared to the healthy controls. The proportion of activated Tregs, non-suppressive Tregs and proliferating Tregs showed no significant difference when compared to controls. Regarding Tregs frequencies, there was no significant difference between the three Hurley stages. Serum concentrations of IL-10, TGF-ß1 and IL-17A did not show significant differences between the HS and control group. CONCLUSION: The reduction of natural Tregs observed in blood of HS patients could be the result of Tregs homing to sites of inflammatory hot spots in HS skin. Further studies are justified evaluating the role of circulating Tregs during the evolution of HS lesions and as a biomarker for treatment response.

Expression of Lefty predicts Merkel cell carcinoma-specific death.

BACKGROUND: Lefty and Nodal are transforming growth factor ß-related proteins, which, beside their role in determination of laterality during embryogenesis, have also been linked with cancer progression. OBJECTIVES: Prompted by the observed significant left-sided laterality of Merkel cell carcinoma (MCC), we addressed whether Lefty and Nodal are expressed in MCC and correlated expression patterns with clinical parameters such as MCC laterality and patient outcome. METHODS: Expression of Lefty and Nodal in primary MCC was assessed in 29 patients by immunohistochemistry. The histology (H-)score was calculated and correlated with clinical parameters. RESULTS: The median (range) H-score of Lefty and Nodal was 17.6 (0-291) and 74.9 (0.7-272), respectively. There was a significant correlation between Lefty expression and Nodal expression (correlation coefficient of 0.60, P = 0.0006). There was no significant correlation between Lefty expression and Nodal expression with either tumour laterality, gender, age, Merkel cell polyomavirus status, disease stage, anatomical localization of primary tumours or disease relapse. On univariate analysis, low Lefty expression and Nodal expression were significantly associated with MCC-specific death (P = 0.010 and P = 0.019, respectively). On univariate analysis, low Lefty expression was the only significant independent predictor for MCC-specific death (P = 0.025) as indicated by an odds ratio of 14 (95% CI: 1.43-137.33). CONCLUSIONS: Lefty and Nodal are frequently expressed in MCC, but not correlated with tumour laterality. Importantly, our data suggest that a low level of Lefty expression in primary MCC is a strong predictor of MCC-specific death.

Cutaneous squamous cell carcinomas are associated with basal proliferating actinic keratoses.

BACKGROUND: In addition to the extent of atypical keratinocytes throughout the epidermis, actinic keratoses (AKs) are histologically characterized by downward-directed basal-layer expansion. It is not known whether this growth pattern correlates with the risk of developing invasive squamous cell carcinoma (iSCC). OBJECTIVES: To characterize the prevalence of downward-directed basal-layer expansion of AKs adjacent to iSCC. METHODS: The epidermis overlying and adjacent to iSCCs was assessed histologically. We determined the histological grade (AK I-III), basal growth pattern (PRO I-III) and accompanying parameters such as adnexal involvement. RESULTS: Among 307 lesions, 52·4% of AKs were histologically classified as AK grade I, 38·1% as AK II and 6·8% as AK III (χ2 -test, P < 0·001). Only 2·6% of adjacent epidermal samples did not show any atypical keratinocytes. The epidermis adjacent to iSCCs was classified as having a PRO I basal growth pattern in 25·7%, PRO II in 31·9% and PROIII in 39·4% of cases. Only 2·9% of AKs showed no basal growth (χ2 -test, P < 0·001). In total 118 AKs (48·8%) showed extension into adnexal structures. These AKs were graded as PRO I in 18·6% of cases, PRO II in 30·5% and PRO III in 50·8%. The epidermis above iSCCs could be assessed only for upwards-directed growth and showed no significant differences in the three AK grades (P = 0·42). CONCLUSIONS: Basal proliferative AKs, as well as atypical keratinocytes restricted to the lower third of the epidermis, are most commonly seen adjacent to iSCC, with less evidence for full-thickness epidermal dysplasia. Our study supports the important role of dysplastic keratinocytes in the epidermal basal layer and their potential association with iSCC.

Melanocytic soluble adenylyl cyclase protein expression around lentigo maligna and in contralateral control skin.

Recurrence rates of both lentigo maligna (LM) and lentigo maligna melanoma (LMM) following conventional surgery are usually relatively high. We aimed to assess the frequencies of melanocytes in tumour-free margins around LM/LMM using soluble adenylyl cyclase (sAC) immunohistochemistry, and to compare these with those of matched healthy contralateral skin. Using the primary mouse-anti-human sAC antibody R21, we evaluated pan-nuclear melanocytic R21 immunostaining, and found that it was significantly (P < 0.001) higher in peritumoural melanocytes (median 20%; range 0-100%) than in contralateral healthy skin (mean 0%; range 0-20%). Accordingly, there was no correlation between peritumoural and contralateral R21 immunoreactivity (r = 0.12; P = 0.18). In conclusion, melanocytic R21 immunoreactivity in melanocytes is higher in tumour-free margins around LM/LMM than in site-matched contralateral skin. This observation may indicate that the biology of 'healthy'-appearing melanocytes around LM/LMM might be different from that of truly benign melanocytes.

Lysyl oxidase-like-2 mutations and reduced mRNA and protein expression in mid-dermal elastolysis.

BACKGROUND: Mid-dermal elastolysis (MDE) is a rare skin condition, characterized by selective loss of elastic fibres in the mid dermis. The pathogenesis of MDE is still unclear. AIM: To investigate expression of lysyl oxidase-like 2 (LOXL2) in a reasonable sample of patients with MDE and to search for mutations in LOXL2. METHODS: We investigated archived lesional tissue of 13 patients with MDE and skin tissue samples of 10 sex- and age-matched healthy controls (HCs). Gene and protein expression of LOXL2 was investigated using real-time reverse-transcription PCR and immunohistochemistry. Mutation analysis was performed using the Sanger method. RESULTS: We observed decreased LOXL2 mRNA expression in lesional skin of patients with MDE (0.48 ± 0.16) compared with healthy skin of the same patients (1.5 ± 0.51) and normal skin of HCs (1.9 ± 0.13). Compared with healthy patient skin (epidermis 2.38 ± 1.6, dermis 1.2 ± 1), LOXL2 protein expression in lesional patient skin (epidermis 1.1 ± 0.7, dermis 0.3 ± 0.45) was significantly decreased (P < 0.04 and P = 0.02, respectively). Mutation analysis of the entire LOXL2 gene could be performed for five patients, all of whom were found to have at least one mutation in the LOXL2 gene. Three of these had a mutation in the promoter region (c.967 G>C, c.1022 C>T, and c.1025 G>A, respectively), and one of them also had a mutation in the splice region of intron 11/exon 12 (IVS11-1 G>A). Of the remaining two patients, one had a mutation in exon 3 (T1391), and the other had a mutation in exon 11 (C663Y). CONCLUSIONS: Our present data suggest that decreased elastin renewal due to LOXL2 mutations and consecutive reduced LOXL2 expression contribute to the pathogenesis of MDE.