BACKGROUND:Monoclonal antibodies, such as cemiplimab and pembrolizumab, against the programmed death receptor (PD)-1 have become the current standard of care and first-line treatment of advanced cutaneous squamous cell carcinoma (cSCC), proving remarkable clinical benefit and acceptable safety. OBJECTIVES:To assess efficacy and safety of the anti-PD-1 antibody nivolumab in patients with locally advanced and metastatic cSCC. METHODS:Patients received open-label nivolumab 240 mg intravenously every 2 weeks for up to 24 months. Patients with concomitant haematological malignancies (CHMs), either non-progressing or stable under active therapy, were eligible for inclusion. RESULTS:Of 31 patients with a median age of 80 years, 22.6% of patients achieved an investigator assessed complete response, resulting in an objective response rate (ORR) of 61.3% and a disease control rate (DCR) of 64.5%. Progression-free survival (PFS) was 11.1 months, and the median overall survival (OS) was not reached after 24 weeks of therapy. Median follow-up was 23.82 months. Subgroup analysis of the CHM cohort (n = 11; 35%) revealed an ORR of 45.5%, a DCR of 54.5%, a median PFS of 10.9 months, and median OS of 20.7 months. Treatment related adverse events were reported in 58.1% of all patients (19.4% grade 3, the remaining grade 1 or 2). PD-L1 expression and CD-8+ T-cell infiltration did not significantly correlate with clinical response, although a trend towards a shorter PFS of 5.6 months was observed with PD-L1 negativity and low CD8+ intratumoral infiltration. CONCLUSION:This study demonstrated robust clinical efficacy of nivolumab in patients with locally advanced and metastatic cSCCs and a tolerability comparable to data of other anti-PD-1 antibodies. Favourable outcomes were obtained despite involving the oldest hitherto reported study cohort for anti-PD-1 antibodies and a significant proportion of CHM patients prone to high risk tumours and an aggressive course otherwise typically excluded from clinical trials.

Background Pleomorphic dermal sarcomas (PDS) are frequent UV-induced sarcomas of the skin of intermediate grade malignant potential. Despite the fact that PDS have a noteworthy potential to recur (up to 28%) as well as to metastasize (up to 20%), there are no specific clinical guidelines with respect to follow-up these patients. Moreover, little is known about clinical, histological or molecular prognostic factors in PDS. Objective The aim of the present study was to identify risk factors to predict relapse in a large multicentre sample cohort of PDS which could aid to optimize personalized treatment recommendations regarding surgical safety margins and adjuvant radiotherapy. Methods Patients with a diagnosis of PDS were selected from nine European institutions based on the histopathologic criteria described by Fletcher. Clinicopathologic and follow-up data were collected and statistically analysed calculating univariate hazard ratios with 95% confidence intervals by use of the Cox proportional-hazards model and a significance level of P < 0.05. Patients with an incomplete excision of the tumour were excluded. Results Univariate Cox regression analysis of possible prognostic factors for progression-free survival (PFS) performed in 92 patients revealed that an excision margin of PDS [hazard ratio 4.478 (95% CI 1.536-13.055), P = 0.006]. Ulceration of the tumour was associated with a significantly better prognosis [0.396 (0.174-0.904), P = 0.028] whereas adjuvant radiotherapy did not reach statistical significance to improve prognosis in patients with PDS [0.775 (0.231-2.593), P = 0.679]. Gender, age, immunosuppression, intratumoural necrosis, tumour location, vertical thickness or horizontal diameter did not significantly influence PFS in PDS. Conclusion We identified surgical safety margins of PDS. These findings may be implemented into both the primary treatment as well as the further monitoring of patients with PDS.

Primary melanoma ulceration is an unfavourable prognostic factor included in current staging systems. Yet, the immunological and molecular alterations responsible for this adverse outcome have not been fully elucidated.

The Warburg theory of cancer postulates that an important driver of tumorigenesis is insufficient respiration caused by mitochondrial defects, and simultaneous boost of lactate generation due to exaggerated aerobic glycolysis. Here we provide direct evidence that two types of malignant melanomas can be distinguished by their bioenergetic characteristics. We analyzed 48 melanoma samples by immunohistochemistry and found that 38% of melanomas are characterized by areas of isolated or combined deficiencies of complexes of the oxidative phosphorylation (OXPHOS). The incidence of OXPHOS deficient areas is associated with an increased Breslow index suggesting pathological significance. 62% of melanomas showed high levels of all OXPHOS complexes. Mitochondrial mass was high in all melanomas. Carbonic anhydrase IX protein levels were low, indicating that melanomas generally are well-oxygenated tumors. Expression of hypoxia-inducible factor-1α (HIF-1α) and monocarboxylate trasporter- 4 (MCT4) was high, which might be explained by the significant increase of lactate dehydrogenase A and presumable elevated levels of lactate in melanomas. Thus, our data indicate that there are two types of malignant melanoma: one that features a classic Warburg signature (high glycolysis, low OXPHOS), whereas the other one, despite being glycolytic, maintains a relatively high level of OXPHOS complexes.

Objective To illuminate pathophysiologic processes in postinflammatory medial meatal fibrosis (PMMF), a rare otologic disease of unknown etiology, which is defined by a progressive, obliterating fibrosis that affects the osseous part of the external auditory canal (EAC) exclusively. Study Design Retrospective clinical and histopathologic study. Setting Tertiary referral center. Patients Eleven patients (4 female and 7 male subjects) who underwent surgery of the bony EAC due to PMMF (13 ears operated). Methods Histologic and immunohistochemical assessment of tissue specimens obtained during surgical excision. Main Outcome Measure Detection of ectopic apocrine glands and concomitant inflammatory infiltrate within tissue harvested from the osseous EAC. Results Additionally to expected histologic findings, such as excessive fibrosis and a chronic inflammatory infiltrate, ectopic spread of apocrine glands was consistently detected in all of our patients. Conclusion Based on our findings, we suggest that an ectopic occurrence of adnexal structures within the bony EAC may predispose susceptible individuals to the development of PMMF. To avoid postoperative recurrence due to iatrogenic spread of cutaneous adnexal structures during surgery, the split-thickness skin graft should not exceed a thickness of 0.4 mm.

Granular cell tumors (Abrikossoff's tumor) are very rare, mostly benign tumors of neurogenic origin which preferentially occur in the upper aerodigestive tract. Granular cell tumors rarely originate in the orbit and are therefore a diagnostic and therapeutic challenge. A 42-year-old male patient presented to the Orthoptic Department of the University Eye Clinic in Salzburg with motility disturbances and diplopia in the right eye. The clinical examination revealed right-sided exophthalmos and shrinking of the choroid and retina due to a retrobulbar mass. The radiological examination showed an infiltrative tumor 1.7 x 1.3 cm in size in the lower temporal quarter of the orbit. Due to the localization a sonographically controlled fine needle puncture was carried out for preoperative diagnostics by a specialist in clinical cytology. The cytological examination confirmed the presence of a granular cell tumor. The tumor was excised via a conjunctival access route. Motility testing in the postoperative course control showed an improvement in the findings and the exophthalmos was clearly regressive. Vision improved from 0.5 preoperatively to 1.0 postoperatively. During the postoperative observational period of 12 months no recurrences occurred. Clinical control examinations are planned every 3 months and imaging controls every 6 months. Granular cell tumors of the orbit should be included in the differential diagnostics of orbital tumors despite the low incidence. A sonographically controlled fine needle puncture is an adequate procedure with respect to the diagnostics and further therapy for poorly differentiated tumors of the orbit with a suspicion of infiltrative growth and for which in toto resection is questionably possible. A complete surgical excision should be the aim of treatment of granular cell tumors. Continuous clinical and imaging control is necessary to enable early recognition of recurrences.

Granularzelltumoren (Abrikossoff-Tumore) sind sehr seltene, meist benigne Tumoren neurogenen Ursprungs, die bevorzugt im oberen Aerodigestivtrakt auftreten. In der Orbita stellt der Granularzelltumor eine Rarität und zugleich eine diagnostische und therapeutische Herausforderung dar.

BACKGROUND:The pathogenic role of nasal carriage as a source for cutaneous and soft-tissue Staphylococcus aureus (SA) infections, and Staphylococcal scalded skin syndrome (SSSS) in particular, is unclear.OBSERVATION:We herein describe a nosocomial outbreak of SSSS in three orthopaedic patients who received intra-articular injections by a single orthopaedic surgeon. Bacteriological samples from the index patients and medical personnel involved in their care were assessed by phage typing, polymerase chain reaction for exfoliative toxin genes, SmaI macro-restriction analysis and molecular spa-typing. These studies first revealed SA cultural growth in synovial fluid of all three patients as well as nasal mucosa of one medical assistant. Moreover, all SA isolates had the same phage typing and antibiotic susceptibilities and were positive for exfoliative toxin ETa by polymerase chain reaction. SmaI macro-restriction and spa-typing further confirmed all proband isolates to be identical.CONCLUSION:These findings provide evidence that SA nasal colonization of otherwise healthy carriers is a risk factor for SA infections, including SSSS, in predisposed individuals.

Epidermolysis bullosa (EB) nevi are large, eruptive, asymmetrical, often irregularly pigmented melanocytic lesions. Such nevi may give rise to small satellite nevi surrounding the primary nevus, and thus frequently manifest clinical features suggestive of melanoma. They usually arise in sites of previous bullae or erosions. At least twice a year all persisting wounds and EB nevi should be evaluated with a low threshold for histopathologic examination if warranted. Our practice is to punch biopsy EB nevi showing dermoscopic features of concern as well as dermoscopically featureless lesions. Given the skin fragility and potentially impaired wound healing in EB patients, we avoid prophylactic total excision of large EB nevi, but rather use the dermoscope to select appropriate sites for punch biopsies within giant EB nevi.

Chronic involvement of orogenital and conjunctival mucosa in the course of either genetically based (epidermolysis bullosa hereditaria) or auto-immunologically mediated (as for example pemphigus vulgaris, mucous membrane pemphigoid or epidermolysis bullosa acquisita) blistering diseases can cause significant morbidity. To provide accurate care, recognition of clinical, pathogenic and diagnostic features as well as awareness of recent advances in the development of new therapeutic modalities are mandatory and thus will be discussed in this review.

Mutations in the gene coding for the transmembrane receptor protein Patched (PTCH) are implicated in the autosomal dominant disorder Gorlin syndrome (also known as naevoid basal cell carcinoma syndrome), characterized by congenital abnormalities and cancer predisposition. Tumour promotion is thought to be associated with aberrant function of PTCH, leading to misregulation of the hedgehog signalling network. However, the transcriptional events that underlie the reduced tumour suppression effects of PTCH have not been studied in detail. We describe a patient with Gorlin syndrome who had three molecular aberrations resulting in biallelic disruption of the PTCH gene, leading to abnormal protein expression and development of basal cell carcinoma. Remarkably, within tumour cells, the somatic nonsense mutation G1019X was associated with activation of a cryptic splice donor site, in which an in-frame deletion of the exon sequence containing the nonsense mutation occurred. However, the function of the resulting PTCH protein variant was still compromised. The pathogenetic alterations described give insights into the sequence of events leading to cellular transformation and underscore the importance of the PTCH protein in skin homeostasis.

PurposeTo report an anti-epiligrin cicatricial pemphigoid (AECP) patient with severe ocular involvement and to provide a practical approach to distinguishing AECP patients from those with other subepidermal blistering diseases.MethodsTechniques included direct and indirect immunofluorescence microscopy, Western blot and immunoprecipitation studies, as well as interdisciplinary examinations of mucous membranes and skin.ResultsThis study describes a patient with clinical features of cicatricial pemphigoid, circulating anti-basement membrane zone IgG antibodies, and subepidermal blisters. Histopathology and immunofluorescence analysis suggested the diagnosis of a cicatricial pemphigoid-like type of epidermolysis bullosa acquisita. However, Western blot and immunoprecipitation studies demonstrated that the patient's serum contained autoantibodies against laminin 5 α3 subunit, leading to the diagnosis of an AECP.ConclusionsSince patients with AECP have an increased relative risk for malignant tumors, it is important to distinguish this entity within the spectrum of cicatricial pemphigoid patients by additional studies such as Western blot or immunoprecipitation.

an immunocompromised host may be coincidental. However, it is also conceivable that long-term immunosuppression and, in addition, fair complexion and a stay in the tropics represent cofactors for tumour development. Although cutaneous MFHs in RTRs are very rare, the case reported here shows that cutaneous MFH with a poor prognosis may arise after RT, especially in patients with several risk factors. To our knowledge, this is the first reported case of cutaneous MFH of the scalp in an RTR.

Journal of the European Academy of Dermatology and VenereologyVolume 20, Issue 7 p. 896-898 Vaginal adenosis induced by Stevens–Johnson syndrome M Emberger, Corresponding Author M Emberger Department of Dermatology and * Corresponding author, Department of Dermatology, Paracelsus Private Medical University Salzburg, Müllner Hauptstrasse 48, A-5020 Salzburg, Austria, tel. +43 6624482 3001; fax +43 6624482 3003; E-mail: m.emberger@lks.atSearch for more papers by this authorCM Lanschuetzer, CM Lanschuetzer Department of Dermatology andSearch for more papers by this authorM Laimer, M Laimer Department of Dermatology andSearch for more papers by this authorT Hawranek, T Hawranek Department of Dermatology andSearch for more papers by this authorA Staudach, A Staudach Department of Gynecology and Obstetrics, Paracelsus Private Medical University Salzburg, Salzburg, Austria.Search for more papers by this authorH Hintner, H Hintner Department of Dermatology andSearch for more papers by this author M Emberger, Corresponding Author M Emberger Department of Dermatology and * Corresponding author, Department of Dermatology, Paracelsus Private Medical University Salzburg, Müllner Hauptstrasse 48, A-5020 Salzburg, Austria, tel. +43 6624482 3001; fax +43 6624482 3003; E-mail: m.emberger@lks.atSearch for more papers by this authorCM Lanschuetzer, CM Lanschuetzer Department of Dermatology andSearch for more papers by this authorM Laimer, M Laimer Department of Dermatology andSearch for more papers by this authorT Hawranek, T Hawranek Department of Dermatology andSearch for more papers by this authorA Staudach, A Staudach Department of Gynecology and Obstetrics, Paracelsus Private Medical University Salzburg, Salzburg, Austria.Search for more papers by this authorH Hintner, H Hintner Department of Dermatology andSearch for more papers by this author First published: 11 May 2006 https://doi.org/10.1111/j.1468-3083.2006.01586.xCitations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume20, Issue7August 2006Pages 896-898 RelatedInformation

BACKGROUND:Large, asymmetrical and irregularly pigmented naevi in patients with epidermolysis bullosa (EB) have been reported often to mimic cutaneous melanoma clinically.OBJECTIVES:As the biological course of these peculiar moles is benign, we assessed EB naevi with a dermatoscope to determine whether they could be reliably differentiated from cutaneous melanoma.METHODS:We evaluated digital dermoscopic images of 23 EB naevi from 11 patients with EB and analysed these pigmented lesions according to pattern analysis, ABCD rule of dermoscopy and the seven-point checklist.RESULTS:Melanoma-associated dermoscopic criteria such as multicomponent pattern (20 of 23), atypical pigment network (17 of 23), irregular dots/globules (16 of 23), irregular pigmentation (22 of 23) and an atypical vascular pattern (seven of 23) were frequently seen in EB naevi. In contrast, other criteria frequently associated with melanoma progression, such as irregular streaks, blue-whitish veil, regression structures (blue-whitish areas) or black dots, were rarely seen. Most lesions gave false-positive results when the scores of the dermoscopic diagnostic algorithms were calculated.CONCLUSIONS:Recurring dermoscopic structures in EB naevi reveal a distinctive dermoscopic pattern of this recently defined entity. Although EB naevi represent an exception to dermoscopic diagnostic algorithms, their dermoscopic evaluation most often allows us to estimate their benign nature. Nevertheless, as an unequivocal discrimination from malignant melanoma in vivo is sometimes not possible, regular clinical follow up of EB naevi with histopathological evaluation of highly suspicious lesions is mandatory.