Extracorporeal Photopheresis as a Treatment Option for Immune-Related Adverse Events: Two Case Reports and a Prospective Study.

The wide use of immune checkpoint inhibitors has increased the frequency of immune-related adverse events (irAEs). While many are managed with corticosteroids or hormone substitution, up to 14.9% of irAEs are steroid-refractory or steroid-dependent and thus require second-line treatment. These should reduce irAE-related morbidity and mortality and induce a few side effects of their own while maintaining the antitumor response. There is little comparative data on second-line therapies for irAEs. Two cases of irAEs could not be sufficiently managed with corticosteroids and subsequently received treatment with extracorporeal photopheresis (ECP), including one patient with immune-related erosive oral lichen planus and one patient with immune-related colitis. In both cases, the irAE resolved with ECP in combination with immunosuppressive drugs, that is 4 weeks and 10 weeks after the start of ECP, respectively. To investigate this approach, a prospective clinical study that compares ECP and other second-line therapies for the treatment of steroid-refractory and steroid-dependent irAEs with regard to immunophenotype and therapy response has been designed. ECP could be a treatment option for steroid-refractory and steroid-dependent irAEs, given its good safety profile and lack of adverse effects on antitumor response. Comparative prospective studies are needed to generate an evidence base.

Ex-vivo fluorescence confocal microscopy with digital staining for characterizing basal cell carcinoma on frozen sections: A comparison with histology.

Ex-vivo fluorescence confocal microscopy (FCM) has been used on fresh tissue, but there is little experience on frozen sections. We evaluated the applicability of FCM on frozen sections of basal cell carcinomas (BCCs), stained with acridine orange and digitally colored to simulate hematoxylin and eosin (H&E) dyes. We compared our diagnostic accuracy in detecting and subtyping BCCs with FCM to our gold standard (H&E stained frozen sections used in 3D horizontal micrographic surgery). Fourty-six primary BCCs were analyzed for free margins as well as histological subtype with all FCM modes and conventional H&E staining. Adnexa, artifacts and diagnostic confidence were evaluated. Free margins were identified with a sensitivity and specificity of 92% and 91%. Concordance for tumor subtype was 88%. FCM may be used on both fresh tissue and frozen samples, although with reduced performance and different artifacts. The device is useful for the intraoperative diagnosis, subtyping and margin-mapping of BCCs.

Ex vivo Confocal Laser Scanning Microscopy: A Potential New Diagnostic Imaging Tool in Onychomycosis Comparable With Gold Standard Techniques.

Ex vivo confocal laser scanning microscopy (CLSM) is an innovative imaging tool that enables real-time examination of specimens and may be used in evaluating fungal infections. We aimed to assess the applicability of ex vivo CLSM in the diagnosis of onychomycosis by comparing results to those obtained by histopathology, potassium hydroxide (KOH) examination, and fungal culture. In this prospective study, 57 patients with the clinical diagnosis of distal nail fungal infection were examined and compared using all four of the above-mentioned diagnostic tools in terms of sensitivity, positive and negative predictive value. Ex vivo CLSM showed the highest sensitivity, followed by KOH examination, histopathology and fungal culture. Regarding positive and negative predictive values, ex vivo CLSM was superior and showed even higher sensitivity than the combined gold standard comprised of KOH examination, fungal culture or histopathology.

Recurrence of Pemphigus Vulgaris Under Nivolumab Therapy.

For many types of cancer, immune checkpoint inhibitors have proven to be a highly effective treatment. The monoclonal anti-PD-1 antibody nivolumab stimulates the immune system and is one of the newest treatment options for non-small cell lung cancer. In doing so, immune checkpoint inhibitors can trigger many skin lesions that have not yet been completely investigated in their entirety. In this case report, pemphigus vulgaris is identified as a potential adverse event that occurs under the treatment with nivolumab. In addition to the standard methods, we examined our patient's samples with ex vivo confocal laser scanning microscopy. This is a new and innovative diagnostic method that uses vertical scanning to provide fast, high-resolution imaging of freshly excised tissue, even using fluorescently labeled antibodies.

Cathelicidin peptide LL-37 increases UVB-triggered inflammasome activation: possible implications for rosacea.

BACKGROUND: In patients with rosacea, environmental stressors, especially UVB radiation, trigger disease flares that are characterized by inflammation and vascular hyperactivity. An altered innate immune detection and response system, modulated to a large extent by the aberrant production and processing of human cathelicidin LL-37, is thought to play a central role in disease pathogenesis. OBJECTIVE: To investigate whether the proinflammatory and proangiogenic effects of UV radiation are enhanced in the presence of cathelicidin LL-37. METHODS: Human skin ex vivo and epidermal keratinocytes in vitro were exposed to UVB irradiation. The proinflammatory effects of UVB exposure in the presence and absence of LL-37 were characterized using immunoblot, transfection, qPCR, and a cell-based second messenger assay. ELISA was used to assess cytokine release and the angiogenic potential of endothelial cells was evaluated using an in vitro angiogenesis assay. RESULTS: UVB irradiation triggered the inflammasome-mediated processing and release of IL-1ß. LL-37 augmented this UV-induced IL-1ß secretion by acting on the P2X7 receptor on keratinocytes. P2X7 receptor activation by UVB and LL-37 resulted in an increase in intracellular calcium concentrations, which enhances inflammasome activation and subsequent IL-1ß release. Furthermore, IL-1ß and LL-37 worked synergistically to increase the angiogenic potential of endothelial cells. CONCLUSION: Cathelicidin LL-37 modulates the proinflammatory and proangiogenic effects of UV radiation and thereby contributes to enhanced sensitivity to sun exposure in rosacea.

Face-to-face with anti-inflammatory therapy for rosacea.

In the past, our understanding of rosacea has been inadequate and limited to descriptions of factors that exacerbate and improve the disease. While the pathophysiology of rosacea is complex and multifactorial, cathelicidin peptides have emerged as key players in the pathogenesis of this common dermatological disorder. This article correlates recent findings in abnormal cathelicidin production and proteolytic processing in rosacea with therapeutic actions of current treatment options and, in this way, highlights potential points of intervention for the development of efficient therapeutic alternatives.