Secukinumab and Dead Sea Climatotherapy Impact Resolved Psoriasis Skin Differently Potentially Affecting Disease Memory.

Secukinumab and Dead Sea treatment result in clear skin for many psoriasis patients, through distinct mechanisms. However, recurrence in the same areas after treatments suggests the existence of a molecular scar. We aimed to compare the molecular and genetic differences in psoriasis patients who achieved complete response from secukinumab and Dead Sea climatotherapy treatments. We performed quantitative immunohistochemical and transcriptomic analysis, in addition to digital spatial profiling of skin punch biopsies. Histologically, both treatments resulted in a normalization of the lesional skin to a level resembling nonlesional skin. Interestingly, the transcriptome was not normalized by either treatments. We revealed 479 differentially expressed genes between secukinumab and Dead Sea climatotherapy at the end of treatment, with a psoriasis panel identifying SERPINB4, SERPINB13, IL36G, IL36RN, and AKR1B10 as upregulated in Dead Sea climatotherapy compared with secukinumab. Using digital spatial profiling, pan-RAS was observed to be differentially expressed in the microenvironment surrounding CD103+ cells, and IDO1 was differentially expressed in the dermis when comparing the two treatments. The differences observed between secukinumab and Dead Sea climatotherapy suggest the presence of a molecular scar, which may stem from mechanistically different pathways and potentially contribute to disease recurrence. This may be important for determining treatment response duration and disease memory.

Method for high-plex analysis of immune cells in human skin using the GeoMx system.

Specific T cell populations in the skin have been demonstrated as important disease drivers in several dermatoses. Due to the unique skin architecture, these cells are not grouped together in structures but dispersedly spread out throughout the epidermis. Following tissue disruption and isolation, only about 10% of skin T cells are recovered and any in vitro expansion may alter their bona fide phenotype. The Nanostring GeoMx system was developed to address cellular phenotype and protein expression in a tissue spatial context. To do so, regions of interest (ROI) must exceed a certain area threshold (usually 100 µm in diameter) to generate a sufficient signal-to-noise ratio. Here, we present an approach that allows for the pooling of numerous smaller ROIs within the skin, enabling T cell and melanocyte phenotyping. Skin samples from healthy individuals and vitiligo patients were analysed using the GeoMx system and several immune profiling panels. A sufficient signal-to-noise ratio was achieved by pooling smaller ROIs and analysing them as a single group. While this prevents spatial analysis, this method allows for detailed analysis of cells as a population in the context of their physiological environment, making it possible to investigate in situ phenotype of rare cells in different tissue compartments.

A skewed pool of resident T cells triggers psoriasis-associated tissue responses in never-lesional skin from patients with psoriasis.

BACKGROUND: Resident T cells are implicated in the maintenance and recurrence of psoriatic lesions. Whether skin that has not yet experienced psoriasis in patients with established disease harbors pathogenic T cells is less investigated. OBJECTIVE: We sought to analyze the composition of resident T cells and T cell-driven tissue responses in skin never affected by psoriasis from patients with mild disease. METHODS: Never-lesional skin from patients with psoriasis (NLP) was collected from those with mild disease. T-cell profiles were assessed by using confocal imaging and flow cytometry. Tissue responses to T-cell stimulation were measured by using multiplex and NanoString technology. RESULTS: T-cell activation ex vivo triggered psoriasiform and type I interferon tissue responses in NLP psoriasis. Accordingly, keratinocytes from NLP responded to IFN-γ stimulation with myxovirus 1 (MX1) expression and IFN-α release. Additionally, CCR6-expressing resident T cells poised to produce IFN-γ and IL-17 were enriched in epidermis from NLP, whereas dermal tissue responses and T-cell compositions were similar to those in healthy skin. Finally, keratinocytes from NLP exposed to IL-17 and skin explants exposed to common fungal antigens responded with upregulation of the CCR6 ligand CCL20. CONCLUSION: Epidermal resident T cells capable of triggering psoriasiform tissue responses accumulate in epidermis from NLP. Our global analysis of NLP reveals that microbial interplay with genetically predisposed keratinocytes might shape the local pool of resident T cells.

Multimodality treatment by FOLFOX plus HIFU in a case of advanced pancreatic carcinoma. A case report.

CONTEXT: Pancreatic cancer is one of the most aggressive malignant diseases in which the survival rate has not improved in the past 40 years. CASE REPORT: A fifty-one-year-old male patient with inoperable metastatic pancreatic cancer and low response to chemotherapy with gemcitabine as single therapy underwent palliative high intensity focused ultrasound (HIFU) ablation. Continuing chemotherapy with folinic acid, oxaliplatin and 5-fluorouracil (FOLFOX) was made. Tools, provided by the European Organization for Research and Treatment of Cancer (EORTC) were used to evaluate his quality of life. The Global Health Status improved from 25 to 42 out of 100 and the body mass index (BMI) increased from 14.9 to 18.1 kg/m(2). Measured by the visual analog scale, the pain was reduced from 7 to 2 out of 10. Twelve months after the HIFU ablation, CT revealed decreased size of the tumor and liver lesions. CONCLUSION: FOLFOX plus interventional, physical destruction of the primary tumor by HIFU sufficiently improved the quality of life, reduced pancreatic pain and provided better survival in this case.