Pain during photodynamic therapy (PDT) is the main limiting adverse effect in its use in dermatology. Given its multifactorial nature, we reviewed both intrinsic and extrinsic factors that are involved in PDT pain. We propose a threshold theory for pain experience in PDT: it correlates positively with fluence rate and dose below a certain threshold (rate of ~60 mW cm , dose of ~50 J cm ); when the threshold is surpassed, pain intensity saturates. Additionally, we carefully compared recent updates on pain management strategies and we suggest that cold-air analgesia and low-irradiance light sources (such as variable pulsed light and daylight PDT) represent the current best analgesic options. Finally, we discuss the possible mechanisms of pain experience during PDT. Reactive oxygen species, transient receptor potential channels and inflammatory responses are key mediators in pain. Further investigation into these pathways should help with the development of more effective analgesic strategies. Taking these points together, for pain management in PDT, an individualized plan of analgesia is possible.

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United States Cutaneous T cell lymphoma (CTCL) is a devastating malignancy of the skin for which the standard treatments are suboptimal. Immunotherapy is a new treatment paradigm, and two promising agents for CTCL include brentuximab (anti-CD30) and pembrolizumab (anti-PD-1). While clinical trials have shown that many CTCL patients achieve durable responses on these treatments, for unclear reasons about one third of patients experience rapidly progressive disease. Given the potential for negative outcomes and the high costs of immunotherapy, it is critical to find predictive biomarkers that enable stratification of CTCL patients into responders and non-responders prior to initiating immunotherapy. Here, we use CO-Detection by antibody indEXing (CODEX), a novel multiparameter imaging tool to interrogate the CTCL microenvironment in response to immunotherapy in matched pre-and post-treatment skin biopsies. Formalin-fixed, paraffin-embedded tissue sections are stained with a cocktail of 50+ DNA-conjugated antibodies and imaged in a multi-cycle reaction using a microfluidics system and fluorescence microscope. In each cycle, three antibodies are rendered visible using complementary florescent DNA probes, followed by imaging, probe stripping, washing and re-rendering until all antibodies are imaged. The CTCL antibody panel contains markers for tumor cells, immune cells (T cells, B cells, NK cells, macrophages, etc.), immunoregulation, vasculature, stroma, extracellular matrix. Results highlight the importance of macrophages and immune checkpoint/activation markers in dictating CTCL response to brentuximab and pembrolizumab. Additionally, key cell-to-cell interactions, cellular neighborhoods and tissue architecture maps of the CTCL microenvironment have been revealed. In sum, CODEX allows us to create a single cell map of intact CTCL tissue and discover novel, predictive biomarkers of immunotherapy response, which will enable the broad leveraging of new CTCL treatments. 111Systemic chemotherapy promotes HIF-1a mediated glycolysis and IL-17F pathways in mycosis fungoides Systemic chemotherapy is often the last resort of advanced Mycosis Fungoides (MF). Tumor reoccurrence and adverse effects of systemic chemotherapy are the main limitations. We aim to investigate the metabolic alterations in tumor cells after CHOP chemotherapy. In patients with advanced MF, CHOP chemotherapy has no survival benefit and the duration of response is significantly inferior to other canonical treatments. HIF-1a is significantly elevated in lesions of advanced MF patients as well as tumor cell line Hut78 and tumor xenograft mice model (p<0.01, 0.05 and 0.05 respectively). CHOP therapy also increased glycolytic activities in a HIF-1a-dependent manner. In xenograft tumor mice model, lesional cells showed a significant increase in IL-17F after chemotherapy (p<0.05), shifting towards a Th17 phenotype, which process is also regulated by HIF-1a. Echinomycin, HIF-1a inhibitor, was coadministered in xenograft tumor mouse models with CHOP and showed a ...

Fragrances are common contact sensitizers, many of which are prohaptens that undergo metabolic activation to a reactive hapten needed to produce a complete antigen. The cutaneous metabolom of the fragrance C was analyzed by HR-MAS NMR (High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance) following its topical application to a 3D human skin equivalent. Identified metabolites of C were 1,2 benzoquinone-hapten-proteinadduct, another up to now unidentified hapten-protein-adduct and formaldehyde by demethylation of C. To clarify the role of cutaneous CYPs we used a modified KeratinoSensÒassay. The addition of single CYP cocktails or CYP-containing microsomes for prohapten bioactivation is highly cytotoxic. This has led to the use of rat liver cytosol whose CYPs differ from those present in human skin .We spiked rat liver cytosol with human cutaneous CYPs and measured the activation of NRF2 in KeratinoSensÒ by the Luciferase assay and cytotoxicity by the MTT-assay. Cinnamic aldehyde served as a positive control since it does not require metabolic activation and SDS was used as an irritant control. Addition of C to the mixture of cytosol-human cutaneous CYPs strongly activated NRF2. Heat inactivated mixtures and preparations containing cytosol alone showed no reactivity. Thus C is a prohapten that undergoes metabolic activation to hapten-protein adducts catalyzed by CYP-isoenzymes present in human skin.