Expression of DNA mismatch repair proteins in melanoma patients treated with immune checkpoint inhibitors.

PURPOSE: To investigate the protein expression of DNA mismatch repair (MMR) proteins in patients with cutaneous melanoma (CM) under immune checkpoint inhibitor (ICI) therapy. METHODS: Immunohistochemistry was performed on tumor tissue for MMR proteins MLH1, MSH2, MSH6, and PMS2 in 50 metastatic CM patients treated with ICI (ipilimumab, nivolumab, pembrolizumab). RESULTS: Best overall response (BOR) rate was 48% (24/50). Reduced MMR protein expression (nuclear expression in < 80% of tumor cells) was observed in 8 patients (16%). Compared to other clinical parameters, baseline neutrophil/lymphocyte ratio and reduced intratumoral MMR protein expression (P = 0.0033) were determined as the only parameters significantly associated with favorable BOR. However, in this small study population, reduced MMR protein expression did not reach statistical significance in multivariate analysis. CONCLUSION: Reduced MMR protein expression is observed in CM and might predict favorable BOR in patients treated with ICI, as was observed for other entities. However, these findings need to be substantiated in larger patient cohorts.

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.

Comparison of systemic and intrarenal converting enzyme inhibition by MK-422 on renal hemodynamics in conscious dogs.

The purpose of this study was to compare the effect of intrarenal angiotensin converting enzyme (ACE) inhibition with that of systemic ACE inhibition in conscious, instrumented dogs. Intrarenal ACE inhibition was achieved by infusing the potent ACE inhibitor MK-422 into the renal artery in a dose (0.32 micrograms/kg/min) that in dogs fed a normal sodium (n = 11) and low sodium (n = 10) diet markedly attenuated the renal blood flow response to intrarenal arterial angiotensin I (0.4 and 0.8 micrograms, respectively). Intrarenal arterial infusion of MK-422 decreased the responses by 76 and 72% in the normal and low sodium groups, respectively, but only decreased renal vascular resistance slightly (-9 and -8%, respectively) in the infused kidney. Following termination of intrarenal arterial infusion of MK-422, the inhibitor was administered intravenously, 0.2 mg/kg. This dose of MK-422 maximally inhibited systemic ACE, as evidenced by the complete abolition of the renal blood flow response to intravenous angiotensin I; the responses were decreased by 95 and 96% in the normal and low sodium groups, respectively. In contrast to the negligible reduction in renal vascular resistance seen during intrarenal arterial infusion of MK-422, systemically administered inhibitor decreased renal vascular resistance by 16 and 39%, respectively, in the normal and low sodium groups. These results lend additional support to our contention that systemically rather than intrarenally formed angiotensin II is mainly responsible for regulation of renal vascular resistance.