Incidence and severity of immune-related hepatitis after dual checkpoint therapy is linked to younger age independent of herpes virus immunity.

BACKGROUND AND AIMS: Dual immune checkpoint blockade (ICB) therapy can result in immune-related-adverse events (irAE) such as ICB-hepatitis. An expansion of effector-memory (TEM) CD4 T cells associated with antiviral immunity against herpesviridae was implicated in ICB-hepatitis. Notably, these memory subsets are frequently associated with age. Here, we sought to understand baseline patient, immune and viral biomarkers associated with the development of ICB-hepatitis to identify currently lacking baseline predictors and test if an expansion of TEM or positive serology against herpesviridae can predict ICB-hepatitis. METHODS: A discovery (n = 39) and validation cohort (n = 67) of patients with advanced melanoma undergoing anti-PD-1&anti-CTLA4 combination therapy (total n = 106) were analyzed for baseline clinical characteristics, occurrence of irAE and oncological outcomes alongside serological status for CMV, EBV and HSV. Immune populations were profiled by high-parametric flow cytometry (n = 29). RESULTS: ICB-hepatitis occurred in 59% of patients within 100 days; 35.9% developed severe (CTCAE 3-4) hepatitis. Incidence of ICB-hepatitis was higher in the younger (< 55y: 85.7%) compared to older (> = 55y: 27.8%) age group (p = 0.0003), occured earlier in younger patients (p < 0.0001). The association of younger age with ICB-Hepatitis was also observed in the validation cohort (p = 0.0486). Incidence of ICB-hepatitis was also associated with additional non-hepatic irAE (p = 0.018), but neither positive IgG serostatus for CMV, EBV or HSV nor TEM subsets despite an association of T cell subsets with age. CONCLUSION: Younger age more accurately predicts ICB-hepatitis after anti-PD-1&anti-CTLA4 checkpoint therapy at baseline compared to herpes virus serology or TEM subsets. Younger patients should be carefully monitored for the development of ICB-hepatitis.

Small-Vessel Vasculitis After ST-Segment Elevation Myocardial Infarction: Clopidogrel or Amiodarone?

We report a case of cutaneous small-vessel vasculitis in a patient treated with clopidogrel after an ST-segment elevation myocardial infarction and with amiodarone caused by persistent atrial fibrillation 6 weeks before. (Level of Difficulty: Intermediate.).

Occurrence of autoantibodies against skin proteins in patients with hereditary epidermolysis bullosa predisposes to development of autoimmune blistering disease.

Skin blistering disorders are associated with inherited defects in proteins involved in the dermal-epidermal adhesion or autoantibodies targeting those proteins. Although blistering in hereditary epidermolysis bullosa (EB) is pathogenetically linked to genetic deficiency of distinct proteins of the epidermis or the dermal-epidermal junction, circulating autoantibodies against these proteins have also been identified in EB patients. So far, autoantibodies have been considered bystanders in EB and active pathogenicity of them in EB has not been disclosed. In sera of a cohort of 258 EB patients, we found by ELISA in 22% of the patients autoantibodies against the bullous pemphigoid antigen BP180. The titers correlated negatively with collagen VII skin expression and positively with disease severity. Among those patients, we identified six (2.33%) with clinical features of an autoimmune bullous disorder (AIBD) and positive indirect immunofluorescence (IIF) staining. In literature, we found four more cases of EB patients developing disease-aggravating AIBD. Co-existence of these two rare skin disorders suggests that EB patients have a predisposition for the development of AIBD. Our work highlights that EB patients with increased itch or blister formation should be evaluated for additional AIBD and repeated screening for changes in autoantibody titers and skin-binding specificities is advised.

eHealth Literacy in German Skin Cancer Patients.

The global incidence of skin cancer has steadily increased in recent years, and malignant melanoma still has one of the fastest-growing incidence rates among all malignant tumors in the western world. Thus, newly diagnosed patients have an increased need for health information concerning their disease. Using a standardized questionnaire, our study aims to investigate our patients' primary sources of health-related information as well as their self-proclaimed eHealth literacy. We received 714 questionnaires. Regardless of age, the primary source of information was the treating dermato-oncologist, followed by the treating general practitioner and the Internet. However, with increasing age, the usage of the Internet decreased. Hence, younger participants were better equipped to find health-related information while using the Internet. Additionally, comprehending health-related information and gaining medical knowledge was significantly increased in better-educated participants. Overall, our study shows that with increased use of eHealth services, accessing web-based information increased, correlating with a better eHealth literacy of our patients. eHealth technologies are increasingly becoming more prevalent as a primary source of information in our modern health care system. Thus, it is crucial to educate cancer patients in eHealth literacy to make autonomous, informed decisions and gain more confidence in dealing with their disease.

Additive Intralesional Interleukin-2 Improves Progression-Free Survival in a Distinct Subgroup of Melanoma Patients with Prior Progression under Immunotherapy.

A considerable amount of melanoma patients show primary resistance to PD-1 and CTLA-4 inhibitors. We have previously reported a beneficial role of intralesional Interleukin-2 (IL-2) in 9 melanoma patients developing new locoregional metastases under immunotherapy. We have now expanded this retrospective cohort to 27 patients. Patients were evaluated for their tumor characteristics, treatment response and progression-free and overall survival (PFS/OS). In 16 patients, tumor biopsies before and under IL-2 treatment were evaluated for immune markers. The median follow-up time was 16 (1-59) months from start of IL-2 treatment. Treatment response of locoregional metastases was seen in 74% of all patients and response of distant organ metastases in 37% of stage IV patients, respectively. A prolonged PFS and OS was significantly associated with absence of active distant metastases (p = 0.008), response of locoregional metastases (p = 0.002), increase of absolute eosinophil count (AEC) (p < 0.001) and an influx of CD8+ tumor infiltrating lymphocytes (TILs) (p = 0.003). Additional intralesional treatment with IL-2 in patients with locoregional progression under immunotherapy is a well-tolerated, easily feasible therapeutic option especially in patients lacking active distant metastases. A careful patient selection can lead to an improved PFS and OS.

Is there an overtreatment of melanoma patients at the end of their life? Results of a multicenter study on 193 melanoma patients.

BACKGROUND AND OBJECTIVES: There is a lack of data regarding the situation of melanoma patients receiving systemic therapies in their last months of life. PATIENTS AND METHODS: All melanoma patients who died in 2016 or 2017 and who had been treated by systemic therapies within the last three months of life were retrospectively analyzed. The study was conducted within the Committee "supportive therapy" of the Work Group Dermatological Oncology (ADO). RESULTS: 193 patients from four dermato-oncological centers were included. More than 60 % of the patients had ECOG ≥ 2 and most of them received immune checkpoint inhibitors (ICI) or targeted therapies (TT). 41 patients benefited from the last therapy in terms of radiological and laboratory findings or state of health. Although ECOG was worse in the TT cohort compared to the ICI group, the proportion of patients benefiting from the last therapy with TT was significantly higher and TT therapy could be carried out more often on an outpatient basis. CONCLUSIONS: This study indicates that there is a tendency towards an overtreatment at the end of life. Nevertheless, TT might be a reasonable therapeutic option for advanced BRAF mutant melanoma, even in highly palliative situations.

Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone.

Systemic immunotherapy with PD-1 inhibitors is established in the treatment of metastatic melanoma. However, up to 60% of patients do not show long-term benefit from a PD-1 inhibitor monotherapy. Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases. Combination therapy of systemic and local immunotherapies is a promising treatment option in melanoma patients. We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4+ and CD8+ T cells and a higher PD-1 expression in the inflammatory infiltrate of the tumor microenvironment in metastases from patients with subsequent treatment response. All responding patients further showed a profound increase of the absolute eosinophil count (AEC) in the blood. Our case series supports the concept that patients with initial resistance to PD-1 inhibitor therapy and injectable lesions can profit from an additional intralesional IL-2 therapy which was well tolerated. Response to this therapy is accompanied by increase in AEC and a strong T cell-based inflammatory infiltrate.

Activation of neutrophils by Chlamydia trachomatis-infected epithelial cells is modulated by the chlamydial plasmid.

The obligate intracellular bacterium Chlamydia trachomatis is the most common bacterial agent of sexually transmitted disease world-wide. Chlamydia trachomatis primarily infects epithelial cells of the genital tract but the infection may be associated with ascending infection. Infection-associated inflammation can cause tissue damage resulting in female infertility and ectopic pregnancy. The precise mechanism of inflammatory tissue damage is unclear but earlier studies implicate the chlamydial cryptic plasmid as well as responding neutrophils. We here rebuilt the interaction of Chlamydia trachomatis-infected epithelial cells and neutrophils in-vitro. During infection of human (HeLa) or mouse (oviduct) epithelial cells with Chlamydia trachomatis, a soluble factor was produced that attracted neutrophils and prolonged neutrophil survival, independently of Toll-like receptor signaling but dependent on the chlamydial plasmid. A number of cytokines, but most strongly GM-CSF, were secreted at higher amounts from cells infected with plasmid-bearing, compared to plasmid-deficient, bacteria. Blocking GM-CSF removed the secreted pro-survival activity towards neutrophils. A second, neutrophil TNF-stimulatory activity was detected in supernatants, requiring MyD88 or TRIF independently of the plasmid. The results identify two pro-inflammatory activities generated during chlamydial infection of epithelial cells and suggest that the epithelial cell, partly through the chlamydial plasmid, can initiate a myeloid immune response and inflammation.