BackgroundSkin cancers are known for their strong immunogenicity, which may contribute to a high treatment efficacy of immune checkpoint inhibition (ICI). However, a considerable proportion of patients with skin cancer is immuno-compromised by concomitant diseases. Due to their previous exclusion from clinical trials, the ICI treatment efficacy is poorly investigated in these patients. The present study analyzed the ICI treatment outcome in advanced patients with skin cancer with a concomitant hematological malignancy.MethodsThis retrospective multicenter study included patients who were treated with ICI for locally advanced or metastatic melanoma (MM), cutaneous squamous cell carcinoma (cSCC), or Merkel cell carcinoma (MCC), and had a previous diagnosis of a hematological malignancy irrespective of disease activity or need of therapy at ICI treatment start. Comparator patient cohorts without concomitant hematological malignancy were extracted from the prospective multicenter skin cancer registry ADOREG. Treatment outcome was measured as best overall response, progression-free (PFS), and overall survival (OS).Results84 patients (MM, n=52; cSCC, n=15; MCC, n=17) with concomitant hematological malignancy were identified at 20 skin cancer centers. The most frequent concomitant hematological malignancies were non-Hodgkin’s lymphoma (n=70), with chronic lymphocytic leukemia (n=32) being the largest entity. While 9 patients received ICI in an adjuvant setting, 75 patients were treated for advanced non-resectable disease (55 anti-PD-1; 8 anti-PD-L1; 5 anti-CTLA-4; 7 combinations). In the latter 75 patients, best objective response (complete response+partial response) was 28.0%, disease stabilization was 25.3%, and 38.6% showed progressive disease (PD). Subdivided by skin cancer entity, best objective response was 31.1% (MM), 26.7% (cSCC), and 18.8% (MCC). Median PFS was 8.4 months (MM), 4.0 months (cSCC), and 5.7 months (MCC). 1-year OS rates were 78.4% (MM), 65.8% (cSCC), and 47.4% (MCC). Comparison with respective ADOREG patient cohorts without hematological malignancy (n=392) revealed no relevant differences in ICI therapy outcome for MM and MCC, but a significantly reduced PFS for cSCC (p=0.002).ConclusionsICI therapy showed efficacy in advanced patients with skin cancer with a concomitant hematological malignancy. Compared with patients without hematological malignancy, the observed ICI therapy outcome was impaired in cSCC, but not in MM or MCC patients.

It is textbook knowledge that human infective forms of Trypanosoma brucei, the causative agent of sleeping sickness, enter the brain across the blood-brain barrier after an initial phase of weeks (rhodesiense) or months (gambiense) in blood. Based on our results using an animal model, both statements seem questionable. As we and others have shown, the first infection relevant crossing of the blood brain border occurs via the choroid plexus, i.e. via the blood-CSF barrier. In addition, counting trypanosomes in blood-free CSF obtained by an atlanto-occipital access revealed a cyclical infection in CSF that was directly correlated to the trypanosome density in blood infection. We also obtained conclusive evidence of organ infiltration, since parasites were detected in tissues outside the blood vessels in heart, spleen, liver, eye, testis, epididymis, and especially between the cell layers of the pia mater including the Virchow-Robin space. Interestingly, in all organs except pia mater, heart and testis, trypanosomes showed either a more or less degraded appearance of cell integrity by loss of the surface coat (VSG), loss of the microtubular cytoskeleton and loss of the intracellular content, or where taken up by phagocytes and degraded intracellularly within lysosomes. This is also true for trypanosomes placed intrathecally into the brain parenchyma using a stereotactic device. We propose a different model of brain infection that is in accordance with our observations and with well-established facts about the development of sleeping sickness.

Background Cutaneous squamous cell carcinoma (cSCC) is one of the most common types of cancer in the Caucasian population, with an increasing incidence. cSCC is mostly a local invasive disease that can be treated surgically in the majority of the cases. However, in the case of advanced cSCC (acSCC), a multimodality approach also involving systemic therapies needs to be considered.Methods One hundred and ninety-five patients diagnosed with acSCC (stages III and IV) treated in our centre between 2011 and 2018 were included. Patient and tumour characteristics along with treatment patterns were documented and analyzed. Descriptive analysis was performed and survival rates were estimated according to Kaplan-Meier and compared with the Log-rank test. Follow-up was defined as the time between diagnosis of advanced disease and last contact or death. All causes of death were considered as events. ResultsThe median follow-up was 21 months [IQR = (10.0; 21.0)]. The median age at time of advanced disease diagnosis was 78 years [IQR = (72; 84)], with 40.5% of the patients in stage III and 59.5% in stage IV. One hundred and forty-five patients had resectable tumours. In this group the median overall survival (mOS) was 59 months (95% CI:28.2-89.8), significantly higher than the mOS in patients with inoperable tumour [n = 50; mOS: 19 months (96% CI: 7-31, P <0.0001)]. Patients receiving immunotherapy (n = 20) showed a statistically significant better survival compared to those treated with other systemic therapies (n = 37; mOS not reached vs. mOS: 22 months (95% CI: 6.5-43.5), P = 0.034). For patients without systemic therapy, a combination of surgery and radiotherapy provided better outcomes compared to radiotherapy alone or best supportive care (P <0.001).Conclusion Surgical complete resection should be the first therapeutic option for patients with acSCC. For patients with inoperable tumour, first-line immunotherapy should be preferably considered.

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