Der Glutathion S-Transferase T1 Genotyp als Biomarker für Lymphopenien bei Psoriasis-Patienten unter Fumarsäureester-Behandlung

Glutathion S-Transferasen sind an der Detoxifikation von Xenobiotika wie z. B. Fumaraten beteiligt. Es erfolgte die Analyse des Geno- und des Phänotyps von Glutathion S-Transferase T1 (GSTT1) bei Patienten mit Psoriasis vulgaris, die mit Fumarsäureestern behandelt werden, um herauszufinden, ob zum einen der Responder-Status und zum anderen das Auftreten von Nebenwirkungen mit allelischen Varianten und enzymatischer Aktivität von GSTT1 auftreten. Es wurden hierfür 106 Psoriasis Patienten, welche mit Fumarsäureestern behandelt wurden, in die Studie eingeschlossen. Ein Ansprechen auf eine systemische Therapie mit Fumaraten ist nicht abhängig vom GSTT1-Status. Jedoch stellte sich erstmalig der homozygote GSTT1 Status als ein Prädiktor für das vermehrte Auftreten von Lymphozytopenien während der Fumarsäure-Therapie heraus. Darüber hinaus kann durch die Therapie mit Fumaraten eine gesteigerte GSTT1-Enzym-Aktivität hervorgerufen werden

Phenotypic plasticity of malignant T cells in blood and skin of a Sézary syndrome patient revealed by single cell transcriptomics

$\bf Background:$ Sézary Syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphomas (CTCL). In SS patients, malignant T cells are circulating through the blood and cause erythroderma. $\bf Objective:$ To compare the transcriptome of single cells in blood and skin samples from a patient with advanced SS. $\bf Methods:$ We utilized combined single cell RNA and T-cell receptor (TCR) sequencing (scRNA-seq). $\bf Results:$ We scrutinized the malignant T cells in blood and skin in an unbiased manner without pre-sorting of cells. We observed different phenotypes of the same monoclonal malignant T-cell population, confirmed by TCR sequencing and inferred copy number variation analysis. Malignant T cells present in the circulating blood expressed genes resembling central memory T cells such as $\it CCR7$, $\it IL7R$ and $\it CD27$. In the skin, we detected two major malignant T-cell populations: One subpopulation was closely related to the malignant T cells from the blood, while the other subpopulation expressed genes reminiscent of skin resident effector memory T cells including $\it GZMB$ and $\it NKG7$. Pseudotime analysis indicated crucial transcriptomic changes in the transition of malignant T cells between blood and skin. These changes included the differential regulation of $\it TXNIP$, a putative tumor suppressor in CTCL, and the adaptation to the hypoxic conditions in the skin. Tumor cell proliferation in the skin was supported by stimulating interactions between myeloid cells and malignant T cells. $\bf Conclusions:$ Using scRNA-seq we detected a high degree of functional heterogeneity within the malignant T-cell population in SS and highlighted crucial differences between SS cells in blood and skin

The antineoplastic effect of dimethyl fumarate on virus-negative Merkel cell carcinoma cell lines

Merkel cell carcinoma (MCC) is a rare, difficult-to-treat skin cancer once immunotherapy has failed. MCC is associated either with the clonal integration of the Merkel cell polyomavirus (MCPyV) or mutagenic UV-radiation. Fumaric acid esters, including dimethyl fumarate (DMF), have been shown to inhibit cell growth in cutaneous melanoma and lymphoma. We aimed to explore the effects of DMF on MCPyV-negative MCC cell lines. Three MCC cell lines (MCC13, MCC14.2, and MCC26) were treated with different doses of DMF. The cytotoxic effects and cell proliferation were assessed by the MTT cytotoxicity assay and BrdU proliferation assay at different time points. A significant reduction in cell viability and proliferation were demonstrated for all the cell lines used, with DMF proving to be effective

Expression of mismatch repair proteins in Merkel cell carcinoma

We aimed to assess for the first time the mismatch repair (MMR) protein expression in Merkel cell carcinoma (MCC). Immunohistochemistry was performed for MLH1, MSH2, MSH6, and PMS2 on patients’ tumor tissue ($\it n$ = 56), including neighbored healthy control tissue. In cases with low-level MMR expression ( 0.05). MCC appears to be a malignancy characterized by low-level MMR rather than completely deficient MMR in a subset of cases, predominantly affecting MCPyV-negative tumors. Future studies will establish whether this subset of MCC patients respond better to immune checkpoint inhibitor therapy

Cancer and immune checkpoint inhibitor treatment in the era of SARS-CoV-2 infection

Whether cancer patients receiving immune checkpoint inhibitors (ICI) are at an increased risk of severe infection and mortality during the corona pandemic is a hotly debated topic that will continue to evolve. Here, we summarize and discuss current studies regarding COVID-19 and anti-cancer treatment with an emphasis on ICI. Importantly, several lines of evidence suggest that patients currently treated with ICI do not display an increased vulnerability to infection with SARS-CoV-2. Data regarding morbidity and mortality associated with COVID-19 in cancer patients receiving ICI are less clear and often conflicting. Although mostly based on experimental data, it is possible that ICI can promote the exacerbated immune response associated with adverse outcome in COVID-19 patients. On the other hand, mounting evidence suggests that ICI might even be useful in the treatment of viral infections by preventing or ameliorating T cell exhaustion. In this context, the right timing of treatment might be essential. Nevertheless, some cancer patients treated with ICI experience autoimmune-related side effects that require the use of immunosuppressive therapies, which in turn may promote a severe course of infection with SARS-CoV-2. Although there is clear evidence that withholding ICI will have more serious consequences, further studies are urgently needed in to better evaluate the effects of ICI in patients with COVID-19 and the use of ICI during the corona pandemic in general

Waiving subsequent complete lymph node dissection in melanoma patients with positive sentinel lymph node does not result in worse outcome on 20-year analysis

The aim of the present study was to investigate long-term outcomes of melanoma patients who had micrometastasis on sentinel lymph node (SLN) biopsy. We focused on the comparison between melanoma patients with and without complete lymph node dissection (CLND) following a positive SLN biopsy result. Patients without CLND did not significantly differ from patients with CLND in regard to age, gender, tumor thickness, tumor ulceration, capsule infiltration of SLN, and invasion level of SLN. On 10-year analysis, we did not observe a significantly increased risk for melanoma relapse or melanoma-specific death in patients who did not undergo CLND after the detection of micrometastases on SLN biopsy. On 20-year analysis, again, the patients without CLND had no significantly increased risk of melanoma relapse and worse melanoma-specific survival. Hence, our 10-year survival data confirm the current notion that waiving CLND in SLN-positive patients does not result in clinical disadvantages with respect to melanoma-specific survival. For the first time, we demonstrate on 20-year survival analysis that relapse rates and melanoma-specific survival does not significantly differ between patients with or without CLND on long-term follow-up