@article{GlutschSchummerKneitzetal.2022,
  author    = {Glutsch, Valerie and Schummer, Patrick and Kneitz, Hermann and Gesierich, Anja and Goebeler, Matthias and Klein, Detlef and Posch, Christian and Gebhardt, Christoffer and Haferkamp, Sebastian and Zimmer, Lisa and Becker, J{\"u}rgen C and Leiter, Ulrike and Weichenthal, Michael and Schadendorf, Dirk and Ugurel, Selma and Schilling, Bastian},
  title     = {Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG},
  series = {Journal for ImmunoTherapy of Cancer},
  volume    = {10},
  journal   = {Journal for ImmunoTherapy of Cancer},
  number    = {11},
  issn      = {2051-1426},
  doi       = {10.1136/jitc-2022-005930},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304613},
  year      = {2022},
  abstract  = {Merkel cell carcinoma is a rare, highly aggressive skin cancer with neuroendocrine differentiation. Immune checkpoint inhibition has significantly improved treatment outcomes in metastatic disease with response rates to programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibition of up to 62\%. However, primary and secondary resistance to PD-1/PD-L1 inhibition remains a so far unsolved clinical challenge since effective and safe treatment options for these patients are lacking.Fourteen patients with advanced (non-resectable stage III or stage IV, Union international contre le cancer 2017) Merkel cell carcinoma with primary resistance to the PD-L1 inhibitor avelumab receiving subsequent therapy (second or later line) with ipilimumab plus nivolumab (IPI/NIVO) were identified in the prospective multicenter skin cancer registry ADOREG. Five of these 14 patients were reported previously and were included in this analysis with additional follow-up. Overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events were analyzed.All 14 patients received avelumab as first-line treatment. Thereof, 12 patients had shown primary resistance with progressive disease in the first tumor assessment, while two patients had initially experienced a short-lived stabilization (stable disease). Six patients had at least one systemic treatment in between avelumab and IPI/NIVO. In total, 7 patients responded to IPI/NIVO (overall response rate 50\%), and response was ongoing in 4 responders at last follow-up. After a median follow-up of 18.85 months, median PFS was 5.07 months (95\% CI 2.43—not available (NA)), and median OS was not reached. PFS rates at 12 months and 24 months were 42.9\% and 26.8 \%, respectively. The OS rate at 36 months was 64.3\%. Only 3 (21\%) patients did not receive all 4 cycles of IPI/NIVO due to immune-related adverse events.In this multicenter evaluation, we observed high response rates, a durable benefit and promising OS rates after treatment with later-line combined IPI/NIVO. In conclusion, our patient cohort supports our prior findings with an encouraging activity of second-line or later-line IPI/NIVO in patients with anti-PD-L1-refractory Merkel cell carcinoma.},
  language  = {en}
}
@article{StrobelSickenbergerSchoenetal.2022,
  author    = {Strobel, Katharina and Sickenberger, Christina and Schoen, Christoph and Kneitz, Hermann and Kolb-M{\"a}urer, Annette and Goebeler, Matthias},
  title     = {Diagnosis and therapy of Mycobacterium marinum: a single-center 21-year retrospective analysis},
  series = {Journal der Deutschen Dermatologischen Gesellschaft},
  volume    = {20},
  journal   = {Journal der Deutschen Dermatologischen Gesellschaft},
  number    = {9},
  doi       = {10.1111/ddg.14847},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318428},
  pages     = {1211 -- 1218},
  year      = {2022},
  abstract  = {Background and Objectives In Europe, infections with Mycobacterium (M.) marinum are rare. We conducted a retrospective single-center study to assess the clinical spectrum of M. marinum infection and its diagnosis, treatment and outcome under real-world conditions. Patients and Methods Eighteen patients presenting with M. marinum infections between 1998 and 2018 were identified in the data warehouse of the University Hospital W{\"u}rzburg and considered for detailed analysis. Results Twelve patients reported aquatic exposure. In 16/18 cases the upper extremities were affected. No invasive infections were detected. Mean time to diagnosis was 15 weeks. Histology revealed granulomatous inflammation in 14 patients while mycobacterial cultures were positive for M. marinum in 16 cases. Most patients received antibiotic monotherapy (14/18) while combination therapy was administered in four cases. Treatment (with a median duration of 10 weeks) was successful in 13 patients. Five patients were lost to follow-up. Conclusions Our retrospective analysis of M. marinum infections at a German tertiary referral center revealed a considerable diagnostic delay and the relevance of microbiological culture, PCR and histology for diagnosis. Monotherapy with clarithromycin (rather than doxycycline) appeared as a reasonable treatment option while immunosuppressed or -compromised patients and those with extended disease received combination therapy.},
  language  = {en}
}
@article{GlutschWobserSchillingetal.2022,
  author    = {Glutsch, Valerie and Wobser, Marion and Schilling, Bastian and Gesierich, Anja and Goebeler, Matthias and Kneitz, Hermann},
  title     = {PRAME expression as helpful immunohistochemical marker in rhabdoid melanoma},
  series = {Dermatopathology},
  volume    = {9},
  journal   = {Dermatopathology},
  number    = {2},
  issn      = {2296-3529},
  doi       = {10.3390/dermatopathology9020019},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284115},
  pages     = {148 -- 157},
  year      = {2022},
  abstract  = {Background: Rhabdoid melanoma is a rare variant of malignant melanoma with characteristic cytomorphologic features. Due to the potential loss of conventional melanocytic markers, histopathologic diagnosis is often challenging. We hypothesize that immunostaining for PReferentially expressed Antigen in MElanoma (PRAME) might have the potential to uncover the melanocytic origin of these dedifferentiated tumors. Methods: Four cases of rhabdoid primary melanomas were assessed by immunohistochemistry for expression of PRAME and conventional melanocytic markers. Immunohistochemical expression patterns were analyzed in the rhabdoid primaries and, if available, associated metastases. Results: All four cases of rhabdoid primary melanomas showed a strong nuclear positivity for PRAME, while the expression of conventional melanocytic markers S100, MART-1, SOX-10 and HMB-45 was variable between the analyzed cases. Conclusions: In summary, we report four cases of rhabdoid primary melanoma with high to intermediate expression of PRAME despite the partial and variable loss of other melanocytic markers. Hence, PRAME might facilitate the recognition of this highly aggressive entity to avoid misdiagnosis due to histopathologic pitfalls.},
  language  = {en}
}
@article{KneitzRoseGlutschetal.2022,
  author    = {Kneitz, Hermann and Rose, Christian and Glutsch, Valerie and Goebeler, Matthias},
  title     = {Recurrence of a cellular blue nevus with satellitosis — a diagnostic pitfall with clinical consequences},
  series = {Dermatopathology},
  volume    = {9},
  journal   = {Dermatopathology},
  number    = {4},
  issn      = {2296-3529},
  doi       = {10.3390/dermatopathology9040042},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297436},
  pages     = {361 -- 367},
  year      = {2022},
  abstract  = {Blue nevus is a benign melanocytic lesion, typically asymptomatic and of unknown etiology. Several histologic and clinical variants have been distinguished, the most frequent being common blue nevus, cellular blue nevus, and combined blue nevus. Although melanocytic nevi with a satellite lesion are usually suggestive of locally advanced malignant melanoma, very few cases of blue nevi with satellite lesions have been reported. The diagnosis of common or cellular blue nevi is generally straightforward; however, the presence of structures such as irregular edges or satellitosis are highly suggestive for malignancy, and differential diagnoses such as locally advanced malignant melanoma and malignant blue nevus should be considered. Recurrent blue nevi can display atypical features not seen in the primary lesion, such as pleomorphism and mitotic activity. They usually tend to follow a benign course; however, in some cases, recurrence may indicate malignant transformation. We here report the unique case of a 64-year-old woman with a recurrent cellular blue nevus accompanied by satellite lesions. Such a biological behavior resulting in a clinical presentation as a melanoma-like lesion is a rarity in blue nevus and has not been described before.},
  language  = {en}
}
@article{WobserSchummerAppenzelleretal.2022,
  author    = {Wobser, Marion and Schummer, Patrick and Appenzeller, Silke and Kneitz, Hermann and Roth, Sabine and Goebeler, Matthias and Geissinger, Eva and Rosenwald, Andreas and Maurus, Katja},
  title     = {Panel sequencing of primary cutaneous B-cell lymphoma},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {21},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14215274},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290330},
  year      = {2022},
  abstract  = {Background: Primary cutaneous follicular B-cell lymphoma (PCFBCL) represents an indolent subtype of Non-Hodgkin's lymphomas, being clinically characterized by slowly growing tumors of the skin and common cutaneous relapses, while only exhibiting a low propensity for systemic dissemination or fatal outcome. Up to now, only few studies have investigated underlying molecular alterations of PCFBCL with respect to somatic mutations. Objectives: Our aim was to gain deeper insight into the pathogenesis of PCFBCL and to delineate discriminatory molecular features of this lymphoma subtype. Methods: We performed hybridization-based panel sequencing of 40 lymphoma-associated genes of 10 cases of well-characterized PCFBCL. In addition, we included two further ambiguous cases of atypical B-cell-rich lymphoid infiltrate/B-cell lymphoma of the skin for which definite subtype attribution had not been possible by routine investigations. Results: In 10 out of 12 analyzed cases, we identified genetic alterations within 15 of the selected 40 target genes. The most frequently detected alterations in PCFBCL affected the TNFRSF14, CREBBP, STAT6 and TP53 genes. Our analysis unrevealed novel mutations of the BCL2 gene in PCFBCL. All patients exhibited an indolent clinical course. Both the included arbitrary cases of atypical B-cell-rich cutaneous infiltrates showed somatic mutations within the FAS gene. As these mutations have previously been designated as subtype-specific recurrent alterations in primary cutaneous marginal zone lymphoma (PCMZL), we finally favored the diagnosis of PCMZL in these two cases based on these molecular findings. Conclusions: To conclude, our molecular data support that PCFBCL shows distinct somatic mutations which may aid to differentiate PCFBCL from pseudo-lymphoma as well as from other indolent and aggressive cutaneous B-cell lymphomas. While the detected genetic alterations of PCFBCL did not turn out to harbor any prognostic value in our cohort, our molecular data may add adjunctive discriminatory features for diagnostic purposes on a molecular level.},
  language  = {en}
}
@article{GlutschKneitzGesierichetal.2021,
  author    = {Glutsch, Valerie and Kneitz, Hermann and Gesierich, Anja and Goebeler, Matthias and Haferkamp, Sebastian and Becker, J{\"u}rgen C. and Ugurel, Selma and Schilling, Bastian},
  title     = {Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma},
  series = {Cancer Immunology, Immunotherapy},
  volume    = {70},
  journal   = {Cancer Immunology, Immunotherapy},
  number    = {7},
  issn      = {14320851},
  doi       = {10.1007/s00262-020-02832-0},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265635},
  pages     = {2087-2093},
  year      = {2021},
  abstract  = {Background Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cutaneous malignancy with poor prognosis. In Europe, approved systemic therapies are limited to the PD-L1 inhibitor avelumab. For avelumab-refractory patients, efficient and safe treatment options are lacking. Methods At three different sites in Germany, clinical and molecular data of patients with metastatic MCC being refractory to the PD-L1 inhibitor avelumab and who were later on treated with combined IPI/NIVO were retrospectively collected and evaluated. Results Five patients treated at three different academic sites in Germany were enrolled. Three out of five patients investigated for this report responded to combined IPI/NIVO according to RECIST 1.1. Combined immunotherapy was well tolerated without any grade II or III immune-related adverse events. Two out of three responders to IPI/NIVO received platinum-based chemotherapy in between avelumab and combined immunotherapy. Conclusion In this small retrospective study, we observed a high response rate and durable responses to subsequent combined immunotherapy with IPI/NIVO in avelumab-refractory metastatic MCC patients. In conclusion, our data suggest a promising activity of second- or third-line PD-1- plus CTLA-4-blockade in patients with anti-PD-L1-refractory MCC.},
  language  = {en}
}
@article{FringsGoebelerSchillingetal.2021,
  author    = {Frings, Verena Gerlinde and Goebeler, Matthias and Schilling, Bastian and Kneitz, Hermann},
  title     = {Aberrant cytoplasmic connexin43 expression as a helpful marker in vascular neoplasms},
  series = {Journal of Cutaneous Pathology},
  volume    = {48},
  journal   = {Journal of Cutaneous Pathology},
  number    = {11},
  doi       = {10.1111/cup.14066},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258412},
  pages     = {1335-1341},
  year      = {2021},
  abstract  = {Background Gap junctions consisting of connexins (Cx) are fundamental in controlling cell proliferation, differentiation, and cell death. Cx43 is the most broadly expressed Cx in humans and is attributed an important role in skin tumor development. Its role in cutaneous vascular neoplasms is yet unknown. Methods Fifteen cases each of cutaneous angiosarcoma (cAS), Kaposi sarcoma (KS), and cherry hemangioma (CH) were assessed by immunohistochemistry for expression of Cx43. Expression pattern, intensity, and percentage of positively stained cells were analyzed. Solid basal cell carcinomas served as positive and healthy skin as negative controls. Results Most cases of cAS presented with a strong Cx43 staining of almost all tumor cells, whereas endothelia of KS showed medium expression and CH showed mostly weak expression. In comparison with KS or cAS, the staining intensity of CH was significantly lower (P ≤ 0.001). All tissue sections of both cAS and KS were characterized by a mostly diffuse, cytoplasmic staining pattern of the vascular endothelia. None of those showed nuclear staining. Conclusion The high-to-intermediate expression of Cx43 observed in all cases of cAS and KS suggests that this Cx may play a role in the development of malignant vascular neoplasms and serve as a helpful diagnostic marker.},
  language  = {en}
}
@article{HoeslFroehlichPoschetal.2021,
  author    = {Hoesl, Christine and Fr{\"o}hlich, Thomas and Posch, Christian and Kneitz, Hermann and Goebeler, Matthias and Schneider, Marlon R. and Dahlhoff, Maik},
  title     = {The transmembrane protein LRIG1 triggers melanocytic tumor development following chemically induced skin carcinogenesis},
  series = {Molecular Oncology},
  volume    = {15},
  journal   = {Molecular Oncology},
  number    = {8},
  doi       = {10.1002/1878-0261.12945},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238925},
  pages     = {2140 -- 2155},
  year      = {2021},
  abstract  = {The incidence of melanoma and nonmelanoma skin cancer has increased tremendously in recent years. Although novel treatment options have significantly improved patient outcomes, the prognosis for most patients with an advanced disease remains dismal. It is, thus, imperative to understand the molecular mechanisms involved in skin carcinogenesis in order to develop new targeted treatment strategies. Receptor tyrosine kinases (RTK) like the ERBB receptor family, including EGFR/ERBB1, ERBB2/NEU, ERBB3, and ERBB4, are important regulators of skin homeostasis and their dysregulation often results in cancer, which makes them attractive therapeutic targets. Members of the leucine-rich repeats and immunoglobulin-like domains protein family (LRIG1-3) are ERBB regulators and thus potential therapeutic targets to manipulate ERBB receptors. Here, we analyzed the function of LRIG1 during chemically induced skin carcinogenesis in transgenic mice expressing LRIG1 in the skin under the control of the keratin 5 promoter (LRIG1-TG mice). We observed a significant induction of melanocytic tumor formation in LRIG1-TG mice and no difference in papilloma incidence between LRIG1-TG and control mice. Our findings also revealed that LRIG1 affects ERBB signaling via decreased phosphorylation of EGFR and increased activation of the oncoprotein ERBB2 during skin carcinogenesis. The epidermal proliferation rate was significantly decreased during epidermal tumorigenesis under LRIG1 overexpression, and the apoptosis marker cleaved caspase 3 was significantly activated in the epidermis of transgenic LRIG1 mice. Additionally, we detected LRIG1 expression in human cutaneous squamous cell carcinoma and melanoma samples. Therefore, we depleted LRIG1 in human melanoma cells (A375) by CRISPR/Cas9 technology and found that this caused EGFR and ERBB3 downregulation in A375 LRIG1 knockout cells 6 h following stimulation with EGF. In conclusion, our study demonstrated that LRIG1-TG mice develop melanocytic skin tumors during chemical skin carcinogenesis and a deletion of LRIG1 in human melanoma cells reduces EGFR and ERBB3 expression after EGF stimulation.},
  language  = {en}
}
@article{UeberschaarGoebelerKneitz2020,
  author    = {Ueberschaar, Simon and Goebeler, Matthias and Kneitz, Hermann},
  title     = {CD10-Positive Cutaneous PEComa: An Extremely Rare Skin Tumour},
  series = {Case Reports in Dermatology},
  volume    = {12},
  journal   = {Case Reports in Dermatology},
  doi       = {10.1159/000510718},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236151},
  pages     = {192-198},
  year      = {2020},
  abstract  = {We here present the case of a 67-year-old woman with a history of a slowly progressive, polypous nodule on her left wrist. The lesion was excised, and the histological analysis revealed a clear cell tumour that was relatively sharply demarked from the surrounding tissue extending into the subcutaneous tissue. The tumour showed a characteristic trabecular pattern in which the tumour cells were arranged around numerous vessels. The neoplastic cells had a predominantly epithelioid shape, granular eosinophilic to clear cytoplasm and prominent centrally located nucleoli. The histological differential diagnosis included a metastatic clear-cell renal cell carcinoma and a primary cutaneous perivascular epithelioid cell tumour (PEComa). Immunohistochemically, the tumour cells revealed homogenous expression of HMB-45, MiTF and CD10, whereas MART-1 and S100 were negative. Antibodies against actin marked the trabecularly arranged vessels, and the neoplastic cells yielded a patchy positivity against actin and desmin. Additional immunohistochemical stains against pan-cytokeratin, CAIX, PAX-8 and EMA were negative. Based on the morphologic and immunophenotypic findings, the histological diagnosis of a CD10-positive cutaneous PEComa was made.},
  language  = {en}
}
@article{WallstabeBussemerGroeberBeckeretal.2020,
  author    = {Wallstabe, Julia and Bussemer, Lydia and Groeber-Becker, Florian and Freund, Lukas and Alb, Mirian and Dragan, Mariola and Waaga-Gasser, Ana Maria and Jakubietz, Rafael and Kneitz, Hermann and Rosenwald, Andreas and Rebhan, Silke and Walles, Heike and Mielke, Stephan},
  title     = {Inflammation-Induced Tissue Damage Mimicking GvHD in Human Skin Models as Test Platform for Immunotherapeutics},
  series = {ALTEX},
  volume    = {37},
  journal   = {ALTEX},
  number    = {3},
  doi       = {10.14573/altex.1907181},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229974},
  pages     = {429-440},
  year      = {2020},
  abstract  = {Due to the rapidly increasing development and use of cellular products, there is a rising demand for non-animal-based test platforms to predict, study and treat undesired immunity. Here, we generated human organotypic skin models from human biopsies by isolating and expanding keratinocytes, fibroblasts and microvascular endothelial cells and seeding these components on a collagen matrix or a biological vascularized scaffold matrix in a bioreactor. We then were able to induce inflammation-mediated tissue damage by adding pre-stimulated, mismatched allogeneic lymphocytes and/or inflammatory cytokine-containing supernatants histomorphologically mimicking severe graft versus host disease (GvHD) of the skin. This could be prevented by the addition of immunosuppressants to the models. Consequently, these models harbor a promising potential to serve as a test platform for the prediction, prevention and treatment of GvHD. They also allow functional studies of immune effectors and suppressors including but not limited to allodepleted lymphocytes, gamma-delta T cells, regulatory T cells and mesenchymal stromal cells, which would otherwise be limited to animal models. Thus, the current test platform, developed with the limitation that no professional antigen presenting cells are in place, could greatly reduce animal testing for investigation of novel immune therapies.},
  language  = {en}
}