TY - JOUR
A1 - Weich, Alexander
A1 - Werner, Rudolf A.
A1 - Buck, Andreas K.
A1 - Hartrampf, Philipp E.
A1 - Serfling, Sebastian E.
A1 - Scheurlen, Michael
A1 - Wester, Hans-Jürgen
A1 - Meining, Alexander
A1 - Kircher, Stefan
A1 - Higuchi, Takahiro
A1 - Pomper, Martin G.
A1 - Rowe, Steven P.
A1 - Lapa, Constantin
A1 - Kircher, Malte
T1 - CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas
JF - Diagnostics
N2 - We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer \(^{68}\)Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard \(^{18}\)F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent \(^{18}\)F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. \(^{68}\)Ga-Pentixafor visualized tumor lesions in 10/11 subjects, while \(^{18}\)F-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, \(^{18}\)F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, n = 107; p < 0.001). Semi-quantitative analysis revealed markedly higher 18F-FDG uptake as compared to \(^{68}\)Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUVmax: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUVmean: 7.4 ± 5.4 vs. 3.1 ± 3.2, p < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, p < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard \(^{18}\)F-FDG PET/CT.
KW - CXCR4
KW - NET
KW - NEC
KW - 68Ga-Pentixafor
KW - 18F-FDG
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234231
SN - 2075-4418
VL - 11
IS - 4
ER -
TY - JOUR
A1 - Sbiera, Iuliu
A1 - Kircher, Stefan
A1 - Altieri, Barbara
A1 - Fassnacht, Martin
A1 - Kroiss, Matthias
A1 - Sbiera, Silviu
T1 - Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues?
JF - Cancers
N2 - A clinically relevant proportion of adrenocortical carcinoma (ACC) cases shows a tendency to metastatic spread. The objective was to determine whether the epithelial to mesenchymal transition (EMT), a mechanism associated with metastasizing in several epithelial cancers, might play a crucial role in ACC. 138 ACC, 29 adrenocortical adenomas (ACA), three normal adrenal glands (NAG), and control tissue samples were assessed for the expression of epithelial (E-cadherin and EpCAM) and mesenchymal (N-cadherin, SLUG and SNAIL) markers by immunohistochemistry. Using real-time RT-PCR we quantified the alternative isoform splicing of FGFR 2 and 3, another known indicator of EMT. We also assessed the impact of these markers on clinical outcome. Results show that both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers but strongly expressed mesenchymal markers N-cadherin and SLUG. FGFR isoform splicing confirmed higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues. In ACC, higher SLUG expression was associated with clinical markers indicating aggressiveness, while N-cadherin expression inversely associated with these markers. In conclusion, we could not find any indication of EMT as all adrenocortical tissues lacked expression of epithelial markers and exhibited closer similarity to mesenchymal tissues. However, while N-cadherin might play a positive role in tissue structure upkeep, SLUG seems to be associated with a more aggressive phenotype.
KW - adrenocortical tissues
KW - EMT
KW - epithelial markers
KW - mesenchymal markers
KW - recurrence-free survival
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236486
SN - 2072-6694
VL - 13
IS - 7
ER -
TY - JOUR
A1 - Rapp, Christina K.
A1 - Van Dijck, Ine
A1 - Laugwitz, Lucia
A1 - Boon, Mieke
A1 - Briassoulis, George
A1 - Ilia, Stavroula
A1 - Kammer, Birgit
A1 - Reu, Simone
A1 - Hornung, Stefanie
A1 - Buchert, Rebecca
A1 - Sofan, Linda
A1 - Froukh, Tawfiq
A1 - Witters, Peter
A1 - Rymen, Daisy
A1 - Haack, Tobias B.
A1 - Proesmans, Marijke
A1 - Griese, Matthias
T1 - Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy
JF - Clinical Genetics
N2 - Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA, MIM#618278) is a rare clinical condition caused by bi‐allelic variants in NHL repeat containing protein 2 (NHLRC2, MIM*618277). Pulmonary disease may be the presenting sign and the few patients reported so far, all deceased in early infancy. Exome sequencing was performed on patients with childhood interstitial lung disease (chILD) and additional neurological features. The chILD‐EU register database and an in‐house database were searched for patients with NHLRC2 variants and clinical features overlapping FINCA syndrome. Six patients from three families were identified with bi‐allelic variants in NHLRC2. Two of these children died before the age of two while four others survived until childhood. Interstitial lung disease was pronounced in almost all patients during infancy and stabilized over the course of the disease with neurodevelopmental delay (NDD) evolving as the key clinical finding. We expand the phenotype of FINCA syndrome to a multisystem disorder with variable severity. FINCA syndrome should also be considered in patients beyond infancy with NDD and a history of distinct interstitial lung disease. Managing patients in registers for rare diseases helps identifying new diagnostic entities and advancing care for these patients.
KW - cerebropulmonary disease
KW - childhood interstitial lung disease
KW - cholesterol pneumonia
KW - FINCA
KW - lung fibrosis
KW - lipoid pneumonitis
KW - multi‐organ disease
KW - NHLRC2
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262732
VL - 100
IS - 4
SP - 453
EP - 461
ER -
TY - JOUR
A1 - Schuch, Luise A.
A1 - Forstner, Maria
A1 - Rapp, Christina K.
A1 - Li, Yang
A1 - Smith, Desiree E. C.
A1 - Mendes, Marisa I.
A1 - Delhommel, Florent
A1 - Sattler, Michael
A1 - Emiralioğlu, Nagehan
A1 - Taskiran, Ekim Z.
A1 - Orhan, Diclehan
A1 - Kiper, Nural
A1 - Rohlfs, Meino
A1 - Jeske, Tim
A1 - Hastreiter, Maximilian
A1 - Gerstlauer, Michael
A1 - Torrent‐Vernetta, Alba
A1 - Moreno‐Galdó, Antonio
A1 - Kammer, Birgit
A1 - Brasch, Frank
A1 - Reu‐Hofer, Simone
A1 - Griese, Matthias
T1 - FARS1‐related disorders caused by bi‐allelic mutations in cytosolic phenylalanyl‐tRNA synthetase genes: Look beyond the lungs!
JF - Clinical Genetics
N2 - Aminoacyl‐tRNA synthetases (ARSs) catalyze the first step of protein biosynthesis (canonical function) and have additional (non‐canonical) functions outside of translation. Bi‐allelic pathogenic variants in genes encoding ARSs are associated with various recessive mitochondrial and multisystem disorders. We describe here a multisystem clinical phenotype based on bi‐allelic mutations in the two genes (FARSA, FARSB) encoding distinct subunits for tetrameric cytosolic phenylalanyl‐tRNA synthetase (FARS1). Interstitial lung disease with cholesterol pneumonitis on histology emerged as an early characteristic feature and significantly determined disease burden. Additional clinical characteristics of the patients included neurological findings, liver dysfunction, and connective tissue, muscular and vascular abnormalities. Structural modeling of newly identified missense mutations in the alpha subunit of FARS1, FARSA, showed exclusive mapping to the enzyme's conserved catalytic domain. Patient‐derived mutant cells displayed compromised aminoacylation activity in two cases, while remaining unaffected in another. Collectively, these findings expand current knowledge about the human ARS disease spectrum and support a loss of canonical and non‐canonical function in FARS1‐associated recessive disease.
KW - aminoacyl‐tRNA synthetases
KW - cholesterol pneumonitis
KW - FARS1
KW - children´s interstitial lung disease (chILD) lipoid pneumonia
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238827
VL - 99
IS - 6
SP - 789
EP - 801
ER -
TY - JOUR
A1 - Lenschow, Christina
A1 - Fuss, Carmina Teresa
A1 - Kircher, Stefan
A1 - Buck, Andreas
A1 - Kickuth, Ralph
A1 - Reibetanz, Joachim
A1 - Wiegering, Armin
A1 - Stenzinger, Albrecht
A1 - Hübschmann, Daniel
A1 - Germer, Christoph Thomas
A1 - Fassnacht, Martin
A1 - Fröhling, Stefan
A1 - Schlegel, Nicolas
A1 - Kroiss, Matthias
T1 - Case Report: Abdominal Lymph Node Metastases of Parathyroid Carcinoma: Diagnostic Workup, Molecular Diagnosis, and Clinical Management
JF - Frontiers in Endocrinology
N2 - Parathyroid carcinoma (PC) is an orphan malignancy accounting for only ~1% of all cases with primary hyperparathyroidism. The localization of recurrent PC is of critical importance and can be exceedingly difficult to diagnose and sometimes futile when common sites of recurrence in the neck and chest cannot be confirmed. Here, we present the diagnostic workup, molecular analysis and multimodal therapy of a 46-year old woman with the extraordinary manifestation of abdominal lymph node metastases 12 years after primary diagnosis of PC. The patient was referred to our endocrine tumor center in 2016 with the aim to localize the tumor causative of symptomatic biochemical recurrence. In view of the extensive previous workup we decided to perform [18F]FDG-PET-CT. A pathological lymph node in the liver hilus showed slightly increased FDG-uptake and hence was suspected as site of recurrence. Selective venous sampling confirmed increased parathyroid hormone concentration in liver veins. Abdominal lymph node metastasis was resected and histopathological examination confirmed PC. Within four months, the patient experienced biochemical recurrence and based on high tumor mutational burden detected in the surgical specimen by whole exome sequencing the patient received immunotherapy with pembrolizumab that led to a biochemical response. Subsequent to disease progression repeated abdominal lymph node resection was performed in 10/2018, 01/2019 and in 01/2020. Up to now (12/2020) the patient is biochemically free of disease. In conclusion, a multimodal diagnostic approach and therapy in an interdisciplinary setting is needed for patients with rare endocrine tumors. Molecular analyses may inform additional treatment options including checkpoint inhibitors such as pembrolizumab.
KW - parathyroid carcinoma
KW - abdominal lymph node metastases
KW - molecular diagnostics
KW - repeated surgery
KW - [18F]FDG-PET-CT
KW - immune check inhibitor
KW - pembrolizumab
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233362
SN - 1664-2392
VL - 12
ER -
TY - JOUR
A1 - Gerhard-Hartmann, Elena
A1 - Wiegering, Verena
A1 - Benoit, Clemens
A1 - Meyer, Thomas
A1 - Rosenwald, Andreas
A1 - Maurus, Katja
A1 - Ernestus, Karen
T1 - A large retroperitoneal lipoblastoma as an incidental finding: a case report
JF - BMC Pediatrics
N2 - Background
Lipoblastoma is a rare benign mesenchymal neoplasm of infancy that most commonly occurs on the extremities and trunk but can arise at variable sites of the body. Retroperitoneal lipoblastomas are particularly rare but can grow to enormous size, and preoperative diagnosis is difficult with diverse, mostly malignant differential diagnoses that would lead to aggressive therapy. Since lipoblastoma is a benign tumor that has an excellent prognosis after resection, correct diagnosis is crucial.
Case presentation
A case of a large retroperitoneal tumor of a 24-month old infant that was clinically suspicious of a malignant tumor is presented. Due to proximity to the right kidney, clinically most probably a nephroblastoma or clear cell sarcoma of the kidney was suspected. Radiological findings were ambiguous. Therefore, the mass was biopsied, and histology revealed an adipocytic lesion. Although mostly composed of mature adipocytes, in view of the age of the patient, the differential diagnosis of a (maturing) lipoblastoma was raised, which was supported by molecular analysis demonstrating a HAS2-PLAG1 fusion. The tumor was completely resected, and further histopathological workup led to the final diagnosis of a 13 cm large retroperitoneal maturing lipoblastoma. The child recovered promptly from surgery and showed no evidence of recurrence so far.
Conclusion
Although rare, lipoblastoma should be included in the differential diagnoses of retroperitoneal tumors in infants and children, and molecular diagnostic approaches could be a helpful diagnostic adjunct in challenging cases.
KW - retroperitoneal tumor
KW - pediatric
KW - lipoblastoma
KW - PLAG1 rearrangement
KW - case report
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260173
VL - 21
ER -
TY - JOUR
A1 - Meyer, Till Jasper
A1 - Gerhard-Hartmann, Elena
A1 - Lodes, Nina
A1 - Scherzad, Agmal
A1 - Hagen, Rudolf
A1 - Steinke, Maria
A1 - Hackenberg, Stephan
T1 - Pilot study on the value of Raman spectroscopy in the entity assignment of salivary gland tumors
JF - PLoS One
N2 - Background
The entity assignment of salivary gland tumors (SGT) based on histomorphology can be challenging. Raman spectroscopy has been applied to analyze differences in the molecular composition of tissues. The aim of this study was to evaluate the suitability of RS for entity assignment in SGT.
Methods
Raman data were collected in deparaffinized sections of pleomorphic adenomas (PA) and adenoid cystic carcinomas (ACC). Multivariate data and chemometric analysis were completed using the Unscrambler software.
Results
The Raman spectra detected in ACC samples were mostly assigned to nucleic acids, lipids, and amides. In a principal component-based linear discriminant analysis (LDA) 18 of 20 tumor samples were classified correctly.
Conclusion
In this proof of concept study, we show that a reliable SGT diagnosis based on LDA algorithm appears possible, despite variations in the entity-specific mean spectra. However, a standardized workflow for tissue sample preparation, measurement setup, and chemometric algorithms is essential to get reliable results.
KW - Head and neck cancers
KW - salivary gland tumors
KW - salivary glands
KW - cancers and neoplasms
KW - malignant tumors
KW - lipids
KW - raman spectroscopy
KW - surgical oncology
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264736
VL - 16
IS - 9
ER -
TY - JOUR
A1 - Danhof, Sophia
A1 - Rasche, Leo
A1 - Mottok, Anja
A1 - Steinmüller, Tabea
A1 - Zhou, Xiang
A1 - Schreder, Martin
A1 - Kilian, Teresa
A1 - Strifler, Susanne
A1 - Rosenwald, Andreas
A1 - Hudecek, Michael
A1 - Einsele, Hermann
A1 - Gerhard-Hartmann, Elena
T1 - Elotuzumab for the treatment of extramedullary myeloma: a retrospective analysis of clinical efficacy and SLAMF7 expression patterns
JF - Annals of Hematology
N2 - Extramedullary disease (EMD) represents a high-risk state of multiple myeloma (MM) associated with poor prognosis. While most anti-myeloma therapeutics demonstrate limited efficacy in this setting, some studies exploring the utility of chimeric antigen receptor (CAR)-modified T cells reported promising results. We have recently designed SLAMF7-directed CAR T cells for the treatment of MM. SLAMF7 is a transmembrane receptor expressed on myeloma cells that plays a role in myeloma cell homing to the bone marrow. Currently, the only approved anti-SLAMF7 therapeutic is the monoclonal antibody elotuzumab, but its efficacy in EMD has not been investigated thoroughly. Thus, we retrospectively analyzed the efficacy of elotuzumab-based combination therapy in a cohort of 15 patients with EMD. Moreover, since the presence of the target antigen is an indispensable prerequisite for effective targeted therapy, we investigated the SLAMF7 expression on extramedullary located tumor cells before and after treatment. We observed limited efficacy of elotuzumab-based combination therapies, with an overall response rate of 40% and a progression-free and overall survival of 3.8 and 12.9 months, respectively. Before treatment initiation, all available EMD tissue specimens (n = 3) demonstrated a strong and consistent SLAMF7 surface expression by immunohistochemistry. Furthermore, to investigate a potential antigen reduction under therapeutic selection pressure, we analyzed samples of de novo EMD (n = 3) outgrown during elotuzumab treatment. Again, immunohistochemistry documented strong and consistent SLAMF7 expression in all samples. In aggregate, our data point towards a retained expression of SLAMF7 in EMD and encourage the development of more potent SLAMF7-directed immunotherapies, such as CAR T cells.
KW - plasma cells
KW - extramedullary disease
KW - monoclonal antibody
KW - CD319
KW - CS1
KW - antigen loss
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266468
SN - 1432-0584
VL - 100
IS - 6
ER -
TY - JOUR
A1 - Friedmann Angeli, José Pedro
A1 - Meierjohann, Svenja
T1 - NRF2‐dependent stress defense in tumor antioxidant control and immune evasion
JF - Pigment Cell & Melanoma Research
N2 - The transcription factor NRF2 is known as the master regulator of the oxidative stress response. Tumor entities presenting oncogenic activation of NRF2, such as lung adenocarcinoma, are associated with drug resistance, and accumulating evidence demonstrates its involvement in immune evasion. In other cancer types, the KEAP1/NRF2 pathway is not commonly mutated, but NRF2 is activated by other means such as radiation, oncogenic activity, cytokines, or other pro‐oxidant triggers characteristic of the tumor niche. The obvious effect of stress‐activated NRF2 is the protection from oxidative or electrophilic damage and the adaptation of the tumor metabolism to changing conditions. However, data from melanoma also reveal a role of NRF2 in modulating differentiation and suppressing anti‐tumor immunity. This review summarizes the function of NRF2 in this tumor entity and discusses the implications for current tumor therapies.
KW - immune evasion
KW - KEAP1
KW - Nrf2
KW - oxidative stress
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224536
VL - 34
IS - 2
SP - 268
EP - 279
ER -
TY - JOUR
A1 - Wobser, Marion
A1 - Roth, Sabine
A1 - Appenzeller, Silke
A1 - Houben, Roland
A1 - Schrama, David
A1 - Goebeler, Matthias
A1 - Geissinger, Eva
A1 - Rosenwald, Andreas
A1 - Maurus, Katja
T1 - Targeted deep sequencing of mycosis fungoides reveals intracellular signaling pathways associated with aggressiveness and large cell transformation
JF - Cancers
N2 - Introduction: Large-cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not been elucidated yet. Materials and Methods: In order to address molecular mechanisms of LCT, we performed hybrid capture panel-based sequencing of skin biopsies from 10 patients suffering from MF with LCT versus 17 patients without LCT including follow-up biopsies during clinical course, respectively (51 samples in total). The analyzed patients were attributed to three different groups based on the presence of LCT and clinical behavior. Results: While indolent MF cases without LCT did not show pathogenic driver mutations, a high rate of oncogenic alterations was detected in patients with LCT and aggressive clinical courses. Various genes of different oncogenic signaling pathways, including the MAPK and JAK-STAT signaling pathways, as well as epigenetic modifiers were affected. A high inter-individual and distinctive intra-individual mutation diversity was observed. Oncogenic RAS mutations were exclusively detected in patients with LCT. Conclusion: Our data demonstrate that LCT transition of MF is associated with increased frequency of somatic mutations in cancer-associated genes. In particular, the activation of RAS signaling — together with epigenetic dysregulation — may crucially contribute to the molecular pathogenesis of the LCT phenotype, thus conveying its adverse clinical behavior.
KW - mycosis fungoides
KW - cutaneous T-cell-lymphoma
KW - panel sequencing
KW - large cell transformation
KW - CD30
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250094
SN - 2072-6694
VL - 13
IS - 21
ER -
TY - JOUR
A1 - Kader, Hidaya A.
A1 - Azeem, Muhammad
A1 - Jwayed, Suhib A.
A1 - Al-Shehhi, Aaesha
A1 - Tabassum, Attia
A1 - Ayoub, Mohammed Akli
A1 - Hetta, Helal F.
A1 - Waheed, Yasir
A1 - Iratni, Rabah
A1 - Al-Dhaheri, Ahmed
A1 - Muhammad, Khalid
T1 - Current insights into immunology and novel therapeutics of atopic dermatitis
JF - Cells
N2 - Atopic dermatitis (AD) is one of the most prevalent inflammatory disease among non-fatal skin diseases, affecting up to one fifth of the population in developed countries. AD is characterized by recurrent pruritic and localized eczema with seasonal fluctuations. AD initializes the phenomenon of atopic march, during which infant AD patients are predisposed to progressive secondary allergies such as allergic rhinitis, asthma, and food allergies. The pathophysiology of AD is complex; onset of the disease is caused by several factors, including strong genetic predisposition, disrupted epidermal barrier, and immune dysregulation. AD was initially characterized by defects in the innate immune system and a vigorous skewed adaptive Th2 response to environmental agents; there are compelling evidences that the disorder involves multiple immune pathways. Symptomatic palliative treatment is the only strategy to manage the disease and restore skin integrity. Researchers are trying to more precisely define the contribution of different AD genotypes and elucidate the role of various immune axes. In this review, we have summarized the current knowledge about the roles of innate and adaptive immune responsive cells in AD. In addition, current and novel treatment strategies for the management of AD are comprehensively described, including some ongoing clinical trials and promising therapeutic agents. This information will provide an asset towards identifying personalized targets for better therapeutic outcomes.
KW - atopic dermatitis
KW - immune system
KW - T cells
KW - B cells
KW - keratinocytes
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241008
SN - 2073-4409
VL - 10
IS - 6
ER -
TY - JOUR
A1 - Porubsky, Stefan
A1 - Popovic, Zoran V.
A1 - Badve, Sunil
A1 - Banz, Yara
A1 - Berezowska, Sabina
A1 - Borchert, Dietmar
A1 - Brüggemann, Monika
A1 - Gaiser, Timo
A1 - Graeter, Thomas
A1 - Hollaus, Peter
A1 - Huettl, Katrin S.
A1 - Kotrova, Michaela
A1 - Kreft, Andreas
A1 - Kugler, Christian
A1 - Lötscher, Fabian
A1 - Möller, Burkhard
A1 - Ott, German
A1 - Preissler, Gerhard
A1 - Roessner, Eric
A1 - Rosenwald, Andreas
A1 - Ströbel, Philipp
A1 - Marx, Alexander
T1 - Thymic hyperplasia with lymphoepithelial sialadenitis (LESA)-like features: strong association with lymphomas and non-myasthenic autoimmune diseases
JF - Cancers
N2 - Thymic hyperplasia (TH) with lymphoepithelial sialadenitis (LESA)-like features (LESA-like TH) has been described as a tumor-like, benign proliferation of thymic epithelial cells and lymphoid follicles. We aimed to determine the frequency of lymphoma and autoimmunity in LESA-like TH and performed retrospective analysis of cases with LESA-like TH and/or thymic MALT-lymphoma. Among 36 patients (21 males) with LESA-like TH (age 52 years, 32–80; lesion diameter 7.0 cm, 1–14.5; median, range), five (14%) showed associated lymphomas, including four (11%) thymic MALT lymphomas and one (3%) diffuse large B-cell lymphoma. One additional case showed a clonal B-cell-receptor rearrangement without evidence of lymphoma. Twelve (33%) patients (7 women) suffered from partially overlapping autoimmune diseases: systemic lupus erythematosus (n = 4, 11%), rheumatoid arthritis (n = 3, 8%), myasthenia gravis (n = 2, 6%), asthma (n = 2, 6%), scleroderma, Sjögren syndrome, pure red cell aplasia, Grave’s disease and anti-IgLON5 syndrome (each n = 1, 3%). Among 11 primary thymic MALT lymphomas, remnants of LESA-like TH were found in two cases (18%). In summary, LESA-like TH shows a striking association with autoimmunity and predisposes to lymphomas. Thus, a hematologic and rheumatologic workup should become standard in patients diagnosed with LESA-like TH. Radiologists and clinicians should be aware of LESA-like TH as a differential diagnosis for mediastinal mass lesions in patients with autoimmune diseases.
KW - autoimmune disease
KW - imaging
KW - LESA
KW - lymphoma
KW - myasthenia
KW - pathology
KW - surgery
KW - thymus
KW - thymic epithelial tumor
KW - thymitis
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223049
SN - 2072-6694
VL - 13
IS - 2
ER -
TY - JOUR
A1 - Schümann, Franziska Lea
A1 - Groß, Elisabeth
A1 - Bauer, Marcus
A1 - Rohde, Christian
A1 - Sandmann, Sarah
A1 - Terziev, Denis
A1 - Müller, Lutz P.
A1 - Posern, Guido
A1 - Wienke, Andreas
A1 - Fend, Falko
A1 - Hansmann, Martin-Leo
A1 - Klapper, Wolfram
A1 - Rosenwald, Andreas
A1 - Stein, Harald
A1 - Dugas, Martin
A1 - Müller-Tidow, Carsten
A1 - Wickenhauser, Claudia
A1 - Binder, Mascha
A1 - Weber, Thomas
T1 - Divergent effects of EZH1 and EZH2 protein expression on the prognosis of patients with T-cell lymphomas
JF - Biomedicines
N2 - T-cell lymphomas are highly heterogeneous and their prognosis is poor under the currently available therapies. Enhancers of zeste homologue 1 and 2 (EZH1/2) are histone H3 lysine-27 trimethyltransferases (H3K27me3). Despite the rapid development of new drugs inhibiting EZH2 and/or EZH1, the molecular interplay of these proteins and the impact on disease progression and prognosis of patients with T-cell lymphomas remains insufficiently understood. In this study, EZH1/2 mutation status was evaluated in 33 monomorphic epitheliotropic intestinal T-cell lymphomas by next generation sequencing and EZH1/2 and H3K27me3 protein expression levels were detected by immunohistochemistry in 46 T-cell lymphomas. Correlations with clinicopathologic features were analyzed and survival curves generated. No EZH1 mutations and one (3%) EZH2 missense mutation were identified. In univariable analysis, high EZH1 expression was associated with an improved overall survival (OS) and progression-free survival (PFS) whereas high EZH2 and H3K27me3 expression were associated with poorer OS and PFS. Multivariable analysis revealed EZH1 (hazard ratio (HR) = 0.183; 95% confidence interval (CI): 0.044–0.767; p = 0.020;) and EZH2 (HR = 8.245; 95% CI: 1.898–35.826; p = 0.005) to be independent, divergent prognostic markers for OS. In conclusion, EZH1/2 protein expression had opposing effects on the prognosis of T-cell lymphoma patients.
KW - T-cell non-Hodgkin's lymphomas
KW - PTCL
KW - epigenetics
KW - EZH1
KW - EZH2
KW - H3K27me3
KW - immunohistochemistry
KW - next generation sequencing
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252155
SN - 2227-9059
VL - 9
IS - 12
ER -
TY - JOUR
A1 - Shaikh, Haroon
A1 - Vargas, Juan Gamboa
A1 - Mokhtari, Zeinab
A1 - Jarick, Katja J.
A1 - Ulbrich, Maria
A1 - Mosca, Josefina Peña
A1 - Viera, Estibaliz Arellano
A1 - Graf, Caroline
A1 - Le, Duc-Dung
A1 - Heinze, Katrin G.
A1 - Büttner-Herold, Maike
A1 - Rosenwald, Andreas
A1 - Pezoldt, Joern
A1 - Huehn, Jochen
A1 - Beilhack, Andreas
T1 - Mesenteric Lymph Node Transplantation in Mice to Study Immune Responses of the Gastrointestinal Tract
JF - Frontiers in Immunology
N2 - Mesenteric lymph nodes (mLNs) are sentinel sites of enteral immunosurveillance and immune homeostasis. Immune cells from the gastrointestinal tract (GIT) are constantly recruited to the mLNs in steady-state and under inflammatory conditions resulting in the induction of tolerance and immune cells activation, respectively. Surgical dissection and transplantation of lymph nodes (LN) is a technique that has supported seminal work to study LN function and is useful to investigate resident stromal and endothelial cell biology and their cellular interactions in experimental disease models. Here, we provide a detailed protocol of syngeneic mLN transplantation and report assays to analyze effective mLN engraftment in congenic recipients. Transplanted mLNs allow to study T cell activation and proliferation in preclinical mouse models. Donor mLNs proved viable and functional after surgical transplantation and regenerated blood and lymphatic vessels. Immune cells from the host completely colonized the transplanted mLNs within 7-8 weeks after the surgical intervention. After allogeneic hematopoietic cell transplantation (allo-HCT), adoptively transferred allogeneic CD4+ T cells from FVB/N (H-2q) mice homed to the transplanted mLNs in C57BL/6 (H-2b) recipients during the initiation phase of acute graft-versus-host disease (aGvHD). These CD4+ T cells retained full proliferative capacity and upregulated effector and gut homing molecules comparable to those in mLNs from unmanipulated wild-type recipients. Wild type mLNs transplanted into MHCII deficient syngeneic hosts sufficed to activate alloreactive T cells upon allogeneic hematopoietic cell transplantation, even in the absence of MHCII+ CD11c+ myeloid cells. These data support that orthotopically transplanted mLNs maintain physiological functions after transplantation. The technique of LN transplantation can be applied to study migratory and resident cell compartment interactions in mLNs as well as immune reactions from and to the gut under inflammatory and non-inflammatory conditions.
KW - acute graft-versus host disease
KW - alloreactive T cells
KW - mesenteric lymph node
KW - lymph node transplantation
KW - mouse models
KW - lymph node stromal cells
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244869
SN - 1664-3224
VL - 12
ER -
TY - JOUR
A1 - Garitano-Trojaola, Andoni
A1 - Sancho, Ana
A1 - Götz, Ralph
A1 - Eiring, Patrick
A1 - Walz, Susanne
A1 - Jetani, Hardikkumar
A1 - Gil-Pulido, Jesus
A1 - Da Via, Matteo Claudio
A1 - Teufel, Eva
A1 - Rhodes, Nadine
A1 - Haertle, Larissa
A1 - Arellano-Viera, Estibaliz
A1 - Tibes, Raoul
A1 - Rosenwald, Andreas
A1 - Rasche, Leo
A1 - Hudecek, Michael
A1 - Sauer, Markus
A1 - Groll, Jürgen
A1 - Einsele, Hermann
A1 - Kraus, Sabrina
A1 - Kortüm, Martin K.
T1 - Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia
JF - Communications Biology
N2 - The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD+AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD+AML. Garitano-Trojaola et al. used a combination of human acute myeloid leukemia (AML) cell lines and primary samples to show that RAC1-dependent actin cytoskeleton remodeling through BCL2 family plays a key role in resistance to the FLT3 inhibitor, Midostaurin in AML. They showed that by targeting RAC1 and BCL2, Midostaurin resistance was diminished, which potentially paves the way for an innovate treatment approach for FLT3 mutant AML.
KW - actin
KW - acute myeloid leukaemia
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260709
VL - 4
IS - 1
ER -
TY - JOUR
A1 - Riederer, P.
A1 - Monoranu, C.
A1 - Strobel, S.
A1 - Iordache, T.
A1 - Sian-Hülsmann, J.
T1 - Iron as the concert master in the pathogenic orchestra playing in sporadic Parkinson's disease
JF - Journal of Neural Transmission
N2 - About 60 years ago, the discovery of a deficiency of dopamine in the nigro-striatal system led to a variety of symptomatic therapeutic strategies to supplement dopamine and to substantially improve the quality of life of patients with Parkinson's disease (PD). Since these seminal developments, neuropathological, neurochemical, molecular biological and genetic discoveries contributed to elucidate the pathology of PD. Oxidative stress, the consequences of reactive oxidative species, reduced antioxidative capacity including loss of glutathione, excitotoxicity, mitochondrial dysfunction, proteasomal dysfunction, apoptosis, lysosomal dysfunction, autophagy, suggested to be causal for ɑ-synuclein fibril formation and aggregation and contributing to neuroinflammation and neural cell death underlying this devastating disorder. However, there are no final conclusions about the triggered pathological mechanism(s) and the follow-up of pathological dysfunctions. Nevertheless, it is a fact, that iron, a major component of oxidative reactions, as well as neuromelanin, the major intraneuronal chelator of iron, undergo an age-dependent increase. And ageing is a major risk factor for PD. Iron is significantly increased in the substantia nigra pars compacta (SNpc) of PD. Reasons for this finding include disturbances in iron-related import and export mechanisms across the blood-brain barrier (BBB), localized opening of the BBB at the nigro-striatal tract including brain vessel pathology. Whether this pathology is of primary or secondary importance is not known. We assume that there is a better fit to the top-down hypotheses and pathogens entering the brain via the olfactory system, then to the bottom-up (gut-brain) hypothesis of PD pathology. Triggers for the bottom-up, the dual-hit and the top-down pathologies include chemicals, viruses and bacteria. If so, hepcidin, a regulator of iron absorption and its distribution into tissues, is suggested to play a major role in the pathogenesis of iron dyshomeostasis and risk for initiating and progressing ɑ-synuclein pathology. The role of glial components to the pathology of PD is still unknown. However, the dramatic loss of glutathione (GSH), which is mainly synthesized in glia, suggests dysfunction of this process, or GSH uptake into neurons. Loss of GSH and increase in SNpc iron concentration have been suggested to be early, may be even pre-symptomatic processes in the pathology of PD, despite the fact that they are progression factors. The role of glial ferritin isoforms has not been studied so far in detail in human post-mortem brain tissue and a close insight into their role in PD is called upon. In conclusion, "iron" is a major player in the pathology of PD. Selective chelation of excess iron at the site of the substantia nigra, where a dysfunction of the BBB is suggested, with peripherally acting iron chelators is suggested to contribute to the portfolio and therapeutic armamentarium of anti-Parkinson medications.
KW - SARS-CoV-2
KW - iron in parkinsonism
KW - parkinson’s disease
KW - iiron transporter
KW - neuromelanin
KW - iron pathology
KW - neuroinflammation
KW - iron model
KW - ferroptosis
KW - ɑ-Synuclein and iron
KW - virus–iron interaction
KW - COVID-19
KW - hepcidin
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-268539
SN - 1435-1463
VL - 128
IS - 10
ER -
TY - JOUR
A1 - Bäuerlein, Carina A.
A1 - Qureischi, Musga
A1 - Mokhtari, Zeinab
A1 - Tabares, Paula
A1 - Brede, Christian
A1 - Jordán Garrote, Ana-Laura
A1 - Riedel, Simone S.
A1 - Chopra, Martin
A1 - Reu, Simone
A1 - Mottok, Anja
A1 - Arellano-Viera, Estibaliz
A1 - Graf, Carolin
A1 - Kurzwart, Miriam
A1 - Schmiedgen, Katharina
A1 - Einsele, Hermann
A1 - Wölfl, Matthias
A1 - Schlegel, Paul-Gerhardt
A1 - Beilhack, Andreas
T1 - A T-Cell Surface Marker Panel Predicts Murine Acute Graft-Versus-Host Disease
JF - Frontiers in Immunology
N2 - Acute graft-versus-host disease (aGvHD) is a severe and often life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). AGvHD is mediated by alloreactive donor T-cells targeting predominantly the gastrointestinal tract, liver, and skin. Recent work in mice and patients undergoing allo-HCT showed that alloreactive T-cells can be identified by the expression of α4β7 integrin on T-cells even before manifestation of an aGvHD. Here, we investigated whether the detection of a combination of the expression of T-cell surface markers on peripheral blood (PB) CD8\(^+\) T-cells would improve the ability to predict aGvHD. To this end, we employed two independent preclinical models of minor histocompatibility antigen mismatched allo-HCT following myeloablative conditioning. Expression profiles of integrins, selectins, chemokine receptors, and activation markers of PB donor T-cells were measured with multiparameter flow cytometry at multiple time points before the onset of clinical aGvHD symptoms. In both allo-HCT models, we demonstrated a significant upregulation of α4β7 integrin, CD162E, CD162P, and conversely, a downregulation of CD62L on donor T-cells, which could be correlated with the development of aGvHD. Other surface markers, such as CD25, CD69, and CC-chemokine receptors were not found to be predictive markers. Based on these preclinical data from mouse models, we propose a surface marker panel on peripheral blood T-cells after allo-HCT combining α4β7 integrin with CD62L, CD162E, and CD162P (cutaneous lymphocyte antigens, CLA, in humans) to identify patients at risk for developing aGvHD early after allo-HCT.
KW - acute graft-versus-host disease
KW - alloreactive T cells
KW - transplantation
KW - prediction
KW - mouse models
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224290
SN - 1664-3224
VL - 11
ER -
TY - JOUR
A1 - Rosenfeldt, Mathias T.
A1 - Hartmann, Elena M.
A1 - Leng, Corinna
A1 - Rosenwald, Andreas
A1 - Anagnostopoulos, Ioannis
T1 - A case of nodular lymphocyte predominant Hodgkin lymphoma with unexpected EBV-latency type
JF - Annals of Hematology
N2 - No abstract available.
KW - nodular lymphcyte
KW - Hodgkin lymphoma
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232571
SN - 0939-5555
VL - 100
ER -
TY - JOUR
A1 - Romero‐Olmedo, Addi J.
A1 - Schulz, Axel R.
A1 - Huber, Magdalena
A1 - Brehm, Corinna U.
A1 - Chang, Hyun‐Dong
A1 - Chiarolla, Cristina M.
A1 - Bopp, Tobias
A1 - Skevaki, Chrysanthi
A1 - Berberich‐Siebelt, Friederike
A1 - Radbruch, Andreas
A1 - Mei, Henrik E.
A1 - Lohoff, Michael
T1 - Deep phenotypical characterization of human CD3\(^{+}\)CD56\(^{+}\) T cells by mass cytometry
JF - European Journal of Immunology
N2 - CD56\(^{+}\) T cells are a group of pro‐inflammatory CD3\(^{+}\) lymphocytes with characteristics of natural killer cells, being involved in antimicrobial immune defense. Here, we performed deep phenotypic profiling of CD3\(^{+}\)CD56\(^{+}\) cells in peripheral blood of normal human donors and individuals sensitized to birch‐pollen or/and house dust mite by high‐dimensional mass cytometry combined with manual and computational data analysis. A co‐regulation between major conventional T‐cell subsets and their respective CD3\(^{+}\)CD56\(^{+}\) cell counterparts appeared restricted to CD8\(^{+}\), MAIT, and TCRγδ\(^{+}\) T‐cell compartments. Interestingly, we find a co‐regulation of several CD3\(^{+}\)CD56\(^{+}\) cell subsets in allergic but not in healthy individuals. Moreover, using FlowSOM, we distinguished a variety of CD56\(^{+}\) T‐cell phenotypes demonstrating a hitherto underestimated heterogeneity among these cells. The novel CD3\(^{+}\)CD56\(^{+}\) subset description comprises phenotypes superimposed with naive, memory, type 1, 2, and 17 differentiation stages, in part represented by a phenotypical continuum. Frequencies of two out of 19 CD3\(^{+}\)CD56\(^{+}\) FlowSOM clusters were significantly diminished in allergic individuals, demonstrating less frequent presence of cells with cytolytic, presumably protective, capacity in these donors consistent with defective expansion or their recruitment to the affected tissue. Our results contribute to defining specific cell populations to be targeted during therapy for allergic conditions.
KW - allergy
KW - CD56
KW - human
KW - mass cytometry
KW - T cells
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225699
VL - 51
IS - 3
SP - 672
EP - 681
ER -
TY - JOUR
A1 - Marquardt, André
A1 - Solimando, Antonio Giovanni
A1 - Kerscher, Alexander
A1 - Bittrich, Max
A1 - Kalogirou, Charis
A1 - Kübler, Hubert
A1 - Rosenwald, Andreas
A1 - Bargou, Ralf
A1 - Kollmannsberger, Philip
A1 - Schilling, Bastian
A1 - Meierjohann, Svenja
A1 - Krebs, Markus
T1 - Subgroup-Independent Mapping of Renal Cell Carcinoma — Machine Learning Reveals Prognostic Mitochondrial Gene Signature Beyond Histopathologic Boundaries
JF - Frontiers in Oncology
N2 - Background: Renal cell carcinoma (RCC) is divided into three major histopathologic groups—clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC). We performed a comprehensive re-analysis of publicly available RCC datasets from the TCGA (The Cancer Genome Atlas) database, thereby combining samples from all three subgroups, for an exploratory transcriptome profiling of RCC subgroups.
Materials and Methods: We used FPKM (fragments per kilobase per million) files derived from the ccRCC, pRCC and chRCC cohorts of the TCGA database, representing transcriptomic data of 891 patients. Using principal component analysis, we visualized datasets as t-SNE plot for cluster detection. Clusters were characterized by machine learning, resulting gene signatures were validated by correlation analyses in the TCGA dataset and three external datasets (ICGC RECA-EU, CPTAC-3-Kidney, and GSE157256).
Results: Many RCC samples co-clustered according to histopathology. However, a substantial number of samples clustered independently from histopathologic origin (mixed subgroup)—demonstrating divergence between histopathology and transcriptomic data. Further analyses of mixed subgroup via machine learning revealed a predominant mitochondrial gene signature—a trait previously known for chRCC—across all histopathologic subgroups. Additionally, ccRCC samples from mixed subgroup presented an inverse correlation of mitochondrial and angiogenesis-related genes in the TCGA and in three external validation cohorts. Moreover, mixed subgroup affiliation was associated with a highly significant shorter overall survival for patients with ccRCC—and a highly significant longer overall survival for chRCC patients.
Conclusions: Pan-RCC clustering according to RNA-sequencing data revealed a distinct histology-independent subgroup characterized by strengthened mitochondrial and weakened angiogenesis-related gene signatures. Moreover, affiliation to mixed subgroup went along with a significantly shorter overall survival for ccRCC and a longer overall survival for chRCC patients. Further research could offer a therapy stratification by specifically addressing the mitochondrial metabolism of such tumors and its microenvironment.
KW - kidney cancer
KW - pan-RCC
KW - machine learning
KW - mitochondrial DNA
KW - mtDNA
KW - mTOR
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232107
SN - 2234-943X
VL - 11
ER -