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Publications (267)
Necrosis in postoperative histology has been reported as being specific for adrenocortical carcinoma (ACC) compared to adenoma. We therefore retrospectively analyzed the diagnostic accuracy of the finding of necrosis in preoperative cross-sectional imaging and postoperative histology as a marker for ACC in our patient cohort. Among the 411 adrenale...
Purpose
Placental alkaline phosphatase (PLAP) is a protein with a poorly understood function that is normally only expressed in the placenta. In cancer, PLAP expression is a hallmark of germ cell neoplasms, but it can also occur in urothelial carcinoma. To evaluate the potential clinical significance of PLAP expression in bladder cancer,
Methods
P...
Homozygous 9p21 deletions usually result in a complete loss of S‐methyl‐5′‐thioadenosine phosphorylase (MTAP) expression visualizable by immunohistochemistry (IHC). MTAP deficiency has been proposed as a marker for predicting targeted treatment response. A tissue microarray including 2,710 urothelial bladder carcinomas were analyzed for 9p21 deleti...
Background
Thyroid Transcription Factor-1 (TTF-1) expression in lung adenocarcinoma (LUAD) has been studied for its prognostic value in early-stage and metastatic disease. Its role in brain metastasis remains unexplored. This study investigates the predictive value and association of TTF-1 status with clinicopathological variables in patients with...
Background
We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other...
GPA33 is a promising surface antigen for targeted therapy in colorectal cancer (CRC). It is expressed almost exclusively in CRC and intestinal epithelia. However, previous clinical studies have not achieved expected response rates. We investigated GPA33 expression and regulation in CRC and developed a GPA33-targeted cellular therapy. We examined GP...
Therapy-related acute myeloid leukemia (t-AML) often exhibits adverse (genetic) features. There is ongoing discussion on the impact of t-AML on long-term outcome in AML. Therefore, we retrospectively analyzed clinical and biological characteristics of 1133 AML patients (225 t-AML patients and 908 de novo AML patients) with a median follow-up of 81....
Objective
There is a shortage of established prognostic biomarkers in bladder cancer. One candidate is tumour protein 63 (p63), a transcription factor of the p53 gene family that is expressed in the normal urothelium. Recently proposed RNA expression‐based molecular classifiers of bladder cancer identified high p63 expression as a component of a ba...
17p13 deletions including TP53 and other genes represent a common cause for reduced/lost p53 function in tumor cells. In this study, we analyzed the impact of 17p13 ( TP53 ) deletions and p53 expression on tumor aggressiveness and patient prognosis in urothelial carcinoma. The 17p13 copy number status was analyzed by fluorescence in situ hybridizat...
Purpose
While elevated Thymidylate synthase (TYMS) levels are observed in many cancers, its specific role in bladder cancer remains unclear. This study aims to clarify its activity in a large tumor cohort.
Methods
A tissue microarray (TMA) containing over 2,700 bladder tumors was analyzed using immunohistochemistry and fluorescence in-situ hybridi...
Single‐cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identification using Som...
Secondary resistance limits the clinical effectiveness of mutation-specific RAS inhibitors in colorectal cancer. It is unknown whether broad-spectrum RAS inhibitors meet similar limitations. Here, we identify and categorize mechanisms of resistance to the broad-spectrum active-state RAS inhibitor RMC-7977 in colorectal cancer cell lines. We found t...
While previous studies have demonstrated the potential of AI to diagnose diseases in imaging data, clinical implementation is still lagging behind. This is partly because AI models require training with large numbers of examples only available for common diseases. In clinical reality, however, only few diseases are common, whereas the majority of d...
3529
Background: CMS were associated with prognostic relevance in RAS WT mCRC, while their role as predictive biomarker is debatable. We aimed to assess the predictive impact of CMS on treatment with anti-EGFR vs. anti-VEGF antibodies vs. cytotoxic treatment alone in a pooled analysis. Methods: Available CMS data (called by predictedCMS method) of...
3506
Background: The randomized open-label phase II PanaMa trial compared FU/FA with or without pmab maintenance after mFOLFOX6+pmab induction for RAS wild-type mCRC. Updated efficacy results of the Full Analysis Set are presented. Methods: Median progression-free survival (PFS), overall survival (OS), PFS of re-induction (PFS re-ind.), time to fai...
3528
Background: mRNA expression of amphiregulin ( AREG) and epiregulin ( EREG) as ligands of the epidermal growth factor receptor (EGFR) were associated with response to anti-EGFR directed antibodies in metastatic colorectal cancer (mCRC). Their role for maintenance treatment remained unclear yet and was investigated in the PanaMa trial (panitumum...
3539
Background: Patterns of tumor immune cell infiltration in the tumor microenvironment are prognostic biomarkers in CRC. Here, the spatially resolved tumor immune microenvironment was analyzed for prognostic and predictive impact in patients with RAS wt mCRC treated with FU/FA +/- Pmab maintenance after Pmab + FOLFOX induction (PanaMa AIO KRK021...
The identification of low-grade urothelial neoplasia in cytologic samples or in biopsies with dysplastic lesions poses a particular problem for pathologists in routine diagnostics. Improved diagnosis of low-grade urothelial neoplasia could help to reduce the number of cystoscopic follow-up examinations. KDM6A, also known as UTX (ubiquitously transc...
Background
A high level of PD-L1 expression is the most relevant predictive parameter for response to immune checkpoint inhibitor (CPI) therapy in urinary bladder cancer. Existing data on the relationship between PD-L1 expression and the natural course of disease are controversial and sparse.
Methods
To expand our understanding of the relationship...
Morphologic heterogeneity of colorectal adenocarcinoma (CRC) is poorly understood. Previously, we identified morphological patterns associated with CRC molecular subtypes, and showed that these patterns have distinct molecular motifs (Budinska et al., 2023). Here, we evaluated the heterogeneity of these patterns across CRC. Three pathologists evalu...
Programmed cell death ligand 1 (PDL1), as an important biomarker, is quantified by immunohistochemistry (IHC) with few established histopathological patterns. Deep learning aids in histopathological assessment, yet heterogeneity and lacking spatially resolved annotations challenge precise analysis. Here, we present a weakly supervised learning appr...
Objectives
Carcinoembryonic antigen (CEA) is a cell surface glycoprotein that represents a promising therapeutic target. Serum measurement of shedded CEA can be utilized for monitoring of cancer patients.
Material and Methods
To evaluate the potential clinical significance of CEA expression in urothelial bladder neoplasms, CEA was analysed by immu...
Background: Thyroid transcription factor 1 (TTF-1) is expressed in 70% to 80% of lung adenocarcinomas (LUAD). Several papers revealed that TTF-1 expression is associated with better patient outcomes independent of the tumor stage. However, it is unknown whether the prognostic impact of TTF-1 only results from a different growth pattern (tumor gradi...
Background: Despite the rapidly increasing number of new targeted and immunotherapeutic options over the past two decades, the prognosis of patients with NSCLC, even with early-stage tumors, is still poor and novel biomarkers are needed to better stratify patients in terms of survival and treatment response. A novel approach is to gain a holistic u...
9p21 deletions are common in urothelial carcinoma and mostly include S-methyl-5′-thioadenosine phosphorylase (MTAP) a critical enzyme for DNA and RNA synthesis. Homozygous MTAP deletions result in a complete loss of expression which can be visualized by immunohistochemistry (IHC). Evidence is emerging that MTAP deficiency results in a critical vuln...
KDM6A, also known as UTX (ubiquitously transcribed X chromosome tetratricopeptide repeat protein) is an epigenetic regulator which is frequently mutated in urothelial carcinoma. Because KDM6A loss causes a dependency on EZH2, a potential therapeutic target, KDM6A analysis may have therapeutic importance. Most data on KDM6A mutations are derived fro...
Background: Thymidylate Synthetase (TYMS) is an import enzyme in the early stage of DNA biosynthesis. It is coded by the TYMS gene at 18p11.32, a region which has been found amplified in urothelial carcinoma. TYMS is a target enzyme for 5-fluorouracil (5-FU) and methotrexate. Elevated TYMS expression has been associated with poor prognosis and unfa...
Background: Loss of chromosome Y (LOY) occurs commonly in cancers of male patients. It was recently proposed to be associated with cancer aggressiveness and altered T-cell function in bladder cancer and it was found to be linked to poor prognosis in a TCGA bladder cancer patient cohort of 300 patients based on a combined analysis of RNAs from Y-chr...
Background: The Glutathione peroxidase 2 (GPX2) is a selenium-dependent glutathione peroxidase with a pivotal role in removing potentially harming reactive oxygen species (ROS) from cells by catalyzing the reduction process of hydrogen peroxide to water. GPX2 is strongly expressed in normal urothelium but can be reduced in urothelial cancer. The ai...
PURPOSE
Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown promising clinical results in the treatment of ovarian cancer. Analysis of biomarker subgroups consistently revealed higher benefits for patients with homologous recombination deficiency (HRD). The test that is most often used for the detection of HRD in clinical studies is the Myria...
Single-cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could potentially adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identificati...
Background
Anaplastic thyroid cancer (ATC) is a rare and aggressive neoplasm. We still lack effective treatment options, so survival rates remain very low. Here, we aimed to evaluate the activity of the combination of lenvatinib and pembrolizumab as systemic first-line therapy in ATC.
Methods
In a retrospective analysis, we investigated the activi...
Neurological symptoms, including cognitive impairment and fatigue, can occur in both the acute infection phase of coronavirus disease 2019 (COVID-19) and at later stages, yet the mechanisms that contribute to this remain unclear. Here we profiled single-nucleus transcriptomes and proteomes of brainstem tissue from deceased individuals at various st...
Background
The aim of this study was to analyse transcriptomic differences between primary and recurrent high-grade serous ovarian carcinoma (HGSOC) to identify prognostic biomarkers.
Methods
We analysed 19 paired primary and recurrent HGSOC samples using targeted RNA sequencing. We selected the best candidates using in silico survival and pathway...
Purpose
Single-cell transcriptional profiling reveals cell heterogeneity and clinically relevant traits in intra-operatively collected patient-derived tissue. So far, single-cell studies have been constrained by the requirement for prospectively collected fresh or cryopreserved tissue. This limitation might be overcome by recent technical developme...
The prognostic role of tumor cells in pancreatic ductal adenocarcinoma (PDAC) of the pancreatic head with direct microscopic infiltration (DMI) or in close proximity (≤1 mm) to the resection margin (RM) remains unclear. This single-center, retrospective study included specimens from 75 patients who underwent oncological resection of pancreatic head...
Purpose
We evaluated additional mutations in RAS wild-type (WT) metastatic colorectal cancer (mCRC) as prognostic and predictive biomarkers for the efficacy of added panitumumab to a 5-fluorouracil plus folinic acid (FU/FA) maintenance as pre-specified analysis of the randomized PanaMa trial.
Patients and Methods
Mutations (MUT) were identified us...
Introduction
Trophoblast cell surface antigen 2 (TROP2; EpCAM2) is a transmembrane glycoprotein which is closely related to EpCAM (EpCAM; EpCAM1). Both proteins share partial overlapping functions in epithelial development and EpCAM expression but have not been comparatively analyzed together in bladder carcinomas. TROP2 constitutes the target for...
Zusammenfassung
Infolge der hohen Zulassungsdynamik sowie der wachsenden Anzahl an immunonkologischen Therapiekonzepten nimmt die Komplexität der Therapieentscheidung und -steuerung im Bereich der Karzinome des Ösophagus, gastroösophagealen Übergangs und Magens stetig zu. Da die Indikationsstellung bei den derzeit in der Europäischen Union zugelass...
Introduction/Objective
Quantity and the spatial relationship of individual immune cell (sub)types can provide prognostic information in muscle-invasive bladder cancer.
Methods/Case Report
To study the prognostic role of different immune cell subpopulations in muscle-invasive bladder cancer, we stained 521 muscle-invasive urothelial bladder carcino...
Introduction/Objective
Gene amplifications of the proto-oncogen MYC are common events in carcinomas. In this study, we analyzed the impact of MYC amplifications on tumor aggressiveness and patient prognosis in urothelial bladder carcinomas.
Methods/Case Report
MYC copy number status was analyzed on more than 2,500 urothelial bladder carcinomas in...
Background:
Most inactivating p53 mutations result in a nuclear p53 accumulation - detectable by immunohistochemistry (IHC). p53 alterations leading to a complete lack of p53 protein and absence of immunostaining do also occur - not easily detectable by IHC. p16 is upregulated in p53 inactivated cells. We hypothesized that a positive p16 IHC may h...
Background
Non-small-cell lung cancer (NSCLC) is the leading cause for cancer death. Current targeted- and immuno-therapies are effective in a patient subset, but causes for resistance and the complexity of the immune reaction are difficult to be identified on a single patient level. It is hypothesized that the tumor microenvironment (TME) and its...
Testing to detect mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) has become an integral part of the routine diagnostic workup for colorectal cancer (CRC). While MSI was initially considered to be a possible indicator of a hereditary disposition to cancer (Lynch syndrome, LS), today the prediction of the therapy...
Background
Uroplakin-1a (Upk1a) and uroplakin-1b (Upk1b) have recently been identified as diagnostic markers for the distinction of urothelial carcinomas from other solid tumor entities. Both proteins play an important role in the stabilization and strengthening of epithelial cells that line the bladder.
Methods
To evaluate the prognostic role of...
Background
The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays a crucial role in regulating the immune system's response to tumors, but its exact role in cancer, especially in high-grade serous ovarian cancer (HGSOC), remains controversial. We aimed to investigate the prognostic impact of IDO1 expression and its correlation with tumor-infiltratin...
Zusammenfassung
Der Nachweis der Mismatch-Reparatur-Defizienz (dMMR) mit konsekutiver hochgradiger Mikrosatelliteninstabilität (MSI-H) ist inzwischen fester Bestandteil der Diagnostik des kolorektalen Karzinoms (KRK). Galt MSI anfänglich als möglicher Indikator einer erblichen Krebsdisposition (Lynch-Syndrom, LS) steht heute die Vorhersage des Ther...
The worldwide approval of the combination maintenance therapy of olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are sufficiently robust for the routine detection of driver mutations in homologous recombination repair (HRR) genes and genomic instability (GI), employing formalin...
Introduction:
Skip-N2 metastasis (N0N2), thus N2 metastasis in the absence of N1 metastasis, occur in approximately 20-30% of non-small cell lung cancer patients. N0N2 patients have a better prognosis than continuous-N2 metastasis (N1N2) patients following surgery. However, this effect remains controversial.Therefore, we conducted a multicentre st...
Background:
Differentiating intrahepatic cholangiocarcinomas (iCCA) from hepatic metastases of pancreatic ductal adenocarcinoma (PAAD) is challenging. Both tumours have similar morphological and immunohistochemical pattern and share multiple driver mutations. We hypothesised that DNA methylation-based machine-learning algorithms may help perform t...
There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous epithelial malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and app...
Sepsis remains a leading cause of human death and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the last decade, deciphering the functions of small non-coding microRNAs (miRNAs) in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA t...
4582
Background: Although it is well known that the quantity of specific immune cell types can provide prognostic information in bladder cancer, only little is known about the prognostic relevance of the localization of immune cells within the tumor microenvironment. Methods: To study the spatial interplay of different immune cell subpopulations an...
Objectives: To investigate the value of gadoxetic acid (Gd-EOB)–enhanced magnetic resonance imaging (MRI) for noninvasive subtype diferentiation of HCCs according to the 5th edition of the WHO Classifcation of Digestive System Tumors in a western population.
Methods: This retrospective study included 262 resected lesions in 240 patients with preop...
Single-cell transcriptional profiling reveals cell heterogeneity and clinically relevant traits in intra-operatively collected patient-derived tissue. However, the established approach to perform such analyses on freshly collected tissue constitutes an important limitation since it requires prospective collection and immediate processing. Therefore...
Background: Molecular bladder cancer (BC) subtypes define distinct biological entities and were shown to predict treatment response in neoadjuvant and adjuvant settings. The extent of intratumoral heterogeneity (ITH) might affect subtyping of individual patients.
Objective: To comprehensively assess the ITH of molecular subtypes in a cohort of musc...
Purpose:
Consensus molecular subtypes (CMSs) were evaluated as prognostic and predictive biomarkers of patients with RAS wild-type metastatic colorectal cancer (mCRC) receiving fluorouracil and folinic acid (FU/FA) with or without panitumumab (Pmab) after Pmab + mFOLFOX6 induction within the randomized phase II PanaMa trial.
Methods:
CMSs were d...
Purpose: Glycoprotein A33 (GPA33) is a membrane protein almost exclusively expressed in intestinal epithelia and in more than 95% of colorectal cancers (CRCs). This renders GPA33 a promising antigen for targeted therapy, but trials did not meet pre-specified response rates. We investigated intratumoral heterogeneity as a reason for low treatment ef...
Background: Tumor protein 63 (p63) is a transcription factor of the p53 gene family which is regularly expressed in the normal urothelium. Recently proposed RNA expression based molecular classifiers of bladder cancer identified high p63 expression as a component of a basal/squamous subtype linked to poor patient prognosis. The interplay between p6...