Gerhard Dyckhoff - Academia.edu (original) (raw)

Papers by Gerhard Dyckhoff

Cancers

Background: The induction and regulation of immune responses depend on human leucocyte antigen (H... more Background: The induction and regulation of immune responses depend on human leucocyte antigen (HLA) molecules that present peptides derived from mutated neoantigens or tumor-associated antigens to cytotoxic T cells. The natural variation of HLA molecules might differ between tumor patients and the normal population. Thus, there might be associations between the frequencies of HLA alleles and the survival of tumor patients. Methods: This issue was studied in a cohort of 84 patients with head and neck squamous cell carcinomas (HNSCCs) of different localizations. The cohort was followed up for more than 10 years. HLA-A/B/C CTS-PCR-SSP typing at 1 field level from blood samples was performed, and the results were correlated with survival. Results: HLA-A*02 was the most prevalent allele in our cohort and was present in 51.1% of patients. The HLA-A*25 and HLA-C*06 alleles exhibited a significantly higher frequency in cancer patients than in the normal population of 174 blood and kidney d...

HNO

ZusammenfassungKann die primäre Radiochemotherapie (pRCT) möglicherweise als alternative Standard... more ZusammenfassungKann die primäre Radiochemotherapie (pRCT) möglicherweise als alternative Standardtherapie zur totalen Laryngektomie (TL) angesehen werden? Gemäß der neuen S3-Leitlinie nehme der Patient zwar eine höhere Rückfallrate in Kauf, habe aber die Salvagechirurgie als kurative Option und insgesamt keinen Überlebensnachteil. In mehreren großen Datenbankanalysen und Fallserien findet sich für das T4-Larynxkarzinom ein signifikanter Überlebensnachteil der pRCT gegenüber der primären TL von über 30 %. Die Erfolgsrate der Salvagelaryngektomie beim T4-Karzinom liegt laut Literatur nur bei 25–50 %. Larynxorganerhaltstudien, die zur Empfehlung der pRCT als alternativer Standardtherapie führen könnten, sollten 1.) T4a-Karzinompatienten innerhalb ihrer T‑Kategorie auswerten, 2.) getrennt nach Larynx- und Hypopharynxkarzinomen, 3.) in aussagekräftiger Kollektivgröße, 4.) mit einem Nachbeobachtungszeitraum von mindestens 5 Jahren, 5.) mit onkologischen und 6.) funktionellen Outcome (Daue...

Figure S1. Differential DNA methylation at the TREX2 locus in the TCGA head and neck squamous cel... more Figure S1. Differential DNA methylation at the TREX2 locus in the TCGA head and neck squamous cell carcinoma cohort. Figure S2. Correlation of TREX2 mRNA expression and DNA methylation in the TCGA HNSC cohort. Figure S3. Differential DNA methylation and TREX2 expression affect overall survival of laryngeal cancer patients. Figure S4. Identification of the TREX2 gene promoter in luciferase reporter assays. Figure S5. Validation of the identified TREX2 promoter in FANTOM5 CAGE-seq data. Figure S6. Chromatin immunoprecipitation of H3K4me1 at the TREX2 gene locus. Figure S7. Correlation of TREX2 mRNA expression in different cell lines and primary cells (n=15) with mRNA expression of transcription factors with predicted binding motifs at the TREX2 DMR. Figure S8. Induction of TREX2 gene regulatory elements by CEBPB. Figure S9. Luciferase reporter assays for different TREX2 promoter and DMR constructs. Figure S10. Proximity ligation assay for predicted CEBPA binding sites at the TREX2 loc...

Clinical Epigenetics, 2019

Background: Genetic aberrations in DNA repair genes are linked to cancer, but less is reported ab... more Background: Genetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences. We investigated the intragenic methylation loss at the three prime repair exonuclease 2 (TREX2) locus in laryngeal (n = 256) and colorectal cancer cases (n = 95) and in pan-cancer data from The Cancer Genome Atlas (TCGA). Results: Significant methylation loss at an intragenic site of TREX2 was a frequent trait in both patient cohorts (p = 0.016 and < 0.001, respectively) and in 15 out of 22 TCGA studies. Methylation loss correlated with immunohistochemically staining for TREX2 (p < 0.0001) in laryngeal tumors and improved overall survival of laryngeal cancer patients (p = 0.045). Chromatin immunoprecipitation, demethylation experiments, and reporter gene assays revealed that the region of methylation loss can function as a CCAAT/enhancer binding protein alpha (CEBPA)-responsive enhancer element regulating TREX2 expression. Conclusions: The data highlight a regulatory role of TREX2 DNA methylation for gene expression which might affect incidence and survival of laryngeal cancer. Altered TREX2 protein levels in tumors may affect drug-induced DNA damage repair and provide new tailored therapies.

Head & Neck, 2018

Background: Cortactin (CTTN) is located on chromosome 11q13 and is associated with invasiveness i... more Background: Cortactin (CTTN) is located on chromosome 11q13 and is associated with invasiveness in various cancer entities. CTTN protein expression could be a prognosticator of oral squamous cell carcinoma (OSCC) in terms of recurrence and survival. Methods: CTTN-dependent invasion was performed using migration assay in human papillomavirus-negative head and neck squamous cell carcinoma (HNSCC) cells. Cortactin protein analysis in tissue microarrays was used for correlation with clinical parameters, as well as for survival analysis. Gene expression profiling in HNSCC cells was performed to unreveal CTTN signaling. Results: Knockdown of CTTN in HNSCC cells showed less invasion in vitro. Gene expression profiling showed various deregulated genes known to be involved in progression. We confirmed the link between CTTN overexpression and progression in a large clinical cohort. High expression was associated with worse overall and progression-free survival. Conclusions: We propose CTTN for managing OSCC in terms of adjuvant therapy and aftercare. Furthermore, our study reveals new potential targets in CTTN signaling for individualized OSCC therapy. K E Y W O R D S biomarker, cortactin, lymph node, metastasis, oral squamous cell carcinoma 1 | INTRODUCTION Cancer of the oral cavity (oral squamous cell carcinoma [OSCC]) and the oropharynx (oropharyngeal squamous cell carcinoma [OPSCC]) have an incidence of 400 000 cases per year; 1 among others as hypopharynx, larynx, and nasopharynx cancers. Their entities are subsumed under

Molecular Cell, 2014

DNA methylation is a dynamic and reversible process that governs gene expression during developme... more DNA methylation is a dynamic and reversible process that governs gene expression during development and disease. Several examples of active DNA demethylation have been documented, involving genome-wide and gene-specific DNA demethylation. How demethylating enzymes are targeted to specific genomic loci remains largely unknown. We show that an antisense lncRNA, termed TARID (for TCF21 antisense RNA inducing demethylation), activates TCF21 expression by inducing promoter demethylation. TARID interacts with both the TCF21 promoter and GADD45A (growth arrest and DNA-damageinducible, alpha), a regulator of DNA demethylation. GADD45A in turn recruits thymine-DNA glycosylase for base excision repair-mediated demethylation involving oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in the TCF21 promoter by ten-eleven translocation methylcytosine dioxygenase proteins. The results reveal a function of lncRNAs, serving as a genomic address label for GADD45A-mediated demethylation of specific target genes.

Analytica Chimica Acta, 2012

Retinoic acid signaling is essential for central nervous system (CNS) differentiation and appears... more Retinoic acid signaling is essential for central nervous system (CNS) differentiation and appears to be impaired in tumors. Thus far, there are no established methods to quantify relevant retinoids (all-transretinoic acid, 9-cis-retinoic acid, 13-cis retinoic acid, and retinol) in human brain tumors. We developed a single step extraction and quantification procedure for polar and apolar retinoids in normal tissue, lipidrich brain tumor tissues, and serum. This quantification procedure is based on high performance liquid chromatography (HPLC) with diode-array detection (DAD) using all-trans-acitretin as an internal standard and extraction by liquid-liquid partition with ethyl acetate and borate buffer at pH 9. Recovery with this extraction procedure was higher than earlier (two-step) liquid-liquid extraction procedures based on hexane, NaOH, and HCl. The overall quantification procedure was validated according to Food and Drug Administration (FDA) guidelines and fulfilled all criteria of accuracy, precision, selectivity, recovery, and stability. The overall method accuracy varied between −5.6% and +5.4% for serum and −3.8% and +6.2% for tissues, and overall precision ranged from 3.1% to 6.9% for serum and 2.1% to 8.3% for tissues (%CV batch-to-batch). The lower limit of quantification for all compounds in tumor tissue (and serum) was 3.9 ng g −1 (ng mL −1). Using this assay, photodegradation of the retinoids was evaluated and endogenous polar and apolar retinoids were quantified in sera and brain tumor tissues of patients and compared with serum and tonsil tissue concentrations of controls. It may thus serve as a suitable method for the characterization of retinoid uptake and metabolism in the respective compartments.

HNO

Zusammenfassung Hintergrund Derzeit gilt das größere, nicht mehr durch Teilresektionen behandelba... more Zusammenfassung Hintergrund Derzeit gilt das größere, nicht mehr durch Teilresektionen behandelbare T3-Larynxkarzinom als optimaler Kandidat für einen Larynxorganerhalt (LP) mittels primärer Radiochemotherapie (pRCT). Wann wäre eine primäre Strahlentherapie (pRT) ggf. auch ohne Chemotherapiezusatz vertretbar, und wann selbst beim T3 doch eher die totale Laryngektomie mit risikoadaptierter adjuvanter Therapie (TL±aR[C]T) zu empfehlen? Methodik In der Literatur wurde nach Parametern gesucht, die bei nichtrandomisierten zweiarmigen LP-Studien als Kriterium für den Einschluss in den chirurgischen anstelle des konservativen Arms genannt wurden oder die sich nach konservativer Therapie als signifikante Prognosemarker herausstellen. Hieraus Entwicklung eines Beratungsinstruments für die Therapieentscheidung. Ergebnisse Als signifikante Prognosemarker beschrieben wurden das Tumorvolumen, das Vorhandensein und die Art der Stimmbandfixierung, das Ausmaß der Knorpelinfiltration, der N‑Status u...

Cancers, 2021

T1 glottic cancer is a highly treatable disease with local control (LC) rates over 90% by either ... more T1 glottic cancer is a highly treatable disease with local control (LC) rates over 90% by either primary radiotherapy (pRT) or transoral laser microsurgery (TLM). LC of T2 glottic cancers is 15 percent points poorer on average. However, salvage after pRT entails more than 50% total laryngectomy. Therefore, there is a need for enhanced LC. Altered fractionation regimens improved LC in T1 but not in T2. For this reason, for T2, alternative strategies must be considered. In a large observational cohort study including 531 early-stage laryngeal cancers, a small number of patients were treated with primary chemoradiotherapy (pCRT). In multivariable analysis, factors associated with significantly poorer outcomes included age, comorbidities, supraglottic localization, and T category. While there was a significant difference between pRT and surgery (HR 1.79; 95%-CI: 1.15–2.79), there was none between pCRT and surgery (HR 0.70; 95%-CI: 0.33–1.51). There is evidence from the literature that p...

European Journal of Cancer, 2012

Laryngo- rhino- otologie, 2018

Filimonov A et al. Postoperative Complications of Total Laryngectomy in Diabetic Patients. Laryng... more Filimonov A et al. Postoperative Complications of Total Laryngectomy in Diabetic Patients. Laryngoscope 2017; 127: 2247–2251 DIABETES MELLITUS GILT ALS RISIKOFAKTOR VIELER KOMORBIDITäTEN UND KOMPLIKATIONEN. OB SICH DIE STOFFWECHSELERKRANKUNG EBENSO NEGATIV AUF DAS ERGEBNIS EINER TOTALEN LARYNGEKTOMIE AUSWIRKEN KANN, HABEN FILIMONOV UND KOLLEGINNEN/KOLLEGEN JETZT ANHAND EINER RETROSPEKTIVEN DATENANALYSE GENAUER BETRACHTET.

Journal of Clinical Oncology

6019Background: Human Papilloma Virus (HPV)-driven head and neck cancer (HNSCC) is associated wit... more 6019Background: Human Papilloma Virus (HPV)-driven head and neck cancer (HNSCC) is associated with good prognosis. The prognostic value of HPV-DNA and p16 IHC was recently reported by this consorti...

International Journal of Cancer

There have been hints that nonviral cancer antigens are differentially expressed in human papillo... more There have been hints that nonviral cancer antigens are differentially expressed in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC). Antibody responses (AR) to cancer antigens may be used to indirectly determine cancer antigen expression in the tumor using a noninvasive and tissue-saving liquid biopsy. Here, we set out to characterize AR to a panel of nonviral cancer antigens in HPV-positive and HPV-negative HNSCC patients. A fluorescent microbead multiplex serology to 29 cancer antigens (16 cancer-testis antigens, 5 cancer-retina antigens and 8 oncogenes) and 29 HPV-antigens was performed in 382 HNSCC patients from five independent cohorts (153 HPV-positive and 209 HPV-negative). AR to any of the cancer antigens were found in 272/382 patients (72%). The ten most frequent AR were CT47, cTAGE5a, c-myc, LAGE-1, MAGE-A1,-A3,-A4, NY-ESO-1, SpanX-a1 and p53. AR to MAGE-A3, MAGE-A9 and p53 were found at significantly different prevalences by HPV status. An analysis of AR mean fluorescent intensity values uncovered remarkably different AR clusters by HPV status. To identify optimal antigen selections covering a maximum of patients with 10 AR, multiobjective optimization revealed distinct antigen selections by HPV status. We identified that AR to nonviral antigens differ by HPV status indicating differential antigen expression. Multiplex serology may be used to characterize antigen expression using serum or plasma as a tissue-sparing liquid biopsy. Cancer antigen panels should address the distinct antigen repertoire of HPV-positive and HPV-negative HNSCC.

Clinical Cancer Research

Purpose: Targeted therapies are regarded as promising approaches to increase 5-year survival rate... more Purpose: Targeted therapies are regarded as promising approaches to increase 5-year survival rate of head and neck squamous cell carcinoma (HNSCC) patients. Experimental design: For the selection of carcinoma-specific peptides membrane proteome of HNO97 tumor cells fractionated by the ProteomeLab PF2D system and corresponding HNO97 cells were deployed for an alternating biopanning using a sunflower trypsin inhibitor1-based phage display (SFTI8Ph) library. Stability, binding properties and affinity of novel candidates were assessed in vitro using radio-HPLC, binding experiments and surface plasmon resonance assay (SPR), respectively. Subsequently, the affinity of the peptide was verified in situ by using peptide histochemistry, in vitro using flow cytometry, and in vivo by positron emissions tomography (PET/CT). Results: We identified a novel ITGa v b 6 binding peptide (SFITGv6) containing the amino acid sequence FRGDLMQL. SFITGv6 provides stability over a period of 24 hours and demonstrates high affinity (K D ¼ 14.8 nmol/L) for ITGa v b 6. In HNO97 cells, a maximal uptake and internalization of up to 37.3% and 37.5%, respectively, was measured. Small-animal PET imaging and biodistribution studies of HNO97 xenografted Balb/c nu/nu mice showed tumor-specific accumulation of 68 Ga-and 177 Lulabeled DOTA-SFITGv6, respectively, 30 to 60 minutes after injection. Moreover, peptide histochemistry revealed a strong and homogenous binding of biotin-labeled SFITGv6 to HNSCC tumors and breast-and lung cancer-derived brain metastases. Finally, first PET/CT scans of HNSCC and NSCLC patients displayed SFITGv6 accumulation specifically in tumors, but not in inflammatory lesions. Conclusions: Thus, SFITGv6 represents a novel powerful tracer for imaging and possibly for endoradiotherapy of ITGa v b 6-positive carcinoma. Clin Cancer Res; 23(15); 4170-80. Ó2017 AACR.

European Journal of Cancer, 2014

Journal of Thrombosis and Haemostasis, 2005

cisplatin in the presence of DMSO and a failure of biological activity of cisplatin in vivo whene... more cisplatin in the presence of DMSO and a failure of biological activity of cisplatin in vivo whenever DMSO was used in their experiments. In regard to doxorubicin, Cervantes and coauthors [3] found a significant inhibition of doxorubicin toxicity after treatment with hydroxyl radical scavengers (N-acetylcysteine, sodium benzoate and also DMSO). They concluded that hydroxyl radicals might be involved in the antitumor activity of doxorubicin. In line with this observation and as a further hint of the underlying mechanism, it was shown that doxorubicin induces reactive oxygen species (ROS) in endothelial cells [4]. The versatile functions of DMSO, including its action as a free radical scavenger, its stabilizing effects on cell membranes and its radioprotective effects were reviewed by Yu and Quinn [5]. According to these properties, DMSO was successfully applied in several clinical trials to protect against drug-induced tissue necrosis after paravasation [6,7]. In summary, the hypothesis of Kaushal and coauthors that thalidomide treatment protects doxorubicin-injured endothelial cells from cell death cannot be proven in the presence of DMSO and needs a further proof of principle. In this regard, CMC may be used as an alternative solvent, because it did not display any disturbing influence on the biological activity of cytotoxic drugs in our experiments. We hope that our comments will be helpful for further studies in this field.