Publications by authors named "Kathrin Scheckenbach"

51 Publications

Association of HLA genotypes, AB0 blood type and chemokine receptor 5 mutant CD195 with the clinical course of COVID-19.

Eur J Med Res 2021 Sep 16;26(1):107. Epub 2021 Sep 16.

Medical Faculty, University of Dusseldorf, Dusseldorf, Germany.

Background: COVID-19, the pandemic disease caused by infection with SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients' adaptive immune responses without progression to severe disease with patients' Human Leukocyte Antigen (HLA) genetics, AB0 blood group antigens, and the presence or absence of near-loss-of-function delta 32 deletion mutant of the C-C chemokine receptor type 5 (CCR5).

Patient And Methods: An exploratory observational study including 157 adult COVID-19 convalescent patients was performed with a median follow-up of 250 days. The impact of different HLA genotypes, AB0 blood group antigens, and the CCR5 mutant CD195 were investigated for their role in the clinical course of COVID-19. In addition, this study addressed levels of severity and morbidity of COVID-19. The association of the immunogenetic background parameters were further related to patients' humoral antiviral immune response patterns by longitudinal observation.

Results: Univariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01). They were associated with reduced durations of disease instead decreased (rather than increased) total anti-S IgG levels. They had a higher virus neutralizing capacity compared to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:02 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A suggestive association of a heterozygous CCR5 delta 32 mutation status with prolonged disease duration was implied by univariate analyses but could not be confirmed by hierarchical multivariate testing.

Conclusion: The current study shows that the presence of HLA class II DRB1*01:01 and HLA class I B*35:01 is of even stronger association with reduced disease duration in mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations also including novel SARS-CoV-2 variants will be required to assess the impact of HLA genetics on the capacity of mounting protective vaccination responses in the future.
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http://dx.doi.org/10.1186/s40001-021-00560-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444184PMC
September 2021

Informed consent and informed intervention: SARS-CoV-2 vaccinations not just call for disclosure of newly emerging safety data but also for hypothesis generation and testing.

Eur J Med Res 2021 Aug 6;26(1):87. Epub 2021 Aug 6.

Department of Radiation Oncology, Medical Faculty, University Hospital Dusseldorf, Heinrich-Heine-University Dusseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.

Background: COVID-19 infection is a major threat to patients and health care providers around the world. One solution is the vaccination against SARS-CoV-2.

Methods: We performed a comprehensive query of the latest publications on the prevention of viral infections including the recent vaccination program and its side effects.

Results: The situation is evolving rapidly and there is no reasonable alternative to population-scale vaccination programs as currently enrolled.

Conclusion: Therefore, regulatory authorities should consider supplementing their conventional mandate of post-approval pharmacovigilance, which is based on the collection, assessment, and regulatory response to emerging safety findings.
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http://dx.doi.org/10.1186/s40001-021-00558-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343366PMC
August 2021

The important role of cisplatin in the treatment of HPV-positive oropharyngeal cancer assessed by real-world data analysis.

Oral Oncol 2021 Oct 23;121:105454. Epub 2021 Jul 23.

Amsterdam UMC, Vrije Universiteit Amsterdam, Otolaryngology / Head and Neck Surgery, Cancer Center Amsterdam, the Netherlands.

Objectives: The prognostic advantage of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) resulted in the initiation of treatment de-intensification studies. Two randomized controlled trials (RCTs) reported inferior survival of HPV-positive OPSCC treated with radiotherapy plus cetuximab compared to standard of care radiotherapy plus cisplatin. In this study we investigated whether the important role of cisplatin in the treatment of HPV-positive OPSCCs would also emerge from causal inference analyses of real-world data.

Material And Methods: A retrospective cohort of 263 advanced-stage OPSCC-patients from 5 European clinics was studied, treated with radiotherapy (RT) alone or cisplatin-based chemoradiotherapy (CRT) based on standard clinical indications. Causal inference was applied to adjust for treatment assignment, thereby simulating a randomized setting. Average treatment effect of concurrent cisplatin on overall survival (OS) probability was estimated using Bayesian Additive Regression Trees (BART) and Bayesian logistic regression.

Results: Significantly better survival probabilities were found for HPV-positive OPSCC treated with CRT compared to RT alone (3-year OS probability 0.961 versus 0.798, p = 0.008).

Conclusion: This study using causal inference of retrospective patient data confirms the important role of cisplatin in the treatment of HPV-positive OPSCC. Causal inference analyses of real-world data complements the evidence from the published RCTs.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105454DOI Listing
October 2021

A Prospectively Validated Prognostic Model for Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck Based on Radiomics of Computed Tomography Images.

Cancers (Basel) 2021 Jun 29;13(13). Epub 2021 Jun 29.

The D-Lab, Department of Precision Medicine, GROW-School for Oncology, Maastricht University, Maastricht, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.

Background: Locoregionally advanced head and neck squamous cell carcinoma (HNSCC) patients have high relapse and mortality rates. Imaging-based decision support may improve outcomes by optimising personalised treatment, and support patient risk stratification. We propose a multifactorial prognostic model including radiomics features to improve risk stratification for advanced HNSCC, compared to TNM eighth edition, the gold standard.

Patient And Methods: Data of 666 retrospective- and 143 prospective-stage III-IVA/B HNSCC patients were collected. A multivariable Cox proportional-hazards model was trained to predict overall survival (OS) using diagnostic CT-based radiomics features extracted from the primary tumour. Separate analyses were performed using TNM8, tumour volume, clinical and biological variables, and combinations thereof with radiomics features. Patient risk stratification in three groups was assessed through Kaplan-Meier (KM) curves. A log-rank test was performed for significance (-value < 0.05). The prognostic accuracy was reported through the concordance index (CI).

Results: A model combining an 11-feature radiomics signature, clinical and biological variables, TNM8, and volume could significantly stratify the validation cohort into three risk groups ( < 0∙01, CI of 0.79 as validation).

Conclusion: A combination of radiomics features with other predictors can predict OS very accurately for advanced HNSCC patients and improves on the current gold standard of TNM8.
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http://dx.doi.org/10.3390/cancers13133271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269129PMC
June 2021

Reconvalescent plasma/camostat mesylate in early SARS-CoV-2 Q-PCR positive high-risk individuals (RES-Q-HR): a structured summary of a study protocol for a randomized controlled trial.

Trials 2021 May 17;22(1):343. Epub 2021 May 17.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty Heinrich-Heine-University Duesseldorf, Moorenstr. 5, D-40225, Duesseldorf, Germany.

Objectives: Currently, there are no approved treatments for early disease stages of COVID-19 and few strategies to prevent disease progression after infection with SARS-CoV-2. The objective of this study is to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate administered within 72 h of diagnosis of SARS-CoV-2 infection in adult individuals with pre-existing risk factors at higher risk of getting seriously ill with COVID-19. Camostat mesylate acts as an inhibitor of the host cell serine protease TMPRSS2 and prevents the virus from entering the cell. CP represents another antiviral strategy in terms of passive immunization. The working hypothesis to be tested in the RES-Q-HR study is that the early use of CP or camostat mesylate reduces the likelihood of disease progression to (modified) WHO stages 4b-8 in SARS-CoV-2-positive adult patients at high risk of moderate or severe COVID-19 progression.

Trial Design: This study is a 4-arm (parallel group), multicenter, randomized (2:2:1:1 ratio), partly double-blind, controlled trial to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate with control or placebo in adult patients diagnosed with SARS-CoV-2 infection and high risk for progression to moderate/severe COVID-19. Superiority of the intervention arms will be tested.

Participants: The trial is conducted at 10-15 tertiary care centers in Germany. Individuals aged 18 years or above with ability to provide written informed consent with SARS-CoV-2 infection, confirmed by PCR within 3 days or less before enrolment and the presence of at least one SARS-CoV-2 symptom (such as fever, cough, shortness of breath, sore throat, headache, fatigue, smell/and or taste disorder, diarrhea, abdominal symptoms, exanthema) and symptom duration of not more than 3 days. Further inclusion criteria comprise: Presence of at least one of the following criteria indicating increased risk for severe COVID-19: Age > 75 years Chronic obstructive pulmonary disease (COPD) and/or pulmonary fibrosis BMI > 40 kg/m Age > 65 years with at least one other risk factor (BMI > 35 kg/m, coronary artery disease (CAD), chronic kidney disease (CKD) with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) BMI > 35 kg/m with at least one other risk factor (CAD, CKD with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) Exclusion criteria: 1. Age < 18 years 2. Unable to give informed consent 3. Pregnant women or breastfeeding mothers 4. Previous transfusion reaction or other contraindication to a plasma transfusion 5. Known hypersensitivity to camostat mesylate and/or severe pancreatitis 6. Volume stress due to CP administration would be intolerable 7. Known IgA deficiency 8. Life expectancy < 6 months 9. Duration SARS-CoV-2 typical symptoms > 3 days 10. SARS-CoV-2 PCR detection older than 3 days 11. SARS-CoV-2 associated clinical condition ≥ WHO stage 3 (patients hospitalized for other reasons than COVID-19 may be included if they fulfill all inclusion and none of the exclusion criteria) 12. Previously or currently hospitalized due to SARS-CoV-2 13. Previous antiviral therapy for SARS-CoV-2 14. ALT or AST > 5 x ULN at screening 15. Liver cirrhosis > Child A (patients with Child B/C cirrhosis are excluded from the trial) 16. Chronic kidney disease with GFR < 30 ml/min 17. Concurrent or planned anticancer treatment during trial period 18. Accommodation in an institution due to legal orders (§40(4) AMG). 19. Any psycho-social condition hampering compliance with the study protocol. 20. Evidence of current drug or alcohol abuse 21. Use of other investigational treatment within 5 half-lives of enrolment is prohibited 22. Previous use of convalescent plasma for COVID-19 23. Concomitant proven influenza A infection 24. Patients with organ or bone marrow transplant in the three months prior to screening visit INTERVENTION AND COMPARATOR: Participants will be randomized to the following 4 groups: 1) Convalescent plasma (CP), 2 units at screening/baseline visit (day 0) or day 1; CP is defined by the presence of neutralizing anti-SARS-CoV-2 antibodies with titers ≥ 1:160; individuals with body weight ≥ 150 kg will receive a third unit of plasma on day 3 2) Camostat mesylate (200 mg per capsule, one capsule taken each in the morning, afternoon and evening on days 1-7) 3) Standard of care (SOC, control for CP) 4) Placebo (identical in appearance to camostat mesylate capsules, one capsule taken each morning, afternoon and evening on days 1-7; for camostat mesylate control group) Participants will be monitored after screening/baseline on day 3, day 5, day 8, and day 14. On day 28 and day 56, telephone visits and on day 90, another outpatient visit are scheduled. Adverse events and serious adverse events will be monitored and reported until the end of the study. An independent data safety monitoring committee will review trial progression and safety.

Main Outcomes: The primary endpoint of the study is the cumulative number of individuals who progress to or beyond category 4b on the modified WHO COVID-19 ordinal scale (defined as hospitalization with COVID-19 pneumonia and additional oxygen demand via nasal cannula or mask) within 28 days after randomization.

Randomization: Participants will be randomized using the Alea-Tool ( aleaclinical.com ) in a 2:2:1:1 ratio to the treatment arms (1) CP, (2) camostat mesylate, (3) standard of care (SoC), and (4) placebo matching camostat mesylate. Randomization will be stratified by study center.

Blinding (masking): The camostat mesylate treatment arm and the respective placebo will be blinded for participants, caregivers, and those assessing outcomes. The treatment arms convalescent plasma and standard of care will not be blinded and thus are open-labeled, unblinded.

Numbers To Be Randomized (sample Size): Overall, n = 994 participants will be randomized to the following groups: n = 331 to convalescent plasma (CP), n = 331 to camostat mesylate, n = 166 to standard of care (SoC), and n = 166 to placebo matching camostat mesylate.

Trial Status: The RES-Q-HR protocol (V04F) was approved on the 18 December 2020 by the local ethics committee and by the regulatory institutions PEI/BfARM on the 2 December 2020. The trial was opened for recruitment on 26 December 2020; the first patient was enrolled on 7 January 2021 and randomized on 8 January 2021. Recruitment shall be completed by June 2021. The current protocol version RES-Q HR V05F is from 4 January 2021, which was approved on the 18 January 2021.

Trial Registration: EudraCT Number 2020-004695-18 . Registered on September 29, 2020. ClinicalTrial.gov NCT04681430 . Registered on December 23, 2020, prior to the start of the enrollment (which was opened on December 26, 2020).

Full Protocol: The full protocol (V05F) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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http://dx.doi.org/10.1186/s13063-021-05181-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127198PMC
May 2021

CD44v6-targeted CAR T-cells specifically eliminate CD44 isoform 6 expressing head/neck squamous cell carcinoma cells.

Oral Oncol 2021 May 22;116:105259. Epub 2021 Apr 22.

Department of Otorhinolaryngology, Head & Neck Surgery, Heinrich Heine University, Düsseldorf, Germany; Department of Pediatrics III, University Children's Hospital, University of Duisburg-Essen, Essen, Germany. Electronic address:

Immune checkpoint blockade can cause regression of recurrent and/or refractory head and neck squamous cell carcinoma (HNSCC). As a second type of immunotherapy, adoptive cellular therapy with genetically modified patient's T-cells redirected against the autologous malignant cells by expressing chimeric antigen receptors (CARs) recognizing tumor-associated antigens has been established as highly efficient personalized treatment for hematological malignancies. In solid cancers however, the application of these genetically modified immune effector cells still lacks equal response rates. CD44v6 is an isoform of the hyaluronic receptor CD44 that is almost exclusively expressed at high levels on solid cancers and has been associated with tumorigenesis, tumor cell invasion and metastasis. Here, we established a highly specific CAR against CD44v6 on HNSCC cells that can be expressed on normal T-cells with lentiviral vectors. Using primary human HNSCC cells in combination with CRISPR/Cas9 and overexpression approaches allowed us to confirm the high specificity of our CAR construct for the tumor-associated CD44v6 as target antigen and to demonstrate a direct correlation between CD44v6 expression levels and cytotoxicity of the CAR T-cells. Importantly, the design of our clinically applicable lentiviral vector facilitates to co-express a second transgene for in vivo control of CAR T-cells, if undesired side-effects or toxicities occur.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105259DOI Listing
May 2021

Development of a multiomics database for personalized prognostic forecasting in head and neck cancer: The Big Data to Decide EU Project.

Head Neck 2021 02 27;43(2):601-612. Epub 2020 Oct 27.

Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Background: Despite advances in treatments, 30% to 50% of stage III-IV head and neck squamous cell carcinoma (HNSCC) patients relapse within 2 years after treatment. The Big Data to Decide (BD2Decide) project aimed to build a database for prognostic prediction modeling.

Methods: Stage III-IV HNSCC patients with locoregionally advanced HNSCC treated with curative intent (1537) were included. Whole transcriptomics and radiomics analyses were performed using pretreatment tumor samples and computed tomography/magnetic resonance imaging scans, respectively.

Results: The entire cohort was composed of 71% male (1097)and 29% female (440): oral cavity (429, 28%), oropharynx (624, 41%), larynx (314, 20%), and hypopharynx (170, 11%); median follow-up 50.5 months. Transcriptomics and imaging data were available for 1284 (83%) and 1239 (80%) cases, respectively; 1047 (68%) patients shared both.

Conclusions: This annotated database represents the HNSCC largest available repository and will enable to develop/validate a decision support system integrating multiscale data to explore through classical and machine learning models their prognostic role.
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http://dx.doi.org/10.1002/hed.26515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820974PMC
February 2021

Computed tomography-derived radiomic signature of head and neck squamous cell carcinoma (peri)tumoral tissue for the prediction of locoregional recurrence and distant metastasis after concurrent chemo-radiotherapy.

PLoS One 2020 22;15(5):e0232639. Epub 2020 May 22.

The D-lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.

Introduction: In this study, we investigate the role of radiomics for prediction of overall survival (OS), locoregional recurrence (LRR) and distant metastases (DM) in stage III and IV HNSCC patients treated by chemoradiotherapy. We hypothesize that radiomic analysis of (peri-)tumoral tissue may detect invasion of surrounding tissues indicating a higher chance of locoregional recurrence and distant metastasis.

Methods: Two comprehensive data sources were used: the Dutch Cancer Society Database (Alp 7072, DESIGN) and "Big Data To Decide" (BD2Decide). The gross tumor volumes (GTV) were delineated on contrast-enhanced CT. Radiomic features were extracted using the RadiomiX Discovery Toolbox (OncoRadiomics, Liege, Belgium). Clinical patient features such as age, gender, performance status etc. were collected. Two machine learning methods were chosen for their ability to handle censored data: Cox proportional hazards regression and random survival forest (RSF). Multivariable clinical and radiomic Cox/ RSF models were generated based on significance in univariable cox regression/ RSF analyses on the held out data in the training dataset. Features were selected according to a decreasing hazard ratio for Cox and relative importance for RSF.

Results: A total of 444 patients with radiotherapy planning CT-scans were included in this study: 301 head and neck squamous cell carcinoma (HNSCC) patients in the training cohort (DESIGN) and 143 patients in the validation cohort (BD2DECIDE). We found that the highest performing model was a clinical model that was able to predict distant metastasis in oropharyngeal cancer cases with an external validation C-index of 0.74 and 0.65 with the RSF and Cox models respectively. Peritumoral radiomics based prediction models performed poorly in the external validation, with C-index values ranging from 0.32 to 0.61 utilizing both feature selection and model generation methods.

Conclusion: Our results suggest that radiomic features from the peritumoral regions are not useful for the prediction of time to OS, LR and DM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232639PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244120PMC
August 2020

Quality In Allergology.

Laryngorhinootologie 2020 03 16;99(S 01):S272-S300. Epub 2020 Mar 16.

Klinik für Hals-Nasen-Ohrenheilkunde, UniversitätsAllergieZentrum (UAZ), Universitätsklinikum Düsseldorf.

High-quality treatment of patients suffering from allergies should be a first priority of ENT specialists. In daily routine of otolaryngologists, allergic diseases play a significant role and have to be diagnosed and treated competently. A multitude of guidelines provide a clear corridor for identification of suitable methods. The most important sensitization tests such as skin tests and the determination of specific IgE in the serum lay the foundations of allergy diagnostics. Nasal provocation tests with allergens as most important and most frequently applied allergen provocation tests can be performed especially by highly qualified ENT specialists. They allow the determination of the clinical relevance of single allergens.Beside pharmacotherapy and avoidance of allergens, the allergen-specific immunotherapy has a central position in the treatment of allergy diseases. Also in this context, correct indication and targeted selection of the pharmaceutics lead to an increased treatment quality.In particular complex or severe allergic diseases require specialized and even highly specialized treatment. In Germany, structured requirements for establishing Comprehensive Allergy Centers have been developed. The involvement of otolaryngology in the further development of such centers should be improved.Sound allergy education and training are the basis for competence and quality of the treatment of allergy patients. In medical studies, allergology is currently underrepresented. In specialization, some basic aspects of allergies are taken into account. The medical education for the additional specialization in allergology is currently changing; it is intended to be simplified but this might lead to devaluation. A full speciality of allergology does currently not exist in Germany.In particular in the areas of allergy training, allergy research, and in the cooperation of ENT specialists in highly specialized allergy centers, an enormous potential for improvement is seen for the discipline of otolaryngology.
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http://dx.doi.org/10.1055/a-1029-6494DOI Listing
March 2020

The landscape of , and DNA methylation in head and neck squamous cell carcinomas.

Epigenetics 2020 11 21;15(11):1195-1212. Epub 2020 Apr 21.

Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn , Bonn, Germany.

CTLA-4 blocking therapeutic antibodies are currently under investigation in head and neck squamous cell carcinoma (HNSCC). A better understanding of the epigenetic regulation of the CD28 superfamily members CD28, CTLA-4, and ICOS and their B7 ligands, CD80 and CD86, could support the development of biomarkers for response prediction to anti-CTLA-4 immunotherapy. We investigated methylation of the encoding genes , and at single CpG resolution (51 CpG sites) in a cohort of HNSCC (528) and normal adjacent tissue samples (50) provided by The Cancer Genome Research Atlas, in isolated blood leukocytes from healthy individuals (28), and HNSCC cell lines ( = 39). We analysed methylation levels with regard to mRNA expression, overall survival, mutational load, interferon-γ signature, and signatures of immune cell infiltrates. Depending on the location of the CpG sites (promoter, promoter flank, gene body, and intergenic sites), we found significant differences in methylation levels among isolated leukocytes, between leukocytes and HNSCC cell lines, and among HNSCCs. Methylation of all analysed genes correlated inversely or positively with mRNA expression, depending on the CpG site. , and revealed almost identical correlation patterns. Furthermore, we found significant correlations with survival and features of response to immunotherapy, i.e. interferon-γ signature, signatures of tumour infiltrating immune cells, and mutational load. Our results suggest , and expression levels are epigenetically co-regulated by DNA methylation. This study provides rationale to test their DNA methylation as potential biomarker for prediction of response to CTLA-4 immune checkpoint inhibitors.
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http://dx.doi.org/10.1080/15592294.2020.1754675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595594PMC
November 2020

Privacy-preserving distributed learning of radiomics to predict overall survival and HPV status in head and neck cancer.

Sci Rep 2020 03 11;10(1):4542. Epub 2020 Mar 11.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

A major challenge in radiomics is assembling data from multiple centers. Sharing data between hospitals is restricted by legal and ethical regulations. Distributed learning is a technique, enabling training models on multicenter data without data leaving the hospitals ("privacy-preserving" distributed learning). This study tested feasibility of distributed learning of radiomics data for prediction of two year overall survival and HPV status in head and neck cancer (HNC) patients. Pretreatment CT images were collected from 1174 HNC patients in 6 different cohorts. 981 radiomic features were extracted using Z-Rad software implementation. Hierarchical clustering was performed to preselect features. Classification was done using logistic regression. In the validation dataset, the receiver operating characteristics (ROC) were compared between the models trained in the centralized and distributed manner. No difference in ROC was observed with respect to feature selection. The logistic regression coefficients were identical between the methods (absolute difference <10). In comparison of the full workflow (feature selection and classification), no significant difference in ROC was found between centralized and distributed models for both studied endpoints (DeLong p > 0.05). In conclusion, both feature selection and classification are feasible in a distributed manner using radiomics data, which opens new possibility for training more reliable radiomics models.
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http://dx.doi.org/10.1038/s41598-020-61297-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066122PMC
March 2020

DNA methylation of indoleamine 2,3-dioxygenase 1 (IDO1) in head and neck squamous cell carcinomas correlates with IDO1 expression, HPV status, patients' survival, immune cell infiltrates, mutational load, and interferon γ signature.

EBioMedicine 2019 Oct 15;48:341-352. Epub 2019 Oct 15.

Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany. Electronic address:

Background: The immune checkpoint, indoleamine 2,3-dioxygenase 1, is under investigation as target of novel immunotherapies for cancers, including head and neck squamous cell carcinomas (HNSCC). The aim of our study was to analyze DNA methylation of the encoding gene (IDO1) in HNSCC.

Methods: Methylation of three CpG sites within the promoter, promoter flank, and gene body was investigated and correlated with mRNA expression, immune cell infiltration, mutational burden, human papillomavirus (HPV)-status, and overall survival in a cohort of N = 528 HNSCC patients obtained from The Cancer Genome Atlas. In addition, IDO1 immunohistochemistry and DNA methylation analysis was performed in an independent cohort of N = 138 HNSCC samples.

Findings: Significant inverse correlations of IDO1 methylation and IDO1 mRNA expression were found in the promoter and promoter flank region (Spearman's ρ = -0.163 and ρ = -0.377, respectively) while a positive correlation was present in the gene body (ρ = 0.502; all P < 0.001). IDO1 DNA methylation significantly correlated with IDO1 protein expressing immune cells as well as tumor cells. IDO1 promoter flank hypermethylation was significantly associated with poor overall survival (P < 0.001). In addition, we discovered significant correlations between IDO1 methylation and expression with RNA signatures of immune cell infiltrates and with HPV-status, mutational load (methylation only), and interferon γ signature.

Interpretation: Our results suggest IDO1 expression levels are epigenetically regulated by DNA methylation. This study provides rationale to test IDO1 methylation as potential biomarker for prediction of response to IDO1 immune checkpoint inhibitors in HNSCC.
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http://dx.doi.org/10.1016/j.ebiom.2019.09.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838413PMC
October 2019

Upregulation of the long non-coding RNA CASC9 as a biomarker for squamous cell carcinoma.

BMC Cancer 2019 Aug 14;19(1):806. Epub 2019 Aug 14.

Department of Urology, Medical Faculty, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.

Background: Few diagnostic and prognostic biomarkers are available for head-and-neck squamous cell carcinoma (HNSCC). Long non-coding RNAs (lncRNAs) have shown promise as biomarkers in other cancer types and in some cases functionally contribute to tumor development and progression. Here, we searched for lncRNAs useful as biomarkers in HNSCC.

Methods: Public datasets were mined for lncRNA candidates. Two independent HNSCC tissue sets and a bladder cancer tissue set were analyzed by RT-qPCR. Effects of lncRNA overexpression or downregulation on cell proliferation, clonogenicity, migration and chemosensitivity were studied in HNSCC cell lines.

Results: Data mining revealed prominently CASC9, a lncRNA significantly overexpressed in HNSCC tumor tissues according to the TCGA RNAseq data. Overexpression was confirmed by RT-qPCR analyses of patient tissues from two independent cohorts. CASC9 expression discriminated tumors from normal tissues with even higher specificity than HOTAIR, a lncRNA previously suggested as an HNSCC biomarker. Specificity of HNSCC detection by CASC9 was further improved by combination with HOTAIR. Analysis of TCGA pan-cancer data revealed significant overexpression of CASC9 across different other entities including bladder, liver, lung and stomach cancers and especially in squamous cell carcinoma (SCC) of the lung. By RT-qPCR analysis we furthermore detected stronger CASC9 overexpression in pure SCC of the urinary bladder and mixed urothelial carcinoma with squamous differentiation than in pure urothelial carcinomas. Thus, CASC9 might represent a general diagnostic biomarker and particularly for SCCs. Unexpectedly, up- or downregulation of CASC9 expression in HNSCC cell lines with low or high CASC9 expression, respectively, did not result in significant changes of cell viability, clonogenicity, migration or chemosensitivity.

Conclusions: CASC9 is a promising biomarker for HNSCC detection. While regularly overexpressed, however, this lncRNA does not seem to act as a major driver of development or progression in this tumor.
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http://dx.doi.org/10.1186/s12885-019-6021-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694542PMC
August 2019

The Wnt-Driven Mll1 Epigenome Regulates Salivary Gland and Head and Neck Cancer.

Cell Rep 2019 01;26(2):415-428.e5

Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany. Electronic address:

We identified a regulatory system that acts downstream of Wnt/β-catenin signaling in salivary gland and head and neck carcinomas. We show in a mouse tumor model of K14-Cre-induced Wnt/β-catenin gain-of-function and Bmpr1a loss-of-function mutations that tumor-propagating cells exhibit increased Mll1 activity and genome-wide increased H3K4 tri-methylation at promoters. Null mutations of Mll1 in tumor mice and in xenotransplanted human head and neck tumors resulted in loss of self-renewal of tumor-propagating cells and in block of tumor formation but did not alter normal tissue homeostasis. CRISPR/Cas9 mutagenesis and pharmacological interference of Mll1 at sequences that inhibit essential protein-protein interactions or the SET enzyme active site also blocked the self-renewal of mouse and human tumor-propagating cells. Our work provides strong genetic evidence for a crucial role of Mll1 in solid tumors. Moreover, inhibitors targeting specific Mll1 interactions might offer additional directions for therapies to treat these aggressive tumors.
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http://dx.doi.org/10.1016/j.celrep.2018.12.059DOI Listing
January 2019

Endoskopische Sinuschirurgie: Checkliste hilft Problemfälle vorab zu entdecken.

Laryngorhinootologie 2018 09 5;97(9):600-601. Epub 2018 Sep 5.

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http://dx.doi.org/10.1055/a-0621-1877DOI Listing
September 2018

[Radiomics: Big Data Instead of Biopsies in the Future?]

Laryngorhinootologie 2018 Mar 22;97(S 01):S114-S141. Epub 2018 Mar 22.

Klinik für Hals-Nasen-Ohrenheilkunde, Universitätsklinikum Düsseldorf.

Precision medicine is increasingly pushed forward, also with respect to upcoming new targeted therapies. Individual characterization of diseases on the basis of biomarkers is a prerequisite for this development. So far, biomarkers are characterized clinically, histologically or on a molecular level. The implementation of broad screening methods ("Omics") and the analysis of big data - in addition to single markers - allow to define biomarker signatures. Next to "Genomics", "Proteomics", and "Metabolicis", "Radiomics" gained increasing interest during the last years. Based on radiologic imaging, multiple radiomic markers are extracted with the help of specific algorithms. These are correlated with clinical, (immuno-) histopathological, or genomic data. Underlying structural differences are based on the imaging metadata and are often not visible and therefore not detectable without specific software. Radiomics are depicted numerically or by graphs. The fact that radiomic information can be extracted from routinely performed imaging adds a specific appeal to this method. Radiomics could potentially replace biopsies and additional investigations. Alternatively, radiomics could complement other biomarkers and thus lead to a more precise, multimodal prediction. Until now, radiomics are primarily used to investigate solid tumors. Some promising studies in head and neck cancer have already been published.
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http://dx.doi.org/10.1055/s-0043-121964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541032PMC
March 2018

Mutational and Functional Analysis of as a Candidate Gene for Sporadic Head and Neck Squamous Cell Carcinomas.

Anticancer Res 2018 03;38(3):1317-1325

Department of Otorhinolaryngology & Head/Neck Surgery, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany

Background/aim: Head and neck squamous cell carcinomas (HNSCCs) form a heterogeneous tumor entity located throughout the oral cavity, pharynx and larynx that is caused predominantly by chemically or virally induced carcinogenesis. Heterozygous germline mutations in cancer susceptibility genes might also lead to increased incidence of HNSCCs. As DNA stability is typically impaired in HNSCC cells and genes of the Fanconi anemia/BRCA DNA repair pathway can be mutated or down-regulated in HNSCCs, we investigated here whether germline mutations occur in the X-chromosomal FANCB as candidate gene.

Materials And Methods: Germline DNA of 85 consecutive HNSCC patients was sequenced. Missense alterations in FANCB were functionally tested in reference cells.

Results And Conclusion: Four single nucleotide polymorphisms were identified, three of which were located in untranslated regions of FANCB (rs2188383, rs2375729, rs2905223) and predicted to be associated with normal function. One missense alteration, c.1004G>A resulting in p.G335E (rs41309679), in exon 4 was detected in five men in homozygous and in five women in heterozygous state. Four in silico prediction programs uniformally predicted p.G335E to be associated with loss-of-function of the protein. To clarify these predictions, we expressed the FANCB p.G335E protein in primary human FANCB deficient fibroblasts. Cell cycle analysis of these fibroblasts established that the FANCB p.G335E was functionally indistinguishable from the wildtype FANCB protein. Thus, functional studies in genetically defined cells showed that the p.G335E germline alteration in FANCB is not associated with impaired function.
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http://dx.doi.org/10.21873/anticanres.12354DOI Listing
March 2018

Prognostic modeling of oral cancer by gene profiles and clinicopathological co-variables.

Oncotarget 2017 Aug 26;8(35):59312-59323. Epub 2017 Jul 26.

Department of Otolaryngology - Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.

Accurate staging and outcome prediction is a major problem in clinical management of oral cancer patients, hampering high precision treatment and adjuvant therapy planning. Here, we have built and validated multivariable models that integrate gene signatures with clinical and pathological variables to improve staging and survival prediction of patients with oral squamous cell carcinoma (OSCC). Gene expression profiles from 249 human papillomavirus (HPV)-negative OSCCs were explored to identify a 22-gene lymph node metastasis signature (LNMsig) and a 40-gene overall survival signature (OSsig). To facilitate future clinical implementation and increase performance, these signatures were transferred to quantitative polymerase chain reaction (qPCR) assays and validated in an independent cohort of 125 HPV-negative tumors. When applied in the clinically relevant subgroup of early-stage (cT1-2N0) OSCC, the LNMsig could prevent overtreatment in two-third of the patients. Additionally, the integration of RT-qPCR gene signatures with clinical and pathological variables provided accurate prognostic models for oral cancer, strongly outperforming TNM. Finally, the OSsig gene signature identified a subpopulation of patients, currently considered at low-risk for disease-related survival, who showed an unexpected poor prognosis. These well-validated models will assist in personalizing primary treatment with respect to neck dissection and adjuvant therapies.
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http://dx.doi.org/10.18632/oncotarget.19576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601734PMC
August 2017

Diagnostic and prognostic value of long noncoding RNAs as biomarkers in urothelial carcinoma.

PLoS One 2017 21;12(4):e0176287. Epub 2017 Apr 21.

Department of Urology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.

Many long noncoding RNAs (lncRNAs) are deregulated in cancer and contribute to oncogenesis. In urothelial carcinoma (UC), several lncRNAs have been reported to be overexpressed and proposed as biomarkers. As most reports have not been confirmed independently in large tissue sets, we aimed to validate the diagnostic and prognostic value of lncRNA upregulation in independent cohorts of UC patients. Thus, expression of seven lncRNA candidates (GAS5, H19, linc-UBC1, MALAT1, ncRAN, TUG1, UCA1) was measured by RT-qPCR in cell lines and tissues and correlated to clinicopathological parameters including follow-up data (set 1: N n = 10; T n = 106). Additionally, publicly available TCGA data was investigated for differential expression in UC tissues (set 2: N n = 19; T n = 252,) and correlation to overall survival (OS). All proposed candidates tended to be upregulated in tumour tissues, with the exception of MALAT1, which was rather diminished in cancer tissues of both data sets. However, strong overexpression was generally limited to individual tumour tissues and statistically significant overexpression was only observed for UCA1, TUG1, ncRAN and linc-UBC1 in tissue set 2, but for no candidate in set 1. Altered expression of individual lncRNAs was associated with overall survival, but not consistently between both patient cohorts. Interestingly, lower expression of TUG1 in a subset of UC patients with muscle-invasive tumours was significantly correlated with worse OS in both cohorts. Further analysis revealed that tumours with low TUG1 expression are characterized by a basal-squamous-like subtype signature accounting for the association with poor outcome. In conclusion, our study demonstrates that overexpression of the candidate lncRNAs is found in many UC cases, but does not occur consistently and strongly enough to provide reliable diagnostic or prognostic value as an individual biomarker. Subtype-dependent expression patterns of lncRNAs like TUG1 could become useful to stratify patients by molecular subtype, thus aiding personalized treatments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176287PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400278PMC
September 2017

Endotypes in Chronic Rhinosinusitis: Biomarkers Based on a Mechanistic Insight for Targeted Treatment?

ORL J Otorhinolaryngol Relat Spec 2017 24;79(1-2):78-84. Epub 2017 Feb 24.

Department of Otorhinolaryngology and Head and Neck Surgery, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Chronic rhinosinusitis is an umbrella term for several phenotypes and mechanistically distinct inflammatory diseases of the nose and the paranasal sinuses affecting around 11% of the population in Europe and the USA. Approximately 20% of the patients present with uncontrolled disease despite adequate treatment, and revision surgery is common. While a clinical characterization alone does not improve treatment results, novel but expensive biologics have increasingly become available, but they require a better understanding of the mechanism. Mechanistic markers of disease may help to allocate the optimal drug to a patient, thus reducing undesirable side effects and avoiding unnecessary treatment and costs with respect to potential non-responders, thereby increasing responder rates and compliance.
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http://dx.doi.org/10.1159/000455721DOI Listing
December 2017

Radiomics in Head and Neck Cancer: Extracting Valuable Information from Data beyond Recognition.

ORL J Otorhinolaryngol Relat Spec 2017 24;79(1-2):65-71. Epub 2017 Feb 24.

Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Düsseldorf, Düsseldorf, Germany.

In oncology, biomarkers that describe the characteristics of a malignancy on different levels (clinical, histological, molecular) and the patient's outcome and treatment response are increasingly integrated into the clinical routine. Extensive screening tools, "omics," offer incredible opportunities and vast amounts of data. During the last years, the field of "omics" gained a new promising partner, the "radiomics." Based on radiological imaging, multiple features can be extracted and linked to clinical, genomic, and histopathological data from other sources. Extracted traits describe radiological intensity, shape and texture characteristics and can be analyzed on routinely performed images. These specific radiomic markers and patterns are currently developed for multiple tumor entities, and first studies for squamous cell carcinoma of the head and neck have been initiated.
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http://dx.doi.org/10.1159/000455704DOI Listing
December 2017

[E-learning in ENT: Usage in University Medical Centers in Germany].

Laryngorhinootologie 2017 Mar 18;96(3):175-179. Epub 2017 Jan 18.

Hals-Nasen-Ohrenklinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Deutschland.

E-learning is an essential part of innovative medical teaching concepts. The challenging anatomy and physiology in ENT is considered particularly suitable for self-assessed and adaptive e-learning. Usage and data on daily experience with e-learning in German ENT-university hospitals are currently unavailable and the degree of implementation of blended learning including feed-back from medical students are currently not known. We investigated the current need and usage of e-learning in academic ENT medical centers in Germany. We surveyed students and chairs for Otorhinolaryngology electronically and paperbased during the summer semester 2015. Our investigation revealed an overall heterogenous picture on quality and quantity of offered e-learning applications. While the overall amount of e-learning in academic ENT in Germany is rather low, at least half of the ENT-hospitals in medical faculties reported that e-learning had improved their own teaching activities. More collaboration among medical faculties and academic ENT-centers may help to explore new potentials, overcome technical difficulties and help to realize more ambitious projects.
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http://dx.doi.org/10.1055/s-0042-117640DOI Listing
March 2017

Influence of dosimetric and clinical criteria on the requirement of artificial nutrition during radiotherapy of head and neck cancer patients.

Radiother Oncol 2016 07 10;120(1):28-35. Epub 2016 Jun 10.

Department of Radiation Oncology, Medical Faculty Heinrich Heine University Hospital Duesseldorf, Germany.

Purpose/objective(s): Intensification of radiotherapy and chemotherapy for head-and-neck cancer (HNC) may lead to increased rates of long term dysphagia as a severe side effect. Mucositis and consequent swallowing problems require artificial nutrition in many HNC patients undergoing radiotherapy or chemoradiation. It is unknown, which predict factors for prophylactic PEG tube insertion appear useful.

Materials/methods: From an institutional database, 101 patients (72 male, 29 female, mean age 59.5years) were identified who underwent radiotherapy or chemoradiation for HNC. Primary end point of the investigation was the need for artificial nutrition for more than 4days during radiotherapy. Dose volume parameters of defined normal tissue structures potentially of relevance for swallowing ability as well as clinical factors were used to develop a predictive model using a binary multiple logistic regression model.

Results: Whereas several dosimetric and clinical factors were significant predictors for the need of artificial nutrition on univariate analysis, on multivariate analysis only three factors remained independently significant: mean dose to the oropharynx+1cm circumferential margin, ECOG performance state (0-1 vs. 2-4), and the use of chemotherapy (yes vs. no).

Conclusions: Using a 3 parameter model we could distinguish HNC-patients with different risks for the need of artificial nutrition during radiotherapy. After independent validation, the model could be helpful to decision on prophylactic PEG tube insertion.
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http://dx.doi.org/10.1016/j.radonc.2016.05.017DOI Listing
July 2016

Cytokine Patterns and Endotypes in Acute and Chronic Rhinosinusitis.

Curr Allergy Asthma Rep 2016 Jan;16(1)

Department of Otorhinolaryngology, Head & Neck Surgery, Heinrich Heine University, Duesseldorf, Germany.

Since rhinosinusitis is an inflammatory disease, cytokines as key regulators of inflammation play a central role in its pathophysiology. In acute rhinosinusitis, several proinflammatory cytokines of different types have been identified. Initial information about the involvement of the inflammasome in rhinosinusitis has been gained, but this area remains open for more detailed research. Although it has been accepted now that chronic rhinosinusitis (CRS) needs to be differentiated into CRS with and without nasal polyps, it has become clear that this distinction is insufficient to clearly define subgroups with uniform pathophysiology and cytokine patterns. While Th1-cytokines are mostly found in CRSsNP and Th2 cytokines in CRSwNP, there is a substantial overlap, and several other cytokines have also been detected. Attempts to identify CRS endotypes based on cytokines are ongoing but not yet generally accepted. Despite the central role of cytokines in rhinosinusitis, no specific cytokine-targeted therapies are currently available, and only very few studies have specifically addressed the effects of such biologicals in rhinosinusitis.
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http://dx.doi.org/10.1007/s11882-015-0583-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7088912PMC
January 2016

Evaluation of Customized Prosthesis for Irregularly Formed Tracheostoma After Laryngectomy.

Ann Otol Rhinol Laryngol 2016 Feb 25;125(2):145-50. Epub 2015 Aug 25.

Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany

Background: After laryngectomy, the tracheostoma forms the functional center for breathing and phonation. An occasionally occurring but typical problem can arise from an oversized and/or irregularly formed tracheostoma, hampering the temporary occlusion necessary for sufficient speech production. As an alternative to a surgical correction of the tracheostoma, an individually adjusted stoma silicone prosthesis may be used.

Materials And Methods: Twenty-one patients suffering from irregularly formed tracheostoma after laryngectomy followed by insertion of a speech valve were provided with a silicone tracheostomal prosthesis. They underwent subjective assessment of voice quality and breathing function according to a standardized general questionnaire and to the Voice Handicap Index (VHI). Furthermore, a clinical evaluation was performed including detection of peristomal leakage and phonation time.

Results And Discussion: Patients described a significant improvement of voice production with the tracheostomal prosthesis (averagely graded as 1.9 with and 3.2 without prosthesis, P = .0026). Breathing was also slightly improved by the prosthesis with an average grade of 1.7 compared to 2.3 with a conventional cannula (P = .063). There was a strong correlation between self-evaluation and the total score of the VHI after insertion of the prosthesis (P < .0001). Minor local skin reactions caused by the adhesive were described by 5 of the 21 patients.

Conclusions: A tracheostomal prosthesis represents an efficient alternative to surgical revision of irregularly formed tracheostoma after laryngectomy, enhancing voice production and breathing function.
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http://dx.doi.org/10.1177/0003489415601686DOI Listing
February 2016

AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia.

Hum Mol Genet 2015 Sep 17;24(18):5093-108. Epub 2015 Jun 17.

Myriad Genetics Inc., Salt Lake City, UT, USA.

Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2-6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2-6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2-6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene.
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http://dx.doi.org/10.1093/hmg/ddv227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550815PMC
September 2015

MicroRNA expression in differentially metastasizing tumors of the head and neck: adenoid cystic versus squamous cell carcinoma.

Anticancer Res 2015 Mar;35(3):1271-7

Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany.

Background/aim: Head and neck adenoid cystic carcinoma (HNACC) is a rare malignancy of the salivary glands with a tendency to metastasize in lung or liver without lymph node involvement, whereas squamous cell carcinoma (HNSCC) preferentially metastasizes to locoregional lymph nodes. The expression patterns of microRNA, a class of small non-coding RNA transcripts, involved in gene regulation and various developmental processes, could be of influence during the metastatic process. The aim of the present study was to compare mircoRNA expression patterns of HNACC and HNSCC.

Materials And Methods: In a total of 21 tissue samples, a genome-wide screening for microRNAs was performed. A microRNA array platform was used for the identification of target microRNA.

Results: Five microRNAs, hsa-MiR-214, hsa-MiR-125a-5p, hsa-MiR-574-3p, hsa-MiR-199a-3p/199b-3p and hsa-miR-199a-5p were identified to be over-expressed in HNACC compared to HNSCC, whereas hsa-MiR-452 showed a lower expression level.

Conclusion: Our data showed significantly different expression patterns of mircoRNA in HNACC and HNSCC supporting the theory of tumor-specific expression and giving hints for different clinical behavior.
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March 2015

Taking a fresh look at the skull base in otorhinolaryngology with web-based simulation: Student's Interactive Skull-Base Trainer (SISTer).

JAMA Otolaryngol Head Neck Surg 2015 Feb;141(2):154-9

Department of Otolaryngology, Klinkum rechts der Isar, Technische Universität, München, Germany.

Importance: The increasing amount of medical knowledge and necessity for time-effective teaching and learning have given rise to emerging online, or e-learning, applications. The base of the skull is a challenging anatomic area in the otorhinolaryngology (ORL) department-for both students and lecturers. Technology-enhanced learning might be an expedient approach to benefit both learners and lecturers.

Objective: To investigate and create for advanced medical students a self-assessed adaptive e-learning application for the skull base within our curriculum of otolaryngology at the University Medical Center of Heinrich Heine University, Düsseldorf, Germany.

Design, Setting, And Participants: Pilot approach with prospective evaluation of a newly implemented web-based e-learning simulation. The e-learning application (Student's Interactive Skull-Base Trainer) was made accessible as an elective course to a total of 269 enrolled medical students during the first 2 semesters after web launch.

Interventions: Spatiotemporal independent e-learning application for the skull base.

Main Outcomes And Measures: Self-assessed evaluation with focus on general acceptance and personal value as well as usage data analysis.

Results: The application was well accepted by the learners. More than 80% of the participating students found the application to be a beneficial tool for enhancing their analytical and clinical problem-solving skills. Although the general matter of the skull base seemed to be of lesser interest, the concept of anchored instructions with the use of high-end, interactive, multimedia-based content was considered to be particularly suitable for this challenging topic. Most of the students would have appreciated an extension of optional e-learning modules.

Conclusions And Relevance: With this pilot approach we were able to implement a useful and now well-accepted tool for blended learning. We showed that it is possible to raise interest even in this very specialized subspecialty of ORL with overall individual learning benefit for the students. There is a demand for more e-learning and web-based simulation to support the existing curricula in a hybrid, blended way.
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http://dx.doi.org/10.1001/jamaoto.2014.3041DOI Listing
February 2015
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