47 results on '"Ralser DJ"'
Search Results
2. BReLasca – Prospektive Beobachtungsstudie zur intraoperativen Anwendung der Laser Speckle Imaging-(Lasca) Technologie in der Onkoplastisch-rekonstruktiven Brustchirurgie
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Ralser, DJ, additional, Recker, F, additional, Bachmann, A, additional, Kaiser, C, additional, Abramian, A, additional, and Faridi, A, additional
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- 2022
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3. Intraoperativer Einsatz der Laser Speckle Contrast Analysis (LASCA) -Technologie in der Onkoplastischen Brustchirurgie - eine Pilotstudie
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Ralser, DJ, additional, Abramian, AV, additional, Lindner, K, additional, Kaiser, C, additional, and Faridi, A, additional
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- 2021
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4. Epigenetische Regulation von PDCD1 (PD-1), PD-L1 (CD274) und PD-L2 (PDCD1LG2) als Biomarker in der Immuntherapie des triple negativen Mammakarzinoms
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Ralser, DJ, additional, Klümper, N, additional, Kaiser, C, additional, Faridi, A, additional, Abramian, A, additional, and Dietrich, D, additional
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- 2020
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5. DNA-Methylierung von PDCD1 (PD-1), PD-L1 (CD274) und PD-L2 (PDCD1LG2) als Biomarker in der Immuntherapie des triple negativen Mammakarzinoms
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Ralser, DJ, additional, Klümper, N, additional, Kaiser, C, additional, Faridi, A, additional, Abramian, A, additional, and Dietrich, D, additional
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- 2020
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6. Determination of endometrial cancer molecular subtypes using a whole exome-sequencing based single-method approach.
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Mustea A, Ralser DJ, Egger EK, Ziehm U, Vivas S, Brock S, Jackson D, Condic M, Rauschendorf MA, Würfel P, Dombrowski F, Otten LA, Sun P, Laib A, Cordova MC, Hartmann R, Stein MA, Koensgen D, and Stope MB
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- Humans, Female, Aged, Middle Aged, Biomarkers, Tumor genetics, Prognosis, Aged, 80 and over, Adult, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology, Endometrial Neoplasms classification, Exome Sequencing methods
- Abstract
Aim: Endometrial cancer (EC) is heterogeneous with respect to epidemiology, clinical course, histopathology and tumor biology. Recently, The Cancer Genome Atlas (TCGA) network has identified four molecular subtypes with distinct clinical courses by an integrated multi-omics approach. These subtypes are of critical importance in the clinical management of EC. However, determination of TCGA molecular subtypes requires a complex methodological approach that is resource intensive and difficult to implement in diagnostic routine procedures. In this context, Talhouk et al. reported the precise determination of modified subtypes based on molecular surrogates obtained by a two-method approach comprising immunohistochemistry and DNA-sequence analysis (Proactive Molecular Risk Classifier for Endometrial Cancer; ProMisE). In this study, we aimed to identify EC molecular subtypes in analogy to TCGA and ProMisE applying an innovative whole exome-sequencing (WES) based single-method approach., Methods: WES was performed in a cohort comprising N = 114 EC patients. WES data were analyzed using the oncology treatment decision support software MH Guide (Molecular Health, Heidelberg, Germany) and EC molecular subtypes in analogy to TCGA and ProMisE were determined. Results from both classifications were compared regarding their prognostic values using overall survival and progression-free survival analyses., Results: Applying a single-method WES-approach, EC molecular subtypes analogue to TCGA and ProMisE were identified in the study cohort. The surrogate marker-analogue classification precisely identified high-risk and low-risk EC, whereas the TCGA-analogue classification failed to obtain significant prognostic values in this regard., Conclusion: Our data demonstrate that determination of EC molecular subtypes analogue to TCGA and ProMisE is feasible by using a single-method WES approach. Within our EC cohort, prognostic implications were only reliably provided by applying the surrogate marker-analogue approach. Designation of molecular subtypes in EC will be increasingly important in routine clinical practice. Thus, the single-method WES approach provides an important simple tool to tailor therapeutic decisions in EC., (© 2024. The Author(s).)
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- 2024
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7. Anterior enterocele after cystectomy: case report and review of the literature.
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Schröder C, Plöger R, Knüpfer S, Tascón Padrón L, Ralser DJ, Otten LA, Egger EK, Mustea A, and Könsgen D
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- Humans, Female, Aged, Postoperative Complications surgery, Postoperative Complications etiology, Hernia etiology, Recurrence, Cystectomy adverse effects, Urinary Bladder Neoplasms surgery
- Abstract
Purpose: Anterior enterocele is a rare but potentially serious complication after cystectomy with heterogeneous treatment options., Methods: Here we report on the management of a 71-year-old patient with recurrence of anterior enterocele after cystectomy and provide a systematic review of the literature using the PubMed/MEDLINE database., Results: The 71-year-old patient with recurrence of anterior enterocele after cystectomy was successfully treated with colpocleisis and anterior colporrhaphy at the Department of Gynecology and Gynecological Oncology, University Hospital Bonn. The use of a synthetic mesh was not needed. At 16-month follow-up postoperatively, the patient was asymptomatic and had no signs of recurrence. n = 14 publications including n = 39 patients were identified for the systematic review including case reports and reviews. The median duration of developing an anterior enterocele after cystectomy was 9 months (range 3 months to 8 years). Patients had a median age of 71 years (range 44-84). In all cases, a surgical approach was described using a wide variety of surgical procedures. In total, 36% of all patients developed a recurrence with an average time period of 7 months after primary surgery. A rare complication represents a vaginal evisceration with the need of urgent surgery. Furthermore, the occurrence of a fistula is a possible long-term complication., Conclusion: Anterior enterocele after cystectomy is a rare complication requiring an individual and interdisciplinary treatment., (© 2024. The Author(s).)
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- 2024
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8. Preclinical evidence for the use of anti-Trop-2 antibody-drug conjugate Sacituzumab govitecan in cerebral metastasized castration-resistant prostate cancer.
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Weiten R, Niemann M, Below E, Friker LL, Ralser DJ, Toma M, Kristiansen G, Hahn O, Zechel S, Grünwald V, Bald T, Siewert J, Pietsch T, Ritter M, Hölzel M, Eckstein M, Alajati A, Krausewitz P, and Klümper N
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- Male, Humans, Cell Line, Tumor, Nectins, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant pathology, Immunoconjugates therapeutic use, Immunoconjugates pharmacology, Cell Adhesion Molecules metabolism, Cell Adhesion Molecules genetics, Antigens, Neoplasm immunology, Brain Neoplasms secondary, Brain Neoplasms drug therapy, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized pharmacology, Camptothecin analogs & derivatives, Camptothecin therapeutic use, Camptothecin pharmacology
- Abstract
Purpose: Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody-drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop-2 and NECTIN-4 in cerebral metastasized CRPC (mCRPC)., Methods: Immunohistochemical staining of Trop-2 and NECTIN-4 with evaluation of H-score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop-2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti-Trop-2 ADC Sacituzumab govitecan (SG) in vitro., Results: Our analysis revealed that most patients exhibited moderate to strong Trop-2 expression [n = 27/31 with H-score ≥100, median H-score 220 (IQR 180-280)], while NECTIN-4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop-2 expression levels in vitro. Overexpression of Trop-2 in Trop-2-negative PC-3 cells led to sensitization to SG, whereas CRISPR-Cas9-mediated knockdown of Trop-2 in Trop-2-expressing DU-145 cells conferred resistance to SG., Conclusion: The substantial expression of Trop-2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2024
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9. Integration of on-treatment modified Glasgow prognostic score (mGPS) to improve imaging-based prediction of outcomes in patients with non-small cell lung cancer on immune checkpoint inhibition.
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Saal J, Bald T, Eckstein M, Ralser DJ, Brossart P, Ellinger J, Hölzel M, and Klümper N
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- Humans, Immune Checkpoint Inhibitors therapeutic use, Prognosis, Carcinoma, Non-Small-Cell Lung diagnostic imaging, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Renal Cell, Kidney Neoplasms, Lung Neoplasms diagnosis, Lung Neoplasms drug therapy
- Abstract
Introduction: A large number of patients with non-small cell lung cancer (NSCLC) on immune checkpoint inhibition (ICI) achieve stable disease (SD) as the best overall response, which is associated with heterogeneous outcomes. In this context, complementary biomarkers that improve outcome prediction are needed. We have recently demonstrated that measuring the on-treatment modified Glasgow prognostic score (mGPS), which is based on the two serum markers C-reactive protein (CRP) and albumin, can improve outcome prediction complementary to radiological staging in metastatic renal cell carcinoma. However, this concept has not been assessed for patients with NSCLC on ICI., Methods: We assessed the prognostic and predictive value of on-treatment mGPS at week six in patients with NSCLC treated with atezolizumab or docetaxel in the phase 3 OAK trial (NCT02008227) comprising n = 750 patients and validated the findings in the phase 2 BIRCH (NCT02031458, n = 560)., Results: On-treatment mGPS assessed at week six demonstrated valuable prognostic information (Hazard Ratio (HR) for mGPS low-risk vs intermediate risk 2.34 (95 % CI 1.76-3.11, p < 0.001) and vs high risk 3.56, (95 % CI 2.57-4.91, p < 0.001) in the atezolizumab-treated subgroup. On-treatment mGPS predicted overall survival more accurately than imaging using RECIST criteria (concordance index: on-treatment mGPS 0.646 (95 % CI 0.615-0.677) vs RECIST 0.606 (95 % CI 0.575-0.637)). On-treatment mGPS provides additional prognostic information to imaging-assessed treatment response at first staging, especially for the patient subgroup with SD. These findings were validated in the BIRCH trial., Conclusions: We highlight the novel concept of integrating on-treatment mGPS for improved outcome prediction in conjunction with radiological imaging for patients with NSCLC on ICI., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JS: grants from BONFOR Program of the Medical Faculty of the University of Bonn and Mildred Scheel School of Oncology (MSSO), Cologne. TB: none. ME: personal fees and nonfinancial support from MSD; grants, personal fees, and nonfinancial support from AstraZeneca and Janssen-Cilag; grants and personal fees from Cepheid; personal fees from Roche, Astellas, and Diaceutics; and grants from Stratifyer and Gilead. DJR: personal fees from Novartis during the conduct of the study. PB: consulting fees from Amgen, Astra-Zeneca, BMS, MSD, Roche, personal fees from Amgen, Roche, MSD, BMS, Astra-Zeneca, Novartis. JE: travel grant from LISA Laser and Advisory Board BAYER Vital and Janssen-Cilag. MH: grants from Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), grants from TME Pharma (previously known as Noxxon Pharma), personal fees from BMS and Novartis. NK: grants from Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) and BMBF-funded Advanced Clinician Scientist Program Bonn (ACCENT) of the Medical Faculty of the University of Bonn, personal fees from Astellas, MSD, Novartis, Ipsen, and Photocure, advisory roles for Astellas, MSD, Eisai., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2024
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10. Hypermethylated SHOX2 in circulating cell-free DNA post renal cell carcinoma surgery as TNM-independent biomarker for recurrence risk.
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Büttner T, Zarbl R, Krausewitz P, Strieth S, Kristiansen G, Eckstein M, Ralser DJ, Hölzel M, Ritter M, Ellinger J, Dietrich D, and Klümper N
- Abstract
Introduction: Adjuvant immune checkpoint inhibitor trials in renal cell carcinoma (RCC) call for improved recurrence risk stratification. Due to limitations of circulating tumor DNA (ctDNA) use in RCC, the use of hypermethylated SHOX2 gene (mSHOX2) in circulating cell-free DNA is explored as a surrogate marker for identifying high-risk patients after RCC surgery., Methods: Liquid biopsies were collected post-surgery from 45 RCC patients (mean duration 4.3 days). Real-time polymerase chain reaction was used to analyze SHOX2 methylation in circulating cell-free DNA. Patients were categorized as mSHOX2 positive or negative by cut-off. Metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) were assessed using Cox regression and Log-rank analyses (median follow-up time: 60 months)., Results: 17 patients were mSHOX2 positive, showing unfavorable OS/CSS (Log-rank P = 0.004 and 0.02) and nearly 6-fold higher recurrence risk (hazard ratio 5.89, 95% CI 1.46-23.8). Multivariable Cox analysis confirmed mSHOX2 as an independent recurrence risk factor, disregarding TNM-based stratification., Conclusions: mSHOX2 effectively identifies high-risk RCC patients post-surgery, indicating minimal residual disease. This easy to implement biomarker has potential for guiding of adjuvant therapy decisions., Competing Interests: DD has been an employee of Epigenomics AG, Berlin, Germany. This company aims to commercialize DNA methylation biomarker SHOX2. DD is co-inventor and owns patents on methylation biomarkers and related technologies. DD receives inventor’s compensation from Epigenomics AG., (AJTR Copyright © 2024.)
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- 2024
11. Founder Variants in KRT5 and POGLUT1 Are Implicated in Dowling-Degos Disease.
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Kumar S, Borisov O, Maj C, Ralser DJ, Humbatova A, Hanneken S, Schmieder A, Groß J, Maintz L, Heineke A, Knuever J, Fagerberg C, Parmentier L, Anemüller W, Oji V, Tantcheva-Poór I, Fölster-Holst R, Wenzel J, Krawitz PM, Frank J, and Betz RC
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- Humans, Keratin-5 genetics, Glucosyltransferases, Skin Diseases, Genetic genetics, Hyperpigmentation genetics, Skin Diseases, Papulosquamous diagnosis, Skin Diseases, Papulosquamous genetics
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- 2024
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12. Optimized complete cytoreduction in ovarian cancer through intraoperative real-time tumor visualization by 5-ALA - a case report.
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Tascón Padrón L, Egger EK, Ralser DJ, Otten L, Toksöz ÖA, Kristiansen G, Stummer W, and Mustea A
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Introduction: Complete macroscopic cytoreduction represents the most important prognostic parameter for overall survival in ovarian cancer. This dogma remains tenacious despite significant improvements in adjuvant systemic treatment. Hence, optimization of surgical therapy is an overarching goal to improve patients' outcomes. In this context, intraoperative tumor-specific imaging might facilitate optimized cytoreduction. In neurosurgery, intraoperative 5-aminolevulinic acid (5-ALA) guided imaging is applied in clinical routine to assess surgical resection margins. Here, we report the case of a patient with ovarian cancer in whom intraoperative 5-ALA tumor visualization led to optimized complete cytoreduction., Objective: Intraoperative administration of 5-ALA led to improved complete cytoreduction by identification and resection of additional ovarian cancer tumor manifestations., Case: The 39-year-old patient, Jehovah`s witness, presented to our department with a left sided ovarian mass, suspicious of ovarian cancer, based on clinical examination, sonographic suspicious features and a CA12-5 elevation. The patient's medical history and family history was unremarkable. Preoperative CT imaging of the thorax and abdomen showed no pathology besides the adnexal mass. Surgery was performed by a midline laparotomy with hysterectomy, bilateral adnexectomy, pelvic peritonectomy, omentectomy, ureterolysis, diaphragm stripping, adhesiolysis and the collection of peritoneal and rectal samples. Intraoperative 5-ALA imaging using a dedicated excitation and detection loupe system (Reveal, DVI) led to tumor detection at the diaphragm, the omentum and the rectum that was not detectable by palpation and visualization using white light. The pathology results revealed that the 5-ALA positive samples (diaphragm, rectum and omentum) obtained by intraoperative 5-ALA were positive for ovarian cancer., Conclusion: Intraoperative administration of 5-ALA represents a promising approach to improve complete cytoreduction in ovarian cancer surgery thereby improving clinical outcomes. Hence, further research and clinical trials are required to investigate the potential of intraoperative 5-ALA imaging in ovarian cancer debulking surgery and its impact on long-term clinical outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tascón Padrón, Egger, Ralser, Otten, Toksöz, Kristiansen, Stummer and Mustea.)
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- 2023
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13. Altered Notch signalling in Dowling-Degos disease: a transcriptomic insight into disease pathogenesis.
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Kumar S, Hausen J, Sivalingam S, Humbatova A, Buness A, Frank J, Ralser DJ, and Betz RC
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- Humans, Transcriptome genetics, Hyperpigmentation genetics, Hyperpigmentation pathology, Skin Diseases, Papulosquamous diagnosis, Skin Diseases, Papulosquamous genetics, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Genetic pathology
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Competing Interests: Conflicts of interest the authors declare no conflicts of interest.
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- 2023
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14. PD-L1 ( CD274 ) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma.
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Klümper N, Wüst L, Saal J, Ralser DJ, Zarbl R, Jarczyk J, Breyer J, Sikic D, Wullich B, Bolenz C, Roghmann F, Hölzel M, Ritter M, Strieth S, Hartmann A, Erben P, Wirtz RM, Landsberg J, Dietrich D, and Eckstein M
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- Humans, B7-H1 Antigen genetics, Interferon-gamma genetics, DNA Methylation, Carcinoma, Transitional Cell drug therapy, Carcinoma, Transitional Cell genetics, Immunotherapy, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms genetics, Promoter Regions, Genetic
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PD-L1 status assessed by immunohistochemistry (IHC) has failed to reliably predict outcomes for patients with metastatic urothelial carcinoma (mUC) on immune checkpoint blockade (ICB). PD-L1 promoter methylation is an epigenetic mechanism that has been shown to regulate PD-L1 mRNA expression in various malignancies. The aim of our present study was to evaluate the predictive potential of PD-L1 promoter methylation status ( mPD-L1 ) in ICB-treated mUC compared to conventional IHC-based PD-L1 assessment. We quantified mPD-L1 in formalin-fixed and paraffin-embedded tissue sections using an established quantitative methylation-specific PCR assay (qMSP) in a well-characterized multicenter ICB-treated cohort comprising N = 107 patients with mUC. Additionally, PD-L1 protein expression in tumor tissues was assessed using regulatory approved IHC protocols. The effect of pharmacological hypomethylation by the DNA methyltransferase inhibitor decitabine in combination with interferon-γ stimulation in urothelial carcinoma cell lines was investigated by IHC and FACS. mPD-L1 hypomethylation predicted objective response rate at the first staging on ICB. Patients with tumors categorized as PD-L1 hypomethylated (lower quartile) showed significantly prolonged progression-free (PFS) and overall survival (OS) after ICB initiation. In contrast, PD-L1 protein expression status neither correlated with response nor survival. In multivariable Cox regression analyses, PD-L1 promoter hypermethylation remained an independent predictor of unfavorable PFS and OS. In urothelial carcinoma cell lines, pharmacological demethylation led to an upregulation of membranous PD-L1 expression and an enhanced inducibility of PD-L1 expression by interferon γ. Hypomethylation of the PD-L1 promoter is a promising predictive biomarker for response to ICB in patients with mUC., Competing Interests: DD owns patents and patent applications on biomarker technologies and methylation of immune checkpoint genes as predictive and prognostic biomarkers (DE 10 2016 005 947.8, DE 10 2015 009 187.5, DE 10 2017 125 780.2, PCT/EP2016/001237). The patents are licensed to Qiagen GmbH (Hilden, Germany). DD is a consultant of Qiagen. The University Hospital Bonn (PI DD) received research funding from Qiagen. RMW is founder and CEO of STRATIFYER Molecular pathology. All other authors declare no conflicts of interest regarding the present study., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)
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- 2023
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15. Intraoperative Utilization of Indocyanine Green (ICG) Dye for the Assessment of Ovarian Perfusion-Case Report and Review of the Literature.
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Plöger R, Condic M, Ralser DJ, Plöger HM, Egger EK, Otten LA, and Mustea A
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The assessment of ovarian perfusion after detorsion is crucial in the surgical management of patients with ovarian torsion. In current routine clinical practice, the surgical decision (preservation of the ovary versus oophorectomy) is based on the subjective impression of the surgeon. Intraoperative indocyanine green (ICG) angiography has been shown to sufficiently reflect tissue perfusion with a potential impact on the surgical procedure. Currently, there are only sparse data available on the utilization of ICG in the surgical treatment of ovarian torsion. Here, we describe the successful intraoperative use of ICG in a 17-year-old female patient with ovarian torsion who underwent ovary-preserving surgery. Further, a systematic literature review was performed. Based on the data available to date, the use of ICG in the surgical treatment of ovarian torsion is feasible and safe. The extent to which this might reduce the necessity for oophorectomy has to be evaluated in further investigations.
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- 2023
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16. TROP-2 is widely expressed in vulvar squamous cell carcinoma and represents a potential new therapeutic target.
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Condic M, Egger EK, Klümper N, Kristiansen G, Mustea A, Thiesler T, and Ralser DJ
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- Humans, Female, Prognosis, Papillomavirus Infections complications, Carcinoma, Squamous Cell pathology, Vulvar Neoplasms pathology
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Purpose: Vulvar squamous cell carcinoma (VSCC) is a rare malignancy of the female genital tract with increasing incidence rates. Etiologically, HPV-dependent and HPV-independent VSCC are distinguished. Surgical treatment and/or radiotherapy represent the therapeutic mainstay for localized disease. For recurrent or metastatic VSCC, treatment options are limited. Research has identified trophoblast cell surface antigen 2 (TROP-2) to be broadly expressed across different tumor entities. The aim of the present study was to systematically investigate the expression of TROP-2 in VSCC., Methods: TROP-2 protein expression was investigated by immunohistochemistry in a cohort comprising n = 103 patients with primary VSCC. A four-tier scoring system (0: no staining, 1 + : low staining, 2 + : moderate staining, 3 + : high staining) was applied for quantification of protein expression. For further analyses, two groups (low TROP-2 expression: 0/1 + ; high TROP-2 expression: 2 + /3 +) were generated. The entire study cohort, as well as HPV-dependent and HPV-independent VSCC were considered separately., Results: In the entire VSCC study cohort, TROP-2 expression was present in 97.1% of all cases (n = 100) with 74.8% displaying high TROP-2 expression (2 + /3 +). Only 2.9% of tumors showed absent TROP-2 expression. Of note, all HPV-dependent VSCC (n = 18) demonstrated high TROP-2 expression (2 + /3 +). In the subgroup of HPV-independent VSCC (n = 70), high TROP-2 expression was associated with favorable clinical outcomes based on log rank test and univariate cox analysis., Conclusion: TROP-2 protein expression is of prognostic value in HPV-independent VSCC. The broad expression of TROP-2 in VSCC indicates the TROP-2 directed ADC Sacituzumab govitecan as a potential new therapeutic strategy for VSCC patients., (© 2023. The Author(s).)
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- 2023
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17. Analysis of the cervical microbiome in women from the German national cervical cancer screening program.
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Condic M, Neidhöfer C, Ralser DJ, Wetzig N, Thiele R, Sieber M, Otten LA, Warwas LK, Hoerauf A, Mustea A, and Parčina M
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- Humans, Female, Early Detection of Cancer methods, Vaginal Smears, Papillomaviridae, Mass Screening methods, Uterine Cervical Neoplasms pathology, Papillomavirus Infections complications, Uterine Cervical Dysplasia pathology
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Purpose: Cervical cancer (CC) is caused by a persistent high-risk human papillomavirus (hrHPV) infection. The cervico-vaginal microbiome may influence the development of (pre)cancer lesions. Aim of the study was (i) to evaluate the new CC screening program in Germany for the detection of high-grade CC precursor lesions, and (ii) to elucidate the role of the cervico-vaginal microbiome and its potential impact on cervical dysplasia., Methods: The microbiome of 310 patients referred to colposcopy was determined by amplicon sequencing and correlated with clinicopathological parameters., Results: Most patients were referred for colposcopy due to a positive hrHPV result in two consecutive years combined with a normal PAP smear. In 2.1% of these cases, a CIN III lesion was detected. There was a significant positive association between the PAP stage and Lactobacillus vaginalis colonization and between the severity of CC precursor lesions and Ureaplasma parvum., Conclusion: In our cohort, the new cervical cancer screening program resulted in a low rate of additional CIN III detected. It is questionable whether these cases were only identified earlier with additional HPV testing before the appearance of cytological abnormalities, or the new screening program will truly increase the detection rate of CIN III in the long run. Colonization with U. parvum was associated with histological dysplastic lesions. Whether targeted therapy of this pathogen or optimization of the microbiome prevents dysplasia remains speculative., (© 2023. The Author(s).)
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- 2023
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18. Integrating On-Treatment Modified Glasgow Prognostic Score and Imaging to Predict Response and Outcomes in Metastatic Renal Cell Carcinoma.
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Saal J, Bald T, Eckstein M, Ralser DJ, Ritter M, Brossart P, Grünwald V, Hölzel M, Ellinger J, and Klümper N
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- Humans, Prognosis, Sunitinib therapeutic use, Risk Assessment, Carcinoma, Renal Cell diagnostic imaging, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell mortality, Kidney Neoplasms diagnostic imaging, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology
- Abstract
Importance: In the era of immuno-oncology, imaging alone seems to be insufficient to capture treatment responses, as patients with stable disease treated with immunotherapy have a wide range of clinical outcomes. There is an unmet need for complementary (ideally cost-efficient) markers that enable assessment of therapy response and outcomes in conjunction with imaging., Objectives: To examine whether longitudinal changes in the modified Glasgow prognostic score (mGPS), which is based on C-reactive protein and albumin, can predict responses and outcomes in patients with metastatic renal cell carcinoma (mRCC)., Design, Setting, and Participants: This post hoc analysis, conducted from October 2022 to April 2023, evaluated the prognostic and predictive performance of on-treatment mGPS in patients with mRCC being treated with atezolizumab (plus bevacizumab) or sunitinib in 2 randomized clinical trials: the phase 3 IMmotion151 study (discovery cohort) and the phase 2 IMmotion150 study (validation cohort)., Main Outcomes and Measures: Outcomes were investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and overall survival (OS) for survival analyses. To compare the prognostic value of the on-treatment mGPS with radiologic staging, we used RECIST assessed by the Independent Review Committee (IRC-RECIST) to ensure high data quality., Results: Of the 915 patients with mRCC in the IMmotion151 discovery cohort, baseline mGPS was available for 861 patients and on-treatment mGPS for 691. The IMmotion150 validation cohort included 305 patients with mRCC, and on-treatment mGPS could be evaluated for 199. In the IMmotion150 study, on-treatment mGPS predicted outcomes as early as 6 weeks following therapy initiation, thereby opening a window for early therapy adjustments. In both clinical trials, on-treatment mGPS provided valuable prognostic information regardless of imaging-assessed treatment response at first staging. Of note, in the disease control subgroup, on-treatment mGPS exhibited superior and independent prognostic information compared with IRC-RECIST (available for 611 patients; C-index, 0.651 [95% CI, 0.588-0.714] for the mGPS during treatment vs 0.574 [95% CI, 0.528-0.619] for IRC-RECIST)., Conclusions and Relevance: These data support the concept of integrating on-treatment mGPS for more holistic and patient-centered therapy monitoring in addition to radiologic staging to improve clinical care at a low cost for patients with mRCC.
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- 2023
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19. ICOS DNA methylation regulates melanoma cell-intrinsic ICOS expression, is associated with melanoma differentiation, prognosis, and predicts response to immune checkpoint blockade.
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Ralser DJ, Herr E, de Vos L, Kulcsár Z, Zarbl R, Klümper N, Gielen GH, Maas AP, Hoffmann F, Dietrich J, Kuster P, Mustea A, Glodde N, Kristiansen G, Strieth S, Landsberg J, and Dietrich D
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Background: Inducible T cell costimulator ICOS is an emerging target in immuno-oncology. The aim of this study was to investigate the epigenetic regulation of ICOS in melanoma by DNA methylation., Methods: We comprehensively investigate ICOS DNA methylation of specific CpG sites and expression pattern within the melanoma microenvironment with regard to immune correlates, differentiation, clinical outcomes, and immune checkpoint blockade (ICB) response., Results: Our study revealed a sequence-contextual CpG methylation pattern consistent with an epigenetically regulated gene. We found a cell type-specific methylation pattern and locus-specific correlations and associations of CpG methylation with ICOS mRNA expression, immune infiltration, melanoma differentiation, prognosis, and response to ICB. High ICOS mRNA expression was identified as a surrogate for enriched immune cell infiltration and was associated with favorable overall survival (OS) in non-ICB-treated patients and predicted response and a prolonged progression-free survival (PFS) following ICB therapy initiation. ICOS hypomethylation, however, significantly correlated with poor OS in non-ICB patients but predicted higher response and prolonged PFS and OS in ICB-treated patients. Moreover, we observed cytoplasmic and sporadically nuclear tumor cell-intrinsic ICOS protein expression. Tumor cell-intrinsic ICOS protein and mRNA expression was inducible by pharmacological demethylation with decitabine., Conclusion: Our study identified ICOS DNA methylation and mRNA expression as promising prognostic and predictive biomarkers for immunotherapy in melanoma and points towards a hitherto undescribed role of ICOS in tumor cells., (© 2023. The Author(s).)
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- 2023
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20. Comprehensive immunohistochemical analysis of N6-methyladenosine (m6A) writers, erasers, and readers in endometrial cancer.
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Ralser DJ, Condic M, Klümper N, Ellinger J, Staerk C, Egger EK, Kristiansen G, Mustea A, and Thiesler T
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- Humans, Female, Adenosine, Carcinogenesis, Cell Transformation, Neoplastic, Methyltransferases, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Endometrial Neoplasms genetics
- Abstract
Purpose: N6-methyladenosine (m6A) is the most frequent type of messenger RNA (mRNA) modification and is implicated in diverse physiological processes. The procedure of m6A RNA modification is regulated by a dynamic interaction of writers (METTL3, METTL4, METTL14, WTAP, KIAA1429), erasers (FTO, ALKBH5), and readers (HNRNPA2B1, HNRNPC, YTHDC1, YTHDC1, YTHDF1-3). In the oncological context, alterations in m6A were identified to be critically involved in tumorigenesis, proliferation, angiogenesis, and drug resistance across diverse cancer entities including endometrial cancer (EC)., Methods: In this study, we comprehensively examined the protein expression of m6A writers, readers and erasers by immunohistochemical staining in a cohort of N = 65 EC patients. Protein expression data were analyzed with regard to clinical outcomes., Results: We identified enhanced protein expression levels of METTL3, METTL14, FTO, HNRNPA2B1, and HNRNPC, respectively to be of prognostic value and linked to a shortened overall survival in EC., Conclusion: Overall, our study points toward dysregulated m6A modification in EC and its possibility to serve as a promising prognostic biomarker., (© 2022. The Author(s).)
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- 2023
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21. Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance.
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Klümper N, Ralser DJ, Ellinger J, Roghmann F, Albrecht J, Below E, Alajati A, Sikic D, Breyer J, Bolenz C, Zengerling F, Erben P, Schwamborn K, Wirtz RM, Horn T, Nagy D, Toma M, Kristiansen G, Büttner T, Hahn O, Grünwald V, Darr C, Erne E, Rausch S, Bedke J, Schlack K, Abbas M, Zschäbitz S, Schwab C, Mustea A, Adam P, Manseck A, Wullich B, Ritter M, Hartmann A, Gschwend J, Weichert W, Erlmeier F, Hölzel M, and Eckstein M
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- Humans, Nectins genetics, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Urinary Bladder Neoplasms pathology, Carcinoma, Transitional Cell drug therapy, Carcinoma, Transitional Cell genetics
- Abstract
Purpose: The antibody-drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET)., Experimental Design: Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4-negative/weak (H-score 0-99) versus moderate/strong (H-score 100-300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9-induced polyclonal NECTIN-4 knockouts., Results: In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0-140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001)., Conclusions: Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV. See related commentary by Aggen et al., p. 1377., (©2022 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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22. Determination of the Cancer Genome Atlas (TCGA) Endometrial Cancer Molecular Subtypes Using the Variant Interpretation and Clinical Decision Support Software MH Guide.
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Mustea A, Ralser DJ, Egger E, Ziehm U, Vivas S, Brock S, Jackson D, Condic M, Meisel C, Otten L, Laib A, Cordova MC, Hartmann R, Stein MA, Koensgen D, and Stope MB
- Abstract
Background: The Cancer Genome Atlas (TCGA) network (United States National Cancer Institute) identified four molecular endometrial cancer (EC) subtypes using an extensive multi-method approach. The aim of this study was to determine the four TCGA EC molecular subtypes using a single-method whole-exome sequencing (WES)-based approach provided by MH Guide (Molecular Health, Heidelberg, Germany)., Methods: WES and clinical data of n = 232 EC patients were obtained from TCGA. The four TCGA EC molecular subtypes designated as (i) Mutated Polymerase ε (POLE), (ii) Microsatellite Instability (MSI), (iii) Copy Number (CN) low and, (iv) CN-high were determined using the MH Guide software. The prognostic value of the subtypes determined by MH Guide were compared with the TCGA classification., Results: Analysis of WES data using the MH Guide software led to the precise identification of the four EC molecular subtypes analogous to the TCGA classification. Both approaches displayed high concordance in terms of prognostic significance., Conclusions: The multi-method-based TCGA EC molecular subtypes can reliably be reproduced by the single-method-based MH Guide approach. The easy-to-implement single-method MH Guide approach represents a promising diagnostic tool.
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- 2023
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23. Evolving treatment landscape of advanced endometrial cancer - A current perspective from a German tertiary referral center for gynecological oncology.
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Ralser DJ, Condic M, Otten LA, Koensgen D, Stope MB, Egger EK, and Mustea A
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- Female, Humans, Tertiary Care Centers, Genital Neoplasms, Female therapy, Ovarian Neoplasms, Endometrial Neoplasms therapy
- Abstract
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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- 2023
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24. The Role of P16, P53, KI-67 and PD-L1 Immunostaining in Primary Vaginal Cancer.
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Egger EK, Condic M, Ralser DJ, Marinova M, Mustea A, Recker F, Kristiansen G, and Thiesler T
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Background: To analyze clinical, pathological and immunohistochemical correlates of survival in vaginal cancer patients., Methods: Retrospective analysis of primary vaginal cancer patients, treated at the Department of Gynecology and Gynecological Oncology of the University Hospital Bonn between 2007 and 2021., Results: The study cohort comprised 22 patients. The median age was 63 years (range: 32-87 years). Squamous cell histology was present in 20 patients. Five-year OS in Stage I, II, III and IV was 100%, 56.25%, 0% and 41.67%, respectively ( p = 0.147). Five-year DFS was 100%, 50%, 0% and 20.83%, respectively ( p = 0.223). The 5-year OS was significantly reduced in the presence of nodal metastasis ( p = 0.004), lymphangiosis ( p = 0.009), hemangiosis ( p = 0.002) and an age above 64 years ( p = 0.029). Positive p 16 staining was associated with significantly improved OS ( p = 0.010). Tumoral and immune cell PD-L1 staining was positive in 19 and in 16 patients, respectively, without significant impact on OS; 2 patients with metastastic disease are long-term survivors treated with either bevacizumab or pembrolizumab., Conclusion: P16 expression, absence of lymph- or hemangiosis, nodal negative disease and an age below 64 years show improved survival rates in PVC. Tumoral PD-L1 expression as well as PD-L1 expression on immune cells is frequent in PVC, without impacting survival. Within our study cohort, long-term survivors with recurrent PVC are treated with anti-VEGF and immunotherapy.
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- 2023
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25. CDK4/6 Inhibitors in Advanced HR+/HER2 - Breast Cancer: A Multicenter Real-World Data Analysis.
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Müller C, Kiver V, Solomayer EF, Wagenpfeil G, Neeb C, Blohmer JU, Abramian AV, Maass N, Schütz F, Kolberg-Liedtke C, Ralser DJ, and Rambow AC
- Abstract
Purpose: CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy are considered standard-of-care for first-line therapy of patients with hormone receptor positive, HER2 negative, advanced breast cancer (HR+/HER2- ABC). Superiority of combination therapy over endocrine monotherapy has been demonstrated in a multitude of randomized controlled trials (RCTs) in phase III and IV. However, RCTs reflect clinical reality only to a limited extent, as narrow inclusion criteria lead to a selected patient collective. Here, we present real-world data (RWD) on CDK4/6i treatment in patients with HR+/HER2- ABC at four certified German university breast cancer centers., Methods: Patients diagnosed with HR+/HER2- ABC who were treated in clinical routine with CDK4/6i between November 2016 and December 2020 at four certified German university breast cancer centers (Saarland University Medical Center, University Medical Center Charité Berlin, University Medical Center Bonn, and University Medical Center Hospital Schleswig-Holstein, Campus Kiel) were identified and enrolled in this retrospective study. Clinicopathological characteristics and clinical outcomes were recorded with particular emphasis on CDK4/6i therapy course [progression-free survival (PFS) following treatment initiation, toxicity, dose reduction, therapy discontinuation, prior and subsequent therapy line]., Results: Data from n = 448 patients were evaluated. The mean patient age was 63 (±12) years. Of these patients, n = 165 (36.8%) were primarily metastasized, and n = 283 (63.2%) had secondary metastatic disease. N = 319 patients (71.3%) received palbociclib, n = 114 patients (25.4%) received ribociclib, and n = 15 patients (3.3%) received abemaciclib, respectively. Dose reduction was performed in n = 132 cases (29.5%). N = 57 patients (12.7%) discontinued the treatment with CDK4/6i due to side effects. N = 196 patients (43.8%) experienced disease progression under CDK4/6i treatment. The median PFS was 17 months. Presence of hepatic metastases and prior therapy lines were associated with shorter PFS, whereas estrogen positivity and dose reduction due to toxicity were positively associated with PFS. Presence of bone and lung metastases, progesterone positivity, Ki67 index, grading, BRCA1/2 and PIK3CA mutation status, adjuvant endocrine resistance, and age did not significantly impact on PFS., Conclusion: Our RWD analysis on CDK4/6i treatment in Germany supports data from RCTs regarding both treatment efficacy and safety of CDK4/6i for treatment of patients with HR+/HER2- ABC. In comparison to data from the pivotal RCTs, median PFS was lower but within the expected range for RWD, which could result from inclusion of patients with more advanced diseases (i.e., higher therapy lines) to our dataset., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)
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- 2023
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26. Evaluation of the Diagnostic Potential of Circulating MicroRNAs miR-1 and miR-21 in Patients With Ovarian Cancer.
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Ralser DJ, Condic M, Egger E, Koensgen D, Mustea A, and Stope MB
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- Female, Humans, CA-125 Antigen, Circulating MicroRNA, MicroRNAs genetics, Ovarian Neoplasms diagnosis, Ovarian Neoplasms genetics
- Abstract
Background/aim: MicroRNA (miR) is implicated in the development of ovarian cancer (OC), the emergence of therapy resistance, and metastatic spread. In the past decade, a variety of relevant miRs have been identified in the context of OC, including miR-1 and miR-21. miR-21 plays a crucial role in OC carcinogenesis via activation of phosphatidylinositol-4,5-bisphosphate 3-kinase signaling and development of platinum resistance, and has prognostic value. miR-1 has been identified as a tumor suppressor across various cancer entities, with reduced expression in malignant tissue compared to benign. This evidence highlights the potential of miR-1 and miR-21 to serve as diagnostic and prognostic biomarkers in OC., Patients and Methods: We studied the diagnostic potential of serum expression of miR-1 and miR-21 in a cohort comprising patients with malignant and benign ovarian tumors. Furthermore, levels of miR expression were analyzed with regard to clinical outcomes in patients with malignant ovarian tumors to evaluate their prognostic value., Results: We identified significant differential expression of miR-1 (p=0.0397) and miR-21 (p=0.0154) in malignant and benign ovarian tumors: Higher expression of miR-1 was found in patients with benign ovarian tumors, whereas expression of miR-21 was higher in patients with malignant ovarian tumors. In receiver operating characteristic analyses, the diagnostic potential of both miRs was confirmed, however, diagnostic significance was inferior to that of cancer antigen 125. No further value, in particular no prognostic value, was obtained for miR-1 and miR-21 in patients with malignant ovarian tumors., Conclusion: Serum levels of miR-1 and miR-21 might serve as promising biomarkers in the diagnosis of ovarian cancer., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
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- 2022
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27. Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals.
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Basmanav FB, Cesarato N, Kumar S, Borisov O, Kokordelis P, Ralser DJ, Wehner M, Axt D, Xiong X, Thiele H, Dolgin V, Gossmann Y, Fricker N, Dewenter MK, Weller K, Suri M, Reichenbach H, Oji V, Addor MC, Ramirez K, Stewart H, Garcia Bartels N, Weibel L, Wagner N, George S, Kilic A, Tantcheva-Poor I, Stewart A, Dikow N, Blaumeiser B, Medvecz M, Blume-Peytavi U, Farrant P, Grimalt R, Bertok S, Bradley L, Eskin-Schwartz M, Birk OS, Bygum A, Simon M, Krawitz P, Fischer C, Hamm H, Fritz G, and Betz RC
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- Female, Male, Humans, Cohort Studies, Exome Sequencing, Hair abnormalities, Transglutaminases, Hair Diseases diagnosis, Hair Diseases genetics
- Abstract
Importance: Uncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed flat. Only about 100 known cases have been reported so far., Objective: To elucidate the genetic spectrum of UHS., Design, Setting, and Participants: This cohort study includes 107 unrelated index patients with a suspected diagnosis of UHS and family members who were recruited worldwide from January 2013 to December 2021. Participants of all ages, races, and ethnicities were recruited at referral centers or were enrolled on their own initiative following personal contact with the authors. Genetic analyses were conducted in Germany from January 2014 to December 2021., Main Outcomes and Measures: Clinical photographs, Sanger or whole-exome sequencing and array-based genotyping of DNA extracted from blood or saliva samples, and 3-dimensional protein modeling. Descriptive statistics, such as frequency counts, were used to describe the distribution of identified pathogenic variants and genotypes., Results: The genetic characteristics of patients with UHS were established in 80 of 107 (74.8%) index patients (82 [76.6%] female) who carried biallelic pathogenic variants in PADI3, TGM3, or TCHH (ie, genes that encode functionally related hair shaft proteins). Molecular genetic findings from 11 of these 80 individuals were previously published. In 76 (71.0%) individuals, the UHS phenotype were associated with pathogenic variants in PADI3. The 2 most commonly observed PADI3 variants account for 73 (48.0%) and 57 (37.5%) of the 152 variant PADI3 alleles in total, respectively. Two individuals carried pathogenic variants in TGM3, and 2 others carried pathogenic variants in TCHH. Haplotype analyses suggested a founder effect for the 4 most commonly observed pathogenic variants in the PADI3 gene., Conclusions and Relevance: This cohort study extends and gives an overview of the genetic variant spectrum of UHS based on molecular genetic analyses of the largest worldwide collective of affected individuals, to our knowledge. Formerly, a diagnosis of UHS could only be made by physical examination of the patient and confirmed by microscopical examination of the hair shaft. The discovery of pathogenic variants in PADI3, TCHH, and TGM3 may open a new avenue for clinicians and affected individuals by introducing molecular diagnostics for UHS.
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- 2022
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28. Tumor Load Matters - the Peritoneal Cancer Index in Patients With High-grade Serous Ovarian Cancer.
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Egger E, Merker F, Ralser DJ, Condic M, Marinova M, Muders M, Stope M, and Mustea A
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- Cytoreduction Surgical Procedures, Female, Humans, Prognosis, Retrospective Studies, Survival Rate, Tumor Burden, Hyperthermia, Induced, Ovarian Neoplasms pathology, Peritoneal Neoplasms pathology, Peritoneal Neoplasms surgery
- Abstract
Background/aim: The aim of this study was to analyze the predictive and prognostic value of the peritoneal cancer index (PCI) with regard to complete cytoreduction and clinical outcomes in patients with high-grade serous ovarian cancer., Patients and Methods: In a cohort comprising 188 patients with high-grade serous ovarian cancer, the PCI was retrospectively assessed. Clinical factors and perioperative complications were analyzed according to different PCI groups. Five-year disease-free survival (DFS) and overall survival (OS) were calculated based on the Kaplan-Meier Log rank analysis. Receiver operating characteristic (ROC) analysis was applied to detect associations of PCI and complete cytoreduction. Multivariate survival analysis was performed by Cox proportional hazards model., Results: In our study, the PCI was predictive of complete cytoreduction (ROC analysis; AUC 0.8227). In patients with optimal cytoreduction, higher PCI scores were associated with poorer 5-year OS (p<0.001) and 5-year DFS (p<0.001). Complications (G1-G5) were significantly more frequent in patients with PCI scores >9 (p=0.0023). Five-year OS was reduced in patients with severe complications compared to patients with none or mild complications (30.88% versus 51.01%; p=0.001). There were significant OS (p<0.001) and DFS (p<0.001) differences between patients with none or mild versus severe complications following complete cytoreduction within the PCI subgroups (PCI: 9-11, PCI: 12-18, PCI >18)., Conclusion: The PCI score showed high predictability for complete cytoreduction and was associated with clinical outcomes. In presence of severe complications, higher PCI scores were associated with poorer survival. Hence, in patients with high tumor load, the prevention of severe perioperative complications is of utmost importance in all cases where complete cytoreduction is deemed to be feasible., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
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- 2022
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29. Translational experimental research in gynaecological oncology.
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Stope MB, Ralser DJ, Egger EK, and Mustea A
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- Humans, Female, Medical Oncology, Genital Neoplasms, Female
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- 2022
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30. CTLA4 , PD-1 , PD-L1 , PD-L2 , TIM-3 , TIGIT , and LAG3 DNA Methylation Is Associated With BAP1 -Aberrancy, Transcriptional Activity, and Overall Survival in Uveal Melanoma.
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de Vos L, Carrillo Cano TM, Zarbl R, Klümper N, Ralser DJ, Franzen A, Herr E, Gabrielpillai J, Vogt TJ, Dietrich J, Strieth S, Landsberg J, and Dietrich D
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- CTLA-4 Antigen genetics, Epigenesis, Genetic, Hepatitis A Virus Cellular Receptor 2 genetics, Hepatitis A Virus Cellular Receptor 2 metabolism, Humans, Melanoma, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor metabolism, RNA, Messenger, Receptors, Immunologic genetics, Receptors, Immunologic metabolism, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Ubiquitin Thiolesterase genetics, Ubiquitin Thiolesterase metabolism, Uveal Neoplasms, B7-H1 Antigen genetics, B7-H1 Antigen metabolism, DNA Methylation
- Abstract
Uveal melanoma (UM) is an aggressive disease with poor response to oncological treatment, including immunotherapy. Loss of the epigenetic modifier BRCA1-associated protein 1 (BAP1) function drives UM oncogenesis and is associated with an immune-suppressive tumor microenvironment, poor prognosis, and a distinct DNA methylation and gene expression profile. Our study aimed to analyze comprehensively the DNA methylation status of the immune checkpoint genes PD-1 , PD-L1 , PD-L2 , CTLA4, TIM-3 ( HAVCR2 ), TIGIT , and LAG3 and its association with mRNA expression, BAP1 -aberrancy, and patients' survival. We analyzed the DNA methylation landscape of immune checkpoint genes at single CpG resolution in N=80 UM samples provided by The Cancer Genome Atlas. We analyzed CpG methylation levels of the immune checkpoints with regard to their transcriptional signatures and patient outcomes.Methylation of specific CpG sites within the immune checkpoint genes PD-1 , PD-L1 , PD-L2 , CTLA4 , TIM-3 , TIGIT , and LAG3 correlated strongly with mRNA expression levels, indicating a strong regulation of gene expression through DNA methylation. Moreover, immune checkpoint gene methylation was strongly associated with BAP1 -mutation status and associated with overall survival in UM. Our data indicate an epigenetic regulation of immune checkpoints through DNA methylation in UM. Further, our data highlight the prognostic significance of DNA methylation of immune checkpoint genes in UM thereby providing a rationale for methylation testing as predictive biomarkers for immunotherapy response., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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31. N6-methyladenosine RNA modification (m6A) is of prognostic value in HPV-dependent vulvar squamous cell carcinoma.
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Condic M, Thiesler T, Staerk C, Klümper N, Ellinger J, Egger EK, Kübler K, Kristiansen G, Mustea A, and Ralser DJ
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- Adenosine analogs & derivatives, Adenosine metabolism, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Female, Humans, Methyltransferases genetics, Methyltransferases metabolism, Prognosis, RNA metabolism, Carcinoma, Squamous Cell genetics, Papillomavirus Infections complications, Papillomavirus Infections genetics, Vulvar Neoplasms genetics
- Abstract
Background: Vulvar squamous cell carcinoma (VSCC) is an uncommon gynecologic malignancy but with an increasing incidence in recent years. Etiologically, VSCC is classified into two subtypes: HPV-dependent and HPV-independent. Localized VSCC is treated surgically and/or with radiation therapy, but for advanced, metastatic or recurrent disease, therapeutic options are still limited. N6-methyladenosine (m6A) is the most prevalent post-transcriptional messenger RNA (mRNA) modification and involved in many physiological processes. The group of m6A proteins can be further divided into: 'writers' (METTL3, METTL4, METTL14, WTAP, KIAA1429), 'erasers' (FTO, ALKBH5), and 'readers' (HNRNPA2B1, HNRNPC, YTHDC1, YTHDF1-3). Dysregulated m6A modification is implicated in carcinogenesis, progression, metastatic spread, and drug resistance across various cancer entities. Up to date, however, only little is known regarding the role of m6A in VSCC., Methods: Here, we comprehensively investigated protein expression levels of a diverse set of m6A writers, readers and erasers by applying immunohistochemical staining in 126 patients with primary VSCC., Results: In the entire study cohort, dominated by HPV-independent tumors, m6A protein expression was not associated with clinical outcome. However, we identified enhanced protein expression levels of the 'writers' METTL3, METTL14 and the 'reader' YTHDC1 as poor prognostic markers in the 23 patients with HPV-dependent VSCC., Conclusion: Our study suggests dysregulated m6A modification in HPV-associated VSCC., (© 2022. The Author(s).)
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- 2022
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32. Postoperative paralytic ileus following debulking surgery in ovarian cancer patients.
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Egger EK, Merker F, Ralser DJ, Marinova M, Vilz TO, Matthaei H, Hilbert T, and Mustea A
- Abstract
Aim: This study aims to evaluate the incidence of postoperative ileus (POI) following cytoreductive surgery in epithelial ovarian cancer (EOC) patients and its impact on anastomotic leakage occurrence and postoperative complications., Methods: A total of 357 surgeries were performed on 346 ovarian cancer patients between 1/2010 and 12/2020 at our institution. The postoperative course regarding paralytic ileus, anastomotic leakage, and postoperative complications was analyzed by Fisher's exact test and through ordinal logistic regression., Results: A total of 233 patients (65.3%) returned to normal gastrointestinal functions within 3 days after surgery. A total of 123 patients (34.5%) developed POI. There were 199 anastomoses in 165 patients and 24 leakages (12.1%). Postoperative antibiotics ( p 0.001), stoma creation ( p 0.0001), and early start of laxatives ( p 0.0048) significantly decreased POI, while anastomoses in general ( p 0.0465) and especially low anastomoses ( p 0.0143) showed increased POI rates. Intraoperative positive fluid excess >5,000 cc was associated with a higher risk for POI ( p 0.0063), anastomotic leakage ( p 0.0254), and severe complications ( p 0.0012)., Conclusion: Postoperative antibiotics, an early start with laxatives, and stoma creation were associated with reduced POI rates. Patients with anastomoses showed an increased risk for POI. Severe complications, anastomotic leakages, and POI were more common in the case of intraoperative fluid balance exceeding 5,000 cc., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Egger, Merker, Ralser, Marinova, Vilz, Matthaei, Hilbert and Mustea.)
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- 2022
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33. Comprehensive Analysis of N6-Methyladenosine (m6A) Writers, Erasers, and Readers in Cervical Cancer.
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Condic M, Ralser DJ, Klümper N, Ellinger J, Qureischi M, Egger EK, Kristiansen G, Mustea A, and Thiesler T
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- Adenosine analogs & derivatives, Adenosine metabolism, Alpha-Ketoglutarate-Dependent Dioxygenase FTO genetics, Female, Humans, Methyltransferases genetics, Methyltransferases metabolism, RNA Processing, Post-Transcriptional, RNA, Messenger genetics, RNA, Messenger metabolism, Uterine Cervical Neoplasms genetics
- Abstract
There is growing scientific evidence for the crucial role of post-transcriptional RNA modifications in carcinogenesis, progression, metastasis, and drug resistance across various cancer entities. N6-methyladenosine (m6A) is the most abundant type of RNA modification. m6A is coordinated by a dynamic interplay of ‘writers’ (METTL3, METTL4, METTL14, WTAP, KIAA1429), ‘erasers’ (FTO, ALKBH5), and ‘readers’ (HNRNPA2B1, HNRNPC, YTHDC1, YTHDC1, YTHDF1-3). In this study, we comprehensively examined protein and mRNA expression levels of m6A writers, readers, and erasers in two cervical cancer (CC) cohorts (UHB CC cohort, N = 118; TCGA CC cohort, N = 307) with regard to clinical outcomes. In the UHB CC cohort, high protein expression levels of METTL14 (p = 0.016), WTAP (p = 0.007), KIAA1439 (p < 0.001), ALKBH5 (p < 0.001), HNRNPC (p = 0.012), YTHDC1 (p < 0.001), and YTHDF3 (p = 0.004) were significantly associated with a shorter overall survival (OS). In the TCGA CC cohort, mRNA expression levels of METTL14 (p = 0.012), WTAP (p = 0.041), KIAA1429 (p = 0.016), and YTHDC1 (p = 0.026) showed prognostic values. However, after correction for multiple testing, statistical significance remained only for m6A protein expression levels (q < 0.1). Our study points towards dysregulated m6A modification in CC. Hence, m6A might serve as a promising prognostic biomarker and therapeutical target in CC.
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- 2022
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34. Evolutionary distinct roles of γ-secretase subunit nicastrin in zebrafish and humans.
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Hermasch MA, Janning H, Perera RP, Schnabel V, Rostam N, Ramos-Gomes F, Muschalek W, Bennemann A, Alves F, Ralser DJ, Betz RC, Schön MP, Dosch R, and Frank J
- Subjects
- Amyloid Precursor Protein Secretases genetics, Animals, Hidradenitis Suppurativa genetics, Humans, Membrane Glycoproteins genetics, Zebrafish, Amyloid Precursor Protein Secretases metabolism, Membrane Glycoproteins metabolism
- Abstract
Background: Mutations in the genes that encode the human γ-secretase subunits Presenilin-1, Presenilin Enhancer Protein 2, and Nicastrin (NCSTN) are associated with familial hidradenitis suppurativa (HS); and, regarding Presenilin Enhancer Protein 2, also with comorbidity for the hereditary pigmentation disorder Dowling-Degos disease., Objective: Here, the consequences of targeted inactivation of ncstn, the zebrafish homologue of human NCSTN, were studied., Methods: After morpholino (MO)-mediated ncstn-knockdown, the possibilities of phenotype rescue through co-injection of ncstn-MO with wildtype zebrafish ncstn or human NCSTN mRNA were investigated. Further, the effects of the co-injection of a human missense, nonsense, splice-site, and frameshift mutation were studied., Results: MO-mediated ncstn-knockdown resulted in a significant reduction in melanophore morphology, size and number; and alterations in their patterns of migration and distribution. This phenotype was rescued by co-injection of zebrafish ncstn RNA, human NCSTN RNA, or a construct encoding the human NCSTN missense mutation p.P211R., Conclusion: Human NCSTN mutations encoding null alleles confer loss-of-function regarding pigmentation homeostasis in zebrafisch. In contrast, the human missense mutation p.P211R was less harmful, asserting sufficient residual ncstn activity to maintain pigmentation in zebrafish. Since fish lack the anatomical structures affected by HS, our data suggest that the zebrafish ncstn gene and the human NCSTN gene have probably acquired different functions during evolution. In fish, one major role of ncstn is the maintenance of pigmentation homeostasis. In contrast, one of the roles of NCSTN in humans is the prevention of inflammatory processes in the adnexal structures of the skin, as seen in familial HS., (Copyright © 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)
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- 2022
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35. Molecular and Immune Correlates of PDCD1 (PD-1), PD-L1 (CD274), and PD-L2 (PDCD1LG2) DNA Methylation in Triple Negative Breast Cancer.
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Ralser DJ, Klümper N, Gevensleben H, Zarbl R, Kaiser C, Landsberg J, Hölzel M, Strieth S, Faridi A, Abramian A, and Dietrich D
- Subjects
- DNA Methylation, Epigenesis, Genetic, Female, Humans, Leukocytes immunology, Triple Negative Breast Neoplasms immunology, Tumor Microenvironment immunology, B7-H1 Antigen genetics, Programmed Cell Death 1 Ligand 2 Protein genetics, Programmed Cell Death 1 Receptor genetics, Triple Negative Breast Neoplasms genetics, Tumor Microenvironment genetics
- Abstract
Immune checkpoints are important targets in oncological therapy. Recent studies have proven efficacy of immune checkpoint inhibition (ICI) in treatment of triple negative breast cancer (TNBC). However, only a proportion of TNBC-patients benefit from ICI. Thus, current scientific efforts in this context are focused on the identification of a robust biomarker that enables patient stratification. In the present study, we investigated the epigenetic regulation of PD-1 (PDCD1), PD-L1 (CD274), and PD-L2 (PDCD1LG2). Methylation data of PD-1, PD-L1, and PD-L2, and complex immunogenomic data were obtained from The Cancer Genome Atlas (TCGA). Methylation were systematically analyzed with regard to the transcriptional activity of the studied immune checkpoint genes and the tumor microenvironment. We found differential methylation of PD-1, PD-L1, and PD-L2 in normal adjacent tissue and TNBC tumor tissue. In the TNBC-TCGA cohort, methylation status of PD-1, PD-L1, and PD-L2 were significantly correlated with mRNA levels indicating a strong epigenetic regulation of the transcriptional activity. Moreover, PD-1, PD-L1, and PD-L2 methylation status was strongly associated with a distinct immune cell infiltration pattern. Our results indicate an epigenetic regulation of immune checkpoint genes through DNA methylation in TNBC. In addition, the methylation status was associated with a distinct composition of the tumor microenvironment. Overall, this provides a strong rationale for assessing the value of PD-1, PD-L1, and PD-L2 DNA methylation to predict response to ICI and immunogenicity in TNBC., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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36. CTLA4 promoter hypomethylation is a negative prognostic biomarker at initial diagnosis but predicts response and favorable outcome to anti-PD-1 based immunotherapy in clear cell renal cell carcinoma.
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Klümper N, Ralser DJ, Zarbl R, Schlack K, Schrader AJ, Rehlinghaus M, Hoffmann MJ, Niegisch G, Uhlig A, Trojan L, Steinestel J, Steinestel K, Wirtz RM, Sikic D, Eckstein M, Kristiansen G, Toma M, Hölzel M, Ritter M, Strieth S, Ellinger J, and Dietrich D
- Subjects
- Adult, Aged, Biomarkers, Tumor genetics, Biomarkers, Tumor immunology, CTLA-4 Antigen immunology, Carcinoma, Renal Cell immunology, Female, Humans, Immune Checkpoint Inhibitors therapeutic use, Immunotherapy methods, Kidney Neoplasms immunology, Male, Middle Aged, Prognosis, Programmed Cell Death 1 Receptor immunology, Treatment Outcome, CTLA-4 Antigen genetics, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell genetics, DNA Methylation, Kidney Neoplasms drug therapy, Kidney Neoplasms genetics, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Background: In metastatic clear cell renal cell carcinoma (ccRCC), different combination therapies, each including anti-PD-1 immune checkpoint blockade (ICB), are applied as first-line treatment. Robust predictive biomarkers for rational upfront therapy decisions are lacking, although they are urgently needed. Recently, we showed that CTLA4 promoter methylation predicts response to ICB in melanoma. Here, we aimed to investigate CTLA4 methylation in ccRCC and its utility to serve as a predictive biomarker for anti-PD-1 based ICB in metastatic ccRCC., Methods: CTLA4 methylation was analyzed with regard to transcriptional gene activity (mRNA expression), intratumoral immune cell composition, and clinical course in two ccRCC cohorts obtained from The Cancer Genome Atlas (TCGA cohort, n=533) and the University Hospital Bonn (UHB Non-ICB Cohort, n=116). In addition, CTLA4 methylation as well as CD8
+ T cell infiltrates and PD-L1 expression were evaluated in pre-treatment samples from a multicenter cohort (RCC-ICB Cohort, n=71). Patients included in the RCC-ICB Cohort were treated with either first line anti-PD-1 based combination therapy (n=25) or monotherapy post-tyrosine kinase inhibition in second line or later. Analyses were performed with regard to treatment response according to RECIST, progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) following treatment initiation., Results: CTLA4 promoter hypomethylation was significantly correlated with CTLA4 mRNA expression, lymphocyte infiltration, and poor OS in both primary ccRCC cohorts (TCGA: HR 0.30 (95% CI 0.18 to 0.49), p<0.001; UHB Non-ICB: HR 0.35 (95% CI 0.16 to 0.75), p=0.007). In contrast, CTLA4 promoter hypomethylation predicted response and, accordingly, favorable outcomes (PFS and OS) in patients with ICB-treated ccRCC, overcompensating the negative prognostic value of CTLA4 hypomethylation at initial diagnosis. Moreover, in multivariable Cox regression, CTLA4 promoter hypomethylation remained an independent predictor of improved outcome in ICB-treated ccRCC after co-adjustment of the International Metastatic Renal Cell Carcinoma Database Consortium score (HR 3.00 (95% CI 1.47 to 6.28), p=0.003)., Conclusions: Our study suggests CTLA4 methylation as a powerful predictive biomarker for immunotherapy response in metastatic RCC., Competing Interests: Competing interests: DD owns patents and patent applications on biomarker technologies and methylation of immune checkpoint genes as predictive and prognostic biomarkers (DE 10 2016 005 947.8, DE 10 2015 009 187.5, DE 10 2017 125 780.2, PCT/EP2016/001237). The patents are licensed to Qiagen GmbH (Hilden, Germany). DD is a consultant of Qiagen. The University Hospital Bonn (PI DD) received research funding from Qiagen., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2021
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37. Diagnostic and Therapeutic Approach in a Metastatic Vaginal Adenocarcinoma: A Case Report.
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Egger EK, Ralser DJ, Lindner K, Recker F, Marinova M, Savchenko O, Lau JF, and Mustea A
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma secondary, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung pathology, Antibodies, Monoclonal, Humanized administration & dosage, Bevacizumab administration & dosage, Cisplatin administration & dosage, DNA-Binding Proteins genetics, Female, Humans, Immunotherapy, Middle Aged, Mutation, Paclitaxel administration & dosage, Receptor, ErbB-2 metabolism, Transcription Factors genetics, Vaginal Neoplasms genetics, Vaginal Neoplasms secondary, Adenocarcinoma drug therapy, Adenocarcinoma of Lung drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Vaginal Neoplasms drug therapy
- Abstract
Background: Vaginal adenocarcinomas (VAC) are most often reported after intrauterine exposition to diethylstilbestrol (DES). Rarely, VACs are reported as a malignant transformation of vaginal adenosis or endometriosis, in the context of chromosomal abnormalities or malformations of the uterus or the vagina. VACs without DES exposition have a poor prognosis and a significantly worse outcome compared to vaginal squamous cell carcinomas or DES-associated VACs., Objective: Here, we report the case of a primarily metastatic VAC, treated successfully with different lines of chemo-, antiangiogenic, antibody, and immunotherapy., Case: The 49-year-old patient presented in 5/2018 with a primarily pulmonary metastatic VAC. Significant tumor reduction was seen after six cycles of carboplatin AUC5/paclitaxel 175 mg/m²/bevacizumab 15 mg/kg q3w. Bevacizumab maintenance therapy and later cisplatin mono 50 mg/m² q2w led to local and distant tumor progression. To identify a potential targeted therapy, new tumor biopsies were obtained. Immunohistochemistry revealed ERBB2 expression, and paclitaxel 80 mg/m² weekly plus trastuzumab 4 mg/m² respectively 2 mg/m² q3w was administered. Due to local and pulmonal tumor progression after 6 months and persistent ERBB2 positivity, the therapy was adjusted to trastuzumab emtansine (T-DM1) 3.6 mg/kg q3w; however, the patient remained locally progressive after three cycles of T-DM1 and additionally showed a new bone metastasis. The new tumor biopsies revealed a combined positive score (CPS) of 2 regarding PD-L1, and pembrolizumab 200 mg q3w was initiated. The bone metastasis was radiated and treated with denosumab 120 mg q4w. Extreme tumor regression followed by stable disease was maintained for 9 months. Due to a slow locoregional progress only with new inguinal lymph node and pararectal lymph node metastases, a new tumor biopsy was taken. Molecular profiling showed an ARID1A mutation, a mutational burden of 5.1 mutations per megabase, and no genfusions. Based on these findings, therapy with PD-L1 antibodies, PD-1 antibodies, gemcitabine, or dasatinib was suggested. Therefore, administration of pembrolizumab was continued and local radiation therapy was performed. This led to a decrease in local tumor manifestations and a stable systemic disease., Conclusion: Our case demonstrates the diagnostic and therapeutic approach in a patient with primary metastatic vaginal adenocarcinoma. By tumorgenetic profiling, different lines of systemic therapy, namely, antiangiogenic therapy, monoclonal antibody therapy, immunotherapy, and local radiation therapy, were identified and successfully administered., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Egger, Ralser, Lindner, Recker, Marinova, Savchenko, Lau and Mustea.)
- Published
- 2021
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38. Identification of a founder mutation in KRT14 associated with Naegeli-Franceschetti-Jadassohn syndrome.
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Ralser DJ, Kumar S, Borisov O, Sarig O, Richard G, Wolf S, Krawitz PM, Sprecher E, Kreiß M, and Betz RC
- Subjects
- Founder Effect, Humans, Keratin-14 genetics, Mutation genetics, Ectodermal Dysplasia, Hypohidrosis, Keratoderma, Palmoplantar
- Published
- 2020
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39. Obstetric and Neonatal Outcome of Pregnancy in Carney Complex: A Case Report.
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Ralser DJ, Strizek B, Kupczyk P, Stoffel-Wagner B, Altengarten J, Müller A, Woelfle J, Gembruch U, Klingmueller D, Merz WM, and Paschkowiak-Christes A
- Subjects
- Adult, Carney Complex drug therapy, Carney Complex surgery, Female, Humans, Infant, Newborn, Pregnancy, Pregnancy Complications, Neoplastic drug therapy, Pregnancy Complications, Neoplastic surgery, Pregnancy Outcome, Antimetabolites therapeutic use, Carney Complex pathology, Cesarean Section methods, Cushing Syndrome physiopathology, Metyrapone therapeutic use, Pregnancy Complications, Neoplastic pathology
- Abstract
Background: Carney complex (CNC) is a rare multiple endocrine neoplasia syndrome with autosomal dominant inheritance. Affected individuals present with mucocutaneous lentigines/blue nevi, cardiac and noncardiac myxomatous tumors, and multiple endocrine tumors. Mutations in PRKAR1A have been identified as genetic cause of the disease. Here, we report on pregnancy, delivery and puerperium in a woman with genetically confirmed CNC and her newborn. Case: The 31 year-old gravida 5 para 1 with CNC was referred at 26 weeks of gestation. Adrenocorticotropin-independent hypercortisolism, hyperglycemia, hypertension, low serum potassium, and osteoporotic fractures were present. Treatment with metyrapone, a reversible 11-beta-hydroxylase inhibitor, was initiated. The maternal condition improved, and a 5 weeks' pregnancy prolongation could be achieved. Elective repeat cesarean section was performed at 31 weeks of gestation for recurrent vaginal bleeding. The neonate developed transient hyponatremia necessitating hydrocortisone substitution for 2 weeks. Conclusion: In our case, treatment of CNC-associated hypercortisolism in pregnancy with metyrapone was effective. Maternal side effects did not occur. The newborn presented with transient hypocortisolism most likely due to transplacental drug effect. Our case illustrates that the treatment of rare diseases in pregnancy represents a challenge requiring interdisciplinary team work., (Copyright © 2020 Ralser, Strizek, Kupczyk, Stoffel-Wagner, Altengarten, Müller, Woelfle, Gembruch, Klingmueller, Merz and Paschkowiak-Christes.)
- Published
- 2020
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40. LAG3 ( LAG-3 , CD223 ) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma.
- Author
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Klümper N, Ralser DJ, Bawden EG, Landsberg J, Zarbl R, Kristiansen G, Toma M, Ritter M, Hölzel M, Ellinger J, and Dietrich D
- Subjects
- Antigens, CD immunology, Carcinoma, Renal Cell genetics, Humans, Kidney Neoplasms genetics, Prognosis, Survival Analysis, Lymphocyte Activation Gene 3 Protein, Antigens, CD biosynthesis, Antigens, CD genetics, Carcinoma, Renal Cell immunology, DNA Methylation, Kidney Neoplasms immunology
- Abstract
Background: Lymphocyte activating 3 (LAG3, LAG-3, CD223) is a promising target for immune checkpoint inhibition in clear cell renal cell carcinoma (KIRC). The aim of this study was to investigate the epigenetic regulation of LAG3 in KIRC by methylation., Methods: We correlated quantitative LAG3 methylation levels with transcriptional activity, immune cell infiltration, and overall survival in a cohort of n=533 patients with KIRC and n=160 normal adjacent tissue (NAT) samples obtained from The Cancer Genome Atlas (TCGA). Furthermore, we analyzed LAG3 methylation in peripheral blood mononuclear cells (PBMCs) and KIRC cell lines. We validated correlations between LAG3 expression, immune cell infiltrates, survival, and methylation in an independent KIRC cohort (University Hospital Bonn (UHB) cohort, n=118) by means of immunohistochemistry and quantitative methylation-specific PCR., Results: We found differential methylation profiles among PBMCs, NAT, KIRC cell lines, and KIRC tumor tissue. Methylation strongly correlated with LAG3 mRNA expression in KIRCs (TCGA cohort) and KIRC cell lines. In the UHB cohort, methylation correlated with LAG3-positive immune cells and tumor-intrinsic LAG3 protein expression. Furthermore, LAG3 methylation strongly correlated with signatures of distinct immune cell infiltrates, an interferon-y signature (TCGA cohort), and immunohistochemically quantified CD45
+ , CD8+ , and CD4+ immune cell infiltrates (UHB cohort). LAG3 mRNA expression (TCGA cohort), methylation (both cohorts), and tumor cell-intrinsic protein expression (UHB cohort) was significantly associated with overall survival., Conclusion: Our data suggest an epigenetic regulation of LAG3 expression in tumor and immune cells via DNA methylation. LAG3 expression and methylation is associated with a subset of KIRCs showing a distinct clinical course and immunogenicity. Our study provides rationale for further testing LAG3 DNA methylation as a predictive biomarker for response to LAG3 immune checkpoint inhibitors., Competing Interests: Competing interests: DD owns patents and patent applications on biomarker technologies and methylation of immune checkpoint genes as predictive and prognostic biomarkers (DE 10 2016 005 947.8, DE 10 2015 009 187.5, DE 10 2017 125 780.2, PCT/EP2016/001237). The patents are licensed to Qiagen GmbH (Hilden, Germany). DD is a consultant of Qiagen. The University Hospital Bonn (PI Dimo Dietrich) receives research funding from Qiagen. The other authors have declared that no conflict of interest exists., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2020
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41. Mast cell activation in Dowling-Degos disease.
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Knuever J, Persa OD, Illerhaus A, Ralser DJ, Hartmann K, Betz RC, and Tantcheva-Poór I
- Subjects
- Biopsy, DNA Mutational Analysis, Diagnosis, Differential, Female, Glucosyltransferases genetics, Histamine Antagonists administration & dosage, Humans, Hyperpigmentation complications, Hyperpigmentation diagnosis, Hyperpigmentation genetics, Keratin-5 genetics, Mast Cells drug effects, Mastocytosis diagnosis, Mutation, Pruritus drug therapy, Skin immunology, Skin pathology, Skin Diseases, Genetic complications, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Papulosquamous complications, Skin Diseases, Papulosquamous diagnosis, Skin Diseases, Papulosquamous genetics, Hyperpigmentation immunology, Mast Cells immunology, Pruritus immunology, Skin cytology, Skin Diseases, Genetic immunology, Skin Diseases, Papulosquamous immunology
- Published
- 2019
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42. Altered Notch Signaling in Dowling-Degos Disease: Additional Mutations in POGLUT1 and Further Insights into Disease Pathogenesis.
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Ralser DJ, Takeuchi H, Fritz G, Basmanav FB, Effern M, Sivalingam S, El-Shabrawi-Caelen L, Degirmentepe EN, Kocatürk E, Singh M, Booken N, Spierings NMK, Schnabel V, Heineke A, Knuever J, Wolf S, Wehner M, Tronnier M, Leverkus M, Tantcheva-Poór I, Wenzel J, Oji V, Has C, Hölzel M, Frank J, Haltiwanger RS, and Betz RC
- Subjects
- DNA Mutational Analysis, Disease Progression, Female, Glucosyltransferases metabolism, Humans, Hyperpigmentation metabolism, Male, Signal Transduction, Skin Diseases, Genetic metabolism, Skin Diseases, Papulosquamous metabolism, Glucosyltransferases genetics, Hyperpigmentation genetics, Mutation, Skin Diseases, Genetic genetics, Skin Diseases, Papulosquamous genetics
- Published
- 2019
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43. Intra- and Interfamilial Phenotype Variability Associated with Mutations in γ-Secretase Subunit-Encoding PSENEN.
- Author
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Frank J, Ralser DJ, and Betz RC
- Subjects
- Dichlorodiphenyldichloroethane, Humans, Hyperpigmentation, Membrane Proteins genetics, Mutation, Phenotype, Skin Diseases, Genetic, Skin Diseases, Papulosquamous, Amyloid Precursor Protein Secretases genetics, Hidradenitis Suppurativa
- Published
- 2018
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44. Exome sequencing in syndromic brain malformations identifies novel mutations in ACTB, and SLC9A6, and suggests BAZ1A as a new candidate gene.
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Weitensteiner V, Zhang R, Bungenberg J, Marks M, Gehlen J, Ralser DJ, Hilger AC, Sharma A, Schumacher J, Gembruch U, Merz WM, Becker A, Altmüller J, Thiele H, Herrmann BG, Odermatt B, Ludwig M, and Reutter H
- Subjects
- Animals, Child, Chromosomal Proteins, Non-Histone, Female, Humans, Male, Mice, Actins genetics, Brain abnormalities, Mutation, Sodium-Hydrogen Exchangers genetics, Transcription Factors genetics, Exome Sequencing
- Abstract
Background: Syndromic brain malformations comprise a large group of anomalies with a birth prevalence of about 1 in 1,000 live births. Their etiological factors remain largely unknown. To identify causative mutations, we used whole-exome sequencing (WES) in aborted fetuses and children with syndromic brain malformations in which chromosomal microarray analysis was previously unremarkable., Methods: WES analysis was applied in eight case-parent trios, six aborted fetuses, and two children., Results: WES identified a novel de novo mutation (p.Gly268Arg) in ACTB (Baraitser-Winter syndrome-1), a homozygous stop mutation (p.R2442*) in ASPM (primary microcephaly type 5), and a novel hemizygous X-chromosomal mutation (p.I250V) in SLC9A6 (X-linked syndromic mentaly retardation, Christianson type). Furthermore, WES identified a de novo mutation (p.Arg1093Gln) in BAZ1A. This mutation was previously reported in only one allele in 121.362 alleles tested (dbSNP build 147). BAZ1A has been associated with neurodevelopmental impairment and dysregulation of several pathways including vitamin D metabolism. Here, serum vitamin-D (25-(OH)D) levels were insufficient and gene expression comparison between the child and her parents identified 27 differentially expressed genes. Of note, 10 out of these 27 genes are associated to cytoskeleton, integrin and synaptic related pathways, pinpointing to the relevance of BAZ1A in neural development. In situ hybridization in mouse embryos between E10.5 and E13.5 detected Baz1a expression in the central and peripheral nervous system., Conclusion: In syndromic brain malformations, WES is likely to identify causative mutations when chromosomal microarray analysis is unremarkable. Our findings suggest BAZ1A as a possible new candidate gene., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
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45. Functional implications of novel ADAM10 mutations in reticulate acropigmentation of Kitamura.
- Author
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Ralser DJ, Lestringant GG, Du-Thanh A, Kokordelis P, Fischer J, Basmanav FBÜ, Wolf S, Thiele H, Altmüller J, Nürnberg P, Oji V, Fritz G, Frank J, and Betz RC
- Subjects
- Codon, Nonsense genetics, Female, Frameshift Mutation genetics, Haploinsufficiency genetics, Humans, INDEL Mutation genetics, Male, Mutation, Missense genetics, ADAM10 Protein genetics, Amyloid Precursor Protein Secretases genetics, Hyperpigmentation genetics, Membrane Proteins genetics, Mutation genetics, Skin Diseases, Genetic genetics, Skin Diseases, Papulosquamous genetics
- Published
- 2017
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46. Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.
- Author
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Ralser DJ, Basmanav FB, Tafazzoli A, Wititsuwannakul J, Delker S, Danda S, Thiele H, Wolf S, Busch M, Pulimood SA, Altmüller J, Nürnberg P, Lacombe D, Hillen U, Wenzel J, Frank J, Odermatt B, and Betz RC
- Subjects
- Animals, Codon, Nonsense, Female, Genetic Association Studies, Genetic Predisposition to Disease, Hidradenitis Suppurativa enzymology, Hyperpigmentation enzymology, Male, Skin Diseases, Genetic enzymology, Skin Diseases, Papulosquamous enzymology, Zebrafish, Amyloid Precursor Protein Secretases genetics, Hidradenitis Suppurativa genetics, Hyperpigmentation genetics, Membrane Proteins genetics, Skin Diseases, Genetic genetics, Skin Diseases, Papulosquamous genetics
- Abstract
Dowling-Degos disease (DDD) is an autosomal-dominant disorder of skin pigmentation associated with mutations in keratin 5 (KRT5), protein O-fucosyltransferase 1 (POFUT1), or protein O-glucosyltransferase 1 (POGLUT1). Here, we have identified 6 heterozygous truncating mutations in PSENEN, encoding presenilin enhancer protein 2, in 6 unrelated patients and families with DDD in whom mutations in KRT5, POFUT1, and POGLUT1 have been excluded. Further examination revealed that the histopathologic feature of follicular hyperkeratosis distinguished these 6 patients from previously studied individuals with DDD. Knockdown of psenen in zebrafish larvae resulted in a phenotype with scattered pigmentation that mimicked human DDD. In the developing zebrafish larvae, in vivo monitoring of pigment cells suggested that disturbances in melanocyte migration and differentiation underlie the DDD pathogenesis associated with PSENEN. Six of the PSENEN mutation carriers presented with comorbid acne inversa (AI), an inflammatory hair follicle disorder, and had a history of nicotine abuse and/or obesity, which are known trigger factors for AI. Previously, PSENEN mutations were identified in familial AI, and comanifestation of DDD and AI has been reported for decades. The present work suggests that PSENEN mutations can indeed cause a comanifestation of DDD and AI that is likely triggered by predisposing factors for AI. Thus, the present report describes a DDD subphenotype in PSENEN mutation carriers that is associated with increased susceptibility to AI.
- Published
- 2017
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47. Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome.
- Author
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Ü Basmanav FB, Cau L, Tafazzoli A, Méchin MC, Wolf S, Romano MT, Valentin F, Wiegmann H, Huchenq A, Kandil R, Garcia Bartels N, Kilic A, George S, Ralser DJ, Bergner S, Ferguson DJP, Oprisoreanu AM, Wehner M, Thiele H, Altmüller J, Nürnberg P, Swan D, Houniet D, Büchner A, Weibel L, Wagner N, Grimalt R, Bygum A, Serre G, Blume-Peytavi U, Sprecher E, Schoch S, Oji V, Hamm H, Farrant P, Simon M, and Betz RC
- Subjects
- Adolescent, Animals, Base Sequence, Cell Line, Codon, Nonsense, Female, Hair abnormalities, Hair anatomy & histology, Hair metabolism, Humans, Hydrolases deficiency, Hydrolases metabolism, Male, Mice, Mice, Knockout, Models, Molecular, Mutation, Missense genetics, Protein Conformation, Protein-Arginine Deiminase Type 3, Protein-Arginine Deiminases, Transglutaminases deficiency, Transglutaminases metabolism, Vibrissae abnormalities, Antigens genetics, Hair growth & development, Hair Diseases genetics, Hydrolases genetics, Intermediate Filament Proteins genetics, Mutation, Transglutaminases genetics
- Abstract
Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili trianguli et canaliculi," or "cheveux incoiffables" is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. Elucidation of the molecular outcomes of the disease-causing mutations by cell culture experiments and tridimensional protein models demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins. Scanning electron microscopy observations revealed morphological alterations in hair coat of Padi3 knockout mice. All together, these findings elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology in general., (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
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