92 results on '"Kitz J"'
Search Results
2. Angioinvasion durch neuroendokrinen Jejunumtumor: Darstellung eines Malignitätszeichens durch Acetonkompression
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Scheel, A.H., Kitz, J., Heimbucher, J., Ströbel, P., and Rüschoff, J.
- Published
- 2013
- Full Text
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3. KRAS mutation heterogeneity in rectal cancer after preoperative chemoradiotherapy: ID 296
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Jo, P., Salendo, J., Kitz, J., Conradi, L. C., Azizian, A., Wolff, H. A., Grade, M., Ströbel, P., Ghadimi, M., and Gaedcke, J.
- Published
- 2014
4. Prognostischer Stellenwert der zusätzlichen HPV-Genotypisierung in p16-stratifizierten Plattenepithelkarzinomen des Oropharynx fortgeschrittenen Stadiums
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Weiss, BG, additional, Anczykowski, MZ, additional, Canis, M, additional, Ihler, F, additional, Kitz, J, additional, and Jakob, M, additional
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- 2020
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5. Die Rolle der Krebs-Stammzellmarker ALDH1, BCL11B, BMI-1 und CD44 in der Prognose fortgeschrittener Kopf-Hals-Plattenepithelkarzinome
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Sharaf, K, additional, Kitz, J, additional, Canis, M, additional, and Jakob, M, additional
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- 2020
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6. Role of cancer stem cell markers ALDH1, BCL11B, BMI-1, and CD44 in the prognosis of advanced HNSCC
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Sharaf, K, additional, Kitz, J, additional, Canis, M, additional, and Jakob, M, additional
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- 2020
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7. Prognostic impact of additional HPV-typing in p16-stratified advanced oropharyngeal squamous cell carcinoma
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Weiss, BG., additional, Anczykowski, Mahalia Zoe, additional, Canis, M, additional, Ihler, F, additional, Kitz, J, additional, and Jakob, M, additional
- Published
- 2020
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8. Chemokine und Chemokinrezeptoren als Signalwege gastrointestinaler Stromatumore (GISTs): PO416
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Cameron, S., Kitz, J., Fuezesi, L., and Ramadori, G.
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- 2010
9. Resektionsstatus beim Pankreaskopfkarzinom: Bedeutung für die Therapie: FV320
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Ghadimi, M., Gaedcke, J., Kitz, J., Grade, M., Cordes, C., Liersch, T., and Becker, H.
- Published
- 2010
10. Comparative proteomics reveals a diagnostic signature for pulmonary head-and-neck cancer metastasis
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Bohnenberger, H., Kaderali, L., Ströbel, P., Yepes, D., Pleßmann, U., Dharia, N., Yao, S., Heydt, C., Merkelbach‐Bruse, S., Emmert, A., Hoffmann, J., Bodemeyer, J., Reuter‐Jessen, K., Lois, A., Dröge, L., Baumeister, P., Walz, C., Biggemann, L., Walter, R., Häupl, B., Comoglio, F., Pan, K., Scheich, S., Lenz, C., Küffer, S., Bremmer, F., Kitz, J., Sitte, M., Beißbarth, T., Hinterthaner, M., Sebastian, M., Lotz, J., Schildhaus, H., Wolff, H., Danner, B., Brandts, C., Büttner, R., Canis, M., Stegmaier, K., Serve, H., Urlaub, H., and Oellerich, T.
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stomatognathic diseases - Abstract
Patients with head‐and‐neck cancer can develop both lung metastasis and primary lung cancer during the course of their disease. Despite the clinical importance of discrimination, reliable diagnostic biomarkers are still lacking. Here, we have characterised a cohort of squamous cell lung (SQCLC) and head‐and‐neck (HNSCC) carcinomas by quantitative proteomics. In a training cohort, we quantified 4,957 proteins in 44 SQCLC and 30 HNSCC tumours. A total of 518 proteins were found to be differentially expressed between SQCLC and HNSCC, and some of these were identified as genetic dependencies in either of the two tumour types. Using supervised machine learning, we inferred a proteomic signature for the classification of squamous cell carcinomas as either SQCLC or HNSCC, with diagnostic accuracies of 90.5% and 86.8% in cross‐ and independent validations, respectively. Furthermore, application of this signature to a cohort of pulmonary squamous cell carcinomas of unknown origin leads to a significant prognostic separation. This study not only provides a diagnostic proteomic signature for classification of secondary lung tumours in HNSCC patients, but also represents a proteomic resource for HNSCC and SQCLC.
- Published
- 2018
11. PV-0533 HPV16 viral load may explain gender differences in treatment outcome of anal squamous cell carcinoma
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Martin, D., primary, Balermpas, P., additional, Winkelmann, R., additional, Wieland, U., additional, Rave-Fränk, M., additional, Kitz, J., additional, Rödel, C., additional, Fokas, E., additional, and Rödel, F., additional
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- 2019
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12. OC-0150: Assessing the immune contexture of anal squamous cell carcinoma
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Martin, D., primary, Balermpas, P., additional, Winkelmann, R., additional, Wieland, U., additional, Rave-Fränk, M., additional, Helmke, C., additional, Raab, M., additional, Kitz, J., additional, Matthess, Y., additional, Strebhardt, K., additional, Rödel, C., additional, Rödel, F., additional, and Fokas, E., additional
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- 2018
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13. Human papillomavirus DNA load and p16INK4a expression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy
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Rödel, F, Wieland, U, Fraunholz, I, Kitz, J, Rave-Fränk, M, Wolff, H, Weiss, C, Wirtz, R, Balermpas, P, Fokas, E, and Rödel, C
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integumentary system ,virus diseases ,neoplasms ,female genital diseases and pregnancy complications - Abstract
As the detection rate of HPV-DNA in anal carcinoma commonly exceeds 90%, a comparison between sole HPV-positive and HPV-negative cancers with respect to treatment response following chemoradiotherapy (CRT) and long-term oncological outcome is challenging. Against this background, we aimed to assess HPV types and HPV DNA load in formalin-fixed paraffin-embedded tissue (FFPE) of 95 patients treated with standard CRT for anal cancer to correlate viral load (≤/> median) with local failure, distant metastases, cancer-specific (CSS) and overall survival (OS) rates. Various clinicopathologic parameters and the immunohistochemical marker p16(INK4a) were evaluated for any correlation with HPV16 DNA load and were included in uni- and multivariate analyses. The overall prevalence of HPV DNA was 95.8% with HPV16 monoinfection being the most commonly encountered HPV type (78.9%), followed by HPV16 and 31, 35, 39, 44, 58, 66 and 81 dual infection in 9 patients (9.5%). HPV16 DNA load was significantly associated with p16(INK4a) expression (p = 0.001). Patients with HPV16 DNA load ≤ median and low p16(INK4a) expression showed significantly worse local control (HPV16 DNA load: univariate p = 0.023, multivariate p = 0.042; p16(INK4a): univariate p = 0.021), and OS (HPV16 DNA load: univariate p = 0.02, multivariate p = 0.03). Moreover, a combined HPV16 DNA load and p16(INK4a) variable revealed a significant correlation to decreased local failure, and increased CSS and OS (p = 0.019, p = 0.04 and p = 0.031). In conclusion, these data indicate that HPV16 DNA load and p16(INK4a) expression are significant prognostic factors for local tumor control and overall survival of patients with anal SCC following CRT.
- Published
- 2015
14. Der Einfluss von miR-1, miR-127-3 p, miR-376a und miR-152-3 p auf das Ansprechen von Rektumkarzinomen auf eine neoadjuvante Radiochemotherapie
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Skarupke, R, primary, Jo, P, additional, Azizian, A, additional, Kitz, J, additional, Rave-Fränk, M, additional, Kramer, F, additional, Ried, T, additional, Ghadimi, M, additional, Spitzner, M, additional, Grade, M, additional, and Gaedcke, J, additional
- Published
- 2014
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15. KRAS Mutations-Heterogenität im Rektumkarzinom nach neoadjuvanter Radiochemotherapie
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Jo, PYJ, primary, Salendo, J, additional, Kitz, J, additional, Conradi, LC, additional, Azizian, A, additional, Wolff, HA, additional, Grade, M, additional, Ströbel, P, additional, Ghadimi, M, additional, and Gaedcke, J, additional
- Published
- 2013
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16. Analysis of a case with disappearance of the primary gastrointestinal stromal tumor and progressive liver metastases under long-term treatment with tyrosine kinase inhibitors.
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Cameron S, Savvoukidis T, Armbrust T, Haller F, Kitz J, Füzesi L, Ramadori G, Cameron, Silke, Savvoukidis, Theodoros, Armbrust, Thomas, Haller, Florian, Kitz, Julia, Füzesi, László, and Ramadori, Giuliano
- Abstract
The response of gastrointestinal stromal tumors (GISTs) to tyrosine kinase receptor inhibitors (TKR-I) has been a breakthrough for small molecular therapy. We report here on the very different long-term outcome of a synchronous metastatic GIST with complete remission of the primary tumor and progressive liver metastases under TKR-I therapy. In 2003, a 52-year-old patient was diagnosed with gastric GIST and synchronous multiple liver metastases. Therapy with imatinib, 400 mg daily, was started immediately. Fifteen months later, the primary was no longer detectable by endoscopy. In 2006, progression of the liver metastases was observed. Mutation analysis of the initial biopsy specimen from the primary, as well as the biopsy from the three main liver metastases after 3 years of imatinib treatment, revealed the common KIT exon 11 deletion (W557_K558del) in all tumor samples. Two of the metastases had a separate secondary mutation in KIT exon 14 and 17, respectively, while the largest cystic metastatic lesion had no other mutation. Imatinib was then increased to a daily dose of 800 mg, and in April 2007 the treatment was changed to sunitinib. Fifty-two months after initial diagnosis, the patient died of liver failure. At no time point, relapse of the gastric primary tumor was observed. Whilst TKR-Is are commonly very effective in treating GISTs, the present case illustrates their varying effects regarding the clinical behavior and genetic variations within different tumors of the same patient after long-term treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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17. Pitfalls in mutational testing and reporting of common KIT and PDGFRA mutations in gastrointestinal stromal tumors
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Penzel Roland, Mechtersheimer Gunhild, Krohn Antje, Kitz Julia, Haller Florian, Gaumann Andreas, Füzesi Laszlo, Dietmaier Wolfgang, Merkelbach-Bruse Sabine, Schildhaus Hans-Ulrich, Schneider-Stock Regine, Simon Ronald, and Wardelmann Eva
- Subjects
Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Mutation analysis of KIT and PDGFRA genes in gastrointestinal stromal tumors is gaining increasing importance for prognosis of GISTs and for prediction of treatment response. Several groups have identified specific mutational subtypes in KIT exon 11 associated with an increased risk of metastatic disease whereas GISTs with PDGFRA mutations often behave less aggressive. Furthermore, in advanced GIST disease with proven KIT exon 9 mutation the doubled daily dose of 800 mg imatinib increases the progression free survival and is now recommended both in the European and the American Guidelines. In Germany, there are still no general rules how to perform mutational analysis. Methods When comparing results from six different molecular laboratories we recognized the need of standardisation. Six German university laboratories with experience in mutation analysis in GISTs joined together to develop recommendations for the mutation analysis of the most common and clinically relevant hot spots, i. e. KIT exons 9 and 11 and PDGFRA exon 18. We performed a three-phased interlaboratory trial to identify pitfalls in performing molecular analysis in GISTs. Results We developed a design for a continuous external laboratory trial. In 2009 this external trial was conducted by 19 laboratories via the initiative for quality assurance in pathology (QuiP) of the German Society of Pathology and the Professional Association of German Pathologists. Conclusions By performing a three-phased internal interlaboratory trial and conducting an external trial in Germany we were able to identify potential pitfalls when performing KIT and PDGFRA mutational analysis in gastrointestinal stromal tumors. We developed standard operation procedures which are provided with the manuscript to allow other laboratories to prevent these pitfalls.
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- 2010
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18. Urokinase-Type Plasminogen Activator Receptor (uPAR) Cooperates with Mutated KRAS in Regulating Cellular Plasticity and Gemcitabine Response in Pancreatic Adenocarcinomas.
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Peng L, Li Y, Yao S, Gaedcke J, Baart VM, Sier CFM, Neesse A, Ellenrieder V, Bohnenberger H, Fuchs F, Kitz J, Ströbel P, and Küffer S
- Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers. Given the currently limited therapeutic options, the definition of molecular subgroups with the development of tailored therapies remains the most promising strategy. Patients with high-level gene amplification of urokinase plasminogen activator receptor ( uPAR/PLAUR ) have an inferior prognosis. We analyzed the uPAR function in PDAC to understand this understudied PDAC subgroup's biology better., Methods: A total of 67 PDAC samples with clinical follow-up and TCGA gene expression data from 316 patients were used for prognostic correlations. Gene silencing by CRISPR/Cas9, as well as transfection of uPAR and mutated KRAS , were used in PDAC cell lines (AsPC-1, PANC-1, BxPC3) treated with gemcitabine to study the impact of these two molecules on cellular function and chemoresponse. HNF1A and KRT81 were surrogate markers for the exocrine-like and quasi-mesenchymal subgroup of PDAC, respectively., Results: High levels of uPAR were correlated with significantly shorter survival in PDAC, especially in the subgroup of HNF1A-positive exocrine-like tumors. uPAR knockout by CRISPR/Cas9 resulted in activation of FAK, CDC42, and p38, upregulation of epithelial makers, decreased cell growth and motility, and resistance against gemcitabine that could be reversed by re-expression of uPAR. Silencing of KRAS in AsPC1 using siRNAs reduced uPAR levels significantly, and transfection of mutated KRAS in BxPC-3 cells rendered the cell more mesenchymal and increased sensitivity towards gemcitabine., Conclusions: Activation of uPAR is a potent negative prognostic factor in PDAC. uPAR and KRAS cooperate in switching the tumor from a dormant epithelial to an active mesenchymal state, which likely explains the poor prognosis of PDAC with high uPAR. At the same time, the active mesenchymal state is more vulnerable to gemcitabine. Strategies targeting either KRAS or uPAR should consider this potential tumor-escape mechanism.
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- 2023
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19. Comparing Apparent Diffusion Coefficient and FNCLCC Grading to Improve Pretreatment Grading of Soft Tissue Sarcoma-A Translational Feasibility Study on Fusion Imaging.
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Hettler M, Kitz J, Seif Amir Hosseini A, Guhlich M, Panahi B, Ernst J, Conradi LC, Ghadimi M, Ströbel P, and Jakob J
- Abstract
Histological subtype and grading are cornerstones of treatment decisions in soft tissue sarcoma (STS). Due to intratumoral heterogeneity, pretreatment grading assessment is frequently unreliable and may be improved through functional imaging. In this pilot study, 12 patients with histologically confirmed STS were included. Preoperative functional magnetic resonance imaging was fused with a computed tomography scan of the resected specimen after collecting core needle biopsies and placing radiopaque markers at distinct tumor sites. The Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading criteria of the biopsies and apparent diffusion coefficients (ADCs) of the biopsy sites were correlated. Concordance in grading between the specimen and at least one biopsy was achieved in 9 of 11 cases (81.8%). In 7 of 12 cases, fusion imaging was feasible without relevant contour deviation. Functional analysis revealed a tendency for high-grade regions (Grade 2/3 (G2/G3)) (median (range) ± standard deviation: 1.13 (0.78-1.70) ± 0.23 × 10
-3 mm2 /s) to have lower ADC values than low-grade regions (G1; 1.43 (0.64-2.03) ± 0.46 × 10-3 mm2 /s). In addition, FNCLCC scoring of multiple tumor biopsies proved intratumoral heterogeneity as expected. The ADC appears to correlate with the FNCLCC grading criteria. Further studies are needed to determine whether functional imaging may supplement histopathological grading.- Published
- 2022
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20. Gene-expression profiles of pretreatment biopsies predict complete response of rectal cancer patients to preoperative chemoradiotherapy.
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Emons G, Auslander N, Jo P, Kitz J, Azizian A, Hu Y, Hess CF, Roedel C, Sax U, Salinas G, Stroebel P, Kramer F, Beissbarth T, Grade M, Ghadimi M, Ruppin E, Ried T, and Gaedcke J
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- Biopsy, Clinical Trials as Topic, Humans, Neoadjuvant Therapy, Treatment Outcome, Chemoradiotherapy, Rectal Neoplasms genetics, Rectal Neoplasms pathology, Rectal Neoplasms therapy
- Abstract
Purpose: Preoperative (neoadjuvant) chemoradiotherapy (CRT) and total mesorectal excision is the standard treatment for rectal cancer patients (UICC stage II/III). Up to one-third of patients treated with CRT achieve a pathological complete response (pCR). These patients could be spared from surgery and its associated morbidity and mortality, and assigned to a "watch and wait" strategy. However, reliably identifying pCR based on clinical or imaging parameters remains challenging., Experimental Design: We generated gene-expression profiles of 175 patients with locally advanced rectal cancer enrolled in the CAO/ARO/AIO-94 and -04 trials. One hundred and sixty-one samples were used for building, training and validating a predictor of pCR using a machine learning algorithm. The performance of the classifier was validated in three independent cohorts, comprising 76 patients from (i) the CAO/ARO/AIO-94 and -04 trials (n = 14), (ii) a publicly available dataset (n = 38) and (iii) in 24 prospectively collected samples from the TransValid A trial., Results: A 21-transcript signature yielded the best classification of pCR in 161 patients (Sensitivity: 0.31; AUC: 0.81), when not allowing misclassification of non-complete-responders (False-positive rate = 0). The classifier remained robust when applied to three independent datasets (n = 76)., Conclusion: The classifier can identify >1/3 of rectal cancer patients with a pCR while never classifying patients with an incomplete response as having pCR. Importantly, we could validate this finding in three independent datasets, including a prospectively collected cohort. Therefore, this classifier could help select rectal cancer patients for a "watch and wait" strategy., Translational Relevance: Forgoing surgery with its associated side effects could be an option for rectal cancer patients if the prediction of a pathological complete response (pCR) after preoperative chemoradiotherapy would be possible. Based on gene-expression profiles of 161 patients a classifier was developed and validated in three independent datasets (n = 76), identifying over 1/3 of patients with pCR, while never misclassifying a non-complete-responder. Therefore, the classifier can identify patients suited for "watch and wait"., (© 2022. The Author(s).)
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- 2022
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21. Ansprechen eines metastasierten akrolentiginösen Melanoms mit Exon-11-BRAF-G469A-Mutation auf BRAF/MEK-Inhibition.
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Julius K, Kromer C, Schnabel V, Vlahova L, Kitz J, Schön MP, Sahlmann CO, and Kretschmer L
- Published
- 2022
- Full Text
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22. Response of metastatic acral melanoma with exon 11 BRAF G469A mutation to BRAF/MEK inhibition.
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Julius K, Kromer C, Schnabel V, Vlahova L, Kitz J, Schön MP, Sahlmann CO, and Kretschmer L
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- 2022
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23. Cure Is Possible: Extensively Metastatic HER2-Positive Gastric Carcinoma with 5 years of Complete Remission after Therapy with the FLOT Regimen and Trastuzumab.
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Schade S, Koenig U, Mekolli A, Gaedcke J, Neesse A, Reinecke J, Brunner M, Amir Hosseini AS, Kitz J, Stroebel P, Lotz J, Ghadimi M, Ellenrieder V, and Koenig A
- Abstract
Gastric cancer (GC) represents one of the most fatal neoplasms in gastrointestinal oncology and affected patients can only hope for cure in limited disease. In a metastatic situation however, patients have a worse prognosis finally resulting in cancer-related death. Some improvements were made by using intensified chemotherapy such as the FLOT protocol (5-FU, leucovorin, oxaliplatin and docetaxel). However, a breakthrough in the treatment of advanced GC has been achieved by pre-therapeutical tumor analysis for potentially targetable alterations. Microsatellite instability, PD-L1 expression, Epstein Barr virus, and human epidermal growth factor receptor-2 (HER2) overexpression or amplification are the most beneficial targets, if addressed, can prolong survival in a palliative situation. Whether the combination of these targeted therapeutics with chemotherapy can bring long-term survival or even a chance of cure in a metastatic situation is not clear. Here, we report the case of a 30-year-old man with GC and extensive metastases who was cured by anti-HER2 antibody Trastuzumab combined with the FLOT regime. Initial staging showed an exophytic Siewert type III tumor and extensive hepatic metastases. Histology resulted in gastric adenocarcinoma with HER2 overexpression (2+, FISH positive). Twelve courses of chemotherapy comprising Trastuzumab and FLOT were administered. After treatment, the extensive liver metastases had disappeared with no evidence of residual tumor growth on the CT scans. Monotherapy of Trastuzumab was continued until gastrectomy with D2 lymph node dissection and probing of liver tissue, which revealed no residual tumor cells. Five years after surgery, there is continued complete remission. In conclusion, Trastuzumab in combination with FLOT may have curative potential even for metastatic stages of HER-2-positive GC., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by S. Karger AG, Basel.)
- Published
- 2022
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24. Effectiveness of fourth-line dual immunotherapy in hepatocellular carcinoma with simultaneous steroid administration for immune-related hepatitis.
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Lowes K, Reinecke J, Brunner M, Scholz M, Kitz J, Michels B, Mekolli A, Gaedcke J, Seif Amir Hosseini A, Ströbel P, Ghadimi M, Ellenrieder V, Koenig A, and Koenig U
- Abstract
Medical therapy of advanced hepatocellular carcinoma (HCC) remains an emerging subject, but therapeutic sequences together with toxicity management are rarely described. Herein, we report the case of a therapeutic sequence and toxicity management in a 72-year old White male with advanced non-cirrhotic HCC. The HCC of this patient was refractory against treatment with several tyrosine kinase inhibitors, including lenvatinib and cabozantinib or immune combination of pembrolizumab and lenvatinib. Double immune combination of nivolumab and ipilimumab was effective in fourth-line treatment but resulted in immunotherapy-related grade 4 hepatitis. This toxicity responded well to high doses of corticosteroids, and reinduction of dual immune combination remained effective despite continuation of high-dose corticosteroids in a non-cirrhotic HCC. This case demonstrated the efficacy of double immune therapy in higher treatment lines in advanced non-cirrhotic HCC even if the patient was treated with other immune modulatory therapies earlier. Moreover, it can remain effective under concomitant administration of high-dose corticosteroids., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)
- Published
- 2022
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25. MicroRNA-182-5p and microRNA-205-5p as potential biomarkers for prognostic stratification of p16-positive oropharyngeal squamous cell carcinoma.
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Weiss BG, Anczykowski MZ, Ihler F, Bertlich M, Spiegel JL, Haubner F, Canis M, Küffer S, Hess J, Unger K, Kitz J, and Jakob M
- Subjects
- Biomarkers, Biomarkers, Tumor genetics, Cyclin-Dependent Kinase Inhibitor p16 metabolism, DNA, Viral, Humans, Prognosis, Squamous Cell Carcinoma of Head and Neck genetics, Head and Neck Neoplasms, MicroRNAs genetics, Oropharyngeal Neoplasms genetics, Papillomavirus Infections complications, Papillomavirus Infections diagnosis, Papillomavirus Infections genetics
- Abstract
Background: MicroRNAs constitute promising biomarkers., Objective: The aim was to investigate diagnostic and prognostic implications of miR-182-5p and miR-205-5p in p16-positive and p16-negative oropharyngeal squamous cell carcinomas (OPSCCs)., Methods: Expression of miR-182-5p, miR-205-5p were determined via quantitative real-time-PCR in fresh frozen tissues of 26 p16-positive, 19 p16-negative OPSCCs and 18 HPV-negative oropharyngeal controls. Associations between miRNA-expression, clinicopathological characteristics and prognosis were analyzed., Results: Higher miR-182-5p expression was associated with significant inferior disease-specific survival for p16-positive OPSCCs (HR = 1.98E+09, 95% CI 0-Inf; P= 0.028) and a similar trend was observed for p16-negative OPSCCs (HR = 1.56E+09, 95% CI 0-Inf; P= 0.051). Higher miR-205-5p expression was associated with an inferior progression-free survival (HR = 4.62, 95% CI 0.98-21.83; P= 0.034) and local control rate (HR = 2.18E+09, 95% CI 0-Inf; P= 0.048) for p16-positive OPSCCs., Conclusions: Results indicate that miR-182-5p and miR-205-5p can further stratify patients with p16-positive OPSCC into prognostic groups.
- Published
- 2022
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26. Surgical treatment of metastatic VIPoma: a case report.
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Azizian A, König A, Hartmann A, Schuppert F, Seif Amir Hosseini A, Kitz J, and Ghadimi M
- Abstract
VIPoma, a neuroendocrine tumour mostly occurring in the human pancreas and producing high levels of vasoactive intestinal peptide, is a rare disease that presents with a wide spectrum of symptoms, including intense diarrhoea, hypokalaemia, and cardiac complications, with life-threatening consequences. In most cases, metastatic lesions are present at VIPoma diagnosis. Treatment options include symptomatic therapy, chemotherapy, radiation and surgery. Due to its low incidence, there are no evidence-based therapy recommendations to date. Here, we present a case of a 39-year-old woman with severe symptoms due to VIPoma of the pancreas with diffuse hepatic metastasis, who underwent simultaneous resection of the primary tumour, extensive liver resection and radiofrequency ablation. The patient was released in good health and was recurrence-free during 12 months surveillance. According to the existing literature and our own experience, surgical procedures appear to be the most promising therapy option for cases with diffuse hepatic metastasis, offering patients relief from their symptoms and (chemo)therapy-free time., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2021.)
- Published
- 2021
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27. Human microRNA-182-5p and kinectin 1: Potential biomarkers for prognosis in oral squamous cell carcinoma.
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Jakob M, Mattes LM, Unger K, Kueffer S, Hess J, Canis M, Schirmer M, Spiegel JL, Haubner F, Ihler F, Weiss BG, and Kitz J
- Subjects
- Biomarkers, Tumor genetics, Humans, Prognosis, Membrane Proteins genetics, MicroRNAs genetics, Mouth Neoplasms diagnosis, Mouth Neoplasms genetics, Squamous Cell Carcinoma of Head and Neck diagnosis, Squamous Cell Carcinoma of Head and Neck genetics
- Abstract
Background: The prognostic impact of hsa-miRNA-182-5p in oral cancer remains unexplored. Therefore, the aim of this study was to investigate the prognostic value of hsa-miRNA-182-5p and its predicted target kinectin 1 (KTN1) in oral squamous cell carcinoma (OSCC)., Method: Expression level of hsa-miRNA-182-5p was analyzed in tumor tissue (n = 36) and healthy oral mucosal tissue (n = 17) using quantitative real-time polymerase chain reaction. Protein level of the predicted target KTN1 was detected via immunohistochemistry. Results were validated in a cohort of The Cancer Genome Atlas (TCGA)., Results: After dividing the data into a subgroup with high and low hsa-miRNA-182-5p expression level, a significant better overall (p = 0.016), recurrence-free (p = 0.009), and progression-free survival (p = 0.004) was observed in an upregulation of hsa-miRNA-182-5p. Staining intensity of KTN1 showed a reciprocal impact on the prognosis. Validation in a TCGA cohort confirmed these results., Conclusion: Our results indicate hsa-miRNA-182-5p and KTN1 as potential biomarkers for OSCC., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
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28. Reduced Zeb1 Expression in Prostate Cancer Cells Leads to an Aggressive Partial-EMT Phenotype Associated with Altered Global Methylation Patterns.
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Kitz J, Lefebvre C, Carlos J, Lowes LE, and Allan AL
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- Antimetabolites, Antineoplastic pharmacology, Azacitidine pharmacology, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Line, Tumor, Cell Movement physiology, Connectin genetics, Connectin metabolism, Epithelial-Mesenchymal Transition, Humans, Male, PC-3 Cells, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Zinc Finger E-box-Binding Homeobox 1 genetics, Zinc Finger E-box-Binding Homeobox 1 metabolism, DNA Methylation, Prostatic Neoplasms metabolism, Zinc Finger E-box-Binding Homeobox 1 biosynthesis
- Abstract
Prostate cancer is the most common cancer in American men and the second leading cause of cancer-related death. Most of these deaths are associated with metastasis, a process involving the epithelial-to-mesenchymal (EMT) transition. Furthermore, growing evidence suggests that partial-EMT (p-EMT) may lead to more aggressive disease than complete EMT. In this study, the EMT-inducing transcription factor Zeb1 was knocked down in mesenchymal PC-3 prostate cancer cells (Zeb1
KD ) and resulting changes in cellular phenotype were assessed using protein and RNA analysis, invasion and migration assays, cell morphology assays, and DNA methylation chip analysis. Inducible knockdown of Zeb1 resulted in a p-EMT phenotype including co-expression of epithelial and mesenchymal markers, a mixed epithelial/mesenchymal morphology, increased invasion and migration, and enhanced expression of p-EMT markers relative to PC-3 mesenchymal controls ( p ≤ 0.05). Treatment of Zeb1KD cells with the global de-methylating drug 5-azacytidine (5-aza) mitigated the observed aggressive p-EMT phenotype ( p ≤ 0.05). DNA methylation chip analysis revealed 10 potential targets for identifying and/or targeting aggressive p-EMT prostate cancer in the future. These findings provide a framework to enhance prognostic and/or therapeutic options for aggressive prostate cancer in the future by identifying new p-EMT biomarkers to classify patients with aggressive disease who may benefit from 5-aza treatment.- Published
- 2021
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29. Interferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy.
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Kettwig M, Ternka K, Wendland K, Krüger DM, Zampar S, Schob C, Franz J, Aich A, Winkler A, Sakib MS, Kaurani L, Epple R, Werner HB, Hakroush S, Kitz J, Prinz M, Bartok E, Hartmann G, Schröder S, Rehling P, Henneke M, Boretius S, Alia A, Wirths O, Fischer A, Stadelmann C, Nessler S, and Gärtner J
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, Cognitive Dysfunction genetics, Cognitive Dysfunction metabolism, Disease Models, Animal, Endoribonucleases genetics, Female, Flow Cytometry, Genotype, Humans, Immunohistochemistry, Leukoencephalopathies genetics, Magnetic Resonance Imaging, Male, Memory T Cells metabolism, Mice, Mice, Knockout, Neuroglia metabolism, Real-Time Polymerase Chain Reaction, Endoribonucleases metabolism, Leukoencephalopathies metabolism, Leukoencephalopathies pathology
- Abstract
Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment. The phenotype is similar to congenital cytomegalovirus brain infection and overlaps with type I interferonopathies, suggesting a role for innate immunity in its pathophysiology. To date, pathophysiological studies have been hindered by the lack of mouse models recapitulating the neuroinflammatory encephalopathy found in patients. In this study, we generated Rnaset2
-/- mice using CRISPR/Cas9-mediated genome editing. Rnaset2-/- mice demonstrate upregulation of interferon-stimulated genes and concurrent IFNAR1-dependent neuroinflammation, with infiltration of CD8+ effector memory T cells and inflammatory monocytes into the grey and white matter. Single nuclei RNA sequencing reveals homeostatic dysfunctions in glial cells and neurons and provide important insights into the mechanisms of hippocampal-accentuated brain atrophy and cognitive impairment. The Rnaset2-/- mice may allow the study of CNS damage associated with RNaseT2 deficiency and may be used for the investigation of potential therapies., (© 2021. The Author(s).)- Published
- 2021
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30. Cancer stem cell markers in adenocarcinoma of the salivary glands - reliable prognostic markers?
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Spiegel JL, Jakob M, Kruizenga M, Freytag S, Bertlich M, Canis M, Ihler F, Haubner F, Kitz J, and Weiss BG
- Subjects
- Biomarkers, Tumor, Humans, Hyaluronan Receptors, Neoplastic Stem Cells, Prognosis, Reproducibility of Results, Retinal Dehydrogenase, Salivary Glands, Adenocarcinoma, Isoenzymes
- Abstract
Purpose: Adenocarcinoma of the salivary glands is of low incidence and a broad range of histopathological subtypes. Cancer stem cell markers (CSC) might serve as novel prognostic parameters. To date, only a few studies examined the expression of CSC in adenocarcinoma of the salivary glands with diverging results. To further investigate the reliability in terms of prognostic value, a histopathological analysis of CSCs on a cohort of patients with adenocarcinomas of the major salivary glands was performed., Methods: Tumor samples of 40 consecutive patients with adenocarcinoma of the major salivary gland treated with curative intend at one tertiary center were stained with the CSCs ALDH1, BMI-1, CD44, Nanog, and SOX2. Expression of these markers was correlated with clinicopathological parameters and survival estimates., Results: Correlation of high expression of ALDH1 with higher grading (p < 0.001) and high expression of CD44 with the localization of the neoplasm (p = 0.05), larger tumor size (p = 0.006), positive pN-category (p = 0.023), and advanced UICC stage (p = 0.002) was found. Furthermore, high expression of SOX2 correlated with a negative perineural invasion (p = 0.02). No significant correlation of any investigated marker with survival estimates was observed., Conclusion: In conclusion, our study did not find a significant correlation of the investigated CSCs with survival estimates in adenocarcinoma of the major salivary glands. Recapitulating the results of our study in conjunction with data in the literature, the CSCs ALDH1, BMI-1, CD44, Nanog, and SOX2 do not seem to serve as reliable prognostic parameters in the treatment of adenocarcinoma of the salivary glands.
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- 2021
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31. Prognostic impact of additional HPV diagnostics in 102 patients with p16-stratified advanced oropharyngeal squamous cell carcinoma.
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Weiss BG, Anczykowski MZ, Küffer S, Spiegel JL, Bertlich M, Canis M, Ihler F, Kitz J, and Jakob M
- Subjects
- Cyclin-Dependent Kinase Inhibitor p16, DNA, Viral, Humans, Papillomaviridae genetics, Prognosis, Squamous Cell Carcinoma of Head and Neck, Alphapapillomavirus, Head and Neck Neoplasms, Oropharyngeal Neoplasms diagnosis, Papillomavirus Infections complications, Papillomavirus Infections diagnosis
- Abstract
Purpose: p16 overexpression was considered as surrogate marker to identify human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCCs)., Methods: 102 patients with advanced stage OPSCCs treated primarily by transoral lasermicrosurgery were included. Prognostic associations of p16- and HPV-status were analyzed separately and combined., Results: In contrast to p16, the HPV-status resulted in no significant survival discrepancies (5-year overall survival (OS) HPV-positive 64.9%, HPV-negative 78.7%). Combining both markers, p16-positive (p16-positive/HPV-positive, p16-positive/HPV-negative) and p16-negative/HPV-negative groups demonstrated comparable high survival (OS 78.1% vs. 85.6% vs. 73.6%). Lowest survival was observed for patients with p16-negative/HPV-positive OPSCCs (OS 40.8%). Never smoking patients with p16-positive OPSCCs demonstrated the highest survival, whereas within former/current smokers with p16-positive and p16-negative disease it was comparable low (OS 90.0% vs. 63.0% vs. 57.4%)., Conclusions: p16- and HPV-status should not be considered as equivalent markers for a better prognosis. Furthermore, they should not generally predominate patient associated factors like smoking.
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- 2021
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32. Role of cancer stem cell markers ALDH1, BCL11B, BMI-1, and CD44 in the prognosis of advanced HNSCC.
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Jakob M, Sharaf K, Schirmer M, Leu M, Küffer S, Bertlich M, Ihler F, Haubner F, Canis M, and Kitz J
- Subjects
- Aged, Female, Head and Neck Neoplasms pathology, Humans, Male, Middle Aged, Prognosis, Retrospective Studies, Squamous Cell Carcinoma of Head and Neck pathology, Survival Analysis, Aldehyde Dehydrogenase 1 Family analysis, Head and Neck Neoplasms diagnosis, Hyaluronan Receptors analysis, Neoplastic Stem Cells pathology, Polycomb Repressive Complex 1 analysis, Repressor Proteins analysis, Squamous Cell Carcinoma of Head and Neck diagnosis, Tumor Suppressor Proteins analysis
- Abstract
Purpose: Cancer stem cells (CSCs) are held accountable for the progress of head and neck squamous cell carcinoma (HNSCC). In the presented study, the authors evaluated the prognostic value of CSC markers in two particular HNSCC cohorts., Methods: This two cohort study consisted of 85 patients with advanced stage HNSCC, treated with primary radio(chemo)therapy (pRCT), and 95 patients with HNSCC, treated with surgery and partially adjuvant radio(chemo)therapy. Overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) were assessed. Samples were assessed for the expression of different molecular stem cell markers (ALDH1, BCL11B, BMI‑1, and CD44)., Results: In the pRCT cohort, none of the baseline patient and tumor features exhibited a statistically significant relation with survival in either the cohort or the human papillomavirus (HPV)-stratified subcohorts. High expression of BMI‑1 significantly decreased OS and DFS, while high expression of CD44 decreased all modes of survival. Multivariate analysis showed significant prognostic influence for all tested CSC markers, with high BMI‑1 and CD44 decreasing survival (BMI-1: OS, DFS, DSS; CD44: OS, DFS) and high ALDH1 and BCL11B showing a beneficial effect on survival (ALDH1: OS, DFS; BCL11B: OS, DSS). In the surgical cohort, classical prognosticators such as HPV status, R1 resection, and nodal status in HPV-negative HNSCC played a significant role, but the tested CSC markers showed no significant effect on prognosis., Conclusion: Although validation in independent cohorts is still needed, testing for CSC markers in patients with advanced or late stage HNSCC might be beneficial, especially if many comorbidities exist or disease is irresectable. The findings might guide the development and earlier use of targeted therapies in the future.
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- 2021
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33. EMT-independent detection of circulating tumor cells in human blood samples and pre-clinical mouse models of metastasis.
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Kitz J, Goodale D, Postenka C, Lowes LE, and Allan AL
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- Animals, Apoptosis, Cell Proliferation, Disease Progression, Female, Humans, Male, Mice, Mice, Nude, Neoplasm Metastasis, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Breast Neoplasms blood, Breast Neoplasms pathology, Epithelial-Mesenchymal Transition, Neoplastic Cells, Circulating pathology, Prostatic Neoplasms blood, Prostatic Neoplasms pathology
- Abstract
Circulating tumor cells (CTCs) present an opportunity to detect/monitor metastasis throughout disease progression. The CellSearch® is currently the only FDA-approved technology for CTC detection in patients. The main limitation of this system is its reliance on epithelial markers for CTC isolation/enumeration, which reduces its ability to detect more aggressive mesenchymal CTCs that are generated during metastasis via epithelial-to-mesenchymal transition (EMT). This Technical Note describes and validates two EMT-independent CTC analysis protocols; one for human samples using Parsortix® and one for mouse samples using VyCap. Parsortix® identifies significantly more mesenchymal human CTCs compared to the clinical CellSearch® test, and VyCap identifies significantly more CTCs compared to our mouse CellSearch® protocol regardless of EMT status. Recovery and downstream molecular characterization of CTCs is highly feasible using both Parsortix® and VyCap. The described CTC protocols can be used by investigators to study CTC generation, EMT and metastasis in both pre-clinical models and clinical samples.
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- 2021
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34. Cancer Stem Cell Markers in Squamous Cell Carcinomas of the Salivary Glands.
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Bertlich M, Kitz J, Kruizenga M, Spiegel JL, Canis M, Ihler F, Haubner F, Weiss BG, and Jakob M
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- Adult, Aged, Aged, 80 and over, Aldehyde Dehydrogenase 1 Family metabolism, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell secondary, Diagnosis, Differential, Female, Gene Expression Regulation, Neoplastic, Humans, Hyaluronan Receptors metabolism, Male, Middle Aged, Neoplasm Grading, Polycomb Repressive Complex 1 metabolism, Prognosis, Retinal Dehydrogenase metabolism, Retrospective Studies, SOXB1 Transcription Factors metabolism, Salivary Gland Neoplasms metabolism, Salivary Gland Neoplasms secondary, Survival Analysis, Biomarkers, Tumor metabolism, Carcinoma, Squamous Cell pathology, Neoplastic Stem Cells metabolism, Salivary Gland Neoplasms pathology
- Abstract
Background: Cancer stem cells (CSC) are cells that exhibit stem cell properties and are pivotal in tumor biology. CSC markers have been described for many tumorous entities. However, to this date, there is no data on CSC markers in respect to squamous cell carcinomas (SCC) of the salivary glands., Methods: Histologic samples from patients with salivary gland SCCs were stained for CSC markers (ALDH-1/BMI-1/SOX-2/CD-44/vimentin) and divided into high and low expression subgroups. These were then correlated with tumor and patient characteristics as well as overall survival (OS), disease-specific survival, recurrence-free survival and local control rates (LCR) after 3 and 5 years., Results: Overall, 31 samples were included. CD-44 and ALDH-1 expression were associated with tumor origin (metastatic/primary disease, p = 0.048 and p = 0.011, respectively). Strong BMI-1 expression was associated with poorer OS (62.9 vs. 27.3%, p = 0.029), strong SOX-2 expression was associated with poorer LCR (62.5 vs. 21.9%, p = 0.007)., Conclusion: CD-44 and ALDH-1 may be useful in differentiating between primary SCCs and metastatic disease. BMI-1 and SOX-2 are correlated with poorer prognosis., (© 2021 S. Karger AG, Basel.)
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- 2021
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35. Enhancer of Zeste Homolog 2 in Colorectal Cancer Development and Progression.
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Bremer SCB, Conradi LC, Mechie NC, Amanzada A, Mavropoulou E, Kitz J, Ghadimi M, Ellenrieder V, Ströbel P, Hessmann E, Gaedcke J, and Bohnenberger H
- Subjects
- Humans, Polycomb Repressive Complex 2 genetics, Prognosis, Prospective Studies, Colorectal Neoplasms genetics, Enhancer of Zeste Homolog 2 Protein genetics
- Abstract
Background: Colorectal cancer (CRC) is the leading gastrointestinal malignancy. The development from premalignant intraepithelial lesions leading to invasive cancer is paradigmatic for the stepwise carcinogenesis of epithelial cancers, but the knowledge of the underlying mechanism of carcinogenesis and progression of CRC is still incomplete. The understanding of epigenetic mechanisms of carcinogenesis has led to new therapeutic approaches during the last years. Enhancer of zeste homolog 2 (EZH2) is one central epigenetic silencer of the polycomb repressor complex 2 (PRC2) that is already in clinical use as a novel drug target and is associated with poorer prognosis in several cancer entities., Patients and Methods: The protein expression of EZH2 and other members of the PRC2 as well as resulting posttranslational modifications were investigated by immunohistochemistry in 187 patients with CRC and in 94 patients with premalignant colorectal lesions and correlated with their clinical outcome. Furthermore, the corresponding mRNA expression levels were analyzed in 217 patients with rectal cancer that were enrolled in a prospective clinical trial., Results: We found a weak expression of EZH2 in normal colon mucosa that increased in low grade, peaked in high grade intraepithelial neoplasia, and decreased again in invasive CRC. The posttranslational modification caused by EZH2 as a measure of EZH2 activity showed the same behavior. Strong protein and mRNA expression of EZH2 were significantly correlated with favorable prognosis in both investigated cohorts., Conclusion: The expression and activity of EZH2 are associated with colorectal carcinogenesis and most expressed in intraepithelial high-grade lesions. Strong expression of EZH2 is associated with a significantly favorable prognosis in patients suffering from CRC., (© 2019 S. Karger AG, Basel.)
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- 2021
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36. Intensified Histopathological Work-Up after Pancreatic Head Resection Reveals Relevant Prognostic Markers.
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Dusch N, Oldani M, Steffen T, Kitz J, Koenig U, Azizian A, König A, Ströbel P, Beissbarth T, Ghadimi M, and Gaedcke J
- Subjects
- Humans, Neoplasm Recurrence, Local, Pancreas diagnostic imaging, Pancreas surgery, Pancreatectomy, Pancreaticoduodenectomy, Prognosis, Retrospective Studies, Survival Rate, Pancreatic Neoplasms surgery
- Abstract
Introduction: Local recurrence remains a major problem after pancreatic head resection. Intensified histopathological work-up of surgical specimens after pancreatic head resection has revealed an increased number of incomplete resections (R1) depending on tumor infiltration front at the resection margins (RMs). It remains unclear to which extent the increased R1 resection rate has a clinical relevance for the patients' prognosis., Materials and Methods: Pancreatic head resections between 2006 and 2012 were histologically intensively worked-up by a previously described protocol. The distance between the tumor infiltration front and the resection planes or organ surfaces was documented. The impact of the size of the tumor and an additional portal vein resection was analyzed. The effect of a R1 resection status on development and type of recurrence was evaluated., Results: A total of 203 pancreatic head resections were evaluated. Different definitions of R1 resection were applied. These led to significantly different prognosis for patients. A greater distance between the tumor infiltration front and the resection plane or organ surface was associated with a better outcome for the patients. For the ventral surface, the mesopancreas and the pancreatic body these differences were statistically significant comparing the different R1 definitions. For the dorsal surface, a significant difference in prognosis was found if the tumor was >2 mm away from the resection surface. A tumor size of 3 cm was identified to play a relevant role for the prognosis. Patients who had a portal vein resection without a histologically proven infiltration showed a statistically significant higher overall survival. Patients with R1 resection were at highest risk for developing local recurrence as well as distant metastasis., Conclusion: Intensified histopathological work-up with an increased number of R1 resections has a clinical relevance for patients' prognosis. Tumors with a smaller size or with a greater distance to the organ surface or RM have a better outcome., (© 2020 S. Karger AG, Basel.)
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- 2021
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37. Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Show Comparable Functionality to Their Autologous Origin.
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Jakob M, Hambrecht M, Spiegel JL, Kitz J, Canis M, Dressel R, and Streckfuss-Bömeke K
- Subjects
- Adult, Aged, Cells, Cultured, Female, Humans, Immunomodulation, Male, Young Adult, Head and Neck Neoplasms therapy, Induced Pluripotent Stem Cells cytology, Mesenchymal Stem Cells cytology, Regenerative Medicine methods, Squamous Cell Carcinoma of Head and Neck therapy, Tissue Engineering methods
- Abstract
A multimodal therapeutic approach involving radiotherapy is required when treating head and neck squamous cell carcinoma. However, radiotherapy is restricted due to its high risk for damages to the surrounding healthy tissue of the treated area. Tissue regeneration and wound healing is promoted by the survival and regenerative capacities of tissue-resident or invading stem cells. Mesenchymal stem cells (MSCs) exhibit a promising therapeutic potential in the field of cell-based tissue engineering and regenerative medicine due to their immunomodulatory properties and differentiation capacity. However, the generation of MSCs for therapeutic applications is still a major challenge. We aimed to produce highly homogeneous induced pluripotent stem cell-derived mesenchymal stem cells (iP-MSCs) in an autologous manner from initially isolated human mucosa mesenchymal stem cells (mMSCs) of the upper respiratory tract. Therefore, mMSCs were reprogrammed into induced pluripotent stem cells (iPSCs) by non-integrative chromosomal technologies and differentiated into corresponding iP-MSCs. We demonstrated that mMSCs and iP-MSCs show similar cell characteristics in terms of morphology, clonogenic potential, differentiation, and surface phenotype. Moreover, iP-MSCs demonstrated related immunosuppressive capacity as mMSCs including the secretion of cytokines, and T cell inhibition. Therefore, generating iP-MSCs in an autologous manner may be a novel personalized treatment option in regenerative medicine.
- Published
- 2020
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38. Benefit of postoperative radiotherapy for early tumors with single ipsilateral lymph node metastasis.
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Weiss BG, Anczykowski MZ, Flach S, Spiegel JL, Kitz J, Bertlich M, Canis M, Jakob M, and Ihler F
- Subjects
- Carcinoma, Squamous Cell pathology, Female, Head and Neck Neoplasms pathology, Humans, Laser Therapy, Male, Microsurgery, Middle Aged, Neck Dissection, Neoplasm Staging, Postoperative Care, Retrospective Studies, Carcinoma, Squamous Cell radiotherapy, Carcinoma, Squamous Cell surgery, Head and Neck Neoplasms radiotherapy, Head and Neck Neoplasms surgery, Lymphatic Metastasis pathology
- Abstract
Objectives/hypothesis: Indication for postoperative radiotherapy in patients with locally circumscribed tumors (pT1-pT2) and a single ipsilateral lymph node metastasis (pN1) is debatable. The aim of this study was to evaluate the oncological long-term outcome of patients with pT1-pT2 pN1 squamous cell carcinoma (SCC) of the oral cavity, the oropharynx, and the hypopharynx without extracapsular spread (ECS) after a margin-negative surgical resection, who either received or did not receive postoperative (chemo)radiotherapy., Study Design: Retrospective case series., Methods: The oncological outcome of patients with pT1-pT2 pN1 SCC without ECS was evaluated retrospectively. All patients underwent primary tumor resection that included transoral laser microsurgery and neck dissection at an academic tertiary referral center., Results: Of 65 identified patients treated between 1986 and 2015 (18 oral cavity, 30 oropharynx, 17 hypopharynx), 21 (32%) received postoperative radiotherapy, and 44 (68%) were treated by surgery alone. The group of patients receiving postoperative treatment showed a significantly superior 5-year disease-specific (94.4% vs. 73.2%, P = .029) and recurrence-free survival (85.2% vs. 43.2%, P = .002), as well as a higher local control rate (90.2% vs. 64.9%, P = .042). The overall survival was 71.4% vs. 62.6% (P = .53). The mean follow-up was 80.7 months., Conclusions: Patients with locally circumscribed carcinomas and a single ipsilateral ECS-negative lymph node metastasis seem to benefit from postoperative radiotherapy., Level of Evidence: 4 Laryngoscope, 130:E530-E538, 2020., (© 2019 The Authors. The Laryngoscope published by Wiley Periodicals, Inc. on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)
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- 2020
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39. KRAS mutation status concordance between the primary tumor and the corresponding metastasis in patients with rectal cancer.
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Jo P, Bernhardt M, Nietert M, König A, Azizian A, Schirmer MA, Grade M, Kitz J, Reuter-Jessen K, Ghadimi M, Ströbel P, Schildhaus HU, and Gaedcke J
- Subjects
- Aged, Female, Genetic Heterogeneity, Humans, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Recurrence, Local pathology, Rectal Neoplasms pathology, Mutation, Missense, Neoplasm Recurrence, Local genetics, Proto-Oncogene Proteins p21(ras) genetics, Rectal Neoplasms genetics
- Abstract
Introduction: Oncogenic mutation within the KRAS gene represents a negative predictor for treatment response to anti-epidermal growth factor receptor (EGFR) in patients with colorectal cancer. Recently, we have shown no relevant heterogeneity for KRAS mutation status within and between pre- and posttherapeutic samples from the primary tumor in patients with locally advanced rectal cancer. The aim of this study was to evaluate the intertumoral heterogeneity of KRAS mutation status between the primary tumor and the corresponding metastasis or local recurrence in the similar cohort and to evaluate the ideal representative tissue for KRAS mutation testing., Materials and Methods: KRAS mutation status was analyzed from 47 patients with locally advanced rectal cancer, which were enrolled in the CAO/ARO/AIO-94 or CAO/ARO/AIO-04 trial. Mutations in KRAS codons 12, 13, and 61 were analyzed by using the KRAS RGQ PCR Kit (therascreen® KRAS test). Six patients needed to be excluded due to incomplete follow up data. 11 patients showed a relapse of the disease during the follow up presented by distant metastases or local recurrence. DNA from representative areas of metastatic tissue was obtained from formalin-fixed paraffin-embedded specimens., Results: The mean patient age was 64.13 ± 10.64 years. In total, 19 patients showed a KRAS mutation (46.34%) in the primary tumor. Of the eleven patients with a metastatic disease or local recurrence, five patients showed a KRAS mutation whereas six patients had a KRAS wildtype status. Metastatic localizations included the liver (n = 2), lung (n = 4), local recurrence (n = 1), liver + lung (n = 3), lung + local recurrence (n = 1). For these eleven patients with paired data available for the primary tumor and metastatic tissue, a significant KRAS mutation status concordance was detected in 81.18% (9/11) of the patients (p = 0.03271). Only two patients showed intertumoral heterogeneity, which harbored in one patient a KRAS G12C mutation status in the primary tumor, but a G12V KRAS mutation status in the corresponding lung lesion, and in the other patient a G12A mutation in the primary lesion and a WT in the lung metastasis., Conclusions: We show a significant concordance of the KRAS mutation status between tumor samples obtained from the primary tumor and the corresponding metastasis and/ or local recurrence in patients with rectal cancer indicating no relevant intertumoral heterogeneity. Our data suggest that sampling either the primary (pre- or posttherapeutical tumor tissue) or metastatic lesion may be valid for the initial evaluation of KRAS mutation status predicting the response to anti-EGFR treatment and guiding clinical decisions., Competing Interests: The authors have declared that no competing interests exist.
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- 2020
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40. MicroRNA expression patterns in oral squamous cell carcinoma: hsa-mir-99b-3p and hsa-mir-100-5p as novel prognostic markers for oral cancer.
- Author
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Jakob M, Mattes LM, Küffer S, Unger K, Hess J, Bertlich M, Haubner F, Ihler F, Canis M, Weiss BG, and Kitz J
- Subjects
- Biomarkers, Tumor genetics, Biopsy, Needle, Carcinoma, Squamous Cell pathology, Case-Control Studies, Disease Progression, Female, Gene Expression Profiling, Humans, Immunohistochemistry, Male, Mouth Neoplasms pathology, Prognosis, ROC Curve, Reference Values, Risk Assessment, Sensitivity and Specificity, Carcinoma, Squamous Cell genetics, Gene Expression Regulation, Neoplastic genetics, MicroRNAs genetics, Mouth Neoplasms genetics
- Abstract
Background: MicroRNAs (miRNA) recently evolved as potential cancer biomarkers. Therefore, the aim of the present study was to evaluate the prognostic impact of eight miRNAs connected to oral squamous cell carcinoma (OSCC)., Method: Expression levels of hsa-mir-21-5p, hsa-mir-29b-3p, hsa-mir-31-5p, hsa-mir-99a-5p, hsa-mir-99b-3p, hsa-mir-100-5p, hsa-mir-143-3p and hsa-mir-155-5p were analyzed in tumor tissue (n = 36) and healthy oral mucosal tissue (n = 17) and correlated with clinical variables. Results of the study cohort were validated in an OSCC cohort of The Cancer Genome Atlas., Results: Increased hsa-mir-99b-3p expression level showed a tendency toward advanced tumor stages, and high levels of hsa-mir-100-5p expression were associated with extracapsular extension. While a high expression level of hsa-mir-99b-3p was associated with better survival, a high expression level of hsa-mir-100-5p was correlated with a poorer survival in the study cohort., Conclusion: Our results indicate that hsa-mir-99b-3p and hsa-mir-100-5p may serve as novel prognostic biomarkers in OSCC., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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41. Transoral laser microsurgery for treatment of oropharyngeal cancer in 368 patients.
- Author
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Weiss BG, Ihler F, Anczykowski MZ, Bertlich M, Kitz J, Steiner W, Canis M, and Jakob M
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell mortality, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Natural Orifice Endoscopic Surgery, Oropharyngeal Neoplasms mortality, Postoperative Care, Postoperative Complications, Retrospective Studies, Carcinoma, Squamous Cell surgery, Laser Therapy, Microsurgery methods, Oropharyngeal Neoplasms surgery
- Abstract
Background: Oncological and functional outcome of transoral laser microsurgery (TLM) for primary treatment of oropharyngeal cancer was examined using a multimodal treatment concept., Methods: A total of 368 patients with oropharyngeal squamous cell carcinoma (pT1-4, pN0-2, M0) underwent TLM +/- neck dissection (85%), +/- (chemo)radiotherapy (57%). The majority of patients had advanced stage III and IVa disease (79%)., Results: Five-year Kaplan-Meier estimates for local control were 83.5% for pT1, 74.1% for pT2, 77.3% for pT3, and 76.0% for pT4a tumors. Five-year estimates of overall, disease-specific, and recurrence-free survival for stage I were 76.0%, 92.8%, and 69.1%; for stage II 71.1%, 85.7%, and 49.6%; for stage III 61.7%, 72.5%, and 58.8%; and for stage IVa 57.3%, 73.7%, and 63.9%, respectively. Postoperative (chemo)radiotherapy improved the outcome for advanced disease. p16-positive tumors had superior survival estimates. Overall, 93.5% maintained regular oral nutrition without feeding tube dependency., Conclusion: Primary TLM in multimodal concepts of treatment offers good oncologic outcome even for advanced-stage oropharyngeal cancer., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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42. Epigenome Mapping Identifies Tumor-Specific Gene Expression in Primary Rectal Cancer.
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Flebbe H, Hamdan FH, Kari V, Kitz J, Gaedcke J, Ghadimi BM, Johnsen SA, and Grade M
- Abstract
Epigenetic alterations play a central role in cancer development and progression. The acetylation of histone 3 at lysine 27 (H3K27ac) specifically marks active genes. While chromatin immunoprecipitation (ChIP) followed by next-generation sequencing (ChIP-seq) analyses are commonly performed in cell lines, only limited data are available from primary tumors. We therefore examined whether cancer-specific alterations in H3K27ac occupancy can be identified in primary rectal cancer. Tissue samples from primary rectal cancer and matched mucosa were obtained. ChIP-seq for H3K27ac was performed and differentially occupied regions were identified. The expression of selected genes displaying differential occupancy between tumor and mucosa were examined in gene expression data from an independent patient cohort. Differential expression of four proteins was further examined by immunohistochemistry. ChIP-seq for H3K27ac in primary rectal cancer and matched mucosa was successfully performed and revealed differential binding on 44 regions. This led to the identification of genes with increased H3K27ac, i.e., RIPK2 , FOXQ1 , KRT23 , and EPHX4 , which were also highly upregulated in primary rectal cancer in an independent dataset. The increased expression of these four proteins was confirmed by immunohistochemistry. This study demonstrates the feasibility of ChIP-seq-based epigenome mapping of primary rectal cancer and confirms the value of H3K27ac occupancy to predict gene expression differences.
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- 2019
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43. Cytosolic 5'-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites.
- Author
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Patzak MS, Kari V, Patil S, Hamdan FH, Goetze RG, Brunner M, Gaedcke J, Kitz J, Jodrell DI, Richards FM, Pilarsky C, Gruetzmann R, Rümmele P, Knösel T, Hessmann E, Ellenrieder V, Johnsen SA, and Neesse A
- Subjects
- Animals, Biomarkers, Tumor, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Cell Line, Tumor, Deoxycytidine pharmacokinetics, Deoxycytidine pharmacology, Disease Models, Animal, Humans, Mice, Mice, Transgenic, Models, Biological, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms pathology, Prognosis, Xenograft Model Antitumor Assays, Gemcitabine, 5'-Nucleotidase genetics, Deoxycytidine analogs & derivatives, Drug Resistance, Neoplasm genetics, Gene Expression, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism
- Abstract
Background: Cytosolic 5'-nucleotidase 1A (NT5C1A) dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Here, we investigate NT5C1A expression in pancreatic ductal adenocarcinoma (PDAC) and its impact on gemcitabine metabolism and therapeutic efficacy., Methods: NT5C1A expression was determined by semiquantitative immunohistochemistry using tissue microarrays. Gemcitabine metabolites and response were assessed in several human and murine PDAC cell lines using crystal violet assays, Western blot, viability assays, and liquid chromatography tandem mass-spectrometry (LC-MS/MS)., Findings: NT5C1A was strongly expressed in tumor cells of a large subgroup of resected PDAC patients in two independent patient cohorts (44-56% score 2 and 8-26% score 3, n = 414). In contrast, NT5C1A was expressed at very low levels in the tumor stroma, and neither stromal nor tumoral expression was a prognostic marker for postoperative survival. In vitro, NT5C1A overexpression increased gemcitabine resistance by reducing apoptosis levels and significantly decreased intracellular amounts of cytotoxic dFdCTP in +NT5C1A tumor cells. Co-culture experiments with conditioned media from +NT5C1A PSCs improved gemcitabine efficacy in tumor cells. In vivo, therapeutic efficacy of gemcitabine was significantly decreased and serum levels of the inactive gemcitabine metabolite dFdU significantly increased in mice bearing NT5C1A overexpressing tumors., Interpretation: NT5C1A is robustly expressed in tumor cells of resected PDAC patients. Moreover, NT5C1A mediates gemcitabine resistance by decreasing the amount of intracellular dFdCTP, leading to reduced tumor cell apoptosis and larger pancreatic tumors in mice. Further studies should clarify the role of NT5C1A as novel predictor for gemcitabine treatment response in patients with PDAC., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2019
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44. The histone methyltransferase DOT1L is required for proper DNA damage response, DNA repair, and modulates chemotherapy responsiveness.
- Author
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Kari V, Raul SK, Henck JM, Kitz J, Kramer F, Kosinsky RL, Übelmesser N, Mansour WY, Eggert J, Spitzner M, Najafova Z, Bastians H, Grade M, Gaedcke J, Wegwitz F, and Johnsen SA
- Subjects
- Cell Line, Tumor, DNA Breaks, Double-Stranded drug effects, Epigenesis, Genetic, HCT116 Cells, Histone-Lysine N-Methyltransferase, Humans, Methylation, Methyltransferases antagonists & inhibitors, Phosphorylation, Prognosis, RNA, Small Interfering pharmacology, Recombinational DNA Repair, Small Molecule Libraries pharmacology, Drug Resistance, Neoplasm, Histones metabolism, Methyltransferases genetics, Methyltransferases metabolism, Rectal Neoplasms metabolism
- Abstract
Background: Disruptor of telomeric silencing 1-like (DOT1L) is a non-SET domain containing methyltransferase known to catalyze mono-, di-, and tri-methylation of histone 3 on lysine 79 (H3K79me). DOT1L-mediated H3K79me has been implicated in chromatin-associated functions including gene transcription, heterochromatin formation, and DNA repair. Recent studies have uncovered a role for DOT1L in the initiation and progression of leukemia and other solid tumors. The development and availability of small molecule inhibitors of DOT1L may provide new and unique therapeutic options for certain types or subgroups of cancer., Methods: In this study, we examined the role of DOT1L in DNA double-strand break (DSB) response and repair by depleting DOT1L using siRNA or inhibiting its methyltransferase activity using small molecule inhibitors in colorectal cancer cells. Cells were treated with different agents to induce DNA damage in DOT1L-depleted or -inhibited cells and analyzed for DNA repair efficiency and survival. Further, rectal cancer patient samples were analyzed for H3K79me3 levels in order to determine whether it may serve as a potential marker for personalized therapy., Results: Our results indicate that DOT1L is required for a proper DNA damage response following DNA double-strand breaks by regulating the phosphorylation of the variant histone H2AX (γH2AX) and repair via homologous recombination (HR). Importantly, we show that small molecule inhibitors of DOT1L combined with chemotherapeutic agents that are used to treat colorectal cancers show additive effects. Furthermore, examination of H3K79me3 levels in rectal cancer patients demonstrates that lower levels correlate with a poorer prognosis., Conclusions: In this study, we conclude that DOT1L plays an important role in an early DNA damage response and repair of DNA double-strand breaks via the HR pathway. Moreover, DOT1L inhibition leads to increased sensitivity to chemotherapeutic agents and PARP inhibition, which further highlights its potential clinical utility. Our results further suggest that H3K79me3 can be useful as a predictive and or prognostic marker for rectal cancer patients.
- Published
- 2019
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45. High Expression of EpCAM and Sox2 is a Positive Prognosticator of Clinical Outcome for Head and Neck Carcinoma.
- Author
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Baumeister P, Hollmann A, Kitz J, Afthonidou A, Simon F, Shakhtour J, Mack B, Kranz G, Libl D, Leu M, Schirmer MA, Canis M, Belka C, Zitzelsberger H, Ganswindt U, Hess J, Jakob M, Unger K, and Gires O
- Subjects
- Adult, Aged, Carcinoma, Squamous Cell radiotherapy, Carcinoma, Squamous Cell surgery, Diagnostic Tests, Routine methods, Female, Gene Expression Profiling, Head and Neck Neoplasms radiotherapy, Head and Neck Neoplasms surgery, Humans, Immunohistochemistry, Male, Middle Aged, Prognosis, Survival Analysis, Treatment Outcome, Young Adult, Biomarkers, Tumor analysis, Carcinoma, Squamous Cell diagnosis, Carcinoma, Squamous Cell pathology, Epithelial Cell Adhesion Molecule analysis, Head and Neck Neoplasms diagnosis, Head and Neck Neoplasms pathology, SOXB1 Transcription Factors analysis
- Abstract
Locally advanced head and neck squamous cell carcinomas (HNSCC) have limited prognosis due to frequent treatment failure. Currently, TNM-classification and human papillomavirus (HPV) infection are the sole clinical prognosticators of outcome. Tumor heterogeneity and stemness based on epithelial-mesenchymal-transition reportedly associate with therapy resistance. The capacity of epithelial marker EpCAM (EpEX), stemness regulator Sox2 and mesenchymal marker vimentin to predict clinical outcome of HSNCC patients was assessed upon immunohistochemistry staining in two cohorts of HNSCC patients treated with surgery and adjuvant radio (chemo) therapy (n = 94) and primary radio (chemo) therapy (n = 94), respectively. Prognostic values with respect to overall, disease-free and disease-specific survival were assessed in uni- and multivariate cox proportional hazard models to generate integrated risk scores. EpEX, Sox2 and vimentin displayed substantial inter- and intratumoral heterogeneity. EpEX
high and Sox2high predicted improved clinical outcome in the discovery cohort and in the HPV-negative sub-cohort. EpEXhigh and Sox2high were confirmed as prognosticators of clinical outcome in the validation cohort treated with definitive radio(chemo)therapy. Importantly, EpEXhigh identified patients with improved survival within the HPV-negative subgroup of the validation cohort. Hence, Sox2high and particularly EpEXhigh have potential as tools to predict clinical performance of HNSCC patients, foremost HPV-negative cases, in the frame of molecular-guided treatment decision-making.- Published
- 2018
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46. EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers.
- Author
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Pan M, Schinke H, Luxenburger E, Kranz G, Shakhtour J, Libl D, Huang Y, Gaber A, Pavšič M, Lenarčič B, Kitz J, Jakob M, Schwenk-Zieger S, Canis M, Hess J, Unger K, Baumeister P, and Gires O
- Subjects
- Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Enzyme Activation drug effects, ErbB Receptors chemistry, ErbB Receptors metabolism, Head and Neck Neoplasms pathology, Humans, Ligands, Models, Biological, Phosphorylation drug effects, Protein Binding drug effects, Protein Domains, Proto-Oncogene Proteins c-akt metabolism, Snail Family Transcription Factors metabolism, Treatment Outcome, Epidermal Growth Factor metabolism, Epithelial Cell Adhesion Molecule chemistry, Epithelial-Mesenchymal Transition, Extracellular Signal-Regulated MAP Kinases metabolism, Head and Neck Neoplasms metabolism
- Abstract
Head and neck squamous cell carcinomas (HNSCCs) are characterized by outstanding molecular heterogeneity that results in severe therapy resistance and poor clinical outcome. Inter- and intratumoral heterogeneity in epithelial-mesenchymal transition (EMT) was recently revealed as a major parameter of poor clinical outcome. Here, we addressed the expression and function of the therapeutic target epidermal growth factor receptor (EGFR) and of the major determinant of epithelial differentiation epithelial cell adhesion molecule (EpCAM) in clinical samples and in vitro models of HNSCCs. We describe improved survival of EGFRlow/EpCAMhigh HNSCC patients (n = 180) and provide a molecular basis for the observed disparities in clinical outcome. EGF/EGFR have concentration-dependent dual capacities as inducers of proliferation and EMT through differential activation of the central molecular switch phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and EMT transcription factors (EMT-TFs) Snail, zinc finger E-box-binding homeobox 1 (Zeb1), and Slug. Furthermore, soluble ectodomain of EpCAM (EpEX) was identified as a ligand of EGFR that activates pERK1/2 and phosphorylated AKT (pAKT) and induces EGFR-dependent proliferation but represses EGF-mediated EMT, Snail, Zeb1, and Slug activation and cell migration. EMT repression by EpEX is realized through competitive modulation of pERK1/2 activation strength and inhibition of EMT-TFs, which is reflected in levels of pERK1/2 and its target Slug in clinical samples. Accordingly, high expression of pERK1/2 and/or Slug predicted poor outcome of HNSCCs. Hence, EpEX is a ligand of EGFR that induces proliferation but counteracts EMT mediated by the EGF/EGFR/pERK1/2 axis. Therefore, the emerging EGFR/EpCAM molecular cross talk represents a promising target to improve patient-tailored adjuvant treatment of HNSCCs., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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47. Comparative proteomics reveals a diagnostic signature for pulmonary head-and-neck cancer metastasis.
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Bohnenberger H, Kaderali L, Ströbel P, Yepes D, Plessmann U, Dharia NV, Yao S, Heydt C, Merkelbach-Bruse S, Emmert A, Hoffmann J, Bodemeyer J, Reuter-Jessen K, Lois AM, Dröge LH, Baumeister P, Walz C, Biggemann L, Walter R, Häupl B, Comoglio F, Pan KT, Scheich S, Lenz C, Küffer S, Bremmer F, Kitz J, Sitte M, Beißbarth T, Hinterthaner M, Sebastian M, Lotz J, Schildhaus HU, Wolff H, Danner BC, Brandts C, Büttner R, Canis M, Stegmaier K, Serve H, Urlaub H, and Oellerich T
- Subjects
- Carcinoma, Squamous Cell pathology, Diagnostic Tests, Routine methods, Head and Neck Neoplasms pathology, Humans, Lung Neoplasms pathology, Machine Learning, Sensitivity and Specificity, Carcinoma, Squamous Cell diagnosis, Carcinoma, Squamous Cell secondary, Head and Neck Neoplasms diagnosis, Head and Neck Neoplasms secondary, Lung Neoplasms diagnosis, Proteome analysis, Proteomics methods
- Abstract
Patients with head-and-neck cancer can develop both lung metastasis and primary lung cancer during the course of their disease. Despite the clinical importance of discrimination, reliable diagnostic biomarkers are still lacking. Here, we have characterised a cohort of squamous cell lung (SQCLC) and head-and-neck (HNSCC) carcinomas by quantitative proteomics. In a training cohort, we quantified 4,957 proteins in 44 SQCLC and 30 HNSCC tumours. A total of 518 proteins were found to be differentially expressed between SQCLC and HNSCC, and some of these were identified as genetic dependencies in either of the two tumour types. Using supervised machine learning, we inferred a proteomic signature for the classification of squamous cell carcinomas as either SQCLC or HNSCC, with diagnostic accuracies of 90.5% and 86.8% in cross- and independent validations, respectively. Furthermore, application of this signature to a cohort of pulmonary squamous cell carcinomas of unknown origin leads to a significant prognostic separation. This study not only provides a diagnostic proteomic signature for classification of secondary lung tumours in HNSCC patients, but also represents a proteomic resource for HNSCC and SQCLC., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2018
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48. Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer: Secondary Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial.
- Author
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Kitz J, Fokas E, Beissbarth T, Ströbel P, Wittekind C, Hartmann A, Rüschoff J, Papadopoulos T, Rösler E, Ortloff-Kittredge P, Kania U, Schlitt H, Link KH, Bechstein W, Raab HR, Staib L, Germer CT, Liersch T, Sauer R, Rödel C, Ghadimi M, and Hohenberger W
- Subjects
- Adenocarcinoma diagnosis, Adenocarcinoma secondary, Chemoradiotherapy, Disease-Free Survival, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoadjuvant Therapy, Neoplasm Metastasis, Prognosis, Rectal Neoplasms pathology, Retrospective Studies, Time Factors, Adenocarcinoma therapy, Digestive System Surgical Procedures methods, Neoplasm Staging, Rectal Neoplasms therapy, Rectum surgery
- Abstract
Importance: Previous retrospective studies have shown that surgical quality affects local control in rectal cancer.., Objective: In this secondary end point analysis, we evaluated the prognostic effect of the total mesorectal excision (TME) plane in the CAO/ARO/AIO-04 phase 3 randomized clinical trial., Design, Setting, and Participants: The CAO/ARO/AIO-04 trial enrolled 1236 patients with cT3-4 and/or node-positive rectal adenocarcinoma from 88 centers in Germany between July 25, 2006, and February 26, 2010., Interventions: Patients were randomized to receive treatment with standard fluorouracil-based preoperative chemoradiotherapy (CRT) alone (control arm) or oxaliplatin (experimental arm) followed by TME and adjuvant chemotherapy., Main Outcomes and Measures: The TME quality (mesorectal, intramesorectal, and muscularis propria plane) was prospectively assessed in 1152 operation specimens. An assessment was performed independently by pathologists and surgeons. The results were correlated with clinicopathologic data and the clinical outcome was tested, including multivariable analysis with the Cox regression model., Results: Of 1152 German Caucasian participants, 332 (28.8) were women and the mean age was 63 years. The plane of TME was mesorectal in 930 patients (80.7%), intramesorectal in 169 (14.7%), and muscularis propria in 53 (4.6%). In a univariable analysis, the TME plane was significantly associated with 3-year disease-free survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 73.1-78.8 vs 61.6-76.0 vs 55.6-81.3, respectively; P = .01), cumulative incidence of local and distant recurrences (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 2.0-4.5 vs 1.2-8.1 vs 2.5-20.5, respectively; P < .001; and mesorectal vs intramesorectal vs muscularis propria, 95% CI, 17.0-22.4 vs 18.3-32.0 vs 14.2-39.0, respectively; P = .03, respectively), and overall survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 88.3-92.3 vs 79.7-91.0 vs 81.6-98.7, respectively; P = .02). In contrast to the pathologist-based evaluation, the assessment of TME plane by the operating surgeon failed to demonstrate prognostic significance for any of these clinical end points. In a multivariable analysis, the plane of surgery (mesorectal vs muscularis propria TME) constituted an independent factor for local recurrence (P = .002)., Conclusions and Relevance: This phase 3 randomized clinical trial confirms the long-term clinical effect of TME plane quality on local recurrence, as initially reported in the MRC CR07 study. The data highlight the key role of pathologists and surgeons in the multidisciplinary management of rectal cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT00349076.
- Published
- 2018
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49. Circulating Tumor Cell Analysis in Preclinical Mouse Models of Metastasis.
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Kitz J, Lowes LE, Goodale D, and Allan AL
- Abstract
The majority of cancer deaths occur because of metastasis since current therapies are largely non-curative in the metastatic setting. The use of in vivo preclinical mouse models for assessing metastasis is, therefore, critical for developing effective new cancer biomarkers and therapies. Although a number of quantitative tools have been previously developed to study in vivo metastasis, the detection and quantification of rare metastatic events has remained challenging. This review will discuss the use of circulating tumor cell (CTC) analysis as an effective means of tracking and characterizing metastatic disease progression in preclinical mouse models of breast and prostate cancer and the resulting lessons learned about CTC and metastasis biology. We will also discuss how the use of clinically-relevant CTC technologies such as the CellSearch
® and Parsortix™ platforms for preclinical CTC studies can serve to enhance the study of cancer biology, new biomarkers, and novel therapies from the bench to the bedside.- Published
- 2018
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50. Epithelial-Mesenchymal Transition during Metastasis of HPV-Negative Pharyngeal Squamous Cell Carcinoma.
- Author
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Ihler F, Gratz R, Wolff HA, Weiss BG, Bertlich M, Kitz J, Salinas G, Rave-Fränk M, and Canis M
- Subjects
- Biomarkers, Tumor metabolism, Cadherins metabolism, Carcinoma, Squamous Cell metabolism, Cell Line, Tumor, Head and Neck Neoplasms metabolism, Humans, Hyaluronan Receptors metabolism, Male, Middle Aged, Papillomaviridae pathogenicity, Pharyngeal Neoplasms metabolism, Prognosis, Squamous Cell Carcinoma of Head and Neck, Carcinoma, Squamous Cell pathology, Epithelial-Mesenchymal Transition physiology, Head and Neck Neoplasms pathology, Neoplasm Metastasis pathology, Pharyngeal Neoplasms pathology
- Abstract
In epithelial tumors, a shift towards a mesenchymal phenotype has been associated with increased invasiveness and metastasis. It is assumed that this phenomenon plays a major role in disease progression and ultimately prognosis. This study investigated epithelial-mesenchymal transition (EMT) in human papillomavirus- (HPV-) negative pharyngeal squamous cell carcinoma. Tissue was obtained from one hypopharyngeal primary tumor and a regional lymph node metastasis during surgery with curative intention. A cell culture was established from the primary tumor and mesenchymal growth conditions were emulated. Gene expression profiling was performed (Human 8 × 60 K design array, Agilent Technologies) and EMT was assessed by a gene set (MSigDB: M5930, Hallmark_epithelial_mesenchymal_transition), applying gene set expression analysis (GSEA). Immunohistochemical staining and flow cytometry of CD44 and E-cadherin were compared in primary tumor, metastasis, and cell cultures. Primary tumor and metastasis were highly positive for CD44. A loss of E-cadherin occurred in the metastasis. Flow cytometry showed the appearance of a population without E-cadherin in spheroid colonies. In GSEA, the EMT phenotype was enriched in the primary tumor compared to metastasis and cell cultures (FDR < 25%, p < 5%). EMT showed variable expression during metastasis. It may thereby be a dynamic state in HPV-negative pharyngeal squamous cell carcinoma that is active only during the process of metastasis itself. Thereby, the primary tumor as well as the metastasis may exhibit fewer EMT properties.
- Published
- 2018
- Full Text
- View/download PDF
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