Publications by authors named "Felix Bremmer"

53 Publications

The developmental origin of cancers defines basic principles of cisplatin resistance.

Cancer Lett 2021 Oct 25;519:199-210. Epub 2021 Jul 25.

Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225 Düsseldorf, Germany. Electronic address:

Cisplatin-based chemotherapy has been used for more than four decades as a standard therapeutic option in several tumor entities. However, being a multifaceted and heterogeneous phenomenon, inherent or acquired resistance to cisplatin remains a major obstacle during the treatment of several solid malignancies and inevitably results in disease progression. Hence, we felt there was an urgent need to evaluate common mechanisms between multifarious cancer entities to identify patient-specific therapeutic strategies. We found joint molecular and (epi)genetic resistance mechanisms and specific cisplatin-induced mutational signatures that depended on the developmental origin (endo-, meso-, ectoderm) of the tumor tissue. Based on the findings of thirteen tumor entities, we identified three resistance groups, where Group 1 (endodermal origin) prominently indicates NRF2-pathway activation, Group 2 (mesodermal origin, primordial germ cells) shares elevated DNA repair mechanisms and decreased apoptosis induction, and Group 3 (ectodermal and paraxial mesodermal origin) commonly presents deregulated apoptosis induction and alternating pathways as the main cisplatin-induced resistance mechanisms. This review further proposes potential and novel therapeutic strategies to improve the outcome of cisplatin-based chemotherapy.
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http://dx.doi.org/10.1016/j.canlet.2021.07.037DOI Listing
October 2021

The signal transducer CD24 suppresses the germ cell program and promotes an ectodermal rather than mesodermal cell fate in embryonal carcinomas.

Mol Oncol 2021 Jul 22. Epub 2021 Jul 22.

Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany.

Testicular germ cell tumors (GCTs) are stratified into seminomas and nonseminomas. Seminomas share many histological and molecular features with primordial germ cells, whereas the nonseminoma stem cell population-embryonal carcinoma (EC)-is pluripotent and thus able to differentiate into cells of all three germ layers (teratomas). Furthermore, ECs are capable of differentiating into extra-embryonic lineages (yolk sac tumors, choriocarcinomas). In this study, we deciphered the molecular and (epi)genetic mechanisms regulating expression of CD24, a highly glycosylated signaling molecule upregulated in many cancers. CD24 is overexpressed in ECs compared with other GCT entities and can be associated with an undifferentiated pluripotent cell fate. We demonstrate that CD24 can be transactivated by the pluripotency factor SOX2, which binds in proximity to the CD24 promoter. In GCTs, CD24 expression is controlled by epigenetic mechanisms, that is, histone acetylation, since CD24 can be induced by the application histone deacetylase inhibitors. Vice versa, CD24 expression is downregulated upon inhibition of histone methyltransferases, E3 ubiquitin ligases, or bromodomain (BRD) proteins. Additionally, three-dimensional (3D) co-cultivation of EC cells with microenvironmental cells, such as fibroblasts, and endothelial or immune cells, reduced CD24 expression, suggesting that crosstalk with the somatic microenvironment influences CD24 expression. In a CRISPR/Cas9 deficiency model, we demonstrate that CD24 fulfills a bivalent role in differentiation via regulation of homeobox, and phospho- and glycoproteins; that is, it is involved in suppressing the germ cell/spermatogenesis program and mesodermal/endodermal differentiation, while poising the cells for ectodermal differentiation. Finally, blocking CD24 by a monoclonal antibody enhanced sensitivity toward cisplatin in EC cells, including cisplatin-resistant subclones, highlighting CD24 as a putative target in combination with cisplatin.
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http://dx.doi.org/10.1002/1878-0261.13066DOI Listing
July 2021

Molecular Characterization of Muellerian Tumors of the Urinary Tract.

Genes (Basel) 2021 06 7;12(6). Epub 2021 Jun 7.

Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany.

In the 2016 WHO classification of genitourinary tumors Muellerian tumors of the urinary tract (MTUT) comprise clear cell adenocarcinomas and endometrioid carcinomas. Since these rare tumors remained understudied, we aimed to characterize their molecular background by performing DNA- and RNA-based targeted panel sequencing. All tumors ( = 11) presented single nucleotide alterations (SNVs), with mutations being the most prevalent (5/11, 45%). Besides frequent mutations, loss of ARID1A protein is not a suitable marker since protein expression is (partly) preserved also in mutated cases. Copy number alterations (CNVs) were found in 64% of cases (7/11), exclusively gene amplifications. Interestingly, a functionally relevant gene fusion/microdeletion was discovered in the endometrioid adenocarcinoma case. Comparing our findings with mutational profiles of other tumor entities, absence of promoter mutations argues for a non-urothelial origin. No similarities were also found between MTUT and kidney cancers while parallels were observed for specific SNVs with endometrial carcinomas. In conclusion, immunohistochemical PAX8-positivity and lack of promoter mutations could serve as key diagnostic features in difficult cases. Thus, understanding the molecular background of these tumors helps to refine treatment options and offers the possibility of targeted therapies in cases where needed.
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http://dx.doi.org/10.3390/genes12060880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228991PMC
June 2021

The sentinel node invasion level (SNIL) as a prognostic parameter in melanoma.

Mod Pathol 2021 Oct 15;34(10):1839-1849. Epub 2021 Jun 15.

Institute of Pathology, University Medical Center, Göttingen, Germany.

Sentinel lymph node (SN) tumor burden is becoming increasingly important and is likely to be included in future N classifications in melanoma. Our aim was to investigate the prognostic significance of melanoma infiltration of various anatomically defined lymph node substructures. This retrospective cohort study included 1250 consecutive patients with SN biopsy. The pathology protocol required description of metastatic infiltration of each of the following lymph node substructures: intracapsular lymph vessels, subcapsular and transverse sinuses, cortex, paracortex, medulla, and capsule. Within the SN with the highest tumor burden, the SN invasion level (SNIL) was defined as follows: SNIL 1 = melanoma cells confined to intracapsular lymph vessels, subcapsular or transverse sinuses; SNIL 2 = melanoma infiltrating the cortex or paracortex; SNIL 3 = melanoma infiltrating the medulla or capsule. We classified 338 SN-positive patients according to the non-metric SNIL. Using Kaplan-Meier estimates and Cox models, recurrence-free survival (RFS), melanoma-specific survival (MSS) and nodal basin recurrence rates were analyzed. The median follow-up time was 75 months. The SNIL divided the SN-positive population into three groups with significantly different RFS, MSS, and nodal basin recurrence probabilities. The MSS of patients with SNIL 1 was virtually identical to that of SN-negative patients, whereas outgrowth of the metastasis from the parenchyma into the fibrous capsule or the medulla of the lymph node indicated a very poor prognosis. Thus, the SNIL may help to better assess the benefit-risk ratio of adjuvant therapies in patients with different SN metastasis patterns.
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http://dx.doi.org/10.1038/s41379-021-00835-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443441PMC
October 2021

A new technological approach in diagnostic pathology: mass spectrometry imaging-based metabolomics for biomarker detection in urachal cancer.

Lab Invest 2021 09 21;101(9):1281-1288. Epub 2021 May 21.

Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Urachal adenocarcinomas (UrC) are rare but aggressive. Despite being of profound therapeutic relevance, UrC cannot be differentiated by histomorphology alone from other adenocarcinomas of differential diagnostic importance. As no reliable tissue-based diagnostic biomarkers are available, we aimed to detect such by integrating mass-spectrometry imaging-based metabolomics and digital pathology, thus allowing for a multimodal approach on the basis of spatial information. To achieve this, a cohort of UrC (n = 19) and colorectal adenocarcinomas (CRC, n = 27) as the differential diagnosis of highest therapeutic relevance was created, tissue micro-arrays (TMAs) were constructed, and pathological data was recorded. Hematoxylin and eosin (H&E) stained tissue sections were scanned and annotated, enabling an automized discrimination of tumor and non-tumor areas after training of an adequate algorithm. Spectral information within tumor regions, obtained via matrix-assisted laser desorption/ionization (MALDI)-Orbitrap-mass spectrometry imaging (MSI), were subsequently extracted in an automated workflow. On this basis, metabolic differences between UrC and CRC were revealed using machine learning algorithms. As a result, the study demonstrated the feasibility of MALDI-MSI for the evaluation of FFPE tissue in UrC and CRC with the potential to combine spatial metabolomics data with annotated histopathological data from digitalized H&E slides. The detected Area under the curve (AUC) of 0.94 in general and 0.77 for the analyte taurine alone (diagnostic accuracy for taurine: 74%) makes the technology a promising tool in this differential diagnostic dilemma situation. Although the data has to be considered as a proof-of-concept study, it presents a new adoption of this technology that has not been used in this scenario in which reliable diagnostic biomarkers (such as immunohistochemical markers) are currently not available.
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http://dx.doi.org/10.1038/s41374-021-00612-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367814PMC
September 2021

Prognostic factor identification by screening changes in differentially expressed genes in oral squamous cell carcinoma.

Oral Dis 2021 Apr 19. Epub 2021 Apr 19.

Department of Oral and Maxillofacial Surgery, University Medical Center Goettingen, Goettingen, Germany.

Objective: This study was designed to identify changes in the expression of proteins occurring during the progression of oral squamous cell carcinoma (OSCC) and to validate their impact on patient prognosis.

Materials And Methods: The human OSCC cell line UPCI-SCC-040 was treated in vitro with TGF-β1, and transcriptome analysis of differentially expressed genes (DEGs) revealed putative candidates relative to untreated cells. The respective protein expression levels of the most important genes were immunohistochemically validated on a tissue microarray (TMA) containing tissue samples from 39 patients with OSCC and were correlated with disease-free survival (DFS) as the primary clinical endpoint.

Results: Our univariate Cox proportional hazard regression (CR) analysis revealed significant correlations among positive N stage (local lymph node metastasis, p = .04), stearoyl-CoA desaturase-1 (p < .01), sclerostin (p = .01), and CD137L expression (p = .04) and DFS. Stearoyl-CoA desaturase-1 and sclerostin remained the main prognostic factors (p < .01) in the multiple CR model.

Conclusion: We identified changes in differentially expressed genes during OSCC progression in vitro and translated the impact of the most deregulated genes on patient prognosis. Stearoyl-CoA desaturase-1 and sclerostin acted as independent prognostic factors in OSCC and could also be interesting candidates for new cancer targeted therapeutic approaches.
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http://dx.doi.org/10.1111/odi.13879DOI Listing
April 2021

The prognostic significance of lactate dehydrogenase levels in seminoma patients with advanced disease: an analysis by the Global Germ Cell Tumor Collaborative Group (G3).

World J Urol 2021 Mar 8. Epub 2021 Mar 8.

SWENOTECA, Trondheim, Norway.

Purpose: The prognostic significance of lactate dehydrogenase (LDH) in patients with metastatic seminoma is not defined. We investigated the prognostic impact of LDH levels prior to first-line systemic treatment and other clinical characteristics in this subset of patients.

Methods: Files from two registry studies and one single-institution database were analyzed retrospectively. Uni- and multivariate analyses were conducted to identify patient characteristics associated with recurrence free survival (RFS), overall survival (OS), and complete response rate (CRR).

Results: The dataset included 351 metastatic seminoma patients with a median follow-up of 5.36 years. Five-year RFS, OS and CRR were 82%, 89% and 52%, respectively. Explorative analysis revealed a cut-off LDH level of < 2.5 upper limit of normal (ULN) (n = 228) vs. ≥ 2.5 ULN (n = 123) to be associated with a significant difference concerning OS associated with 5-years OS rates of 93% vs. 83% (p = 0.001) which was confirmed in multivariate analysis (HR 2.87; p = 0.004). Furthermore, the cut-off LDH < 2.5 ULN vs. ≥ 2.5 ULN correlated with RFS and CRR associated with a 5-years RFS rate and CRR of 76% vs. 86% (p = 0.012) and 32% vs. 59% (p  ≤  0.001), respectively.

Conclusions: LDH levels correlate with treatment response and survival in metastatic seminoma patients and should be considered for their prognostic stratification.
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http://dx.doi.org/10.1007/s00345-021-03635-3DOI Listing
March 2021

The pioneer and differentiation factor FOXA2 is a key driver of yolk-sac tumour formation and a new biomarker for paediatric and adult yolk-sac tumours.

J Cell Mol Med 2021 02 14;25(3):1394-1405. Epub 2021 Jan 14.

Department of Urology, Urological Research Lab, Translational UroOncology, University Hospital Düsseldorf, Düsseldorf, Germany.

Yolk-sac tumours (YSTs), a germ cell tumour subtype, occur in newborns and infants as well as in young adults of age 14-44 years. In clinics, adult patients with YSTs face a poor prognosis, as these tumours are often therapy-resistant and count for many germ cell tumour related deaths. So far, the molecular and (epi)genetic mechanisms that control development of YST are far from being understood. We deciphered the molecular and (epi)genetic mechanisms regulating YST formation by meta-analysing high-throughput data of gene and microRNA expression, DNA methylation and mutational burden. We validated our findings by qRT-PCR and immunohistochemical analyses of paediatric and adult YSTs. On a molecular level, paediatric and adult YSTs were nearly indistinguishable, but were considerably different from embryonal carcinomas, the stem cell precursor of YSTs. We identified FOXA2 as a putative key driver of YST formation, subsequently inducing AFP, GPC3, APOA1/APOB, ALB and GATA3/4/6 expression. In YSTs, WNT-, BMP- and MAPK signalling-related genes were up-regulated, while pluripotency- and (primordial) germ cell-associated genes were down-regulated. Expression of FOXA2 and related key factors seems to be regulated by DNA methylation, histone methylation / acetylation and microRNAs. Additionally, our results highlight FOXA2 as a promising new biomarker for paediatric and adult YSTs.
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http://dx.doi.org/10.1111/jcmm.16222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875904PMC
February 2021

[What does the oncologist need from the pathologist in testicular cancer?]

Pathologe 2020 Dec;41(Suppl 2):111-117

Institut für Pathologie, Universitätsmedizin Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Deutschland.

Background: Testicular type II germ cell tumours (GCTs) are an exemplar of a curable cancer and the most common malignancy in males aged ≤35 years. Even in metastatic stages, about 70% of patients can be cured by cisplatin-based chemotherapy and multimodal treatments. For patients failing platinum-based standard therapy, prognosis is poor and novel biomarkers and therapeutic options are urgently needed.

Objectives: Discussion of desired histopathological information to guide urologists' and oncologists' decision making in the treatment of male GCTs.

Material And Methods: A narrative review of histopathological key features of male GCT tissue samples for clinical decision making.

Results: Histopathological workup is crucial to identify (i) a GCT origin in cancers of unknown primary based on isochromosome 12p (i(12p)) detection, (ii) the different type II GCT subtypes, and (iii) risk factors, i.e. lymphovascular or rete testis invasion, among others. Proper histopathological diagnosis is indispensable for guideline-endorsed, histology-driven, and risk-adapted treatment decisions, hereby helping to maintain treatment success while reducing the therapeutic burden and potential long-term sequelae of multimodal treatments. For refractory patients failing standard treatment options, prognosis remains poor and, so far, neither predictive or prognostic biomarkers nor novel therapeutic targets have been established.

Conclusions: Close interaction and interdisciplinary discussion of histopathologic and radiologic findings and established risk factors including serum tumour markers is crucial for successful treatment including intensified strategies, where necessary, or prevention of overtreatment, where possible.
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http://dx.doi.org/10.1007/s00292-020-00872-yDOI Listing
December 2020

Radiomic Features and Machine Learning for the Discrimination of Renal Tumor Histological Subtypes: A Pragmatic Study Using Clinical-Routine Computed Tomography.

Cancers (Basel) 2020 Oct 16;12(10). Epub 2020 Oct 16.

Institute of Urologic Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

This study evaluates the diagnostic performance of radiomic features and machine learning algorithms for renal tumor subtype assessment in venous computed tomography (CT) studies from clinical routine. Patients undergoing surgical resection and histopathological assessment of renal tumors at a tertiary referral center between 2012 and 2019 were included. Preoperative venous-phase CTs from multiple referring imaging centers were segmented, and standardized radiomic features extracted. After preprocessing, class imbalance handling, and feature selection, machine learning algorithms were used to predict renal tumor subtypes using 10-fold cross validation, assessed as multiclass area under the curve (AUC). In total, = 201 patients were included (73.7% male; mean age 66 ± 11 years), with = 131 clear cell renal cell carcinomas (ccRCC), = 29 papillary RCC, = 11 chromophobe RCC, = 16 oncocytomas, and = 14 angiomyolipomas (AML). An extreme gradient boosting algorithm demonstrated the highest accuracy (multiclass area under the curve (AUC) = 0.72). The worst discrimination was evident for oncocytomas vs. AML and oncocytomas vs. chromophobe RCC (AUC = 0.55 and AUC = 0.45, respectively). In sensitivity analyses excluding oncocytomas, a random forest algorithm showed the highest accuracy, with multiclass AUC = 0.78. Radiomic feature analyses from venous-phase CT acquired in clinical practice with subsequent machine learning can discriminate renal tumor subtypes with moderate accuracy. The classification of oncocytomas seems to be the most complex with the lowest accuracy.
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http://dx.doi.org/10.3390/cancers12103010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603020PMC
October 2020

The detection of isochromosome i(12p) in malignant germ cell tumours and tumours with somatic malignant transformation by the use of quantitative real-time polymerase chain reaction.

Histopathology 2021 Mar 21;78(4):593-606. Epub 2020 Nov 21.

Institute of Pathology, University Medical Centre, Göttingen, Germany.

Aims: Malignant germ cell tumours (GCTs) of the testis are rare neoplasms, but the most common solid malignancies in young men. World Health Organization guidelines divide GCTs into five types, for which numerous immunohistochemical markers allow exact histological subtyping in the majority of cases. In contrast, a germ cell origin is often hard to prove in metastatic GCTs that have developed so-called somatic malignant transformation. A high percentage, up to 89%, of GCTs are characterised by the appearance of isochromosome 12p [i(12p)]. Fluorescence in-situ hybridisation has been the most common diagnostic method for the detection of i(12p) so far, but has the disadvantages of being time-consuming, demanding, and not being a stand-alone method. The aim of the present study was to establish a quantitative real-time polymerase chain reaction assay as an independent method for detecting i(12p) and regional amplifications of the short arm of chromosome 12 by using DNA extracted from formalin-fixed paraffin-embedded tissue.

Methods And Results: A cut-off value to distinguish between the presence and absence of i(12p) was established in a control set consisting of 36 tumour-free samples. In a training set of 149 GCT samples, i(12p) was detectable in 133 tumours (89%), but not in 16 tumours (11%). In a test set containing 27 primary and metastatic GCTs, all 16 tumours with metastatic spread and/or somatic malignant transformation were successfully identified by the detection of i(12p).

Conclusion: In summary, the qPCR assay presented here can help to identify, further characterise and assign a large proportion of histologically inconclusive malignancies to a GCT origin.
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http://dx.doi.org/10.1111/his.14258DOI Listing
March 2021

[Therapy-Resistant Unilateral Headache with Protrusio Bulbi, Ptosis and Diplopia - a Malignant Surprise?]

Laryngorhinootologie 2020 09 26;99(9):641-644. Epub 2020 Aug 26.

Augenklinik der Universitätsmedizin Göttingen, Georg-August-Universität Göttingen, Göttingen.

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http://dx.doi.org/10.1055/a-1089-4093DOI Listing
September 2020

Prevalence of APC and PTEN Alterations in Urachal Cancer.

Pathol Oncol Res 2020 Oct 4;26(4):2773-2781. Epub 2020 Aug 4.

Department of Urology, Semmelweis University, Budapest, 1082, Hungary.

Urachal carcinoma (UrC) is a rare tumor with remarkable histological and molecular similarities to colorectal cancer (CRC). Adenomatous polyposis coli (APC) is the most frequently affected gene in CRC, but the prevalence and significance of its alterations in UrC is poorly understood. In addition, loss of phosphatase and tensin homologue (PTEN) was shown to be associated with therapy resistance in CRC. Our primary aim was to assess specific genetic alterations including APC and PTEN in a large series of UrC samples in order to identify clinically significant genomic alterations. We analyzed a total of 40 UrC cases. Targeted 5-gene (APC, PTEN, DICER1, PRKAR1A, TSHR, WRN) panel sequencing was performed on the Illumina MiSeq platform (n = 34). In addition, ß-catenin (n = 38) and PTEN (n = 30) expressions were assessed by immunohistochemistry. APC and PTEN genes were affected in 15% (5/34) and 6% (2/34) of cases. Two of five APC alterations (p.Y1075*, p.K1199*) were truncating pathogenic mutations. One of the two PTEN variants was a pathogenic frameshift insertion (p.C211fs). In 29% (11/38) of samples, at least some weak nuclear ß-catenin immunostaining was detected and PTEN loss was observed in 20% (6/30) of samples. The low prevalence of APC mutations in UrC represents a characteristic difference to CRC. Based on APC and ß-catenin results, the Wnt pathway seems to be rarely affected in UrC. Considering the formerly described involvement of PTEN protein loss in anti-EGFR therapy-resistance its immunohistochemical testing may have therapeutic relevance.
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http://dx.doi.org/10.1007/s12253-020-00872-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471184PMC
October 2020

CDK4/6 inhibition presents as a therapeutic option for paediatric and adult germ cell tumours and induces cell cycle arrest and apoptosis via canonical and non-canonical mechanisms.

Br J Cancer 2020 08 18;123(3):378-391. Epub 2020 May 18.

Department of Urology, Urological Research Lab, Translational UroOncology, University Hospital Düsseldorf, Düsseldorf, Germany.

Background: Germ cell tumours (GCTs) are the most common solid malignancies in young men. Although high cure rates can be achieved, metastases, resistance to cisplatin-based therapy and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In this study, we analysed the potential of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors palbociclib and ribociclib (PaRi) as molecular drugs to treat cisplatin-resistant and -sensitive paediatric and adult GCTs.

Methods: Ten GCT cell lines, including cisplatin-resistant subclones and non-malignant controls, were treated with PaRi and screened for changes in viability (triphenyl tetrazolium chloride (XTT) assay), apoptosis rates (flow cytometry, caspase assay), the cell cycle (flow cytometry), the transcriptome (RNA-sequencing, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and on protein level (western blot). Expression profiling was performed on paediatric and adult GCT tissues (expression microarrays, qRT-PCR, immunohistochemistry, 'The Cancer Genome Atlas' database).

Results: We demonstrate that adult GCTs highly express CDK4, while paediatric GCTs strongly express CDK6 instead. Thus, both GCT types are potentially treatable by PaRi. GCTs presented as highly sensitive towards PaRi, which caused a decrease in viability, cell cycle arrest and apoptosis. Although GCTs mainly arrested in the G1/G0 phase, some embryonal carcinoma cell lines were able to bypass the G1/S checkpoint and progressed to the G2/M phase. We found that upregulation of CDK3 and downregulation of many mitosis regulation factors, like the HAUS genes, might be responsible for bypassing the G1/S checkpoint and termination of mitosis, respectively. We postulate that GCT cells do not tolerate these alterations in the cell cycle and eventually induce apoptosis.

Conclusion: Our study highlights PaRi as therapeutic options for cisplatin-resistant and -sensitive paediatric and adult GCTs.
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http://dx.doi.org/10.1038/s41416-020-0891-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403155PMC
August 2020

Human chorionic gonadotropin-positive seminoma patients: A registry compiled by the global germ cell tumor collaborative group (G3).

Eur J Cancer 2020 06 29;132:127-135. Epub 2020 Apr 29.

Department of Oncology, Hematology and Bone Marrow Transplantation with Division of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: The prognostic role of human chorionic gonadotropin (hCG) and lactate dehydrogenase (LDH) serum levels in seminoma patients remains uncertain. This observational study evaluates the prognostic impact of tumour marker levels, and other clinicopathological findings, in hCG-positive seminoma patients.

Methods: Seminoma patients with serum hCG levels above normal at first diagnosis were eligible for recruitment. Statistical analysis, including multivariate regression, was performed to identify risk factors. Primary end-points were overall survival (OS) and recurrence-free survival (RFS).

Results: We recruited 1031 hCG-positive patients (stage I: n = 586; stage II + III: n = 427) diagnosed between 1981 and 2018. In metastatic disease, LDH levels ≥3 above upper normal limit (UNL) pre- (n = 109) or post-orchiectomy (n = 73) and patients aged ≥40 years (n = 187) were associated with poor prognosis: 5-year OS rates of 84% (LDH ≥3 UNL pre-orchiectomy) versus 92% (<3 UNL pre-orchiectomy) (hazard ratio [HR]: 3.155, [95% confidence interval {CI}: 1.28-7.75], P = 0.012), 82% (≥3 UNL post-orchiectomy) versus 92% (<3 UNL post-orchiectomy) (HR: 6.877, [95% CI: 1.61-29.34]; P = 0.009) and 86% (≥40 years) versus 91% (<40 years) (HR: 6.870, [95% CI: 1.45-13.37], P = 0.009), respectively. A subset of patients with hCG levels ≥2000 IU/l pre-orchiectomy (n = 17) exhibited a poor prognosis, with 5-year OS rates of 73% (≥2000 IU/l) versus 94% (<2000 IU/l) (HR: 3.936, [95% CI: 1.02-12.61], P = 0.047).

Conclusions: Age and LDH levels are significantly associated with poor prognosis in hCG-positive seminoma patients. A small number of patients, with levels of hCG ≥2000 IU/l, may represent a separate prognostic subgroup associated with impaired survival rates.
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http://dx.doi.org/10.1016/j.ejca.2020.03.022DOI Listing
June 2020

Comparative genomic profiling of glandular bladder tumours.

Virchows Arch 2020 Sep 20;477(3):445-454. Epub 2020 Mar 20.

Institute of Pathology, University Hospital RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany.

Primary glandular bladder tumours (bladder adenocarcinoma [BAC], urachal adenocarcinoma [UAC], urothelial carcinoma with glandular differentiation [UCg]) are rare malignancies with histological resemblance to colorectal adenocarcinoma (CORAD) in the majority of this subgroup. Definite case numbers are very low, molecular data are limited and the pathogenesis remains poorly understood. Therefore, this study was designed to complement current knowledge by in depth analysis of BAC (n = 12), UAC (n = 13), UCg (n = 11) and non-invasive glandular lesions (n = 19). In BAC, in addition to known alterations in TP53, Wnt, MAP kinase and MTOR pathway, mutations in SMAD4, ARID1A and BRAF were identified. Compared to published data on muscle invasive bladder cancer (BLCA) and CORAD, UCg exhibited frequent "urothelial" like alterations while BAC and UAC were characterised by a more "colorectal" like mutational pattern. Immunohistochemically, there was no evidence of DNA mismatch repair deficiency or PD-L1 tumour cell positivity in any sample. Depending on the used antibody 0-45% of BAC, 0-30% of UCg and 0% UAC cases exhibited PD-L1 expressing tumour associated immune cells. A single BAC (9%, 1/11) showed evidence of ARID1A protein loss, and two cases of UCg (20%, 2/10) showed loss of SMARCA1 and PBRM1, respectively. Taken together, our data suggest at least in part involvement of similar pathways driving tumourigenesis of adenocarcinomas like BAC, UAC and CORAD independent of their tissue origin. Alterations of TERT and FBXW7 in single cases of intestinal metaplasia further point towards a possible precancerous character in line with previous reports.
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http://dx.doi.org/10.1007/s00428-020-02787-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443184PMC
September 2020

Proteomic Comparison of Malignant Human Germ Cell Tumor Cell Lines.

Dis Markers 2019 3;2019:8298524. Epub 2019 Sep 3.

Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.

Malignant germ cell tumors (GCT) are the most common malignant tumors in young men between 18 and 40 years. The correct identification of histological subtypes, in difficult cases supported by immunohistochemistry, is essential for therapeutic management. Furthermore, biomarkers may help to understand pathophysiological processes in these tumor types. Two GCT cell lines, TCam-2 with seminoma-like characteristics, and NTERA-2, an embryonal carcinoma-like cell line, were compared by a quantitative proteomic approach using high-resolution mass spectrometry (MS) in combination with stable isotope labelling by amino acid in cell culture (SILAC). We were able to identify 4856 proteins and quantify the expression of 3936. 347 were significantly differentially expressed between the two cell lines. For further validation, CD81, CBX-3, PHF6, and ENSA were analyzed by western blot analysis. The results confirmed the MS results. Immunohistochemical analysis on 59 formalin-fixed and paraffin-embedded (FFPE) normal and GCT tissue samples (normal testis, GCNIS, seminomas, and embryonal carcinomas) of these proteins demonstrated the ability to distinguish different GCT subtypes, especially seminomas and embryonal carcinomas. In addition, siRNA-mediated knockdown of these proteins resulted in an antiproliferative effect in TCam-2, NTERA-2, and an additional embryonal carcinoma-like cell line, NCCIT. In summary, this study represents a proteomic resource for the discrimination of malignant germ cell tumor subtypes and the observed antiproliferative effect after knockdown of selected proteins paves the way for the identification of new potential drug targets.
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http://dx.doi.org/10.1155/2019/8298524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745167PMC
February 2020

[Challenges in diagnostics for intestinal tuberculosis - Pitfalls of a forgotten infectious disease: case series and literature review].

Z Gastroenterol 2019 Sep 16;57(9):1067-1076. Epub 2019 Sep 16.

Klinik für Gastroenterologie und gastrointestinale Onkologie der Universitätsmedizin Göttingen.

Intestinal tuberculosis is an infectious disease of the extrapulmonary manifestation with the Mycobacteria tuberculosis complex. In developed countries, this disease is rarely seen. The clinical features are heterogeneous and unspecific. Furthermore, intestinal tuberculosis poses diagnostic challenges. Regarding intestinal tuberculosis the Ziehl-Neelsen staining for acid-fast bacillus, PCR examination and culture methods show only poor sensitivity and specificity. In this case series, we present three patients suffering from intestinal tuberculosis, who were diagnosed and treated successfully. Furthermore, we review the literature about the pitfalls of the diagnostic approaches and the treatment options of intestinal tuberculosis.
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http://dx.doi.org/10.1055/a-0981-6580DOI Listing
September 2019

Of Cestodes and Men: Surgical Treatment of a Spinal Hydatid Cyst.

J Neurol Surg A Cent Eur Neurosurg 2020 Jan 4;81(1):86-90. Epub 2019 Sep 4.

Department of Trauma, Orthopedics and Reconstructive Surgery, Georg-August-University of Göttingen, Göttingen, Germany.

Background:  The cestode causes hydatid disease. In addition to manifestations in the liver and lung, it can lead to cystic lesions in the spine.

Case Description:  We report a 42-year-old male patient with primary hydatid disease in the eighth thoracic vertebra. The only clinical symptom was chronic back pain. Although laboratory findings were normal, imaging displayed lytic destruction that raised the suspicion of a metastatic disease. Diagnostics of the thoraces and abdomen did not reveal other pathologic abnormalities. Follow-up magnetic resonance imaging (MRI) depicted a progressive compression of the spinal cord and inhomogeneous structure in the fat-suppressed sequences. Because the Jamshidi biopsy was inconclusive, the tumor board recommended surgery. Dorsal decompression, spondylodesis of T6-T10, and vertebral column resection of T8 with complete cyst removal were performed. The resected vertebrae showed a mucous-like lesion with white granular tissue interfusing the whole vertebral body. A pathologic examination and enzyme-linked immunosorbent assay confirmed . Thus chemotherapy with albendazole was initiated. A follow-up MRI of the whole spine confirmed complete remission and found no additional resettlements. The patient's back pain was resolved without neurologic deficits.

Conclusions:  For lytic manifestations of the vertebral column, hydatid cysts should be considered a differential diagnosis in addition to malignant metastasis, tuberculosis, and osteomyelitis. Thorough surgical resection and strict follow-up are necessary.
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http://dx.doi.org/10.1055/s-0039-1693707DOI Listing
January 2020

Transcription factor TAp73 and microRNA-449 complement each other to support multiciliogenesis.

Cell Death Differ 2019 12 8;26(12):2740-2757. Epub 2019 May 8.

Molecular & Experimental Pneumology Group, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Goettingen, Germany.

Motile cilia serve vital functions in development, homeostasis, and regeneration. We recently demonstrated that TAp73 is an essential transcriptional regulator of respiratory multiciliogenesis. Here, we show that TAp73 is expressed in multiciliated cells (MCCs) of diverse tissues. Analysis of TAp73 mutant animals revealed that TAp73 regulates Foxj1, Rfx2, Rfx3, axonemal dyneins Dnali1 and Dnai1, plays a pivotal role in the generation of MCCs in male and female reproductive ducts, and contributes to fertility. However, the function of MCCs in the brain appears to be preserved despite the loss of TAp73, and robust activity of cilia-related networks is maintained in the absence of TAp73. Notably, TAp73 loss leads to distinct changes in ciliogenic microRNAs: miR34bc expression is reduced, whereas the miR449 cluster is induced in diverse multiciliated epithelia. Among different MCCs, choroid plexus (CP) epithelial cells in the brain display prominent miR449 expression, whereas brain ventricles exhibit significant increase in miR449 levels along with an increase in the activity of ciliogenic E2F4/MCIDAS circuit in TAp73 mutant animals. Conversely, E2F4 induces robust transcriptional response from miR449 genomic regions. To address whether increased miR449 levels in the brain maintain the multiciliogenesis program in the absence of TAp73, we deleted both TAp73 and miR449 in mice. Although loss of miR449 alone led to a mild ciliary defect in the CP, more pronounced ciliary defects and hydrocephalus were observed in the brain lacking both TAp73 and miR449. In contrast, miR449 loss in other MCCs failed to enhance ciliary defects associated with TAp73 loss. Together, our study shows that, in addition to the airways, TAp73 is essential for generation of MCCs in male and female reproductive ducts, whereas miR449 and TAp73 complement each other to support multiciliogenesis and CP development in the brain.
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http://dx.doi.org/10.1038/s41418-019-0332-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224178PMC
December 2019

[Therapy-Resistant Unilateral Headache with Protrusio Bulbi, Ptosis and Diplopia - a Malignant Surprise?]

Klin Monbl Augenheilkd 2019 01 19;236(1):39-42. Epub 2018 Dec 19.

Augenklinik der Universitätsmedizin Göttingen, Georg-August-Universität Göttingen, Göttingen.

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http://dx.doi.org/10.1055/a-0764-5013DOI Listing
January 2019

Primary signet-ring stromal tumour of the testis: case report with literature review.

APMIS 2019 Jan;127(1):45-49

Institute of Pathology, University of Göttingen, Göttingen, Germany.

Primary signet-ring stromal tumour of the testis (PSRSTT) is a very rare type of primary testicular tumour, which is not actually mentioned in the current WHO categorization of tumours of the male genital organs. In this case we report about histologically and immunohistochemically features of this rare tumour. In the present case, PSRTT was found in the orchiectomy preparation of a 69-year-old man with painless swelling of his left testicle. The tumour was well circumscribed and separated from the normal testicular tissue by a fibrous capsule. The tumour cells showed a signet-ring pattern and were separated by thin collagen bundles. No mitotic activity and necrosis were found inside the tumour. Immunohistochemically, the tumour was positive for vimentin, neuron-specific enolase (NSE), S-100 protein, β-catenin and cyclin D1. No expression of cytokeratin, actin, SALL4, OCT3/4, and especially, inhibin and calretinin were detected. In conclusion, the presence of signet-ring cell formation can be found in different tumours of the testis. PSRSTT is a rare tumour that needs to be considered, in particular, to distinct them from other tumours with signet-ring cell pattern.
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http://dx.doi.org/10.1111/apm.12907DOI Listing
January 2019

Detecting Early Markers of Ventilator-Associated Pneumonia by Analysis of Exhaled Gas.

Crit Care Med 2019 03;47(3):e234-e240

Department of Anesthesiology, University Medical Center Göttingen, Göttingen, Germany.

Objectives: The detection of microbial volatile organic compounds or host response markers in the exhaled gas could give an earlier diagnosis of ventilator-associated pneumonia. Gas chromatography-ion mobility spectrometry enables noninvasive, rapid, and sensitive analysis of exhaled gas. Using a rabbit model of ventilator-associated pneumonia we determined if gas chromatography-ion mobility spectrometry is able to detect 1) ventilator-associated pneumonia specific changes and 2) bacterial species-specific changes in the exhaled gas.

Design: Experimental in vivo study.

Setting: University research laboratory.

Subjects: Female New Zealand White rabbits.

Interventions: Animals were anesthetized and mechanically ventilated. To induce changes in the composition of exhaled gas we induced ventilator-associated pneumonia via endobronchial instillation of either Escherichia coli group (n = 11) or Pseudomonas aeruginosa group (n = 11) after 2 hours of mechanical ventilation. In a control group (n = 11) we instilled sterile lysogeny broth endobronchially.

Measurements And Main Results: Gas chromatography-ion mobility spectrometry gas analysis, CT scans of the lungs, and blood samples were obtained at four measurement points during the 10 hours of mechanical ventilation. The volatile organic compound patterns in the exhaled gas were compared and correlated with ventilator-associated pneumonia severity. Sixty-seven peak areas showed changes in signal intensity in the serial gas analyses. The signal intensity changes in 10 peak regions differed between the groups. Five peak areas (P_648_36, indole, P_714_278, P_700_549, and P_727_557) showed statistically significant changes of signal intensity.

Conclusions: This is the first in vivo study that shows the potential of gas chromatography-ion mobility spectrometry for early detection of ventilator-associated pneumonia specific volatile organic compounds and species differentiation by noninvasive analyses of exhaled gas.
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http://dx.doi.org/10.1097/CCM.0000000000003573DOI Listing
March 2019

CIC fusion-positive sarcoma of the spermatic cord.

Virchows Arch 2019 Feb 11;474(2):253-257. Epub 2018 Oct 11.

Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Str.40, 37075, Göttingen, Germany.

In addition to germ cell tumors and tumors of the sex cord stroma, the WHO classification of testis and paratesticular tumors also contains malignant soft tissue tumors. Among them, liposarcomas of the spermatic cord are the most common entities. Other mesenchymal tumors with smooth muscle, skeletal muscle, fibroblastic/myofibroblastic, or nerve sheath differentiation are rare. Ewing sarcoma is composed of uniform small round cells and typically characterized by translocations of the EWSR1 gene. In rare cases, Ewing sarcoma-like tumors lack an EWSR1 gene fusion. Some of these tumors harbor a specific CIC translocation. However, Ewing-like sarcoma has up to now never been described in the testis or spermatic cord. The present case describes the first EWSR1-negative, undifferentiated round cell sarcoma with CIC translocation of the spermatic cord. Potential differential diagnoses are discussed.
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http://dx.doi.org/10.1007/s00428-018-2471-5DOI Listing
February 2019

Comparative proteomics reveals a diagnostic signature for pulmonary head-and-neck cancer metastasis.

EMBO Mol Med 2018 09;10(9)

Department of Thoracic and Cardiovascular Surgery, University Medical Center, Göttingen, Germany.

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.
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http://dx.doi.org/10.15252/emmm.201708428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127892PMC
September 2018

Testosterone metabolites inhibit proliferation of castration- and therapy-resistant prostate cancer.

Oncotarget 2018 Mar 30;9(24):16951-16961. Epub 2018 Mar 30.

Department of Urology, University Medical Center, Göttingen 37075, Germany.

Novel treatments for castration-resistant prostate cancer (CRPC) such as abiraterone acetate (AA) or enzalutamide effectively target the androgen pathway to arrest aberrant signalling and cell proliferation. Testosterone is able to inhibit tumour cell growth in CRPC. Estrogen receptor-beta (ERβ) binds the testosterone-metabolites 3β-androstanediol and 3α-androstanediol in parallel to the canonical estradiol. In the prostate it is widely accepted that ERβ regulates estrogen signalling, mediating anti-proliferative effects. We used the prostate cancer cell lines LNCaP, PC-3, VCaP, and the non-neoplastic BPH-1. VCaP cells were treated with 1 nmol/L testosterone over 20 passages, yielding the cell line VCaPrev, sensitive to hormone therapies. In contrast, LNCaP cells were grown for more than 100 passages yielding a high passage therapy resistant cell line (LNCaP). VCaP and LNCaP cell lines were treated with 5 μmol/L AA for more than 20 passages, respectively, generating the AA-tolerant-subtypes VCaP and hiPLNCaP. Cell lines were treated with testosterone, dihydrotestosterone (DHT), R1881, and the androgen-metabolites 3β-androstanediol and 3α-androstanediol. 3β-androstanediol or 3α-androstanediol significantly reduced proliferation in all cell lines except the BPH-1 and androgen receptor-negative PC-3 and markedly downregulated AR and estrogen receptor alpha (ERα). Whereas ERβ expression was increased in all cell lines except BPH-1 or PC-3. In summary, 3β-adiol or 3α-adiol, as well as DHT and R1881, significantly reduced tumour cell growth in CRPC cells. Thus, these compounds represent novel potential therapeutic approaches to overcome drug-resistance in CRPC, especially with regard to AR-V7 function in therapy resistance. Furthermore, these data confirm the tumour suppressor properties of ERβ in CRPC.
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http://dx.doi.org/10.18632/oncotarget.24763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908297PMC
March 2018

Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas.

Int J Cancer 2018 10 10;143(7):1764-1773. Epub 2018 May 10.

German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany.

Urachal cancer (UrC) is a rare but aggressive malignancy often diagnosed in advanced stages requiring systemic treatment. Although cytotoxic chemotherapy is of limited effectiveness, prospective clinical studies can hardly be conducted. Targeted therapeutic treatment approaches and potentially immunotherapy based on a biological rationale may provide an alternative strategy. We therefore subjected 70 urachal adenocarcinomas to targeted next-generation sequencing, conducted in situ and immunohistochemical analyses (including PD-L1 and DNA mismatch repair proteins [MMR]) and evaluated the microsatellite instability (MSI) status. The analytical findings were correlated with clinicopathological and outcome data and Kaplan-Meier and univariable/multivariable Cox regression analyses were performed. The patients had a mean age of 50 years, 66% were male and a 5-year overall survival (OS) of 58% and recurrence-free survival (RFS) of 45% was detected. Sequence variations were observed in TP53 (66%), KRAS (21%), BRAF (4%), PIK3CA (4%), FGFR1 (1%), MET (1%), NRAS (1%), and PDGFRA (1%). Gene amplifications were found in EGFR (5%), ERBB2 (2%), and MET (2%). We detected no evidence of MMR-deficiency (MMR-d)/MSI-high (MSI-h), whereas 10 of 63 cases (16%) expressed PD-L1. Therefore, anti-PD-1/PD-L1 immunotherapy approaches might be tested in UrC. Importantly, we found aberrations in intracellular signal transduction pathways (RAS/RAF/PI3K) in 31% of UrCs with potential implications for anti-EGFR therapy. Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA. The molecular profile strengthens the notion that UrC is a distinct entity on the genomic level with closer resemblance to colorectal than to bladder cancer.
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http://dx.doi.org/10.1002/ijc.31547DOI Listing
October 2018

The incidence of occult metastasis and the status of elective neck dissection in salivary adenoid cystic carcinoma: a single center study.

Oral Surg Oral Med Oral Pathol Oral Radiol 2018 06 2;125(6):516-519. Epub 2018 Feb 2.

Department of Pathology, University of Göttingen, Göttingen, Germany.

Objective: Adenoid cystic carcinoma (ACC) is characterized by a high rate of local recurrence and late distant metastasis. The status of an elective neck dissection (END) is controversial in the literature.

Study Design: In this study we retrospectively analyzed the surgical treatment and follow-up examinations of 59 patients with ACCs of a salivary gland treated in a single center between 1980 and 2016.

Results: The incidence of occult nodal metastases among all patients who underwent END was 20.6%. The overall survival and the disease-free survival of patients who underwent END versus patients without END had no significant differences. Even in the case of positive lymph nodes metastasis there was no significant benefit in survival or local recurrence control.

Conclusion: The incidence of occult neck metastases in patients with ACC was 20.6%. There was no significant enhanced survival in the group of patients who underwent an END.
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http://dx.doi.org/10.1016/j.oooo.2018.01.013DOI Listing
June 2018

Telomerase reverse transcriptase (TERT) promoter mutations are rare in urachal cancer.

Pathol Int 2017 Dec 19;67(12):597-601. Epub 2017 Oct 19.

Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.

High rates of telomerase reverse transcriptase (TERT) promoter mutations have recently been described in urothelial carcinoma (UC). Unlike UC in the bladder, adenocarcinomas account for the majority of urachal cancer (UrC) cases. As data in UrC is unclear, we analyzed TERT promoter mutations in a large cohort of UrC for its differential diagnostic, clinicopathological and prognostic significance. UrC cases from six academic centers were analyzed for c.-146C>T (C250T) and c.-124C>T (C228T) TERT promoter mutations by PCR and Sanger sequencing. Clinicopathological and survival data were collected. The cohort consisted of 15 men (56%) and 12 women (44%) with a median age of 50 years including 23 adenocarcinomas, two squamous cell carcinomas (SCC), one UC and one undifferentiated carcinoma. In one case of (mucinous) urachal adenocarcinoma a C228T mutation was detected (1/23; 4%), like in a case of SCC in addition to one C250T mutation in the UC case. TERT promoter mutations are very rare in urachal adenocarcinomas (unlike in UC) with differential diagnostic implications. Additionally, the low TERT promoter mutation rate in urachal adenocarcinomas is more comparable to colorectal adenocarcinomas than to UC, giving further support to recent genetic findings and therapeutic considerations.
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http://dx.doi.org/10.1111/pin.12594DOI Listing
December 2017
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