Publications by authors named "Gerhard Seitz"

31 Publications

Amplification in Non-Small Cell Lung Cancer (NSCLC)-A Consecutive Evaluation Using Next-Generation Sequencing (NGS) in a Real-World Setting.

Cancers (Basel) 2021 Oct 7;13(19). Epub 2021 Oct 7.

Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.

In non-small cell lung cancer (NSCLC), approximately 1-3% of cases harbor an increased gene copy number (GCN) of the gene. This alteration can be due to de novo amplification of the gene or can represent a secondary resistance mechanism in response to targeted therapies. To date, the gold standard method to evaluate the GCN of is fluorescence in situ hybridization (FISH). However, next-generation sequencing (NGS) is becoming more relevant to optimize therapy by revealing the mutational profile of each NSCLC. Using evaluable = 205 NSCLC cases of a consecutive cohort, this study addressed the question of whether an amplicon based NGS assay can completely replace the FISH method regarding the classification of GCN status. Out of the 205 evaluable cases, only = 9 cases (43.7%) of = 16 high-level amplified cases assessed by FISH were classified as amplified by NGS. Cases harboring a GCN > 10 showed the best concordance when comparing FISH versus NGS (80%). This study confirms that an amplicon-based NGS assessment of the GCN detects high-level amplified cases harboring a GCN > 10 but fails to detect the various facets of gene amplification in the context of a therapy-induced resistance mechanism.
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http://dx.doi.org/10.3390/cancers13195023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508248PMC
October 2021

[A rare case of renal ectopic thyroid tissue].

Aktuelle Urol 2021 Feb 23;52(1):64-66. Epub 2020 Sep 23.

Sozialstiftung Bamberg, Klinik für Urologie, Kinderurologie und roboterassistierte minimalinvasive Urologie, Bamberg.

We present a rare case of ectopic thyroid tissue found during robotic nephrectomy of a kidney with a suspected malignant tumour. Such cases of ectopic thyroid tissue are extremely rare in the literature. If ectopic thyroid tissue occurs, it is usually found in the neck region or in the upper mediastinum. Clinical symptoms depend on size, localisation and hormonal function of the ectopic tissue. Surgical resection remains the treatment of choice; in individual cases, conservative treatment can be an option. This case report aims to emphasise that renal tumours of unknown origin might be paraneoplastic or ectopic tissue of other organs.
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http://dx.doi.org/10.1055/a-1182-1961DOI Listing
February 2021

Sporadic adenoma or ulcerative colitis associated neoplasia? The endoscopist's information has an impact on diagnosis and patient management.

Pathol Res Pract 2020 Nov 15;216(11):153162. Epub 2020 Aug 15.

Institute of Pathology, Klinikum Bayreuth GmbH, Bayreuth, Germany.

Background: Diagnosing low grade intraepithelial neoplasia (LGIN) in patients with ulcerative colitis (UC) is difficult. Distinguishing between sporadic adenoma (SA) and UC associated LGIN is even more challenging but has clinical impact. We aimed to examine, if the morphological distinction between both entities is reliably possible, how it influences patient's outcome and the role of the endoscopist in this decision with respect to current endoscopy classification schemes.

Methods: Seven pathologists retrospectively reevaluated 425 cases of LGIN in UC patients, diagnosed between 2009 and 2017 with preceding expert consensus and follow up in two separate readings, based on published morphological differentiation criteria. In the first evaluation, the observers were blinded to any clinical data. In the second evaluation, they knew patients' age as well as endoscopic features. They also rated their subjective diagnostic certainty.

Results: Diagnostic correctness improved significantly in the second assessment as did the pathologists' confidence in their diagnoses (p < 0.001 - p = 0.019). Knowledge of clinical and endoscopical data led to a higher percentage of SA (71.8% vs. 85.6%). UC associated LGIN showed significant earlier LGIN relapse as well as more high grade intraepithelial neoplasia and carcinoma during follow up (p < 0.001, p < 0.001, p = 0.005).

Conclusions: Distinction between SA and UC associated LGIN is important as it has an impact on patients' follow up and treatment. Morphological distinction remains difficult with moderate interobserver variability. Adequate clinical information significantly improves pathologists' diagnoses as well as their confidence in their diagnoses.
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http://dx.doi.org/10.1016/j.prp.2020.153162DOI Listing
November 2020

Hard palate hyperpigmentation-a rare side effect of antimalarials.

Arthritis Rheumatol 2018 01 28;70(1):152. Epub 2017 Nov 28.

Friedrich-Alexander University Erlangen-Nürnberg Universitätsklinikum Erlangen, Erlangen, Germany.

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http://dx.doi.org/10.1002/art.40327DOI Listing
January 2018

An international study comparing conventional versus mRNA level testing (TargetPrint) for ER, PR, and HER2 status of breast cancer.

Virchows Arch 2016 Sep 4;469(3):297-304. Epub 2016 Jul 4.

Gynecology Oncology Unit, Centre Hospitalier Chrétien, Liège, Belgium.

To compare results from messenger RNA (mRNA)-based TargetPrint testing with those from immunohistochemistry (IHC) and in situ hybridization (ISH) conducted according to local standard procedures at hospitals worldwide. Tumor samples were prospectively obtained from 806 patients at 22 hospitals. The mRNA level of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) was assessed by TargetPrint quantitative gene expression readouts. IHC/ISH assessments were performed according to local standards at the participating hospitals. TargetPrint readout showed a high concordance with IHC/ISH of 95 % (kappa 0.81) for ER, 81 % (kappa 0.56) for PR, and 94 % (kappa 0.76) for HER2. The positive/negative agreement between TargetPrint and IHC for ER, PR, and HER2 was 96 %/87 %, 84 %/74 %, and 74 %/98 %, respectively. The concordance rate in IHC/ISH results between hospitals varied: 88-100 % for ER (kappa 0.50-1.00); 50-100 % for PR (kappa 0.20-1.00); and 90-100 % for HER2 (kappa 0.59-1.00). mRNA readout of ER, PR, and HER2 status by TargetPrint was largely comparable to local IHC/ISH analysis. However, there was substantial discordance in IHC/ISH results between different hospitals. When results are discordant, the use of TargetPrint would improve the reliability of hormone receptor and HER2 results by prompting retesting in a reference laboratory.
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http://dx.doi.org/10.1007/s00428-016-1979-9DOI Listing
September 2016

Intraductal carcinoma of prostate reporting practice: a survey of expert European uropathologists.

J Clin Pathol 2016 Oct 29;69(10):852-7. Epub 2016 Feb 29.

Institute of Pathology, University Hospital Bonn, Bonn, Germany.

Background: It is unclear whether the reported variation in the diagnosis of intraductal carcinoma of the prostate (IDC-P) is due to variable interpretation of borderline morphology, use of different diagnostic criteria or both.

Aims: We sought to determine the degree of variation in the diagnostic criteria and reporting rules for IDC-P in prostate biopsies employed by expert uropathologists.

Methods: A questionnaire survey was circulated to 23 expert uropathologists from 11 European countries.

Results: Criteria used for diagnosis of IDC-P included solid intraductal growth (100%), dense cribriform (96%), loose cribriform/micropapillary with nuclear size >6× normal (83%) or comedonecrosis (74%) and dilated ducts >2× normal (39%). 'Nuclear size' was interpreted as nuclear area by 74% and nuclear diameter by 21%. Pure IDC-P in needle biopsies was reported by 100% and Gleason graded by 30%. All would perform immunohistochemistry in such cases to rule out invasive cancer. An IDC-P component associated with invasive cancer would be included in the determination of tumour extent and number of cores involved by 74% and 83%, respectively. 52% would include IDC-P component when grading invasive cancer. 48% would perform immunohistochemistry in solid or cribriform nests with comedonecrosis to exclude IDC-P (17% routinely, 30% if the focus appeared to have basal cells on H&E). 48% graded such foci as Gleason pattern 5 even if immunohistochemistry demonstrated the presence of basal cells.

Conclusions: There is a need for more clarity in the definition of some of the diagnostic criteria for IDC-P as well as for greater standardisation of IDC-P reporting.
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http://dx.doi.org/10.1136/jclinpath-2016-203658DOI Listing
October 2016

Molecular patterns in the evolution of serrated lesion of the colorectum.

Int J Cancer 2013 Apr 17;132(8):1800-10. Epub 2012 Oct 17.

Section of Cancer Genomics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Colorectal cancer (CRC) mostly develops from a variety of polyps following mainly three different molecular pathways: chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylation (CIMP). Polyps are classified histologically as conventional adenomas, hyperplastic polyps, sessile serrated adenomas/polyps (SSA/P) and traditional serrated adenomas (TSA). However, the association of these polyps with the different types of CRCs and the underlying genetic and epigenetic aberrations has yet to be resolved. In order to address this question we analyzed 140 tumors and 20 matched mucosae by array comparative genomic hybridization, by sequence analysis of the oncogenes BRAF, KRAS, PI3K3CA and by methylation arrays. MSI was tested indirectly by immunohistochemistry (IHC) and a loss of MLH1, MSH2, MSH6 or PMS2 was assigned as high microsatellite instability (MSI-H), while low microsatellite instability (MSI-L) was defined as MGMT IHC negativity only. CIN was detected in 78% of all MSI-H CRCs, most commonly as a gain of chromosome 8. Methylation data analyses allowed classification of samples into four groups and detected similar methylation profiles in SSA/P and MSI-H CRC. TSA also revealed aberrant methylation pattern, but clustered more heterogeneously and closer to microsatellite stable (MSS) CRCs. SSA/P, TSA and MSI-H CRCs had the highest degree of promotor methylation (CIMP pathway). Chromosomal instability, in contrast to the established doctrine, is a common phenomenon in MSI CRCs, yet to a lower extent and at later stages than in MSS CRCs. Methylation analyses suggest that SSA/P are precursors for MSI-H CRCs and follow the CIMP pathway.
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http://dx.doi.org/10.1002/ijc.27869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542204PMC
April 2013

Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals.

Gene 2011 Aug 4;481(2):83-92. Epub 2011 May 4.

Ganymed Pharmaceuticals AG, Freiligrathstr. Mainz, Germany.

Claudin-18 isoform 2 (CLDN18.2) is one of the few members of the human claudin family of tight junction molecules with strict restriction to one cell lineage. The objective of the current study was to compare molecular structure and tissue distribution of this gastrocyte specific molecule in mammals. We show here that the CLDN18.2 protein sequence is highly conserved, in particular with regard to functionally relevant domains in mouse, rat, rabbit, dog, monkey and human and also in lizards. Moreover, promoter regions of orthologs are highly homologous, including the binding site of the transcription factor cyclic AMP-responsive element binding protein (CREB), which is known to regulate activation of human CLDN18.2. Employing RT-PCR and immunohistochemistry, we found that, analogous to the human gene, all orthologous CLDN18.2 transcripts and proteins are exclusively expressed in differentiated gastric cells. Gene structure, promoter elements and RNA expression pattern of the lung-tissue specific Claudin-18 isoform 1 (CLDN18.1) as well, are homologous across species. These findings exemplify phylogenetic conservation of lineage-specific members of a multigene family. Given that CLDN18.2 is a novel drug target candidate, our data is also relevant for drug development as it reveals all six investigated mammalian species as suitable models for testing safety of CLDN18.2 targeting regimen.
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http://dx.doi.org/10.1016/j.gene.2011.04.007DOI Listing
August 2011

Primary follicular lymphoma of the duodenum is a distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases.

J Clin Oncol 2011 Apr 7;29(11):1445-51. Epub 2011 Mar 7.

Medical University Vienna, Vienna General Hospital, Vienna, Austria.

Purpose: Small series with limited follow-up have suggested primary follicular lymphoma of the duodenum (FL-D) to be an indolent disease. We report our experience on a large series of patients followed for a median time period of longer than 6 years.

Patients And Methods: The study comprised 63 patients with primary FL-D defined as stage I disease. Endoscopy and detailed pathologic work-up was performed at diagnosis and at restaging to monitor the behavior of the neoplastic process.

Results: Histologically, all 63 patients had FL, low grade (1 to 2). Duodenal endosonography demonstrated lesions confined to mucosa/submucosa in 19 of 20 patients. At an overall median follow-up of 77 months (range, 12 to 177 months), only two untreated patients had developed nodal disease, the remaining 61 patients never experienced extrasmall intestinal disease and large cell transformation did not occur at all. Among 24 patients followed by watch and wait strategy, seven showed spontaneous complete regression and 17 had stable disease; radiotherapy resulted in complete regression in all 19 patients; anti-CD20 antibody monotherapy achieved complete regression in four patients and stable disease in one patient. Various chemotherapy protocols in eight patients caused complete regression in all of them, but local relapses occurred in three. No patients required surgery or died of disease.

Conclusion: These findings characterize primary FL-D as a remarkably indolent FL variant, which, even left untreated, does not develop tumorous growth, very rarely disseminates (two of 63 patients) and does not transform to high grade disease. A watch and wait approach appears to be the most sensible strategy.
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http://dx.doi.org/10.1200/JCO.2010.32.9193DOI Listing
April 2011

ERG rearrangement in small cell prostatic and lung cancer.

Histopathology 2010 Jun;56(7):937-43

Institute of Pathology, University Hospital Tuebingen, Tuebingen, Germany.

Aims: Small cell prostatic cancer is a rare but aggressive disease. Currently, its histogenetic origin is unclear and its distinction from metastatic small cell lung cancer is challenging. The aim of our study was to determine whether the ERG rearrangement commonly observed in acinar prostatic cancer can distinguish small cell prostatic cancer from small cell lung cancer samples.

Methods And Results: We assessed 15 small cell prostatic cancers and 22 small cell lung cancers for ERG rearrangement using fluorescence in situ hybridization. Commonly used and novel immunohistochemical markers (i.e. androgen receptor, calcium activated nucleotidase 1, Golgi phosphoprotein 2, prostate-specific antigen, prostate-specific membrane antigen, CD56, epithelial membrane antigen, thyroid transcription factor 1, chromogranin A, synaptophysin and Ki67) were further studied. ERG rearrangement occurred in 86% of small cell prostatic cancers but in none of the small cell lung cancers and was the best marker to differentiate between both tumours (P < 0.0001).

Conclusions: The ERG rearrangement is commonly observed in small cell prostatic cancer, supporting the hypothesis that ERG rearrangement occurs in aggressive prostatic cancers. Furthermore, the ERG rearrangement is the most significant marker to differentiate between small cell prostatic cancer and small cell lung cancer. Moreover, our data suggest that small cell prostatic cancer is not a tumour entity on its own, but a dedifferentiated variant of common acinar prostatic cancer.
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http://dx.doi.org/10.1111/j.1365-2559.2010.03564.xDOI Listing
June 2010

Selective activation of trophoblast-specific PLAC1 in breast cancer by CCAAT/enhancer-binding protein beta (C/EBPbeta) isoform 2.

J Biol Chem 2009 Oct 3;284(42):28607-15. Epub 2009 Aug 3.

Department of Internal Medicine III, Experimental and Translational Oncology, Johannes Gutenberg University, 55131 Mainz, Germany.

The trophoblast-specific gene PLAC1 (placenta-specific 1) is ectopically expressed in a wide range of human malignancies, most frequently in breast cancer, and is essentially involved in cancer cell proliferation, migration, and invasion. Here we show that basal activity of the PLAC1 promoter is selectively controlled by ubiquitous transcription factor SP1 and isoform 2 of CCAAT/enhancer-binding protein beta that we found to be selectively expressed in placental tissue and cancer cells. Binding of both factors to their respective elements within the PLAC1 promoter was essential to attain full promoter activity. Estrogen receptor alpha (ERalpha) signaling further augmented transcription and translation of PLAC1 and most likely accounts for the positive correlation between PLAC1 expression levels and the ERalpha status we observed in primary breast cancer specimens. DNA affinity precipitation and chromatin immunoprecipitation assays revealed that transactivation of the PLAC1 promoter by ligand-activated ERalpha is based on a nonclassical pathway independent of estrogen-response elements, by tethering of ERalpha to DNA-bound CCAAT/enhancer-binding protein beta-2, and SP1. Our findings provide first insight into a novel and hitherto unknown regulatory mechanism governing selective activation of trophoblast-specific gene expression in breast cancer.
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http://dx.doi.org/10.1074/jbc.M109.031120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781404PMC
October 2009

Budesonide is effective in treating lymphocytic colitis: a randomized double-blind placebo-controlled study.

Gastroenterology 2009 Jun 17;136(7):2092-100. Epub 2009 Mar 17.

Medical Department I, Technical University Hospital, Dresden, Germany.

Background & Aims: Budesonide is effective in treating collagenous colitis, but no treatment is established for lymphocytic colitis. We performed a randomized, double-blind, placebo-controlled study to evaluate the effects of budesonide in patients with lymphocytic colitis.

Methods: Forty-two patients (median age, 61 years) with lymphocytic colitis and chronic diarrhea were randomly assigned to groups that were given oral doses of budesonide (9 mg/d) or placebo for 6 weeks. Nonresponders at week 6 were given open-label budesonide (9 mg/d) for 6 additional weeks. A complete colonoscopy and histologic and quality-of-life analyses were performed at baseline and at week 6. The primary end point was clinical remission at 6 weeks, with last observation carried forward (LOCF). All patients who left the study in clinical remission were followed for relapse.

Results: At week 6, 86% of patients given budesonide were in clinical remission (with LOCF) compared with 48% of patients given placebo (P = .010). Furthermore, open-label budesonide therapy induced clinical remission in 7 of 8 patients given placebo. Histologic remission was observed in 73% of patients given budesonide compared with 31% given placebo (P = .030). Only 1 patient discontinued budesonide therapy prematurely. During a mean follow-up period of 14 months, 15 patients (44.1%) experienced a clinical relapse (after a mean of 2 months); 8 of the relapsing patients were retreated with and responded again to budesonide.

Conclusions: Budesonide effectively induces clinical remission in patients with lymphocytic colitis and significantly improves histology results after 6 weeks. Clinical relapses occur but can be treated again with budesonide.
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http://dx.doi.org/10.1053/j.gastro.2009.02.078DOI Listing
June 2009

Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development.

Clin Cancer Res 2008 Dec;14(23):7624-34

Ganymed Pharmaceuticals, Johannes Gutenberg University, Mainz, Germany.

Purpose: Antibody-based cancer therapies have emerged as the most promising therapeutics in oncology. The purpose of this study was to discover novel targets for therapeutic antibodies in solid cancer.

Experimental Design: We combined data mining and wet-bench experiments to identify strictly gastrocyte lineage-specific cell surface molecules and to validate them as therapeutic antibody targets.

Results: We identified isoform 2 of the tight junction molecule claudin-18 (CLDN18.2) as a highly selective cell lineage marker. Its expression in normal tissues is strictly confined to differentiated epithelial cells of the gastric mucosa, but it is absent from the gastric stem cell zone. CLDN18.2 is retained on malignant transformation and is expressed in a significant proportion of primary gastric cancers and the metastases thereof. In addition to its orthotopic expression, we found frequent ectopic activation of CLDN18.2 in pancreatic, esophageal, ovarian, and lung tumors, correlating with distinct histologic subtypes. The activation of CLDN18.2 depends on the binding of the transcription factor cyclic AMP-responsive element binding protein to its unmethylated consensus site. Most importantly, we were able to raise monoclonal antibodies that bind to CLDN18.2 but not to its lung-specific splice variant and recognize the antigen on the surface of cancer cells.

Conclusions: Its highly restricted expression pattern in normal tissues, its frequent ectopic activation in a diversity of human cancers, and the ability to specifically target this molecule at the cell surface of tumor cells qualify CLDN18.2 as a novel, highly attractive pan-cancer target for the antibody therapy of epithelial tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-1547DOI Listing
December 2008

Persistent diarrhea.

J Gastrointestin Liver Dis 2008 Sep;17(3):327-8

Department of Medicine, Klinikum of the Sozialstiftung, Bamberg, Germany.

A 63-year-old man presented with massive diarrhea and weight loss. This was preceded by nonspecific symptoms for three years, which resembled sarcoidosis. By duodenal biopsy, the diagnosis of Whipples disease was confirmed. Antibiotic treatment resulted in rapid and complete disappearance of signs and symptoms.
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September 2008

In silico strategy for detection of target candidates for antibody therapy of solid tumors.

Gene 2008 May 19;414(1-2):76-84. Epub 2008 Feb 19.

Ganymed Pharmaceuticals AG, Mainz, Germany.

In contrast to earlier attempts for the identification of target candidates suitable for monoclonal antibody (mAb) based cancer therapies we concentrated on highly selective lineage-specific genes additionally preserved or even overexpressed in orthotopic cancers. In a script aided workflow we reduced all human entries of the RefSeq mRNA database to those encoding transmembrane domain bearing gene products and subjected them to BLAST analysis against the human EST database. All BLAST results were validated in a gene centric way allowing two types of data curation prior to expression profiling of matching ESTs in selected healthy tissues: (i) exclusion of questionable ESTs arising e.g. from genomic contamination and (ii) elimination of erroneously predicted mRNAs as well as transcripts with only weak EST coverage. The impact of such stringent input control on accuracy of prediction is underlined by RT-PCR confirmation of predicted tissue distribution patterns for a number of selected candidates.
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http://dx.doi.org/10.1016/j.gene.2008.02.009DOI Listing
May 2008

A placenta-specific gene ectopically activated in many human cancers is essentially involved in malignant cell processes.

Cancer Res 2007 Oct;67(19):9528-34

Department of Internal Medicine III, Division of Experimental and Translational Oncology, Johannes Gutenberg University, Mainz, Germany.

The identification and functional characterization of tumor-specific genes is a prerequisite for the development of targeted cancer therapies. Using an integrated data mining and experimental validation approach for the discovery of new targets for antibody therapy of cancer, we identified PLAC1. PLAC1 is a placenta-specific gene with no detectable expression in any other normal human tissue. However, it is frequently aberrantly activated and highly expressed in a variety of tumor types, in particular breast cancer. RNAi-mediated silencing of PLAC1 in MCF-7 and BT-549 breast cancer cells profoundly impairs motility, migration, and invasion and induces a G1-S cell cycle block with nearly complete abrogation of proliferation. Knockdown of PLAC1 is associated with decreased expression of cyclin D1 and reduced phosphorylation of AKT kinase. Moreover, PLAC1 is localized on the surface of cancer cells and is accessible for antibodies which antagonize biological functions of this molecule. These features, in summary, make PLAC1 an attractive candidate for targeted immunotherapeutic approaches.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-1350DOI Listing
October 2007

Conclusions from the histological diagnosis of low-grade intraepithelial neoplasia in Barrett's oesophagus.

Scand J Gastroenterol 2007 Jun;42(6):682-8

Department of Medicine II, HSK Wiesbaden, Teaching Hospital of the University of Mainz, Germany.

Objective: It is well known that low-grade intraepithelial neoplasia (LGIN) in Barrett's oesophagus (BE) might progress to high-grade intraepithelial neoplasia (HGIN) or carcinoma. Since accurate diagnosis of LGIN is difficult, general pathologists are frequently uncertain about the diagnosis of LGIN and its follow-up risks. The purpose of this study was to analyse the divergence between the diagnoses of general and specialized gastrointestinal pathologists.

Material And Methods: Fifty consecutive patients with a previous diagnosis of LGIN in BE, made by a general pathologist, were included in our study. The histopathological slides of every patient were reassessed in a blinded fashion by two specialized gastrointestinal (GI) pathologists. Inter-observer variability was calculated using kappa statistics.

Results: LGIN was confirmed by specialized pathologists in only 25/50 patients (50%). Twenty-one patients (42%) had Barrett's metaplasia without intraepithelial neoplasia and in 4 patients (8%) HGIN or Barrett's carcinoma (BC) was revealed. Inter-observer agreement between the general and specialized pathologists for the diagnosis of LGIN was poor (kappa = - 0.17) and good between both of the specialized pathologists (kappa = 0.69). Patients with HGIN/BC were treated by endoscopic resection or surgery. In patients with LGIN, ablative therapy was performed. Complete response was achieved in 25 patients, but 3 patients developed HGIN and 1 patient developed BC after 10+/-3.6 months.

Conclusions: BE with LGIN is difficult to diagnose. Inter-observer variability is unacceptable between general and specialized pathologists and therefore when diagnosing LGIN a second opinion should always be sought by a specialized GI pathologist. Ablation therapy seems to be effective in patients with LGIN, but follow-up endoscopies are necessary to detect metachronous neoplasia.
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http://dx.doi.org/10.1080/00365520601075803DOI Listing
June 2007

Expression of multiple epigenetically regulated cancer/germline genes in nonsmall cell lung cancer.

Int J Cancer 2006 May;118(10):2522-8

Department of Internal Medicine III, Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany, and University Hospital Ghent, Belgium.

Cancer/germline (CG) antigens represent promising targets for widely applicable mono- and multiantigen cancer vaccines for nonsmall cell lung cancer (NSCLC). Since little is known about their composite expression in this tumor type, we analyzed 7 CG genes (MAGE-A3, NY-ESO-1, LAGE-1, BRDT, HOM-TES-85, TPX-1 and LDHC) in 102 human NSCLC specimens. About 81% of NSCLC express at least 1 and half of the specimen at least 2 CG genes. Activation of most of these genes occurs more frequently in squamous cell cancer than in adenocarcinomas. Even though we found all genes but one to be regulated by genomic methylation, not all of them are co-expressed. In particular, combining CG genes not localized on the X-chromosome may provide effective treatment for an extended number of patients.
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http://dx.doi.org/10.1002/ijc.21669DOI Listing
May 2006

Frequent nonrandom activation of germ-line genes in human cancer.

Cancer Res 2004 Sep;64(17):5988-93

Department of Internal Medicine III, Johannes-Gutenberg University, Mainz, Germany.

The growing class of cancer/germ-line genes is characterized by a unique expression pattern with transcription restricted to germ cells and cancer cells. It is not known which fraction of germ-line genes is ectopically activated in tumor cells and whether this fraction displays common features as compared with strictly germ-line genes remaining silent in cancer. Using an unbiased genome-wide scanning approach, representative samples of both cancer/germ-line genes as well as strictly germ-line-specific genes were determined. Comparative analysis disclosed highly significant diametric characteristics for these two categories of genes with regard to sex specificity, developmental stage of physiological expression during gametogenesis, chromosomal localization, and epigenetic regulation of expression. Our findings provide class predictors for germ cell-specific gene activation in cancer. The identification of highly congruent expression patterns in cancer and in DNA methyltransferase-deficient cells suggests an underlying common epigenetic mechanism for activation of germ-line genes in cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-04-1187DOI Listing
September 2004

Frequent nonrandom activation of germ-line genes in human cancer.

Cancer Res 2004 Sep;64(17):5988-93

Department of Internal Medicine III, Johannes-Gutenberg University, Mainz, Germany.

The growing class of cancer/germ-line genes is characterized by a unique expression pattern with transcription restricted to germ cells and cancer cells. It is not known which fraction of germ-line genes is ectopically activated in tumor cells and whether this fraction displays common features as compared with strictly germ-line genes remaining silent in cancer. Using an unbiased genome-wide scanning approach, representative samples of both cancer/germ-line genes as well as strictly germ-line-specific genes were determined. Comparative analysis disclosed highly significant diametric characteristics for these two categories of genes with regard to sex specificity, developmental stage of physiological expression during gametogenesis, chromosomal localization, and epigenetic regulation of expression. Our findings provide class predictors for germ cell-specific gene activation in cancer. The identification of highly congruent expression patterns in cancer and in DNA methyltransferase-deficient cells suggests an underlying common epigenetic mechanism for activation of germ-line genes in cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-04-1187DOI Listing
September 2004

Assessing optimal promoter activity for constructs in gastrointestinal gene therapy.

Anticancer Res 2003 Sep-Oct;23(5A):4011-5

Division of Molecular Genetics, University of Tübingen, Wilhelmstr 27, D-72074 Tübingen, Germany.

Background: During recent decades, studies of various cancer-related genes has led to a growing understanding of molecular mechanisms of gastrointestinal cancer resulting in a genetic progression model. Nevertheless, with a few exceptions, our knowledge of participating genes has not been exploited for gene therapeutic approaches. Therefore, we monitored the promoter activity of genes shown to be significantly expressed in gastrointestinal tumors to select optimally active promoters for recombinant DNA constructs. Such molecules will contain a suicide gene under a suitable cell type-specific regulatory element.

Materials And Methods: Using promoter-reporter gene (luciferase) constructs we compared the activities of KRT19, TFF1, SEL1L, MUC4, MUC1, CEL and hTERT by transfecting them into the gastrointestinal cell lines MKN45 and DAN-G for transient expression. Furthermore we tested the endogenous expression of these genes by RT-PCR.

Results: From a selection of 9 promoter constructs SEL1L, KRT19 and MUC1 displayed the highest activity levels while others were moderately expressed.

Conclusion: These three appear the most capable ones to drive suicide genes, like thymidine kinase or cytosine deaminase, a study presently initiated.
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February 2004

Pattern of lipofuscin pigmentation in nitrergic and non-nitrergic, neurofilament immunoreactive myenteric neuron types of human small intestine.

Histochem Cell Biol 2004 Jan 9;121(1):13-20. Epub 2003 Dec 9.

Institute of Anatomy I, University of Erlangen-Nuremberg, Krankenhausstrasse 9, 91054, Erlangen, Germany.

Lipofuscin, an autofluorescent age pigment, occurs in enteric neurons. Due to its broad excitation and emission spectra, it overlaps with commonly used fluorophores in immunohistochemistry. We investigated the pattern of lipofuscin pigmentation in neurofilament (NF)-reactive nitrergic and non-nitrergic human myenteric neuron types. Subsequently, we tested two methods for reduction of lipofuscin-like autofluorescence. Myenteric plexus/longitudinal muscle wholemounts of small intestines of five patients undergoing surgery for carcinoma (aged between 18 and 69 years) were double stained for NF and neuronal nitric oxide synthase (nNOS). Lipofuscin pigmentation patterns were semiquantitatively evaluated by using confocal laser scanning microscopy with three different excitation wave lengths (one for undisturbed lipofuscin autofluorescence and two for specific labellings). Two pigmentation patterns could be detected in the five NF-reactive neuron types investigated. In nitrergic/spiny as well as in non-nitrergic/stubby neurons, coarse, intensely autofluorescent pigment granules were prominent. In non-nitrergic type II, III and V neurons, a fine granular, diffusely distributed and less intensely autofluorescent pigment was obvious. After incubation of wholemounts in either CuSO(4) or Sudan black B solutions, unspecific autofluorescence could be substantially reduced whereas specific NF and nNOS fluorescence remained largely unaffected. We conclude that NF immunohistochemistry is useful for morphological representation of subpopulations of human myenteric neurons. The lipofuscin pigmentation in human myenteric neurons reveals at least two different patterns which can be related to distinct neuron types. Incubations of multiply stained whole mounts in both CuSO(4) or Sudan black B are suitable methods for reducing autofluorescence thus facilitating discrimination between specific (immunohistochemical) and non-specific (lipofuscin) fluorescence.
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http://dx.doi.org/10.1007/s00418-003-0603-7DOI Listing
January 2004

The pro-apoptotic FAS-associated factor 1 is specifically reduced in human gastric carcinomas.

Int J Oncol 2003 Oct;23(4):1015-23

University of Southern Denmark, Institute for Biochemistry and Molecular Biology, DK-5230 Odense, Denmark.

The Fas-associated factor 1, FAF1, is a protein, which was first identified as an interaction partner of the death receptor Fas. Not much is known about the function of FAF1, but it has been found that it is able to potentiate Fas-induced apoptosis in cell lines. To clarify the role of FAF1 in human cancer, a number of tumors from different organs were screened for expression of the protein, and it was only found reduced in gastric carcinoma tissue. Thus, 58 human gastric carcinomas were collected, and the expression of FAF1 was analyzed by Western blotting and in a few cases also by immunohistochemistry. The hypothesis was that since FAF1 is able to potentiate apoptosis, it would likely be reduced in the gastric carcinomas in order for them to escape apoptosis. We found that FAF1 was reduced in 50% (29/58) of the gastric carcinomas analyzed as compared to non-neoplastic gastric mucosa from the same patients. 26 of the investigated carcinomas contained signet ring cells, and FAF1 was significantly reduced in 69% of these (p=0.017), whereas it was only reduced in 34% of the carcinomas without signet ring cells. The observed reduction of FAF1 was predominantly caused by proteolytic cleavage of the protein. Additionally, 31 colorectal carcinomas were analyzed for expression of FAF1. Here, FAF1 was only reduced in 16% of the carcinomas when compared to non-neoplastic colorectal mucosa. Our findings support the hypothesis that FAF1 is reduced in gastric carcinomas compared to non-neoplastic tissue, and there was a significant relation between FAF1 reduction and content of signet ring cells in the gastric carcinomas. Also, the reduction of FAF1 is likely to be specific for gastric cancer, which might be due to the fact that signet ring cells are most frequently found in gastric cancers.
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October 2003

Hepatitis induced by Kava (Piper methysticum rhizoma).

J Hepatol 2003 Jul;39(1):62-7

Department of Medicine I, Friedrich-Alexander-University Erlangen-Nuremberg, Ulmenweg 18, D-91054 Erlangen, Germany.

Background/aims: Botanical drugs are widely used and often contain highly active compounds. Kava root (Piper methysticum rhizoma), used frequently in Europe as a remedy against anxiety, contains kavapyrones with sedative effects. Seven case reports suggested the development of hepatitis after the intake of Kava.

Methods: We analyzed 29 novel cases of hepatitis along with Kava ingestion which occurred between 1990 and 2002 in addition to the seven already published case reports using a clinical diagnostic scale established for adverse hepatic drug reactions.

Results: Hepatic necrosis or cholestatic hepatitis were noticed with both alcoholic and acetonic Kava extracts. The majority of the 29 patients and the additional seven published reports were women (27 females, nine males). Both the cumulative dose and the latency to when the hepatotoxic reaction emerged were highly variable. Nine patients developed fulminant liver failure, of which eight patients underwent liver transplantation. Three patients died, two following unsuccessful liver transplantation and one without. In all other patients, a complete recovery was noticed after the withdrawal of Kava. Pathophysiologically, both immunoallergic and idiosyncratic factors may be responsible.

Conclusions: The present report emphasizes the potentially severe hepatotoxicity of Kava which has recently led to the retraction of Kava-containing drugs by the pharmacovigilance authorities in Germany.
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http://dx.doi.org/10.1016/s0168-8278(03)00175-2DOI Listing
July 2003

Computational dissection of tissue contamination for identification of colon cancer-specific expression profiles.

FASEB J 2003 Mar;17(3):376-85

III. Medizinische Klinik und Poliklinik, Johannes Gutenberg Universität Mainz, D-55131 Mainz, Germany.

Microarray profiles of bulk tumor tissues reflect gene expression corresponding to malignant cells as well as to many different types of contaminating normal cells. In this report, we assess the feasibility of querying baseline multitissue transcriptome databases to dissect disease-specific genes. Using colon cancer as a model tumor, we show that the application of Boolean operators (AND, OR, BUTNOT) for database searches leads to genes with expression patterns of interest. The BUTNOT operator for example allows the assignment of "expression signatures" to normal tissue specimens. These expression signatures were then used to computationally identify contaminating cells within conventionally dissected tissue specimens. The combination of several logic operators together with an expression database based on multiple human tissue specimens can resolve the problem of tissue contamination, revealing novel cancer-specific gene expression. Several markers, previously not known to be colon cancer associated, are provided.
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http://dx.doi.org/10.1096/fj.02-0478comDOI Listing
March 2003

Multiple splice variants of lactate dehydrogenase C selectively expressed in human cancer.

Cancer Res 2002 Nov;62(22):6750-5

Department of Internal Medicine, University Mainz, 55131 Mainz, Germany.

We applied a combined data mining and experimental validation Approach for the discovery of germ cell-specific genes aberrantly expressed in cancer. Six of 21 genes with confirmed germ cell specificity were detected in tumors, indicating that ectopic activation of testis-specific genes in cancer is a frequent phenomenon. Most surprisingly one of the genes represented lactate dehydrogenase C (LDHC), the germ cell-specific member of the lactate dehydrogenase family. LDHC escapes from transcriptional repression, resulting in significant expression levels in virtually all tumor types tested. Moreover, we discovered aberrant splicing of LDHC restricted to cancer cells, resulting in four novel tumor-specific variants displaying structural alterations of the catalytic domain. Expression of LDHC in tumors is neither mediated by gene promotor demethylation, as previously described for other germ cell-specific genes activated in cancer, nor induced by hypoxia as demonstrated for enzymes of the glycolytic pathway. LDHC represents the first lactate dehydrogenase isoform with restriction to tumor cells. In contrast to other LDH isoenzymes, LDHC has a preference for lactate as a substrate. Thus LDHC activation in cancer may provide a metabolic rescue pathway in tumor cells by exploiting lactate for ATP delivery.
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November 2002

Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett's oesophagus: acute-phase and intermediate results of a new treatment approach.

Eur J Gastroenterol Hepatol 2002 Oct;14(10):1085-91

Department of Internal Medicine II, Dr Horst Schmidt Kliniken, Ludwig-Erhard-Strasse 100, 65199 Wiesbaden, Germany.

Background: Radical oesophageal resection has until now been regarded as the gold standard for treatment in intraepithelial high-grade neoplasia or early adenocarcinoma of the oesophagus. However, the mortality and morbidity rates are substantial.

Design: A new therapeutic approach involving low-risk endoscopic therapy modalities was examined in the framework of a prospective study.

Patients: A total of 115 patients with intraepithelial high-grade neoplasia (19) and early adenocarcinoma (96) in Barrett's oesophagus.

Methods: Endoscopic mucosal resection (EMR) was used in 70 patients, and photodynamic therapy (PDT) was used in 32 patients. The two procedures were combined in ten patients. Three patients underwent primary treatment with argon plasma coagulation (APC). The average follow-up was 34 +/- 10 months (range 24-60 months).

Results: Complete local remission was achieved in 98%. The overall complication rate was 9.5%. Major complications, such as perforation and severe bleeding, did not occur. Minor complications included not haemoglobin relevant bleeding (drop of haemoglobin less than 2 g/dl) (5) and stenosis (3) after EMR, and long-lasting odynophagia (1) and sunburn (2) after PDT. In all, 13 patients have died so far, but in only one case due to the underlying disease. The calculated overall 3-year survival rate is 88%. During the follow-up period, a 30% rate of metachronous lesions was observed; endoscopic therapy was performed successfully in all but one of these patients.

Conclusions: These good acute-phase and intermediate results, along with low morbidity rates and no mortality, suggest that the organ-preserving local endoscopic procedure including EMR and PDT is an attractive alternative to oesophageal resection. Therefore, endoscopic therapy might replace radical oesophageal resection in future in cases of intraepithelial high-grade neoplasia and early mucosal adenocarcinoma in Barrett's oesophagus.
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http://dx.doi.org/10.1097/00042737-200210000-00009DOI Listing
October 2002
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