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2. Standardization through education of molecular pathology: a spotlight on the European Masters in Molecular Pathology

Author

Ilié, Marius, Lake, Vivien, de Alava, Enrique, Bonin, Serena, Chlebowski, Sandra, Delort, Aurélie, Dequeker, Elisabeth, Al-Dieri, Raed, Diepstra, Arjan, Carpén, Olli, Eloy, Catarina, Fassina, Ambrogio, Fend, Falko, Fernandez, Pedro L., Gorkiewicz, Gregor, Heeke, Simon, Henrique, Rui, Hoefler, Gerald, Huertas, Pablo, Hummel, Michael, Kashofer, Karl, van der Laak, Jeroen, de Pablos, Rocio Martinez, Schmitt, Fernando, Schuuring, Ed, Stanta, Giorgio, Timens, Wim, Westphalen, Benedikt, and Hofman, Paul

Published
2024
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3. Acquisition of Genetic Aberrations During the Progression of High-Grade Intraepithelial Lesions/Micro-Invasive Squamous Cancers to Widely Invasive Cervical Squamous Cell Cancer

Author

Kashofer, Karl, Reich, Olaf, and Regauer, Sigrid

Subjects
Thermo Fisher Scientific Inc. -- Mergers, acquisitions and divestments, Scientific equipment and supplies industry -- Mergers, acquisitions and divestments -- Analysis, Papillomavirus infections -- Genetic aspects -- Development and progression -- Analysis, Company acquisition/merger, Health
Abstract

* Context.--Acquisition of genetic aberrations during cervical carcinogenesis in individual patients is poorly documented. Objective.--To provide a comparative analysis of high-grade squamous intraepithelial lesions (n = 7) and pT1a squamous cancers (n = 1) and their recurrences, subsequent widely invasive cancers, and metastases developed during 1-24 years. Design.--Archival tissues of 8 patients were analyzed immunohistochemically for reserve-cell origin, human papillomavirus genotypes, mutations in 50 cancer genes, and chromosomal copy number variations. Results.--Intraepithelial lesions arose either from cytokeratin 17- or 7-expressing reserve cells. All preinvasive and invasive tumors carried human papillomavirus high-risk genotypes and lacked somatic mutations. Chromosomal copy number variations were identified in all intraepithelial lesions and invasive cancers. Four of 8 high-grade intraepithelial lesions progressed to invasive cancer after incomplete treatment, and 4 of 8 invasive cancers arose de novo after in sano resection. Four of 8 cancers carried mutations with high mutational frequency (PIK3CA E545K [n = 2]; PIK3CA and SMAD1 [n = 1]; HRAS, RB1, and EGFR [n = 1]), as did their corresponding regional metastases. One nonmetastasized cancer had a subclonal PIK3CA mutation, and an initially nonmutated, low-stage cancer developed ovarian metastases with PIK3CA amplification. One patient had neither mutations nor metastases. The patient with treated PIK3CA E545K-mutated pT1a cancer developed a subsequent nonmutated intraepithelial lesion that progressed to invasive cancer with a subclonal PIK3CA-H1047R mutation. Cancer-related deaths in 4 of 8 (50%) patients occurred independent of mutational status or metastatic disease. Conclusions.--Recurrences arose after persistent or de novo human papillomavirus infection of residual reserve cells or squamous metaplasia. Activating driver mutations were identified in invasive cancers only. High mutational load correlated with metastases, which in turn represented clonal disease. (Arch Pathol Lab Med. 2023;147:1438-1445; doi: 10.5858/arpa.2022-0310-OA), The natural course and temporal sequence of genetic events in progression from high-grade squamous intraepithelial lesion (HSIL) to invasive and metastatic cancer in individual patients is poorly documented. Numerous publications [...]

Published
2023
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8. Host and microbiome features of secondary infections in lethal covid-19

Author

Zacharias, Martin, Kashofer, Karl, Wurm, Philipp, Regitnig, Peter, Schütte, Moritz, Neger, Margit, Ehmann, Sandra, Marsh, Leigh M., Kwapiszewska, Grazyna, Loibner, Martina, Birnhuber, Anna, Leitner, Eva, Thüringer, Andrea, Winter, Elke, Sauer, Stefan, Pollheimer, Marion J., Vagena, Fotini R., Lackner, Carolin, Jelusic, Barbara, Ogilvie, Lesley, Durdevic, Marija, Timmermann, Bernd, Lehrach, Hans, Zatloukal, Kurt, and Gorkiewicz, Gregor

Published
2022
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11. Rapid Antigen Test for Postmortem Evaluation of SARS-CoV-2 Carriage

Author

Zacharias, Martin, Stangl, Verena, Thuringer, Andrea, Loibner, Martina, Wurm, Philipp, Wolfgruber, Stella, Zatloukal, Kurt, Kashofer, Karl, and Gorkiewicz, Gregor

Subjects
Autopsy -- Methods, Immune system -- Testing, Polymerase chain reaction -- Usage, Health
Abstract

Rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential to prevent viral dissemination. Rapid antigen tests (RATs) have recently been approved and are now widely used in [...]

Published
2021
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12. The Influence of Proton Pump Inhibitors on the Fecal Microbiome of Infants with Gastroesophageal Reflux-A Prospective Longitudinal Interventional Study.

Author

Castellani, Christoph, Singer, Georg, Kashofer, Karl, Huber-Zeyringer, Andrea, Flucher, Christina, Kaiser, Margarita, and Till, Holger

Subjects
Clostridium difficile, GERD, infants, microbiome, proton pump inhibitors, Clostridioides difficile, Clostridium Infections, Esomeprazole, Feces, Female, Gastroesophageal Reflux, Humans, Infant, Longitudinal Studies, Male, Microbiota, Prospective Studies, Proton Pump Inhibitors, Statistics, Nonparametric, Time Factors
Abstract

Proton pump inhibitors (PPIs) are the standard therapy for gastroesophageal reflux disease. In adults, PPI treatment is associated with Clostridium difficile infections (CDI). In contrast to adults the microbiome of infants develops from sterility at birth toward an adult-like profile in the first years of life. The effect of PPIs on this developing microbiome has never been studied. The aim of the present study was to determine the effect of oral PPIs on the fecal microbiome in infants with gastroesophageal reflux disease (GERD). In this prospective longitudinal study 12 infants with proven GERD received oral PPIs for a mean period of 18 weeks (range 8-44). Stool samples were collected before (before PPI) and 4 weeks after initiation of PPI therapy (on PPI). A third sample was obtained 4 weeks after PPI discontinuation (after PPI). The fecal microbiome was determined by NGS based 16S rDNA sequencing. This trial was registered with clinicaltrials.gov (NCT02359604). In a comparison of before PPI and on PPI neither α- nor β-diversity changed significantly. On the genus level, however, the relative abundances showed a decrease of Lactobacillus and Stenotrophomonas and an increase of Haemophilus. After PPI therapy there was a significant increase of α- and β-diversity. Additionally, the relative abundances of the phyla Firmicutes, Bacteroidetes, and Proteobacteria were significantly changed and correlated to patients age and the introduction of solid foods. PPI treatment has only minor effects on the fecal microbiome. After discontinuation of PPI treatment the fecal microbiome correlated to patients age and nutrition.

Published
2017

20. Characterisation of Candida within the Mycobiome/Microbiome of the Lower Respiratory Tract of ICU Patients.

Author

Krause, Robert, Halwachs, Bettina, Thallinger, Gerhard G, Klymiuk, Ingeborg, Gorkiewicz, Gregor, Hoenigl, Martin, Prattes, Jürgen, Valentin, Thomas, Heidrich, Katharina, Buzina, Walter, Salzer, Helmut JF, Rabensteiner, Jasmin, Prüller, Florian, Raggam, Reinhard B, Meinitzer, Andreas, Moissl-Eichinger, Christine, Högenauer, Christoph, Quehenberger, Franz, Kashofer, Karl, and Zollner-Schwetz, Ines

Subjects
Mouth, Respiratory System, Humans, Candida, Candidiasis, Pneumonia, Anti-Bacterial Agents, Risk Factors, Phylogeny, Aged, Middle Aged, Intensive Care Units, Female, Male, High-Throughput Nucleotide Sequencing, Microbiota, Mycobiome, General Science & Technology
Abstract

Whether the presence of Candida spp. in lower respiratory tract (LRT) secretions is a marker of underlying disease, intensive care unit (ICU) treatment and antibiotic therapy or contributes to poor clinical outcome is unclear. We investigated healthy controls, patients with proposed risk factors for Candida growth in LRT (antibiotic therapy, ICU treatment with and without antibiotic therapy), ICU patients with pneumonia and antibiotic therapy and candidemic patients (for comparison of truly invasive and colonizing Candida spp.). Fungal patterns were determined by conventional culture based microbiology combined with molecular approaches (next generation sequencing, multilocus sequence typing) for description of fungal and concommitant bacterial microbiota in LRT, and host and fungal biomarkes were investigated. Admission to and treatment on ICUs shifted LRT fungal microbiota to Candida spp. dominated fungal profiles but antibiotic therapy did not. Compared to controls, Candida was part of fungal microbiota in LRT of ICU patients without pneumonia with and without antibiotic therapy (63% and 50% of total fungal genera) and of ICU patients with pneumonia with antibiotic therapy (73%) (p

Published
2016

30. Expanding Broad Molecular Reflex Testing in Non-Small Cell Lung Cancer to Squamous Histology.

Author

Zacharias, Martin, Konjic, Selma, Kratochwill, Nikolaus, Absenger, Gudrun, Terbuch, Angelika, Jost, Philipp J., Wurm, Robert, Lindenmann, Jörg, Kashofer, Karl, Gollowitsch, Franz, Gorkiewicz, Gregor, and Brcic, Luka

Subjects
SQUAMOUS cell carcinoma, SMOKING, TUMOR markers, AGE distribution, RETROSPECTIVE studies, DESCRIPTIVE statistics, LONGITUDINAL method, DRUG approval, MEDICAL records, ACQUISITION of data, LUNG cancer, GENETIC mutation, MOLECULAR diagnosis, SEQUENCE analysis, EPIDERMAL growth factor receptors
Abstract

Simple Summary: Targeted therapies have revolutionized the treatment of patients with non-small cell lung cancer (NSCLC). Adenocarcinoma, the most common histological subtype of NSCLC, is the posterchild of this therapeutic approach because of its high rate of treatable targets. In our study, we provide evidence that squamous cell carcinoma (SCC), the second most common histological subtype of NSCLC, also harbors a significant number of treatable targets, although at a lower rate than adenocarcinoma. Furthermore, we show that most SCC patients harboring such an alteration were >50 years of age and current or former smokers, questioning restrictive molecular testing strategies. Based on our data, we propose that broad molecular profiling should be performed in all newly diagnosed NSCLC cases, irrespective of histological subtype, but also irrespective of age or smoking status. Due to the success story of biomarker-driven targeted therapy, most NSCLC guidelines agree that molecular reflex testing should be performed in all cases with non-squamous cell carcinoma (non-SCC). In contrast, testing recommendations for squamous cell carcinoma (SCC) vary considerably, specifically concerning the exclusion of patients of certain age or smoking status from molecular testing strategies. We performed a retrospective single-center study examining the value of molecular reflex testing in an unselected cohort of 316 consecutive lung SCC cases, tested by DNA- and RNA-based next-generation sequencing (NGS) at our academic institution between 2019 and 2023. Clinicopathological data from these cases were obtained from electronic medical records and correlated with sequencing results. In 21/316 (6.6%) cases, we detected an already established molecular target for an approved drug. Among these were seven cases with an EGFR mutation, seven with a KRAS G12C mutation, four with an ALK fusion, two with an EGFR fusion and one with a METex14 skipping event. All patients harboring a targetable alteration were >50 years of age and most of them had >15 pack-years, questioning restrictive molecular testing strategies. Based on our real-world data, we propose a reflex testing workflow using DNA- and RNA-based NGS that includes all newly diagnosed NSCLC cases, irrespective of histology, but also irrespective of age or smoking status. [ABSTRACT FROM AUTHOR]

Published
2024
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31. A distinct T cell receptor signature associates with cardiac outcome in myocardial infarction patients

Author

Le Gouge, Kenz, primary, Ashour, Diyaa, additional, Heinrichs, Margarete, additional, Stys, Paul, additional, Barennes, Pierre, additional, Stangl, Verena, additional, Rech, Lavinia, additional, Hoefler, Gerald, additional, Kashofer, Karl, additional, Gassenmaier, Tobias, additional, Boivin-Jahns, Valerie, additional, Jahns, Roland, additional, Hofmann, Ulrich, additional, Schmitt, Dominik, additional, Frey, Ann, additional, Stoerk, Stefan Stork, additional, Frantz, Stefan, additional, Rainer, Peter P, additional, Campos Ramos, Gustavo, additional, and Mariotti-Ferrandiz, Encarnita, additional

Published
2023
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34. Developmental potential of human haematopoietic stem cells in the NOD/Scid xenotransplantation model

Author

Kashofer, Karl

Subjects
617.954
Abstract

Early reports indicated cell engraftment from bone marrow transplants into non- hematopoietic tissues in mouse to mouse and in human allogeneic bone marrow transplants. To investigate the developmental potential of human stem cells I used xenotransplantation of stem cells purified from cord blood into a mouse model. Human stem cells introduced into the NOD/Scid mouse after partial myeloablation repopulate the bone marrow and contribute to the hematopoietic system of the mouse. Engraftment into the bone marrow was measured by FACS and human genetic material was found in the spleen, skin, lung and liver. Engraftment in the liver was studied with a variety of methods, ranging from PCR based assays to FISH analysis and immunohistochemistry. To allow better identification of human cells transduction with a lentivirus carrying the GFP gene was used. Liver damage has been suggested as one of the factors influencing homing of stem cells to the liver and transdifferentiation of bone marrow cells into hepatocytes. To assess the role of tissue damage a model of severe liver injury induced by CCU was utilised. Two stages of damage might be important in this context, damage during the process of homing, and damage during transdifferentiation both of which were studied. I demonstrate that stem cell homing to the liver is significantly increased upon liver injury. Human albumin and a-anti-trypsin messenger RNA is expressed in the livers of some animals by RT-PCR and large GFP positive hepatocytes and hepatocytes staining with HepPar-1, thought to be specific for human hepatocytes, are present. However, transdifferentiation defined as the emergence of mature human hepatocytes after bone marrow transplantation could not be found. A variety of methods used to determine the genetic identity in GFP positive hepatocytes only identified remnants of the human genome. In addition to small amounts of human DNA the murine Y chromosome and the murine TNFa locus were readily detected in these hepatocytes. I conclude that transdifferentiation of human stem cells to a mature hepatocyte phenotype does not occur in the NOD/Scid model of bone marrow transplantation even after severe CCU induced liver damage. Instead human cells most probably of haematopoietic origin fuse with resident hepatocytes to give rise to mixed heterokaryons expressing some, but not all markers of human hepatocytes. To achieve true transdifferentiation a different, more chronic type of tissue damage, or a better defined stem cell population might be required.

Published
2006

42. Human melanoma brain metastases cell line MUG-Mel1, isolated clones and their detailed characterization

Author

Heitzer, Ellen, Groenewoud, Arwin, Meditz, Katharina, Lohberger, Birgit, Liegl-Atzwanger, Bernadette, Prokesch, Andreas, Kashofer, Karl, Behrens, Diana, Haybaeck, Johannes, Kolb-Lenz, Dagmar, Koefeler, Harald, Riedl, Sabrina, Schaider, Helmut, Fischer, Carina, Snaar-Jagalska, B. Ewa, de’Jong, Danielle, Szuhai, Karoly, Zweytick, Dagmar, and Rinner, Beate

Published
2019
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45. Interleukin‐6 initiates muscle‐ and adipose tissue wasting in a novel C57BL/6 model of cancer‐associated cachexia

Author

Pototschnig, Isabella, primary, Feiler, Ursula, additional, Diwoky, Clemens, additional, Vesely, Paul W., additional, Rauchenwald, Thomas, additional, Paar, Margret, additional, Bakiri, Latifa, additional, Pajed, Laura, additional, Hofer, Peter, additional, Kashofer, Karl, additional, Sukhbaatar, Nyamdelger, additional, Schoiswohl, Gabriele, additional, Weichhart, Thomas, additional, Hoefler, Gerald, additional, Bock, Christoph, additional, Pichler, Martin, additional, Wagner, Erwin F., additional, Zechner, Rudolf, additional, and Schweiger, Martina, additional

Published
2022
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