Publications by authors named "Sven Perner"

240 Publications

[Detection of BRAF V600E mutation in metastatic colorectal carcinoma : A QuIP round robin test].

Pathologe 2021 Nov 22. Epub 2021 Nov 22.

Institut für Pathologie, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Virchowweg 15, 10117, Berlin, Deutschland.

Round robin testing is an important instrument for quality assurance. Increasingly, this also applies to the results of molecular diagnostics in pathology, which directly influence therapy decisions in precision oncology. In metastatic colorectal carcinoma (mCRC), the focus has been on detecting KRAS and NRAS mutations, whose absence allows therapy with EGFR blocking antibodies. Recently, BRAF has been added as another predictive marker, since mCRC patients with BRAF V600E mutation benefit significantly from treatment with encorafenib (a BRAF inhibitor) in combination with cetuximab (anti-EGFR antibody) after systemic therapy. Due to the approval of this treatment in 2020, it is a pre-requisite that BRAF V600E mutation detection in diagnostic pathologies is reliably performed. Therefore, this round robin test with BRAF V600E testing either by immunohistochemistry or molecular methods was performed. The round robin test results demonstrate that molecular BRAF V600E detection is currently clearly superior to immunohistochemical detection.
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http://dx.doi.org/10.1007/s00292-021-01022-8DOI Listing
November 2021

Chromothripsis followed by circular recombination drives oncogene amplification in human cancer.

Nat Genet 2021 Nov 15. Epub 2021 Nov 15.

Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

The mechanisms behind the evolution of complex genomic amplifications in cancer have remained largely unclear. Using whole-genome sequencing data of the pediatric tumor neuroblastoma, we here identified a type of amplification, termed 'seismic amplification', that is characterized by multiple rearrangements and discontinuous copy number levels. Overall, seismic amplifications occurred in 9.9% (274 of 2,756) of cases across 38 cancer types, and were associated with massively increased copy numbers and elevated oncogene expression. Reconstruction of the development of seismic amplification showed a stepwise evolution, starting with a chromothripsis event, followed by formation of circular extrachromosomal DNA that subsequently underwent repetitive rounds of circular recombination. The resulting amplicons persisted as extrachromosomal DNA circles or had reintegrated into the genome in overt tumors. Together, our data indicate that the sequential occurrence of chromothripsis and circular recombination drives oncogene amplification and overexpression in a substantial fraction of human malignancies.
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http://dx.doi.org/10.1038/s41588-021-00951-7DOI Listing
November 2021

Spatial Distribution of Immune Cells in Head and Neck Squamous Cell Carcinomas.

Front Oncol 2021 28;11:712788. Epub 2021 Oct 28.

Department of Otorhinolaryngology, MRI Technical University Munich, Munich, Germany.

Background: Head and neck squamous cell carcinomas (HNSCCs) have a very moderate response rate to immune checkpoint inhibitor (ICI) treatment compared to other cancer types. Lacking predictive markers for treatment response, we analyzed the immune status of HNSCC and assessed the spatial distribution of immune cells.

Materials And Methods: assessing hematoxylin-eosin (H&E) stains, we divided HNSCCs by the immune cell distribution in hot, cold, and excluded tumors. For each group, each with 10 tumors, we performed serial immunohistochemical (IHC) staining of the immune cell markers, checkpoint molecules, and immune regulators.

Results: The spatial distributions were different for each immune cell type, allocating regulatory T cells (Tregs) and CD11b cells predominantly in the stroma. CD4 and CD8 cells were present either in the tumor stroma or between cancer cells. Interestingly, the expressions of PD-1 (programmed cell death 1 receptor) and PD-L1 (programmed death-ligand 1) were higher in hot tumors in comparison to cold and excluded tumors. The expression of pSMAD [indicating active transforming growth factor beta (TGF-β)] was higher in excluded tumors.

Conclusion: Different immune cell distribution patterns within tumors might be crucial for ICI treatment response since hot tumors have the highest expressions of PD-1 and PD-L1. TGF-β might be a key regulator for immune cell distribution and a promising therapeutic target that determines the formation of hot or excluded immune patterns.
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http://dx.doi.org/10.3389/fonc.2021.712788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581660PMC
October 2021

Delta-Like Protein 3 Expression in Paired Chemonaive and Chemorelapsed Small Cell Lung Cancer Samples.

Front Med (Lausanne) 2021 8;8:734901. Epub 2021 Oct 8.

Institute of Pathology, Luebeck, University Hospital Schleswig-Holstein, Luebeck, Germany.

Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC). DLL3 is expressed on the majority of SCLC samples. Because SCLC is rarely biopsied in the course of disease, data regarding DLL3 expression in relapses is not available. The aim of this study was to investigate the expression of DLL3 in chemorelapsed (but untreated with Rova-T) SCLC samples and compare the results with chemonaive counterparts. Two evaluation methods to assess DLL3 expression were explored. Additionally, we assessed if DLL3 expression of chemorelapsed and/or chemonaive samples has prognostic impact and if it correlates with other clinicopathological data. The study included 30 paired SCLC samples, which were stained with an anti DLL3 antibody. DLL3 expression was assessed using tumor proportion score (TPS) and H-score and was categorized as DLL3 low (TPS < 50%, H-score ≤ 150) and DLL3 high (TPS ≥ 50%, H-score > 150). Expression data were correlated with clinicopathological characteristics. Kaplan-Meier curves were used to illustrate overall survival (OS) depending on DLL3 expression in chemonaive and chemorelapsed samples, respectively, and depending on dynamics of expression during course of therapy. DLL3 was expressed in 86.6% chemonaive and 80% chemorelapsed SCLC samples without significant differences between the two groups. However, the extent of expression varied in a substantial proportion of pairs (36.6% with TPS, 43.3% with H-score), defined as a shift from low to high or high to low expression. TPS and H-score provided comparable results. There were no profound correlations with clinicopathological data. Survival analysis revealed a trend toward a more favorable OS in DLL low-expressing chemonaive SCLC ( = 0.57) and, in turn, in DLL3 high-expressing chemorelapsed SCLC ( = 0.42) as well as in SCLC demonstrating a shift from low to high expression ( = 0.56) without being statistically significant. This is the first study to investigate DLL3 expression in a large cohort of rare paired chemonaive-chemorelapsed SCLC specimens. Comparative analysis revealed that DLL3 expression was not stable during the course of therapy, suggesting therapy-based alterations. Unlike in chemonaive samples, a high DLL3 expression in chemorelapsed samples indicated a trend for a more favorable prognosis. Our results highlight the importance to investigate DLL3 in latest chemorelapsed SCLC tumor tissue.
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http://dx.doi.org/10.3389/fmed.2021.734901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531433PMC
October 2021

Paraneoplastic encephalomyeloradiculits with multiple autoantibodies against ITPR-1, GFAP and MOG: case report and literature review.

Neurol Res Pract 2021 Oct 11;3(1):48. Epub 2021 Oct 11.

Department of Neurology, University Hospital of Schleswig-Holstein Lübeck, Lübeck, Germany.

Background: Recently, antibodies against the alpha isoform of the glial-fibrillary-acidic-protein (GFAPα) were identified in a small series of patients with encephalomyelitis. Coexisting autoantibodies (NMDA receptor, GAD65 antibodies) have been described in a few of these patients. We describe a patient with rapidly progressive encephalomyeloradiculitis and a combination of anti-ITPR1, anti-GFAP and anti-MOG antibodies.

Case Presentation And Literature Review: A 44-year old caucasian woman with a flu-like prodrome presented with meningism, progressive cerebellar signs and autonomic symptoms, areflexia, quadriplegia and respiratory insufficiency. MRI showed diffuse bilateral T2w-hyperintense brain lesions in the cortex, white matter, the corpus callosum as well as a longitudinal lesion of the medulla oblongata and the entire spinal cord. Anti-ITPR1, anti-GFAP and anti-MOG antibodies were detected in cerebrospinal fluid along with lymphocytic pleocytosis. Borderline tumor of the ovary was diagnosed. Thus, the disease of the patient was deemed to be paraneoplastic. The patient was treated by surgical removal of tumor, steroids, immunoglobulins, plasma exchange and rituximab. Four months after presentation, the patient was still tetraplegic, reacted with mimic expressions to pain or touch and could phonate solitary vowels. An extensive literature research was performed.

Conclusion: Our case and the literature review illustrate that multiple glial and neuronal autoantibodies can co-occur, that points to a paraneoplastic etiology, above all ovarian teratoma or thymoma. Clinical manifestation can be a mixture of typically associated syndromes, e.g. ataxia associated with anti-ITPR1 antibodies, encephalomyelitis with anti-GFAPα antibodies and longitudinal extensive myelitis with anti-MOG antibodies.
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http://dx.doi.org/10.1186/s42466-021-00145-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504129PMC
October 2021

The treatment of Merkel cell carcinoma with immune checkpoint inhibitors: implications for patients with rheumatoid arthritis.

Rheumatol Adv Pract 2021 28;5(3):rkab037. Epub 2021 Sep 28.

Department of Dermatology.

Objectives: Merkel cell carcinoma (MCC) is a rare, highly aggressive neuroendocrine skin cancer, which typically affects elderly and immunocompromised and/or immunosuppressed patients. The checkpoint inhibitor avelumab, a mAb targeting the anti-programmed cell death ligand 1 (anti-PD-L1), has revolutionized the treatment of metastatic MCC, achieving dramatic improvements in disease control and overall survival. However, checkpoint inhibitors are associated with the development of immune-related adverse events, such as exacerbation of pre-existing RA. Although most immune-related adverse events can be managed successfully with CSs, their frequent and/or long-term use runs the risk of undermining the efficacy of immune checkpoint inhibition.

Methods: We report two cases of MCC, in which immunosuppressive therapy for the management of RA was administered.

Results: Immunosuppression for (i) pre-existing and (ii) immune checkpoint inhibitor-exacerbated RA was associated with progression of metastatic MCC.

Conclusion: Any decision to initiate immunosuppressive treatment for RA in patients receiving immune checkpoint inhibitor therapy should include careful consideration of the risk of potentially fatal cancer progression and be taken after consultation with the patient's oncologist and rheumatologist. When the immunosuppressive treatment is required, it should be administered for as short a time as possible and under strict clinical and radiological surveillance.
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http://dx.doi.org/10.1093/rap/rkab037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493100PMC
September 2021

PD-L1 Dependent Immunogenic Landscape in Hot Lung Adenocarcinomas Identified by Transcriptome Analysis.

Cancers (Basel) 2021 Sep 11;13(18). Epub 2021 Sep 11.

Institute of Pathology, University Hospital Schleswig-Holstein, Campus Luebeck, 23538 Luebeck, Germany.

Background: Lung cancer is the most frequent cause of cancer-related deaths worldwide. The clinical development of immune checkpoint blockade has dramatically changed the treatment paradigm for patients with lung cancer. Yet, an improved understanding of PD-1/PD-L1 checkpoint blockade-responsive biology is warranted.

Methods: We aimed to identify the landscape of immune cell infiltration in primary lung adenocarcinoma (LUAD) in the context of tumoral PD-L1 expression and the extent of immune infiltration ("hot" vs. "cold" phenotype). The study comprises LUAD cases ( = 138) with "hot" (≥150 lymphocytes/HPF) and "cold" (<150 lymphocytes/HPF) tumor immune phenotype and positive (>50%) and negative (<1%) tumor PD-L1 expression, respectively. Tumor samples were immunohistochemically analyzed for expression of PD-L1, CD4, and CD8, and further investigated by transcriptome analysis.

Results: Gene set enrichment analysis defined complement, IL-JAK-STAT signaling, KRAS signaling, inflammatory response, TNF-alpha signaling, interferon-gamma response, interferon-alpha response, and allograft rejection as significantly upregulated pathways in the PD-L1-positive hot subgroup. Additionally, we demonstrated that STAT1 is upregulated in the PD-L1-positive hot subgroup and KIT in the PD-L1-negative hot subgroup.

Conclusion: The presented study illustrates novel aspects of PD-L1 regulation, with potential biological relevance, as well as relevance for immunotherapy response stratification.
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http://dx.doi.org/10.3390/cancers13184562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469831PMC
September 2021

Machine learning methods for automated classification of tumors with papillary thyroid carcinoma-like nuclei: A quantitative analysis.

PLoS One 2021 22;16(9):e0257635. Epub 2021 Sep 22.

Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.

When approaching thyroid gland tumor classification, the differentiation between samples with and without "papillary thyroid carcinoma-like" nuclei is a daunting task with high inter-observer variability among pathologists. Thus, there is increasing interest in the use of machine learning approaches to provide pathologists real-time decision support. In this paper, we optimize and quantitatively compare two automated machine learning methods for thyroid gland tumor classification on two datasets to assist pathologists in decision-making regarding these methods and their parameters. The first method is a feature-based classification originating from common image processing and consists of cell nucleus segmentation, feature extraction, and subsequent thyroid gland tumor classification utilizing different classifiers. The second method is a deep learning-based classification which directly classifies the input images with a convolutional neural network without the need for cell nucleus segmentation. On the Tharun and Thompson dataset, the feature-based classification achieves an accuracy of 89.7% (Cohen's Kappa 0.79), compared to the deep learning-based classification of 89.1% (Cohen's Kappa 0.78). On the Nikiforov dataset, the feature-based classification achieves an accuracy of 83.5% (Cohen's Kappa 0.46) compared to the deep learning-based classification 77.4% (Cohen's Kappa 0.35). Thus, both automated thyroid tumor classification methods can reach the classification level of an expert pathologist. To our knowledge, this is the first study comparing feature-based and deep learning-based classification regarding their ability to classify samples with and without papillary thyroid carcinoma-like nuclei on two large-scale datasets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257635PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457451PMC
November 2021

Cracking it - successful mRNA extraction for digital gene expression analysis from decalcified, formalin-fixed and paraffin-embedded bone tissue.

PLoS One 2021 16;16(9):e0257416. Epub 2021 Sep 16.

Pathology of the University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.

With the advance of precision medicine, the availability of tumor tissue for molecular analysis has become a limiting factor. This is particularly the case for bone metastases which are frequently occurring in cancer types such as prostate cancer. Due to the necessary decalcification process it was long thought that transcriptome analysis will not be feasible from decalcified formalin-fixed, paraffin-embedded (DFFPE) in a large manner. Here we demonstrate that mRNA extraction from DFFPE is feasible, quick, robust and reproducible and that decalcification does not hamper subsequent gene expression analysis. This might assist in implementing transcriptome analysis from DFFPE into every day practice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257416PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445430PMC
November 2021

Manuscript Title: Analysis of tripartite motif (TRIM) family gene expression in prostate cancer bone metastases.

Carcinogenesis 2021 Sep 6. Epub 2021 Sep 6.

Institute of Pathology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.

Tripartite motif (TRIM) family proteins are post-translational protein modifiers with E3-ubiquitin ligase activity, thereby involved in various biological processes. The molecular mechanisms driving prostate cancer (PCa) bone metastasis (BM) are incompletely understood, and targetable genetic alterations are lacking in the majority of cases. Therefore, we aimed to explore the expression and potential functional relevance of 71 TRIM members in bone metastatic PCa. We performed transcriptome analysis of all human TRIM family members and 770 cancer-related genes in 29 localized PCa and 30 PCa BM using Nanostring. KEGG, STRING and Ubibrowser were used for further bioinformatic gene correlation and pathway enrichment analyses. Compared to localized tumors, six TRIMs are under-expressed while nine TRIMs are over-expressed in BM. The differentially expressed TRIM proteins are linked to TNF-, TGFβ-, PI3K/AKT- and HIF-1-signaling, and to features such as proteoglycans, platelet activation, adhesion and ECM-interaction based on correlation to cancer-related genes. The identification of TRIM-specific E3-ligase-substrates revealed insight into functional connections to oncogenes, tumor suppressors and cancer-related pathways including androgen receptor- and TGFβ signaling, cell cycle regulation and splicing. In summary, this is the first study that comprehensively and systematically characterizes the expression of all TRIM members in PCa BM. Our results describe post-translational protein modification as an important regulatory mechanism of oncogenes, tumor suppressors, and pathway molecules in PCa progression. Therefore, this study may provide evidence for novel therapeutic targets, in particular for the treatment or prevention of BM.
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http://dx.doi.org/10.1093/carcin/bgab083DOI Listing
September 2021

GPA-Induced Granulomatous Endocarditis Mimicking a Thrombotic Mitral Valve Stenosis.

JACC Case Rep 2020 Nov 14;2(14):2151-2155. Epub 2020 Oct 14.

Department of Cardiology, Angiology and Intensive Care, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany.

We present the case of a patient with granulomatous endocarditis of the mitral valve leading to severe valve stenosis caused by granulomatosis with polyangiitis. Endocarditis is a rare complication of granulomatosis with polyangiitis that may be misdiagnosed as infectious endocarditis or, as in our case, thrombotic lesions. ().
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http://dx.doi.org/10.1016/j.jaccas.2020.07.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299858PMC
November 2020

CDK19 as a diagnostic marker for high-grade prostatic intraepithelial neoplasia.

Hum Pathol 2021 Nov 24;117:60-67. Epub 2021 Jul 24.

Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck, 23562 Germany; Institute of Pathology, Research Center Borstel, Leibniz Lung Center, Borstel, 23845 Germany. Electronic address:

High-grade prostatic intraepithelial neoplasia (HGPIN) is a facultative precursor lesion of prostate cancer (PCa). Multifocal HGPIN in needle biopsies in the absence of PCa indicates a higher risk of cancer detection in subsequent biopsies. Therefore, a reliable diagnosis of HGPIN is of high clinical relevance guiding the management of patients with cancer-negative biopsies. Detection of HGPIN is merely based on morphological features while biomarkers aiding in the diagnosis of HGPIN and its differentiation from benign glands and other glandular lesions are lacking yet. Here, we investigated the expression of cyclin-dependent kinase 19 (CDK19) by immunohistochemistry on prostate needle biopsies of 140 patients who were all diagnosed with PCa using whole-tissue sections and compared CDK19 levels between HGPIN, PCa, and adjacent benign glands. In addition, CDK19 was compared with AMACR expression in a subset of intraductal carcinomas (IDCs) on radical prostatectomy (RP) specimens. HGPIN was present in 65.7% of biopsies and in 88% associated to adjacent PCa. CDK19 overexpression defined as moderate to high CDK19 expression visible at low magnification was found in 82.6% of HGPIN. In contrast, 89.3% of benign glands were CDK19-negative or demonstrated only low CDK19 expression highlighting a high sensitivity and specificity to accurately detect HGPIN based on CDK19 expression levels. CDK19 was overexpressed in 59% of PCa but did not correlate significantly with the expression of intermingled HGPIN. On RP, CDK19 and AMACR showed no significant difference in the detection rate of IDC. In summary, assessment of CDK19 facilitates accurate and simplified diagnosis of HGPIN with high sensitivity and specificity and aides the differentiation to non-neoplastic glandular alterations. Considering the high clinical significance of diagnosis HGPIN that still has a limited reproducibility among pathologists, we suggest CDK19 as diagnostic biomarker for HGPIN.
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http://dx.doi.org/10.1016/j.humpath.2021.07.006DOI Listing
November 2021

IDH2 R172 Mutations Across Poorly Differentiated Sinonasal Tract Malignancies: Forty Molecularly Homogenous and Histologically Variable Cases With Favorable Outcome.

Am J Surg Pathol 2021 09;45(9):1190-1204

Departments of Neuropathology.

IDH2 R172 mutations occur in sinonasal undifferentiated carcinoma (SNUC), large-cell neuroendocrine carcinoma (LCNEC), sinonasal adenocarcinomas, and olfactory neuroblastoma (ONB). We performed a clinical, pathologic, and genetic/epigenetic analysis of a large IDH2-mutated sinonasal tumor cohort to explore their distinct features. A total 165 sinonasal/skull base tumors included 40 IDH2 mutants studied by light microscopy, immunohistochemistry, and genome-wide DNA methylation, and 125 IDH2 wild-type tumors used for comparison. Methylation profiles were analyzed by unsupervised hierarchical clustering, t-distributed stochastic neighbor embedding dimensionality reduction and assessed for copy number alterations (CNA). Thirty-nine histologically assessable cases included 25 (64.1%) SNUC, 8 (20.5%) LCNEC, 2 (5.1%) poorly differentiated adenocarcinomas, 1 (2.7%) ONB, and 3 (7.7%) IDH2-mutated tumors with ONB features. All cases were high-grade showing necrosis (82.4%), prominent nucleoli (88.9%), and median 21 mitoses/10 HPFs. AE1/AE3 and/or CAM 5.2 were positive in all and insulinoma-associated protein 1 (INSM1) in 80% cases. All IDH2 mutants formed one distinct group by t-distributed stochastic neighbor embedding dimensionality reduction separating from all IDH2 wild-type tumors. There was no correlation between methylation clusters and histopathologic diagnoses. Recurrent CNA included 1q gain (79.3%), 17p loss (75.9%), and 17q gain (58.6%). No CNA differences were observed between SNUC and LCNEC. IDH2 mutants showed better disease-specific survival than SMARCB1-deficient (P=0.027) and IDH2 wild-type carcinomas overall (P=0.042). IDH2-mutated sinonasal tumors are remarkably homogeneous at the molecular level and distinct from IDH2 wild-type sinonasal malignancies. Biology of IDH2-mutated sinonasal tumors might be primarily defined by their unique molecular fingerprint rather than by their respective histopathologic diagnoses.
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http://dx.doi.org/10.1097/PAS.0000000000001697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373679PMC
September 2021

Palliative Local Radiotherapy for Advanced Squamous Cell Carcinoma of the Head-and-Neck: Prognostic Factors of Survival.

Anticancer Res 2021 Jun;41(6):3205-3210

Department of Radiation Oncology, University of Lübeck, Lübeck, Germany;

Background/aim: A considerable number of patients with advanced head-and-neck cancer (SCCHN) receive palliative radiotherapy. This study aimed to identify prognostic factors for survival to facilitate personalized treatment for these patients.

Patients And Methods: Ninety-two patients receiving palliative radiotherapy for SCCHN were retrospectively analyzed. Fourteen characteristics were evaluated for survival including age, gender, performance score, pre-radiotherapy hemoglobin, tumor site and stage, histologic grade, p16-status, equivalent dose in 2 Gy-fractions (EQD2), completion of radiotherapy, upfront surgery and systemic therapy.

Results: On univariate analysis, improved survival was significantly associated with pre-radiotherapy hemoglobin ≥12 g/dl (p=0.003), EQD2 >42.3 Gy (p=0.003) and completion of radiotherapy (p<0.001). In the multivariate analysis, hemoglobin levels remained significant (p=0.024). Trends were found for EQD2 (p=0.057) and completion of radiotherapy (p=0.093).

Conclusion: Prognostic factors for survival were identified that can facilitate treatment personalization. The fact that higher EQD2 and completion of radiotherapy were associated with improved survival demonstrates the importance of close monitoring and care of these patients during radiotherapy.
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http://dx.doi.org/10.21873/anticanres.15107DOI Listing
June 2021

A New Survival Score for Patients Scheduled for Palliative Irradiation of Locally Advanced Carcinoma of the Head-and-Neck.

Anticancer Res 2021 Jun;41(6):3055-3058

Department of Radiation Oncology, Mayo Clinic, Scottsdale, AZ, U.S.A.

Background/aim: Patients with advanced squamous cell carcinoma of the head-and-neck (SCCHN) may be assigned to palliative irradiation. A survival score was developed for this group to support treatment personalization.

Patients And Methods: Seventy-eight patients who received palliative irradiation for SCCHN and had complete data regarding performance score, pre-radiotherapy hemoglobin levels, and main tumor site were included in this retrospective study. Six-month survival rates of these factors were divided by 10 (factor scores) and added for each patient (total patient scores).

Results: Total patient scores ranged between 8 and 15 points. Three groups were designed based on the 6-month survival rates, namely 8-9 (n=15), 11-13 (n=36), and 14-15 (n=27) points. Six-month survival rates were 13%, 28%, and 63%, and median survival times were 1, 2, and 11 months (p=0.001).

Conclusion: A new survival score including three prognostic groups was developed. This new tool can help physicians when designing personalized treatments for patients with SCCHN scheduled for palliative irradiation.
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http://dx.doi.org/10.21873/anticanres.15088DOI Listing
June 2021

Confocal laser microscopy without fluorescent dye in minimal-invasive thoracic surgery: an pilot study in lung cancer.

Biomed Tech (Berl) 2021 Jun 10;66(3):285-292. Epub 2020 Dec 10.

Department of Surgery, University Medical Centre Schleswig-Holstein, Campus Luebeck, Lübeck, Germany.

Cancer will be the leading cause of death in a few decades. In line with minimal invasive lung cancer surgery, surgeons loose most of their tactile tissue information and need an additional tool of intraoperative tissue navigation during surgery. Confocal laser microscopy is a well-established method of tissue investigation. In this pilot study, we evaluated an endoscopic confocal laser microscope (eCLM) that does not need any fluorescent dye as a diagnostic tool in non-malignant and malignant pulmonary tissue and distal stapler resection margins, respectively. In seven cases, an eCLM was used for examining pulmonary tissue . Images of non-malignant and non-small cell lung cancer tissue and distal stapler resection margins were characterized in terms of specific signal-patterns. No fluorescent dye was used. Correlations to findings in conventional histology were systematically recorded and described. Healthy lung tissue showed hyperreflectoric alveolar walls with dark alveolar spaces. Hyperreflective nets indicated the tumor stroma; whereas the hyperreflective areas indicated the tumor cell clusters. Compared to adenocarcinoma tissue, tissue from squamous cell carcinoma showed more distinctive hyperreflective stroma nets. eCLM characteristics seen in non-malignant and malignant tissue were also visible in distal stapler resection margins and so therefore it was feasible to distinguish between healthy lung tissue and lung cancer. This pilot study shows that the assessment of pulmonary tissue with this eCLM for minimally invasive surgical approach without any fluorescent dye is feasible. It enables to differentiate between benign and malignant tissue in pulmonary specimen by easy to evaluate and reproducible parameters.
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http://dx.doi.org/10.1515/bmt-2020-0162DOI Listing
June 2021

Performance of Different Diagnostic PD-L1 Clones in Head and Neck Squamous Cell Carcinoma.

Front Med (Lausanne) 2021 27;8:640515. Epub 2021 Apr 27.

Institute of Pathology, University of Luebeck and University Hospital Schleswig-Holstein, Luebeck, Germany.

The approval of immune checkpoint inhibitors in combination with specific diagnostic biomarkers presents new challenges to pathologists as tumor tissue needs to be tested for expression of programmed death-ligand 1 (PD-L1) for a variety of indications. As there is currently no requirement to use companion diagnostic assays for PD-L1 testing in Germany different clones are used in daily routine. While the correlation of staining results has been tested in various entities, there is no data for head and neck squamous cell carcinomas (HNSCC) so far. We tested five different PD-L1 clones (SP263, SP142, E1L3N, 22-8, 22C3) on primary HNSCC tumor tissue of 75 patients in the form of tissue microarrays. Stainings of both immune and tumor cells were then assessed and quantified by pathologists to simulate real-world routine diagnostics. The results were analyzed descriptively and the resulting staining pattern across patients was further investigated by principal component analysis and non-negative matrix factorization clustering. Percentages of positive immune and tumor cells varied greatly. Both the resulting combined positive score as well as the eligibility for certain checkpoint inhibitor regimens was therefore strongly dependent on the choice of the antibody. No relevant co-clustering and low similarity of relative staining patterns across patients was found for the different antibodies. Performance of different diagnostic anti PD-L1 antibody clones in HNSCC is less robust and interchangeable compared to reported data from other tumor entities. Determination of PD-L1 expression is critical for therapeutic decision making and may be aided by back-to-back testing of different PD-L1 clones.
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http://dx.doi.org/10.3389/fmed.2021.640515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110724PMC
April 2021

Identification of molecular signatures associated with early relapse after complete resection of lung adenocarcinomas.

Sci Rep 2021 05 5;11(1):9532. Epub 2021 May 5.

LungenClinic Grosshansdorf, 22927, Grosshansdorf, Germany.

The only potentially curative treatment for lung adenocarcinoma patients remains complete resection of early-stage tumors. However, many patients develop recurrence and die of their disease despite curative surgery. Underlying mechanisms leading to establishment of systemic disease after complete resection are mostly unknown. We therefore aimed at identifying molecular signatures of resected lung adenocarcinomas associated with the risk of an early relapse. The study comprised 89 patients with totally resected stage IA-IIIA lung adenocarcinomas. Patients suffering from an early relapse within two years after surgery were compared to patients without a relapse in two years. Patients were clinically and molecular pathologically characterized. Tumor tissues were immunohistochemically analyzed for the expression of Ki67, CD45, CD4, CD8, PD1, PD-L1, PD-L2 and CD34, by Nanostring nCounter PanCancer Immune Profiling Panel as well as a comprehensive methylome profiling using the Infinium MethylationEPIC BeadChip. We detected differential DNA methylation patterns as well as significantly differentially expressed genes associated with an early relapse after complete resection. Especially, CD1A was identified as a potential biomarker, whose reduced expression is associated with an early relapse. These findings might help to develop biomarkers improving risk assessment and patient selection for adjuvant therapy as well as establish novel targeted therapeutic strategies.
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http://dx.doi.org/10.1038/s41598-021-89030-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099905PMC
May 2021

Novel approaches to target the microenvironment of bone metastasis.

Nat Rev Clin Oncol 2021 08 19;18(8):488-505. Epub 2021 Apr 19.

Department of Tumor Biology, Center of Experimental Medicine, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Bone metastases are a frequent and severe complication of advanced-stage cancers. Breast and prostate cancers, the most common malignancies in women and men, respectively, have a particularly high propensity to metastasize to bone. Conceptually, circulating tumour cells (CTCs) in the bloodstream and disseminated tumour cells (DTCs) in the bone marrow provide a snapshot of the dissemination and colonization process en route to clinically apparent bone metastases. Many cell types that constitute the bone microenvironment, including osteoblasts, osteocytes, osteoclasts, adipocytes, endothelial cells, haematopoietic stem cells and immune cells, engage in a dialogue with tumour cells. Some of these cells modify tumour biology, while others are disrupted and out-competed by tumour cells, thus leading to distinct phases of tumour cell migration, dormancy and latency, and therapy resistance and progression to overt bone metastases. Several current bone-protective therapies act by interrupting these interactions, mainly by targeting tumour cell-osteoclast interactions. In this Review, we describe the functional roles of the bone microenvironment and its components in the initiation and propagation of skeletal metastases, outline the biology and clinical relevance of CTCs and DTCs, and discuss established and future therapeutic approaches that specifically target defined components of the bone microenvironment to prevent or treat skeletal metastases.
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http://dx.doi.org/10.1038/s41571-021-00499-9DOI Listing
August 2021

Phosphorylation of SMAD3 in immune cells predicts survival of patients with early stage non-small cell lung cancer.

J Immunother Cancer 2021 02;9(2)

Laboratory of Molecular and Tumor Immunology, Earle A Chiles Research Institute, Portland, Oregon, USA.

Background: The interplay of immune and cancer cells takes place in the tumor microenvironment where multiple signals are exchanged. The transforming growth factor beta (TGFB) pathway is known to be dysregulated in lung cancer and can impede an effective immune response. However, the exact mechanisms are yet to be determined. Especially which cells respond and where does this signaling take place with respect to the local microenvironment.

Methods: Human non-small cell lung cancer samples were retrospectively analyzed by multiplexed immunohistochemistry for SMAD3 phosphorylation and programmed death ligand 1 expression in different immune cells with respect to their localization within the tumor tissue. Spatial relationships were studied to examine possible cell-cell interactions and analyzed in conjunction with clinical data.

Results: TGFB pathway activation in CD3, CD8, Foxp3 and CD68 cells, as indicated by SMAD3 phosphorylation, negatively impacts overall and partially disease-free survival of patients with lung cancerindependent of histological subtype. A high frequency of Foxp3 regulatory T cells positive for SMAD3 phosphorylation in close vicinity of CD8 T cells within the tumor discriminate a rapidly progressing group of patients with lung cancer.

Conclusions: TGFB pathway activation of local immune cells within the tumor microenvironment impacts survival of early stage lung cancer. This might benefit patients not eligible for targeted therapies or immune checkpoint therapy as a therapeutic option to re-activate the local immune response.
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http://dx.doi.org/10.1136/jitc-2020-001469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887360PMC
February 2021

Immunologic "Cold" Squamous Cell Carcinomas of the Head and Neck Are Associated With an Unfavorable Prognosis.

Front Med (Lausanne) 2021 27;8:622330. Epub 2021 Jan 27.

Department of Otorhinolaryngology, University of Luebeck, Luebeck, Germany.

Head and neck squamous cell carcinoma (HNSCC) represents a common cancer worldwide. Past therapeutic advances have not significantly improved HNSCC prognosis. Therefore, it is necessary to further stratify HNSCC, especially with recent advances in tumor immunology. Tissue microarrays were assembled from tumor tissue samples and were complemented with comprehensive clinicopathological data of = 419 patients. H&E whole slides from resection specimen ( = 289) were categorized according to their immune cell infiltrate as "hot," "cold," or "excluded." Investigating tumor immune cell patterns, we found significant differences in survival rates. Immunologic "hot" and "excluded" HNSCCs are associated with better overall survival than "cold" HNSCC patients ( < 0.05). Interestingly, the percentage of all three patterns is nearly identical in p16 positive and negative HNSCCs. Using a plain histological H&E approach to categorize HNSCC as being immunologic "hot," "cold," or "excluded" can offer a forecast of patients' prognosis and may thus aid as a potential prognostic tool in routine pathology reports. This "hot-cold-excluded" scheme needs to be applied to more HNSCC cohorts and possibly to other cancer types to determine prognostic meaning, e.g., regarding OS or DFS. Furthermore, our cohort reflects epidemiological data in the national, European, and international context. It may, therefore, be of use for future HNSCC characterization.
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http://dx.doi.org/10.3389/fmed.2021.622330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873597PMC
January 2021

Editorial for the Special Issue "Squamous Cell Cancer of the Head and Neck-Time to Arrive in the 21st Century of Oncology".

Int J Mol Sci 2021 Feb 5;22(4). Epub 2021 Feb 5.

Department of Otorhinolaryngology, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.

Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most common cancer worldwide [...].
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http://dx.doi.org/10.3390/ijms22041592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914512PMC
February 2021

[Non-neoplastic lung diseases].

Pathologe 2021 02 3;42(1):2-3. Epub 2021 Feb 3.

Pathologie, Forschungszentrum Borstel, Leibniz Lungenzentrum, Parkallee 1-40, 23845, Borstel, Deutschland.

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http://dx.doi.org/10.1007/s00292-021-00909-wDOI Listing
February 2021

[Intravesical Gemcitabine instillations following BCG failure and allergy to Mitomycin: A unique case of a patient with an inverted papilloma of the bladder].

Aktuelle Urol 2021 Feb 1;52(1):43-46. Epub 2021 Feb 1.

University Hospital Schleswig-Holstein, Campus Luebeck, Department of Urology, Luebeck.

Intravesical chemotherapy instillation is a unique method of treatment confined to urothelial neoplasia. Within the last decades, the substances Bacillus Calmette-Guerin (BCG) and mitomycin C (MMC) have evolved as the standard regimens for intravesical therapy. However, there are other chemotherapeutic substances, which are used less frequently, such as gemcitabine. In this article we aim to highlight the clinical relevance of intravesical gemcitabine instillations as treatment of non-muscle invasive bladder cancer.The histological subtypes of bladder tumours are as diverse as the intravesical regimens. Inverted papilloma is a rare entity in the spectrum of urological diseases. There seems to be an association with non-muscle invasive bladder cancer.We report a rare case of an inverted bladder papilloma treated with intravesical gemcitabine instillations after BCG failure and an allergic reaction to MMC.
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http://dx.doi.org/10.1055/a-1312-9032DOI Listing
February 2021

Loss of Mucosal p32/gC1qR/HABP1 Triggers Energy Deficiency and Impairs Goblet Cell Differentiation in Ulcerative Colitis.

Cell Mol Gastroenterol Hepatol 2021 27;12(1):229-250. Epub 2021 Jan 27.

Division of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; Division of Nutritional Medicine, 1st Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. Electronic address:

Background & Aims: Cell differentiation in the colonic crypt is driven by a metabolic switch from glycolysis to mitochondrial oxidation. Mitochondrial and goblet cell dysfunction have been attributed to the pathology of ulcerative colitis (UC). We hypothesized that p32/gC1qR/HABP1, which critically maintains oxidative phosphorylation, is involved in goblet cell differentiation and hence in the pathogenesis of UC.

Methods: Ex vivo, goblet cell differentiation in relation to p32 expression and mitochondrial function was studied in tissue biopsies from UC patients versus controls. Functional studies were performed in goblet cell-like HT29-MTX cells in vitro. Mitochondrial respiratory chain complex V-deficient, ATP8 mutant mice were utilized as a confirmatory model. Nutritional intervention studies were performed in C57BL/6 mice.

Results: In UC patients in remission, colonic goblet cell differentiation was significantly decreased compared to controls in a p32-dependent manner. Plasma/serum L-lactate and colonic pAMPK level were increased, pointing at high glycolytic activity and energy deficiency. Consistently, p32 silencing in mucus-secreting HT29-MTX cells abolished butyrate-induced differentiation and induced a shift towards glycolysis. In ATP8 mutant mice, colonic p32 expression correlated with loss of differentiated goblet cells, resulting in a thinner mucus layer. Conversely, feeding mice an isocaloric glucose-free, high-protein diet increased mucosal energy supply that promoted colonic p32 level, goblet cell differentiation and mucus production.

Conclusion: We here describe a new molecular mechanism linking mucosal energy deficiency in UC to impaired, p32-dependent goblet cell differentiation that may be therapeutically prevented by nutritional intervention.
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http://dx.doi.org/10.1016/j.jcmgh.2021.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135049PMC
January 2021

Genomic Testing in Patients with Metastatic Castration-resistant Prostate Cancer: A Pragmatic Guide for Clinicians.

Eur Urol 2021 04 23;79(4):519-529. Epub 2021 Jan 23.

Guy's Hospital, London, UK; Sarah Cannon Research Institute, London, UK.

Context: Genomic testing is becoming increasingly important in patients with advanced prostate cancer (PC) and is being incorporated in clinical practice to guide treatment.

Objective: To review the current understanding of genomic alterations and the status of genomic testing in patients with metastatic castration-resistant PC (mCRPC), and the potential use of genomic tests in clinical practice.

Evidence Acquisition: We reviewed recent publications (past 15 yr) from PubMed, proceedings of scientific conferences, and published guidelines. Reports on mCRPC in the following areas were selected: development, testing, and validation of techniques for identifying genomic alterations; molecular characterization; and trials of genetically targeted therapies.

Evidence Synthesis: mCRPC tumors harbor molecular alterations that are possible targets for treatment, and a number of therapies are in development to exploit these alterations (eg, PD-1 inhibitors, PARP inhibitors, tyrosine kinase inhibitors). Next-generation sequencing of DNA from tumor tissue can identify somatic alterations that would not be identified by germline testing. Work is ongoing to evaluate the use of less invasive somatic testing methods (eg, sequencing of cell-free circulating tumor DNA). Current international guidelines recommend germline and/or somatic testing for men with advanced and/or high-risk PC regardless of family history to identify those with homologous recombination repair gene mutations or mismatch repair defects/microsatellite instability who may be eligible for treatment with a PARP inhibitor or pembrolizumab, respectively.

Conclusions: Genomic testing for mCRPC may provide information on prognostic, predictive, and resistance biomarkers. Although the incorporation of testing into clinical practice remains challenging, routine genomic testing of men with advanced PC is recommended to guide management and treatment decisions.

Patient Summary: Similar to many cancers, prostate cancer is caused by defects in the cancer's DNA, which are called genetic or genomic defects. New treatments targeting these defects are approved for metastatic castration-resistant prostate cancer. Specific new tests are under development to detect these potentially treatable genetic defects.
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http://dx.doi.org/10.1016/j.eururo.2020.12.039DOI Listing
April 2021

[IgG4-associated lung disease with granulomatous lesions : Coexistence of two entities or the spectrum of one disease?]

Pathologe 2021 Feb 25;42(1):95-101. Epub 2021 Jan 25.

Institut für Pathologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, Gebäude V50, 23538, Lübeck, Deutschland.

A 54-year-old patient with a history of pulmonary tuberculosis and occupational exposure to dust in early adulthood presented with symptoms of coughing with sputum, weight loss, occasional night sweats, and thoracic pain. Non-necrotizing granulomatosis in lung and lymph-node biopsies indicated sarcoidosis. Combined immunosuppressive therapy did not lead to an improvement. An atypical lung resectate with fibroinflammatory changes and obliterative endothelialitis may finally lead to the diagnosis of IgG4-associated lung disease with a bronchovascular pattern of involvement. The question discussed here is whether this is a coexistence of IgG4-associated lung disease with sarcoidosis or the spectrum of one disease.
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http://dx.doi.org/10.1007/s00292-020-00904-7DOI Listing
February 2021

[Histopathology of pulmonary tuberculosis].

Pathologe 2021 Feb 21;42(1):71-77. Epub 2021 Jan 21.

Pathologie, Forschungszentrum Borstel, Leibniz Lungenzentrum, Parkallee 1-40, 23845, Borstel, Deutschland.

Although typical histological findings of tuberculosis are well known, the diagnosis of nonmicrobiologically proven tuberculosis with the instruments available to pathology is challenging. Indeed, necrotizing epithelioid cell granulomatosis is typical for tuberculosis, but it is also seen in a number of different infectious or noninfectious lung diseases. The tools of microscopy and molecular pathology are suitable for confirming the diagnosis or paving the way to a differential diagnosis, but molecular pathology applied to formalin-fixated and paraffin-embedded material is limited. This should be openly communicated to the referring clinician. After interdisciplinary re-evaluation of the findings, an alternative solution to confirm the diagnosis must therefore be found if the additional examinations are negative.
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http://dx.doi.org/10.1007/s00292-021-00910-3DOI Listing
February 2021

[Overview: granulomatous diseases of the lung].

Pathologe 2021 Feb 21;42(1):64-70. Epub 2021 Jan 21.

Pathologie, Forschungszentrum Borstel, Leibniz Lungenzentrum, Parkallee 1-40, 23845, Borstel, Deutschland.

The spectrum of pulmonary granulomatoses is wide and includes infectious and noninfectious entities, each with very different therapeutic consequences. The first step of histological examination discriminates between necrotizing and non-necrotizing granulomatosis. After this, an infectious cause of the granulomatosis has to be excluded by special histological stains and molecular-pathologic methods, if necessary. Diagnosis also includes clinical, radiological, and microbiological findings. The process of pathological examination should be standardized as described.
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http://dx.doi.org/10.1007/s00292-020-00893-7DOI Listing
February 2021

[Mycobacterium szulgai as positive control helps to detect contaminations in the detection of Mycobacterium tuberculosis-complex in formalin fixed, paraffin embedded tissues by 16SrDNA PCR].

Pathologe 2021 Feb 21;42(1):83-85. Epub 2021 Jan 21.

Pathologie, Forschungszentrum Borstel, Leibniz Lungenzentrum, Parkallee 1-40, 23845, Borstel, Deutschland.

The detection of Mycobacterium tuberculosis complex DNA by PCR using formalin-fixed paraffin-embedded material has become an integral part of molecular-pathological diagnostics. We describe an approach that enables the detection of contamination by using Mycobacterium szulgai as a positive control, contributing to the reduction of false-positive results.
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http://dx.doi.org/10.1007/s00292-021-00912-1DOI Listing
February 2021
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