Publications by authors named "Jeremias Wohlschlaeger"

85 Publications

Pulmonary echinococcosis: A rare pseudotumour of the lung.

Rare Tumors 2021 11;13:20363613211009769. Epub 2021 Apr 11.

Institut für Pathologie, DIAKO Hospital Flensburg, Flensburg, Germany.

Cystic echinococcosis is a widely endemic helminthic disease worldwide but occurs only rarely in Central Europe. Humans are infected as 'aberrant' hosts by and develop cysts in numerous different organs. 20%-30% of the affected individuals develop hydatid disease in the lungs with associated complications including pleuritis, lung abscess and pneumothorax. Radiologically, the pulmonary lesions of cystic echinococcosis occasionally pose difficulties in the differential diagnosis of primary lung carcinoma or metastatic disease and vice versa. Herein we report on a case of pulmonary hydatid disease in a 25-year-old Iraqi male presenting with a cystic lesion of the lung associated with thoracic pain and involuntary weight loss. Despite of its rare occurrence in Central Europe, clinicians, radiologists and pathologists should be aware of this entity and its pulmonary manifestations. During frozen section examination, imprint cytology specimens may facilitate the detection of the pathogens.
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http://dx.doi.org/10.1177/20363613211009769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044558PMC
April 2021

Digital Gene Expression Analysis of Epithelioid and Sarcomatoid Mesothelioma Reveals Differences in Immunogenicity.

Cancers (Basel) 2021 Apr 7;13(8). Epub 2021 Apr 7.

Institute of Pathology, University Hospital Essen, University of Duisburg Essen, 45147 Essen, Germany.

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with asbestos exposure. Median survival ranges from 14 to 20 months after initial diagnosis. As of November 2020, the FDA approved a combination of immune checkpoint inhibitors after promising intermediate results. Nonetheless, responses remain unsatisfying. Adequate patient stratification to improve response rates is still lacking. This retrospective study analyzed formalin fixed paraffin embedded specimens from a cohort of 22 MPM. Twelve of those samples showed sarcomatoid, ten epithelioid differentiation. Complete follow-up, including radiological assessment of response by modRECIST and time to death, was available with reported deaths of all patients. RNA of all samples was isolated and subjected to digital gene expression pattern analysis. Our study revealed a notable difference between epithelioid and sarcomatoid mesothelioma, showing differential gene expression for 304/698 expressed genes. Whereas antigen processing and presentation to resident cytotoxic T cells as well as phagocytosis is highly affected in sarcomatoid mesothelioma, cell-cell interaction via cytokines seems to be of greater importance in epithelioid cases. Our work reveals the specific role of the immune system within the different histologic subtypes of MPM, providing a more detailed background of their immunogenic potential. This is of great interest regarding therapeutic strategies including immunotherapy in mesothelioma.
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http://dx.doi.org/10.3390/cancers13081761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067687PMC
April 2021

Impact of metallothionein-knockdown on cisplatin resistance in malignant pleural mesothelioma.

Sci Rep 2020 10 29;10(1):18677. Epub 2020 Oct 29.

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

Malignant pleural mesothelioma (MPM) is a rare, but aggressive tumor with dismal prognosis. Platinum-based chemotherapy is regularly used as part of multimodality therapy. The expression of metallothioneins (MT) has been identified as a reason for cisplatin resistance, which often leads to early therapy failure or relapse. Thus, knockdown of MT expression may improve response to cisplatin treatment. The MT gene- and protein expression of the MPM-cell lines MSTO-211H, NCI-H2052 and NCI-H2452 and the human fibroblast cell line MRC-5, as well as their sensitivity to cisplatin treatment have been evaluated. Knockdown of MT1A, 1B and 2A expression was induced by RNA interference. MT expression was measured using quantitative real-time PCR. An in vitro Assay based on enzyme activity was used to detect cell viability, necrosis and apoptosis before and after incubation with cisplatin. MT2A gene expression could be detected in all MPM cell lines, showing the highest expression in NCI-H2452 and NCI-H2052, whereas gene expression levels of MT1A and MT1B were low or absent. The immunohistochemically protein expression of MT-I/II reflect MT2A gene expression levels. Especially for MSTO-211H cell presenting low initial MT2A levels, a strong induction of MT2A expression could be observed during cisplatin treatment, indicating a cell line-specific and platin-dependent adaption mechanism. Additionally, a MT2A-dependent cellular evasion of apoptosis during cisplatin could be observed, leading to three different MT based phenotypes. MSTO-211H cells showed lower apoptosis rates at an increased expression level of MT2A after cisplatin treatment (from sixfold to fourfold). NCI-H2052 cells showed no changes in MT2A expression, while apoptosis rate is the highest (8-12-fold). NCI-H2452 cells showed neither changes in alteration rate of MT2A expression nor changes in apoptosis rates, indicating an MT2A-independent resistance mechanism. Knockdown of MT2A expression levels resulted in significantly induced apoptotic rates during cisplatin treatment with strongest induction of apoptosis in each of the MPM cell lines, but in different markedness. A therapeutic meaningful effect of MT2A knockdown and subsequent cisplatin treatment could be observed in MSTO-211H cells. The present study showed MT2A to be part of the underlying mechanism of cisplatin resistance in MPM. Especially in MSTO-211H cells we could demonstrate major effects by knockdown of MT2A expression, verifying our hypothesis of an MT driven resistance mechanism. We could prove the inhibition of MT2A as a powerful tool to boost response rates to cisplatin-based therapy in vitro. These data carry the potential to enhance the clinical outcome and management of MPM in the future.
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http://dx.doi.org/10.1038/s41598-020-75807-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596082PMC
October 2020

Villitis of unknown etiology and chronic deciduitis are not associated with human papilloma virus and enterovirus infection.

Virchows Arch 2020 Jul 5;477(1):73-81. Epub 2020 Feb 5.

Department of Virology, Medical School Hannover, Hannover, Germany.

Villitis of unknown etiology (VUE) and chronic deciduitis with plasma cells (CD) are supposed to be non infectious placental lesions caused by a pathologic immune reaction similar to a host versus graft mechanism. In some investigations, infection of human trophoblastic cells with human papilloma virus (HPV) has been described, and a relationship with miscarriage, preeclampsia, and chronic inflammatory placental lesions has been suspected. Infection with enterovirus, especially Coxsackievirus, has been observed in cases with spontaneous abortion and adverse perinatal outcome, respectively. We investigated 20 cases with VUE and 30 cases with chronic deciduitis with plasma cells. The placenta specimens were analyzed for expression of HPV capsid protein by immunohistochemistry, for presence of HPV DNA via polymerase chain reaction (PCR), and for presence of enterovirus mRNA using RT-PCR, respectively. VUE was associated with maternal diseases: atopic lesions in 21%, other autoimmune diseases in 15.5%, and obesity in 31.5%, respectively. Birth weight below the 10th percentile was detected in 63% of the cases with VUE. Chronic deciduitis was associated with preterm labor and preterm premature rupture of membranes (26%). Intrauterine fetal demise occurred in 5 cases with CD (18.5%). HPV DNA, HPV capsid protein, and enterovirus mRNA were not detected in all investigated VUE or CD cases. Our investigations show that a causal role for enterovirus and human papilloma virus in the development of VUE and CD is unlikely. Therefore, HPV vaccination is unlikely to reduce the incidence of VUE and CD in the future.
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http://dx.doi.org/10.1007/s00428-020-02765-0DOI Listing
July 2020

Screening of Pleural Mesothelioma Cell Lines for Kinase Activity May Identify New Mechanisms of Therapy Resistance in Patients Receiving Platin-Based Chemotherapy.

J Oncol 2019 23;2019:2902985. Epub 2019 Dec 23.

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

Background: Malignant pleural mesothelioma (MPM) is a rare, predominantly asbestos-related and biologically highly aggressive tumor associated with a dismal prognosis. Multimodal therapy consisting of platinum-based chemotherapy is the treatment of choice. The reasons underlying the rather poor efficacy of platinum compounds remain largely unknown. Kinase activity might influence cellular response to these regimens.

Materials And Methods: For this exploratory study, we screened MPM cell lines (NCI-H2452, NCI-H2052, and MSTO-211H) differing in response to cisplatin and benign control fibroblasts (MRC-5) for overall phosphorylation patterns as well as kinase activity with respect to cellular response to cisplatin-based therapeutics. We analysed the cell lines for cellular kinases in a high-throughput manner using the highly innovative technique PamGene. Cell state analysis including apoptosis, necrosis, and cell viability was performed by using enzyme activity and fluorescent-based assays.

Results: Cisplatin alters cellular phosphorylation patterns affecting cell cycle, migration, adhesion, signal transduction, immune modulation, and apoptosis. In cisplatin-responsive cell lines, phosphorylation of AKT1 and GSK3B was decreased but could not be influenced in cisplatin-resistant NCI-H2452 cells. Cisplatin-responsive cell lines showed increased phosphorylation levels of JNK1/2/3 but decreased phosphorylation in cisplatin-resistant NCI-H2452 cells.

Conclusion: Kinase phosphorylation and activity might play a crucial role in cellular response to cytostatic agents. Cisplatin influences phosphorylation patterns with distinct features in cisplatin-resistant cells. These alterations exert a significant impact on cell cycle, migration, adhesion, signal transduction, immune modulation, and apoptosis of the respective tumor cells. Based on our results, the induction of p38 or JNK1/3, or inhibition of AKT1 by, for example, BIA-6, might offer a positive synergistic effect by induction of an apoptotic response to cisplatin-based treatment, thus potentially enhancing the clinical outcome of MPM patients.
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http://dx.doi.org/10.1155/2019/2902985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942867PMC
December 2019

Bortezomib sensitivity is tissue dependent and high expression of the 20S proteasome precludes good response in malignant pleural mesothelioma.

Cancer Manag Res 2019 24;11:8711-8720. Epub 2019 Sep 24.

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

Background: Bortezomib is an approved proteasome inhibitor for the treatment of certain lymphoma subtypes. Two clinical trials investigated bortezomib in patients with malignant pleural mesothelioma (MPM) and failed to improve outcome. We present a potential explanation for this event.

Methods: 171 patients with MPM were analyzed for their mRNA expression of proteasomal subunits and via qPCR (n=84) or sequencing (n=87 TCGA/cBioPortal data set "Mesothelioma"). Outcome and subunit expression were correlated. Four mesothelial and one fibroblast cell line were treated with bortezomib and cisplatin. Cellular response was measured after 0, 6, 12, 24, 48 and 72 hrs. Enzyme activity of proteasomal subunits was assessed via functional enzyme activity assays.

Results: Patients with MPM presented with elevated expression of proteasomal subunits compared to benign controls (<0.001). correlated with outcome (Cox propotiortional-hazards model (COXPH): <0.0175, TCGA/cBioPortal data). In cell lines, apoptosis was the main event with a peak after 48 hr incubation for bortezomib or cisplatin. Only two cell lines with comparably low proteasome activity (PSMB2 and PSMB5) responded to 50 nM and 100 nM bortezomib better than to cisplatin (MRC-5, NCI-H2052). MSTO-211H responded to cisplatin only, whereas the other two cell lines were considered therapy resistant (Met-5A, NCI-H2452).

Interpretation: Two clinical trials testing bortezomib in MPM failed, although MPM presents with high proteasome expression, which predicts bortezomib sensitivity in several tumors. Bortezomib induced apoptosis in MPM cell lines with low proteasome activity only. Bortezomib is not suitable for the treatment of MPM, and biomarker-based stratification could have improved both clinical trials.

Trial Registration: NCT00513877 and NCT00458913.
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http://dx.doi.org/10.2147/CMAR.S194337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765394PMC
September 2019

Pathoanatomical Lesions in Placentas With Excessively Hypercoiled Umbilical Cords: Frequent Detection of Massive Perivillous Fibrin Deposition.

Pediatr Dev Pathol 2020 Mar-Apr;23(2):107-114. Epub 2019 Jul 25.

Department of Pathology, Diakonissenkrankenhaus Flensburg, Flensburg, Germany.

This study focused to investigate a possible association of extensive umbilical hypercoiling (displaying an umbilical coiling index [UCI] of at least 1.0 coils/cm), clinical outcome, and associated pathoanatomical placental lesions. Of the 771 singleton placentas from the second and third trimesters submitted for pathoanatomical evaluation, 15 cases (2%) displayed extensive hypercoiling. There was an association of excessive hypercoiling with hypotrophy of fetuses and children (11 cases) and fetal demise (12 cases). Thin cord syndrome and umbilical stricture were observed in 9 cases and 4 cases, respectively. Seven of the 15 cases with excessive umbilical hypercoiling showed increased placental fibrin deposition (47% of the cases with hypercoiling), in 4 cases sufficient for rendering the diagnosis of massive perivillous fibrin deposition. Signs of maternal vascular malperfusion (n = 6) and chorangiosis (n = 2) were also detected in cases with hypercoiling. Recurrence of excessive umbilical hypercoiling was observed in 2 families, suggesting a genetic predisposition for the development of this lesion. Extensive hypercoiling could be a hitherto underrecognized pathogenetic factor for the development of massive perivillous fibrin deposition. A high UCI measured in the second trimester by ultrasound may be predictive of fetal hypotrophy, and intensified fetal monitoring is warranted, particularly if there is a history of hypercoiling and adverse fetal outcome.
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http://dx.doi.org/10.1177/1093526619865426DOI Listing
January 2021

Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro.

BMC Cancer 2019 Jan 30;19(1):108. Epub 2019 Jan 30.

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

Background: Malignant pleural mesothelioma (MPM) is a tumour arising from pleural cavities with poor prognosis. Multimodality treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy of chemotherapeutic treatment are largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed genes compiled under the term "BRCAness". An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis.

Methods: We investigated the response of three MPM cell lines and lung fibroblasts serving as a control to treatment with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find possible correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members.

Results: A BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines was observed. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM.

Conclusions: Defects in HR compiled under the term BRCAness are a common event in MPM. The present data can lead to a better understanding of the underlaying cellular mechanisms and leave the door wide open for new therapeutic approaches for this severe disease with infaust prognosis. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. Thus, this combination therapy might be effective for up to 2/3 of patients, promising to enhance patients' clinical management and outcome.
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http://dx.doi.org/10.1186/s12885-019-5314-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354412PMC
January 2019

Setting out the frame conditions for feasible use of FFPE derived RNA.

Pathol Res Pract 2019 Feb 28;215(2):381-386. Epub 2018 Dec 28.

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

Introduction: The usage of formalin-fixed paraffin embedded (FFPE) tissue is characterized by its long shelf-life and simple handling. Therefore it is the most commonly available tissue specimen in routine diagnostics and histological studies. Formaldehyde fixation may result in RNA degradation and cross linking with proteins, while storage conditions also affect RNA integrity. The present study was designed to investigate the influence of these factors on RNA analysis.

Design: FFPE-derived RNA from sections of 23 patients with spontaneous pneumothoraxes was used. Unstained sections of FFPE tissue were stored at various temperatures (-80 °C, -20 °C, 4 °C, 24 °C) prior to RNA extraction. The potential impact on RNA quality of semi-automatic and manual RNA isolation and three different deparaffinization agents (mineral oil, xylene and d-limonene) were compared.

Results: The storage temperature of FFPE sections affects RNA concentration and fragmentation, with the optimal storage temperature below -20 °C. The RNA extracted with d-limonene shows equivalent quality to the RNA extracted using more toxic standard agents. The manual isolation provides a higher RNA yield compared to the semi-automatic isolation. However, no differences in the amount of longer RNA fragments were observed. Furthermore, the semi-automatic isolation showed an enhanced RNA quality.

Conclusion: FFPE sections not directly used for RNA extraction should be stored below -20 °C to increase quality and yield of the RNA. Usage of semi-automatic isolation produces superior results and simplifies routine processes by having less hands-on-time. Replacement of toxic xylene by d-limonene may contribute to improved occupational safety while not influencing analytical results.
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http://dx.doi.org/10.1016/j.prp.2018.12.027DOI Listing
February 2019

Inhibition of MDM2 via Nutlin-3A: A Potential Therapeutic Approach for Pleural Mesotheliomas with MDM2-Induced Inactivation of Wild-Type P53.

J Oncol 2018 17;2018:1986982. Epub 2018 Jul 17.

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

Previously, our group demonstrated that nuclear expression of E3 ubiquitin ligase (MDM2) in malignant pleural mesothelioma (MPM) is significantly associated with decreased overall survival. A possible explanation may be that overexpression of MDM2 leads to a proteasomal degradation of TP53 that eventually results in a loss of TP53-induced apoptosis and senescence. It is well known from other tumor entities that restoration of TP53 activity, e.g., by MDM2 inhibition, results in an instant TP53-induced stress and/or DNA damage response of cancer cells. Nutlin-3A (a -imidazoline analogue) has been described as a potent and selective MDM2 inhibitor preventing MDM2-TP53-interaction by specific binding to the hydrophobic TP53-binding pocket of MDM2. In the present study, the effects of MDM2 inhibition in MPM via Nutlin-3A and standard platinum based chemotherapeutic agents were comparatively tested in three MPM cell lines (NCI-H2052, MSTO-211H, and NCI-H2452) showing different expression profiles of TP53, MDM2, and its physiological inhibitor of MDM2-P14/ARF. Our experiments on MPM cell lines revealed that Nutlin-3A in combination with cisplatin resulted in up to 9.75 times higher induction of senescence (p=0.0050) and up to 5 times higher apoptosis rate (p=0.0067) compared to the commonly applied cisplatin and pemetrexed regimens. Thus Nutlin-3A, a potent inhibitor of MDM2, is associated with a significant induction of senescence and apoptosis in MPM cell lines, making Nutlin-3A a promising substance for a targeted therapy in the subgroup of MPM showing MDM2 overexpression.
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http://dx.doi.org/10.1155/2018/1986982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077509PMC
July 2018

Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy.

Oncotarget 2018 Apr 27;9(32):22254-22268. Epub 2018 Apr 27.

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

Background: Malignant pleural mesothelioma (MPM) is a biologically highly aggressive tumor arising from the pleura with a dismal prognosis. Cisplatin is the drug of choice for the treatment of MPM, and carboplatin seems to have comparable efficacy. Nevertheless, cisplatin treatment results in a response rate of merely 14% and a median survival of less than seven months. Due to their role in many cellular processes, methallothioneins (MTs) have been widely studied in various cancers. The known heavy metal detoxifying effect of MT-I and MT-II may be the reason for heavy metal drug resistance of various cancers including MPM.

Methods: 105 patients were retrospectively analyzed immunohistochemically for their MT expression levels. Survival analysis was done by Cox-regression, and statistical significance determined using likelihood ratio, Wald test and Score (logrank) tests.

Results: Cox-regression analyses were done in a linear and logarithmic scale revealing a significant association between expression of MT and shortened overall survival (OS) in a linear (p=0.0009) and logarithmic scale (p=0.0003). Reduced progression free survival (PFS) was also observed for MT expressing tumors (linear: p=0.0134, log: p=0.0152).

Conclusion: Since both, overall survival and progression-free survival are negatively correlated with detectable MT expression in MPM, our results indicate a possible resistance to platin-based chemotherapy associated with MT expression upregulation, found exclusively in progressive MPM samples. Initial cell culture studies suggest promoter DNA hypomethylation and expression of miRNA-566 a direct regulator of copper transporter SLC31A1 and a putative regulator of MT1A and MT2A gene expression, to be responsible for the drug resistance.
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http://dx.doi.org/10.18632/oncotarget.24962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976462PMC
April 2018

Papilloma of the Fallopian Tube: A Rare Gynecologic Neoplasm Harboring a BRAF (c.1799T>A) Mutation (V600E).

Int J Gynecol Pathol 2019 Sep;38(5):459-463

Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Essen (J.W., K.W., T.H., K.W.S) Institute of Pathology (J.W., H.F., J.P.) Department of Gynecology and Obstetrics (H.O.), Lutheran Diakonissen-Hospital Flensburg, Flensburg, Germany Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (B.D.).

Papillomas of the fallopian tube are exceedingly rare benign tumors, and only very few cases have been reported in the literature. Clinically, they may present as a mass lesion or occur without symptoms. Histomorphologically, they are papillary tumors covered by nonatypical epithelium with occasional ciliated or goblet cells growing in the lumen, and they are most frequently located in the infundibular region of the fallopian tube. They require a number of differential diagnostic evaluations and can be mistaken for either other benign tumors or malignant neoplasms. Because of their rare occurrence, molecular data about this entity have been lacking so far. Herein, a case of a papilloma with a BRAF (c.1799T>A) mutation (V600E) in a 45-yr-old woman with tumor-like dilation of the fallopian tube is presented.
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http://dx.doi.org/10.1097/PGP.0000000000000526DOI Listing
September 2019

The diagnostic role of BAP1 in serous effusions.

Hum Pathol 2018 09 24;79:122-126. Epub 2018 May 24.

Unit of Pathology, Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34151, Italy.

The aim of this study was to analyze the diagnostic role of BAP1 in effusion cytology. Effusions (n = 258), consisting of 53 malignant mesotheliomas and 205 other cancers, the majority carcinomas (62 breast, 60 ovarian, 31 lung, 51 carcinomas of other origin, 1 melanoma), were analyzed for BAP1 expression using immunohistochemistry. BAP1 was lost in 46 (87%) mesotheliomas compared with 4 (2%) of 205 other cancers (P < .001), resulting in sensitivity and specificity of 87% and 98%, respectively. There was no significant difference between peritoneal (n = 14) and pleural (n = 39) mesotheliomas. The 4 carcinomas with loss of BAP1 included 1 ovarian, 1 breast, 1 uterine cervical, and 1 gastric carcinoma. The present study supports the role of BAP1 as a highly sensitive and specific marker for malignant mesothelioma in serous effusions and argues for inclusion of this test in all specimens in which this diagnosis is considered.
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http://dx.doi.org/10.1016/j.humpath.2018.05.012DOI Listing
September 2018

Antiretroviral therapy suppresses rectal HIV-RNA shedding despite inflammation in MSM with rectal and infections-a cross-sectional, single-center study.

Sex Transm Infect 2019 03 3;95(2):95-98. Epub 2018 Feb 3.

Department of Dermatology, University Hospital, University of Duisburg-Essen, Essen, Germany.

Objectives: Rectal infections with and/or (CT/NG) are common in men who have sex with men (MSM) and are linked to HIV transmission. However, rectal CT/NG infections are often asymptomatic and it is not known how they contribute to HIV transmission. We assessed clinical and cytological signs of inflammation as well as rectal HIV-RNA in HIV-infected MSM with and without CT/NG infection.

Methods: 112 HIV-positive MSM with or without rectal symptoms and with or without antiretroviral therapy who underwent high-resolution anoscopy (HRA) at the proctological outpatient centre of the University Hospital Essen, Germany, between November 2013 and February 2014 were included in this cross-sectional study. During the examination, rectal swabs for the assessment of CT/NG, HIV-RNA and inflammatory cells (granulocytes, lymphocytes, histiocytes) were collected. 110 patients were assessed according to the study protocol, and no imputation of missing data was performed.

Results: Rectal infections with CT or NG were detected in 17 participants, and 4 participants were coinfected. Only symptomatic CT/NG infections (8/17) showed signs of inflammation in HRA. Symptomatic CT/NG infections were also associated with the detection of lymphocytes and histiocytes in rectal cytology (both P<0.001). In contrast, asymptomatic CT/NG infections neither resulted in clinical nor cytological signs of inflammation. Rectal HIV-RNA was undetectable in all participants with rectal CT/NG infections who received combined antiretroviral therapy (ART) when plasma HIV-RNA was below the limit of detection (n=13). Besides rectal CT/NG infections, syphilis (n=4) and HPV-associated lesions (n=37) were frequently detected, and proctological symptoms were associated with simultaneous infection with ≥2 STDs.

Conclusions: Only symptomatic but not asymptomatic rectal infections with CT and/or NG were associated with clinical and cytological signs of inflammation. Rectal HIV shedding was not promoted by CT/NG infections in patients receiving ART with suppressed plasma HIV-RNA.

Trial Registration Number: UTN: U1111-1150-4804. German Clinical Trials Register (DRKS): DRKS00005468.
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http://dx.doi.org/10.1136/sextrans-2017-053409DOI Listing
March 2019

The diagnostic role of PTEN and ARID1A in serous effusions.

Virchows Arch 2018 Mar 24;472(3):425-432. Epub 2017 Nov 24.

Institute of Cytology, Medical University of Graz, Auenbruggerplatz 20/1, A-8036, Graz, Austria.

The aim of this study was to analyze the diagnostic role of PTEN and ARID1A in effusion cytology. Effusions (n = 279), consisting of 226 carcinomas (70 ovarian, 64 breast, 36 lung, and 15 uterine corpus carcinomas; 41 carcinomas of other origin) and 53 malignant mesotheliomas, were analyzed for PTEN and ARID1A expression using immunohistochemistry. PTEN was preserved in 166 (59%) tumors, partially lost in 38 (14%), and absent in 75 (27%), with lower expression in malignant mesotheliomas compared to carcinomas, though not significantly (p = 0.084). ARID1A was preserved in 243 (88%) tumors, partially lost in 18 (6%), and absent in 18 (6%). The majority of tumors with absent ARID1A were ovarian carcinomas, predominantly of clear cell or low-grade serous type. Reactive mesothelial cells in carcinoma specimens were uniformly positive for both proteins. ARID1A mutation analysis showed no mutations in eight analyzed specimens negative by immunohistochemistry. Loss of PTEN and ARID1A expression is highly specific for malignancy in effusion pathology. Loss of PTEN is not informative of organ of origin, whereas absence of ARID1A should raise suspicion of an ovarian primary.
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http://dx.doi.org/10.1007/s00428-017-2273-1DOI Listing
March 2018

miRNA regulation is important for DNA damage repair and recognition in malignant pleural mesothelioma.

Virchows Arch 2017 Jun 2;470(6):627-637. Epub 2017 May 2.

Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.

Platin-containing regimes are currently considered as state-of-the-art therapies in malignant pleural mesotheliomas (MPM) but show dissatisfying response rates ranging from 6 to 16% only. Still, the reasons for the rather poor efficacy remain largely unknown. A clear stratification of patients based on new biomarkers seems to be a promising approach to enhance clinical management, which would be a long-needed improvement for MPM patients but does not seem likely soon unless new biomarkers can be validated. Twenty-four formalin-fixed, paraffin-embedded (FFPE) tumour specimens were subjected to a miRNA expression screening of 800 important miRNAs using digital quantification via the nCounter technique (NanoString). We defined a small subset of miRNAs regulating the key enzymes involved in the repair of platin-associated DNA damage. Particularly, the TP53 pathway network for DNA damage recognition as well as genes related to the term "BRCAness" are the main miRNA targets within this context. The TP53 pathway network for DNA damage recognition as well as genes related to the term "BRCAness" are the main players for risk stratification in patients suffering from this severe disease. Taking the specific molecular profile of the tumour into account can help to enhance the clinical management prospectively and to smooth the way to better response prediction.
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http://dx.doi.org/10.1007/s00428-017-2133-zDOI Listing
June 2017

Massive parallel sequencing and digital gene expression analysis reveals potential mechanisms to overcome therapy resistance in pulmonary neuroendocrine tumors.

J Cancer 2016 25;7(15):2165-2172. Epub 2016 Oct 25.

Institute of Pathology, Charité Universitaetsmedizin, Berlin.

: Lung cancer is the leading cause of cancer-related deaths worldwide. 25% show neuroendocrine differentiation (typical/atypical carcinoids, large-/small-cell neuroendocrine carcinomas). Carcinoids present with long survival rates, but metastatic carcinoids correlate with decreased survival and are commonly insensitive to standard chemotherapy or radiation. Therefore, novel therapeutic strategies are urgently needed. : 70 representative tumor specimens were used for next-generation sequencing analysis of 14 genes related to therapy response. Additionally, mRNA-expression profiles of 60 matching samples were determined for 13 selected drug targets by using the NanoString nCounter technology. : A number of features known to sensitize tumors for different targeted therapies could be identified, which hopefully improve the clinical management of this subgroup of lung neoplasias. In particular, expression was observed in the investigated tumors in a noteworthy manner. Additionally, was strongly expressed in the majority of all samples whereas the expression of its physiological inhibitor, , was nearly absent in all low-grade tumors. showed a high frequency of variants in high-grade tumors but mutations were rare in carcinoids. : Based on our results, therapeutic approaches with MDM2-inhibitors and monoclonal anti-EGFR antibodies may be promising in pulmonary carcinoid tumors.
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http://dx.doi.org/10.7150/jca.16925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5166524PMC
October 2016

Association of high HLA-E expression during acute cellular rejection and numbers of HLA class I leader peptide mismatches with reduced renal allograft survival.

Immunobiology 2017 03 4;222(3):536-543. Epub 2016 Nov 4.

Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands, Netherlands.

Non-classical Human Leukocyte Antigen (HLA)-E preferentially presents leader peptides derived from classical HLA-class I molecules. HLA-E can trigger opposed immune responses by interacting with inhibitory NKG2A or by activating NKG2C receptors on NK and T-cells. We studied the impact of HLA-E on renal allograft survival during acute cellular rejection. HLA-E expression was up-regulated in acute cellular rejection (ACR) biopsies (n=12) compared to biopsies from 13 renal allografts with no rejection-signs. HLA-E up-regulation was correlated with numbers of HLA-class I leader peptide mismatches (p=0.04). CD8+ and CD56+ infiltrating cells correlated with HLA-E expression (p<0.0001 and p=0.0009, respectively). Activating NKG2C receptor dominated on effector cells in biopsies and peripheral blood during ACR potentially allowing HLA-E-mediated immune activation. Moreover, HLA-E expression correlated with deterioration in renal allograft function (p<0.008) and reduced allograft survival (p=0.002). Our findings provide evidence that during renal allograft rejection HLA-E along with high numbers of mismatched HLA-class I leader peptides might represent additional targets for immune-activating responses.
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http://dx.doi.org/10.1016/j.imbio.2016.10.021DOI Listing
March 2017

ACTB, CDKN1B, GAPDH, GRB2, RHOA and SDCBP Were Identified as Reference Genes in Neuroendocrine Lung Cancer via the nCounter Technology.

PLoS One 2016 1;11(11):e0165181. Epub 2016 Nov 1.

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

Background: Neuroendocrine lung cancer (NELC) represents 25% of all lung cancer cases and large patient collectives exist as formalin-fixed, paraffin-embedded (FFPE) tissue only. FFPE is controversially discussed as source for molecular biological analyses and reference genes for NELC are poorly establishes.

Material And Methods: Forty-three representative FFPE-specimens were used for mRNA expression analysis using the digital nCounter technology (NanoString). Based on recent literature, a total of 91 mRNA targets were investigated as potential tumor markers or reference genes. The geNorm, NormFinder algorithms and coefficient of correlation were used to identify the most stable reference genes. Statistical analysis was performed by using the R programming environment (version 3.1.1).

Results: RNA integrity (RIN) ranged from 1.8 to 2.6 and concentrations from 34 to 2,109 ng/μl. However, the nCounter technology gave evaluable results for all samples tested. ACTB, CDKN1B, GAPDH, GRB2, RHOA and SDCBP were identified as constantly expressed genes with high stability (M-)values according to geNorm, NormFinder and coefficients of correlation.

Conclusion: FFPE-derived mRNA is suitable for molecular biological investigations via the nCounter technology, although it is highly degraded. ACTB, CDKN1B, GAPDH, GRB2, RHOA and SDCBP are potent reference genes in neuroendocrine tumors of the lung.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165181PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089548PMC
June 2017

Screening of Pleural Mesotheliomas for DNA-damage Repair Players by Digital Gene Expression Analysis Can Enhance Clinical Management of Patients Receiving Platin-Based Chemotherapy.

J Cancer 2016 13;7(13):1915-1925. Epub 2016 Sep 13.

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

Background: Malignant pleural mesothelioma (MPM) is a rare, predominantly asbestos-related and biologically highly aggressive tumour leading to a dismal prognosis. Multimodality therapy consisting of platinum-based chemotherapy is the treatment of choice. The reasons for the rather poor efficacy of platinum compounds remain largely unknown.

Material And Methods: For this exploratory mRNA study, 24 FFPE tumour specimens were screened by digital gene expression analysis. Based on data from preliminary experiments and recent literature, a total of 366 mRNAs were investigated using a Custom CodeSet from NanoString. All statistical analyses were calculated with the R i386 statistical programming environment.

Results: and gene expression were correlated with lymph node spread, and expression levels with higher IMIG stage. and expression was associated with TNM stage. as well as expression levels were correlated with tumour progression in the overall cohort of patients. and gene expression influenced overall survival in this collective. In the adjuvant treated cohort only, , as well as were significantly associated with overall survival. Furthermore, expression was associated with progression in this subgroup.

Conclusion: DNA-damage response plays a crucial role in response to platin-based chemotherapeutic regimes. In particular, , and are strongly associated with tumour progression. , and most promising are prognostic markers for OS in MPM. , , and seem to be also predictive markers in adjuvant treated MPMs. After a prospective validation, these markers may improve clinical and pathological practice, finally leading to a patients' benefit by an enhanced clinical management.
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http://dx.doi.org/10.7150/jca.16390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039377PMC
September 2016

Folic-acid metabolism and DNA-repair phenotypes differ between neuroendocrine lung tumors and associate with aggressive subtypes, therapy resistance and outcome.

Oncotarget 2016 Apr;7(15):20166-79

Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Purpose: 25% of all lung cancer cases are neuroendocrine (NELC) including typical (TC) and atypical carcinoid (AC), large-cell neuroendocrine (LCNEC) and small cell lung cancer (SCLC). Prognostic and predictive biomarkers are lacking.

Experimental Design: Sixty patients were used for nCounter mRNA expression analysis of the folic-acid metabolism (ATIC, DHFR, FOLR1, FPGS, GART, GGT1, SLC19A1, TYMS) and DNA-repair (ERCC1, MLH1, MSH2, MSH6, XRCC1). Phenotypic classification classified tumors (either below or above the median expression level) with respect to the folic acid metabolism or DNA repair.

Results: Expression of FOLR1, FPGS, MLH1 and TYMS (each p<0.0001) differed significantly between all four tumor types. FOLR1 and FPGS associated with tumor differentiation (both p<0.0001), spread to regional lymph nodes (FOLR1 p=0.0001 and FPGS p=0.0038), OS and PFS (FOLR1 p<0.0050 for both and FPGS p<0.0004 for OS). Phenotypic sorting revealed the Ft-phenotype to be the most prominent expression profile in carcinoids, whereas SCLC presented nearly univocal with the fT and LCNEC with fT or ft. These results were significant for tumor subtype (p<0.0001).

Conclusions: The assessed biomarkers and phenotypes allow for risk stratification (OS, PFS), diagnostic classification and enhance the biological understanding of the different subtypes of neuroendocrine tumors revealing potential new therapy options and clarifying known resistance mechanisms.
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http://dx.doi.org/10.18632/oncotarget.7737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991445PMC
April 2016

microRNAs are differentially regulated between MDM2-positive and negative malignant pleural mesothelioma.

Oncotarget 2016 Apr;7(14):18713-21

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

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive tumour first-line treated with a combination of cisplatin and pemetrexed. MDM2 and P14/ARF (CDKN2A) are upstream regulators of TP53 and may contribute to its inactivation. In the present study, we now aimed to define the impact of miRNA expression on this mechanism.

Material And Methods: 24 formalin-fixed paraffin-embedded (FFPE) tumour specimens were used for miRNA expression analysis of the 800 most important miRNAs using the nCounter technique (NanoString). Significantly deregulated miRNAs were identified before a KEGG-pathway analysis was performed.

Results: 17 miRNAs regulating TP53, 18 miRNAs regulating MDM2, and 11 miRNAs directly regulating CDKN2A are significantly downregulated in MDM2-expressing mesotheliomas. TP53 is downregulated in MDM2-negative tumours through miRNAs with a miSVR prediction score of 11.67, RB1 with a prediction score of 8.02, MDM2 with a prediction score of 4.50 and CDKN2A with a prediction score of 1.27.

Conclusion: MDM2 expression seems to impact miRNA expression levels in MPM. Especially, miRNAs involved in TP53-signaling are strongly decreased in MDM2-positive mesotheliomas. A better understanding of its tumour biology may open the chance for new therapeutic approaches and thereby augment patients' outcome.
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http://dx.doi.org/10.18632/oncotarget.7666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951323PMC
April 2016

Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group.

Br J Cancer 2015 Dec 8;113(12):1704-11. Epub 2015 Dec 8.

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

Background: Lung cancer is the leading cause of cancer-related deaths worldwide. The typical and atypical carcinoid (TC and AC), the large-cell neuroendocrine carcinoma (LCNEC) and the small-cell lung cancers (SCLC) are subgroups of pulmonary tumours that show neuroendocrine differentiations. With the rising impact of molecular pathology in routine diagnostics the interest for reliable biomarkers, which can help to differentiate these subgroups and may enable a more personalised treatment of patients, grows.

Methods: A collective of 70 formalin-fixed, paraffin-embedded (FFPE) pulmonary neuroendocrine tumours (17 TCs, 17 ACs, 19 LCNECs and 17 SCLCs) was used to identify biomarkers by high-throughput sequencing. Using the Illumina TruSeq Amplicon-Cancer Panel on the MiSeq instrument, the samples were screened for alterations in 221 mutation hot spots of 48 tumour-relevant genes.

Results: After filtering >26 000 detected variants by applying strict algorithms, a total of 130 mutations were found in 29 genes and 49 patients. Mutations in JAK3, NRAS, RB1 and VHL1 were exclusively found in SCLCs, whereas the FGFR2 mutation was detected in LCNEC only. KIT, PTEN, HNF1A and SMO were altered in ACs. The SMAD4 mutation corresponded to the TC subtype. We prove that the frequency of mutations increased with the malignancy of tumour type. Interestingly, four out of five ATM-mutated patients showed an additional alteration in TP53, which was by far the most frequently altered gene (28 out of 130; 22%). We found correlations between tumour type and IASLC grade for ATM- (P=0.022; P=0.008) and TP53-mutated patients (P<0.001). Both mutated genes were also associated with lymph node invasion and distant metastasis (P⩽0.005). Furthermore, PIK3CA-mutated patients with high-grade tumours showed a reduced overall survival (P=0.040) and the mutation frequency of APC and ATM in high-grade neuroendocrine lung cancer patients was associated with progression-free survival (PFS) (P=0.020).

Conclusions: The implementation of high-throughput sequencing for the analysis of the neuroendocrine lung tumours has revealed that, even if these tumours encompass several subtypes with varying clinical aggressiveness, they share a number of molecular features. An improved understanding of the biology of neuroendocrine tumours will offer the opportunity for novel approaches in clinical management, resulting in a better prognosis and prediction of therapeutic response.
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http://dx.doi.org/10.1038/bjc.2015.397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701994PMC
December 2015

MMP-7 is a highly specific negative marker for benign and malignant mesothelial cells in serous effusions.

Hum Pathol 2016 Jan 25;47(1):104-8. Epub 2015 Sep 25.

Department of Pathology, University Hospital Essen, Essen, 45147, Germany.

The aim of this study was to analyze the diagnostic role of MMP-7 in effusion cytology. Effusions (n = 356), consisting of 307 carcinomas (184 ovarian, 55 breast, 32 lung, 36 carcinomas of other origin) and 49 malignant mesotheliomas, were analyzed for MMP-7 expression using immunohistochemistry. MMP-7 was expressed in 124/307 (40%) carcinomas and was uniformly absent in malignant mesotheliomas (0/49; 0%; P < .001). Reactive mesothelial cells were similarly MMP-7 negative in all carcinoma specimens. In carcinomas, expression was most frequent in tumors of ovarian and other female genital (cervical and endometrial) origin (P < .001). The sensitivity and specificity of this marker in the differential diagnosis between high-grade serous carcinoma and malignant mesothelioma were 46% and 100%, respectively. In conclusion, MMP-7 expression is highly specific, though only of moderate sensitivity, for the diagnosis of carcinoma in the differential diagnosis from both benign and malignant mesothelial cells.
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http://dx.doi.org/10.1016/j.humpath.2015.08.020DOI Listing
January 2016

[Coronary atherosclerosis and progression to unstable plaques : Histomorphological and molecular aspects].

Herz 2015 Sep;40(6):837-44

Institut für Pathologie, Universitätsklinik Essen, Essen, Deutschland.

Atherosclerosis causes clinical symptoms through luminal narrowing by stenosis or by precipitating thrombi that obstruct blood flow to the myocardium (coronary artery disease), central nervous system (ischemic stroke) or lower extremities (peripheral vascular disease). The most common of these manifestations of atherosclerosis is coronary artery disease, clinically presenting as either stable angina or acute coronary syndromes. Atherosclerosis is a mainly lipoprotein-driven disease, which is associated with the formation of atherosclerotic plaques at specific sites of the vascular system through inflammation, necrosis, fibrosis and calcification. In most cases, plaque rupture of a so-called thin-cap fibroatheroma leads to contact of the necrotic core material of the underlying atherosclerotic plaque with blood, resulting in the formation of a thrombus with acute occlusion of the affected (coronary) artery. The atherosclerotic lesions that can cause acute coronary syndromes by formation of a thrombotic occlusion encompass (1) thin-cap fibroatheroma, (2) plaque erosion and (3) so-called calcified nodules in calcified and tortuous arteries of aged individuals. The underlying pathomechanisms remain incompletely understood so far. In this review, the mechanisms of atherosclerotic plaque initiation and progression are discussed.
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http://dx.doi.org/10.1007/s00059-015-4341-0DOI Listing
September 2015

Transbronchial Catheter Aspiration and Transbronchial Needle Aspiration in the Diagnostic Workup of Peripheral Lung Lesions.

Lung 2015 Oct 9;193(5):767-72. Epub 2015 Jul 9.

Institute of Pathology, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45122, Essen, Germany.

Purpose: Increasingly frequent, it is clinically indicated to obtain tissue from a peripheral lung lesion (PLL) to yield a pathological diagnosis. The aim of the present study was to evaluate the diagnostic sensitivity of transbronchial needle aspiration (TBNA) and transbronchial catheter aspiration (TBCA) in addition to transbronchial forceps biopsy (TBB) at conventional bronchoscopy.

Methods: Eligible patients showing a PLL on computed tomography scans were included in the study. In all patients, following TBB, TBNA and TBCA were employed in randomised order under fluoroscopy.

Results: Fourty-eight patients were enrolled, of whom 46 patients with 46 PLLs were included in the analysis. The mean ± SD diameter of the PLL was 27.0 ± 13.3 mm. The overall sensitivity for all modalities was 69.6%; PLL ≤20 or >20 and ≤30 mm in diameter showed a sensitivity of 60.0 and 72.2%, respectively. For malignant PLL (n = 33), the combined sensitivity of TBNA + TBCA versus TBB was significantly higher (63.6 vs. 33.3%, p ≤ 0.05), and could not further be improved by TBB. For benign PLL, TBB was superior to TBNA + TBCA (76.9 vs. 38.5%).

Conclusions: TBB, TBNA and TBCA are complementary to one another. Combining the three techniques, even allows transbronchial specimen collection of PLL <3 cm in diameter at conventional bronchoscopy.
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http://dx.doi.org/10.1007/s00408-015-9763-1DOI Listing
October 2015

Identification of deregulation of apoptosis and cell cycle in neuroendocrine tumors of the lung via NanoString nCounter expression analysis.

Oncotarget 2015 Sep;6(28):24690-8

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

Background: Neuroendocrine tumors of the lung comprise typical (TC) and atypical carcinoids (AC), large-cell neuroendocrine cancer (LCNEC) and small-cell lung cancer (SCLC). Cell cycle and apoptosis are key pathways of multicellular homeostasis and deregulation of these pathways is associated with cancerogenesis.

Materials And Methods: Sixty representative FFPE-specimens (16 TC, 13 AC, 16 LCNEC and 15 SCLC) were used for mRNA expression analysis using the NanoString technique. Eight genes related to apoptosis and ten genes regulating key points of cell cycle were investigated.

Results: ASCL1, BCL2, CASP8, CCNE1, CDK1, CDK2, CDKN1A and CDKN2A showed lower expression in carcinoids compared to carcinomas. In contrast, CCNE1 and CDK6 showed elevated expression in carcinoids compared to carcinomas. The calculated BCL2/BAX ratio showed increasing values from TC to SCLC. Between SCLC and LCNEC CDK2, CDKN1B, CDKN2A and PNN expression was significantly different with higher expression in SCLC.

Conclusion: Carcinoids have increased CDK4/6 and CCND1 expression controlling RB1 phosphorylation via this signaling cascade. CDK2 and CCNE1 were increased in carcinomas showing that these use the opposite way to control RB1. BAX and BCL2 are antagonists in regulating apoptosis. BCL2 expression increased over BAX expression with increasing malignancy of the tumor from TC to SCLC.
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http://dx.doi.org/10.18632/oncotarget.3992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694788PMC
September 2015

Prognostic model for long-term survival of locally advanced non-small-cell lung cancer patients after neoadjuvant radiochemotherapy and resection integrating clinical and histopathologic factors.

BMC Cancer 2015 May 6;15:363. Epub 2015 May 6.

Department of Medical Oncology, West German Cancer Center, University of Duisburg-Essen, Essen, Germany.

Background: Outcome of consecutive patients with locally advanced non-small cell lung cancer and histopathologically proven mediastional lymph node metastases treated with induction chemotherapy, neoadjuvant radiochemotherapy and thoracotomy at the West German Cancer Center between 08/2000 and 06/2012 was analysed. A clinico-pathological prognostic model for survival was built including partial or complete response according to computed tomography imaging (CT) as clinical parameters as well as pathologic complete remission (pCR) and mediastinal nodal clearance (MNC) as histopathologic factors.

Methods: Proportional hazard analysis (PHA) and recursive partitioning analysis (RPA) were used to identify prognostic factors for survival. Long-term survival was defined as survival ≥ 36 months.

Results: A total of 157 patients were treated, median follow-up was 97 months. Among these patients, pCR and MNC were observed in 41 and 85 patients, respectively. Overall survival was 56 ± 4% and 36 ± 4% at 24 and 60 months, respectively. Sensitivities of pCR and MNC to detect long-term survivors were 38% and 61%, specificities were 84% and 52%, respectively. Multivariable survival analysis revealed pCR, cN3 category, and gender, as prognostic factors at a level of α < 0.05. Considering only preoperative available parameters, CT response became significant. Classifying patients with a predicted hazard above the median as high risk group and the remaining as low risk patients yielded better separation of the survival curves by the inclusion of histopathologic factors than by preoperative factors alone (p < 0.0001, log rank test). Using RPA, pCR was identified as the top prognostic factor above clinical factors (p = 0.0006). No long term survivors were observed in patients with cT3-4 cN3 tumors without pCR.

Conclusions: pCR is the dominant histopathologic response parameter and improves prognostic classifiers, based on clinical parameters. The validated prognostic model can be used to estimate individual prognosis and forms a basis for patient selection for treatment intensification.
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http://dx.doi.org/10.1186/s12885-015-1389-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428235PMC
May 2015

Kidney transplantation after oxygenated machine perfusion preservation with Custodiol-N solution.

Transpl Int 2015 Sep 30;28(9):1102-8. Epub 2015 Apr 30.

Clinic of General, Visceral and Transplantation Surgery, University Hospital of Essen, Essen, Germany.

Custodiol-N, a new preservation solution, has been shown particularly suitable for hypothermic machine perfusion preservation (HMP) in isolated porcine kidneys. These preliminary results should be confirmed in an actual transplant model in vivo. Kidney function after 21 h of HMP was studied in an autotransplant model using Landrace pigs (25-30 kg; n = 6 per group). Perfusion was performed with oxygenated perfusate, using either Custodiol-N solution including 50 g/l dextran 40 (CND) or kidney perfusion solution 1 (KPS-1) as gold standard. Viability of the grafts was followed for 1 week after bilateral nephrectomy in the recipient pigs. HMP with CND resulted in less acute tubular injury, evaluated by levels of fatty acid-binding protein and better clearance function during the first 24 h after Tx than with KPS-1 (P < 0.05, resp.). Serum creatinine tended to be lower in the CND group during the whole observation period. Histological tissue scores one week after Tx were similar in both groups. Expression of endothelin-1 as well as of Toll-like receptor 4 15 min after reperfusion was lower in the CND group (P < 0.05), suggesting less endothelial stress response. The data provide first in vivo evidence for the suitability of Custodiol-N as an effective perfusate for renal machine perfusion.
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http://dx.doi.org/10.1111/tri.12593DOI Listing
September 2015

SOX4, SOX11 and PAX6 mRNA expression was identified as a (prognostic) marker for the aggressiveness of neuroendocrine tumors of the lung by using next-generation expression analysis (NanoString).

Future Oncol 2015 ;11(7):1027-36

Ruhrlandklinik, West German Lung Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Background: Neuroendocrine tumors of the lung (NELC) account for 25% of all lung cancer cases and transcription factors may drive dedifferentiation of these tumors. This study was conducted to identify supportive diagnostic and prognostic biomarkers.

Materials & Methods: A total of 16 TC, 13 AC, 16 large cell neuroendocrine carcinomas and 15 small cell lung cancer were investigated for the mRNA expression of 11 transcription factors and related genes (MYB, MYBBP1A, OCT4, PAX6, PCDHB, RBP1, SDCBP, SOX2, SOX4, SOX11, TEAD2).

Results: SOX4 (p = 0.0002), SOX11 (p < 0.0001) and PAX6 (p = 0.0002) were significant for tumor type. Elevated PAX6 and SOX11 expression correlated with poor outcome in large cell neuroendocrine carcinomas and small cell lung cancer (p < 0.0001 and p = 0.0232, respectively) based on survival data of 34 patients (57%).

Conclusion: Aggressiveness of NELC correlated with increasing expression of transcription factors. SOX11 seems to be a highly valuable diagnostic and prognostic marker for aggressive NELC.
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http://dx.doi.org/10.2217/fon.15.18DOI Listing
February 2016