Publications by authors named "Luka Brcic"

112 Publications

Rituximab as a Treatment Option after Autologous Hematopoietic Stem Cell Transplantation in a Patient with Systemic Sclerosis.

J Pers Med 2021 Jun 25;11(7). Epub 2021 Jun 25.

Division of Rheumatology and Immunology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.

Systemic sclerosis (SSc) is an intractable autoimmune disease characterized by vasculopathy and organ fibrosis. Autologous hematopoietic stem cell transplantation (AHSCT) should be considered for the treatment of selected patients with rapid progressive SSc at high risk of organ failure. It, however, remains elusive whether immunosuppressive therapies such as rituximab (RTX) are still necessary for such patients after AHSCT, especially in those with bad outcomes. In the present report, a 43-year-old man with diffuse cutaneous SSc received AHSCT. Despite AHSCT, SSc further progressed with progressive symptomatic heart failure with newly developed concomitant mitral and tricuspid valve insufficiency, thus the patient started on RTX 8 months after AHSCT. Shortly after initiation of RTX, clinical symptoms and organ functions ameliorated subsequently. Heart valve regurgitations were reversible after initiation of RTX treatment. Currently, the patient remains in a stable condition with significant improvement of clinical symptoms and organ functions. Reporting about therapies after AHSCT in SSc is a very important issue, as randomized controlled trials are lacking, and therefore this report adds to evidence that RTX can be considered as a treatment option in patients with SSc that do not respond to AHSCT.
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http://dx.doi.org/10.3390/jpm11070600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305780PMC
June 2021

Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma: an international multicenter study.

Transl Lung Cancer Res 2021 Apr;10(4):1594-1607

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Background: Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) immune-checkpoint blockade is a promising new therapeutic strategy in cancer. However, expression patterns and prognostic significance of PD-L1 and PD-1 are still controversial in human malignant pleural mesothelioma (MPM).

Methods: Formalin-fixed paraffin-embedded (FFPE) tumor samples from 203 MPM patients receiving standard treatment without immunotherapy were collected from 5 European centers. PD-L1 and PD-1 expression of tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemistry and correlated with clinical parameters and long-term outcome.

Results: High (>10%) PD-L1 TC and PD-1 TILs expressions were found in 18 (8%) and 39 (24%) patients, respectively. PD-L1 was rarely expressed by TILs [≥1%, n=13 (8%); >10%, n=1]. No significant associations were found between the PD-L1 or PD-1 expression of TCs or TILs and clinicopathological parameters such as stage or histological subtype. Notably, patients with high (>10%) TC-specific PD-L1 expression exhibited significantly worse median overall survival (OS) (6.3 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P<0.001). In multivariate cox regression analysis adjusted for clinical parameters, high TC PD-L1 expression (>10%) proved to be an independent negative prognostic factor for OS (HR: 2.486, P=0.005). There was no significant correlation between PD-L1 or PD-1 expression of TILs and OS.

Conclusions: In this multicenter cohort study, we demonstrate that high (>10%) PD-L1 expression of TCs independently predicts worse OS in MPM. Further studies are warranted to investigate the value of PD-L1/PD-1 expression as a marker for treatment response in MPM patients receiving immunotherapy.
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http://dx.doi.org/10.21037/tlcr-20-1114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107750PMC
April 2021

Comparison of Nuclear Grade, Necrosis, and Histologic Subtype Between Biopsy and Resection in Pleural Malignant Mesothelioma.

Am J Clin Pathol 2021 May 12. Epub 2021 May 12.

Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Objectives: Numerous studies on malignant mesothelioma (MM) highlight the prognostic importance of histologic subtype, nuclear grade, and necrosis. This study compares these parameters in paired biopsy and resection specimens of pleural MM.

Methods: Histologic subtype, percentage of epithelioid morphology, nuclear grade, and the presence or absence of necrosis were compared in 429 paired biopsies and resection specimens of pleural MM from 19 institutions.

Results: Histologic subtype was concordant in 81% of cases (κ = 0.58). When compared with resection specimens, epithelioid morphology at biopsy had a positive predictive value (PPV) of 78.9% and a negative predictive value (NPV) of 93.5%; sarcomatoid morphology showed high PPV (92.9%) and NPV (99.3%), and biphasic morphology PPV was 89.7% and NPV was 79.7%. Agreement of the percentage of epithelioid morphology was fair (κ = 0.27). Nuclear grade and necrosis were concordant in 75% (κ = 0.59) and 81% (κ = 0.53) of cases, respectively. Nuclear grade showed moderate (κ = 0.53) and substantial (κ = 0.67) agreement from patients with and without neoadjuvant therapy, respectively, and necrosis showed moderate (κ = 0.47 and κ = 0.60) agreement, respectively, in the same subsets of paired specimens.

Conclusions: Paired biopsy-resection specimens from pleural MM show overall moderate agreement in pathologic parameters. These findings may help guide postbiopsy management and triage of patients with MM.
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http://dx.doi.org/10.1093/ajcp/aqab054DOI Listing
May 2021

Applicability of pan-TRK immunohistochemistry for identification of NTRK fusions in lung carcinoma.

Sci Rep 2021 May 7;11(1):9785. Epub 2021 May 7.

Diagnostic and Research Institute of Pathology, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010, Graz, Austria.

In the last two decades, various therapies have been introduced for lung carcinoma patients, including tyrosine-kinase inhibitors for different mutations. While some of them are specific to specific tumor types, others, like NTRK1-3 fusions, are found in various solid tumors. The occurrence of an NTRK1,2 or 3 fusion acts as a biomarker for efficient treatment with NTRK inhibitors, irrespectively of the tumor type. However, the occurrence of the NTRK1-3 fusions in lung carcinomas is extremely rare. We performed a retrospective analysis to evaluate the applicability of immunohistochemistry with the pan-TRK antibody in the detection of NTRK fusions in lung carcinomas. The study cohort included 176 adenocarcinomas (AC), 161 squamous cell carcinomas (SCC), 31 large-cell neuroendocrine carcinomas (LCNEC), and 19 small cell lung carcinomas (SCLC). Immunohistochemistry (IHC) was performed using the pan-TRK antibody (clone EPR17341, Ventana) on tissue microarrays, while confirmation for all positive cases was done using RNA-based Archer FusionPlex MUG Lung Panel. On IHC staining, 12/387 samples (3.1%) demonstrated a positive reaction. Ten SCC cases (10/161, 6.2%), and two LCNEC cases (2/31, 6.5%) were positive. Positive cases demonstrated heterogeneous staining of tumor cells, mostly membranous with some cytoplasmic and in one case nuclear pattern. RNA-based sequencing did not demonstrate any NTRK1-3 fusion in our patients' collective. Our study demonstrates that pan-TRK expression in lung carcinoma is very low across different histologic types. NTRK1-3 fusions using an RNA-based sequencing approached could not be detected. This stresses the importance of confirmation of immunohistochemistry results by molecular methods.
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http://dx.doi.org/10.1038/s41598-021-89373-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105314PMC
May 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

The concept of mesothelioma in situ, with consideration of its potential impact on cytology diagnosis.

Pathology 2021 Jun 26;53(4):446-453. Epub 2021 Mar 26.

Department of Pathology, University of Chicago, Chicago, IL, USA.

Diffuse malignant mesothelioma (MM) is an incurable tumour of the serosal membranes, which is often caused by exposure to asbestos and commonly diagnosed at advanced stage. Malignant mesothelioma in situ (MMIS) is now included as diagnostic category by the World Health Organization (WHO). However, our international survey of 34 pulmonary pathologists with an interest in MM diagnosis highlights inconsistency regarding how the diagnosis is being made by experts, despite published guidelines. Whilst the WHO restricts the diagnosis to surgical samples, the very concept has implication for cytological diagnosis, which is already regarded as controversial in itself by some. MMIS is currently only applicable as precursor to MM with an epithelioid component, and raises the possibility for different molecular pathways for different histological MM subtypes. The clinical implications of MMIS at this stage are uncertain, but aggressive therapies are being initiated in some instances. Based on the results of the survey we here present a critical appraisal of the concept, its clinical and conceptual implications and provide practice suggestions for diagnosis. A low threshold for ancillary testing is suggested. The designations of 'malignant mesothelioma, cannot exclude MMIS' or 'atypical mesothelial proliferation with molecular indicators of malignancy, so-called MMIS' could be used on cytology samples, adding 'no evidence of invasion in sample provided' for surgical samples. Clinical and radiological correlation are integral to diagnosis and best done at multidisciplinary meetings. Finally, collaborative studies are required to improve our understanding of MMIS.
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http://dx.doi.org/10.1016/j.pathol.2020.12.005DOI Listing
June 2021

Identification of serum biomarkers to predict pemetrexed/platinum chemotherapy efficacy for advanced lung adenocarcinoma patients by data-independent acquisition (DIA) mass spectrometry analysis with parallel reaction monitoring (PRM) verification.

Transl Lung Cancer Res 2021 Feb;10(2):981-994

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Medical Oncology, Peking University Cancer Hospital & Institute, Beijing, China.

Background: Pemetrexed/platinum chemotherapy has been the standard chemotherapy regimen for lung adenocarcinoma patients, but the efficacy varies considerably.

Methods: To discover new serum biomarkers to predict the efficacy of pemetrexed/platinum chemotherapy, we analyzed 20 serum samples from advanced lung adenocarcinoma patients who received pemetrexed/platinum chemotherapy with the data-independent acquisition (DIA) quantitative mass spectrometry (MS).

Results: The 20 patients were categorized as "good response" [12 patients achieving partial response (PR)] and "poor response" [8 patients with progressive disease (PD)] groups. Altogether 23 significantly different expressed proteins were identified, which had relative ratios higher than 1.2 or lower than -0.83, with 7 proteins having an area under the curve (AUC) above 0.8. To further validate the DIA results, we used the parallel reaction monitoring (PRM) method to examine 16 candidate serum biomarkers in the study cohort of 20 patients and another cohort of 22 advanced lung adenocarcinoma patients (16 PR and 6 PD). Quantitative validation using PRM correlated well with the DIA results, and 10 promising proteins exhibited a similar up- or downregulation. It is worth noting that glutathione peroxidase 3 (GPX3) exhibits significant upregulation in the poor response group compared with the good response group, which was validated by both DIA and PRM methods.

Conclusions: Our study confirmed that combined DIA MS and PRM approaches were effective in identifying serum predictive biomarkers for advanced lung adenocarcinoma patients. Further studies are needed to explore the potential biological mechanism underlying these biomarkers.
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http://dx.doi.org/10.21037/tlcr-21-153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947410PMC
February 2021

CpG islands in MyD88 and ASC/PYCARD/TMS1 promoter regions are differentially methylated in head and neck squamous cell carcinoma and primary lung squamous cell carcinoma.

Diagn Pathol 2021 Feb 26;16(1):17. Epub 2021 Feb 26.

Division of Molecular Medicine, Laboratory for Advanced Genomics, Ruđer Bošković Institute, Zagreb, Croatia.

Background: Patients with head and neck squamous cell carcinoma (HNSCC) can develop lung squamous cell carcinoma (LuSCC), which could be the second primary tumor or HNSCC metastasis. Morphologically it is difficult to distinguish metastatic HNSCC from a second primary tumor which presents a significant diagnostic challenge. Differentiation of those two malignancies is important because the recommended treatments for metastatic HNSCC and primary LuSCC differ significantly. We investigated if the quantification of the promotor methylation status in HNSCC and LuSCC differs.

Methods: Primary HNSCC (N = 36) and LuSCC (N = 17) were included in this study. Methylation status in the ASC/TMS1/PYCARD (apoptosis-associated speck-like protein containing a caspase recruitment domain; 8 CpG sites) and MyD88 (Myeloid differentiation primary response protein 88; 10 CpG sites) promoters was analyzed. Bisulfite converted DNA, isolated from tumor tissue was quantified using pyrosequencing. Results of pyrosequencing analysis were expressed as a percentage for each tested CpG site. Receiver-operating characteristic (ROC) curve analysis was used for the evaluation of the diagnostic properties of selected biomarkers.

Results: CpG sites located in the promoters of ASC/TMS1/PYCARD_CpG8 (- 65 upstream) and MyD88_CpG4 (- 278 upstream) are significantly hypermethylated in the HNSCC when compared with LuSCC (p ≤ 0.0001). By performing ROC curve analysis we showed that corresponding areas under the curve (AUC) were 85-95%, indicating that selected CpG sites are useful for a distinction between primary LuSCC and primary HNSCC.

Conclusions: Results of the present study indicate that there is a significant difference in the methylation status of tested genes between primary HNSCC and LuSCC. However, to prove this approach as a useful tool for distinguishing second primary LuSCC from HNSCC metastasis, it would be necessary to include a larger number of samples, and most importantly, metastatic samples.
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http://dx.doi.org/10.1186/s13000-021-01078-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913417PMC
February 2021

Shifting the Immune-Suppressive to Predominant Immune-Stimulatory Radiation Effects by SBRT-PArtial Tumor Irradiation Targeting HYpoxic Segment (SBRT-PATHY).

Cancers (Basel) 2020 Dec 26;13(1). Epub 2020 Dec 26.

MedAustron Ion Therapy Center, Marie Curie-Straße 5, 2700 Wiener Neustadt, Austria.

Radiation-induced immune-mediated abscopal effects (AE) of conventional radiotherapy are very rare. Whole-tumor irradiation leads to lymphopenia due to killing of immune cells in the tumor microenvironment, resulting in immunosuppression and weak abscopal potential. This limitation may be overcome by partial tumor irradiation sparing the peritumoral immune-environment, and consequent shifting of immune-suppressive to immune-stimulatory effect. This would improve the radiation-directed tumor cell killing, adding to it a component of immune-mediated killing. Our preclinical findings showed that the high-single-dose irradiation of hypoxic tumor cells generates a stronger bystander effect (BE) and AE than the normoxic cells, suggesting their higher "immunogenic potential". This led to the development of a novel Stereotactic Body RadioTherapy (SBRT)-based PArtial Tumor irradiation targeting HYpoxic segment (SBRT-PATHY) for induction of the immune-mediated BE and AE. Encouraging SBRT-PATHY-clinical outcomes, together with immunohistochemical and gene-expression analyses of surgically removed abscopal-tumor sites, suggested that delivery of the high-dose radiation to the partial (hypoxic) tumor volume, with optimal timing based on the homeostatic fluctuation of the immune response and sparing the peritumoral immune-environment, would significantly enhance the immune-mediated anti-tumor effects. This review discusses the current evidence on the safety and efficacy of SBRT-PATHY in the treatment of unresectable hypoxic bulky tumors and its bystander and abscopal immunomodulatory potential.
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http://dx.doi.org/10.3390/cancers13010050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795882PMC
December 2020

Response to: "Study results and related evidence do not support use of HPV16 L1 DRH1 antibodies as a cancer screening test".

EBioMedicine 2020 12 27;62:103139. Epub 2020 Nov 27.

Department of Otorhinolaryngology-Head&Neck Surgery, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1016/j.ebiom.2020.103139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701314PMC
December 2020

Outsourcing predictive biomarker testing in non-small cell carcinoma: a personal view of pathologists.

Transl Lung Cancer Res 2020 Oct;9(5):2194-2198

Cytology and Pathology Laboratory, University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.

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http://dx.doi.org/10.21037/tlcr-20-297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653138PMC
October 2020

Malignant peritoneal mesothelioma: prognostic significance of clinical and pathologic parameters and validation of a nuclear-grading system in a multi-institutional series of 225 cases.

Mod Pathol 2021 02 15;34(2):380-395. Epub 2020 Oct 15.

Department of Pathology, University of Chicago, Chicago, IL, USA.

Malignant peritoneal mesothelioma historically carried a grim prognosis, but outcomes have improved substantially in recent decades. The prognostic significance of clinical, morphologic, and immunophenotypic features remains ill-defined. This multi-institutional cohort comprises 225 malignant peritoneal mesotheliomas, which were assessed for 21 clinical, morphologic, and immunohistochemical parameters. For epithelioid mesotheliomas, combining nuclear pleomorphism and mitotic index yielded a composite nuclear grade, using a previously standardized grading system. Correlation of clinical, morphologic, and immunohistochemical parameters with overall and disease-free survival was examined by univariate and multivariate analyses. On univariate analysis, longer overall survival was significantly associated with diagnosis after 2000 (P = 0.0001), age <60 years (P = 0.0001), ECOG performance status 0 or 1 (P = 0.01), absence of radiographic lymph-node metastasis (P = 0.04), cytoreduction surgery (P < 0.0001), hyperthermic intraperitoneal chemotherapy (P = 0.0001), peritoneal carcinomatosis index <27 (P = 0.01), absence of necrosis (P = 0.007), and epithelioid histotype (P < 0.0001). Among epithelioid malignant mesotheliomas only, longer overall survival was further associated with female sex (P = 0.03), tubulopapillary architecture (P = 0.005), low nuclear pleomorphism (P < 0.0001), low mitotic index (P = 0.0007), and low composite nuclear grade (P < 0.0001). On multivariate analyses, the low composite nuclear grade was independently associated with longer overall and disease-free survival (P < 0.0001). Our data further clarify the interactions of clinical and pathologic features in peritoneal mesothelioma prognosis and validate the prognostic significance of a standardized nuclear-grading system in epithelioid malignant mesothelioma of the peritoneum.
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http://dx.doi.org/10.1038/s41379-020-00688-4DOI Listing
February 2021

Senescence and autophagy in usual interstitial pneumonia of different etiology.

Virchows Arch 2021 Mar 27;478(3):497-506. Epub 2020 Aug 27.

Diagnostic and Research Institute of Pathology, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010, Graz, Austria.

Idiopathic pulmonary fibrosis (IPF) is a disease with a dismal prognosis. Currently, the causing agent(s) are poorly understood. Recent data suggest that senescence and autophagy might play a role in its development, as well as changes in metabolism due to hypoxic conditions. In this study, the expression of senescence markers in 23 cases of usual interstitial pneumonia (UIP)/IPF and UIP/chronic autoimmune diseases (UIP/AuD) was investigated. The status of autophagy was evaluated with respect to either antiinflammatory or antihypoxia function. Formalin-fixed paraffin-embedded tissues of UIP were selected for immunohistochemistry with antibodies for p21, p16, and β-galactosidase (senescence); for LC3, SIRT1, MAP1S, and pAMKα (autophagy); and for LDH and GLUT1 (metabolism). Epithelial cells in cystic remodeled areas of UIP stained for p16 and p21, p16 being more specific compared with p21. Myofibroblasts were negative in all cases. An upregulation of all four autophagy markers was seen not only in epithelia within remodeled areas and proliferating myofibroblasts, but also in bronchial epithelia and pneumocytes. Upregulated autophagy points to a compensatory mechanism for hypoxia; therefore, LDH and GLUT1 were investigated. Their expression was present in epithelia within cystic remodeling and in myofibroblasts. The cells within the remodeled areas stained for cytokeratin 5, but coexpressed TTF1, confirming their origin from basal cells of bronchioles. Within this population, senescent cells arise. Our results indicated that autophagy in UIP very likely helps cells to survive in hypoxic condition. By phagocytosis of cellular debris, they supplement their need for nutrition, and by upregulating LDH and GLUT1, they compensate for local hypoxia.
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http://dx.doi.org/10.1007/s00428-020-02917-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973921PMC
March 2021

Distribution and prognostic significance of gluconeogenesis and glycolysis in lung cancer.

Mol Oncol 2020 11 1;14(11):2853-2867. Epub 2020 Sep 1.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Austria.

Inhibition of glycolysis has been considered as a therapeutic approach in aggressive cancers including lung cancer. Abbreviated gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (PEPCK), was recently discovered to partially circumvent the need for glycolysis in lung cancer cells. However, the interplay of glycolysis and gluconeogenesis in lung cancer is still poorly understood. Here, we analyzed the expression of GLUT1, the prime glucose transporter, and of PCK1 and PCK2, the cytoplasmic and mitochondrial isoforms of PEPCK, in 450 samples of non-small cell lung cancer (NSCLC) and in 54 NSCLC metastases using tissue microarrays and whole tumor sections. Spatial distribution was assessed by automated image analysis. Additionally, glycolytic and gluconeogenic gene expression was inferred from The Cancer Genome Atlas (TCGA) datasets. We found that PCK2 was preferentially expressed in the lung adenocarcinoma subtype, while GLUT1 expression was higher in squamous cell carcinoma. GLUT1 and PCK2 were inversely correlated, GLUT1 showing elevated expression in larger tumors while PCK2 was highest in smaller tumors. However, a mixed phenotype showing the presence of both, glycolytic and gluconeogenic cancer cells was frequent. In lung adenocarcinoma, PCK2 expression was associated with significantly improved overall survival, while the opposite was found for GLUT1. The metabolic tumor microenvironment and the 3-dimensional context play an important role in modulating both pathways, since PCK2 expression preferentially occurred at the tumor margin and hypoxia regulated both, glycolysis and gluconeogenesis, in NSCLC cells in vitro, albeit in opposite directions. PCK1/2 expression was enhanced in metastases compared to primary tumors, possibly related to the different environment. The results of this study show that glycolysis and gluconeogenesis are activated in NSCLC in a tumor size and oxygenation modulated manner and differentially correlate with outcome. The frequent co-activation of gluconeogenesis and glycolysis in NSCLC should be considered in potential future therapeutic strategies targeting cancer cell metabolism.
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http://dx.doi.org/10.1002/1878-0261.12780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607181PMC
November 2020

International real-world study of DLL3 expression in patients with small cell lung cancer.

Lung Cancer 2020 09 27;147:237-243. Epub 2020 Jul 27.

University Clermont Auvergne, Jean Perrin Center, INSERM, IMoST, 63000 Clermont-Ferrand, France.

Objectives: Expression of the Notch-family ligand delta-like protein 3 (DLL3), a potential therapeutic target in small cell lung cancer (SCLC), has not been assessed in the real-world setting. To identify the real-world utility of DLL3 as an SCLC therapeutic target, we performed the largest retrospective international noninterventional study to date to evaluate DLL3 prevalence in SCLC patients.

Materials And Methods: DLL3 expression was assessed using immunohistochemistry in archived histological and cytological specimens (independent and paired) and correlated to patient demographics, clinical disease characteristics, and survival. The primary endpoint was the proportion of patients with DLL3 expression in ≥25 % of tumor cells. DLL3 expression concordance was assessed in paired specimens.

Results: Independent tumor specimens were collected from 1073 patients. The mean age at biopsy was 66 years (SD, 10); 682 (64 %) patients were male. Paired specimens were collected from 36 patients. The mean age at biopsy was 62 years (SD, 11); 16 (44 %) patients were male. Most patients had ECOG performance status of 0-1, were smokers/ex-smokers, and received ≥1 prior therapy. Positive DLL3 expression (defined as ≥25 % of tumor cells) was identified in 895/1050 (85 %) patients with 1 specimen and evaluable DLL3 expression; 719/1050 (68 %) patients had high DLL3 expression (defined as ≥75 % of tumor cells). DLL3 expression concordance was 88 % between paired specimens (n = 17; Cohen's kappa P value, .9412). There was no significant difference in median overall survival from SCLC diagnosis for evaluable patients with nonmissing data based on DLL3 expression (negative DLL3 expression [n = 139], 9.5 months; positive DLL3 expression [n = 747], 9.5 months; all evaluable patients [n = 893, 9.5 months).

Conclusion: These real-world epidemiologic findings indicate that DLL3 is robustly expressed across SCLC disease stages and remains stable despite treatment, consistent with available clinical trial data. There was no prognostic role for DLL3 observed in this study for overall survival.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.026DOI Listing
September 2020

Hazard Curves for Tumor Recurrence and Tumor-Related Death Following Esophagectomy for Esophageal Cancer.

Cancers (Basel) 2020 Jul 27;12(8). Epub 2020 Jul 27.

Division of Thoracic and Hyperbaric Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria.

Background: The knowledge of both patterns and risk of relapse following resection for esophageal cancer is crucial for establishing appropriate surveillance schedules. The aim of this study was to evaluate the pattern of hazards for tumor recurrence and tumor-related death in the postoperative long-term follow-up after esophagectomy.

Methods: Retrospective single-center analysis of 362 patients, with resected esophageal cancer. Multivariate Cox proportional hazard model was used.

Results: A total of 192 (53%) had postoperative tumor recurrence. The relapse patterns of adenocarcinoma and squamous-cell carcinoma showed that each had a single peak, 12 months after surgery. After induction there was one peak at 5 months, the non-induced patients peaked 11 months, postoperatively. At 18 months, the recurrence hazard declined sharply in all cases. The hazard curves for tumor-related death were bimodal for adenocarcinoma, with two peaks at 6 and 22 months and one single peak for squamous-cell carcinoma at 18 months after surgery, showing pronounced decline later on.

Conclusion: In curatively resected esophageal cancer, both tumor recurrence hazard and hazard for tumor-related death showed distinct, partly bimodal patterns. It could be justified to intensify the surveillance during the first two postoperative years by initiating a close-meshed follow-up to detect and treat tumor recurrence, as early as possible.
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http://dx.doi.org/10.3390/cancers12082066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466063PMC
July 2020

Clinical significance of histologic subtyping of malignant pleural mesothelioma.

Transl Lung Cancer Res 2020 Jun;9(3):924-933

Cytology and Pathology Laboratory, University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.

Malignant mesothelioma (MM) is uncommon, but very aggressive tumor arising from the mesothelial cells of pleura, pericardium, peritoneum, and tunica vaginalis. Despite multimodality treatments 5-year survival is only 5% after the diagnosis. Histology and TNM staging system are still the best prognostic factors. Furthermore, histologic subtype of MM determines the clinical management of the patients. According to the 2015 WHO classification, MM is divided into diffuse, localized and well differentiated papillary mesothelioma. Major histologic subtypes of diffuse MM, namely epithelioid, biphasic and sarcomatoid, have different prognosis. However, in the last decade it has become evident that more detailed subclassification and histologic/cytological characterization of MM have prognostic and perhaps predictive implications. In this review, major histologic subtypes and cytological features of MM are presented and their relation with prognosis and predictive biomarkers is discussed.
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http://dx.doi.org/10.21037/tlcr.2020.03.38DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354152PMC
June 2020

Lung cancer biomarker testing: perspective from Europe.

Transl Lung Cancer Res 2020 Jun;9(3):887-897

The Fingerland Department of Pathology, Charles University Medical Faculty and University Hospital, Hradec Kralove, Czech Republic.

A questionnaire on biomarker testing previously used in central European countries was extended and distributed in Western and Central European countries to the pathologists participating at the Pulmonary Pathology Society meeting 26-28 June 2019 in Dubrovnik, Croatia. Each country was represented by one responder. For recent biomarkers the availability and reimbursement of diagnoses of molecular alterations in non-small cell lung carcinoma varies widely between different, also western European, countries. Reimbursement of such assessments varies widely between unavailability and payments by the health care system or even pharmaceutical companies. The support for testing from alternative sources, such as the pharmaceutical industry, is no doubt partly compensating for the lack of public health system support, but it is not a viable or long-term solution. Ideally, a structured access to testing and reimbursement should be the aim in order to provide patients with appropriate therapeutic options. As biomarker enabled therapies deliver a 50% better probability of outcome success, improved and unbiased reimbursement remains a major challenge for the future.
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http://dx.doi.org/10.21037/tlcr.2020.04.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354119PMC
June 2020

Expanding the Molecular Spectrum of Secretory Carcinoma of Salivary Glands With a Novel VIM-RET Fusion.

Am J Surg Pathol 2020 10;44(10):1295-1307

Institute of Biomedicine, Pathology, University of Turku, Turku, Finland.

Background: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET, ETV6-MAML3, and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements.

Design: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6, RET, and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction.

Results: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients' age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts.

Conclusions: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET-targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B. The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non-ETV6 5' fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.
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http://dx.doi.org/10.1097/PAS.0000000000001535DOI Listing
October 2020

Differences in food consumption between patients with Hashimoto's thyroiditis and healthy individuals.

Sci Rep 2020 06 30;10(1):10670. Epub 2020 Jun 30.

Department of Medical Biology, University of Split School of Medicine, Soltanska 2, 21000, Split, Croatia.

Food is considered as important environmental factor that plays a role in development of Hashimoto's thyroiditis (HT). The goal of our study was to identify food groups, assessed by food frequency questionnaire, that differ in consumption frequency between 491 patients with HT and 433 controls. We also analysed association of food groups with the wealth of HT-related clinical traits and symptoms. We found significantly increased consumption of animal fat (OR 1.55, p < 0.0001) and processed meat (OR 1.16, p = 0.0012) in HT cases, whereas controls consumed significantly more frequently red meat (OR 0.80, p < 0.0001), non-alcoholic beverages (OR 0.82, p < 0.0001), whole grains (OR 0.82, p < 0.0001) and plant oil (OR 0.87, p < 0.0001). We also observed association of plant oil consumption with increased triiodothyronine levels in HT patients (β = 0.07, p < 0.0001), and, association of olive oil consumption with decreased systolic blood pressure (β = - 0.16, p = 0.001) in HT patients on levothyroxine (LT4) therapy. Analysis of food consumption between HT patients with and without LT4 therapy suggest that patients do not tend to modify their diet upon HT diagnosis in our population. Our study may be of relevance to nutritionists, nutritional therapists and clinicians involved in developing dietary recommendations for HT patients.
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http://dx.doi.org/10.1038/s41598-020-67719-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327046PMC
June 2020

DRH1 - a novel blood-based HPV tumour marker.

EBioMedicine 2020 Jun 11;56:102804. Epub 2020 Jun 11.

Department of Otorhinolaryngology-Head&Neck Surgery, General Hospital Ried im Innkreis, Ried, Austria.

Background: To date, no studies have successfully shown that a highly specific, blood-based tumour marker to detect clinically relevant HPV-induced disease could be used for screening, monitoring therapy response or early detection of recurrence. This study aims to assess the clinical performance of a newly developed HPV16-L1 DRH1 epitope-specific serological assay.

Methods: In a multi-centre study sera of 1486 patients (301 Head and Neck Squamous Cell Carcinoma (HNSCC) patients, 12 HIV+ anal cancer patients, 80 HIV-positive patients, 29 Gardasil-9-vaccinees, 1064 healthy controls) were tested for human HPV16-L1 DRH1 antibodies. Analytical specificity was determined using WHO reference-sera for HPV16/18 and 29 pre- and post-immune sera of Gardasil-9-vaccinees. Tumour-tissue was immunochemically stained for HPV-L1-capsidprotein-expression.

Findings: The DRH1-competitive-serological-assay showed a sensitivity of 95% (95% CI, 772-999%) for HPV16-driven HNSCC, and 90% (95% CI, 555-997%) for HPV16-induced anal cancer in HIV-positives. Overall diagnostic specificity was 9946% for men and 9929% for women ≥ 30 years. After vaccination, antibody level increased from average 364 ng/ml to 37,500 ng/ml. During post-therapy-monitoring, HNSCC patients showing an antibody decrease in the range of 30-100% lived disease free over a period of up to 26 months. The increase of antibodies from 2750 to 12,000 ng/ml mirrored recurrent disease. We can also show that the L1-capsidprotein is expressed in HPV16-DNA positive tumour-tissue.

Interpretation: HPV16-L1 DRH1 epitope-specific antibodies are linked to HPV16-induced malignant disease. As post-treatment biomarker, the assay allows independent post-therapy monitoring as well as early diagnosis of tumour recurrence. An AUC of 096 indicates high sensitivity and specificity for early detection of HPV16-induced disease.

Funding: The manufacturer provided assays free of charge.
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http://dx.doi.org/10.1016/j.ebiom.2020.102804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300133PMC
June 2020

Concordance of tumor infiltrating lymphocytes, PD-L1 and p16 expression in small biopsies, resection and lymph node metastases of oropharyngeal squamous cell carcinoma.

Oral Oncol 2020 07 23;106:104719. Epub 2020 Apr 23.

Diagnostic and Research Institute of Pathology, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria. Electronic address:

Objective: The incidence of oropharyngeal squamous cell carcinoma (OPSCC), especially human papillomavirus (HPV)-associated, is increasing worldwide. Immunotherapy become available for patients with carcinomas in the head and neck region, however without ideal biomarker. Markers like PD-L1 vary in the clone of the antibody used, and the method of evaluation. Adequate and reliable immune cells characterization and evaluation is still not found. Furthermore, studies analyzing representativeness of different tissue samples are scarce. We analyzed small biopsy, lymph node (LN) metastasis and resected OPSCC, in regards of tumor infiltrating lymphocyte (TIL) density, PD-L1 and p16 expression.

Material And Methods: Patients with OPSCC diagnosed from 2000 to 2016, with small biopsy, resection specimen and LN metastasis samples were selected. We analyzed TILs on hematoxylin-eosin stain, and PD-L1 and p16 expression in tumor cells. Concordance between different tumor locations was evaluated.

Results: 93 patients, with 65 small biopsies, 72 resection specimens, and 70 LN metastases were included. TILs, p16 and PD-L1 demonstrated very high concordance. Additionally, PD-L1 expression in the small biopsies was more representative of the PD-L1 expression in the resection specimens, than the LN samples.

Conclusion: TILs density can be reliably assessed using hematoxylin-eosin stain with high concordance between the small biopsy, resection specimen and LN metastasis. Evaluation of concordance of p16 expression is very high, nevertheless some cases might be misdiagnosed on a small biopsy or lymph node metastasis. Evaluation of PD-L1 expression is very reliable on the biopsy specimen. Different PD-L1 clones and methods of evaluation still remain to be addressed.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104719DOI Listing
July 2020

Telomerase Reverse Transcriptase Promoter Mutations Identify a Genomically Defined and Highly Aggressive Human Pleural Mesothelioma Subgroup.

Clin Cancer Res 2020 07 21;26(14):3819-3830. Epub 2020 Apr 21.

Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Purpose: Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate whether activating mutations in the telomerase reverse transcriptase () gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns.

Experimental Design: promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for immortalization. The respective MPM cell models ( = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays.

Results: promoter mutations were detected in 19 of 182 (10.4%) MPM cases and significantly associated with advanced disease and nonepithelioid histology. Mutations independently predicted shorter overall survival in both histologic MPM subtypes. Moreover, 9 of 9 (100%) mutated but only 13 of 36 (36.1%) wild-type samples formed immortalized cell lines promoter mutations were associated with enforced promoter activity and mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. promoter-mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While mutations/deletions were exclusive with promoter mutations, homozygous deletions at the and the loci were clearly enriched in mutated cases.

Conclusions: promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3573DOI Listing
July 2020

Differentiating Between Malignant Mesothelioma and Other Pleural Lesions Using Fourier Transform Infrared Spectroscopy.

Appl Spectrosc 2020 Jul 29;74(7):808-818. Epub 2020 May 29.

Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia.

Histopathology, despite being the gold standard as a diagnostic tool, does not always provide a correct diagnosis for different pleural lesions. Although great progress was made in this field, the problem to differentiate between reactive and malignant pleural lesions still stimulates the search for additional diagnostic tools. Our research using vibrational spectroscopy and principal component analysis (PCA) statistical modeling represents a potentially useful tool to approach the problem. The objective method this paper explores is based on the correlation between different types of pleural lesions and their vibrational spectra. Obtained tissue spectra recorded by infrared spectroscopy allowed us to categorize spectra in different groups using a created PCA statistical model. The PCA model was built using tissues of known pathology as the model group. The validation samples were then used to confirm the functionality of our PCA model. Student's -test was also used for comparing samples in paired groups. The PCA model was able to clearly differentiate the spectra of mesothelioma, metastasis and reactive changes (inflammation), and place them in discrete groups. Thus, we showed that Fourier transform infrared spectroscopy combined with PCA can differentiate pleural lesions with high sensitivity and specificity. This new approach could contribute in objectively differentiating specific pleural lesions, thus helping pathologists to better diagnose difficult pleural samples but also could shed additional light into the biology of malignant pleural mesothelioma.
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http://dx.doi.org/10.1177/0003702820924726DOI Listing
July 2020

Pleuropulmonary blastoma type I might arise in congenital pulmonary airway malformation type 4 by acquiring a Dicer 1 mutation.

Virchows Arch 2020 Sep 19;477(3):375-382. Epub 2020 Mar 19.

Diagnostic and Research Institute of Pathology, Medical University of Graz, Neue Stiftingtalstrasse 6, 8036, Graz, Austria.

Congenital pulmonary airway malformation (CPAM) occurs most commonly in infants. It is divided into 5 types. The most common types 1 and 2 are cystic, type 0 presents as bronchial buds without alveolar tissue, most likely corresponding to alveolar dysgenesis, while type 3 is composed of branching bronchioles and appears as a solid lesion. A defect in the epithelial-mesenchymal crosstalk might be the underlying mechanism for all. Type 4 is a peripheral cystic lesion with a thin cyst wall covered by pneumocytes. CPAM 4 has been mixed up with pleuropulmonary blastoma (PPB) type I and some authors question its existence. We investigated five cases of CPAM type 4 for the presence or absence of rhabdomyoblasts, and for markers associated with CPAM development. In addition, all cases were evaluated for mutations within the Dicer gene and for mutations of the RAS family of oncogenes. All five cases showed smooth muscle actin and desmin-positive cells; however, only one case showed a few cells positive for MyoD. The same case showed a mutation of Dicer 1. All cases were negative for mutations of the RAS family of genes. Fibroblast growth factor 10 was similarly expressed in all cases, and thus cannot be used to differentiate CPAM4 from PPB-I. Low expression of the proliferation marker Ki67 was seen in our CPAM 4 cases and the probable PPB-I case. YingYang-1 protein seems to play an active role in the development of PPB-I. CPAM 4 can be separated from PPB-I based on the presence of rhabdomyoblasts and mutations in Dicer 1 gene. These cells might not be numerous; therefore, all available tissue has to be evaluated. As CPAM 4 morphologically looks very similar to PPB-I, it might be speculated, that there exists a potential for progression from CPAM 4 to PPB-I, by acquiring somatic mutations in Dicer 1.
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http://dx.doi.org/10.1007/s00428-020-02789-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443180PMC
September 2020

Persistent Stridor in a 10-Year-Old Patient with Cystic Fibrosis.

Am J Respir Crit Care Med 2020 08;202(3):e72-e73

Division of Pediatric Pulmonology and Allergology, Department of Pediatrics and Adolescent Medicine.

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http://dx.doi.org/10.1164/rccm.201907-1297IMDOI Listing
August 2020

Comparative analysis of prognostic histopathologic parameters in subtypes of epithelioid pleural mesothelioma.

Histopathology 2020 Jul 25;77(1):55-66. Epub 2020 May 25.

2nd Institute of Pathology, Semmelweis University, Budapest, Hungary.

Aims: Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal prognosis. While the epithelioid type is associated with a more favourable outcome, additional factors are needed to further stratify prognosis and to identify patients who can benefit from multimodal treatment. As epithelioid MPM shows remarkable morphological variability, the prognostic role of the five defined morphologies, the impact of the nuclear grading system and the mitosis-necrosis score were investigated in this study.

Methods And Results: Tumour specimens of 192 patients with epithelioid MPM from five European centres were histologically subtyped. Nuclear grading and mitosis-necrosis score were determined and correlated with clinicopathological parameters and overall survival (OS). Digital slides of 55 independent cases from The Cancer Genome Atlas (TCGA) database were evaluated for external validation. Histological subtypes were collapsed into three groups based on their overlapping survival curves. The tubulopapillary/microcystic group had a significantly longer OS than the solid/trabecular group (732 days versus 397 days, P = 0.0013). Pleomorphic tumours had the shortest OS (173 days). The solid/trabecular variants showed a significant association with high nuclear grade and mitosis-necrosis score. The mitosis-necrosis score was a robust and independent prognostic factor in our patient cohort. The prognostic significance of all three parameters was externally validated in the TCGA cohort. Patients with tubulopapillary or microcystic tumours showed a greater improvement in OS after receiving multimodal therapy than those with solid or trabecular tumours.

Conclusions: Histological subtypes of epithelioid MPM have a prognostic impact, and might help to select patients for intensive multimodal treatment approaches.
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http://dx.doi.org/10.1111/his.14105DOI Listing
July 2020

Comprehensive Molecular and Pathologic Evaluation of Transitional Mesothelioma Assisted by Deep Learning Approach: A Multi-Institutional Study of the International Mesothelioma Panel from the MESOPATH Reference Center.

J Thorac Oncol 2020 06 9;15(6):1037-1053. Epub 2020 Mar 9.

MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Cochin-Hotel Dieu, Department of Pathology, Paris, France.

Introduction: Histologic subtypes of malignant pleural mesothelioma are a major prognostic indicator and decision denominator for all therapeutic strategies. In an ambiguous case, a rare transitional mesothelioma (TM) pattern may be diagnosed by pathologists either as epithelioid mesothelioma (EM), biphasic mesothelioma (BM), or sarcomatoid mesothelioma (SM). This study aimed to better characterize the TM subtype from a histological, immunohistochemical, and molecular standpoint. Deep learning of pathologic slides was applied to this cohort.

Methods: A random selection of 49 representative digitalized sections from surgical biopsies of TM was reviewed by 16 panelists. We evaluated BAP1 expression and CDKN2A (p16) homozygous deletion. We conducted a comprehensive, integrated, transcriptomic analysis. An unsupervised deep learning algorithm was trained to classify tumors.

Results: The 16 panelists recorded 784 diagnoses on the 49 cases. Even though a Kappa value of 0.42 is moderate, the presence of a TM component was diagnosed in 51%. In 49% of the histological evaluation, the reviewers classified the lesion as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 observed in 44% was less frequent in TM than in EM and BM. p16 homozygous deletion was higher in TM (73%), followed by BM (63%) and SM (46%). RNA sequencing unsupervised clustering analysis revealed that TM grouped together and were closer to SM than to EM. Deep learning analysis achieved 94% accuracy for TM identification.

Conclusion: These results revealed that the TM pattern should be classified as non-EM or at minimum as a subgroup of the SM type.
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http://dx.doi.org/10.1016/j.jtho.2020.01.025DOI Listing
June 2020
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