Publications by authors named "Janos Fillinger"

40 Publications

Bone-Specific Metastasis Pattern of Advanced-Stage Lung Adenocarcinoma According to the Localization of the Primary Tumor.

Pathol Oncol Res 2021 23;27:1609926. Epub 2021 Sep 23.

Department of Thoracic Surgery, National Institute of Oncology, Semmelweis University, Budapest, Hungary.

Patients with advanced-stage lung adenocarcinoma (LADC) often develop distant metastases in the skeletal system. Yet, the bone-specific metastasis pattern is still controversial. We, therefore, aimed to examine how the primary tumor location affects bone specificity and survival in LADC patients diagnosed with skeletal metastases. In total, 209 bone-metastatic Caucasian LADC patients from two thoracic centers were included in this study. Focusing on the specific location of primary tumors and bone metastatic sites, clinicopathological variables were included in a common database and analyzed retrospectively. Skeletal metastases were diagnosed according to the contemporary diagnostic guidelines and confirmed by bone scintigraphy. Besides region- and side-specific localization, primary tumors were also classified as central or peripheral tumors based on their bronchoscopic visibility. The most common sites for metastasis were the spine ( = 103) and the ribs ( = 60), followed by the pelvis ( = 36) and the femur ( = 22). Importantly, femoral ( = 0.022) and rib ( = 0.012) metastases were more frequently associated with peripheral tumors, whereas centrally located LADCs were associated with humeral metastases ( = 0.018). Moreover, we deduced that left-sided tumors give rise to skull metastases more often than right-sided primary tumors ( = 0.018). Of note, however, the localization of the primary tumor did not significantly influence the type of affected bones. Multivariate Cox regression analysis adjusted for clinical parameters demonstrated that central localization of the primary tumor was an independent negative prognostic factor for overall survival (OS). Additionally, as expected, both chemotherapy and bisphosphonate therapy conferred a significant benefit for OS. The present study demonstrates unique bone-specific metastasis patterns concerning primary tumor location. Peripherally located LADCs are associated with rib and femoral metastases and improved survival outcomes. Our findings might contribute to the development of individualized follow-up strategies in bone-metastatic LADC patients and warrant further clinical investigations on a larger sample size.
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http://dx.doi.org/10.3389/pore.2021.1609926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496061PMC
September 2021

[Heterogeneity of small cell lung cancer: biological and clinicopathological implications].

Magy Onkol 2020 Sep 9;64(3):243-255. Epub 2020 Aug 9.

Mellkassebészeti Osztály, Országos Onkológiai Intézet, Budapest, Hungary.

Small cell lung cancer (SCLC; comprising approximately 14% of all lung cancer cases in Hungary) is an aggressive tumor type characterized by rapid growth and early metastasis. Although SCLC is a particularly malignant form of cancer, targeted therapies in its treatment have remained largely unsuccessful and thus there were no major therapeutic advances in the last three decades. SCLC was once considered a molecularly homogeneous malignancy. However, recent analyses led to the classification of neuroendocrine and molecular subtypes, based on the dominant expression of one of the following four transcriptional regulator genes: ASCL1, NEUROD1, YAP1 and POU2F3. Because these genetically and biologically distinct subtypes might contribute to therapeutic resistance, the better understanding of their biological and clinicopathological characteristics may help in the development of more effective SCLC therapies.
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September 2020

Normalization of Enzyme Expression and Activity Regulating Vitamin A Metabolism Increases RAR-Beta Expression and Reduces Cellular Migration and Proliferation in Diseases Caused by Tuberous Sclerosis Gene Mutations.

Front Oncol 2021 11;11:644592. Epub 2021 Jun 11.

Departments of Pharmaceutical Biotechnology, University of Pecs, Pecs, Hungary.

Background: Mutation in a tuberous sclerosis gene (TSC1 or 2) leads to continuous activation of the mammalian target of rapamycin (mTOR). mTOR activation alters cellular including vitamin A metabolism and retinoic acid receptor beta (RARβ) expression. The goal of the present study was to investigate the molecular connection between vitamin A metabolism and TSC mutation. We also aimed to investigate the effect of the FDA approved drug rapamycin and the vitamin A metabolite retinoic acid (RA) in cell lines with TSC mutation.

Methods: Expression and activity of vitamin A associated metabolic enzymes and RARβ were assessed in human kidney angiomyolipoma derived cell lines, primary lymphangioleiomyomatosis (LAM) tissue derived LAM cell lines. RARβ protein levels were also tested in primary LAM lung tissue sections. TaqMan arrays, enzyme activities, qRT-PCRs, immunohistochemistry, immunofluorescent staining, and western blotting were performed and analysed. The functional effects of retinoic acid (RA) and rapamycin were tested in a scratch and a BrDU assay to assess cell migration and proliferation.

Results: Metabolic enzyme arrays revealed a general deregulation of many enzymes involved in vitamin A metabolism including aldehyde dehydrogenases (ALDHs), alcohol dehydrogenases (ADHs) and Cytochrome P450 2E1 (CYP2E1). Furthermore, RARβ downregulation was a characteristic feature of all TSC-deficient cell lines and primary tissues. Combination of the two FDA approved drugs -RA for acute myeloid leukaemia and rapamycin for TSC mutation- normalised ALDH and ADH expression and activity, restored RARβ expression and reduced cellular proliferation and migration.

Conclusion: Deregulation of vitamin A metabolizing enzymes is a feature of TSC mutation. RA can normalize RARβ levels and limit cell migration but does not have a significant effect on proliferation. Based on our data, translational studies could confirm whether combination of RA with reduced dosage of rapamycin would have more beneficial effects to higher dosage of rapamycin monotherapy meanwhile reducing adverse effects of rapamycin for patients with TSC mutation.
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http://dx.doi.org/10.3389/fonc.2021.644592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226169PMC
June 2021

A subset of lung cancer cases shows robust signs of homologous recombination deficiency associated genomic mutational signatures.

NPJ Precis Oncol 2021 Jun 18;5(1):55. Epub 2021 Jun 18.

Danish Cancer Society Research Center, Copenhagen, Denmark.

PARP inhibitors are approved for the treatment of solid tumor types that frequently harbor alterations in the key homologous recombination (HR) genes, BRCA1/2. Other tumor types, such as lung cancer, may also be HR deficient, but the frequency of such cases is less well characterized. Specific DNA aberration profiles (mutational signatures) are induced by homologous recombination deficiency (HRD) and their presence can be used to assess the presence or absence of HR deficiency in a given tumor biopsy even in the absence of an observed alteration of an HR gene. We derived various HRD-associated mutational signatures from whole-genome and whole-exome sequencing data in the lung adenocarcinoma and lung squamous carcinoma cases from TCGA, and in a patient of ours with stage IVA lung cancer with exceptionally good response to platinum-based therapy, and in lung cancer cell lines. We found that a subset of the investigated cases, both with and without biallelic loss of BRCA1 or BRCA2, showed robust signs of HR deficiency. The extreme platinum responder case also showed a robust HRD-associated genomic mutational profile. HRD-associated mutational signatures were also associated with PARP inhibitor sensitivity in lung cancer cell lines. Consequently, lung cancer cases with HRD, as identified by diagnostic mutational signatures, may benefit from PARP inhibitor therapy.
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http://dx.doi.org/10.1038/s41698-021-00199-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213828PMC
June 2021

[Predictive relevance of KRAS mutational status in bone metastatic lung adenocarcinoma treated with bisphosphonate therapy].

Magy Onkol 2021 Jun 8;65(2):103-111. Epub 2021 May 8.

Mellkassebészeti Osztály, Országos Onkológiai Intézet, Budapest, Hungary.

The therapeutic impact of KRAS mutations remains controversial in bone metastatic lung adenocarcinoma (LADC). Therefore, our aim was to investigate the effects of KRAS mutational status on overall survival (OS) in these patients according to bisphosphonate therapy (BTx) and radiation therapy (RTx). In total, 134 LADC patients diagnosed with simultaneous bone metastasis were included in this study. The results of the univariate (p=0.008) and multivariate (p=0.004) survival analyses indicated that KRAS mutation is a negative prognostic factor. Both BTx and RTx can increase the OS with a pronounced benefit for patients with KRAS wild-type tumors. Importantly, the concomitant use of BTx and RTx might increase the OS irrespective of KRAS status compared to BTx or RTx alone. In summary, our results might contribute to the development of new therapeutic approaches with regards to KRAS mutational status in bone metastatic LADC.
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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

Activated p53 in the anti-apoptotic milieu of tuberous sclerosis gene mutation induced diseases leads to cell death if thioredoxin reductase is inhibited.

Apoptosis 2021 06 16;26(5-6):253-260. Epub 2021 Apr 16.

Department of Pharmaceutical Biotechnology, University of Pecs, Pecs, Hungary.

Tuberous sclerosis, angiomyolipoma and lymphangioleiomyomatosis are a group of diseases characterized by mutation in tuberous sclerosis genes (TSC 1-2). TSC mutation leads to continuous activation of the mTOR pathway that requires adaptation to increased ATP requirement. With limited treatment options, there is an increasing demand to identify novel therapeutic targets and to understand the correlations between mTOR pathway activation and the lack of cell death in the presence of TSC mutation. In the current study, we demonstrate deregulation of p53 controlled and mitochondria associated cell death processes. The study also reveals that treatment of TSC mutant cells with the drug candidate Proxison combined with reduced concentration of rapamycin can increase production of reactive oxygen species (ROS), can modify miRNA expression pattern associated with p53 regulation and can reduce cell viability.
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http://dx.doi.org/10.1007/s10495-021-01670-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197715PMC
June 2021

Molecular profiles of small cell lung cancer subtypes: therapeutic implications.

Mol Ther Oncolytics 2021 Mar 6;20:470-483. Epub 2021 Feb 6.

Department of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria.

Small cell lung cancer (SCLC; accounting for approximately 13%-15% of all lung cancers) is an exceptionally lethal malignancy characterized by rapid doubling time and high propensity to metastasize. In contrast to the increasingly personalized therapies in other types of lung cancer, SCLC is still regarded as a homogeneous disease and the prognosis of SCLC patients remains poor. Recently, however, substantial progress has been made in our understanding of SCLC biology. Advances in genomics and development of new preclinical models have facilitated insights into the intratumoral heterogeneity and specific genetic alterations of this disease. This worldwide resurgence of studies on SCLC has ultimately led to the development of novel subtype-specific classifications primarily based on the neuroendocrine features and distinct molecular profiles of SCLC. Importantly, these biologically distinct subtypes might define unique therapeutic vulnerabilities. Herein, we summarize the current knowledge on the molecular profiles of SCLC subtypes with a focus on their potential clinical implications.
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http://dx.doi.org/10.1016/j.omto.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917449PMC
March 2021

The effects of bisphosphonate and radiation therapy in bone-metastatic lung adenocarcinoma: the impact of KRAS mutation.

Transl Lung Cancer Res 2021 Feb;10(2):675-684

Department of Thoracic Surgery, Ruhrlandklinik, University Clinic Essen, Essen, Germany.

Background: KRAS mutation is the most common genetic alteration in lung adenocarcinoma (LADC) in Western countries and is associated with worse outcome in bone-metastatic cases. Yet, to date, no effective treatment guidelines were developed for these patients. Accordingly, our aim was to investigate the impact of KRAS mutation on bisphosphonate (BTx) and radiation therapy (RTx) in bone-metastatic LADC patients.

Methods: Clinicopathological variables of 134 consecutive LADC patients with bone metastases at diagnosis and known KRAS status were retrospectively analyzed. The effects of BTx, RTx and KRAS mutation on overall survival (OS) were investigated.

Results: Of the total cohort, 93 patients were identified as KRAS wild-type (WT) (69.4%) and 41 (30.6%) as KRAS mutant patients. The presence of KRAS mutation was associated with significantly reduced median OS (5.1 10.2 months in KRAS WT patients; P=0.008). Irrespective of KRAS mutational status both BTx (P=0.007) and RTx (P=0.021) conferred a significant benefit for OS. Notably, however, when analyzing the patients with KRAS-mutant and KRAS WT tumors separately, the benefit from BTx and RTx on OS remained statistically significant only in KRAS WT patients (P=0.032 and P=0.031, respectively).

Conclusions: KRAS mutation is a strong negative prognostic factor in bone-metastatic LADC patients. Both BTx and RTx can increase the OS with a pronounced benefit for patients with KRAS WT tumors. Altogether, KRAS mutational status should be considered during therapeutic decision making in bone-metastatic LADC patients.
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http://dx.doi.org/10.21037/tlcr-20-754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947398PMC
February 2021

EGFR variant allele frequency predicts EGFR-TKI efficacy in lung adenocarcinoma: a multicenter study.

Transl Lung Cancer Res 2021 Feb;10(2):662-674

National Koranyi Institute of Pulmonology, Budapest, Hungary.

Background: Although lung adenocarcinoma (LADC) with sensitizing mutations of the epidermal growth factor receptor () is highly sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs), in most cases disease progression inevitably occurs. Our aim was to investigate the predictive and prognostic significance of adjusted tumoral variant allele frequency (EGFR-aVAF) in the above setting.

Methods: Eighty-nine Caucasian advanced-stage LADC patients with known exon-specific mutations undergoing EGFR-TKI treatment were included. The correlations of EGFR-aVAF with clinicopathological variables including progression-free and overall survival (PFS and OS, respectively) were retrospectively analyzed.

Results: Of 89 -mutant LADC patients, 46 (51.7%) had exon 19 deletion, while 41 (46.1%) and 2 (2.2%) patients had exon 21- and exon 18-point mutations, respectively. Tumoral EGFR-aVAF was significantly higher in patients harboring exon 19 mutations than in those with exon 21-mutant tumors (P<0.001). Notably, patients with exon 19 mutant tumors demonstrated significantly improved PFS (P=0.003) and OS (P=0.02) compared to patients with exon 21 mutations. Irrespective of specific exon mutations, a statistically significant positive linear correlation was found between EGFR-aVAF of tumoral tissue and PFS (r=0.319; P=0.002). High (≥70%) EGFR-aVAF was an independent predictor of longer PFS [ low (<70%) EGFR-aVAF; median PFSs were 52 26 weeks, respectively; P<0.001]. Additionally, patients with high EGFR-aVAF also had significantly improved OS than those with low EGFR-aVAF (P=0.011).

Conclusions: Our study suggests that high (≥70%) EGFR-aVAF of tumoral tissue predicts benefit from EGFR-TKI treatment in advanced LADC and, moreover, that exon 19 mutation is associated with high EGFR-aVAF and improved survival outcomes.
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http://dx.doi.org/10.21037/tlcr-20-814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947383PMC
February 2021

The landscape of small cell lung cancer metastases: Organ specificity and timing.

Thorac Cancer 2021 03 3;12(6):914-923. Epub 2021 Feb 3.

Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary.

Background: Early metastasis is a hallmark of small cell lung cancer (SCLC). However, the mechanisms and resulting patterns of SCLC dissemination are unclear. Our aim was thus to investigate the organ specificity and timing of blood-borne metastases in a comprehensive large cohort of SCLC patients.

Methods: In this retrospective non-interventional cross-sectional study of 1009 Caucasian SCLC patients, we investigated the correlation between the distinct locations of the primary tumor and metastatic sites.

Results: The onset of bone (p < 0.001), brain (p < 0.001), and pericardial (p = 0.02) metastases were late events, whereas adrenal gland (p = 0.005) and liver (p < 0.001) metastases occurred earlier. No significant difference was found in the distribution of early versus late metastases when comparing central and peripheral primary tumors. Patients with bone metastases had a higher than expected likelihood of having liver metastases, while brain metastases tended to appear together with adrenal gland metastases. Pleural and both lung and pericardial metastases also tended to co-metastasize together more frequently than expected if metastatic events occurred independently. Notably, patients with central primary tumors had decreased median overall survival (OS) compared to those with peripheral tumors, although this tendency does not appear to be significant (p = 0.072).

Conclusion: Our results are suggestive for particular site- and sequence-specific metastasis patterns in human SCLC. SCLC bone metastases tend to appear together with liver metastases, while brain metastases occur together with adrenal gland metastases. Better understanding of metastasis distribution patterns might help to improve the diagnosis and therapeutic decision-making in SCLC patients.
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http://dx.doi.org/10.1111/1759-7714.13854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952793PMC
March 2021

Jobb oldali videoasszisztált thoracoscopos thymectomia a thymoma nélküli, felnőttkori myasthenia gravis sebészi kezelésében.

Magy Seb 2020 Dec 12;73(4):125-139. Epub 2020 Dec 12.

1 Országos Korányi Pulmonológiai Intézet, 1121 Budapest, Korányi Frigyes út 1.

Összefoglaló. Bevezetés: A myasthenia gravis javallatával végzett csecsemőmirigy-eltávolítás sebésztechnikai szempontból lényegesen megváltozott az elmúlt közel 30 évben. A standard műtétnek számító transsternalis és transcervicalis thymectomia mellett elterjedt a videoasszisztált thoracoscopos sebészeti (VATS), később pedig a robot sebészeti megoldás is. Két intézetünkben 2011-2012-ben vezettük be a VATS thymectomiát. Módszer: A többféle technikai megoldás közül a mediastinumot a jobb mellüreg felől megközelítő utat választottuk. Eleinte 3, később 2 pontos perimammaris portot készítettünk a thymus elérésére a beteg háton fekvő helyzetében. Minden esetben ultrahangos vágóeszközt alkalmaztunk. Kiterjesztett thymectomiára törekedve a perithymikus zsírszövetet is eltávolítottuk, szélesen megnyitva a bal oldali mellüreget is. A betegek kiválasztásában az átlagos testsúlyú vagy soványabb betegeket részesítettük előnyben. Eredmények: 8 év és 4 hónap alatt 92 beteget műtöttünk a fenti módszerrel thymoma nélküli myasthenia gravis alapbetegséggel. 20 férfi és 72 nő. Átlagéletkor 33,1 év (19-75 év). A műtéti idő 35-160 percig terjedt, átlagosan 82,3 perc volt. A tömegesebb mediastinalis zsírszövet néhány betegnél nehezítette a tájékozódást és a maradéktalan eltávolítást. Műtét alatt 4 esetben érsérülés és 3 ellenoldali tüdősérülés következett be. Két konverziót végeztünk (1-1 sternotomia és thoracotomia). Idegsérülés nem történt. Tíz beteg igényelt néhány órás művi lélegeztetést a műtét után, a többi beteget a műtőasztalon extubáltuk. Reintubáció, tracheostomia, légzési elégtelenség, műtéti halálozás nem volt. Az intenzív ápolási idő átlaga: 1,1 (0-11) nap. A teljes kórházi ápolási idő átlaga: 4,8 (3-15) nap. A drenázsidő 1-4 nap, átlagosan 1,16 nap. Két beteg (2,41%) halt meg a műtétet követően 1 és 5 éven belül. További 81 beteg 12-108 (átlag: 48) hónapos követése során a myastheniás állapotban 21 (25,3%) betegnél komplett, 4 (4,82%) betegnél gyógyszeres remisszió, 20 (24,1%) betegnél minimális manifesztáció, 28 (33,73%) betegnél egyéb javulás volt megállapítható. 4 (4,82%) beteg állapota változatlan maradt, 4 (4,82%) betegé pedig romlott. Következtetés: A VATS thymectomia teljesen új utat jelent a transsternalis módszerben járatos sebészek számára. A tömegesebb mediastinalis zsírszövet nagyon megnehezíti a műtétet. A perioperatív szak nagyon kedvező a betegek számára, és a késői eredmények is elfogadhatóak. Kérdéses, hogy a thymus minden esetben maradéktalanul eltávolítható-e ezzel a módszerrel.

Summary:

Introduction: Surgical technique of thymectomy performed for treatment of myasthenia gravis has considerably changed in the last almost 30 years. In addition to standard interventions - transsternal and transcervical thymectomy -, video-assisted thoracoscopic interventions (VATS), later on robotic surgery came into general use. In our two institutions, we apply VATS thymectomy since 2011.

Methods: There are several different surgical techniques for this purpose; we approached the mediastinum through the right thoracic cavity. We prepared initially 3, later on 2 perimammal ports for the access of the thymus; the patients were in supine position during surgery. We used an ultrasonic cutting device in all cases. In order to perform extended thymectomy, we removed the fatty tissue around the thymus and opened widely the left thoracic cavity, too. During patient enrollment, we preferred patients with normal or lower body weight.

Results: During 8 years and 4 months, we operated on 92 patients using this method for myasthenia gravis without thymoma; there were 20 male and 72 female patients at the age of 33 years on average (19-75 years). Duration of surgery was 35-160 minutes, 82.3 minutes on average. The bulky fatty tissue around the thymus made the orientation and the complete removal more difficult in a few patients. We experienced vascular injury in 4 cases and injury of the contralateral lung in 3 cases. Conversion was necessary in 2 cases (1 sternotomy and 1 thoracotomy), there were no nerve injuries. Assisted ventilation was necessary in case of ten patients in the postoperative period for a few hours; all other patients were extubated on the operating table. There was no need for repeated intubation and tracheostomy; there was no respiratory insufficiency and perioperative mortality. Duration of ICU care was 1.1 days on the average (0-11 days), that of the total hospital care 4.8 days on average (3-15 days). Duration of thoracic drainage was 1.16 days on average (1-4 days). Two patients (2.41%) died within one and five years after surgery. During 12-108 months (48 months on average) follow-up of 81 patients, 21 patients (25.3%) suffering from myasthenia total recovery was observed, pharmacologic remission was achieved in 4 patients (5.3%), minimal manifestation remained in 23 patients (24.1%), while in 28 patients (33.73%) other improvement was observed. The status of 4 patients (4.82%) remained unchanged and that of 4 patients (5.3%) worsened.

Conclusion: VATS thymectomy represents a completely new surgical method for surgeons having experience in transsternal surgical technique. Bulky mediastinal fatty tissue makes surgery very difficult. The perioperative period is advantageous for the patients and also the long term follow-up results are acceptable. It is questionable that the thymus can be completely removed with this method in all cases.
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http://dx.doi.org/10.1556/1046.73.2020.4.1DOI Listing
December 2020

Proteomic Workflows for High-Quality Quantitative Proteome and Post-Translational Modification Analysis of Clinically Relevant Samples from Formalin-Fixed Paraffin-Embedded Archives.

J Proteome Res 2021 01 10;20(1):1027-1039. Epub 2020 Dec 10.

Div. Clinical Protein Science & Imaging, Dept. of Clinical Sciences (Lund) and Dept. of Biomedical Engineering, Lund University, Lund 22100, Sweden.

Well-characterized archival formalin-fixed paraffin-embedded (FFPE) tissues are of much value for prospective biomarker discovery studies, and protocols that offer high throughput and good reproducibility are essential in proteomics. Therefore, we implemented efficient paraffin removal and protein extraction from FFPE tissues followed by an optimized two-enzyme digestion using suspension trapping (S-Trap). The protocol was then combined with TMTpro 16plex labeling and applied to lung adenocarcinoma patient samples. In total, 9585 proteins were identified, and proteins related to the clinical outcome were detected. Because acetylation is known to play a major role in cancer development, a fast on-trap acetylation protocol was developed for studying endogenous lysine acetylation, which allows identification and localization of the lysine acetylation together with quantitative comparison between samples. We demonstrated that FFPE tissues are equivalent to frozen tissues to study the degree of acetylation between patients. In summary, we present a reproducible sample preparation workflow optimized for FFPE tissues that resolves known proteomic-related challenges. We demonstrate compatibility of the S-Trap with isobaric labeling and for the first time, we prove that it is feasible to study endogenous lysine acetylation stoichiometry in FFPE tissues, contributing to better utility of the existing global tissue archives. The MS proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifiers PXD020157, PXD021986, and PXD021964.
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http://dx.doi.org/10.1021/acs.jproteome.0c00850DOI Listing
January 2021

[Therapeutic possibilities in KRAS-mutant lung adenocarcinoma].

Magy Onkol 2020 Sep 6;64(3):231-244. Epub 2020 Aug 6.

Mellkassebészeti Osztály, Országos Onkológiai Intézet, Budapest, Hungary.

KRAS mutations are the most common gain-of-function alterations in lung adenocarcinoma (LADC) in the western countries. Although the different mutations of the KRAS gene have been identified decades ago, the development of drugs targeting the KRAS protein directly have not been successful due to the lack of small molecule binding sites and the extremely high affinity to cellular GTP. Indirect strategies to inhibit KRAS (e.g. inhibitors of farnesyltransferase, prenylation, synthetic lethal partners and KRAS downstream signaling) have so far also failed. In recent times, however several compounds have been developed that target subtype- specific KRAS mutations. Covalent KRAS G12C-specific inhibitors showed the most promising preclinical results. Below, we summarize the predictive and prognostic value of KRAS mutations in LADC as well as the current targeting strategies.
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September 2020

Current therapy of KRAS-mutant lung cancer.

Cancer Metastasis Rev 2020 12;39(4):1159-1177

Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Rath Gyorgy u. 7-9, Budapest, 1122, Hungary.

KRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors, prenylation inhibition, impairment of KRAS downstream signaling, and synthetic lethality screens have been unsuccessful. Moreover, the role of KRAS oncogene in LADC is still not fully understood, and its prognostic and predictive impact with regards to the standard of care therapy remains controversial. Of note, KRAS-related studies that included general non-small cell lung cancer (NSCLC) population instead of LADC patients should be very carefully evaluated. Recently, however, comprehensive genomic profiling and wide-spectrum analysis of other co-occurring genetic alterations have identified unique therapeutic vulnerabilities. Novel targeted agents such as the covalent KRAS G12C inhibitors or the recently proposed combinatory approaches are some examples which may allow a tailored treatment for LADC patients harboring KRAS mutations. This review summarizes the current knowledge about the therapeutic approaches of KRAS-mutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications.
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http://dx.doi.org/10.1007/s10555-020-09903-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680319PMC
December 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

[Indications and perioperative results of completion pneumonectomy].

Magy Seb 2019 Dec;72(4):149-160

SE ÁOK Mellkassebészeti Tanszéki Csoport, Mellkassebészeti Osztály, Országos Korányi Pulmonológiai Intézet 1029 Budapest, Pihenő út 1.

Completion pneumonectomy (CP) means the removal of the entire residual lung tissue after previously performed lung resection. Mortality and morbidity of CP are higher when compared to those of standard pneumonectomy. In this article, we give an overview on indications and perioperative results of CP. We analysed the perioperative results of CP performed during a period of 15 years in a retrospective manner, based on the patients' medical records, descriptions of surgeries and histological findings. We divided the indications into three groups: rescue surgery for complications in the early postoperative period (rescue: rCP), incomplete resection verified by histological results (pathological: pCP) and conventional surgeries performed in the late postoperative period (conventional: cCP). We classified the complications according to an international scale. The overall surgery-related morbidity of 102 patients was 70.5% (minor: 36.27%, major: 34.23%), the mortality was 16.6%. There were no lethal complications during the surgical procedures. rCP: 24 patients (18 men, 6 women, 46-77 years, average 61.7 years). Intervals between operations: 10.87 days (0-32 days). necrosis or abscess formation (8 cases), bronchial fistula (5 cases), insufficient or blocked anastomosis (3 cases), massive haemoptysis (3 cases), intrathoracic bleeding (2 cases), non-expanding lung (3 cases). Overall morbidity: 79.19%. Nine patients died (37.5%). pCP: 7 patients (5 men, 2 women), 45-66 years (average: 56.3 years). Primary surgery: 6 lobectomies, 1 bilobectomy. Intervals between operations: 1-5 months (average: 2.84 months). Three patients did not develop complications, four had anaemia requiring blood transfusion, one empyema requiring fenestration, one died (14.28%) due to intrathoracic bleeding. There were no tumours in the removed lung tissues in cases of four patients. cCP: 71 patients (22 women, 44 men, 29-79 years (average: 60.3 years). Intervals between operations: 34 days - 40 years (average: 6.7 years). Histological findings of the previous surgeries: primary lung tumour (64 patients), metastases of tumours in other organs (1 patient), bronchiectasia (1 patient) and tuberculosis (5 patients). late bronchial fistula (2 patients), verified or suspected tumour (65 patients), other (4 patients). Histological findings with primary lung tumour in the patient's history: 32 new tumours, 15 local recurrences, 9 metastases, 2 metastases or recurrences, 7 non-malignant. Histological findings without malignancy in the patient's history: 3 new tumours, 1 tuberculosis and 2 chronic inflammations. Overall morbidity was 76.2%, mortality within 30 days or in the hospital 9.8%. Morbidity and mortality are the highest after rCP, but these patients usually do not have any other chance for healing. We have not performed repeat surgery for incomplete tumour resection in the last 10 years. Comparing our results to the international data, the morbidity after cCP is high, the mortality is similar.
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http://dx.doi.org/10.1556/1046.72.2019.4.1DOI Listing
December 2019

A clonal expression biomarker associates with lung cancer mortality.

Nat Med 2019 10 7;25(10):1540-1548. Epub 2019 Oct 7.

Danish Cancer Society Research Center, Copenhagen, Denmark.

An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types. Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.
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http://dx.doi.org/10.1038/s41591-019-0595-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984959PMC
October 2019

Use of cholesterol and soluble tumour markers CEA and syndecan-2 in pleural effusions in cases of inconclusive cytology.

J Clin Pathol 2019 Aug 26;72(8):529-535. Epub 2019 Apr 26.

Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.

Aims: In order to improve diagnostics in pleural effusions, additional value of effusion cholesterol, carcinoembryonic antigen (CEA) and syndecan-2 assays to cytology was studied.

Methods: Biomarkers were measured in effusion supernatants from 247 patients, of whom 126 had malignant pleural involvement, and their additional diagnostic efficacy to cytology was assessed.

Results: Syndecan-2 measurement, although gave detectable concentrations in all effusions with highest median value in mesotheliomas, was non-discriminative between different pathological conditions. CEA concentrations exceeding 5 ng/mL cut-off point indicated carcinomas, regardless of pleural involvement, which gave a sensitivity of 62% and specificity of 100% for carcinoma. Cholesterol concentration over 1.21 mmol/L cut-off value indicated neoplastic pleural involvement with 99% sensitivity and 'merely' 69% specificity, the latter mainly due to raised levels being associated also with benign inflammatory effusions. Combined CEA and cholesterol determinations increased the sensitivity for diagnosing carcinomatosis from 70% with cytology alone to 84% and established the correct diagnosis in 16 of 31 carcinomatosis cases with inconclusive cytology. Cholesterol measurement alone, with elevated level, in combination with absence of substantial number of inflammatory cells in effusion sediment proved to be a magnificent marker for neoplastic pleural involvement with 99% efficacy, and recognised all 36 such cases with inconclusive cytology.

Conclusions: Simultaneous measurement of CEA and cholesterol concentrations in effusion, or at least cholesterol alone, in combination with non-inflammatory fluid cytology, provides additional specific information about neoplastic pleural involvement, and can therefore be used as an adjunct to cytology, above all, in inconclusive cases.
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http://dx.doi.org/10.1136/jclinpath-2018-205650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678041PMC
August 2019

[Pathology of lung neuroendocrine tumors].

Authors:
János Fillinger

Magy Onkol 2018 Jul 10;62(2):83-89. Epub 2018 Apr 10.

Daganatpatológiai Központ, Országos Onkológiai Intézet, Citopatológiai Osztály, Budapest, Hungary.

The heterogeneous group of lung neuroendocrine tumors are divided into four main types: typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). Classification is based on the analysis of surgical resection specimens, which, in addition to basic morphological features, takes into account the mitotic count in 2 mm², the presence or absence of necrosis. According to prognosis, TC is low grade, AC is intermediate grade, while SCLC and LCNEC are high grade carcinomas with very poor prognosis. The morphological diagnosis can be refined by the use of neuroendocrine immunohistochemical markers. Based on the histological diagnosis, clinical prognosis is not always clear. Application of Ki-67 labeling can get closer to real biological behavior. Recently, more than 2/3 of the cases are small samples (core biopsy, bronchoscopic biopsy, cytological smears). Diagnostic algorithms developed for resection specimens has limited usage for these samples. In a single case, a wide range of histological techniques should be used in the processing of the sample, and still only an unsatisfactory result is obtained. Knowing the potential information content of the samples can help the clinician to set up a diagnostic and therapeutic plan.
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July 2018

Chemotherapy treatment is associated with altered PD-L1 expression in lung cancer patients.

J Cancer Res Clin Oncol 2018 Jul 19;144(7):1219-1226. Epub 2018 Apr 19.

VI. Department of Pulmonology, National Korányi Institute of Pulmonology, Pihenő u. 1, Budapest, 1121, Hungary.

Objectives: While the predictive value of programmed cell death ligand-1 (PD-L1) protein expression for immune checkpoint inhibitor therapy of lung cancer has been extensively studied, the impact of standard platinum-based chemotherapy on PD-L1 or programmed cell death-1 (PD-1) expression is unknown. The aim of this study was to determine the changes in PD-L1 expression of tumor cells (TC) and immune cells (IC), in PD-1 expression of IC, and in the amount of stromal mononuclear cell infiltration after platinum-based chemotherapy in patients with lung cancer.

Materials And Methods: We determined the amount of stromal mononuclear cells and PD-L1/PD-1 expressions by immunohistochemistry in bronchoscopic biopsy samples including 20 adenocarcinomas (ADC), 15 squamous cell carcinomas (SCC), 2 other types of non-small cell lung cancer, and 4 small cell lung cancers together with their corresponding surgical resection tissues after platinum-based chemotherapy.

Results: PD-L1 expression of TC decreased in ten patients (24.4%) and increased in three patients (7.32%) after neoadjuvant chemotherapy (p = 0.051). The decrease in PD-L1 expression, however, was significant only in patients who received cisplatin-gemcitabine combination (p = 0.020), while in the carboplatin-paclitaxel group, no similar tendency could be observed (p = 0.432). There was no difference between ADC and SCC groups. Neither PD-1 expression nor the amount of stromal IC infiltration showed significant changes after chemotherapy.

Conclusions: This is the first study, in which both PD-L1 and PD-1 expression were analyzed together with the amount of stromal IC infiltration in different histological subtypes of lung cancer before and after platinum-based chemotherapy. Our results confirm that chemotherapy decreases PD-L1 expression of TC in a subset of patients, therefore, rebiopsy and re-evaluation of PD-L1 expression may be necessary for the indication of immune checkpoint inhibitor therapy.
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http://dx.doi.org/10.1007/s00432-018-2642-4DOI Listing
July 2018

[Doege-Potter syndrome with giant malignant solitary fibrous tumour of the pleura].

Orv Hetil 2018 Jan;159(4):149-153

Mellkassebészet, Országos Korányi Pulmonológiai Intézet Budapest, Pihenő út 1., 1529.

Infrequent solitary fibrous tumours of the pleura are associated with hypoglycaemia only in a few percent of the cases; this condition is called Doege-Potter syndrome, named after its first descriptors. Our 63 years old male patient has previously undergone clinical treatment for intrathoracic fluid accumulation on the left side caused by a giant tumour-like mass in the lower left lobe detected by CT scan. In the course of further investigations performed due to increasing load-induced dyspnoea, lung core biopsy verified low grade sarcoma in the tumour. Tumour board suggested surgery. The patient was transferred from the intensive care unit into the operation theater due to increasing dyspnoea and repeated hypoglycaemic periods in rapidly worsening general condition. Pneumonectomy and removal of the tumour was performed on the left side. Histology showed solitary fibrous tumour of the pleura corresponding to Doege-Potter syndrome. The patient was discharged without complications and underwent adjuvant chemotherapy due to pleural dissemination of the tumour observed intraoperatively. One year after surgery the patient underwent surgical removal of a locally recurrent tumour. In spite of repeated chemotherapy local and multiplex contralateral pulmonary progression was observed. Three-year survival was noted from the time of the first surgery. Orv Hetil. 2018; 159(41): 149-153.
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http://dx.doi.org/10.1556/650.2018.30925DOI Listing
January 2018

Intrathoracic solitary fibrous tumor - an international multicenter study on clinical outcome and novel circulating biomarkers.

Sci Rep 2017 10 2;7(1):12557. Epub 2017 Oct 2.

Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Intrathoracic solitary fibrous tumor (SFT) is a rare disease. Radical resection is the standard of care. However, estimating prognosis and planning follow-up and treatment strategies remains challenging. Data were retrospectively collected by five international centers to explore outcome and biomarkers for predicting event-free-survival (EFS). 125 histological proven SFT patients (74 female; 59.2%; 104 benign; 83.2%) were analyzed. The one-, three-, five- and ten-year EFS after curative-intent surgery was 98%, 90%, 77% and 67%, respectively. Patients age (≥59 vs. <59 years hazard ratio (HR) 4.23, 95 confidence interval (CI) 1.56-11.47, p = 0.005), tumor-dignity (malignant vs. benign HR 6.98, CI 3.01-16.20, p <0.001), tumor-size (>10 cm vs. ≤10 cm HR 2.53, CI 1.10-5.83, p = 0.030), de Perrot staging (late vs. early HR 3.85, CI 1.65-8.98, p = 0.002) and resection margins (positive vs. negative HR 4.17, CI 1.15-15.17, p = 0,030) were associated with EFS. Furthermore, fibrinogen (elevated vs. normal HR 4.00, CI 1.49-10.72, p = 0.006) and the neutrophil-to-lymphocyte-ratio (NLR > 5 vs. < 5 HR 3.91, CI 1.40-10.89, p = 0.009) were prognostic after univariate analyses. After multivariate analyses tumor-dignity and fibrinogen remained as independent prognosticators. Besides validating the role of age, tumor-dignity, tumor-size, stage and resection margins, we identified for the first time inflammatory markers as prognosticators in SFT.
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http://dx.doi.org/10.1038/s41598-017-12914-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624895PMC
October 2017

Claudin-1 Protein Expression Is a Good Prognostic Factor in Non-Small Cell Lung Cancer, but only in Squamous Cell Carcinoma Cases.

Pathol Oncol Res 2017 Jan 29;23(1):151-156. Epub 2016 Sep 29.

2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary.

The aim of the study was to investigate the correlation between claudin (CLDN) protein expression and clinicopathological parameters as well as survival in histological subtypes of non-small cell lung cancer. Archived surgical resection specimens of 137 pathologic stage I primary bronchial cancers including 49 adenocarcinomas of non-lepidic variants (ADC), 46 adenocarcinomas of lepidic variants (L-ADC), and 42 squamous cell carcinomas (SCC) were examined. Immunohistochemistry (IHC) using antibodies against CLDN1,-2,-3,-4,-7 proteins as well as semiquantitative estimation (IHC scores 0-5) were performed. Claudin IHC scores of L-ADC differed significantly from ADC (CLDN1: p = 0.009, CLDN2: p = 0.005, CLDN3: p = 0.004, CLDN4: p = 0.001, CLDN7: p < 0.001, respectively) and SCC (CLDN1: p < 0.001, CLDN3: p < 0.001, CLDN7: p < 0.001, respectively). Highly significant CLDN3-CLDN4 parallel expression could be demonstrated in ADC and L-ADC (p < 0.001 in both), which was not observed in SCC (p = 0.131). ADC and SCC showed no correlation with smoking, whereas in case of L-ADC heavier smoking correlated with higher CLDN3 expression (p = 0.020). Regarding claudin expression and survival, in SCC significant correlation could be demonstrated between CLDN1 IHC positivity and better survival (p = 0.038). In NSCLC as a whole, high CLDN2 expression proved to be a better prognostic factor when compared with cases where CLDN2 IHC score was 0-1 vs. 2-5 (p = 0.009), however, when analyzed separately, none of the histological subgroups showed correlation between CLDN2 expression and overall survival. The claudin expression pattern was significantly different not only between the SCC-ADC and SCC-L-ADC but also between the L-ADC and ADC histological subgroups, which strongly underlines that L-ADC represents a distinct entity within the ADC group. CLDN1 overexpression is a good prognostic factor in NSCLC, but only in the SCC subgroup.
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http://dx.doi.org/10.1007/s12253-016-0115-0DOI Listing
January 2017

Comparison of Predictive Immunohistochemical Marker Expression of Primary Breast Cancer and Paired Distant Metastasis using Surgical Material: A Practice-Based Study.

J Histochem Cytochem 2016 04;64(4):256-67

2nd Department of Pathology, Semmelweis University, Hungary (JK, BS, LVL, OK, AMT, AMS)

Parallel studies of primary breast carcinomas and corresponding distant metastases samples reveal considerable differences. Our aim was to highlight this issue from another perspective and provide further data based on 98 patient samples: 69 primary breast carcinoma and 85 distant metastases from bone, central nervous system (CNS) and lung (56 paired). Two independent series of immunohistochemical reactions with different antibodies for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (Her2), along with HER2 fluroscence in situ hybridization (FISH) were performed on tissue microarrays to classify breast carcinoma and distant metastases samples into Luminal A, Luminal B-proliferating, Luminal B-HER2+, HER2+ and triple negative (TNBC) surrogate breast cancer groups. Correlation and agreement between the two assessments of ER and PgR were fair-to-moderate, and almost perfect for HER2 and Ki67. There was 40% discordance concerning immunophenotype between breast carcinomas and distant metastases. Most common metastatic site of ER+ breast carcinoma was the skeletal system (59.2%), whereas that of TNBCs was the CNS (58.8%) and lungs (23.5%). Distant metastases in bones were mostly luminal (54.3%), in the CNS, Luminal B (53.2%), and in the lung, TNBC (37.5%). The change of drugable properties of primary breast cancers in the respective bone and CNS metastases suggests that characterization of the metastasis is necessary for appropriate treatment planning.
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http://dx.doi.org/10.1369/0022155416639013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817733PMC
April 2016

Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth.

Oncotarget 2016 Apr;7(17):23919-32

Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

We hypothesized that tumor-associated macrophages (TAMs) are controlled by the diffusible gas carbon monoxide (CO). We demonstrate that induction of apoptosis in lung tumors treated with low doses of CO is associated with increased CD86 expression and activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (Erk) 1/2 pathway in tumor microenvironment. Presence of CD86-positive cells was required for the anti-tumoral effects of CO in established A549 xenografts. We show that the effects of CO on tumor stroma and reprogramming of macrophages towards the anti-tumoral phenotype is mediated by reactive oxygen species (ROS)-dependent activation of MAPK/Erk1/2-c-myc pathway as well as Notch 1-dependent negative feedback on the metabolic enzyme heme oxygenase-1 (HO-1). We find a similar negative correlation between HO-1 and active MAPK-Erk1/2 levels in human lung cancer specimens.In summary, we describe novel non-cell autonomous mechanisms by which the diffusible gas CO dictates changes in the tumor microenvironment through the modulation of macrophages.
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http://dx.doi.org/10.18632/oncotarget.8081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029674PMC
April 2016

[In Process Citation].

Magy Seb 2015 Jun;68(3):94-8

Mellkassebészet, Országos Korányi Tbc és Pulmonológiai Intézet 1121 Budapest, Pihenő út 1.

Surgery of mostly benign giant tumours involving large part of the chest is a special surgical challenge. The problems comprise difficulties of surgical technique, management of the narcosis and postoperative intensive care. An additional peculiarity of our case is the extreme confliction of the otherwise presumably evident indication for surgery. Our 64-years-old male patient has been suffering from increasing dyspnoea on exercise for one and a half years. A chest X-ray performed for other reasons demonstrated a large, expansive structural change in the right thoracic cavity. Lung biopsy performed as part of respiratory investigations, which showed a solitaire fibrous tumour of the pleura. Oncological consultation suggested consideration of surgery. The general condition of the patient worsened rapidly in the course of preassessment; he had to be admitted to ICU due to dyspnoea and atrial fibrillation, where respiratory insufficiency developed and required respiratory therapy. Surgery was performed in this high anaesthetic risk patient, since removal of the tumour was the only chance for surviving. The patient left the hospital healthy after successful surgery and cumbersome postoperative period. He returned to his original job and no recurrence was detected one year after surgery.
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http://dx.doi.org/10.1556/1046.68.2015.3.3DOI Listing
June 2015

Expression of proliferation markers Ki67, cyclin A, geminin and aurora-kinase A in primary breast carcinomas and corresponding distant metastases.

J Clin Pathol 2015 Apr 16;68(4):274-82. Epub 2015 Jan 16.

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

Aims: To assess the expression of the following cell cycle regulatory proteins in primary metastatic breast carcinomas (MBCs) and on availability in matched distant metastases (DMs): Ki67, cyclin A, geminin and aurora-kinase A (aurkA); and to compare the expression of these markers in early MBC (EMBC) and late MBC separated into groups according to median time point on metastatic event occurred (28 months).

Methods: The expression of the above mentioned markers was analysed in a total of 47 primary MBCs and 59 DMs (out of which 37 were pairs) by immunohistochemistry. Fourteen breast carcinomas with no relapse over a 10-year follow-up period were utilised as control cases (CBC).

Results: Among the MBCs, 22 metastasised to the bone, 4 to the lung and 21 to the central nervous system (CNS). Geminin (p<0.001) and Ki67 (p=0.001) were increased in the MBCs while aurkA and cyclin A showed no difference when compared with CBCs. There were no differences between aurkA, cyclin A and geminin expression in MBCs and DMs in general. Expression of Ki67 was, however, elevated (p=0.027) in DMs. In CNS metastases all markers showed elevated expression as compared to MBCs. In bone metastases, geminin was lower (p<0.001) compared with primary MBCs. In the metastases of the lung, the evaluated markers did not show different expression. According to the median follow-up until the metastatic event, Ki67 was found to be significantly elevated in EMBC (p=0.018).

Conclusions: Ki67 index and geminin distinguish a fraction of MBC with worse prognosis, showing increased levels in the latter in comparison to CBC being tumour-free over a 10-year follow-up period. Ki67 could possibly identify a group of MBCs that develop early DMs.
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http://dx.doi.org/10.1136/jclinpath-2014-202607DOI Listing
April 2015

EGFR autophosphorylation but not protein score correlates with histologic and molecular subtypes in lung adenocarcinoma.

Diagn Mol Pathol 2013 Dec;22(4):204-9

*Department of Pulmonology †2nd Department of Pathology, Semmelweis University ‡National Korányi Institute of Pulmonology ∥HAS-SU Molecular Oncology Research Group, Budapest, Hungary §Department of Pathology, Medical University of Graz, Graz, Austria.

Established clinicopathologic characteristics of non-small cell lung cancer patients define a subgroup responding better to EGFR-TK inhibitors: adenocarcinoma histology, ethnicity, sex, smoking status, presence of activating EGFR mutation, and/or K-RAS wild type. However, EGFR mutation does not automatically lead to increased activity of the protein influenced by several factors. As adenocarcinoma can be further divided into histologic subclasses, we compared adenocarcinomas without lepidic growth pattern (NLAC) to those characterized by pure or predominant lepidic growth (LAC) for EGFR protein expression and autophosphorylation activity (Y1173), as determined by immunohistochemistry. This pretarget therapy cohort comprised a total of 110 surgically operated patients of stage I non-small cell lung cancer: 49 NLAC and 61 LAC variants. The LAC group had a significantly better prognosis and the incidence of phospho-EGFR-positive tumors was significantly higher compared with NLAC. Patient sex did not influence EGFR activity, but the incidence of pEGFR-positive tumors was significantly lower among smoker patients. There was no statistically significant difference in EGFR or KRAS mutation frequencies between the 2 groups. In NLAC, pEGFR-positive tumors occurred exclusively among EGFR-mutant/K-RAS wild-type tumors. On the contrary, in LAC tumors, pEGFR-positive tumors were similarly frequent in the EGFR or K-RAS mutant groups indicating an interesting feedback activation of EGFR signaling in K-RAS mutant tumors. Our data also indicate that EGFR mutation leads to EGFR autophosphorylation only in a small fraction of adenocarcinoma patients, which might have clinical significance.
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http://dx.doi.org/10.1097/PDM.0b013e3182936957DOI Listing
December 2013
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