Publications by authors named "Mir Alireza Hoda"

50 Publications

Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders.

Cancer Discov 2021 Oct 11. Epub 2021 Oct 11.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. SIGNIFICANCE: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0538DOI Listing
October 2021

Clinical relevance of circulating activin A and follistatin in small cell lung cancer.

Lung Cancer 2021 11 20;161:128-135. Epub 2021 Sep 20.

National Koranyi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary. Electronic address:

Objectives: Circulating levels of activin A (ActA) and follistatin (FST) have been investigated in various disorders including malignancies. However, to date, their diagnostic and prognostic relevance is largely unknown in small cell lung cancer (SCLC). Our aim was to evaluate circulating ActA and FST levels as potential biomarkers in this devastating disease.

Methods: Seventy-nine Caucasian SCLC patients and 67 age- and sex-matched healthy volunteers were included in this study. Circulating ActA and FST concentrations were measured by ELISA and correlated with clinicopathological parameters and long-term outcomes.

Results: Plasma ActA and FST concentrations were significantly elevated in SCLC patients when compared to healthy volunteers (p < 0.0001). Furthermore, extensive-stage SCLC patients had significantly higher circulating ActA levels than those with limited-stage disease (p = 0.0179). Circulating FST concentration was not associated with disease stage (p = 0.6859). Notably, patients with high (≥548.8 pg/ml) plasma ActA concentration exhibited significantly worse median overall survival (OS) compared to those with low (<548.8 pg/ml) ActA levels (p = 0.0009). Moreover, Cox regression analysis adjusted for clinicopathological parameters revealed that high ActA concentration is an independent predictor of shorter OS (HR: 1.932; p = 0.023). No significant differences in OS have been observed with regards to plasma FST levels (p = 0.1218).

Conclusion: Blood ActA levels are elevated and correlate with disease stage in SCLC patients. Measurement of circulating ActA levels might help in the estimation of prognosis in patients with SCLC.
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http://dx.doi.org/10.1016/j.lungcan.2021.09.008DOI Listing
November 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

Lung Cancer in Austria.

J Thorac Oncol 2021 05;16(5):725-733

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

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http://dx.doi.org/10.1016/j.jtho.2020.10.158DOI Listing
May 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 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

Targeted Therapy Recommendations for Therapy Refractory Solid Tumors-Data from the Real-World Precision Medicine Platform MONDTI.

J Pers Med 2020 Oct 23;10(4). Epub 2020 Oct 23.

Department of Medicine I, Division of Clinical Oncology, Medical University of Vienna, 1090 Vienna, Austria.

Advanced therapy-refractory solid tumors bear a dismal prognosis and constitute a major challenge in offering effective treatment strategies. In this real-world retrospective analysis of our precision medicine platform MONDTI, we describe the molecular profile of 554 patients diagnosed with 17 different types of advanced solid tumors after failure of all standard treatment options. In 304 cases (54.9% of all patients), a molecular-driven targeted therapy approach could be recommended, with a recommendation rate above 50% in 12 tumor entities. The three highest rates for therapy recommendation per tumor classification were observed in urologic malignancies (90.0%), mesothelioma (78.6%), and male reproductive cancers (71.4%). Tumor type (p = 0.46), expression of p-mTOR (p = 0.011), expression of EGFR (p = 0.046), and expression of PD-L1 (p = 0.023) had a significant impact on the targeted therapy recommendation rate. Therapy recommendations were significantly more often issued for men ( = 0.015) due to gender-specific differences in the molecular profiles of patients with head and neck cancer and malignant mesothelioma. This analysis demonstrates that precision medicine was feasible and provided the basis for molecular-driven therapy recommendations in patients with advanced therapy refractory solid tumors.
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http://dx.doi.org/10.3390/jpm10040188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712019PMC
October 2020

Activin A: an emerging target for improving cancer treatment?

Expert Opin Ther Targets 2020 10 6;24(10):985-996. Epub 2020 Aug 6.

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

Introduction: Activin A is involved in the regulation of a surprisingly broad number of processes that are relevant for cancer development and treatment; it is implicated in cell autonomous functions and multiple regulatory functions in the tumor microenvironment.

Areas Covered: This article summarizes the current knowledge about activin A in cell growth and death, migration and metastasis, angiogenesis, stemness and drug resistance, regulation of antitumor immunity, and cancer cachexia. We explore the role of activin A as a biomarker and discuss strategies for using it as target for cancer therapy. Literature retrieved from Medline until 25 June 2020 was considered.

Expert Opinion: While many functions of activin A were investigated in preclinical models, there is currently limited experience from clinical trials. Activin A has growth- and migration-promoting effects, contributes to immune evasion and cachexia and is associated with shorter survival in several cancer types. Targeting activin A could offer the chance to simultaneously limit tumor growth and spreading, improve drug response, boost antitumor immune responses and improve cancer-associated or treatment-associated cachexia, bone loss, and anemia. Nevertheless, defining which patients have the highest likelihood of benefiting from these effects is challenging and will require further work.
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http://dx.doi.org/10.1080/14728222.2020.1799350DOI Listing
October 2020

Long-term Survival After Salvage Surgery for a Giant Primary Rib Osteosarcoma.

Ann Thorac Surg 2021 01 15;111(1):e45-e47. Epub 2020 Jun 15.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria. Electronic address:

A 29-year-old woman with a primary rib osteosarcoma declined treatment and was readmitted 20 months later in life-threatening condition caused by major local tumor progression with severe mediastinal shifting, and without distant metastases. She underwent extended tumor resection with palliative intent and recovered well after a prolonged course with post-pneumonectomy empyema. Further treatment was declined, and she presented again 4.5 years later with local chest wall recurrence that was completely resected. Currently, 7 years after diagnosis, the patient is free from disease. In this rare case, salvage surgery was associated with an unexpected favorable long-term outcome.
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http://dx.doi.org/10.1016/j.athoracsur.2020.04.116DOI Listing
January 2021

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

KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy.

Cancers (Basel) 2019 Oct 9;11(10). Epub 2019 Oct 9.

Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, 1122 Budapest, Hungary.

Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking ( = 0.008) and female gender ( = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group ( = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS ( = 0.0255) and OS ( = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; = 0.011) and OS (hazard ratio, 0.645; = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.
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http://dx.doi.org/10.3390/cancers11101514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827133PMC
October 2019

Results of the extended analysis for cancer treatment (EXACT) trial: a prospective translational study evaluating individualized treatment regimens in oncology.

Oncotarget 2019 Jan 29;10(9):942-952. Epub 2019 Jan 29.

Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.

Background: The concept of personalized medicine defines a promising approach in cancer care. High-throughput genomic profiling of tumor specimens allows the identification of actionable mutations that potentially lead to tailored treatment for individuals' benefit. The aim of this study was to prove efficacy of a personalized treatment option in solid tumor patients after failure of standard treatment concepts.

Results: Final analysis demonstrates that 34 patients (62%) had a longer PFS upon experimental treatment (PFS1) when compared to previous therapy (PFS0); PFS ratio > 1.0 ( = 0.002). The median PFS under targeted therapy based on molecular profiling (PFS1) was 112 days (quartiles 66/201) and PFS0 = 61 days (quartiles 51/92; = 0.002). Of the 55 patients, 31 (56%) showed disease control (DCR), consisting of 2 (4%) patients which achieved a complete remission, 14 (25%) patients with a partial remission and 15 (27%) patients who had a stabilization of disease. Median OS from start of experimental therapy was 348 days (quartiles 177/664).

Conclusion: The prospective trial EXACT suggests that treatment based on real-time molecular tumor profiling leads to superior clinical benefit.

Materials And Methods: In this prospective clinical phase II trial, 55 cancer patients, after failure of standard treatment options, aimed to achieve a longer progression-free survival on the experimental treatment based on the individual's molecular profile (PFS1) when compared to the last treatment given before (PFS0). The personalized medicine approach was conceived to be clinical beneficial for patients who show a PFS ratio (PFS 1/PFS0) of > 1.0.
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http://dx.doi.org/10.18632/oncotarget.26604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398177PMC
January 2019

Solid predominant subtype in lung adenocarcinoma is related to poor prognosis after surgical resection: A systematic review and meta-analysis.

Eur J Surg Oncol 2019 Jul 4;45(7):1156-1162. Epub 2019 Feb 4.

Division of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. Electronic address:

Background: Recent studies have indicated that solid predominant (SP) subtype of lung adenocarcinoma (LADC) may be associated with early recurrence and worse prognosis. Hence, a systematic review and meta-analysis were performed to evaluate the association between LADC subtype and survival.

Methods: The MEDLINE, SCOPUS, Web of Science and Cochrane Libraries were reviewed for eligible studies in December 2017. Studies were included if they compared outcomes of patients with and without SP subtype in resection specimens of LADC patients after surgical treatment by using multivariate Cox regression analysis. A meta-analysis for overall survival (OS) and disease-free survival (DFS) was performed. The hazard ratios (HR) or odds ratios with 95% confidence intervals (CIs) from each study were used to calculate pooled HRs. Statistical analyses were performed using Review Manager 5.3.

Results: In total, 14 eligible studies including 12,137 LADC patients were identified, which assessed the impact of SP subtype on OS and DFS in patients treated with pulmonary resection. SP subtype was reported in 1246 (10.2%) patients and was associated with significantly worse OS (pooled HR, 1.51; 1.29-1.75) and DFS (pooled HR, 1.26; 1.14-1.40).

Conclusions: SP subtype is associated with significantly worse OS and DFS in patients with LADC after pulmonary resection. These data provide evidence for the integration of the distinct histological LADC subtyping into prognostic tools and guidelines for adjuvant treatment after complete surgical resection.
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http://dx.doi.org/10.1016/j.ejso.2019.01.220DOI Listing
July 2019

The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma.

J Mol Med (Berl) 2019 02 11;97(2):231-242. Epub 2018 Dec 11.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria.

No tyrosine kinase inhibitors are approved for malignant pleural mesothelioma (MPM). Preclinical studies identified focal adhesion kinase (FAK) as a target in MPM. Accordingly, we assessed the novel, highly selective FAK inhibitor (BI 853520) in 2D and 3D cultures and in vivo. IC values were measured by adherent cell viability assay. Cell migration and 3D growth were quantified by video microscopy and spheroid formation, respectively. Phosphorylation of FAK, Akt, S6, and Erk was measured by immunoblot. The mRNA expression of the putative tumor stem cell markers SOX2, Nanog, CD44, ALDH1, c-myc, and Oct4 was analyzed by qPCR. Cell proliferation, apoptosis, and tumor tissue microvessel density (MVD) were investigated in orthotopic MPM xenografts. In all 12 MPM cell lines, IC exceeded 5 μM and loss of NF2 did not correlate with sensitivity. No synergism was found with cisplatin in adherent cells. BI 853520 decreased migration in 3 out of 4 cell lines. FAK phosphorylation was reduced upon treatment but activation of Erk, Akt, or S6 remained unaffected. Nevertheless, BI 853520 inhibited spheroid growth and significantly reduced tumor weight, cell proliferation, and MVD in vivo. BI 853520 has limited effect in adherent cultures but demonstrates potent activity in spheroids and in orthotopic tumors in vivo. Based on our findings, further studies are warranted to explore the clinical utility of BI 853520 in human MPM. KEY MESSAGES: Response to FAK inhibition in MPM is independent of NF2 expression or histotype. FAK inhibition strongly interfered with MPM spheroid formation. BI 853520 has been shown to exert anti-tumor effect in MPM.
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http://dx.doi.org/10.1007/s00109-018-1725-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348072PMC
February 2019

New insights into the impact of primary lung adenocarcinoma location on metastatic sites and sequence: A multicenter cohort study.

Lung Cancer 2018 12 5;126:139-148. Epub 2018 Nov 5.

National Korányi Institute of Pulmonology, Budapest, Hungary. Electronic address:

Introduction: The presence of organ metastases is a major factor for unfavorable prognosis in lung adenocarcinoma (LADC). However, the influence of primary tumor location on metastatic sites and sequence has not been extensively analyzed.

Methods: We performed a multicenter cohort study, evaluating clinicopathological data of 1126 Caucasian LADC patients, focusing on the distinct location of primary tumors and metastatic sites during disease progression.

Results: Metastases to the lung (p < 0.001), pleura (p < 0.001) and adrenal glands (p < 0.001) occurred earlier during disease progression and central primary tumors were associated with early metastases (OR 1.43, p = 0.02). In secondary exploratory analysis we found that bone metastases were more frequent in patients with central tumors (OR 1.86, p = 0.017), whereas lung metastases in those with peripheral tumors (OR 1.35, p = 0.015). Central primary LADCs were associated with decreased median overall survival (vs. peripheral tumors, 10.2 vs. 22 months) both in univariate (HR 2.075, p = 0.001) and in multivariate (HR 1.558, p < 0.001) analyses and independent from stage and T factor. By subsequent analysis, we found that bone metastases tend to appear together with adrenal and liver metastases, and adrenal with skin, and pleural with pericardial metastases more frequently than expected if metastatic events occurred independently.

Conclusion: This comprehensive large cohort analysis demonstrates metastatic site- and sequence-specific variations in patients with LADC. Central LADC is associated with early metastatic disease, bone involvement and, consequently, decreased survival.
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http://dx.doi.org/10.1016/j.lungcan.2018.11.004DOI Listing
December 2018

Nintedanib Is Active in Malignant Pleural Mesothelioma Cell Models and Inhibits Angiogenesis and Tumor Growth .

Clin Cancer Res 2018 08 3;24(15):3729-3740. Epub 2018 May 3.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Centre Vienna, Medical University Vienna, Austria.

Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor type with limited treatment options and poor prognosis. The angiokinase inhibitor nintedanib has shown promising activity in the LUME-Meso phase II MPM trial and thus is currently being evaluated in the confirmatory LUME-Meso phase III trial. However, the anti-MPM potential of nintedanib has not been studied in the preclinical setting. We have examined the antineoplastic activity of nintedanib in various and models of human MPM. Nintedanib's target receptors were (co)expressed in all the 20 investigated human MPM cell lines. Nintedanib inhibited MPM cell growth in both short- and long-term viability assays. Reduced MPM cell proliferation and migration and the inhibition of Erk1/2 phosphorylation were also observed upon nintedanib treatment Additive effects on cell viability were detected when nintedanib was combined with cisplatin, a drug routinely used for systemic MPM therapy. In an orthotopic mouse model of human MPM, survival of animals receiving nintedanib showed a favorable trend, but no significant benefit. Nintedanib significantly reduced tumor burden and vascularization and prolonged the survival of mice when it was administered intraperitoneally. Importantly, unlike bevacizumab, nintedanib demonstrated significant antivascular and antitumor potential independently of baseline VEGF-A levels. Nintedanib exerts significant antitumor activity in MPM both and These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1507DOI Listing
August 2018

Controversies in oncology: surgery for small cell lung cancer? It's time to rethink the case.

ESMO Open 2018 27;3(3):e000366. Epub 2018 Apr 27.

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

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http://dx.doi.org/10.1136/esmoopen-2018-000366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926649PMC
April 2018

FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal.

Carcinogenesis 2018 04;39(4):534-545

Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna.

Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial-mesenchymal transition (EMT) and confers the worst prognosis, but the signals and pathways controlling EMT in MPM are not well understood. We demonstrate that treatment with FGF2 or EGF induced a fibroblastoid morphology in several cell lines from biphasic MPM, accompanied by scattering, decreased cell adhesion and increased invasiveness. This depended on the MAP-kinase pathway but was independent of TGFβ or PI3-kinase signaling. In addition to changes in known EMT markers, microarray analysis demonstrated differential expression of MMP1, ESM1, ETV4, PDL1 and BDKR2B in response to both growth factors and in epithelioid versus sarcomatoid MPM. Inhibition of MMP1 prevented FGF2-induced scattering and invasiveness. Moreover, in MPM cells with sarcomatoid morphology, inhibition of FGF/MAP-kinase signaling induced a more epithelioid morphology and gene expression pattern. Our findings suggest a critical role of the MAP-kinase axis in the morphological and behavioral plasticity of mesothelioma.
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http://dx.doi.org/10.1093/carcin/bgy018DOI Listing
April 2018

Author Correction: Down-regulated GATA-1 up-regulates interferon regulatory factor 3 in lung adenocarcinoma.

Sci Rep 2018 Mar 6;8(1):4299. Epub 2018 Mar 6.

Dpartment of Pediatrics, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-22517-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840352PMC
March 2018

Circulating complement component 4d (C4d) correlates with tumor volume, chemotherapeutic response and survival in patients with malignant pleural mesothelioma.

Sci Rep 2017 11 28;7(1):16456. Epub 2017 Nov 28.

Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Only limited information is available on the role of complement activation in malignant pleural mesothelioma (MPM). Thus, we investigated the circulating and tissue levels of the complement component 4d (C4d) in MPM. Plasma samples from 55 MPM patients, 21 healthy volunteers (HV) and 14 patients with non-malignant pleural diseases (NMPD) were measured by ELISA for C4d levels. Tissue specimens from 32 patients were analyzed by C4d immunohistochemistry. Tumor volumetry was measured in 20 patients. We found no C4d labeling on tumor cells, but on ectopic lymphoid structures within the tumor stroma. Plasma C4d levels did not significantly differ between MPM, HV or NMPD. Late-stage MPM patients had higher plasma C4d levels compared to early-stage (p = 0.079). High circulating C4d was associated with a higher tumor volume (p = 0.047). Plasma C4d levels following induction chemotherapy were significantly higher in patients with stable/progressive disease compared to those with partial/major response (p = 0.005). Strikingly, patients with low C4d levels at diagnosis had a significantly better overall survival, confirmed in a multivariate cox regression model (hazard ratio 0.263, p = 0.01). Our findings suggest that circulating plasma C4d is a promising new prognostic biomarker in patients with MPM and, moreover, helps to select patients for surgery following induction chemotherapy.
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http://dx.doi.org/10.1038/s41598-017-16551-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705645PMC
November 2017

Down-regulated GATA-1 up-regulates interferon regulatory factor 3 in lung adenocarcinoma.

Sci Rep 2017 05 31;7(1):2551. Epub 2017 May 31.

Dpartment of Pediatrics, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.

Interferon regulatory factor 3 (IRF-3) is widely known for its prompt response against viral infection by activating the interferon system. We previously reported that E2F1, Sp1 and Sp3 regulated transcriptional activity of IRF-3. Recently, different expression patterns of IRF-3 were found in lung cancer, leading to the alternation of the immunomodulatory function in tumorigenesis. However, the mechanism of transcriptional regulation of IRF-3 in lung cancer has not been extensively studied. Here, we investigated the characterization of IRF-3 promoter and found that GATA-1 bound to a specific domain of IRF-3 promoter in vitro and in vivo. We found elevated IRF-3 and decreased GATA-1 gene expression in lung adenocarcinoma in Oncomine database. Additionally, higher IRF-3 gene expression was observed in human lung adenocarcinoma, accompanied by aberrant GATA-1 protein expression. We further analyzed the relationship of GATA-1 and IRF-3 expression in lung adenocarcinoma cell lines and found that inhibition of GATA-1 by siRNA increased the promoter activity, mRNA and protein levels of IRF-3, while over-expression of GATA-1 down-regulated IRF-3 gene expression. Taken together, we conclude that reduced GATA-1 could be responsible for the upregulation of IRF-3 in lung adenocarcinoma cells through binding with a specific domain of IRF-3 promoter.
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http://dx.doi.org/10.1038/s41598-017-02700-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451405PMC
May 2017

Trimodality therapy for Pancoast tumors: T4 is not a contraindication to radical surgery.

J Surg Oncol 2017 Aug 13;116(2):227-235. Epub 2017 Apr 13.

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

Objective: This study aims to evaluate the impact of T stage and extended surgery on the outcome of patients with Pancoast tumors after induction chemoradiation therapy.

Methods: Forty-six consecutive patients who underwent chemoradiation therapy (platin-based, 45-66 Gy) followed by surgery between 1998 and 2013 were retrospectively reviewed and analyzed.

Results: In 28 (61%) patients with T4 tumors, extended procedures (more than rib resection) were performed. There were 37 (80%) lobectomies, 6 (13%) pneumonectomies, and 3 (7%) sublobar resections. A total of 44 (96%) patients had R0 resection. About 30-day mortality was 0%, major surgical complications occurred in 9 (19.6%) patients. Overall survival (OS) at 5-years was 63%. Disease-free survival (DFS) at 5-years was 45%. At multivariate cox regression analysis adjusted for clinical factors, T factor (T3/T4) and extended surgical procedures did not impact survival. However, pathological positive N stage had a negative impact on OS and lack of pathological response negatively impacted both OS and DFS.

Conclusion: Trimodality treatment including radical resection for Pancoast tumors provides good surgical outcome and favorable long-term results. Survival of patients with T4 tumors and extended surgical procedures comparable to that of patients with T3 tumors undergoing rib resection only.
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http://dx.doi.org/10.1002/jso.24629DOI Listing
August 2017

Limited Tumor Tissue Drug Penetration Contributes to Primary Resistance against Angiogenesis Inhibitors.

Theranostics 2017 1;7(2):400-412. Epub 2017 Jan 1.

National Korányi Institute of Pulmonology, Budapest, Hungary;; Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria;; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary;; Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Vienna, Austria.

Resistance mechanisms against antiangiogenic drugs are unclear. Here, we correlated the antitumor and antivascular properties of five different antiangiogenic receptor tyrosine kinase inhibitors (RTKIs) (motesanib, pazopanib, sorafenib, sunitinib, vatalanib) with their intratumoral distribution data obtained by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). In the first mouse model, only sunitinib exhibited broad-spectrum antivascular and antitumor activities by simultaneously suppressing vascular endothelial growth factor receptor-2 (VEGFR2) and desmin expression, and by increasing intratumoral hypoxia and inhibiting both tumor growth and vascularisation significantly. Importantly, the highest and most homogeneous intratumoral drug concentrations have been found in sunitinib-treated animals. In another animal model, where - in contrast to the first model - vatalanib was detectable at homogeneously high intratumoral concentrations, the drug significantly reduced tumor growth and angiogenesis. In conclusion, the tumor tissue penetration and thus the antiangiogenic and antitumor potential of antiangiogenic RTKIs vary among the tumor models and our study demonstrates the potential of MALDI-MSI to predict the efficacy of unlabelled small molecule antiangiogenic drugs in malignant tissue. Our approach is thus a major technical and preclinical advance demonstrating that primary resistance to angiogenesis inhibitors involves limited tumor tissue drug penetration. We also conclude that MALDI-MSI may significantly contribute to the improvement of antivascular cancer therapies.
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http://dx.doi.org/10.7150/thno.16767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5197073PMC
October 2017

The evidence for and against different modes of tumour cell extravasation in the lung: diapedesis, capillary destruction, necroptosis, and endothelialization.

J Pathol 2017 03 27;241(4):441-447. Epub 2017 Jan 27.

Department of Thoracic Surgery, Medical University of Vienna, Austria.

The development of lung metastasis is a significant negative prognostic factor for cancer patients. The extravasation phase of lung metastasis involves interactions of tumour cells with the pulmonary endothelium. These interactions may have broad biological and medical significance, with potential clinical implications ranging from the discovery of lung metastasis biomarkers to the identification of targets for intervention in preventing lung metastases. Because of the potential significance, the mechanisms of tumour cell extravasation require cautious, systematic studies. Here, we discuss the literature pertaining to the proposed mechanisms of extravasation and critically compare a recently proposed mechanism (tumour cell-induced endothelial necroptosis) with the already described extravasation mechanisms in the lung. We also provide novel data that may help to explain the underlying physiological basis for endothelialization as a mechanism of tumour cell extravasation in the lung. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4855DOI Listing
March 2017

Management of malignant pleural mesothelioma - part 1: epidemiology, diagnosis, and staging : Consensus of the Austrian Mesothelioma Interest Group (AMIG).

Wien Klin Wochenschr 2016 Sep 12;128(17-18):611-7. Epub 2016 Sep 12.

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

Malignant pleural mesothelioma is a rare malignant disease that in the majority of cases is associated with asbestos exposure. The incidence in Europe is about 20 per million inhabitants and it is increasing worldwide. Initial symptoms are shortness of breath, pleural effusion, cough, and chest pain. The typical growth pattern is along the pleural surface; however, infiltration of the lung and/or mediastinal and chest wall structures can occur in a more advanced stage. Ultimately, distant metastases outside the chest can result. Several histological subtypes of pleural mesothelioma exist, which must be differentiated from either benign diseases or metastases in the pleural space by other tumor entities. This differential diagnosis can be very difficult and a large panel of immunohistochemical markers is required to establish the exact diagnosis. The standard procedure for confirming the disease and obtaining sufficient tissue for the diagnosis is videothoracoscopy. Full thickness biopsies are required, while transthoracic needle puncture of pleural fluid or tissue is considered to be insufficient for a cytological diagnosis. Complete and detailed staging is mandatory for categorization of the disease as well as for therapeutic decision making.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033998PMC
http://dx.doi.org/10.1007/s00508-016-1080-zDOI Listing
September 2016

Management of malignant pleural mesothelioma - part 3 : Data from the Austrian Mesothelioma Interest Group (AMIG) database.

Wien Klin Wochenschr 2016 Sep 25;128(17-18):627-34. Epub 2016 Jul 25.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor originating from the pleural cavity with a strong link to previous asbestos exposure. In order to determine the demographics, diagnostics, therapeutic strategies, and prognosis of MPM patients in Austria, the Austrian Mesothelioma Interest Group (AMIG) was founded in 2011. In this report the data from the AMIG MPM database collected to date are reported.

Methods: A prospective observational registry was initiated, including patients with histologically verified MPM diagnosed and treated at specialized centers in Austria. Patient inclusion started in January 2011 and follow-up was completed until September 2015.

Results: A total number of 210 patients were included. There were 167 male and 43 female patients with a mean age of 67.0 years (SD ± 11.3) at the time of diagnosis. Asbestos exposure was confirmed in 109 (69.4 %) patients. The histological subtype was epithelioid in 141 (67.2 %), sarcomatoid in 16 (7.6 %), biphasic in 28 (13.3 %), and MPM not otherwise specified in 25 (11.9 %) patients. Of the patients, 30 (14.3 %) received best supportive care (BSC) only, 71 (33.8 %) chemotherapy (CHT) alone, four (1.9 %) radiotherapy (RT) alone, 23 (11.9 %) CHT/RT, two (0.9 %) surgery alone, and 76 (36.2 %) curative surgery within a multimodality treatment (MMT), which was more frequently performed for patients younger than 65 years and with early-stage disease (I + II). Median overall survival (OS) was 19.1 months (95 % CI 14.7-23.5). The 1‑, 3‑, and 5‑year OS rates were 66 %, 30 %, and 23 %, respectively, and OS was significantly better in patients undergoing surgery within MMT (5-year survival 5 % vs. 40 %, p = 0.001).

Conclusion: Patients with earlier disease stages, younger age, good performance status, and epithelioid histology were more likely to undergo MMT including surgery, which resulted in a more favorable outcome.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033994PMC
http://dx.doi.org/10.1007/s00508-016-1037-2DOI Listing
September 2016

Management of malignant pleural mesothelioma-part 2: therapeutic approaches : Consensus of the Austrian Mesothelioma Interest Group (AMIG).

Wien Klin Wochenschr 2016 Sep 25;128(17-18):618-26. Epub 2016 Jul 25.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Treatment of malignant pleural mesothelioma (MPM) depends on performance status of the patient, tumor stage, and histological differentiation. Chemotherapy (CHT) can be administered as first- and second-line treatment in unresectable MPM or as neoadjuvant or adjuvant treatment before or after surgery. A combination of an antifolate and platinum-based CHT is the only approved standard of care. Several targeted and immunotherapies are in evaluation and further studies are warranted to determine the therapeutic value of these new treatment options. Radiotherapy (RT) can be considered either as adjuvant treatment after surgery or for palliation of pain-related tumor growth. Recent data support the use of RT in a neoadjuvant setting. Macroscopic complete resection by pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) is indicated in selected patients with good performance status. Surgery should only be applied as part of a multimodality treatment (MMT) in combination with chemo- and/or radiotherapy. In a large number of cases, palliative attempts are needed to improve quality of life and to achieve symptom control.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033993PMC
http://dx.doi.org/10.1007/s00508-016-1036-3DOI Listing
September 2016

Circulating activin A is a novel prognostic biomarker in malignant pleural mesothelioma - A multi-institutional study.

Eur J Cancer 2016 08 8;63:64-73. Epub 2016 Jun 8.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria; Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Vienna, Austria; MTA-SE Molecular Oncology Research Group, Hungarian Academy of Sciences, Budapest, Hungary. Electronic address:

Introduction: The deregulation of activin expression is often observed in various malignancies. Previous studies indicate that activin A plays a protumourigenic role in malignant pleural mesothelioma (MPM). The aim of the study was to evaluate circulating activin A level as a biomarker in MPM.

Methods: Plasma samples were collected from 129 MPM patients in four institutions at the time of diagnosis or before surgical resection. Samples from 45 healthy individuals and from 16 patients with non-malignant pleural diseases served as controls. Circulating activin A was measured by enzyme-linked immunosorbent assay and correlated to clinicopathological variables.

Results: Plasma activin A level was significantly elevated in MPM patients (862 ± 83 pg/ml) when compared to healthy controls (391 ± 21 pg/ml; P < 0.0001). Patients with pleuritis or fibrosis only showed a modest increase (versus controls; 625 ± 95 pg/ml; P = 0.0067). Sarcomatoid (n = 10, 1629 ± 202 pg/ml, P = 0.0019) and biphasic (n = 23, 1164 ± 233 pg/ml, P = 0.0188) morphology were associated with high activin A levels when compared to epithelioid histology (n = 94, 712 ± 75 pg/ml). The tumour volume showed a positive correlation with increased circulating activin A levels. MPM patients with below median activin A levels had a significantly longer overall survival when compared to those with high activin A levels (median survival 735 versus 365 d, P < 0.0001). Importantly, circulating activin A levels were exclusively prognostic in epithelioid MPM.

Conclusions: Our findings suggest that the measurement of circulating activin A may support the histological classification of MPM and at the same time help to identify epithelioid MPM patients with poor prognosis.
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http://dx.doi.org/10.1016/j.ejca.2016.04.018DOI Listing
August 2016

Lung transplantation in patients with incidental early stage lung cancer-institutional experience of a high volume center.

Clin Transplant 2016 08 16;30(8):912-7. Epub 2016 Jun 16.

Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.

Background: Incidentally discovered lung cancers in lung transplant (LuTX) recipients are rare but may affect outcome. We aim to report our single center experience with incidence, management, and survival of patients with previously unverified primary lung cancer discovered at the time of LuTX.

Methods: A total of 1262 patients undergoing LuTX between 1989 and 2012 were retrospectively analyzed in our prospective database.

Results: Patients identified were six men and five women with a mean age of 54.4±9.9 years. The indication for LuTX was COPD (n=9), pulmonary fibrosis (n=1), and cystic fibrosis (n=1). Histological diagnosis of the explanted lung revealed adenocarcinoma in six, squamous cell carcinoma in three, and lepidic predominant adenocarcinoma in two cases, respectively. Staging revealed stage IA (pT1a/b pN0) in eight and IB (pT2a pN0) in two cases and one patient in stage IIA (pT1b pN1). Subsequent cancer staging after LuTX revealed no metastasis. Immunosuppression was adjusted and no adjuvant chemo- or radiotherapy was administered. The 5-year survival rate was 90.5% with no detection of recurrence.

Conclusion: In patients with incidentally detected early stage lung cancer at the time of LuTX, rates of recurrence and survival based on this sample appear to be acceptable.
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http://dx.doi.org/10.1111/ctr.12764DOI Listing
August 2016
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