Publications by authors named "Marcin Skrzypski"

24 Publications

  • Page 1 of 1

Cancer cachexia in thoracic malignancy: a narrative review.

Curr Opin Support Palliat Care 2019 12;13(4):316-322

Institute of Immunity, Infection and Inflammation, University of Glasgow.

Purpose Of Review: Thoracic malignancies are amongst the most lethal of all cancers. Cancer cachexia lacks unanimously accepted diagnostic criteria, and therefore is referenced to as a conceptual framework whereby cancer cachexia is 'an ongoing loss of skeletal muscle mass (termed sarcopenia), with or without loss of fat mass that cannot be reversed by conventional nutritional support and leads to progressive functional impairment'. This review summarises the current evidence base in this field, including imaging techniques currently used to define sarcopenia, inflammatory and metabolic changes associated with the syndrome and ongoing research into potential treatment strategies.

Recent Findings: Sarcopenia is a key component of the cancer cachexia syndrome. It is common in patients with both early-stage and advanced NSCLC. Patients with sarcopenia have more treatment-related side effects and poorer overall survival compared with nonsarcopenic patients.

Summary: Early identification of cancer cachexia may facilitate stratification of patients most-at-risk and initiation of emerging anticachexia treatments. If these are proven to be effective, this strategy has the potential to improve tolerance to anti-cancer therapies, improving the quality of life, and perhaps the survival, of patients with thoracic malignancies.
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http://dx.doi.org/10.1097/SPC.0000000000000465DOI 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.

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, London, UK.

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

Acquired SETD2 mutation and impaired CREB1 activation confer cisplatin resistance in metastatic non-small cell lung cancer.

Oncogene 2019 01 9;38(2):180-193. Epub 2018 Aug 9.

Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA.

Resistance to chemotherapy remains a critical barrier to effective cancer treatment. Although cisplatin is one of the most commonly used chemotherapeutic agents in the treatment of non-small cell lung cancer (NSCLC), mechanisms of resistance to this drug are not fully understood. Here, we report a novel cisplatin-resistance mechanism involving SET Domain Containing 2 (SETD2), a histone H3 lysine 36 (H3K36) trimethyltransferase, and cAMP-responsive element-binding protein 1 (CREB1). A549 cells selected in vivo to give brain metastases exhibited cisplatin resistance and decreased expression of phosphorylated CREB1. Next-generation sequencing (NGS) analysis identified a missense mutation in SETD2 (p.T1171K), and we demonstrated that SETD2-mediated trimethylation of H3K36 (H3K36me3) and CREB1 phosphorylation are critical for cellular sensitivity to cisplatin. Moreover, we showed that suppression of SETD2 or CREB1 and ectopic expression of mutant SETD2 conferred cisplatin resistance through inhibition of H3K36me3 and ERK activation in NSCLC cells. Our results provide evidence that SETD2 and CREB1 contribute to cisplatin cytotoxicity via regulation of the ERK signaling pathway, and their inactivation may lead to cisplatin resistance.
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http://dx.doi.org/10.1038/s41388-018-0429-3DOI Listing
January 2019

Consolidation systemic treatment after radiochemotherapy for unresectable stage III non-small cell lung cancer.

Cancer Treat Rev 2018 May 5;66:114-121. Epub 2018 Apr 5.

Department of Oncology and Radiotherapy, Medical University of Gdańsk, 7 Dębinki St., 80-211 Gdańsk, Poland.

The majority of stage III NSCLC patients managed with a combination of radiotherapy and chemotherapy will develop a locoregional or distant relapse. Concomitant radiochemotherapy allows for improved local control but has no impact on extrathoracic recurrences. To ameliorate this inefficiency the concept of consolidation treatment has been put forward, whereby systemically active doses of chemotherapy, targeted therapy or immune therapy are administered after completion of radiochemotherapy. Randomized trials failed to provide support for consolidation chemotherapy or anti-EGFR therapies. Recently durvalumab, an anti-PD-L1 checkpoint inhibitor, administered as consolidation treatment, was shown to substantially improve progression-free survival. This article critically reviews major studies addressing the role of consolidation systemic therapies following definitive concurrent radiochemotherapy and discusses prospects for future research.
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http://dx.doi.org/10.1016/j.ctrv.2018.04.001DOI Listing
May 2018

MiR-192 and miR-662 enhance chemoresistance and invasiveness of squamous cell lung carcinoma.

Lung Cancer 2018 04 6;118:111-118. Epub 2018 Feb 6.

Laboratory of Cell Biology, Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, ul. Dębinki 1, 80-211 Gdańsk, Poland. Electronic address:

Objectives: Overexpression of miR-192, miR-192* and miR-662 was previously found to correlate with poor prognosis of early-stage squamous cell lung cancer (SCC) patients. In this study, we investigated the relevance of these miRNAs to cancer cell biology and chemoresistance.

Materials And Methods: MiRNA expression profile was analysed in 10 non-small cell lung cancer (NSCLC) cell lines using RT-qPCR. H520 and H1703 cells were transfected with miRNA inhibitors (anti-miR-192, -192* and -662) for functional studies. Chemoresistance to cisplatin and etoposide was evaluated using MTT colorimetric assay. H520 cells were subjected to 3D soft-agar colony formation assay and H1703 cells to wound healing assay. Whole transcriptome analysis was used to assess the effect of miR-192 and miR-662 inhibition on gene expression.

Results: SCC cell lines, H520 and H1703, differed in miRNA expression and phenotypic features. MiR-192 and miR-662 inhibition decreased clonogenicity and motility of SCC cells. MiR-192 and miR-662 inhibition sensitized SCC cells to etoposide but not to cisplatin. Whole transcriptome analysis revealed genes regulated by miR-192 and miR-662 in SCC, relevant to maintaining chemoresistance, invasiveness, epithelial-mesenchymal transition (EMT) and immune evasion.

Conclusions: We showed for the first time that miR-192 and miR-662 have functional role in SCC cells. Our findings suggest that targeting these miRNAs may impact both chemoresistance and invasiveness of SCC, and add to the evidence linking these aspects of tumour biology. Overexpression of miR-192 and miR-662 might be useful as a marker of resistance to etoposide.
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http://dx.doi.org/10.1016/j.lungcan.2018.02.002DOI Listing
April 2018

Osimertinib - effective treatment of NSCLC with activating mutations after progression on EGFR tyrosine kinase inhibitors.

Contemp Oncol (Pozn) 2017 29;21(3):254-258. Epub 2017 Sep 29.

Department of Oncology and Radiotherapy, Medical University of Gdansk, Poland.

Non-small cell lung cancer (NSCLC) driven by activating mutations in epidermal growth factor receptor (EGFR) constitutes up to 10% of NSCLC cases. According to the NCCN recommendations, all patients (with the exception of smoking patients with squamous cell lung cancer) should be screened for the presence of activating EGFR mutations, i.e. deletion in exon 19 or point mutation L858R in exon 21, in order to select the group that benefits from EGFR tyrosine kinase inhibitors (EGFR TKIs) treatment. Among approved agents there are the 1 generation reversible EGFR TKIs, erlotinib and gefitinib, and the 2 generation irreversible EGFR TKI, afatinib. The objective response rates to these drugs in randomised clinical trials were in the range of 56-74%, and median time to progression 9-13 months. The most common determinant of resistance to these drugs is the clonal expansion of cancer cells with T790M mutation (Thr790Met) in exon 20 of EGFR. Osimertinib (Tagrisso™), a 3 generation, irreversible EGFR tyrosine kinase inhibitor, constitutes a novel, highly efficacious treatment for NSCLC patients progressing on EGFR TKIs with T790M mutation confirmed as the resistance mechanism. Resistance mutation can be determined in tissue or liquid biopsy obtained after progression on EGFR TKIs. Osimertinib has a favourable toxicity profile, with mild rash and diarrhoea being the most common. In this article, we present three cases that were successfully treated with osimertinib after progression on 1st and 2nd generation EGFR TKIs.
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http://dx.doi.org/10.5114/wo.2017.70116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701587PMC
September 2017

Keratin 7 expression in lymph node metastases but not in the primary tumour correlates with distant metastases and poor prognosis in colon carcinoma.

Pol J Pathol 2016;67(3):228-234

Department of Pathomorphology, Medical University of Gdańsk, Gdańsk, Poland.

Colorectal carcinoma (CRC) is one of the leading causes of cancer-related deaths worldwide. Alterations in keratin expression, including keratin 7 (K7), are frequent findings in multiple cancers, and they constitute a prognostic factor. The aim of our study was to evaluate the prognostic significance of K7 in the primary tumour and lymph node metastases in two separate cohorts of patients: the first one with lymph node involvement (LN+, 129 cases) and the second one free of LN metastases (LN-, 85 cases). Keratin 7 expression in CRC was analysed on tissue microarrays with immunohistochemistry and evaluated using the h-score. In the LN+ group K7 positivity was identified in 7/129 (5.4%) of primary tumours (PT) and lymph node metastases (LNM); concordance between them was 94% ( 0.396). Keratin 7 was expressed in 8/85 cases (9.4%) in the LN- group. K7 expression in LNM of the LN+ cohort correlated with shorter overall survival (OS) (p = 0.047) and presence of distant metastases at diagnosis (p = 0.005). Expression of K7 in the primary tumour in both cohorts did not correlate with survival. We conclude that the status of K7 expression in metastatic lymph nodes from CRC is a poor prognostic factor.
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http://dx.doi.org/10.5114/pjp.2016.63774DOI Listing
June 2017

The Role of TRAF4 and B3GAT1 Gene Expression in the Food Hypersensitivity and Insect Venom Allergy in Mastocytosis.

Arch Immunol Ther Exp (Warsz) 2016 Dec 16;64(6):497-503. Epub 2016 Apr 16.

Department of Allergology, Medical University of Gdansk, Gdańsk, Poland.

Mastocytosis is an uncommon disease classified as a myeloproliferative neoplasm, however, its symptoms are broad and place patients at crossroads between dermatology, hematology and allergology. Patients with mastocytosis often suffer from symptoms resulting from the activation and release of mediators from the mast cells, such as generalized itching, redness, headache, abdominal cramps, diarrhea, bone pain or arthritis, hypotension and shock. The possible severe, fatal or near fatal reactions caused by food hypersensitivity are reasons for the research focused on marker identification. The aim of the study was to analyse the gene expression differences in mastocytosis patients with and without food and drug hypersensitivity and insect venom allergy (IVA). A total of 57 Caucasian patients with mastocytosis were studied [median age 41.8; range 18-77 years; 15 (26.3 %) males and 42 (73.7 %) females]. Quantitative RT-PCRs of 11 genes plus ribosomal 18S RNA were run. Symptoms of food hypersensitivity were found in 12 patients (21 %), including 3 patients (13 %) with cutaneous mastocytosis (CM), and 9 (28 %) with indolent systemic mastocytosis (ISM). IVA was confirmed in 13 patients (22.8 %) including 6 patients (10.5 %) with CM, and 7 patients (12.3 %) with ISM. Drug hypersensitivity was diagnosed in 10 patients (17.5 %). Significant differences in the gene expression were found for TRAF4 (p = 0.008) in the comparison of the mastocytosis patients with and without concomitant food hypersensitivity. Furthermore significant differences were found in gene expression for B3GAT1 (p = 0.003) in patients with IVA compared to patients without insect sting anaphylaxis in the medical history. The expression of studied genes did not differ according to the presence of drug hypersensitivity. The TRAF4 expression was higher in mastocytosis patients with food hypersensitivity in their medical history, the B3GAT1 expression was lower in mastocytosis patients with IVA in history.
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http://dx.doi.org/10.1007/s00005-016-0397-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085980PMC
December 2016

Prognostic value of 5-microRNA based signature in T2-T3N0 colon cancer.

Clin Exp Metastasis 2016 12 2;33(8):765-773. Epub 2016 Aug 2.

Department of Oncology and Radiotherapy, Medical University of Gdansk, 7 Dębinki St., 80-211, Gdańsk, Poland.

The role of adjuvant chemotherapy in stage T2-T3N0 colon cancer (CC) is controversial and there are currently no reliable factors allowing for individual selection of patients with high risk of relapse for such therapy. We searched for microRNA-based signature with prognostic significance in this group. We assessed by qRT-PCR expression of 754 microRNAs (miRNAs) in tumour samples from 85 stage pT2-3N0 CC patients treated with surgery alone. MiRNA expression was compared between two groups of patients: 40 and 45 patients who did and did not develop distant metastases after resection, respectively. Additionally, miRNA expression was compared between CC and normal colon mucosa samples and between the mismatch repair (MMR) competent and deficient tumours. Low expression of miR-1300 and miR-939 was significantly correlated with shorter distant metastasis-free survival (DMFS) in Cox univariate analysis (p.adjusted = 0.049). The expression signature of five miRNAs (miR-1296, miR-135b, miR-539, miR-572 and miR-185) was found to be prognostic [p = 1.28E-07, HR 8.4 (95 % CI: 3.81-18.52)] for DMFS and cross-validated in a leave-one-out analysis, with the sensitivity and specificity of 74 and 78 %, respectively. The expression of miR-592 was significantly associated with the MMR status (p.adjusted <0.01). The expression of several novel miRNAs were found to be tumour specific, e.g. miR-888, miR-523, miR-18b, miR-302a, miR-423-5p, miR-582-3p (p < 0.05). We developed a miRNA expression signature that may be predictive for the risk of distant relapse in early stage CC and confirmed previously reported association between miR-592 expression and MMR status.
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http://dx.doi.org/10.1007/s10585-016-9810-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110606PMC
December 2016

Combined clinical and genomic signatures for the prognosis of early stage non-small cell lung cancer based on gene copy number alterations.

BMC Genomics 2015 Oct 6;16:752. Epub 2015 Oct 6.

Laboratory of Biomarkers, Program in Solid Tumors and Biomarkers, Center for Applied Medical Research, University of Navarra, Pio XII, 55, 31008, Pamplona, Spain.

Background: The development of a more refined prognostic methodology for early non-small cell lung cancer (NSCLC) is an unmet clinical need. An accurate prognostic tool might help to select patients at early stages for adjuvant therapies.

Results: A new integrated bioinformatics searching strategy, that combines gene copy number alterations and expression, together with clinical parameters was applied to derive two prognostic genomic signatures. The proposed methodology combines data from patients with and without clinical data with a priori information on the ability of a gene to be a prognostic marker. Two initial candidate sets of 513 and 150 genes for lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), respectively, were generated by identifying genes which have both: a) significant correlation between copy number and gene expression, and b) significant prognostic value at the gene expression level in external databases. From these candidates, two panels of 7 (ADC) and 5 (SCC) genes were further identified via semi-supervised learning. These panels, together with clinical data (stage, age and sex), were used to construct the ADC and SCC hazard scores combining clinical and genomic data. The signatures were validated in two independent datasets (n = 73 for ADC, n = 97 for SCC), confirming that the prognostic value of both clinical-genomic models is robust, statistically significant (P = 0.008 for ADC and P = 0.019 for SCC) and outperforms both the clinical models (P = 0.060 for ADC and P = 0.121 for SCC) and the genomic models applied separately (P = 0.350 for ADC and P = 0.269 for SCC).

Conclusion: The present work provides a methodology to generate a robust signature using copy number data that can be potentially used to any cancer. Using it, we found new prognostic scores based on tumor DNA that, jointly with clinical information, are able to predict overall survival (OS) in patients with early-stage ADC and SCC.
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http://dx.doi.org/10.1186/s12864-015-1935-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595201PMC
October 2015

Main histologic types of non-small-cell lung cancer differ in expression of prognosis-related genes.

Clin Lung Cancer 2013 Nov 17;14(6):666-673.e2. Epub 2013 Jul 17.

Medical University of Gdansk, Department of Oncology and Radiotherapy, Gdansk, Poland. Electronic address:

Background: There is increasing evidence that suggests that particular histopathologic types of non-small-cell lung cancer (NSCLC) display distinct molecular characteristics. We analyzed, in lung squamous cell carcinoma (SCC) and adenocarcinoma (AC), the expression of 8 genes that constitute 2 previously reported prognostic expression signatures in NSCLC.

Methods: Fresh-frozen tumor and normal lung samples were obtained at surgery from 135 patients with stage I-III NSCLC (89 (65.9%) SCC, 46 (34.1%) AC). Expression of CSF1 (colony stimulating factor for macrophages), carbonic anhydrase 9 (CA9), epithelial growth factor receptor (EGFR), dual specificity phosphatase 6 (DUSP6), v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3), monocyte to macrophage differentiation-associated (MMD), lymphocyte-specific protein tyrosine kinase (LCK) and signal transducer and activator of transcription 1 (STAT1) was assessed in SCC, AC, and in normal lung by quantitative reverse transcriptase - polymerase chain reaction (qRT-PCR). Metastasis-free survival was analyzed according to the median value of gene expression in the entire NSCLC cohort and separately in SCC and AC.

Results: Expression of CA9, CSF1, DUSP6, STAT1, and MMD differed between NSCLC and normal lung. EGFR was more abundant in SCC compared with AC, whereas the reverse was true for DUSP6 and ERBB3. A high expression of CSF1 correlated with shorter metastasis-free survival in the entire NSCLC group (P = .016) and in SCC (P = .049) and AC (P = .034) cohorts.

Conclusions: Several genes considered prognostic in NSCLC showed significantly different expression in SCC and AC, and thus should be analyzed separately in these 2 subtypes for their prognostic significance. CSF1 is similarly expressed in SCC and AC, and portends a poor outcome in the entire group of patients with NSCLC, and in SCC and AC when considered separately.
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http://dx.doi.org/10.1016/j.cllc.2013.04.010DOI Listing
November 2013

MicroRNA in lung cancer diagnostics and treatment.

Mutat Res 2011 Dec 20;717(1-2):25-31. Epub 2011 Apr 20.

Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdańsk, Poland.

MicroRNAs (miRs) are short RNA chains that regulate gene expression by inhibition of mRNA translation. Their expression is often deranged in cancer. Increasing evidence indicates that these molecules play an important role in oncogenesis and cancer progression. This review focuses on the clinical application of miRs in lung cancer, with the emphasis on detection of early lung cancer, prognostication and chemotherapy sensitivity prediction. Methodological aspects of studies on prognostic markers in early NSCLC are outlined in detail. Finally, modulation of miR expression in lung cancer as a therapeutic possibility is discussed.
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http://dx.doi.org/10.1016/j.mrfmmm.2011.04.002DOI Listing
December 2011

An immune response enriched 72-gene prognostic profile for early-stage non-small-cell lung cancer.

Clin Cancer Res 2009 Jan;15(1):284-90

Agendia BV.

Purpose: Current staging methods are imprecise for predicting prognosis of early-stage non-small-cell lung cancer (NSCLC). We aimed to develop a gene expression profile for stage I and stage II NSCLC, allowing identification of patients with a high risk of disease recurrence within 2 to 3 years after initial diagnosis.

Experimental Design: We used whole-genome gene expression microarrays to analyze frozen tumor samples from 172 NSCLC patients (pT1-2, N0-1, M0) from five European institutions, who had undergone complete surgical resection. Median follow-up was 89 months (range, 1.2-389) and 64 patients developed a recurrence. A random two thirds of the samples were assigned as the training cohort with the remaining samples set aside for independent validation. Cox proportional hazards models were used to evaluate the association between expression levels of individual genes and patient recurrence-free survival. A nearest mean analysis was used to develop a gene-expression classifier for disease recurrence.

Results: We have developed a 72-gene expression prognostic NSCLC classifier. Based on the classifier score, patients were classified as either high or low risk of disease recurrence. Patients classified as low risk showed a significantly better recurrence-free survival both in the training set (P < 0.001; n = 103) and in the independent validation set (P < 0.01; n = 69). Genes in our prognostic signature were strongly enriched for genes associated with immune response.

Conclusions: Our 72-gene signature is closely associated with recurrence-free and overall survival in early-stage NSCLC patients and may become a tool for patient selection for adjuvant therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-1258DOI Listing
January 2009

A multigene assay is prognostic of survival in patients with early-stage lung adenocarcinoma.

Clin Cancer Res 2008 Sep;14(17):5565-70

Thoracic Oncology Program, Department of Surgery, University of California, San Francisco, San Francisco, California 94131, USA.

Purpose: Clinical staging does not adequately risk stratify patients with early stage non-small cell lung cancer. We sought to generate a real-time PCR (RT-PCR)-based prognostic model in patients with early stage lung adenocarcinoma, the dominant histology of lung cancer in the United States.

Experimental Design: We studied gene expression of 61 candidate genes in 107 patients with completely surgically resected lung adenocarcinoma using RT-PCR. We used crossvalidation methods to select and validate a prognostic model based on the expression of a limited number of genes. A risk score was generated based on model coefficients, and survival of patients with high- and low-risk scores were analyzed.

Results: We generated a four-gene model based on expression of WNT3a, ERBB3, LCK, and RND3. Risk score predicted mortality better than clinical stage or tumor size (adjusted hazard ratio, 6.7; 95% confidence interval, 1.6-28.9; P=0.001). Among 70 patients with stage I disease, 5-year overall survival was 87% among patients with low-risk scores, and 38% among patients with high-risk scores (P=0.0002). Among all patients, 5-year overall survival was 62% and 41%, respectively (P=0.0054). Disease-free survival was also significantly different among low- and high-risk score patients.

Conclusions: This multigene assay predicts overall and disease-free survival significantly better than clinical stage and tumor size in patients with early stage lung adenocarcinoma and performs especially well in patients with stage I disease. Prospective clinical trials are needed to determine whether high-risk patients with stage I disease benefit from adjuvant chemotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-0544DOI Listing
September 2008

Three-gene expression signature predicts survival in early-stage squamous cell carcinoma of the lung.

Clin Cancer Res 2008 Aug;14(15):4794-9

University of Gdansk, Gdansk, Poland.

Purpose: Adjuvant treatment may improve survival in early-stage squamous cell carcinoma (SCC) of the lung; however, the absolute gain is modest and mainly limited to stage II-IIIA. Current staging methods are imprecise indications of prognosis, but high-risk patients can be identified by gene expression profiling and considered for adjuvant therapy.

Experimental Design: The expression of 29 genes was assessed by reverse transcriptase quantitative PCR in frozen primary tumor specimens obtained from 66 SCC patients who had undergone surgical resection. Expression values were dichotomized using the median as a cutoff value. We used a risk score to develop a gene expression model for the prediction of survival.

Results: The univariate analysis of gene expression in the training cohort identified 10 genes with significant prognostic value: CSF1, EGFR, CA IX, PH4, KIAA0974, ANLN, VEGFC, NTRK1, FN1, and INR1. In the multivariate Cox model, CSF1 (hazard ratio, 3.5; P = 0.005), EGFR (hazard ratio, 2.7; P = 0.02), CA IX (hazard ratio, 0.2; P < 0.0001), and tumor size >4 cm (hazard ratio, 2.7; P = 0.02) emerged as significant markers for survival. The high prognostic value of a risk score based on the expression of the three genes (CSF1, EGFR, and CA IX) was positively validated in a separate cohort of 26 patients in an independent laboratory (P = 0.05).

Conclusions: The three-gene signature is strongly associated with prognosis in early-stage SCC. Positive independent validation suggests its suitability for selecting SCC patients with an increased risk of death who might benefit from adjuvant treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-0576DOI Listing
August 2008

Analysis of safety, risk factors and pretreatment methods during rush hymenoptera venom immunotherapy.

Int Arch Allergy Immunol 2008 2;147(3):241-5. Epub 2008 Jul 2.

Department of Allergology, Medical University of Gdańsk, Gdańsk, Poland.

Background: The safety profile of venom immunotherapy is a relevant issue. We evaluated the frequency of severe adverse events (SAE), associated risk factors, retrospective comparison of pretreatment protocols including solely H1 receptor blockers and a combination of H1 and H2 receptor blockers during rush Hymenoptera venom immunotherapy.

Methods: The study group comprised 118 patients. The treatment was initiated according to a 5-day rush protocol with the use of standardized venom allergens of either wasp or honeybee.

Results: During the rush induction, side effects occurred in 18 patients (15.2%), whereas SAE were present in 7 patients (5.9%). Twelve out of 18 (66.6%) developed anaphylactic reactions on the fourth day of the rush protocol, with the majority of cases at a dose of 40 or 60 microg of the venom extract (p = 0.001). The frequency of SAE was also significantly higher on the fourth day than thereafter (p = 0.0001) as well as in patients allergic to bee venom (p = 0.049). All systemic side effects were more frequent in women (p = 0.0065). However, this relation was not true when SAE were consider (p = 0.11). A higher percentage of SAE was observed in the subjects pretreated with both H1 and H2 receptor antagonists than in those pretreated with H1 blocker only (8.8 vs. 4.1%); however, the difference was not significant.

Conclusions: Considerable severity of allergic adverse events requires particular attention to patients allergic to bee venom and during rush phase, especially when rapidly increasing doses are administered. Pretreatment with H2 blockers is debatable and warrants further investigation.
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http://dx.doi.org/10.1159/000142048DOI Listing
November 2008

Quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR) in translational oncology: lung cancer perspective.

Authors:
Marcin Skrzypski

Lung Cancer 2008 Feb 4;59(2):147-54. Epub 2008 Jan 4.

Medical University of Gdansk, Department of Allergology, 7 Debinki St, 80-211 Gdansk, Poland.

Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) is rapidly becoming a basic method in lung cancer research. Analysis of transcriptional activity of tumor cells or detection of tumor markers by this technique has the potential to change lung cancer diagnosis and treatment. Quantitative RT-PCR is characterized by unparalleled sensitivity and specificity, with very reliable reproducibility. Its prime advantage for gene expression analysis is its broad dynamic range of 10(7)-fold. Moreover, it is cost-effective, feasible in every day laboratory routine and efficient in terms of biological material consumption. Still, there are a number of methodological aspects that need to be carefully considered before it can sensibly be implemented into clinical practice. Three major technical issues: the choice of chemistries, gene expression data normalization and statistical processing of the results will be specifically highlighted in this review. Further, clinical applications of qRT-PCR will be thoroughly discussed: detection and staging of lung cancer and construction and validation of prognostic and predictive gene expression signatures.
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http://dx.doi.org/10.1016/j.lungcan.2007.11.008DOI Listing
February 2008

BRCA1: a novel prognostic factor in resected non-small-cell lung cancer.

PLoS One 2007 Nov 7;2(11):e1129. Epub 2007 Nov 7.

Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.

Background: Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1).

Methodology And Principal Findings: We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04).

Conclusions: Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy, especially in stage IB, where the role of adjuvant chemotherapy has not been clearly demonstrated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001129PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042516PMC
November 2007

Expression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective study.

Lancet Oncol 2007 Oct;8(10):889-97

Translational Oncology Unit, CSIC-UAM-La Paz, National Center of Biotechnology, Madrid, Spain.

Background: Adequate prognostic markers to predict outcome of patients with lung cancer are still needed. The aim of this study was to assess whether choline kinase alpha (ChoKalpha) gene expression could identify patients with different prognoses. ChoKalpha is an enzyme involved in cell metabolism and proliferation and has a role in oncogene-mediated transformation in several human tumours, including lung cancer.

Methods: 60 patients with non-small-cell lung cancer (NSCLC) who had undergone surgical resection in a single centre were enrolled into the study as the training group. We used real-time reverse-transcriptase PCR (RT-PCR) to measure ChoKalpha gene expression and analyse the association between ChoKalpha expression and survival in evaluable patients. Additionally, a second group of 120 patients with NSCLC from a different hospital were enrolled into the study as the validation group. We did an overall analysis of all 167 patients who had available tissue to confirm the cut-off point for future studies. The primary endpoints were lung-cancer-specific survival and relapse-free survival.

Findings: Seven of the 60 patients in the training group were not evaluable due to insufficient tissue. In the 53 evaluable patients, the cut-off for those with ChoKalpha overexpression was defined by receiver operator under the curve (ROC) methodology. 4-year lung-cancer-specific survival was 54.43% (95% CI 28.24-80.61) for 25 patients with ChoKalpha expression above the ROC-defined cut-off compared with 88.27% (75.79-100) for 28 patients with concentrations of the enzyme below this cut-off (hazard ratio [HR] 3.14 [0.83-11.88], p=0.07). In the validation group, six of the 120 enrolled patients were not evaluable due to insufficient tissue. For the other 114 patients, 4-year lung-cancer-specific survival was 46.66% (32.67-59.65) for those with ChoKalpha expression above the ROC-defined cut-off compared with 67.01% (50.92-81.11) for patients with concentrations of ChoKalpha below the cut-off (HR 1.87 [1.01-3.46], p=0.04). A global analysis of all 167 patients further confirmed the association between ChoKalpha overexpression and worse clinical outcome of patients with NSCLC: 4-year lung-cancer-specific survival for ChoKalpha expression above the ROC-defined cut-off was 49.00% (36.61-60.38) compared with 70.52% (59.80-76.75) for those with concentrations of ChoKalpha below the cut-off (HR 1.98 [1.14-3.45], p=0.01). The overall analysis confirmed the cut-off for ChoKalpha expression should be 1.91-times higher than concentrations noted in healthy tissues when ChoKalpha is used as an independent predictive factor of relapse-free and lung-cancer-specific survival in patients with early-stage NSCLC.

Interpretation: ChoKalpha expression is a new prognostic factor that could be used to help identify patients with early-stage NSCLC who might be at high risk of recurrence, and to identify patients with favourable prognosis who could receive less aggressive treatment options or avoid adjuvant systemic treatment. New treatments that inhibit ChoKalpha expression or activity in patients with lung cancer should be studied further.
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http://dx.doi.org/10.1016/S1470-2045(07)70279-6DOI Listing
October 2007

[Analysis of prognostic value of TP53 gene mutations in non-small cell lung cancer].

Pneumonol Alergol Pol 2005 ;73(3):264-9

Klinika Alergologii, AM w Gdańsku.

The aim of this study was to assess the frequency and prognostic value of TP53 gene somatic mutations in non-small cell lung cancer. The study group included 240 NSCLC patients who underwent pulmonary resection at the Department of Thoracic Surgery, Medical University of Gdańsk. Tumour samples were evaluated for the presence of TP53 gene mutations in exons 5-8. In 157 cases SSCP method was used as a screening followed by sequencing of positive samples. In the remaining 83 patients mutations were analysed by direct sequencing. A total of 76 mutations (32%) were found, of those a missense type was dominant (67%), followed by silent and null type mutations (14% and 10%, respectively). There was no correlation between mutations and clinical characteristics, including age, sex, histological subtype, differentiation, tumour size, lymph node metastases, pTNM stage and smoking status. A multivariate Cox analysis demonstrated that tumour differentiation and pTNM stage were independent prognostic factors, whereas TP53 gene mutations were not. The results of this study indicate that TP53 gene mutations in NSCLC patients are not correlated with clinical characteristics and have no impact on survival.
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January 2007

P53 and K-ras mutations are frequent events in microscopically negative surgical margins from patients with nonsmall cell lung carcinoma.

Cancer 2004 May;100(9):1951-60

Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland.

Background: The objective of the current study was to determine whether tumor cells harboring P53 and K-ras mutations could be detected in histopathologically tumor-free surgical margins in patients with nonsmall cell lung carcinoma who underwent complete pulmonary resection.

Methods: In 118 consecutive patients, DNA obtained from primary tumors and from surgical margins was extracted for molecular analysis. A fragment of P53 gene encompassing exons 5-8 and codon 12 of the K-ras gene were amplified with the polymerase chain reaction technique and were assayed for the presence of mutations.

Results: P53 and K-ras mutations were found in 30% and 39% of primary tumors, respectively, and in 11 (9%) and 22 (18%) apparently tumor-free surgical margins, respectively. At least 1 of those mutations was found in surgical margins in 29 patients (25%), and both mutations were found in 2 patients (1.7%). P53 mutations in surgical margins accompanied mutations in primary tumors in 9 of 35 patients (26%), and K-ras mutations accompanied mutations in primary tumors in 20 of 46 patients (44%). Among patients with either mutation in primary tumors, the incidence of at least 1 mutation in surgical margins was 43% (28 of 65 patients). In four patients, mutations (two K-ras mutations and two P53 mutations) were found in surgical margins despite the absence of the corresponding mutations in primary tumors. The presence of mutations in primary tumors and in surgical margins was not related significantly to clinical characteristics or to patient outcomes.

Conclusions: P53 and K-ras mutations are frequent events in surgical margins determined to be tumor free on light microscopy. The clinical relevance of these findings remains to be established.
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http://dx.doi.org/10.1002/cncr.20191DOI Listing
May 2004

[Alterations of locus P16INK4a/P14ARF in non-small cell lung cancer].

Pneumonol Alergol Pol 2003 ;71(9-10):471-8

Klinika Alergologii AM w Gdańsku.

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June 2004

[Serum anti-P53 antibodies (AB-anti-P53) in patients with advanced non-small cell lung cancer (NSCLC)].

Pneumonol Alergol Pol 2002 ;70(7-8):353-8

Klinika Chorób Płuc i Gruźlicy AM, Gdańsku.

The aim of the study was to assess the frequency of serum Ab-anti-p53 in 39 patients with advanced NSCLC and to evaluate the predictive value of the test. Antibodies were present in 10 (25.6%) of patients. There was no correlation between Ab-anti-p53 and clinical characteristics including age, gender, and histological type of tumor. In 17 patients response to chemotherapy (CT) was obtained (in one patient--complete, and in 16--partial response). The percentage of patients responding to CT in group with and without serum antibodies did not differ significantly (33% and 48%, respectively; p = 0.48). The results of the study indicate that serum Ab-anti-p53 are relatively often present in advanced NSCLC patients, however the clinical value of this test needs further evaluation.
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May 2003