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Green, H., Hasmats, J., Kupershmidt, I., Edsgard, D., de Petris, L., Lewensohn, R., . . . Lundeberg, J. (2016). Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities. Clinical Cancer Research, 22(2), 366-373
Open this publication in new window or tab >>Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities
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2016 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 2, p. 366-373Article in journal (Refereed) Published
Abstract [en]

Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression. Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis. Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P = 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P = 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia. Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/ carboplatin chemotherapy. (C)2015 AACR.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2016
National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-125314 (URN)10.1158/1078-0432.CCR-15-0964 (DOI)000369076500013 ()26378035 (PubMedID)
Note

Funding Agencies|European Commission [CHEMORES LSHC-CT-2007-037665]; Swedish Cancer Society; Swedish Research Council; Fondkistan; Stiftelsen Sigurd och Elsa Goljes Minne; Marcus Borgstroms stiftelse

Available from: 2016-02-24 Created: 2016-02-19 Last updated: 2018-01-10
Sörenson, S., Fohlin, H., Lindgren, A., Lindskog, M., Bergman, B., Sederholm, C., . . . Clinchy, B. (2013). Predictive role of plasma vascular endothelial growth factor for the effect of celecoxib in advanced non-small cell lung cancer treated with chemotherapy. European Journal of Cancer, 49(1), 115-120
Open this publication in new window or tab >>Predictive role of plasma vascular endothelial growth factor for the effect of celecoxib in advanced non-small cell lung cancer treated with chemotherapy
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2013 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, no 1, p. 115-120Article in journal (Refereed) Published
Abstract [en]

Aim of the study: The primary purpose of this study is to investigate if pretreatment plasma levels of vascular endothelial growth factor (VEGF) are predictive of the effect of celecoxib on survival in advanced non-small cell lung cancer (NSCLC) treated with palliative chemotherapy. A secondary objective is to describe the course of plasma VEGF levels during and after treatment with cytotoxic chemotherapy combined with celecoxib or placebo. less thanbrgreater than less thanbrgreater thanMethods: In a previously published double-blind multicenter phase III trial, 316 patients with NSCLC stage IIIB or IV and World Health Organisation (WHO) performance status 0-2 were randomised to receive celecoxib 400 mg b.i.d. or placebo in combination with two-drug platinum-based chemotherapy. Chemotherapy cycle length was three weeks and planned duration of chemotherapy was four cycles. Celecoxib was given for a maximum of one year but was stopped earlier in case of disease progression or prohibitive toxicity. In a subset of patients, plasma VEGF levels were examined at onset of treatment and at 6, 12 and 20 weeks. less thanbrgreater than less thanbrgreater thanResults: VEGF levels at start of treatment were obtained in 107 patients at four study sites. The median value was 70 pg/ml. Mean values declined during the first 12 weeks and then increased at 20 weeks. A subpopulation treatment effect pattern plot (STEPP) analysis showed an inverse relationship between initial plasma VEGF and the impact of celecoxib on survival with zero effect at 200 pg/ml. The effect on survival by celecoxib in the whole subset of patients was positive (hazard ratio (HR)=0.64 [confidence interval (CI) 0.43-0.95], p=0.028). less thanbrgreater than less thanbrgreater thanConclusion: Low pretreatment plasma levels of VEGF appear to be predictive of a positive effect of celecoxib on survival.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Non-small cell lung cancer, Celecoxib, Chemotherapy, Survival, Plasma VEGF
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-88362 (URN)10.1016/j.ejca.2012.07.032 (DOI)000312896700015 ()
Note

Funding Agencies|Ostergotland County Council, Medical Research Council of South-East Sweden (FORSS)||

Available from: 2013-02-04 Created: 2013-02-04 Last updated: 2017-12-06
Koch, A. (2011). Clinical Aspects of Inflammation in Non-small Cell Lung Cancer. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Clinical Aspects of Inflammation in Non-small Cell Lung Cancer
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lung cancer is the most common cause of cancer death worldwide, with about 1.2 million deaths every year. In Sweden, about 3500 new cases are diagnosed every year. The majority of patients presents with advanced non-small cell lung cancer (NSCLC) and is treated with palliative intent. Standard treatment in these patients in performance status 0-2 is combination chemotherapy. Radiotherapy may be added for palliative purposes. Median survival time with such treatment is 6-10 months. New treatment strategies are urgently needed. There is growing evidence for a link between cancer and inflammation and consequently, inflammation may be a possible target for the treatment of lung cancer.

The aim of this thesis was to study clinical aspects of inflammation in non-small cell lung cancer. A central issue was to adapt the projects as close to clinical routine as possible.

In a retrospective study of 289 patients (paper I), we investigated the prognostic value of Creactive protein (CRP), a nonspecific marker of systemic inflammation, and smoking in patients with advanced NSCLC treated with palliative first-line chemotherapy. We found that patients with elevated CRP values (≥10 mg/ml) and current smokers at onset of treatment had inferior survival compared to patients with normal CRP values and patients who were not smoking. CRP and smoking status were independent prognostic factors and provided additional information to established prognostic factors such as stage of disease and performance status.

The expression of COX-2, an important enzyme involved in inflammation, was prospectively analysed in 53 patients with cytologically diagnosed lung cancer (paper II). The study showed that the analysis of COX-2 expression in cytological material is technically easy to perform with routine diagnostic methods and results in good quality slides. There was great variation in the proportion of COX-2 positive cells between the patients as well as in the intensity of staining between individual cells in many single cases.

The major project (paper III) of this thesis was the CYCLUS study, an academic, randomised, double-blind, phase III trial. The scientific question was if addition of the COX-2 inhibitor celecoxib to first-line palliative chemotherapy would prolong survival in patients with advanced NSCLC. 316 patients were included at 13 centres in Sweden. There was no survival difference between the treatment arms. Celecoxib appeared to have more favourable effect on survival in women than in men, but the differences were not significant. Small but not statistically significant differences in global quality of life and pain were seen favouring the celecoxib group. No increased incidence of cardiovascular events was observed in the celecoxib group.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. p. 74
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1232
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68749 (URN)978-91-7393-212-7 (ISBN)
Public defence
2011-05-24, Elsa Brändströmsalen, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2011-06-01 Created: 2011-06-01 Last updated: 2014-04-08Bibliographically approved
Koch, A., Gustafsson, B., Fohlin, H. & Sörenson, S. (2011). Cyclooxygenase-2 expression in lung cancer cells evaluated by immunocytochemistry. Diagnostic Cytopathology, 39(3), 188-193
Open this publication in new window or tab >>Cyclooxygenase-2 expression in lung cancer cells evaluated by immunocytochemistry
2011 (English)In: Diagnostic Cytopathology, ISSN 8755-1039, E-ISSN 1097-0339, Vol. 39, no 3, p. 188-193Article in journal (Refereed) Published
Abstract [en]

Cyclooxygenase-2 (COX-2) expression may be a prognostic factor in lung cancer. In previous studies, COX-2 expression has almost exclusively been evaluated with immunohistochemical methods performed on histology sections of tissue biopsies. However, in clinical practice, lung cancer is often diagnosed with cytological techniques only. We present methodology and results from analysis of COX-2 expression with immunochemistry on cytological material in 53 patients with lung cancer. Preparation and staining with the method established at our laboratory were easy to perform and resulted in good quality slides. The percentage COX-2-stained cells and the intensity of staining varied widely between and within the different cases. The proportion of positively stained tumor cells was as follows: <1% in 20 patients, 1-10% in 7 patients, 11-50% in 17 patients, and more than 50% in 9 patients. In 17 cases, groups of cells with different intensity of COX-2 staining were found in the same slide. In conclusion, immunocytochemical analysis of COX-2 expression is technically easy to perform with routine diagnostic procedures. There is a great variation in the proportion of COX-2-positive cells among patients and in the intensity of staining among individual cells in many single cases. Diagn. Cytopathol.2011;39:188-193. © 2010 Wiley-Liss, Inc.

Place, publisher, year, edition, pages
John Wiley and Sons, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-66083 (URN)10.1002/dc.21366 (DOI)000288035400006 ()21319320 (PubMedID)
Available from: 2011-03-04 Created: 2011-03-02 Last updated: 2017-12-11Bibliographically approved
Koch, A., Bergman, B., Holmberg, E., Sederholm, C., Ek, L., Kosieradzki, J., . . . Sörenson, S. (2011). Effect of celecoxib on survival in patients with advanced non-small cell lung cancer: A double blind randomised clinical phase III trial (CYCLUS study) by the Swedish Lung Cancer Study Group. European Journal of Cancer, 47(10), 1546-1555
Open this publication in new window or tab >>Effect of celecoxib on survival in patients with advanced non-small cell lung cancer: A double blind randomised clinical phase III trial (CYCLUS study) by the Swedish Lung Cancer Study Group
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2011 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 47, no 10, p. 1546-1555Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Increased expression of cyclooxygenase-2 (COX-2) is common in non-small cell lung cancer (NSCLC) and has been associated with poor prognosis. Experimental and clinical phase II trials have indicated that the addition of the COX-2 inhibitor celecoxib to palliative chemotherapy might increase survival time in patients with advanced NSCLC.

METHODS: We performed a double-blind, placebo-controlled multicentre phase III trial at 13 centres in Sweden. Three hundred and nineteen patients with advanced NSCLC stage IIIB-IV and performance status 0-2 were randomised to receive celecoxib 400mg b.i.d. or placebo in addition to palliative chemotherapy. The primary objective was to compare overall survival. Other end-points were quality of life, progression-free survival, toxicity, cardiovascular events and biological markers. The trial is registered with ClinicalTrials.gov, No. NCT00300729.

FINDINGS: Three hundred and sixteen patients were included in the analysis, 158 in each treatment group. Median survival time was 8.5months. There was no survival difference between the treatment arms. Small but not statistically significant differences in global quality of life and pain were seen favouring the celecoxib group. No increased incidence of cardiovascular events was observed in the celecoxib group.

INTERPRETATION: This study failed to demonstrate a survival benefit of the addition of celecoxib to palliative chemotherapy.

Place, publisher, year, edition, pages
Elsevier, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68748 (URN)10.1016/j.ejca.2011.03.035 (DOI)000292946200015 ()21565487 (PubMedID)
Available from: 2011-06-01 Created: 2011-06-01 Last updated: 2017-12-11Bibliographically approved
Koch, A., Sörenson, S., Fohlin, H. & Gustafsson, B. (2009). Expression of cyclooxygenase-2 in cytological material from patients with lung cancer in EJC SUPPLEMENTS, vol 7, issue 2, pp 513-513. In: EJC SUPPLEMENTS (pp. 513-513). , 7(2)
Open this publication in new window or tab >>Expression of cyclooxygenase-2 in cytological material from patients with lung cancer in EJC SUPPLEMENTS, vol 7, issue 2, pp 513-513
2009 (English)In: EJC SUPPLEMENTS, 2009, Vol. 7, no 2, p. 513-513Conference paper, Published paper (Refereed)
Abstract [en]

n/a

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53064 (URN)000270645902370 ()
Available from: 2010-01-15 Created: 2010-01-15 Last updated: 2014-04-08
Koch, A., Fohlin, H. & Sörenson, S. (2009). Prognostic significance of C-reactive protein and smoking in patients with advanced non-small cell lung cancer treated with first-line palliative chemotherapy.. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 4(3), 326-32
Open this publication in new window or tab >>Prognostic significance of C-reactive protein and smoking in patients with advanced non-small cell lung cancer treated with first-line palliative chemotherapy.
2009 (English)In: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, ISSN 1556-1380, Vol. 4, no 3, p. 326-32Article in journal (Refereed) Published
Abstract [en]

HYPOTHESIS: The objective of the study was to analyze if C-reactive protein (CRP) and smoking status provide prognostic information in patients with advanced non-small cell lung cancer (NSCLC) receiving palliative first-line chemotherapy. METHODS: Retrospective, single-institutional study, comprising all patients with NSCLC stage IIIB/IV and World Health Organization performance status (PS) 0-2 who started palliative first-line chemotherapy between January 1, 2002, and January 31, 2007. Patient records were reviewed. Cox's proportional hazards model was used to identify prognostic factors. RESULTS: Two hundred eight-nine consecutive patients were evaluable. Sixty-eight percent had stage IV disease and 67% had PS 0 or 1. Median survival was 7.4 months. At onset of chemotherapy, 206 patients (71%) had elevated CRP values (> or = 10 mg/liter). One-hundred-forty-four patients (50%) were current smokers. On univariate analysis, patients with elevated CRP levels had inferior survival (hazard ratio [HR] = 1.67, 95% confidence interval [CI], 1.28-2.19, p < 0.001). Smoking at onset of treatment was associated with shorter survival (HR 1.56, 95% CI, 1.22-1.98, p < 0.001). Ever smokers had shorter survival than never smokers (HR 1.80, 95% CI, 1.25-2.59, p = 0.001). On multivariate analysis, with stage, PS, albumin, and gender as covariates, both smoking at start of chemotherapy and CRP elevation were independent negative prognostic factors for survival. CONCLUSIONS: CRP and smoking status are independent prognostic factors for survival in patients with advanced NSCLC receiving palliative first-line chemotherapy and provide additional information to established prognostic factors such as stage of disease and performance status.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18964 (URN)10.1097/JTO.0b013e31819578c8 (DOI)19155996 (PubMedID)
Available from: 2009-06-06 Created: 2009-06-06 Last updated: 2014-04-08
Koch, A., Sörenson, S., Askeland, A. & Aasen, T. (2003). Rapportering av yrkesrelatert lungekreft.. Lungeforum, 13, 12-16
Open this publication in new window or tab >>Rapportering av yrkesrelatert lungekreft.
2003 (Swedish)In: Lungeforum, ISSN 0803-4079, E-ISSN 1891-1587, Vol. 13, p. 12-16Article in journal (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27310 (URN)11961 (Local ID)11961 (Archive number)11961 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-8365-3132

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