uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Ekman, Simon
Publications (10 of 19) Show all publications
Grinberg, M., Djureinovic, D., Brunnström, H. R., Mattsson, J. S., Edlund, K., Hengstler, J. G., . . . Micke, P. (2017). Reaching the limits of prognostication in non-small cell lung cancer: an optimized biomarker panel fails to outperform clinical parameters.. Modern Pathology, 30(7), 964-977.
Open this publication in new window or tab >>Reaching the limits of prognostication in non-small cell lung cancer: an optimized biomarker panel fails to outperform clinical parameters.
Show others...
2017 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 30, no 7, 964-977 p.Article in journal (Refereed) Published
Abstract [en]

Numerous protein biomarkers have been analyzed to improve prognostication in non-small cell lung cancer, but have not yet demonstrated sufficient value to be introduced into clinical practice. Here, we aimed to develop and validate a prognostic model for surgically resected non-small cell lung cancer. A biomarker panel was selected based on (1) prognostic association in published literature, (2) prognostic association in gene expression data sets, (3) availability of reliable antibodies, and (4) representation of diverse biological processes. The five selected proteins (MKI67, EZH2, SLC2A1, CADM1, and NKX2-1 alias TTF1) were analyzed by immunohistochemistry on tissue microarrays including tissue from 326 non-small cell lung cancer patients. One score was obtained for each tumor and each protein. The scores were combined, with or without the inclusion of clinical parameters, and the best prognostic model was defined according to the corresponding concordance index (C-index). The best-performing model was subsequently validated in an independent cohort consisting of tissue from 345 non-small cell lung cancer patients. The model based only on protein expression did not perform better compared to clinicopathological parameters, whereas combining protein expression with clinicopathological data resulted in a slightly better prognostic performance (C-index: all non-small cell lung cancer 0.63 vs 0.64; adenocarcinoma: 0.66 vs 0.70, squamous cell carcinoma: 0.57 vs 0.56). However, this modest effect did not translate into a significantly improved accuracy of survival prediction. The combination of a prognostic biomarker panel with clinicopathological parameters did not improve survival prediction in non-small cell lung cancer, questioning the potential of immunohistochemistry-based assessment of protein biomarkers for prognostication in clinical practice.Modern Pathology advance online publication, 10 March 2017; doi:10.1038/modpathol.2017.14.

National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:uu:diva-318128 (URN)10.1038/modpathol.2017.14 (DOI)000404718100006 ()28281552 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2018-01-13Bibliographically approved
Ekman, S., Harmenberg, J., Frödin, J.-E., Bergström, S., Wassberg, C., Eksborg, S., . . . Bergqvist, M. (2016). A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma: A phase I clinical trial.. Acta Oncologica, 55(2), 140-148.
Open this publication in new window or tab >>A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma: A phase I clinical trial.
Show others...
2016 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 2, 140-148 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors.

MATERIAL AND METHODS: This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing.

RESULTS AND CONCLUSION: Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-268087 (URN)10.3109/0284186X.2015.1049290 (DOI)000369302000004 ()26161618 (PubMedID)
External cooperation:
Available from: 2015-12-02 Created: 2015-12-02 Last updated: 2017-12-01Bibliographically approved
Djureinovic, D., Hallström, B. M., Horie, M., Mattsson, J. S., La Fleur, L., Fagerberg, L., . . . Micke, P. (2016). Profiling cancer testis antigens in non-small-cell lung cancer. JCI INSIGHT, 1(10), Article ID e86837.
Open this publication in new window or tab >>Profiling cancer testis antigens in non-small-cell lung cancer
Show others...
2016 (English)In: JCI INSIGHT, ISSN 2379-3708, Vol. 1, no 10, e86837Article in journal (Refereed) Published
Abstract [en]

Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-310039 (URN)10.1172/jci.insight.86837 (DOI)000387113300012 ()27699219 (PubMedID)
Available from: 2016-12-09 Created: 2016-12-09 Last updated: 2016-12-09Bibliographically approved
Holgersson, G., Bergström, S., Harmenberg, J., Ringbom, M., Klockare, M., Jerling, M., . . . Bergqvist, M. (2015). A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer. Medical Oncology, 32(4), Article ID 129.
Open this publication in new window or tab >>A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer
Show others...
2015 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 32, no 4, 129Article in journal (Refereed) Published
Abstract [en]

AXL1717 is an orally bioavailable IGF-1R pathway modulator that has been shown to have anti-tumoral effects. The objectives of the present study were to define maximum tolerated dose and the recommended phase II dose (RPTD) of AXL1717 in combination with gemcitabine HCl and carboplatin in non-small cell lung cancer (NSCLC). Patients with previously untreated, locally advanced, or metastatic NSCLC (squamous cell cancer or adenocarcinoma) in good performance status and with preserved major organ functions were enrolled in the study. The study was an open-label phase I study with planned cohorts of three patients per dose level of AXL1717 (215, 290, and 390 mg BID). In total, 12 patients were enrolled in the study, and of these, two were prematurely excluded. AXL1717 was administered at one dose level, 215 mg BID. A total number of 81 unique adverse events were reported. Bone marrow toxicity was reported in 10 out of 12 patients, and this organ class showed the largest number of related events. AXL1717 in combination with gemcitabine HCl and carboplatin is a possible treatment approach in previously untreated, locally advanced, or metastatic non-small cell lung cancer. However, due to the bone marrow toxicity profile shown in the present study, further dose increases of AXL1717 above 215 mg BID will probably not be feasible. Therefore, 215 mg BID constitutes maximum tolerated dose and RPTD.

Keyword
Phase I, IGF-1, AXL1717, Chemotherapy, NSCLC
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-258837 (URN)10.1007/s12032-015-0578-y (DOI)000351474100043 ()25794491 (PubMedID)
Available from: 2015-07-23 Created: 2015-07-20 Last updated: 2017-12-04Bibliographically approved
Mattsson, J. S. M., Svensson, M. A., Hallström, B., Koyi, H., Branden, E., Brunnström, H., . . . Micke, P. (2015). ALK Rearrangements in Non-Small Cell Lung Cancer: Comprehensive Integration of Genomic, Gene Expression and Protein Analysis. Journal of Thoracic Oncology, 10(9), S298-S298.
Open this publication in new window or tab >>ALK Rearrangements in Non-Small Cell Lung Cancer: Comprehensive Integration of Genomic, Gene Expression and Protein Analysis
Show others...
2015 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, no 9, S298-S298 p.Article in journal, Meeting abstract (Other academic) Published
Keyword
NSCLC, ALK, IHC, Gene Expression
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-298975 (URN)000370365101103 ()
Available from: 2016-07-13 Created: 2016-07-12 Last updated: 2017-11-28Bibliographically approved
Holgersson, G., Bergström, S., Liv, P., Nilsson, J., Edlund, P., Blomberg, C., . . . Bergqvist, M. (2015). Effect of Increased Radiotoxicity on Survival of Patients with Non-small Cell Lung Cancer Treated with Curatively Intended Radiotherapy. Anticancer Research, 35(10), 5491-5497.
Open this publication in new window or tab >>Effect of Increased Radiotoxicity on Survival of Patients with Non-small Cell Lung Cancer Treated with Curatively Intended Radiotherapy
Show others...
2015 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 35, no 10, 5491-5497 p.Article in journal (Refereed) Published
Abstract [en]

Aim: To elucidate the impact of different forms of radiation toxicities (esophagitis, radiation pneumonitis, mucositis and hoarseness), on the survival of patients treated with curatively intended radiotherapy for non-small cell lung cancer (NSCLC). Patients and Methods: Data were individually collected retrospectively for all patients diagnosed with NSCLC subjected to curatively intended radiotherapy (>= 50 Gy) in Sweden during the time period 1990 to 2000. Results: Esophagitis was the only radiation-induced toxicity with an impact on survival (hazard ratio=0.83, p=0.016). However, in a multivariate model, with clinical-and treatment-related factors taken into consideration, the impact of esophagitis on survival was no longer statistically significant (hazard ratio=0.88, p=0.17). Conclusion: The effect on survival seen in univariate analysis may be related to higher radiation dose and to the higher prevalence of chemotherapy in this group. The results do not suggest that the toxicities examined have any detrimental effect on overall survival.

Keyword
NSCLC, radiotherapy, toxicity, esophagitis, survival
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-265679 (URN)000361823200042 ()26408714 (PubMedID)
Available from: 2015-11-04 Created: 2015-11-02 Last updated: 2017-12-01Bibliographically approved
Sooman, L., Freyhult, E., Jaiswal, A., Navani, S., Edqvist, P.-H., Pontén, F., . . . Ekman, S. (2015). FGF2 as a potential prognostic biomarker for proneural glioma patients. Acta Oncologica, 54(3), 385-394.
Open this publication in new window or tab >>FGF2 as a potential prognostic biomarker for proneural glioma patients
Show others...
2015 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 3, 385-394 p.Article in journal (Refereed) Published
Abstract [en]

Background. The survival of high-grade glioma patients is poor and the treatment of these patients can cause severe side effects. This fosters the necessity to identify prognostic biomarkers, in order to optimize treatment and diminish unnecessary suffering of patients. The aim of this study was to identify prognostic biomarkers for high-grade glioma patients.

Methods. Eleven proteins were selected for analysis due to their suggested importance for survival of patients with other types of cancers and due to a high variation in protein levels between glioma patients (according to the Human Protein Atlas, www.proteinatlas.org). Protein expression patterns of these 11 proteins were analyzed by immunohistochemistry in tumor samples from 97 high-grade glioma patients. The prognostic values of the proteins were analyzed with univariate and multivariate Cox regression analyses for the high-grade glioma patients, including subgroup analyses of histological subtypes and immunohistochemically defined molecular subtypes.

Results. The proteins with the most significant (univariate and multivariate p < 0.05) correlations were analyzed further with cross-validated Kaplan-Meier analyses for the possibility of predicting survival based on the protein expression pattern of the corresponding candidate. Random Forest classification with variable subset selection was used to analyze if a protein signature consisting of any combination of the 11 proteins could predict survival for the high-grade glioma patients and the subgroup with glioblastoma patients. The proteins which correlated most significantly (univariate and multivariate p < 0.05) to survival in the Cox regression analyses were Myc for all high-grade gliomas and FGF2, CA9 and CD44 for the subgroup of proneural gliomas, with FGF2 having a strong negative predictive value for survival. No prognostic signature of the proteins could be found.

Conclusion. FGF2 is a potential prognostic biomarker for proneural glioma patients, and warrants further investigation.

Keyword
Prognostic biomarkers, tissue microarray, immunohistochemistry, FGF2, CA9, CD44
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-214802 (URN)10.3109/0284186X.2014.951492 (DOI)000350646400012 ()25263081 (PubMedID)
Available from: 2014-01-09 Created: 2014-01-09 Last updated: 2018-01-11Bibliographically approved
La Fleur, L., Moens, L., Falk-Sörqvist, E., Sundström, M., Mattsson, J. S. M., Koyi, H., . . . Botling, J. (2015). Mutation Profiling by Targeted Next-Generation Sequencing for Diagnostics and Patient Cohort Screening in FFPE NSCLC Samples. Journal of Thoracic Oncology, 10(9), S697-S697.
Open this publication in new window or tab >>Mutation Profiling by Targeted Next-Generation Sequencing for Diagnostics and Patient Cohort Screening in FFPE NSCLC Samples
Show others...
2015 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, no 9, S697-S697 p.Article in journal, Meeting abstract (Other academic) Published
Keyword
target enrichment, formalin-fixed paraffin embedded, next-generation sequencing, non-small cell lung cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-298974 (URN)000370365103337 ()
Available from: 2016-07-13 Created: 2016-07-12 Last updated: 2017-11-28Bibliographically approved
Ekman, S. (2015). Overview of Current International Randomized Trials. Journal of Thoracic Oncology, 10(9), S108-S108.
Open this publication in new window or tab >>Overview of Current International Randomized Trials
2015 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, no 9, S108-S108 p.Article in journal, Meeting abstract (Other academic) Published
Keyword
stage III, NSCLC, locally advanced, combined modality
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-298970 (URN)000370365100086 ()
Available from: 2016-07-13 Created: 2016-07-12 Last updated: 2017-11-28Bibliographically approved
Sandelin, M., Berglund, A., Sundström, M., Micke, P., Ekman, S., Bergqvist, M., . . . Botling, J. (2015). Patients with Non-small Cell Lung Cancer Analyzed for EGFR: Adherence to Guidelines, Prevalence and Outcome. Anticancer Research, 35(7), 3979-3985.
Open this publication in new window or tab >>Patients with Non-small Cell Lung Cancer Analyzed for EGFR: Adherence to Guidelines, Prevalence and Outcome
Show others...
2015 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 35, no 7, 3979-3985 p.Article in journal (Refereed) Published
Abstract [en]

Background: Epidermal growth factor receptor (EGFR) analysis is the first molecular test introduced in the routine care of patients with non-small cell lung cancer (NSCLC). In the present study, we describe the prevalence of EGFR mutations and the adherence to testing and treatment guidelines in a population-based Swedish NSCLC cohort. Materials and Methods: Patients with NSCLC analyzed for EGFR mutations were identified and their characteristics and survival data were retrieved. We compared the study cohort to a matched lung cancer population. Results: The EGFR mutation frequency was 10%. Mutations were enriched in women and in adenocarcinoma cases. Out of patients with advanced-stage NSCLC with non-squamous histology, only 49% were referred for EGFR analysis. Out of the patients with EGFR mutation and advanced disease, only 38% received EGFR-tyrosine kinase inhibitor (TKI) in first-line therapy. Conclusion: The EGFR-mutated NSCLC population studied is similar to other Western populations. Surprisingly, a large proportion of patients were not referred for EGFR analysis. Out of the patients with EGFR mutation, fewer than 40% received EGFR-TKI as first-line treatment. Our results highlight the need for follow-up of treatment and diagnostic algorithms in routine healthcare.

Keyword
Non-small cell lung cancer, EGFR, mutation, outcome, population, prevalence
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-259096 (URN)000357116400029 ()26124345 (PubMedID)
Available from: 2015-07-28 Created: 2015-07-27 Last updated: 2017-12-04Bibliographically approved
Organisations

Search in DiVA

Show all publications