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  • 1.
    Asklund, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Malmström, Annika
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Björ, Ove
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brain tumors in Sweden: Data from a population-based registry 1999-20122015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 3, p. 377-384Article in journal (Refereed)
    Abstract [en]

    Background. The Swedish brain tumor registry has, since it was launched in 1999, provided significant amounts of data on histopathological diagnoses and on important aspects of surgical and medical management of these patients. The purpose is mainly quality control, but also as a resource for research.

    Methods. Three Swedish healthcare regions, constituting 40% of the Swedish population, have had an almost complete registration. The following parameters are registered: diagnosis according to SNOMED/WHO classification, symptoms, performance status, pre- and postoperative radiology, tumor size and localization, extent of surgery and occurrence of postoperative complications, postoperative treatment, such as radiotherapy and/or chemotherapy, other treatments, complications and toxicity, occurrence of reoperation/s, participation in clinical trials, multidisciplinary conferences and availability of a contact nurse.

    Results. Surgical radicality has been essentially constant, whereas the use of early (within 72 hours) postoperative CT and MRI has increased, especially for high-grade glioma, which is a reflection of quality of surgery. Survival of patients with high-grade glioma has increased, especially in the age group 60-69. Patients aged 18-39 years had a five-year survival of 40%. Waiting times for the pathological report has been slightly prolonged. Geographical differences do exist for some of the variables.

    Conclusion. Population-based registration is valuable for assessment of clinical management, which could have impact on patient care. As a result of short survival and/or the propensity to affect cognitive functions this patient group has considerable difficulties to make their voices heard in society. We therefore believe that a report like the present one can contribute to the spread of knowledge and increase the awareness for this patient group among caregivers and policy makers.

  • 2.
    Bergqvist, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Christensen, H. Nordahl
    Wiklund, F.
    Bergström, S.
    Characteristics and Long-Term OS of Non-Small Cell Lung Cancer Patients Receiving EGFR Tyrosine Kinase Inhibitor Treatment2018In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 10, p. S419-S419Article in journal (Other academic)
    Abstract [en]

    Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are important therapeutic agents in treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC) patients. However, long-term follow-up and knowledge of clinical factors and TKI treatment patterns, which may be associated with longer OS, remains unclear. Using nationwide registry data, the aim was to investigate survival, prognostic factors for OS, and first line TKI treatment pattern of stage IIIB/IV NSCLC patients in Sweden.

    Method: In this cohort study, data on all patients diagnosed with stage IIIB-IV NSCLC during 2010—2015 from the nationwide Cancer Registry of Sweden were linked with data on dispensed EGFR-TKI drugs, comorbidity, and mortality data from Swedish national health registries. OS was defined as the interval from date of diagnosis until date of death. Survival rates were estimated using the Kaplan-Meier method. Assessment of predictive factors for OS was performed in multivariable Cox regression.

    Result: Of 9,992 stage IIIB/IV NSCLC patients (mean age 70 years, female 49%), 1419 (14%) received first-line TKI treatment. Overall, 59% of TKI treated patients (median age 68 years) were female, 44% had at least one comorbidity, 85% had adenocarcinoma, and 89% were stage IV. Median follow-up time was 15 months and median OS was 16 months; 1- and 3-years survival rates were 62% and 15%, respectively. Predictors of longer OS were younger age at diagnosis, adenocarcinoma, less advanced clinical stage, and less comorbid disease. Furthermore, patients included in the end of the period had a longer OS compared to earlier. TKI treatment switching/re-challenging, as well as prolonged TKI treatment, also predicted longer OS.

    Conclusion: This is the first nationwide study on NSCLC patients receiving first-line EGFR TKIs in routine clinical practice in Sweden. In addition to the reported prolonged TKI treatment length and TKI switching/re-challenging during the observation period, improvements and extension of EGFR testing targeting the appropriate NSCLC patient population may further have contributed to the observed relatively long overall survival.

  • 3.
    Bergqvist, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Center for Research & Development, Uppsala University, County Council of Gävleborg, Gävle Hospital, Gävle, Sweden.
    Christensen, Helene N.
    Wiklund, Fredrik
    Bergström, Stefan
    Real world utilization of EGFR TKIs and prognostic factors for survival in NSCLC during 2010-2016 in Sweden: A nationwide observational study2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article in journal (Refereed)
    Abstract [en]

    The purpose of our study was to investigate time trends in treatment pattern and prognostic factors for overall survival (OS) in epidermal growth factor receptor (EGFR) targeting tyrosine kinase inhibitors (TKIs) treated nonsmall cell lung cancer (NSCLC) patients. Utilizing Swedish nationwide registers, we identified all Stage IIIB-IV NSCLC patients treated with EGFR TKIs and followed them from diagnosis (2010-2015) until death or end of observation (2016). Multivariable Cox regression analyses were performed to test associations of patient-, tumor-related factors with OS. Of 9,992 Stage IIIB-IV NSCLC patients, the 1,419 (14%) who initiated EGFR TKI treatment during observation were younger (median age 68 vs. 71 years), less >= 1 comorbidities (34% vs. 46%), more often female (59% vs. 47%), Stage IV (89% vs. 85%) and adenocarcinoma (85% vs. 66%) compared to non-TKI treated patients. After TKI initiation, 7% (n = 100) of the patients switched, 4% (n = 62) rechallenged a TKI treatment, 65% (n = 919) discontinued and 24% (n = 338) had died. A more recent diagnosis demonstrated shorter time to EGFR TKI initiation, prolonged treatment length and longer median OS (15.3 months 2010-2011; 14.4 months 2012-2013; 18.6 months 2014-2015). Prognostic factors for longer OS when treated with EGFR TKIs were younger age, adenocarcinoma, less advanced clinical stage and less comorbid disease. In conclusion, during the observation period, survival improved for EGFR TKI treated NSCLC patients, as did the accessibility for targeted therapies for these patients.

  • 4.
    Bergqvist, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Gävle Hospital, Center for Research & Development, Uppsala University/County Council of Gävleborg, Gävle, Sweden.
    Holgersson, Georg
    Bondarenko, Igor
    Grechanaya, Elena
    Maximovich, Alexey
    Andor, Gyorgy
    Klockare, Maria
    Thureson, Marcus
    Jerling, Markus
    Harmenberg, Johan
    Phase II randomized study of the IGF-1R pathway modulator AXL1717 compared to docetaxel in patients with previously treated, locally advanced or metastatic non-small cell lung cancer2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 3, p. 441-447Article in journal (Refereed)
    Abstract [en]

    Background: The primary objective of this study was to compare the progression-free survival (PFS) at 12 weeks between patients treated with IGF-1R pathway modulator AXL1717 (AXL) and patients treated with docetaxel (DCT).

    Material and methods: The study was conducted at 19 study centers in five countries. A total of 99 patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC) of the squamous cell carcinoma (SCC) or adenocarcinoma (AC) subtypes in need of additional treatment were randomized and treated with either 300 or 400 mg of AXL as daily BID treatment (58 patients) or DCT given as 75 mg/m2 in three-week cycles (41 patients) as monotherapy in a 3:2 ratio for each NSCLC subtype. Patients were treated in the primary study treatment period for a maximum of four treatment cycles.

    Results: The 12-week PFS rate, median PFS and overall survival (OS), as well Kaplan-Meier hazard ratio for PFS and OS, did not show any statistically significant differences between the treatment groups. For the primary endpoint, the AXL group had a lower percentage of patients (25.9%) who were progression-free at Week 12 as compared to the DCT group (39.0%), although the difference was not statistically significant. The most notable difference in the incidence of treatment emergent adverse effects (TEAEs) was the lower incidence of treatment-related grade 3/4 neutropenia in patients treated with AXL.

    Conclusion: These results suggest neither of the treatments to be superior of the other when treating locally advanced or metastatic NSCLC. Considering the lower incidence of grade 3/4 neutropenia in the AXL group this treatment warrants further research.

  • 5. Bergström, S.
    et al.
    Christensen, H. Nordahl
    Wiklund, F.
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    EGFR tyrosine kinase inhibitors in non-small cell lung cancer: Nationwide register-based cohort study in Sweden2018In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 29, p. 526-526Article in journal (Other academic)
  • 6. Bystrom, Sanna
    et al.
    Fredolini, Claudia
    Edqvist, Per-Henrik
    Nyaiesh, Etienne-Nicholas
    Drobin, Kimi
    Uhlen, Mathias
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Centre for Research and Development, Uppsala University, 751 85 Uppsala, Sweden; Region Gävleborg, Gävle sjukhus, 801 88 Gävle, Sweden.
    Ponten, Fredrik
    Schwenk, Jochen M.
    Affinity Proteomics Exploration of Melanoma Identifies Proteins in Serum with Associations to T-Stage and Recurrence2017In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 10, no 3, p. 385-395Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Blood-based proteomic profiling may aid and expand our understanding of diseases and their different phenotypes. The aim of the presented study was to profile serum samples from patients with malignant melanoma using affinity proteomic assays to describe proteins in the blood stream that are associated to stage or recurrence of melanoma.

    MATERIAL AND METHODS: Multiplexed protein analysis was conducted using antibody suspension bead arrays. A total of 232 antibodies against 132 proteins were selected from (i) a screening with 4595 antibodies and 32 serum samples from melanoma patients and controls, (ii) antibodies used for immunohistochemistry, (iii) protein targets previously related with melanoma. The analysis was performed with 149 serum samples from patients with malignant melanoma. Antibody selectivity was then assessed by Western blot, immunocapture mass spectrometry, and epitope mapping. Lastly, indicative antibodies were applied for IHC analysis of melanoma tissues.

    RESULTS: Serum levels of regucalcin (RGN) and syntaxin 7 (STX7) were found to be lower in patients with both recurring tumors and a high Breslow's thickness (T-stage 3/4) compared to low thickness (T-stage 1/2) without disease recurrence. Serum levels of methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) were instead elevated in sera of T3/4 patients with recurrence. The analysis of tissue sections with S100A6 and MTHFD1L showed positive staining in a majority of patients with melanoma, and S100A6 was significantly associated to T-stage.

    CONCLUSIONS: Our findings provide a starting point to further study RGN, STX7, MTHFD1L and S100A6 in serum to elucidate their involvement in melanoma progression and to assess a possible contribution to support clinical indications.

  • 7. Ekman, Simon
    et al.
    Harmenberg, Johan
    Frödin, Jan-Erik
    Bergström, Stefan
    Wassberg, Cecilia
    Eksborg, Staffan
    Larsson, Olle
    Axelson, Magnus
    Jerling, Markus
    Abrahmsen, Lars
    Hedlund, Åsa
    Alvfors, Carina
    Ståhl, Birgitta
    Bergqvist, Michael
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    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 trial2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 2, p. 140-148Article in journal (Refereed)
    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.

  • 8. Holgersson, Georg
    et al.
    Bergqvist, Michael
    Uppsala University Hospital.
    Nyman, Jan
    Hoye, Even
    Helsing, Martin
    Friesland, Signe
    Holgersson, Margareta
    Ekberg, Lars
    Mörth, Charlotte
    Ekman, Simon
    Blystad, Thomas
    Ewers, Sven-Börje
    Löden, Britta
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergström, Stefan
    The impact of hyperfractionated radiotherapy regimen in patients with non-small cell lung cancer2013In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 30, no 1, article id 320Article in journal (Refereed)
    Abstract [en]

    The prognosis for patients with lung cancer is poor with an average of 5-year overall survival rate of only 10-15 % taking all clinical stages together. The aim of this study was to elucidate the impact of the radiotherapy regimen on survival. Clinical data were collected from all the Swedish Oncology Departments for 1,287 patients with a diagnosed non-small cell lung cancer (NSCLC) subjected to curatively intended irradiation (>= 50 Gy) during the years 1990 to 2000. The included patients were identified based on a manual search of all medical and radiation charts at the oncology departments from which the individual patient data were collected. Patients who did not have a histopathological diagnosis date and/or death date/last follow-up date as well as patients being surgically treated were excluded from the study (n = 592). Thus, 695 patients were included in the present study. Patients who received hyperfractionated radiotherapy (HR) had a higher local control rate compared with patients receiving conventional fractionation (CF) (38 vs. 49 % local relapse). The difference in survival between the two radiotherapy regimens was statistically significant in a univariate Cox analysis (p = 0.023) in favor of HR. This significance was, however, not retained in a multivariate Cox analysis (p = 0.56). Thus, the possible beneficial effects of hyperfractionation are still unclear and need to be further investigated in well-controlled prospective clinical trials, preferably including systemic treatment with novel drugs.

  • 9.
    Holgersson, Georg
    et al.
    Institutionen för Immunologi, Genitik och Patologi Umeå Universitet /Centrum för forskning och utveckling Region Gävleborg.
    Bergström, Stefan
    Institutionen för Immunologi, Genitik och Patologi Umeå Universitet /Centrum för forskning och utveckling Region Gävleborg.
    Hallqvist, Anders
    Institutionen för Onkologi, Sahlgrenska Universitetssjukhuset.
    Liv, Per
    Centrum för forskning och utveckling Region Gävleborg.
    Nilsson, R. Jonas A.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Centrum för forskning och utveckling, Uppsala Universitet / Region Gävleborg, Gävle sjukhus, Gävle, Sverige.
    Willén, Linda
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Centrum för forskning och utveckling, Uppsala Universitet / Region Gävleborg, Gävle sjukhus, Gävle, Sverige.
    Nyman, Jan
    Institutionen för Onkologi, Sahlgrenska Universitetssjukhuset.
    Ekman, Simon
    Institutionen för Onkologi, Karolinska Universitetssjukhuset.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Centrum för forskning och utveckling Region Gävleborg.
    The prognostic value of pre-treatment thrombocytosis in two cohorts of patients with non-small cell lung cancer treated with curatively intended chemoradiotherapy2017In: Neoplasma (Bratislava), ISSN 0028-2685, E-ISSN 1338-4317, Vol. 64, no 6, p. 909-915Article in journal (Refereed)
    Abstract [en]

    Chemoradiotherapy is the standard of care for inoperable stage III non-small cell lung cancer (NSCLC). This treatment, however, offers only a small chance of cure and is associated with many side effects. Little research has been made concerning which patients benefit most/least from the treatment. The present study evaluates the prognostic value of anemia, leukocytosis and thrombocytosis at diagnosis in this treatment setting. In the present study, data were collected retrospectively for 222 patients from two different phase II studies conducted between 2002-2007 in Sweden with patients treated with chemoradiotherapy for stage IIIA-IIIB NSCLC. Clinical data and the serum values of hemoglobin (Hgb), White blood cells (WBC) and Platelets (Plt) at enrollment were collected for all patients and studied in relation to overall survival using Kaplan-Meier product-limit estimates and a multivariate Cox proportional hazards regression model. The results showed that patients with thrombocytosis (Plt > 350 x 109 /L) had a shorter median overall survival (14.5 months) than patients with normal Plt at baseline (23.7 months). Patients with leukocytosis (WBC > 9 x 109 /L) had a shorter median survival (14.9 months) than patients with a normal WBC at baseline (22.5 months). However, in a multivariate model including all lab parameters and clinical factors, only thrombocytosis and performance status displayed a prognostic significance. In Conclusion, thrombocytosis showed to be an independent prognostic marker associated with shorter overall survival in stage III NSCLC treated with curatively intended chemoradiotherapy. This knowledge can potentially be used together with established prognostic factors, such as performance status when choosing the optimal therapy for the individual patient in this clinical setting

  • 10. Holgersson, Georg
    et al.
    Bergström, Stefan
    Harmenberg, Johan
    Ringbom, Magnus
    Klockare, Maria
    Jerling, Markus
    Ekman, Simon
    Lamberg Lundström, Kristina
    Koyi, Hirsh
    Brandén, Eva
    Larsson, Olle
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Department of Oncology, Gävle Hospital, 801 87 Gävle, Sweden.
    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 cancer2015In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 32, no 4, article id 129Article in journal (Refereed)
    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.

  • 11. Holgersson, Georg
    et al.
    Bergström, Stefan
    Liv, Per
    Nilsson, Jonas
    Edlund, Per
    Blomberg, Carl
    Nyman, Jan
    Friesland, Signe
    Ekman, Simon
    Asklund, Thomas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Center for Research and Development, Uppsala University, Gävle Hospital, Gävle, Sweden ; Department of Oncology, Gävle Hospital, Gävle, Sweden.
    Effect of Increased Radiotoxicity on Survival of Patients with Non-small Cell Lung Cancer Treated with Curatively Intended Radiotherapy2015In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 35, no 10, p. 5491-5497Article in journal (Refereed)
    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.

  • 12. Libard, Sylwia
    et al.
    Popova, Svetlana N.
    Amini, Rose-Marie
    Karja, Vesa
    Pietilainen, Timo
    Hamalainen, Kirsi M.
    Sundstrom, Christer
    Hesselager, Goran
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ekman, Simon
    Zetterling, Maria
    Smits, Anja
    Nilsson, Pelle
    Pfeifer, Susan
    de Stahl, Teresita Diaz
    Enblad, Gunilla
    Ponten, Fredrik
    Alafuzoff, Irina
    Human Cytomegalovirus Tegument Protein pp65 Is Detected in All Intra- and Extra-Axial Brain Tumours Independent of the Tumour Type or Grade2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108861-Article in journal (Refereed)
    Abstract [en]

    Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, lowgrade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.

  • 13. Lugano, Roberta
    et al.
    Vemuri, Kalyani
    Yu, Di
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Centre for Research and Development, Uppsala University, Gävle Hospital, Gävle, Sweden.
    Smits, Anja
    Essand, Magnus
    Johansson, Staffan
    Dejana, Elisabetta
    Dimberg, Anna
    CD93 promotes beta(1) integrin activation and fibronectin fibrillogenesis during tumor angiogenesis2018In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 8, p. 3280-3297Article in journal (Refereed)
    Abstract [en]

    Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is upregulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates beta(1) integrin signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytic cleavage. The CD93-MMRN2 complex was required for activation of beta(1) integrin, phosphorylation of focal adhesion kinase (FAK), and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of beta(1) integrin and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.

  • 14.
    Nilsson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Blomberg, Carl
    Holgersson, Georg
    Carlsson, Tobias
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Bergström, Stefan
    End-of-life care: Where do cancer patients want to die? A systematic review2017In: Asia-Pacific Journal of Clinical Oncology, ISSN 1743-7563, E-ISSN 1743-7563, Vol. 13, no 6, p. 356-364Article, review/survey (Refereed)
    Abstract [en]

    The importance to die at preferred death place is substantial among terminally ill cancer patients. Previously, several studies have investigated this issue, but no systematic review has been made for many years. This systematic review was made in order to investigate preferred death place among cancer patients. A systematic search was made in PubMed library and a total of 399 articles were found, of which 23 were eligible and included in the review. Preference of home death averaged by 59.9% (39.7-100%) across all studies. Information about actual death place was only reported in 12 studieswith an average of 40.4% (14-65.2%); thus, the incongruence between preferred and actual death place seems to be substantial. This highlights the importance of health care providers to discuss the issue with the patients and their families. However, study designs must improve and publications of socioeconomic data should be unified to ease interpretation in future studies.

  • 15.
    Nilsson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holgersson, Georg
    Järås, Jacob
    Bergström, Stefan
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Center for Research and Development, Uppsala University/ County Council of Gävleborg, Gävle Hospital, 801 87 Gävle, Sweden; Department of Oncology, Gävle Hospital, 801 87 Gävle, Sweden.
    The role of income in brain tumor patients: a descriptive register-based study2018In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 35, no 4, article id 52Article in journal (Refereed)
    Abstract [en]

    Socioeconomic status (SES) and its association with cancer in general have been thoroughly studied in the last decades. Several studies have shown associations between SES and many types of cancer such as lung cancer, breast cancer, and prostate cancer. For gliomas, no clear occupational or exposure risk factors have been identified, although some possible risk factors such as use of cellular telephone are still controversial. The aim in the present study is to analyze whether there is an association between SES and development of brain cancer. Data from 1999 through 2013 were collected from the Swedish Cancer Registry and from the National Statistics of Sweden. Age-standardized incidence rates for people with different income were calculated using linear regression model. A total of 11,892 patients were included, of which 5675 were meningiomas, 1216 low-grade gliomas, and 5001 high-grade gliomas. No clear trend between increasing incidence rates and higher income was seen in neither of the investigated brain tumor histologies. In conclusion, the results should be interpreted with caution, but there does not seem to be a correlation in this material between increased income and development of brain cancer.

  • 16.
    Nilsson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Gävle Hospital, Gävle, Sweden.
    Järås, Jacob
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm-Gotland, Stockholm, Sweden.
    Holgersson, Georg
    Bergström, Stefan
    Estenberg, Jimmy
    Augustsson, Torsten
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Gävle Hospital, Gävle, Sweden.
    No Evidence for Increased Brain Tumour Incidence in the Swedish National Cancer Register Between Years 1980-20122019In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 39, no 2, p. 791-796Article in journal (Refereed)
    Abstract [en]

    Background/Aim: The main objective of this study was to evaluate if there was an increased incidence of brain tumours between years 1980-2012, a time period when mobile phone usage has increased substantially. Materials and Methods: From the Swedish Cancer Registry, cases of meningiomas, low-grade gliomas (LGG) and high-grade gliomas (HGG) were identified in patients between 1980-2012. Direct age-standardised incidence rates were used to calculate incidence trends over time. Results: A total of 13,441 cases of meningiomas, 12,259 cases of high-grade gliomas and 4,555 cases of LGG were reported to the register during the study period. The results suggest that there may be a negative development in the trend for LGG of -0,016 cases per 100,000 and year, corresponding to a mean reduction of approximately 1% per year. Conclusion: The present study was not able to demonstrate an increased incidence of glioma during the past 30 years in Sweden.

  • 17. Roy, Ananya
    et al.
    Attarha, Sanaz
    Weishaupt, Holger
    Edqvist, Per-Henrik
    Swartling, Fredrik J.
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Siebzehnrubl, Florian A.
    Smits, Anja
    Ponten, Fredrik
    Tchougounova, Elena
    Serglycin as a potential biomarker for glioma: association of serglycin expression, extent of mast cell recruitment and glioblastoma progression2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 15, p. 24815-24827Article in journal (Refereed)
    Abstract [en]

    Serglycin is an intracellular proteoglycan with a unique ability to adopt highly divergent structures by glycosylation with variable types of glycosaminoglycans (GAGs) when expressed by different cell types. Serglycin is overexpressed in aggressive cancers suggesting its protumorigenic role. In this study, we explored the expression of serglycin in human glioma and its correlation with survival and immune cell infiltration. We demonstrate that serglycin is expressed in glioma and that increased expression predicts poor survival of patients. Analysis of serglycin expression in a large cohort of low-and high-grade human glioma samples reveals that its expression is grade dependent and is positively correlated with mast cell (MC) infiltration. Moreover, serglycin expression in patient-derived glioma cells is significantly increased upon MC co-culture. This is also accompanied by increased expression of CXCL12, CXCL10, as well as markers of cancer progression, including CD44, ZEB1 and vimentin. In conclusion, these findings indicate the importance of infiltrating MCs in glioma by modulating signaling cascades involving serglycin, CD44 and ZEB1. The present investigation reveals serglycin as a potential prognostic marker for glioma and demonstrates an association with the extent of MC recruitment and glioma progression, uncovering potential future therapeutic opportunities for patients.

  • 18. Sooman, Linda
    et al.
    Freyhult, Eva
    Jaiswal, Archita
    Navani, Sanjay
    Edqvist, Per-Henrik
    Pontén, Fredrik
    Tchougounova, Elena
    Smits, Anja
    Elsir, Tamador
    Gullbo, Joachim
    Lennartsson, Johan
    Bergqvist, Michael
    Department of Radiology, Oncology and Radiation Sciences, Section of Oncology, Rudbeck Laboratory, Uppsala, Sweden.
    Ekman, Simon
    FGF2 as a potential prognostic biomarker for proneural glioma patients2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 3, p. 385-394Article in journal (Refereed)
    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.

  • 19.
    Willén, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Center for Research and Development, Uppsala University/Region Gävleborg, Sweden; Department of Oncology, Gävle Hospital, Gävle, Sweden.
    Berglund, Anders
    Epistat, Uppsala.
    Bergström, Stefan
    Centrum för forskning och utveckling Region Gävleborg.
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Center for Research and Development, Uppsala University/Region Gävleborg, Sweden; Department of Oncology, Gävle Hospital, Gävle, Sweden.
    Öjdahl-Boden, Anna
    Department of Respiratory diseases, Karolinska universitetssjukhuset i Huddinge.
    Wagenius, Gunnar
    Division of Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Lambe, Mats
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Regional Cancer Center Uppsala Örebro, Uppsala, Sweden.
    Educational level and management and outcomes in non-small cell lung cancer. A nationwide population-based study2019In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 131, p. 40-46Article in journal (Refereed)
    Abstract [en]

    Objectives: We examined associations between educational level and clinical presentation, patterns of management and mortality in patients with non-small cell lung cancer (NSCLC) in Sweden, a country with a National Health Care System.

    Materials and Methods: We identified 39,671 patients with a NSCLC diagnosis 2002–2016 in Lung Cancer Data Base Sweden (LCBaSe), a population-based research database. In analyses adjusted for comorbidity and other prognostic factors, odds Ratios (OR) and hazard Ratios (HR) were estimated to examine associations between patients’ educational level and aspects of management and mortality.

    Results: Stage at diagnosis and waiting times did not differ between educational groups. In multivariable analysis, the likelihood to undergo PET/CT and assessment in a multidisciplinary team setting were higher in patients with high compared to low education (aOR 1.14; CI 1.05–1.23 and aOR 1.22; CI 1.14–1.32, respectively). In patients with early stage IA-IIB disease, the likelihood to undergo stereotactic radiotherapy was elevated in patients with high education (aOR 1.40; CI 1.03–1.91). Both all-cause (aHR 0.86; CI 0.77-0.92) and cause-specific mortality (aHR 0.83; CI 0.74-0.92) was lower in patients with high compared to low education in early stage disease (IA-IIB). In higher stage NSCLC no differences were observed. Patterns were similar in separate assessments stratified by sex and histopathology.

    Conclusions: While stage at diagnosis and waiting times did not differ between educational groups, we found socioeconomic differences in diagnostic intensity, multidisciplinary team assessment, stereotactic radiotherapy and mortality in patients with NSCLC. These findings may in part reflect social gradients in implementation and use of novel diagnostic and treatment modalities. Our findings underscore the need for improved adherence to national guidelines.

  • 20.
    Willén, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Centrum för forskning och utveckling Region Gävleborg.
    Isaksson, Johan
    Centrum för forskning och utveckling Region Gävleborg; Uppsala Universitet.
    Bergström, Stefan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Centrum för forskning och utveckling Region Gävleborg.
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Centrum för forskning och utveckling Region Gävleborg.
    Berglund, Anders
    Epistat, Uppsala.
    Öjdahl-Boden, Anna
    Wagenius, Gunnar
    Nationella lungcancerregistret.
    Lambe, Mats
    Medicinsk epidemiologi och biostatistik, Karolinska institutet; Regionalt cancercentrum Uppsala-Örebro.
    Små och minskande skillnader i lungcancervården2019In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518Article in journal (Other academic)
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