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  • 1.
    Andersson, Britta
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Behnam Motlagh, Parviz
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology. Onkologi.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology. Onkologi.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Pharmacological modulation of lung cancer cells for potassium ion depletion2005In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 25, no 4, p. 2609-2616Article in journal (Refereed)
  • 2.
    Andersson, Britta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Janson, Veronica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Behnam Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Onkologi.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Induction of apoptosis by intracellular potassium ion depletion: using the fluorescent dye PBFI in a 96-well plate method in cultured lung cancer cells.2006In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 20, no 6, p. 986-994Article in journal (Refereed)
  • 3.
    Andersson, Ronny
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Hofer, Åke
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Dermatology and Venerology.
    Riklund-Åhlström, Katrine
    Umeå University, Faculty of Medicine, Radiation Sciences, Diagnostic Radiology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Effects of interferon-[alpha], verapamil and dacarbazine in the treatment of advanced malignant melanoma2003In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 13, no 1, p. 87-91Article in journal (Refereed)
    Abstract [en]

    Treatment of patients with metastatic melanoma with either dacarbazine (DTIC) or interferon-[alpha] (IFN[alpha]) as single drugs, or in combination, results in a response rate of approximately 15–20%. This study evaluated the activity and toxicity following treatment with a combination of DTIC, IFN[alpha]2b and verapamil (VPL). Thirty patients with disseminated metastatic melanoma received DTIC 250 mg/m2 on days 1–5 of a 4 week schedule, IFN[alpha]2b 3 MIU on days 1–5 each week, and VPL 80 mg three times a day throughout the cycle, until either disease progression or serious toxicity was observed. Among the 28 evaluable patients, there were four complete responses (CRs), five partial responses (PRs) and eight patients with stable disease (SD). The overall response rate (CR + PR) was 32%. Two patients with a CR were long-term survivors (45 and 34 months) and a third is still in complete remission after 49 months. The fourth CR patient relapsed and died with progressive brain metastases after 8 months. Among the eight patients with SD, one survived for 22 months and another for 34 months. Despite one toxic death, these results suggest that this treatment regimen is well tolerated and seems to be more effective than DTIC alone in a subset of patients. A controlled randomized study would be required to determine the value of adding VPL and IFN[alpha]2b to DTIC.

  • 4.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Behnam-Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rapid induction of long-lasting drug efflux activity in brain vascular endothelial cells but not malignant glioma following irradiation2002In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 19, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    The influence of radiotherapy on malignant glioma multidrug resistance to chemotherapy was evaluated because patients with glioma often are treated with a combination of radiotherapy and chemotherapy. Multidrug resistance gene (MDR1, mdr1a, and mdr1b) transcripts were found in human and rat glioma cell lines. P-Glycoprotein (Pgp) was immunohistochemically detected in glioma cell lines and in the rat brain vascular endothelial cell line (RBE4). A multidrug resistance pump efflux activity assay demonstrated increased calcein efflux of RBE4 endothelial cells, but not glioma cells, 2 h after irradiation and still increased 14 d after irradiation. The increased efflux was equally inhibited by verapamil with or without irradiation. In the rat intracranial glioma model (BT4C), Pgp was demonstrated in capillary endothelial cells of the tumor tissue and surrounding normal brain, but not in tumor cells. The expression of gene transcripts or Pgp was not affected by irradiation. The results indicate that long-lasting verapamil-resistant drug efflux mechanisms are activated in brain endothelial cells after irradiation. The results might explain the poor efficacy of chemotherapy following radiotherapy and contribute to consideration of new treatment strategies in the management of malignant glioma.

  • 5.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Guo, Dongsheng
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas2004In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 108, no 2, p. 135-142Article in journal (Refereed)
    Abstract [en]

    Overexpression of epidermal growth factor receptor (EGFR, ErbB1) correlates with enhanced malignant potential of many human tumor types including glioblastoma multiforme. The significance of EGFR expression in meningiomas is, however, unclear. Reports regarding the other EGFR family members, ErbB2-4, in brain tumors are sparse. In this study, the expression of the EGFR family members was analyzed in relation to various parameters for the clinical importance of these receptors in 44 gliomas and 26 meningiomas. In gliomas, quantitative real-time reverse transcription (RT)-PCR revealed the highest EGFR mRNA expression in high-grade gliomas, while ErbB2 and ErbB3 mRNA were detected only in a few high-grade gliomas. In contrast, ErbB4 expression was most pronounced in low-grade gliomas. Immunohistochemistry showed significantly higher EGFR protein expression in high-grade gliomas compared to low-grade gliomas (P= 0.004). ErbB2 protein expression was mainly seen in high-grade gliomas. ErbB3 protein expression was low in all gliomas analyzed. ErbB4 protein expression was significantly higher in low-grade gliomas than in high-grade gliomas (P= 0.007). In meningiomas, quantitative real-time RT-PCR revealed expression of EGFR, ErbB2, and ErbB4 mRNA in the majority of the tumors. ErbB3 was detected in only one of the meningiomas analyzed. Immunohistochemistry demonstrated high ErbB2 protein expression in meningiomas. An intriguing observation in astrocytomas and oligodendrogliomas grade II, was a significantly decreased overall survival for patients with high EGFR protein expression (P= 0.04). The high ErbB4 expression in low-grade compared to high-grade gliomas might suggest that ErbB4 acts as a suppressor of malignant transformation in brain tumors, which is in line with previous studies in other tumor types.

  • 6.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Heterogeneity in the expression of markers for drug resistance in brain tumors2004In: Clinical Neuropathology, ISSN 0722-5091, Vol. 23, no 1, p. 21-27Article in journal (Refereed)
    Abstract [en]

    Brain tumors, in general, display a multidrug-resistant phenotype. This study evaluated the immunohistochemical expression and distribution of P-glycoprotein (Pgp), multidrug resistance protein (MRP1), lung resistance protein (LRP) and O6 methylguanine-DNA methyltransferase (MGMT) in low- and high-grade astrocytoma, oligodendroglioma and in different subgroups of meningioma. The results revealed a marked heterogeneity in the expression and distribution among the analyzed tumors. In astrocytoma and oligodendroglioma, Pgp and MRP1 were observed in the capillary endothelium and in scattered tumor cells, whereas LRP occurred only in tumor cells. A pronounced expression of MGMT was found independent of the histopathological grade. An enhanced expression of MRP1 and LRP in astrocytoma and oligodendroglioma were more often evident in older patients (> 50 years). Survival analysis suggested a markedly decreased overall survival for patients suffering from low-grade glioma overexpressing Pgp. In meningioma, a heterogeneous expression of Pgp, MRP1, LRP and MGMT was seen with the most prominent staining localized to the capillary endothelium. Pgp was significantly more often overexpressed (p < 0.05) in transitional compared to meningothelial meningioma. The marked heterogeneity in the expression suggests that analysis of these factors can be of importance in the selection of individualized chemotherapy, regardless of tumor type.

  • 7.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Osterman, Pia
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Sjöström, Sara
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Johansen, Christoffer
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Broholm, Helle
    Christensen, Helle Collatz
    Ahlbom, Anders
    Auvinen, Anssi
    Feychting, Maria
    Lönn, Stefan
    Kiuru, Anne
    Swerdlow, Anthony
    Schoemaker, Minouk
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    MNS16A minisatellite genotypes in relation to risk of glioma and meningioma and to glioblastoma outcome.2009In: International journal of cancer. Journal international du cancer, ISSN 1097-0215, Vol. 125, no 4, p. 968-972Article in journal (Refereed)
    Abstract [en]

    The human telomerase reverse transcriptase (hTERT) gene is upregulated in a majority of malignant tumours. A variable tandem repeat, MNS16A, has been reported to be of functional significance for hTERT expression. Published data on the clinical relevance of MNS16A variants in brain tumours have been contradictory. The present population-based study in the Nordic countries and the United Kingdom evaluated brain-tumour risk and survival in relation to MNS16A minisatellite variants in 648 glioma cases, 473 meningioma cases and 1,359 age, sex and geographically matched controls. By PCR-based genotyping all study subjects with fragments of 240 or 271 bp were judged as having short (S) alleles and subjects with 299 or 331 bp fragments as having long (L) alleles. Relative risk of glioma or meningioma was estimated with logistic regression adjusting for age, sex and country. Overall survival was analysed using Kaplan-Meier estimates and equality of survival distributions using the log-rank test and Cox proportional hazard ratios. The MNS16A genotype was not associated with risk of occurrence of glioma, glioblastoma (GBM) or meningioma. For GBM there were median survivals of 15.3, 11.0 and 10.7 months for the LL, LS and SS genotypes, respectively; the hazard ratio for having the LS genotype compared with the LL was significantly increased HR 2.44 (1.56-3.82) and having the SS genotype versus the LL was nonsignificantly increased HR 1.46 (0.81-2.61). When comparing the LL versus having one of the potentially functional variants LS and SS, the HR was 2.10 (1.41-3.1). However, functionality was not supported as there was no trend towards increasing HR with number of S alleles. Collected data from our and previous studies regarding both risk and survival for the MNS16A genotypes are contradictory and warrant further investigations.

  • 8.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Schwartzbaum, Judith
    Wiklund, Fredrik
    Sjöström, Sara
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Liu, Yanhong
    Tsavachidis, Spyros
    Ahlbom, Anders
    Auvinen, Anssi
    Collatz-Laier, Helle
    Feychting, Maria
    Johansen, Christoffer
    Kiuru, Anne
    Lönn, Stefan
    Schoemaker, Minouk J
    Swerdlow, Anthony J
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk2010In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 49, no 6, p. 767-775Article in journal (Refereed)
    Abstract [en]

    Glioma is the most common type of adult brain tumor and glioblastoma, its most aggressive form, has a dismal prognosis. Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR, ERBB2, ERBB3, ERBB4) family, and the vascular endothelial growth factor receptor (VEGFR), play a central role in tumor progression. We investigated the genetic variants of EGFR, ERBB2, VEGFR and their ligands, EGF and VEGF on glioma and glioblastoma risk. In addition, we evaluated the association of genetic variants of a newly discovered family of genes known to interact with EGFR: LRIG2 and LRIG3 with glioma and glioblastoma risk. Methods. We analyzed 191 tag single nucleotide polymorphisms (SNPs) capturing all common genetic variation of EGF, EGFR, ERBB2, LRIG2, LRIG3, VEGF and VEGFR2 genes. Material from four case-control studies with 725 glioma patients (329 of who were glioblastoma patients) and their 1 610 controls was used. Haplotype analyses were conducted using SAS/Genetics software. Results. Fourteen of the SNPs were significantly associated with glioma risk at p< 0.05, and 17 of the SNPs were significantly associated with glioblastoma risk at p< 0.05. In addition, we found that one EGFR haplotype was related to increased glioblastoma risk at p=0.009, Odds Ratio [OR] = 1.67 (95% confidence interval (CI): 1.14, 2.45). The Bonferroni correction made all p-values non-significant. One SNP, rs4947986 next to the intron/exon boundary of exon 7 in EGFR, was validated in an independent data set of 713 glioblastoma and 2 236 controls, [OR] = 1.42 (95% CI: 1.06,1.91). Discussion. Previous studies show that regulation of the EGFR pathway plays a role in glioma progression but the present study is the first to find that certain genotypes of the EGFR gene may be related to glioblastoma risk. Further studies are required to reinvestigate these findings and evaluate the functional significance.

  • 9.
    Asklund, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Björ, Ove
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Malmström, Annika
    Blomquist, Erik
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Överlevnanden vid maligna gliom har ökat senaste tio åren. Analys av kvalitetsregisterdata.2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 17-18, p. 875-878Article in journal (Refereed)
    Abstract [en]

    The annual incidence rate of high grade malignant glioma (WHO grade III-IV) in Sweden is approximately 400 patients. The objective for the Swedish National CNS-tumor Group is to lay a foundation for research efforts and facilitate implementation and assessment of therapeutic strategies and health care for this patient group. In the analyses the diagnoses of high grade malignant gliomas are compared for the years 1999-2003, 2004-2006 and 2007-2009 for the Northern Region, the Uppsala Region and the South-east Region of Sweden, a population of 1844 patients. Survival was estimated from Kaplan-Meier survival curves, and a log-rank test was performed to assess whether the survival curves differed. The crude hazard ratio between years of diagnosis was estimated from a Cox regression model. Median survival for all patients 2004-2006 was 10.0 months (95 % confidence interval (CI) 8.9-10.9) compared to 8.1 months 1999-2003 (95 % CI 7.3-8.8). For patients 60-69 years of age almost a doubling of the survival rate has occurred during the last decade. Medan survival has increased from 5.8 months (95 % CI 5.1-7.5) 1999-2003 to 8.5 months (95 % CI 7.0-10.3) for 2004-2006 and to 10.5 months (95 % CI 9.0-12.6) for 2007-2009. Concomitant radiochemotherapy, but also the development of neurosurgical and radiotheraputic techniques and a more active therapeutic attitude, including the older patient groups, have probably contributed to the improved survival rate. A national population based registry, with a close to 100% registration compliance for important diagnostic and outcome parameters is probably an efficient instrument for evaluation of quality measures and implementation of new therapeutic strategies.

  • 10.
    Asklund, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Danfors, T
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    PET response and tumor stabilization under erlotinib and bevacizumab treatment of an intracranial lesion non-invasively diagnosed as likely chordoma2011In: Clinical Neuropathology, ISSN 0722-5091, Vol. 30, no 5, p. 242-246Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Chordoma is a rare and a slow-growing tumor originating from the notochord and commonly localized in the skull base. Surgery and occasionally radiotherapy have emerged as the treatments of choice. In the relapsed situations available treatment options are strictly limited; however, recently molecularly targeted agents have been proposed to be of potential beneficial value. THE CASE: A 63-year-old male presenting with seizures and an extradural mass in the left brain hemisphere. An attempt to resect the tumor was followed by severe bradycardia when manipulating with the dura and therefore discontinued. It was considered too hazardous even to take a biopsy specimen. The tumor was considered radiologically and macroscopically as a chordoma. As the tumor progressed after radiotherapy, chemotherapy with erlotinib in combination with cetuximab was initiated. This treatment was interrupted due to progressive disease and toxicity. However, combination treatment with erlotinib and bevacizumab normalized the uptake of [11C]methionine PET signal and resulted in a slight tumor shrinkage on MRI. The patient is still (March 2011) free of symptoms, without cranial nerve deficits or seizures. DISCUSSION: This report shows that erlotinib and bevacizumab in combination may completely quench the transport of the essential amino acid methionine to a treatment refractory intracranial tumor bearing radiological and clinical characteristics of a chordoma. Further studies are necessary to establish this strategy as a treatment option for this indication.

  • 11.
    Asklund, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergström, Åsa
    Kasper, Maria
    Ögren, Margareta
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Toftgård, Rune
    Riklund, Katrine Åhlström
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Early and persisting response to vismodegib in a patient with bone metastasizing medulloblastoma2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 4, p. 862-865Article in journal (Refereed)
  • 12.
    Asklund, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kvarnbrink, Samuel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holmlund, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Synergistic Killing of Glioblastoma Stem-like Cells by Bortezomib and HADC Inhibitors.2012In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 7, p. 2407-2413Article in journal (Refereed)
    Abstract [en]

    Background: The malignant brain tumour glioblastoma is a devastating disease that remains a therapeutic challenge. Materials and Methods: Effects of combinations of the US Food and Drug Administation (FDA) approved proteasome inhibitor bortezomib and the histone deacetylase (HDAC) inhibitors vorinostat, valproic acid and sodium phenylbutyrate were studied on primary glioblastoma stem cell lines and conventional glioblastoma cell lines. Cell survival, proliferation and death were analyzed by fluorometric microculture cytotoxicity assay (FMCA), propidium iodide labeling and flow cytometry, and cell cloning through limiting dilution and live-cell bright-field microscopy. Results: Bortezomib and the HDAC inhibitors showed synergistic cell killing at clinically relevant drug concentrations, while the conventional cell lines cultured in serum-containing medium were relatively resistant to the same treatments. Conclusion: These findings of synergistic glioblastoma stem cell killing by bortezomib and three different FDA-approved HDAC inhibitors confirm and expand previous observations on co-operative effects between these classes of drugs.

  • 13.
    Asklund, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kvarnbrink, Samuel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holmlund, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Synergistic killing of Glioblastoma Stem-like cells by Bortezomib and HDAC Inhibitors2012In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 7 ; Special Issue, p. 2407-2413Article in journal (Refereed)
    Abstract [en]

    Background: The malignant brain tumour glioblastoma is a devastating disease that remains a therapeutic challenge. Materials and Methods: Effects of combinations of the US Food and Drug Administation (FDA) approved proteasome inhibitor bortezomib and the histone deacetylase (HDAC) inhibitors vorinostat, valproic acid and sodium phenylbutyrate were studied on primary glioblastoma stem cell lines and conventional glioblastoma cell lines. Cell survival, proliferation and death were analyzed by fluorometric microculture cytotoxicity assay (FMCA), propidium iodide labeling and flow cytometry, and cell cloning through limiting dilution and live-cell bright-field microscopy. Results: Bortezomib and the HDAC inhibitors showed synergistic cell killing at clinically relevant drug concentrations, while the conventional cell lines cultured in serum-containing medium were relatively resistant to the same treatments. Conclusion: These findings of synergistic glioblastoma stem cell killing by bortezomib and three different FDA-approved HDAC inhibitors confirm and expand previous observations on co-operative effects between these classes of drugs.

  • 14.
    Asklund, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Malmstrom, Annika
    Björ, Ove
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Blomquist, Erik
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Considerable improvement in survival for patients aged 60-84 years with high grade malignant gliomas - Data from the Swedish Brain Tumour Population-based Registry2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 5, p. 1043-1046Article in journal (Refereed)
  • 15.
    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.

  • 16.
    Asklund, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nyholm, Tufve
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Garpebring, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Hauksson, Jon
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Brynolfsson, Patrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Karlsson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Evaluation of advanced MR techniques for development of early biomarkers for treatment efficacy in malignant brain tumors2010Conference paper (Refereed)
  • 17.
    Asklund, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sandström, Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Shahidi, Saeed
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Durable stabilization of three chordoma cases by bevacizumab and erlotinib2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 7, p. 980-984Article in journal (Refereed)
  • 18.
    Bergenheim, A Tommy
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
    Capala, Jacek
    Roslin, Michael
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Distribution of BPA and metabolic assessment in glioblastoma patients during BNCT treatment: a microdialysis study2005In: J Neurooncol, ISSN 0167-594X, Vol. 71, no 3, p. 287-293Article in journal (Refereed)
  • 19.
    Bergenheim, A Tommy
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
    Roslin, Michael
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
    Ungerstedt, Urban
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Ronquist, Gunnar
    Metabolic manipulation of glioblastoma in vivo by retrograde microdialysis of L-2, 4 diaminobutyric acid (DAB).2006In: J Neurooncol, ISSN 0167-594X, Vol. 80, no 3, p. 285-293Article in journal (Refereed)
  • 20.
    Bergenheim, Tommy
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
    Malmström, Annika
    Bolander, Hans
    Michanek, Annika
    Stragliotto, Giuseppe
    Damber, Lena
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Björ, Ove
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Registrering av primära hjärntumörer mått på nationell vårdkvalitet. Regionala skillnader avslöjade.2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104, no 5, p. 332-341Article in journal (Refereed)
  • 21. Bergh, Jonas
    et al.
    Jönsson, Per-Ebbe
    Lidbrink, Elisabet Kerstin
    Trudeau, Maureen
    Eiermann, Wolfgang
    Brattström, Daniel
    Lindemann, Justin P O
    Wiklund, Fredrik
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    FACT: An Open-Label Randomized Phase III Study of Fulvestrant and Anastrozole in Combination Compared With Anastrozole Alone as First-Line Therapy for Patients With Receptor-Positive Postmenopausal Breast Cancer2012In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 16, p. 1919-1925Article in journal (Refereed)
    Abstract [en]

    Purpose: To compare the effect of therapy with anastrozole versus a combination of fulvestrant and anastrozole in women in first relapse of endocrine-responsive breast cancer.

    Patients and Methods: Postmenopausal women, or premenopausal women receiving a gonadotropin-releasing hormone agonist, with estrogen receptor– and/or progesterone receptor–positive disease at first relapse after primary treatment of localized disease were open-label randomly assigned to a fulvestrant loading dose (LD) regimen followed by monthly injection plus 1 mg of anastrozole daily or to 1 mg of anastrozole daily alone. The primary end point was time to progression (TTP).

    Results: In all, 514 women were randomly assigned to fulvestrant plus anastrozole (experimental arm; n = 258) or anastrozole (standard arm; n = 256). Approximately two thirds had received adjuvant antiestrogens, but only eight individuals had received an aromatase inhibitor. Median TTP was 10.8 and 10.2 months in the experimental versus standard arm, respectively (hazard ratio [HR] = 0.99; 95% CI, 0.81 to 1.20; P = .91); median overall survival was 37.8 and 38.2 months, respectively (HR = 1.0; 95% CI, 0.76 to 1.32; P = 1.00). Incidences of prespecified adverse events (AEs) were similar. Hot flashes were more common in the experimental arm: 63 patients (24.6%) versus 35 patients (13.8%) in the standard arm (P = .0023). Death owing to AEs was reported in 11 (4.3%) and five patients (2.0%) in the experimental versus standard arm, respectively.

    Conclusion: Fulvestrant (250 mg + LD regimen) in combination with anastrozole offered no clinical efficacy advantage over anastrozole monotherapy in this population of individuals with a relatively high proportion of previous adjuvant antiestrogen exposure.

  • 22. Bergqvist, Jenny
    et al.
    Iderberg, Hanna
    Mesterton, Johan
    Bengtsson, Nils
    Wettermark, Bjorn
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Centre Stockholm-Gotland, Stockholm County Council, Stockholm, Sweden.
    Healthcare resource use, comorbidity, treatment and clinical outcomes for patients with primary intracranial tumors: a Swedish population-based register study2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 3, p. 405-414Article in journal (Refereed)
    Abstract [en]

    Background: Primary intracranial tumors are relatively uncommon and heterogeneous, which make them challenging to study. We coupled data from unique Swedish population-based registries in order to deeper analyze the most common intracranical tumor types. Patient characteristics (e.g. comorbidities), care process measures like adherence to national guidelines, healthcare resource use and clinical outcome was evaluated.

    Materials and methods: A register-based study including several population-based registries for all patients living in Stockholm-Gotland, diagnosed with primary intracranial tumor between 2001 and 2013 was performed. Patient characteristics were captured and investigated in relation to survival, healthcare resource use (inpatient-, outpatient- and primary care) and treatment process.

    Results: High-grade glioma and meningioma were the most common tumor types and most patients (76%) were above the age of 40 in the patient population (n = 3664). Older age, comorbidity (Elixhauser comorbidity index) and type of tumor (high-grade glioma) were associated with lower survival rate and increased use of healthcare resources, analyzed for patients living in Stockholm (n = 3031). The analyses of healthcare use and survival showed no differences between males and females, when stratifying by tumor types. Healthcare processes were not always consistent with existing national treatment recommendations for patients with high-grade gliomas (n = 474) with regard to specified lead times, analyzed in the Swedish Brain Tumor Registry, as also observed at the national level.

    Conclusions: Age, comorbidity and high-grade gliomas, but not sex, were associated with decreased survival and increased use of healthcare resources. Fewer patients than aimed for in national guidelines received care according to specified lead times. The analysis of comprehensive population-based register data can be used to improve future care processes and outcomes.

  • 23. Bergqvist, Jenny
    et al.
    Iderberg, Hanna
    Mesterton, Johan
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Centre Stockholm Gotland, Stockholm County Council, Stockholm, Sweden.
    The effects of clinical and sociodemographic factors on survival, resource use and lead times in patients with high-grade gliomas: a population-based register study2018In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 139, no 3, p. 599-608Article in journal (Refereed)
    Abstract [en]

    Background: Previous studies indicate an effect of sociodemographic factors on risk for being diagnosed with, as well as on survival of cancer in general. Our primary aim was to analyse sociodemographic factors, resource use and lead times in health care after diagnosis with high grade malignant glioma (HGG) in a large population based cohort.

    Methods: A register-based study using several unique high-coverage registries. All patients over the age of 18 diagnosed with HGG in the Swedish Stockholm-Gotland region between 2001 and 2013 (n=1149) were included.

    Results: In multivariable cox proportional hazard model of survival, older age, male sex and high tumour grade were associated with worse survival. No significant differences could be seen related to country of birth. A high disposable income was associated with better survival and fewer occasions of pre-diagnostic inpatient care. Older age and comorbidities were correlated with a significantly increased number of outpatient visits the year before HGG diagnosis. In addition, male sex, being born outside Sweden was associated to a higher number of outpatient visits the year after diagnosis in multivariable analysis. Leadtime from diagnosis (first suspicion on brain scan) to surgery showed that the oldest patients, patients with comorbidity and patients born outside Europe had to wait longer for surgery.

    Conclusions: Sociodemographic factors like education, income and country of birth have impact on care processes both before and after the diagnosis HGG. This needs to be acknowledged in addition to important clinical factors like age, comorbidity and tumour grade, in order to accomplish more equal cancer care.

  • 24. Bergqvist, Michael
    et al.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Brattström, Daniel
    Novel agents in the treatment of non-small cell lung cancer: implications for neoadjuvant chemotherapy?2005In: In Vivo, ISSN 0258-851X, Vol. 19, no 3, p. 523-533Article in journal (Refereed)
  • 25. Berntsson, Shala Ghaderi
    et al.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sjöström, Sara
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Broholm, Helle
    Johansson, Christoffer
    Fleming, Sarah J
    McKinney, Patricia A
    Bethke, Lara
    Houlston, Richard
    Smits, Anja
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas2011In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 105, no 3, p. 531-538Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to explore the variation in DNA repair genes in adults with WHO grade II and III gliomas and their relationship to patient survival. We analysed a total of 1,458 tagging single-nucleotide polymorphisms (SNPs) that were selected to cover DNA repair genes, in 81 grade II and grade III gliomas samples, collected in Sweden and Denmark. The statistically significant genetic variants from the first dataset (P < 0.05) were taken forward for confirmation in a second dataset of 72 grade II and III gliomas from northern UK. In this dataset, eight gene variants mapping to five different DNA repair genes (ATM, NEIL1, NEIL2, ERCC6 and RPA4) which were associated with survival. Finally, these eight genetic variants were adjusted for treatment, malignancy grade, patient age and gender, leaving one variant, rs4253079, mapped to ERCC6, with a significant association to survival (OR 0.184, 95% CI 0.054-0.63, P = 0.007). We suggest a possible novel association between rs4253079 and survival in this group of patients with low-grade and anaplastic gliomas that needs confirmation in larger datasets.

  • 26. Bethke, Lara
    et al.
    Murray, Anne
    Webb, Emily
    Schoemaker, Minouk
    Muir, Kenneth
    McKinney, Patricia
    Hepworth, Sarah
    Dimitropoulou, Polyxeni
    Lophatananon, Artitaya
    Feychting, Maria
    Lönn, Stefan
    Ahlbom, Anders
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Auvinen, Anssi
    Kiuru, Anne
    Salminen, Tiina
    Johansen, Christoffer
    Collatz Christensen, Helle
    Kosteljanetz, Michael
    Swerdlow, Anthony
    Houlston, Richard
    Comprehensive analysis of DNA repair gene variants and risk of meningioma.2008In: J Natl Cancer Inst, ISSN 1460-2105, Vol. 100, no 4, p. 270-276Article in journal (Refereed)
  • 27. Bethke, Lara
    et al.
    Sullivan, Kate
    Webb, Emily
    Murray, Anne
    Schoemaker, Minouk
    Auvinen, Anssi
    Kiuru, Anne
    Salminen, Tiina
    Johansen, Christoffer
    Collatz Christensen, Helle
    Muir, Kenneth
    McKinney, Patricia
    Hepworth, Sarah
    Dimitropoulou, Polyxeni
    Lophatananon, Artitaya
    Feychting, Maria
    Lönn, Stefan
    Ahlbom, Anders
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Swerdlow, Anthony
    Houlston, Richard
    CASP8 D302H and meningioma risk.: An analysis of five case-control series.2009In: Cancer Lett, ISSN 1872-7980, Vol. 273, no 2, p. 312-315Article in journal (Refereed)
    Abstract [en]

    Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and hence a defence against cancer. The CASP8 polymorphism D302H has recently been shown to influence the risk of breast cancer. We tested the hypothesis that the CASP8 polymorphism D302H may influence risk of meningioma through analysis of five independent series of case patients and controls (n=631 and 637, respectively). Carrier status for 302H was not associated with a statistically significantly increased risk (OR=1.16; 95% CI: 0.87-1.53; P=0.31) making it unlikely that this variant contributes to the inherited risk of meningioma.

  • 28. Bethke, Lara
    et al.
    Sullivan, Kate
    Webb, Emily
    Murray, Anne
    Schoemaker, Minouk
    Auvinen, Anssi
    Kiuru, Anne
    Salminen, Tiina
    Johansen, Christoffer
    Collatz Christensen, Helle
    Muir, Kenneth
    McKinney, Patricia
    Hepworth, Sarah
    Dimitropoulou, Polyxeni
    Lophatananon, Artitaya
    Feychting, Maria
    Lönn, Stefan
    Ahlbom, Anders
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Swerdlow, Anthony
    Houlston, Richard
    The Common D302H Variant of CASP8 Is Associated with Risk of Glioma.2008In: Cancer Epidemiol Biomarkers Prev, ISSN 1055-9965, Vol. 17, no 4, p. 987-989Article in journal (Refereed)
    Abstract [en]

    Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and, hence, a defense against cancer. We tested the hypothesis that the CASP8 polymorphism D302H influences risk of glioma through analysis of five series of glioma case patients and controls (n = 1,005 and 1,011, respectively). Carrier status for the rare allele of D302H was associated with a 1.37-fold increased risk (95% confidence interval, 1.10-1.70; P = 0.004). The association of CASP8 D302H with glioma risk indicates the importance of inherited variation in the apoptosis pathway in susceptibility to this form of primary brain tumor.

  • 29. Bethke, Lara
    et al.
    Webb, Emily
    Murray, Anne
    Schoemaker, Minouk
    Feychting, Maria
    Lönn, Stefan
    Ahlbom, Anders
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Auvinen, Anssi
    Kiuru, Anne
    Salminen, Tiina
    Johansen, Christoffer
    Collatz Christensen, Helle
    Muir, Kenneth
    McKinney, Patricia
    Hepworth, Sarah
    Dimitropoulou, Polyxeni
    Lophatananon, Artitaya
    Swerdlow, Anthony
    Houlston, Richard
    Functional polymorphisms in folate metabolism genes influence the risk of meningioma and glioma.2008In: Cancer Epidemiol Biomarkers Prev, ISSN 1055-9965, Vol. 17, no 5, p. 1195-1202Article in journal (Refereed)
    Abstract [en]

    Folate metabolism plays an important role in carcinogenesis. To test the hypothesis that polymorphic variation in the folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) influences the risk of primary brain tumors, we genotyped 1,005 glioma cases, 631 meningioma cases, and 1,101 controls for the MTHFR C677A and A1298C, MTRR A66G, and MTR A2756G variants. MTHFR C677T-A1298C diplotypes were associated with risk of meningioma (P = 0.002) and glioma (P = 0.02); risks were increased with genotypes associated with reduced MTHFR activity. The highest risk of meningioma was associated with heterozygosity for both MTHFR variants [odds ratio (OR), 2.11; 95% confidence interval (95% CI), 1.42-3.12]. The corresponding OR for glioma was 1.23 (95% CI, 0.91-1.66). A significant association between risk of meningioma and homozygosity for MTRR 66G was also observed (OR, 1.41; 95% CI, 1.02-1.94). Our findings provide support for the role of folate metabolism in the development of primary brain tumors. In particular, genotypes associated with increased 5,10-methylenetetrahydrofolate levels are associated with elevated risk.

  • 30. Bethke, Lara
    et al.
    Webb, Emily
    Murray, Anne
    Schoemaker, Minouk
    Johansen, Christoffer
    Collatz Christensen, Helle
    Muir, Kenneth
    McKinney, Patricia
    Hepworth, Sarah
    Dimitropoulou, Polyxeni
    Lophatananon, Artitaya
    Feychting, Maria
    Lönn, Stefan
    Ahlbom, Anders
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Auvinen, Anssi
    Kiuru, Anne
    Salminen, Tiina
    Swerdlow, Anthony
    Houlston, Richard
    Comprehensive analysis of the role of DNA repair gene polymorphisms on risk of glioma.2008In: Hum Mol Genet, ISSN 1460-2083, Vol. 17, no 6, p. 800-805Article in journal (Refereed)
  • 31. Bottomley, A.
    et al.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Taphoorn, M. J. B.
    Cloughesy, T.
    Wick, W.
    Mason, W.
    Saran, F.
    Nishikawa, R.
    Ravelo, A.
    Chinot, O. L.
    Health-related quality of life (HRQoL) in AVAglio, a randomized, placebo (P)-controlled phase III study of bevacizumab (B), temozolomide (T) and radiotherapy (RI) in patients (pts) with newly diagnosed glioblastoma (GBM)2013In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, no Supplement 2, p. S780-S780, Meeting Abstract: 3316Article in journal (Other academic)
  • 32. Brendle, Annika
    et al.
    Lei, Haixin
    Brandt, Andreas
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Enquist, Kerstin
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hemminki, Kari
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Försti, Asta
    Polymorphisms in predicted microRNA-binding sites in integrin genes and breast cancer ITGB4 as prognostic marker.2008In: Carcinogenesis, ISSN 1460-2180, Vol. 29, no 7, p. 1394-1399Article in journal (Refereed)
    Abstract [en]

    Integrins control the cell attachment to the extracellular matrix and play an important role in mediating cell proliferation, migration and survival. A number of important cancer-associated integrin genes can be regulated by microRNAs (miRNAs) that bind to their target sites in the 3' untranslated regions. We examined the effect of single-nucleotide polymorphisms (SNPs) in predicted miRNA target sites of six integrin genes (ITGA3, ITGA6, ITGAv, ITGB3, ITGB4 and ITGB5) on breast cancer (BC) risk and clinical outcome. Six SNPs were genotyped in 749 Swedish incident BC cases with detailed clinical data and up to 15 years of follow-up together with 1493 matched controls. We evaluated associations between genotypes and BC risk and clinical tumour characteristics. Survival probabilities were compared between different subgroups. As a novel finding, several SNPs seemed to associate with the hormone receptor status. The strongest association was observed between the A allele of the SNP rs743554 in the ITGB4 gene and oestrogen receptor-negative tumours [odds ratio 2.09, 95% confidence intervals (CIs) 1.19-3.67]. The same SNP was associated with survival. The A allele carriers had a worse survival compared with the wild-type genotype carriers (hazard ratio 2.11, 95% CIs 1.21-3.68). The poor survival was significantly associated with the aggressive tumour characteristics: high grade, lymph node metastasis and high stage. None of the SNPs was significantly associated with BC risk. As the ITGB4 SNP seems to influence tumour aggressiveness and survival, it may have prognostic value in the clinic.

  • 33.
    Brynolfsson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nilsson, David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Hauksson, Jon
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Karlsson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Garpebring, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nyholm, Tufve
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Asklund, Thomas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    ADC texture-An imaging biomarker for high-grade glioma?2014In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 41, no 10, p. 101903-Article in journal (Refereed)
    Abstract [en]

    Purpose:

    Survival for high-grade gliomas is poor, at least partly explained by intratumoral heterogeneity contributing to treatment resistance. Radiological evaluation of treatment response is in most cases limited to assessment of tumor size months after the initiation of therapy. Diffusion-weighted magnetic resonance imaging (MRI) and its estimate of the apparent diffusion coefficient (ADC) has been widely investigated, as it reflects tumor cellularity and proliferation. The aim of this study was to investigate texture analysis of ADC images in conjunction with multivariate image analysis as a means for identification of pretreatment imaging biomarkers.

    Methods:

    Twenty-three consecutive high-grade glioma patients were treated with radiotherapy (2 Gy/60 Gy) with concomitant and adjuvant temozolomide. ADC maps and T1-weighted anatomical images with and without contrast enhancement were collected prior to treatment, and (residual) tumor contrast enhancement was delineated. A gray-level co-occurrence matrix analysis was performed on the ADC maps in a cuboid encapsulating the tumor in coronal, sagittal, and transversal planes, giving a total of 60 textural descriptors for each tumor. In addition, similar examinations and analyses were performed at day 1, week 2, and week 6 into treatment. Principal component analysis (PCA) was applied to reduce dimensionality of the data, and the five largest components (scores) were used in subsequent analyses. MRI assessment three months after completion of radiochemotherapy was used for classifying tumor progression or regression.

    Results:

    The score scatter plots revealed that the first, third, and fifth components of the pretreatment examinations exhibited a pattern that strongly correlated to survival. Two groups could be identified: one with a median survival after diagnosis of 1099 days and one with 345 days, p = 0.0001.

    Conclusions:

    By combining PCA and texture analysis, ADC texture characteristics were identified, which seems to hold pretreatment prognostic information, independent of known prognostic factors such as age, stage, and surgical procedure. These findings encourage further studies with a larger patient cohort. (C) 2014 Author(s).

  • 34. Chinot, O.
    et al.
    Cloughesy, T.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Saran, F.
    Mason, W.
    Nishikawa, R.
    Hilton, M.
    Abrey, L.
    Wick, W.
    Efficacy and safety of bevacizumab (By) plus standard combination temozolomide (T) and radiotherapy (RT) in newly diagnosed glioblastoma: final results from AVAglio2013In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, no Supplement 2, p. S774-S775, Meeting Abstract: 3301AArticle in journal (Other academic)
  • 35. Chinot, Olivier
    et al.
    Garcia, Josep
    Romain, Sylvie
    Revil, Cedric
    Cloughesy, Timothy
    Mason, Warren
    Nishikawa, Ryo
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm, Stockholm, Sweden.
    Saran, Frank
    Carpentier, Antoine F.
    Hoang-Xuan, Khe
    Kavan, Petr
    Cernea, Dana M.
    Brandes, Alba A.
    Kerloeguen, Yannick
    Mancao, Christoph
    Ouafik, L'Houcine
    Abrey, Lauren
    Wick, Wolfgang
    Tabouret, Emeline
    BASELINE PLASMA MATRIX METALLOPROTEINASE 9 (MMP9) PREDICTS OVERALL SURVIVAL (OS) BENEFIT FROM BEVACIZUMAB INDEPENDENTLY OF MOLECULAR SUBTYPES IN NEWLY DIAGNOSED GLIOBLASTOMA: RETROSPECTIVE ANALYSIS OF AVAglio2016In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, p. 5-5Article in journal (Refereed)
  • 36. Chinot, Olivier L.
    et al.
    Nishikawa, Ryo
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm Gotland, Stockholm, Sweden.
    Saran, Frank
    Cloughesy, Timothy
    Garcia, Josep
    Revil, Cedric
    Abrey, Lauren
    Wick, Wolfgang
    Upfront bevacizumab may extend survival for glioblastoma patients who do not receive second-line therapy: an exploratory analysis of AVAglio2016In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, no 9, p. 1313-1318Article in journal (Refereed)
    Abstract [en]

    Background: In this post-hoc, exploratory analysis, we examined outcomes for patients enrolled in the AVAglio trial of front-line bevacizumab or placebo plus radiotherapy/temozolomide who received only a single line of therapy. Methods: Patients with newly diagnosed glioblastoma received protocol-defined treatment until progressive disease (PD). Co-primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). After confirmed PD, patients were treated at the investigators' discretion. PFS/OS were assessed in patients with a PFS event who did not receive post-PD therapy (Group 1) and patients with a PFS event who received post-PD therapy plus patients who did not have a PFS event at the final data cutoff (Group 2). Kaplan-Meier methodology was used. A multivariate Cox proportional hazards model for known prognostic variables was generated. Results: Baseline characteristics were balanced. In patients with a PFS event who did not receive post-PD therapy (Group 1; n = 225 [24.4% of the intent-to-treat population]), the addition of bevacizumab to radiotherapy/temozolomide resulted in a 3.6-month extension in both median PFS (hazard ratio [HR]: 0.62, P =.0016) and median OS (HR: 0.67, P =.0102). Multivariate analyses supported this OS benefit (HR: 0.66). In the remaining patients (Group 2; n = 696), a 5.2-month PFS extension was observed in bevacizumab-treated patients (HR: 0.61, P<.0001); OS was comparable between the treatment arms (HR: 0.88, P =.1502). No significant differences in safety were observed between the 2 groups. Conclusion: This exploratory analysis suggests that the addition of bevacizumab to standard glioblastoma treatment prolongs PFS and OS for patients with PD who receive only one line of therapy.

  • 37. Chinot, Olivier L.
    et al.
    Taphoorn, Martin J. B.
    Bais, Carlos
    Bourgon, Richard
    Phillips, Heidi S.
    Abrey, Lauren E.
    Wick, Wolfgang
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm, Stockholm.
    Saran, Frank
    Nishikawa, Ryo
    Cloughesy, Timothy
    Identification of Patients Who Benefit From Bevacizumab in High-Grade Glioma-An Easy Question Turned Difficult: Treat the Scan or the Patient? Reply2016In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, no 11, p. 1282-1283Article in journal (Other academic)
  • 38. Chinot, Olivier L.
    et al.
    Wick, Wolfgang
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Saran, Frank
    Nishikawa, Ryo
    Carpentier, Antoine F.
    Hoang-Xuan, Khe
    Kavan, Petr
    Cernea, Dana
    Brandes, Alba A.
    Hilton, Magalie
    Abrey, Lauren
    Cloughesy, Timothy
    Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, no 8, p. 709-722Article in journal (Refereed)
    Abstract [en]

    BackgroundStandard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. MethodsWe randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival. ResultsA total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%). ConclusionsThe addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo. 

  • 39. Chinot, Olivier L.
    et al.
    Wick, Wolfgang
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Reg Canc Ctr Stockholm,.
    Saran, Frank
    Nishikawa, Ryo
    Carpentier, Antoine F.
    Hoang-Xuan, Khe
    Kavan, Petr
    Cernea, Dana
    Brandes, Alba A.
    Hilton, Magalie
    Kerloeguen, Yannick
    Guijarro, Abajo
    Cloughsey, Timothy
    FINAL EFFICACY AND SAFETY RESULTS FROM AVAglio, A PHASE III TRIAL OF BEVACIZUMAB (BEV) PLUS TEMOZOLOMIDE (TMZ) ANDRADIOTHERAPY (RT) IN NEWLY DIAGNOSED GLIOBLASTOMA2013In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, no Supplement: 3, p. 105-106Article in journal (Other academic)
  • 40. Chinot, Olivier L.
    et al.
    Wick, Wolfgang
    van den Bent, Martin J.
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center, Karolinska University Hospital, Stockholm, Sweden.
    Saran, Frank
    Nishikawa, Ryo
    Revil, Cedric
    Kerloeguen, Yannick
    Cloughesy, Timothy
    Re-analysis of PFS/response using original Macdonald criteria and response evaluation criteria in solid tumors in the phase III AVAglio study of bevacizumab plus radiotherapy and temozolomide in newly diagnosed glioblastoma2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, no suppl 5Article in journal (Other academic)
  • 41. Cloughesy, Tim
    et al.
    Wick, Wolfgang
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center, Karolinska University Hospital, Stockholm, Sweden.
    Saran, Frank
    Nishikawa, Ryo
    Carpentier, Antoine F.
    Hoang-Xuan, Khe
    Kavan, Petr
    Cernea, Dana
    Brandes, Alba A.
    Revil, Cedric
    Abrey, Lauren
    Chinot, Olivier L.
    Survival analysis of patients with a PFS event who did not receive post-progression therapy in AVAglio (bevacizumab [BEV] plus radiotherapy [RT] and temozolomide [TMZ] for newly diagnosed glioblastoma [GBM])2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, no 5Article in journal (Other academic)
  • 42. Dahlrot, R. H.
    et al.
    Dowsett, J.
    Fosmark, S.
    Malmstrom, A.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm Gotland Stockholm Sweden.
    Boldt, H.
    de Stricker, K.
    Sorensen, M. D.
    Poulsen, H. S.
    Lysiak, M.
    Soderkvist, P.
    Rosell, J.
    Hansen, S.
    Kristensen, B. W.
    Prognostic value of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression in glioblastoma excluding nontumour cells from the analysis2018In: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 44, no 2, p. 172-184Article in journal (Refereed)
    Abstract [en]

    Aims: It is important to predict response to treatment with temozolomide (TMZ) in glioblastoma (GBM) patients. Both MGMT protein expression and MGMT promoter methylation status have been reported to predict the response to TMZ. We investigated the prognostic value of quantified MGMT protein levels in tumour cells and the prognostic importance of combining information of MGMT protein level and MGMT promoter methylation status.

    Methods: MGMT protein expression was quantified in tumour cells in 171 GBMs from the population‐based Region of Southern Denmark (RSD)‐cohort using a double immunofluorescence approach. Pyrosequencing was performed in 157 patients. For validation we used GBM‐patients from a Nordic Study (NS) investigating the effect of radiotherapy and different TMZ schedules.

    Results: When divided at the median, patients with low expression of MGMT protein (AF‐low) had the best prognosis (HR = 1.5, P = 0.01). Similar results were observed in the subgroup of patients receiving the Stupp regimen (HR = 2.0, P = 0.001). In the NS‐cohort a trend towards superior survival (HR = 1.6, P = 0.08) was seen in patients with AF‐low. Including MGMT promoter methylation status, we found for both cohorts that patients with methylated MGMT promoter and AF‐low had the best outcome; median OS 23.1 and 20.0 months, respectively.

    Conclusion: Our data indicate that MGMT protein expression in tumour cells has an independent prognostic significance. Exclusion of nontumour cells contributed to a more exact analysis of tumour‐specific MGMT protein expression. This should be incorporated in future studies evaluating MGMT status before potential integration into clinical practice.

  • 43.
    Danell, Rickard
    et al.
    Umeå University, Faculty of Social Sciences, Sociology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Kan forskning ha stordriftsfördelar?2008In: Onkologi i Sverige, no 2, p. 32-40Article in journal (Refereed)
  • 44. Dobbins, Sara E.
    et al.
    Broderick, Peter
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Feychting, Maria
    Johansen, Christoffer
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Schramm, Johannes
    Olver, Bianca
    Lloyd, Amy
    Ma, Yussanne P.
    Hosking, Fay J.
    Lönn, Stefan
    Ahlbom, Anders
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Schoemaker, Minouk J.
    Hepworth, Sarah J.
    Hoffmann, Per
    Muehleisen, Thomas W.
    Noethen, Markus M.
    Moebus, Susanne
    Eisele, Lewin
    Kosteljanetz, Michael
    Muir, Kenneth
    Swerdlow, Anthony
    Simon, Matthias
    Houlston, Richard S.
    Common variation at 10p12.31 near MLLT10 influences meningioma risk2011In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, no 9, p. 825-827Article in journal (Refereed)
    Abstract [en]

    To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 x 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.

  • 45. Ekman, Simon
    et al.
    Eriksson, Peter
    Bergström, Stefan
    Johansson, Peter
    Goike, Helena
    Gullbo, Joachim
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Larsson, Anders
    Bergqvist, Michael
    Clinical value of using serological cytokeratins as therapeutic markers in thoracic malignancies.2007In: Anticancer Res, ISSN 0250-7005, Vol. 27, no 5B, p. 3545-3553Article in journal (Refereed)
  • 46. Ellingson, Benjamin
    et al.
    Abrey, Lauren
    Garcia, Josep
    Chinot, Olivier
    Aftab, Dana
    Schwab, Gisela
    Revil, Cedric
    Saran, Frank
    Nishikawa, Ryo
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm, Stockholm, Sweden.
    Hessel, Colin
    Harris, Robert
    Woodworth, Davis
    Leu, Kevin
    Lai, Albert
    Sahebjam, Solmaz
    Pope, Whitney
    Mason, Warren
    Wick, Wolfgang
    Wen, Patrick
    Cloughesy, Timothy
    RESIDUAL ENHANCING TUMOR VOLUME IS A STRONG PROGNOSTIC BIOMARKER FOR SURVIVAL IN BOTH NEWLY DIAGNOSED AND RECURRENT GBM REGARDLESS OF THERAPY: EVIDENCE FROM 1,535 PATIENTS IN SINGLE AND MULTICENTER TRIALS2016In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, p. 131-131Article in journal (Refereed)
  • 47. Ellingson, Benjamin M.
    et al.
    Abrey, Lauren E.
    Garcia, Josep
    Chinot, Olivier
    Wick, Wolfgang
    Saran, Frank
    Nishikawa, Ryo
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm, Stockholm, Sweden.
    Mason, Warren P.
    Harris, Robert J.
    Leu, Kevin
    Woodworth, Davis C.
    Mehta, Arnav
    Raymond, Catalina
    Chakhoyan, Ararat
    Pope, Whitney B.
    Cloughesy, Timothy F.
    Post-chemoradiation volumetric response predicts survival in newly diagnosed glioblastoma treated with radiation, temozolomide, and bevacizumab or placebo2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 11, p. 1525-1535Article in journal (Refereed)
    Abstract [en]

    Background. In the current study we used contrast-enhanced T1 subtraction maps to test whether early changes in enhancing tumor volume are prognostic for overall survival (OS) in newly diagnosed glioblastoma (GBM) patients treated with chemoradiation with or without bevacizumab (BV). Methods. Seven hundred ninety-eight patients (404 BV and 394 placebo) with newly diagnosed GBM in the AVAglio trial (NCT00943826) had baseline MRI scans available, while 337 BV-treated and 269 placebo-treated patients had > 4 MRI scans for response evaluation. The volume of contrast-enhancing tumor was quantified and used for subsequent analyses. Results. A decrease in tumor volume during chemoradiation was associated with a longer OS in the placebo group (hazard ratio [HR] = 1.578, P < 0.0001) but not BV-treated group (HR = 1.135, P = 0.4889). Results showed a higher OS in patients on the placebo arm with a sustained decrease in tumor volume using a post-chemoradiation baseline (HR = 1.692, P = 0.0005), and a trend toward longer OS was seen in BV-treated patients (HR = 1.264, P = 0.0724). Multivariable Cox regression confirmed that sustained response or stable disease was prognostic for OS (HR = 0.7509, P = 0.0127) when accounting for age (P = 0.0002), KPS (P = 0.1516), postsurgical tumor volume (P < 0.0001), O6-methylguanine-DNA methyltransferase status (P < 0.0001), and treatment type (P = 0.7637) using the post-chemoradiation baseline. Conclusions. The post-chemoradiation timepoint is a better baseline for evaluating efficacy in newly diagnosed GBM. Early progression during the maintenance phase is consequential in predicting OS, supporting the use of progression-free survival rates as a meaningful surrogate for GBM.

  • 48. Ellingson, Benjamin M.
    et al.
    Abrey, Lauren E.
    Nelson, Sarah J.
    Kaufmann, Timothy J.
    Garcia, Josep
    Chinot, Olivier
    Saran, Frank
    Nishikawa, Ryo
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm.
    Mason, Warren P.
    Wick, Wolfgang
    Butowski, Nicholas
    Ligon, Keith L.
    Gerstner, Elizabeth R.
    Colman, Howard
    de Groot, John
    Chang, Susan
    Mellinghoff, Ingo
    Young, Robert J.
    Alexander, Brian M.
    Colen, Rivka
    Taylor, Jennie W.
    Arrillaga-Romany, Isabel
    Mehta, Arnav
    Huang, Raymond Y.
    Pope, Whitney B.
    Reardon, David
    Batchelor, Tracy
    Prados, Michael
    Galanis, Evanthia
    Wen, Patrick Y.
    Cloughesy, Timothy F.
    Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 9, p. 1240-1250Article in journal (Refereed)
    Abstract [en]

    Background. In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS). Methods. Data from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O-6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS. Results. A log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status. Conclusion. Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.

  • 49.
    Faraz, Mahmood
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Herdenberg, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holmlund, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    A protein interaction network centered on leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) regulates growth factor receptors2018In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 9, p. 3421-3435Article in journal (Refereed)
    Abstract [en]

    Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a tumor suppressor and a negative regulator of several receptor tyrosine kinases. The molecular mechanisms by which LRIG1 mediates its tumor suppressor effects and regulates receptor tyrosine kinases remain incompletely understood. Here, we performed a yeast two-hybrid screen to identify novel LRIG1-interacting proteins and mined data from the BioPlex (biophysical interactions of ORFeome-based complexes) protein interaction data repository. The putative LRIG1 interactors identified in the screen were functionally evaluated using a triple co-transfection system in which HEK293 cells were co-transfected with platelet-derived growth factor receptor α, LRIG1, and shRNAs against the identified LRIG1 interactors. The effects of the shRNAs on the ability of LRIG1 to down-regulate platelet-derived growth factor receptor α expression were evaluated. On the basis of these results, we present an LRIG1 protein interaction network with many newly identified components. The network contains the apparently functionally important LRIG1-interacting proteins RAB4A, PON2, GAL3ST1, ZBTB16, LRIG2, CNPY3, HLA-DRA, GML, CNPY4, LRRC40, and LRIG3, together with GLRX3, PTPRK, and other proteins. In silico analyses of The Cancer Genome Atlas data sets revealed consistent correlations between the expression of the transcripts encoding LRIG1 and its interactors ZBTB16 and PTPRK and inverse correlations between the transcripts encoding LRIG1 and GLRX3. We further studied the LRIG1 function–promoting paraoxonase PON2 and found that it co-localized with LRIG1 in LRIG1-transfected cells. The proposed LRIG1 protein interaction network will provide leads for future studies aiming to understand the molecular functions of LRIG1 and the regulation of growth factor signaling.

  • 50.
    Franzén, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gustafsson, H
    Sundström, S
    Karlsson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Littbrand, Bo
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Fractionated-irradiation and late changes in rat parotid-gland: effects on the number of acinar-cells, potassium efflux, and amylase secretion1993In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 64, no 1, p. 93-101Article in journal (Refereed)
    Abstract [en]

    Irradiation of head- and neck cancer commonly results in oral dryness and discomfort for the patients due to salivary gland damage. The exact mechanisms behind the inherent radiosensitivity of salivary glands remain to be elucidated. In the present study, we used different in vitro secretory models and quantitative morphological characterization of rat parotid gland following fractionated unilateral irradiation to one gland on a 5-day fraction schedule (Monday-Friday) with 6 MV photons (total dose 30, 35, 40 and 45 Gy) or a two-fractions regimen in 5 days (Monday and Friday) with total dose of 24 and 32 Gy. The contralateral shielded gland served as control, and parallel analyses of irradiated and control glands were performed 180 days following the last irradiation treatment. The relative noradrenaline stimulated electrolyte secretion (rubidium-86 tracer for potassium) was decreased in the irradiated compared with control glands. The noradrenaline-stimulated exocytotic amylase release was not significantly affected by irradiation, but the gland content of amylase was decreased dose-dependently. The quantitative morphological analysis revealed a dose-dependent decline in the number of acinar cells, whereas the other parenchymal cells (intercalated, striated- and excretory duct cells) were un-, affected by the irradiation compared with control glands.

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