| 1. |
- Sandstrom, Maria, et al.
(author)
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A Retrospective Evaluation of Bevacizumab Treatment in Patients with Progressive Malignant Glioma in Northern Sweden
- 2017
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In: Anticancer Research. - : INT INST ANTICANCER RESEARCH. - 0250-7005 .- 1791-7530. ; 37:4, s. 1869-1874
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Journal article (peer-reviewed)abstract
- Background/Aim: Overall survival for glioblastoma patients is short. Standard treatment is surgery followed by radiochemotherapy and adjuvant temozolomide. The aim of this study was to evaluate the outcome for all patients with progressive disease treated with bevacizumab-based treatment combinations in the northern region of Sweden. Patients and Methods: This was a single-center retrospective analysis after bevacizumab-based second-line treatment for malignant glioma. All patients treated with bevacizumab, between 2007 and 2011 in our Center were retrospectively evaluated. Results: Progression-free survival after the start of bevacizumab-based treatment was 20 weeks and overall survival was 31 weeks. Treatment was well tolerated, but 9% of patients (n=6) suffered from serious adverse events. In 68% of patients, a >= 25% decrease in contrast enhancement was seen at best response. Conclusion: Results from this retrospective study are comparable with earlier phase-II. studies and motivate randomized trials of bevacizumab-based treatment in the second-line setting.
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| 2. |
- Asklund, Thomas, et al.
(author)
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Brain tumors in Sweden : Data from a population-based registry 1999-2012
- 2015
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In: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 54:3, s. 377-384
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Journal article (peer-reviewed)abstract
- 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.
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| 3. |
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| 4. |
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| 6. |
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| 7. |
- Asklund, Thomas, et al.
(author)
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PET response and tumor stabilization under erlotinib and bevacizumab treatment of an intracranial lesion non-invasively diagnosed as likely chordoma
- 2011
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In: Clinical Neuropathology. - Deisenhofen : Dustri-Verlag Feistle. - 0722-5091. ; 30:5, s. 242-246
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Journal article (peer-reviewed)abstract
- 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.
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| 8. |
- Asklund, Thomas, et al.
(author)
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Synergistic Killing of Glioblastoma Stem-like Cells by Bortezomib and HADC Inhibitors.
- 2012
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In: Anticancer Research. - : International Institute of Anticancer Research. - 0250-7005 .- 1791-7530. ; 32:7, s. 2407-2413
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Journal article (peer-reviewed)abstract
- 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.
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| 9. |
- Asklund, Thomas
(author)
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Two novel combination therapies of glioblastoma multiforme from a Cx43 perspective : studies of in vitro models
- 2008
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Doctoral thesis (other academic/artistic)abstract
- The group of patients suffering from the malignant brain tumour glioblastoma multiforme (GBM) have a median survival of only about one year. Thus, new treatment strategies are urgently needed. Gap junctions are intercellular channels, permitting intercellular transfer of water soluble substances. They are vital for cellular homesostasis, proliferation and differentiation. Gap junctions are composed of multimeric proteins termed connexins (Cxs), of which Cx43 is the most ubiquitous. Cx43 serves as a tumour suppressor independent of its ability to form gap junctions. Herpes simplex virus thymidine kinase (HSV-tk) mediated suicide gene therapy has shown promising results in preclinical research, but has as yet failed to prove clinical efficacy. Intriguingly, neural progenitor cells (NPCs) have shown tropism for intracranial tumours and could be exploited for improving the delivery of therapeutic genes or gene products. Epigenetic regulators, such as histone deacetylase inhibitors (HDACi) and receptor tyrosine kinase inhibitors (RTKIs), including gefitinib and vandetanib, have recently entered clinical trials. In the present study, primary cultures of GBM cells were established and showed positivity for neuroepithelial markers. Additionally, they were Cx43 positive and functional gap junctions were demonstrated. The bystander effect in the HSV-tk/ganciclovir (HSV-tk/GCV) suicide gene therapy system was attenuated by a specific gap junction inhibitor, AGA, showing that this phenomenon is dependent on gap junction coupling in glioma cells. The HDAC inhibitor 4-phenylbutyrate (4-PB) up regulated Cx43 and enhanced gap junction communication (GJC), a strategy which could have potential for improving efficacy of suicide gene therapy. NPCs exposed to 4-PB also increased Cx43 expression and gap junction formation. This, together with the propensity of NPCs of tracking down tumour cells, could add a new dimension to gene therapy. Cooperative antitumoural effects were evident in combination treatment of 4-PB and the RTKIs gefitinib and vandetanib. These RTKIs showed an up regulating effect on the tumour suppressor Cx43, which could show to be of importance in the downstream effects of RTKIs.
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| 10. |
- Asklund, Thomas, et al.
(author)
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Överlevnaden vid maligna gliom har ökat senaste tio åren - Analys av kvalitetsregisterdata : [Survival in malignant gliomas has increased the last decade. Analysis of quality data]
- 2012
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In: Läkartidningen. - : Läkartidningen Förlag. - 0023-7205 .- 1652-7518. ; 109:17-18, s. 875-878
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Journal article (peer-reviewed)abstract
- Den årliga incidensen av högmaligna gliom, WHO grad III–IV, i Sverige är ungefär 400.Medianöverlevnaden för höggradiga gliom har ökat från 8,1 månader till 10,0 månader under det senaste decenniet i en oselekterad svensk population.För åldersgruppen 60–69 år har medianöverlevnaden ökat från 5,8 månader till 10,5 månader under denna period, dvs nästan en fördubbling.Utveckling av befintliga behandlingsmetoder, nya behandlingsstrategier och en mer aktiv inställning till terapi har sannolikt bidragit till de beskrivna överlevnadsvinsterna.
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| 11. |
- Asklund, Thomas, et al.
(author)
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Överlevnanden vid maligna gliom har ökat senaste tio åren. Analys av kvalitetsregisterdata.
- 2012
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In: Läkartidningen. - : Läkartidningen Förlag AB. - 0023-7205 .- 1652-7518. ; 109:17-18, s. 875-878
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Journal article (peer-reviewed)abstract
- 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.
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| 12. |
- Björkblom, Benny, et al.
(author)
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Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma
- 2020
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In: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 122:2, s. 221-232
-
Journal article (peer-reviewed)abstract
- BACKGROUND: High-grade gliomas are associated with poor prognosis. Tumour heterogeneity and invasiveness create challenges for effective treatment and use of systemically administrated drugs. Furthermore, lack of functional predictive response-assays based on drug efficacy complicates evaluation of early treatment responses.METHODS: We used microdialysis to deliver cisplatin into the tumour and to monitor levels of metabolic compounds present in the tumour and non-malignant brain tissue adjacent to tumour, before and during treatment. In parallel, we collected serum samples and used multivariate statistics to analyse the metabolic effects.RESULTS: We found distinct metabolic patterns in the extracellular fluids from tumour compared to non-malignant brain tissue, including high concentrations of a wide range of amino acids, amino acid derivatives and reduced levels of monosaccharides and purine nucleosides. We found that locoregional cisplatin delivery had a strong metabolic effect at the tumour site, resulting in substantial release of glutamic acid, phosphate, and spermidine and a reduction of cysteine levels. In addition, patients with long-time survival displayed different treatment response patterns in both tumour and serum. Longer survival was associated with low tumour levels of lactic acid, glyceric acid, ketoses, creatinine and cysteine. Patients with longer survival displayed lower serum levels of ketohexoses, fatty acid methyl esters, glycerol-3-phosphate and alpha-tocopherol, while elevated phosphate levels were seen in both tumour and serum during treatment.CONCLUSION: We highlight distinct metabolic patterns associated with high-grade tumour metabolism, and responses to cytotoxic cisplatin treatment.
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| 13. |
- Brynolfsson, Patrik, et al.
(author)
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ADC texture-An imaging biomarker for high-grade glioma?
- 2014
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In: Medical physics (Lancaster). - : Wiley. - 0094-2405. ; 41:10, s. 101903-
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Journal article (peer-reviewed)abstract
- 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).
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| 14. |
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| 15. |
- Brynolfsson, Patrik, et al.
(author)
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Haralick texture features from apparent diffusion coefficient (ADC) MRI images depend on imaging and pre-processing parameters
- 2017
-
In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7
-
Journal article (peer-reviewed)abstract
- In recent years, texture analysis of medical images has become increasingly popular in studies investigating diagnosis, classification and treatment response assessment of cancerous disease. Despite numerous applications in oncology and medical imaging in general, there is no consensus regarding texture analysis workflow, or reporting of parameter settings crucial for replication of results. The aim of this study was to assess how sensitive Haralick texture features of apparent diffusion coefficient (ADC) MR images are to changes in five parameters related to image acquisition and pre-processing: noise, resolution, how the ADC map is constructed, the choice of quantization method, and the number of gray levels in the quantized image. We found that noise, resolution, choice of quantization method and the number of gray levels in the quantized images had a significant influence on most texture features, and that the effect size varied between different features. Different methods for constructing the ADC maps did not have an impact on any texture feature. Based on our results, we recommend using images with similar resolutions and noise levels, using one quantization method, and the same number of gray levels in all quantized images, to make meaningful comparisons of texture feature results between different subjects.
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| 16. |
- Eriksson, Magnus, et al.
(author)
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Theodor Kallifatides, Bodil Malmsten, Hugo Hamilton,Fransk 1800-talsprosa, Marcel Pagnol, Vilhelm Moberg,Språkundervisning
- 2010
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Reports (other academic/artistic)abstract
- Theodor Kallifatides var gäst vid Mälardalens högskolas författardag 2008 och 2010 stod Bodil Malmsten i fokus under detta årliga evenemang. De fyra första bidragen i detta nummer av Litteratur och språk är föredrag som hölls under dessa båda dagar.Magnus Eriksson visar hur Kallifatides i sitt skrivande utforskat kärlekens vägval, de många variationer och moraliska konflikter kärleks- och vänskapstemat kan bjuda på. Inkännande följer han författarens skildringar av kärlekens väsen och vånda, svek och livslögn, men också den självuppgivande ögonblicklighetens förvillelse som drabbar den förälskade. Enligt Magnus Eriksson har Kallifatides bild av kärleken ”slående likheter med den medeltida mystikerns upplevelse av uppgåendet i Gud.”Birgitta Cremnitzer å sin sida gör en interkulturell resa genom Kallifatides författarskap, en resa ”som främst handlar om sökandet efter identitet och kampen mot främlingsskapets dilemma”. Hon tar sina egna upplevelser av två länder, två språk och två kulturer som utgångspunkt och visar hur Kallifatides förmår göra läsaren till medresenär kring emigrantskapets villkor. Detta innebär enligt Cremnitzer bl.a. att differensperspektivet alltid finns hos den som emigrerat och att livet i exil kan upplevas som ett slags amputation med återkommande fantomsmärtor.Sara Granath tar i sitt bidrag till författardagen upp personliga intryck av Bodil Malmstens dramatik. Hon talar bl.a. om svårigheterna i att levandegöra ett samhälle sceniskt och framhåller betydelsen av den rumsliga gestaltningen i Malmstens pjäser. Här är det inte enbart yttre rum det är fråga om, utan lika mycket människors inre rum. För Granath är det just Malmstens speciella sätt att behandla yttre och inre rum som verkar vara en ”fruktbar tråd att följa i hennes dramatik och teater”.Ingemar Haag återvänder i sin essä till lyrikern Bodil Malmsten, som under senare år överskuggats av ”självbiografen” och dramatikern Malmsten. I hennes lyrik stiftar vi bekantskap med ett tilltal som spänner mellan högt och lågt, tyst och uppfordrande. I dialogen med Samuel Beckett, ett av 1900-talets stora författarskap, anknyter Malmsten till såväl föregångarens existentiella perspektiv som det humoristiska anslaget.I sin studie om intratextuell motivering kommenterar Hans Färnlöf hur olika narrativa element länkas samman i några franska 1800-talsberättelser. Med motivering menas hur författaren kan ”motivera” (i betydelsen ”berättiga”, ”rättfärdiga”), hur karaktärer agerar eller varför vissa händelser bör – eller inte bör – inträffa enligt berättelsens logik. Det handlar således om att etablera orsak och verkan i en fiktiv värld. Färnlöf visar hur man genom att fokusera på den intratextuella motiveringen, dvs. de orsakssamband som byggs upp genom referenser inne i texten i stället för att hänvisa till verkligheten, tydligare kan skönja textens etapper och progression, från inledning till avslutning.Utifrån kortberättelserna Nazi Christmas och The Irish Worker av den irländsktyske författaren Hugo Hamilton lyfter Thorsten Päplow och Birte Schulz fram frågor som hänger samman med formandet av den kulturella identiteten hos barn med bakgrund i två kulturer. Deras bidrag ger en kort introduktion till forskningen kring ”biculturalism” och använder sig av psykologiska och sociologiska insikter från detta område vid den litterära analysen. Fokus ligger här på huruvida kortberättelsernas huvudfigur, som växer upp med en tysk mor och en irländsk far, genomgår en identitetskris på grund av sitt dubbla kulturella arv.I sitt andra bidrag behandlar Hans Färnlöf Marcel Pagnol som genom sitt filmskapande på framför allt 1930-talet tillhör den franska filmens klassiska regissörer. Som författare ses han dock huvudsakligen som ”regional” berättare. Det innebär att tema, struktur, bildspråk, stilistik och andra litterära aspekter i hans verk sällan diskuteras. Med sin studie av de fyra elementen i romandiptyken L’Eau des collines (”Vattnet från kullarna”) visar Färnlöf hur det vid första anblicken transparenta, referentiella landskapet, liksom handlingen och karaktärerna, innehåller både episk bredd och symboliskt djup.Om litterär skildring handlar det även i Thomas Asklunds artikel som tar upp Vilhelm Mobergs berättarteknik i utvandrarserien. Med exempel från olika passager ur ett kapitel i Invandrarna visar Asklund hur Moberg använder växlande berättarperspektiv och upprepande stilfigurer för att skapa verklighetsillusion i den fiktiva berättelsen.I det avslutande bidraget framhåller Helena Darnell-Berggren att skolans kunskapsuppdrag är en självklarhet för varje lärare, men hon frågar sig samtidigt hur det ska kunna vara möjligt att få undervisningstiden att räcka till för att även fostra elever till demokratiska samhällsmedborgare. I sin genomgång av olika styrdokument för skolan och även tillämplig didaktisk forskning ger Darnell-Berggren olika perspektiv på hur språkundervisning kan bli till ett meningsskapande, där båda dessa uppdrag kan kombineras.Red.
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| 17. |
- Garpebring, Anders, et al.
(author)
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Phase-based arterial input functions in humans applied to dynamic contrast-enhanced MRI: potential usefulness and limitations
- 2011
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In: Magma. - : Springer Science and Business Media LLC. - 1352-8661 .- 0968-5243. ; 24:4, s. 233-245
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Journal article (peer-reviewed)abstract
- Object Phase-based arterial input functions (AIFs) provide a promising alternative to standard magnitude-based AIFs, for example, because inflow effects are avoided. The usefulness of phase-based AIFs in clinical dynamic contrast-enhanced MRI (DCE-MRI) was investigated, and relevant pitfalls and sources of uncertainty were identified. Materials and methods AIFs were registered from eight human subjects on, in total, 21 occasions. AIF quality was evaluated by comparing AIFs from right and left internal carotid arteries and by assessing the reliability of blood plasma volume estimates. Results Phase-based AIFs yielded an average bolus peak of 3.9 mM and a residual concentration of 0.37 mM after 3 min, (0.033 mmol/kg contrast agent injection). The average blood plasma volume was 2.7% when using the AIF peak in the estimation, but was significantly different (p < 0.0001) and less physiologically reasonable when based on the AIF tail concentration. Motion-induced phase shifts and accumulation of contrast agent in background tissue regions were identified as main sources of uncertainty. Conclusion Phase-based AIFs are a feasible alternative to magnitude AIFs, but sources of errors exist, making quantification difficult, especially of the AIF tail. Improvement of the technique is feasible and also required for the phase-based AIF approach to reach its full potential.
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| 18. |
- Garpebring, Anders, et al.
(author)
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Uncertainty estimation in dynamic contrast-enhanced MRI
- 2013
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In: Magnetic Resonance in Medicine. - : Wiley-Blackwell. - 0740-3194 .- 1522-2594. ; 69:4, s. 992-1002
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Journal article (peer-reviewed)abstract
- Using dynamic contrast-enhanced MRI (DCE-MRI), it is possible to estimate pharmacokinetic (PK) parameters that convey information about physiological properties, e.g., in tumors. In DCE-MRI, errors propagate in a nontrivial way to the PK parameters. We propose a method based on multivariate linear error propagation to calculate uncertainty maps for the PK parameters. Uncertainties in the PK parameters were investigated for the modified Kety model. The method was evaluated with Monte Carlo simulations and exemplified with in vivo brain tumor data. PK parameter uncertainties due to noise in dynamic data were accurately estimated. Noise with standard deviation up to 15% in the baseline signal and the baseline T1 map gave estimated uncertainties in good agreement with the Monte Carlo simulations. Good agreement was also found for up to 15% errors in the arterial input function amplitude. The method was less accurate for errors in the bolus arrival time with disagreements of 23%, 32%, and 29% for Ktrans, ve, and vp, respectively, when the standard deviation of the bolus arrival time error was 5.3 s. In conclusion, the proposed method provides efficient means for calculation of uncertainty maps, and it was applicable to a wide range of sources of uncertainty.
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| 19. |
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| 20. |
- Henriksson, Roger, et al.
(author)
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Brain Tumors - Prognostic and Predictive Markers
- 2009
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In: Histological and Serological Tumor Markers and Gene Expression and Their Clinical Usefulness in Cancers. - Hauppauge : Nova Science Publishers, Inc.. - 9781607413820 ; , s. 53-75
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Book chapter (peer-reviewed)abstract
- This review summarizes the status of prognostic and predictive markers in brain tumors with a focus on the most frequent tumors, gliomas. Brain tumors are a heterogeneous group of different tumors with a huge variation in outcome. Although the most common tumor, high-grade malignant glioma, still has a dismal prognosis, the last years have seen a significant improvement in the management in this tumor as well as in most other brain tumors. Age, tumor grade and KPS are still the most reliable prognostic and predictive variables available for patients with brain tumors. Although chromosome 1p/19q co-deletion and methylation status of the promoter of the MGMT gene (encoding O6-methylguanine-DNA methyl transferase) have been identified as the most promising potential predictors of response to chemotherapy in malignant gliomas, there are as yet no reliable biomarkers for tumour grading or tumour monitoring in the clinical setting.
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| 21. |
- Henriksson, Roger, et al.
(author)
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Impact of therapy on quality of life, neurocognitive function and their correlates in glioblastoma multiforme : a review
- 2011
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In: Journal of Neuro-Oncology. - Boston : Nijhoff. - 0167-594X .- 1573-7373. ; 104:3, s. 639-646
-
Research review (peer-reviewed)abstract
- The maintenance of quality of life (QoL) in patients with high-grade glioma is an important endpoint during treatment, particularly in those with glioblastoma multiforme (GBM) given its dismal prognosis despite limited advances in standard therapy. It has proven difficult to identify new therapies that extend survival in patients with recurrent GBM, so one of the primary aims of new therapies is to reduce morbidity, restore or preserve neurologic functions, and the capacity to perform daily activities. Apart from temozolomide, cytotoxic chemotherapeutic agents do not appear to significantly impact response or survival, but produce toxicity that is likely to negatively impact QoL. New biological agents, such as bevacizumab, can induce a clinically meaningful proportion of durable responses among patients with recurrent GBM with an acceptable safety profile. Emerging evidence suggests that bevacizumab produces an improvement or preservation of neurocognitive function in GBM patients, suggestive of QoL improvement, in most poor-prognosis patients who would otherwise be expected to show a sudden and rapid deterioration in QoL.
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| 22. |
- Hildeman, Anders, et al.
(author)
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Hildeman, A., Bolin, D., Wallin, J., Johansson, A., Nyholm, T., Asklund, T., and Yu, J. Whole-brain substitute CT generation using Markov random field mixture models.
- 2016
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Other publication (other academic/artistic)abstract
- Computed tomography (CT) equivalent information is needed for attenuation correction in PET imaging and for dose planning in radiotherapy. Prior work has shown that Gaussian mixture models can be used to generate a substitute CT (s-CT) image from a specific set of MRI modalities. This work introduces a more flexible class of mixture models for s-CT generation, that incorporates spatial dependency in the data through a Markov random field prior on the latent field of class memberships associated with a mixture model. Furthermore, the mixture distributions are extended from Gaussian to normal inverse Gaussian (NIG), allowing heavier tails and skewness. The amount of data needed to train a model for s-CT generation is of the order of 10^8 voxels. The computational efficiency of the parameter estimationand prediction methods are hence paramount, especially when spatial dependency is included in the models. A stochastic Expectation Maximization (EM) gradient algorithm is proposed in order to tackle this challenge. The advantages of the spatial model and NIG distributions are evaluated with a cross-validation study based ondata from 14 patients. The study show that the proposed model enhances the predictive quality of the s-CT images by reducing the mean absolute error with 17.9%. Also, the distribution of CT values conditioned on the MR images are better explainedby the proposed model as evaluated using continuous ranked probability scores.
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| 23. |
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| 24. |
- Holgersson, Georg, et al.
(author)
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Effect of Increased Radiotoxicity on Survival of Patients with Non-small Cell Lung Cancer Treated with Curatively Intended Radiotherapy
- 2015
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In: Anticancer Research. - 0250-7005 .- 1791-7530. ; 35:10, s. 5491-5497
-
Journal article (peer-reviewed)abstract
- 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.
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| 25. |
- Johansson, Adam, 1984-, et al.
(author)
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CT substitutes derived from MR images reconstructed with parallel imaging
- 2014
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In: Medical physics (Lancaster). - : Wiley. - 0094-2405. ; 41:8, s. 474-480
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Journal article (peer-reviewed)abstract
- Purpose: Computed tomography (CT) substitute images can be generated from ultrashort echo time (UTE) MRI sequences with radial k-space sampling. These CT substitutes can be used as ordinary CT images for PET attenuation correction and radiotherapy dose calculations. Parallel imaging allows faster acquisition of magnetic resonance (MR) images by exploiting differences in receiver coil element sensitivities. This study investigates whether non-Cartesian parallel imaging reconstruction can be used to improve CT substitutes generated from shorter examination times.Methods: The authors used gridding as well as two non-Cartesian parallel imaging reconstruction methods, SPIRiT and CG-SENSE, to reconstruct radial UTE and gradient echo (GE) data into images of the head for 23 patients. For each patient, images were reconstructed from the full dataset and from a number of subsampled datasets. The subsampled datasets simulated shorter acquisition times by containing fewer radial k-space spokes (1000, 2000, 3000, 5000, and 10 000 spokes) than the full dataset (30 000 spokes). For each combination of patient, reconstruction method, and number of spokes, the reconstructed UTE and GE images were used to generate a CT substitute. Each CT substitute image was compared to a real CT image of the same patient.Results: The mean absolute deviation between the CT number in CT substitute and CT decreased when using SPIRiT as compared to gridding reconstruction. However, the reduction was small and the CT substitute algorithm was insensitive to moderate subsampling (≥5000 spokes) regardless of reconstruction method. For more severe subsampling (≤3000 spokes), corresponding to acquisition times less than aminute long, the CT substitute quality was deteriorated for all reconstructionmethods but SPIRiT gave a reduction in the mean absolute deviation of down to 25 Hounsfield units compared to gridding.Conclusions: SPIRiT marginally improved the CT substitute quality for a given number of radial spokes as compared to gridding. However, the increased reconstruction time of non-Cartesian parallel imaging reconstruction is difficult to motivate from this improvement. Because the CT substitute algorithm was insensitive to moderate subsampling, data for a CT substitute could be collected in as little as minute and reconstructed with gridding without deteriorating the CT substitute quality.
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| 26. |
- Johansson, Adam, et al.
(author)
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Improved quality of computed tomography substitute derived from magnetic resonance (MR) data by incorporation of spatial information : potential application for MR-only radiotherapy and attenuation correction in positron emission tomography
- 2013
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In: Acta Oncologica. - 0284-186X .- 1651-226X. ; 52:7, s. 1369-1373
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Journal article (peer-reviewed)abstract
- Background: Estimation of computed tomography (CT) equivalent data, i.e. a substitute CT (s-CT), from magnetic resonance (MR) images is a prerequisite both for attenuation correction of positron emission tomography (PET) data acquired with a PET/MR scanner and for dose calculations in an MR-only radiotherapy workflow. It has previously been shown that it is possible to estimate Hounsfield numbers based on MR image intensities, using ultra short echo-time imaging and Gaussian mixture regression (GMR). In the present pilot study we investigate the possibility to also include spatial information in the GMR, with the aim to improve the quality of the s-CT. Material and methods: MR and CT data for nine patients were used in the present study. For each patient, GMR models were created from the other eight patients, including either both UTE image intensities and spatial information on a voxel by voxel level, or only UTE image intensities. The models were used to create s-CT images for each respective patient. Results: The inclusion of spatial information in the GMR model improved the accuracy of the estimated s-CT. The improvement was most pronounced in smaller, complicated anatomical regions as the inner ear and post-nasal cavities. Conclusions: This pilot study shows that inclusion of spatial information in GMR models to convert MR data to CT equivalent images is feasible. The accuracy of the s-CT is improved and the spatial information could make it possible to create a general model for the conversion applicable to the whole body.
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| 27. |
- Johansson, Adam, et al.
(author)
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Voxel-wise uncertainty in CT substitute derived from MRI
- 2012
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In: Medical physics (Lancaster). - : American Association of Physicists in Medicine. - 0094-2405. ; 39:6, s. 3283-3290
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Journal article (peer-reviewed)abstract
- Purpose: In an earlier work, we demonstrated that substitutes for CT images can be derived from MR images using ultrashort echo time (UTE) sequences, conventional T2 weighted sequences, and Gaussian mixture regression (GMR). In this study, we extend this work by analyzing the uncertainties associated with the GMR model and the information contributions from the individual imaging sequences.Methods: An analytical expression for the voxel-wise conditional expected absolute deviation (EAD) in substitute CT (s-CT) images was derived. The expression depends only on MR images and can thus be calculated along with each s-CT image. The uncertainty measure was evaluated by comparing the EAD to the true mean absolute prediction deviation (MAPD) between the s-CT and CT images for 14 patients. Further, the influence of the different MR images included in the GMR model on the generated s-CTs was investigated by removing one or more images and evaluating the MAPD for a spectrum of predicted radiological densities.Results: The largest EAD was predicted at air-soft tissue and bone-soft tissue interfaces. The EAD agreed with the MAPD in both these regions and in regions with lower EADs, such as the brain. Two of the MR images included in the GMR model were found to be mutually redundant for the purpose of s-CT generation.Conclusions: The presented uncertainty estimation method accurately predicts the voxel-wise MAPD in s-CT images. Also, the non-UTE sequence previously used in the model was found to be redundant.
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| 28. |
- Jonsson, Joakim H., et al.
(author)
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Accuracy of inverse treatment planning on substitute CT images derived from MR data for brain lesions
- 2015
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In: Radiation Oncology. - : Springer Science and Business Media LLC. - 1748-717X. ; 10
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Journal article (peer-reviewed)abstract
- Background: In this pilot study we evaluated the performance of a substitute CT (s-CT) image derived from MR data of the brain, as a basis for optimization of intensity modulated rotational therapy, final dose calculation and derivation of reference images for patient positioning. Methods: S-CT images were created using a Gaussian mixture regression model on five patients previously treated with radiotherapy. Optimizations were compared using D-max, D-min, D-median and D-mean measures for the target volume and relevant risk structures. Final dose calculations were compared using gamma index with 1%/1 mm and 3%/3 mm acceptance criteria. 3D geometric evaluation was conducted using the DICE similarity coefficient for bony structures. 2D geometric comparison of digitally reconstructed radiographs (DRRs) was performed by manual delineation of relevant structures on the s-CT DRR that were transferred to the CT DRR and compared by visual inspection. Results: Differences for the target volumes in optimization comparisons were small in general, e.g. a mean difference in both D-min and D-max within similar to 0.3%. For the final dose calculation gamma evaluations, 100% of the voxels passed the 1%/1 mm criterion within the PTV. Within the entire external volume between 99.4% and 100% of the voxels passed the 3%/3 mm criterion. In the 3D geometric comparison, the DICE index varied between approximately 0.8-0.9, depending on the position in the skull. In the 2D DRR comparisons, no appreciable visual differences were found. Conclusions: Even though the present work involves a limited number of patients, the results provide a strong indication that optimization and dose calculation based on s-CT data is accurate regarding both geometry and dosimetry.
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| 29. |
- Jonsson, Joakim, 1984-, et al.
(author)
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Treatment planning of intracranial targets on MRI derived substitute CT data
- 2013
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In: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 108:1, s. 118-122
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Journal article (peer-reviewed)abstract
- BACKGROUND: The use of magnetic resonance imaging (MRI) as a complement to computed tomography (CT) in the target definition procedure for radiotherapy is increasing. To eliminate systematic uncertainties due to image registration, a workflow based entirely on MRI may be preferable. In the present pilot study, we investigate dose calculation accuracy for automatically generated substitute CT (s-CT) images of the head based on MRI. We also produce digitally reconstructed radiographs (DRRs) from s-CT data to evaluate the feasibility of patient positioning based on MR images. METHODS AND MATERIALS: Five patients were included in the study. The dose calculation was performed on CT, s-CT, s-CT data without inhomogeneity correction and bulk density assigned MRI images. Evaluation of the results was performed using point dose and dose volume histogram (DVH) comparisons, and gamma index evaluation. RESULTS: The results demonstrate that the s-CT images improves the dose calculation accuracy compared to the method of non-inhomogeneity corrected dose calculations (mean improvement 2.0 percentage points) and that it performs almost identically to the method of bulk density assignment. The s-CT based DRRs appear to be adequate for patient positioning of intra-cranial targets, although further investigation is needed on this subject. CONCLUSIONS: The s-CT method is very fast and yields data that can be used for treatment planning without sacrificing accuracy.
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| 30. |
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| 31. |
- Larsson, Anne, et al.
(author)
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Evaluation of an attenuation correction method for PET/MR imaging of the head based on substitute CT images
- 2013
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In: Magnetic Resonance Materials in Physics, Biology and Medicine. - : Springer Science and Business Media LLC. - 0968-5243 .- 1352-8661. ; 26:1, s. 127-136
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Journal article (peer-reviewed)abstract
- The aim of this study was to evaluate MR-based attenuation correction of PET emission data of the head, based on a previously described technique that calculates substitute CT (sCT) images from a set of MR images. Images from eight patients, examined with F-18-FLT PET/CT and MRI, were included. sCT images were calculated and co-registered to the corresponding CT images, and transferred to the PET/CT scanner for reconstruction. The new reconstructions were then compared with the originals. The effect of replacing bone with soft tissue in the sCT-images was also evaluated. The average relative difference between the sCT-corrected PET images and the CT-corrected PET images was 1.6 % for the head and 1.9 % for the brain. The average standard deviations of the relative differences within the head were relatively high, at 13.2 %, primarily because of large differences in the nasal septa region. For the brain, the average standard deviation was lower, 4.1 %. The global average difference in the head when replacing bone with soft tissue was 11 %. The method presented here has a high rate of accuracy, but high-precision quantitative imaging of the nasal septa region is not possible at the moment.
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| 32. |
- Malmstrom, A., et al.
(author)
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GENDER DIFFERENCES IN GLIOMA - FINDINGS FROM THE SWEDISH NATIONAL QUALITY REGISTRY FOR PRIMARY BRAIN TUMORS
- 2018
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In: Neuro-Oncology. - : OXFORD UNIV PRESS INC. - 1522-8517 .- 1523-5866. ; 20, s. 267-267
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Journal article (other academic/artistic)abstract
- BackgroundAn often debated topic in neuro-oncology are the differences in incidence and survival between men and women with glioma. To the Swedish National Quality Registry for Primary Brain Tumors (SNQR) over 90% of all Swedish patients with primary brain tumor have been reported since 1999. We therefore conducted a study of clinical factors in relation to gender in patients registered with high grade glioma using data from the SNQR.MethodsThe SNQR was searched for patients diagnosed with high grade glioma from 1999 through 2016 and clinical data were analyzed for gender differences regarding prognostic factors, tumor location and survival.ResultsIn all 5470 patients were identified, 2268 women and 3202 men, giving a ratio of 1:1.4. We found a survival benefit for women when analyzing the whole time period. While there was no difference in median survival (315 versus 326 days for women versus men), there were significantly more long term survivors among women, with mean survival being 742 versus 628 days (p=0.03). The survival benefit for women was also only present in those being younger than 50 years at diagnosis. We looked at the prognostic factors age, performance status (PS) and surgery in relation to gender. We found that median age for being diagnosed with high grade glioma was significantly higher in women than men (63 versus 62 years, p=0.002) and the ratio of women in relation to men increases with increasing age, the ratios for younger than 50 years being 1:1.5 and over 50 years 1:1.39. A higher fraction of the women are over 60 years when diagnosed compared to men (57% vs 53%, p=0.002). For PS we identified that significantly more women were reported to have PS 3 and for men more PS 0 was registered. For type of surgery we found no gender differences. For tumor location more women had tumors in the frontal and less in the temporal lobe as compared to men.ConclusionIn the Swedish National Quality Registry for Primary Brain Tumors we identified differences in incidence and survival between men and women related to age and also a disparity regarding PS and tumor location. If the cause of these clinical differences is due to molecular background or has other causes warrants further study.
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| 33. |
- Malmström, Annika, et al.
(author)
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Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial
- 2017
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In: Acta Oncologica. - : TAYLOR & FRANCIS LTD. - 0284-186X .- 1651-226X. ; 56:12, s. 1776-1785
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Journal article (peer-reviewed)abstract
- Introduction: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ.Patients and methods: Patients, after surgery for GBM or AA, age 60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200mg/m(2) days 1-5 every 28 days, followed by RT 60Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75mg/m(2) was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety.Results: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p=.76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p=.022). For patients with GBM, no difference in survival was observed (p=.10). MGMT and IDH status affected outcome.Conclusions: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.
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| 34. |
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| 35. |
- Tabatabaei, Pedram, et al.
(author)
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Intratumoral retrograde microdialysis treatment of high-grade glioma with cisplatin
- 2020
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In: Acta Neurochirurgica. - : Springer. - 0001-6268 .- 0942-0940. ; 162:12, s. 3043-3053
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Journal article (peer-reviewed)abstract
- Purpose: This study evaluates the application of a microdialysis technique for interstitial chemotherapy using cisplatin in high-grade glioma.Method: An in vitro study demonstrated that cisplatin can be administered through retrograde microdialysis and defined the recovery for cisplatin. In a subsequent phase I study, 1–4 microdialysis catheters were implanted in tumor tissue, brain adjacent to tumor (BAT) tissue, and subcutaneous tissue in 10 patients with recurrent high-grade glioma. Cisplatin was administered continuously in daily doses between 0.3 and 3.9 mg for 4 to12 days. Microdialysis samples were continuously collected and analyzed for glucose metabolites, glutamate, glycerol, and cisplatin concentrations. Treatment tolerability was evaluated through clinical monitoring. Quality of life was assessed using the EORTC-QLQ-C30 questionnaire for up to 3 months after treatment.Results: This in vitro study showed that cisplatin could be administrated with a recovery of 41–97%, depending on flowrate, type of catheter, and cisplatin concentration. During the treatment, patients were exposed to a total dose of 1.2–36.8 mg cisplatin. The concentration of cisplatin in BAT, serum, and subcutaneous tissue was close to detection level in all but two patients. A transient neurologic deterioration due to edema was commonly observed, but no systemic side effects were recorded. After onset of treatment, concentrations of glutamate and glycerol were significantly increased in tumor tissue but not in BAT, with a peak after 3 days, and consistent for the rest of the treatment. Five of the patients survived between 153 and 492 days after treatment.Conclusion: This phase I study demonstrates that retrograde microdialysis can be used to administer cisplatin interstitially into high-grade glioma tissue. A high cytotoxicity was detected in tumor tissue, but not in the surrounding brain. Retrograde microdialysis appears to be a clinically useful method for intratumoral drug administration in high-grade glioma.
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