| 1. |
- Eberstål, Sofia, et al.
(författare)
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Immunizations with unmodified tumor cells and simultaneous COX-2 inhibition eradicate malignant rat brain tumors and induce a long-lasting CD8(+) T cell memory.
- 2014
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 274:1-2, s. 161-167
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Tidskriftsartikel (refereegranskat)abstract
- Malignant brain tumors induce pronounced immunosuppression, which diminishes immune responses generated by immunotherapy. Here we report that peripheral immunotherapy, using irradiated unmodified whole tumor cells, and systemic cyclooxygenase-2 inhibition induce cure in glioma-bearing rats (60% cure rate), whereas neither monotherapy was sufficient to cure any animal. Moreover, the combined therapy protected against secondary tumor challenges (89% cure rate) and the secondary immune response was correlated with increased plasma interferon-gamma levels and CD8(+) T cells systemically and intratumorally. In conclusion, we demonstrate that cyclooxygenase-2 inhibition is sufficient to render unmodified tumor cells immunogenic in immunotherapy of experimental brain tumors.
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| 2. |
- Eberstål, Sofia, et al.
(författare)
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Inhibition of cyclooxygenase-2 enhances immunotherapy against experimental brain tumors.
- 2012
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Ingår i: Cancer immunology, immunotherapy. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 61:8, s. 1191-1199
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme is the most common and aggressive malignant brain tumor in humans, and the prognosis is very poor despite conventional therapy. Immunotherapy represents a novel treatment approach, but the effect is often weakened by release of immune-suppressive molecules such as prostaglandins. In the current study, we investigated the effect of immunotherapy with irradiated interferon-γ (IFN-γ)-secreting tumor cells and administration of the selective cyclooxygease-2 (COX-2) inhibitor parecoxib as treatment of established rat brain tumors. COX-2 inhibition and immunotherapy significantly enhanced the long-term cure rate (81% survival) compared with immunotherapy alone (19% survival), and there was a significant increase in plasma IFN-γ levels in animals treated with the combined therapy, suggesting a systemic T helper 1 immune response. COX-2 inhibition alone, however, did neither induce cure nor prolonged survival. The tumor cells were identified as the major source of COX-2 both in vivo and in vitro, and unmodified tumor cells produced prostaglandin E(2) in vitro, while the IFN-γ expressing tumor cells secreted significantly lower levels. In conclusion, we show that immunotherapy of experimental brain tumors is greatly potentiated when combined with COX-2 inhibition. Based on our results, the clinically available drug parecoxib may be added to immunotherapy against human brain tumors. Furthermore, the discovery that IFN-γ plasma levels can be used to determine the ongoing in vivo immune response has translational potential.
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| 3. |
- Eberstål, Sofia, et al.
(författare)
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Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors.
- 2014
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 134:11, s. 2748-2753
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy has shown effectiveness against experimental malignant brain tumors, but the clinical results have been less convincing most likely due to immunosuppression. Prostaglandin E2 (PGE2 ) is the key immunosuppressive product of cyclooxygenase-2 (COX-2) and increased levels of PGE2 and COX-2 have been shown in several tumor types including brain tumors. In the current study, we report enhanced cure rate of mice with established mouse GL261 brain tumors when immunized with granulocyte macrophage-colony stimulating factor (GM-CSF) secreting tumor cells and simultaneously treated with the selective COX-2 inhibitors parecoxib systemically (5 mg/kg/day; 69% cure rate) or valdecoxib intratumorally (5.3 µg/kg/day; 63% cure rate). Both combined therapies induced a systemic anti-tumor response of proliferating CD4(+) and CD8(+) T cells and further analysis revealed T helper 1 (Th 1) cell supremacy. The GL261 tumor cell line produced very low levels of PGE2 in vitro and co-staining at the tumor site demonstrated that a large fraction of the COX-2(+) cells were derived from CD45(+) immune cells and more specifically macrophages (F4/80(+) ), indicating that tumor-infiltrating immune cells constitute the primary source of COX-2 and PGE2 in this model. We conclude that intratumoral COX-2 inhibition potentiates GM-CSF immunotherapy against established brain tumors at substantially lower doses than systemic administration. These findings underscore the central role of targeting COX-2 during immunotherapy and implicate intratumoral COX-2 as the primary target. © 2013 Wiley Periodicals, Inc.
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| 4. |
- Fritzell, Peter, et al.
(författare)
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Cost-Effectiveness of Balloon Kyphoplasty Versus Standard Medical Treatment in Patients With Osteoporotic Vertebral Compression Fracture
- 2011
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Ingår i: Spine. - 0362-2436. ; 36:26, s. 2243-2251
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Tidskriftsartikel (refereegranskat)abstract
- Study Design. A multicenter, randomized, controlled, cost-effectiveness analysis. Objective. To assess the cost-effectiveness of balloon kyphoplasty (BKP) compared with standard medical treatment (control) in patients with acute/subacute (<3 months) vertebral compression fracture (VCF) due to osteoporosis. Summary of Background Data. Patients with a VCF due to osteoporosis are common and will increase in number in an aging population, putting a substantial strain on health care. Selected patients may benefit from stabilizing the fracture with cement through BKP, a minimally invasive procedure. BKP has been reported to give good short-time clinical results, and economic modeling has suggested that the procedure could be cost-effective after 2 years compared with standard treatment. Methods. Hospitalized patients with back pain due to VCF were randomized to BKP or to control using a computer-generated random list. All costs associated with VCF and cost-effectiveness were reported primarily from the perspective of society. We used EQ-5D to assess quality of life (QoL). The accumulated quality-adjusted life years (QALYs) gained and costs/QALY gained were assessed using intention to treat. Results. Between February 2003 and December 2005, a total of 63 out of 67 Swedish patients were analyzed: BKP (n = 32) and control (n = 31). Societal cost per patient for BKP was SEK 160,017 (SD = 151,083) = (sic)16,668 (SD = 15,735), and for control SEK 84,816 (SD = - 40,954) = (sic) 8835 (SD = 4266), a significant difference of 75,198 (95% confidence intervals [CI] = 16,037-120,104) = (sic)7833 (95% CI = 1671-12,511). The accumulated difference in QALYs was 0.085 (95% CI = -0.132 to 0.306) in favor of BKP. Cost/QALY gained using BKP was SEK 884,682 = (sic)92,154 and US (sic)134,043. Conclusion. In this randomized controlled trial, it was not possible to demonstrate that BKP was cost-effective compared with standard medical treatment in patients treated for an acute/subacute vertebral fracture due to osteoporosis. However, sensitivity analysis indicated a certain degree of uncertainty, which needs to be considered.
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| 5. |
- Fritzell, Peter, et al.
(författare)
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Cost effectiveness of disc prosthesis versus lumbar fusion in patients with chronic low back pain: randomized controlled trial with 2-year follow-up :
- 2011
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Ingår i: European spine journal. - : Springer. - 0940-6719 .- 1432-0932. ; 20:7, s. 1001-1011
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Tidskriftsartikel (refereegranskat)abstract
- When low back pain becomes chronic, surgery is sometimes performed. The gold standard today is lumbar fusion (FUS), using a variety of procedures. Total disc replacement (TDR) aimed at motion preservation is increasing in popularity. This randomized controlled health economic study assesses the cost-effectiveness of TDR (Charité/Prodisc/Maverick) compared with instrumented FUS (posterior lumbar fusion (PLF)/posterior lumbar interbody fusion (PLIF). Social and healthcare perspectives after two years are reported. In all, 152 patients were randomized to either TDR (n=80) or FUS (n=72). Cost to society, (total mean cost/patient, Swedish kronor=SEK, standard deviation) for TDR was SEK 599,560 (400,272), and for FUS SEK 685,919 (422,903) (ns). TDR was significantly less costly from a healthcare perspective, SEK 22,996 (43,055- -1,202). Number of days on sick leave among those who returned to work was 185 (146) in the TDR group, and 252 (189) in the FUS group (ns). Using EQ-5D, the total gain in quality adjusted life years (QALYs) over two years was 0.41 units for TDR and 0.40 units for FUS (ns). Based on EQ-5D, the incremental cost effectiveness ratio (ICER) of using TDR instead of FUS was difficult to analyze due to the “non-difference” in treatment outcome, which is why cost/QALY could not be defined. Using cost-effectiveness probabilistic analysis, the net benefit with CI) was found to be SEK 91,359 (-73,643 – 249,114) (ns). Conclusion: It is not possible to state whether TDR or FUS is more cost-effective after two years. Since disc replacement and lumbar fusion are based on different conceptual approaches, it is important to follow these results over time.
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| 6. |
- Fritzell, Sara, et al.
(författare)
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IFNγ in combination with IL-7 enhances immunotherapy in two rat glioma models.
- 2013
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 258:1-2, s. 91-95
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Tidskriftsartikel (refereegranskat)abstract
- Peripheral immunization, using a combination of interferon-gamma (IFNγ)- and interleukin-7 (IL-7)-producing tumor cells, eradicated 75% of pre-established intracerebral N32 rat glioma tumors, and prolonged survival in the more aggressive RG2 model. Rats immunized with IFNγ- and IL7-transduced N32 cells displayed increases in IFNγ plasma levels and proliferating circulating T cells when compared with rats immunized with N32-wild type cells. Following irradiation, the expression of MHC I and II was high on N32-IFNγ cells, but low on RG2-IFNγ cells. In conclusion, IFNγ and IL-7 immunizations prolong survival in two rat glioma models.
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| 7. |
- Fritzell, Sara, et al.
(författare)
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Intratumoral temozolomide synergizes with immunotherapy in a T cell-dependent fashion.
- 2013
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Ingår i: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 62:9, s. 1463-1474
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Tidskriftsartikel (refereegranskat)abstract
- Despite temozolomide (TMZ) treatment, the prognosis for patients with glioblastoma multiforme is still dismal. As dose escalation of TMZ is limited by systemic toxicity, intratumoral delivery emerges as an attractive treatment modality, which may sustain cytotoxic drug concentrations intratumorally and induce immunogenic cell death. Both clinical and experimental gliomas have responded to immunotherapy, but the benefit of simultaneous chemo- and immunotherapy is inadequately studied. Here, we monitored survival of GL261-bearing C57BL/6 mice following a 3-day treatment with either intratumoral TMZ (micro-osmotic pump, 4.2 mg/kg/day) or systemic TMZ (i.p. injections, 50 mg/kg/day) alone, or combined with immunization using GM-CSF secreting GL261 cells. Peripheral and intratumoral leukocytes were analyzed by flow cytometry and immunohistochemistry. Intratumoral TMZ induced higher survival rate than systemic TMZ (45 vs. 8 %). When T cells were depleted following intratumoral TMZ, the therapeutic effect was completely abrogated (0 % survival). Intratumoral TMZ synergistically increased survival rate of immunized mice (from 25 to 83 %), while systemic TMZ failed (0 %). While systemic TMZ induced a transient leukopenia, intratumoral TMZ and immunotherapy sustained the proliferation of CD8(+) T cells and decreased the number of intratumoral immunosuppressive cells. In conclusion, intratumoral TMZ alone or in combination with immunotherapy could cure glioma-bearing mice, due to attenuation of local immunosuppression and increase in potential effector immune cells.
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| 8. |
- Stromqvist, Bjorn, et al.
(författare)
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Swespine : the Swedish spine register
- 2013
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Ingår i: European spine journal. - : Springer Science and Business Media LLC. - 0940-6719 .- 1432-0932. ; 22:4, s. 953-974
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Tidskriftsartikel (refereegranskat)abstract
- Swespine, the Swedish National Spine Register, has existed for 20 years and is in general use within the country since over 10 years regarding degenerative lumbar spine disorders. Today there are protocols for registering all disorders of the entire spinal column. Patient-based pre- and postoperative questionnaires, completed before surgery and at 1, 2, 5 and 10 years postoperatively. Among patient-based data are VAS pain, ODI, SF-36 and EQ-5D. Postoperatively evaluation of leg and back pain as compared to preoperatively ("global assessment"), overall satisfaction with outcome and working conditions are registered in addition to the same parameters as preoperatively evaluation. A yearly report is produced including an analytic part of a certain topic, in this issue disc prosthesis surgery. More than 75,000 surgically treated patients are registered to date with an increasing number yearly. The present report includes 7,285 patients; 1-, 2- and 5-year follow-up data of previously operated patients are also included for lumbar disorders as well as for disc prosthesis surgery. For the degenerative lumbar spine disorders (disc herniation, spinal stenosis, spondylolisthesis and DDD) significant improvements are seen in all aspects as exemplified by pronounced improvement regarding EQ-5D and ODI. Results seem to be stable over time. Spinal stenosis is the most common indication for spine surgery. Disc prosthesis surgery yields results on a par with fusion surgery in disc degenerative pain. The utility of spine surgery is well documented by the results. Results of spine surgery as documented on a national basis can be utilized for quality assurance and quality improvement as well as for research purposes, documenting changes over time and bench marking when introducing new surgical techniques. A basis for international comparisons is also laid.
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| 9. |
- Ströjby, Salina, et al.
(författare)
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Intratumorally implanted mesenchymal stromal cells potentiate peripheral immunotherapy against malignant rat gliomas.
- 2014
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 274:1-2, s. 240-243
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Tidskriftsartikel (refereegranskat)abstract
- Bone marrow-derived mesenchymal stromal cells (MSCs) target glioma extensions and micro-satellites efficiently when implanted intratumorally. Here, we report that intratumoral implantation of MSCs and peripheral immunotherapy with interferon-gamma (IFNγ) producing tumor cells improve the survival of glioma-bearing rats (54% cure rate) compared to MSC alone (0% cure rate) or immunotherapy alone (21% cure rate) by enforcing an intratumoral CD8(+) T cell response. Further analysis revealed that the MSCs up-regulate MHC classes I and II in response to IFNγ treatment in vitro and secrete low amounts of immunosuppressive molecules prostaglandin E2 and interleukin-10.
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| 10. |
- Strömqvist, Björn, et al.
(författare)
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Swespine: the Swedish spine register : The 2012 report.
- 2013
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Ingår i: European Spine Journal. - : Springer Science and Business Media LLC. - 0940-6719 .- 1432-0932. ; 22:4, s. 953-974
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Tidskriftsartikel (refereegranskat)abstract
- Swespine, the Swedish National Spine Register, has existed for 20 years and is in general use within the country since over 10 years regarding degenerative lumbar spine disorders. Today there are protocols for registering all disorders of the entire spinal column.
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