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- Axcrona, Karol, et al.
(författare)
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Androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer: degarelix vs goserelin plus bicalutamide.
- 2012
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Ingår i: BJU international. - 1464-410X. ; 110:11, s. 1721-1728
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Tidskriftsartikel (refereegranskat)abstract
- Study Type - Therapy (RCT) Level of Evidence1b What's known on the subject? and What does the study add? Androgen deprivation therapy (ADT) is commonly used as a primary treatment for patients with prostate cancer (PCa) who are not eligible for radical treatment options. ADT is also used in patients with PCa as neo-adjuvant hormone therapy to reduce prostate volume and down-stage the disease before radiotherapy with curative intent. The present study showed that ADT with the gonadotropin hormone-releasing hormone (GhRH) antagonist degarelix is non-inferior to combined treatment with the LHRH agonist goserelin and bicalutamide in terms of reducing prostate volume during the treatment period of 3 months. Degarelix treatment evokes, however, significantly better relief of lower urinary tract symptoms in patients having moderate and severe voiding problems. OBJECTIVE: • To assess the efficacy of monthly degarelix treatment for reduction of total prostate volume (TPV), relief of lower urinary tract symptoms (LUTS) and improvement of quality of life (QoL) in patients with prostate cancer (PCa) using monthly goserelin as active control. METHODS: • This was a randomized, parallel-arm, active-controlled, open-label, multicentre trial on 182 patients treated with either monthly degarelix (240/80mg) or goserelin (3.6mg) for 12 weeks. • For flare protection, goserelin-treated patients also received daily bicalutamide (50mg) during the initial 28 days. • Key trial variables monitored monthly were TPV (primary endpoint), serum testosterone, prostate-specific antigen (PSA), the International Prostate Symptom Score (IPSS) and the Benign Prostate Hyperplasia Impact Index. RESULTS: • In all, 175 patients completed the trial (96.1%). • At week 12, changes in TPV for degarelix and goserelin were similar (-37.2% vs -39.0%) and met the predefined non-inferiority criterion. • Decreases in IPSS were greater in degarelix than in goserelin-treated patients, differences being statistically significant in patients with baseline IPSS > 13 (-6.7 ± 1.8 vs -4.0 ± 1.0; P= 0.02). • The number of patients with an IPSS change of ≥3 over baseline was also significantly higher in patients treated with degarelix (61.0 vs 44.3%, P= 0.02). • Both treatments were safe and well tolerated. CONCLUSIONS: • Medical castration reduces TPV and could also improve LUTS in patients with PCa. • While the short-term efficacy of degarelix and goserelin + bicalutamide was the same in terms of TPV reduction, degarelix showed superiority in LUTS relief in symptomatic patients, which could highlight the different actions of these drugs on extrapituitary gonadotrophin-releasing hormone (GnRH) receptors in the bladder and/or the prostate.
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- Axcrona, Karol
(författare)
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B cell activation in vitro: thymus-dependent immune responses and bacterial cell surface proteins
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis aspects of peripheral B lymphocyte differentiation were studied. Through in vitro experiments, B lymphocyte activation was assessed. B lymphocytes express immunoglobulin (Ig) specific for a certain antigen on the cell surface, and when surface Ig is crosslinked by an antigen, the cell is activated. Antigens giving rise to a T cell dependent immune response are internalized by the B cell, degraded, and presented on MHC II. In order to differentiate, an activated B cell has to interact with a T cell bearing a T cell receptor specific for the same antigen. During B cell/T cell interaction a crosstalk mediated by cell surface molecules is initiated. For example, the CD40/CD40 ligand (CD40L) receptor interaction plays a critical role in B cell activation; genetically engineered animals deficient for either the CD40L or CD40, lack germinal centres, Ig switch and immunological memory. When B cells were activated with anti-CD40 monoclonal antibodies (mAbs) together with anti-CD21 mAbs coupled to Sepharose differentiation to Ig secretion was detected. Addition of anti-CD40 mAbs to lipopolysaccharide (LPS) stimulated B cells was, however, shown to inhibit B cell differentiation in the same manner as addition of anti-Ig mAbs to LPS treated cultures. Further, B cells prestimulated with anti-CD40 were shown to undergo apoptosis when restimulated with anti-Ig. Because of the pivotal role of the CD40L/CD40 interaction in T cell dependent immune responses, the CD40L promoter was analyzed. The CD40L promoter and deletants of that promoter were cloned into an expression vector containing the structural gene for luciferase, as a reporter gene. Upon transient transfection into Jurkat T cells CD40L promoter function was shown to be dependent on signaling via the T cell receptor and CD28. A 270 bp region upstream of the translational start was shown to suffice for full promoter activity. A putative CD28 responsive DNA element distinct from the one in the IL-2 promoter was identified. Streptococcal Ig-binding surface proteins L, M1, and H were shown to bind various cells of the hematopoetic lineage; proteins L and H coupled to Sepharose induced B cell proliferation, whereas protein H coupled to Sepharose also induced B cell differentiation. Soluble protein H was shown to be taken up by T and B cells and transported to the nucleus. Protein H was found to interact with nucleophosmin/B23 (NPM), a protein previously shown to traffic from the cytoplasm to the nucleus, but which was isolated from a membrane preparation from Jurkat T cells. In the nucleus protein H was found to interact with hnRNP A2/B1 and the SET protein. Affinities of protein H with NPM and a nuclear extract prepared from Jurkat T cells were determined. Lastly, when murine B cells were stimulated with LPS, addition of protein H was shown to exert a cytostatic effect.
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- Frick, Inga-Maria, et al.
(författare)
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Uptake and intracellular transportation of a bacterial surface protein in lymphoid cells.
- 2002
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Ingår i: Molecular Microbiology. - : Wiley. - 1365-2958 .- 0950-382X. ; 44:4, s. 917-934
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Tidskriftsartikel (refereegranskat)abstract
- Some strains of the human pathogen Streptococcus pyogenes express a surface protein called protein H, which is released from the streptococcal surface by a cysteine proteinase produced by the bacteria. Here, we find that soluble protein H binds to the surface of lymphocytes and granulocytes, and that the molecule is taken up by lymphocytes and transported to the perinuclear region. The translocation over the cell membrane is rapid, and the uptake and intracellular transportation is not dependent on actin polymerization. Protein H could be immunoprecipitated from cell extracts and nuclear preparations of lymphocytes, and analysis of molecular interactions between pro-tein H and proteins of different cellular compart-ments demonstrated a binding to nucleophosmin/ B23, a protein known to shuttle between the cytoplasm and the nucleus, and to the nuclear proteins SET and hnRNP A2/B1. Nucleophosmin/B23 was co-immunoprecipitated with protein H from cell and nuclear extracts, and binding experiments, including kinetic analyses, suggest that protein H dissociating from nucleophosmin/B23 complexes in the perinuclear region or in the nucleus binds to proteins SET and hnRNP A2/B1. Finally, the uptake and intracellular transportation of protein H was found to result in a cytostatic effect on B and T lymphocytes.
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- Steinsvik, E Andreas Svaboe, et al.
(författare)
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Do perceptions of adverse events differ between patients and physicians? Findings from a randomized, controlled trial of radical treatment for prostate cancer
- 2010
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Ingår i: Journal of Urology. - : Elsevier. - 0022-5347 .- 1527-3792. ; 184:2, s. 525-531
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Previous cross-sectional studies show considerable discrepancies between patient and physician ratings of adverse events after prostate cancer treatment. We used data from a randomized, controlled trial to examine such discrepancies.MATERIAL AND METHODS: The Scandinavian Prostate Cancer Groups Study 7 randomized men with locally advanced prostate cancer to antiandrogen monotherapy or to the same hormone treatment combined with external beam radiotherapy after 3 months of total androgen blockade. We selected a subsample of 333 men with valid ratings at baseline, and at 12 and 24-month followup for this prospective substudy. We also examined a cross-sectional sample of 305 men at the end of radiotherapy. We compared patient and physician ratings of frequency of daytime and nighttime urination, urinary incontinence, erectile dysfunction, bowel problems, nausea/vomiting, breast tenderness and gynecomastia.RESULTS: Perfect agreement between patient and physician ratings was observed in 70% to 100% of cases at baseline, in 73% to 98% at 12 months and in 65% to 97% at 24 months. There were 1% to 20% changes in perfect agreement with time. With patient ratings as the gold standard physicians more often underrated than overrated adverse events, except bowel problems, which were overrated at all posttreatment points.CONCLUSIONS: In a randomized, controlled trial of external beam radiotherapy and hormone manipulation physicians recorded pelvis related adverse events in acceptable accordance with their patients with prostate cancer. The oncologist tendency to overestimate bowel problems after radiotherapy needs further investigation. Our positive findings from a formal trial should not be transferred to daily clinical practice without further studies of discrepancies in routine clinical practice.
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