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- Bylund, Annika, 1954-
(författare)
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Phytoestrogens and prostate cancer : experimental, clinical, and epidemiological studies
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dietary factors may affect development and progression of prostate cancer. Experimental and epidemiological studies have suggested an effect of phytoestrogens on prostate cancer. Lignans are the predominant phytoestrogen in a Western diet. The effects of a diet rich in phytoestrogens and in particular lignans, as compared to a control diet, were assessed in several prostate cancer models. In paper I, 70 athymic nude mice with transplanted subcutaneous LNCaP tumours, an androgen sensitive human prostate cancer cell line, were fed one out of six phytoestrogen rich diets or a control diet after tumour injection. The rye diet, with high lignan content, decreased tumour take and growth, decreased secretion of prostate specific antigen and increased apoptosis. Addition of fat to the rye diet decreased the beneficial effects. In paper II, transgenic mice designed to develop prostate cancer (TRAMP) were fed rye bran or a control diet from the age of four weeks. Rye bran decreased prostate epithelial cell volume by 20%, and increased cell apoptosis by 31% as compared to the control diet. In paper III, we examined the effects of 7-hydroxymatairesinol (HMR), a purified lignan, in nude mice with subcutaneous LNCaP tumours in two different concentrations as compared to a control diet. Mice on the HMR diets had a reduced tumour take rate, lower total tumour volume, increased proportion of non-growing tumours, and increased apoptosis as compared to the control diet. Paper IV was a three week intervention study exploring the effects of rye bran bread vs. a control diet in men with prostate cancer. The men in the rye group had increased levels of plasma enterolactone and in biopsies from the prostate after the intervention an increase in apoptosis was observed in comparison with biopsies obtained before the intervention. In paper V, we examined the association between plasma levels of enterolactone, and risk of prostate cancer in a nested case control study. In the Northern Sweden Health and Disease Cohort, enterolactone concentrations were measured in plasma obtained at a mean time of 5 years before diagnosis from 265 cases of prostate cancer, and from 525 matched controls. We found no significant association between plasma enterolactone and risk of prostate cancer. Men with very low enterolactone levels (bottom decile) however, had significantly higher risk of prostate cancer. Phytoestrogen rich diet including soy, rye bran, substances purified from rye, and a purified lignan (HMR) all inhibited prostate tumour growth. However, it cannot be concluded that the effects observed were due solely to lignans as other components in rye grain such as tannins, phytic acid, ferulic acid, vitamins and minerals may have contributed to the beneficial effects. Thus, additional studies are needed to further elucidate the effects of phytoestrogens on prostate cancer development and progression.
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- Fant, Federica, et al.
(författare)
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Early perioperative immunological effects of anesthesia and analgesia in patients undergoing prostate cancer surgery
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background:Clinical studies in humans as well as experimental evidence from animal studiessuggests that the immune system plays an important role in perioperative metastases following cancer surgery. However, the precise role of the different components of the immune system in this process appears conflicting. Our primary aim was to assess T cell activity and natural killer (NK) cell toxicity in patients undergoing prostate cancer surgery and randomized to epidural or intravenous analgesia.Methods:26 patients were randomized to receive general anaesthesia and patient controlled analgesia (PCA) with morphine postoperatively (Group P) or combined, general and epidural anaestesia with patient-controlled thoracic epidural analgesia postoperatively (Group E). Blood sample were obtained perioperatively at different time points for analyses of: subpopulations of leukocytes, cell- ediated immune response after mitogen stimulation, NK cell cytotoxicity, vascular endothelial growth factor (VEGF), IFN-g/IL-10 ratio, C-reactive protein (CRP) and white blood cell (WBC) count. In addition, pain and morphine consumtion were also determined.Results: T lymphocytes decreased more in Group P compared to Group E at 24 hours postoperatively while T-helper lymphocytes decreased more in Group E compared to Group P at the same time point without reaching statistically significant difference.No differences were seen in NK cells or cytotoxic T lymphocytes between the groups. The CD4+/CD8+ ratio remained constant between the groups over time. Natural Killer Cell cytotoxicity did not show statistically significant differences between the groups at the different postoperative time points. No other differences ere found between the groups except in pain intensity which was lower in Group E, and morphine consumption which was greater in Group P. Conclusions:Our findings suggest that regional anaesthesia and analgesia appears to play a minor role in immunomodulation following surgery for prostate cancer. If regional anesthesia does prevent tumour growth or metastases perioperatively, the mechanism for this needs to be further elucidated.
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- Fant, Federica, 1972-
(författare)
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Optimization of the perioperative anaesthetic care for prostate cancer surgery : clinical studies on pain, stress response and immunomodulation
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer (PC) is the most common cancer form in men. Surgery is the treatment of choice for localized form of PC and half of all surgical procedures are radical retropubic prostatectomies (RRP). In the first two studies, we compared the efficacy of thoracic epidural analgesia to patientcontrolled analgesia (PCA) with intravenous morphine (I) and to patientcontrolled local analgesia by intra-abdominal injection of local anaesthetic(LA) (II) in treating postoperative pain after RRP. In studies III and IV we evaluated the effects of thoracic epidural analgesia compared to PCA with morphine in reducing the surgical stress reaction, inflammatory response (III) as well as the immune suppression (IV) following RRP. In studies I and II, we found better pain relief both at rest and on coughing, lower morphine consumption and better respiratory function postoperatively in patients having epidural analgesia. However, we did not register differences in time to home readiness or length of hospital stay. Painmanagement did not significantly affect health-related quality of life. In study III, early surgical stress response (plasma glucose and cortisol) was reduced two hours after the skin incision in patients having epidural analgesia compared with those having intravenous morphine analgesia but no differences in inflammatory mediators were seen except IL-17 which was lower in the epidural group. In study IV, no differences were found between epidural and PCA groups in leucocyte subpopulations, immunecell activation after mitogen stimulation or in natural killer cell cytotoxicityas a measure of innate immunity. We observed a low incidence of side effects and postoperative complications in all studies with no differences between the groups. In summary, thoracic epidural analgesia provided better postoperative pain relief, improved respiratory function and reduction in early stress response to radical retropubic prostatectomy, without any significant effects on inflammation or immune suppression.
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- Fant, Federica, et al.
(författare)
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Thoracic epidural analgesia inhibits the neuro-hormonal but not the acute inflammatory stress response following radical retropubic prostatectomy
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Epidural anesthesia and analgesia has been shown to suppress the neurohormonalstress response in certain types of surgery, but its role in the inflammatory responseto surgery is unclear. The primary aim of this study was to assess whether the choice ofanalgesic technique influences these processes in patients undergoing radical retropubicprostatectomy (RRP).Method: 26 patients undergoing RRP were randomized to Group P (systemic opioid-basedanalgesia) or Group E (thoracic epidural-based analgesia) perioperatively. Induction andmaintenance of anesthesia in both groups followed a standardized protocol. The followingmeasurements were made perioperatively : plasma cortisol, glucose, insulin, plasma cytokines(IL-6, TNF-a) and pokeweed mitogen-stimulated cytokines (IFN-g, IL-2, IL-12p70, IL-10,IL-4, and IL-17), C-reactive proteins and leucocyte count. Other parameters recordedincluded pain, morphine consumption and perioperative complications during 72 hours.Results: Plasma concentration of cortisol and glucose were significantly higher in Group Pcompared to Group E at the end of surgery with a mean difference between groups of 232nmol/L (95% CI 84-381) (P=0.004) and 1.6 mmol/L (95% CI 0.6-2.5) (P=0.003) respectively.No significant differences were seen in any plasma cytokine except IL-17, which was higherin Group P compared with Group E, both at 24 h (P< 0.001) and 72 h (P=0.018)postoperatively. Significantly higher pain intensity was seen up to 24 hours postoperatively inGroup P compared to Group E (p < 0.05).Conclusion: Thoracic epidural analgesia reduces the early postoperative stress response butnot the acute inflammatory response to radical retrobupic prostatectomy suggesting that otherpathways are involved during the acute phase reaction.
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- Fiorentino, M., et al.
(författare)
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Immunohistochemical Expression of BRCA1 in Prostate Cancer
- 2009
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Ingår i: Laboratory Investigation. - : Nature Publishing Group. - 0023-6837 .- 1530-0307. ; 22, s. 169A-169A
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: BRCA1 is a multifunctional protein involved in DNA repair, gene transcription and the regulation of cell-cycle check-points. While germline mutations of BRCA1 are rare in prostate cancer and seem to play a limited role in tumor susceptibility, BRCA1 expression has not been investigated to date.Design: We analyzed the immunohistochemical expression of BRCA1 in paraffin embedded samples from 524 men with prostate cancer belonging to the Physicians’ Health Study and the Swedish Watchful Waiting cohorts of prostate cancer patients. High density tissue micro-arrays (TMA) including at least three tumor cores for each case were utilized for the immunohistochemical staining with the monoclonal MS110 antibody specific for the N-terminus of the 220 kDa BRCA1 protein. Cases were scored as negative or positive for BRCA1 immunostaining. The Ki67 proliferation index was also assessed on the same TMAs and evaluated by quantitative image analysis.Results: A positive nuclear immunostaining for BRCA1 was revealed in 62 of 524 (11.9%) patients while normal prostate control cores were all negative. BRCA1 positive tumors were associated with 4 times greater proliferation rate compared to BRCA1 negative tumors (p ∼ 0.0003). In addition, we found a linear trend such that tumors with greater number of TMA cores expressing BRCA1 had stronger extent of proliferation. Men with BRCA1 positive tumors had a slightly higher Gleason’s score (mean 7.5) compared to those negative for BRCA1 (mean 7) No significant correlation was found between BRCA1 staining and cancer-specific death.Conclusions: BRCA1 protein is expressed in a small subset of prostate cancers characterized by high proliferation index but not in normal prostate tissue. Expression of BRCA1 might be acquired in selected tumors to prevent DNA damage in actively replicating cells. A different role independent of germline mutations might be disclosed for BRCA1 as cell cycle regulator in prostate cancer.
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- Svensson, Maria A., et al.
(författare)
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A comparative study of ERG status assessment on DNA-, mRNA-, and proteinlevels using unique samples from a Swedish biopsy cohort
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The ERG rearrangement is identified in approximately 50% of prostate cancer (PCa) screened cohorts and is known to be highly specific. This genetic aberration, most commonly leading to the TMPRSS2-ERG fusion, but also SLC45A3-ERG or NDRG1- ERG fusions, all leading to an over expression of a truncated ERG protein. Most studies have applied in situ hybridization (FISH) methods or mRNA based assays to investigate the ERG status. Recently, studies showed that ERG protein levels assessed by ERG antibodies can be used as a surrogate marker for ERG rearrangement. In the current study we investigate ERG status on a series of diagnostic biopsies using DNA-, mRNA- and protein based assays. We formally compare three assay results (i.e. FISH, fusion mRNA and immunohistochemistry) to identify which method could be most appropriate to use when having limited amount of tissue. ERG rearrangement was found in 56% of the cases. Comparing ERG rearrangement status by FISH with ERG over expression and TMPRSS2-ERG fusion transcript we found 95.1% (154/162, Fisher’s exact test 9.50E-36) and 85.2% (138/162, Fisher’s exact test 7.26E-22) concordance, respectively. We show that the ERG antibody highly correlates with the ERG rearrangement with high sensitivity and specificity. We also identified the most common TMPRSS2-ERG isoform in the majority of ERG rearranged cases. These results provide compelling evidence that the ERG antibody can be used to further investigate the role of ERG in PCa.
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