| 1. |
- Bill-Axelson, Anna, et al.
(författare)
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Radical prostatectomy versus watchful waiting in localized prostate cancer : the Scandinavian prostate cancer group-4 randomized trial
- 2008
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:16, s. 1144-1154
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up.METHODS: From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided.RESULTS: During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001).CONCLUSION: Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery.
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| 2. |
- Carlsson, Jörgen, et al.
(författare)
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EGFR-expression in primary urinary bladder cancer and corresponding metastases and the relation to HER2-expression. On the possibility to target these receptors with radionuclides
- 2015
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Ingår i: Radiology and Oncology. - : Walter de Gruyter GmbH. - 1318-2099 .- 1581-3207. ; 49:1, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- Background. There is limited effect of tyrosine kinase inhibitors or "naked" antibodies binding EGFR or HER2 for therapy of metastasized urinary bladder canter and these methods are therefore not routinely used. Targeting radionuclides to the extracellular domain of the receptors is potentially a better possibility. Methods. EGFR- and HER2-expression was analyzed for primary tumors and corresponding metastases from 72 patients using immunohistochemistry and the internationally recommended HercepTest. Intracellular mutations were not analyzed since only the receptors were considered as targets and intracellular abnormalities should have minor effect on radiation dose. Results. EGFR was positive in 71% of the primary tumors and 69% of corresponding metastases. Local and distant metastases were EGFR-positive in 75% and 66% of the cases, respectively. The expression frequency of HER2 in related lesions was slightly higher (data from previous study). The EGFR-positive tumors expressed EGFR in metastases in 86% of the cases. The co-expression of EGFR and HER2 was 57% for tumors and 53% for metastases. Only 3% and 10% of the lesions were negative for both receptors in tumors and metastases, respectively. Thus, targeting these receptors with radionuclides might be applied for most patients. Conclusions. At least one of the EGFR- or HER2-receptors was present in most cases and co-expressed in more than half the cases. It is therefore interesting to deliver radionuclides for whole-body receptor-analysis, dosimetry and therapy. This can hopefully compensate for resistance to other therapies and more patients can hopefully be treated with curative instead of palliative intention.
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| 3. |
- Dyrskjøt, Lars, et al.
(författare)
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Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma : a multicenter validation study
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:12, s. 3545-3551
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Clinically useful molecular markers predicting the clinical course of patients diagnosed with non–muscle-invasive bladder cancer are needed to improve treatment outcome. Here, we validated four previously reported gene expression signatures for molecular diagnosis of disease stage and carcinoma in situ (CIS) and for predicting disease recurrence and progression. Experimental Design: We analyzed tumors from 404 patients diagnosed with bladder cancer in hospitals in Denmark, Sweden, England, Spain, and France using custom microarrays. Molecular classifications were compared with pathologic diagnosis and clinical outcome. Results: Classification of disease stage using a 52-gene classifier was found to be highly significantly correlated with pathologic stage (P < 0.001). Furthermore, the classifier added information regarding disease progression of Ta or T1 tumors (P < 0.001). The molecular 88-gene progression classifier was highly significantly correlated with progression-free survival (P < 0.001) and cancer-specific survival (P = 0.001). Multivariate Cox regression analysis showed the progression classifier to be an independently significant variable associated with disease progression after adjustment for age, sex, stage, grade, and treatment (hazard ratio, 2.3; P = 0.007). The diagnosis of CIS using a 68-gene classifier showed a highly significant correlation with histopathologic CIS diagnosis (odds ratio, 5.8; P < 0.001) in multivariate logistic regression analysis. Conclusion: This multicenter validation study confirms in an independent series the clinical utility of molecular classifiers to predict the outcome of patients initially diagnosed with non–muscle-invasive bladder cancer. This information may be useful to better guide patient treatment.
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| 4. |
- Gullbo, Joachim, et al.
(författare)
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Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo.
- 2004
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Ingår i: Investigational new drugs. - 0167-6997. ; 22:4, s. 411-20
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Tidskriftsartikel (refereegranskat)abstract
- The novel alkylating dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) was evaluated for acute toxicity and antitumor activity in mice, with melphalan as a reference. To determine a safe and tolerable dose for efficacy studies the acute toxicity following intravenous injection in the tail vein was monitored using a 14-day schedule with up to four doses. The highest tested dose, 25 micromoles/kg, was considered close to this level, with minor effects on body weight gain but significant effects on hematological parameters. Melphalan and J1 appeared equitoxic with no statistically significant differences. Subsequently a mouse hollow fiber model was employed with subcutaneous implantation of fibers containing human tumor cells. Three different human tumor cell lines as well as two samples of primary human tumor cells (ovarian carcinoma and chronic lymphatic leukemia) were used as tumor models. At the dose level tested there was a marked and statistically significant decrease in both T-cell leukemia CCRF-CEM and small cell lung cancer NCI-H69 tumor cell growth and viability in response to J1 as compared with both placebo and melphalan treated groups. In primary ovarian carcinoma cells only J1 treatment resulted in significant tumor regression (net cell kill). In summary the results indicate that, despite an expected short half time in the blood circulation, the promising in vitro data from the previous studies of J1 seems translatable into the in vivo situation. At equal doses of alkylating units J1, compared to melphalan, was more active in the mouse hollow-fiber model, but showed similar general toxicity.
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| 5. |
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| 6. |
- Gårdmark, Truls, et al.
(författare)
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Analysis of HER2 expression in primary urinary bladder carcinoma and corresponding metastases
- 2005
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Ingår i: BJU International. - 1464-4096 .- 1464-410X. ; 95:7, s. 982-986
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate the expression of HER2 receptors (previously reported to be over-expressed in malignant urothelium) in both primary tumours and metastases of transitional cell cancer, using two different staining methods and two different scoring techniques, considering the potential use of these receptors as targets for planned systemic anti-HER2 nuclide-based treatment. MATERIALS AND METHODS: HER2 expression was evaluated with two different immunohistochemical methods in 90 patients with primary urinary bladder cancer tumours and corresponding metastases. Sections were first stained with the commercially available breast cancer test kit (HercepTest, Dako, Glostrup, Denmark). Parallel sections were then stained with a modified HercepTest procedure. Two different evaluation criteria were compared; the HercepTest score that requires > or = 10% stained tumour cells (as for breast cancer) and a proposed 'Target score' that requires > 67% stained tumour cells. The latter score is assumed to be preferable for HER2-targeted radionuclide therapy. RESULTS: Using the HercepTest kit, the Target score gave lower fractions of positive primary tumours and metastases than the HercepTest score. The modified HercepTest staining procedure and Target score gave high HER2 values in 80% of primary tumours and 62% of metastases, which is considerably more than that obtained with the HercepTest staining and score. There was a significant decrease in HER2 positivity with increasing distance from the primary tumour. In nine sentinel-node metastases assessed, all but one were HER2-positive. Considering all regional metastases, 74% were positive, and of distant metastases, 47%; 72% of the patients with positive primary tumours also expressed HER2 in their metastases. CONCLUSIONS: When combining the modified HercepTest with customised evaluation criteria, more HER2-positive tumours were diagnosed. The degree of HER2 down-regulation was significantly higher in distant than in regional metastases. HER2-targeted therapy may be an alternative or complementary to other methods in the future treatment of metastatic urinary bladder carcinoma.
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| 7. |
- Hassan, Saadia Bashir, et al.
(författare)
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A hollow fiber model for in vitro studies of cytotoxic compounds : Activity of the cyanoguanidine CHS 828
- 2001
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 12:1, s. 33-42
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Tidskriftsartikel (refereegranskat)abstract
- The hollow fiber assay is currently used as an in vivo model for anticancer drug screening in nude mice, but it can also be used as an in vitro model. In the current study, an in vitro hollow fiber model was used to study the effect and mode of induced cell death of a new cyanoguanidine, CHS 828. Human leukemia, adenocarcinoma and lymphoma cell lines as well as primary cultures of human tumor cells from patients with chronic lymphocytic leukemia (CLL) and ovarian cancer (OC) and normal human lymphocytes were cultured in semipermeable hollow fibers. The fibers were incubated for 3 or 14 days prior to CHS 828 exposure for 72 h, followed by determination of living cell density by MTT staining. For cell morphology, using harvested cultures on cytospin slides had technical advantages compared to using paraffin sections of the formalin-fixed fibers. CHS 828 showed higher antitumor activity on CLL and normal human lymphocyte cultures compared to OC cultures, and cell lines cultured 3 days were more sensitive than those cultured 14 days. Morphological examination of CHS 828-treated cultures revealed a mixture of apoptosis and necrosis.
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| 8. |
- Hemdan, Tammer, et al.
(författare)
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Stathmin-1 is a promising prognostic factor and potential therapeutic target in urinary bladder cancer
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Aim: The oncoprotein 18/stathmin 1 (STMN1), involved in cell cycle progression and cell migration, has been reported to be expressed in several types of cancer, and is associated with clinical outcome in e.g. breast and liver cancer. The aims in this study were to investigate the clinical significance of STMN1 and to examine if STMN1 might be a possible therapeutic target in urinary bladder cancer.Experimental design: Immunohistochemical analyses of STMN1 protein expression were performed in a wide-range tissue microarray (115 Ta-, 115 T1-, 112 T2-4-tumors) and in a metastatic primary tumor/matched metastasis-material (90 patients). In the T24 cell line, the effect of STMN1 on cell proliferation was evaluated by inhibiting the cellular expression of STMN using STMN1-siRNA.Results: Patients with T1- or muscle-invasive disease exhibiting high expression of the STMN1 protein had a poorer overall survival (OS) and disease specific survival (DSS). In a multivariate analysis adjusting for stage, age and gender the results were for T2-T4 patients: OS (HR=1.77 95% CI 1.02-3.07; p=0.04) and DSS (HR=2.04 95% CI 1.13-3.68; p=0.02); for T1-4 patients: DSS (HR=1.83 95% CI 1.09-3.08; p=0.02). In the metastatic bladder cancer material, the majority of the patients with one metastasis (69%) and with several matched metastases (70%) were STMN1-positive in both the primary tumor and the matched metastases. Moreover, the ability of the urinary bladder cancer cell line to grow was significantly reduced after 72 hours (p<0.0001) when transfecting the cells with a siRNA targeting STMN1.Conclusion: Our results suggest that STMN1 protein-expression has a potential both as a prognostic marker and a novel treatment target in urinary bladder cancer.
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| 9. |
- Koliadi, Anthoula, et al.
(författare)
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Cyclin B is an immunohistochemical proliferation marker which can predict for breast cancer death in low-risk node negative breast cancer
- 2010
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 49:6, s. 816-820
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Tidskriftsartikel (refereegranskat)abstract
- Patients with low-risk node negative breast cancer have an excellent prognosis with 5% breast cancer mortality at 10 years. However, prognostic factors are needed to identify poor prognostic patients who might benefit from adjuvant systemic therapy. Proliferation has been identified as the most important component of gene expression profiles. Cyclin B is a proliferative marker easily assessed by immunohistochemistry. We wanted to examine cyclin B as a prognostic factor in low-risk breast cancer patients. Patients and methods. Using an experimental study design, we compared women dying early from their breast cancer (n=17) with women free from relapse more than eight years after initial diagnosis (n=24). All women had stage I, node negative and hormone receptor positive disease. None had received adjuvant chemotherapy. Tumor samples were immunostained for cyclin B using commercial antibodies. Results. The mean percentage of cyclin B (12%) was significantly higher (p=0.001) in women dying from their breast cancer compared with women free from relapse ( 5%). High cyclin B (>= 9%) identified 11/17 patients dying from breast cancer and low cyclin B identified 22/24 patients free from relapse. The sensitivity and specificity of cyclin B was 65% and 92%, respectively. Discussion. We found that low-risk node negative patients with high expression of cylin B had a significantly worse outcome than patients with low expression of cyclin B. Cyclin B could separate patients with poor survival from those with good survival with 80% accuracy. We suggest that cyclin B might be a potent prognostic factor in this low-risk patient group.
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| 10. |
- Lindén, Mårten, et al.
(författare)
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Galectin-1, a potential therapeutic target, in primary tumors and metastases of urinary bladder carcinomas
- 2013
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Urinary bladder cancer would gain from new protein biomarkers due to the heterogeneity of disease. The beta-galactoside-binding protein (GAL1) is one such candidate and in present study its prognostic value and expression at protein level in metastatic bladder cancer-disease, have been evaluated. The protein expression of GAL1 was investigated by immunohistochemistry in two tumor cohorts, one with primary tumors of different stage and grade (n=344) and another with primary tumors matched with metastases (n=90). The expression in the actual cancer cells as well as in stroma and blood vessels were considered since the presence of GAL1 in different tissue compartments has shown cancer relevance. The cellular expression increased with increased tumor stage and grade (p<0.001). For the majority of the patients, cells from both primary tumor and metastasis showed a positive immunoreactivity for GAL1 (91% (n=64) for primary tumors with single metastasis (n=70) and 100% (n=20) for primary tumors with multiple metastasis (n=20). Further, strong immunoreactivity in T1 tumor cells correlated with lower risk of recurrence (p<0.05). Both tumors and metastasis exhibited strong stromal-GAL1 staining that could not be correlated with clinical parameters. The expression in vessels showed that T1 tumors surrounded by GAL1 negative blood vessels had a higher risk of progression (p<0.0001) into muscle invasive T2-4 stages. The results show that GAL1 is an important bladder cancer-protein from several aspects. Further, GAL1 is a promising therapeutic target in bladder cancer due to the general expression in advanced disease.
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