| 51. |
- Nemes, Szilard, 1977
(författare)
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Integrative genomic and survival analysis of breast tumors
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- With the continued accumulation of genomic data at ever increasing resolution the challenge ahead lies in reading out meaningful clinical/biological information form the data that can contribute to a better understanding of the cancerous process. The need for novel approaches, new statistical methods is therefore strong. The present thesis aims to contribute to the field with three problem specific applications that that expectantly will aid researchers in a better understanding of genomic data. The first paper exemplifies the adaptation of a piecewise-linear regression framework to integrative analysis of DNA copy number aberrations and gene expression (mRNA) data. The methods allows it helps identify the association between copy number and gene expression but it takes a further step and allows detection of changing patterns and changepoints could serve as a proxy for the degree of genomic instability that causes disruptions in feedback-mechanisms. The second paper advocates the adaptation of a mediation analysis for a concomitant analysis of DNA copy number aberrations, mRNA and survival data. The paper offers ways of statistical inference by the means of Delta-method applicable concomitantly on a large number of genes. If a mediation effect is observed for a specific gene, we hypothesize that the specific gene is a driver gene. If no mediation effect is observed then possible associations between DNA copy number aberrations and the outcome are likely to indicate passenger genes. The third paper is a more applied/clinical work and using applied statistics identified a novel panel of 12-genes that can serve prognostic toll for breast cancer specific survival. The thesis concludes with a methodological description in which we describe an easy permutation based approach for testing the clonal origins of multiple tumors. The main assumption of the proposed method is that if two tumors that share a common origin or if the alleged secondary tumor is clonally related to the primary tumor then they share a higher and tumor specific amount of matching chromosomal aberrations (gains or deletions) than recurrent chromosomal aberrations can explain.
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| 52. |
- Holmberg, Lars, et al.
(författare)
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Results from the scandinavian prostate cancer group trial number 4 : a randomized controlled trial of radical prostatectomy versus watchful waiting
- 2012
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Ingår i: Journal of the National Cancer Institute. Monographs. - Cary, USA : Oxford University Press. - 1052-6773 .- 1745-6614. ; 2012:45, s. 230-233
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Tidskriftsartikel (refereegranskat)abstract
- In the Scandinavian Prostate Cancer Group Trial Number 4 (SPCG-4), 347 men were randomly assigned to radical prostatectomy and 348 to watchful waiting. In the most recent analysis (median follow-up time = 12.8 years), the cumulative mortality curves had been stable over the follow-up. At 15 years, the absolute risk reduction of dying from prostate cancer was 6.1% following randomization to radical prostatectomy, compared with watchful waiting. Hence, 17 need to be randomized to operation to avert one death. Data on self-reported symptoms, stress from symptoms, and quality of life were collected at 4 and 12.2 years of median follow-up. These questionnaire studies show an intricate pattern of symptoms evolving after surgery, hormonal treatments, signs of tumor progression, and also from natural aging. This article discusses some of the main findings of the SPCG-4 study. The Scandinavian Prostate Cancer Group Trial Number 4 (SPCG-4) started in 1989 when radical prostatectomy was newly introduced in Scandinavia and when there was essentially no prostate-specific antigen (PSA) testing in asymptomatic men; such testing only became common at the end of the inclusion of the trial a decade later. However, the trial data continue to be important for several reasons. In many parts of the world, the clinical panorama of prostate cancer still resembles that in Sweden in the early 1990s. The trial results point to many of the issues that modern diagnosis and treatment have to solve. SPCG-4 is to date the only trial to inform about both forces of mortality and self-reported symptoms and quality of life in men after radical prostatectomy or watchful waiting two decades and more out after a primary diagnosis of prostate cancer. According to the protocol (http://www.roc.se/prostata/SPCG-4.pdf), the main trial data have been updated every 3 years since 2002 (1–6). In this presentation, we highlight some of the main findings with bearing on the topic of this conference and discuss some issues that have been raised when the trial results have been presented.
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| 53. |
- Hägglöf, Christina, et al.
(författare)
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The stroma : a key regulator in prostate function and malignancy
- 2012
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 4:2, s. 531-548
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Forskningsöversikt (refereegranskat)abstract
- Prostate cancer is a very common and highly unpredictable form of cancer. Whereas many prostate cancers are slow growing and could be left without treatment, others are very aggressive. Additionally, today there is no curative treatment for prostate cancer patients with local or distant metastasis. Identification of new, improved prognostic and diagnostic biomarkers for prostate cancer and the finding of better treatment strategies for metastatic prostate cancer is therefore highly warranted. Interactions between epithelium and stroma are known to be important already during prostate development and this interplay is critical also in development, progression of primary tumors and growth of metastases. It is therefore reasonable to expect that future biomarkers and therapeutic targets can be identified in the prostate tumor and metastasis stroma and this possibility should be further explored.
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| 54. |
- Ladjevardi, Sam
(författare)
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Imaging and Treatment Outcome of Potentially Curable Prostate Cancer
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The over-all aim of the present study was to compare the results of treatment with curative intent, with conservative treatment in men with prostate cancer (PCa) without distant metastases.In a population-based cohort in Sweden, the predictive value of prostate-specific antigen (PSA) was evaluated and the relative survival of men considered plausible candidates for treatment with curative intent was investigated.We also evaluated the association between curative treatment and cause-specific mortality, and over-all as well as relative survival in men diagnosed with PCa with a serum PSA level between 20 and 100 ng/ml.Due to the uncertainly of transrectal ultrasound-guided biopsy in the diagnosis of PCa, we created a model for prostate imaging to increase the safety of guided Core Needle Biopsy (CNB) in men with suspect PCa, thereby improving staging. Material and methods. The cohorts in the first three studies were prospectively included in a population-based register (the National Prostate Cancer Register). Study IV was a clinical study on patients included between 2010 and 2011.Results. Regardless of Gleason Score, a positive relationship between survival and serum PSA level categories in patients with a PSA level> 4 ng/ml was found, but a paradoxical inverse relationship was observed in men with a PSA level < 4 ng/ml. Men with a well-differentiated tumour had a 5-year relative survival exceeding 100% regardless of treatment. The survival rate for moderately and poorly differentiated tumours was poor for men managed conservatively. The 10-year cause-specific mortality for patients with PSA 20-50 ng/ml was 36% for patients treated without and 13% for patients treated with curative intent. For patients with a PSA 50-100 ng/ml the 10-year cause-specific mortality was 55% for conservative and 20% for patients treated with curative intent.PCa detection by CNB, magnetic resonance imaging (MR) with ADC (Apparent diffusion coefficient), magnetic resonance spectroscopic imaging (MRSI) and Positron Emission Tomography (PET/CT) ¹¹C Acetate imaging applied to 10 sections of the prostate demonstrated clear conformity between MRI ADC mapping and postoperative findings, showing high specificity (87%) and sensitivity (95%).Conclusion. The inverse relationship between relative survival and PSA at levels below 4 ng/ml should be considered when choosing a PSA cut-off level. Outcome differs little between conservative management and treatment with curative intent in men with localised well- to moderately differentiated tumours over a 10-yr period. For men with poorly differentiated tumours, on the other hand, choice of treatment is crucial for outcome. Treatment with curative intent is beneficial in the group of men with prostate cancer and PSA levels between 20 and 100 ng/ml without distant metastases. A combination of MRI , diffusion ADC and MRSI may provide an improved model for imaging of the prostate for targeted biopsy.
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| 55. |
- Beskow, Catharina, et al.
(författare)
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Biological effective dose evaluation and assessment of rectal and bladder complications for cervical cancer treated with radiotherapy and surgery
- 2012
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Ingår i: Journal of Contemporary Brachytherapy. - : Termedia Sp. z.o.o.. - 1689-832X .- 2081-2841. ; 4:4, s. 205-212
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study aims to retrospectively evaluate dosimetric parameters calculated as biological effective dose in relation to outcome in patients with cervical cancer treated with various treatment approaches including radiotherapy, with and without surgery.Methods and Materials: Calculations of biological effective dose (BED) were performed on data from a retrospective analysis of 171 patients with cervical carcinoma stages IB-IIB treated with curative intent between January 1989 and December 1991. 43 patients were treated only with radiotherapy and 128 patients were treated with a combination of radiotherapy and surgery. External beam radiotherapy was delivered with 6-21 MV photons from linear accelerators. Brachytherapy was delivered either with a manual radium technique or with a remote afterloading technique. The treatment outcome was evaluated at 5 years.Results: The disease-specific survival rate was 87% for stage IB, 75% for stage IIA and 54% for stage IIB, while the overall survival rates were 84% for stage IB, 68% for stage IIA and 43% for stage IIB. Patients treated only with radiotherapy had a local control rate of 77% which was comparable to that for radiotherapy and surgery patients (78%). Late complications were recorded in 25 patients (15%). Among patients treated with radiotherapy and surgery, differences in radiation dose calculated as BED10 did not seem to influence survival. For patients treated with radiotherapy only, a higher BED10 was correlated to a higher overall survival (p=0.0075). The dose response parameters found based on biological effective dose calculations were D50=85.2 Gy10 and γ=1.62 for survival and D50=61.6 Gy10 and γ=0.92 for local control.Conclusions: The outcome correlates with biological effective dose for patients treated with radiation therapy alone, but not for patients treated with radiotherapy and surgery. No correlations were found between BED and late toxicity from bladder and rectum.
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| 56. |
- Quant, Eva, et al.
(författare)
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Prophylactic treatment of local reactions to i.v. vinorelbine: a randomized study
- 2012
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Ingår i: Supportive Care in Cancer. - : Springer Science and Business Media LLC. - 0941-4355 .- 1433-7339. ; 20:8, s. 1737-1744
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Tidskriftsartikel (refereegranskat)abstract
- Local reactions on the site of infusion are common with i.v. vinorelbine treatment. The study aims were to evaluate whether an i.v. saline infusion or steroid injection, or the combination of these measures, could decrease vinorelbine-related local reactions and to study to what extent such reactions actually occur. Patients with lung cancer and planned chemotherapy containing i.v. vinorelbine were randomized in a 2 x 2 factorial design to receive either 4 mg betamethasone or placebo i.v. prior to and either 20 or 250 ml saline infusion following the vinorelbine infusion. Local infusion site signs and symptoms were recorded during and 1 h after the vinorelbine infusion and collected by a study-specific diary 24-48 h following each treatment course. A total of 79 patients were randomized and evaluable. Local infusion site signs, symptoms and reactions occurred in 63% of all patients (49% during vinorelbine monotherapy courses), with local pain being most frequently reported. Pre-treatment with i.v. betamethasone was associated with a reduced risk of local pain (5/38 vs. 20/39; p < 0.001) or any symptoms (14/38 vs. 29/39; p = 0.01) compared with placebo during the 48 h following the vinorelbine infusion. The reduced pain effect was seen both during vinorelbine monotherapy courses and during combination chemotherapy with carboplatin. In contrast, there was no difference between post-treatment infusion with 20 or 250 ml saline with regard to local signs or symptoms. Local infusion site side effects are common with i.v. vinorelbine. Pre-treatment with 4 mg betamethasone i.v. is associated with a reduced risk of local symptoms or reactions, local pain in particular.
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| 57. |
- Brännström, Margareta, et al.
(författare)
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Unequal care for dying patients in Sweden : a comparative registry study of deaths from heart disease and cancer
- 2012
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Ingår i: European Journal of Cardiovascular Nursing. - : Elsevier. - 1474-5151 .- 1873-1953. ; 11:4, s. 454-459
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Swedish Palliative Registry is a nationwide quality registry aimed at facilitating improvement in end-of-life care. The goal is for the registry to list and report quality indicators related to care during the last week of life in all cases expected death in Sweden.AIM: To examine the quality of care during the last week of life as reported to the registry for patients with heart disease compared to those with cancer.METHOD: A retrospective registry study.RESULTS: Patients dying of heart disease compared to those dying from cancer had more shortness of breath, fewer drugs prescribed as needed against the usual symptoms and often died alone. Furthermore, they and their close relatives received less information about the imminence of death and bereavement follow-up was less common. The healthcare personnel were less aware of the heart disease patients' symptoms and less often knew about where they wished to die.CONCLUSION: Great differences were found in registered end-of-life care suggesting that the care given to patients with heart disease and cancer was unequal even after adjustment for age, sex and setting at the time of death. If our observational findings are confirmed in future studies there is obviously a need for new models for end-of-life management in order to facilitate the provision of equal care to dying patients regardless of diagnosis.
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| 58. |
- Cashin, Peter H, 1984-
(författare)
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Cytoreductive Surgery and Intraperitoneal Chemotherapy in Patients with Peritoneal Metastases from Colorectal Cancer : Aspects of loco-regional treatment outcome, patient selection, and chemo-sensitivity
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Previously, peritoneal metastases(PM) from colorectal cancer(CRC) have been considered a terminal and generalised form of cancer. A new treatment strategy combining cytoreductive surgery(CRS) and intraperitoneal chemotherapy(IPC) has recently shown promising results. The aim of this thesis was to investigate different aspects of this treatment in order to optimise the treatment and to clarify its potential as a new treatment option. Treatment outcome, patient selection, method of IPC (hyperthermic intraperitoneal chemotherapy-HIPEC vs. sequential postoperative intraperitoneal chemotherapy-SPIC) and choice of drugs for IPC were the aspects covered in this thesis.The treatment outcome of CRS and IPC according to the median overall survival ranged from 24 to 34 months with 5-year overall survival ranging from 20 to 40% depending on the IPC treatment administered. Furthermore, the 5-year disease-free survival was impressive at 32% for patients receiving HIPEC. This establishes the curative potential of this treatment. Due to current inadequacies of radiological imaging, a score (Corep score) was developed for patient selection purposes. This score had a sensitivity of 80% and specificity of 100% in identifying patients with short cancer-specific survival after the treatment (<12 months). Further studies are needed to elucidate the clinical usefulness of the Corep score. HIPEC was associated with better survival than the SPIC method at similar morbidity and mortality rates, suggesting that HIPEC be the method of preference. Concerning the choice of drugs, the last study investigated the chemo-sensitivity of different PM tumour-types with a special focus on CRC. While CRC samples were generally more resistant, the ratio of the in vivo concentration compared to the ex vivo concentration giving a 50% tumour cell death showed that oxaliplatin had the best profile across all PM tumour types as well as for CRC. This needs further confirmation in a clinical trial.
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| 59. |
- Grote, Verena A., et al.
(författare)
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The associations of advanced glycation end products and its soluble receptor with pancreatic cancer risk: A case-control study within the prospective EPIC cohort
- 2012
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Ingår i: Cancer Epidemiology Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 21:4, s. 619-628
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Tidskriftsartikel (refereegranskat)abstract
- Background: Advanced glycation end products (AGE) and their receptors (RAGE) have been implicated in cancer development through their proinflammatory capabilities. However, prospective data on their association with cancer of specific sites, including pancreatic cancer, are limited. Methods: Prediagnostic blood levels of the AGE product Nε-(carboxymethyl)lysine (CML) and the endogenous secreted receptor for AGE (esRAGE) were measured using ELISA in 454 patients with exocrine pancreatic cancer and individually matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC). Pancreatic cancer risk was estimated by calculating ORs with corresponding 95% confidence intervals (CI). Results: Elevated CML levels tended to be associated with a reduction in pancreatic cancer risk [OR = 0.57 (95% CI, 0.32-1.01) comparing highest with lowest quintile), whereas no association was observed for esRAGE (OR = 0.98; 95% CI, 0.62-1.54). Adjustments for body mass index and smoking attenuated the inverse associations of CML with pancreatic cancer risk (OR = 0.78; 95% CI, 0.41-1.49). There was an inverse association between esRAGE and risk of pancreatic cancer for cases that were diagnosed within the first 2 years of follow-up [OR = 0.46 (95% CI, 0.22-0.96) for a doubling in concentration], whereas there was no association among those with a longer follow-up (OR = 1.11; 95% CI, 0.88-1.39; P interaction = 0.002). Conclusions and Impact: Our results do not provide evidence for an association of higher CML or lower esRAGE levels with risk of pancreatic cancer. The role of AGE/RAGE in pancreatic cancer would benefit from further investigations. ©2012 AACR.
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| 60. |
- Hakelius, Malin, et al.
(författare)
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Interleukin-1-mediated effects of normal oral keratinocytes and head and neck squamous carcinoma cells on extracellular matrix related gene expression in fibroblasts
- 2012
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Ingår i: Oral Oncology. - : Elsevier. - 1368-8375 .- 1879-0593. ; 48:12, s. 1236-1241
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The composition of tumor stroma and the activity of tumor associated fibroblasts are important for tumor growth. Interactions between carcinoma cells and fibroblasts regulate the turnover of extracellular matrix (ECM). Here, the in vitro effects of oral squamous cell carcinoma (SCC) cells (UT-SCC-30 and UT-SCC-87) on fibroblast expression of genes for ECM components and connective tissue growth factor (CTGF/CCN2), were compared to those of normal oral keratinocytes (NOK).Materials and Methods: Cocultures with fibroblasts in collagen gels and keratinocytes with the two cell types separated by a semi permeable membrane were used, and relative gene expression was measured with real-time PCR.Results: All investigated genes were regulated by NOK and the SCCs. The downregulation of pro-collagens alpha 1(I) and alpha 1(III) was more pronounced in cocultures with NOK, while the expression of CCN2 and fibronectin was downregulated by both NOK and the SCCs to a similar extent. UT-SCC-87, but not UT-SCC-30, secreted significantly more IL-1 alpha than NOK. A recombinant interleukin-1 receptor antagonist reversed many of the observed effects on fibroblast gene expression suggesting involvement of IL-1 in cocultures with NOK as well as with SCCs.Conclusion: The observed differential effects on fibroblast gene expression suggest that NOK are more antifibrotic compared to UT-SCC-30 and UT-SCC-87. These findings may contribute to a better understanding of the mechanisms behind ECM turnover in tumors. (C) 2012 Elsevier Ltd. All rights reserved.
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