| 561. |
- Westerberg, Marcus
(författare)
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Modelling short and long term consequences of changes in diagnostic activity and treatment
- 2020
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Since the late 90’s the diagnostic activity for prostate cancer has increased in Sweden, primarily due to increased use of PSA testing, and this has led to a large increase in diagnoses. Simultaneously, there have been changes in treatment strategies, and more effective treatments have been introduced. This thesis aims to increase the understanding of short and long term consequences of these changes by use of high quality data on virtually all men diagnosed with prostate cancer in Sweden.In paper I, the survival of men with metastatic prostate cancer at diagnosis was investigatedby use of survival models, including Kaplan-Meier analyses and Cox proportional hazards regression.The median survival from diagnosis increased with 6 months when comparing mendiagnosed 1998-2001 with men diagnosed 2010-2015, and the risk of death decreased with 13%, while median levels of prostate specific antigen at diagnosis dropped with up to 50%.In paper II, the interplay between diagnostic activity, incidence and risk of death by prostate cancer was modelled using a discrete time model. Data on diagnostic activity, e.g. in termsof testing frequencies, was not available and therefore a proxy for the diagnostic activity wasused. The hazards were estimated within the framework of generalized additive models. Two simulations were performed, assuming low and high diagnostic activity respectively, to compare incidence and mortality from 2017-2060. Higher diagnostic activity, compared to lower, led to more men being diagnosed, primarily with lower risk prostate cancer, but in the long run it led to fewer men diagnosed with metastatic disease and fewer prostate cancer deaths.
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| 562. |
- Westerberg, Marcus, 1990-
(författare)
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Prostate cancer incidence, treatment and mortality : Empirical longitudinal register-based studies and methods for handling missing data
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The diagnostic activity for prostate cancer has increased substantially in Sweden, primarily due to increased use of prostate-specific antigen (PSA) testing in asymptomatic men, and this has led to a large increase in diagnoses. There have also been changes in the diagnostic workup, guidelines, treatment strategies, and more effective treatments have been introduced in different phases of the disease. This thesis aims to increase the understanding of consequences of changes in diagnostic activity and treatment, with a focus on empirical studies, methodological development, and handling of missing data.In paper I, the survival of men with metastatic prostate cancer was investigated across calendar time periods by use of Kaplan-Meier analyses and Cox regression. The median survival from diagnosis increased with six months comparing men diagnosed 1998-2001 with men diagnosed 2010-2015, while median PSA decreased.In paper II, a discrete time multivariate longitudinal model was combined with a proxy for the unobserved level of diagnostic activity to produce prognoses of incidence and mortality. Simulations indicated that a higher diagnostic activity was associated with fewer men diagnosed with metastatic disease and fewer prostate cancer deaths.In paper III, we looked for clinical variables predictive of the survival of men with castration-resistant prostate cancer (CRPC). A new data base was created including longitudinal data on prescriptions of hormonal treatment, PSA, and cause of death. We found that PSA doubling time and PSA at time of CRCP were highly predictive and could be used for treatment decision.In paper IV, we estimated annual incidence of metastatic prostate cancer using different methods for handling missing data in metastatic status (M stage). Missing data in M stage was high and varied over calendar time and risk groups, yet each method indicated a downward trend in incidence. Although men with unknown metastatic status cannot be assumed to have nonmetastatic disease in general, this may be reasonable among those with tumour characteristics that indicate a low risk of metastases.In paper V, the estimation of multivariate longitudinal models was considered in a context where some events are observed on a coarser level (e.g. grouped) at some time points, causing gaps in the data. The likelihood function, score and observed information were derived under an independent coarsening mechanism. A simulation study was conducted comparing properties of several estimators including direct maximum likelihood and Monte Carlo Expectation Maximisation.
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| 563. |
- Westerberg, Marcus, et al.
(författare)
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Simulation model of disease incidence driven by diagnostic activity
- 2021
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Ingår i: Statistics in Medicine. - : John Wiley & Sons. - 0277-6715 .- 1097-0258. ; 40:5, s. 1172-1188
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Tidskriftsartikel (refereegranskat)abstract
- It is imperative to understand the effects of early detection and treatment of chronic diseases, such as prostate cancer, regarding incidence, overtreatment and mortality. Previous simulation models have emulated clinical trials, and relied on extensive assumptions on the natural history of the disease. In addition, model parameters were typically calibrated to a variety of data sources. We propose a model designed to emulate real-life scenarios of chronic disease using a proxy for the diagnostic activity without explicitly modeling the natural history of the disease and properties of clinical tests. Our model was applied to Swedish nation-wide population-based prostate cancer data, and demonstrated good performance in terms of reconstructing observed incidence and mortality. The model was used to predict the number of prostate cancer diagnoses with a high or limited diagnostic activity between 2017 and 2060. In the long term, high diagnostic activity resulted in a substantial increase in the number of men diagnosed with lower risk disease, fewer men with metastatic disease, and decreased prostate cancer mortality. The model can be used for prediction of outcome, to guide decision-making, and to evaluate diagnostic activity in real-life settings with respect to overdiagnosis and prostate cancer mortality.
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| 564. |
- Westerlund, Joakim, et al.
(författare)
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A note on the pooling of individual panic unit root tests
- 2009
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Ingår i: Econometric Theory. - 0266-4666 .- 1469-4360. ; 25:6, s. 1851-1868
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Tidskriftsartikel (refereegranskat)abstract
- One of the most cited studies in recent years within the field of nonstationary panel data analysis is that of Bai and Ng (2004), in which the authors propose PANIC, a new framework for analyzing the nonstationarity of panels with idiosyncratic and common components. The problem is that the asymptotic validity of PANIC as a platform for constructing pooled panel unit root tests based on averaging is not fully proven. This paper provides the required results, whose usefulness is verified through simulations.
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| 565. |
- Westerlund, Joakim, et al.
(författare)
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New tools for understanding the local asymptotic power of panel unit root tests
- 2015
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Ingår i: Journal of Econometrics. - : Elsevier BV. - 0304-4076 .- 1872-6895. ; 188:1, s. 59-93
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Tidskriftsartikel (refereegranskat)abstract
- Motivated by the previously documented discrepancy between actual and predicted power, the present paper provides new tools for analyzing the local asymptotic power of panel unit root tests. These tools are appropriate in general when considering panel data with a dominant autoregressive root of the form rho(i)= 1 + ciN(-k)T(-tau), where i = 1,..., N indexes the cross-sectional units, T is the number of time periods and ci is a random local-to-unity parameter. A limit theory for the sample moments of such panel data is developed and is shown to involve infinite-order series expansions in the moments of ch in which existing theories can be seen as mere first-order approximations. The new theory is applied to study the asymptotic local power functions of some known test statistics for a unit root. These functions can be expressed in terms of the expansions in the moments of ci, and include existing local power functions as special cases. Monte Carlo evidence is provided to suggest that the new results go a long way toward bridging the gap between actual and predicted power.
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| 566. |
- Westerlund, Joakim, et al.
(författare)
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Testing for a Unit Root in a Random Coefficient Panel Data Model
- 2012
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Ingår i: Journal of Econometrics. - : Elsevier BV. - 0304-4076 .- 1872-6895. ; 167:1, s. 254-273
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Tidskriftsartikel (refereegranskat)abstract
- This paper proposes new unit root tests in the context of a random autoregressive coefficient panel data model, in which the null of a unit root corresponds to the joint restriction that the autoregressive coefficient has unit mean and zero variance. The asymptotic distributions of the test statistics are derived and simulation results are provided to suggest that they perform very well in small samples.
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| 567. |
- Wiberg, Kristina, et al.
(författare)
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In vitro activity of bortezomib in cultures of patient tumour cells-potential utility in haematological malignancies
- 2009
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Ingår i: Medical Oncology. - : Springer Science and Business Media LLC. - 1357-0560 .- 1559-131X. ; 26:2, s. 193-201
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Tidskriftsartikel (refereegranskat)abstract
- Bortezomib represents a new class of anti-cancer drugs, the proteasome inhibitors. We evaluated the in vitro activity of bortezomib with regard to tumour-type specificity and possible mechanisms of drug resistance in 115 samples of tumour cells from patients and in a cell-line panel, using the short-term fluorometric microculture cytotoxicity assay. Bortezomib generally showed dose-response curves with a steep slope. In patient cells, bortezomib was more active in haematological than in solid tumour samples. Myeloma and chronic myeloid leukaemia were the most sensitive tumour types although with great variability in drug response between the individual samples. Colorectal and kidney cancer samples were the least sensitive. In the cell-line panel, only small differences in response were seen between the different cell lines, and the proteasome inhibitors, lactacystin and MG 262, showed an activity pattern similar to that of bortezomib. The cell-line data suggest that resistance to bortezomib was not mediated by MRP-, PgP, GSH-; tubulin and topo II-associated MDR. Combination experiments indicated synergy between bortezomib and arsenic trioxide or irinotecan. The data support the current use of bortezomib but also points to its potential utility in other tumour types and in combination with cytotoxic drugs.
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| 568. |
- Wickstrom, Malin, et al.
(författare)
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Targeting the hedgehog signal transduction pathway at the level of GLI inhibits neuroblastoma cell growth in vitro and in vivo
- 2013
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 132:7, s. 1516-1524
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Tidskriftsartikel (refereegranskat)abstract
- Hedgehog (HH) signaling is an important regulator of embryogenesis that has been associated with the development of several types of cancer. HH signaling is characterized by Smoothened (SMO)-dependent activation of the GLI transcription factors, which regulate the expression of critical developmental genes. Neuroblastoma, an embryonal tumor of the sympathetic nervous system, was recently shown to express high levels of key molecules in this signaling cascade. Using compounds blocking SMO (cyclopamine and SANT1) or GLI1/GLI2 (GANT61) activity revealed that inhibition of HH signaling at the level of GLI was most effective in reducing neuroblastoma growth. GANT61 sensitivity positively correlated to GLI1 and negatively to MYCN expression in the neuroblastoma cell lines tested. GANT61 downregulated GLI1, c-MYC, MYCN and Cyclin D1 expression and induced apoptosis of neuroblastoma cells. The effects produced by GANT61 were mimicked by GLI knockdown but not by SMO knockdown. Furthermore, GANT61 enhanced the effects of chemotherapeutic drugs used in the treatment of neuroblastoma in an additive or synergistic manner and reduced the growth of established neuroblastoma xenografts in nude mice. Taken together this study suggests that inhibition of HH signaling is a highly relevant therapeutic target for high-risk neuroblastoma lacking MYCN amplification and should be considered for clinical testing.
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| 569. |
- Wickström, Malin, et al.
(författare)
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Aminopeptidase N (CD13) as a target for cancer chemotherapy
- 2011
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Ingår i: Cancer Science. - : Wiley. - 1347-9032 .- 1349-7006. ; 102:3, s. 501-508
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Forskningsöversikt (refereegranskat)abstract
- The enzyme aminopeptidase N (APN, also known as CD13) is a Zn2+ dependent membrane-bound ectopeptidase that degrades preferentially proteins and peptides with a N-terminal neutral amino acid. Aminopeptidase N has been associated with the growth of different human cancers and suggested as a suitable target for anti-cancerous therapy. Different approaches have been used to develop new drugs directed to this target, including enzyme inhibitors as well as APN-targeted carrier constructs. This review discusses the prevalence and possible function of APN in malignant diseases, mainly solid tumors, as well as its “drugability” evaluated in preclinical in vivo models, and also provides a brief overview of current clinical trials focused on APN.
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| 570. |
- Wickström, Malin, et al.
(författare)
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Melflufen : a peptidase-potentiated alkylating agent in clinical trials
- 2017
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:39, s. 66641-66655
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Forskningsöversikt (refereegranskat)abstract
- Aminopeptidases like aminopeptidase N (APN, also known as CD13) play an important role not only in normal cellular functioning but also in the development of cancer, including processes like tumor cell invasion, differentiation, proliferation, apoptosis, motility, and angiogenesis. An increased expression of APN has been described in several types of human malignancies, especially those characterized by fast-growing and aggressive phenotypes, suggesting APN as a potential therapeutic target. Melphalan flufenamide ethyl ester (melflufen, previously denoted J1) is a peptidase-potentiated alkylating agent. Melflufen readily penetrates membranes and an equilibrium is rapidly achieved, followed by enzymatic cleavage in aminopeptidase positive cells, which results in trapping of less lipophilic metabolites. This targeting effect results in very high intracellular concentrations of its metabolite melphalan and subsequent apoptotic cell death. This results in a potency increase (melflufen vs melphalan) ranging from 10- to several 100-fold in different in vitro models. Melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in multiple myeloma cells. Furthermore, anti-angiogenic properties of melflufen have been described. Consequently, it is hypothesized that melflufen could provide better efficacy but no more toxicity than what is achieved with melphalan, an assumption so far supported by experiences from hollow fiber and xenograft studies in rodents as well as by clinical data from patients with solid tumors and multiple myeloma. This review summarizes the current preclinical and clinical knowledge of melflufen.
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