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| 2. |
- Dreifaldt, Ann Charlotte, 1964-
(författare)
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Epidemiological aspects on malignant diseases in childhood
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The trends of malignant diseases in children aged 0 to 14 years, reported to the Swedish Cancer Registry 1960–1998 (n=9 298) were analyzed. The most common diagnoses were leukemia, 29.7%, tumors of the central nervous system (CNS), 27.6%, and lymphomas, 10.2%. The average annual incidence rate of childhood malignant diseases 1990–1998 was 16.19/100 000 person-years. Average annual change in incidence rate of all childhood cancer was +1.01% (95% confidence interval (CI)=0.80-1.22). Statistically significant increase was seen for leukemia +0.85% (95% CI=0.42–1.28), lymphomas +1.87% (95% CI=1.17–2.58), CNS tumors +1.45% (95% CI=1.02–1.88), sympathetic nervous system tumors +1.61% (95% CI=0.79–2.44), hepatic tumors +2.62% (95% CI=2.02–3.21), and germ cell and gonadal tumors +1.21% (95% CI=0.23–2.19). Children are exposed to persistent organic pollutants (POPs) during fetal life and breast-feeding. In a case-control study including cases of childhood cancer reported to the Cancer Registry 1988–1991 (n=962) we used breastfeeding duration as a surrogate for exposure to POPs. One matched control per case was used. Information on breast-feeding, vaccinations and chronic illness was collected from copies of the children’s Child Health Center records. Overall, breast-feeding did not affect the risk of childhood cancer, OR=1.0 (95% CI=0.7–1.3) using breast-feeding up to one month as reference. For non-Hodgkin lymphoma (NHL) OR for breast-feeding for >1 month yielded OR=5.0 (95% CI=1.1–23). No association was seen between preschool vaccinations and childhood cancer except for lymphomas and measles/measles-mumps-rubella vaccination, OR=0.2 (95% CI=0.1–0.6). Increased risk of all cancer was found for congenital malformations, OR=1.7 (95% CI=0.97–2.9), especially of leukemia, OR=3.0 (95% CI=1.5–5.8). Children with disorders of brain function had an increased risk of all cancer, OR=6.0 (95% CI=1.3–27), especially of brain tumors, OR=10 (95% CI=1.3–78). A childhood population expected to be more exposed to POPs is children of fishermen. In a register-based study, the cancer incidence rates in a cohort of fishermen children (at age 0-19 years) were compared to the rates of referent children. A modestly increased incidence rate ratio (IRR) of childhood cancer was found, IRR=1.38 (95% CI=0.96–2.00) and an increased IRR for acute lymphoid leukemia, IRR=2.65 (95% CI=1.005–6.97). In west coast fishermen children, an increased IRR was observed for NHL, IRR=3.19 (95% CI=0.98–10.4).
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| 3. |
- Ericson Lindquist, Kajsa
(författare)
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Tumors associated with Hereditary Nonpolyposis Colorectal Cancer: Defective Mismatch Repair and Familial Risk of Cancer
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inactivation of the DNA mismatch repair (MMR) system is a tumorigenic mechanism involved in 15-20% of tumor types such as colorectal and endometrial cancer and is specifically associated with the Hereditary Nonpolyposis Colorectal Cancer (HNPCC) syndrome. These MMR defective tumors are characterized by microsatellite instability (MSI), a phenomenon that reflects alterations in length of repeated sequences, and 90% of MSI tumors show loss of immunohistochemical expression for the MMR protein affected. HNPCC yields an increased risk for several tumor types; cancer of the colorectum (80-90% lifetime risk), endometrium (40-60%), ovary (5-15%), stomach (5-15%), urinary tract, small bowel, skin, and brain. The syndrome is characterized by an early age (mean 45 years) at diagnosis and one third of the patients develop metachronous tumors. The major aims of this thesis were to assess the contribution of defective MMR to the development of the more rare tumor types associated with HNPCC and to assess cancer risks in children whose parents had developed HNPCC-associated tumors. In study I, patients who developed multiple (at least 4) primary tumors, including two colorectal cancers, were assessed for MSI and immunohistochemical expression of the MMR proteins MLH1 and MSH2. MSI was identified in 63/154 (40%) tumors, 55 of which also showed immunohistochemical loss of MMR protein expression. A concordant finding of MSI and loss of the same MMR protein, which strongly suggest HNPCC, was found in 17/45 (38%) patients, which suggests that a high fraction of such multiple tumors are caused by HNPCC. In studies II and III, the frequency of defective MMR was studied in adenocarcinomas of the small intestine and in upper urinary tract cancers (UUC). MSI was detected in 16/89 (18%) of cancers of the small intestine and in 9/194 (4%) UUC. MMR protein expression loss affected 11 cancers of the small intestine and 11 UUC. Malignant fibrous histiocytoma (MFH) represents one of the largest subsets of soft tissue sarcomas, and occasional MFHs have been described in HNPCC-families. In study IV, we assessed MMR expression in a series of 209 MFH and found loss of MSH2 and MSH6 in 2 MFH. Study V is based on the national Swedish cancer registry and analyses familial risk of HNPCC-associated tumors. Cancer risks were calculated in 204 358 offspring whose 102 814 parents had developed HNPCC-associated cancer and the risks were correlated to the age of the parent, metachronous tumors in the parent, and presence of several HNPCC-associated cancers in the family. Significantly increased risks were observed for several tumor types, including colon cancer, rectal cancer, endometrial cancer, gastric cancer, and ovarian cancer. The highest offspring risks were observed in the subgroup with multiple HNPCC-associated cancers in the parent. In summary, we have demonstrated that MMR defects are common in patients who develop multiple primary tumors, occur at similar frequencies in cancers of the small intestine and the colon, contribute to development of UUC and MFH at low frequencies, and that HNPCC-associated tumor in a parent confer an increased risk of several cancer types in the offspring, especially if the parent developed more than one cancer or cancer at a young age.
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| 4. |
- Högberg, Thomas, et al.
(författare)
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Gynekologisk onkologi
- 2008. - 2
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Ingår i: Onkologi. - Stockholm : Liber. - 9789147084012 ; , s. 488-533
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Gruvberger, Sofia
(författare)
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Estrogen receptor alpha and beta in breast cancer - gene expression profiles and clinical implications
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is the most common malignancy in women in the Western world with about 10% of women developing breast cancer during their lifetime, of which one third will eventually succumb to the metastatic form of the disease. Breast cancer arises from the epithelial cells of the breast mammary gland, but the mechanisms involved in tumor initiation, progression, and metastasis are still not fully understood. However, estrogen and its receptors are believed to play a crucial role in these events. Estrogen receptor alpha (ERalpha) has long been identified as a target for treatment and numerous studies have shown that patients expressing ERalpha are more likely to respond to endocrine therapy such as tamoxifen; however a significant fraction become resistant. Little is known of the role of the second estrogen receptor, estrogen receptor beta (ERbeta), in breast tumor biology and therapy response. This thesis is primarily concerned with investigating the global differences in gene expression between tumors that express and do not express ERalpha and/or ERbeta, and the relationship of such profiles to outcome in the setting of tamoxifen therapy. The present study shows that ERalpha status in primary breast tumor biopsies is associated with a very distinct gene expression profile, as determined by cDNA microarrays, involving a large number of genes (Papers I and III). Only a small fraction of these ERalpha-associated genes have previously been identified as estrogen-responsive in cell culture (Paper I). In addition, not only is the ERalpha status as a binary variable encoded in the gene expression profiles, but also the actual level of protein content can be predicted, as well as the percent cells in the DNA synthesis phase of the cell cycle and other prognostic markers (Paper III). However, predicting response to tamoxifen using gene expression profiles from primary breast tumors was not possible in a cohort of 44 patient with varying ERalpha status and clinical outcome (Paper II). Additionally, a previously published prognosis predictor did not have any prognostic significance in this data, suggesting that different data sets and various tumor/patient/treatment characteristics selected influence the success of an array-based predictor for prognosis (Paper II). Much less is known about the transactivating properties of ERbeta and its relationship to ERalpha and tamoxifen response. Herein, the ERbeta protein is shown to have prognostic value after adjuvant tamoxifen therapy in a large patient set (n=353; Paper IV). However, subgroup analysis shows the effect to be only significant in patients with tumors lacking ERalpha. From cDNA microarray analysis of a subset of these tumors, an ERbeta-associated gene expression profile could be generated from the ERalpha negative group of tumors but not for the ERalpha positive group, further corroborating the notion that ERbeta selectively influences the biological processes in tumors lacking ERalpha (Paper IV). These results suggest that the small subset of ERalpha negative tumors responding to tamoxifen may be explained by the presence of ERbeta, and that ERbeta is not a surrogate marker for ERalpha but is associated with its own biological processes and may respond to tamoxifen via different target genes. In conclusion, together these studies have added to our understanding of the importance of estrogen receptor status and their biological consequences in breast cancer.
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| 6. |
- Hedenus, Michael, 1945-
(författare)
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Clinical impact of epoetins in the treatment of anemia with special emphasis on patients with lymphoid malignancies. : dosing, iron supplementation and safety
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to determine the relevant dose of arbepoetin-alfa (DA) in patients with lymphoproliferative diseases (LPD) and chemotherapy induced anemia (CIA), to study the clinical impact of intravenous (IV) iron supplementation combined with epoetin beta treatment, to identify factors that might predict hemoglobin (Hb) response to treatment with epoetins and to investigate safety of DA.A dose-finding phase II study was able to assess a reasonable DA dose of 2.25 μg/kg once weekly for the treatment of CIA in patients with LPD. Dose-response trends were observed for the different dose cohorts although not statistically significant for any of the endpoints. However a significantly higher proportion of patients achieved Hb response (increase ≥2 g/dL) in the combined DA groups than in placebo (P<0.001).A larger pivotal phase II trial was performed in a similar setting o confirm that the dose 2.25μg/kg once weekly was appropriate and safe. The proportion of patients achieving Hb response was significantly higher in the DA group (60%) than in the placebo group (18%) (P<0,001) and resulted in higher mean changes in Hb than placebo from baseline, 2.66 g/dl versus 0.69 /dl. Also a significantly lower proportion of patients in the DA group (31%) received RBC tranfusions than in the placebo group (48%). The short-term safety of DA with the tested dose was confirmed. The efficacy of DA was consistent for all end points independent of malignancy type or baseline endogenous erythropoietin serum levels.The correction of moderate anemia in truly iron repleted patients with clinically stable LPD not receiving hemotherapy or RBC transfusions with epoetin beta treatment, with or without IV iron treatment was studied in an open label randomized trial. Also the impact on iron kinetics was assessed. The mean change in Hb concentration from baseline to end of treatment (EOT ) was 2.91 versus 1.50 g/dL respectively (P<0.0001). There was a significant (P<0.0001) difference in mean Hb at EOT between the iron and no-iron groups (13.0 g/dL versus 11.8 g/dL). Hb response was achieved by significantly more patients in the iron group (P=0.0012)than in the no-iron group (93% versus 53%) and the median time to achieve a Hb response was 6 weeks in the iron group compared with 12 weeks in the no-iron group. The mean weekly epoetin dose per patient was statistically significant lower in the iron group at week 13 (P =0.029) and at least 25% lower at EOT.To investigate the long-term safety of DA in cancer patients with CIA four previously published double blind, randomized placebo-controlled phase II -III studies were analysed (n = 1.129). Median durations of progression-free survival and overall survival was comparable between DA and placebo for lung cancer (median follow up 15.8 months), for LPD (median follow up 32.6 months) and in the pooled population (follow up 4 months).
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| 7. |
- Schultz, Anna
(författare)
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Localisation of Protein Kinase C in Apoptosis and Neurite Outgrowth
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Protein kinase C (PKC) is a family of serine/threonine kinases, which are subgrouped into classical (a, bI, bII, g), novel (d, e, h, q) and atypical (z, i/l) isoforms. One major aim of this thesis work was to investigate if altered levels of PKC isoforms influence the apoptotic responses of malignant cell-lines. We show that overexpression of PKCd or PKCq renders SK-N-BE(2) neuroblastoma cells sensitive to apoptosis induced by phorbol esters or C2-ceramide. Moreover, overexpression of PKCa, PKCd or PKCe sensitises both androgen-dependent and androgen-independent prostate cancer cells to phorbol ester-induced cell-death. The apoptotic effects of PKCd and PKCq in neuroblastoma cells are independent on the catalytic activity of the enzymes and the isolated regulatory domain (RD) of PKCq induces apoptosis in neuroblastoma cells. Induction of apoptosis depends on the localisation of PKCqRD to the Golgi complex, which is mediated by the C1b domain of the protein. Mutation of a single amino acid residue, Met-267 in PKCqC1b, blocks both the Golgi localisation and the apoptotic effect of the PKCqRD. Previous studies have shown that PKCe induces neurites in neuroblastoma cells. Here we report that treatment with cell-permeable C2-ceramide inhibits PKCe-induced neurite formation, conceivably by relocating the protein from the cytosol to the perinuclear region. Mutation of Asp-257 and Met-278 (the latter corresponding to Met-267 in PKCq) in PKCe blocks the C2-ceramide induced translocation of PKCe. Furthermore, the mutated variant of PKCe still induces neurites after C2-ceramide treatment. Thus, the specific subcellular localisation of PKCq and PKCe are important for their biological activities.
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| 8. |
- Vallon-Christersson, Johan
(författare)
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Functional and Molecular Characterization of BRCA1 and BRCA2 Associated Breast Cancer
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This doctoral dissertation is based on five appended papers primarily concerned with three main topics, namely: the functional characterization of specific and clinically relevant perturbations found in BRCA1 ? one of the major breast cancer susceptibility genes; the use of microarray technologies for molecular characterization of hereditary breast tumor samples from a genomic perspective; and finally, the development of software to address some of the logistical problems of data analysis and management that arise when utilizing microarrays. Results obtained from the work presented herein demonstrate the following: that transcription az says can aid in the characterization of C-terminal missense mutations but that it may not be possible to unambiguously characterize variants with a yeast-based assay alone; that a naturally occurring C-terminal germline mutation in BRCA1 encodes a protein with apparent temperature-dependant functional properties; that open-source software can provide comprehensive solutions to meet data management needs of microarray experimenters; that BRCA1 and BRCA2 associated breast tumors exhibit markedly different copy number aberrations when compared to each other as well as to sporadic tumors; and that gene expression profiling in BRCA1 and BRCA2 associated breast tumors reveals specific gene expression patterns.
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| 9. |
- Kronblad, Åsa
(författare)
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Role of cyclin D1 as an estrogen receptor cofactor and the influence of hypoxia on estrogen receptor regulation, with focus on prognositic and treatment predictive features in breast cancer
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Estrogen receptor (ER) status can define breast cancer patients who would benefit from adjuvant tamoxifen therapy. However, resistance to tamoxifen is often observed and possible mechanisms may be loss or reduction of ER, dysfunctional ER- signaling and ligand independent activation of the receptor. Hypoxia and hypoxia inducible factor-1? (HIF-1) expression has been correlated to loss of ER in breast tumors. Cyclin D1, initially described as a cell cycle regulator, might also function as a cofactor to ER inducing ligand independent activation of the receptor. We therefore determined the relation between ER, cyclin D1 and HIF-1 expression in primary breast tumors and cell lines. Further, the prognostic and treatment predictive value of cyclin D1 and HIF-1 was analyzed in breast cancer patients receiving two years of tamoxifen versus no adjuvant treatment. The results indicated that ER heterogeneity in primary breast tumors was associated with cyclin D1 and HIF-1 expression. Further, breast cancer patients with cyclin D1 high tumors did not benefit from tamoxifen treatment. The survival for untreated patients with cyclin D1 high tumors was nevertheless slightly better than for patients with cyclin D1 low tumors. Hypoxia was also strongly linked to ER downregulation in DCIS and invasive breast cancer and caused ER downregulation in breast cancer cell lines. Interestingly, hypoxic cells were less differentiated, showing changes in morphology, proliferation and cytokeratin 19 expression. The hypoxia induced ER reduction was due to both proteasomal degradation and decreased transcription and active extracellular regulated kinase (ERK1/2)was involved in the transcriptional regulation of ER. Consequently, tamoxifen treatment did not affect proliferation as efficiently in hypoxia as in normoxia, but ERK1/2 inhibitors efficiently increased the tamoxifen effect in hypoxia. Unexpectedly, tumor specific HIF-1 expression was not a predictive marker for tamoxifen response in premenopausal breast cancer patients but associated with a worse recurrence free survival. These results suggest that cyclin D1 is a predictive marker for tamoxifen resistance and HIF 1 a marker of poor prognosis in breast cancer. Targeting cyclin D1 and/or ERK1/2 in conjunction with tamoxifen represent new treatment strategies for improving the tamoxifen response.
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| 10. |
- Stendahl, Maria
(författare)
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Predictive markers for tamoxifen response in primary breast cancer
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is well-known that a majority of breast cancers are hormone-dependent, making endocrine therapy an important adjuvant treatment after surgery. Susceptibility to endocrine treatment is determined by the presence of estrogen receptors (ER) and progesterone receptors (PR) in the tumors. Tamoxifen is the most well-established endocrine treatment available, inhibiting tumor growth and improving survival. Resistance to tamoxifen despite ER/PR positivity is a well-known clinical problem. Cyclin D1, initially described as a cell cycle regulator, also functions as a co-factor to the ER, activating the receptor in the absence of ligand. We investigated the predictive impact of cyclin D1 on tamoxifen treatment response in tumors from patients previously enrolled in randomized trials and found that high levels of cyclin D1 in tumors of tamoxifen treated patients predicted for poor response and reduced recurrence-free survival despite ER positivity. Furthermore, amplification of the cyclin D1 gene (CCND1) was associated with an adverse outcome upon tamoxifen treatment. P27 is a cell cycle regulator, acting as a cdk-inhibitor but also as an assembly factor to the cyclin D1-cdk4/6 complex. We found that low levels of p27 correlated to a poor tamoxifen response but had no prognostic value in untreated patients. ER and PR are the only clinical tools available for predicting treatment response, with a cut-off at 10% positive tumor cell nuclei. We investigated if a more detailed mapping of hormone receptor levels could provide additional information and found that it was predominantly tumors with high levels of PR (>75%) that responded well to tamoxifen treatment. Further studies, confirming cyclin D1, p27 and other factors possibly inducing tamoxifen treatment resistance, are needed. In the meantime, a more precise assessment of hormone receptor status could be informative.
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