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  • 1. Aaltonen, Kirsimari
    et al.
    Ahlin, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Salonen, Laura
    Fjällskog, Marie Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Heikkilä, Pävi
    Nevanlinna, Heli
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Reliability of cyclin A assessment on tissue microarrays in breast cancer compared to conventional histological slides2006In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 94, no 11, p. 1697-1702Article in journal (Refereed)
    Abstract [en]

    Cyclin A has in some studies been associated with poor breast cancer survival, although all studies have not confirmed this. Its prognostic significance in breast cancer needs evaluation in larger studies. Tissue microarray (TMA) technique allows a simultaneous analysis of large amount of tumours on a single microscopic slide. This makes a rapid screening of molecular markers in large amount of tumours possible. Because only a small tissue sample of each tumour is punched on an array, the question has arisen about the representativeness of TMA when studying markers that are expressed in only a small proportion of cells. For this reason, we wanted to compare cyclin A expression on TMA and on traditional large sections. Two breast cancer TMAs were constructed of 200 breast tumours diagnosed between 1997-1998. TMA slides and traditional large section slides of these 200 tumours were stained with cyclin A antibody and analysed by two independent readers. The reproducibility of the two readers' results was good or even very good, with kappa values 0.71-0.87. The agreement of TMA and large section results was good with kappa value 0.62-0.75. Cyclin A overexpression was significantly (P<0.001) associated with oestrogen receptor and progesterone receptor negativity and high grade both on TMA and large sections. Cyclin A overexpression was significantly associated with poor metastasis-free survival both on TMA and large sections. The relative risks for metastasis were similar on TMA and large sections. This study suggests that TMA technique could be useful to study histological correlations and prognostic significance of cyclin A on breast cancer on a large scale.

  • 2. Aaltonen, Kirsimari
    et al.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Heikkilä, Päivi
    Aittomäki, Kristiina
    Tamminen, A.
    Nevanlinna, Heli
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    High cyclin B1 expression is associated with poor survival in breast cancer2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 100, no 7, p. 1055-60Article in journal (Refereed)
    Abstract [en]

    Cyclin B1 regulates the G(2)-M transition of the cell cycle. Cyclin B1 expression is higher in premalignant and malignant than normal breast lesions. Correlation of cyclin B1 expression with other histopathological variables and prognostic role in breast cancer are not fully understood. Traditionally used prognostic criteria identify large subset of patients to receive adjuvant chemotherapy and to be exposed to adverse effects. A reliable and simple method helping prognostic evaluation in breast cancer is needed. We analysed cyclin B1 expression on 1348 invasive breast cancers and studied correlations with other histopathological variables and survival. High cyclin B1 correlated with high tumour grade, large tumour size and positive nodal status, oestrogen and progesterone receptor negativity, positive HER2 and p53 status, young age at diagnosis, and high cyclin E, cyclin A and Ki67 expression. Among patients not given adjuvant chemotherapy high cyclin B1 was a strong predictor of shorter overall and metastasis-free survival (RR 3.74, P<0.0005 and RR 3.51, P<0.0005, respectively), and remained as an independent prognostic factor also in multivariate analysis (RR 1.80, P=0.04 and RR 2.31, P=0.02, respectively). This study suggests high cyclin B1 associates with aggressive phenotype and is an independent prognostic factor in breast cancer.

  • 3. Adami, Johanna
    et al.
    Gäbel, H.
    Lindelöf, B.
    Ekström, K.
    Rydh, B.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ekbom, A.
    Adami, Hans-Olov
    Granath, F.
    Cancer risk following organ transplantation: a nationwide cohort study in Sweden2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 89, no 7, p. 1221-1227Article in journal (Refereed)
    Abstract [en]

    A substantial excess risk of lymphomas and nonmelanoma skin cancer has been demonstrated following organ transplantation. Large sample size and long follow-up time may, however, allow more accurate risk estimates and detailed understanding of long-term cancer risk. The objective of the study was to assess the risk of cancer following organ transplantation. A nationwide cohort study comprising 5931 patients who underwent transplantation of kidney, liver or other organs during 1970-1997 in Sweden was conducted. Complete follow-up was accomplished through linkage to nationwide databases. We used comparisons with the entire Swedish population to calculate standardised incidence ratios (SIRs), and Poisson regression for multivariate internal analyses of relative risks (RRs) with 95% confidence intervals (CI). Overall, we observed 692 incident first cancers vs 171 expected (SIR 4.0; 95% CI 3.7-4.4). We confirmed marked excesses of nonmelanoma skin cancer (SIR 56.2; 95% CI 49.8-63.2), lip cancer (SIR 53.3; 95% CI 38.0-72.5) and of non-Hodgkin's lymphoma (NHL) (SIR 6.0; 95% CI 4.4-8.0). Compared with patients who underwent kidney transplantation, those who received other organs were at substantially higher risk of NHL (RR 8.4; 95% CI 4.3-16). Besides, we found, significantly, about 20-fold excess risk of cancer of the vulva and vagina, 10-fold of anal cancer, and five-fold of oral cavity and kidney cancer, as well as two- to four-fold excesses of cancer in the oesophagus, stomach, large bowel, urinary bladder, lung and thyroid gland. In conclusion, organ transplantation entails a persistent, about four-fold increased overall cancer risk. The complex pattern of excess risk at many sites challenges current understanding of oncogenic infections that might become activated by immunologic alterations.

  • 4. Andersson, Anne
    et al.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Tavelin, B.
    Björkholm, M.
    Linderoth, J.
    Lagerlöf, I.
    Merup, M.
    Sender, M.
    Malmer, B.
    Family history of cancer as a risk factor for second malignancies after Hodgkin's lymphoma2008In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 98, no 5, p. 1001-1005Article in journal (Refereed)
    Abstract [en]

    This study estimated the risk of second primary malignancies after Hodgkin's lymphoma (HL) in relation to family history of cancer, age at diagnosis and latency, among 6946 patients treated for HL in Sweden in 1965-1995 identified through the Swedish Cancer Register (SCR). First-degree relatives (FDRs) to the HL patients and their malignancies were then ascertained together with their malignancies through the Multi-Generation Registry and SCR. The HL patient cohort was stratified on the number of FDRs with cancer, and standardised incidence ratios (SIRs) of developing SM were analysed. In the HL cohort, 781 SM were observed 1 year or longer after HL diagnosis. The risk for developing SM increased with the number of FDRs with cancer, SIRs being 2.26, 3.01, and 3.45 with 0, 1, or >or=2 FDRs with cancer, respectively. Hodgkin's lymphoma long-term survivors treated at a young age with a family history of cancer carry an increased risk for developing SM and may represent a subgroup where standardised screening for the most common cancer sites could be offered in a stringent surveillance programme.

  • 5. Barnes, N. L. P.
    et al.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Farnie, G.
    White, D.
    Jiang, W
    Anderson, E.
    Bundred, N. J.
    Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer2007In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 96, no 4, p. 575-582Article in journal (Refereed)
    Abstract [en]

    Cyclooxygenase-2 (COX-2) is associated with poor-prognosis breast cancer. We used a nude mouse xenograft model to determine the effects of COX-2 inhibition in breast cancer. Oestrogen receptor (ER)-positive MCF7/HER2-18 and ER-negative MDAMB231 breast cancer cell lines were injected into nude mice and allowed to form tumours. Mice then received either chow containing Celecoxib (a COX-2 inhibitor) or control and tumour growth measured. Tumour proliferation, apoptosis, COX-2, lymphangiogenesis and angiogenesis were assessed by immunohistochemistry (IHC), Western blotting or Q-PCR. Celecoxib inhibited median tumour growth in MCF7/HER2-18 (58.7%, P=0.029) and MDAMB231 (46.3%, P=0.0002) cell lines compared to control. Cyclooxygenase-2 expression decreased following Celecoxib treatment (MCF7/HER2-18 median control 65.3% vs treated 22.5%, P=0.0001). Celecoxib increased apoptosis in MCF7/HER2-18 tumours (TUNEL 0.52% control vs 0.73% treated, P=0.0004) via inactivation of AKT (median pAKT(ser473) 57.3% control vs 35.5% treated, P=0.0001--confirmed at Western blotting). Q-PCR demonstrated decreased podoplanin RNA (lymphangiogenesis marker) in the MCF7/HER2-18 - median 2.9 copies treated vs 66.6 control (P=0.05) and MDAMB231-treated groups--median 160.7 copies vs 0.05 control copies (P=0.015), confirmed at IHC. Cyclooxygenase-2 is associated with high levels of activated AKT(ser473) and lymphangiogenesis in breast cancer. Cyclooxygenase-2 inhibition decreases tumour growth, and may potentially decrease recurrence, by inactivating AKT and decreasing lymphangiogenesis.

  • 6.
    Bellomo, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Transforming growth factor beta as regulator of cancer stemness and metastasis2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, no 7, p. 761-769Article, review/survey (Refereed)
    Abstract [en]

    Key elements of cancer progression towards metastasis are the biological actions of cancer stem cells and stromal cells in the tumour microenvironment. Cross-communication between tumour and stromal cells is mediated by secreted cytokines, one of which, the transforming growth factor beta (TGF beta), regulates essentially every cell within the malignant tissue. In this article, we focus on the actions of TGF beta on cancer stem cells, cancer-associated fibroblasts and immune cells that assist the overall process of metastatic dissemination. We aim at illustrating intricate connections made by various cells in the tumour tissue and which depend on the action of TGF beta.

  • 7. Bernhard, J.
    et al.
    Dietrich, D.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Hess, V.
    Bodoky, G.
    Scheithauer, W.
    Herrmann, R.
    Estimating prognosis and palliation based on tumour marker CA 19-9 and quality of life indicators in patients with advanced pancreatic cancer receiving chemotherapy2010In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 103, no 9, p. 1318-1324Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To investigate the prognostic value of quality of life (QOL) relative to tumour marker carbohydrate antigen (CA) 19-9, and the role of CA 19-9 in estimating palliation in patients with advanced pancreatic cancer receiving chemotherapy. METHODS: CA 19-9 serum concentration was measured at baseline and every 3 weeks in a phase III trial (SAKK 44/00-CECOG/PAN.1.3.001). Patients scored QOL indicators at baseline, and before each administration of chemotherapy (weekly or bi-weekly) for 24 weeks or until progression. Prognostic factors were investigated by Cox models, QOL during chemotherapy by mixed-effect models. RESULTS: Patient-rated pain (P<0.02) and tiredness (P<0.03) were independent predictors for survival, although less prognostic than CA 19-9 (P<0.001). Baseline CA 19-9 did not predict QOL during chemotherapy, except for a marginal effect on pain (P<0.05). Mean changes in physical domains across the whole observation period were marginally correlated with the maximum CA 19-9 decrease. Patients in a better health status reported the most improvement in QOL within 20 days before maximum CA 19-9 decrease. They indicated substantially less pain and better physical well-being, already, early on during chemotherapy with a maximum CA 19-9 decrease of >= 50% vs <50%. CONCLUSION: In advanced pancreatic cancer, pain and tiredness are independent prognostic factors for survival, although less prognostic than CA 19-9. Quality of life improves before best CA 19-9 response but the maximum CA 19-9 decrease has no impact on subsequent QOL. To estimate palliation by chemotherapy, patient's perception needs to be taken into account.

  • 8.
    Bjørge, Tone
    et al.
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway.;Canc Registry Norway, Oslo, Norway..
    Gissler, Mika
    Natl Inst Hlth & Welf THL, Helsinki, Finland..
    Ording, Anne Gulbech
    Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark..
    Engeland, Anders
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway.;Norwegian Inst Publ Hlth, Dept Pharmacoepidemiol, Div Mental & Phys Hlth, Bergen, Norway..
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Leinonen, Maarit
    Finnish Canc Registry, Canc Soc Finland, Helsinki, Finland..
    Sørensen, Henrik Toft
    Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark..
    Tretli, Steinar
    Canc Registry Norway, Oslo, Norway..
    Ekbom, Anders
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Troisi, Rebecca
    NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD USA..
    Grotmol, Tom
    Canc Registry Norway, Oslo, Norway..
    Reproductive history and risk of colorectal adenocarcinoma in parous women: a Nordic population-based case-control study2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, no 11, p. 1416-1420Article in journal (Refereed)
    Abstract [en]

    Background: Data are conflicting regarding the role of endogenous sex hormones in colorectal carcinogenesis. In this large population-based study, we pooled data from birth and cancer registries in four Nordic countries, to evaluate the risk of colorectal adenocarcinoma in relation to women's reproductive history. Methods: We conducted a population-based case-control study among women registered in Nordic birth registries. The study included colorectal adenocarcinoma cases diagnosed in Denmark, Finland, Norway, and Sweden during 1967-2013 and up to 10 matched controls per case, in total 22 185 cases and 220 246 controls. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were derived from conditional logistic regression models. We had limited information available on possible confounders. Results: We found no evidence for associations between colorectal adenocarcinoma and parity, age at first and last birth, and time since first and last birth. The risk estimates were also close to unity for specific cancer subsites (proximal and distal colon and rectum). As well, when the analyses were stratified on menopausal status, parity, and mother's year of birth, no indication of associations was found. Conclusions: In this large, Nordic population-based study, no evidence for associations was found between women's reproductive history and colorectal adenocarcinoma in parous women.

  • 9.
    Bogdanovic, G
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Pou, C
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Barrientos-Somarribas, M
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Bjerkner, A
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Honkaniemi, E
    Department of Pediatrics, Södertälje Hospital, Stockholm, Swden.
    Allander, T
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Andersson, B
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Gustafsson, B
    Department of Clinical Science, Intervention and Technology, CLINTEC, Karolinska Institutet, Stokholm, Sweden.
    Virome characterisation from Guthrie cards in children who later developed acute lymphoblastic leukaemia.2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, no 8, p. 1008-1014Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Some childhood acute lymphoblastic leukaemias (ALL) can be traced back to a prenatal origin, where a virus infection could be involved in the first pre-leukaemic clone development. The DNA virome of 95 children who later developed ALL was characterised from neonatal blood spots (NBS) using unbiased next-generation sequencing (NGS) and compared with the virome of 95 non-ALL controls.

    METHODS: DNA was individually extracted from the ALL-patients and controls, pooled, randomly amplified and sequenced using the Illumina MiSeq Sequencing System.

    RESULTS: Virus-like sequences identified in both groups mapped to human endogenous retroviruses and propionibacterium phage, considered a part of the normal microbial flora. Potential pathogens human herpesvirus type 6 (HHV-6) and parvovirus B19 were also identified, but only few samples in both ALL and controls tested positive by PCR follow-up.

    CONCLUSIONS: Unbiased NGS was employed to search for DNA from potential infectious agents in neonatal samples of children who later developed ALL. Although several viral candidates were identified in the NBS samples, further investigation by PCR suggested that these viruses did not have a major role in ALL development.

  • 10. Boldrup, L.
    et al.
    Coates, P. J.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Wilms, T.
    Fahraeus, R.
    Nylander, K.
    Downregulation of miRNA-424: a sign of field cancerisation in clinically normal tongue adjacent to squamous cell carcinoma2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, no 11, p. 1760-1765Article in journal (Refereed)
    Abstract [en]

    Background: The overall survival for patients with squamous cell carcinoma of the tongue is low and the search for early diagnostic and prognostic markers is thus essential. MicroRNAs have been suggested as potential prognostic and diagnostic candidates in squamous cell carcinoma of head and neck in general. Methods: On the basis of the known differences between sub-sites within the oral cavity, we investigated the expression and role of microRNA-424 in squamous cell carcinoma arising in tongue. MicroRNA levels were measured by qRT-PCR in both tissue and plasma samples. Results: Levels of microRNA-424 were upregulated in tongue squamous cell carcinoma, but not in tumours originating from gingiva or floor of the mouth. Interestingly, microRNA-424 was downregulated in clinically normal tongue tissue next to tumour compared with completely healthy tongue, indicating that microRNA-424 could be a marker of field cancerisation in this tumour type. However, expression of microRNA-424 in a tongue-derived epithelial cell line revealed no significant changes in the expression profile of proteins and genes. Conclusions: Our patient data show that microRNA-424 alterations are a marker of field cancerisation specific for tongue tumourigenesis, which also could have a role in development of tongue squamous cell carcinoma.

  • 11. Boman, K
    et al.
    Larsson, A H
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Kuteeva, E
    Johannesson, H
    Nodin, B
    Eberhard, J
    Uhlén, M
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Jirström, K
    Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, p. 2321-2328Article in journal (Refereed)
    Abstract [en]

    Background:

    Membranous expression of the anti-adhesive glycoprotein podocalyxin-like (PODXL) has previously been found to correlate with poor prognosis in several major cancer forms. Here we examined the prognostic impact of PODXL expression in urothelial bladder cancer.

    Methods:

    Immunohistochemical PODXL expression was examined in tissue microarrays with tumours from two independent cohorts of patients with urothelial bladder cancer: n=100 (Cohort I) and n=343 (Cohort II). The impact of PODXL expression on disease-specific survival (DSS; Cohort II), 5-year overall survival (OS; both cohorts) and 2-year progression-free survival (PFS; Cohort II) was assessed.

    Results:

    Membranous PODXL expression was significantly associated with more advanced tumour (T) stage and high-grade tumours in both cohorts, and a significantly reduced 5-year OS (unadjusted HR=2.25 in Cohort I and 3.10 in Cohort II, adjusted HR=2.05 in Cohort I and 2.18 in Cohort II) and DSS (unadjusted HR=4.36, adjusted HR=2.70). In patients with Ta and T1 tumours, membranous PODXL expression was an independent predictor of a reduced 2-year PFS (unadjusted HR=6.19, adjusted HR=4.60) and DSS (unadjusted HR=8.34, adjusted HR=7.16).

    Conclusion:

    Membranous PODXL expression is an independent risk factor for progressive disease and death in patients with urothelial bladder cancer.

  • 12. Borg, A
    et al.
    Lennerstrand, Johan
    AB Sangtec Medical.
    Stenmark-Askmalm, M
    Fernö, M
    Brisfors, A
    Ohrvik, A
    Stål, O
    Killander, D
    Lane, D
    Brundell, J
    Prognostic significance of p53 overexpression in primary breast cancer: a novel luminometric immunoassay applicable on steroid receptor cytosols.1995In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 71, no 5, p. 1013-1017Article in journal (Refereed)
    Abstract [en]

    A novel quantitative luminometric immunoassay (LIA) has been developed for the measurement of wild-type and mutant p53 protein in extracts from breast tumour tissue. The LIA was found to yield reliable estimates of p53 expression in cytosol samples routinely prepared for steroid receptor analysis as compared with results obtained with immunohistochemical analysis. The LIA was evaluated on 205 primary breast tumour cytosols prepared for steroid receptor analysis and stored frozen at -80 degrees C for 6-8 years, p53 protein being detected in 65% of the samples (range 0.01-23 ng mg-1 protein). Using an arbitrary cut-off value of 0.15 ng mg-1 protein, 30% of the tumours were classified as manifesting p53 overexpression. Significant and independent correlations were found to exist between p53 overexpression and shorter disease-free (P < 0.001) and overall survival (P = 0.039) at a median duration of follow-up of 50 months. p53 overexpression was related to low oestrogen receptor content and high proliferation rate (S-phase fraction). No relationship was found to tumour size or the presence of lymph node metastasis. Three tumours possessed an extremely high p53 content (> 10 ng mg-1 protein), all of which were of medullary or high-grade ductal type, oestrogen and progesterone receptor negative, DNA non-diploid, had S-phase fractions of > 22% and recurred within 1-2 years. In summary, a new sensitive and quantitative LIA suitable for routine analysis of p53 protein in steroid receptor cytosol preparations from breast tumours has been developed to confirm the prognostic importance of p53 protein accumulation in human breast cancer.

  • 13. Bratt, O.
    et al.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Ahlgren, G.
    Nordle, O.
    Björk, A.
    Damber, Jan-Erik
    Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 101, no 8, p. 1233-40Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Tasquinimod is a quinoline-3-carboxamide derivative with anti-angiogenic activity. Two open-label phase I clinical trials in patients were conducted to evaluate the safety and tolerability of tasquinimod, with additional pharmacokinetic and efficacy assessments. METHODS: Patients with castration-resistant prostate cancer with no previous chemotherapy were enrolled in this study. The patients received tasquinimod up to 1 year either at fixed doses of 0.5 or 1.0 mg per day or at an initial dose of 0.25 mg per day that escalated to 1.0 mg per day. RESULTS: A total of 32 patients were enrolled; 21 patients were maintained for >or=4 months. The maximum tolerated dose was determined to be 0.5 mg per day; but when using stepwise intra-patient dose escalation, a dose of 1.0 mg per day was well tolerated. The dose-limiting toxicity was sinus tachycardia and asymptomatic elevation in amylase. Common treatment-emergent adverse events included transient laboratory abnormalities, anaemia, nausea, fatigue, myalgia and pain. A serum prostate-specific antigen (PSA) decline of >or=50% was noted in two patients. The median time to PSA progression (>25%) was 19 weeks. Only 3 out of 15 patients (median time on study: 34 weeks) developed new bone lesions. CONCLUSION: Long-term continuous oral administration of tasquinimod seems to be safe, and the overall efficacy results indicate that tasquinimod might delay disease progression.

  • 14. Brismar-Wendel, S
    et al.
    Fröberg, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Hjerpe, A
    Andersson, S
    Johansson, B
    Age-specific prevalence of HPV genotypes in cervical cytology samples with equivocal or low-grade lesions2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 101, no 3, p. 511-517Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To define the spectrum of human papillomavirus (HPV) types and establish an age limit for triage HPV testing in atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL). MATERIALS AND METHODS: 343 liquid-based cytological samples from the population-based screening programme with minor abnormalities were subjected to HPV genotyping (Linear Array, Roche, Basel, Switzerland). RESULTS: High-risk human papillomavirus (HR-HPV) was found in 71% of LSIL and 49% of ASCUS cases (P<0.001). High-risk human papillomavirus prevalence was age-dependent in LSIL (P = 0.01), with decreasing prevalence until the age of 50 years, followed by a slight increase. Human papillomavirus type 16 was the most common HR-HPV, found in 23% of HPV-positive women. Human papillomavirus type 18 was the sixth most common, found in 9.9% (P<0.001). An age-dependent quadratic trend was observed for multiple infections (P=0.01) with a trough at about 42 years. The most common HR-HPV types to show a coinfection with HPV16 (clade 9) were HPV39 (28%), 45 (38%), and 59 (46%), belonging to HPV18 clade 7. The frequency of low-risk (LR) vs probable HR and HR-HPV also followed an age-dependent quadratic trend. CONCLUSIONS: After the age of 25 years, HR-HPV prevalence is similar in LSIL and ASCUS cases, motivating a low age limit for triage HPV testing. Multiple infections and LR/HR-HPV dominance are age-dependent. Genotyping in longitudinal design is needed to elucidate the importance of multiple infections in cancer progression and in cross-protection from vaccination. British Journal of Cancer (2009) 101, 511-517. doi:10.1038/sj.bjc.6605165 www.bjcancer.com Published online 21 July 2009 (C) 2009 Cancer Research UK

  • 15. Brooks, D. R.
    et al.
    Klint, Å.
    Dickman, P. W.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Lambe, M.
    Temporal trends in non-small cell lung cancer survival in Sweden2007In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 96, no 3, p. 519-522Article in journal (Refereed)
    Abstract [en]

    We modeled temporal trends in the 1- and 5-year survival of 32 499 patients with adenocarcinoma and squamous cell carcinoma of the lung in the Swedish Cancer Register between 1961 and 2000. The 1-year relative survival for adenocarcinoma improved from 37% for patients diagnosed 1961–1965 to 45% for those diagnosed 1996–2000 and from 39 to 45% for squamous cell carcinoma. The adjusted excess mortality ratios for the period 1996–2000 compared with 1961–1965 were 0.80 for adenocarcinoma and 0.81 for squamous cell carcinoma. Thus, a previous report in a Dutch study of a relatively worsening prognosis for adenocarcinoma over time could not be confirmed.

  • 16.
    Carlsson, Jörgen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sjöström, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Villman, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bengtsson, N. O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ostenstad, B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    HER2 expression in breast cancer primary tumours and corresponding metastases: Original data and literature review2004In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 90, no 12, p. 2344-2348Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to evaluate whether the HER2 expression in breast cancer is retained in metastases. The HER2 expression in primary tumours and the corresponding lymph node metastases were evaluated in parallel samples from 47 patients. The HercepTest was used for immunohistochemical analyses of HER2 overexpression in all cases. CISH/FISH was used for analysis of gene amplification in some cases. HER2 overexpression (HER2-scores 2+ or 3+) was found in 55% of both the primary tumours and of the lymph node metastases. There were only small changes in the HER2-scores; six from 1+ to 0 and one from 3+ to 2+ when the metastases were compared to the corresponding primary tumours. However, there were no cases with drastic changes in HER2 expression between the primary tumours and the corresponding lymph node metastases. The literature was reviewed for similar investigations, and it is concluded that breast cancer lymph node metastases generally overexpress HER2 to the same extent as the corresponding primary tumours. This also seems to be the case when distant metastases are considered. It has been noted that not all patients with HER2 overexpression respond to HER2-targeted Trastuzumab treatment. The stability in HER2 expression is encouraging for efforts to develop complementary forms of therapy, for example, therapy with radionuclide-labelled Trastuzumab.

  • 17.
    Cavalli-Björkman, Nina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Qvortrup, Camilla
    Sebjørnssen, Sigrunn
    Pfeiffer, Per
    Wentzel-Larsen, Tore
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sorbye, Halfdan
    Lower treatment intensity and poorer survival in metastatic colorectal cancer patients who live alone2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 107, no 1, p. 189-194Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Socioeconomic status (SES) and social support influences cancer survival. If SES and social support affects cancer treatment has not been thoroughly explored. METHODS: A cohort consisting of all patients who were initially diagnosed with or who developed metastatic colorectal cancer (mCRC, n = 781) in three Scandinavian university hospitals from October 2003 to August 2006 was set up. Clinical and socioeconomic data were registered prospectively. RESULTS: Patients living alone more often had synchronous metastases at presentation and were less often treated with combination chemotherapy than those cohabitating (HR 0.19, 95% CI 0.04-0.85, P = 0.03). Surgical removal of metastases was less common in patients living alone (HR 0.29, 95% CI 0.10-0.86, P = 0.02) but more common among university-educated patients (HR 2.22, 95% CI 1.10-4.49, P = 0.02). Smoking, being married and having children did not influence treatment or survival. Median survival was 7.7 months in patients living alone and 11.7 months in patients living with someone (P < 0.001). Living alone remained a prognostic factor for survival after correction for age and comorbidity. CONCLUSION: Patients living alone received less combination chemotherapy and less secondary surgery. Living alone is a strong independent risk factor for poor survival in mCRC. 

  • 18. Dyrskjot, L.
    et al.
    Reinert, T.
    Novoradovsky, A.
    Zuiverloon, T. C. M.
    Beukers, W.
    Zwarthoff, E.
    Malats, N.
    Real, F. X.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Knowles, M.
    Hurst, C.
    Sorge, J.
    Borre, M.
    Orntoft, T. F.
    Analysis of molecular intra-patient variation and delineation of a prognostic 12-gene signature in non-muscle invasive bladder cancer; technology transfer from microarrays to PCR2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 107, no 8, p. 1392-1398Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Multiple clinical risk factors and genetic profiles have been demonstrated to predict progression of non-muscle invasive bladder cancer; however, no easily clinical applicable gene signature has been developed to predict disease progression independent of disease stage and grade. METHODS: We measured the intra-patient variation of an 88-gene progression signature using 39 metachronous tumours from 17 patients. For delineation of the optimal quantitative reverse transcriptase PCR panel of markers, we used 115 tumour samples from patients in Denmark, Sweden, UK and Spain. RESULTS: Analysis of intra-patient variation of the molecular markers showed 71% similar classification results. A final panel of 12 genes was selected, showing significant correlation with outcome. In multivariate Cox regression analysis, we found that the 12-gene signature was an independent prognostic factor (hazard ratio = 7.4 (95% confidence interval: 3.4-15.9), P < 0.001) when adjusting for stage, grade and treatment. Independent validation of the 12-gene panel and the determined cut-off values is needed and ongoing. CONCLUSION: Intra-patient marker variation in metachronous tumours is present. Therefore, to increase test sensitivity, it may be necessary to test several metachronous tumours from a patient's disease course. A PCR-based 12-gene signature significantly predicts disease progression in patients with non-muscle invasive bladder cancer.

  • 19.
    Elander, N. O.
    et al.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Aughton, K.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Ghaneh, P.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Neoptolemos, J. P.
    Heidelberg Univ, Dept Surg, Heidelberg, Germany..
    Palmer, D. H.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Cox, T. F.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Campbell, F.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Costello, E.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Halloran, C. M.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Mackey, J. R.
    Cross Canc Inst, Edmonton, AB, Canada.;Univ Alberta, Edmonton, AB, Canada..
    Scarfe, A. G.
    Cross Canc Inst, Edmonton, AB, Canada.;Univ Alberta, Edmonton, AB, Canada..
    Valle, J. W.
    Univ Manchester, Christie NHS Fdn Trust, Manchester, Lancs, England..
    McDonald, A. C.
    Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland..
    Carter, R.
    Glasgow Royal Infirm, Glasgow, Lanark, Scotland..
    Tebbutt, N. C.
    Austin Hlth, Melbourne, Vic, Australia..
    Goldstein, D.
    Univ New South Wales, Prince Wales Hosp, Sydney, NSW, Australia.;Univ New South Wales, Clin Sch, Sydney, NSW, Australia..
    Shannon, J.
    Nepean Canc Ctr, Sydney, NSW, Australia.;Univ Sydney, Sydney, NSW, Australia..
    Dervenis, C.
    Agia Olga Hosp, Athens, Greece..
    Glimelius, B.
    Deakin, M.
    Univ Hosp, Stoke On Trent, North Staffs, England..
    Charnley, R. M.
    Freeman Rd Hosp, Newcastle Upon Tyne, Tyne & Wear, England..
    Anthoney, Alan
    St James Univ Hosp, Leeds, W Yorkshire, England..
    Lerch, M. M.
    Univ Med Greifswald, Dept Med A, Greifswald, Germany..
    Mayerle, J.
    Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Med 2, Munich, Germany..
    Olah, A.
    Petz Aladar Hosp, Gyor, Hungary..
    Buechler, M. W.
    Heidelberg Univ, Dept Surg, Heidelberg, Germany..
    Greenhalf, W.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer2018In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 118, no 7, p. 947-954Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy.

    METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA).

    RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009).

    CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

  • 20.
    Elander, N. O.
    et al.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England.
    Aughton, K.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England.
    Ghaneh, P.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England.
    Neoptolemos, J. P.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England.
    Palmer, D. H.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England.
    Cox, T. F.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England.
    Campbell, F.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England.
    Costello, E.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England.
    Halloran, C. M.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England.
    Mackey, J. R.
    Cross Canc Ctr, Edmonton, AB, Canada;Univ Alberta, Edmonton, AB, Canada.
    Scarfe, A. G.
    Cross Canc Ctr, Edmonton, AB, Canada;Univ Alberta, Edmonton, AB, Canada.
    Valle, J. W.
    Univ Manchester, Christie NHS Fdn Trust, Manchester, Lancs, England.
    McDonald, A. C.
    Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland.
    Carter, R.
    Glasgow Royal Infirm, Glasgow, Lanark, Scotland.
    Tebbutt, N. C.
    Austin Hlth, Melbourne, Vic, Australia.
    Goldstein, D.
    Univ New South Wales, Prince Wales Hosp, Sydney, NSW, Australia;Univ New South Wales, Clin Sch, Sydney, NSW, Australia.
    Shannon, J.
    Nepean Canc Ctr, Camperdown, NSW, Australia;Univ Sydney, Camperdown, NSW, Australia.
    Dervenis, C.
    Agia Olga Hosp, Athens, Greece.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Deakin, M.
    Univ Hosp, North Staffordshire, Staffs, England.
    Charnley, R. M.
    Freeman Rd Hosp, Newcastle Upon Tyne, Tyne & Wear, England.
    Anthoney, A.
    St James Univ Hosp, Leeds, W Yorkshire, England.
    Lerch, M. M.
    Univ Med Greifswald, Dept Med A, Greifswald, Germany.
    Mayerle, J.
    Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Med 2, Munich, Germany.
    Olah, A.
    Petz Aladar Hosp, Gyor, Hungary.
    Buchler, M. W.
    Heidelberg Univ, Dept Surg, Heidelberg, Germany.
    Greenhalf, W.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England.
    Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy2018In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 118, no 8, p. 1084-1088Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma.

    METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups.

    RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group.

    CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

  • 21. Elsir, T.
    et al.
    Qu, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Berntsson, Shala G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Orrego, A.
    Olofsson, T.
    Lindström, M. S.
    Nistér, M.
    von Deimling, A.
    Hartmann, C.
    Ribom, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    PROX1 is a predictor of survival for gliomas WHO grade II2011In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, no 11, p. 1747-1754Article in journal (Refereed)
    Abstract [en]

    Background:The clinical course of World Health Organisation grade II gliomas remains variable and their time point of transformation into a more malignant phenotype is unpredictable. Identification of biological markers that can predict prognosis in individual patients is of great clinical value. PROX1 is a transcription factor that has a critical role in the development of various organs. PROX1 has been ascribed both oncogenic and tumour suppressive functions in human cancers. We have recently shown that PROX1 may act as a diagnostic marker for high-grade gliomas. The aim of this study was to address the prognostic value of PROX1 in grade II gliomas.Methods:A total of 116 samples were evaluated for the presence of PROX1 protein. The number of immunopositive cells was used as a variable in survival analysis, together with established prognostic factors for this patient group.Results:Higher PROX1 protein was associated with poor outcome. In the multivariate analysis, PROX1 was identified as an independent factor for survival (P=0.024), together with the presence of mutated isocitrate dehydrogenase 1 R132H protein, and with combined losses of chromosomal arms 1p/19q in oligodendrocytic tumours.Conclusion:PROX1 is a novel predictor of survival for grade II gliomas.

  • 22. Frisch, Morten
    et al.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    van den Brule, Adriaan J.
    Wohlfahrt, J.
    Meijer, Chris J.
    Walboomers, Jan M.
    Adami, Hans-Olov
    Melbye, Mads
    Benign anal lesions, inflammatory bowel disease and risk for high-riskive and -negative anal carcinoma1998In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 78, no 11, p. 1534-1538Article in journal (Refereed)
    Abstract [en]

    A central role in anal carcinogenesis of high-risk types of human papillomaviruses (hrHPV) was recently established, but the possible role of benign anal lesions has not been addressed in hrHPV-positive and -negative anal cancers. As part of a population-based case-control study in Denmark and Sweden, we interviewed 417 case patients (93 men and 324 women) diagnosed during the period 1991-94 with invasive or in situ anal cancer, 534 patients with adenocarcinoma of the rectum and 554 population controls. Anal cancer specimens (n = 388) were tested for HPV by the polymerase chain reaction. Excluding the 5 years immediately before diagnosis, men, but not women, with anal cancer reported a history of haemorrhoids [multivariate odds ratio (OR) 1.8; 95% confidence interval (CI) 1.04-3.2] and unspecific anal irritation (OR 4.5; CI 2.3-8.7) significantly more often than controls. Women with anal cancer did not report a history of benign anal lesions other than anal abscess to any greater extent than controls, but they had used anal suppositories more often (OR 1.5; CI 1.1-2.0). Patients with hrHPV in anal cancer tissue (84%) and those without (16%) reported similar histories of most benign anal lesions, but anal fissure or fistula was more common among hrHPV-positive cases. Ulcerative colitis and Crohn's disease, reported by <1% of study participants, were not associated with anal cancer risk. The higher proportion of hrHPV-positive anal cancers among case patients with anal fissure or fistula suggests that such mucosal lesions may provide direct viral access to basal epithelial layers. Since risk associations with benign anal lesions in men may be confounded by unreported sexual behaviour, and since risk associations in women were generally negative, it seems unlikely that benign anal lesions act as promoters in hrHPV-associated anal carcinogenesis. Moreover, benign anal lesions appear not to be linked to an alternative, hrHPV-unassociated causal pathway to anal cancer. Ulcerative colitis and Crohn's disease were not supported as causal factors for anal cancer.

  • 23.
    Fröberg, M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Johansson, B.
    Hjerpe, A.
    Andersson, S.
    Human papillomavirus 'reflex' testing as a screening method in cases of minor cytological abnormalities2008In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 99, no 4, p. 563-568Article in journal (Refereed)
    Abstract [en]

    The aim was to evaluate human papillomavirus (HPV) 'reflex genotyping' in cases of minor cytological abnormalities detected in the gynaecological screening programme in Stockholm, Sweden. Liquid-based cytology samples showing minor cytological abnormalities were analysed using HPV genotyping (Linear Array, Roche diagnostics). Colposcopically directed cervical biopsies were obtained and the HPV test results were correlated with the histological results. In all, 63% (70/112) of the samples were high-risk (HR) HPV (HR-HPV) positive. A statistically significant correlation was found between high-grade cervical lesions and HR-HPV (P = 0.019), among which HPV 16, 18, and 31 were the most important. The negative predictive value of HR-HPV detection for histologically confirmed high-grade lesions was 100%. An age limit for HPV reflex testing may be motivated in cases of low-grade squamous intraepithelial neoplasia (LSIL), because of high HR-HPV prevalence among younger women. By using HPV reflex genotyping, additional extensive workup can safely be avoided in about 50% of all cases of atypical squamous cells of undetermined significance ( ASCUS) and LSIL among women > ;= 30 years. This screening strategy could potentially reduce the total abnormal cytology-reporting rate in the Swedish screening programme by about 1% and provide more accurately directed follow-up, guided by cytological appearance and HPV test results.

  • 24. Gaber, A.
    et al.
    Johansson, M.
    Stenman, U-H.
    Hotakainen, K.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bjartell, A.
    Jirström, K.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    High expression of tumour-associated trypsin inhibitor correlates with liver metastasis and poor prognosis in colorectal cancer2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 100, no 10, p. 1540-1548Article in journal (Refereed)
    Abstract [en]

    Increased expression of tumour-associated trypsin inhibitor (TATI) in tumour tissue and/or serum has been associated with poor survival in various cancer forms. Moreover, a proinvasive function of TATI has been shown in colon cancer cell lines. In this study, we have examined the prognostic significance of tumour-specific TATI expression in colorectal cancer, assessed by immunohistochemistry (IHC) on tissue microarrays (TMAs) with tumour specimens from two independent patient cohorts. Kaplan-Meier analysis and Cox proportional hazards modelling were used to estimate time to recurrence, disease-free survival and overall survival. In both cohorts, a high (>50% of tumour cells) TATI expression was an independent predictor of a significantly shorter overall survival. In cohort II, in multivariate analysis including age, gender, disease stage, differentiation grade, vascular invasion and carcinoembryonal antigen (CEA), high TATI expression was associated with a significantly decreased overall survival (HR=1.82; 95% CI=1.19-2.79) and disease-free survival (HR=1.56; 95% CI=1.05-2.32) in curatively treated patients. Moreover, there was an increased risk for liver metastasis in both cohorts that remained significant in multivariate analysis in cohort II (HR=2.85; 95% CI=1.43-5.66). In conclusion, high TATI expression is associated with liver metastasis and is an independent predictor of poor prognosis in patients with colorectal cancer.

  • 25.
    Ghuan, Sundeep
    et al.
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England..
    Van Hemelrijck, Mieke
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England..
    Garmo, Hans
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England.;Reg Canc Ctr, Uppsala, Sweden..
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England.;Reg Canc Ctr, Uppsala, Sweden..
    Malmström, Håkan
    Karolinska Inst, Inst Environm Med, Dept Epidemiol, Stockholm, Sweden..
    Lambe, Mats
    Reg Canc Ctr, Uppsala, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Hammar, Niklas
    AstraZeneca R&D, Molndal, Sweden.;Karolinska Inst, Inst Environm Med, Dept Cardiovasc Epidemiol, Stockholm, Sweden..
    Walldius, Göran
    Karolinska Inst, Inst Environm Med, Dept Cardiovasc Epidemiol, Stockholm, Sweden..
    Jungner, Ingmar
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.;CALAB Res, Stockholm, Sweden..
    Wulaningsih, Wahyu
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England.;UCL, MRC, Unit Lifelong Hlth & Ageing, London, England..
    Serum inflammatory markers and colorectal cancer risk and survival2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 116, no 10, p. 1358-1365Article in journal (Refereed)
    Abstract [en]

    Background: Inflammation has been linked with development of some cancers. We investigated systemic inflammation in relation to colorectal cancer incidence and subsequent survival using common serum inflammatory markers

    Design: A cohort of men and women aged 20 years and older in greater Stockholm area with serum C-reactive protein (CRP) and albumin measured between 1986 and 1999 were included (n-325 599). A subset of these had baseline measurements of haptoglobin and leukocytes. Multivariable Cox regression was performed to assess risk of colorectal cancer by levels of inflammatory markers, adjusting for potential confounders. Analyses were stratified by circulating glucose, total cholesterol and triglycerides. Overall and CRC-specific death following diagnosis were assessed as secondary outcomes.

    Results: A total of 4764 individuals were diagnosed with colorectal cancer. A positive association between haptoglobin and colorectal cancer incidence was found (hazard ratio (HR): 1.17; 95% CI: 1.06-1.28). A positive association was also observed with leukocytes (HR: 1.21; 95% CI: 1.03-1.42). No evidence of association was noted between CRP and colorectal cancer risk. Higher risks of all-cause death were seen with haptoglobin and leukocytes levels. Higher haptoglobin levels were linked with an increased risk of colorectal cancer death (HR: 1.19; 95% CI: 1.01-1.41).

    Conclusions: Prediagnostic systemic inflammation may impact colorectal cancer incidence and survival; therefore, prompting investigations linking inflammatory pathways preceding colorectal cancer with disease severity and progression.

  • 26. Gremel, G.
    et al.
    Ryan, D.
    Rafferty, M.
    Lanigan, F.
    Hegarty, S.
    Lavelle, M.
    Murphy, I.
    Unwin, L.
    Joyce, C.
    Faller, W.
    McDermott, E. W.
    Sheahan, K.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gallagher, W. M.
    Functional and prognostic relevance of the homeobox protein MSX2 in malignant melanoma2011In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 105, no 4, p. 565-574Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The homeobox containing transcription factor MSX2 is a key regulator of embryonic development and has been implicated to have a role in breast and pancreatic cancer. METHODS: Using a selection of two-and three-dimensional in vitro assays and tissue microarrays (TMAs), the clinical and functional relevance of MSX2 in malignant melanoma was explored. A doxycyline-inducible over-expression system was applied to study the relevance of MSX2 in vitro. For TMA construction, tumour material from 218 melanoma patients was used. RESULTS: Ectopic expression of MSX2 resulted in the induction of apoptosis and reduced the invasive capacity of melanoma cells in three-dimensional culture. MSX2 over-expression was shown to affect several signalling pathways associated with cell invasion and survival. Downregulation of N-Cadherin, induction of p21 and inhibition of both BCL2 and Survivin were observed. Cytoplasmic MSX2 expression was found to correlate significantly with increased recurrence-free survival (P = 0.008). Nuclear expression of MSX2 did not result in significant survival correlations, suggesting that the beneficial effect of MSX2 may be independent of its DNA binding activity. CONCLUSIONS: MSX2 may be an important regulator of melanoma cell invasion and survival. Cytoplasmic expression of the protein was identified as biomarker for good prognosis in malignant melanoma patients.

  • 27.
    Guren, Tormod Kyrre
    et al.
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway..
    Thomsen, Maria
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway..
    Kure, Elin H.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway..
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.;Univ Southern Denmark, Inst Clin Res, Odense, Denmark..
    Osterlund, Pia
    Tampere Univ Hosp, Dept Oncol, Tampere, Finland..
    Sigurdsson, Fridbjorn
    Landspitali, Dept Oncol, Reykjavik, Iceland..
    Lothe, Inger Marie Bowitz
    Oslo Univ Hosp, Dept Pathol, Oslo, Norway..
    Dalsgaard, Astrid Marie
    Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway..
    Skovlund, Eva
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, Trondheim, Norway..
    Christoffersen, Thoralf
    Univ Oslo, Fac Med, Inst Clin Med, Dept Pharmacol, Oslo, Norway..
    Tveit, Kjell Magne
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway.;Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway..
    Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 116, no 10, p. 1271-1278Article in journal (Refereed)
    Abstract [en]

    Background: The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival analysis with BRAF and extended RAS mutational status, 5 years after the primary analysis.

    Methods: A total of 566 patients were included in the intention-to-treat (ITT) population of the NORDIC-VII study. Updated survival status was obtained from 176 patients who were alive in the primary survival analyses. Samples from 223 tumours previously found to be KRAS (exon 2) and BRAF (V600E) wild-type, were re-analysed for KRAS (exons 3 and 4) and NRAS (exons 2-4) mutations.

    Results: Including the extended RAS analyses, RAS and BRAF mutational status was available from 457 patients (81% of the ITT population). RAS was mutated in 46% and BRAF in 12% of the tumours. RAS and BRAF, if mutated, were negative prognostic factors. The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours, neither on progression-free nor overall survival. However, the outcomes in a subset of patients, which, after the first eight treatment cycles, received cetuximab alone, suggested a beneficial effect of cetuximab monotherapy.

    Conclusions: Adding cetuximab to Nordic FLOX did not provide any clinical benefit, but the data suggested an effect of cetuximab monotherapy in patients with RAS/BRAF wild-type tumours in the NORDIC-VII cohort. The data were compatible with a negative interaction between cetuximab and the Nordic FLOX chemotherapy backbone.

  • 28. Gustafsson, L.
    et al.
    Sparén, P.
    Gustafsson, M.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bergström, R.
    Adami, Hans-Olov
    Efficency of organized and oppurtunistic cytological screening for cancer in situ of the cervix1995In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 72, no 2, p. 498-505Article in journal (Refereed)
    Abstract [en]

    Cervical cancer incidence and mortality can be reduced by removal of precursor lesions detected at cytological screening. Organised screening, i.e. regular invitation of defined target groups, is generally considered more effective than opportunistic screening. The latter method however, is predominant in most settings. There is no scientific basis for advocating one type of screening or the other. Our aim was to compare the two types and to analyse their efficiency. We analysed 466,275 smears taken in an open cohort of 118,890 women during 1969-88. A computerised database permitted standardised classification of all smears and complete ascertainment of cancer in situ through record linkage. The number of in situ cancers detected per 1000 smears, the detection ratio, was used as an outcome measure both in univariate analyses and in multivariate logistic regression models. Cancer in situ was detected in 1076 women in the study cohort, with a detection ratio of 3.0 at organised and 2.1 at opportunistic screening, yielding an unadjusted odds ratio of 0.69 (95% CI 0.61-0.79). After adjustment for age and time period, the probability of detecting cancer in situ was around 25% higher with opportunistic than with organised screening (OR = 1.26; 95% CI 1.09-1.46). This difference in favour of opportunistic screening was most pronounced in the first 10 year period and disappeared during the last decade. The difference in efficiency between organised and opportunistic screening in the detection of cancer in situ was slight, if any. The dogma that organised screening is significantly more efficient than the opportunistic type needs reconsideration.

  • 29. Gustavsson, Inger
    et al.
    Aarnio, Riina
    Berggrund, Malin
    Hedlund-Lindberg, Julia
    Strand, Ann-Sofi
    Sanner, Karin
    Wikström, Ingrid
    Enroth, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Olovsson, Matts
    Gyllensten, Ulf
    Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology.2018In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 118, no 6, p. 896-904Article in journal (Refereed)
    Abstract [en]

    This corrects the article DOI: 10.1038/bjc.2017.85.

  • 30.
    Gyllensten, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sanner, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Gustavsson, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindell, Monica
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wikström, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Short-time repeat high-risk HPV testing by self-sampling for screening of cervical cancer2011In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 105, no 5, p. 694-697Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Testing for high-risk human papillomavirus (HPV) in primary screening for cervical cancer is considered more sensitive, but less specific, in comparison with Pap-smear cytology. Women with persistent HPV infections have a higher risk of developing cervical intraepithelial neoplasia 2+ (CIN2+) lesions. This study was performed to evaluate the gain in specificity for detection of histologically confirmed CIN2+ lesions achieved by short-time repeat testing for high-risk HPV in women aged 30-65 years, with the primary sample for HPV analysis taken by self-sampling. METHODS: A total of 8000 women in Uppsala County, aged 30-65 years, who had not attended organised screening for 6 years or longer, were offered self-sampling of vaginal fluid at home and the samples sent for HPV typing. Of these, 8% (669) were not possible to contact or had performed hysterectomy. Women positive for high-risk HPV in the self-sampling test were invited for a follow-up HPV test and a cervical biopsy on average 3 months after the initial HPV test. RESULTS: In all, 39% (2850/7331) of invited women chose to perform self-sampling of vaginal fluid at home. High-risk HPV infection was found in 6.6% (188) of the women. In all, 89% of the women testing HPV positive performed a follow-up examination, on average 2.7 months, after the first test and 59% of these women were HPV positive in the follow-up test. The prevalence of CIN2+ lesions in women with an initial HPV-positive test was 23% (95% CI 18-30%) and in women with two consecutive HPV-positive tests was 41% (95% CI 31-51%). In women with two positive HPV tests, the prevalence of CIN2+ lesions varied from 49% in women at age 30-39 years to 24% in women at age 50-65 years. Short-time repeat HPV testing increased the specificity for detection of CIN2+ lesions from about 94.2% to 97.8%. The most prevalent HPV types were HPV16 (32%), followed by HPV18/45 (19%) and HPV 33/52/58 (19%). CONCLUSION: The short-time persistence of high-risk HPV infection in this age group was about 60%. Repeat testing for high-risk HPV using self-sampling of vaginal fluid can be used to increase the specificity in the screening for cervical cancer in women aged 30-65 years.

  • 31.
    Hansson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Ethics and biobanks2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 100, no 1, p. 8-12Article, review/survey (Refereed)
    Abstract [en]

    Biobank research has been the focus of great interest of scholars and regulatory bodies who have addressed different ethical issues. On the basis of a review of the literature it may be concluded that, regarding some major themes in this discussion, a consensus seems to emerge on the international scene after the regular exchange of arguments in scientific journals. Broad or general consent is emerging as the generally preferred solution for biobank studies and straightforward instructions for coding will optimise privacy while facilitating research that may result in new methods for the prevention of disease and for medical treatment. The difficult question regarding the return of information to research subjects is the focus of the current research, but a helpful analysis of some of the issues at stake and concrete recommendations have recently been suggested.

  • 32. Harris, H. R.
    et al.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Wolk, A.
    Alcohol intake and mortality among women with invasive breast cancer2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 106, no 3, p. 592-595Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Alcohol intake has consistently been associated with increased breast cancer incidence in epidemiological studies. However, the relation between alcohol and survival after breast cancer diagnosis is less clear.

    METHODS: We investigated whether alcohol intake was associated with survival among 3146 women diagnosed with invasive breast cancer in the Swedish Mammography Cohort. Alcohol consumption was estimated using a food frequency questionnaire. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs).

    RESULTS: From 1987 to 2008 there were 385 breast cancer-specific deaths and 860 total deaths. No significant association was observed between alcohol intake and breast cancer-specific survival. Women who consumed 10 g per day (corresponding to approximately 0.75 to 1 drinks) or more of alcohol had an adjusted HR (95% CI) of breast cancer-specific death of 1.36 (0.82-2.26; p(trend) = 0.47) compared with non-drinkers. A significant inverse association was observed between alcohol and non-breast cancer deaths. Those who consumed 3.4-9.9 g per day of alcohol had a 33% lower risk of death compared with non-drinkers (95% CI 0.50-0.90; p(trend) = 0.04).

    CONCLUSION: Our findings suggest that alcohol intake up to approximately one small drink per day does not negatively impact breast cancer-specific survival and a half drink per day is associated with a decreased risk of mortality from other causes.

  • 33. Harris, H R
    et al.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Wolk, A
    Coffee and black tea consumption and breast cancer mortality in a cohort of Swedish women2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 107, no 5, p. 874-878Article in journal (Refereed)
    Abstract [en]

    Background:

    Coffee and black tea contain a mixture of compounds that have the potential to influence breast cancer risk and survival. However, epidemiologic data on the relation between coffee and black tea consumption and breast cancer survival are sparse.

    Methods:

    We investigated the association between coffee and black tea consumption and survival among 3243 women with invasive breast cancer in the Swedish Mammography Cohort. Intake was estimated using a food frequency questionnaire. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs).

    Results:

    From 1987 to 2010 there were 394 breast cancer-specific deaths and 973 total deaths. Coffee and black tea were not associated with breast cancer-specific or overall mortality. Women consuming 4+ cups of coffee per day had a covariate and clinical characteristics-adjusted HR (95% CI) of death from breast cancer of 1.14 (0.71-1.83; ptrend=0.81) compared with those consuming <1 cup per day. Women consuming 2+ cups of black tea per day had a covariate and clinical characteristics-adjusted HR (95% CI) of death from breast cancer of 1.02 (0.67-1.55; ptrend=0.94) compared with non-tea drinkers. Caffeine was also not associated with breast cancer-specific (HR for top to bottom quartile=1.06; 95% CI=0.79-1.44; ptrend=0.71) or overall mortality.

    Conclusion:

    Our findings suggest that coffee, black tea, and caffeine consumption before breast cancer diagnosis do not influence breast cancer-specific and overall survival.

  • 34. Harris, H. R.
    et al.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Wolk, A.
    Vitamin C intake and breast cancer mortality in a cohort of Swedish women2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 109, no 1, p. 257-264Article in journal (Refereed)
    Abstract [en]

    Background: Vitamin C may influence cancer progression through its antioxidant properties. However, the evidence from observational epidemiologic studies on vitamin C intake and survival following breast cancer diagnosis is not consistent, and the safety of vitamin C supplements following breast cancer diagnosis has not been extensively studied. Methods: Using a food-frequency questionnaire we investigated whether vitamin C intake was associated with survival among 3405 women diagnosed with invasive breast cancer in the Swedish Mammography Cohort. Results: From 1987-2010, there were 1055 total deaths with 416 deaths from breast cancer. Women in the highest quartile of pre-diagnosis vitamin C intake had an adjusted HR (95% CI) of breast cancer death of 0.75 (0.57-0.99) compared with those in the lowest quartile (P-trend=0.03). There was a borderline significant association between vitamin C intake and total mortality (HR 0.84; 95% CI 0.71-1.00; P-trend=0.08). Among 717 breast cancer cases for whom post-diagnosis supplement use was available, there was no association between vitamin C supplement use (approximate to 1000 mg) and breast cancer-specific mortality (HR=1.06; 95% CI=0.52-2.17). Conclusion: Our findings suggest that dietary vitamin C intake before breast cancer diagnosis may be associated with breast cancer survival. In addition, post-diagnosis vitamin C supplementation at the level observed in our population was not associated with survival.

  • 35.
    Heikkila, Katriina
    et al.
    London Sch Hyg & Trop Med, Dept Hlth Serv Res & Policy, London WC1, England.;Finnish Inst Occupat Hlth, Tampere 33100, Finland.;Finnish Inst Occupat Hlth, Turku 205200, Finland..
    Nyberg, Solja T.
    Finnish Inst Occupat Hlth, Tampere 33100, Finland.;Finnish Inst Occupat Hlth, Turku 205200, Finland..
    Madsen, Ida E. H.
    Natl Res Ctr Working Environm, DK-2100 Copenhagen, Denmark..
    de Vroome, Ernest
    TNO, NL-2316 ZL Leiden, Netherlands..
    Alfredsson, Lars
    Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden.;Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden..
    Bjorner, Jacob J.
    Natl Res Ctr Working Environm, DK-2100 Copenhagen, Denmark..
    Borritz, Marianne
    Koge Hosp, DK-4600 Koge, Denmark..
    Burr, Hermann
    Fed Inst Occupat Safety & Hlth, D-10317 Berlin, Germany..
    Erbel, Raimund
    Univ Duisburg Essen, West German Heart Ctr Essen, Dept Cardiol, D-45122 Essen, Germany..
    Ferrie, Jane E.
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.;Univ Bristol, Sch Social & Community Med, Bristol BS8 2PS, Avon, England..
    Fransson, Eleonor I.
    Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden.;Jonkoping Univ, Sch Hlth & Welf, SE-55111 Jonkoping, Sweden.;Stockholm Univ, Stress Res Inst, SE-10691 Stockholm, Sweden..
    Geuskens, Goedele A.
    TNO, NL-2316 ZL Leiden, Netherlands..
    Hooftman, Wendela E.
    TNO, NL-2316 ZL Leiden, Netherlands..
    Houtman, Irene L.
    TNO, NL-2316 ZL Leiden, Netherlands..
    Joeckel, Karl-Heinz
    Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Fac Med, D-45122 Essen, Germany..
    Knutsson, Anders
    Mid Sweden Univ, Dept Hlth Sci, S-85170 Sundsvall, Sweden..
    Koskenvuo, Markku
    Univ Helsinki, Dept Publ Hlth, Helsinki 00140, Finland..
    Lunau, Thorsten
    Univ Dusseldorf, Fac Med, Inst Med Sociol, D-40225 Dusseldorf, Germany..
    Nielsen, Martin L.
    Frederiksberg Univ Hosp, Unit Social Med, DK-2000 Frederiksberg, Denmark..
    Nordin, Maria
    Stockholm Univ, Stress Res Inst, SE-10691 Stockholm, Sweden.;Umea Univ, Dept Psychol, S-90187 Umea, Sweden..
    Oksanen, Tuula
    Finnish Inst Occupat Hlth, Tampere 33100, Finland.;Finnish Inst Occupat Hlth, Turku 205200, Finland..
    Pejtersen, Jan H.
    Danish Natl Ctr Social Res, DK-1052 Copenhagen, Denmark..
    Pentti, Jaana
    Finnish Inst Occupat Hlth, Tampere 33100, Finland.;Finnish Inst Occupat Hlth, Turku 205200, Finland..
    Shipley, Martin J.
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England..
    Steptoe, Andrew
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England..
    Suominen, Sakari B.
    Univ Turku, Dept Publ Hlth, Turku 20014, Finland.;Folkhalsan Res Ctr, Helsinki 00290, Finland.;Nord Sch Publ Hlth, S-42671 Gothenburg, Sweden..
    Theorell, Toeres
    Stockholm Univ, Stress Res Inst, SE-10691 Stockholm, Sweden..
    Vahtera, Jussi
    Finnish Inst Occupat Hlth, Tampere 33100, Finland.;Finnish Inst Occupat Hlth, Turku 205200, Finland.;Univ Turku, Dept Publ Hlth, Turku 20014, Finland.;Turku Univ Hosp, Turku 20521, Finland..
    Westerholm, Peter J. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Westerlund, Hugo
    Stockholm Univ, Stress Res Inst, SE-10691 Stockholm, Sweden..
    Dragano, Nico
    Univ Dusseldorf, Fac Med, Inst Med Sociol, D-40225 Dusseldorf, Germany..
    Rugulies, Reiner
    Natl Res Ctr Working Environm, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Dept Publ Hlth, DK-2200 Copenhagen, Denmark.;Univ Copenhagen, Dept Psychol, DK-2200 Copenhagen, Denmark..
    Kawachi, Ichiro
    Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, 665 Huntington Ave, Boston, MA 02115 USA..
    Batty, G. David
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Singh-Manoux, Archana
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.;INSERM, U1018, Ctr Res Epidemiol & Populat Hlth, F-94807 Villejuif, France..
    Virtanen, Marianna
    Finnish Inst Occupat Hlth, Tampere 33100, Finland.;Finnish Inst Occupat Hlth, Turku 205200, Finland..
    Kivimaki, Mika
    Finnish Inst Occupat Hlth, Tampere 33100, Finland.;Finnish Inst Occupat Hlth, Turku 205200, Finland.;UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.;Univ Helsinki, Fac Med, Clinicum, FI-00014 Helsinki, Finland..
    Long working hours and cancer risk: a multi-cohort study2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 114, no 7, p. 813-818Article in journal (Refereed)
    Abstract [en]

    Background: Working longer than the maximum recommended hours is associated with an increased risk of cardiovascular disease, but the relationship of excess working hours with incident cancer is unclear. Methods: This multi-cohort study examined the association between working hours and cancer risk in 116 462 men and women who were free of cancer at baseline. Incident cancers were ascertained from national cancer, hospitalisation and death registers; weekly working hours were self-reported. Results: During median follow-up of 10.8 years, 4371 participants developed cancer (n colorectal cancer: 393; n lung cancer: 247; n breast cancer: 833; and n prostate cancer: 534). We found no clear evidence for an association between working hours and the overall cancer risk. Working hours were also unrelated the risk of incident colorectal, lung or prostate cancers. Working >= 55 h per week was associated with 1.60-fold (95% confidence interval 1.12-2.29) increase in female breast cancer risk independently of age, socioeconomic position, shift-and night-time work and lifestyle factors, but this observation may have been influenced by residual confounding from parity. Conclusions: Our findings suggest that working long hours is unrelated to the overall cancer risk or the risk of lung, colorectal or prostate cancers. The observed association with breast cancer would warrant further research.

  • 36. Hellman, K.
    et al.
    Lindquist, D.
    Ranhem, C.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Andersson, S.
    Human papillomavirus, p16(INK4A), and Ki-67 in relation to clinicopathological variables and survival in primary carcinoma of the vagina2014In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 110, no 6, p. 1561-1570Article in journal (Refereed)
    Abstract [en]

    Background: This study aimed to determine human papillomavirus (HPV) status and to investigate p16(INK4A) and Ki-67 expression and their correlation with clinical parameters and survival in women with primary carcinoma of the vagina (PCV). Methods: The presence of HPV DNA was evaluated by PCR. Genotyping was performed by Luminex in 68 short-term (<= 2 years) and long-term (>= 8 years) PCV survivors. p16(INK4A) and Ki-67 expression was evaluated by immunohistochemistry. Results: Human papillomavirus DNA was detected in 43% of patients, the majority (63%) of whom were HPV16 positive. High p16INK4A expression was significantly correlated with low histopathological grade (P =0.004), HPV positivity (P =0.032), and long-term survival (P =0.045). High Ki-67 expression was negatively correlated with histopathological grade (P < 0.001) and tumour size (P =0.047). There was an association between HPV positivity and low histopathological grade, but not between HPV positivity and survival. Conclusion: High p16(INK4A) expression was associated with long-term survival, but the only independent predictors for survival were tumour size and histopathological grade. Our results indicate that p16(INK4A) and Ki-67 expression might be useful in tumour grading, and that it might be possible to use p16(INK4A) expression as a marker for HPV positivity, but this has to be further elucidated.

  • 37.
    Hellman, Kristina
    et al.
    Department of Gynaecologic Oncology, Radiumhemmet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
    Alaiya, Ayodele A.
    Proteomics Unit, Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Center, Box 3354, (MBC#03), 11211, Riyadh, Saudi Arabia.
    Becker, Susanne
    Unit of Cancer Proteomics, Department of Oncology and Pathology, Karolinska Institute and Hospital, SE-171 76 Stockholm, Sweden.
    Lomnytska, Marta
    Institute for Clinical Science, Department of Obstetrics and Gynaecology, Karolinska University Hospital, Huddinge, Karolinska Institute, SE-14186 Stockholm, Sweden.
    Schedvins, Kjell
    Department of Gynaecology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
    Steinberg, Winfried
    Institution of Cytological Diagnosis (Kloster-Paradiese), Im Stiftsfeld, 159494 Soest, Germany.
    Hellström, Ann-Cathrin
    Department of Gynaecologic Oncology, Radiumhemmet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
    Andersson, Sonia
    Institute for Clinical Science, Department of Obstetrics and Gynaecology, Karolinska University Hospital, Huddinge, Karolinska Institute, SE-14186 Stockholm, Sweden.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Auer, Gert
    Unit of Cancer Proteomics, Department of Oncology and Pathology, Karolinska Institute and Hospital, SE-171 76 Stockholm, Sweden.
    Differential tissue-specific protein markers of vaginal carcinoma2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 100, no 8, p. 1303-1314Article, review/survey (Refereed)
    Abstract [en]

    The objective was to identify proteins differentially expressed in vaginal cancer to elucidate relevant cancer-related proteins. A total of 16 fresh-frozen tissue biopsies, consisting of 5 biopsies from normal vaginal epithelium, 6 from primary vaginal carcinomas and 5 from primary cervical carcinomas, were analysed using two-dimensional gel electrophoresis (2-DE) and MALDI-TOF mass spectrometry. Of the 43 proteins identified with significant alterations in protein expression between non-tumourous and tumourous tissue, 26 were upregulated and 17 were downregulated. Some were similarly altered in vaginal and cervical carcinoma, including cytoskeletal proteins, tumour suppressor proteins, oncoproteins implicated in apoptosis and proteins in the ubiquitin-proteasome pathway. Three proteins were uniquely altered in vaginal carcinoma (DDX48, erbB3-binding protein and biliverdin reductase) and five in cervical carcinoma (peroxiredoxin 2, annexin A2, sarcomeric tropomyosin kappa, human ribonuclease inhibitor and prolyl-4-hydrolase beta). The identified proteins imply involvement of multiple different cellular pathways in the carcinogenesis of vaginal carcinoma. Similar protein alterations were found between vaginal and cervical carcinoma suggesting common tumourigenesis. However, the expression level of some of these proteins markedly differs among the three tissue specimens indicating that they might be useful molecular markers.

  • 38.
    Hemdan, Tammer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lindén, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lind, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Namuduri, Arvind
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sjöstedt, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    D de Ståhl, T
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    The prognostic value and therapeutic target role of stathmin-1 in urinary bladder cancer2014In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 111, no 6, p. 1180-1187Article in journal (Refereed)
    Abstract [en]

    Background:The oncoprotein-18/stathmin 1 (STMN1), involved in cell progression and migration, is associated with clinical outcome in breast cancer. Here we aim to investigate its clinical significance in urinary bladder cancer and its possibilities as a therapeutic target.Methods:Immunohistochemical analyses of STMN1 protein expression were performed in three patient cohorts: cohort I (n=115 Ta, n=115 T1, n=112 T2-4 stages), cohort II, based on randomised controlled trials (n=239 T1-T4), and cohort III of primary tumour/matched metastasis (n=90 T1-T4). The effects of STMN1 on cell proliferation and migration were evaluated in the urinary bladder cancer cell line, T24, by inhibiting STMN1-cellular expression using siRNA.Results:In cohort I, high STMN1 expression correlated to shorter disease-specific survival hazard ratio (HR)=2.04 (95% confidence interval (CI) 1.13-3.68; P=0.02), elevated p53- (P<0.001) and Ki67-protein levels (P<0.001). The survival result was validated in cohort II: HR=1.76 (95% CI 1.04-2.99; P=0.03). In the metastatic bladder cancer material, 70% of the patients were STMN1-positive in both the primary tumour and matched metastases. In vitro, the growth and migration of the T24 cells were significantly reduced (P<0.01, P<0.0001, respectively), when transfecting the cells with STMN1-siRNA.Conclusions:STMN1 protein expression has prognostic significance but is primarily a potential treatment target in urinary bladder cancer. 

  • 39.
    Holmberg, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wong, Y. N. S.
    Tabar, Laszlo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ringberg, A.
    Karlsson, P.
    Arnesson, L-G
    Sandelin, K.
    Anderson, H.
    Garmo, H.
    Emdin, S.
    Mammography casting-type calcification and risk of local recurrence in DCIS: analyses from a randomised study2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, no 4, p. 812-819Article in journal (Refereed)
    Abstract [en]

    Background: We studied the association between mammographic calcifications and local recurrence in the ipsilateral breast. Methods: Case-cohort study within a randomised trial of radiotherapy in breast conservation for ductal cancer in situ of the breast (SweDCIS). We studied mammograms from cases with an ipsilateral breast event (IBE) and from a subcohort randomly sampled at baseline. Lesions were classified as a density without calcifications, architectural distortion, powdery, crushed stone-like or casting-type calcifications. Results: Calcifications representing necrosis were found predominantly in younger women. Women with crushed stone or casting-type microcalcifications had higher histopathological grade and more extensive disease. The relative risk (RR) of a new IBE comparing those with casting-type calcifications to those without calcifications was 2.10 (95% confidence interval (Cl) 0.92-4.80). This risk was confined to in situ recurrences; the RR of an IBE associated with casting-type calcifications on the mammogram adjusted for age and disease extent was 16.4 (95% Cl 2.20-140). Conclusion: Mammographic appearance of ductal carcinoma in situ of the breast is prognostic for the risk of an in situ IBE and may also be an indicator of responsiveness to RT in younger women.

  • 40. Jakubowska, A.
    et al.
    Rozkrut, D.
    Antoniou, A.
    Hamann, U.
    Scott, R. J.
    McGuffog, L.
    Healy, S.
    Sinilnikova, O. M.
    Rennert, G.
    Lejbkowicz, F.
    Flugelman, A.
    Andrulis, I. L.
    Glendon, G.
    Ozcelik, H.
    Thomassen, M.
    Paligo, M.
    Aretini, P.
    Kantala, J.
    Aroer, B.
    Von Wachenfeldt, A.
    Liljegren, A.
    Loman, N.
    Herbst, K.
    Kristoffersson, U.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Karlsson, P.
    Stenmark-Askmalm, M.
    Melin, B.
    Nathanson, K. L.
    Domchek, S. M.
    Byrski, T.
    Huzarski, T.
    Gronwald, J.
    Menkiszak, J.
    Cybulski, C.
    Serrano, P.
    Osorio, A.
    Cajal, T. R.
    Tsitlaidou, M.
    Benitez, J.
    Gilbert, M.
    Rookus, M.
    Aalfs, C. M.
    Kluijt, I.
    Boessenkool-Pape, J. L.
    Meijers-Heijboer, H. E. J.
    Oosterwijk, J. C.
    van Asperen, C. J.
    Blok, M. J.
    Nelen, M. R.
    van den Ouweland, A. M. W.
    Seynaeve, C.
    van der Luijt, R. B.
    Devilee, P.
    Easton, D. F.
    Peock, S.
    Frost, D.
    Platte, R.
    Ellis, S. D.
    Fineberg, E.
    Evans, D. G.
    Lalloo, F.
    Eeles, R.
    Jacobs, C.
    Adlard, J.
    Davidson, R.
    Eccles, D.
    Cole, T.
    Cook, J.
    Godwin, A.
    Bove, B.
    Stoppa-Lyonnet, D.
    Caux-Moncoutier, V.
    Belotti, M.
    Tirapo, C.
    Mazoyer, S.
    Barjhoux, L.
    Boutry-Kryza, N.
    Pujol, P.
    Coupier, I.
    Peyrat, J-P
    Vennin, P.
    Muller, D.
    Fricker, J-P
    Venat-Bouvet, L.
    Johannsson, OTh
    Isaacs, C.
    Schmutzler, R.
    Wappenschmidt, B.
    Meindl, A.
    Arnold, N.
    Varon-Mateeva, R.
    Niederacher, D.
    Sutter, C.
    Deissler, H.
    Preisler-Adams, S.
    Simard, J.
    Soucy, P.
    Durocher, F.
    Chenevix-Trench, G.
    Beesley, J.
    Chen, X.
    Rebbeck, T.
    Couch, F.
    Wang, X.
    Lindor, N.
    Fredericksen, Z.
    Pankratz, V. S.
    Peterlongo, P.
    Bonanni, B.
    Fortuzzi, S.
    Peissel, B.
    Szabo, C.
    Mai, P. L.
    Loud, J. T.
    Lubinski, J.
    Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 106, no 12, p. 2016-2024Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

  • 41.
    Johansson, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Brandberg, Y.
    Hellbom, M.
    Persson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Petersson, L-M.
    Berglund, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Health-related quality of life and distress in cancer patients: results from a large randomised study2008In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 99, no 12, p. 1975-1983Article in journal (Refereed)
    Abstract [en]

    To compare the effectiveness of individual support, group rehabilitation and a combination of the two in improving health-related quality of life (HRQOL) and psychological well-being in cancer patients during 24 months after diagnosis, as compared with standard care (SC). Furthermore, to compare the study sample and a random sample of the Swedish population with regard to HRQOL. A total of 481 consecutive patients, newly diagnosed with cancer, were randomly assigned to one of the four alternatives. Data on HRQOL and psychological well-being were collected at baseline and after 3, 6, 12 and 24 months. The interventions did not improve HRQOL or psychological well-being, as compared with SC. At 3 months, the study sample reported an HRQOL comparable with the normal population. Many cancer patients are able to manage their cancer-related concerns with the support available from SC. However, it is reasonable to assume that the findings suffer from a lack of data from especially vulnerable patients and a possible Hawthorne effect. It cannot be concluded that cancer patients have no need for additional psychosocial interventions. Future projects should include screening and target interventions for those at risk for significant and prolonged psychological distress.

  • 42. Kaliszczak, M
    et al.
    Trousil, S
    Åberg, O
    Perumal, M
    Nguyen, Q-D
    Aboagye, E O
    A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth.2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, no 2, p. 342-50Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: This study investigates whether a histone deacetylase subtype 6 (HDAC6) inhibitor could be used in the treatment of solid tumours.

    METHODS: We evaluated the effect of a novel inhibitor, C1A, on HDAC6 biochemical activity and cell growth. We further examined potential of early noninvasive imaging of cell proliferation by [(18)F]fluorothymidine positron emission tomography ([(18)F]FLT-PET) to detect therapy response.

    RESULTS: C1A induced sustained acetylation of HDAC6 substrates, α-tubulin and HSP90, compared with current clinically approved HDAC inhibitor SAHA. C1A induced apoptosis and inhibited proliferation of a panel of human tumour cell lines from different origins in the low micromolar range. Systemic administration of the drug inhibited the growth of colon tumours in vivo by 78%. The drug showed restricted activity on gene expression with <0.065% of genes modulated during 24 h of treatment. C1A treatment reduced tumour [(18)F]FLT uptake by 1.7-fold at 48 h, suggesting that molecular imaging could provide value in future studies of this compound.

    CONCLUSION: C1A preferentially inhibits HDAC6 and modulates HDAC6 downstream targets leading to growth inhibition of a diverse set of cancer cell lines. This property together with the favourable pharmacokinetics and efficacy in vivo makes it a candidate for further pre-clinical and clinical development.

  • 43. Larsson, Susanna C.
    et al.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wolk, Alicja
    Fruit and vegetable consumption in relation to ovarian cancer incidence: the Swedish Mammography Cohort2004In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 90, no 11, p. 2167-70Article in journal (Refereed)
    Abstract [en]

    We prospectively examined the incidence of epithelial ovarian cancer and its subtypes in relation to baseline fruit and vegetable consumption in the Swedish Mammography Cohort, a population-based cohort study of 61 084 women aged 38-76 years in 1987-1990. During an average follow-up of 13.5 years, 266 incident cases of invasive epithelial ovarian cancer were diagnosed. After adjustment for potential confounders, we observed a statistically significant inverse association between consumption of vegetables and ovarian cancer risk (P-value for trend=0.01); the multivariate rate ratio (RR) for the comparison of three or more servings of vegetables per day with one or fewer servings per day was 0.61 (95% confidence interval (CI), 0.38-0.97). For fruit consumption a modest, not statistically significant, positive association was found (P-value for trend=0.07); the multivariate RR for the highest compared with the lowest category of consumption being 1.37 (95% CI, 0.90-2.06). The associations with fruit and vegetable consumption did not vary by subtype of ovarian cancer. These findings suggest that high consumption of vegetables, but not of fruits, may reduce the risk of ovarian cancer.

  • 44. Li, Q.
    et al.
    Zhang, Xiao-Qun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nie, L.
    Chen, G-S
    Li, H.
    Zhang, F.
    Zhang, L-Y
    Hong, L.
    Wang, S-F
    Wang, H.
    Expression of interferon-gamma in human adrenal gland and kidney tumours2007In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 97, no 3, p. 420-425Article in journal (Refereed)
    Abstract [en]

    It is known that interferon-γ (IFN-γ) is produced by activated T and NK lymphoid cells, mononuclear cells, and macrophage and dendritic cells. Our previous studies have shown that IFN-γ-like immunoreactivity also appears in human adrenal cortical tumour and phaeochromocytoma. To investigate whether human tumour cells can produce IFN-γ, we examined 429 biopsy specimens of 30 kinds of tumour and tumour-surrounding tissues in adrenal glands and in kidneys by using immunohistochemistry and in situ hybridisation. IFN-γ immunoactivity was shown in 34.3% of the adrenal cortical adenomas, 50% of the adrenal cortical carcinomas, 26.7% of the phaeochromocytomas, 26.7% of the clear cell renal cell carcinomas (RCCs), 22% of the adrenal cortexes and 40% of medullas adjacent to tumours. The positive samples and expression areas were well overlapped between the IFN-γ mRNA and the immunohistochemistry staining. Western blot analysis has further confirmed the immunohistochemistry results by showing a distinct IFN-γ band corresponding to 17.4 kDa in tissue extracts from adrenal cortical adenoma, phaeochromocytoma and clear cell RCCs. These results indicate that IFN-γ is produced by some types of tumour cells, suggesting it may play a dual role in the development of these tumours.

  • 45. Lipworth, L.
    et al.
    Hsieh, C-Ce.
    Wide, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ekbom, A.
    Yu, S-Z.
    Yu, G-P.
    Xu, B.
    Hellerstein, S.
    Carlstrom, K.
    Trichopoulos, D.
    Adami, Hans-Olov
    Maternal pregnancy hormone levels in an area with a high incidence (Boston, USA) and in an area with a low incidence (Shanghai, China) of breast cancer1999In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 79, no 1, p. 7-12Article in journal (Refereed)
    Abstract [en]

    Characteristics probably associated with the fetal hormonal milieu have recently been shown to increase (birth size indicators, prematurity, neonatal jaundice) or decrease (pregnancy toxaemia) breast cancer risk in the female offspring. However, it is unknown whether differences in pregnancy hormone levels may contribute to the marked geographical variation in breast cancer incidence. We have compared, in a highly standardized manner, pregnancy hormone levels in a population with high incidence and one with low incidence of breast cancer. Three hundred and four pregnant Caucasian women in Boston and 334 pregnant Chinese women in Shanghai were enrolled from March 1994 to October 1995. Levels of oestradiol, oestriol, prolactin, progesterone, human growth hormone, albumin and sex hormone-binding globulin were measured in maternal blood at weeks 16 and 27 of gestation and compared between the two study sites using non-parametric Wilcoxon's rank-sum test. Demographical, anthropometrical and pregnancy characteristics were ascertained through interview, and relevant variables concerning delivery and the newborn were abstracted from medical records and paediatric charts. During the first visit, median serum levels of all studied hormones were statistically significant, and in most instances substantially, higher among Chinese women, who have a low incidence of breast cancer, compared with American women, who have a high incidence of breast cancer. An analogous pattern was evident during the second visit, although the relative differences tended to be smaller. Further research is needed to identify lifestyle or other exogenous determinants of pregnancy hormone levels, as well as possible mechanisms by which they may influence carcinogenic processes in the breast and possibly other organs.

  • 46.
    Lomnytska, M. I.
    et al.
    Department of Obstetrics and Gynecology, Institute for Clinical Science and Technology, CLINTEC, Karolinska University Hospital, Huddinge, Karolinska Institutet, Stockholm SE-14186, Sweden.
    Becker, S.
    Unit of Cancer Proteomics, Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-171 76, Sweden.
    Bodin, I.
    Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-171 76, Sweden.
    Olsson, A.
    Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-171 76, Sweden.
    Hellman, K.
    Department of Gynecologic Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm SE-171 76, Sweden.
    Hellström, A-C
    Department of Gynecologic Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm SE-171 76, Sweden.
    Mints, M.
    Department of Obstetrics and Gynecology, Karolinska University Hospital, Solna, Karolinska Institutet, SE-17176 Stockholm, Sweden.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Auer, G.
    Unit of Cancer Proteomics, Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-171 76, Sweden.
    Andersson, S.
    Department of Obstetrics and Gynecology, Institute for Clinical Science and Technology, CLINTEC, Karolinska University Hospital, Huddinge, Karolinska Institutet, Stockholm SE-14186, Sweden.
    Differential expression of ANXA6, HSP27, PRDX2, NCF2, and TPM4 during uterine cervix carcinogenesis: diagnostic and prognostic value2011In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, no 1, p. 110-119Article in journal (Refereed)
    Abstract [en]

    Background:Cytology-based diagnostics of squamous cervical cancer (SCC) precursor lesions is subjective and can be improved by objective markers.Methods:IHC-based analysis of ANXA6, HSP27, peroxiredoxin 2 (PRDX2), NCF2, and tropomyosin 4 (TPM4) during SCC carcinogenesis.Results:Expression of ANXA6, HSP27, PRDX2, and NCF2 in the cytoplasm of dysplastic cells increased from cervical intraepithelial neoplasia 2/3 (CIN2/3) to microinvasive cancer. Invasive SCC showed lower expression of TPM4 than CIN and normal epithelium. CIN2/3 with the highest sensitivity and specificity differed from normal epithelium by cytoplasmic expression of HSP27. Patients with cytoplasmic HSP27 expression in SCC deviating from that observed in normal epithelium had worse relapse-free (P0.019) and overall (P0.014) survival. Invasive SCC with the highest sensitivity and specificity differed from normal epithelium by expression of PRDX2 and TPM4 in the cytoplasm, from CIN2/3 by the expression of ANXA6 and TPM4 in the cytoplasm, and from microinvasive SCC by the expression of PRDX2 and ANXA6 in the cytoplasm. The number of sporadic ANXA6 cells between the atypical cells increased from CIN2/3 to invasive SCC.Conclusion:Detection of expression changes of the proteins ANXA6, HSP27, PRDX2, NCF2, and TPM4 in SCC precursor lesions may aid current cytological and pathological diagnostics and evaluation of prognosis.

  • 47.
    Lomnytska, M. I.
    et al.
    Department of Obstetrics and Gynaecology, Karolinska University Hospital, Solna, Karolinska Institute, SE-17176 Stockholm, Sweden.
    Becker, S.
    Unit of Cancer Proteomics, Department of Oncology and Pathology, Karolinska Institute, Karolinska University Hospital, SE-17176 Stockholm, Sweden.
    Gemoll, T.
    Unit of Cancer Proteomics, Department of Oncology and Pathology, Karolinska Institute, Karolinska University Hospital, SE-17176 Stockholm, Sweden.
    Lundgren, C.
    Department of Gynaecological Oncology, Radiumhemmet, Karolinska University Hospital, Solna, SE-17176 Stockholm, Sweden.
    Habermann, J.
    Department of Surgery, University of Lübeck, D-23538 Lübeck, Germany.
    Olsson, A.
    Department of Oncology and Pathology, Karolinska Institute, Karolinska University Hospital, SE-17176 Stockholm, Sweden.
    Bodin, I.
    Department of Oncology and Pathology, Karolinska Institute, Karolinska University Hospital, SE-17176 Stockholm, Sweden.
    Engström, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Hellman, K.
    Department of Gynaecological Oncology, Radiumhemmet, Karolinska University Hospital, Solna, SE-17176 Stockholm, Sweden.
    Hellström, A-C
    Department of Gynaecological Oncology, Radiumhemmet, Karolinska University Hospital, Solna, SE-17176 Stockholm, Sweden.
    Andersson, S.
    Department of Obstetrics and Gynaecology, Karolinska University Hospital, Solna, Karolinska Institute, SE-17176 Stockholm, Sweden.
    Mints, M.
    Department of Obstetrics and Gynaecology, Karolinska University Hospital, Solna, Karolinska Institute, SE-17176 Stockholm, Sweden.
    Auer, G.
    Unit of Cancer Proteomics, Department of Oncology and Pathology, Karolinska Institute, Karolinska University Hospital, SE-17176 Stockholm, Sweden.
    Impact of genomic stability on protein expression in endometrioid endometrial cancer2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 106, no 7, p. 1297-1305Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Genomic stability is one of the crucial prognostic factors for patients with endometrioid endometrial cancer (EEC). The impact of genomic stability on the tumour tissue proteome of EEC is not yet well established.

    METHODS: Tissue lysates of EEC, squamous cervical cancer (SCC), normal endometrium and squamous cervical epithelium were subjected to two-dimensional (2D) gel electrophoresis and identification of proteins by MALDI TOF MS. Expression of selected proteins was analysed in independent samples by immunohistochemistry.

    RESULTS: Diploid and aneuploid genomically unstable EEC displayed similar patterns of protein expression. This was in contrast to diploid stable EEC, which displayed a protein expression profile similar to normal endometrium. Approximately 10% of the differentially expressed proteins in EEC were specific for this type of cancer with differential expression of other proteins observed in other types of malignancy (e.g., SCC). Selected proteins differentially expressed in 2D gels of EEC were further analysed in an EEC precursor lesion, that is, atypical hyperplasia of endometrium, and showed increased expression of CLIC1, EIF4A1 and PRDX6 and decreased expression of ENO1, ANXA4, EMD and Ku70.

    CONCLUSION: Protein expression in diploid and aneuploid genomically unstable EEC is different from the expression profile of proteins in diploid genomically stable EEC. We showed that changes in expression of proteins typical for EEC could already be detected in precursor lesions, that is, atypical hyperplasia of endometrium, highlighting their clinical potential for improving early diagnostics of EEC.

  • 48. Lophatananon, Artitaya
    et al.
    Stewart-Brown, Sarah
    Kote-Jarai, Zsofia
    Olama, Ali Amin Al
    Garcia, Sara Benlloch
    Neal, David E
    Hamdy, Freddie C
    Donovan, Jenny L
    Giles, Graham G
    Fitzgerald, Liesel M
    Southey, Melissa C
    Pharoah, Paul
    Pashayan, Nora
    Gronberg, Henrik
    Wiklund, Fredrik
    Aly, Markus
    Stanford, Janet L
    Brenner, Hermann
    Dieffenbach, Aida K
    Arndt, Volker
    Park, Jong Y
    Lin, Hui-Yi
    Sellers, Thomas
    Slavov, Chavdar
    Kaneva, Radka
    Mitev, Vanio
    Batra, Jyotsna
    Spurdle, Amanda
    Clements, Judith A
    Easton, Douglas
    Eeles, Rosalind A
    Muir, Kenneth
    Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium.2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 117, no 5, p. 734-743Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer.

    METHODS: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions.

    RESULTS: The results suggest that height is associated with high-grade prostate cancer risk. Men with height >180 cm are at a 22% increased risk as compared to men with height <173 cm (OR 1.22, 95% CI 1.01-1.48). Genetic variants in the growth pathway gene showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as compared to lowest score group.

    CONCLUSIONS: There was no evidence of gene-environment interaction between height and the selected candidate SNPs.Our findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures.

  • 49.
    Loskog, Angelica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Maleka, Aglaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mangsbo, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Lundberg, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Nilsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Krause, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Agnarsdóttir, Margrét
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Tötterman, Thomas H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Immunostimulatory AdCD40L gene therapy combined with low-dose cyclophosphamide in metastatic melanoma patients2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 114, no 8, p. 872-880Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Current approaches for treating metastatic malignant melanoma (MM) are not effective enough and are associated with serious adverse events. Due to its immunogenicity, melanoma is an attractive target for immunostimulating therapy. In this phase I/IIa study, local AdCD40L immunostimulatory gene therapy was evaluated in patients with MM.

    METHODS: AdCD40L is an adenovirus carrying the gene for CD40 ligand. Patients that failed standard treatments were enrolled. Six patients received four weekly intratumoral AdCD40L injections. Next, nine patients received low-dose cyclophosphamide conditioning before the first and fourth AdCD40L injection. The blood samples were collected at multiple time points for chemistry, haematology and immunology evaluations. Radiology was performed at enrolment and repeated twice after the treatment.

    RESULTS: AdCD40L was safe with mild transient reactions. No objective responses were recorded by MRI, however, local and distant responses were seen on FDG-PET. The overall survival at 6 months was significantly better when cyclophosphamide was added to AdCD40L. The patients with the best survival developed the highest levels of activated T cells and experienced a pronounced decrease of intratumoral IL8.

    CONCLUSIONS: AdCD40L therapy for MM was well tolerated. Local and distant responses along with better survival in the low-dose cyclophosphamide group are encouraging.

  • 50.
    Martikainen, Miika
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Eastern Finland, AI Virtanen Inst Mol Sci, Dept Biotechnol & Mol Med, Kuopio 70211, Finland.
    Ruotsalainen, Janne
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Dept Biotechnol & Mol Med, Kuopio 70211, Finland.;Univ Hosp Magdeburg, Dept Dermatol, D-39120 Magdeburg, Germany..
    Tuomela, Johanna
    Univ Turku, Inst Biomed, FIN-20520 Turku, Finland..
    Harkonen, Pirkko
    Univ Turku, Inst Biomed, FIN-20520 Turku, Finland..
    Essand, Magnus
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Heikkila, Jari
    Abo Akad Univ, Dept Biochem & Pharm, Turku 20500, Finland..
    Hinkkanen, Ari
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Dept Biotechnol & Mol Med, Kuopio 70211, Finland..
    Oncolytic alphavirus SFV-VA7 efficiently eradicates subcutaneous and orthotopic human prostate tumours in mice2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 117, no 1, p. 51-55Article in journal (Refereed)
    Abstract [en]

    Background: Despite recent therapeutic and diagnostic advances, prostate cancer remains the second leading cause of cancer-related deaths among men in the Western world. Oncolytic viruses that replicate selectively in tumour cells represent a novel treatment candidate for these malignancies.

    Methods: We analysed infectivity of avirulent Semliki Firest virus SFV-VA7 in human prostate cancer cell lines VCaP, LNCaP and 22Rv1 and in nonmalignant prostate epithelial cell line RWPE-1. Therapeutic potency of SFV-VA7 was evaluated in subcutaneous and orthotopic mouse LNCaP xenograft models.

    Results: SFV-VA7 infected and killed the tested human prostate cancer cell lines irrespective of their hormone response status, while the nonmalignant prostate epithelial cell line RWPE-1 proved highly virus resistant. Notably, a single peritoneal dose of SFV-VA7 was sufficient to eradicate all subcutaneous and orthotopic LNCaP tumours.

    Conclusions: Our results indicate that SFV-VA7 is a novel, promising therapeutic virus against prostate cancer warranting further testing in early clinical trials.

12 1 - 50 of 91
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