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  • 1. Adami, Hans-Olov
    et al.
    Tsai, Shirng-wern
    Lambe, Mats
    Hsich, Chung-cheng
    Adami, Johanna
    Trichopoulus, Dimitrios
    Melbye, Mads
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Pregnancy and risk of non-Hodgkin´s lymphoma: a prospective study1997In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 70, no 2, p. 155-158Article in journal (Refereed)
    Abstract [en]

    The etiology of non-Hodgkin's lymphomas (NHL), including chronic lymphocytic leukemia (CLL), is likely to be related to immune function. In the light of the established immunologic effects of a pregnancy, we decided to examine the risk of NHL and CLL in relationship to full-term pregnancies. Within a nationwide cohort we identified 1,546 women with NHL and 198 women with CLL, all 15 years or older, born 1925-1972. Five age-matched controls were selected for each case patient. Conditional logistic regression was used to estimate the odds ratios after mutual adjustment for number of births and age at first birth. We found a weak, negative association between parity and risk of NHL (p for trend 0.11) and a transient, 10-40% decrease in risk within 5-14 years after the last birth among women with various parity status. The risk of CLL decreased more markedly, and orderly with increasing parity, but the trend was not significant (p = 0.18). Small numbers of cases with CLL prevented more detailed analyses of temporal relationships. Age at first birth appeared unrelated to the risk of both NHL and CLL. We conclude that the immunologic alterations associated with a pregnancy have limited, if any, relevance to the etiology of NHL and CLL; changing reproductive pattern is an unlikely contributor to the marked increase in incidence of NHL seen in many populations.

  • 2. Adami, Johanna
    et al.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Cnattingius, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Ekbom, A.
    Zahm, S.H.
    Linet, M.
    Zack, M.
    Maternal and perinatal factors associated with non-Hodgkin's lymphoma among children1996In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 65, no 6, p. 774-777Article in journal (Refereed)
    Abstract [en]

    This nested case-control study based on 1.7 million live births in Sweden explores the associations between maternal and perinatal factors and the occurrence of childhood non-Hodgkin's lymphoma (NHL). The National Swedish Cancer Registry ascertained 168 cases in successive birth cohorts from 1973 through 1989 recorded in the Swedish Medical Birth Registry. From the nationwide Birth Registry, 5 controls without NHL and alive at the date the case was diagnosed were randomly selected from the pool of children, with each case matched by gender, birth year and birth month. Standardized information on selected maternal and perinatal factors up to one month after delivery were recorded in the Medical Birth Registry. Mothers of children with NHL were more likely than mothers of controls to have undergone Cesarean section [Odds ratio (OR) 1.6] and to have been exposed to paracervical anesthesia during delivery (OR 1.8). Children with NHL were more likely than controls to have endocrine-metabolic disorders (OR 3.3). This study is one of the largest focusing on the etiology of childhood NHL. Most of the maternal and perinatal characteristics studied did not markedly affect risk for childhood NHL, which may be due to maternal and perinatal factors not included in these data or to exposures later in life.

  • 3. Adami, Johanna
    et al.
    Gridley, Gloria
    Nyrén, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Dosemeci, Mustafa
    Linet, Martha
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ekbom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Zahm, Shelia Hoar
    Sunlight and non-Hodgkin's lymphoma: a population-based cohort study in Sweden1999In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 80, no 5, p. 641-645Article in journal (Refereed)
    Abstract [en]

    Indirect evidence, notably ecological comparisons and an association with skin cancer, links non-Hodgkin's lymphoma (NHL) with exposure to sunlight. We conducted a population-based, nationwide cohort study with exposure to outdoor work inferred from job titles reported in the population and housing censuses in 1960 and/or 1970 and by classifying each individual's work and home addresses according to latitude. Follow-up for cancer incidence was accomplished through record linkages with the virtually complete Swedish Cancer Registry. The cohort included all Swedish residents who were recorded as gainfully employed in both censuses. Altogether 4,171,175 individuals contributing 69,639,237 person-years accrued through 1989 were included in the analyses. We identified 10,381 cases of NHL, 4,018 cases of chronic lymphocytic leukemia (CLL), 11,398 cases of malignant melanoma (MM) and 11,913 cases of squamous cell skin cancer (SCC). We calculated age-adjusted relative risks for NHL, CLL, MM and SCC in strata based on estimated residential and occupational sunlight exposure. Interaction effects were considered for pesticide and solvent exposure. NHL, MM and SCC, but not CLL, were positively associated with increasingly southerly residential latitude, with stronger associations seen for skin cancer compared to NHL. Occupational sun exposure was not associated with the risk of developing any of the studied cancers. Pesticides and solvents also were not related to an increased risk of NHL, nor did these exposures enhance effects of residential or occupational sunlight exposure. Our results provide some support for an association of sunlight exposure with NHL incidence based on the associations seen using geographic latitude of residence as a proxy for exposure. Although type of occupation may be an imperfect index of the biologically relevant ultraviolet (UV) light dose, our data on individual exposure are not consistent with an important role of sunlight in the etiology of NHL.

  • 4. Akre, Olof
    et al.
    Lipworth, Loren
    Tretli, Steinar
    Linde, Annika
    Engstrand, Lars
    Adami, Hans-Olov
    Melbye, Mads
    Andersen, Aaage
    Ekbom, Anders
    Epstein-Barr virus and cytomegalovirus in relation to testicular-cancer risk: a nested case-control study1999In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 82, no 1, p. 1-5Article in journal (Refereed)
    Abstract [en]

    An infectious etiology of testicular cancer has been suggested. We have evaluated seroreactivity against cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in relation to testicular-cancer risk in a case-control study, nested within a cohort of prospectively collected serum specimens from 293,692 individuals. For each of 81 cases of testicular cancer identified, 3 controls were randomly selected from the cohort. Serum IgG antibody titers against CMV and EBV were determined using enzyme-linked immunosorbent assays (ELISAs) and immunofluorescence methods. Odds ratios (OR) were obtained from conditional logistic-regression models. No association was found between CMV positivity and testicular cancer overall (OR = 1.08; 95% confidence interval 0.60-1.94); risk for testicular seminoma was increased among CMV seropositive [OR = 1.70 (0.80-3.59)], whereas seropositivity was associated with decreased risk for testicular non-seminoma [OR = 0.54 (0.19-1.56)] (p for heterogeneity, 0.09). For EBV, the risk for testicular cancer was increased among individuals seropositive for viral capsid antigen (VCA) [OR = 2.74 (0.62-12.12)]. The results lend some support to the hypothesis of an infectious etiology, and we propose that future studies should take into account age at infection.

  • 5.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Patients suffering from both Hodgkin's disease and non-Hodgkin's lymphoma: a clinico-pathological and immuno-histochemical population-based study of 32 patients1997In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 71, no 4, p. 510-516Article in journal (Refereed)
    Abstract [en]

    The occurrence of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) appearing in the same individual indicates a closer relationship between the 2 diseases than previously believed. The purpose of our study was to analyze cases of HD and NHL in a defined population clinically, histopathologically and immunohistochemically to look for similarities indicating a common cellular origin. Between 1974 and 1994, 77 individuals were identified from the Swedish Cancer Registry and the National Health Care Programme for HD as potentially having both diagnoses. Thirty-two patients who had both HD and NHL were available for histo-pathological re-examination and immunohistochemical staining with CD30, CD15, LMP, p53, CD45 (LCA), CD3, CD45R0 (UCHL-1), L26, MB2 and CD45R (4KB5). The most common relation was HD preceding a high-grade malignant NHL (16 of 32 patients), unexpectedly often of T-cell phenotype (7 of 16 patients). The next common association was NHL of B-CLL type followed by HD (7 of 32 patients). At clinical presentation, the first lymphoma did not differ from lymphomas not associated with a second lymphoma, whereas the second one often appeared with a disseminated and aggressive clinical form. There was a significant correlation between the expression of p53 and LMP in first and second lymphomas. CD3 antibody was frequently expressed both in HD and NHL, whereas positivity for B-cell-related antibodies, CD30, CD15 and CD45R0, was less frequent and generally lower than previously described. The occurrence of HD and NHL in an individual is unusual. Tumour biological features common to both HD and NHL may indicate a similar cellular origin, regardless of the time interval between the diagnoses, and may contribute to the understanding of the pathogenesis of lymphoma.

  • 6. Andersson, Anne
    et al.
    Näslund, Ulf
    Tavelin, Björn
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Gustavsson, Anita
    Malmer, Beatrice
    Long-term risk of cardiovascular disease in Hodgkin lymphoma survivors: retrospective cohort analyses and a concept for prospective intervention2009In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 124, no 8, p. 1914-1917Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown increased cardiovascular mortality as late side effects in Hodgkin lymphoma (HL) patients. This study identifies stratifying risk factors for surveillance and defines concepts for a clinical feasible and noninvasive prospective protocol for intervention of cardiovascular side effects. HL patients diagnosed between 1965 and 1995 (n = 6.946) and their first-degree relatives (FDR) were identified through the Swedish Cancer Registry and the Swedish Multigeneration Registry. For the HL and FDR cohort, in-patient care for cardiovascular disease (CVD) was registered through the Hospital Discharge Registry, Sweden. Standard incidence ratios of developing CVD for the HL cohort were calculated. A markedly increased risk for in-patient care of CVD was observed in HL patients with HL diagnosed at age 40 years or younger and with more than 10 years follow-up. In the HL survivors, a family history of congestive heart failure (CHF) and coronary artery disease (CAD) increased the risk for these diseases. The Swedish Hodgkin Intervention and Prevention study started in 2007. In the pilot feasibility study for prospective intervention (47 patients), about 25% of the cases had side effects and laboratory abnormalities. These patients were referred to a cardiologist or general practitioner. In the prospective cohort, a positive family history for CHF or CAD could be a stratifying risk factor when setting up a surveillance model. The prospective on-going study presents an intervention model that screens and treats for comorbidity factors. This article also presents an overview of the study concept.

  • 7.
    Arthur, R.
    et al.
    Kings Coll London, Fac Life Sci & Med, Div Canc Studies, TOUR, London, England;Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA.
    Williams, R.
    Kings Coll London, Fac Life Sci & Med, Div Canc Studies, TOUR, London, England.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Kings Coll London, Fac Life Sci & Med, Div Canc Studies, TOUR, London, England.
    Holmberg, L.
    Kings Coll London, Fac Life Sci & Med, Div Canc Studies, TOUR, London, England.
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology. Karolinska Inst, Inst Environm Med, Unit Epidemiol, Stockholm, Sweden.
    Malmstrom, H.
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, Stockholm, Sweden;Swedish Orphan Biovitrum, Stockholm, Sweden.
    Lambe, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Hammar, N.
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, Stockholm, Sweden;AstraZeneca, Global Med Dev Med Evidence & Observat Res, Stockholm, Sweden.
    Walldius, G.
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, Stockholm, Sweden.
    Robinsson, D.
    Ryhov Hosp, Dept Urol, Jonkoping, Sweden.
    Jungner, I.
    Karolinska Inst, Dept Clin Epidemiol, Stockholm, Sweden;CALAB Res, Stockholm, Sweden.
    Van Hemelrijck, M.
    Kings Coll London, Fac Life Sci & Med, Div Canc Studies, TOUR, London, England;Karolinska Inst, Inst Environm Med, Unit Epidemiol, Stockholm, Sweden.
    Serum inflammatory markers in relation to prostate cancer severity and death in the Swedish AMORIS study2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 142, no 11, p. 2254-2262Article in journal (Refereed)
    Abstract [en]

    Inflammation is a well-documented driver of cancer development and progression. However, little is known about its role in prostate carcinogenesis. Thus, we examined the association of C-reactive protein (CRP), haptoglobin, albumin and white blood cells (WBC) with prostate cancer (PCa) severity (defined by PCa risk category and clinicopathological characteristics) and progression (defined by PCa death). We selected 8,471 Swedish men with newly diagnosed PCa who had exposure measurements taken approximately 14 years prior to diagnosis. We calculated odds ratio (OR) and 95% confidence interval (CI) for the associations between the inflammatory markers and PCa severity using logistic regression, while Cox proportional hazard regression was used for the associations with overall and PCa death. Serum CRP levels were associated with increased odds of high risk and metastatic PCa, and high PSA levels (20 mu g/L) (OR: 1.29; 95% CI: 1.06-1.56, 1.32; 1.05-1.65 and 1.51; 1.26-1.81, respectively). Similarly, higher haptoglobin levels were associated with increased odds of metastatic PCa, high PSA level and possibly high grade PCa (1.38; 1.10-1.74, 1.50; 1.17-1.93 and 1.25; 1.00-1.56, respectively). Albumin was positively associated with Gleason 4+3 tumour (1.38; 1.02-1.86) and overall death (HRunit increase in log: 1.60; 95% CI: 1.11-2.30), but inversely associated with high risk PCa and high PSA levels (20 mu g/L) (0.71; 0.56-0.89 and 0.72; 0.5 9-0.90). WBC was associated with increased odds of T3-T4 PCa. Except for albumin, none of these markers were associated with PCa death or overall death. Systemic inflammation as early as 14 years prior to diagnosis may influence prostate cancer severity. What's new? High levels of C-reactive protein can presage a particularly malignant prostate cancer, new results show. Cancers certainly arise in the wake of chronic inflammation, but it's not known exactly how markers of inflammation initiate prostate cancer. Here, the authors show that systemic inflammation can worsen the severity of the cancer, even if it occurred long before the cancer's onset. High levels of CRP and haptoglobin, they found, were associated with prostate cancer with high PSA and metastasis. The question remains whether inflammation pushes cancer cells into a more malignant mode, or selects for the more dangerous cells early on.

  • 8.
    Babaei, Masoud
    et al.
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.;German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis NCT, Heidelberg, Germany..
    Balavarca, Yesilda
    German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis NCT, Heidelberg, Germany..
    Jansen, Lina
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany..
    Lemmens, Valery
    Netherlands Comprehens Canc Org IKNL, Utrecht, Netherlands.;Erasmus MC Univ, Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands..
    van Erning, Felice N.
    Netherlands Comprehens Canc Org IKNL, Utrecht, Netherlands.;Erasmus MC Univ, Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands..
    van Eycken, Liesbet
    Belgian Canc Registry, Brussels, Belgium..
    Vaes, Evelien
    Belgian Canc Registry, Brussels, Belgium..
    Sjövall, Annika
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ulrich, Cornelia M.
    German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis NCT, Heidelberg, Germany.;Huntsman Canc Inst, Salt Lake City, UT USA.;Univ Utah, Salt Lake City, UT USA..
    Schrotz-King, Petra
    German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis NCT, Heidelberg, Germany..
    Brenner, Hermann
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.;German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis NCT, Heidelberg, Germany.;German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany..
    Administration of adjuvant chemotherapy for stage II-III colon cancer patients: An European population-based study2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 142, no 7, p. 1480-1489Article in journal (Refereed)
    Abstract [en]

    The advantage of adjuvant chemotherapy (ACT) for treating Stage III colon cancer patients is well established and widely accepted. However, many patients with Stage III colon cancer do not receive ACT. Moreover, there are controversies around the effectiveness of ACT for Stage II patients. We investigated the administration of ACT and its association with overall survival in resected Stage II (overall and stratified by low-/high-risk) and Stage III colon cancer patients in three European countries including The Netherlands (2009-2014), Belgium (2009-2013) and Sweden (2009-2014). Hazard ratios (HR) for death were obtained by Cox regression models adjusted for potential confounders. A total of 60244 resected colon cancer patients with pathological Stages II and III were analyzed. A small proportion (range 9-24%) of Stage II and over half (range 55-68%) of Stage III patients received ACT. Administration of ACT in Stages II and III tumors decreased with higher age of patients. Administration of ACT was significantly associated with higher overall survival in high-risk Stage II patients (in The Netherlands (HR; 95%CI = 0.82 (0.67-0.99), Belgium (0.73; 0.59-0.90) and Sweden (0.58; 0.44-0.75)), and in Stage III patients (in The Netherlands (0.47; 0.43-0.50), Belgium (0.46; 0.41-0.50) and Sweden (0.48; 0.43-0.54)). In Stage III, results were consistent across subgroups including elderly patients. Our results show an association of ACT with higher survival among Stage III and high-risk Stage II colon cancer patients. Further investigations are needed on the selection criteria of Stages II and III colon cancer patients for ACT.

  • 9.
    Baltzer, Nicholas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Stockholm County, Sweden.
    Sundström, Karin
    Karolinska Inst, Dept Lab Med, Stockholm, Stockholm Count, Sweden..
    Nygård, Jan F.
    Canc Registry Norway, Dept Registry Informat, Oslo, Oslo County, Norway..
    Dillner, Joakim
    Karolinska Inst, Dept Lab Med, Stockholm, Stockholm Count, Sweden..
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Polish Acad Sci, Inst Comp Sci, Warsaw, Warsaw County, Poland..
    Risk stratification in cervical cancer screening by complete screening history: Applying bioinformatics to a general screening population2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 141, no 1, p. 200-209Article in journal (Refereed)
    Abstract [en]

    Women screened for cervical cancer in Sweden are currently treated under a one-size-fits-all programme, which has been successful in reducing the incidence of cervical cancer but does not use all of the participants' available medical information. This study aimed to use women's complete cervical screening histories to identify diagnostic patterns that may indicate an increased risk of developing cervical cancer. A nationwide case-control study was performed where cervical cancer screening data from 125,476 women with a maximum follow-up of 10 years were evaluated for patterns of SNOMED diagnoses. The cancer development risk was estimated for a number of different screening history patterns and expressed as Odds Ratios (OR), with a history of 4 benign cervical tests as reference, using logistic regression. The overall performance of the model was moderate (64% accuracy, 71% area under curve) with 61-62% of the study population showing no specific patterns associated with risk. However, predictions for high-risk groups as defined by screening history patterns were highly discriminatory with ORs ranging from 8 to 36. The model for computing risk performed consistently across different screening history lengths, and several patterns predicted cancer outcomes. The results show the presence of risk-increasing and risk-decreasing factors in the screening history. Thus it is feasible to identify subgroups based on their complete screening histories. Several high-risk subgroups identified might benefit from an increased screening density. Some low-risk subgroups identified could likely have a moderately reduced screening density without additional risk.

  • 10.
    Benetkiewicz, Magdalena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    de Ståhl, Teresita Díaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gördör, Anita
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology.
    Pfeifer, Susan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wittmann, Stefanie
    Gessler, Manfred
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Identification of limited regions of genetic aberrations in patients affected with Wilms' tumor using a tiling-path chromosome 22 array2006In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 119, no 3, p. 571-578Article in journal (Refereed)
    Abstract [en]

    Wilms' tumor (WT) is one of the most common solid tumors of childhood. The genetics of this disorder is complex and few studies have suggested allelic loss of chromosome 22 as a frequent aberration. To assess tumor- and possible germline-specific regions affected with gene copy number variations on this chromosome, we applied a high-resolution genomic clone-based chromosome 22 array to a series of 28 WT samples and the paired blood-derived DNA of the patients. The group of tumors was enriched for cases with metastases, relapse or fatal outcome, criteria that were expected to yield a higher number of alterations on chromosome 22. Overall, the array-based form of comparative genomic hybridization (array-CGH) analysis revealed genomic changes in 53% (15 out of 28) of cases. We identified hemizygous deletion of the whole arm of 22q in 3 tumors (11%). Furthermore, a complex amplifier genotype was detected in 8 samples, presenting regions of gain along the chromosome, which defined 7 distinct minimal overlapping segments. The distribution of aberrations in 4 additional cases displaying regional genomic imbalances delimited 2 tumor suppressor/oncogene candidate loci, 1 in the proximal and the other in the terminal part of 22q. Analysis of these regions revealed the presence of several candidate genes that may play a role in the development of WT. These findings demonstrate the power of array-CGH in the determination of DNA copy number alterations and further strength the notion that WT-associated genes exist on this chromosome.

  • 11.
    Berndtsson, Maria
    et al.
    Karolinska Institutet.
    Beaujouin, Melanie
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Havelka, Aleksandra Mandic
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Westman, Jacob
    Liaudet-Coopman, Emmanuelle
    Linder, Stig
    Karolinska Institutet.
    Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin-proteasome system2009In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 124, no 6, p. 1463-1469Article in journal (Refereed)
    Abstract [en]

    The lysosomal apoptosis pathway is a potentially interesting therapeutic target. Since apoptosis involving the lysosomal pathway has been described to involve cathepsins, we screened a drug library for agents that induce cathepsin-dependent apoptosis. Using pharmacological inhibitors and siRNA, we identified 2 structurally related agents (NSC687852 and NSC638646) that induced cathepsin D-dependent caspase-cleavage activity in human breast cancer cells. Both agents were found to induce the mitochondrial apoptosis pathway. NSC687852 and NSC638646 were found to inhibit the activity of ubiquitin isopeptidases and to induce the accumulation of high-molecular-mass ubiquitins in cells. We show that 3 other inhibitors of the proteasome degradation pathway induce lysosomal membrane permeabilization (LMP) and that cathepsin-D siRNA inhibits apoptosis induced by these agents. We conclude that a screen for cathepsin-dependent apoptosis-inducing agents resulted in the identification of ubiquitin isopeptidase inhibitors and that proteasome inhibitors with different mechanisms of action induce LMP and cathepsin D-dependent apoptosis.

  • 12.
    Berntsson, Jonna
    et al.
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, SE-22185 Lund, Sweden..
    Nodin, Björn
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, SE-22185 Lund, Sweden..
    Eberhard, Jakob
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, SE-22185 Lund, Sweden..
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jirström, Karin
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, SE-22185 Lund, Sweden..
    Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer2016In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 139, no 5, p. 1129-1139Article in journal (Refereed)
    Abstract [en]

    Multiple studies have described associations between infiltrating immune cells and prognosis in cancer; however, the clinical relevance has most often been attributed to the T-cell linage. This study aimed to further investigate the clinicopathological correlates and prognostic impact of B cell and plasma cell infiltration in CRC. Immunohistochemical expression of CD20, CD138 and immunoglobulin kappa C (IGKC) was analysed in tissue microarrays with tumours from 557 incident cases of CRC from a prospective population-based cohort. Kaplan-Meier analysis and Cox regression analysis were used to determine the impact of CD20, CD138 and IGKC expression on 5-year overall survival. Immune cell-specific CD20, CD138, and IGKC expression correlated significantly with lower T-stage (p < 0.001, p < 0.001, and p=0.006, respectively). A higher density of CD201 cells correlated significantly with an improved OS (HR=0.53, 95% CI 0.36-0.78), remaining significant in multivariable analysis adjusted for age, TNM stage, differentiation grade and vascular invasion (HR=0.51; 95% CI 0.33-0.80). Immune cell-specific CD138 and IGKC expression correlated significantly with an improved OS in univariable Cox regression analysis; however, these associations did not remain significant in multivariable analysis. Finally, tumour cell-specific CD138 expression was found to be an independent factor of poor prognosis (HR 1.52; 95% CI 1.03-2.24). The results from the present study demonstrate that B cell infiltration in CRC has a significant impact on tumour progression and prognosis. These findings supplement and extend the current knowledge of the immune landscape in colorectal cancer, and merit further study.

  • 13.
    Berntsson, Jonna
    et al.
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol..
    Svensson, Maria C.
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol..
    Leandersson, Karin
    Lund Univ, Dept Translat Med, Canc Immunol..
    Nodin, Bjorn
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol..
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Larsson, Anna H.
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol..
    Eberhard, Jakob
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol..
    Jirstrom, Karin
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol..
    The clinical impact of tumour-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite: A cohort study2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 141, no 8, p. 1654-1666Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence demonstrates an association between dense infiltration of lymphocytes and prognosis in colorectal cancer (CRC), but whether this prognostic impact differs by tumour location remains unknown. This study investigated the prognostic impact of cytotoxic and regulatory T cells in CRC, with particular referennfiltrating T cce to the anatomical subsite of the primary tumour. The density of CD3(+), CD8(+) and FoxP3(+) tumour-iells was calculated in tissue microarrays with tumours from 557 incident CRC cases from a prospective population-based cohort. Kaplan-Meier and Cox regression analyses were applied to determine the impact of high and low lymphocyte density on 5-year overall survival, in subgroup analysis of right colon, left colon and rectum. High CD8(+) cell density was a favourable prognostic factor for patients with right-sided colon tumours (hazard ratio [HR]=0.53, 95% confidence interval [CI] 0.29-0.95), independent of age, sex, TNM stage, differentiation grade and vascular invasion, with a significant prognostic interaction between CD8(+) cells and right-sidedness (p=0.031). High FoxP3(+) cell density was an independent favourable prognostic factor only in patients with rectal tumours (HR=0.54, 95% CI 0.30-0.99), and CD3(+) cell density was an independent favourable prognostic factor for tumours in the right colon and rectum, but there was no significant prognostic interaction between CD3(+) or FoxP3(+) cells and sidedness. These results demonstrate that the prognostic impact of tumour-infiltrating lymphocytes in CRC differs by primary tumour site, further indicating that tumour location may be an important factor to take into consideration in therapeutic decisions, including eligibility for immunotherapy.

  • 14.
    Beskow, Anna H.
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Engelmark, Malin T.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Magnusson, Jessica J.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Gyllensten, Ulf B.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Interaction of host and viral risk factors for development of cervical carcinoma in situ2005In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 117, no 4, p. 690-692Article in journal (Other academic)
    Abstract [en]

    Infection by oncogenic human papillomavirus (HPV) is a necessary but not sufficient cause of cervical carcinoma. Several host genetic and viral factors have been reported to increase the risk of carcinoma development given an HPV infection. In our study, we have analysed the contribution of HPV 16 E6 sequence subtype and allelic variation at human leukocyte antigen (HLA) class II loci to the risk of developing cervical carcinoma in situ. Non-European-like HPV 16 E6 sequence subtypes were not found to be associated with an increased risk of cervical carcinoma, as compared to European-like variants. However, an association was found between the HPV 16 E6 L83V variant and the DR*04-DQ*03 haplotype. This association has been observed in several independent studies and shows that both the host HLA class II genotype and viral subtype will affect the risk of an infection progressing into cervical carcinoma.

  • 15. Biggar, Robert J.
    et al.
    Christiansen, Michael
    Rostgaard, Klaus
    Smedby, Karin Ekström
    Adami, Hans-Olov
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hjalgrim, Henrik
    Melbye, Mads
    Immunoglobulin subclass levels in patients with non-Hodgkin lymphoma2009In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 124, no 11, p. 2616-20Article in journal (Refereed)
    Abstract [en]

    Allergy/atopy has been suggested to protect against non-Hodgkin lymphoma (NHL) and specific IgE levels are decreased in patients with NHL. We speculated that all immunoglobulin subclass levels might be downregulated in NHL and examined levels of IgM, IgD, IgA, IgE, IgG and IgG(4) in 200 NHL patients and 200 age- and sex-matched controls. Patients with B-cell NHL of many types had consistently lower median immunoglobulin subclass levels than controls. In every subclass except IgD, about 10-15% of B-cell NHL patients had absolute levels below the 2.5 percentile of controls. Subclass levels correlated with each other and many patients had more than one significantly low level. Levels were lowest for IgG(4) and IgE. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma had especially low total IgE levels. In other B-cell NHL types, total IgE levels were decreased to a similar extent as other immunoglobulin subclasses. In conclusion, low IgE levels are only part of a more generalized loss of immunoglobulins of all subtypes in a wide variety of B-cell NHL types. Low immunoglobulin levels appear to be a consequence of B-cell NHL presence, and we speculate about molecular mechanisms that could reduce all immunoglobulin subclasses in B-cell NHL.

  • 16.
    Blom, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Yin, Li
    Liden, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Dolk, Anders
    Jeppsson, Bengt
    Pahlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Nyren, Olof
    Toward understanding non participation in sigmoidoscopy screening for colorectal cancer2008In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 122, no 7, p. 1618-1623Article in journal (Refereed)
    Abstract [en]

    Understanding the reasons for nonparticipation in cancer screening may give clues about how to improve compliance. However, limited cooperation has hampered research on nonparticipant profiles. We took advantage of Sweden's comprehensive demographic and health care registers to investigate characteristics of all participants and nonparticipants in a pilot program for colorectal cancer screening with sigmoidoscopy. A population-based sample of 1986 Swedish residents 59-61 years old was invited. Registers provided information on each individual's gender, country of birth, marital status, education, income, hospital contacts, place of residence, distance to screening center and cancer within the family. Odds ratios (ORs) with 95% confidence intervals (CIs), modeled with multivariable logistic regression, estimated the independent associations between each background factor and the propensity for nonparticipation after control for the effects of other factors. All statistical tests were 2-sided. Being male (OR = 1.27, 95% CI = 1.03-1.57, relative to female), unmarried or divorced (OR = 1.69, 95% CI = 1.23-2.30 and OR = 1.49, 95% CI = 1.14-1.95, respectively, relative to married) and having an income in the lowest tertile (OR = 1.68, 95% CI = 1.27-2.23, relative to highest tertile) was associated with increased nonparticipation. Living in the countryside or in small communities and having a documented family history of colorectal cancer was associated with better participation. Distance to the screening center did not significantly affect participation, nor did recent hospital care consumption or immigrant status. To increase compliance, invitations must appeal to men, unmarried or divorced people and people with low socioeconomic status.

  • 17. Borgquist, Signe
    et al.
    Djerbi, Soraya
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Anagnostaki, Lola
    Goldman, Malin
    Gaber, Alexander
    Manjer, Jonas
    Landberg, Göran
    Jirström, Karin
    HMG-CoA reductase expression in breast cancer is associated with a less aggressive phenotype and influenced by anthropometric factors2008In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 123, no 5, p. 1146-53Article in journal (Refereed)
    Abstract [en]

    Although several studies have reported on the anti-tumoural properties exerted by 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) inhibitors (statins), the in vivo expression of HMG-CoAR in human cancer has been considerably less investigated. In our study, we examined the immunohistochemical expression of HMG-CoAR in 511 incident breast cancers within the Malmö Diet and Cancer Study in order to explore its relationship to established clinicopathological and tumour biological parameters. Furthermore, the potential influence of estrogen exposure on HMG-CoAR expression was assessed by performing Cox's proportional hazards analyses of the relationship between the use of hormone replacement therapy (HRT), obesity (waist circumference) and tumour-cell specific HMG-CoAR expression. We found that HMG-CoAR was present in various fractions and intensities in the cytoplasm, sometimes with a membranous pattern, but not in the tumour cell nuclei. The expression of HMG-CoAR was associated with a smaller tumour size (p = 0.02), low histological grade (p = 0.001), low Ki67 index (p = 0.004), ERalpha+ (p = 0.02), ERbeta+ (p = 0.005), and high p27 expression (p = <0.001). The incidence of tumours with a high HMG-CoAR-expression was increased among HRT-users, although this was not statistically significant in a heterogeneity analysis. Obesity was significantly associated with a high HMG-CoAR expression assessed both as a high (>50%) fraction of positive cells (relative risk: 2.06; 95% confidence interval: 1.20-3.51), and a strong staining intensity (2.33: 1.08-5.02). In summary, we demonstrate that HMG-CoAR is differentially expressed in breast cancer and that a high expression is associated with prognostically favourable tumour parameters. Moreover, estrogen related life-style and anthropometric factors might indeed regulate HMG-CoAR expression.

  • 18. Bozóky, Benedek
    et al.
    Savchenko, Andrii
    Csermely, Péter
    Korcsmáros, Tamás
    Dúl, Zoltán
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Székely, László
    Klein, George
    Novel signatures of cancer-associated fibroblasts2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 2, p. 286-293Article in journal (Refereed)
    Abstract [en]

    Increasing evidence indicates the importance of the tumor microenvironment, in particular cancer-associated fibroblasts, in cancer development and progression. In our study, we developed a novel, visually based method to identify new immunohistochemical signatures of these fibroblasts. The method employed a protein list based on 759 protein products of genes identified by RNA profiling from our previous study, comparing fibroblasts with differential growth-modulating effect on human cancers cells, and their first neighbors in the human protein interactome. These 2,654 proteins were analyzed in the Human Protein Atlas online database by comparing their immunohistochemical expression patterns in normal versus tumor-associated fibroblasts. Twelve new proteins differentially expressed in cancer-associated fibroblasts were identified (DLG1, BHLHE40, ROCK2, RAB31, AZI2, PKM2, ARHGAP31, ARHGAP26, ITCH, EGLN1, RNF19A and PLOD2), four of them can be connected to the Rho kinase signaling pathway. They were further analyzed in several additional tumor stromata and revealed that the majority showed congruence among the different tumors. Many of them were also positive in normal myofibroblast-like cells. The new signatures can be useful in immunohistochemical analysis of different tumor stromata and may also give us an insight into the pathways activated in them in their true in vivo context. The method itself could be used for other similar analysis to identify proteins expressed in other cell types in tumors and their surrounding microenvironment.

  • 19.
    Caglayan, Demet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lundin, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ferletta, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sox21 inhibits glioma progression in vivo by forming complexes with Sox2 and stimulating aberrant differentiation2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 6, p. 1345-1356Article in journal (Refereed)
    Abstract [en]

    Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas. What's new? Glioma formation is driven by brain tumor-initiating cells with stem cell-like properties. Here the authors show for the first time that the transcription factor Sox21 can act as a suppressor gene in gliomagenesis. Induced expression of Sox21 in human glioma cells results in reduced tumor growth and prolonged survival of xenotranplanted mice. Sox21 reduces the stem-cell like properties of the tumor cells, leading to abnormal differentiation, induced apoptosis, and decreased proliferation. The results point to a shift in balance between the counteracting and widely distributed Sox2 and Sox21, revealing the Sox2/Sox21 axis as a target for novel therapy of gliomas.

  • 20.
    Caglayan, Demet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lundin, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ferletta, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sox21 inhibits glioma progression in vivo by reducing Sox2 and stimulating aberrant differentiation2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 6, p. 1345-1356Article in journal (Refereed)
    Abstract [en]

    Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100β, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas.

  • 21. Castro, Felipe A
    et al.
    Ivansson, Emma L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Schmitt, Markus
    Juko-Pecirep, Ivana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Kjellberg, Lennart
    Hildesheim, Allan
    Gyllensten, Ulf B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Pawlita, Michael
    Contribution of TMC6 and TMC8 (EVER1 and EVER2) variants to cervical cancer susceptibility2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 2, p. 349-355Article in journal (Refereed)
    Abstract [en]

    Cervical cancer (CxCa) is caused by persistent human papillomavirus (HPV) infection; genetic predisposition is also suspected to play a role. Our study is a targeted candidate gene follow-up based on: (i) strong clinical evidence demonstrating that mutations in the TMC6 and TMC8 (EVER1 and EVER2) genes associate with the HPV-associated disease epidermodysplasia verruciformis (EV) and (ii) recent epidemiological data suggesting a genetic susceptibility conferred by polymorphisms in such genes for skin and CxCa. Clarifying the association of the TMC6/8 genes with risk of CxCa will help in understanding why some HPV-infected women develop persistent infection, cervical lesions and eventually cancer while others do not. Twenty-two single nucleotide polymorphisms (SNPs) harboring the TMC6/8 genes were genotyped in 2,989 cases with cervical intraepithelial neoplasia grade III or invasive CxCa and 2,281 controls from the Swedish population. Association was evaluated in logistic regression models. Two SNPs displayed association with cervical disease: rs2290907 [odds ratio (OR)(GGvsAA) = 0.6, 95% confidence interval (95% CI): 0.3-0.9, p = 0.02)] and rs16970849 (OR(AGvsGG) = 0.8, 95% CI: 0.66-0.98, p = 0.03). The present data support the involvement of the TMC6/8 region in CxCa susceptibility but further analyses are needed to replicate our findings, fully characterize the region and understand the function of the genetic variants involved.

  • 22.
    Crawley, Danielle
    et al.
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England..
    Garmo, Hans
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England..
    Rudman, Sarah
    Guys & St Thomas NHS Fdn Trust, London, England.;Kings Coll Londons Comprehens, Biomed Res Ctr, London, England..
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology. Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden..
    Häggström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden.;Umea Univ, Dept Biobank Res, Umea, Sweden..
    Zethelius, Björn
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Holmberg, Lars
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England..
    Adolfsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Van Hemelrijck, Mieke
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England..
    Association between duration and type of androgen deprivation therapy and risk of diabetes in men with prostate cancer2016In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 139, no 12, p. 2698-2704Article in journal (Refereed)
    Abstract [en]

    Androgen deprivation therapy (ADT) for prostate cancer (PCa) increases risk of type 2 diabetes (T2DM); however the association between types and duration of ADT has not been fully elucidated. We examined how type and duration of ADT affects risk of T2DM. Using data from Prostate Cancer database Sweden (PCBaSe) we investigated risk of T2DM in a cohort of 34,031 men with PCa on ADT; i.e., anti-androgens (AA), orchiectomy, or gonadotropin-releasing hormone (GnRH) agonists compared to an age-matched, PCa-free comparison cohort (n=167,205) using multivariate Cox proportional hazard regression. T2DM was defined as a newly filled prescription for metformin, sulphonylurea, or insulin in the Prescribed Drug Register. A total of 21,874 men with PCa received GnRH agonists, 9,143 AA and 3,014 underwent orchiectomy. Risk of T2DM was increased in men in the GnRH agonists/orchiectomy group during the first 3 years of ADT [i.e., 121.5 years HR: 1.61 (95% CI: 1.36-1.91)], compared to PCa-free men. The risk decreased thereafter (e.g., 324 years HR: 1.17 (95% CI: 0.98-1.40)). Conversely, no increased risk was seen in men on AA (HR: 0.74 (95% CI: 0.65-0.84). The incidence of T2DM per 1,000 person-years was 10 for PCa-free men, 8 for men on AA, and 13 for men on GnRH agonists/orchiectomy. Duration of ADT has a significant impact on risk of T2DM. With the peak after three years of treatment, our data indicates that men on ADT, even for a limited period of time, such as adjuvant to radiotherapy, are at increased risk of T2DM.

  • 23.
    Dahlman, Thèrése
    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, Faculty of Medicine, Department of Medical Sciences.
    Lammerts, Ellen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergström, Danel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Franzén, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Westermark, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Collagen type I expression in experimental anaplastic thyroid carcinoma: regulation and relevance for tumorigenicity2002In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 98, no 2, p. 186-192Article in journal (Refereed)
    Abstract [en]

    Fibrosis in solid malignancies plays a significant role in tumor pathophysiology. Potential mechanisms for collagen type I deposition in anaplastic thyroid carcinoma (ATC) were investigated using 6 characterized ATC cell lines. Three of these cell lines, which produced collagen type I, had, as a group, a poor tumorigenicity when inoculated in athymic mice. This group of cells generated tumors in 4 of 24 injected animals (17%). Pro-alpha 1(I) collagen mRNA-expressing carcinoma and stromal cells were interdispersed in the tumors generated by these ATC cells. By contrast, the 3 noncollagen-producing ATC cell lines were all tumorigenic with a tumor take of 60% in the whole group. In the latter tumors, pro-alpha 1(I) collagen mRNA-expressing cells were confined to the stromal compartment, well delineated from carcinoma cell islets. To study the influence of ATC cells on collagen type I synthesis by fibroblasts, we used AG 1518 diploid human fibroblasts cultured on poly-(2-hydroxyethyl methacrylate) (poly[HEMA])-coated plates. This culture condition allows the study of the effect of collagen mRNA translation in the regulation of collagen type I synthesis. Conditioned media from the 6 ATC cell lines did not influence collagen synthesis. The ATC cell line KAT-4 stimulated fibroblast synthesis of collagen type I when the two cell types were cocultured on poly[HEMA]-coated substrates. Specific inhibitors of PDGF and TGF-beta reduced the KAT 4 carcinoma cell-induced stimulation of collagen type I synthesis. Our data suggest that collagen type I production by carcinoma cells correlates negatively with tumorigenicity and that the formation of a well-defined stroma is of importance for tumor growth. Furthermore, our data suggest that tumor cells are able to stimulate collagen mRNA translation in stromal fibroblasts in direct cell-cell contact by, at least in part, transferring PDGF or TGF-beta.

  • 24.
    Danielsson, Carina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Carlberg, Carsten
    Positive and negative interaction of 1,25-dihydroxyvitamin D3 and the retinoid CD437 on the induction of apoptosis of human melanoma cells1999In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 81, no 3, p. 467-470Article in journal (Refereed)
    Abstract [en]

    The natural ligands of the nuclear receptors vitamin D receptor (VDR) and retinoic acid receptor (RAR), i.e., 1alpha,25-dihydroxyvitamin D3 (VD) and all-trans retinoic acid, have important effects on the proliferation, differentiation and apoptosis of a variety of malignant cells, including melanoma. The therapeutic potential of the 2 nuclear hormones can be enhanced by the use of synthetic analogues. In this study, the 2 human melanoma cell lines WM1341 and MeWo were compared for the combined effect of VD and synthetic retinoids. Both cell lines expressed reasonable amounts of VDR, RARgamma and retinoid X receptor alpha and differed only in the relative expression of RARalpha and beta. From 9 functional variants of retinoids, only the RARgamma-selective retinoid CD437 showed, in both cell lines, a significant anti-proliferative effect. In MeWo cells, but not in WM1341 cells, VD induced growth arrest but showed no synergistic interaction with the effects of CD437. In contrast, VD induced apoptosis in WM1341, but not in MeWo, cells. CD437 was a strong inducer of apoptosis in both melanoma cell lines. Parallel treatment with CD437 and VD resulted in synergistic enhancement of apoptosis in WM1341 cells, whereas a clear decrease in induction of apoptosis in MeWo cells occurred. Our results indicate that a combined treatment of melanoma with VD and selected retinoids is promising but should be adapted to individual types of tumor.

  • 25. de Witte, H H
    et al.
    Foekens, J A
    Lennerstrand, Johan
    AB Sangtec Medical.
    Smid, M
    Look, M P
    Klijn, J G
    Benraad, T J
    Berns, E M
    Prognostic significance of TP53 accumulation in human primary breast cancer: comparison between a rapid quantitative immunoassay and SSCP analysis.1996In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 69, no 2, p. 125-130Article in journal (Refereed)
    Abstract [en]

    TP53 accumulation in human primary breast carcinomas was studied by a quantitative luminometric immunoassay (LIA), and TP53 gene alterations, exons 5-8, were examined by single-strand conformation polymorphism (SSCP) analysis. In 48 of 142 breast tumor samples, a TP53 gene alteration was identified. In tumor samples without a TP53 gene alteration, the median cytosolic TP53 protein level, as determined by LIA, was 0.4 ng/mg protein (range 0-70.8 ng/mg protein), whereas the median TP53 protein level for tumor samples with a TP53 gene alteration was 10 times higher, i.e., 4.1 ng/mg protein (range 0.1-176.0 ng/mg protein). Despite a significant correlation between the outcome of LIA and SSCP, a disagreement was found in 22% of cases analyzed. Significant correlations were found between TP53 protein accumulation and low estrogen receptor content, and with a shorter relapse-free as well as overall survival, with a median duration of follow-up of 100 months. Due to its rapid and easy performance on routinely prepared cytosols, the LIA for TP53 protein may be useful in evaluating the prognostic impact of TP53 protein accumulation in human primary breast cancer.

  • 26. Downer, Mary K
    et al.
    Batista, Julie L
    Mucci, Lorelei A
    Stampfer, Meir J
    Epstein, Mara Meyer
    Håkansson, Niclas
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Johansson, Jan-Erik
    Andrén, Ove
    Fall, Katja
    Andersson, Sven-Olof
    Dairy intake in relation to prostate cancer survival.2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 9, p. 2060-2069Article in journal (Refereed)
    Abstract [en]

    Dairy intake has been associated with increased risk of advanced prostate cancer. Two US cohort studies reported increased prostate cancer-specific mortality with increased high-fat milk intake. We examined whether dairy and related nutrient intake were associated with prostate cancer progression in a Swedish patient population with high dairy consumption. We prospectively followed 525 men with newly diagnosed prostate cancer (diagnosed 1989-1994). We identified and confirmed deaths through February 2011 (n = 222 prostate cancer-specific, n = 268 from other causes). Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between food or nutrient intake and prostate cancer-specific death. On average, patients consumed 5.0 servings/day of total dairy products at diagnosis. In the whole population, high-fat milk intake was not associated with prostate cancer-specific death (95% CI: 0.78, 2.10; p-trend = 0.32; multivariate-adjusted model). However, among patients diagnosed with localized prostate cancer, compared to men who consumed <1 servings/day of high-fat milk, those who drank ≥3 servings/day had an increased hazard of prostate cancer mortality (HR = 6.10; 95% CI: 2.14, 17.37; p-trend = 0.004; multivariate-adjusted model). Low-fat milk intake was associated with a borderline reduction in prostate cancer death among patients with localized prostate cancer. These associations were not observed among patients diagnosed with advanced stage prostate cancer. Our data suggest a positive association between high-fat milk intake and prostate cancer progression among patients diagnosed with localized prostate cancer. Further studies are warranted to investigate this association and elucidate the mechanisms by which high-fat milk intake may promote prostate cancer progression.

  • 27.
    Eaker, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Halmin, Märit
    Bellocco, Rino
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lambe, Mats
    Social differences in breast cancer survival in relation to patient management within a National Health Care System (Sweden)2009In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 124, no 1, p. 180-187Article in journal (Refereed)
    Abstract [en]

    Epidemiologic studies have shown that cancer survival is poorer in low compared with high socioeconomic groups. We investigated whether these differences were associated with disparities in tumour characteristics and management. This cohort study was based on 9,908 women aged 20-79 years at diagnosis with primary breast cancer identified in a Swedish population-based clinical register. Information on socioeconomic standing was obtained from a social database. The 5-year cause-specific survival (CSS) and mortality hazard ratios (HR) were estimated by Cox proportional hazard models to assess differences in survival between socioeconomic groups while adjusting for diagnostic intensity, tumour characteristics and treatment. Following adjustment for age, year and stage at diagnosis, the risk of dying of breast cancer was 35% lower among women with high education compared with that of low education (HR = 0.65, 95% CI 0.53-0.80). When compared with women with high education, a lower percentage of women with low education had been investigated for proliferation (84 vs. 76%) or hormone receptor status (89 vs. 81%), had tumours <or=20 mm (68 vs. 64%), were treated at a main hospital (75 vs. 68%) and had received radiation treatment (80 vs. 67%) or chemotherapy (31 vs. 18%). However, these proportional differences could not explain the observed social gradient in survival. To minimize social differences in breast cancer survival, further research should address not only factors leading to inequities in management but also focus on patient factors such as health awareness, comorbidity burden and compliance to adjuvant treatment.

  • 28.
    Edlund, Karolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Saito, Akira
    Berglund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Göransson-Kultima, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Isaksson, Anders
    Jirström, Karin
    Planck-Sturegård, Maria
    Johansson, Leif
    Lambe, Mats
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Nyberg, Fredrik
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Landelius, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Lamberg, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Östman, Arne
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    CD99 is a novel prognostic stromal marker in non-small cell lung cancer2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, no 10, p. 2264-2273Article in journal (Refereed)
    Abstract [en]

    The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumour-stroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC, VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p=0.037) and multivariate (p=0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells, and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p=0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.

  • 29.
    Ek, Weronica E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lagergren, Katarina
    Cook, Michael
    Wu, Anna H
    Abnet, Christian C
    Levine, David
    Chow, Wong-Ho
    Bernstein, Leslie
    Risch, Harvey A
    Shaheen, Nicholas J
    Bird, Nigel C
    Corley, Douglas A
    Hardie, Laura J
    Fitzgerald, Rebecca C
    Gammon, Marilie D
    Romero, Yvonne
    Liu, Geoffrey
    Ye, Weimin
    Vaughan, Thomas L
    MacGregor, Stuart
    Whiteman, David C
    Westberg, Lars
    Lagergren, Jesper
    Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma2016In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 138, no 5, p. 1146-1152Article in journal (Refereed)
    Abstract [en]

    The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p = 0.002) and in males (p = 0.003), but not in females separately (p = 0.3). This association was found in tobacco smokers (p = 0.003) and in BE patients without reflux (p = 0.004), but not in nonsmokers (p = 0.2) or those with reflux (p = 0.036). SNPs within JMJD1C were associated with risk of EAC in females (p = 0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.

  • 30. Ekbom, Anders
    et al.
    Thurfjell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hsieh, Chung-chen
    Trichopoulos, Dimitrios
    Adami, Hans-Olov
    Perinatal characteristics and adult mammographic patterns1995In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 61, no 2, p. 177-180Article in journal (Refereed)
    Abstract [en]

    We retrieved breast mammograms for 370 women 40 to 74 years old with no history of breast cancer, for whom birth weight, birth length, placental weight and other birth characteristics were indicated in their standard birth records at the Uppsala University Hospital. Blind evaluation of the mammograms allowed these to be classified according to Wolfe's pattern. Logistic regression analysis was applied using as independent variables the recorded birth characteristics and as outcome variable, high risk (P2 and DY) versus low risk (N1 and P1) mammographic parenchymal pattern. After controlling for all the recorded variables, the odds ratio for a high-risk pattern (P2 or DY) increased consistently and significantly (P for trend 0.02) with the weight of the placenta, i.e. the main estrogen-producing organ during pregnancy. There were weak and non-significant positive associations with increasing birth weight (P for trend 0.53) and birth length (P for trend 0.52). These results are compatible with hypotheses suggesting that pregnancy estrogens or other perinatal characteristics may play a risk-modulating role influencing breast cancer in the offspring.

  • 31.
    Elsir, Tamador
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Edqvist, Per-Henrik
    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.
    Carlson, Joseph
    Ribom, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Popova, Svetlana N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Pontén, Fredrik
    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.
    Nistér, Monica
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    A study of embryonic stem cell-related proteins in human astrocytomas: Identification of Nanog as a predictor of survival2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 5, p. 1123-1131Article in journal (Refereed)
    Abstract [en]

    Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO grade II) and 98 high-grade human gliomas (WHO grade III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low- and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n=42) with high levels of Nanog protein (p=0.0067) and of Klf4 protein (p=0.0368), in high-grade astrocytomas (n=85) with high levels of Nanog (p=0.0042), Klf4 (p=0.0447), and c-Myc (p=0.0078) and in glioblastomas only (n=71) with high levels of Nanog (p=0.0422) and of c-Myc (p= 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p=0.0039), high-grade astrocytomas (p=0.0124) and glioblastomas only (p=0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.

  • 32. Engholm, Gerda
    et al.
    Kejs, Anne Mette T.
    Brewster, David H.
    Gaard, Maria
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hartley, Roger
    Iddenden, Robert
    Möller, Henrik
    Sankila, Risto
    Thomson, Catherine S.
    Storm, Hans H.
    Colorectal cancer survival in the Nordic countries and the United Kingdom: Excess mortality risk analysis of 5 year relative period survival in the period 1999 to 20002007In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 121, no 5, p. 1115-1122Article in journal (Refereed)
    Abstract [en]

    A deficit in colorectal cancer survival in Denmark and in the UK compared to Sweden, Norway and Finland was found in the EUROCARE studies. We set out to explore if these differences still exist. Patients diagnosed with colorectal cancer as their first invasive cancer at age 15-89 in the period 1994-2000 were identified using data from 11 cancer registries in the UK and from four Nordic countries. Five-year relative period survival using deaths in 1999-2000 following cancers diagnosed in 1994-2000 was analysed with excess mortality risk modelling. Follow-up time since diagnosis with age as an effect-modifier in the first half year was the most important factor with the highest excess risk of death immediately after diagnosis and with higher age and decreasing with length of follow-up. Variations between countries were bigger in the first half year following diagnosis than in the interval 0.5-5 years with about 30% higher risk in UK and Denmark. The differences between countries are still substantial and the order has not changed, even if the five year relative survival has improved since the EUROCARE studies. Patient management, diagnostics, and comorbidity likely explain the excess deaths in UK and Denmark during the first 6 months. The effect of stage and quality of management and treatment should be examined in population based studies with detailed patient information. Use of more detailed age-intervals than conventionally applied in survival studies proved to be important in statistical modelling and is recommended for future studies.

  • 33.
    Eriksson, Louise
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, S-17176 Stockholm, Sweden;Karolinska Inst, Radiumhemmet, Dept Oncol, Dept Oncol Pathol,Canc Ctr Karolinska, S-17176 Stockholm, Sweden.
    Bergh, Jonas
    Karolinska Univ Hosp, S-17176 Stockholm, Sweden;Karolinska Inst, Radiumhemmet, Dept Oncol, Dept Oncol Pathol,Canc Ctr Karolinska, S-17176 Stockholm, Sweden.
    Humphreys, Keith
    Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Törnberg, Sven
    Stockholm Gotland Reg Canc Ctr, Dept Canc Screening, Stockholm, Sweden.
    Czene, Kamila
    Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden.
    Time from breast cancer diagnosis to therapeutic surgery and breast cancer prognosis: A population-based cohort study2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 5, p. 1093-1104Article in journal (Refereed)
    Abstract [en]

    Theoretically, time from breast cancer diagnosis to therapeutic surgery should affect survival. However, it is unclear whether this holds true in a modern healthcare setting in which breast cancer surgery is carried out within weeks to months of diagnosis. This is a population- and register-based study of all women diagnosed with invasive breast cancer in the Stockholm-Gotland healthcare region in Sweden, 2001-2008, and who were initially operated. Follow-up of vital status ended 2014. 7,017 women were included in analysis. Our main outcome was overall survival. Main analyses were carried out using Cox proportional hazards models. We adjusted for likely confounders and stratified on mode of detection, tumor size and lymph node metastasis. We found that a longer interval between date of morphological diagnosis and therapeutic surgery was associated with a poorer prognosis. Assuming a linear association, the hazard rate of death from all causes increased by 1.011 (95% CI 1.006-1.017) per day. Comparing, for example, surgery 6 weeks after diagnosis to surgery 3 weeks after diagnosis, thereby confers a 1.26-fold increased hazard rate. The increase in hazard rate associated with surgical delay was strongest in women with largest tumors. Whilst there was a clear association between delays and survival in women without lymph node metastasis, the association may be attenuated in subgroups with increasing number of lymph node metastases. We found no evidence of an interaction between time to surgery and mode of detection. In conclusion, unwarranted delays to primary treatment of breast cancer should be avoided. What's new? Theoretically, an increase in the interval between breast-cancer diagnosis and therapeutic surgery should affect survival, but it is uncertain whether that holds true in a modern healthcare setting. In this prospective study, the authors found that even fairly short delays (on the order of days or weeks) from diagnosis to surgery are associated with decreased survival. These results suggest that the time between diagnosis and therapeutic surgery should be kept as short as possible without hampering diagnostic work-up and preoperative patient optimization.

  • 34.
    Ferletta, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Caglayan, Demet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mokvist, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Yiwen, Jiang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Forced expression of Sox21 inhibits Sox2 and induces apoptosis in human glioma cells2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 129, no 1, p. 45-60Article in journal (Refereed)
    Abstract [en]

    Numerous studies support a role for Sox2 to keep stem cells and progenitor cells in an immature and proliferative state. Coexpression of Sox2 and GFAP has been found in regions of the adult brain where neural stem cells are present and in human glioma cells. In our study, we have investigated the roles of Sox2 and its counteracting partner Sox21 in human glioma cells. We show for the first time that Sox21 is expressed in both primary glioblastoma and in human glioma cell lines. We found that coexpression of Sox2, GFAP and Sox21 was mutually exclusive with expression of fibronectin. Our result suggests that glioma consists of at least two different cell populations: Sox2+/GFAP+/Sox21+/FN- and Sox2-/GFAP-/Sox21-/FN1+. Reduction of Sox2 expression by using siRNA against Sox2 or by overexpressing Sox21 using a tetracyclineregulated expression system (Tet-on) caused decreased GFAP expression and a reduction in cell number due to induction of apoptosis. We suggest that Sox21 can negatively regulate Sox2 in glioma. Our findings imply that Sox2 and Sox21 may be interesting targets for the development of novel glioma therapy.

  • 35.
    Folkesson, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Engholm, Gerda
    Ehrnrooth, Eva
    Kejs, Anne-Mette
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Harling, Henrik
    Wibe, Arne
    Gaard, Maria
    Thornorvaldur, Jónsson
    Tryggvadottir, Laufey
    Brewster, David H.
    Hakulinen, Timo
    Storm, Hans H.
    Rectal cancer survival in the Nordic countries and Scotland2009In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 125, no 10, p. 2406-12Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to present detailed population-based survival estimates for patients with a rectal adenocarcinoma, using cancer register data supplemented with clinical data. Based on cancer register data, differences in rectal cancer survival have been reported between countries in Europe. Variation in the distribution of stage at diagnosis, initial therapy including surgical technique, and comorbidity are possible explanatory factors. Adenocarcinomas in the rectum, diagnosed in 1997 and identified in the national cancer registries in the Nordic countries and Scotland were included. Age standardized 5-year relative survival and multiplicative regression models for the relative excess mortality were calculated. 3888 patients were included in the survival study. Men in Denmark, Finland and Iceland had lower 5-year relative survival and poorer stage distribution compared to Norway, Sweden and Scotland. Danish men had the highest rate of excess deaths in the first six months after diagnosis. Stage adjusted, the elevated relative excess mortality decreased and after six months the excess mortality rates were the same in all countries. The poor 5-year relative survival in Danish men was mainly due to a high excess rate of death during the first six months after diagnosis. The low survival in Finland and Iceland was not in accordance with other periods. For both countries this may be explained by random variation due to small numbers. The study emphasizes the need for high quality and detailed data in order to understand international survival differences, and cautions comparisons between large national samples and those of smaller areas.

  • 36.
    Fryknäs, Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dhar, Sumeer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Rydåker, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines2007In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 120, no 1, p. 189-195Article in journal (Refereed)
    Abstract [en]

    The myeloma cell line RPMI 8226/S and its doxorubicin resistant subline 8226/Dox40 were used as models to explore the potential importance of the STAT1 signaling pathway in drug and radiation resistance. The 40-fold doxorubicin resistant subline 8226/Dox40 was found to be crossresistant to single doses of 4 and 8 Gy of radiation. A genome-wide mRNA expression study comparing the 8226/Dox40 cell line to its parental line was performed to identify the underlying molecular mechanisms. Seventeen of the top 50 overexpressed genes have previously been implicated in the STAT1 signaling pathway. STAT1 was over expressed both at the mRNA and protein level. Moreover, analyses of nuclear extracts showed higher abundance of phosphorylated STAT1 (Tyr 701) in the resistant subline. Preexposure of the crossresistant cells to the STAT1 inhibiting drug fludarabine reduced expression of overexpressed genes and enhanced the effects of both doxorubicin and radiation. These results show that resistance to doxorubicin and radiation is associated with increased STAT1 signaling and can be modulated by fludarabine. The data support further development of therapies combining fludarabine and radiation.

  • 37.
    Fuchs, Dieter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Rodriguez, Alejandro
    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, Faculty of Medicine, Department of Women's and Children's Health.
    Eriksson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christofferson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sundberg, Christian
    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, Faculty of Medicine, Department of Women's and Children's Health.
    Azarbayjani, Faranak
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Metronomic administration of the drug GMX1777, a cellular NAD synthesis inhibitor, results in neuroblastoma regression and vessel maturation without inducing drug resistance2010In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 126, no 12, p. 2772-2789Article in journal (Refereed)
    Abstract [en]

    High-risk neuroblastoma is a rapidly growing tumor with a survival rate below 50%. A new treatment strategy is to administer chemotherapeutic drugs metronomically, i.e. at lower doses and frequent intervals. The aim of the study was to investigate the effects of GMX1777, a chemotherapeutic drug affecting cellular energy metabolism, in a mouse model for high-risk neuroblastoma.Female SCID mice were injected s.c. with MYCN-amplified human neuroblastoma cells and randomized to either treatment with GMX1777 or vehicle. In some animals, treatment was discontinued allowing tumor relapse. Treatment response was evaluated using the Pediatric Preclinical Testing Program (PPTP). Immunohistochemistry and qRT-PCR was performed on tumor cryosections to investigate the microscopic and molecular changes in tumors in response to GMX1777.Despite an increase in vessel density, tumor regression and a high group response score according to PPTP criteria was induced by GMX1777 without inducing drug resistance. Treatment resulted in inhibition of tumor cell proliferation, vessel maturation, reduced hypoxia, increased infiltration of MHC class II negative macrophages and expansion of the non-vascular stromal compartment. Decreased stromal VEGF-A and PDGF-B mRNA in response to treatment together with the structural data suggest a "deactivation" or "silencing" of the tumor stroma as a paracrine entity.In conclusion, GMX1777 was highly efficient against high-risk neuroblastoma xenografts through modulation of both the tumor cell and stromal compartment.

  • 38. Gleissman, Helena
    et al.
    Segerström, Lova
    Hamberg, Mats
    Ponthan, Frida
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Johnsen, John Inge
    Kogner, Per
    Omega-3 fatty acid supplementation delays the progression of neuroblastoma in vivo2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 128, no 7, p. 1703-1711Article in journal (Refereed)
    Abstract [en]

    Epidemiological and preclinical studies have revealed that omega-3 fatty acids have anticancer properties. We have previously shown that the omega-3 fatty acid docosahexaenoic acid (DHA) induces apoptosis of neuroblastoma cells in vitro by mechanisms involving intracellular peroxidation of DHA by means of 15-lipoxygenase or autoxidation. In our study, the effects of DHA supplementation on neuroblastoma tumor growth in vivo were investigated using two complementary approaches. For the purpose of prevention, DHA as a dietary supplement was fed to athymic rats before the rats were xenografted with human neuroblastoma cells. For therapeutic purposes, athymic rats with established neuroblastoma xenografts were given DHA daily by gavage and tumor growth was monitored. DHA levels in plasma and tumor tissue were analyzed by gas liquid chromatography. DHA delayed neuroblastoma xenograft development and inhibited the growth of established neuroblastoma xenografts in athymic rats. A revised version of the Pediatric Preclinical Testing Program evaluation scheme used as a measurement of treatment response showed that untreated control animals developed progressive disease, whereas treatment with DHA resulted in stable disease or partial response, depending on the DHA concentration. In conclusion, prophylactic treatment with DHA delayed neuroblastoma development, suggesting that DHA could be a potential agent in the treatment of minimal residual disease and should be considered for prevention in selected cases. Treatment results on established aggressive neuroblastoma tumors suggest further studies aiming at a clinical application in children with high-risk neuroblastoma.

  • 39.
    Granberg, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Decreased survival in patients with CD44-negative typical bronchial carcinoid tumors1999In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 84, no 5, p. 484-488Article in journal (Refereed)
    Abstract [en]

    Tumor tissues from 43 patients with typical bronchial carcinoids have been immunostained with monoclonal antibodies (mAbs) against the standard form (CD44s) and the splice variants v4, v5, v6, v7, v7-8, v9 and v10 of the adhesion molecule CD44. The staining results were correlated with clinical data. Ten patients (23%) had regional lymph node metastases at diagnosis. Distant metastases have occurred in 12% of the patients; 9% died during the observation period of median 65 months (14-325). Positive staining for CD44s was correlated with decreased risk for distant metastases and disease related death. All patients with distant metastases were v6-negative. Patients with CD44v7-8-positive tumors had decreased risk for distant metastases, but the differences in mortality did not reach statistical significance. CD44v9 correlated significantly with decreased risk for distant metastases and death. The remaining CD44 variants (v4, v5 and v10) did not correlate significantly with clinical outcome. Our results confirm earlier observations that typical bronchial carcinoids are potentially malignant. However, positive staining for CD44s, v7-8 and v9 seems to be associated with a more favorable outcome, and may be taken into consideration in prognostic evaluation.

  • 40.
    Gremel, Gabriela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liew, Markus
    Hamzei, Farzaneh
    Hardell, Elin
    Selling, Jonas
    Ghaderi, Mehran
    Stemme, Sten
    Pontén, Fredrik
    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.
    Carlson, Joseph W.
    A prognosis based classification of undifferentiated uterine sarcomas: Identification of mitotic index, hormone receptors and YWHAE-FAM22 translocation status as predictors of survival2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 7, p. 1608-1618Article in journal (Refereed)
    Abstract [en]

    Undifferentiated uterine sarcomas (UUS) are rare tumors with a heterologous biology and a poor prognosis. The goal of this study was to examine clinicopathology, biomarkers and YWHAE-FAM22 translocation status, in the prognosis of these tumors. Twenty-six cases of UUS were included. All original slides were rereviewed and age at diagnosis, tumor stage, Kurihara diagnosis, mitotic index, presence of necrosis and grade of nuclear atypia were recorded. Additionally, a tissue microarray was constructed from 22 of the cases, and the protein biomarkers P53, P16, Ki-67, Cyclin-D1, ER, PR and ANLN were evaluated by immunohistochemistry. All tumors were evaluated for the presence of a YWHAE-FAM translocation; the translocation was demonstrated in the three Cyclin-D1 positive tumors. Follow-up data in the form of overall survival were available on all patients. These tumors could be divided into two prognostic groups, a high mitotic index group (10 cases, M=36.8, SD=5.4) and a low mitotic index group (16 cases, M=8.7, SD=5.8). These two groups showed a statistically significant difference in prognosis. The expression of ER, PR or presence of the YWHAE-FAM22 translocation correlated with low mitotic index and an additionally improved prognosis, although the number of cases was small. These results indicate that UUS can be divided into two prognostic groups using mitotic index as a primary criteria, followed by expression of either ER, PR or the presence of a YWHAE-FAM22 translocation as a secondary criteria. This study demonstrates the presence of statistically significant prognostic subgroups within UUS, and provides treatment insights.

  • 41. Gustafsson, L.
    et al.
    Sparén, P.
    Gustafsson, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pettersson, B.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bergström, Reinhold
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Information Science.
    Adami, Hans-Olov
    Low efficiency of cytologic screening for cancer in situ of the cervix in older women1995In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 63, no 6, p. 804-809Article in journal (Refereed)
    Abstract [en]

    Cytologic screening for cervical cancer has proven to be beneficial in many countries, although the value of this intervention in women older than 50 years remains controversial. The purpose of this study was to investigate the efficiency of detecting cancer in situ by means of a cytologic smear at different ages, with special emphasis on the benefit of screening in women above the age of 50. We analyzed 466,275 smears taken in an open cohort of 118,890 women in Sweden between 1969 and 1988. The number of cancers in situ detected per 1,000 smears, the detection ratio, was used as an outcome measure in univariate analyses and in multivariate regression models. Cancer in situ was detected in 1,076 women in the study cohort. The detection ratio peaked at ages 30 to 34 and decreased heavily during the next 15 years of age. The efficiency of taking smears at ages above 50 was only 20 per cent (OR, 0.19; 95% CI, 0.14-0.26) of that at ages 30 to 34. These results were not changed when adjusting for time period and time interval since the previous smear. In spite of a high incidence of invasive cervical cancer in older women, the benefit of cytologic screening to detect cancer in situ above the age of 50 is uncertain.

  • 42. Gustafsson, Leif
    et al.
    Pontén, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bergström, Reinhold
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Information Science.
    Adami, Hans-Olov
    International incidence rates of invasive cervical cancer before cytological screening1997In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 71, no 2, p. 159-165Article in journal (Refereed)
    Abstract [en]

    Huge differences in incidence rates of invasive cervical cancer occur among populations. These differences reflect the influences of both etiological environmental factors and removal of precursor lesions detected upon screening. The purposes of this article are (i) to describe similarities and differences in the shapes and magnitudes of age-specific incidence rates of invasive cervical cancer before screening had an effect, (ii) to provide baseline data for further global study of screening effects, and (iii) to provide baseline incidence data for the design of optimal screening programs. To eliminate the impact of screening effects, we have selected age-specific incidence rates from times when and from populations in which screening was insignificant. The selected rates were suitably scaled and compared regarding age at onset of increase in incidence, age at peak incidence, and rate of subsequent decline. Despite a 16-fold difference in incidence rates, all curves had the same basic structure, with an increase to a peak followed by a decline or a plateau. Although all populations but one had an onset around age 25, 7 European countries showed an earlier peak age (mean = 46 vs. 59) and a more rapid decline after the peak than most other populations. The common basic shape of the age-specific incidence curve, overall, suggests a relatively similar development of invasive cervical cancer in different populations. These results illustrate the underlying similarities in the markedly different age-specific incidence rates of invasive cervical cancer. They also provide a basis for studying screening effects and for optimizing screening programs in specific geographic areas.

  • 43.
    Harris, Holly R.
    et al.
    Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden.;Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA..
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Cent Hosp Vasteras, Dept Surg, Vasteras, Sweden..
    Wolk, Alicja
    Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden..
    Adherence to the World Cancer Research Fund/American Institute for Cancer Research recommendations and breast cancer risk2016In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 138, no 11, p. 2657-2664Article in journal (Refereed)
    Abstract [en]

    The World Cancer Research Fund/American Association for Cancer Research (WCRF/AICR) has published eight nutrition-related recommendations for the prevention of cancer. However, few prospective studies have examined these recommendations by breast cancer hormone receptor subtype and only one case-control study has included the dietary supplements recommendation in their evaluation. We investigated whether adherence to the WCRF/AICR cancer prevention recommendations was associated with breast cancer incidence, overall and by hormone receptor subtype, in the Swedish Mammography Cohort. Among 31,514 primarily postmenopausal women diet and lifestyle factors were assessed with a self-administered food frequency questionnaire. A score was constructed based on adherence to the recommendations for body fatness, physical activity, energy density, plant foods, animal foods, alcoholic drinks and dietary supplements (score range 0-7). Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). During 15 years of follow-up 1,388 cases of breast cancer were identified. Women who met six to seven recommendations had a 51% decreased risk of breast cancer compared to women meeting only zero to two recommendations (95% CI = 0.35-0.70). The association between each additional recommendation met and breast cancer risk was strongest for the ER-positive/PR-positive subtype (HR = 0.86; 95% CI = 0.79-0.94), while for the ER-negative/PR-negative subtype the individual recommendations regarding plant and animal foods were most strongly associated with reduced risk. Our findings support that adherence to the WCRF/AICR recommendations reduces breast cancer risk in a population of primarily postmenopausal women. Promoting these recommendations to the public could help reduce breast cancer incidence.

  • 44. Harris, Holly 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, Alicja
    An estrogen-associated dietary pattern and breast cancer risk in the Swedish Mammography Cohort2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 9, p. 2149-2154Article in journal (Refereed)
    Abstract [en]

    High endogenous hormone levels have been associated with breast cancer and dietary factors have the potential to influence breast cancer risk through effects on hormone levels. Dietary patterns derived from reduced rank regression provide a way to identify food groups correlated with hormones and subsequently examine food patterns that may be associated with breast cancer risk. We investigated whether a dietary pattern previously correlated with estradiol and estrone sulfate was associated with breast cancer in the prospective Swedish Mammography Cohort. Among 37,004 primarily postmenopausal women diet was assessed with a food frequency questionnaire. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). During 15 years of follow-up 1,603 cases of breast cancer were identified. A higher estrogen dietary pattern score was associated with an increased risk of breast cancer. Women in the highest quartile of estrogen pattern score had a 29% (95% CI=1.08-1.55) increased risk of breast cancer compared to women in the lowest quartile (p(trend) = 0.006). When the association was examined by estrogen-receptor status, it was only significant for those with estrogen-receptor-positive tumors; however, in the competing risk analysis there were no significant differences in the effect estimates by receptor subtype (p(heterogeneity) = 0.65). Our findings suggest that a dietary pattern associated with higher estrogen levels may increase breast cancer risk. However, whether the influence of this dietary pattern is through a direct effect on estrogen levels deserves further study.

  • 45.
    Hasumi, Yoko
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Kłosowska-Wardega, Agnieszka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Furuhashi, Masao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Östman, Arne
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Hellberg, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Identification of a subset of pericytes that respond to combination therapy targeting PDGF and VEGF signaling2007In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 121, no 12, p. 2606-2614Article in journal (Refereed)
    Abstract [en]

    The aim of our study was to further explore the use of anti-angiogenic therapy targeting the vascular endothelial growth factor receptor (VEGFR) on endothelial cells while simultaneously targeting platelet-derived growth factor receptors (PDGFRs) on adjacent pericytes. B16 mouse melanoma tumors exogenously expressing PDGF-BB (B16/PDGF-BB) display higher pericyte coverage on the vasculature compared to the parental B16 tumors (B16/mock). These models were used to investigate the effects of combination therapy targeting VEGFR and PDGFR signaling on size-matched tumors. Combination therapy using 25 mg/kg/day of the VEGFR inhibitor PTK787 and 100 mg/kg/day of the PDGFR inhibitor STI571 decreased the tumor growth rate of both tumor types, but the inhibition was only significant in the B16/PDGF-BB tumors. Combination therapy induced vessel remodeling, primarily by reducing the vessel density in B16/mock tumors, and by reducing the vessel size in B16/PDGF-BB tumors. When analyzing the effects of combination therapy on tumor vessel pericytes, it was found to primarily reduce the subpopulation of alpha-smooth muscle actin and PDGFRbeta-positive pericytes partly detached from the tumor vessels, without affecting the number of pericytes closely attached to the endothelium, which also express desmin. Taken together, these data demonstrate an increased benefit of targeting both VEGFR and PDGFR pathways in B16/PDGF-BB tumors, and demonstrates that the increased tumor growth inhibition in this model is accompanied by a reduction in a specific subset of pericytes, characterized by being loosely attached to endothelial cells and negative for the pericyte marker desmin.

  • 46. Hjalgrim, Henrik
    et al.
    Frisch, Morten
    Storm, Hans H.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Pedersen, Jakob Böje
    Melbye, Mads
    Non-melanoma skin cancer may be a marker of poor prognosis in patients with non-Hodgkin's lymphoma2000In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 85, no 5, p. 639-642Article in journal (Refereed)
    Abstract [en]

    According to recent results, patients with non-melanoma skin cancers are at increased risk of developing non-Hodgkin's lymphoma (NHL). The prognostic significance of this association is unknown. Two cohorts of patients with a first diagnosis of non-melanoma skin cancer and a subsequent diagnosis of either NHL (n = 170) or colon cancer (n = 435) were established using national cancer registry data in Denmark. Two other cohorts of patients in whom NHL (n = 600) or colon cancer (n = 1,541) was the patients' first known malignancy served as comparison groups. Mortality rates were compared using Cox's regression analysis. Among patients younger than 80 years at NHL diagnosis, a history of non-melanoma skin cancer was associated with significantly increased mortality [relative risk (RR) = 1.54; 95% confidence interval: 1.19-1.99]. This association was present in both men (RR = 1.38; 1.02-1.86) and women (RR = 2.15; 1.31-3.54) and was similar after both major subtypes of non-melanoma skin cancer. Overall, antedating non-melanoma skin cancer had no prognostic significance for colon cancer patients (RR = 1.00; 0.84-1.18). Whatever the underlying mechanism, our observation has potential clinical implications. If substantiated in other settings, NHL patients with prior non-melanoma skin cancer may constitute a subgroup of lymphoma patients in need of particular therapeutic attention.

  • 47.
    Häggström, Christel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden.; Umea Univ, Dept Biobank Res, S-90185 Umea, Sweden..
    Van Hemelrijck, Mieke
    Kings Coll London, Div Canc Studies, Fac Life Sci & Med, London, England.;Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Med Prod Agcy, Dept Sci Support, Uppsala, Sweden..
    Robinson, David
    Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden..
    Grundmark, Birgitta
    Med Prod Agcy, Dept Sci Support, 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, Fac Life Sci & Med, London, England.
    Gudbjörnsdottir, Soffia
    Gothenburg Univ, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Kings Coll London, Div Canc Studies, Fac Life Sci & Med, London, England.
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology. Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden.
    Prospective study of Type 2 diabetes mellitus, anti-diabetic drugs and risk of prostate cancer2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 3, p. 611-617Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes mellitus (T2DM) has consistently been associated with decreased risk of prostate cancer; however, if this decrease is related to the use of anti-diabetic drugs is unknown. We prospectively studied men in the comparison cohort in the Prostate Cancer data Base Sweden 3.0, with data on T2DM, use of metformin, sulfonylurea and insulin retrieved from national health care registers and demographic databases. Cox proportional hazards regression models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) of prostate cancer, adjusted for confounders. The study consisted of 612,846 men, mean age 72 years (standard deviation; SD=9 years), out of whom 25,882 men were diagnosed with prostate cancer during follow up, mean time of 5 years (SD=3 years). Men with more than 1 year's duration of T2DM had a decreased risk of prostate cancer compared to men without T2DM (HR=0.85, 95% CI=0.82-0.88) but among men with T2DM, those on metformin had no decrease (HR=0.96, 95% CI=0.77-1.19), whereas men on insulin (89%) or sulfonylurea (11%) had a decreased risk (HR=0.73, 95% CI=0.55-0.98), compared to men with T2DM not on anti-diabetic drugs. Men with less than 1 year's duration of T2DM had no decrease in prostate cancer risk (HR=1.11, 95% CI=0.95-1.31). Our results gave no support to the hypothesis that metformin protects against prostate cancer as recently proposed. However, our data gave some support to an inverse association between T2DM severity and prostate cancer risk.

    What's new? Although Type 2 diabetes mellitus (T2DM) increases the risk of several cancers, multiple studies point toward a significantly inverse relationship between T2DM and prostate cancer risk in men. Use of the anti-diabetic drug metformin is suspected of underlying the association. In this prospective study in Sweden, however, metformin failed to decrease the risk of prostate cancer. By comparison, risk was decreased in association with the use of insulin or sulfonylurea. These findings add some support to an inverse association between T2DM severity and prostate cancer risk.

  • 48. Ibrahim, S O
    et al.
    Johannessen, A C
    Idris, A M
    Hirsch, Jan M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Vasstrand, E N
    Magnusson, B
    Nilsen, R
    Immunohistochemical detection of p53 in non-malignant and malignant oral lesions associated with snuff dipping in the Sudan and Sweden1996In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 68, no 6, p. 749-753Article in journal (Refereed)
    Abstract [en]

    Immunohistochemistry was used to examine the expression of p53 in pre-malignant oral lesions and oral squamous-cell carcinomas (SCCs) from Swedish and Sudanese snuff-dippers, as well as in pre-malignant oral lesions and oral SCCs from non-snuff-dippers from the Sudan, Sweden and Norway. Of the 14 SCCs from Sudanese snuff-dippers, 21% (3/14) expressed p53. Of the 14, 60 and 41 SCCs from non-snuff-dippers from the Sudan, Sweden and Norway, 64% (9/14), 65% (39/60) and 68% (28/41) expressed p53, respectively. A statistically significant difference in expression of p53 was found in SCCs from Sudanese snuff-dippers compared to those from non-snuff-dippers from all/or any of the 3 countries. None of the suspected pre-malignant oral lesions from Sudanese snuff dippers or non-snuff-dippers expressed p53. Only 2 out of the 15 oral fibro-epithelial hyperplastic lesions from Swedish snuff-dippers expressed p53. Some of the oral epithelial dysplastic lesions, as well as the carcinoma in situ lesions from Norwegian non-snuff-dippers, expressed p53, while the oral fibro-epithelial hyperplastic lesions did not. The low relative frequency of p53 expression found in oral SCCs from snuff-dippers compared to those from non-snuff-dippers might suggest differences in mechanisms of oncogenic action induced by snuff. Alternatively, the pathogenesis of malignant oral lesions from snuff-dippers may follow a p53-independent pathway. In view of the unusually high levels of the tobacco-specific nitrosamines (TSNA) found in the type of snuff used in the Sudan, investigations of p53 mutations or oncogenes are needed.

  • 49.
    Ivansson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gustavsson, Inger M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Magnusson, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Steiner, Lori
    Magnusson, Patrik
    Erlich, Henry
    Gyllensten, Ulf B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer2007In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 121, no 11, p. 2451-2457Article in journal (Refereed)
    Abstract [en]

    Cervical cancer is caused by persistent infection of oncogenichuman papillomavirus (HPV). Most infected women clear the viruswithout developing cervical lesions and it is likely that immunologicalhost factors affect susceptibility to cervical cancer. Theimpact of the human leukocyte antigen (HLA) locus on the risk ofcervical cancer is established and several other genes involved inimmunological pathways have been suggested as biologically plausiblecandidates. The aim of this study was to examine the potentialrole of polymorphisms in 4 candidate genes by analysis of1,306 familial cervical cancer cases and 288 controls. The followinggenes and polymorphisms were studied: Chemokine receptor2 (CCR-2) V64I; Interleukin 4 receptor a (IL-4R) I75V, S503P andQ576R; Interleukin 10 (IL-10) 2592; and Fas ligand (FasL) 2844.The CCR-2 64I variant was associated with decreased risk of cervicalcancer; homozygote carriers of the 64I variant had an oddsratio of 0.31 (0.12–0.77). This association was detected in both carriersand noncarriers of the HLA DQB1*0602 cervical cancer riskallele. The IL-4R 75V variant was associated with increased riskof cervical tumors, cases homozygote for 75V had an odds ratio of1.91 (1.27–2.86) with a tendency that the association was strongerin noncarriers of the DQB1*0602 allele. We did not find any associationfor IL-10 2592, or FasL 2844, previously reported to beassociated with cervical cancer in the Dutch and Chinese populations,respectively.

  • 50.
    Ivansson, Emma L
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gustavsson, Inger M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Magnusson, Patrik K E
    Gyllensten, Ulf B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Temporal trends over 3 decades and intrafamilial clustering of HPV types in Swedish patients with cervical cancer in situ2009In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 125, no 12, p. 2930-2935Article in journal (Refereed)
    Abstract [en]

    Information on HPV type distribution in cervical cancer in situ in different populations is needed for evaluation of prophylactic vaccination programs targeting HPV 16 and 18. In our study, the HPV type prevalence in 1,079 Swedish women from multicase families diagnosed with cervical cancer in situ 1965-1993 was investigated using real-time PCR and archival tissue material. HPV type information was obtained for 974 samples. Among these, HPV 16 (61%) was the dominant type followed by HPV 33/52/58 (24%), HPV 31 (13%) and HPV 18/45 (12%). The detected prevalence of HPV 16 among cancer in situ decreased by 13% over the study period while the group of low frequency high-risk types increased. Related women were not prone to infection by the same type. These data suggest that the prevalence of individual HPV types has changed over time in Swedish patients with cervical cancer in situ. Large-scale studies of pathology biobank materials will enable further insight into the temporal changes of individual HPV types, as baseline information to properly evaluate the effect of vaccine programs. The findings also indicate that genetic susceptibility to cervical cancer operates through general and not type specific susceptibility to HPV infection.

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