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  • 401.
    Forsberg, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zhang, Yingshuang
    Reiners, Johanna
    Ander, Martina
    Niedermayer, Alexandra
    Fang, Lubin
    Neugebauer, Hermann
    Kassubek, Jan
    Katona, Istvan
    Weis, Joachim
    Ludolph, Albert C.
    Del Tredici, Kelly
    Braak, Heiko
    Yilmazer-Hanke, Deniz
    Endothelial damage, vascular bagging and remodeling of the microvascular bed in human microangiopathy with deep white matter lesions2018In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 6, article id 128Article in journal (Refereed)
    Abstract [en]

    White matter lesions (WMLs) are a common manifestation of small vessel disease (SVD) in the elderly population. They are associated with an enhanced risk of developing gait abnormalities, poor executive function, dementia, and stroke with high mortality. Hypoperfusion and the resulting endothelial damage are thought to contribute to the development of WMLs. The focus of the present study was the analysis of the microvascular bed in SVD patients with deep WMLs (DWMLs) by using double- and triple-label immunohistochemistry and immunofluorescence. Simultaneous visualization of collagen IV (COLL4)-positive membranes and the endothelial glycocalyx in thick sections allowed us to identify endothelial recession in different types of string vessels, and two new forms of small vessel/capillary pathology, which we called vascular bagging and ghost string vessels. Vascular bags were pouches and tubes that were attached to vessel walls and were formed by multiple layers of COLL4-positive membranes. Vascular bagging was most severe in the DWMLs of cases with pure SVD (no additional vascular brain injury, VBI). Quantification of vascular bagging, string vessels, and the density/size of CD68-positive cells further showed widespread pathological changes in the frontoparietal and/or temporal white matter in SVD, including pure SVD and SVD with VBI, as well as a significant effect of the covariate age. Plasma protein leakage into vascular bags and the white matter parenchyma pointed to endothelial damage and basement membrane permeability. Hypertrophic IBA1-positive microglial cells and CD68-positive macrophages were found in white matter areas covered with networks of ghost vessels in SVD, suggesting phagocytosis of remnants of string vessels. However, the overall vessel density was not altered in our SVD cohort, which might result from continuous replacement of vessels. Our findings support the view that SVD is a progressive and generalized disease process, in which endothelial damage and vascular bagging drive remodeling of the microvasculature.

  • 402.
    Forsberg, Karl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Reasons for hospitalisation and decision to give intravenous fluids during end of life for patients with dementia2018Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 403. Fortner, Renee T.
    et al.
    Huesing, Anika
    Kuehn, Tilman
    Konar, Meric
    Overvad, Kim
    Tjonneland, Anne
    Hansen, Louise
    Boutron-Ruault, Marie-Christine
    Severi, Gianluca
    Fournier, Agnes
    Boeing, Heiner
    Trichopoulou, Antonia
    Benetou, Vasiliki
    Orfanos, Philippos
    Masala, Giovanna
    Agnoli, Claudia
    Mattiello, Amalia
    Tumino, Rosario
    Sacerdote, Carlotta
    Bueno-de-Mesquita, H. B(as)
    Peeters, Petra H. M.
    Weiderpass, Elisabete
    Gram, Inger T.
    Gavrilyuk, Oxana
    Ramon Quiros, J.
    Maria Huerta, Jose
    Ardanaz, Eva
    Larranaga, Nerea
    Lujan-Barroso, Leila
    Sanchez-Cantalejo, Emilio
    Butt, Salma Tuna
    Borgquist, Signe
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Allen, Naomi E.
    Rinaldi, Sabina
    Dossus, Laure
    Gunter, Marc
    Merritt, Melissa A.
    Tzoulaki, Ioanna
    Riboli, Elio
    Kaaks, Rudolf
    Endometrial cancer risk prediction including serum-based biomarkers: results from the EPIC cohort2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 6, p. 1317-1323Article in journal (Refereed)
    Abstract [en]

    Endometrial cancer risk prediction models including lifestyle, anthropometric and reproductive factors have limited discrimina-tion. Adding biomarker data to these models may improve predictive capacity; to our knowledge, this has not been investigat-ed for endometrial cancer. Using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the improvement in discrimination gained by adding serum biomarker concentrations to risk estimates derived from an existing risk prediction model based on epidemiologic factors. Serum concentrations of sex steroid hormones, metabolic markers, growth factors, adipokines and cytokines were evaluated in a step-wise backward selec-tion process; biomarkers were retained at p < 0.157 indicating improvement in the Akaike information criterion (AIC). Improvement in discrimination was assessed using the C-statistic for all biomarkers alone, and change in C-statistic from addition of biomarkers to preexisting absolute risk estimates. We used internal validation with bootstrapping (1000-fold) to adjust for over-fitting. Adiponectin, estrone, interleukin-1 receptor antagonist, tumor necrosis factor-alpha and triglycerides were select-ed into the model. After accounting for over-fitting, discrimination was improved by 2.0 percentage points when all evaluated biomarkers were included and 1.7 percentage points in the model including the selected biomarkers. Models including eti-ologic markers on independent pathways and genetic markers may further improve discrimination.

  • 404. Fortner, Renee T.
    et al.
    Ose, Jennifer
    Merritt, Melissa A.
    Schock, Helena
    Tjonneland, Anne
    Hansen, Louise
    Overvad, Kim
    Dossus, Laure
    Clavel-Chapelon, Francoise
    Baglietto, Laura
    Boeing, Heiner
    Trichopoulou, Antonia
    Benetou, Vassiliki
    Lagiou, Pagona
    Agnoli, Claudia
    Mattiello, Amalia
    Masala, Giovanna
    Tumino, Rosario
    Sacerdote, Carlotta
    Bueno-de-Mesquita, H. B(as)
    Onland-Moret, N. Charlotte
    Peeters, Petra H.
    Weiderpass, Elisabete
    Gram, Inger Torhild
    Duell, Eric J.
    Larranaga, Nerea
    Ardanaz, Eva
    Sanchez, Maria-Jose
    Chirlaque, M-D
    Braendstedt, Jenny
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C.
    Rinaldi, Sabina
    Romieu, Isabelle
    Gunter, Marc J.
    Riboli, Elio
    Kaaks, Rudolf
    Reproductive and hormone-related risk factors for epithelial ovarian cancer by histologic pathways, invasiveness and histologic subtypes: results from the EPIC cohort2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 5, p. 1196-1208Article in journal (Refereed)
    Abstract [en]

    Whether risk factors for epithelial ovarian cancer (EOC) differ by subtype (i.e., dualistic pathway of carcinogenesis, histologic subtype) is not well understood; however, data to date suggest risk factor differences. We examined associations between reproductive and hormone-related risk factors for EOC by subtype in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Among 334,126 women with data on reproductive and hormone-related risk factors (follow-up: 1992-2010), 1,245 incident cases of EOC with known histology and invasiveness were identified. Data on tumor histology, grade, and invasiveness, were available from cancer registries and pathology record review. We observed significant heterogeneity by the dualistic model (i.e., type I [low grade serous or endometrioid, mucinous, clear cell, malignant Brenner] vs. type II [high grade serous or endometrioid]) for full-term pregnancy (p(het)=0.02). Full-term pregnancy was more strongly inversely associated with type I than type II tumors (ever vs. never: type I: relative risk (RR) 0.47 [95% confidence interval (CI): 0.33-0.69]; type II, RR: 0.81 [0.61-1.06]). We observed no significant differences in risk in analyses by major histologic subtypes of invasive EOC (serous, mucinous, endometrioid, clear cell). None of the investigated factors were associated with borderline tumors. Established protective factors, including duration of oral contraceptive use and full term pregnancy, were consistently inversely associated with risk across histologic subtypes (e.g., ever full-term pregnancy: serous, RR: 0.73 [0.58-0.92]; mucinous, RR: 0.53 [0.30-0.95]; endometrioid, RR: 0.65 [0.40-1.06]; clear cell, RR: 0.34 [0.18-0.64]; p(het)=0.16). These results suggest limited heterogeneity between reproductive and hormone-related risk factors and EOC subtypes. What's new? Reproductive and hormone-related risk factors for epithelial ovarian cancer (EOC) have been extensively investigated. However, EOC is increasingly recognized as a heterogeneous disease and risk factor differences across EOC subtypes, as defined by the recently proposed dualistic pathway of ovarian carcinogenesis and histological characteristics, are not well understood. Here, the authors present a detailed prospective investigation on reproductive and hormone-related risk factors for borderline tumors and epithelial ovarian cancer by main histological subtypes and, for the first time, by the types defined by the dualistic pathway. The results suggest limited heterogeneity between reproductive and hormone-related risk factors and EOC subtypes.

  • 405. Fortner, Renee T.
    et al.
    Poole, Elizabeth M.
    Wentzensen, Nicolas A.
    Trabert, Britton
    White, Emily
    Arslan, Alan A.
    Patel, Alpa, V
    Setiawan, V. Wendy
    Visvanathan, Kala
    Weiderpass, Elisabete
    Adami, Hans-Olov
    Black, Amanda
    Bernstein, Leslie
    Brinton, Louise A.
    Buring, Julie
    Clendenen, Tess, V
    Fournier, Agnes
    Fraser, Gary
    Gapstur, Susan M.
    Gaudet, Mia M.
    Giles, Graham G.
    Gram, Inger T.
    Hartge, Patricia
    Hoffman-Bolton, Judith
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Kaaks, Rudolf
    Kirsh, Victoria A.
    Knutsen, Synnove
    Koh, Woon-Puay
    Lacey, James V., Jr.
    Lee, I-Min
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Merritt, Melissa A.
    Milne, Roger L.
    Onland-Moret, N. Charlotte
    Peters, Ulrike
    Poynter, Jenny N.
    Rinaldi, Sabina
    Robien, Kim
    Rohan, Thomas
    Sanchez, Maria-Jose
    Schairer, Catherine
    Schouten, Leo J.
    Tjonneland, Anne
    Townsend, Mary K.
    Travis, Ruth C.
    Trichopoulou, Antonia
    van den Brandt, Piet A.
    Vineis, Paolo
    Wilkens, Lynne
    Wolk, Alicja
    Yang, Hannah P.
    Zeleniuch-Jacquotte, Anne
    Tworoger, Shelley S.
    Ovarian cancer risk factors by tumor aggressiveness: an analysis from the Ovarian Cancer Cohort Consortium2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 1, p. 58-69Article in journal (Refereed)
    Abstract [en]

    Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58–0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92–1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47–2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2, 1.93 [1.46–2.56] and current smoking (vs. never, 1.30 [1.07–1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.

  • 406. Fortner, Renee T.
    et al.
    Tolockiene, Egle
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schock, Helena
    Oda, Husam
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lakso, Hans-Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Kaaks, Rudolf
    Toniolo, Paolo
    Zeleniuch-Jacquotte, Anne
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Early pregnancy sex steroids during primiparous pregnancies and maternal breast cancer: a nested case-control study in the Northern Sweden Maternity Cohort2017In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 19, article id 82Article in journal (Refereed)
    Abstract [en]

    Background: Pregnancy and parity are associated with subsequent breast cancer risk. Experimental and epidemiologic data suggest a role for pregnancy sex steroid hormones.

    Methods: We conducted a nested case–control study in the Northern Sweden Maternity Cohort (1975–2007). Eligible women had provided a blood sample in the first 20 weeks of gestation during a primiparous pregnancy leading to a term delivery. The current study includes 223 cases and 417 matched controls (matching factors: age at and date of blood collection). Estrogen receptor (ER) and progesterone receptor (PR) status was available for all cases; androgen receptor (AR) data were available for 41% of cases (n = 92). Sex steroids were quantified by high-performance liquid chromatography tandem mass spectrometry. Odds ratios (ORs) and 95% confidence intervals were estimated using conditional logistic regression.

    Results: Higher concentrations of circulating progesterone in early pregnancy were inversely associated with ER+/PR+ breast cancer risk (ORlog2: 0.64 (0.41–1.00)). Higher testosterone was positively associated with ER+/PR+ disease risk (ORlog2: 1.57 (1.13–2.18)). Early pregnancy estrogens were not associated with risk, except for relatively high estradiol in the context of low progesterone (split at median, relative to low concentrations of both; OR: 1.87 (1.11–3.16)). None of the investigated hormones were associated with ER–/PR– disease, or with AR+ or AR+/ER+/PR+ disease.

    Conclusions: Consistent with experimental models, high progesterone in early pregnancy was associated with lower risk of ER+/PR+ breast cancer in the mother. High circulating testosterone in early pregnancy, which likely reflects nonpregnant premenopausal exposure, was associated with higher risk of ER+/PR+ disease.

  • 407. Fortner, Renee T.
    et al.
    Vitonis, Allison F.
    Schock, Helena
    Huesing, Anika
    Johnson, Theron
    Fichorova, Raina N.
    Fashemi, Titilayo
    Yamamoto, Hidemi S.
    Tjonneland, Anne
    Hansen, Louise
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Kvaskoff, Marina
    Severi, Gianluca
    Boeing, Heiner
    Trichopoulou, Antonia
    Benetou, Vassiliki
    La Vecchia, Carlo
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Matullo, Giuseppe
    Mattiello, Amalia
    Onland-Moret, N. Charlotte
    Peeters, Petra H.
    Weiderpass, Elisabete
    Gram, Inger Torhild
    Jareid, Mie
    Ramon Quiros, J.
    Duell, Eric J.
    Sanchez, Maria-Jose
    Dolores Chirlaque, Maria
    Ardanaz, Eva
    Larranaga, Nerea
    Nodin, Bjorn
    Brandstedt, Jenny
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Khaw, Kay-Tee
    Allen, Naomi
    Gunter, Marc
    Johansson, Mattias
    Dossus, Laure
    Merritt, Melissa A.
    Riboli, Elio
    Cramer, Daniel W.
    Kaaks, Rudolf
    Terry, Kathryn L.
    Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models: results from the EPIC cohort2017In: Journal of Ovarian Research, ISSN 1757-2215, E-ISSN 1757-2215, Vol. 10, article id 20Article in journal (Refereed)
    Abstract [en]

    Background: Ovarian cancer early detection markers CA125, CA15.3, HE4, and CA72.4 vary between healthy women, limiting their utility for screening.

    Methods: We evaluated cross-sectional relationships between lifestyle and reproductive factors and these markers among controls (n = 1910) from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Improvements in discrimination of prediction models adjusting for correlates of the markers were evaluated among postmenopausal women in the nested case-control study (n = 590 cases). Generalized linear models were used to calculate geometric means of CA125, CA15.3, and HE4. CA72.4 above vs. below limit of detection was evaluated using logistic regression. Early detection prediction was modeled using conditional logistic regression.

    Results: CA125 concentrations were lower, and CA15.3 higher, in post- vs. premenopausal women (p ≤ 0.02). Among postmenopausal women, CA125 was higher among women with higher parity and older age at menopause (ptrend ≤ 0.02), but lower among women reporting oophorectomy, hysterectomy, ever use of estrogen-only hormone therapy, or current smoking (p < 0.01). CA15.3 concentrations were higher among heavier women and in former smokers (p ≤ 0.03). HE4 was higher with older age at blood collection and in current smokers, and inversely associated with OC use duration, parity, and older age at menopause (≤ 0.02). No associations were observed with CA72.4. Adjusting for correlates of the markers in prediction models did not improve the discrimination.

    Conclusions: This study provides insights into sources of variation in ovarian cancer early detection markers in healthy women and informs about the utility of individualizing marker cutpoints based on epidemiologic factors.

  • 408. Fortner, Renée T.
    et al.
    Schock, Helena
    Jung, Seungyoun
    Allen, Naomi E.
    Arslan, Alan A.
    Brinton, Louise A.
    Egleston, Brian L.
    Falk, Roni T.
    Gunter, Marc J.
    Helzlsouer, Kathy J.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Johnson, Theron S.
    Kaaks, Rudolf
    Krogh, Vittorio
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Merritt, Melissa A.
    Navarro, Carmen
    Onland-Moret, N. Charlotte
    Palli, Domenico
    Shu, Xiao-Ou
    Sluss, Patrick M.
    Staats, Paul N.
    Trichopoulou, Antonia
    Weiderpass, Elisabete
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Dorgan, Joanne F.
    Anti-Mullerian hormone and endometrial cancer: a multi-cohort study2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 117, no 9, p. 1412-1418Article in journal (Refereed)
    Abstract [en]

    Background: The Mullerian ducts are the embryological precursors of the female reproductive tract, including the uterus; anti-Mullerian hormone (AMH) has a key role in the regulation of foetal sexual differentiation. Anti-Mullerian hormone inhibits endometrial tumour growth in experimental models by stimulating apoptosis and cell cycle arrest. To date, there are no prospective epidemiologic data on circulating AMH and endometrial cancer risk. Methods: We investigated this association among women premenopausal at blood collection in a multicohort study including participants from eight studies located in the United States, Europe, and China. We identified 329 endometrial cancer cases and 339 matched controls. AntiMullerian hormone concentrations in blood were quantified using an enzyme-linked immunosorbent assay. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) across tertiles and for a doubling of AMH concentrations (ORlog2). Subgroup analyses were performed by ages at blood donation and diagnosis, oral contraceptive use, and tumour characteristics. Results: Anti-Mullerian hormone was not associated with the risk of endometrial cancer overall (ORlog(2): 1.07 (0.99-1.17)), or with any of the examined subgroups. Conclusions: Although experimental models implicate AMH in endometrial cancer growth inhibition, our findings do not support a role for circulating AMH in the aetiology of endometrial cancer.

  • 409. Fortner, Renée T
    et al.
    Schock, Helena
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Kaaks, Rudolf
    Lehtinen, Matti
    Pukkala, Eero
    Lakso, Hans-Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Tanner, Minna
    Kallio, Raija
    Joensuu, Heikki
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zeleniuch-Jacquotte, Anne
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Toniolo, Paolo
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Surcel, Helja-Marja
    Early pregnancy sex steroids and maternal breast cancer: a nested case-control study2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 23, p. 6958-6967Article in journal (Refereed)
    Abstract [en]

    Pregnancy, parity, and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (<140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breast cancer risk in a nested case-control study in the Finnish Maternity Cohort. The cohort includes 98% of pregnancies registered in Finland since 1983. Individuals with samples collected in the first pregnancy leading to a live birth were eligible. Breast cancer cases (n = 1,199) were identified through linkage with the Finnish Cancer Registry; 2,281 matched controls were selected using incidence density sampling. ORs were calculated using conditional logistic regression. Hormone concentrations were not associated with breast cancer overall. Estradiol was positively associated with risk of breast cancer diagnosed age <40 [4th vs. 1st quartile OR 1.60 (1.07-2.39); Ptrend = 0.01], and inversely associated with breast cancer diagnosed at age ≥40 [4th vs. 1st quartile OR 0.71 (0.51-1.00); Ptrend = 0.02]. Elevated concentrations of the steroid hormones were associated with increased risk of estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors in women age <40 at diagnosis. We observed no association between steroid hormones and ER(+)/PR(+) disease. These data suggest a positive association between high concentrations of early pregnancy steroid hormones and risk of ER(-)/PR(-) breast cancer in women diagnosed age <40, and an inverse association for overall breast cancer diagnosed age ≥40. Further research on pregnancy hormones and risk of steroid receptor-negative cancers is needed to further characterize this association.

  • 410. Fortner, Renée T
    et al.
    Schock, Helena
    Kaaks, Rudolf
    Lehtinen, Matti
    Pukkala, Eero
    Lakso, Hans-Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Tanner, Minna
    Kallio, Raija
    Joensuu, Heikki
    Korpela, Jaana
    Toriola, Adetunji T
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zeleniuch-Jacquotte, Anne
    Toniolo, Paolo
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Surcel, Heljä-Marja
    Human Chorionic Gonadotropin Does Not Correlate with Risk for Maternal Breast Cancer: Results from the Finnish Maternity Cohort2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 1, p. 134-141Article in journal (Refereed)
    Abstract [en]

    Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early-pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case-control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort, a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (<140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22 to 58 years (mean: 41 years). hCG was measured using a solid-phase competitive chemiluminescence assay. Odds ratios (OR) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall [Quartile 4 vs. 1, OR, 1.14; 95% confidence interval (CI), 0.94-1.39], by estrogen and progesterone receptor status, or by ages at first-term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., <5 years, ORQ4 vs. Q1, 1.10; 95% CI, 0.64-1.89; ≥15 years, ORQ4 vs. Q1, 1.36; 95% CI, 0.86-2.13; pheterogeneity = 0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk. 

  • 411. Fortner, Renée T.
    et al.
    Schock, Helena
    Le Cornet, Charlotte
    Hüsing, Anika
    Vitonis, Allison F.
    Johnson, Theron S.
    Fichorova, Raina N.
    Fashemi, Titilayo
    Yamamoto, Hidemi S.
    Tjonneland, Anne
    Hansen, Louise
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Kvaskoff, Marina
    Severi, Gianluca
    Boeing, Heiner
    Trichopoulou, Antonia
    Papatesta, Eleni-Maria
    La Vecchia, Carlo
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Onland-Moret, N. Charlotte
    Peeters, Petra H.
    Bueno-de-Mesquita, H. B(as)
    Weiderpass, Elisabete
    Quirós, J. Ramón
    Duell, Eric J.
    Sánchez, Maria-Jose
    Navarro, Carmen
    Ardanaz, Eva
    Larrañaga, Nerea
    Nodin, Björn
    Jirström, Karin
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Travis, Ruth C.
    Gunter, Marc
    Johansson, Mattias
    Dossus, Laure
    Merritt, Melissa A.
    Riboli, Elio
    Terry, Kathryn L.
    Cramer, Daniel W.
    Kaaks, Rudolf
    Ovarian cancer early detection by circulating CA125 in the context of anti-CA125 autoantibody levels: Results from the EPIC cohort2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 142, no 7, p. 1355-1360Article in journal (Refereed)
    Abstract [en]

    CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and non-cases. Anti-CA125 autoantibodies are observed in circulation. Our objective was to evaluate whether these antibodies (1) can serve as early detection markers, providing evidence of an immune response to a developing tumor, and (2) modify the discriminatory capacity of CA125 by either masking CA125 levels (resulting in lower discrimination) or acting synergistically to improve discrimination between cases and non-cases. We investigated these objectives using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) including 250 cases diagnosed within 4 years of blood collection and up to four matched controls. Circulating CA125 antigen and antibody levels were quantified using an electrochemiluminescence assay. Adjusted areas under the curve (aAUCs) by 2-year lag-time intervals were calculated using conditional logistic regression calibrated toward the absolute risk estimates from a pre-existing epidemiological risk model as an offset-variable. Anti-CA125 levels alone did not discriminate cases from controls. For cases diagnosed <2 years after blood collection, discrimination by CA125 antigen was suggestively higher with higher anti-CA125 levels (aAUC, highest antibody tertile: 0.84 [0.76-0.92]; lowest tertile: 0.76 [0.67-0.86]; p(het)=0.06). We provide the first evidence of potentially synergistic discrimination effects of CA125 and anti-CA125 antibodies in ovarian early detection. If these findings are replicated, evaluating CA125 in the context of its antibody may improve ovarian cancer early detection. What's new? Although CA125, a mucin produced in epithelial cells, is a known marker for ovarian cancer, complementary biomarkers are necessary for reliable early cancer detection. Here, the authors examined autoantibodies against CA125 as potential pre-diagnosis markers. Although anti-CA125 levels did not discriminate between ovarian cases and controls, discrimination of CA125 differed by levels of its antibody, with the highest discrimination among women with the highest antibody levels. The authors propose that CA125 and anti-CA125 may act synergistically for ovarian cancer early detection.

  • 412. Fossa, Sophie D.
    et al.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Klepp, Olbjørn Harald
    Wiklund, Fredrik
    Angelsen, Anders
    Damber, Jan-Erik
    Ten-and 15-year prostate cancer-specific survival in patients with nonmetastatic high-risk prostate cancer randomized to lifelong hormone treatment alone or combined with radiotherapy (SPCG VII)2014In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, no 4Article in journal (Other academic)
    Abstract [en]

    Background: After a median observation time of 7.6 years, Scandinavian Prostate Cancer Group VII randomized trial showed a significant 12% reduction of prostate cancer-specific mortality in patients with locally advanced or histologically aggressive prostate cancer who received three months of total androgen blockade followed by radiotherapy and continuous antiandrogen therapy compared to patients with hormonal treatment only (Widmark et al :Lancet [2009]; 373,1174). Here we provide the 10 (15)-year survival results after a median observation time of 10.7 years. Methods: Between February 1996 and December 2002, 875 patients with locally advanced prostate cancer were randomized (Randomization ratio 1:1). Primary endpoint was prostate cancer-specific survival analyzed by intention to treat. This updated analysis is based on death registry data of the Norwegian patients (2/3 of the population), and on data recorded in CRF database available for the Swedish patients. A Swedish death registry analysis is underway, and will be included in the final analysis at the meeting. Results: Prostate cancer death occurred in 118 out of 439 of the antiandrogen treatment group and in 45 out of 436 men in the combination treatment group (p< 0.0001), with death due to any cause in 210 out of 439 and 161 out of 436 men (p=0.0006), respectively. The 10 (15) year cumulative prostate cancer-specific mortality was more than halved after combined treatment: 18.9% (30.7%) and 8.3% (12.4%) (HR=0.35;[p<4.1E-10 for 15 year results]), and overall mortality was 35.3% (56.7%) and 26.4% (43.4%) (HR=0.70; P=0.0006 for 15 year results), respectively. Conclusions: Addition of local radiotherapy to hormonal treatment in patients with non-metastatic locally advanced or high-risk prostate cancer more than halved the 10 and 15 year prostate cancer-specific mortality and substantially decreased overall mortality.

  • 413. Fossa, Sophie D.
    et al.
    Wiklund, Fredrik
    Klepp, Olbjorn
    Angelsen, Anders
    Solberg, Arne
    Dumber, Jan-Erik
    Hoyer, Morten
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ten- and 15-yr Prostate Cancer-specific Mortality in Patients with Nonmetastatic Locally Advanced or Aggressive Intermediate Prostate Cancer, Randomized to Lifelong Endocrine Treatment Alone or Combined with Radiotherapy: Final Results of The Scandinavian Prostate Cancer Group-72016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 70, no 4, p. 684-691Article in journal (Refereed)
    Abstract [en]

    Background: In high-risk prostate cancer (PCa), no study with observation times beyond 10 yr has demonstrated survival improvement after addition of prostatic radiotherapy (RAD) to endocrine treatment (ET) alone. Objective: To compare mortality rates in patients receiving ET alone versus ET + RAD. Design, settings, and participants: From 1996 to 2002, 875 Scandinavian patients with high-risk (90%) or intermediate PCa were randomized to ET or ET + RAD (The Scandinavian Prostate Cancer Group-7). After 3 mo with total androgen blockade in all patients, all individuals continued lifelong antiandrogen monotherapy. Those randomized to ET + RAD started prostate radiotherapy (70 Gy) at 3 mo. Outcome, measurements and statistical analysis: PCa-specific 15-yr mortality represented the primary endpoint. Assessment of the combination treatment effect and prognostic factors was performed in competing risk analyses and Cox proportional-hazard models. Intervention: RAD added to ET. Results and limitations: With a median observation time of 12 yr, the 15-yr PCa-specific mortality rates were 34% (95% confidence interval, 29-39%) and 17% (95% confidence interval, 13-22%) in the ET and ET + RAD arms respectively (p < 0.001). Compared with the ET arm, the median overall survival in the ET + RAD arm was prolonged by 2.4 yr. Treatment with ET alone, age >= 65 yr and increasing histology grade independently increased the risk of PCa-specific and overall mortality. Limitations include nonformal evaluation of comorbidity, the inability to calculate progression-free survival, and lack of information about salvage therapy and toxicity. Conclusions: In patients with nonmetastatic locally advanced or aggressive PCa, ET + RAD reduces the absolute risk of PCa-specific death by 17% at 15 yr compared with ET alone; the comparable 15-yr PCa-specific mortality rates being 17% and 34%. The results warrant a phase 3 study comparing ET + RAD with radical prostatectomy in high-risk PCa. Patient summary: Adding prostatic therapy to lifelong antiandrogen therapy halves the absolute risk of death from prostate cancer from 34% to 17% 15 yr after diagnosis. 

  • 414.
    Franck-Lissbrant, I
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström, S
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Damber, J E
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, A
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Testosterone stimulates angiogenesis and vascular regrowth in the ventral prostate in castrated adult rats.1998In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 139, no 2, p. 451-6Article in journal (Refereed)
    Abstract [en]

    The castration-induced regression and testosterone stimulated regrowth of the vasculature in the rat ventral prostate lobe were studied using stereological techniques. Seven days after castration, the endothelial cell proliferation rate (bromodeoxyuridine labeling index); the total weights of blood vessel walls, blood vessel lumina, endothelial cells, glandular epithelial cells; and total organ weight were all decreased. Within 2 days after sc treatment with testosterone, the total weights of blood vessel walls, endothelial cells, and vascular lumina, as well as the endothelial cell proliferation rate, were all normalized. In contrast to the rapid response of the vasculature, the total weight of glandular epithelium and total organ weight were not normalized during the 4 days of testosterone treatment. Growth of the vasculature apparently precedes growth of the glandular epithelium. The testosterone- dependent factors stimulating the vasculature are unknown, but factors derived from epithelial cells, mast cells (which accumulate in the prostate during the first day of testosterone treatment), and tissue macrophages could all be involved. Castration-induced regression and testosterone-stimulated regrowth of the prostatic vasculature can be used as an experimental model to study factors regulating angiogenesis and organ growth in the prostate.

  • 415.
    Franklin, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stromal components and micro-RNAs as biomarkers in pancreatic cancer2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Pancreatic ductal adenocarcinoma (PDAC) patients have the poorest 5-year survival rates of all cancer forms. It is difficult to diagnose at early disease stages, tumour relapse after surgery is common, and current chemotherapies are ineffective. Carbohydrate antigen 19-9 (Ca 19-9), the only clinically implemented PDAC biomarker, is insufficient for diagnostic and screening purposes.

    PDAC tumours are characterised by a voluminous stroma that is rich in extracellular matrix (ECM) molecules such as collagens, hyaluronan (HA) and matricellular proteins. These stromal components have been suggested to promote PDAC cell migration, proliferation, evasion of apoptosis and chemotherapy resistance. Those events are mediated via interactions with adhesion receptors, such as integrins and CD44 receptors expressed on cancer cell surfaces.

    Micro-RNAs (miRNA) post-transcriptionally regulate gene expression in health and disease. At the time of PDAC diagnosis, miRNA levels are altered both in plasma and tumour tissue. Before PDAC diagnosis, tissue miRNA levels are altered in precursor lesions, raising the possibility that plasma miRNAs might aid in early detection.

    In this thesis, it is hypothesised that stromal components and miRNAs can serve as tissue or blood based biomarkers in PDAC. The aims are: (1) to characterise the expression of stromal components and their receptors in normal and cancerous tissue; (2) to find potential stroma-associated tissue and blood-based biomarkers for diagnosis and prognosis estimates; (3) to determine the cellular effects of type IV collagen (Col IV) in PDAC; (4) to determine if plasma miRNAs that are altered in manifest PDAC can be used to diagnose PDAC earlier.

    Methods The expression patterns of Col IV, Col IV-binding integrin subunits (α1, α2, β1), Endostatin, Osteopontin (OPN) and Tenascin C (TNC) were analysed in frozen PDAC and normal pancreatic tissue. A tissue microarray (TMA) was constructed using formalin-fixed, paraffin-embedded primary tumours and lymph node metastases. The TMA was used to study the expression levels and associations with survival of the standard CD44 receptor (CD44s), its variant isoform 6 (CD44v6), HA, OPN and Col IV. Circulating levels of HA, Col IV, Endostatin, OPN and TNC were measured in PDAC patients and healthy individuals, and compared with conventional tumour markers (Ca 19-9, CEA, Ca 125 and TPS). The functional roles of Col IV were studied in PDAC cell lines by: (1) growth on different matrices (2) blocking Col IV binding integrin subunits, (3) blocking the Col IV domains 7s, CB3 and NC1, and (4) by down regulation of PDAC cell synthesis of Col IV using siRNA transfection. Plasma miRNAs alterations were screened for in samples from patients with manifest disease, using real-time quantitative PCR (RT-qPCR). To find early miRNA alterations, levels of those miRNAs that were altered at diagnosis were measured in prediagnostic plasma samples.

    Results High tissue expression of both the standard CD44 receptor (CD44s) and its variant isoform CD44v6 as well as low expression of stromal OPN were associated with poor survival. In addition, high CD44s and low OPN predicted poor survival independent of established prognostic factors.

    Circulating Col IV, Endostatin, OPN, TNC and HA were increased in preoperative samples from PDAC patients. Preoperatively, higher levels of serum-HA and plasma-Endostatin were associated with shorter survival. Postoperatively, higher levels of Col IV, Endostatin and OPN were associated with shorter survival. On the contrary, only one of the conventional tumour markers was associated with survival (Ca 125).

    Col IV stimulated PDAC cell proliferation and migration and inhibited apoptosis in vitro, dependent on the collagenous domain (CB3) of Col IV and the Col IV binding integrin subunit β1. Reduced endogenous Col IV synthesis inhibited these effects, suggesting that PDAC cells synthesise Col IV to stimulate tumour-promoting events via a newly discovered autocrine loop.

    15 miRNAs were altered in early stage PDAC patients and the combination of these markers outperformed Ca 19-9 in discriminating patients from healthy individuals. However, none of the miRNAs were altered in prediagnostic samples, suggesting that plasma miRNA alterations appear late in the disease course.

    Conclusions Up regulated stromal components in PDAC tumours are detectable in blood samples and are potential diagnostic and prognostic biomarkers in PDAC. High circulating levels of Col IV, Endostatin, OPN and HA predict poor survival, as well as high expression of CD44s and CD44v6 and low expression of OPN in tumour tissue. PDAC cells synthesise Col IV, which forms BM-like structures close to cancer cells and promote tumour progression in vitro via an autocrine loop. Several plasma-miRNAs are altered in PDAC, but are not useful for early discovery. 

  • 416.
    Franklin, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Billing, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Berglund, Anette
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Herdenberg, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wang, Wanzhong
    Department of Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer2019In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 5, no 2, p. 130-141Article in journal (Refereed)
    Abstract [en]

    The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44-stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas-phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.

  • 417.
    Franklin, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öman, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Wang, Wanzhong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma2015In: Cancer Biomarkers, ISSN 1574-0153, Vol. 15, no 1, p. 1-10Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A lack of disease-specific symptoms and good tumour markers makes early detection and diagnosis of pancreatic ductal adenocarcinoma (PDAC) challenging. OBJECTIVE: To analyse the tissue expression and circulating levels of four stroma-derived substances (type IV collagen, endostatin/type XVIII collagen, osteopontin and tenascin C) and four conventional tumour markers (CA 19-9, TPS, CEA and Ca 125) in a PDAC cohort.

    METHODS: Tissue expression of markers in normal pancreas and PDAC tissue was analysed with immunofluorescence. Plasma concentrations of markers were measured before and after surgery. Patients with non-malignant disorders served as controls.

    RESULTS: The conventional and stromal substances were expressed in the cancer cell compartment and the stroma, respectively. Although most patients had increased levels of many markers before surgery, 2/12 (17%) of patients had normal levels of Ca 19-9 at this stage. High preoperative endostatin/type XVIII collagen, and postoperative type IV collagen was associated with short survival. Neither the pre-nor postoperative levels of TPS, Ca 125 or CA 19-9 were associated to survival.

    CONCLUSIONS: PDAC is characterized by an abundant stroma. These initial observations indicate that the stroma can be a source of PDAC tumour markers that are found in different compartments of the cancer, thus reflecting different aspects of tumour biology.

  • 418.
    Fransson, Per
    Umeå University, Faculty of Medicine, Department of Nursing.
    Fatigue in prostate cancer patients treated with external beam radiotherapy: a prospective 5-year long-term patient-reported evaluation2010In: Journal of Cancer Research and Therapeutics, ISSN 0973-1482, E-ISSN 1998-4138, Vol. 6, no 4, p. 516-520Article in journal (Refereed)
    Abstract [en]

    Background: Limited information is available regarding the long-term effect of external beam radiotherapy (EBRT) on fatigue in individuals with prostate cancer (PC).

    Materials and Methods: Men with PC treated with EBRT from January 1992 to June 2003 were enrolled in a prospective study. The QLQ-C30 questionnaire was used to evaluate pre-treatment fatigue and up to 5 years post-treatment.

    Results: 407 men with 5-year assessments were analyzed. Fatigue increased between pre-treatment (mean: 15.5; CI: 13.6-17.4) and 5-years post-treatment (mean: 22.8; CI: 20.5-25.1; P<0.001). Pre-treatment fatigue was absent in 206/407 (59%) patients and 5-year post-treatment was reported by 264/407 (66%). Sixteen of 407 patients (4%) reported severe fatigue after 5 years. Physical-, emotional-, cognitive function, and dyspnea were the factors that correlated most to higher level of fatigue 5-year post-treatment.

    Conclusions: Fatigue is a common symptom among patients with PC. A large percentage of patients reported pre-treatment fatigue. Fatigue increased over time, with the highest level seen at the end of EBRT. Severe fatigue was reported by 4% 5-year post-treatment. More work is needed in order to identify which patients are most susceptible to developing fatigue especially during radiotherapy.

  • 419.
    Fransson, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Patient-reported lower urinary tract symptoms, urinary incontinence, and quality of life after external beam radiotherapy for localized prostate cancer - 15 years' follow-up. A comparison with age-matched controls2008In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, p. 852-861Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To prospectively examine the urinary toxicity and quality of life (QOL) in patients 15 years after external beam radiotherapy (EBRT) for localized prostate cancer (LPC) and compare the outcomes with results for age-matched controls.

    MATERIAL AND METHODS: Urinary symptoms were assessed using the symptom-specific Prostate Cancer Symptom Scale (PCSS) questionnaire, and QOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC)'s Quality of Life Questionnaire (QLQ-C30). Both questionnaires were sent to the surviving 41 patients(25%) and the PCSS questionnaire was sent to 69 age-matched controls for comparison.

    RESULTS: The response rate was 71% in the patient group and 59% in the control group. Two patients and four controls were excluded due to other cancer diagnoses, resulting in a total of 27 patients and 37 controls for inclusion in the analyses. The mean age in both groups was 78 years. In the patient group, incontinence had increased between the 8-year (mean 0.6) and the 15-year follow-up (mean 2.1; p0.038). No other differences in urinary problems were seen between these two follow-ups. Increased incontinence, stress incontinence, and pain while urinating were reported by the patients in comparison with the controls at 15 years. Role function was worse in the patient group (mean 67.3) compared with the controls (mean 82.4; p0.046). The patients also reported more appetite loss, diarrhea, nausea/vomiting, and pain than the controls.

    CONCLUSION: EBRT for LPC has divergent effects on urinary symptoms and QOL in comparison with age-matched controls. In our patient population, urinary incontinence increased between 8 and 15 years of follow-up. Otherwise, no differences in urinary symptoms were seen between 4 and 15 years. Incontinence, stress incontinence, and pain while urinating were increased after EBRT in comparison with the controls. Conventional EBRT did not result in a major deterioration in QOL 15 years after treatment.

  • 420.
    Fransson, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Quality of life and side effects in patients with localized prostate cancer: evaluation with self-assessment questionnaires2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Localized prostate cancer (LPC) is predominantly a tumor among older men, and few patients will get symptoms from the disease. All methods to treat LPC with a curative intent have different types and degrees of side effects. It is therefore very important to evaluate the side effects thoroughly to make sure that treatment complications will not decrease the quality of life more than the disease would have done. In search for new and better treatments, complications has to be registered and evaluated in relation to quality of life (QOL) for the patients. Few validated self-assessment questionnaires for evaluation of external radiotherapy (EBRT) induced side effects has yet been developed. The present project focus on the development of the PC-specific questionnaire, QUFW94, and evaluation of symptoms in patients treated with EBRT and un-treated (watchful waiting) patients with a LPC.

    In the newly developed LPC-specific questionnaire a reliability and responsiveness test was performed. Both the inter-rater test and the test-retest show high correlation coefficients (ICC), above 0.60 for all scales. The internal reliability exceeded the lower acceptable limit (Cronbach a >0.70). The questionnaire was proven to be valid for the evaluations of EBRT side effects in LPC patients.

    Late side effects were evaluated 4 years after treatment in 181 LPC patients, treated with conventional large field EBRT, and compared with 141 age-matched PC disease free men. The most prominent urinary side effects were urgency and leakage which were doubled in the patient group. A ten fold increase was seen in comparison to controls at the most prominent intestinal problems, blood, mucus and leakage. The results support the use 3-D conformai therapy to decrease irradiation dose to the rectum and the bladder and thereby decreased side effects. A prospective additional evaluation 8 years after EBRT did not show any changes in urinary problems between 4 and 8-yr follow-up in the patients or the controls.

    EBRT of LPC is also accompanied by disturbances in sexual function. These problems were therefore evaluated, 4 years after EBRT, in relation to the function in PC free men. Patients treated with EBRT indicated higher levels of sexual dysfunction than age-matched controls. No erection was reported from 12% of the control subjects, 56% of the patients who had only received radiotherapy (RT) and 87% of the RT+castration (RT+A) patients. The extended evaluation 8 years after EBRT show similar sexual function in all groups.

    QOL and late side effects/symptoms were evaluated in the first and only randomized trial between RT and deferred treatment (DT) and compared to age-matched controls. QOL was evaluated with the general QOL formula, EORTC's QLQ-C30 (+3), and LPC specific side effects with QUFW94 in 108 randomized patients with LPC 3 years after diagnosis. Social functioning was the only QOL scale where a significant difference was found between the two patient groups and in comparison with the control group. Multivariate regression analysis showed that hematuria, incontinence, mucus, and planning of the daily activities due to intestinal problems caused this decrease in QOL in the RT group. In conclusion, the LPC specific QUFW94 questionnaire was proven to be valid for evaluation of side effects and showed increased intestinal problems in the patients treated with conventional large field EBRT in comparison to untreated LPC patients. No difference in urinary and intestinal late side effects or sexual function was seen between a 4 year vs. 8 year follow-up.

  • 421.
    Fransson, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Nursing.
    Quality of life for members of Swedish Prostate Cancer Patient Associations2008In: Cancer Nursing, ISSN 0162-220X, E-ISSN 1538-9804, Vol. 31, no 1, p. 23-31Article in journal (Refereed)
    Abstract [en]

    Prostate Cancer Patient Associations (PCPAs) have become common. The aim of this study was to evaluate the quality of life of patients belonging to PCPAs. Members of 10 PCPAs in Sweden with prostate cancer completed 2 quality of life questionnaires (Quality-of-Life Questionnaire [QLQ-C30] and Prostate Cancer Symptom Scale). Of 2,028 members, 1,301 (64%) responded to the survey. Sixty percent of the members felt "healthy," and 38% were "free from the cancer." Ninety-five percent scored >80 on the physical function scale compared with 44% on the overall quality of life/health scale. The most severe symptom was sleeping disturbances (mean = 29). Seventeen percent scored "Quite a bit/Much" tiredness. More than 50% did not report any bladder or bowel problems. Fifty percent had "Much" sexual problems, and almost 80% did not have sufficient erection. Those reported as being "disease free" scored higher on the functioning scales than those with "metastatic disease." Those with an experience of a "metastatic disease" had more symptoms than those with less advanced disease. This is the first descriptive study of quality of life in members of Swedish PCPAs with prostate cancer. These findings show that it is possible to gain valid data to further study the situation of patients living with prostate cancer by collecting data from PCPAs.

  • 422.
    Fransson, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Damber, Jan-Erik
    Department of Urology, Göteborg University, Göteborg, Sweden.
    Tomic, Radisa
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Modig, Hans
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nyberg, Gunnar
    Department of Urology, Boden Hospital, Boden, Sweden.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Quality of life and symptoms in a randomized trial of radiotherapy versus deferred treatment of localized prostate carcinoma2001In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 92, no 12, p. 3111-3119Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Treatment of localized prostate carcinoma (LPC) using radiotherapy (RT) can induce disturbances in a patient's quality of life (QOL) and urinary and intestinal function. Late symptoms and QOL were evaluated in a randomized trial between RT and deferred treatment (DT).

    METHODS: Quality of life was evaluated with European Organization for Research and Treatment of Cancer's QLQ-C30 (+3) formula. Urinary and intestinal problems were evaluated with a validated symptom specific self-assessment questionnaire, QUFW94. The questionnaires were sent to 108 randomized patients with LPC and to an age-matched control group (n = 68). Mean age was 72 years. Mean total dose was 65 grays (Gy; 62.3-70 Gy). The median follow-up time from randomization was 40.6 months for the RT group and 30.4 months for the DT group.

    RESULTS: Social functioning was the only QOL scale in which a significant difference was found between the two patient groups and compared with the control group. Multivariate regression analysis showed that hematuria, incontinence, mucus, and planning of daily activities in response to intestinal problems caused this decrease in QOL in the RT group. A significant increase of intestinal problems was observed in the RT versus DT groups regarding mucus, stool leakage, intestinal blood, and planning of daily activity in response to intestinal problems.

    CONCLUSIONS: The RT patients showed increased levels of minor intestinal side effects compared with the DT patients and the controls, but the RT patients reported no decreased QOL except for decreased social functioning. This could be because this group developed coping skills or because of a low magnitude of side effects to influence the QOL.

  • 423.
    Fransson, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Damber, Jan-Erik
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Health-related quality of life 10 years after external beam radiotherapy or watchful waiting in patients with localized prostate cancer2009In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 43, no 2, p. 119-126Article in journal (Refereed)
    Abstract [en]

    Objective. To evaluate long-term randomized comparisons of patient-reported outcome of symptoms and health-related quality of life (HRQoL) in men with localized prostate cancer 10 years after external beam radiotherapy (RT) or watchful waiting (WW). Material and methods. Three-year HRQoL and specific symptoms in surviving patients recruited between 1986 and 1996 were previously evaluated in a randomized trial; definitive RT versus WW. Two questionnaires were used: the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the Prostate Cancer Symptom Scale (PCSS). The present study is a prolonged follow-up with the same cohorts. Results. Fifty-four of 72 eligible patients (75%) returned the questionnaires at the present follow-up. The median age was 77 years in the RT group and 78 years in the WW group. The median follow-up time from randomization was 10 years. No differences in HRQoL or bowel symptoms were measured between the RT and WW. Cognitive (RT) and physical function (WW) decreased between 4 years and 10years. Weak urinary stream differed between the RT and WW groups. Fatigue and nocturia were increased in the RT group, and erections decreased in the WW patients over time. No difference in erectile function was seen between the RT and WW groups (p=0.292). Conclusion. The pattern of urinary and bowel symptoms and sexual function was rather similar, independent of RT or WW. Treatment with RT had minimal influence on HRQoL, in comparison with that of WW, at 10-year follow-up.

  • 424.
    Fransson, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lund, Jo-Asmund
    Damber, Jan-Erik
    Klepp, Olbjörn
    Wiklund, Fredrik
    Fosså, Sophie
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Quality of life in patients with locally advanced prostate cancer given endocrine treatment with or without radiotherapy: 4-year follow-up of SPCG-7/SFUO-3, an open-label, randomised, phase III trial.2009In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 10, no 4, p. 370-380Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Androgen treatment for prostate cancer can adversely affect functional domains of quality of life. We aimed to assess quality of life in men with locally advanced prostate cancer in an open-label phase III randomised comparison between lifelong endocrine treatment with and without radiotherapy.

    METHODS: We obtained quality-of-life information from 872 (99%) of 875 eligible men with locally advanced prostate cancer (T3; 78%) who were randomly assigned, between 1996 and 2002, to 3 months of total androgen blockade followed by continuous endocrine treatment (439 patients) or the same hormonal treatment with radiotherapy 3 months after randomisation (436 patients). Prospective outcomes included patient-reported symptoms and quality of life assessed with questionnaires from baseline to 4 years after randomisation. Analysis was by intention to treat. This study is registered as an international standard randomised controlled trial, number ISRCTN01534787.

    FINDINGS: 438 of 439 men assigned endocrine treatment and 434 of 436 assigned endocrine plus radiotherapy completed at least one questionnaire. Missing data at baseline and during follow-up was equally distributed between groups. At 4 years, 64 (18%) of 353 patients on combined therapy and 39 (12%) of 337 on endocrine-alone therapy had moderate to severe urinary bother (p=0.005), and 16 (4%) of 355 on combined therapy and five (2%) of 338 on endocrine treatment alone had pain while urinating (p=0.024). 37 (11%) of 350 in the combined group and 23 (7%) of 35 in the endocrine-only group had overall bother from all bowel symptoms (p=0.022). 281 (85%) of 332 in the combined-treatment group and 227 (72%) of 313 in the endocrine-only group had erectile dysfunction (p=0.0002). Quality of life at 4 years was similar, with the exception of decreased social function in patients receiving endocrine treatment plus radiotherapy.

    INTERPRETATION: Although addition of radiotherapy to endocrine treatment significantly increased some treatment-related symptoms, none were serious. Given the substantial survival benefit of combined treatment, the increase of symptoms seems acceptable and has little extra effect on quality of life after 4 years compared with endocrine treatment alone.

  • 425.
    Fransson, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing.
    Olofsson, Sebastian
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Thellenberg Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Patient-reported gastrointestinal and genitourinary toxicity after prostate cancer treatment: A comparison between radiotherapy including pelvic nodes and prostate-only radiotherapy2015In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 33, no 7 SArticle in journal (Other academic)
    Abstract [en]

    Background: To evaluate side effects of radiotherapy (RT) including the pelvic nodes in patients with prostate cancer. Methods: 143 patients with high risk prostate cancer (Pca) receiving whole pelvic radiotherapy (WPRT) was matched to a group of 142 patients receiving RT towards the prostate and seminal vesicles only (PORT). Both groups were given 78 Gy towards the prostate and 50 Gy towards the seminal vesicles. The WPRT group also received 50 Gy towards the pelvic nodes. WPRT was given with intensity modulated RT or volumetric modulated arc therapy technique and the group treated towards the prostate and seminal vesicles only was treated with 3-dimensional conformal RT. Gastrointestinal (GI) and genitourinary (GU) side effects were evaluated with patient-reported questionnaires and with the RTOG scale, scored by treating physician, at baseline and one-year after RT. Results: Overall the side effects were mild. At one-year follow up there were significant differences regarding morning urgency, mucus- and blood in stool between the two groups (Table 1). The WPRT group expressed lesser complications in all of these cases. In the RTOG GU and GI scores there were no differences between the groups. About 20% had RTOG grade 2 GU score and 2%/1% had RTOG grade 3 score in the PORT and WPRT groups, respectively. The numbers for RTOG grade 2 GI scores were 11% and 5% in the PORT and WPRT groups, respectively. None of the groups reported RTOG grade 3 GI symptoms. Conclusions: Whole pelvic RT can be done with a very satisfying profile of side effects. Sometimes even lesser gastrointestinal reported side effects are seen with the newer techniques compared to prostate only radiotherapy with older techniques.

  • 426.
    Fransson, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Reliability and responsiveness of a prostate cancer questionnaire for radiotherapy-induced side effects2001In: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 9, no 3, p. 187-198Article in journal (Refereed)
    Abstract [en]

    Few self-assessment cancer-specific questionnaires / modules have yet been developed for radiotherapy-induced side effects. The aim of the present study was to test the reliability and responsiveness of a prostate cancer (PC)specific questionnaire. Thirty-one patients with PC graded their urinary and intestinal symptoms and their sexual function on the questionnaire. A doctor and a nurse performed a structured interview and graded the patient's symptoms with the same questions. The procedure was performed at both the start and the end of the treatment. A high concordance regarding symptom detection was seen between the patient, nurse and the doctor. The inter-rater test shows intraclass correlation coefficient (ICC) values above 0.60 in all scales. The internal reliability exceeded the lower limit (Cronbach alpha > 0.70) for all scales. The test-retest gave acceptable reliability for all scales (ICC greater than or equal to 0.60). All scales indicated increased problems during radiotherapy. The questionnaire was proven to be valid for the evaluations of urinary and intestinal problems and for sexual function in PC patients.

  • 427.
    Fransson, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Does one have a sexual life 15 years after external beam radiotherapy for prostate cancer? Prospective patient-reported outcome of sexual function comparison with age-matched controls2011In: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 29, no 2, p. 137-144Article in journal (Refereed)
    Abstract [en]

    Background and purpose: We previously published research on 4- and 8-year follow-ups of patient-reported sexual function after conventional external beam radiotherapy (EBRT) for localized prostate cancer (LPC) compared with age-matched controls. The current study is a prolonged 15-year follow-up with the same cohorts.

    Material and methods: The cohort consisted of 29 men surviving from a group of 181 men treated between 1986 and 1989, and who were reported on previously. Of the originally reported 141 controls, 62 were eligible and 34 completed the questionnaires. Sexual function was assessed using two questionnaires, Prostate Cancer Symptom Scale (PCSS) and International Index of Erectile Function (IIEF-5).

    Results: Twenty-three patients (78%) and 13 controls (38%) were not sexually active. None of the patients and 14 controls had enough of an erection to perform intercourse. Seventeen patients (94%) and 14 controls (64%) had severe erectile dysfunction. Patients with clinical progression and who had received hormone treatment had decreased sexual desire. No significant differences were measured between patients without progression/hormone treatment and the controls.

    Conclusion: The sexual activity 15 years after EBRT for LPC was very low, as was the probability of achieving an erection. Patients with a progressive disease and treated with hormones reported worse sexual and erectile function. The LPC free men showed higher sexual activity, lower sexual bother, and better erectile function than the patients.

  • 428.
    Fransson, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Nursing.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Late side effects unchanged 4-8 years after radiotherapy for prostate carcinoma: A comparison with age-matched controls1999In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 85, no 3, p. 678-688Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. The authors of this study previously evaluated pelvic irradiation-induced late side effects in patients with localized prostatic carcinoma 4 years after external irradiation by administering a validated self-assessment questionnaire (QUFW94), and compared the results with those of age-matched controls. The current study was designed to evaluate prospectively the patients' problems 8 years after radiotherapy and to compare them with those reported by the same controls. METHODS. The questionnaire was sent out at a mean of 8 years (range, 72-104 months) after irradiation to 120 patients and 125 controls. For analysis of sexual function, the patient group was divided into two subgroups, one treated with radiotherapy only (RT) and one group treated with radiotherapy plus castration (RT+A). A value of >1 on a 0-10 scale indicated that the patient was having a problem. RESULTS, The mean age was 73 years for both patients and controls. No changes in urinary problems were seen between the 4-year and the 8-year follow-up in the 2 groups. Sixty percent and 54% of the patients (P = 0.096) and 24% and 31% of the controls (P = 0.988) reported urinary problems at the 4-year and 8-year follow-ups, respectively. No changes in gastrointestinal late side effects in the patient group were seen between the 4-year (65%) and the 8-year (62%) follow-ups (P = 0.490). However, there was a decrease in intestinal problems in the control group between the 4-year (12%) and the 8-year (9%) follow-ups (P = 0.001). The sexual problems did not change during the two periods, in the patient groups or in the control groups. Fifty-six percent and 65% of the RT group (P = 0.052), 67% and 54% of the RT + A group (P = 0.555), and 27% and 33% of the control group (P = 0.243) indicated some kind of sexual problem at the 4-year and 8-year follow-ups, respectively. CONCLUSIONS. The amount of pelvic irradiation-induced urinary late side effects, intestinal late side effects, and sexual function, evaluated with a self-assessment questionnaire, did not change between 4 and 8 years after RT. The age-matched controls reported no change in urinary or sexual problems despite advanced age, but there was a reported decrease in intestinal problems, Cancer 1999;85:678-88. (C) 1999 American Cancer Society.

  • 429.
    Fransson, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Self-assessed sexual function after pelvic irradiation for prostate carcinoma: Comparison with an age-matched control group1996In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 78, no 5, p. 1066-1078Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Treatment of localized prostate carcinoma is often accompanied by disturbances in sexual function. The patient's own opinion and experience with these problems can be of great importance for his quality of life. In men older than 50 years, disturbances in sexual function are common. Treatment such as radiotherapy (RT), which can induce sexual dysfunction, should be evaluated in relation to the problems in an age-matched population without prostate carcinoma. METHODS. Sexual function was evaluated with a self-assessment questionnaire using linear-analogue scales. The questionnaire was sent to 199 patients with prostate carcinoma, median age 71 years (range, 51-86 years), who had received pelvic RT with curative intent and to 200 age-matched men in northern Sweden. Mean follow-up time after RT was 48 months (range, 24-56 months). RESULTS. The response rate was high: 141 (71%) and 181 (91%) in the control and patient groups, respectively. Field reduction and treatment pause during RT was not associated with decreased problems in the patient groups. A failure to achieve erection was indicated in 12% of the control subjects, 56% of the patients who had received (RT only) and 87% of the RT + castration (RT + A) patients. In general, patients < 70 years treated with RT + A indicated more sexual problems than the RT only patients < 70 years. There was a strong negative correlation between age and sexual problems in the RT 9 A < 70 years group. However, in patients < 70 years, sexual activity after RT only, was not significantly different from the age-matched control population. CONCLUSIONS. Patients with prostate carcinoma treated with RT only indicated higher levels of sexual dysfunction than age-matched controls. This was most obvious in patients younger than 70 years, although their sexual activity was comparable to age-matched controls. The addition of castration to RT tended to increase sexual problems, especially in patients < 70 years. In men between 70 and 74 years, the maintenance of sexual function seems to be very susceptible to disturbances. For patients older than 74 years, decreased sexual function was not perceived as such a significant problem, despite abolished desire and erection. (C) 1996 American Cancer Society.

  • 430. Fransson, Susanne
    et al.
    Hansson, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Univ Gothenburg, Sahlgrenska Acad, Dept Pathol, SE-40530 Gothenburg, Sweden.
    Ruuth, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Djos, Anna
    Berbegall, Ana
    Javanmardi, Niloufar
    Abrahamsson, Jonas
    Palmer, Ruth H.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Univ Gothenburg, Sahlgrenska Acad, Dept Med Chem & Cell Biol, SE-40530 Gothenburg, Sweden.
    Noguera, Rosa
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Univ Gothenburg, Sahlgrenska Acad, Dept Med Chem & Cell Biol, SE-40530 Gothenburg, Sweden.
    Kogner, Per
    Martinsson, Tommy
    Intragenic Anaplastic Lymphoma Kinase (ALK) Rearrangements: Translocations as a Novel Mechanism of ALK Activation in Neuroblastoma Tumors2015In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 54, no 2, p. 99-109Article in journal (Refereed)
    Abstract [en]

    Anaplastic lymphoma kinase (ALK) has been demonstrated to be deregulated in sporadic as well as in familiar cases of neuroblastoma (NB). Whereas ALK-fusion proteins are common in lymphoma and lung cancer, there are few reports of ALK rearrangements in NB indicating that ALK mainly exerts its oncogenic capacity via activating mutations and/or overexpression in this tumor type. In this study, 332 NB tumors and 13 cell lines were screened by high resolution single nucleotide polymorphism microarray. Gain of 2p was detected in 23% (60/332) of primary tumors and 46% (6/13) of cell lines, while breakpoints at the ALK locus were detected in four primary tumors and two cell lines. These were further analyzed by next generation sequencing and a targeted enrichment approach. Samples with both ALK and MYCN amplification displayed complex genomic rearrangements with multiple breakpoints within the amplicon. None of the translocations characterized in primary NB tumors are likely to result in a chimeric protein. However, immunohistochemical analysis reveals high levels of phosphorylated ALK in these samples despite lack of initial exons, possibly due to alternative transcription initiation sites. Both ALK proteins predicted to arise from such alterations and from the abnormal ALK exon 4-11 deletion observed in the CLB-BAR cell line show strong activation of downstream targets STAT3 and extracellular signal-regulated kinase (ERK) when expressed in PC12 cells. Taken together, our data indicate a novel, although rare, mechanism of ALK activation with implications for NB tumorigenesis. 

  • 431.
    Franzén, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Effects of fractionated irradiation on salivary glands1992Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The thesis is a study of the effects of radiation on the salivary glands in an experimental and a clinical study. Irradiation is a cornerstone in the management of head and neck cancer and is as other modalities of cancer treatment, afflicted with adverse reactions. An optimal radiotherapy regime is limited by the sensitivity of the normal tissues with regard to early and late effects. In certain cases the early effects can be so troublesome that it will cause interruption in the irradiation and questioning of the curative intention. Although DNA is the lethal target, other parts of the cell have been proposed as sensitive targets to irradiation. Different in vitro secretory models and quantitative morphological characterization and immunohistochemical evaluation of neuropeptides were performed in rat salivary glands after irradiation. The irradiation was given unilaterally or bilaterally once a day for a five-day schedule with 6 MV photons (total dose 20, 30, 35, 40, 45 Gy) or a two fractions regime in five days with a total dose of 24 or 32 Gy. The contralateral gland served as a control for unilaterally treated animals and parallel analyses were done 10 days or 180 days following the last irradiation dose. An early, dose-dependent effect of fractionated irradiation on noradrenaline-stimulated potassium fluxes (86Rb+ fluxes) was demonstrated. In contrast, the exocytotic amylase release displayed no obvious alterations, and morphologically no changes were seen. Regarding late effects (180 days) the noradrenaline-stimulated electrolyte secretion was decreased at least for the higher doses of irradiation. Amylase content and loss of acini was also dose-dependently decreased. At 10 days after bilateral irradiation there was a marked increase in the expression of the neuropeptides substance P, leu-enkephalin and bombesin in the ganglionic cells associated with the submandibular glands and in nerve fibers of the glandular parenchyme.

    In addition, a clinical prospective evaluation of 25 patients was performed before, during radiotherapy and 6, 12 and 18 months after the end of treatment. A great interindividual variation in the recovery was demonstrated with regard to salivary flow rate. Irradiation doses about 40-50 Gy caused generally reversible changes; sometimes salivary secretion was almost completely restored 6-18 months after the end of radiotherapy. Doses exceeding 65 Gy induced almost irreversible alterations.

    Even if DNA is the target for the lethal effect of irradiation, other constituents, such as the cell membrane or neuropeptide expression can be significantly affected by irradiation and cause important physiological changes.

  • 432. Freisling, Heinz
    et al.
    Moskal, Aurelie
    Ferrari, Pietro
    Nicolas, Genevieve
    Knaze, Viktoria
    Clavel-Chapelon, Francoise
    Boutron-Ruault, Marie-Christine
    Nailler, Laura
    Teucher, Birgit
    Grote, Verena A.
    Boeing, Heiner
    Clemens, Matthias
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Ramon Quiros, J.
    Duell, Eric J.
    Sanchez, Maria-Jose
    Amiano, Pilar
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nicholas J.
    Crowe, Francesca L.
    Gallo, Valentina
    Oikonomou, Eleni
    Naska, Androniki
    Trichopoulou, Antonia
    Palli, Domenico
    Agnoli, Claudia
    Tumino, Rosario
    Polidoro, Silvia
    Mattiello, Amalia
    Bueno-de-Mesquita, H. Bas
    Ocke, Marga C.
    Peeters, Petra H. M.
    Wirfalt, Elisabet
    Ericson, Ulrika
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hjartaker, Anette
    Engeset, Dagrun
    Skeie, Guri
    Riboli, Elio
    Slimani, Nadia
    Dietary acrylamide intake of adults in the European Prospective Investigation into Cancer and Nutrition differs greatly according to geographical region2013In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 52, no 4, p. 1369-1380Article in journal (Refereed)
    Abstract [en]

    Methodological differences in assessing dietary acrylamide (AA) often hamper comparisons of intake across populations. Our aim was to describe the mean dietary AA intake in 27 centers of 10 European countries according to selected lifestyle characteristics and its contributing food sources in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. In this cross-sectional analysis, 36 994 men and women, aged 35-74 years completed a single, standardized 24-hour dietary recall using EPIC-Soft. Food consumption data were matched to a harmonized AA database. Intake was computed by gender and center, and across categories of habitual alcohol consumption, smoking status, physical activity, education, and body mass index (BMI). Adjustment was made for participants' age, height, weight, and energy intake using linear regression models. Adjusted mean AA intake across centers ranged from 13 to 47 mu g/day in men and from 12 to 39 mu g/day in women; intakes were higher in northern European centers. In most centers, intake in women was significantly higher among alcohol drinkers compared with abstainers. There were no associations between AA intake and physical activity, BMI, or education. At least 50 % of AA intake across centers came from two food groups "bread, crisp bread, rusks" and "coffee." The third main contributing food group was "potatoes". Dietary AA intake differs greatly among European adults residing in different geographical regions. This observed heterogeneity in AA intake deserves consideration in the design and interpretation of population-based studies of dietary AA intake and health outcomes.

  • 433. Frentzas, Sophia
    et al.
    Simoneau, Eve
    Bridgeman, Victoria L.
    Vermeulen, Peter B.
    Foo, Shane
    Kostaras, Eleftherios
    Nathan, Mark R.
    Wotherspoon, Andrew
    Gao, Zu-Hua
    Shi, Yu
    Van den Eynden, Gert
    Daley, Frances
    Peckitt, Clare
    Tan, Xianming
    Salman, Ayat
    Lazaris, Anthoula
    Gazinska, Patrycja
    Berg, Tracy J.
    Eltahir, Zak
    Ritsma, Laila
    van Rheenen, Jacco
    Khashper, Alla
    Brown, Gina
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Van Laere, Steven
    Loyer, Evelyne
    Dirix, Luc
    Cunningham, David
    Metrakos, Peter
    Reynolds, Andrew R.
    Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases2016In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 22, no 11, p. 1294-1302Article in journal (Refereed)
    Abstract [en]

    The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.

  • 434. Fridriksson, Jon
    et al.
    Gunseus, Katarina
    Stattin, Pär
    Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York City, USA.
    Information on pros and cons of prostate-specific antigen testing to men prior to blood draw: A study from the National Prostate Cancer Register (NPCR) of Sweden2012In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 46, no 5, p. 326-331Article in journal (Refereed)
    Abstract [en]

    Objective. Recent guidelines on serum testing of prostate-specific antigen (PSA) levels in asymptomatic men emphasize the importance of an informed decision. This study assessed the proportion of men who had received written or oral information on the possible consequences of testing of serum levels of PSA before blood draw.

    Material and methods. From the National Prostate Cancer Register (NPCR) in Sweden, 600 men per year were randomly selected out of all men with T1c prostate cancer who were diagnosed in the work-up of a PSA test as a part of health examination in 2006-2008. In a mailed questionnaire these men were asked whether and how they had been informed about the pros and cons of a PSA test prior to blood draw.

    Results. In total, 1621 out of 1800 men (90.1%) responded to the questionnaire; 39/1563 (2.5%) reported that they had received only written information before testing, 179/1563 (11.5%) had received both oral and written information, 763/1563 (48.8%) had received oral information only, 423/1563 (27.1%) had not received any information and 159/1563 (10.2%) were not aware of that a PSA test had been performed.

    Conclusions. The proportion of men who had received written information on the pros and cons of a PSA test before blood draw in the setting of a health examination was low. Improved routines for giving information to the patient before a PSA test are warranted.

  • 435.
    Fridriksson, Jon Örn
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Folkvaljon, Yasin
    Lundström, Karl-Johan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Robinson, David
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Ryhov Hospital, Jönköping, Sweden.
    Carlsson, Stefan
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Long-term adverse effects after retropubic and robot-assisted radical prostatectomy: Nationwide, population-based study2017In: Journal of Surgical Oncology, ISSN 0022-4790, E-ISSN 1096-9098, Vol. 116, no 4, p. 500-506Article in journal (Refereed)
    Abstract [en]

    Background and Objectives: Surgery for prostate cancer is associated with adverse effects. We studied long-term risk of adverse effects after retropubic (RRP) and robot-assisted radical prostatectomy (RARP).

    Methods: In the National Prostate Cancer Register of Sweden, men who had undergone radical prostatectomy (RP) between 2004 and 2014 were identified. Diagnoses and procedures indicating adverse postoperative effects were retrieved from the National Patient Register. Relative risk (RR) of adverse effects after RARP versus RRP was calculated in multivariable analyses adjusting for year of surgery, hospital surgical volume, T stage, Gleason grade, PSA level at diagnosis, patient age, comorbidity, and educational level.

    Results: A total of 11 212 men underwent RRP and 8500 RARP. Risk of anastomotic stricture was lower after RARP than RRP, RR for diagnoses 0.51 (95%CI = 0.42-0.63) and RR for procedures 0.46 (95%CI = 0.38-0.55). Risk of inguinal hernia was similar after RARP and RRP but risk of incisional hernia was higher after RARP, RR for diagnoses 1.48 (95%CI = 1.01-2.16), and RR for procedures 1.52 (95%CI = 1.02-2.26).

    Conclusions: The postoperative risk profile for RARP and RRP was quite similar. However, risk of anastomotic stricture was lower and risk of incisional hernia higher after RARP.

  • 436.
    Fridriksson, Jón O.
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Folkvaljon, Yasin
    Nilsson, Per
    Robinson, David
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Ryhov Hospital, J€onk€oping, Sweden.
    Franck-Lissbrant, Ingela
    Ehdaie, Behfar
    Eastham, James A.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Karlsson, Camilla T.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Long-term adverse effects after curative radiotherapy and radical prostatectomy: population-based nationwide register study2016In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 50, no 5, p. 338-345Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to assess the risk of serious adverse effects after radiotherapy (RT) with curative intention and radical prostatectomy (RP).

    Materials and methods: Men who were diagnosed with prostate cancer between 1997 and 2012 and underwent curative treatment were selected from the Prostate Cancer data Base Sweden. For each included man, five prostate cancer-free controls, matched for birth year and county of residency, were randomly selected. In total, 12,534 men underwent RT, 24,886 underwent RP and 186,624 were controls. Adverse effects were defined according to surgical and diagnostic codes in the National Patient Registry. The relative risk (RR) of adverse effects up to 12 years after treatment was compared to controls and the risk was subsequently compared between RT and RP in multivariable analyses.

    Results: Men with intermediate- and localized high-risk cancer who underwent curative treatment had an increased risk of adverse effects during the full study period compared to controls: the RR of undergoing a procedures after RT was 2.64 [95% confidence interval (CI) 2.56–2.73] and after RP 2.05 (95% CI 2.00–2.10). The risk remained elevated 10–12 years after treatment. For all risk categories of prostate cancer, the risk of surgical procedures for urinary incontinence was higher after RP (RR 23.64, 95% CI 11.71–47.74), whereas risk of other procedures on the lower urinary tract and gastrointestinal tract or abdominal wall was higher after RT (RR 1.67, 95% CI 1.44–1.94, and RR 1.86, 95% CI 1.70–2.02, respectively).

    Conclusion: The risk of serious adverse effects after curative treatment for prostate cancer remained significantly elevated up to 12 years after treatment.

  • 437. Frisk, Gabriella
    et al.
    Ekberg, Sara
    Lidbrink, Elisabet
    Eloranta, Sandra
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Fredriksson, Irma
    Lambe, Mats
    Smedby, Karin E.
    No association between low-dose aspirin use and breast cancer outcomes overall: a Swedish population-based study2018In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 20, article id 142Article in journal (Refereed)
    Abstract [en]

    Background: Results from previous studies indicate that use of low-dose aspirin may improve breast cancer prognosis. We evaluated aspirin use and breast cancer outcomes in relation to clinical characteristics as well as dose and duration of aspirin use.

    Methods: We used information from the Regional Breast Cancer Quality-of-Care Registries in three Swedish regions to identify 21,414 women diagnosed with a first stage I-III breast cancer between 1 April 2006 and 31 December 2012. The cohort was further linked to nationwide registers to retrieve information about dispensing low-dose aspirin before and after breast cancer diagnosis, comorbidity and causes of death. In a separate analysis, we investigated time to breast cancer death among 621 women with stage IV disease at diagnosis. Associations were evaluated using a multivariable Cox proportional hazards model.

    Results: Among women with stage I-III breast cancer, 2660 (12.4%) used low-dose aspirin shortly before breast cancer diagnosis and 4091 (19.1%) were users during follow-up. Women were followed for a median of 3.8years after diagnosis. There was no association between aspirin use and breast cancer-specific death in multivariable analyses (use before diagnosis: hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.77-1.12; use after diagnosis: HR 1.00, 95% CI 0.74-1.37). Similarly, aspirin use was not associated with risk of first recurrence/metastases in a subgroup of stage I-III breast cancer patients (HR 0.97, 95% CI 0.86-1.10). However, in analyses stratified by stage, an inverse association between low-dose aspirin use after diagnosis and breast cancer death was found for women with stage I tumors (HR 0.53, 95% CI 0.29-0.96). Among women with stage IV disease at diagnosis, aspirin use was not associated with time to breast cancer death (HR 0.91, 95% CI 0.67-1.23).

    Conclusion: In this large population-based cohort study there was no evidence that low-dose aspirin use before or after breast cancer diagnosis is associated with a reduced risk of adverse outcomes overall in breast cancer. However, a potential benefit was noted among women with stage I tumors, warranting further investigation.

  • 438. Fritz, Helena K.
    et al.
    Gustafsson, Anna
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ceder, Yvonne
    Axelson, Hakan
    Dahlback, Bjorn
    The Axl-Regulating Tumor Suppressor miR-34a Is Increased in ccRCC but Does Not Correlate with Axl mRNA or Axl Protein Levels2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 8, article id e0135991Article in journal (Refereed)
    Abstract [en]

    High expression of the receptor tyrosine kinase Axl is associated with poor prognosis in patients with Renal Cell Carcinoma (RCC), the most common malignancy of the kidney. The miR-34a has been shown to directly regulate Axl in cancer cells. The miR-34a is a mediator of p53-dependent tumor suppression, and low expression of miR-34a has been associated with worse prognosis in several cancers. Our aim was to elucidate whether miR-34a or the other members of the miR-34 family (miR-34b/c) regulate Axl in RCC.

  • 439. Fritz, Helena K. M.
    et al.
    Lindgren, David
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Axelson, Håkan
    Dahlbäck, Björn
    The miR(21/10b) ratio as a prognostic marker in clear cell renal cell carcinoma2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no 10, p. 1758-1765Article in journal (Refereed)
    Abstract [en]

    Purpose: Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer in the adult kidney, and the prognosis of metastatic ccRCC remains poor with high mortality. In ccRCC, microRNAs (miRs) differentially expressed in tumour tissue have been identified and have been proposed to predict prognosis. The purpose of this study was to evaluate candidate miR markers identified from analysis of The Cancer Genome Atlas (TCGA) datasets in a large RCC cohort and to elucidate whether a ratio of miRs provided additional prognostic information. Experimental design: Deep sequencing data from TCGA datasets were analysed using biostatistical methods to identify candidate miRs that correlate with factors such as survival and stage of disease. Candidate miRs were analysed by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) in a cohort of 198 RCC tumours (ccRCC, n = 152) and 50 normal kidney samples. Results: Four candidate miRs (miR-10b, miR-21, miR-101 and miR-223) were selected from the TCGA analysis and analysed in our cohort. Of these, miR-21 and miR-10b were differentially expressed in RCC subtypes and in ccRCC nuclear grades. Individually, the two miRs demonstrated a non-significant trend to correlate with survival. Importantly, the ratio of miR-21/miR10b (miR(21/10b),) correlated significantly with disease severity and survival, a high miR(21/10b) being associated with poor prognosis (P = 0.0095). In particular, the miR(21/10b) was found to be an independent prognostic factor in metastasis-free patients (P = 0.016; confidence interval (CI) 1.201-5.736). Conclusions: We have shown that the miR(21/10b) ratio is an independent prognostic factor for M0 ccRCC patients, which could be useful to identify high-risk M0 patients who could benefit from increased surveillance.

  • 440. Fritz, Helena K. M.
    et al.
    Lindgren, David
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Axelson, Håkan
    Dahlbäck, Björn
    The miR21/10b ratio as a prognostic marker in metastasis-free clear cell renal cell carcinoma patients2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, p. S143-S144Article in journal (Other academic)
  • 441. Fritz, Josef
    et al.
    Bjorge, Tone
    Nagel, Gabriele
    Concin, Hans
    Manjer, Jonas
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Uppsala universitet.
    Stattin, Pär
    Stocks, Tanja
    Ulmer, Hanno
    Insulin resistance measured by the triglyceride-glucose index and risk of obesity-related cancers: An epidemiological investigation in more than 500,000 individuals.2019In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 37, no 15, p. 1552-1552Article in journal (Other academic)
    Abstract [en]

    Background: The role of insulin resistance as a mediator in the association of body mass index (BMI) with site-specific cancer risk has, to our knowledge, never been systematically quantified. We aimed to determine to what extent insulin resistance measured as the logarithmized triglyceride glucose product (TyG index) mediates the effect of BMI on risk of obesity-related cancers. Methods: A total of 510,471 individuals from six European cohorts with a mean age of 43.1 years were included in the study. We fitted Cox models, adjusted for relevant confounders, to investigate associations of TyG index with ten common obesity-related cancer sites, and quantified the proportion of the effect of BMI mediated through TyG index. Results: During a median follow-up of 17.2 years, 16 052 individuals developed obesity-related cancers. TyG index was associated with the risk of cancers of the kidney (hazard ratio (HR) per one standard deviation increase 1.13, 95% confidence interval: 1.07-1.20), liver (1.13, 1.04-1.23), pancreas (1.12, 1.06-1.19), colon (1.07, 1.03-1.10), and rectum (1.09, 1.04-1.14). Substantial proportions of the effect of BMI were mediated by TyG index for cancers of the pancreas (42%), rectum (34%), and colon (20%); smaller proportions for kidney (15%) and liver (11%); none for endometrium, ovary and breast (postmenopausal). Conclusions: In this pooled cohort study including more than 500,000 individuals, insulin resistance measured as the logarithmized triglyceride glucose product significantly mediated the effect of overweight and obesity on risk of cancers of the kidney, liver, pancreas, colon, and rectum. In contrast, insulin resistance did not mediate the risk for cancers of the endometrium, ovary and breast. Our results confirm a promoting role of insulin resistance in the pathogenesis of gastrointestinal cancers. Although often claimed, insulin resistance does not appear to connect excess body weight with cancers of the female reproductive organs.

  • 442. Fritz, Josef
    et al.
    Bjørge, Tone
    Nagel, Gabriele
    Manjer, Jonas
    Engeland, Anders
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Concin, Hans
    Teleka, Stanley
    Tretli, Steinar
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lang, Alois
    Stattin, Pär
    Stocks, Tanja
    Ulmer, Hanno
    The triglyceride-glucose index as a measure of insulin resistance and risk of obesity-related cancers2019In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, p. 1-12, article id dyz053Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The role of insulin resistance as a mediator in the association of body mass index (BMI) with site-specific cancer risk has, to our knowledge, never been systematically quantified.

    METHODS: Altogether 510 471 individuals from six European cohorts, with a mean age of 43.1 years, were included. We used the triglyceride glucose product (TyG index) as a surrogate measure for insulin resistance. We fitted Cox models, adjusted for relevant confounders, to investigate associations of TyG index with 10 common obesity-related cancers, and quantified the proportion of the effect of BMI mediated through TyG index on the log-transformed hazard ratio (HR) scale.

    RESULTS: During a median follow-up of 17.2 years, 16 052 individuals developed obesity-related cancers. TyG index was associated with the risk of cancers of the kidney HR per one standard deviation increase 1.13, 95% confidence interval: 1.07 to 1.20], liver (1.13, 1.04 to 1.23), pancreas (1.12, 1.06 to 1.19), colon (1.07, 1.03 to 1.10) and rectum (1.09, 1.04 to 1.14). Substantial proportions of the effect of BMI were mediated by TyG index for cancers of the pancreas (42%), rectum (34%) and colon (20%); smaller proportions for kidney (15%) and liver (11%). Little or no mediation was observed for breast (postmenopausal), endometrial and ovarian cancer. Results were similar for males and females, except for pancreatic cancer where the proportions mediated were 20% and 91%, respectively.

    CONCLUSIONS: The TyG index was associated with increased risk of cancers of the digestive system and substantially mediated the effect of BMI, suggesting that insulin resistance plays a promoting role in the pathogenesis of gastrointestinal cancers.

  • 443.
    Fritzson, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Axelsson, Bertil
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Association between parenteral fluids and symptoms in hospital end-of-life care: an observational study of 280 patients2015In: BMJ Supportive & Palliative Care, ISSN 2045-435X, E-ISSN 2045-4368, Vol. 5, no 2, p. 160-168Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To investigate whether dying patients receiving parenteral fluids (PF) suffer from more or less symptoms than patients who do not receive PF. Today's evidence on how PF affects palliative patients' symptoms is very scarce. Nevertheless, 40% of the patients who die expectedly in Swedish hospitals receive PF during their last 24 h of life.

    METHODS: A historical cohort study of medical records was performed. Of the 530 patients who were reported to have died expectedly at hospital in Västerbotten county (Sweden) between 1 January 2011 and 30 June 2012, 140 cases who had received PF and 140 controls who had not received PF were identified by stratified randomisation and matched by age, sex and main disease. The groups were compared regarding documented presence of dyspnoea, respiratory secretions, anxiety, nausea and confusion during the last 24 h and the last week of life.

    RESULTS: The prevalence of documented dyspnoea in the PF groups was higher than in the non-PF groups (51% vs 22% last 24 h, p<0.0001; 70% vs 45% last 7 days, p<0.001). The proportions of patients suffering from dyspnoea increased with larger administered volume. Although our main hypothesis--that the prevalence of respiratory secretions would be higher in the PF group--was not confirmed, we found a tendency in that direction (63% vs 50% last week, p=0.072). No clinically significant differences in anxiety, nausea or confusion were found.

    CONCLUSIONS: There is an association between PF administration and increased frequency of documented dyspnoea for terminally ill patients in their last week of life.

  • 444.
    Frängsmyr, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Prall, F
    Yeung, Moorix Mo-Wai
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Wagener, C
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Cell- and region-specific expression of biliary glycoprotein and its messenger RNA in normal human colonic mucosa1995In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 55, no 14, p. 2963-2967Article in journal (Refereed)
    Abstract [en]

    The localization of biliary glycoprotein (BGP) and its mRNA in normal colonic mucosa was studied by immunohistochemistry and in situ hybridization. BGP mRNA was confined to columnar epithelial cells and expressed abundantly in the superficial mature cells and at low levels in differentiating cells in the upper crypts. Epithelial expression of BGP coincided with that of BGP mRNA. Ultrastructurally, BGP was localized to microfilaments of the fuzzy coat of the columnar cells at the luminal surface and the upper crypts. Additionally, BGP was found in cryptal caveolated cells. The results are consistent with primary transcriptional regulation of BGP production and suggest that BGP synthesis is controlled by the degree of cytodifferentiation. The fuzzy-coat localization of BGP implies a role in nonspecific defense mechanisms against pathogens.

  • 445.
    Frängsmyr, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Israelsson, Anne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Teglund, S
    Matsunaga, T
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Evolution of the carcinoembryonic antigen family: Structures of CGM9, CGM11 and pregnancy-specific glycoprotein promoters.2000In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 21, no 2, p. 63-81Article in journal (Refereed)
  • 446. Fu, Yi-Ping
    et al.
    Kohaar, Indu
    Moore, Lee E.
    Lenz, Petra
    Figueroa, Jonine D.
    Tang, Wei
    Porter-Gill, Patricia
    Chatterjee, Nilanjan
    Scott-Johnson, Alexandra
    Garcia-Closas, Montserrat
    Muchmore, Brian
    Baris, Dalsu
    Paquin, Ashley
    Ylaya, Kris
    Schwenn, Molly
    Apolo, Andrea B.
    Karagas, Margaret R.
    Tarway, McAnthony
    Johnson, Alison
    Mumy, Adam
    Schned, Alan
    Guedez, Liliana
    Jones, Michael A.
    Kida, Masatoshi
    Hosain, G. M. Monawar
    Malats, Nuria
    Kogevinas, Manolis
    Tardon, Adonina
    Serra, Consol
    Carrato, Alfredo
    Garcia-Closas, Reina
    Lloreta, Josep
    Wu, Xifeng
    Purdue, Mark
    Andriole, Gerald L., Jr.
    Grubb, Robert L., III
    Black, Amanda
    Landi, Maria T.
    Caporaso, Neil E.
    Vineis, Paolo
    Siddiq, Afshan
    Bueno-de-Mesquita, H. Bas
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Severi, Gianluca
    Weiderpass, Elisabete
    Krogh, Vittorio
    Dorronsoro, Miren
    Travis, Ruth C.
    Tjonneland, Anne
    Brennan, Paul
    Chang-Claude, Jenny
    Riboli, Elio
    Prescott, Jennifer
    Chen, Constance
    De Vivo, Immaculata
    Govannucci, Edward
    Hunter, David
    Kraft, Peter
    Lindstrom, Sara
    Gapstur, Susan M.
    Jacobs, Eric J.
    Diver, W. Ryan
    Albanes, Demetrius
    Weinstein, Stephanie J.
    Virtamo, Jarmo
    Kooperberg, Charles
    Hohensee, Chancellor
    Rodabough, Rebecca J.
    Cortessis, Victoria K.
    Conti, David V.
    Gago-Dominguez, Manuela
    Stern, Mariana C.
    Pike, Malcolm C.
    Van Den Berg, David
    Yuan, Jian-Min
    Haiman, Christopher A.
    Cussenot, Olivier
    Cancel-Tassin, Geraldine
    Roupret, Morgan
    Comperat, Eva
    Porru, Stefano
    Carta, Angela
    Pavanello, Sofia
    Arici, Cecilia
    Mastrangelo, Giuseppe
    Grossman, H. Barton
    Wang, Zhaoming
    Deng, Xiang
    Chung, Charles C.
    Hutchinson, Amy
    Burdette, Laurie
    Wheeler, William
    Fraumeni, Joseph, Jr.
    Chanock, Stephen J.
    Hewitt, Stephen M.
    Silverman, Debra T.
    Rothman, Nathaniel
    Prokunina-Olsson, Ludmila
    The 19q12 Bladder Cancer GWAS Signal: Association with Cyclin E Function and Aggressive Disease2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 20, p. 5808-5818Article in journal (Refereed)
    Abstract [en]

    A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) >= 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 x 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P-trend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.

  • 447.
    Försti, Asta
    et al.
    Department of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany / Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
    Li, Xuchen
    Department of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
    Wagner, Kerstin
    Department of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Enquist, Kerstin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Altieri, Andrea
    Department of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hemminki, Kari
    Department of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany / Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Polymorphisms in the transforming growth factor beta 1 pathway in relation to colorectal cancer progression2010In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 49, no 3, p. 270-281Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor beta1 (TGFB1) acts as a growth inhibitor of normal colonic epithelial cells, however, as a tumor promoter of colorectal cancer (CRC) cells. To explore the association between genetic polymorphisms in the TGFB1 pathway and CRC susceptibility and clinical outcome, we carried out a case-control study on a Swedish population of 308 CRC cases and 585 age- and gender-matched controls. The cases were sampled prospectively and had up to 16 years follow-up, making the study material particularly suitable for survival analysis. On the basis of their reported or predicted functional effect, nine single-nucleotide polymorphisms (TGFB1: Leu10Pro; TGFBR1: 9A/6A and IVS7G+24A; FURIN: C-229T; THBS1: T+42C; LTBP1L: C-256G; LTBP4: T-893G and Thr750Ala; BAMBI: T-779A) were selected for genotyping. We evaluated the associations between genotypes and CRC and Dukes' stage. Survival probabilities were compared between different subgroups. The observed statistically significant associations included a decreased CRC risk for TGFBR1 IVS7G+24A minor allele carriers (odds ratio (OR): 0.72, 95% confidence interval (CI): 0.53-0.97), less aggressive tumors with Dukes' stage A+B for carriers of LTBP4 Thr750Ala and BAMBI T-779A minor alleles (OR: 0.58, 95%CI: 0.36-0.93 and OR: 0.51, 95%CI: 0.29-0.89, respectively) and worse survival for FURIN C-229T heterozygotes (hazard ratio: 1.63, 95%CI: 1.08-2.46). As this is the first study about the influence of the polymorphisms in the TGFB1 pathway on CRC progression, further studies in large independent cohorts are warranted.

  • 448. Galon, Jerome
    et al.
    Mlecnik, Bernhard
    Bindea, Gabriela
    Angell, Helen K.
    Berger, Anne
    Lagorce, Christine
    Lugli, Alessandro
    Zlobec, Inti
    Hartmann, Arndt
    Bifulco, Carlo
    Nagtegaal, Iris D.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Masucci, Giuseppe V.
    Botti, Gerardo
    Tatangelo, Fabiana
    Delrio, Paolo
    Maio, Michele
    Laghi, Luigi
    Grizzi, Fabio
    Asslaber, Martin
    D'Arrigo, Corrado
    Vidal-Vanaclocha, Fernando
    Zavadova, Eva
    Chouchane, Lotfi
    Ohashi, Pamela S.
    Hafezi-Bakhtiari, Sara
    Wouters, Bradly G.
    Roehrl, Michael
    Nguyen, Linh
    Kawakami, Yutaka
    Hazama, Shoichi
    Okuno, Kiyotaka
    Ogino, Shuji
    Gibbs, Peter
    Waring, Paul
    Sato, Noriyuki
    Torigoe, Toshihiko
    Itoh, Kyogo
    Patel, Prabhu S.
    Shukla, Shilin N.
    Wang, Yili
    Kopetz, Scott
    Sinicrope, Frank A.
    Scripcariu, Viorel
    Ascierto, Paolo A.
    Marincola, Francesco M.
    Fox, Bernard A.
    Pages, Franck
    Towards the introduction of the 'Immunoscore' in the classification of malignant tumours2014In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 232, no 2, p. 199-209Article, review/survey (Refereed)
    Abstract [en]

    The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named Immunoscore' has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).

  • 449.
    Garpebring, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    MRI based radiotherapy - what can go wrong and how to QA?2018In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 127, p. S339-S339Article in journal (Other academic)
  • 450. Garvin, Stina
    et al.
    Oda, Husam
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Department of Pathology, County Hospital Ryhov, Jönköping, Sweden.
    Arnesson, Lars-Gunnar
    Lindström, Annelie
    Shabo, Ivan
    Tumor cell expression of CD163 is associated to postoperative radiotherapy and poor prognosis in patients with breast cancer treated with breast-conserving surgery2018In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 144, no 7, p. 1253-1263Article in journal (Refereed)
    Abstract [en]

    Cancer cell fusion with macrophages results in highly tumorigenic hybrids that acquire genetic and phenotypic characteristics from both maternal cells. Macrophage traits, exemplified by CD163 expression, in tumor cells are associated with advanced stages and poor prognosis in breast cancer (BC). In vitro data suggest that cancer cells expressing CD163 acquire radioresistance. Tissue microarray was constructed from primary BC obtained from 83 patients treated with breast-conserving surgery, 50% having received postoperative radiotherapy (RT) and none of the patients had lymph node or distant metastasis. Immunostaining of CD163 in cancer cells and macrophage infiltration (MI) in tumor stroma were evaluated. Macrophage:MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation (0, 2.5 and 5 Gy gamma-radiation), both hybrids and their maternal MCF-7 cells were examined by clonogenic survival. CD163-expression by cancer cells was significantly associated with MI and clinicopathological data. Patients with CD163-positive tumors had significantly shorter disease-free survival (DFS) after RT. In vitro generated macrophage:MCF-7 hybrids developed radioresistance and exhibited better survival and colony forming ability after radiation compared to maternal MCF-7 cancer cells. Our results suggest that macrophage phenotype in tumor cells results in radioresistance in breast cancer and shorter DFS after radiotherapy.

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