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  • 301.
    Mirza, Mansoor Raza
    et al.
    NSGO, Denmark; Rigshosp, Denmark.
    Bergmann, Troels K.
    Odense Univ Hosp, Denmark.
    Mau-Sorensen, Morten
    Rigshosp, Denmark.
    Christensen, Rene dePont
    NSGO, Denmark; Univ Southern Denmark, Denmark.
    Åvall Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. NSGO, Denmark.
    Birrer, Michael J.
    Univ Alabama Birmingham, AL USA.
    Jorgensen, Morten
    NSGO, Denmark; Rigshosp, Denmark.
    Roed, Henrik
    NSGO, Denmark; Rigshosp, Denmark.
    Malander, Susanne
    NSGO, Denmark; Lund Univ Hosp, Sweden.
    Nielsen, Flemming
    Univ Southern Denmark, Denmark.
    Lassen, Ulrik
    Rigshosp, Denmark.
    Brosen, Kim
    Univ Southern Denmark, Denmark.
    Bjorge, Line
    NSGO, Denmark; Univ Bergen, Norway; Haukeland Hosp, Norway.
    Maenpaa, Johanna
    NSGO, Denmark; Univ Tampere, Finland.
    A phase I study of the PARP inhibitor niraparib in combination with bevacizumab in platinum-sensitive epithelial ovarian cancer: NSGO AVANOVA1/ENGOT-OV242019Ingår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 84, nr 4, s. 791-798Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Combining poly(ADP-ribose) polymerase (PARP) inhibitors with antiangiogenic agents appeared to enhance activity vs PARP inhibitors alone in a randomized phase II trial. Materials and methods In AVANOVA (NCT02354131) part 1, patients with measurable/evaluable high-grade serous/endometrioid platinum-sensitive ovarian cancer received bevacizumab 15 mg/kg every 21 days with escalating doses of niraparib capsules (100, 200, or 300 mg daily) in a 3 + 3 dose-escalation design. Primary objectives were to evaluate safety and tolerability and to determine the recommended phase II dose (RP2D). Results Three of 12 enrolled patients had germline BRCA2 mutations. In cycle 1, nine patients experienced grade 3 toxicities: five with hypertension, three with anemia, and one with thrombocytopenia. There was one dose-limiting toxicity (grade 4 thrombocytopenia with niraparib 300 mg), thus the RP2D was bevacizumab 15 mg/kg with niraparib 300 mg. The response rate was 50%; disease was stabilized in a further 42%. Median progression-free survival was 11.6 (95% confidence interval 8.4-20.1) months. Niraparib pharmacokinetics were consistent with historical single-agent data. Overlapping exposure was observed across the dose ranges tested on days 1 and 21. Conclusions There was one dose-limiting toxicity; other adverse events were typical PARP inhibitor and antiangiogenic class effects. Niraparib-bevacizumab showed promising activity; Part 2 (vs bevacizumab) was recently reported and phase III comparison with standard-of-care therapy is planned.

  • 302.
    Mirza, Mansoor Raza
    et al.
    Nordic Soc Gynaecol Oncol, Denmark; Copenhagen Univ Hosp, Denmark.
    Åvall Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Nordic Soc Gynaecol Oncol, Denmark.
    Birrer, Michael
    Univ Alabama Birmingham, AL USA.
    Christensen, Rene DePont
    Nordic Soc Gynaecol Oncol, Denmark; Univ Southern Denmark, Denmark.
    Nyvang, Gitte-Bettina
    Nordic Soc Gynaecol Oncol, Denmark; Odense Univ Hosp, Denmark.
    Malander, Susanne
    Nordic Soc Gynaecol Oncol, Denmark; Lund Univ Hosp, Sweden.
    Anttila, Maarit
    Nordic Soc Gynaecol Oncol, Denmark; Kuopio Univ Hosp, Finland.
    Werner, Theresa L.
    Univ Utah, UT USA.
    Lund, Bente
    Nordic Soc Gynaecol Oncol, Denmark; Aalborg Univ Hosp, Denmark.
    Lindahl, Gabriel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Nordic Soc Gynaecol Oncol, Denmark.
    Hietanen, Sakari
    Nordic Soc Gynaecol Oncol, Denmark; Turku Univ Hosp, Finland.
    Peen, Ulla
    Nordic Soc Gynaecol Oncol, Denmark; Hedev Univ Hosp, Denmark.
    Dimoula, Maria
    Nordic Soc Gynaecol Oncol, Denmark; Sahlgrens Univ Hosp, Sweden.
    Roed, Henrik
    Nordic Soc Gynaecol Oncol, Denmark; Copenhagen Univ Hosp, Denmark.
    Knudsen, Anja Or
    Nordic Soc Gynaecol Oncol, Denmark; Odense Univ Hosp, Denmark.
    Staff, Synnove
    Nordic Soc Gynaecol Oncol, Denmark; Tampere Univ, Finland; Tampere Univ, Finland; Univ Hosp, Finland.
    Vistisen, Anders Krog
    Aalborg Univ Hosp, Denmark.
    Bjorge, Line
    Nordic Soc Gynaecol Oncol, Denmark; Haukeland Hosp, Norway; Univ Bergen, Norway.
    Maenpaa, Johanna U.
    Nordic Soc Gynaecol Oncol, Denmark; Tampere Univ, Finland; Tampere Univ, Finland; Univ Hosp, Finland.
    Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial2019Ingår i: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 20, nr 10, s. 1409-1419Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Platinum-based chemotherapy is the foundation of treatment for platinum-sensitive recurrent ovarian cancer, but has substantial toxicity. Bevacizumab and maintenance poly(ADP-ribose) polymerase (PARP) inhibitors both significantly improve efficacy versus standard therapy, primarily in terms of progression-free survival, and offer the potential for chemotherapy-free treatment. AVANOVA2 compared niraparib and bevacizumab versus niraparib alone as definitive treatment for platinum-sensitive recurrent ovarian cancer. Methods This open-label, randomised, phase 2, superiority trial in 15 university hospitals in Denmark, Sweden, Finland, Norway, and the USA enrolled women aged 18 years or older with measurable or evaluable high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, and had to have previously received platinum-containing therapy for primary disease but amp;lt;= 1 prior non-platinum-containing regimen for recurrent disease. Previous treatment with bevacizumab or first-line maintenance PARP inhibitors was permitted. Eligible patients were randomly assigned 1:1 (by random permuted blocks with block sizes of two and four, no masking), stratified by homologous recombination deficiency status and chemotherapy-free interval, to receive once-daily oral niraparib 300 mg alone or with intravenous bevacizumab 15 mg/kg once every 3 weeks until disease progression. The primary endpoint was progression-free survival, assessed by the investigators in the intention-to-treat population after events in at least 62 patients. Safety was analysed in all patients who received at least one dose of study drug. This ongoing trial is registered with ClinicalTrials.gov , number NCT02354131. Findings Between May 23,2016, and March 6,2017,97 patients were enrolled and randomly assigned: 48 to niraparib plus bevacizumab and 49 to single-agent niraparib. Median follow-up was 16.9 months (IQR 15.4-20.9). Niraparib plus bevacizumab significantly improved progression-free survival compared with niraparib alone (median progression-free survival 11.9 months [95% CI 8.5-16.7] vs 5.5 months [3.8-6.3], respectively; adjusted hazard ratio [HR] 0.35 [95% CI 0.21-0.57], pamp;lt;0.0001). Grade 3 or worse adverse events occurred in 31 (65%) of 48 patients who received niraparib plus bevacizumab and 22 (45%) of 49 who received single-agent niraparib. The most common grade 3 or worse adverse events in both groups were anaemia (7 [15%] of 48 vs 9 [18%] of 49) and thrombocytopenia (5 [10%] vs 6 [12%]), and hypertension in the combination group (10 [21%] vs 0). Niraparib plus bevacizumab was associated with increased incidences of any-grade proteinuria (10 [21%] of 48 patients vs 0) and hypertension (27[56%] of 48 vs 11 [22%] of 49) compared with niraparib alone. No treatment-related deaths occurred. Interpretation The efficacy observed with this chemotherapy-free combination of approved agents in women with platinum-sensitive recurrent ovarian cancer warrants further evaluation. A randomised phase 3 trial investigating niraparib plus bevacizumab versus chemotherapy plus bevacizumab in platinum-sensitive recurrent ovarian cancer is planned. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

  • 303.
    Mishra, Ameet K.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fulvestrant inhibits growth of triple negative breast cancer and synergizes with tamoxifen in ER alpha positive breast cancer by up-regulation of ER beta2016Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 35, s. 56876-56888Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The estrogen receptor-alpha (ER alpha) is used as a predictive marker for antiestrogen therapy in breast cancer patients. In addition to aromatase inhibitors, ER alpha can be targeted at the receptor level using the receptor modulator tamoxifen or by the pure anti-estrogen fulvestrant. The role of the second ER, ER-beta (ER beta), as a therapeutic target or prognostic marker in breast cancer is still elusive. Hitherto, it is not known if ER alpha+/ER beta+ breast cancers would benefit from a treatment strategy combining tamoxifen and fulvestrant or if fulvestrant exert any therapeutic effects in ER alpha-/ER beta+ breast cancer. Here, we report that fulvestrant up-regulated ER beta in ER alpha+/ER beta+ breast cancer and in triple negative ER beta+ breast cancers (ER alpha-/ER beta+). In ER alpha+/ER beta+ breast cancer, a combination therapy of tamoxifen and fulvestrant significantly reduced tumor growth compared to either treatment alone both in vivo and in vitro. In ER alpha-/ER beta+ breast cancer fulvestrant had potent effects on cancer growth, in vivo as well as in vitro, and this effect was dependent on intrinsically expressed levels of ER beta. The role of ER beta was further confirmed in cells where ER beta was knocked-in or knocked-down. Inhibition of DNA methyltransferase (DNMT) increased the levels of ER beta and fulvestrant exerted similar potency on DNMT activity as the DNMT inhibitor decitabine. We conclude that fulvestrant may have therapeutic potential in additional groups of breast cancer patients; i) in ER alpha+/ER beta+ breast cancer where fulvestrant synergizes with tamoxifen and ii) in triple negative/ER beta+ breast cancer patients, a subgroup of breast cancer patients with poor prognosis.

  • 304. Molassiotis, Alex
    et al.
    Börjeson, Sussanne
    Linköpings universitet, Institutionen för medicin och vård, Omvårdnad. Linköpings universitet, Hälsouniversitetet.
    Nausea and vomiting2006Ingår i: Nursing patients with cancer: principles and practice / [ed] Nora Kearney, Alison Richardson, Elsevier Churchill Livingstone , 2006, 1, s. 415-437Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    This title is directed primarily towards health care professionals outside of the United States.  Nurses are in the vanguard of the international fight against cancer. National policies on reducing or eradicating cancer highlight the vital contribution nurses make in its prevention, identification, treatment and management. This book, which is based on the internationally acclaimed Core Curriculum for a Post-Registration Course in Cancer Nursing developed by the European Oncology Nursing Society (EONS), covers all the key areas nurses caring for patients in this demanding specialty will need to consider. Focusing on the needs of the patient, it provides the essential scientific, psychological and sociological information necessary for nurses to provide care that minimises the trauma of cancer, and maximises outcomes for

  • 305.
    Moor, Andreas E.
    et al.
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Anderle, Pascale
    SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
    Rodriguez, Patrick
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Wiedemann, Norbert
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Baruthio, Frédérique
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Deka, Jürgen
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    André, Sylvie
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Valenta, Tomas
    Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
    Moor, Matthias B
    Department of Pharmacology and Toxicology, University of Lausanne, CH-1005 Lausanne, Switzerland.
    Győrffy, Balázs
    MTA TTK Lendület Cancer Biomarker Research Group, 2nd Dept. of Pediatrics, Semmelweis University, Budapest, Hungary.
    Barras, David
    SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
    Delorenzi, Mauro
    SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland; Ludwig Center for Cancer Research, University of Lausanne, CH-1066 Lausanne, Switzerland; Oncology Department, University of Lausanne, CH-1015 Lausanne, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
    Aguet, Michel
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer2015Ingår i: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 2, nr 12, s. 1932-1943Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BCL9/9L proteins enhance the transcriptional output of the β-catenin/TCF transcriptional complex and contribute critically to upholding the high WNT signaling level required for stemness maintenance in the intestinal epithelium. Here we show that a BCL9/9L-dependent gene signature derived from independent mouse colorectal cancer (CRC) models unprecedentedly separates patient subgroups with regard to progression free and overall survival. We found that this effect was by and large attributable to stemness related gene sets. Remarkably, this signature proved associated with recently described poor prognosis CRC subtypes exhibiting high stemness and/or epithelial-to-mesenchymal transition (EMT) traits. Consistent with the notion that high WNT signaling is required for stemness maintenance, ablating Bcl9/9l-β-catenin in murine oncogenic intestinal organoids provoked their differentiation and completely abrogated their tumorigenicity, while not affecting their proliferation. Therapeutic strategies aimed at targeting WNT responses may be limited by intestinal toxicity. Our findings suggest that attenuating WNT signaling to an extent that affects stemness maintenance without disturbing intestinal renewal might be well tolerated and prove sufficient to reduce CRC recurrence and dramatically improve disease outcome.

  • 306.
    Moparthi, Lavanya
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten.
    Pizzolato, Giulia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten.
    Koch, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten.
    Wnt activator FOXB2 drives the neuroendocrine differentiation of prostate cancer2019Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 44, s. 22189-22195Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Wnt signaling pathway is of paramount importance for development and disease. However, the tissue-specific regulation of Wnt pathway activity remains incompletely understood. Here we identify FOXB2, an uncharacterized forkhead box family transcription factor, as a potent activator of Wnt signaling in normal and cancer cells. Mechanistically, FOXB2 induces multiple Wnt ligands, including WNT7B, which increases TCF/LEF-dependent transcription without activating Wnt coreceptor LRP6 or beta-catenin. Proximity ligation and functional complementation assays identified several transcription regulators, including YY1, JUN, and DDX5, as cofactors required for FOXB2-dependent pathway activation. Although FOXB2 expression is limited in adults, it is induced in select cancers, particularly advanced prostate cancer. RNA-seq data analysis suggests that FOXB2/WNT7B expression in prostate cancer is associated with a transcriptional program that favors neuronal differentiation and decreases recurrence-free survival. Consistently, FOXB2 controls Wnt signaling and neuroendocrine differentiation of prostate cancer cell lines. Our results suggest that FOXB2 is a tissue-specific Wnt activator that promotes the malignant transformation of prostate cancer.

  • 307.
    Morad, Vivian
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Hormonal regulation of immune modulators in human breast tissue2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Breast cancer is the most common form of cancer and the second leading cause of malignancy-associated death in women worldwide. Estrogens are the main sex hormones in women. They are essential for the development and function of normal breast mammary glands; however, prolonged exposure to estrogens increases the risk of breast cancer development and progression. Approximately two-thirds of all breast cancer patients are positive for estrogen receptor (ER), but only 50% of those cases can benefit from antiestrogen therapy.

    In this thesis we investigated the effects of estrogen, diet modification, and anti-estrogen drugs on several immune modulators in normal human breast tissue. We used the microdialysis technique to sample the immune modulators in situ in normal human breast tissue, in malignant breast tissue, and in tumor tissue from both the immune competent mice with murine breast cancer and immune deficient mice bearing human breast tumors. Furthermore, we also used ex vivo culture of normal breast tissue and in vitro cell culture of breast cancer cell lines. A combined cell culture (co-culture) of breast cancer cell lines, together with the primary mature adipocytes, was also used in this thesis.

    In Paper I and Paper II, our results suggested that estrogen exerted both proinflammatory and pro-tumorigenic effects in normal human breast tissue. Estradiol increased extracellular interleukin-1β (IL-1β) and leptin levels and decreased IL-1Ra and adiponectin levels in normal human breast tissue. In contrast, tamoxifen decreased IL-1β and leptin levels and increased IL-1Ra and adiponectin levels, shifting the environment towards an antiinflammatory and antitumorigenic state. Diet modification with flaxseed for 30 days also increased IL-1Ra levels, creating an anti-inflammatory environment in normal breast tissue. In the breast cancer tissue, we found that extracellular IL-1β levels and leptin levels were significantly higher, whereas adiponectin levels were significantly lower, compared with normal adjacent breast tissue, which suggested a more proinflammatory state.

    In the third paper, our in vivo investigation of normal breast tissue revealed significant correlations between vascular endothelial growth factor (VEGF) and leptin, IL-1β and leptin, and between VEGF and IL-1β. No correlations were found in the abdominal subcutaneous (s.c.) fat tissue. Our in vitro inhibition experiments suggested that VEGF was a potent regulator of leptin, but that leptin was not a potent regulator of VEGF. Co-culture per se altered the release of VEGF and leptin and enhanced the effects of estradiol, compared with monocultures of the included cell types.

    In conclusion, the results presented in this thesis will increase the overall understanding of the role of estrogens in breast cancer, which may be useful in future treatment studies.

    Delarbeten
    1. Estradiol, Tamoxifen, and Flaxseed Alter IL-1 beta and IL-1Ra Levels in Normal Human Breast Tissue in Vivo
    Öppna denna publikation i ny flik eller fönster >>Estradiol, Tamoxifen, and Flaxseed Alter IL-1 beta and IL-1Ra Levels in Normal Human Breast Tissue in Vivo
    2012 (Engelska)Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, nr 11, s. E2044-E2054Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Introduction: Sex steroid exposure increases the risk of breast cancer by unclear mechanisms. Diet modifications may be one breast cancer prevention strategy. The proinflammatory cytokine family of IL-1 is implicated in cancer progression. IL-1Ra is an endogenous inhibitor of the proinflammatory IL-1 alpha and IL-1 beta. less thanbrgreater than less thanbrgreater thanObjective: The objective of this study was to elucidate whether estrogen, tamoxifen, and/or diet modification altered IL-1 levels in normal human breast tissue. less thanbrgreater than less thanbrgreater thanDesign and Methods: Microdialysis was performed in healthy women under various hormone exposures, tamoxifen therapy, and diet modifications and in breast cancers of women before surgery. Breast tissue biopsies from reduction mammoplasties were cultured. less thanbrgreater than less thanbrgreater thanResults: We show a significant positive correlation between estradiol and in vivo levels of IL-1 beta in breast tissue and abdominal sc fat, whereas IL-1Ra exhibited a significant negative correlation with estradiol in breast tissue. Tamoxifen or a dietary addition of 25 g flaxseed per day resulted in significantly increased levels of IL-1Ra in the breast. These results were confirmed in ex vivo culture of breast biopsies. Immunohistochemistry of the biopsies did not reveal any changes in cellular content of the IL-1s, suggesting that mainly the secreted levels were affected. In breast cancer patients, intratumoral levels of IL-1 beta were significantly higher compared with normal adjacent breast tissue. less thanbrgreater than less thanbrgreater thanConclusion: IL-1 may be under the control of estrogen in vivo and may be attenuated by antiestrogen therapy and diet modifications. The increased IL-1 beta in breast cancers of women strongly suggests IL-1 as a potential therapeutic target in breast cancer treatment and prevention.

    Ort, förlag, år, upplaga, sidor
    Endocrine Society, 2012
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-86651 (URN)10.1210/jc.2012-2288 (DOI)000310710500002 ()
    Anmärkning

    Funding Agencies|Swedish Cancer Society|2009/799|Swedish Research Council|2010-3458|Research Funds of Linkoping University Hospital||

    Tillgänglig från: 2012-12-20 Skapad: 2012-12-20 Senast uppdaterad: 2017-12-06
    2. Estradiol Affects Extracellular Leptin: Adiponectin Ratio in Human Breast Tissue in Vivo
    Öppna denna publikation i ny flik eller fönster >>Estradiol Affects Extracellular Leptin: Adiponectin Ratio in Human Breast Tissue in Vivo
    2014 (Engelska)Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, nr 9, s. 3460-3467Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Context: Exposure to sex steroids is associated with increased breast cancer risk, and adipokines, leptin and adiponectin have been implicated in cancer progression. However, it is not known whether sex steroids affect adipokine secretion in breast tissue. Objective: To elucidate the role of estrogen and tamoxifen on adipokine release in normal human breast tissue and breast cancer. Setting and Design: Microdialysis sampling was used to collect extracellular in vivo leptin and adiponectin from normal human breast tissue in premenopausal healthy volunteers during the menstrual cycle and in postmenopausal women before tamoxifen treatment and after 6 weeks of treatment. In women with breast cancer, microdialysis was performed intratumorally before surgery. In addition, whole normal breast tissue biopsies were cultured ex vivo, and murine breast cancer models were evaluated. Results: In normal breast tissue, plasma estradiol negatively correlated with local extracellular adiponectin levels (r = -0.34; P less than .05) and positively correlated with leptin (r = 0.37; P less than .05) and leptin: adiponectin ratio (r = 0.38; P less than .05). In postmenopausal women, tamoxifen treatment increased adiponectin (P less than 0.05) and decreased leptin (P less than .01) and the leptin: adiponectin ratio (P less than .01). These in vivo results were confirmed in breast tissue biopsies cultured ex vivo. In patients with breast cancer, extracellular leptin was higher (P less than .01) and adiponectin lower (P less than .05) in tumors than in normal adjacent breast tissue. In a murine model of breast cancer, estrogen exposure increased leptin secretion (P less than .05). Conclusions: Estrogen exposure may have a critical role in the regulation of adipokines in human breast tissue and may serve as therapeutic targets for treatment and prevention.

    Ort, förlag, år, upplaga, sidor
    Endocrine Society, 2014
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-111611 (URN)10.1210/jc.2014-1129 (DOI)000342341400088 ()24796929 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Cancer Society [2012/454]; Swedish Research Council [2010-3458]; Research Funds of Linkoping University Hospital

    Tillgänglig från: 2014-10-27 Skapad: 2014-10-27 Senast uppdaterad: 2017-12-05
    3. Correlation between vascular endothelial growth factor and leptin in normal human breast tissue in vivo
    Öppna denna publikation i ny flik eller fönster >>Correlation between vascular endothelial growth factor and leptin in normal human breast tissue in vivo
    2015 (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Introduction: Events in the microenvironment are important for carcinogenesis of the breast. Adipocytes, which produce adipokines with paracrine effects, are the most abundant cell type in breast tissue. Exposure to sex steroids affects the risk of breast cancer. It has previously been shown that estrogen regulates the extracellular levels of leptin, adiponectin, IL-1β, and VEGF in normal human breast tissue in vivo.

    Objective: We aimed to determine if there were any relationships between leptin, adiponectin, IL-1β, and/or VEGF in normal human breast tissue in vivo and to elucidate the role of adipocytes in the regulation of these factors.

    Design and methods: Microdialysis was used to sample proteins of normal human breast tissue and abdominal subcutaneous (s.c.) fat in situ in pre-and postmenopausal women. An in vitro co-culture model of breast cancer cells and primary mature human adipocytes was used.

    Results: In vivo, in normal breast tissue, significant positive correlations between VEGF and leptin, and VEGF and leptin/adiponectin ratio were detected. No correlations were found in s.c. abdominal fat tissue. Co-culture of adipocytes and breast cancer cells per se increased the secretion of VEGF and leptin and enhanced the effects of estradiol compared to culture of either cell type alone. In vitro, inhibition of VEGF diminished the release of leptin while inhibition of leptin had no influence on VEGF secretion. In breast tissue, significant correlations between IL-1β and leptin and VEGF were revealed.

    Conclusions: Our results suggest that VEGF regulates leptin in normal human breast tissue. Moreover, physical contact between adipocytes and breast cancer cells, induces phenotypic changes and enhances the effects of estradiol. These mechanisms may be involved in breast cancer progression.

    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-117982 (URN)
    Tillgänglig från: 2015-05-19 Skapad: 2015-05-19 Senast uppdaterad: 2019-06-28Bibliografiskt granskad
  • 308.
    Morad, Vivian
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska fakulteten.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Kjölhede, Preben
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Adipokines and Vascular Endothelial Growth Factor in Normal Human Breast Tissue in Vivo - Correlations and Attenuation by Dietary Flaxseed2016Ingår i: Journal of mammary gland biology and neoplasia, ISSN 1083-3021, E-ISSN 1573-7039, Vol. 21, nr 1-2, s. 69-76Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Exposure to sex steroids increases the risk of breast cancer but the exact mechanisms are yet to be elucidated. Events in the microenvironment are important for carcinogenesis. Diet containing phytoestrogens can affect the breast microenvironment and alter the risk of breast cancer. It has previously been shown that estrogen regulates extracellular levels of leptin, adiponectin, and VEGF in normal breast tissue in vivo. Whether these proteins correlate in breast tissue in vivo or if diet addition of flaxseed, a major source of phytoestrogens in Western diets, alters adipokine levels in breast tissue are unknown. We used microdialysis to sample proteins of normal human breast tissue and abdominal subcutaneous fat in situ in 34 pre-and postmenopausal women. In vitro, co-culture of breast cancer cells and primary human adipocytes was used. In vivo, in normal breast tissue, a significant positive correlation between VEGF and leptin was detected. No correlations were found in fat tissue. Co-culture of adipocytes and breast cancer cells per se increased the secretion of VEGF and leptin and enhanced the effects of estradiol compared to culture of either cell type alone. In vitro, inhibition of VEGF diminished the release of leptin while inhibition of leptin had no influence on VEGF secretion. The levels of leptin decreased and adiponectin increased after a dietary addition of 25 g of flaxseed/day for one menstrual cycle. We conclude that VEGF and leptin correlate significantly in normal human breast tissue in vivo and that dietary addition of flaxseed affect adipokine levels in the breast.

  • 309.
    Mulligan, Stephen P.
    et al.
    Royal N Shore Hospital, Australia.
    -Karlsson, Karin
    Department of Hematology, Skåne University Hospital, Lund , Sweden.
    Stromberg, Mats
    Karolinska University Hospital, Sweden.
    Jonsson, Viggo
    National Hospital, Denmark.
    Gill, Devinder
    Princess Alexandra Hospital, Australia.
    Hammerstrom, Jens
    St Olavs University Hospital, Norway.
    Hertzberg, Mark
    Westmead Hospital, Australia.
    McLennan, Roger
    Ballarat Base Hospital, Australia.
    Uggla, Bertil
    University Hospital Örebro, Sweden.
    Norman, John
    Royal Adelaide Hospital, Australia.
    Wallvik, Jonas
    Department Med, Sweden.
    Sundstrom, Gunnel
    Norrlands University Hospital, Sweden.
    Johansson, Hemming
    Karolinska Institute, Sweden.
    Brandberg, Yvonne
    Karolinska Institute, Sweden.
    Liliemark, Jan
    Karolinska University Hospital, Sweden; Swedish Council Health Technology Assessment, Sweden.
    Juliusson, Gunnar
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US. Department of Hematology, Sk å ne University Hospital, Lund, Sweden.
    Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic2014Ingår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, nr 12, s. 2769-2777Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We conducted a randomized phase III trial to compare the efficacy and safety of two purine analogs, cladribine and fludarabine, with high-dose chlorambucil, in patients with previously untreated chronic lymphocytic leukemia (CLL). Between 1997 and 2004, 223 patients with CLL were randomly assigned to cladribine, fludarabine or chlorambucil, for six cycles of therapy with frequent health-related quality of life assessments. There was no statistical difference for the primary endpoint of overall response with cladribine (70%), fludarabine (67%) and chlorambucil (59%), or complete remission (12%, 7% and 8%), respectively. However, the median progression-free survival (25, 10, 9 months) and median time to second treatment (40, 22, 21 months) were superior with cladribine. There was no significant difference in overall survival (96, 82 and 91 months), nor in toxicity or HRQoL assessments. Monotherapy with cladribine gives superior PFS and longer response duration than fludarabine and chlorambucil as first-line treatment of CLL.

  • 310.
    Muszynska, Carolina
    et al.
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Lundgren, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Andersson, Roland
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Soland, Torunn
    Ostfold Hosp, Norway.
    Lindell, Gert
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Sandström, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Andersson, Bodil
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Incidental metastases and lymphoma of the gallbladder - an analysis of ten rare cases identified from a large national database2019Ingår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 54, nr 3, s. 350-358Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The aim was to identify and characterize rare malignancies of the gallbladder, incidentally found at cholecystectomy, and describe the diagnostic work-up, treatment and outcome.Methods: Data from cholecystectomies during 2007-2014 registered in the Swedish Register for Gallstone Surgery (GallRiks) were analyzed for incidental cancer. For completion of the pathology report, data were linked with the Swedish Registry for Cancer in the liver and biliary tract (SweLiv) and/or the Swedish Cancer Registry.Results: From 36,355 patients that underwent cholecystectomy on a benign indication 215 cases of incidental gallbladder cancer (IGBC) were identified. In total seven patients with metastases to the gallbladder from different primary tumors (breast cancer, malignant melanoma, gastric cancer, renal cell carcinoma, upper gastrointestinal cancer, colon cancer and pancreatic cancer) and three patients with lymphoma involvement of the gallbladder were found. Most patients were female with no difference between the groups (8/10 versus 171/215). The median age for the metastasis and lymphoma (MOL) group was equal to the IGBC group, 70 (64-72) years versus 70 (63-78) years. All patients in the MOL group underwent preoperative imaging with ultrasound or computed tomography, on which no metastases were identified. In only two patients a tumor was seen by the surgeon during the perioperative examination of the gallbladder. The median survival was 5.8 months for MOL patients and 23 months for IGBC patients.Conclusion: Metastases and lymphoma of the gallbladder are rare. Traditional imaging methods prior to cholecystectomy may miss gallbladder malignancies. A liberal approach of histopathological analysis of the gallbladder should be applied.

  • 311.
    Neumann, Hartmut P.
    et al.
    Albert Ludwigs Univ, Germany.
    Young, William F. Jr.
    Mayo Clin, NY USA.
    Krauss, Tobias
    Univ Freiburg, Germany.
    Bayley, Jean-Pierre
    Leiden Univ, Netherlands.
    Schiavi, Francesca
    IRCCS, Italy.
    Opocher, Giuseppe
    IRCCS, Italy.
    Boedeker, Carsten C.
    HELIOS Hanseklinikum Stralsund, Germany.
    Tirosh, Amit
    Tel Aviv Univ, Israel.
    Castinetti, Frederic
    Aix Marseille Univ, France; Hop Conception, France.
    Ruf, Juri
    Albert Ludwigs Univ, Germany.
    Beltsevich, Dmitry
    Endocrinol Res Ctr, Russia.
    Walz, Martin
    Kliniken Essen Mitte, Germany; Kliniken Essen Mitte, Germany.
    Groeben, Harald-Thomas
    Kliniken Essen Mitte, Germany.
    von Dobschuetz, Ernst
    Univ Hamburg, Germany.
    Gimm, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Wohllk, Nelson
    Univ Chile, Spain.
    Pfeifer, Marija
    Univ Med Ctr Ljubljana, Slovenia.
    Lourenco, Delmar M. Jr.
    Univ Sao Paulo, Brazil.
    Peczkowska, Mariola
    Inst Cardiol, Poland.
    Patocs, Attila
    Hungarian Acad Sci, Hungary; Semmelweis Univ, Hungary.
    Ngeow, Joanne
    Nanyang Technol Univ Singapore, Singapore; Natl Canc Ctr Singapore, Singapore.
    Makay, Ozer
    Ege Univ, Turkey.
    Shah, Nalini S.
    King Edward Mem Hosp, India.
    Tischler, Arthur
    Tufts Med Ctr, MA USA; Tufts Univ, MA 02111 USA.
    Leijon, Helena
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Pennelli, Gianmaria
    Univ Padua, Italy.
    Villar Gomez de las Heras, Karina
    Serv Salud Castilla La Mancha SESCAM, Spain.
    Links, Thera P.
    Univ Groningen, Netherlands.
    Bausch, Birke
    Univ Freiburg, Germany.
    Eng, Charis
    Cleveland Clin, OH 44106 USA; Cleveland Clin, OH 44106 USA.
    65 YEARS OF THE DOUBLE HELIX Genetics informs precision practice in the diagnosis and management of pheochromocytoma2018Ingår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 25, nr 8, s. T201-T219Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with amp;gt;35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.

  • 312.
    Nilsson, Cathrine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Impact of Lysosomal Function in Cancer and Apoptosis2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Programmerad celldöd eller apoptos är en viktig mekanism för att upprätthålla balans mellan kroppens celler. Vid exempelvis cancer fungerar inte styrningen av denna process, vilket leder till att för få celler dör och en tumör kan växa ohämmat. Denna avhandling fokuserar på lysosomen, en mycket sur organell i cellen som är ansvarig för nedbrytning av cellmaterial. Hos cancerceller är lysosomerna ofta förändrade. Vi har undersökt lysosomernas roll under apoptos hos normala celler och hos cancerceller. För att kunna undersöka pH-förändringar under apoptos har vi utvecklat metoder att mäta cytosoliskt och lysosomalt pH med hjälp av en teknik som kallas flödescytometri. I apoptotiska celler ser vi att det cytosoliska pH:t sjunker med 1.4 pH-enheter till pH 5.7 samtidigt som det lysosomala pH:t ökar från 4.3 till 5.5. Detta tyder på att läckage av vätejoner från lysosomerna kan orsaka en försurning av cytosolen under apoptos. Genom att studera normala orala keratinocyter och jämföra dessa mot fem olika cellinjer eeablerade från skivepitelcancer från munhåla har vi också funnit ett samband mellan det lysosomala pH:t och känsligheten för cellgiftet cisplatin. Cisplatinbehandling leder till apoptos hos alla celler men en högre dos krävs hos celler som har ett högt lysosomalt pH. Tumörer tros innehålla ett litet antal sk cancerstamceller, som har förmåga att kontinuerligt kopiera sig själva utan att åldras. Överlevnad av dessa celler tros vara orsaken till att en tumör återkommer efter en behandling. Vi visar i denna avhandling att cellinjer från skivepitelcancer innehåller celler som har cancerstamcellsegenskaper, och att dessa celler kan ha en lägre känslighet mot cisplatin jämfört med mer utvecklade cancerceller.

    Lysosomerna utgör ett intressant framtida mål för nya cancerläkemedel. I denna avhandling visar vi att förändringar i det lysosomala systemet kan påverka effekten av ett läkemedel och att skillnader mellan olika sub-populationer av celler från samma tumör kan påverka resultatet av en behandling.

    Delarbeten
    1. Analysis of cytosolic and lysosomal pH in apoptotic cells by flow cytometry
    Öppna denna publikation i ny flik eller fönster >>Analysis of cytosolic and lysosomal pH in apoptotic cells by flow cytometry
    2004 (Engelska)Ingår i: Methods in Cell Science, ISSN 1381-5741, Vol. 25, nr 3-4, s. 185-194Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Several reports indicate that the cytosol is acidified during apoptosis although the mechanism is not yet fully elucidated. The most acidic organelle found in the cell is the lysosome, raising the possibility that lysosomal proton release may contribute to the cytosolic acidification. We here describe methods for measurement of the cytosolic and lysosomal pH in U937 cells by a dual-emission ratiometric technique suitable for flow cytometry. Cytosolic pH was analysed in cells loaded with the fluorescent probe BCECF, while lysosomal pH was determined after endocytosis of FITC-dextran. Standard curves were obtained by incubating cells in buffers with different pH in the presence of the proton ionophore nigericin. Apoptosis was induced by exposure of cells to 10ng/ml TNF- for 4h, and apoptotic cells were identified using a fluorescent marker for active caspases. By gating of control and apoptotic cells, the cytosolic and lysosomal pH were calculated in each population. The cytosolic pH was found to decrease from 7.2 ± 0.1 to 5.8s±0.1 and the lysosomal increased from 4.3±0.4 to 5.2±0.3. These methods will be useful in future attempts to evaluate the involvement of lysosomes in the acidification of the cytosol during apoptosis.

    Nyckelord
    Apoptosis, Flow cytometry, Lysosomes, pH measurement
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-15134 (URN)10.1007/s11022-004-8228-3 (DOI)
    Tillgänglig från: 2008-10-17 Skapad: 2008-10-17 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    2. Cytosolic acidification and lysosomal alkalinization during TNF-α induced apoptosis in U937 cells
    Öppna denna publikation i ny flik eller fönster >>Cytosolic acidification and lysosomal alkalinization during TNF-α induced apoptosis in U937 cells
    Visa övriga...
    2006 (Engelska)Ingår i: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 11, nr 7, s. 1149-1159Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Apoptosis is often associated with acidification of the cytosol and since loss of lysosomal proton gradient and release of lysosomal content are early events during apoptosis, we investigated if the lysosomal compartment could contribute to cytosolic acidification. After exposure of U937 cells to tumor necrosis factor-α, three populations; healthy, pre-apoptotic, and apoptotic cells, were identified by flow cytometry. These populations were investigated regarding intra-cellular pH and apoptosis-associated events. There was a drop in cytosolic pH from 7.2 ± 0.1 in healthy cells to 6.8 ± 0.1 in pre-apoptotic, caspase-negative cells. In apoptotic, caspase-positive cells, the pH was further decreased to 5.7 ± 0.04. The cytosolic acidification was not affected by addition of specific inhibitors towards caspases or the mitochondrial F0F1-ATPase. In parallel to the cytosolic acidification, a rise in lysosomal pH from 4.3 ± 0.3, in the healthy population, to 4.8 ± 0.3 and 5.5 ± 0.3 in the pre-apoptotic- and apoptotic populations, respectively, was detected. In addition, lysosomal membrane permeability increased as detected as release of cathepsin D from lysosomes to the cytosol in pre-apoptotic and apoptotic cells. We, thus, suggest that lysosomal proton release is the cause of the cytosolic acidification of U937 cells exposed to TNF-α.

    Ort, förlag, år, upplaga, sidor
    Springer Netherlands, 2006
    Nyckelord
    Apoptosis, Cathepsin, Cytosolic acidification, Lysosomal alkalinization, pH, TNF-α
    Nationell ämneskategori
    Cellbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-15135 (URN)10.1007/s10495-006-7108-5 (DOI)
    Tillgänglig från: 2008-10-17 Skapad: 2008-10-17 Senast uppdaterad: 2018-10-08Bibliografiskt granskad
    3. Intrinsic differences in cisplatin sensitivity of head and neck cancer celllines correlates to lysosomal pH
    Öppna denna publikation i ny flik eller fönster >>Intrinsic differences in cisplatin sensitivity of head and neck cancer celllines correlates to lysosomal pH
    2010 (Engelska)Ingår i: Head and Neck, ISSN 1043-3074, E-ISSN 1097-0347, Vol. 32, nr 9, s. 1185-1194Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Cisplatin is part of the treatment regime of head and neck squamous cell carcinomas (HNSCC). In order to predict the clinical outcome of the treatment, markers for evaluation of the intrinsic cisplatin sensitivity are inquired. In this study we characterize the lysosomal compartment and compare cisplatin sensitivity in five HNSCC lines and normal oral keratinocytes (NOKs). Cisplatin sensitivity differed 3-fold between the least and most sensitive cell lines, and the cisplatin LD50 correlated significantly to lysosomal pH, which varied from 4.3 in NOKs to 4.9 in the most resistant HNSCC line. Lysosomes are acidified by the V0V1-ATPase complex located in the lysosomal membrane. Interestingly, in cell lines exhibiting high lysosomal pH, we found decreased expression of the V0V1-ATPase B2 subunit, possibly explaining the defective acidification. In all cell lines, exposure to cisplatin caused activation of caspase-3. Cisplatin exposure was accompanied by lysosomal membrane permeabilization and inhibition of the llysosomal cathepsins B, D and L partly prevented cell death. No correlation between cisplatin sensitivity and expression of cathepsins B, D and L or secretion of their respective proforms into the culture medium was found in the cell lines studied. We conclude that lysosomal pH and expression of V0V1-ATPase subunits are possible future markers of intrinsic cisplatin sensitivity.

    Ort, förlag, år, upplaga, sidor
    John Wiley & Sons, 2010
    Nyckelord
    apoptosis, cathepsin, chemotherapy resistance, lysosome, V0V1-ATPase
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-15136 (URN)10.1002/hed.21317 (DOI)000281528100008 ()
    Anmärkning

    The previous status of this article was Manuscript and the working title was Radiation and cisplatin sensitivity in head and neck cancer cells with stem cell properties.

    Tillgänglig från: 2008-10-17 Skapad: 2008-10-17 Senast uppdaterad: 2018-02-12Bibliografiskt granskad
    4. Intrinsic differences in cisplatin sensitivity of head and neck cancer celllines correlates to lysosomal pH
    Öppna denna publikation i ny flik eller fönster >>Intrinsic differences in cisplatin sensitivity of head and neck cancer celllines correlates to lysosomal pH
    2010 (Engelska)Ingår i: Head and Neck, ISSN 1043-3074, E-ISSN 1097-0347, Vol. 32, nr 9, s. 1185-1194Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Cisplatin is part of the treatment regime of head and neck squamous cell carcinomas (HNSCC). In order to predict the clinical outcome of the treatment, markers for evaluation of the intrinsic cisplatin sensitivity are inquired. In this study we characterize the lysosomal compartment and compare cisplatin sensitivity in five HNSCC lines and normal oral keratinocytes (NOKs). Cisplatin sensitivity differed 3-fold between the least and most sensitive cell lines, and the cisplatin LD50 correlated significantly to lysosomal pH, which varied from 4.3 in NOKs to 4.9 in the most resistant HNSCC line. Lysosomes are acidified by the V0V1-ATPase complex located in the lysosomal membrane. Interestingly, in cell lines exhibiting high lysosomal pH, we found decreased expression of the V0V1-ATPase B2 subunit, possibly explaining the defective acidification. In all cell lines, exposure to cisplatin caused activation of caspase-3. Cisplatin exposure was accompanied by lysosomal membrane permeabilization and inhibition of the llysosomal cathepsins B, D and L partly prevented cell death. No correlation between cisplatin sensitivity and expression of cathepsins B, D and L or secretion of their respective proforms into the culture medium was found in the cell lines studied. We conclude that lysosomal pH and expression of V0V1-ATPase subunits are possible future markers of intrinsic cisplatin sensitivity.

    Ort, förlag, år, upplaga, sidor
    John Wiley & Sons, 2010
    Nyckelord
    apoptosis, cathepsin, chemotherapy resistance, lysosome, V0V1-ATPase
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-15136 (URN)10.1002/hed.21317 (DOI)000281528100008 ()
    Anmärkning

    The previous status of this article was Manuscript and the working title was Radiation and cisplatin sensitivity in head and neck cancer cells with stem cell properties.

    Tillgänglig från: 2008-10-17 Skapad: 2008-10-17 Senast uppdaterad: 2018-02-12Bibliografiskt granskad
  • 313.
    Nilsson, Ulrika W.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Effects of sex steroids and tamoxifen on matrix metalloproteinase activity and generation of endostatin in the breast2007Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Sex steroids are inevitable in women. However, long-term exposure to sex steroids increases the risk of breast cancer. A complete understanding of sex steroid control of the breast and how it relates to breast cancer risk is still lacking. Angiogenesis and proteolytic enzyme activity are crucial for the process by which tumors evolve into a vascularized, invasive phenotype. Matrix metalloproteinases are potent matrixdegrading enzymes that affect several steps in tumor progression including angiogenesis. In the female reproductive organs, sex steroids regulate angiogenesis and MMP activity, yet little is known how sex steroids affect these crucial events in normal and malignant breast tissue.

    This thesis elucidates a link between sex steroids, MMP activity, and angiogenesis. It is shown that estradiol down-regulates while tamoxifen up-regulates the protein expression and activity of MMP-2 and MMP-9 in human breast cancer cells in vitro and in human breast cancer xenografts in vivo. The results further suggest that a biological consequence of this regulation may be modulation of tumor angiogenesis. The net effect of adding tamoxifen to estradiol treatment was an increase in extracellular levels of the endogenous angiogenesis inhibitor endostatin and decreased levels of the tumor promoter TGF-β1 compared to estradiol treatment only. This was accompanied by reduced vasculature and decreased tumor growth. Similarly, a regulatory effect of estradiol and tamoxifen on endostatin generation was observed in normal human breast tissue by whole-tissue culture and microdialysis in human breast tissue in situ.

    In conclusion, the results presented in this thesis suggest previously unknown mechanisms of action of estradiol and tamoxifen in breast cancer and in normal human breast tissue, and novel means by which estradiol may tip the scale to favor angiogenesis. This knowledge may be important for the understanding of sex steroid dependent breast carcinogenesis and in the future development of tissue-specific preventive as well as therapeutic strategies against breast cancer.

    Delarbeten
    1. MMP‐2 and MMP‐9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells
    Öppna denna publikation i ny flik eller fönster >>MMP‐2 and MMP‐9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells
    2007 (Engelska)Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, Vol. 102, nr 3, s. 253-261Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Sex steroids play a dominant role in breast carcinogenesis by still largely unknown mechanisms. Matrix metalloproteinases (MMPs) have been extensively studied in the context of matrix biology but it is not known if sex steroids affect MMPs in breast cancer. MMPs degrade extracellular matrix components enabling tumor cell invasion and metastasis, but may also regulate the bioavailability of a variety of biologically active molecules such as anti-angiogenic fragments, which may be beneficial for the host. This study shows that estradiol and tamoxifen regulate MMP-2 and MMP-9 as well as TIMP-1 and TIMP-2 in ER + PR + human breast cancer cells. The main finding was a significant effect of tamoxifen exposure, which increased intracellular and secreted protein levels whereas estradiol induced a significant decrease. The overall net effect of these alterations resulted in increased MMP-2/MMP-9 activity by tamoxifen treatment, which also significantly increased extracellular endostatin levels. We conclude that estradiol and tamoxifen have the ability to modulate MMP-2/MMP-9 activity, and endostatin levels in human breast cancer in vitro. The results suggest a possible role of MMP modulation associated with a generation of anti-angiogenic fragments in the therapeutic effect of tamoxifen in breast cancer.

    Nyckelord
    Breast cancer, Endostatin, Estrogen, Matrix metalloproteinases, Tamoxifen, Tissue inhibitors of matrix metalloproteinases, MCF-7 cells
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14550 (URN)10.1007/s10549-006-9335-4 (DOI)
    Tillgänglig från: 2007-05-30 Skapad: 2007-05-30 Senast uppdaterad: 2009-08-20
    2. Estradiol and tamoxifen regulate endostatin generation via matrix metalloproteinase activity in breast cancer in vivo
    Öppna denna publikation i ny flik eller fönster >>Estradiol and tamoxifen regulate endostatin generation via matrix metalloproteinase activity in breast cancer in vivo
    2006 (Engelska)Ingår i: Cancer Research, ISSN 0008-5472, Vol. 66, nr 9, s. 4789-4794Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Matrix metalloproteinases (MMP) are important regulators of tumor progression and angiogenesis. MMPs generate both proangiogenic and antiangiogenic fragments, such as vascular endothelial growth factor and endostatin. The in vivo activation of MMPs and endostatin generation occur mainly in the extracellular environment by interactions of different cell types. Therefore, these processes are necessary to study in the extracellular space in vivo. Sex steroids play a dominant role in breast carcinogenesis, by largely unknown mechanisms. In the present study, we used in vivo microdialysis to directly quantify MMP-2 and MMP-9 activity and sample endostatin from both stroma (murine) and tumor (human) cells in vivo in solid MCF-7 tumors in nude mice. We found that tamoxifen in combination with estradiol increased tumor MMP-2/MMP-9 in vivo activity, endostatin levels, and decreased tumor vascularization compared with estradiol treatment only. The stroma-derived endostatin was three to five times higher than cancer cell–generated endostatin. After inhibition of MMP-2/MMP-9, endostatin levels decreased, providing evidence that these proteases are highly involved in the generation of endostatin. Our results support the previously reported concept that MMPs may serve as negative regulators of angiogenesis. The regulation of endostatin generation by modulation of MMP-2/MMP-9 activities suggests a previously unrecognized mechanism of estradiol and tamoxifen, which may have implications for the pathogenesis of breast cancer.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14551 (URN)10.1158/0008-5472.CAN-05-4012 (DOI)
    Tillgänglig från: 2007-05-30 Skapad: 2007-05-30 Senast uppdaterad: 2009-05-28
    3. Tamoxifen downregulatesTGF‐β1 protein levels via matrix metalloproteinase activity in breast cancer in vivo
    Öppna denna publikation i ny flik eller fönster >>Tamoxifen downregulatesTGF‐β1 protein levels via matrix metalloproteinase activity in breast cancer in vivo
    2007 (Engelska)Artikel i tidskrift (Refereegranskat) Submitted
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14552 (URN)
    Tillgänglig från: 2007-05-30 Skapad: 2007-05-30
    4. Estradiol decreases endostatin levels in normal human breast tissue in vivo
    Öppna denna publikation i ny flik eller fönster >>Estradiol decreases endostatin levels in normal human breast tissue in vivo
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:liu:diva-14553 (URN)
    Tillgänglig från: 2007-05-30 Skapad: 2007-05-30 Senast uppdaterad: 2010-01-13
  • 314.
    Nordenskjold, A. E.
    et al.
    Southern Alvsborg Hospital, Sweden; Sahlgrens University Hospital, Sweden.
    Fohlin, Helena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Region Östergötland, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum. Linköpings universitet, Medicinska fakulteten. Regional Cancer Centre South East Sweden, Linkoping, Sweden.
    Albertsson, P.
    Sahlgrens University Hospital, Sweden.
    Arnesson, Lars-Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Chamalidou, C.
    Southern Alvsborg Hospital, Sweden; Sahlgrens University Hospital, Sweden.
    Einbeigi, Z.
    Sahlgrens University Hospital, Sweden.
    Holmberg, E.
    Regional Cancer Centre, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Karlsson, P.
    Sahlgrens University Hospital, Sweden.
    No clear effect of postoperative radiotherapy on survival of breast cancer patients with one to three positive nodes: a population-based study2015Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 26, nr 6, s. 1149-1154Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: In published radiotherapy trials, the failure rate in the control arm among patients with one to three positive nodes is high compared with that seen with modern adjuvant treatments. Therefore, the generalizability of the results has been questioned. The aim of the present study was to compare relative survival in breast cancer patients between two Swedish regions with screening mammography programs and adjuvant treatment guidelines similar with the exception of the indication of radiotherapy for patients with one to three positive nodes. Patients and methods: Between 1989 and 2006, breast cancer patients were managed very similarly in the west and southeast regions, except for indication for postoperative radiotherapy. In patients with one to three positive nodes, post-mastectomy radiotherapy was generally given in the southeast region (89% of all cases) and generally not given in the west region (15% of all cases). For patients with one to three positive nodes who underwent breast-conserving surgery, patients in the west region had breast radiotherapy only, while patients in the southeast region had both breast and lymph nodes irradiated. Results: The 10-year relative survival for patients with one to three positive lymph nodes was 78% in the west region and 77% in the southeast region (P = 0.12). Separate analyses depending on type of surgery, as well as number of examined nodes, also revealed similar relative survival. Conclusion: Locoregional postoperative radiotherapy has well-known side-effects, but in this population-based study, there was little or no influence of this type of radiotherapy on survival when one to three lymph nodes were involved.

  • 315.
    Nordenskjold, Anna
    et al.
    Sahlgrens Acad, Sweden; Southern Alvsborg Hospital, Sweden.
    Fohlin, Helena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Fornander, Tommy
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden; Regional Cancer Centre Stockholm Gotland, Sweden.
    Lofdahl, Britta
    St Göran Hospital, Sweden.
    Skoog, Lambert
    Karolinska University Hospital, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Progesterone receptor positivity is a predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive breast cancer2016Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 160, nr 2, s. 313-322Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The independent predictive information from progesterone receptor (PgR) positivity for breast cancer treated with tamoxifen has been questioned after an overview by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). However, the studies in the overview were to a large content performed before modern PgR immunohistochemistry (IHC) was developed. We therefore investigated the predictive value of PgR determined with IHC in estrogen receptor (ER)-positive tumors from patients participating in the Stockholm trial of adjuvant tamoxifen therapy. The Stockholm Breast Cancer Study Group conducted a randomized trial during 1976 through 1990 comparing adjuvant tamoxifen versus control. The patients were stratified according to tumor size and lymph node status in high-risk and low-risk groups. In this study, we evaluated 618 patients with ER-positive "low-risk" breast cancer (size aecurrency sign 30 mm, lymph node-negative) for whom PgR was determined by IHC at one pathology laboratory. The median time of follow-up was 21 years. Patients with ER-positive tumors that were also PgR-positive by IHC did benefit from tamoxifen, while we could not show any long-term benefit for those with tumors positive for ER only (recurrence rate ratio 0.43, 95 % CI 0.29-0.62 and 0.87, 95 % CI 0.52-1.46, respectively). We further investigated the influence of different levels of PgR positivity on recurrence risk. The results show that at all receptor levels with aeyen10 % stained PgR-positive cells, the patients did benefit from tamoxifen. There was no clear linear trend in benefit with increasing proportion of stained cells. PgR positivity determined by IHC is a marker indicating long-term benefit from adjuvant tamoxifen in patients with ER-positive tumors.

  • 316.
    Nordgren, Anders
    Linköpings universitet, Institutionen för kultur och kommunikation, Avdelningen för kulturvetenskaper, KVA. Linköpings universitet, Filosofiska fakulteten.
    First-in-human trials on genome editing: Strategies for handling uncertainty about benefit and uncertainty about harm2017Konferensbidrag (Refereegranskat)
    Abstract [en]

    Human genome editing can be carried out on somatic cells as well as on the germline. In this paper I discuss first-in-human trials on both types of editing. At first sight, risk and risk/benefit assessment might seem to be key issues in such trials. However, according to decision theory, risk presupposes numerical values. In ‘decision-making under risk’, decisionmakers have sufficient information to assign probabilities to alternative outcomes. This is not the case in first-in-human trials. These trials are rather characterized by ‘decision-making under uncertainty’. My overall objective is to clarify the implications of uncertainty about benefit and uncertainty about harm in first-in-human trials on genome editing. A special aim is to analyse strategies for handling uncertainty.

  • 317.
    Nordlund, Lars Anders
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    Pershagen, Göran
    Karolinska institutet, Stockholm.
    Are male and female smokers at equal risk of smoking-related cancer: evidence from a Swedish prospective study1999Ingår i: Scandinavian Journal of Public Health, ISSN 1403-4948, E-ISSN 1651-1905, Vol. 27, nr 1, s. 56-62Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study examines sex differences in the relative risks of lung cancer and other smoking-related cancers (i.e. cancers of the upper respiratory tract, oesophagus, pancreas, bladder, and renal pelvis). Data on smoking habits in 1963 from a random sample of 56,000 men and women were linked with information on new cases of cancer for 1964-89. Compared with people who have never smoked, the relative risks of lung cancer at different levels of pack-years completed in 1963 (>5, 6-15, 16-25 and 25 + pack-years) were 1.6, 4.4, 14.2, and 17.9 for men, and 2.1, 6.3, 10.3, and 16.5 for women. The corresponding relative risks of other smoking-related cancers were 1.8, 3.0 5.4, and 6.4 for men, and 2.0, 3.1, 5.0, and 6.5 for women. These results suggest that men and women have similar relative risks of smoking-related cancers at different levels of smoking.

  • 318.
    Nordlund, Lars Anders
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    Pershagen, Göran
    Karolinska institutet, Stockholm.
    Cancer incidence in female smokers: a 26-year follow-up1997Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 73, nr 5, s. 625-628Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A random sample of 26,000 Swedish women who were asked about their smoking habits in the early 1960s have now been followed for 26 years with respect to cancer incidence. Most findings regarding tobacco smoking and cancer from studies of men were confirmed also among the women. Elevated relative risk for current smokers compared with women who never smoked regularly were seen for cancers of the lung, upper aerodigestive sites, pancreas, bladder, cervix and all cancers combined, as well as a notably high relative risk for cancers of organs of the urinary tract other than kidney and bladder. Relative risk increased with dose, measured as grams of tobacco smoked per day, for cancers of the upper aerodigestive sites, lung, cervix, bladder, organs of the urinary tract other than kidney and bladder and all cancers combined. For cancers of the lung, bladder and cervix, there was an inverse relationship with age when starting to smoke tobacco. The reported inverse relationship between smoking and endometrial cancer could not be corroborated, nor was there any significant relationship between smoking and colorectal or breast cancer.

  • 319.
    Oliva, Delmy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Prediction of side effects from anticancer treatment with the purpose of increasing quality of life2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Cancer and its treatments can cause a variety of symptoms. Some of these symptoms are related to the disease and others are seen as a consequence of the treatment. Since patients experience side effects to different degrees despite undergoing the same treatment, it is hypothesized that there is a genetic factor. The individual variation that exists between different patients regarding nausea triggered by chemotherapy, radiotherapy induced skin reactions as well as sleep disorders associated with cancer could partly be explained by genetic differences. We have in these studies confirmed these individual differences. Previous nursing research has mainly focused on the symptoms themselves. The focus in this thesis are the following three main symptoms; nausea and vomiting related to chemotherapy, acute skin inflammation following radiotherapy and sleep problems associated with cancer diagnosis and -treatment.

    The aim of this thesis was to find biological markers that can identify the risk of and/or protective factors for nausea and/or vomiting (CINV) as well as understand its heterogeneity (Study 1 and 2). It also aimed to understand the individual factors behind acute radiation skin reactions (ARSR) (Study 3) and sleeping disturbances in patients treated for cancer (Study 4), permitting a more individualized care and optimized health-related quality of life (HRQoL).

    In Study 1 and 2 the patients themselves had to document in a diary their experience of nausea and vomiting and well-being. Well-being was considered as synonymous with quality of life. We found a variability and heterogeneity of those symptoms (Study 1). Three genetic markers, FAS/CD95, RB1/LPAR6 and CCL2 that could explain the individual differences and assess the risk of chemotherapy-induced nausea were found in Study 2.

    Acute radiation skin reactions (ARSR) along with itching and burning sensation associated with radiotherapy (RT) was assessed by the patients themselves (Study 3) with help of the VAS- and RTOG scales, scoring for visible redness. We found two possible genetic markers, XRCC2 and IFNG. Also, individual differences in symptoms behavior were found.

    Sleep disturbances were common and were reported with obvious individual differences [1]. For data collection were used a sleep questionnaire, the Medical Outcomes Study Sleep Scale (MOS), open ended questions and EORTC QLQ- C30 questionnaire of quality of life. Sleep, which is important for all primary body functions, is often affected in connection with cancer diagnosis and -treatment.

    Through collaboration between nursing staff and specialists in basic science, we have found that biological markers can help in creating individualized care. Knowledge of individual variations in the severity of chemo- or radiotherapy-induced side effects is important in order to better personalize the treatment and care, improve the treatment results and alleviate or prevent the side effects of oncological treatments. By linking symptoms to biological markers, it will hopefully be able to increase the patients’ total health-related quality of life, this being the main goal of this thesis.

    Delarbeten
    1. Variations in Self-Reported Nausea, Vomiting, and Well-Being During the First 10 Days Postchemotherapy in Women With Breast Cancer
    Öppna denna publikation i ny flik eller fönster >>Variations in Self-Reported Nausea, Vomiting, and Well-Being During the First 10 Days Postchemotherapy in Women With Breast Cancer
    2014 (Engelska)Ingår i: Clinical Journal of Oncology Nursing, ISSN 1092-1095, E-ISSN 1538-067X, Vol. 18, nr 2, s. E32-E36Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Women with breast cancer undergoing chemotherapy experience nausea and vomiting, both common symptoms affecting quality of life. The aim of the current study was to describe how nausea, vomiting, and well-being vary during the first 10 days after chemotherapy in women with breast cancer. A pilot study with a repeated-measurements design was conducted at a Swedish county hospital where 39 women with breast cancer treated with adjuvant chemotherapy were observed. A structured 10-day diary was used for data collection. Of the 39 women in the study, 33 experienced nausea and 6 also experienced vomiting after chemotherapy. Changes in well-being as a result of nausea or vomiting during any part of the day, as well as distress for other reasons, were reported. Well-being also varied among the individuals. The pattern of change in experienced levels of well-being was not homogeneous, nor did it move in any certain direction. The results of this study show that an individualized treatment approach is required to better meet individual women's needs.

    Ort, förlag, år, upplaga, sidor
    Pittsburgh: Oncology Nursing Society, 2014
    Nationell ämneskategori
    Omvårdnad Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-162105 (URN)10.1188/14.CJON.E32-E36 (DOI)
    Tillgänglig från: 2019-11-19 Skapad: 2019-11-19 Senast uppdaterad: 2019-11-20Bibliografiskt granskad
    2. Single nucleotide polymorphisms might influence chemotherapy induced nausea in women with breast cancer
    Öppna denna publikation i ny flik eller fönster >>Single nucleotide polymorphisms might influence chemotherapy induced nausea in women with breast cancer
    Visa övriga...
    2017 (Engelska)Ingår i: Clinical and Translational Radiation Oncology, ISSN 2405-6308, Vol. 2, s. 1-6Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background Women receiving FEC (5 fluorouracil, epirubicin and cyclophosphamide) chemotherapy (CT) for breast cancer (BC) often experience side effects such as nausea and vomiting. Individual variations of side effects occur in patients despite similar cancer therapy. The purpose of this study was to investigate a possible genetic background as a predictor for individual variations in nausea induced by CT. Methods 114 women were included in the study. All women received adjuvant CT for BC. Self-reported nausea and vomiting was recorded in a structured diary over ten days following treatment. Blood samples were collected before the treatment and used for the detection of 48 single nucleotide polymorphisms (SNPs) in 43 genes. SNPs from each individual woman were analyzed for their relation to the patient-reported frequency and intensity of nausea and vomiting. Results Eighty-four percent (n=96) of the women reported acute or delayed nausea or combined nausea and vomiting during the ten days following CT. Three out of the forty-eight SNPs in the following genes: FAS/CD95, RB1/LPAR6 and CCL2 were found to be associated with a risk of nausea. Conclusion SNPs in the FAS/CD95, RB1/LPAR6 and CCL2 genes were found to be associated with nausea among women treated with adjuvant FEC for BC. SNPs analysis is fast and cost effective and can be done prior to any cancer therapy. The association between individual SNPs and severe side effects from FEC may contribute to a more personalized care of patients with BC.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2017
    Nyckelord
    Single nucleotide polymorphisms, Chemotherapy, Nausea, Breast cancer
    Nationell ämneskategori
    Omvårdnad Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-162106 (URN)10.1016/j.ctro.2016.12.001 (DOI)
    Tillgänglig från: 2019-11-19 Skapad: 2019-11-19 Senast uppdaterad: 2019-11-20Bibliografiskt granskad
    3. Individual Genetic Variation Might Predict Acute Skin Reactions in Women Undergoing Adjuvant Breast Cancer Radiotherapy
    Öppna denna publikation i ny flik eller fönster >>Individual Genetic Variation Might Predict Acute Skin Reactions in Women Undergoing Adjuvant Breast Cancer Radiotherapy
    Visa övriga...
    2018 (Engelska)Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 38, nr 12, s. 6763-6770Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Adverse skin reactions during radiotherapy (RT) are common. The aim of this study was to explore whether genetic variation might be linked to acute radiation skin reactions (ARSR). Materials and Methods: One hundred and nineteen women undergoing adjuvant RT for breast cancer were included. The symptoms of itching, burning and irritation were self-reported twice using the visual analogue scale. Assessments used the Radiation Therapy Oncology Group scoring system for acute RT skin reaction (RTOG scale). Blood-based single nucleotide polymorphism (SNP) analysis was performed. Thirty SNPs of well-defined functional genes were investigated. Results: All women were assessed with ARSR. After RT, the women self-reported itching (n=97), burning (n=64) and irritation (n=96). Two SNPs in X-Ray Repair Cross Complementing 2 gene (XRCC2) rs2040639 and interferon gamma (IFNG) rs2069705 genes were found to be associated with ARSR. Conclusion: An association between two SNPs and ARSR was found. The possibility of using these SNPs as prognostic biomarkers for ARSR as tools to improve the care of patients needs further investigation.

    Ort, förlag, år, upplaga, sidor
    The International Institute of Anticancer Research, 2018
    Nyckelord
    Radiotherapy; breast cancer; skin reactions; single nucleotide polymorphism
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-153515 (URN)10.21873/anticanres.13047 (DOI)000451742800022 ()30504388 (PubMedID)
    Anmärkning

    Funding Agencies|Uppsala University; Knut & Alice Wallenberg Foundation of Uppsala, Sweden; Foundation for Clinical Cancer Research in Jonkoping; Futurum Academy for Health and Care, Region Jonkoping County, Sweden; FORSS-Medical Research Council of Southeast Sweden

    Tillgänglig från: 2019-01-02 Skapad: 2019-01-02 Senast uppdaterad: 2019-11-20Bibliografiskt granskad
  • 320.
    Oliva, Delmy
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Department of Oncology, Ryhov County Hospital, SE-551 85 Jönköping, Sweden.
    Nilsson, Mats
    Futurum – The Academy for Healthcare, Region Jönköping County, SE-551 85 Jönköping, Sweden.
    Andersson, Bengt-Åke
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Division of Medical Diagnostics, Region Jönköping County, SE-551 85 Jönköping, Sweden.
    Sharp, Lena
    Regional Cancer Centre, Stockholm-Gotland, SE-10239 Stockholm, Sweden / Karolinska Institutet, Department of Learning, Informatics Management and Ethics, SE-171 77 Stockholm, Sweden.
    Lewin, Freddi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Department of Oncology, Ryhov County Hospital, SE-551 85 Jönköping, Sweden.
    Laytragoon-Lewin, Nongnit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Single nucleotide polymorphisms might influence chemotherapy induced nausea in women with breast cancer2017Ingår i: Clinical and Translational Radiation Oncology, ISSN 2405-6308, Vol. 2, s. 1-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Women receiving FEC (5 fluorouracil, epirubicin and cyclophosphamide) chemotherapy (CT) for breast cancer (BC) often experience side effects such as nausea and vomiting. Individual variations of side effects occur in patients despite similar cancer therapy. The purpose of this study was to investigate a possible genetic background as a predictor for individual variations in nausea induced by CT. Methods 114 women were included in the study. All women received adjuvant CT for BC. Self-reported nausea and vomiting was recorded in a structured diary over ten days following treatment. Blood samples were collected before the treatment and used for the detection of 48 single nucleotide polymorphisms (SNPs) in 43 genes. SNPs from each individual woman were analyzed for their relation to the patient-reported frequency and intensity of nausea and vomiting. Results Eighty-four percent (n=96) of the women reported acute or delayed nausea or combined nausea and vomiting during the ten days following CT. Three out of the forty-eight SNPs in the following genes: FAS/CD95, RB1/LPAR6 and CCL2 were found to be associated with a risk of nausea. Conclusion SNPs in the FAS/CD95, RB1/LPAR6 and CCL2 genes were found to be associated with nausea among women treated with adjuvant FEC for BC. SNPs analysis is fast and cost effective and can be done prior to any cancer therapy. The association between individual SNPs and severe side effects from FEC may contribute to a more personalized care of patients with BC.

  • 321.
    Oliva, Delmy
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Department of Oncology, Ryhov County Hospital, Jönköping, Sweden .
    Nilsson, Mats
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Futurum-The Academy for Healthcare, Region Jönköping County, Jönköping, Sweden.
    Strandeus, Michael
    Department of Oncology, Ryhov County Hospital, Jönköping, Sweden.
    Andersson, Bengt-Åke
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Department of Laboratory medicine, Region Jönköping County, Jönköping, Sweden.
    Sharp, Lena
    Regional Cancer Centre, Stockholm-Gotland, Stockholm, Sweden / Department of Learning, Informatics, Management and Ethics, Karolinska Institute, Stockholm, Sweden .
    Lewin, Nongnit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Department of Laboratory medicine, Region Jönköping County, Jönköping, Sweden.
    Lewin, Freddi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Department of Oncology, Ryhov County Hospital, Jönköping, Sweden.
    Individual Genetic Variation Might Predict Acute Skin Reactions in Women Undergoing Adjuvant Breast Cancer Radiotherapy2018Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 38, nr 12, s. 6763-6770Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adverse skin reactions during radiotherapy (RT) are common. The aim of this study was to explore whether genetic variation might be linked to acute radiation skin reactions (ARSR). Materials and Methods: One hundred and nineteen women undergoing adjuvant RT for breast cancer were included. The symptoms of itching, burning and irritation were self-reported twice using the visual analogue scale. Assessments used the Radiation Therapy Oncology Group scoring system for acute RT skin reaction (RTOG scale). Blood-based single nucleotide polymorphism (SNP) analysis was performed. Thirty SNPs of well-defined functional genes were investigated. Results: All women were assessed with ARSR. After RT, the women self-reported itching (n=97), burning (n=64) and irritation (n=96). Two SNPs in X-Ray Repair Cross Complementing 2 gene (XRCC2) rs2040639 and interferon gamma (IFNG) rs2069705 genes were found to be associated with ARSR. Conclusion: An association between two SNPs and ARSR was found. The possibility of using these SNPs as prognostic biomarkers for ARSR as tools to improve the care of patients needs further investigation.

  • 322.
    Oliva, Delmy
    et al.
    Department of Oncology, Ryhov County Hospital, Jönköping, Sweden.
    Sandgren, Anna
    School of Health Sciences, Jönköping University, Jönköping, Sweden.
    Nilsson, Mats
    Futurum–the Academy for Healthcare, Jönköping County Council, Jönköping, sweden.
    Lewin, Freddi
    Department of Oncology, Ryhov County Hospital, Jönköping, Sweden.
    Variations in Self-Reported Nausea, Vomiting, and Well-Being During the First 10 Days Postchemotherapy in Women With Breast Cancer2014Ingår i: Clinical Journal of Oncology Nursing, ISSN 1092-1095, E-ISSN 1538-067X, Vol. 18, nr 2, s. E32-E36Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Women with breast cancer undergoing chemotherapy experience nausea and vomiting, both common symptoms affecting quality of life. The aim of the current study was to describe how nausea, vomiting, and well-being vary during the first 10 days after chemotherapy in women with breast cancer. A pilot study with a repeated-measurements design was conducted at a Swedish county hospital where 39 women with breast cancer treated with adjuvant chemotherapy were observed. A structured 10-day diary was used for data collection. Of the 39 women in the study, 33 experienced nausea and 6 also experienced vomiting after chemotherapy. Changes in well-being as a result of nausea or vomiting during any part of the day, as well as distress for other reasons, were reported. Well-being also varied among the individuals. The pattern of change in experienced levels of well-being was not homogeneous, nor did it move in any certain direction. The results of this study show that an individualized treatment approach is required to better meet individual women's needs.

  • 323.
    Olofsson, Roger
    et al.
    University of Gothenburg, Sweden .
    Ny, Lars
    University of Gothenburg, Sweden .
    Sternby Eilard, Malin
    University of Gothenburg, Sweden .
    Rizell, Magnus
    University of Gothenburg, Sweden .
    Cahlin, Christian
    University of Gothenburg, Sweden .
    Stierner, Ulrika
    University of Gothenburg, Sweden .
    Lönn, Ulf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Hansson, Johan
    Karolinska University Hospital, Sweden .
    Ljuslinder, Ingrid
    Norrlands University Hospital, Sweden .
    Lundgren, Lotta
    Skåne University Hospital, Sweden .
    Ullenhag, Gustav
    Uppsala University, Sweden .
    Folke Kiilgaard, Jens
    University of Copenhagen, Denmark .
    Nilsson, Jonas
    University of Gothenburg, Sweden .
    Lindner, Per
    University of Gothenburg, Sweden .
    Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases (the SCANDIUM trial): study protocol for a randomized controlled trial2014Ingår i: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 15, nr 317Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of patients, with the liver being the most common site for metastases. The median survival for patients with liver metastases is between 6 and 12 months, and no treatment has in randomized trials ever been shown to prolong survival. A previous phase II trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival compared with a historic control group consisting of the longest surviving patients in Sweden during the same time period (26 versus 12 months). Methods/Design: This is the protocol for a multicenter phase III trial randomizing patients with isolated liver metastases of uveal melanoma to IHP or best alternative care (BAC). Inclusion criteria include liver metastases (verified by biopsy) and no evidence of extra-hepatic tumor manifestations by positron emission tomography-computed tomography (PET-CT). The primary endpoint is overall survival at 24 months, with secondary endpoints including response rate, progression-free survival, and quality of life. The planned sample size is 78 patients throughout five years. Discussion: Patients with isolated liver metastases of uveal melanoma origin have a short expected survival and no standard treatment option exists. This is the first randomized clinical trial to evaluate IHP as a treatment option with overall survival being the primary endpoint.

  • 324.
    Olsson, Erik
    et al.
    Göteborgs universitet.
    Eckerström, Carl
    Göteborgs universitet.
    Berg, Gertrud
    Göteborgs universitet.
    Borga, Magnus
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatik. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Tekniska högskolan.
    Ekholm, Sven
    University of Rochester.
    Johannsson, Gudmundur
    Göteborgs universitet.
    Ribbelin, Susanne
    Göteborgs universitet.
    Starck, Görgan
    Göteborgs universitet.
    Wysocka, Anna
    Göteborgs universitet.
    Löfdahl, Elisabet
    Göteborgs universitet.
    Malmgren, Helge
    Göteborgs universitet.
    Hippocampal volumes in patients exposed to low-dose radiation to the basal brain: a case–control study in long-term survivors from cancer in the head and neck region2012Ingår i: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 7, nr 202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    An earlier study from our group of long time survivors of head and neck cancer who had received a low radiation dose to the hypothalamic-pituitary region, with no signs of recurrence or pituitary dysfunction, had their quality of life (QoL) compromised as compared with matched healthy controls. Hippocampal changes have been shown to accompany several psychiatric conditions and the aim of the present study was to test whether the patients’ lowered QoL was coupled to a reduction in hippocampal volume.

    Methods

    Patients (11 men and 4 women, age 31–65) treated for head and neck cancer 4–10 years earlier and with no sign of recurrence or pituitary dysfunction, and 15 matched controls were included. The estimated radiation doses to the basal brain including the hippocampus (1.5 – 9.3 Gy) had been calculated in the earlier study. The hippocampal volumetry was done on coronal sections from a 1.5 T MRI scanner. Measurements were done by two independent raters, blinded to patients and controls, using a custom method for computer assisted manual segmentation. The volumes were normalized for intracranial volume which was also measured manually. The paired t test and Wilcoxon’s signed rank test were used for the main statistical analysis.

    Results

    There was no significant difference with respect to left, right or total hippocampal volume between patients and controls. All mean differences were close to zero, and the two-tailed 95% confidence interval for the difference in total, normalized volume does not include a larger than 8% deficit in the patients.

    Conclusion

    The study gives solid evidence against the hypothesis that the patients’ lowered quality of life was due to a major reduction of hippocampal volume.

  • 325.
    Pagella, Pierfrancesco
    et al.
    Orofacial Development & Regeneration, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Cantù, Claudio
    Orofacial Development & Regeneration, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Mitsiadis, Thimios A.
    Orofacial Development & Regeneration, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Linking dental pathologies and cancer via Wnt signalling2017Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 59, s. 99213-99214Artikel i tidskrift (Refereegranskat)
  • 326.
    Palmebäck Wegman, Pia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Studies of tamoxifen resistance in breast cancer2007Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Oestrogen is one of the most important hormonal regulators and is known to play a key role in the development and growth of breast cancer. The majority of tumours have a hormone dependent growth, and this is indicated by the presence of oestrogen receptors (ERs). About two thirds of breast cancers occur after the menopause when the ovaries have ceased to produce oestrogen and despite the low levels of circulating oestrogen’s the tumour concentrations of oestrone, oestradiol and their sulfates have been shown to be significant. Patients with hormone dependent tumours are candidates for treatment with the anti-oestrogen tamoxifen, which acts by competing with oestrogen for binding to the ER thereby, diminish the transcription of oestrogen regulated genes. The drug is mainly metabolised by cytochrome P450 enzymes in the liver and to a lesser extent locally in the breast, where upon several produced metabolites have higher affinity for the ER than the mother substance. Patients treated with tamoxifen have in general a prolonged disease-free survival. Even if most patients respond well to tamoxifen about 30-50 % either fail to respond or become resistant by incompletely understood mechanisms. Therefore, the aim of this thesis was to investigate possible mechanisms responsible for tamoxifen resistance. In paper I and II we studied genetic variants of enzymes participating in the metabolism of tamoxifen and assessed whether these variants correlated to breast cancer prognosis and/or to the benefit of tamoxifen. The results indicate an influence of CYP2D6, CYP3A5, and SULT1A1 genotypes in tamoxifen response. Further, tamoxifen has shown to compete with oestrogen for the binding to ER. In paper III we measured the expression levels of enzymes involved in the local synthesis of oestrogens in order to see if they correlated to clinical outcome. The protein expression of stromal aromatase was shown to have a prognostic significance, especially in ER-positive patients. Finally, tamoxifen and its ER-active metabolites have shown to induce both cell cycle arrest and apoptosis and one central mediator in these processes is the tumour suppressor protein p53. The proapoptotic activity of p53 is dependent on a proline rich domain containing a common Pro-to-Arg polymorphism. In paper IV we examined the value of this genetic variant as a predictive marker for anti-cancer therapy and found that patients carrying the Pro-allele might be good responders of tamoxifen therapy. The present thesis further indicates the complexity of the mechanisms underlying tamoxifen resistance. In summary, genetic variants of metabolic enzymes, genetic variants in p53, as well as expression levels of enzymes involved in local oestrogen synthesis, may have influence on breast cancer prognosis and may be useful markers in the prediction of tamoxifen response.

    Delarbeten
    1. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients
    Öppna denna publikation i ny flik eller fönster >>Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients
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    2005 (Engelska)Ingår i: Breast Cancer Research, ISSN 1465-5411, Vol. 7, nr 3, s. R284-R290Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background

    Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy.

    Methods

    The patients were genotyped using PCR followed by cleavage with restriction enzymes.

    Results

    Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11–0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21–1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19–0.74, P = 0.0041).

    Conclusion

    The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.

    Nyckelord
    breast cancer, CYP2D6, polymorphism, SULT1A1, tamoxifen
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14534 (URN)10.1186/bcr993 (DOI)
    Anmärkning

    Original Publication: Pia Wegman, Linda Vainikka, Olle Stål, Bo Nordenskjöld, Lambert Skoog, Lars-Erik Rutqvist and Sten Wingren, Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients, 2005, Breast Cancer Research, (7), R284-290. http://dx.doi.org/10.1186/bcr993 Licensed by: CURRENT SCIENCE LTD

    Tillgänglig från: 2009-02-22 Skapad: 2009-02-22 Senast uppdaterad: 2018-02-06Bibliografiskt granskad
    2. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal breast cancer patients
    Öppna denna publikation i ny flik eller fönster >>Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal breast cancer patients
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    2007 (Engelska)Ingår i: Breast Cancer Research, ISSN 1465-5411, Vol. 9, nr 1, s. R7-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Introduction

    Tamoxifen therapy reduces the risk of recurrence and prolongs the survival of oestrogen-receptor-positive patients with breast cancer. Even if most patients benefit from tamoxifen, many breast tumours either fail to respond or become resistant. Because tamoxifen is extensively metabolised by polymorphic enzymes, one proposed mechanism underlying the resistance is altered metabolism. In the present study we investigated the prognostic and/or predictive value of functional polymorphisms in cytochrome P450 3A5 CYP3A5 (*3), CYP2D6 (*4), sulphotransferase 1A1 (SULT1A1; *2) and UDP-glucuronosyltransferase 2B15 (UGT2B15; *2) in tamoxifen-treated patients with breast cancer.

    Methods

    In all, 677 tamoxifen-treated postmenopausal patients with breast cancer, of whom 238 were randomised to either 2 or 5 years of tamoxifen, were genotyped by using PCR with restriction fragment length polymorphism or PCR with denaturing high-performance liquid chromatography.

    Results

    The prognostic evaluation performed in the total population revealed a significantly better disease-free survival in patients homozygous for CYP2D6*4. For CYP3A5, SULT1A1 and UGT2B15 no prognostic significance was observed. In the randomised group we found that for CYP3A5, homozygous carriers of the *3 allele tended to have an increased risk of recurrence when treated for 2 years with tamoxifen, although this was not statistically significant (hazard ratio (HR) = 2.84, 95% confidence interval (CI) = 0.68 to 11.99, P = 0.15). In the group randomised to 5 years' tamoxifen the survival pattern shifted towards a significantly improved recurrence-free survival (RFS) among CYP3A5*3-homozygous patients (HR = 0.20, 95% CI = 0.07 to 0.55, P = 0.002). No reliable differences could be seen between treatment duration and the genotypes of CYP2D6, SULT1A1 or UGT2B15. The significantly improved RFS with prolonged tamoxifen treatment in CYP3A5*3 homozygotes was also seen in a multivariate Cox model (HR = 0.13, CI = 0.02 to 0.86, P = 0.03), whereas no differences could be seen for CYP2D6, SULT1A1 and UGT2B15.

    Conclusion

    The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely to be explained by a single polymorphism; instead it is a combination of several mechanisms. However, the present data suggest that genetic variation in CYP3A5 may predict response to tamoxifen therapy.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14535 (URN)10.1186/bcr1640 (DOI)
    Anmärkning

    Original Publication: Pia Wegman, Sauli Elingarami, John Carstensen, Olle Stål, Bo Nordenskjöld and Sten Wingren, Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal breast cancer patients, 2007, Breast Cancer Research, (9), R7. http://dx.doi.org/10.1186/bcr1640 Licensed by: CURRENT SCIENCE LTD

    Tillgänglig från: 2009-02-22 Skapad: 2009-02-22 Senast uppdaterad: 2018-02-12Bibliografiskt granskad
    3. In situ levels of oestrogen producing enzymes and its prognostic significance in tamoxifen treated postmenopausal breast cancer patients
    Öppna denna publikation i ny flik eller fönster >>In situ levels of oestrogen producing enzymes and its prognostic significance in tamoxifen treated postmenopausal breast cancer patients
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    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:liu:diva-14536 (URN)
    Tillgänglig från: 2007-06-01 Skapad: 2007-06-01 Senast uppdaterad: 2010-01-13
    4. p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients
    Öppna denna publikation i ny flik eller fönster >>p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients
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    2006 (Engelska)Ingår i: Pharmacogenetics and Genomics, ISSN 1744-6872, Vol. 16, nr 5, s. 347-351Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Adjuvant therapy of breast cancer patients reduces the risk of recurrence and mortality, although, a substantial proportion of patients acquire resistance and relapse in the disease. Predictors of therapeutic response are therefore important to avoid both therapy resistance and the side effects of inefficient regimes. The p53 protein is a key determinant to induce either growth arrest or apoptosis in response to cytotoxic stress.

     

    Methods: In the search for predictive markers of cancer therapy we investigated a common Arg72/Pro72 polymorphism in the p53 gene, which has been shown to influence the apoptotic potential. Using PCR and RFLP we genotyped 220 breast cancer patients randomized to radiotherapy versus chemotherapy and tamoxifen versus no tamoxifen.

     

    Results: Oestrogen-receptor positive patients possessing at least one Pro72 allele had better distant recurrence-free survival when randomized to tamoxifen compared to those who were not (P=0.0033), as also demonstrated by the significantly decreased hazard ratio (HR=0.28, 95% CI 0.12–0.65). Among patients homozygous for the Arg72 genotype the outcome was approximately equal between tamoxifen treated and non-tamoxifen treated patients (P=0.65). When the calculated hazard ratios for the genotypes were compared by an interaction test a significant difference was found (P=0.0088).

     

    Conclusion: The present report indicates that the codon 72 polymorphism in the p53 gene may be a predictor of tamoxifen response, suggesting that breast cancer patients lacking the Pro72 allele might be candidates for other therapies.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14537 (URN)10.1097/01.fpc.0000204997.84182.69 (DOI)
    Tillgänglig från: 2007-06-01 Skapad: 2007-06-01 Senast uppdaterad: 2013-03-28
  • 327.
    Panigrahi, Soumya
    et al.
    Department of Physiology, University of Manitoba, Winnipeg, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada, .
    Klonisch, Thomas
    Department of Human Anatomy and Cell Sciences, and Manitoba Institute of Child Health, Winnipeg, Canada.
    Los, Marek Jan
    BioApplications Enterprises, Winnipeg, MB, Canada.
    The art of killing: double stroke with apoptin and survivin as a novel approach in cancer therapy2008Ingår i: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 7, nr 7, s. 1061-1062Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Commentary to:

    Survivin knockdown combined with apoptin overexpression inhibits cell growth significantly

     

  • 328.
    Pathak, Surajit
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Meng, Wen-Jian
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Sichuan University, Peoples R China.
    Kumar Nandy, Suman
    University of Kalyani, India.
    Ping, Jie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Bisgin, Atil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Helmfors, Linda
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Waldmann, Patrik
    Linköpings universitet, Institutionen för datavetenskap, Statistik. Linköpings universitet, Filosofiska fakulteten.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Radiation and SN38 treatments modulate the expression of microRNAs, cytokines and chemokines in colon cancer cells in a p53-directed manner2015Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 42, s. 44758-44780Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aberrant expression of miRNAs, cytokines and chemokines are involved in pathogenesis of colon cancer. However, the expression of p53 mediated miRNAs, cyto- and chemokines after radiation and SN38 treatment in colon cancer remains elusive. Here, human colon cancer cells, HCT116 with wild-type, heterozygous and a functionally null p53, were treated by radiation and SN38. The expression of 384 miRNAs was determined by using the TaqMan (R) miRNA array, and the expression of cyto- and chemokines was analyzed by Meso-Scale-Discovery instrument. Up- or down-regulations of miRNAs after radiation and SN38 treatments were largely dependent on p53 status of the cells. Cytokines, IL-6, TNF-alpha, IL-1 beta, Il-4, IL-10, VEGF, and chemokines, IL-8, MIP-1 alpha were increased, and IFN-gamma expression was decreased after radiation, whereas, IL-6, IFN-gamma, TNF-alpha, IL-1 beta, Il-4, IL-10, IL-8 were decreased, and VEGF and MIP-1 alpha were increased after SN38 treatment. Bioinformatic analysis pointed out that the highly up-regulated miRNAs, let-7f-5p, miR-455-3p, miR-98, miR-155-5p and the down-regulated miRNAs, miR-1, miR-127-5p, miR-142-5p, miR-202-5p were associated with colon cancer pathways and correlated with cyto- or chemokine expression. These miRNAs have the potential for use in colon cancer therapy as they are related to p53, pro- or anti-inflammatory cyto- or chemokines after the radiation and SN38 treatment.

  • 329.
    Pathak, Surajit
    et al.
    Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India.
    S, Sushmitha
    Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India.
    Banerjee, Antara
    Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India.
    Marotta, Francesco
    ReGenera Research Group for Aging-Intervention, Milano, Italy and San Babila Clinic, Healthy Aging Unit by Genomics and Biotechnology, Milano, Italy.
    Gopinath, Madhumala
    Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India.
    Murugesan, Ramachandran
    Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India.
    Zhang, Hong
    School of Medicine, Orebro University, Örebro, Sweden.
    B, Bhavani
    Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India.
    Girigoswami, Agnishwar
    Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India.
    Sollano, Jose
    Gastroenterology Department, University of Santo Tomas, Manila, The Philippines.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Review on comparative efficacy of bevacizumab, panitumumab and cetuximab antibody therapy with combination of FOLFOX-4 in KRAS-mutated colorectal cancer patients2018Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, nr 7, s. 7739-7748Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Colorectal cancer, fourth leading form of cancer worldwide and is increasing in alarming rate in the developing countries. Treating colorectal cancer has become a big challenge worldwide and several antibody therapies such as bevacizumab, panitumumab and cetuximab are being used with limited success. Moreover, mutation in KRAS gene which is linked with the colorectal cancer initiation and progression further interferes with the antibody therapies. Considering median progression free survival and overall survival in account, this review focuses to identify the most efficient antibody therapy in combination with chemotherapy (FOLFOX-4) in KRAS mutated colorectal cancer patients. The bevacizumab plus FOLFOX-4 therapy shows about 9.3 months and 8.7 months of progression free survival for KRAS wild and mutant type, respectively. The overall survival is about 34.8 months for wild type whereas for the mutant it is inconclusive for the same therapy. In comparison, panitumumab results in better progression-free survival which is about (9.6 months) and overall survival is about (23.9 months) for the wild type KRAS and the overall survival is about 15.5 months for the mutant KRAS. Cetuximab plus FOLFOX-4 therapy shows about 7.7 months and 5.5 months of progression-free survival for wild type KRAS and mutant type, respectively. Thus, panitumumab shows significant improvement in overall survival rate for wild type KRAS, validating as a cost effective therapeutic for colorectal cancer therapy. This review depicts that panitumumab along with FOLFOX-4 has a higher response in colorectal cancer patients than the either of the two monoclonal antibodies plus FOLFOX-4.

  • 330.
    Pathak, Surajit
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. West China Hospital, Sichuan University, Chengdu, China.
    Zhang, Hong
    Örebro University, Örebro, Sweden.
    Gnosa, Sebastian
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Kumar Nandy, Suman
    Kalyani University, Kalyani, West Bengal, India.
    Adell, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Tafazzin protein expression is associated with tumorigenesis and radiation response in rectal cancer: a study of Swedish clinical trial on preoperative radiotherapy.2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 5, s. e98317-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Tafazzin (TAZ), a transmembrane protein contributes in mitochondrial structural and functional modifications through cardiolipin remodeling. TAZ mutations are associated with several diseases, but studies on the role of TAZ protein in carcinogenesis and radiotherapy (RT) response is lacking. Therefore we investigated the TAZ expression in rectal cancer, and its correlation with RT, clinicopathological and biological variables in the patients participating in a clinical trial of preoperative RT.

    Methods

    140 rectal cancer patients were included in this study, of which 65 received RT before surgery and the rest underwent surgery alone. TAZ expression was determined by immunohistochemistry in primary cancer, distant, adjacent normal mucosa and lymph node metastasis. In-silico protein-protein interaction analysis was performed to study the predictive functional interaction of TAZ with other oncoproteins.

    Results

    TAZ showed stronger expression in primary cancer and lymph node metastasis compared to distant or adjacent normal mucosa in both non-RT and RT patients. Strong TAZ expression was significantly higher in stages I-III and non-mucinious cancer of non-RT patients. In RT patients, strong TAZ expression in biopsy was related to distant recurrence, independent of gender, age, stages and grade (p = 0.043, HR, 6.160, 95% CI, 1.063–35.704). In silico protein-protein interaction study demonstrated that TAZ was positively related to oncoproteins, Livin, MAC30 and FXYD-3.

    Conclusions

    Strong expression of TAZ protein seems to be related to rectal cancer development and RT response, it can be a predictive biomarker of distant recurrence in patients with preoperative RT.

  • 331.
    Patra, Hirak Kumar
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Imani, Roghayeh
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten. Univ,of Ljubljana, Slovenia; University of Ljubljana, Slovenia.
    Jangamreddy, Jaganmohan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Pazoki, Meysam
    Uppsala University, Sweden.
    Iglic, Ales
    University of Ljubljana, Slovenia.
    Turner, Anthony
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Tiwari, Ashutosh
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska fakulteten. Tekidag AB, SE-58330 Linkoping, Sweden.
    On/off-switchable anti-neoplastic nanoarchitecture2015Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, nr 14571, s. 1-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Throughout the world, there are increasing demands for alternate approaches to advanced cancer therapeutics. Numerous potentially chemotherapeutic compounds are developed every year for clinical trial and some of them are considered as potential drug candidates. Nanotechnology-based approaches have accelerated the discovery process, but the key challenge still remains to develop therapeutically viable and physiologically safe materials suitable for cancer therapy. Here, we report a high turnover, on/off-switchable functionally popping reactive oxygen species (ROS) generator using a smart mesoporous titanium dioxide popcorn (TiO2 Pops) nanoarchitecture. The resulting TiO2 Pops, unlike TiO2 nanoparticles (TiO2 NPs), are exceptionally biocompatible with normal cells. Under identical conditions, TiO2 Pops show very high photocatalytic activity compared to TiO2 NPs. Upon on/off-switchable photo activation, the TiO2 Pops can trigger the generation of high-turnover flash ROS and can deliver their potential anticancer effect by enhancing the intracellular ROS level until it crosses the threshold to open the death gate, thus reducing the survival of cancer cells by at least six times in comparison with TiO2 NPs without affecting the normal cells.

  • 332.
    Paulsson, Janna
    et al.
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Rydén, Lisa
    Division of Surgery, Department of Clinical Sciences Lund UniversityLundSweden; Department of Surgery Skåne University Hospital Lund, Sweden.
    Strell, Carina
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Frings, Oliver
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Tobin, Nicholas P
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Fornander, Tommy
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Bergh, Jonas
    Department of Oncology-PathologyCancer Center Karolinska, Karolinska InstitutetStockholmSweden; Radiumhemmet, Karolinska University Hospital Stockholm, Sweden.
    Landberg, Göran
    Department of Pathology Sahlgrenska Cancer Centre, University of Gothenburg Gothenburg, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Östman, Arne
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    High expression of stromal PDGFRß is associated with reduced benefit of tamoxifen in breast cancer2017Ingår i: The journal of pathology. Clinical research, ISSN 2056-4538, Vol. 3, nr 1, s. 38-43Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cancer-associated fibroblasts (CAFs) regulate tumour growth, metastasis and response to treatment. Recent studies indicate the existence of functionally distinct CAF subsets. Suggested mechanisms whereby CAFs can impact on treatment response include paracrine signalling affecting cancer cell drug sensitivity and effects on tumour drug uptake. PDGFRß is an important regulator of fibroblasts. Experimental studies have linked PDGFRß-positive fibroblasts to metastasis and also to reduced tumour drug uptake. This study has investigated the potential role of PDGFRß-positive fibroblasts in response to adjuvant tamoxifen treatment of breast cancer. Analyses of two breast cancer collections from randomised studies analysing adjuvant tamoxifen treatment in early breast cancer demonstrated significant benefit of tamoxifen in the group with low stromal PDGFRß, which was not observed in the group with high stromal PDGFRß. In general terms these findings provide novel evidence, derived from analyses of randomised clinical studies, of response-predictive capacity of a marker-defined subset of CAFs and, more specifically, identify stromal PDGFRß as a marker related to tamoxifen benefit in early breast cancer.

  • 333.
    Pellegrini, Paola
    et al.
    Karolinska Inst, Sweden.
    Serviss, Jason T.
    Karolinska Inst, Sweden.
    Lundback, Thomas
    Chem Biol Consortium Sweden, Sweden; AstraZeneca, Sweden.
    Bancaro, Nicolo
    Karolinska Inst, Sweden.
    Mazurkiewicz, Magdalena
    Karolinska Inst, Sweden.
    Kolosenko, Iryna
    Karolinska Inst, Sweden.
    Yu, Di
    Karolinska Inst, Sweden.
    Haraldsson, Martin
    Chem Biol Consortium Sweden, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    De Milito, Angelo
    Karolinska Inst, Sweden.
    A drug screening assay on cancer cells chronically adapted to acidosis2018Ingår i: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, Vol. 18, artikel-id 147Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Drug screening for the identification of compounds with anticancer activity is commonly performed using cell lines cultured under normal oxygen pressure and physiological pH. However, solid tumors are characterized by a microenvironment with limited access to nutrients, reduced oxygen supply and acidosis. Tumor hypoxia and acidosis have been identified as important drivers of malignant progression and contribute to multicellular resistance to different forms of therapy. Tumor acidosis represents an important mechanism mediating drug resistance thus the identification of drugs active on acid-adapted cells may improve the efficacy of cancer therapy. Methods: Here, we characterized human colon carcinoma cells (HCT116) chronically adapted to grow at pH 6.8 and used them to screen the Prestwick drug library for cytotoxic compounds. Analysis of gene expression profiles in parental and low pH-adapted cells showed several differences relating to cell cycle, metabolism and autophagy. Results: The screen led to the identification of several compounds which were further selected for their preferential cytotoxicity towards acid-adapted cells. Amongst 11 confirmed hits, we primarily focused our investigation on the benzoporphyrin derivative Verteporfin (VP). VP significantly reduced viability in low pH-adapted HCT116 cells as compared to parental HCT116 cells and normal immortalized epithelial cells. The cytotoxic activity of VP was enhanced by light activation and acidic pH culture conditions, likely via increased acid-dependent drug uptake. VP displayed the unique property to cause light-dependent cross-linking of proteins and resulted in accumulation of polyubiquitinated proteins without inducing inhibition of the proteasome. Conclusions: Our study provides an example and a tool to identify anticancer drugs targeting acid-adapted cancer cells.

  • 334.
    Perez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Berglund, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Esguerra Merca, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Rutqvist, Lars Erik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Institutionen för cytology, Karolinska Hospital, Stockholm, Sweden.
    Stål , Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer2006Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 28, nr 5, s. 1031-1042Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    P21WAF1/Cip1 (p21) translocates to the cytoplasm inducing cell cycle progression and survival upon Akt/PKB activation. We studied whether heregulin beta1 (HRGbeta1), that activates the PI3K/Akt and MAPK pathways, also misallocates p21. We also explored whether HRGbeta1 interferes with the effects of tamoxifen. The clinical material studied helped us to clarify whether p21 was associated with phosphorylated Akt, recurrence-free survival and response to tamoxifen. MCF-7 cells treated with HRGbeta1 -/+ E2 were analyzed by flow cytometry to observe how the different compounds affected tamoxifen-induced cell cycle arrest and apoptosis. Total cell lysate and nuclear and cytoplasmic fractions were used to detect p21, phospho-Akt and other proteins by Western blotting. Immunofluorescence was used to visualize p21+ cells upon HRGbeta1 and E2 stimulation. The localization of p21 in breast cancer was studied by immunohistochemistry in frozen tumor sections from 280 patients. In MCF-7 we found that HRGbeta1 counteracted the inhibition of p21 expression by tamoxifen and caused p21 cytoplasmic accumulation. HRGbeta1 partially counteracted the cytostatic effect of tamoxifen but abrogated its cytotoxic effect. The clinical material revealed that nuclear p21 (P=0.022) and cytoplasmic p21 (P=0.00001) were associated with phospho-Akt. Based on p21 cell location, we identified 3 subgroups of ER+ patients: the p21N+/C- group for whom tamoxifen was needed otherwise the survival was poor (P=0.0082), the p21N+/C+ or p21N-/C- group, that responded to tamoxifen (P=0.034), and the p21C+/N- group, that might not benefit from this treatment (P=0.7). In conclusion, HRGbeta1 inhibits tamoxifen-induced apoptosis, contributes to p21 cytoplasmic expression while the cellular localization of p21 interacts with the benefit from tamoxifen treatment.

  • 335.
    Perez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Elin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ahnström Waltersson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Fornander, Tommy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Department of Cytology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Clinical Value of RPS6KB1 and RPS6KB2 Gene Amplification in Postmenopausal Breast Cancer2008Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mammalian target of rapamycin (mTOR) and its substrates the ribosomal S6 kinases (S6K)1 and 2 integrate nutrient and hormonal/growth factor mediated signals and are implicated indiabetes, obesity and cancer. The genes encoding S6K1 (RPS6KB1) and S6K2 (RPS6KB2) aresituated close to well known amplicons but information regarding its expression and clinicalvalue is scarce. In this study we quantified RPS6KB1/2 gene copy number, establishedassociations with other clinical factors and explored their clinical value in breast cancer. RPS6KB1/2 copy number was determined by fast real-time PCR in 207 breast tumors.RPS6KB1 was amplified (≥ 4 copies) in 10.7% (22/206) and RPS6KB2 in 4.3% (9/207) of thetumors. Amplification of RPS6KB1 was associated with HER2 gene amplification (P=0.025)and protein expression (P=0.014) while RPS6KB2 correlated with ER+ status (P=0.046) and CCND1 amplification (P<0.00001). In a multivariate analysis, both genes were independentprognostic factors indicating higher risk to develop recurrences. In terms of loco regionalcontrol, amplification of the RPS6KB1 gene predicted less response to radiotherapy (P=0.035) while RPS6KB2 gene copy gain (≥ 3 copies) indicated increased benefit from tamoxifen (P=0.03) among ER+ patients. S6K1/2 gene amplification could be used as an indicator oftherapy response among postmenopausal breast cancer patients.

  • 336.
    Peterlongo, Paolo
    et al.
    Fdn Ist FIRC Oncology Molecolare, Italy; Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Chang-Claude, Jenny
    German Cancer Research Centre, Germany.
    Moysich, Kirsten B.
    Roswell Pk Cancer Institute, NY 14263 USA.
    Rudolph, Anja
    German Cancer Research Centre, Germany.
    Schmutzler, Rita K.
    University Hospital Cologne, Germany; University Hospital Cologne, Germany; University of Cologne, Germany.
    Simard, Jacques
    Centre Hospital University of Quebec Research Centre, Canada; University of Laval, Canada.
    Soucy, Penny
    Centre Hospital University of Quebec Research Centre, Canada; University of Laval, Canada.
    Eeles, Rosalind A.
    Institute Cancer Research, England; Royal Marsden NHS Fdn Trust, England.
    Easton, Douglas F.
    University of Cambridge, England.
    Hamann, Ute
    German Cancer Research Centre, Germany.
    Wilkening, Stefan
    German Cancer Research Centre, Germany.
    Chen, Bowang
    German Cancer Research Centre, Germany.
    Rookus, Matti A.
    Netherlands Cancer Institute, Netherlands.
    Schmidt, MarjankaK.
    Netherlands Cancer Institute, Netherlands.
    van der Baan, Frederieke H.
    Netherlands Cancer Institute, Netherlands.
    Spurdle, Amanda B.
    QIMR Berghofer, Australia.
    Walker, Logan C.
    University of Otago, New Zealand; Churchill Hospital, England.
    Lose, Felicity
    QIMR Berghofer, Australia.
    Maia, Ana-Teresa
    University of Algarve, Portugal.
    Montagna, Marco
    IRCCS, Italy.
    Matricardi, Laura
    IRCCS, Italy.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    Gomez Garcia, Encarna B.
    MUMC, Netherlands.
    Olopade, Olufunmilayo I.
    University of Chicago, IL 60637 USA.
    Nussbaum, Robert L.
    University of Calif San Francisco, CA USA; University of Calif San Francisco, CA 94143 USA.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA.
    Domchek, Susan M.
    University of Penn, PA 19104 USA.
    Rebbeck, Timothy R.
    University of Penn, PA 19104 USA.
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Orsulic, Sandra
    Cedars Sinai Medical Centre, CA 90048 USA.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Chung, Wendy K.
    Columbia University, NY 10027 USA; Columbia University, NY USA.
    Miron, Alex
    Case Western Reserve Medical Sch, OH USA.
    Southey, Melissa C.
    University of Melbourne, Australia.
    Goldgar, David E.
    University of Utah, UT USA.
    Buys, Saundra S.
    University of Utah, UT USA.
    Janavicius, Ramunas
    Vilnius University Hospital Santariskiu Clin, Lithuania; State Research Institute Centre Innovat Med, Lithuania.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Chun Ding, Yuan
    Beckman Research Institute City Hope, CA USA.
    Neuhausen, Susan L.
    Beckman Research Institute City Hope, CA USA.
    Hansen, Thomas V. O.
    University of Copenhagen Hospital, Denmark.
    Gerdes, Anne-Marie
    University of Copenhagen Hospital, Denmark.
    Ejlertsen, Bent
    University of Copenhagen Hospital, Denmark.
    Jonson, Lars
    University of Copenhagen Hospital, Denmark.
    Osorio, Ana
    Biomed Network Rare Disease CIBERER, Spain; Spanish National Cancer Centre CNIO, Spain.
    Martinez-Bouzas, Cristina
    Cruces Hospital Barakaldo, Spain.
    Benitez, Javier
    Biomed Network Rare Disease CIBERER, Spain; Spanish National Cancer Centre CNIO, Spain; Spanish National Cancer Centre CNIO, Spain.
    Conway, Edye E.
    City Hope Clin Cancer Genet Community Research Network, CA USA.
    Blazer, Kathleen R.
    City Hope National Medical Centre, CA USA.
    Weitzel, Jeffrey N.
    City Hope Clin Cancer Genet Community Research Network, CA USA.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Zaffaroni, Daniela
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Scuvera, Giulietta
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Barile, Monica
    Ist Europeo Oncol, Italy.
    Ficarazzi, Filomena
    Fdn Ist FIRC Oncology Molecolare, Italy; Cogentech Cancer Genet Test Lab, Italy.
    Mariette, Frederique
    Fdn Ist FIRC Oncology Molecolare, Italy; Cogentech Cancer Genet Test Lab, Italy.
    Fortuzzi, Stefano
    Fdn Ist FIRC Oncology Molecolare, Italy; Cogentech Cancer Genet Test Lab, Italy.
    Viel, Alessandra
    CRO Aviano National Cancer Institute, Italy.
    Giannini, Giuseppe
    University of Roma La Sapienza, Italy.
    Papi, Laura
    University of Florence, Italy.
    Martayan, Aline
    Ist Nazl Tumori Regina Elena, Italy.
    Grazia Tibiletti, Maria
    Polo University of Varese, Italy.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Vratimos, Athanassios
    National Centre Science Research Demokritos, Greece.
    Fostira, Florentia
    National Centre Science Research Demokritos, Greece.
    Garber, Judy E.
    Dana Farber Cancer Institute, MA 02115 USA.
    Donaldson, Alan
    St Michaels Hospital, England.
    Brewer, Carole
    Royal Devon and Exeter Hospital, England.
    Foo, Claire
    Liverpool Womens NHS Fdn Trust, England.
    Evans, D. Gareth R.
    Central Manchester University Hospital NHS Fdn Trust, England.
    Frost, Debra
    University of Cambridge, England.
    Eccles, Diana
    University of Southampton, England.
    Brady, Angela
    Kennedy Galton Centre, England.
    Cook, Jackie
    Sheffield Childrens Hospital, England.
    Tischkowitz, Marc
    Addenbrookes Hospital, England.
    Adlard, Julian
    Yorkshire Regional Genet Serv, England.
    Barwell, Julian
    University Hospital Leicester NHS Trust, England.
    Walker, Lisa
    University of Otago, New Zealand; Churchill Hospital, England.
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust, England.
    Side, Lucy E.
    Great Ormond St Hospital Sick Children, England.
    John Kennedy, M.
    University of Dublin Trinity Coll, Ireland; St James Hospital, Ireland.
    Rogers, Mark T.
    University of Wales Hospital, Wales.
    Porteous, Mary E.
    Western Gen Hospital, Scotland.
    Morrison, Patrick J.
    Queens University of Belfast, North Ireland.
    Platte, Radka
    University of Cambridge, England.
    Davidson, Rosemarie
    So Gen Hospital, Scotland.
    Hodgson, Shirley V.
    St Georges University of London, England.
    Ellis, Steve
    University of Cambridge, England.
    Cole, Trevor
    Birmingham Womens Hospital Healthcare NHS Trust, England.
    Godwin, Andrew K.
    University of Kansas, MO USA.
    Claes, Kathleen
    University of Ghent, Belgium.
    Van Maerken, Tom
    University of Ghent, Belgium.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Gehrig, Andrea
    University of Wurzburg, Germany.
    Sutter, Christian
    Heidelberg University, Germany.
    Engel, Christoph
    University of Leipzig, Germany.
    Niederacher, Dieter
    University of Dusseldorf, Germany.
    Steinemann, Doris
    Hannover Medical Sch, Germany.
    Plendl, Hansjoerg
    University of Kiel, Germany.
    Kast, Karin
    Technical University of Dresden, Germany.
    Rhiem, Kerstin
    University Hospital Cologne, Germany; University Hospital Cologne, Germany; University of Cologne, Germany.
    Ditsch, Nina
    University of Munich, Germany.
    Arnold, Norbert
    University of Kiel, Germany.
    Varon-Mateeva, Raymonda
    Charite, Germany.
    Wappenschmidt, Barbara
    University Hospital Cologne, Germany; University Hospital Cologne, Germany; University of Cologne, Germany.
    Wang-Gohrke, Shan
    University Hospital Ulm, Germany.
    Bressac-de Paillerets, Brigitte
    Fdn Jean Dausset, France; Institute Cancerol Gustave Roussy, France.
    Buecher, Bruno
    Institute Curie, France.
    Delnatte, Capucine
    Centre Rene Gauducheau, France.
    Houdayer, Claude
    Institute Curie, France; University of Paris 05, France.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; University of Paris 05, France; INSERM U830, France.
    Damiola, Francesca
    University of Lyon 1, France.
    Coupier, Isabelle
    CHU Arnaud Villeneuve, France; CRLCC Val Aurelle, France.
    Barjhoux, Laure
    CRLCC Val Aurelle, France.
    Venat-Bouvet, Laurence
    Centre Hospital University of Dupuytren, France.
    Golmard, Lisa
    Institute Curie, France.
    Boutry-Kryza, Nadia
    Hospital Civils Lyon, France.
    Sinilnikova, Olga M.
    University of Lyon 1, France; Hospital Civils Lyon, France.
    Caron, Olivier
    Institute Cancerol Gustave Roussy, France.
    Pujol, Pascal
    CHU Arnaud Villeneuve, France; INSERM 896, France.
    Mazoyer, Sylvie
    University of Lyon 1, France.
    Belotti, Muriel
    Institute Curie, France.
    Piedmonte, Marion
    Roswell Pk Cancer Institute, NY 14263 USA.
    Friedlander, Michael L.
    Australia New Zealand Gynaecol Oncology Grp, Australia.
    Rodriguez, Gustavo C.
    NorthShore University of HealthSyst, IL USA.
    Copeland, Larry J.
    Ohio State University, OH USA.
    de la Hoya, Miguel
    Hospital Clin San Carlos, Spain.
    Perez Segura, Pedro
    Hospital Clin San Carlos, Spain.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Aittomaeki, Kristiina
    University of Helsinki, Finland.
    van Os, Theo A. M.
    University of Amsterdam, Netherlands.
    Meijers-Heijboer, Hanne E. J.
    Vrije University of Amsterdam Medical Centre, Netherlands.
    van der Hout, Annemarie H.
    University of Groningen, Netherlands.
    Vreeswijk, Maaike P. G.
    Leiden University, Netherlands.
    Hoogerbrugge, Nicoline
    Radboud University of Nijmegen, Netherlands.
    Ausems, Margreet G. E. M.
    University of Medical Centre Utrecht, Netherlands.
    van Doorn, Helena C.
    Erasmus University, Netherlands.
    Margriet Collee, J.
    Erasmus University, Netherlands.
    Olah, Edith
    National Institute Oncol, Hungary.
    Diez, Orland
    University Hospital Vall Hebron, Spain; University of Autonoma Barcelona, Spain; Vall Hebron Institute Oncol, Spain; Vall Hebron Research Institute, Spain.
    Blanco, Ignacio
    IDIBELL Catalan Institute Oncol, Spain.
    Lazaro, Conxi
    IDIBELL Catalan Institute Oncol, Spain.
    Brunet, Joan
    IDIBGI Catalan Institute Oncol, Spain.
    Feliubadalo, Lidia
    University of Iceland, Iceland.
    Cybulski, Cezary
    Pomeranian Medical University, Poland.
    Gronwald, Jacek
    Pomeranian Medical University, Poland.
    Durda, Katarzyna
    Pomeranian Medical University, Poland.
    Jaworska-Bieniek, Katarzyna
    Pomeranian Medical University, Poland.
    Sukiennicki, Grzegorz
    Pomeranian Medical University, Poland.
    Arason, Adalgeir
    University of Iceland, Iceland; Landspitali University Hospital, Iceland.
    Chiquette, Jocelyne
    University of Quebec, Canada.
    Teixeira, Manuel R.
    University of Porto, Portugal; Portuguese Oncology Institute, Portugal.
    Olswold, Curtis
    Mayo Clin, NY USA.
    Couch, Fergus J.
    Mayo Clin, NY USA.
    Lindor, Noralane M.
    Mayo Clin, AZ USA.
    Wang, Xianshu
    Mayo Clin, NY USA.
    Szabo, Csilla I.
    NIH, MD 20892 USA.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Corines, Marina
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Jacobs, Lauren
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Robson, Mark E.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Zhang, Liying
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Joseph, Vijai
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Berger, Andreas
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Singer, Christian F.
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Rappaport, Christine
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Geschwantler Kaulich, Daphne
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Pfeiler, Georg
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Tea, Muy-Kheng M.
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Phelan, Catherine M.
    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
    Greene, Mark H.
    NIH, MD USA.
    Mai, Phuong L.
    NIH, MD USA.
    Rennert, Gad
    Clalit National Cancer Control Centre, Israel.
    Marie Mulligan, Anna
    University of Toronto, Canada; University of Health Network, Canada.
    Glendon, Gord
    Mt Sinai Hospital, Canada.
    Tchatchou, Sandrine
    Mt Sinai Hospital, Canada.
    Andrulis, Irene L.
    Mt Sinai Hospital, Canada; Ohio State University, OH 43210 USA.
    Ewart Toland, Amanda
    Ohio State University, OH 43210 USA; Ohio State University, OH 43210 USA.
    Bojesen, Anders
    Vejle Hospital, Denmark.
    Sokilde Pedersen, Inge
    Aalborg University Hospital, Denmark.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Birk Jensen, Uffe
    Aarhus University Hospital, Denmark.
    Laitman, Yael
    Sheba Medical Centre, Israel.
    Rantala, Johanna
    Karolinska University Hospital, Sweden.
    von Wachenfeldt, Anna
    Karolinska University Hospital, Sweden.
    Ehrencrona, Hans
    University of Lund Hospital, Sweden; Uppsala University, Sweden.
    Askmalm Stenmark, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Borg, Ake
    Lund University, Sweden.
    Kuchenbaecker, Karoline B.
    University of Cambridge, England.
    McGuffog, Lesley
    University of Cambridge, England.
    Barrowdale, Daniel
    University of Cambridge, England.
    Healey, Sue
    QIMR Berghofer, Australia.
    Lee, Andrew
    University of Cambridge, England.
    Pharoah, Paul D. P.
    University of Cambridge, England.
    Chenevix-Trench, Georgia
    QIMR Berghofer, Australia.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Friedman, Eitan
    Sheba Medical Center, Israel.
    Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers2015Ingår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 24, nr 1, s. 308-316Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

  • 337.
    Petridou, Elia
    et al.
    Department of Radiology, Norfolk and Norwich University hospitals, Norwich, Norfolk, United Kingdom.
    Kibiro, Minnie
    Department of Radiology, Norfolk and Norwich University hospitals, Norwich, Norfolk, United Kingdom.
    Gladwell, Christina
    Department of Radiology, Norfolk and Norwich University hospitals, Norwich, Norfolk, United Kingdom.
    Malcolm, Paul
    Department of Radiology, Norfolk and Norwich University hospitals, Norwich, Norfolk, United Kingdom.
    Juette, Arne
    Department of Radiology, Norfolk and Norwich University hospitals, Norwich, Norfolk, United Kingdom.
    Toms, Andoni
    Department of Radiology, Norfolk and Norwich University hospitals, Norwich, Norfolk, United Kingdom.
    Borga, Magnus
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Advanced MR Analytics AB, Linköping, Sweden.
    Dahlqvist Leinhard, Olof
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Advanced MR Analytics AB, Linköping, Sweden.
    Denton, Erika
    Department of Radiology, Norfolk and Norwich University hospitals, Norwich, Norfolk, United Kingdom.
    Breast fat volume measurement in a wide-bore 3T MR: comparison of traditional mammographic density evaluation with MR density measurements using automatic segmentation.2015Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    Aims and objectives

    Variations in breast density in imaging are caused by varying proportions of fat and fibro-glandular tissue. Breast density is an independent marker of breast cancer risk and therefore a number of techniques have been developed to measure breast density using different imaging modalities. The aim of this research was to compare a fully automated technique of producing volumetric measurements of fat and fibroglandular breast tissue from segmented magnetic resonance imaging (MRI) and to compare with the well-established, observer-dependent Breast Imaging Reporting and Data Systems (BI-RADS) density classification using mammography.

    Methods and materials

    This was a prospective inter-method comparison study. The study design was a prospective analysis of volumetric breast density obtained from breast MRI scans compared with mammographic breast density using BIRADS. Ethical approval for the study was obtained from the local Research Ethics Committee. 40 women undergoing mammography and dynamic breast MRI as part of their clinical management were recruited. Fat-water separated MR images derived from a 2 point Dixon technique using phase-sensitive reconstruction and atlas based segmentation were obtained before and after the administration of intravenous gadolinium. Breast density, which was defined the proportion of breast fat subtracted from the total volume of the breast, was assessed using proprietary software (Advanced MR Analytics (AMRA), Linköping, Sweden). The method was previously described and first used for measurement of abdominal fat.

    The results were compared to the widely used four-quartile quantitative BIRADS scale undertaken by two experienced breast radiologists. 

    Results

    The mean unenhanced breast percentage of fibro-glandular tissue measured on MRI was 0.31 ± 0.22 (mean ± SD) for the left and 0.29 ± 0.21 for the right. The mean density on the contrast-enhanced images was 0.32 ± 0.19 for the left and 0.32 ± 0.2 for right. There was "almost perfect" correlation between the quantification pre and post-contrast breast fibro- glandular tissue quantification: Spearman correlation rho=0.98 (95% confidence intervals (CI): 0.97-0.99) for the left and rho=0.99 (CI: 0.98-0.99) for the right.

    For each of the BIRADS scores 1-4 observer 1 scored a total number of breasts as n=2,35,26,15 (total 80) and observer 2 scored n=4,25,45,16 respectively. Correlation between BIRADS scores and automated MRI breast density was significant for both operators, Spearman Correlation coefficient rho=0.75. 

    Conclusion

    Automated breast fat density measurement using MR correlates strongly with the current mammographic standard BIRADS. Results for percentage fibro-glandular component on unenhanced breast MR correlate very closely with post-contrast MR. Breast density measurements derived from automated segmentation of unenhanced breast MRI could be used instead of mammographic measurements for assessing breast cancer risk. 

  • 338.
    Pfeifer, Daniella
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Wallin, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Protein expression following gamma-irradiation relevant to growth arrest and apoptosis in colon cancer cells with mutant p532009Ingår i: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 135, nr 11, s. 1583-1592Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We previously found that p53, p73, survivin and PRL were implicated in the outcome of radiotherapy in rectal cancer patients. In the present study, we tried to understand mechanisms of colon cancer cell line response to radiation based on protein expression related to proliferation and apoptosis. KM12C, KM12SM and KM12L4a, cell lines with one origin, were radiated with 0, 10 or 15 Gy γ-radiation. Radiosensitivity was determined with cell cycle and apoptosis analysis, and protein expression of TAp73, ΔNp73, mutated p53, survivin and PRL-3 was determined by Western blot. KM12C showed transient G2-arrest, low apoptosis and up-regulation of resistance factors such as PRL-3. In KM12C expression of ΔNp73 increased after 10Gy, but not after 15Gy. KM12SM had permanent G2-arrest, low apoptosis and showed up-regulation of the anti-apoptotic survivin and down-regulation of the pro-apoptotic TAp73 and the radioresistance factor PRL-3 was down-regulated. KM12L4a, the most radiosensitive cell line, showed up-regulation of TAp73 and down-regulation/no up-regulation of resistance factors such as ΔNp73, survivin and PRL-3 after radiation. In conclusion, the KM12C cell line was more radioresistant than KM12L4a regarding apoptosis and certain apoptotic proteins. The radiosensitivity of KM12L4a might partly depend on the lack of up-regulation of proteins negative for the outcome of radiotherapy.

     

  • 339.
    Philchenkov, A.
    et al.
    R.E. Kavetsky Institute of Experimental Pathology, Oncology, and Radiobiology, National Academy of Sciences of Ukraine, Kyiv 03022, Ukraine..
    Zavelevich, M.
    R.E. Kavetsky Institute of Experimental Pathology, Oncology, and Radiobiology, National Academy of Sciences of Ukraine, Kyiv 03022, Ukraine..
    Kroczak, T. J.
    R.E. Kavetsky Institute of Experimental Pathology, Oncology, and Radiobiology, National Academy of Sciences of Ukraine, Kyiv 03022, Ukraine..
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada.
    Caspases and cancer: Mechanisms of inactivation and new treatment modalities2004Ingår i: Experimental Oncology, ISSN 0204-3564, Vol. 26, nr 2, s. 82-97Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Elimination of superfluous or mutated somatic cells is provided by various mechanisms including apoptosis. Deregulation of apoptotic signaling pathways may contribute to oncogenesis. Aspartate specific cysteine proteases, termed caspases are the key effector molecules in apoptosis. The aim of this review is to summarize the various defects in caspase-dependent cell death machinery identified in the neoplastic cells. These include not only mutations, but also alterations of gene methylation, and altered mRNA stability. Among the molecules that we discuss are elements of the extrinsic death pathway like CD95 (APO-1/Fas), FADD, FLIPs, FLICE, other apical caspases, components of the intrinsic apoptotic pathway like Apaf-1, caspase-9, and modulators of apoptotic pathways like IAPs, Smac/DIABLO, OMI/HtrA2, and other apoptosis regulating proteins. We also discuss recent data on cancer-specific agents that target effector mechanisms of apoptosis. Particular emphasis is given to the prospects for combining cell suicide-activating approaches with classical cancer therapies.

  • 340.
    Pietzner, Klaus
    et al.
    Charite, Germany.
    Vergote, Ignace
    University Hospital Leuven, Belgium; Leuven Cancer Institute, Belgium.
    Santoro, Armando
    Ist Clin Humanitas, Italy.
    Chekerov, Radoslav
    Charite, Germany.
    Marme, Frederik
    University of Frauenklin Heidelberg, Germany.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Martinius, Holger
    Neovu Biotech GmbH, Germany.
    Friccius-Quecke, Hilke
    Neovu Biotech GmbH, Germany.
    Sehouli, Jalid
    Charite, Germany; North Eastern German Soc Gynecol NOGGO, Germany.
    Re-challenge with catumaxomab in patients with malignant ascites: results from the SECIMAS study2014Ingår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 31, nr 12, s. 308-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Malignant ascites is a common phenomenon in cancer patients. It poses a great challenge to the clinician, because of limited treatment options and strong impairment of the quality of life of the often palliative patients. The SECIMAS study investigated the feasibility of a re-challenge with four catumaxomab intraperitoneal infusions in patients who had already received a first cycle of four infusions in the phase III CASIMAS study, which compared catumaxomab with and without prednisolone premedication. The primary endpoint was the proportion of patients who received at least three catumaxomab infusions. Secondary endpoints included a composite safety score (CSS) summarising the worst grades for the main catumaxomab-related adverse events (pyrexia, nausea, vomiting and abdominal pain), safety, efficacy and the occurrence of anti-drug antibodies (ADAs). Eight of nine screened patients received a second catumaxomab cycle. Compliance with a catumaxomab re-challenge was high: all eight patients (100 %) received all four infusions. The median CSS was 3.0 versus 3.4 in CASIMAS. The tolerability profile of the second catumaxomab cycle was comparable to that of the first cycle. Median puncture-free survival (48 days) and overall survival (407 days) were longer than in CASIMAS (35 and 103 days, respectively), although median time to next puncture was shorter (60 vs. 97 days). Of six patients sampled, all were ADA positive at screening and remained ADA positive until the end of the study. The presence of ADAs did not affect catumaxomabs safety or efficacy. The CSS and tolerability profile for catumaxomab in SECIMAS were comparable to those in CASIMAS. The majority of patients benefitted from a second cycle of catumaxomab. A re-challenge seems to be feasible and safe for selected patients with recurrent malignant ascites due to carcinoma after a first cycle of catumaxomab.

  • 341.
    Priftakis, Peter
    et al.
    Karolinska institutet.
    Dalianis, Tina
    Karolinska institutet.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiskt centrum.
    Samuelsson, Ulf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Lewensohn-Fuchs, Ilona
    Karolinska institutet.
    Bogdanovic, Gordana
    Karolinska institutet.
    Winiarski, Jacek
    Karolinska institutet.
    Gustafsson, Britt
    Karolinska institutet.
    Human polyomavirus DNA is not detected in Guthrie cards (dried blood spots) from children who developed acute lymphoblastic leukemia2003Ingår i: Medical and Pediatric Oncology, ISSN 0098-1532, E-ISSN 1096-911X, Vol. 40, nr 4, s. 219-223Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Epidemiological evidence has suggested that some childhood acute lymphoblastic leukemia (ALL) may be initiated in utero and may have an infectious etiology. The human polyomavirus JC virus (JCV) has been discussed as a candidate virus, but its presence has not been demonstrated in leukemia cells from children with ALL. The aim of this study was, therefore, to investigate if prenatal human polyomavirus infection could still indirectly be correlated to the development of childhood ALL.

    Procedure

    Fifty-four Guthrie cards (stored, dried blood spots filter papers, routinely collected from newborns for different screening analyses), collected at 3–5 days of age, from Swedish children who subsequently developed ALL, as well as from 37 healthy controls, were investigated by nested PCR for the presence of human polyomaviruses JCV and BK virus (BKV).

    Results

    JCV and BKV DNA were not detected in any of the Guthrie cards from ALL patients or from healthy controls, although all tested samples had amplifiable DNA as confirmed by an HLA DQ PCR.

    Conclusions

    JCV or BKV were not found in any of the dried blood spots of children who later developed ALL or in the healthy controls. These findings suggest that it is unlikely that childhood ALL is associated with an in utero infection with JCV or BKV, although it is not possible to exclude an association with an in utero infection that has become latent in the kidneys with very low levels of circulating virus at birth.

  • 342.
    Pujade-Lauraine, Eric
    et al.
    Hôpital Hôtel-Dieu, Paris, France .
    Wagner, Uwe
    Philipps University Marburg, Marburg, Germany.
    Åvall-Lundqvist, Elisabeth
    Karolinska University Hospital, Stockholm, Sweden.
    Gebski, Val
    NHMRC Clinical Trials Centre, Sydney, NSW, Australia.
    Heywood, Mark
    BC Cancer Agency, Vancouver, BC, Canada .
    Vasey, Paul A
    Wesley Medical Centre, Auchenflower, QLD, Australia .
    Volgger, Birgit
    Medical University Innsbruck, Innsbruck, Austria .
    Vergote, Ignace
    University Hospital Leuven, Leuven, Belgium.
    Pignata, Sandro
    Cancer National Institute, Naples, Italy .
    Ferrero, Annamaria
    Gynecological Oncology Institute for Cancer Research and Treatment (IRCC) of Candiolo & AO Ordine Mauriziano, Turin, Italy .
    Sehouli, Jalid
    University Hospital Charité, Berlin, Germany .
    Lortholary, Alain
    Centre Catherine De Sienne, Nantes, France.
    Kristensen, Gunnar
    Norwegian Radium Hospital, Oslo, Norway .
    Jackisch, Christian
    Klinikum Offenbach, Offenbach, Germany .
    Joly, Florence
    CHU-Centre François Baclesse, Caen, France.
    Brown, Chris
    NHMRC Clinical Trials Centre, Sydney, NSW, Australia .
    Le Fur, Nathalie
    ARCAGY-GINECO, Paris, France .
    du Bois, Andreas
    Dr Horst Schmidt Klinik, Wiesbaden, Germany .
    Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late relapse.2010Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 28, nr 20, s. 3323-3329Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) with carboplatin (CD) compared with standard carboplatin and paclitaxel (CP) in patients with platinum-sensitive relapsed/recurrent ovarian cancer (ROC).

    PATIENTS AND METHODS: Patients with histologically proven ovarian cancer with recurrence more than 6 months after first- or second-line platinum and taxane-based therapies were randomly assigned by stratified blocks to CD (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m(2)) every 4 weeks or CP (carboplatin AUC 5 plus paclitaxel 175 mg/m(2)) every 3 weeks for at least 6 cycles. Primary end point was progression-free survival (PFS); secondary end points were toxicity, quality of life, and overall survival.

    RESULTS: Overall 976 patients were recruited. With median follow-up of 22 months, PFS for the CD arm was statistically superior to the CP arm (hazard ratio, 0.821; 95% CI, 0.72 to 0.94; P = .005); median PFS was 11.3 versus 9.4 months, respectively. Although overall survival data are immature for final analysis, we report here a total of 334 deaths. Overall severe nonhematologic toxicity (36.8% v 28.4%; P < .01) leading to early discontinuation (15% v 6%; P < .001) occurred more frequently in the CP arm. More frequent grade 2 or greater alopecia (83.6% v 7%), hypersensitivity reactions (18.8% v 5.6%), and sensory neuropathy (26.9% v 4.9%) were observed in the CP arm; more hand-foot syndrome (grade 2 to 3, 12.0% v 2.2%), nausea (35.2% v 24.2%), and mucositis (grade 2-3, 13.9% v 7%) in the CD arm.

    CONCLUSION: To our knowledge, this trial is the largest in recurrent ovarian cancer and has demonstrated superiority in PFS and better therapeutic index of CD over standard CP.

  • 343.
    Pérez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Alterations in the PI3K/AKT Signaling Pathway and Response to Adjuvant Treatment in Breast Cancer2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Bröstcancer är en vanlig sjukdom och dödsorsak bland kvinnor i Sverige. Könshormonet östrogen tillsammas med cellernas receptorer för hormonet spelar en viktig roll för bröstcancerutvecklingen. Därför behandlas denna sjukdom med anti-hormonella substanser inriktade mot hämning av östrogensyntes/östrogen receptorn. Tamoxifen är den vanligaste formen av anti-östrogenbehandling som används efter operation. Tamoxifenbehandling förbättrar betydligt 5-årsöverlevnaden hos patienter med östrogenreceptorpositiva tumörer. Emellertid finns det patienter som återkommer med metastaser efter en tid. I det här projektet studerar vi andra receptorer samt deras signalvägar som kan aktivera östrogenreceptorn och därmed orsaka tamoxifenresistens.

    En sådan receptor är HER-2 vilken överuttrycks i 15-20% vid bröstumörer. HER-2 receptorn kan rekrytera proteiner med enzymatisk aktivitet, till exempel PI3K. PI3K aktiverar ett annat enzym, AKT, vilket är inblandat i en kaskad som leder till tumörtillväxt och tumöröverlevnad (genom till exempel aktivering av östrogenreceptorn). Våra resultat hitills visar att patienter med aktiverat AKT (pAKT) har större risk att få metastaser och därmed sämre överlevnad än patienter utan pAKT, detta trots hormonell behandling. I större material där HER-2 proteinuttrycket korrelerar med pAKT har vi också funnit att patienter med AKTnegativa tumörer kunde dra nytta av både tamoxifen och strålbehandling. Vi har även undersökt PIK3CA genen (som kodar för en del av PI3K) och hittat mutationer i 24% av bröstumörerna. Det är dock ännu oklart hur dessa mutationer ska tas hänsyn till för att kunna bestämma en effektiv behandling. PTEN är ett annat enzym som motverkar PI3K-aktivitet. Bortfall av PTEN förekommer ofta i bröstcancer och  har associerats med PI3K/AKT aktivering. I vårt material var PTEN-förlust frekvent (37%) och associerades med PIK3CA mutationer. PTEN förlust som ensam faktor eller tillsammans med PIK3CA mutationer ökade strålkänslighet. Andra proteiner som är inblandade i PI3K signalvägen är S6K1 och S6K2 och dessa har betydelse för cellens proteinsyntes. Nyligen har vi kunnat visa att generna för både S6K1/2 finns i många kopior (genamplifering) I tumörcellerna hos bröstcancerpatienter. Dessutom fanns det ett positivt samband mellan S6K1/2 amplifiering och amplifiering av andra kända cancergener (som t. ex HER-2 och cyclin D1) men förhållandet till PIK3CA-mutationer var det omvända. Patienter med antigen S6K1 eller HER-2 amplifierade tumörer svarade dåligt på strålbehandling men skulle möjligen kunna behandlas med en specifik substans riktad mot S6K1 eller HER-2. Ett ökat antal kopior av S6K2 indikerade dålig prognos men bra nytta av tamoxifen. Våra resultat visar att PI3K/AKT signalvägen ofta är aktiverad vid bröstcancer och skulle kunna vara en viktig måltavla för behandling.

    Delarbeten
    1. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients
    Öppna denna publikation i ny flik eller fönster >>Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients
    2002 (Engelska)Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 86, nr 4, s. 540-545Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin β1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged < 50 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P = 0.001) and the presence of heregulin β1-expressing stromal cells (P = 0.017). Neither Akt-1 nor pAkt was related with other factors Turnout cells-derived heregulin β1 was found mainly in oestrogen receptor negative (P = 0.026) and node negative (P = 0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P = 0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer

    Nyckelord
    Breast cancer, endocrine treatment, Akt, PKB, erbB-2, hergulin ß1
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-15031 (URN)10.1038/sj.bjc.6600126 (DOI)
    Tillgänglig från: 2008-10-10 Skapad: 2008-10-10 Senast uppdaterad: 2017-12-11
    2. Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer
    Öppna denna publikation i ny flik eller fönster >>Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer
    Visa övriga...
    2006 (Engelska)Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 28, nr 5, s. 1031-1042Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    P21WAF1/Cip1 (p21) translocates to the cytoplasm inducing cell cycle progression and survival upon Akt/PKB activation. We studied whether heregulin beta1 (HRGbeta1), that activates the PI3K/Akt and MAPK pathways, also misallocates p21. We also explored whether HRGbeta1 interferes with the effects of tamoxifen. The clinical material studied helped us to clarify whether p21 was associated with phosphorylated Akt, recurrence-free survival and response to tamoxifen. MCF-7 cells treated with HRGbeta1 -/+ E2 were analyzed by flow cytometry to observe how the different compounds affected tamoxifen-induced cell cycle arrest and apoptosis. Total cell lysate and nuclear and cytoplasmic fractions were used to detect p21, phospho-Akt and other proteins by Western blotting. Immunofluorescence was used to visualize p21+ cells upon HRGbeta1 and E2 stimulation. The localization of p21 in breast cancer was studied by immunohistochemistry in frozen tumor sections from 280 patients. In MCF-7 we found that HRGbeta1 counteracted the inhibition of p21 expression by tamoxifen and caused p21 cytoplasmic accumulation. HRGbeta1 partially counteracted the cytostatic effect of tamoxifen but abrogated its cytotoxic effect. The clinical material revealed that nuclear p21 (P=0.022) and cytoplasmic p21 (P=0.00001) were associated with phospho-Akt. Based on p21 cell location, we identified 3 subgroups of ER+ patients: the p21N+/C- group for whom tamoxifen was needed otherwise the survival was poor (P=0.0082), the p21N+/C+ or p21N-/C- group, that responded to tamoxifen (P=0.034), and the p21C+/N- group, that might not benefit from this treatment (P=0.7). In conclusion, HRGbeta1 inhibits tamoxifen-induced apoptosis, contributes to p21 cytoplasmic expression while the cellular localization of p21 interacts with the benefit from tamoxifen treatment.

    Nyckelord
    PI3K, heregulin ß1, cell cycle, cell survival
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-15032 (URN)16596219 (PubMedID)
    Tillgänglig från: 2008-10-10 Skapad: 2008-10-10 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
    3. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer
    Öppna denna publikation i ny flik eller fönster >>PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer
    Visa övriga...
    2007 (Engelska)Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, nr 12, s. 3577-3584Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Purpose: The phosphatidylinositol 3'-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol 3'-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer.

    Experimental Design: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors.

    Results: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor(+) status, small size, negative HER2 status, high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor(+), small in size, and HER2(-). PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction.

    Conclusions: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.

    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-15041 (URN)10.1158/1078-0432.CCR-06-1609 (DOI)17575221 (PubMedID)
    Tillgänglig från: 2008-10-13 Skapad: 2008-10-13 Senast uppdaterad: 2017-12-11
    4. Clinical Value of RPS6KB1 and RPS6KB2 Gene Amplification in Postmenopausal Breast Cancer
    Öppna denna publikation i ny flik eller fönster >>Clinical Value of RPS6KB1 and RPS6KB2 Gene Amplification in Postmenopausal Breast Cancer
    Visa övriga...
    2008 (Engelska)Artikel i tidskrift (Refereegranskat) Submitted
    Abstract [en]

    The mammalian target of rapamycin (mTOR) and its substrates the ribosomal S6 kinases (S6K)1 and 2 integrate nutrient and hormonal/growth factor mediated signals and are implicated indiabetes, obesity and cancer. The genes encoding S6K1 (RPS6KB1) and S6K2 (RPS6KB2) aresituated close to well known amplicons but information regarding its expression and clinicalvalue is scarce. In this study we quantified RPS6KB1/2 gene copy number, establishedassociations with other clinical factors and explored their clinical value in breast cancer. RPS6KB1/2 copy number was determined by fast real-time PCR in 207 breast tumors.RPS6KB1 was amplified (≥ 4 copies) in 10.7% (22/206) and RPS6KB2 in 4.3% (9/207) of thetumors. Amplification of RPS6KB1 was associated with HER2 gene amplification (P=0.025)and protein expression (P=0.014) while RPS6KB2 correlated with ER+ status (P=0.046) and CCND1 amplification (P<0.00001). In a multivariate analysis, both genes were independentprognostic factors indicating higher risk to develop recurrences. In terms of loco regionalcontrol, amplification of the RPS6KB1 gene predicted less response to radiotherapy (P=0.035) while RPS6KB2 gene copy gain (≥ 3 copies) indicated increased benefit from tamoxifen (P=0.03) among ER+ patients. S6K1/2 gene amplification could be used as an indicator oftherapy response among postmenopausal breast cancer patients.

    Nyckelord
    PI3K, AKT, mTOR, CCND1, HER2, ER, Tamoxifen
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-15042 (URN)
    Tillgänglig från: 2008-10-13 Skapad: 2008-10-13 Senast uppdaterad: 2009-04-09
  • 344.
    Pérez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Alkhori, Liza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Ahnstro Waltersson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Rutqvist, Lars Erik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Institutionen för Cytology, Karolinska Hospital, Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer2007Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, nr 12, s. 3577-3584Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: The phosphatidylinositol 3'-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol 3'-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer.

    Experimental Design: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors.

    Results: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor(+) status, small size, negative HER2 status, high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor(+), small in size, and HER2(-). PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction.

    Conclusions: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.

  • 345.
    Pérez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Members of the Southeast Sweden Breast Cancer Group,
    Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients2002Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 86, nr 4, s. 540-545Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin β1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged < 50 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P = 0.001) and the presence of heregulin β1-expressing stromal cells (P = 0.017). Neither Akt-1 nor pAkt was related with other factors Turnout cells-derived heregulin β1 was found mainly in oestrogen receptor negative (P = 0.026) and node negative (P = 0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P = 0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer

  • 346. Quinn, M
    et al.
    Åvall-Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    du Bois, A
    Vermorken, J
    Parmar, M
    Pfisterer, J
    Stuart, G
    Thigpen, T
    Neijt, J
    University Medical Center Utrecht, Utrecht, The Netherlands.
    History, scope and methodology of the 3rd International Consensus Workshop on Ovarian Cancer 2004.2005Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 16, nr 8, s. viii5-viii6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This document reports the history of the two previous ovarian cancer consensus meetings and the scope and methodology of the 3rd International Ovarian Cancer Consensus Conference, which was held by the GCIG from 5–9 September 2004 in Baden-Baden, Germany. This conference was supported by an unrestricted grant from Bristol-Myers-Squibb. Selection of participants, agenda and deliberations were not influenced by the financial support provider.

  • 347. Ramus, Susan J
    et al.
    Antoniou, Antonis C
    Kuchenbaecker, Karoline B
    Soucy, Penny
    Beesley, Jonathan
    Chen, Xiaoqing
    McGuffog, Lesley
    Sinilnikova, Olga M
    Healey, Sue
    Barrowdale, Daniel
    Lee, Andrew
    Thomassen, Mads
    Gerdes, Anne-Marie
    Kruse, Torben A
    Jensen, Uffe Birk
    Skytte, Anne-Bine
    Caligo, Maria A
    Liljegren, Annelie
    Lindblom, Annika
    Olsson, Håkan
    Kristoffersson, Ulf
    Stenmark-Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Melin, Beatrice
    Domchek, Susan M
    Nathanson, Katherine L
    Rebbeck, Timothy R
    Jakubowska, Anna
    Lubinski, Jan
    Jaworska, Katarzyna
    Durda, Katarzyna
    Złowocka, Elżbieta
    Gronwald, Jacek
    Huzarski, Tomasz
    Byrski, Tomasz
    Cybulski, Cezary
    Toloczko-Grabarek, Aleksandra
    Osorio, Ana
    Benitez, Javier
    Duran, Mercedes
    Tejada, Maria-Isabel
    Hamann, Ute
    Rookus, Matti
    van Leeuwen, Flora E
    Aalfs, Cora M
    Meijers-Heijboer, Hanne E J
    van Asperen, Christi J
    van Roozendaal, K E P
    Hoogerbrugge, Nicoline
    Collée, J Margriet
    Kriege, Mieke
    van der Luijt, Rob B
    Peock, Susan
    Frost, Debra
    Ellis, Steve D
    Platte, Radka
    Fineberg, Elena
    Evans, D Gareth
    Lalloo, Fiona
    Jacobs, Chris
    Eeles, Ros
    Adlard, Julian
    Davidson, Rosemarie
    Eccles, Diana
    Cole, Trevor
    Cook, Jackie
    Paterson, Joan
    Douglas, Fiona
    Brewer, Carole
    Hodgson, Shirley
    Morrison, Patrick J
    Walker, Lisa
    Porteous, Mary E
    Kennedy, M John
    Pathak, Harsh
    Godwin, Andrew K
    Stoppa-Lyonnet, Dominique
    Caux-Moncoutier, Virginie
    de Pauw, Antoine
    Gauthier-Villars, Marion
    Mazoyer, Sylvie
    Léoné, Mélanie
    Calender, Alain
    Lasset, Christine
    Bonadona, Valérie
    Hardouin, Agnès
    Berthet, Pascaline
    Bignon, Yves-Jean
    Uhrhammer, Nancy
    Faivre, Laurence
    Loustalot, Catherine
    Buys, Saundra
    Daly, Mary
    Miron, Alex
    Terry, Mary Beth
    Chung, Wendy K
    John, Esther M
    Southey, Melissa
    Goldgar, David
    Singer, Christian F
    Tea, Muy-Kheng
    Pfeiler, Georg
    Fink-Retter, Anneliese
    Hansen, Thomas v O
    Ejlertsen, Bent
    Johannsson, Oskar Th
    Offit, Kenneth
    Kirchhoff, Tomas
    Gaudet, Mia M
    Vijai, Joseph
    Robson, Mark
    Piedmonte, Marion
    Phillips, Kelly-Anne
    Van Le, Linda
    Hoffman, James S
    Ewart Toland, Amanda
    Montagna, Marco
    Tognazzo, Silvia
    Imyanitov, Evgeny
    Issacs, Claudine
    Janavicius, Ramunas
    Lazaro, Conxi
    Blanco, Iganacio
    Tornero, Eva
    Navarro, Matilde
    Moysich, Kirsten B
    Karlan, Beth Y
    Gross, Jenny
    Olah, Edith
    Vaszko, Tibor
    Teo, Soo-Hwang
    Ganz, Patricia A
    Beattie, Mary S
    Dorfling, Cecelia M
    van Rensburg, Elizabeth J
    Diez, Orland
    Kwong, Ava
    Schmutzler, Rita K
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Ditsch, Nina
    Arnold, Norbert
    Heidemann, Simone
    Niederacher, Dieter
    Preisler-Adams, Sabine
    Gadzicki, Dorotehea
    Varon-Mateeva, Raymonda
    Deissler, Helmut
    Gehrig, Andrea
    Sutter, Christian
    Kast, Karin
    Fiebig, Britta
    Schäfer, Dieter
    Caldes, Trinidad
    de la Hoya, Miguel
    Nevanlinna, Heli
    Aittomäki, Kristiina
    Plante, Marie
    Spurdle, Amanda B
    Neuhausen, Susan L
    Ding, Yuan Chun
    Wang, Xianshu
    Lindor, Noralane
    Fredericksen, Zachary
    Pankratz, V Shane
    Peterlongo, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Bonanni, Bernardo
    Bernard, Loris
    Dolcetti, Riccardo
    Papi, Laura
    Ottini, Laura
    Radice, Paolo
    Greene, Mark H
    Mai, Phuong L
    Andrulis, Irene L
    Glendon, Gord
    Ozcelik, Hilmi
    Pharoah, Paul D P
    Gayther, Simon A
    Simard, Jacques
    Easton, Douglas F
    Couch, Fergus J
    Chenevix-Trench, Georgia
    Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.2012Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 33, nr 4, s. 690-702Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

  • 348.
    Ray-Coquard, I.
    et al.
    GINECO and Medical Oncology Department, Centre Léon Bérard, University Claude Bernard Lyon, Lyon, France.
    Cibula, D.
    AGO and Oncogynecologic Center, Department of Obstetrics and Gynecology, General Faculty Hospital, Charles University of Prague, Prague, Czech Republic.
    Mirza, M.R.
    NSGO and Department of Oncology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark.
    Reuss, A.
    AGO and Coordinating Center for Clinical Trials, Philipps-University of Marburg, Marburg, Germany.
    Ricci, C.
    MITO and Division of Gynecologic Oncology, Department of Women and Childrens Health and Public Health, Fondazione Policlinico Gemelli IRCCS, Rome, Italy.
    Colombo, N.
    MaNGO and European Institute of Oncology and University of Milan Bicocca, Milan, Italy.
    Koch, H.
    AGO Austria and Department of Obstetrics and Gynecology, Paracelsus Medical University, Salzburg, Austria.
    Goffin, F.
    BGOG and CHU de Liège, University of Liège, Liège, Belgium.
    González-Martin, A.
    GEICO and Medical Oncology Department, Clínica Universidad de Navarra, Madrid, Spain.
    Ottevanger, P.B.
    DGOG and Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, Netherlands.
    Baumann, K.
    AGO and Department of Gynecology, Klinikum der Stadt Ludwigshafen GmbH, Ludwigshafen, Germany.
    Bjørge, L.
    NSGO and Department of Gynecology, Haukeland Universitetssykehus, Bergen, Norway; Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
    Lesoin, A.
    GINECO and Department of Gynecologic Cancer and Medical Oncology, Centre Oscar Lambret, Lille, France.
    Burges, A.
    AGO and Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Germany.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Gropp-Meier, M.
    AGO and Department of Gynecology and Obstetrics, Oberschwabenklinik, Krankenhaus St. Elisabeth, Ravensburg, Germany.
    Harrela, M.
    NSGO and Department of Gynoncology and Gynecology and Obstetrics, Kymenlaakso Central Hospital, Kotka, Finland.
    Harter, P.
    AGO and Department of Gynecology and Gynecologic Oncology, Kliniken Essen Mitte, Essen, Germany.
    Frenel, J.-S.
    GINECO and Centre René Gauducheau, Institut de Cancerologie de lOuest, Saint Herblain, France.
    Minarik, T.
    NSGO and National Institute of Oncology, Bratislava, Slovakia.
    Pisano, C.
    MITO and Department of Uro-Gynecologic Oncology, Istituto Nazionale per Io Studio e la Cura dei Tumori ‘Fondazione G. Pascale’ IRCCS, Naples, Italy.
    Hasenburg, A.
    AGO and Department of Obstetrics and Gynecology, University Medical Center, Mainz, Germany.
    Merger, M.
    Oncology Medicine, Boehringer Ingelheim International GmbH, Biberach, Germany.
    du, Bois A.
    AGO and Department of Gynecology and Gynecologic Oncology, Kliniken Essen Mitte, Essen, Germany.
    Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer2019Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB–IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2–21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with amp;gt;1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83–1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75–0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports. © 2019 UICC

  • 349.
    Reed, Nicholas Simon
    et al.
    Beatson Oncology Centre, Glasgow, UK.
    Pautier, Patricia
    Institut Gustave Roussy, Villejuif, France.
    Åvall-Lundqvist, Elisabeth
    Karolinska Intitute, Stockholm, Sweden.
    Choi, Chel-Hun
    Samsung Medical Centre, Sung Kyun Kwan University Medical Centre, Seoul, South Korea.
    du Bois, Andreas
    University of Duisberg, Essen, Germany.
    Friedlander, Michael
    National Health and Medical Research Council, Clinical Trials Centre, New South Wales, Australia.
    Fyles, Anthony
    Princess Margaret Hospital, Toronto, Canada.
    Kichenadasse, Ganessan
    Flinders Centre for Innovation in Cancer, South Australia, Australia.
    Provencher, Diane M
    Centre hospitalier de l'Universite de Montreal, Montreal, Canada.
    Ray-Coquard, Isabelle
    Centre Leon Berard, Lyon, France.
    Gynecologic Cancer InterGroup (GCIG) consensus review for ovarian small cell cancers.2014Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 24, nr 9, s. S30-S34Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Small cell carcinomas of the ovary are uncommon and account for less than 1% of ovarian cancers. They were first recognized in 1979, and a number of reports appeared during the next 2 decades. They are highly aggressive tumors and usually carry a poor prognosis, although this may reflect that most are diagnosed at advanced stage; however, those diagnosed as stage 1A have only 30% to 40% of long-term survivors. More reports followed extending our experience in the diagnosis and management of these rare cancers. The classification is described below and shown in Table 1, but a revision is expected to be published from the World Health Organization in 2014.

  • 350.
    Robinson, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Prediction of survival in prostate cancer: aspects on localised, locally advanced and metastatic disease2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Background and aims: The clinical course of prostate cancer is highly variable and difficult to predict.Stage at presentation, grade and PSA at diagnosis are traditionally used to predict outcome. The aimof this thesis was to identify strategies for improved survival prediction in men with prostate cancer.The way in which prostate cancer affects a population based‐cohort and how routinely measuredvariables can be used to predict survival in an intermediate to long follow‐up period were explored.From this large cohort we separately evaluated how survival can be predicted in men with incidentalcarcinoma (T1a and b) and locally advanced disease (lymph node‐ positive). Immunohistochemistrywas added to routinely measured variables in the subgroup of men with incidental carcinoma.Furthermore, we assessed how the outcome of metastatic disease may be predicted from informationavailable at diagnosis, and during the first six months after treatment. Finally we predicted survivalfor men with metastatic hormone‐refractory prostate cancer (HRPC).

    Material and methods: From the Swedish South‐East Region Prostate Cancer Register data on 8887men were studied and the impact of tumour grade, serum PSA concentration, TNM classification andtreatment was studied in relation to survival.Furthermore, an evaluation of the disease‐specific mortality of conservatively managed incidentalcarcinoma in relation to T‐category, Gleason score, p53, Ki‐67, Chromogranin A and serotonin wasmade. From the same register we studied whether common predictive factors such as serum‐PSA, Tcategoryand biopsy tumour grade could be used to better assess the prognosis of men with nodepositiveprostate cancer. Using data from the clinical trial SPCG‐5 we studied the possibility of serialmeasurements of PSA and ALP being to predict survival early in the course of hormone‐treatedmetastatic prostate cancer. From the same trial, we also assessed the value of PSA kinetics inpredicting survival and related this to baseline variables in men with metastatic HRPC.

    Results: In the South–East Region, where screening was seldom done the median age at diagnosisand death was 75 and 80 years respectively, and 12% were diagnosed before the age of 65 years. Hightumour grade, high serum PSA and high T category were associated with poor outcome. The projected 15‐year disease‐specific survival rate was 44% for the whole population. In total, 18% ofpatients had metastases at diagnosis and their median survival was 2.5 years.

    In the cohort of men with incidental carcinoma, 17% died of prostate cancer. Of 86 patients withGleason score ≤5, three died of prostate cancer. Independent predictors of disease‐specific mortality inmultivariate analysis were category T1b prostate cancer, Gleason score >5 and high immunoreactivityof Ki‐67. Men with lymph‐node positive disease have a median cancer‐specific survival of 8 years.Preoperatively known factors such as PSA, T‐category, age, mode of treatment, failed to predictoutcome, but there was a weak, not statistically significant difference in cancer‐specific survival inrelation to tumour grade.

    Initial ALP, and ALP and PSA after 6 months of treatment were the serum markers that provided thebest prognostic information about the long‐term outcome of metastatic prostate cancer. In men withHRPC, PSA velocity alone gave a better prediction of survival than all other PSA kinetic variables.

    Conclusion: In an almost unscreened population, prostate cancer is the elderly mans disease but themortality is high. Ki‐67 may be of value in addition to stage and Gleason score for predicting theprognosis in men with incidental carcinoma.The impact of lymph node metastases on survival overrides all other commonly used prognosticfactors.

    By following ALP and PSA for 6 months it is possible to predict outcome in metastatic prostate cancer.This gives a much better prediction than baseline PSA and helps to select men with a poor prognosis.By combining PSAV with the variables available at baseline, a better ground for treatment decisionmakingin men with HRPC is achieved.

    Delarbeten
    1. Survival in prostate carcinoma - Outcomes from a prospective, population-based cohort of 8887 men with up to 15 years of follow-up: Results from three counties in the population-based National Prostate Cancer Registry of Sweden
    Öppna denna publikation i ny flik eller fönster >>Survival in prostate carcinoma - Outcomes from a prospective, population-based cohort of 8887 men with up to 15 years of follow-up: Results from three counties in the population-based National Prostate Cancer Registry of Sweden
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    2005 (Engelska)Ingår i: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 103, nr 5, s. 943- 951Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND To decide on screening strategies and curative treatments for prostate carcinoma, it is necessary to determine the incidence and survival in a population that is not screened.

    METHODS The 15-year projected survival data were analyzed from a prospective, complete, population-based registry of 8887 patients with newly diagnosed prostate carcinoma from 1987 to 1999.

    RESULTS The median patient age at diagnosis was 75 years (range, 40-96 years), and 12% of patients were diagnosed before the age 65 years. The median follow-up was 80 months for patients who remained alive. In total, 5873 of 8887 patients (66.1%) had died, and 2595 of those patients (44.2%) died directly due to prostate carcinoma. The overall median age at death was 80 years (range, 41-100 years). The projected 15-year disease-specific survival rate was 44% for the whole population. In total, 18% of patients had metastases at diagnosis (M1), and their median survival was 2.5 years. Patients with nonmetastatic T1-T3 prostate carcinoma (age < 75 years at diagnosis; n = 2098 patients) had a 15-year projected disease-specific survival rate of 66%. Patients who underwent radical prostatectomy had a significantly lower risk of dying from prostate carcinoma (relative risk, 0.40) compared with patients who were treated with noncurative therapies or radiotherapy.

    CONCLUSIONS The disease-specific mortality was comparatively high, but it took 15 years to reach a disease-specific mortality rate of 56%. These data form a truly population-based baseline on how prostate carcinoma will affect a population when screening is not applied and can be used for comparison with other health care strategies. Cancer 2005. © 2005 American Cancer Society.

    Nyckelord
    prostate carcinoma, registries, therapy, survival
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-14793 (URN)10.1002/cncr.20855 (DOI)
    Tillgänglig från: 2008-09-24 Skapad: 2008-09-24 Senast uppdaterad: 2017-12-13
    2. Long-term follow-up of conservatively managed incidental carcinoma of the prostate A multivariate analysis of prognostic factors
    Öppna denna publikation i ny flik eller fönster >>Long-term follow-up of conservatively managed incidental carcinoma of the prostate A multivariate analysis of prognostic factors
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    2007 (Engelska)Ingår i: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 41, nr 2, s. 103-109Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective: To evaluate the disease-specific mortality of conservatively managed incidental carcinoma of the prostate (T1a and T1b) in relation to prognostic factors.

    Material and methods: Since 1987 all patients with prostate cancer have been recorded and followed in the population-based Prostate Cancer Register of the South-East Healthcare Region in Sweden, which is covered by four departments of pathology. At two of these departments, tissue was obtained from 197 consecutive, previously untreated patients (aged <80 years) with incidental carcinoma who underwent transurethral resection of the prostate between 1987 and 1991. The amount of tumour, Gleason score and levels of Ki-67, p53, chromogranin A and serotonin were determined. Univariate analysis and multiple Cox regression hazard analysis were used for analysis.

    Results: During follow-up (mean 7.8 years; maximum 17.5 years), 158 patients (80%) had died, 33 of them of prostate cancer, corresponding to 17% of the entire cohort. Of 86 patients with Gleason score ≤5, three died of prostate cancer. Independent predictors of disease-specific mortality in multivariate analysis were category T1b prostate cancer, Gleason score >5 and high immunoreactivity of Ki-67.

    Conclusions: Elderly men with category T1a and/or Gleason score 4-5 prostate cancer have a favourable prognosis with conservative management. Immunohistochemical staining with Ki-67 may be of help in situations where further prognostic information is required.

    Nyckelord
    Prostate cancer, prognostic factors, incidental carcinoma, survival, p53, Ki-67, chromogranin A
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-14794 (URN)10.1080/00365590600991268 (DOI)
    Tillgänglig från: 2008-09-24 Skapad: 2008-09-24 Senast uppdaterad: 2017-12-13
    3. Prognostic Factors and Survival in Node-Positive (N1) Prostate Cancer: A Prospective Study Based on Data from a Swedish Population-Based Cohort
    Öppna denna publikation i ny flik eller fönster >>Prognostic Factors and Survival in Node-Positive (N1) Prostate Cancer: A Prospective Study Based on Data from a Swedish Population-Based Cohort
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    2003 (Engelska)Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 43, nr 6, s. 627-631Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective: At presentation of prostate cancer, patients with proven lymph node metastasis (N1) are comparatively rare. It is difficult to give prognostic information based on the present literature. The aim of this study was to evaluate the impact of known risk factors in patients with pelvic node involvement and without distant metastasis.

    Methods: From the population-based, prospective prostate cancer tumour registry of the South–East Region in Sweden, we collected data on all 181 patients with N1, M0 prostate cancer diagnosed from January 1987 to October 2000 with a follow-up to December 2001. Mean follow-up was 62 months. Pre-operative risk factors as age, T-category, serum PSA, tumour grade and also primary treatment given was correlated to the outcome.

    Results: Median age at diagnosis was 65 years. Cancer-specific survival was highly variable with 5-year survival of 72%, a median of 8 years and the projected 13-year figure was 31%. T-category, age, PSA or treatment did not affect the outcome while poorly differentiated tumours had a tendency towards lower cancer-specific survival (p=0.0523) when compared to well and moderately differentiated tumours.

    Conclusions: This population-based cohort of prostate cancer patients with pelvic node involvement treated principally with non-curative intent had a median cancer-specific survival of 8 years. Preoperatively known risk factors seem to have but a modest impact on the prognosis for patients in this stage of the disease.

    Nyckelord
    Prostate cancer; Lymph node metastasis; N-category; Prognosis; Risk factors; Treatment
    Nationell ämneskategori
    Cancer och onkologi Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14795 (URN)10.1016/S0302-2838(03)00156-8 (DOI)
    Tillgänglig från: 2008-09-24 Skapad: 2008-09-24 Senast uppdaterad: 2017-12-13
    4. Prediction of Survival of Metastatic Prostate Cancer Based on Early Serial Measurements of Prostate Specific Antigen and Alkaline Phosphatase
    Öppna denna publikation i ny flik eller fönster >>Prediction of Survival of Metastatic Prostate Cancer Based on Early Serial Measurements of Prostate Specific Antigen and Alkaline Phosphatase
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    2008 (Engelska)Ingår i: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 179, nr 1, s. 117-123Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Purpose: We determined how serial measurements of prostate specific antigen and alkaline phosphatase can be used to predict survival early in the course of hormone treated metastatic prostate cancer.

    Materials and Methods: The study was based on a prospective randomized trial of 915 patients with metastatic prostate carcinoma designed to compare parenteral estrogen (polyestradiol phosphate) vs total androgen blockade. We included 697 men who survived at least 6 months and had complete serial measurements of prostate specific antigen and alkaline phosphatase. Six models were constructed based on prostate specific antigen and alkaline phosphatase at start, and after 6 months of treatment, alkaline phosphatase flare and relative prostate specific antigen velocity. We constructed time dependent receiver operating characteristic curves with corresponding area under the curve to predict death from prostate cancer within 3 years.

    Results: The best variables to predict outcome were alkaline phosphatase at 6 months (AUC 0.79 for polyestradiol phosphate and 0.72 for total androgen blockade), alkaline phosphatase at baseline (AUC 0.70 for polyestradiol phosphate and total androgen blockade) and prostate specific antigen at 6 months (AUC 0.70 for polyestradiol phosphate and total androgen blockade). Prostate specific antigen and alkaline phosphatase levels 6 months after start of treatment give better prediction of survival than baseline levels.

    Conclusions: Alkaline phosphatase at start of treatment and alkaline phosphatase and prostate specific antigen after 6 months can be used to predict survival of hormone treated metastatic prostate cancer.

    Nyckelord
    Prostatic neoplasms, prostate-specific antigen, alkaline phosphatase, survival
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-14796 (URN)10.1016/j.juro.2007.08.132 (DOI)
    Tillgänglig från: 2008-09-24 Skapad: 2008-09-24 Senast uppdaterad: 2017-12-13
    5. PSA Kinetics Provide Improved Prediction of Survival in Metastatic Hormone-Refractory Prostate Cancer
    Öppna denna publikation i ny flik eller fönster >>PSA Kinetics Provide Improved Prediction of Survival in Metastatic Hormone-Refractory Prostate Cancer
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    2008 (Engelska)Ingår i: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 72, nr 4, s. 903-907Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objectives: To assess the value of prostate-specific antigen (PSA) kinetics in predicting survival and relate this to the baseline variables in men with metastatic hormone-refractory prostate cancer (HRPC).

    Methods: The data from 417 men with HRPC were included in a logistic regression model that included hemoglobin, PSA, alkaline phosphatase, Soloway score, and performance status pain analgesic score at baseline. The posttreatment variables included the PSA level halving time after the start of treatment, PSA level at nadir, interval to nadir, PSA velocity (PSAV), PSA doubling time after reaching a nadir, patient age, and treatment. These variables were added to the baseline model, forming new logistic regression models that were tested for net reclassification improvement.

    Results: The area under the receiver operating characteristics curve for the baseline model was 0.67. Of all variables related to PSA kinetics, the PSAV was the best predictor. The addition of PSAV to the baseline model increased the area under the receiver operating characteristics curve to 0.81. Only a moderate increase in the area under the receiver operating characteristics curve (0.83) was achieved by combining the baseline model in a multivariate model with PSAV, PSA doubling time, interval to nadir, and patient age at diagnosis of HRPC.

    Conclusions: The PSAV alone gave a better prediction of survival value than all other PSA kinetics variables. By combining PSAV with the variables available at baseline, a better ground for treatment decision-making in men with HRPC can be achieved.

    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-14797 (URN)10.1016/j.urology.2008.05.026 (DOI)
    Tillgänglig från: 2008-09-24 Skapad: 2008-09-24 Senast uppdaterad: 2017-12-13
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