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  • 251.
    Lind, H
    et al.
    Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Waldenström, A-C
    Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Dunberger, G
    Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    al-Abany, M
    Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. Department of Medical Physics, Karolinska University Hospital, Stockholm, Sweden.
    Alevronta, E
    Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Johansson, K-A
    Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Olsson, C
    Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Nyberg, T
    Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Wilderäng, U
    Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Steineck, G
    Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Åvall-Lundqvist, Elisabeth
    Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. Department of Gynecologic Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Late symptoms in long-term gynaecological cancer survivors after radiation therapy: a population-based cohort study.2011Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 105, nr 6, s. 737-745Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: We surveyed the occurrence of physical symptoms among long-term gynaecological cancer survivors after pelvic radiation therapy, and compared with population-based control women.

    METHODS: We identified a cohort of 789 eligible gynaecological cancer survivors treated with pelvic radiation therapy alone or combined with surgery in Stockholm or Gothenburg, Sweden. A control group of 478 women was randomly sampled from the Swedish Population Registry. Data were collected through a study-specific validated postal questionnaire with 351 questions concerning gastrointestinal and urinary tract function, lymph oedema, pelvic bones and sexuality. Clinical characteristics and treatment details were retrieved from medical records.

    RESULTS: Participation rate was 78% for gynaecological cancer survivors and 72% for control women. Median follow-up time after treatment was 74 months. Cancer survivors reported a higher occurrence of symptoms from all organs studied. The highest age-adjusted relative risk (RR) was found for emptying of all stools into clothing without forewarning (RR 12.7), defaecation urgency (RR 5.7), difficulty feeling the need to empty the bladder (RR 2.8), protracted genital pain (RR 5.0), pubic pain when walking indoors (RR 4.9) and erysipelas on abdomen or legs at least once during the past 6 months (RR 3.6). Survivors treated with radiation therapy alone showed in general higher rates of symptoms.

    CONCLUSION: Gynaecological cancer survivors previously treated with pelvic radiation report a higher occurrence of symptoms from the urinary and gastrointestinal tract as well as lymph oedema, sexual dysfunction and pelvic pain compared with non-irradiated control women. Health-care providers need to actively ask patients about specific symptoms in order to provide proper diagnostic investigations and management.

  • 252.
    Lind, Helena
    et al.
    Karolinska Institute, Sweden.
    Alevronta, Eleftheria
    Karolinska Institute, Sweden; University of Gothenburg, Sweden.
    Steineck, Gunnar
    Karolinska Institute, Sweden; University of Gothenburg, Sweden.
    Waldenström, Ann-Charlotte
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Nyberg, Tommy
    Karolinska Institute, Sweden.
    Olsson, Caroline
    University of Gothenburg, Sweden.
    Wilderang, Ulrica
    University of Gothenburg, Sweden.
    Dunberger, Gail
    Karolinska Institute, Sweden; Ersta Skondal University of Coll, Sweden.
    al-Abany, Massoud
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Åvall-Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Defecation into clothing without forewarning and mean radiation dose to bowel and anal-sphincter among gynecological cancer survivors2016Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, nr 11, s. 1285-1293Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: To analyze the relationship between mean radiation dose to the bowels and the anal-sphincter and occurrence of defecation into clothing without forewarning, a specific and serious fecal incontinence symptom after gynecological radiotherapy. Additional potential risk factors associated with the symptom are explored.Material and methods: Data were collected for 519 eligible gynecological cancer survivors, treated with pelvic radiotherapy, with a median follow-up of 5.8 years, using a study-specific questionnaire and medical records. Correlations between defecation into clothing without forewarning and mean dose to organs at risk; the anal-sphincter region, the rectum, the sigmoid and the small intestines were investigated, also taking other risk factors into account.Results: Twelve percent reported having had the symptom at least once in the preceding six months. Mean dosesamp;gt;50Gy to the anal-sphincter region, the rectum, the sigmoid and the small intestines were related to the occurrence of the symptom. Significantly associated risk factors were deliveries with high birth weight, heart failure and lactose and/or gluten intolerance. After adjusting for these factors, mean dosesamp;gt;50Gy to the anal-sphincter region, the sigmoid and the small intestines remained related to the occurrence of the symptom.Conclusion: Mean doses to the bowels and anal-sphincter region are related to the risk of defecation into clothing without forewarning in long-term gynecological cancer survivors treated with pelvic radiotherapy. Further radiobiological modeling may distinguish which organ(s) contribute most to development of the symptom.

  • 253.
    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.
    The effects of flaxseed and tamoxifen on the inflammatory microenvironment in normal breast tissue and in breast cancer2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Breast cancer is the most common cancer among women worldwide today. Nearly 9000 women are diagnosed with breast cancer in Sweden yearly and despite advantages in diagnostics and treatments approximately 1400 women still die from their disease every year. Breast cancer has a diverse etiology and hormonal factors and life-style factors contribute to an increased breast cancer risk. High mammographic density is also considered a risk factor but the underlying mechanisms are not fully understood. Inflammation is associated with poor survival in several malignancies and is considered a hallmark of cancer. There is evidence indicating that increased inflammation is associated with dense breast tissue and may contribute to an increased risk of breast cancer in these patients.

    There is an urgent need to find risk reduction strategies in breast cancer prevention. Several studies have shown that antiestrogens significantly reduce breast cancer incidence in women with high risk of developing breast cancer and can be used for chemoprevention. These drugs may have potentially severe side effects and other strategies are needed. Dietary interventions may influence breast cancer risk without any major side effects. Studies indicate that dietary phytoestrogens may reduce breast cancer risk. The most common phytoestrogens in Western populations are lignans, mainly found in flaxseed, but results from several studies with lignans for breast cancer prevention have been inconsistent.

    In this thesis we investigated the effects of tamoxifen and flaxseed on inflammatory mediators in normal breast tissue and in breast cancer. We used the microdialysis technique to sample proteins from the extracellular space in vivo. This technique gives us the opportunity to study proteins in their bioactive compartment in situ and to study changes in protein levels at different time points without affecting the tissue of interest. We also used experimental models and cell cultures to study tumor growth of human breast cancer xenografts, cancer cell proliferation and angiogenesis.

    In paper I, we investigated whether tamoxifen, flaxseed, enterolactone or genestein reduced growth of human breast cancer xenografts and their association with pro-inflammatory cytokine interleukin 1β (IL-1β) and its antagonist interleukin 1 receptor antagonist (IL-1Ra). In paper II, we investigated whether tamoxifen and flaxseed exerted similar effects on inflammatory mediators in normal breast tissue in vivo. In paper III, we investigated whether osteopontin (OPN), a pro-inflammatory cytokine, was associated with dense breast tissue and breast cancer and if tamoxifen and flaxseed could alter OPN levels in normal breast tissue in vivo. We also investigated the correlation between OPN and inflammatory mediators in normal breast tissue and in breast cancer in vivo.

    In conclusion, we showed that tamoxifen and flaxseed affected breast cancer growth in an experimental model and may exert an anti-inflammatory effect in breast cancer and normal breast tissue by increasing the IL-1Ra/IL-1β ratio in vivo. We showed that dense breast tissue and breast cancer were associated with increased levels of OPN. Circulating estrogen did not correlate to OPN and tamoxifen and flaxseed did not affect OPN levels suggesting an estrogen independent regulation of OPN in vivo. These finding contributes to our understanding of how tamoxifen and flaxseed affects inflammation and the role of inflammation in the pathogenesis of breast cancer.

    Delarbeten
    1. Tamoxifen, Flaxseed, and the Lignan Enterolactone Increase Stroma- and Cancer Cell-Derived IL-1Ra and Decrease Tumor Angiogenesis in Estrogen-Dependent Breast Cancer
    Öppna denna publikation i ny flik eller fönster >>Tamoxifen, Flaxseed, and the Lignan Enterolactone Increase Stroma- and Cancer Cell-Derived IL-1Ra and Decrease Tumor Angiogenesis in Estrogen-Dependent Breast Cancer
    2011 (Engelska)Ingår i: CANCER RESEARCH, ISSN 0008-5472, Vol. 71, nr 1, s. 51-60Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The proinflammatory cytokines IL-1 alpha and IL-1 beta promote tumor angiogenesis that might be counteracted by the IL-1 receptor antagonist (IL-1Ra), anakinra, a clinically approved agent. A diet with high amounts of phytoestrogens, such as flaxseed (Flax), genistein (GEN), and the mammalian lignan enterolactone (ENL), may affect breast cancer progression in a similar fashion as the antiestrogen tamoxifen. Both cancer cells and tumor stroma may be targets for cancer therapy. By using microdialysis in a model of human breast cancers in nude mice, we could perform species-specific analyses of released proteins in the microenvironment. We show that tumors treated with tamoxifen and fed Flax or ENL exhibited decreased in vivo release of IL-1 beta derived from the murine stroma and decreased microvessel density whereas dietary GEN had no effects. Cancer cell-released IL-1Ra were approximately 5 times higher than stroma-derived IL-1Ra. Tamoxifen, Flax, and ENL increased IL-1Ra levels significantly whereas GEN did not. The tumor stroma contained macrophages, which expressed the estrogen receptor. In vitro, estradiol decreased IL-1Ra released from breast cancer cells and from cultured macrophages. IL-1Ra decreased endothelial cell proliferation significantly in vitro whereas breast cancer cell proliferation was unaffected in presence of estradiol. Finally, IL-1Ra therapy of tumor-bearing mice opposed estrogen-dependent breast cancer growth and decreased angiogenesis. We conclude that the release of IL-1s both by cancer cells and the stroma, where macrophages are a key component, may offer feasible targets for antiestrogen therapy and dietary interventions against breast cancer.

    Ort, förlag, år, upplaga, sidor
    American Association for Cancer Research, 2011
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-65567 (URN)10.1158/0008-5472.CAN-10-2289 (DOI)000285826800007 ()
    Tillgänglig från: 2011-02-11 Skapad: 2011-02-11 Senast uppdaterad: 2019-11-01
    2. Dietary flaxseed and tamoxifen affect the inflammatory microenvironment in vivo in normal human breast tissue of postmenopausal women
    Öppna denna publikation i ny flik eller fönster >>Dietary flaxseed and tamoxifen affect the inflammatory microenvironment in vivo in normal human breast tissue of postmenopausal women
    2019 (Engelska)Ingår i: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 73, nr 9, s. 1250-1259Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background Anti-oestrogens such as tamoxifen, decrease the risk of breast cancer but are unsuitable for prevention because of their side-effects. Diet modifications may be a breast cancer prevention strategy. Here, we investigated if a diet addition of flaxseed, which can be converted to the phytoestrogen enterolactone by the gut microbiota, exhibited similar effects as tamoxifen on normal human breast tissue in vivo, with special emphasis on inflammatory mediators implicated in cancer progression. Subjects A total of 28 postmenopausal women were included. Thirteen women added 25 g of ground flaxseed per day and 15 were treated with tamoxifen as an adjuvant for early breast cancer for 6 weeks. Microdialysis of normal breast tissue and, as a control, in subcutaneous abdominal fat was performed for sampling of extracellular proteins in vivo before and after exposures. Results Enterolactone levels increased significantly after flaxseed. IL-1Ra and IL-1Ra/IL-1 beta ratio in the breast increased in a similar fashion after the two different treatments. Flaxseed also increased breast specific levels of IL-1RT2, IL-18 and sST2 and an overall increase of MMP-9. These changes correlated significantly with enterolactone levels. Tamoxifen decreased breast tissue levels of IL-8 and IL-18. None of the treatments induced any changes of IL-1 beta, IL-1RT1, IL-18BP, IL-33, IL-6, IL-6RA, MMP-1, MMP-2 and MMP-3. Conclusions We conclude that dietary flaxseed and tamoxifen exert both similar and different effects, as listed above, on normal breast tissue in vivo and that a relatively modest diet change can induce significant effects on the breast microenvironment.

    Ort, förlag, år, upplaga, sidor
    NATURE PUBLISHING GROUP, 2019
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-160614 (URN)10.1038/s41430-019-0396-y (DOI)000484395100006 ()30692654 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [2015/309]; Swedish Research CouncilSwedish Research Council [20132457]; ALF of Linkoping University Hospital

    Tillgänglig från: 2019-10-21 Skapad: 2019-10-21 Senast uppdaterad: 2019-11-01
    3. Increased Extracellular Osteopontin Levels in Normal Human Breast Tissue at High Risk of Developing Cancer and Its Association With Inflammatory Biomarkers in situ
    Öppna denna publikation i ny flik eller fönster >>Increased Extracellular Osteopontin Levels in Normal Human Breast Tissue at High Risk of Developing Cancer and Its Association With Inflammatory Biomarkers in situ
    2019 (Engelska)Ingår i: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 9, artikel-id 746Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Mammographic breast density is a strong independent risk factor for breast cancer (BC), but the molecular mechanisms behind this risk is yet undetermined and prevention strategies for these women are lacking. The anti-estrogen tamoxifen may reduce the risk of BC but this treatment is associated with severe side effects. Thus, other means for BC prevention, such as diet interventions, need to be developed. Osteopontin (OPN) is a major mediator of inflammation which is key in carcinogenesis. OPN may be cleaved by proteases in the tissue and cleaved OPN may in turn induce an inflammatory cascade in the extracellular microenvironment. We aimed to determine if extracellular OPN was altered in BC and in normal breast tissue with different densities and if tamoxifen or a diet of flaxseed could modify OPN levels. The study comprised 103 women; 13 diagnosed with BC, 42 healthy post-menopausal women with different breast densities at their mammography screen, and 34 post-menopausal women who added 25 g of ground flaxseed/day or were treated with tamoxifen 20 mg/day and were investigated before and after 6 weeks of exposure. Additionally, 10 premenopausal women who added flaxseed for one menstrual cycle and four who were investigated in two unexposed consecutive luteal phases of the menstrual cycle. Microdialysis was used to sample extracellular proteins in vivo in breast tissue and proteins were quantified using a multiplex proximity extension assay. We found that, similar to BC, extracellular in vivo OPN levels were significantly increased in dense breast tissue. Additionally, significant correlations were found between OPN and chemokine (C-X-C motif) ligand (CXCL)-1, -8, -9, -10, and - 11, interleukin-6, vascular endothelial growth factor, matrix metalloproteinase (MMP)-1, - 2, -3, 7, and -12 and urokinase-type plasminogen activator whereas no correlations were found with MMP-9, chemokine (C-C motif) ligand (CCL)-2, and -5. Estradiol did not affect OPN levels in breast tissue. None of the interventions altered OPN levels. The pro-tumorigenic protein OPN may indeed be a molecular target for BC prevention in women with increased breast density but other means than tamoxifen or flaxseed i.e., more potent anti-inflammatory approaches, need to be evaluated for this purpose.

    Ort, förlag, år, upplaga, sidor
    FRONTIERS MEDIA SA, 2019
    Nyckelord
    inflammation; microdialysis; tamoxifen; flaxseed; enterolactone
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-160039 (URN)10.3389/fonc.2019.00746 (DOI)000481427600001 ()31475105 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Cancer Society [2018/464]; Swedish Research Council [2018-02584]; LiU-Cancer; ALF of Linkoping University Hospital

    Tillgänglig från: 2019-09-06 Skapad: 2019-09-06 Senast uppdaterad: 2019-11-26
  • 254.
    Lindahl, Gabriel
    et al.
    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.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Dabrosin, Charlotta
    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.
    Dietary flaxseed and tamoxifen affect the inflammatory microenvironment in vivo in normal human breast tissue of postmenopausal women2019Ingår i: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 73, nr 9, s. 1250-1259Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Anti-oestrogens such as tamoxifen, decrease the risk of breast cancer but are unsuitable for prevention because of their side-effects. Diet modifications may be a breast cancer prevention strategy. Here, we investigated if a diet addition of flaxseed, which can be converted to the phytoestrogen enterolactone by the gut microbiota, exhibited similar effects as tamoxifen on normal human breast tissue in vivo, with special emphasis on inflammatory mediators implicated in cancer progression. Subjects A total of 28 postmenopausal women were included. Thirteen women added 25 g of ground flaxseed per day and 15 were treated with tamoxifen as an adjuvant for early breast cancer for 6 weeks. Microdialysis of normal breast tissue and, as a control, in subcutaneous abdominal fat was performed for sampling of extracellular proteins in vivo before and after exposures. Results Enterolactone levels increased significantly after flaxseed. IL-1Ra and IL-1Ra/IL-1 beta ratio in the breast increased in a similar fashion after the two different treatments. Flaxseed also increased breast specific levels of IL-1RT2, IL-18 and sST2 and an overall increase of MMP-9. These changes correlated significantly with enterolactone levels. Tamoxifen decreased breast tissue levels of IL-8 and IL-18. None of the treatments induced any changes of IL-1 beta, IL-1RT1, IL-18BP, IL-33, IL-6, IL-6RA, MMP-1, MMP-2 and MMP-3. Conclusions We conclude that dietary flaxseed and tamoxifen exert both similar and different effects, as listed above, on normal breast tissue in vivo and that a relatively modest diet change can induce significant effects on the breast microenvironment.

  • 255.
    Lindahl, Gabriel
    et al.
    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.
    Rzepecka, Anna
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Dabrosin, Charlotta
    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.
    Increased Extracellular Osteopontin Levels in Normal Human Breast Tissue at High Risk of Developing Cancer and Its Association With Inflammatory Biomarkers in situ2019Ingår i: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 9, artikel-id 746Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mammographic breast density is a strong independent risk factor for breast cancer (BC), but the molecular mechanisms behind this risk is yet undetermined and prevention strategies for these women are lacking. The anti-estrogen tamoxifen may reduce the risk of BC but this treatment is associated with severe side effects. Thus, other means for BC prevention, such as diet interventions, need to be developed. Osteopontin (OPN) is a major mediator of inflammation which is key in carcinogenesis. OPN may be cleaved by proteases in the tissue and cleaved OPN may in turn induce an inflammatory cascade in the extracellular microenvironment. We aimed to determine if extracellular OPN was altered in BC and in normal breast tissue with different densities and if tamoxifen or a diet of flaxseed could modify OPN levels. The study comprised 103 women; 13 diagnosed with BC, 42 healthy post-menopausal women with different breast densities at their mammography screen, and 34 post-menopausal women who added 25 g of ground flaxseed/day or were treated with tamoxifen 20 mg/day and were investigated before and after 6 weeks of exposure. Additionally, 10 premenopausal women who added flaxseed for one menstrual cycle and four who were investigated in two unexposed consecutive luteal phases of the menstrual cycle. Microdialysis was used to sample extracellular proteins in vivo in breast tissue and proteins were quantified using a multiplex proximity extension assay. We found that, similar to BC, extracellular in vivo OPN levels were significantly increased in dense breast tissue. Additionally, significant correlations were found between OPN and chemokine (C-X-C motif) ligand (CXCL)-1, -8, -9, -10, and - 11, interleukin-6, vascular endothelial growth factor, matrix metalloproteinase (MMP)-1, - 2, -3, 7, and -12 and urokinase-type plasminogen activator whereas no correlations were found with MMP-9, chemokine (C-C motif) ligand (CCL)-2, and -5. Estradiol did not affect OPN levels in breast tissue. None of the interventions altered OPN levels. The pro-tumorigenic protein OPN may indeed be a molecular target for BC prevention in women with increased breast density but other means than tamoxifen or flaxseed i.e., more potent anti-inflammatory approaches, need to be evaluated for this purpose.

  • 256.
    Lindblom, Emely
    et al.
    Stockholm University.
    Antonovic, Laura
    Stockholm University.
    Dasu, Alexandru
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Lax, Ingmar
    Karolinska University Hospital.
    Wersäll, Peter
    Karolinska University Hospital.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Treatment fractionation for stereotactic radiotherapy of lung tumours: a modelling study of the influence of chronic and acute hypoxia on tumour control probability2014Ingår i: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 9, s. Article ID 149-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC) has led to promising local control and overall survival for fractionation schemes with increasingly high fractional doses. A point has however been reached where the number of fractions used might be too low to allow efficient local inter-fraction reoxygenation of the hypoxic cells residing in the tumour. It was therefore the purpose of this study to investigate the impact of hypoxia and extreme hypofractionation on the tumour control probability (TCP) from SBRT.

    Methods: A three-dimensional model of tumour oxygenation able to simulate oxygenation changes on the microscale was used. The TCP was determined for clinically relevant SBRT fractionation schedules of 1, 3 and 5 fractions assuming either static tumour oxygenation or that the oxygenation changes locally between fractions due to fast reoxygenation of acute hypoxia without an overall reduction in chronic hypoxia.

    Results: For the schedules applying three or five fractions the doses required to achieve satisfying levels of TCP were considerably lower when local oxygenation changes were assumed compared to the case of static oxygenation; a decrease in D50 of 17.7 Gy was observed for a five-fractions schedule applied to a 20% hypoxic tumour when fast reoxygenation was modelled. Assuming local oxygenation changes, the total doses required for a tumor control probability of 50% were of similar size for one, three and five fractions.

    Conclusions: Although attractive from a practical point of view, extreme hypofractionation using just one single fraction may result in impaired local control of hypoxic tumours, as it eliminates the possibility for any kind of reoxygenation.

  • 257.
    Lindblom, Emely
    et al.
    Stockholm University, Stockholm, Sweden.
    Dasu, Alexandru
    The Skandion Clinic, Uppsala, Sweden.
    Beskow, Catharina
    Karolinska Hospital, Stockholm, Sweden.
    Toma-Dasu, Iuliana
    Stockholm Universitym Stockholm Sweden; Karolinska Institutet, Stockholm, Sweden.
    High brachytherapy doses can counteract hypoxia in cervical cancer – a modelling study2017Ingår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 62, nr 2, s. 560-572Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tumour hypoxia is a well-known adverse factor for the outcome of radiotherapy. For cervical tumours in particular, several studies indicate large variability in tumour oxygenation. However, clinical evidence shows that the management of cervical cancer including brachytherapy leads to high rate of success. It was the purpose of this study to investigate whether the success of brachytherapy for cervical cancer, seemingly regardless of oxygenation status, could be explained by the characteristics of the brachytherapy dose distributions.

    To this end, a previously used in silico model of tumour oxygenation and radiation response was further developed to simulate the treatment of cervical cancer employing a combination of external beam radiotherapy and intracavitary brachytherapy. Using a clinically-derived brachytherapy dose distribution and assuming a homogeneous dose delivered by external radiotherapy, cell survival was assessed on voxel level by taking into account the variation of sensitivity with oxygenation as well as the effects of repair, repopulation and reoxygenation during treatment. Various scenarios were considered for the conformity of the brachytherapy dose distribution to the hypoxic region in the target.

    By using the clinically-prescribed brachytherapy dose distribution and varying the total dose delivered with external beam radiotherapy in 25 fractions, the resulting values of the dose for 50% tumour control, D50, were in agreement with clinically-observed values for high cure rates if fast reoxygenation was assumed. The D50 was furthermore similar for the different degrees of conformity of the brachytherapy dose distribution to the tumour, regardless of whether the hypoxic fraction was 10%, 25%, or 40%. To achieve 50% control with external RT only, a total dose of more than 70 Gy in 25 fractions would be required for all cases considered.

    It can thus be concluded that the high doses delivered in brachytherapy can counteract the increased radioresistance caused by hypoxia if fast reoxygenation is assumed.

  • 258.
    Lindblom, Emely
    et al.
    Stockholm University.
    Dasu, Alexandru
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Lax, Ingmar
    Karolinska University Hospital.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Survival and tumour control probability in tumours with heterogeneous oxygenations: A comparison between the linear-quadratic and the universal survival curve models for high doses2014Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, nr 8, s. 1035-1040Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The validity of the linear-quadratic (LQ) model at high doses has been questioned due to a decreasing agreement between predicted survival and experimental cell survival data. A frequently proposed alternative is the universal survival curve (USC) model, thought to provide a better fit in the high-dose region. The comparison between the predictions of the models has mostly been performed for uniform populations of cells with respect to sensitivity to radiation. This study aimed to compare the two models in terms of cell survival and tumour control probability (TCP) for cell populations with mixed sensitivities related to their oxygenation.

    Methods: The study was performed in two parts. For the first part, cell survival curves were calculated with both models assuming various homogeneous populations of cells irradiated with uniform doses. For the second part, a realistic 3D-model of complex tumour oxygenation was used to study the impact of the differences in cell survival on the modelled tumour control probability. Cellular response was assessed with the LQ and USC models at voxel level and a Poisson TCP model at tumour level.

    Results: For hypoxic tumours, the disputed continuous bend of the LQ survival curve was counteracted by the increased radio-resistance of the hypoxic cells and the survival curves started to diverge only at much higher doses than for oxic tumours. This was also reflected by the TCP curves for hypoxic tumours for which the difference in D50 values for the LQ and USC models was reduced from 5.4 to 0.2 Gy for 1 and 3 fractions respectively in a tumour with only 1.1% hypoxia and from 9.5 to 0.4 Gy in a tumour with 11.1% hypoxia.

    Conclusions: For a large range of fractional doses including hypofractionated schemes, the difference in predicted survival and tumour control probability between the LQ and USC models for tumours with heterogeneous oxygenation was found to be negligible.

  • 259.
    Lindblom, Emely
    et al.
    Stockholm University.
    Dasu, Alexandru
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Optimal fractionation in radiotherapy for non-small cell lung cancer - a modelling approach2015Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, nr 9, s. 1592-1598Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. Conventionally fractionated radiotherapy (CFRT) has proven ineffective in treating non-small cell lung cancer while more promising results have been obtained with stereotactic body radiotherapy (SBRT). Hypoxic tumours, however, might present a challenge to extremely hypofractionated schedules due to the decreased possibility for inter-fraction fast reoxygenation. A potentially successful compromise might be found in schedules employing several fractions of varying fractional doses. In this modelling study, a wide range of fractionation schedules from single-fraction treatments to heterogeneous, multifraction schedules taking into account repair, repopulation, reoxygenation and radiosensitivity of the tumour cells, has been explored with respect to the probability of controlling lung tumours.

    Material and methods. The response to radiation of tumours with heterogeneous spatial and temporal oxygenation was simulated including the effects of accelerated repopulation and intra-fraction repair. Various treatments with respect to time, dose and fractionation were considered and the outcome was estimated as Poisson-based tumour control probability for local control.

    Results. For well oxygenated tumours, heterogeneous fractionation could increase local control while hypoxic tumours are not efficiently targeted by such treatments despite reoxygenation. For hypofractionated treatments employing large doses per fraction, a synergistic effect was observed between intra-fraction repair and inter-fraction fast reoxygenation of the hypoxic cells as demonstrated by a reduction in D50 from 53.3 Gy for 2 fractions to 52.7 Gy for 5 fractions.

    Conclusions. For well oxygenated tumours, heterogeneous fractionation schedules could increase local control rates substantially compared to CFRT. For hypoxic tumours, SBRT-like hypofractionated schedules might be optimal despite the increased risk of intra-fraction repair due to a synergistic effect with inter-fraction reoxygenation.

  • 260.
    Lindblom, Emely
    et al.
    Stockholm University, Sweden.
    Dasu, Alexandru
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. The Skandion Clinic, Uppsala, Sweden.
    Uhrdin, Johan
    RaySearch Laboratories AB.
    Even, Aniek J. G.
    Maastricht University Medical Center, Maastricht, The Netherlands.
    van Elmpt, Wouter
    Maastricht University Medical Center, Maastricht, The Netherlands.
    Lambin, Philippe
    Maastricht University Medical Center, Maastricht, The Netherlands.
    Wersäll, Peter
    Karolinska University Hospital, Stockholm, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet, Sweden.
    Defining the hypoxic target volume based on positron emission tomography for image guided radiotherapy - the influence of the choice of the reference region and conversion function2017Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, nr 6, s. 819-825Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Hypoxia imaged by positron emission tomography (PET) is a potential target for optimization in radiotherapy. However, the implementation of this approach with respect to the conversion of intensities in the images into oxygenation and radiosensitivity maps is not straightforward. This study investigated the feasibility of applying two conversion approaches previously derived for 18F-labeled fluoromisonidazole (18F-FMISO)-PET images for the hypoxia tracer 18F-flortanidazole (18F-HX4).

    Material and methods: Ten non-small-cell lung cancer patients imaged with 18F-HX4 before the start of radiotherapy were considered in this study. PET image uptake was normalized to a well-oxygenated reference region and subsequently linear and non-linear conversions were used to determine tissue oxygenations maps. These were subsequently used to delineate hypoxic volumes based partial oxygen pressure (pO2) thresholds. The results were compared to hypoxic volumes segmented using a tissue-to-background ratio of 1.4 for 18F-HX4 uptake.

    Results: While the linear conversion function was not found to result in realistic oxygenation maps, the non-linear function resulted in reasonably sized sub-volumes in good agreement with uptake-based segmented volumes for a limited range of pO2 thresholds. However, the pO2 values corresponding to this range were significantly higher than what is normally considered as hypoxia. The similarity in size, shape, and relative location between uptake-based sub-volumes and volumes based on the conversion to pO2 suggests that the relationship between uptake and pO2 is similar for 18F-FMISO and 18F-HX4, but that the model parameters need to be adjusted for the latter.

    Conclusions: A non-linear conversion function between uptake and oxygen partial pressure for 18F-FMISO-PET could be applied to 18F-HX4 images to delineate hypoxic sub-volumes of similar size, shape, and relative location as based directly on the uptake. In order to apply the model for e.g., dose-painting, new parameters need to be derived for the accurate calculation of dose-modifying factors for this tracer.

  • 261.
    Lindemann, K
    et al.
    Department of Gynecological Cancer, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
    Christensen, R D
    Department of Medical Statistics, University of Southern Denmark, Odense, Denmark.
    Vergote, I
    Department of Obstetrics and Gynecology, University Hospital Leuven, Leuven, Belgium .
    Stuart, G
    Department of Gynecologic Oncology, University of British Columbia, Vancouver, Canada.
    Izquierdo, M A
    Institute of Oncology, Catalán Hospital, Catalania, Spain.
    Kærn, J
    Department of Gynecological Cancer, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
    Havsteen, H
    Department of Oncology, Herlev University Hospital, Herlev, Denmark.
    Eisenhauer, E
    Department of Oncology, Queen’s University, Kingston, Ontario, Canada.
    Ridderheim, M
    Department of Gynecologic Oncology, Lund University Hospital, Lund, Sweden.
    Lopez, A B
    Department of Gynecologic Oncology, Queen Elizabeth Hospital, Gateshead, UK.
    Hirte, H
    Department of Oncology, Division of Medical Oncology, Juravinski Cancer Centre, Hamilton, Ontario, Canada.
    Åvall-Lundquvist, Elisabeth
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Vrdoljak, E
    Department of Oncology, University Hospital, Split, Croatia.
    Green, J
    Department of Oncology, Clatterbridge Hospital, Wirral, UK.
    Kristensen, G B
    Department of Gynecological Cancer, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway / Department of Gynecological Cancer, Institute for Medical Informatics, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
    First-line treatment of advanced ovarian cancer with paclitaxel/carboplatin with or without epirubicin (TEC versus TC)--a gynecologic cancer intergroup study of the NSGO, EORTC GCG and NCIC CTG.2012Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 23, nr 10, s. 2613-2619Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The addition of anthracyclines to platinum-based chemotherapy may provide benefit in survival in ovarian cancer patients. We evaluated the effect on survival of adding epirubicin to standard carboplatin and paclitaxel.

    PATIENTS AND METHODS: We carried out a prospectively randomized phase III study comparing carboplatin plus paclitaxel (TC; area under the curve 5 and 175 mg/m(2)) with the same combination and epirubicin (TEC; 75 mg/m(2) i.v.). Between March 1999 and August 2001, 887 patients with epithelial ovarian, tubal or peritoneal cancer International Federation of Gynecology and Obstetrics stages IIB-IV were randomized to receive either TC (442 patients) or TEC (445 patients).

    RESULTS: Median time to progression was 16.4 months in the TEC arm and 16.0 months in the TC arm (hazard ratio 0.99; 95% confidence interval [CI]: 0.9-1.2). Median overall survival time was 42.4 months for the TEC arm and 40.2 for the TC arm (hazard ratio 0.96; 95% CI: 0.8-1.1). Grade 3/4 hematologic toxic effects and most grade 3/4 non-hematologic toxic effects were more frequent in the TEC arm. Accordingly, a quality-of-life analysis showed inferiority of TEC versus TC.

    CONCLUSION: The addition of epirubicin to standard carboplatin and paclitaxel treatment did not improve survival in patients with advanced ovarian, tubal or peritoneal cancer.

  • 262.
    Lindemann, Kristina
    et al.
    Oslo University Hospital, Norway .
    Malander, Susanne
    University of Lund Hospital, Sweden .
    Christensen, Rene D.
    University of Southern Denmark, Denmark .
    Mirza, Mansoor R.
    University of Copenhagen Hospital, Denmark .
    Kristensen, Gunnar B.
    Oslo University Hospital, Norway Oslo University Hospital, Norway .
    Åvall-Lundqvist, Elisabeth
    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. Karolinska University Hospital, Sweden .
    Vergote, Ignace
    University Hospital Leuven, Belgium University Hospital Leuven, Belgium .
    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.
    Boman, Karin
    University Hospital, Sweden .
    Nordstrom, Britta
    Karolinska University Hospital, Sweden .
    Examestane in advanced or recurrent endometrial carcinoma: a prospective phase II study by the Nordic Society of Gynecologic Oncology (NSGO)2014Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, nr 68Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma. Methods: We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients. Results: Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated. Conclusion: Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients.

  • 263.
    Lindner, Claus
    et al.
    ICFO - Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology.
    Mora, Mireia
    Department of Endocrinology and Nutrition, Hospital Clínic, Barcelona, Spain.
    Farzam, Parisa
    ICFO - Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology.
    Squarcia, Mattia
    Department of Endocrinology and Nutrition, Hospital Clínic, Barcelona, Spain.
    Johansson, Johannes
    ICFO - Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology.
    Weigel, Udo M
    ICFO - Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology.
    Halperin, Irene
    Department of Endocrinology and Nutrition, Hospital Clínic, Barcelona, Spain.
    Hanzu, Felicia A
    Department of Endocrinology and Nutrition, Hospital Clínic, Barcelona, Spain.
    Durduran, Turgut
    ICFO - Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology.
    Diffuse Optical Characterization of the Healthy Human Thyroid Tissue and Two Pathological Case Studies.2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The in vivo optical and hemodynamic properties of the healthy (n = 22) and pathological (n = 2) human thyroid tissue were measured non-invasively using a custom time-resolved spectroscopy (TRS) and diffuse correlation spectroscopy (DCS) system. Medical ultrasound was used to guide the placement of the hand-held hybrid optical probe. TRS measured the absorption and reduced scattering coefficients (μa, μs') at three wavelengths (690, 785 and 830 nm) to derive total hemoglobin concentration (THC) and oxygen saturation (StO2). DCS measured the microvascular blood flow index (BFI). Their dependencies on physiological and clinical parameters and positions along the thyroid were investigated and compared to the surrounding sternocleidomastoid muscle. The THC in the thyroid ranged from 131.9 μM to 144.8 μM, showing a 25-44% increase compared to the surrounding sternocleidomastoid muscle tissue. The blood flow was significantly higher in the thyroid (BFIthyroid = 16.0 × 10-9 cm2/s) compared to the muscle (BFImuscle = 7.8 × 10-9 cm2/s), while StO2 showed a small (StO2, muscle = 63.8% to StO2, thyroid = 68.4%), yet significant difference. Two case studies with thyroid nodules underwent the same measurement protocol prior to thyroidectomy. Their THC and BFI reached values around 226.5 μM and 62.8 × 10-9 cm2/s respectively showing a clear contrast to the nodule-free thyroid tissue as well as the general population. The initial characterization of the healthy and pathologic human thyroid tissue lays the ground work for the future investigation on the use of diffuse optics in thyroid cancer screening.

  • 264.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Mårtensson, Lars-Göran
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Almer, Sven
    Karolinska institutet - Institutionen för medicin Linköping, Sweden Karolinska institutet - Institutionen för medicin Linköping, Sweden..
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Nyttan av farmakogenetik för en mer individualiserad behandling: Exemplet tiopuriner vid inflammatorisk tarmsjukdom och barnleukemi2015Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, s. 1229-1233, artikel-id DF7LArtikel i tidskrift (Refereegranskat)
    Abstract [en]

    Thiopurines are chemotherapeutic drugs used for treatment of inflammatory bowel diseases and childhood leukemia. Thiopurine methyltransferase (TPMT) is a polymorphic enzyme involved in the metabolism of thiopurines. Individuals lacking TPMT are at increased risk for severe side effects when treated with conventional doses of thiopurines. A research group at the division of drug research at Linköping University is studying thiopurine pharmacogenetics. Since the year 2000, the lab has determined the TPMT status in over 12000 individuals, as an aid to decide thiopurine doses before starting treatment. New knowledge of how genetic factors influence thiopurine treatment effect are anticipated to improve the possibilities for individualization of thiopurine therapy.

  • 265.
    Lindstrom, Linda S.
    et al.
    Karolinska Inst, Sweden.
    Yau, Christina
    Univ Calif San Francisco, CA USA; Buck Inst Res Aging, CA USA.
    Czene, Kamila
    Karolinska Inst, Sweden.
    Thompson, Carlie K.
    Univ Calif San Francisco, CA USA.
    Hoadley, Katherine A.
    Univ North Carolina Chapel Hill, NC USA.
    vant Veer, Laura J.
    Univ Calif San Francisco, CA 94140 USA; Univ Calif San Francisco, CA 94143 USA.
    Balassanian, Ron
    Univ Calif San Francisco, CA 94140 USA.
    Bishop, John W.
    Univ Calif Davis, CA 95616 USA.
    Carpenter, Philip M.
    Univ Southern Calif, CA USA; Univ Calif Irvine, CA USA.
    Chen, Yunn-Yi
    Univ Calif San Francisco, CA 94140 USA.
    Datnow, Brian
    Univ Calif San Diego, CA 92093 USA.
    Hasteh, Farnaz
    Univ Calif San Diego, CA 92093 USA.
    Krings, Gregor
    Univ Calif San Francisco, CA 94140 USA.
    Lin, Fritz
    Univ Calif Irvine, CA USA.
    Zhang, Yanhong
    Univ Calif Davis, CA 95616 USA.
    Nordenskjöld, Bo
    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.
    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.
    Benz, Christopher C.
    Univ Calif San Francisco, CA USA; Buck Inst Res Aging, CA USA.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Borowsky, Alexander D.
    Univ Calif Davis, CA 95616 USA.
    Esserman, Laura J.
    Univ Calif San Francisco, CA USA.
    Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer2018Ingår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 110, nr 7, s. 726-733, artikel-id djx270Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods: The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Raos quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results: A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P amp;lt; .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio (HR] = 1.98, 95% confidence interval (CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI -1.18 to 4.99). Conclusions: Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors.

  • 266.
    Lindström, L.
    et al.
    Karolinska universitetet, Södersjukhuset, Sweden.
    Nordenskjöld, Bo
    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.
    Fornander, T.
    Karolinska universitetet, Södersjukhuset, Sweden.
    Test identifierade patienter med mycket låg risk att dö i bröstcancer2017Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, nr 41Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    [No abstract available]

  • 267.
    Liu, Caifeng
    et al.
    Karolinska Institute, Sweden; Shandong University, Peoples R China.
    Zhang, Yunjian
    Karolinska Institute, Sweden; Sun Yat Sen University, Peoples R China.
    Lim, Sharon
    Karolinska Institute, Sweden.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Yang, Yunlong
    Karolinska Institute, Sweden; Shenzhen University, Peoples R China.
    Pavlova, Tatiana
    Karolinska Institute, Sweden.
    Alkasalias, Twana
    Karolinska Institute, Sweden.
    Hartman, Johan
    Karolinska Institute, Sweden.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. Karolinska Institute, Sweden.
    Xing, Xiaoming
    Qingdao University, Peoples R China; Qingdao University, Peoples R China.
    Wang, Xinsheng
    Qingdao University, Peoples R China; Qingdao University, Peoples R China.
    Lu, Yongtian
    Shenzhen University, Peoples R China.
    Nie, Guohui
    Shenzhen University, Peoples R China.
    Cao, Yihai
    Karolinska Institute, Sweden; Shenzhen University, Peoples R China; Qingdao University, Peoples R China; Qingdao University, Peoples R China.
    A Zebrafish Model Discovers a Novel Mechanism of Stromal Fibroblast-Mediated Cancer Metastasis2017Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, nr 16, s. 4769-4779Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: Cancer metastasis can occur at the early stage of tumor development when a primary tumor is at the microscopic size. In particular, the interaction of malignant cells with other cell types including cancer-associated fibroblasts (CAF) in promoting metastasis at the early stage of tumor development remains largely unknown. Here, we investigated the role of CAFs in facilitating the initial events of cancer metastasis when primary tumors were at microscopic sizes. Experimental Design: Multicolor-coded cancer cells and CAFs were coimplanted into the transparent zebrafish body and metastasis at a single-cell level was monitored in living animals. Healthy fibroblasts, tumor factor-educated fibroblasts, and CAFs isolated from various tumors were tested for their ability to facilitate metastasis. Results: We showed that CAFs promoted cancer cell metastasis at the very early stage during primary tumor development. When a primary tumor was at the microscopic size consisting of a few hundred cells, CAFs were able to hijack cancer cells for dissemination from the primary site. Surprisingly, a majority of metastatic cancer cells remained in tight association with CAFs in the circulation. Furthermore, stimulation of non-metastasis-promoting normal fibroblasts with TGF-B, FGF-2, HGF, and PDGF-BB led to acquisition of their metastatic capacity. Conclusions: Cancer metastasis occurs at the very early stage of tumor formation consisting of only a few hundred cells. CAFs are the key cellular determinant for metastasis. Our findings provide novel mechanistic insights on CAFs in promoting cancer metastasis and targeting CAFs for cancer therapy should be aimed at the early stage during cancer development. (C) 2017 AACR.

  • 268.
    Liu, Na
    et al.
    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. State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, China.
    Cox, Thomas R.
    Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
    Cui, Weiyingqi
    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.
    Adell, Gunnar
    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.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Ping, Jie
    Shanghai Center for Bioinformation Technology, Shanghai, China.
    Jarlsfelt, Ingvar
    Department of Pathology, Ryhov Hospital, Jönköping, Sweden.
    Erler, Janine T.
    Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
    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.
    Nuclear expression of lysyl oxidase enzyme is an independent prognostic factor in rectal cancer patients.2017Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 36, s. 60015-60024Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Emerging evidence has implicated a pivotal role for lysyl oxidase (LOX) in cancer progression and metastasis. Whilst the majority of work has focused on the extracellular matrix cross-linking role of LOX, the exact function of intracellular LOX localisation remains unclear. In this study, we analysed the LOX expression patterns in the nuclei of rectal cancer patient samples and determined the clinical significance of this expression. Nuclear LOX expression was significantly increased in patient lymph node metastases compared to their primary tumours. High nuclear LOX expression in tumours was correlated with a high rate of distant metastasis and increased recurrence. Multivariable analysis showed that high nuclear LOX expression was also correlated with poor overall survival and disease free survival. Furthermore, we are the first to identify LOX enzyme isoforms (50 kDa and 32 kDa) within the nucleus of colon cancer cell lines by confocal microscopy and Western blot. Our results show a powerful link between nuclear LOX expression in tumours and patient survival, and offer a promising prognostic biomarker for rectal cancer patients.

  • 269.
    Liu, Na
    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. Xi An Jiao Tong Univ, Peoples R China.
    Cui, Weiyingqi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jiang, Xia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Hebei Med Univ, Peoples R China.
    Zhang, Zhiyong
    Fourth Mil Med Univ, Peoples R China.
    Gnosa, Sebastian
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Ali, Zaheer
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för hematopoes och utvecklingsbiologi. Linköpings universitet, Medicinska fakulteten.
    Blockhuys, Stephanie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lam, Eric W-F
    Imperial Coll London, England.
    Zhao, Zengren
    Hebei Med Univ, Peoples R China.
    Ping, Jie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Xie, Ning
    Xi An Jiao Tong Univ, Peoples R China.
    Kopsida, Maria
    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.
    Wang, Xin
    Fourth Mil Med Univ, Peoples R China.
    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.
    The Critical Role of Dysregulated RhoB Signaling Pathway in Radioresistance of Colorectal Cancer2019Ingår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 104, nr 5, s. 1153-1164Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose

    To explore whether the Rho protein is involved in the radioresistance of colorectal cancer and investigate the underlying mechanisms.

    Methods and Materials

    Rho GTPase expression was measured after radiation treatment in colon cancer cells. RhoB knockout cell lines were established using the CRISPR/Cas9 system. In vitro assays and zebrafish embryos were used for analyzing radiosensitivity and invasive ability. Mass cytometry was used to detect RhoB downstream signaling factors. RhoB and Forkhead box M1 (FOXM1) expression were detected by immunohistochemistry in rectal cancer patients who participated in a radiation therapy trial.

    Results

    RhoB expression was related to radiation resistance. Complete depletion of the RhoB protein increased radiosensitivity and impaired radiation-enhanced metastatic potential in vitro and in zebrafish models. Probing signaling using mass cytometry–based single-cell analysis showed that the Akt phosphorylation level was inhibited by RhoB depletion after radiation. FOXM1 was downregulated in RhoB knockout cells, and the inhibition of FOXM1 led to lower survival rates and attenuated migration and invasion abilities of the cells after radiation. In the patients who underwent radiation therapy, RhoB overexpression was related to high FOXM1, late Tumor, Node, Metastasis stage, high distant recurrence, and poor survival independent of other clinical factors.

    Conclusions

    RhoB plays a critical role in radioresistance of colorectal cancer through Akt and FOXM1 pathways.

  • 270.
    Loftås, Per
    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 ViN.
    Response to neoadjuvant treatment in rectal cancer surgery2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT.

    Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer.

    Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer.

    Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour.

    Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, specificity, and positive and negative predicted values for correct staging of positive lymph nodes was 37%, 84%, 70% and 57%. The size of the largest lymph node (4.5 mm, p=0.04) seemed to indicate presence of a tumour positive lymph node. We concluded that MRI couldn’t correctly stage patients for lymph node metastases in patients with complete response to CRT in the luminal tumour.

    Delarbeten
    1. EXPRESSION OF FXYD-3 IS AN INDEPENDENT PROGNOSTIC FACTOR IN RECTAL CANCER PATIENTS WITH PREOPERATIVE RADIOTHERAPY
    Öppna denna publikation i ny flik eller fönster >>EXPRESSION OF FXYD-3 IS AN INDEPENDENT PROGNOSTIC FACTOR IN RECTAL CANCER PATIENTS WITH PREOPERATIVE RADIOTHERAPY
    Visa övriga...
    2009 (Engelska)Ingår i: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, ISSN 0360-3016, Vol. 75, nr 1, s. 137-142Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Purpose: FXYD-3 (MAT-8) is overexpressed in several types of cancers; however, its clinical relevance in rectal cancers has not been studied. Therefore, we examined FXYD-3 expression in rectal cancers from the patients who participated in a Swedish clinical trial of preoperative radiotherapy (RT) to determine whether FXYD-3 was overexpressed in rectal cancers and correlated with RT, survival, and other clinicopathologic variables. Methods and Materials: The study included 140 rectal cancer patients who participated in a clinical trial of preoperative RT, 65 with and 75 without RT before surgery. FXYD-3 expression was immumohistochemically examined in distant (n = 70) and adjacent (n = 101) normal mucosa, primary tumors (n = 140), and lymph node metastasis (n = 36). Results: In the whole cohort, strong FXYD-3 expression was correlated with infiltrative tumor growth (p = 0.02). In the RT group, strong FXYD-3 expression alone (p = 0.02) or combined with phosphatase of regenerating liver was associated with an unfavorable prognosis (p = 0.02), independent of both TNM stage and tumor differentiation. In tumors with strong FXYD-3 expression, there was less tumor necrosis (p = 0.02) and a trend toward increased incidence of distant metastasis (p = 0.08) after RT. None of these effects was seen in the non-RT group. FXYD-3 expression in the primary tumors tended to he increased compared with normal mucosa regardless of RT. Conclusion: FXYD-3 expression was a prognostic factor independent of tumor stage and differentiation in patients receiving preoperative RT for rectal cancer.

    Nyckelord
    FXYD-3, Rectal cancer, Radiotherapy, Prognosis, Immunohistochemistry
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-20598 (URN)10.1016/j.ijrobp.2008.10.076 (DOI)
    Tillgänglig från: 2009-09-16 Skapad: 2009-09-15 Senast uppdaterad: 2016-11-24
    2. FXYD-3 expression in relation to local recurrence of rectal cancer
    Öppna denna publikation i ny flik eller fönster >>FXYD-3 expression in relation to local recurrence of rectal cancer
    Visa övriga...
    2016 (Engelska)Ingår i: Radiation Oncology Journal, ISSN 2234-1900, Vol. 34, nr 1, s. 52-58Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Purpose: In a previous study, the transmembrane protein FXYD-3 was suggested as a biomarker for a lower survival rate and reduced radiosensitivity in rectal cancer patients receiving preoperative radiotherapy. The purpose of preoperative irradiation in rectal cancer is to reduce local recurrence. The aim of this study was to investigate the potential role of FXYD-3 as a biomarker for increased risk for local recurrence of rectal cancer.

    Materials and Methods: FXYD-3 expression was immunohistochemically examined in surgical specimens from a cohort of patients with rectal cancer who developed local recurrence (n = 48). The cohort was compared to a matched control group without recurrence (n = 81).

    Results: Weak FXYD-3 expression was found in 106/129 (82%) of the rectal tumors and strong expression in 23/129 (18%). There was no difference in the expression of FXYD-3 between the patients with local recurrence and the control group. Furthermore there was no difference in FXYD-3 expression and time to diagnosis of local recurrence between patients who received preoperative radiotherapy and those without.

    Conclusion: Previous findings indicated that FXYD-3 expression may be used as a marker of decreased sensitivity to radiotherapy or even overall survival. We were unable to confirm this in a cohort of rectal cancer patients who developed local recurrence.

    Ort, förlag, år, upplaga, sidor
    Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea, 2016
    Nyckelord
    Rectal cancer, Human FXYD3 protein, Local recurrence
    Nationell ämneskategori
    Radiologi och bildbehandling Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-132758 (URN)10.3857/roj.2016.34.1.52 (DOI)27104167 (PubMedID)
    Tillgänglig från: 2016-11-23 Skapad: 2016-11-23 Senast uppdaterad: 2016-12-07Bibliografiskt granskad
    3. Nodal involvement in luminal complete response after neoadjuvant treatment for rectal cancer
    Öppna denna publikation i ny flik eller fönster >>Nodal involvement in luminal complete response after neoadjuvant treatment for rectal cancer
    2016 (Engelska)Ingår i: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 42, nr 6, s. 801-807Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Pathological complete response (pCR) after neoadjuvant therapy in rectal cancer is correlated with improved survival. There is limited knowledge on the incidence of pCR at a national level with uniform guidelines. The aim of this prospective register-based study was to investigate the incidence and outcome of pCR in relation to neoadjuvant therapy in a national cohort. Method: All patients abdominally operated for rectal cancer between 2007 and 2012 (n = 7885) were selected from The Swedish Colorectal Cancer Register. Twenty-six per cent (n = 2063) had neoadjuvant therapy with either long or short course radiotherapy with amp;gt;4 weeks delay with the potential to achieve pCR. The primary endpoints were pCR and survival in relation to neoadjuvant therapy. Results: Complete eradication of the luminal tumor, ypTO was found in 161 patients (8%). In 83% of the ypTO the regional lymph nodes were tumor negative (ypTONO), 12% had 1-3 positive lymph nodes (ypTON1) and 4% had more than three positive lymph nodes (ypTON2). There was significantly greater survival with ypTO compared to ypT+ (hazard ratio 0.38 (C.I 0.25-0.58)) and survival was significantly greater in patients with ypTONO compared to ypT0N1-2 (hazard ratio 0.36 (C.I 0.15-0.86)). In ypTO, cT3-4 tumors had the greater risk of node-positivity. The added use of chemotherapy resulted in 10% ypTO compared to 5.1% in the group without chemotherapy (p amp;lt; 0.00004). Conclusion: Luminal pathological complete response occurred in 8%, 16% of them had tumor positive nodes. The survival benefit of luminal complete response is dependent upon nodal involvement status. (C) 2016 Elsevier Ltd. All rights reserved.

    Ort, förlag, år, upplaga, sidor
    ELSEVIER SCI LTD, 2016
    Nyckelord
    Rectal cancer; Complete response; Lymph nodes; Neoadjuvant treatment
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-130432 (URN)10.1016/j.ejso.2016.03.013 (DOI)000379559300007 ()27146960 (PubMedID)
    Tillgänglig från: 2016-08-07 Skapad: 2016-08-05 Senast uppdaterad: 2017-05-02
  • 271.
    Loftås, Per
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken ViN. Linköpings universitet, Medicinska fakulteten.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken ViN.
    Fomichov Casaballe, Victoria
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Hallböök, Olof
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US. Linköpings universitet, Medicinska fakulteten.
    Nodal involvement in luminal complete response after neoadjuvant treatment for rectal cancer2016Ingår i: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 42, nr 6, s. 801-807Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Pathological complete response (pCR) after neoadjuvant therapy in rectal cancer is correlated with improved survival. There is limited knowledge on the incidence of pCR at a national level with uniform guidelines. The aim of this prospective register-based study was to investigate the incidence and outcome of pCR in relation to neoadjuvant therapy in a national cohort. Method: All patients abdominally operated for rectal cancer between 2007 and 2012 (n = 7885) were selected from The Swedish Colorectal Cancer Register. Twenty-six per cent (n = 2063) had neoadjuvant therapy with either long or short course radiotherapy with amp;gt;4 weeks delay with the potential to achieve pCR. The primary endpoints were pCR and survival in relation to neoadjuvant therapy. Results: Complete eradication of the luminal tumor, ypTO was found in 161 patients (8%). In 83% of the ypTO the regional lymph nodes were tumor negative (ypTONO), 12% had 1-3 positive lymph nodes (ypTON1) and 4% had more than three positive lymph nodes (ypTON2). There was significantly greater survival with ypTO compared to ypT+ (hazard ratio 0.38 (C.I 0.25-0.58)) and survival was significantly greater in patients with ypTONO compared to ypT0N1-2 (hazard ratio 0.36 (C.I 0.15-0.86)). In ypTO, cT3-4 tumors had the greater risk of node-positivity. The added use of chemotherapy resulted in 10% ypTO compared to 5.1% in the group without chemotherapy (p amp;lt; 0.00004). Conclusion: Luminal pathological complete response occurred in 8%, 16% of them had tumor positive nodes. The survival benefit of luminal complete response is dependent upon nodal involvement status. (C) 2016 Elsevier Ltd. All rights reserved.

  • 272.
    Loftås, Per
    et al.
    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 ViN.
    Arbman, 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 ViN.
    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.
    Edler, David
    Department of Surgery, Karolinska Institute, Stockholm, Sweden.
    Syk, Erik
    Department of Surgery, Ersta Hospital, Stockholm, Sweden.
    Hallböök, Olof
    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.
    FXYD-3 expression in relation to local recurrence of rectal cancer2016Ingår i: Radiation Oncology Journal, ISSN 2234-1900, Vol. 34, nr 1, s. 52-58Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: In a previous study, the transmembrane protein FXYD-3 was suggested as a biomarker for a lower survival rate and reduced radiosensitivity in rectal cancer patients receiving preoperative radiotherapy. The purpose of preoperative irradiation in rectal cancer is to reduce local recurrence. The aim of this study was to investigate the potential role of FXYD-3 as a biomarker for increased risk for local recurrence of rectal cancer.

    Materials and Methods: FXYD-3 expression was immunohistochemically examined in surgical specimens from a cohort of patients with rectal cancer who developed local recurrence (n = 48). The cohort was compared to a matched control group without recurrence (n = 81).

    Results: Weak FXYD-3 expression was found in 106/129 (82%) of the rectal tumors and strong expression in 23/129 (18%). There was no difference in the expression of FXYD-3 between the patients with local recurrence and the control group. Furthermore there was no difference in FXYD-3 expression and time to diagnosis of local recurrence between patients who received preoperative radiotherapy and those without.

    Conclusion: Previous findings indicated that FXYD-3 expression may be used as a marker of decreased sensitivity to radiotherapy or even overall survival. We were unable to confirm this in a cohort of rectal cancer patients who developed local recurrence.

  • 273.
    Lolas, Georgios
    et al.
    Athens School Med, Greece.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. Karolinska Institute, Sweden.
    Bourantas, George C.
    University of Luxembourg, Luxembourg.
    Tsikourkitoudi, Vasiliki
    Athens School Med, Greece.
    Syrigos, Konstantinos
    Athens School Med, Greece.
    Modeling Proteolytically Driven Tumor Lymphangiogenesis2016Ingår i: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 936, s. 107-136Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    With the exception of a limited number of sites in the body, primary tumors infrequently lead to the demise of cancer patients. Instead, mortality and a significant degree of morbidity result from the growth of secondary tumors in distant organs. Tumor survival, growth and dissemination are associated with the formation of both new blood vessels (angiogenesis) and new lymph vessels (lymphagenesis or lymphangiogenesis). Although intensive research in tumor angiogenesis has been going on for the past four decades, experimental results in tumor lymphangiogenesis began to appear only in the last 10 years. In this chapter we expand the models proposed by Friedman, Lolas and Pepper on tumor lymphangiogenesis mediated by proteolytically and un-proteolytically processed growth factors (Friedman and Lolas G, Math Models Methods Appl Sci 15(01): 95-107, 2005; Pepper and Lolas G, Selected topics in cancer modeling: genesis, evolution, immune competition, and therapy. In: The lymphatic vascular system in lymphangiogenesis invasion and metastasis a mathematical approach. Birkhauser Boston, Boston, pp 1-22, 2008). The variables represent different cell densities and growth factors concentrations, and where possible the parameters are estimated from experimental and clinical data. The results obtained from computational simulations carried out on the model equations produce dynamic heterogeneous ("anarchic") spatio-temporal solutions. More specifically, we observed coherent masses of tumor clusters migrating around and within the lymphatic network. Our findings are in line with recent experimental evidence that associate cluster formation with the minimization of cell loss favoring high local extracellular matrix proteolysis and thus protecting cancer invading cells from an immunological assault driven by the lymphatic network.

  • 274.
    Los, Marek Jan
    et al.
    Institute of Experimental Dermatology, University of Muenster, Germany.
    Burek, C. J.
    Institute of Experimental Dermatology, University of Muenster, Germany.
    Stroh, C.
    Institute of Experimental Dermatology, University of Muenster, Germany.
    Benedyk, K.
    Dept of Tumor Biology Oncology Center, Maria Sklodowska-Curie Memorial Institute, Wybrzeze Armii Krajowej 15, PL-44100 Gliwice, Poland.
    Hug, H.
    TheraSTrat AGGewerbestrasse 25, CH-4123, Allschwil, Switzerland.
    Mackiewicz, A.
    Dept of Cancer Immunology, University of Medical Sciences, at Great-Poland Cancer Center, Poznan, Poland.
    Anticancer drugs of tomorrow: apoptotic pathways as targets for drug design2003Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 8, nr 2, s. 67-77Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Apoptosis or programmed cell death is a set of ordered events that enables the selective removal of cells from tissue and is essential for homeostasis and proper function of multicellular organisms. Components of this signaling network, which include ligands, such as CD95, tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand, as well as downstream molecules, such as caspases, Bcl-2 family members, and inhibitor-of-apoptosis proteins, which trigger and regulate apoptosis, are crucial targets for conventional drug development and gene therapy of cancer and other diseases. Here, we focus on apoptotic pathways and propose new potential molecular targets that could prove effective in controlling cell death in the clinical setting.

  • 275.
    Lund, Johan
    et al.
    Karolinska Univ Hosp, Sweden.
    Gruber, Astrid
    Karolinska Univ Hosp, Sweden.
    Lauri, Birgitta
    Sunderby Hosp, Sweden.
    Duru, Adil Doganay
    Karolinska Univ Hosp, Sweden; NSU, FL USA.
    Blimark, Cecilie
    Sahlgrens Univ Hosp, Sweden.
    Swedin, Agneta
    Skane Univ Hosp, Sweden.
    Hansson, Markus
    Skane Univ Hosp, Sweden.
    Forsberg, Karin
    Norrland Univ Hosp, Sweden.
    Ahlberg, Lucia
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Carlsson, Conny
    Hallands Hosp, Sweden.
    Waage, Anders
    Norwegian Univ Sci and Technol, Norway.
    Gimsing, Peter
    Rigshosp, Denmark.
    Vangsted, Annette Juul
    Rigshosp, Denmark; Zealand Univ, Denmark.
    Frolund, Ulf
    Zealand Univ, Denmark.
    Holmberg, Erik
    Inst Clin Sci, Sweden.
    Gahrton, Gösta
    Karolinska Univ Hosp, Sweden.
    Alici, Evren
    Karolinska Univ Hosp, Sweden.
    Hardling, Mats
    Uddevalla Cent Hosp, Sweden.
    Mellqvist, Ulf-Henrik
    Sahlgrens Univ Hosp, Sweden.
    Nahi, Hareth
    Karolinska Univ Hosp, Sweden.
    Lenalidomide versus lenalidomide plus dexamethasone prolonged treatment after second-line lenalidomide plus dexamethasone induction in multiple myeloma2018Ingår i: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 7, nr 6, s. 2256-2268Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lenalidomide (Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (RRMM). It is possible that single-agent Len may be effective as prolonged treatment regimen in RRMM once patients demonstrate an initial response to Len+Dex induction. Patients with RRMM who responded to first-line Len+Dex in an observational study (NCT01430546) received up to 24 cycles of either Len (25mg/day) or Len+Dex (25mg/day and 40mg/week) as prolonged treatment in a subsequent phase 2 clinical trial (NCT01450215). In the observational study (N = 133), median time to response was 1.7 (range 0.6-9.6) months. A complete response to all treatments received in both studies was observed in 11% of patients; very good partial response and partial response rates were 31% and 38%, respectively. Corresponding response rates in the subgroup of patients who did not enter the phase 2 trial (n = 71) were 3%, 18%, and 39%, respectively. Rates of disease progression at 2years in the phase 2 trial were 47% versus 31% for Len versus Len+Dex (P = 0.14). After 36months median follow-up in surviving patients, median time to progression was not reached with Len+Dex and was 24.9months (95% confidence interval 12.5-not calculable, P amp;lt; 0.001) with Len. Three-year OS among the total observational study population was 61% (95% CI, 52-69%). The corresponding rate among patients who entered the phase 2 clinical trial was 73% (95% CI, 60-83%) and was significantly lower among those patients who achieved PR but did not proceed into the phase 2 trial (55%; P = 0.01). In the phase 2 trial, OS was 73% in both treatment arms (P = 0.70). Neutropenia and thrombocytopenia were more common with prolonged (phase 2 trial) versus short-term (observational study) Len administration but remained manageable. Prolonged treatment with Len with or without Dex provides sustained, clinically relevant responses and demonstrates an acceptable safety profile.

  • 276.
    Lundgren, Christine
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Dept Oncol, Region Jönköping County, Sweden; Lund Univ, Sweden.
    Bendahl, Par-Ola
    Lund Univ, Sweden.
    Borg, Ake
    Lund Univ, Sweden.
    Ehinger, Anna
    Lund Univ, Sweden.
    Hegardt, Cecilia
    Lund Univ, Sweden.
    Larsson, Christer
    Lund Univ, Sweden.
    Loman, Niklas
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Malmberg, Martin
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Olofsson, Helena
    Uppsala Univ, Sweden.
    Saal, Lao H.
    Lund Univ, Sweden.
    Sjoblom, Tobias
    Uppsala Univ, Sweden.
    Lindman, Henrik
    Uppsala Univ, Sweden.
    Klintman, Marie
    Lund Univ, Sweden.
    Hakkinen, Jari
    Lund Univ, Sweden.
    Vallon-Christersson, Johan
    Lund Univ, Sweden.
    Ferno, Marten
    Lund Univ, Sweden.
    Ryden, Lisa
    Lund Univ, Sweden.
    Ekholm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Dept Oncol, Region Jönköping County, Sweden; Lund Univ, Sweden.
    Agreement between molecular subtyping and surrogate subtype classification: a contemporary population-based study of ER-positive/HER2-negative primary breast cancer2019Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 178, nr 2, s. 459-467Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose Oestrogen receptor-positive (ER+) and human epidermal receptor 2-negative (HER2-) breast cancers are classified as Luminal A or B based on gene expression, but immunohistochemical markers are used for surrogate subtyping. The aims of this study were to examine the agreement between molecular subtyping (MS) and surrogate subtyping and to identify subgroups consisting mainly of Luminal A or B tumours. Methods The cohort consisted of 2063 patients diagnosed between 2013-2017, with primary ER+/HER2- breast cancer, analysed by RNA sequencing. Surrogate subtyping was performed according to three algorithms (St. Gallen 2013, Maisonneuve and our proposed Grade-based classification). Agreement (%) and kappa statistics (kappa) were used as concordance measures and ROC analysis for luminal distinction. Ki67, progesterone receptor (PR) and histological grade (HG) were further investigated as surrogate markers. Results The agreement rates between the MS and St. Gallen 2013, Maisonneuve and Grade-based classifications were 62% (kappa = 0.30), 66% (kappa = 0.35) and 70% (kappa = 0.41), respectively. PR did not contribute to distinguishing Luminal A from B tumours (auROC = 0.56). By classifying HG1-2 tumours as Luminal A-like and HG3 as Luminal B-like, agreement with MS was 80% (kappa = 0.46). Moreover, by combining HG and Ki67 status, a large subgroup of patients (51% of the cohort) having amp;gt; 90% Luminal A tumours could be identified. Conclusions Agreement between MS and surrogate classifications was generally poor. However, a post hoc analysis showed that a combination of HG and Ki67 could identify patients very likely to have Luminal A tumours according to MS.

  • 277.
    Lundgren, Christine
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Dept Oncol, Region Jönköping County, Sweden; Lund Univ, Sweden.
    Bendahl, Par-Ola
    Lund Univ, Sweden.
    Borg, Ake
    Lund Univ, Sweden.
    Ehinger, Anna
    Lund Univ, Sweden.
    Hegardt, Cecilia
    Lund Univ, Sweden.
    Larsson, Christer
    Lund Univ, Sweden.
    Loman, Niklas
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Malmberg, Martin
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Olofsson, Helena
    Uppsala Univ, Sweden.
    Saal, Lao H.
    Lund Univ, Sweden.
    Sjoblom, Tobias
    Uppsala Univ, Sweden.
    Lindman, Henrik
    Uppsala Univ, Sweden.
    Klintman, Marie
    Lund Univ, Sweden.
    Hakkinen, Jari
    Lund Univ, Sweden.
    Vallon-Christersson, Johan
    Lund Univ, Sweden.
    Ferno, Marten
    Lund Univ, Sweden.
    Ryden, Lisa
    Lund Univ, Sweden.
    Ekholm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Dept Oncol, Region Jönköping County, Sweden; Lund Univ, Sweden.
    Agreement between molecular subtyping and surrogate subtype classification: a contemporary population-based study of ER-positive/HER2-negative primary breast cancer2019Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 178, nr 2, s. 459-467Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose Oestrogen receptor-positive (ER+) and human epidermal receptor 2-negative (HER2-) breast cancers are classified as Luminal A or B based on gene expression, but immunohistochemical markers are used for surrogate subtyping. The aims of this study were to examine the agreement between molecular subtyping (MS) and surrogate subtyping and to identify subgroups consisting mainly of Luminal A or B tumours. Methods The cohort consisted of 2063 patients diagnosed between 2013-2017, with primary ER+/HER2- breast cancer, analysed by RNA sequencing. Surrogate subtyping was performed according to three algorithms (St. Gallen 2013, Maisonneuve and our proposed Grade-based classification). Agreement (%) and kappa statistics (kappa) were used as concordance measures and ROC analysis for luminal distinction. Ki67, progesterone receptor (PR) and histological grade (HG) were further investigated as surrogate markers. Results The agreement rates between the MS and St. Gallen 2013, Maisonneuve and Grade-based classifications were 62% (kappa = 0.30), 66% (kappa = 0.35) and 70% (kappa = 0.41), respectively. PR did not contribute to distinguishing Luminal A from B tumours (auROC = 0.56). By classifying HG1-2 tumours as Luminal A-like and HG3 as Luminal B-like, agreement with MS was 80% (kappa = 0.46). Moreover, by combining HG and Ki67 status, a large subgroup of patients (51% of the cohort) having amp;gt; 90% Luminal A tumours could be identified. Conclusions Agreement between MS and surrogate classifications was generally poor. However, a post hoc analysis showed that a combination of HG and Ki67 could identify patients very likely to have Luminal A tumours according to MS.

  • 278.
    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.
    Incidental Gallbladder Cancer: Incidence, predictors, management and outcome in a Swedish population2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Background: Cholecystectomy is a common surgical procedure and incidental gallbladder cancer is a rare and unexpected finding at a cholecystectomy performed upon benign indications. Whether to perform routine or selective histopathology of the gallbladder specimen is still a subject for discussion. The prognosis of gallbladder cancer is largely affected by tumour stage and treatment.

    Aims: The overall aim was to study whether routine histological examination of the gallbladder specimen is of clinical and health economic value; determine if there are any predictive factors of incidental gallbladder cancer at benign cholecystectomy and compare the management and outcome of incidental gallbladder cancer patients in Sweden.

    Methods: All studies were based on registry data from GallRiks (The Swedish Registry for Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography) between 2007 and 2016, with some modifications between studies. Complemental cross-linkage was made to national registries, and medical records were reviewed. Papers I, II and III were population-based observational studies with prospectively and retrospectively collected data. Paper IV was a health economic evaluation based on the results from papers I and III.

    Results and conclusions: Hospitals submitting >75 per cent of gallbladder specimens diagnosed a higher proportion of incidental gallbladder cancer than did hospitals submitting ≤25 per cent of samples (paper I). Incidental gallbladder cancer was more prevalent in older patients, women and patients with acute or previous cholecystitis, as well as ongoing jaundice. The risk model based on predictive preoperative factors was further improved by adding a macroscopic assessment of the gallbladder (paper II). Predictive factors for gallbladder cancer appeared to have an impact on which specimens were submitted in hospitals with a selective approach of histopathology (paper I). For pT2 and pT3 patients, re-resection improved diseasespecific survival, although these groups differed in terms of age and comorbidity (paper III). Residual disease was an independent factor for impaired survival. A change to routine histopathology of gallbladder specimens in Sweden would lead to increased costs with little improved health outcomes. Instead, a more standardized approach to selective histology would be needed (paper IV).

    Delarbeten
    1. Are Incidental Gallbladder Cancers Missed with a Selective Approach of Gallbladder Histology at Cholecystectomy?
    Öppna denna publikation i ny flik eller fönster >>Are Incidental Gallbladder Cancers Missed with a Selective Approach of Gallbladder Histology at Cholecystectomy?
    Visa övriga...
    2018 (Engelska)Ingår i: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 42, nr 4, s. 1092-1099Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Incidental gallbladder cancer (IGBC) is an unexpected finding when a cholecystectomy is performed upon a benign indication, and the use of routine or selective histological analysis of gallbladder specimen is still debated. The aim of this study was to investigate whether the proportion of submitted gallbladder specimens for pathological investigation influences the proportion of IGBC found, and what possible factors preoperatively or perioperatively could influence the selection process. All cholecystectomies between January 2007 and September 2014 registered in the Swedish Registry of Gallstone Surgery and ERCP (GallRiks) were included. Proportion of histological analysis was divided into four subgroups (0-25%, amp;gt; 25-50%, amp;gt; 50-75%, amp;gt; 75-100%). A total of 81,349 cholecystectomies were registered, and 36,010 (44.3%) gallbladder specimens were sent for histological analysis. A total of 213 cases of IGBC were discovered, which constituted 0.26% of all cholecystectomies performed and 0.59% of the number of gallbladder specimens sent for histological analysis. Hospitals submitting amp;gt; 75-100% of the gallbladder specimens had significantly more IGBC/1000 cholecystectomies performed (p = 0.003). Hospitals with the most selective approach had a significantly higher proportion of IGBC/1000 gallbladders that were sent for histological analysis (p amp;lt; 0.001). Factors such as higher age (p amp;lt; 0.001), female gender (p = 0.048) and macroscopic cholecystitis (p amp;lt; 0.001) were more common in gallbladder specimens from hospitals that had a selective approach to histological analysis. A routine approach to histological analysis in cholecystectomies with a benign indication for surgery can uncover a higher proportion of IGBC cases. When a selective approach is used, risk factors should be taken into account.

    Ort, förlag, år, upplaga, sidor
    SPRINGER, 2018
    Nationell ämneskategori
    Kirurgi
    Identifikatorer
    urn:nbn:se:liu:diva-147095 (URN)10.1007/s00268-017-4215-0 (DOI)000427050900023 ()28900706 (PubMedID)
    Tillgänglig från: 2018-04-20 Skapad: 2018-04-20 Senast uppdaterad: 2019-08-23
    2. Predictors of incidental gallbladder cancer in patients undergoing cholecystectomy for benign gallbladder disease: Results from a population-based gallstone surgery registry
    Öppna denna publikation i ny flik eller fönster >>Predictors of incidental gallbladder cancer in patients undergoing cholecystectomy for benign gallbladder disease: Results from a population-based gallstone surgery registry
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    2017 (Engelska)Ingår i: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 162, nr 2, s. 256-263Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background. Gallbladder cancer is a rare neoplasm with a poor prognosis. Early diagnosis and correct treatment strategy is important. The aim of this study was to identify predictors for incidental gallbladder cancer. Methods. Data from cholecystectomies registered in the nationwide Swedish Register for Gallstone Surgery between 2007 and 2014 were analyzed for incidental gallbladder cancer. Exclusion criteria were patients with a gallbladder not sent for histopathology, preoperative suspicion of polyps/gallbladder cancer, and indication for operation for other reasons than gallstone disease. Predictive factors for incidental gallbladder cancer were identified using multivariable logistic regression. Results. A total of 86,154 procedures were registered in the Swedish Register for Gallstone Surgery. Of these, 36,355 patients were included in the analysis, and 215 of the included patients had incidental gallbladder cancer (0.59%). Mean age was 70 11 years for index cases and 54 16 years for the control group, and 80% of cases and 60% of controls were female. Predictors for incidental gallbladder cancer were older age (odds ratio = 1.08; P amp;lt; .001), female sex (odds ratio = 3.58; P amp;lt; .001), previous cholecystitis (odds ratio = 1.37; P = .045), and the combination of acute cholecystitis without jaundice (odds ratio = 1.39; P = .041) and jaundice without acute cholecystitis (odds ratio = 2.02; P = .009). A preoperative risk model including these factors gave an area under receiver operating characteristic curve of 0.82. By adding macroscopic evaluation of the gallbladder by the surgeon, the area under receiver operating characteristic curve increased to 0.87. Intraoperatively suspected gallbladder cancer was confirmed as cancer in 31 % of the cases. Conclusion. Incidental gallbladder cancer is more likely to be diagnosed in older patients, women, and after previous cholecystitis. Jaundice and acute cholecystitis were also shown to be important risk factors. Intraoperative inspection of the gallbladder improved the risk model.

    Ort, förlag, år, upplaga, sidor
    MOSBY-ELSEVIER, 2017
    Nationell ämneskategori
    Kirurgi
    Identifikatorer
    urn:nbn:se:liu:diva-139810 (URN)10.1016/j.surg.2017.02.009 (DOI)000406087900006 ()28400123 (PubMedID)
    Tillgänglig från: 2017-08-24 Skapad: 2017-08-24 Senast uppdaterad: 2019-08-23
    3. Management of incidental gallbladder cancer in a national cohort
    Öppna denna publikation i ny flik eller fönster >>Management of incidental gallbladder cancer in a national cohort
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    2019 (Engelska)Ingår i: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 106, nr 9, s. 1216-1227Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background Incidental gallbladder cancer is a rare event, and its prognosis is largely affected by the tumour stage and treatment. The aim of this study was to analyse the management, treatment and survival of patients with incidental gallbladder cancer in a national cohort over a decade. Methods Patients were identified through the Swedish Registry of Gallstone Surgery (GallRiks). Data were cross-linked to the national registry for liver surgery (SweLiv) and the Cancer Registry. Medical records were collected if registry data were missing. Survival was measured as disease-specific survival. The study was divided into two intervals (2007-2011 and 2012-2016) to evaluate changes over time. Results In total, 249 patients were identified with incidental gallbladder cancer, of whom 92 (36 center dot 9 per cent) underwent re-resection with curative intent. For patients with pT2 and pT3 disease, median disease-specific survival improved after re-resection (12 center dot 4 versus 44 center dot 1 months for pT2, and 9 center dot 7 versus 23 center dot 0 months for pT3). Residual disease was present in 53 per cent of patients with pT2 tumours who underwent re-resection; these patients had a median disease-specific survival of 32 center dot 2 months, whereas the median was not reached in patients without residual disease. Median survival increased by 11 months for all patients between the early and late periods (P = 0 center dot 030). Conclusion Re-resection of pT2 and pT3 incidental gallbladder cancer was associated with improved survival, but survival was impaired when residual disease was present. A higher re-resection rate and more R0 resections in the later time period may have been associated with improved survival.

    Ort, förlag, år, upplaga, sidor
    John Wiley & Sons, 2019
    Nationell ämneskategori
    Kirurgi
    Identifikatorer
    urn:nbn:se:liu:diva-159068 (URN)10.1002/bjs.11205 (DOI)000474059700001 ()31259388 (PubMedID)
    Tillgänglig från: 2019-07-22 Skapad: 2019-07-22 Senast uppdaterad: 2019-08-23
  • 279.
    Lundström, Staffan
    et al.
    Department of Palliative Medicine, Stockholms Sjukhem, Stockholm, Sweden.
    Fürst, Carl Johan
    Department of Palliative Medicine, Stockholms Sjukhem, Stockholm, Sweden.
    Börjeson, Sussanne
    Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
    Steineck, Gunnar
    Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
    Åvall-Lundqvist, Elisabeth
    Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
    Hursti, Timo J.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Aspects of delayed chemotherapy-induced nausea: Dexamethasone and adrenal response patterns in patients and healthy volunteers2000Ingår i: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 8, nr 5, s. 431-434Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Delayed chemotherapy-induced nausea is still a clinical problem, and the underlying mechanisms are poorly understood. Previous studies have suggested that corticosteroids are involved, although the mechanisms by which corticosteroids exert their anti-emetic effect are largely unknown. We have previously found impaired control of delayed nausea after injection of dexamethasone. The possibility of differences in the recovery of the hypothalamic-pituitary-adrenal (HPA) axis after injection of dexamethasone was investigated in patients (n = 5) with gynaecological cancer being treated with platinum-based chemotherapy and in healthy female volunteers (n = 10). Urinary free cortisol was used to assess the levels of endogenous cortisol. Results showed that in both patients and controls injections of dexamethasone led to a significant decline in endogenous cortisol levels in 24 h and a subsequent significant recovery in the next 24 h. We conclude that the recovery of the HPA axis is rapid after a single dose of dexamethasone in patients and controls. The absence of an abnormal response pattern in patients makes it probable that the suppression and recovery of the HPA axis after injection of dexamethasone does not influence the corticosteroid-induced rebound effect on delayed platinum-induced nausea.

  • 280.
    Luo, B.
    et al.
    Sichuan Prov Peoples Hosp, Peoples R China.
    Yang, H. W.
    Sichuan Univ, Peoples R China.
    Long, F. W.
    Sichuan Univ, Peoples R China.
    Zhou, B.
    Sichuan Univ, Peoples R China.
    Lv, Z. Y.
    Sichuan Univ, Peoples R China.
    Cheng, K. L.
    Sichuan Univ, Peoples R China.
    Li, Y.
    Sichuan Univ, Peoples R China.
    Zhou, Z. G.
    Sichuan Univ, Peoples R China.
    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. Sichuan Univ, Peoples R China; Sichuan Univ, Peoples R China.
    Intratumoral polymorphism of peroxisome proliferator-activated receptor delta-87 T > C in colorectal cancer2019Ingår i: Neoplasma (Bratislava), ISSN 0028-2685, E-ISSN 1338-4317, Vol. 66, nr 4, s. 609-618Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Peroxisome proliferator-activated receptor delta (PPARD) is a nuclear receptor transcription factor whose single nucleotide polymorphism (SNP), especially PPARD -87 Tamp;gt;C (rs2016520), may play an important role in regulation of PPARD expression. However its expression patterns as well as contribution to colorectal cancer (CRC) are still controversial. In this study, the presence of the intratumoral heterogeneity of PPARD -87 Tamp;gt;C (rs2016520) polymorphism and its influence in CRC were investigated. Tumor masses from primary CRC patients were collected during the tumorectomy, specimens from different sites of the same tumor mass were sampled and stored individually. The SNP of PPARD -87 Tamp;gt;C was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the expression of PPARD in vivo was observed by immunohistochemistry. The correlation of PPARD -87 Tamp;gt;C intra-tumoral polymorphism and the clinicopathological parameters of patients was analyzed statistically. Tumor samples were collected from 106 CRC patients (70 males and 36 females) with an average age of 61.04 +/- 13.67 years. A total number of 808 samples (7.60 +/- 1.60 per patient) were mainly harvested at peripheral superficial (n=376), central superficial (n=163), invasive front (n=112) and mesenteric cancer foci (n=42) of tumor tissues as well as cancerous adjacent mucosa (n=104). PCR-RFLP analysis showed that T/T (n=460, 56.9%) and T/C (n=334, 41.3%) were the main genotypes of -87 Tamp;gt;C among these samples. Furthermore, intratumoral genotype of -87 Tamp;gt;C was homogeneous in 90 patients and heterogeneous in other 16 patients. The intratumoral heterogeneity was related to patient age (p=0.016), tumor location (p=0.011) and the grade of differentiation (p=0.022). For patients with intratumoral heterogeneity, immunochemistry showed that the expressions of PPARD were not influenced by T/T or T/C genotypes. Intratumoral heterogeneity of PPARD -87 Tamp;gt;C widely existed in CRC, and associated with patient age, tumor location and differentiation. However, the immunochemistry assay revealed that there is no significant link between heterogeneity and expression of PPARD.

  • 281.
    Ma, Ran
    et al.
    Karolinska Institute, Sweden.
    Karthik, Govindasamy-Muralidharan
    Karolinska Institute, Sweden.
    Lovrot, John
    Karolinska Institute, Sweden.
    Haglund, Felix
    Karolinska Institute, Sweden; Karolinska University of Lab, Sweden.
    Rosin, Gustaf
    Karolinska Institute, Sweden.
    Katchy, Anne
    University of Houston, TX USA.
    Zhang, Xiaonan
    Karolinska Institute, Sweden.
    Viberg, Lisa
    Karolinska Institute, Sweden.
    Frisell, Jan
    Karolinska University Hospital, Sweden.
    Williams, Cecilia
    Karolinska Institute, Sweden; University of Houston, TX USA; Royal Institute Technology, Sweden.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
    Fredriksson, Irma
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Hartman, Johan
    Karolinska Institute, Sweden; Karolinska University of Lab, Sweden.
    Estrogen Receptor beta as a Therapeutic Target in Breast Cancer Stem Cells2017Ingår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 109, nr 3, artikel-id djw236Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Breast cancer cells with tumor-initiating capabilities (BSCs) are considered to maintain tumor growth and govern metastasis. Hence, targeting BSCs will be crucial to achieve successful treatment of breast cancer. Methods: We characterized mammospheres derived from more than 40 cancer patients and two breast cancer cell lines for the expression of estrogen receptors (ERs) and stem cell markers. Mammosphere formation and proliferation assays were performed on cells from 19 cancer patients and five healthy individuals after incubation with ER-subtype selective ligands. Transcriptional analysis was performed to identify pathways activated in ER beta-stimulated mammospheres and verified using in vitro experiments. Xenograft models (n = 4 or 5 per group) were used to study the role of ERs during tumorigenesis. Results: We identified an absence of ERa but upregulation of ER beta in BSCs associated with phenotypic stem cell markers and responsible for the proliferative role of estrogens. Knockdown of ER beta caused a reduction of mammosphere formation in cell lines and in patient-derived cancer cells (40.7%, 26.8%, and 39.1%, respectively). Gene set enrichment analysis identified glycolysis-related pathways (false discovery rate amp;lt; 0.001) upregulated in ER beta-activated mammospheres. We observed that tamoxifen or fulvestrant alone was insufficient to block proliferation of patient-derived BSCs while this could be accomplished by a selective inhibitor of ER beta (PHTPP; 53.7% in luminal and 45.5% in triple-negative breast cancers). Furthermore, PHTPP reduced tumor initiation in two patient-derived xenografts (75.9% and 59.1% reduction in tumor volume, respectively) and potentiated tamoxifen-mediated inhibition of tumor growth in MCF7 xenografts. Conclusion: We identify ER beta as a mediator of estrogen action in BSCs and a novel target for endocrine therapy.

  • 282.
    Maddika, Subbareddy
    et al.
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics,University of Manitoba, Winnipeg, Canada .
    Ande, Sudharsana Rao
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
    Panigrahi, Soumya
    Department of Physiology, University of Manitoba, Winnipeg, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada, .
    Paranjothy, Ted
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
    Weglarczyk, Kazimierz
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada; Department of Clinical Immunology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.
    Zuse, Anne
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
    Eshraghi, Mehdi
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada; Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada; D.
    Manda, Kamala D.
    Department of Immunology, University of Manitoba, Winnipeg, Canada.
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark,.
    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, .
    Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy2007Ingår i: Drug resistance updates, ISSN 1368-7646, E-ISSN 1532-2084, Vol. 10, nr 1-2, s. 13-29Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16(Ink4a), p15(Ink4b), P18(Ink4c), p19(Ink4d)), and the Cip1/Waf1/Kip1-2-family (p21(Cip1/Waf1), p27(Kip1), p57(Kip2)) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bc12-family members (i.e. Bcl2, Bcl-X-L Mcl-1(L); Bax, Bok/Mtd, Bak, and Bcl-X-S; Bad, Bid, Bim(EL), Bmf, Mcl-1(S)) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G(1)-S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells. (c) 2007 Elsevier Ltd. All rights reserved.

  • 283.
    Maddika, Subbareddy
    et al.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.
    Ande, Sudharsana Rao
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, R3E 0V9, Canada.
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark; Department of Experimental and Clinical Radiobiology, Oncology Center, Maria Sklodowka-Curie Memorial Institute, Wybrzeze Armii Krajowej 15, PL-44100 Gliwice, Poland .
    Hansen, Lise Lotte
    Department of Experimental and Clinical Radiobiology, Oncology Center, Maria Sklodowka-Curie Memorial Institute, Wybrzeze Armii Krajowej 15, PL-44100 Gliwice, Poland .
    Wesselborg, Sebastian
    Department of Internal Medicine I, University of Tübingen, Tübingen, Germany.
    Los, Marek Jan
    BioApplications Enterprises, Winnipeg, MB, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, R3E 0V9, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, R3E 0V9, Canada .
    Akt-mediated phosphorylation of CDK2 regulates its dual role in cell cycle progression and apoptosis2008Ingår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 121, s. 979-988Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Here, we show that CDK2, an S-phase cyclin-dependent kinase, is a novel target for Akt during cell cycle progression and apoptosis. Akt phosphorylates CDK2 at threonine 39 residue both in vitro and in vivo. Although CDK2 threonine 39 phosphorylation mediated by Akt enhances cyclin-A binding, it is dispensable for its basal binding and the kinase activity. In addition, for the first time, we report a transient nucleo-cytoplasmic shuttling of Akt during specific stages of the cell cycle, in particular during the late S and G2 phases. The Akt that is re-localized to the nucleus phosphorylates CDK2 and causes the temporary cytoplasmic localization of the CDK2–cyclin-A complex. The CDK2 cytoplasmic redistribution is required for cell progression from S to G2-M phase, because the CDK2 T39A mutant, which lacks the phosphorylation site and is defective in cytoplasmic localization, severely affects cell cycle progression at the transition from S to G2-M. Interestingly, we also show that the Akt/CDK2 pathway is constitutively activated by some anticancer drugs, such as methotrexate and docetaxel, and under these conditions it promotes, rather than represses, cell death. Thus, the constitutive activation of the Akt/CDK2 pathway and changed subcellular localization promotes apoptosis. By contrast, the transient, physiological Akt/CDK2 activation is necessary for cell cycle progression.

  • 284.
    Maddika, Subbareddy
    et al.
    University of Manitoba, Winnipeg, Canada .
    Booy, Evan P.
    University of Manitoba, Winnipeg, Canada .
    Johar, Dina
    University of Manitoba, Winnipeg, Canada .
    Gibson, Spencer B.
    University of Manitoba, Winnipeg, Canada .
    Ghavami, Saeid
    University of Manitoba, Winnipeg, Canada .
    Los, Marek Jan
    University of Manitoba, Winnipeg, Canada .
    Cancer-specific toxicity of apoptin is independent of death receptors but involves the loss of mitochondrial membrane potential and the release of mitochondrial cell-death mediators by a Nur77-dependent pathway2005Ingår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 118, s. 4485-4493Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Apoptin, a small proline-rich protein derived from the chicken anaemia virus, induces cell death selectively in cancer cells. The signalling pathways of apoptin-induced, cancer cell-selective apoptosis are not well understood. Here, we demonstrate that apoptin triggers apoptosis by activating the mitochondrial/intrinsic pathway, and that it acts independently of the death receptor/extrinsic pathway. Jurkat cells deficient in either FADD or caspase-8 (which are both necessary for the extrinsic pathway) were equally as sensitive to apoptin as their parental clones. This demonstrates that apoptin is likely to act through the mitochondrial death pathway. Apoptin treatment causes a loss of mitochondrial membrane potential, and release of the mitochondrial proteins cytochrome c and apoptosis-inducing factor. Apoptin-induced cell death is counteracted by the anti-apoptotic Bcl-2 family members, Bcl-2 itself and Bcl-XL, as shown in Jurkat leukaemia cells. In addition, we describe the processing and activation of caspase-3. By contrast, cleavage of caspase-8, which is predominantly triggered by the death receptor pathway, is not observed. Furthermore, apoptin triggers the cytoplasmic translocation of Nur77, and the inhibition of Nur77 expression by siRNA significantly protects MCF7 cells from apoptin-triggered cell death. Thus, our data indicate that the apoptin death signal(s) ultimately converges at the mitochondria, and that it acts independently of the death receptor pathway.                               

  • 285.
    Maddika, Subbareddy
    et al.
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics,University of Manitoba, Winnipeg, Canada .
    Kroczak, T.
    Manitoba Inst Cell Biol, Winnipeg, MB R3E 0V9, Canada.
    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, .
    Apoptin triggered apoptotic signaling in cancer cells2005Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 16, s. 36-36Artikel i tidskrift (Refereegranskat)
  • 286.
    Maddika, Subbareddy
    et al.
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Mendoza, F. J.
    University of Manitoba; Winnipeg, Canada.
    Hauff, K.
    University of Manitoba; Winnipeg, Canada.
    Zamzow, C. R.
    University of Manitoba; Winnipeg, Canada.
    Paranjothy, T.
    University of Manitoba; Winnipeg, Canada.
    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, .
    Cancer-selective therapy of the future: Apoptin and its mechanism of action2006Ingår i: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 5, nr 1, s. 10-19Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Classical chemotherapy that specifically targets rapidly proliferating cells has been in existence for over eighty years and has proven to be fully successful in only a limited number of cancers. Thus, this review focuses on a novel, emerging approach for cancer therapy that uses alternative, and more unique features of cancer cells. This new approach facilitates the selective targeting of cancer, while sparing normal, non-transformed cells. Examples of molecules that kill cancer cells selectively are: apoptin, E4orf4, viral protein R (VpR), and Brevinin-2R. Below we focus on apoptin, a product of the third open reading frame (VP3) of the chicken anemia virus. Besides discussing apoptin's mechanism of action, we also provide concise insight into the biology of a chicken anemia virus infection. Since apoptin's cancer-selective toxicity depends on its nuclear localization, we broadly discuss mechanism(s) involved in its nuclear retention (both nuclear import and export). We also discuss recent findings on apoptin's molecular mechanism of action, with a focus on the role of Nur77 in apoptin's nucleo-cytoplasmic signaling. Finally, we compare the current findings on apoptin to the mechanism of cancer selective toxicity of E4orf4. In the 'summary' section, besides highlighting important issues related to cancer-selective therapy, we also discuss concurrent approaches towards therapy personalization, particularly those related to the in vivo, and real time cancer therapy efficacy monitoring, using "lab-on-the-chip" and other emerging technologies.

  • 287.
    Maddika, Subbareddy
    et al.
    Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, USA.
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark,.
    Ande, S. R.
    Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada.
    Poon, I. K.
    Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
    Fischer, Ute
    Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany.
    Wesselborg, Sebastian
    Department of Internal Medicine I, University of Tübingen, Tübingen, Germany; and BioApplications Enterprises, Winnipeg, Manitoba, Canada.
    Jans, D. A.
    Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
    Schulze-Osthoff, Klaus
    Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany .
    Los, Marek Jan
    BioApplications Enterprises, Winnipeg, MB, Canada; Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
    Interaction with PI3-kinase contributes to the cytotoxic activity of Apoptin2008Ingår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 27, s. 3060-3065Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Apoptin, a small protein from the chicken anemia virus, has attracted attention because of its specificity in killing tumor cells. Localization of apoptin in the nucleus of tumor cells has been shown to be vital for proapoptotic activity, however, targeted expression of apoptin in the nucleus of normal cells does not harm the cells, indicating that nuclear localization of apoptin is insufficient for its cytotoxicity. Here, we demonstrate for the first time that apoptin interacts with the SH3 domain of p85, the regulatory subunit of phosphoinositide 3-kinase (PI3-K), through its proline-rich region. Apoptin derivatives devoid of this proline-rich region do not interact with p85, are unable to activate PI3-K, and show impaired apoptosis induction. Moreover, apoptin mutants containing the proline-rich domain are sufficient to elevate PI3-K activity and to induce apoptosis in cancer cells. Downregulation of p85 leads to nuclear exclusion of apoptin and impairs cell death induction, indicating that interaction with the p85 PI3-K subunit essentially contributes to the cytotoxic activity of apoptin.

  • 288.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Studies for Better Treatment of Patients with Glioma2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    In Sweden annually over 500 people will be diagnosed with the malignant brain tumor glioma. They are graded from I-IV. The majority are glioblastoma (grade IV) (GBM), these being the most aggressive type. Median survival for those treated with standard of care is expected to be around 15 months. This tumor will mainly affect those 60 years or older.

    The studies in this thesis focus on treatment of patients with malignant gliomas grade III and IV. The aim of the studies is to improve the care of glioma patients. Papers I and II explored different therapeutic options in randomized trials, to facilitate individualized treatment recommendations. Findings from studies I and II, together with additional trials, demonstrated the importance of analyzing the tumor marker O6-methylguanine DNA methyltransferase (MGMT) methylation status for survival of GBM patients treated with Temozolomide (TMZ). The third paper investigated how the analysis of this marker is implemented internationally.

    The first study (paper I, Nordic trial) investigated treatment options for patients 60 years or older with GBM. The trial compared standard radiotherapy (SRT) over 6 weeks versus hypofractionated radiotherapy (HRT) over 2 weeks versus single agent TMZ administered in up to six 4 weekly cycles. In all, 342 patients were included in the trial. This study demonstrated that those randomized to TMZ had superior survival as compared to SRT. In addition, quality of life (QoL) data also suggested a better QoL for TMZ treatment than for radiotherapy. The benefit of TMZ treatment seemed to be limited to those with the tumor molecular marker MGMT methylated (inactivated).

    The second trial (paper II, Neoadjuvant trial) studied whether integrating TMZ treatment with SRT for patients younger than 60 years with GBM (grade IV) and astrocytoma grade III would confer a survival benefit, if administered postoperatively, before the start of SRT (neoadjuvant). TMZ was provided for 2-3 four weekly cycles followed by SRT to patients randomized to neoadjuvant treatment and was compared to postoperative SRT alone. Although this trial could not illustrate any advantage of delaying the start of SRT while administering TMZ for the study cohort in general, for those included as astrocytoma grade III the median survival was found to be superior by 5 years when randomized to neoadjuvant TMZ. This trial also confirmed the importance of MGMT promoter methylation for the efficacy of TMZ.

    The third study (paper III) investigated international practices for analyzing tumor MGMT promoter methylation status. MGMT analysis can be conducted by various laboratory methods, which in some cases can provide opposing results regarding the MGMT methylation status of the patient´s tumor. This can lead to incorrect treatment recommendations. To establish which methods and cut-offs that are regularly used to determine tumor MGMT status in the clinic, an international survey was provided to those working in the field. We also inquired about opinions regarding an international consensus on how MGMT should be tested. The 152 respondents reported several methodologies and different cut-off levels also for the same method. A majority of respondents warrant international guidelines.

    In conclusion, the results of the 2 randomized trials contribute to individualized treatment recommendations for patients affected by GBM or astrocytoma grade III. The results of the survey regarding analyses of MGMT clarify the current problematic situation. The request of the respondents regarding international guidelines might contribute to their future development, so that personalized treatment recommendations can be improved.

    Delarbeten
    1. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial
    Öppna denna publikation i ny flik eller fönster >>Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial
    Visa övriga...
    2012 (Engelska)Ingår i: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 13, nr 9, s. 916-926Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background Most patients with glioblastoma are older than 60 years, but treatment guidelines are based on trials in patients aged only up to 70 years. We did a randomised trial to assess the optimum palliative treatment in patients aged 60 years and older with glioblastoma. less thanbrgreater than less thanbrgreater thanMethods Patients with newly diagnosed glioblastoma were recruited from Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. They were assigned by a computer-generated randomisation schedule, stratified by centre, to receive temozolomide (200 mg/m(2) on days 1-5 of every 28 days for up to six cycles), hypofractionated radiotherapy (34.0 Gy administered in 3.4 Gy fractions over 2 weeks), or standard radiotherapy (60.0 Gy administered in 2.0 Gy fractions over 6 weeks). Patients and study staff were aware of treatment assignment. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered, number ISRCTN81470623. less thanbrgreater than less thanbrgreater thanFindings 342 patients were enrolled, of whom 291 were randomised across three treatment groups (temozolomide n=93, hypofractionated radiotherapy n=98, standard radiotherapy n=100) and 51 of whom were randomised across only two groups (temozolomide n=26, hypofractionated radiotherapy n=25). In the three-group randomisation, in comparison with standard radiotherapy, median overall survival was significantly longer with temozolomide (8.3 months [95% CI 7.1-9.5; n=93] vs 6.0 months [95% CI 5.1-6.8; n=100], hazard ratio [HR] 0.70; 95% CI 0.52-0.93, p=0.01), but not with hypofractionated radiotherapy (7.5 months [6.5-8.6; n=98], HR 0.85 [0.64-1.12], p=0.24). For all patients who received temozolomide or hypofractionated radiotherapy (n=242) overall survival was similar (8.4 months [7.3-9.4; n=119] vs 7.4 months [6.4-8.4; n=123]; HR 0.82, 95% CI 0.63-1.06; p=0.12). For age older than 70 years, survival was better with temozolomide and with hypofractionated radiotherapy than with standard radiotherapy (HR for temozolomide vs standard radiotherapy 0.35 [0.21-0.56], pandlt;0.0001; HR for hypofractionated vs standard radiotherapy 0.59 [95% CI 0.37-0.93], p=0.02). Patients treated with temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (9.7 months [95% CI 8.0-11.4] vs 6.8 months [5.9-7.7]; HR 0.56 [95% CI 0.34-0.93], p=0.02), but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy (HR 0.97 [95% CI 0.69-1.38]; p=0.81). As expected, the most common grade 3-4 adverse events in the temozolomide group were neutropenia (n=12) and thrombocytopenia (n=18). Grade 3-5 infections in all randomisation groups were reported in 18 patients. Two patients had fatal infections (one in the temozolomide group and one in the standard radiotherapy group) and one in the temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed. less thanbrgreater than less thanbrgreater thanInterpretation Standard radiotherapy was associated with poor outcomes, especially in patients older than 70 years. Both temozolomide and hypofractionated radiotherapy should be considered as standard treatment options in elderly patients with glioblastoma. MGMT promoter methylation status might be a useful predictive marker for benefit from temozolomide.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2012
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-84333 (URN)10.1016/S1470-2045(12)70265-6 (DOI)000308425600019 ()
    Anmärkning

    Funding Agencies|Merck||Lions Cancer Research Foundation||University of Umea||Swedish Cancer Society||Schering-Plough||University of Umea, Sweden||Cancer Fonden, Sweden||

    Tillgänglig från: 2012-10-05 Skapad: 2012-10-05 Senast uppdaterad: 2019-11-06
    2. Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial
    Öppna denna publikation i ny flik eller fönster >>Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial
    Visa övriga...
    2017 (Engelska)Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, nr 12, s. 1776-1785Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Introduction: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ.Patients and methods: Patients, after surgery for GBM or AA, age 60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200mg/m(2) days 1-5 every 28 days, followed by RT 60Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75mg/m(2) was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety.Results: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p=.76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p=.022). For patients with GBM, no difference in survival was observed (p=.10). MGMT and IDH status affected outcome.Conclusions: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.

    Ort, förlag, år, upplaga, sidor
    TAYLOR & FRANCIS LTD, 2017
    Nationell ämneskategori
    Kirurgi
    Identifikatorer
    urn:nbn:se:liu:diva-144005 (URN)10.1080/0284186X.2017.1332780 (DOI)000418118800016 ()28675067 (PubMedID)
    Anmärkning

    Funding Agencies|Merck; Linkoping University Hospital for Neuro-research; Lions Cancer Foundation; Cancer Foundation Norrland, Umea, Sweden; LIUCancer; South-East Sweden FORSS

    Tillgänglig från: 2018-01-02 Skapad: 2018-01-02 Senast uppdaterad: 2019-11-06
    3. Do we really know who has an MGMT methylated glioma?: Results of an international survey regarding use of MGMT analyses for glioma
    Öppna denna publikation i ny flik eller fönster >>Do we really know who has an MGMT methylated glioma?: Results of an international survey regarding use of MGMT analyses for glioma
    Visa övriga...
    2019 (Engelska)Ingår i: Neuro-Oncology Practice, ISSN 2054-2577, s. 1-9Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Glioma O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status informs clinical decision making. Worldwide different methods and cutoff levels are used, which can lead to discordant methylation results.We conducted an international survey to clarify which methods are regularly used and why. We also explored opinions regarding international consensus on methods and cutoff.The survey had 152 respondents from 25 countries. MGMT methylation status is determined for all glioblastomas in 37% of laboratories. The most common methods are methylation-specific polymerase chain reaction (msPCR) (37%) and pyrosequencing (34%). A method is selected for simplicity (56%), cost-effectiveness (50%), and reproducibility of results (52%). For sequencing, the number of CpG sites analyzed varies from 1–3 up to more than 16. For 50% of laboratories, the company producing the kit determines which CpG sites are examined, whereas 33% select the sites themselves. Selection of cutoff is equally distributed among a cutoff defined in the literature, by the local laboratory, or by the outside laboratory performing the analysis. This cutoff varies, reported from 1% to 30%, and in 1 laboratory tumor is determined as methylated in case of 1 methylated CpG site of 17 analyzed. Some report tumors as unmethylated or weakly vs highly methylated. An international consensus on MGMT methylation method and cutoff is warranted by 66% and 76% of respondents, respectively. The method preferred would be msPCR (45%) or pyrosequencing (42%), whereas 18% suggest next-generation sequencing.Although analysis of MGMT methylation status is routine, there is controversy regarding laboratory methods and cutoff level. Most respondents favor development of international consensus guidelines.

    Ort, förlag, år, upplaga, sidor
    Oxford: Oxford University Press, 2019
    Nationell ämneskategori
    Medicinsk biovetenskap Klinisk laboratoriemedicin
    Identifikatorer
    urn:nbn:se:liu:diva-160808 (URN)10.1093/nop/npz039 (DOI)
    Tillgänglig från: 2019-10-09 Skapad: 2019-10-09 Senast uppdaterad: 2019-11-06Bibliografiskt granskad
  • 289.
    Manna, Subrata
    et al.
    Department of Biology; Stern College for Women of Yeshiva University; New York, New York, USA.
    Bostner, Josefine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Sun, Yang
    Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
    Miller, Lance D
    Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina. The Comprehensive Cancer Center of Wake Forest University, Winston Salem, North Carolina, USA.
    Alayev, Anya
    Department of Biology; Stern College for Women of Yeshiva University; New York, New York, USA.
    Schwartz, Naomi S
    Department of Biology; Stern College for Women of Yeshiva University; New York, New York, USA.
    Lager, Elin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital, Stockholm South General Hospital, Karolinska Institute, Stockholm, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Yu, Jane J
    Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Holz, Marina K
    Department of Biology; Stern College for Women of Yeshiva University; New York, New York. Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, New York, USA.
    ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer.2016Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, nr 6, s. 1421-1431Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: Estrogen-related receptor alpha (ERRα) signaling has recently been implicated in breast cancer. We investigated the clinical value of ERRα in randomized cohorts of tamoxifen-treated and adjuvant-untreated patients.

    EXPERIMENTAL DESIGN: Cox proportional hazards regression was used to evaluate the significance of associations between ERRα gene expression levels and patient DMFS in a previously published microarray dataset representing 2,000 breast tumor cases derived from multiple medical centers worldwide. The 912 tumors used for immunostaining were from a tamoxifen-randomized primary breast cancer trial conducted in Stockholm, Sweden, during 1976-1990. Mouse model was used to study the effect of tamoxifen treatment on lung colonization of MDA-MB-231 control cells and MDA-MB-231 cells with stable knockdown of ERRα. The phenotypic effects associated with ERRα modulation were studied using immunoblotting analyses and wound-healing assay.

    RESULTS: We found that in ER-negative and triple-negative breast cancer (TNBC) adjuvant-untreated patients, ERRα expression indicated worse prognosis and correlated with poor outcome predictors. However, in tamoxifen-treated patients, an improved outcome was observed with high ERRα gene and protein expression. Reduced ERRα expression was oncogenic in the presence of tamoxifen, measured by in vitro proliferation and migration assays and in vivo metastasis studies.

    CONCLUSION: Taken together, these data show that ERRα expression predicts response to tamoxifen treatment, and ERRα could be a biomarker of tamoxifen sensitivity and a prognostic factor in TNBC. Clin Cancer Res; 1-11. ©2015 AACR.

  • 290.
    Marcu, Loredana G.
    et al.
    University of Oradea, Romania and University of Adelaide, Australia.
    Bezak, Eva
    Royal Adelaide Hospital, Australia.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet, Sweden.
    Dasu, Alexandru
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper.
    Predictive models of tumour response to treatment using functional imaging techniques2015Ingår i: Computational & Mathematical Methods in Medicine, ISSN 1748-670X, E-ISSN 1748-6718, Vol. 2015, s. Article ID 571351-Artikel i tidskrift (Övrigt vetenskapligt)
  • 291.
    Marcu, Loredana G.
    et al.
    University of Oradea, Romania and University of Adelaide, Australia.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Dasu, Alexandru
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    The six Rs of head and neck cancer radiotherapy2015Ingår i: Contemporary Issues in Head and Neck Cancer Management / [ed] Loredana G. Marcu, Rijeka: InTech , 2015, s. 35-58Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    While the management of head and neck cancer has evolved over the last few decades, there are still several challenges and unanswered questions that need solutions. This book is a small compilation of some topical aspects regarding head and neck cancer treatment, including the etiology of HPV-positive oropharyngeal cancers and risk factors in the young population, the challenge of surgical margin definition and the perennial problem of systemic treatment due to distant metastases. Radiobiological aspects are also covered through the Rs of radiotherapy, with a couple of chapters being dedicated to radioresistance and tumour microenvironment. Contemporary Issues in Head and Neck Cancer Management comes as an addition to the existing literature that aims to tackle this radiobiologically challenging tumour.

  • 292.
    Marcu, Loredana G.
    et al.
    University of Oradea and University of South Australia.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Dasu, Alexandru
    The Skandion Clinic.
    Mercke, Claes
    Karolinska University Hospital, Sweden.
    Radiotherapy and clinical radiobiology of head and neck cancer2018Bok (Refereegranskat)
    Abstract [en]

    Common factors that lead to treatment failure in head and neck cancer are the lack of tumour oxygenation, the accelerated division of cancer cells during treatment, and radioresistance. These tumour-related challenges and possible ways to overcome them are covered in this book, authored by three medical physicists and a clinical oncologist who explain how different radiobiological findings have led to the development of various treatment techniques for head and neck cancer. Novel treatment techniques as supported by current scientific evidence are comprehensively explored, as well as the major challenges that arise in the retreatment of patients who have already undergone a form of radiotherapy for primary head and neck cancer.

  • 293.
    Melissaridou, Styliani
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Magan, Mustafa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Jain, Mayur Vilas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
    Chung, Man Ki
    Department of Otorhinolaryngology-Head & Neck Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea.
    Farnebo, Lovisa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US.
    The effect of 2D and 3D cell cultures on treatment response, EMT profile and stem cell features in head and neck cancer.2019Ingår i: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, Vol. 19, nr 16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Head and Neck Squamous Cell Carcinoma (HNSCC) tumors are often resistant to therapies. Therefore searching for predictive markers and new targets for treatment in clinically relevant in vitro tumor models is essential. Five HNSCC-derived cell lines were used to assess the effect of 3D culturing compared to 2D monolayers in terms of cell proliferation, response to anti-cancer therapy as well as expression of EMT and CSC genes.

    Methods

    The viability and proliferation capacity of HNSCC cells as well as induction of apoptosis in tumor spheroids cells after treatment was assessed by MTT assay, crystal violet- and TUNEL assay respectively. Expression of EMT and CSC markers was analyzed on mRNA (RT-qPCR) and protein (Western blot) level.

    Results

    We showed that HNSCC cells from different tumors formed spheroids that differed in size and density in regard to EMT-associated protein expression and culturing time. In all spheroids, an up regulation of CDH1, NANOG and SOX2 was observed in comparison to 2D but changes in the expression of EGFR and EMT markers varied among the cell lines. Moreover, most HNSCC cells grown in 3D showed decreased sensitivity to cisplatin and cetuximab (anti-EGFR) treatment.

    Conclusions

    Taken together, our study points at notable differences between these two cellular systems in terms of EMT-associated gene expression profile and drug response. As the 3D cell cultures imitate the in vivo behaviour of neoplastic cells within the tumor, our study suggest that 3D culture model is superior to 2D monolayers in the search for new therapeutic targets.

  • 294.
    Mendoza, F. J.
    et al.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
    Espino, P. S.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
    Cann, K. L.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
    Bristow, N.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
    McCrea, K.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
    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, .
    Anti-tumor chemotherapy utilizing peptide-based approaches - apoptotic pathways, kinases, and proteasome as targets2005Ingår i: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 53, nr 1, s. 47-60Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The pharmacological sciences are taking advantage of recent discoveries that have defined the molecular pathways governing apoptosis. These signaling cascades are frequently inactivated or distorted by mutations in cancer cells. Peptides derived from critical interaction, phosphorylation, or cleavage sites are the preferred leads (starting points) for the development of new drugs. In this review we summarize recent peptide-based approaches that target MDM2, p53, NF-kappaB, ErbB2, MAPK, as well as Smac/DIABLO, IAP BIR domains, and Bcl-2 interaction domains, with a specific focus on the BH3 domain. Separate parts of the review deal with proteasome inhibitors, integrin-derived peptides, and molecules that are being tested for tumor-selective delivery of anticancer drugs ("magic bullet" approach). The proteasome inhibitors and integrin-derived peptides show a variety of effects, targeting not only tumor growth, but also angiogenesis, metastasizing potential, and other cancer cell functions. The last part of this review describes approaches that use specific properties (surface receptors, increased enzymatic activities) of cancer cells in order to target them specifically. These new generations of anticancer drugs provide the foundations for therapies with fewer side effects and higher efficacy.

  • 295.
    Mi, Yushuai
    et al.
    Shanghai Jiao Tong University, Peoples R China.
    Zhang, Dongyuan
    Shanghai Jiao Tong University, Peoples R China.
    Jiang, Weiliang
    Shanghai Jiao Tong University, Peoples R China.
    Weng, Junyong
    Shanghai Jiao Tong University, Peoples R China.
    Zhou, Chongzhi
    Shanghai Jiao Tong University, Peoples R China.
    Huang, Kejian
    Shanghai Jiao Tong University, Peoples R China.
    Tang, Huamei
    Shanghai Jiao Tong University, Peoples R China.
    Yu, Yang
    Shanghai Jiao Tong University, Peoples R China.
    Liu, Xisheng
    Shanghai Jiao Tong University, Peoples R China.
    Cui, Weiyingqi
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Zhang, Meng
    Fudan University, Peoples R China.
    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.
    Zhou, Zongguang
    Sichuan University, Peoples R China.
    Peng, Zhihai
    Shanghai Jiao Tong University, Peoples R China.
    Zhao, Senlin
    Shanghai Jiao Tong University, Peoples R China.
    Wen, Yugang
    Shanghai Jiao Tong University, Peoples R China.
    miR-181a-5p promotes the progression of gastric cancer via RASSF6-mediated MAPK signalling activation2017Ingår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 389, s. 11-22Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We previously discovered that Ras association domain family member 6 (RASSF6) was downregulated and predicted poor prognosis in GC patients. However, the mechanisms of the down regulation of RASSF6 in GC remained unclear. Increasing evidence indicates that dysregulation of microRNAs promotes the progression of cancer through the repression of tumour suppressors. Here, we identified miR-181a-5p as a novel regulator of RASSF6 in GC. Functionally, ectopic expression or silencing of miR-181a-5p, respectively, promoted or inhibited GC cell proliferation, colony formation and cell cycle transition, as well as enhanced or prevented the invasion, metastasis of GC cells and epithelial to mesenchymal transition of GC cells in vitro and in vivo. Molecularly, miR-181a-5p functioned as an onco-miRNA by activating the RASSF6-regulated MAKP pathway. Overexpression or silencing of RASSF6 could partially reverse the effects of the overexpression or repression of miR-181a-5p on GC progress caused by activation of the MAKP pathway in vitro and in vivo. Clinically, high miR-181a-5p expression predicted poor survival in GC patients, especially combined with low RASSF6 expression. Collectively, we identified miR-181a-5p as an onco-miRNA, which acts by directly repressing RASSF6 in GC. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.

  • 296.
    Mi, Yushuai
    et al.
    Shanghai Jiao Tong University, Peoples R China.
    Zhao, Senlin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Shanghai Jiao Tong University, Peoples R China.
    Zhang, Weihao
    Shanghai Jiao Tong University, Peoples R China.
    Zhang, Dongyuan
    Shanghai Jiao Tong University, Peoples R China.
    Weng, Junyong
    Shanghai Jiao Tong University, Peoples R China.
    Huang, Kejian
    Shanghai Jiao Tong University, Peoples R China.
    Sun, Huimin
    Shanghai Jiao Tong University, Peoples R China.
    Tang, Huamei
    Shanghai Jiao Tong University, Peoples R China.
    Zhang, Xin
    Zhejiang Prov Peoples Hospital, Peoples R China.
    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.
    Peng, Zhihai
    Shanghai Jiao Tong University, Peoples R China.
    Wen, Yugang
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Shanghai Jiao Tong University, Peoples R China.
    Down-regulation of Barx2 predicts poor survival in colorectal cancer2016Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 478, nr 1, s. 67-73Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human BarH-like homeobox 2 (Barx2), a homeodomain factor of the Bar family, has an important role in controlling the expression of cell adhesion molecules and has been reported in an increasing array of tumor types except colorectal cancer (CRC). The purpose of the current study was to characterize the expression of Barx2 and assess the clinical significance of Barx2 in CRC. First, we analyzed the expression of Barx2 in two independent public datasets from Oncomine. Subsequently, we evaluated Barx2 mRNA and protein expression by quantitative real-time PCR and western blotting, respectively. It was determined that Barx2 expression was lower in tumor tissues than in adjacent non-tumorous colorectal tissues of CRC patients, consistent with results from the public datasets. Subsequently, a tissue microarray containing 196 CRC specimens was evaluated for Barx2 expression by immunohistochemical staining. It was found that low expression of Barx2 significantly correlated with TNM stage, AJCC stage, differentiation, and relapse in patients with CRC. Patients with lower levels of Barx2 expression showed reduced disease-free survival and overall survival. Furthermore, a trend toward shorter overall survival in the patient group with Barx2-negative tumors independent of advanced AJCC stage and poor differentiation was determined by Kaplan-Meier survival analysis. Based on univariate and multivariate analyses, Barx2 expression was an independent prognostic factor for determining CRC prognosis. Taken together, low Barx2 expression was associated with the progression of CRC and could serve as a potential independent prognostic biomarker for patients with CRC. (C) 2016 The Authors. Published by Elsevier Inc.

  • 297.
    Mi, Yushuai
    et al.
    Shanghai Jiao Tong University, Peoples R China.
    Zhao, Senlin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Shanghai Jiao Tong University, Peoples R China.
    Zhou, Chongzhi
    Shanghai Jiao Tong University, Peoples R China.
    Weng, Junyong
    Shanghai Jiao Tong University, Peoples R China.
    Li, Jikun
    Shanghai Jiao Tong University, Peoples R China.
    Wang, Zhanshan
    Shanghai Jiao Tong University, Peoples R China.
    Sun, Huimin
    Shanghai Jiao Tong University, Peoples R China.
    Tang, Huamei
    Shanghai Jiao Tong University, Peoples R China.
    Zhang, Xin
    Zhejiang Prov Peoples Hospital, Peoples R China.
    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.
    Peng, Zhihai
    Shanghai Jiao Tong University, Peoples R China.
    Wen, Yugang
    Region Östergötland, 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. Shanghai Jiao Tong University, Peoples R China.
    Downregulation of homeobox gene Barx2 increases gastric cancer proliferation and metastasis and predicts poor patient outcomes2016Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 37, s. 60593-60608Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Barx2 is a Bar family homeodomain transcription factor shown to play a critical role in cell adhesion and cytoskeleton remodeling, key processes in carcinogenesis and metastasis. Using quantitative real-time PCR, Western blotting, and immunohistochemistry, we found that Barx2 is expressed at lower levels in human gastric cancer (GC) tissues than in adjacent normal mucosa. In a multivariate analysis, Barx2 expression emerged as an independent prognostic factor for disease-free and overall survival. Kaplan-Meier survival analysis showed a trend toward even shorter overall survival in the patient group with Barx2-negative tumors, independent of advanced UICC stage and tumor relapse. Using in vitro and in vivo assays, we demonstrated that under normal conditions Barx2 inhibited GC cell proliferation and invasiveness through inhibition of the Wnt/beta-catenin signaling pathway. These findings indicate that reduction or loss of Barx2 dis-inhibits GC cell proliferation and invasion, and that reduction in Barx2 could serve as an independent prognostic biomarker for poor outcome in GC patients.

  • 298.
    Miger, Jasmine
    et al.
    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.
    Holmqvist, Annica
    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.
    Albertsson, Maria
    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.
    Low-dose capecitabine (Xeloda) for treatment for gastrointestinal cancer2014Ingår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 31, nr 3, s. 870-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The prodrug capecitabine (Xeloda) has been an important drug for treatment for gastrointestinal cancer (GI-cancer). This study explores the efficacy of continuous metronomic Xeloda, as well as tolerability and best response during treatment. Patients (n=35) with stage IV GI-cancer were included in the study and were divided into two groups; upper (n=13) and lower (n=22) GI-cancer. All patients were given continuous metronomic Xeloda (500 mg×2). Best response was measured by radiological and clinical examination including laboratory results. Standard RECIST criteria were used. Median age was 66 (range 29-86). Those patients who received first and second line had the longest duration of treatment. For patients with metastatic gastrointestinal cancer, metronomic capecitabine (Xeloda) may be beneficial both as far as tumor control and quality of life is concerned. In this pilot study, palliation for more than 2 years is observed for 6 of the 35 patients.

  • 299.
    Mirza, M. R.
    et al.
    Nordic Soc Gynecol Oncol, Denmark; Copenhagen University Hospital, Denmark.
    Monk, B. J.
    University of Arizona, AZ USA; Creighton University of Phoenix, AZ USA; Arizona Oncology Associates, AZ USA.
    Herrstedt, J.
    University of Southern Denmark, Denmark.
    Oza, A. M.
    University of Toronto, Canada.
    Mahner, S.
    Arbeitsgemeinschaft Gynakol Onkol, Germany; University of Munich, Germany.
    Redondo, A.
    GEICO, Spain; Hospital University of La Paz, Spain.
    Fabbro, M.
    French Investigator Grp Ovarian and Breast Cancer GIN, France; Institute Cancer Montpellier, France.
    Ledermann, J. A.
    UCL, England; UCL, England.
    Lorusso, D.
    Ist Nazl Tumori, Italy.
    Vergote, I.
    Luxembourg Gynecol Oncology Grp, Belgium; University of Leuven, Belgium.
    Ben-Baruch, N. E.
    Kaplan Medical Centre, Israel.
    Marth, C.
    AGO Austria, Austria; Medical University of Innsbruck, Austria.
    Madry, R.
    Central and Eastern European Gynecol Oncology Grp, Poland; Uniwersytet Medical Poznaniu, Poland.
    Christensen, R. D.
    University of Southern Denmark, Denmark.
    Berek, J. S.
    Stanford Comprehens Cancer Institute, CA USA.
    Dorum, A.
    Oslo University Hospital, Norway.
    Tinker, A. V.
    British Columbia Cancer Agency, Canada.
    du Bois, A.
    Kliniken Essen Mitte, Germany.
    Gonzalez-Martin, A.
    GEICO, Spain; MD Anderson Cancer Centre Madrid, Spain.
    Follana, P.
    GINECO, France; Centre Antoine Lacassagne, France.
    Benigno, B.
    Northside Hospital, GA USA.
    Rosenberg, Per
    Region Östergötland, 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.
    Gilbert, L.
    McGill University, Canada.
    Rimel, B. J.
    Cedars Sinai Medical Centre, CA USA.
    Buscema, J.
    Arizona Oncology Associates, AZ USA.
    Balser, J. P.
    Veristat, MA USA.
    Agarwal, S.
    Tesaro, MA USA.
    Matulonis, U. A.
    Dana Farber Cancer Institute, MA 02115 USA.
    Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer2016Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 375, nr 22, s. 2154-2164Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. METHODS In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2: 1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival. RESULTS Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P amp;lt; 0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications. CONCLUSIONS Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274.)

  • 300.
    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.

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