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  • 1.
    Bjersand, Kathrine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Predictive and prognostic factors of epithelial ovarian cancer and pseudomyxoma peritonei2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The overall aim of my thesis was to investigate potential prognostic and predictive factors associated with the tumor cells of epithelial ovarian cancer (EOC) and the gastrointestinal tumor pseudomyxoma peritonei (PMP) to improve and individualize cancer therapy. Both PMP and EOC can develop into peritoneal carcinomatosis (PC), which is characterized by widespread metastasis of cancer tumors in the peritoneal cavity. Major improvements in the management of PC, such as cytoreductive surgery in combination with chemotherapy, have dramatically changed the prognosis.

    To further optimize and tailor treatment, increased knowledge on tumor biology and pathogenesis is needed. Today’s choice of treatment is mainly based on clinical trials and standard protocols that have not taken individual differences in drug sensitivity into consideration. With ex vivo testing of tumor drug sensitivity, individuals at risk of side effects only (and no treatment benefit) could potentially be identified prior to treatment.

    Napsin A is an anti-apoptotic protein that promotes platinum resistance by degradation of the cell cycle regulator and tumor suppressor TP53. Immunohistochemical stainings of 131 early EOC tumors in study I showed that expression of Napsin A was associated with expression of the apoptosis regulators p21 and p53 and with histological subtype. Positivity of Napsin A in an epithelial ovarian tumor strengthens the morphological diagnosis of clear cell carcinoma and should be useful in diagnostics. In study II, the relevance of the proteins HRNPM and SLC1A5 as prognostic factors for recurrent disease, survival and impact on clinical or pathological features was evaluated in 123 patients with early EOC. Our results support concomitant positivity of HRMPM and PUMA/p21 in ovarian cancer and indicate that HRNPM may trigger activity in systems of cell cycle regulation and apoptosis. In subgroup analyses of tumors from patients with non-serous EOC histology, expression of SLC1A5 was shown to be a prognostic factor in terms of prolonged disease-free survival. In studies III and VI, we investigated the ex vivo drug sensitivity of tumor cells from EOC and PMP with the 72-h cell viability assay fluorometric microculture cytotoxicity assay (FMCA). The two studies confirm that drug sensitivity varies considerably between tumor samples from patients within the same diagnostic group. In ovarian cancer, ex vivo results show that type I tumors were generally less sensitive to cytotoxic agents than type II tumors. Samples from patients previously exposed to cytotoxic drugs generally tended to be more resistant to most drugs than samples from unexposed patients in both EOC and PMP. This observation is in line with clinical experience and findings supporting that exposure to cytotoxic treatments contribute to development of chemo-resistance mechanisms. In ovarian cancer, resistance to the kinase inhibitors after exposure varied but was less pronounced than that for standard cytotoxic drugs. In PMP patients, ex vivo drug sensitivity provided prognostic information for progression-free survival, and this is in line with earlier findings.

    List of papers
    1. Napsin A as a marker of clear cell ovarian carcinoma
    Open this publication in new window or tab >>Napsin A as a marker of clear cell ovarian carcinoma
    2013 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, no 1, p. 524-Article in journal (Refereed) Published
    Abstract [en]

    Background: Clear cell carcinomas are aggressive tumors with a distinct biologic behaviour. In a genome-widescreening for genes involved in chemo-resistance, NAPA was over-expressed in cisplatin-resistant cells. The NAPA(protein) Napsin A was described to promote resistance to cisplatin by degradation of the tumor suppressor p53.

    Methods: Totally 131 patients were included in this study all in FIGO-stages I-II; 16 were clear cell tumors which were compared with 40 Type I tumors and 75 type II tumors according to the markers Napsin A, p21, p53 and p27 and some clinical features. For detection of the markers tissue microarrays and immunohistochemistry were used.

    Results: Positivity for Napsin A was detected in 12 (80%) out of the 15 clear cell tumors available for analysis compared with 3 (4%) out of the Type I and II tumors in one group (p < 0.001). Differences in p21 status, p53 status, and p21 + p53- status were striking when clear cell tumors were compared with Type I, Type II, and Type I and II tumors in one group, respectively. The p21 + p53-status was associated to positive staining of Napsin A (p = 0.0015)and clear cell morphology (p = 0.0003). In two separate multivariate logistic regression analyses with Napsin A as endpoint both clear cell carcinoma with OR = 153 (95% C.I. 21–1107); (p < 001) and p21 + p53- status with OR = 5.36(95% C.I. 1.6-17.5); (p = 0.005) were independent predictive factors. ROC curves showed that AUC for Napsin A alone was 0.882, for p21 + p53- it was 0.720 and for p21 + p53-Napsin A + AUC was 0.795. Patients with clear cell tumors had lower (p = 0.013) BMI than Type I patients and were younger (p = 0.046) at diagnosis than Type II patients. Clearcell tumors had a higher frequency (p = 0.039) of capsule rupture at surgery than Type I and II tumors.

    Conclusions: Positivity of Napsin A in an epithelial ovarian tumor might strengthen the morphological diagnosis ofclear cell ovarian carcinoma in the process of differential diagnosis between clear cell ovarian tumors and other histological subtypes.

    Keywords
    Age, BMI, Capsule rupture, CCC, Concomitant p21p53, NAPA, Napsin A, Ovarian cancer, ROC curves
    National Category
    Clinical Medicine
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-213614 (URN)10.1186/1471-2407-13-524 (DOI)000329028300002 ()
    Available from: 2013-12-30 Created: 2013-12-30 Last updated: 2018-04-23Bibliographically approved
    2. The clinical and prognostic correlation of HRNPM and SLC1A5 in pathogenesis and prognosis in epithelial ovarian cancer
    Open this publication in new window or tab >>The clinical and prognostic correlation of HRNPM and SLC1A5 in pathogenesis and prognosis in epithelial ovarian cancer
    Show others...
    2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0179363Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES: To evaluate the prognostic effect of the Heterogeneous nuclear ribonucleoprotein type M (HNRPM) and Solute carrier 1A5 (SLC1A5) in FIGO-stages I-II epithelial ovarian cancer.

    METHODS: A retrospective cohort study was designed to investigate the prognostic effect of HNRPM and SLC1A5, and the association with clinical-pathologic characteristics in 131 patients with FIGO-stages I-II epithelial ovarian cancer. Tissue microarrays were constructed and protein levels were assessed by immunohistochemistry (IHC).

    RESULTS: Positive HRNPM status was associated with positive staining for PUMA (P = 0.04), concomitant PUMA and p21 staining (P = 0.005), and VEGF-R2 (P = 0.003). Positive SLC1A5 staining was associated with positive staining of p27 (P = 0.030), PUMA (P = 0.039), concomitant PUMA and p27 staining, and VEGF-R2 (P = 0.039). In non-serous tumors (n = 72), the SLC1A5 positivity was associated with recurrent disease (P = 0.01). In a multivariable logistic regression analysis FIGO-stage (OR = 12.4), tumor grade (OR = 5.1) and SLC1A5 positivity (OR = 0.1) were independent predictive factors for recurrent disease. Disease-free survival (DFS) in women with SLC1A5-positive non-serous tumors was 92% compared with of 66% in patients with SLC1A5-negative non-serous tumors (Log-rank = 15.343; P = 0.008). In Cox analysis with DFS as endpoint, FIGO-stage (HR = 4.5) and SLC1A5 status (HR = 0.3) were prognostic factors.

    CONCLUSIONS: As the proteins HRNPM and SLC1A5 are associated with the cell cycle regulators p21 or p27, the apoptosis regulators PTEN and PUMA, and the VEGF-R2 it is concluded that both proteins have role in the pathogenesis of ovarian cancer. In patients with non-serous ovarian cancer SLC1A5 protects from recurrent disease, presumably by means of biological mechanisms that are unrelated to cytotoxic drug sensitivity.

    National Category
    Obstetrics, Gynecology and Reproductive Medicine Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-327289 (URN)10.1371/journal.pone.0179363 (DOI)000403274700031 ()28609484 (PubMedID)
    Available from: 2017-08-08 Created: 2017-08-08 Last updated: 2018-04-23Bibliographically approved
    3. Assessment ex vivo of cancer drug sensitivity in epithelial ovarian cancer and its relationship to histopathological type, treatment history and clinical outcome
    Open this publication in new window or tab >>Assessment ex vivo of cancer drug sensitivity in epithelial ovarian cancer and its relationship to histopathological type, treatment history and clinical outcome
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-348140 (URN)
    Available from: 2018-04-10 Created: 2018-04-10 Last updated: 2018-04-23
    4. Drug Sensitivity Testing in Cytoreductive Surgery and Intraperitoneal Chemotherapy of Pseudomyxoma Peritonei
    Open this publication in new window or tab >>Drug Sensitivity Testing in Cytoreductive Surgery and Intraperitoneal Chemotherapy of Pseudomyxoma Peritonei
    Show others...
    2015 (English)In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 22, p. S810-S816Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) is an established therapy for pseudomyxoma peritonei (PMP). However, the role of IPC is unclear. By ex vivo assessment of PMP tumor cell sensitivity to cytotoxic drugs, we investigated the basis for IPC drug selection and the role of IPC in the management of PMP.

    METHODS: Tumor cells were prepared by collagenase digestion of tumor tissue from 133 PMP patients planned for CRS and IPC. Tumor cell sensitivity to oxaliplatin, 5FU, mitomycin C, doxorubicin, irinotecan, and cisplatin was assessed in a 72-h cell-viability assay. Drug sensitivity was correlated to progression-free survival (PFS) and overall survival (OS).

    RESULTS: Samples from 92 patients were analyzed successfully. Drug sensitivity varied considerably between samples. Peritoneal mucinous carcinomatosis (PMCA), compared with PMCA intermediate or disseminated peritoneal adenomucinosis, was slightly more resistant to platinum and 5FU and tumor cells from patients previously treated with chemotherapy were generally less sensitive than those from untreated patients. Multivariate analysis showed patient performance status and completeness of CRS to be prognostic for OS. Among patients with complete CRS (n = 61), PFS tended to be associated with sensitivity to mitomycin C and cisplatin (p ≈ 0.06). At the highest drug concentration tested, the hazard ratio for disease relapse increased stepwise with drug resistance for all drugs.

    CONCLUSIONS: Ex vivo assessment of drug sensitivity in PMP provides prognostic information. The results suggest a role for IPC as therapeutic adjunct to CRS and for individualization of IPC by pretreatment assessment of drug sensitivity.

    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-265752 (URN)10.1245/s10434-015-4675-0 (DOI)000367288100072 ()26193962 (PubMedID)
    Funder
    Swedish Cancer Society
    Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2018-04-23Bibliographically approved
  • 2.
    Bjersand, Kathrine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Andreasson, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Graf, Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Drug Sensitivity Testing in Cytoreductive Surgery and Intraperitoneal Chemotherapy of Pseudomyxoma Peritonei2015In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 22, p. S810-S816Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) is an established therapy for pseudomyxoma peritonei (PMP). However, the role of IPC is unclear. By ex vivo assessment of PMP tumor cell sensitivity to cytotoxic drugs, we investigated the basis for IPC drug selection and the role of IPC in the management of PMP.

    METHODS: Tumor cells were prepared by collagenase digestion of tumor tissue from 133 PMP patients planned for CRS and IPC. Tumor cell sensitivity to oxaliplatin, 5FU, mitomycin C, doxorubicin, irinotecan, and cisplatin was assessed in a 72-h cell-viability assay. Drug sensitivity was correlated to progression-free survival (PFS) and overall survival (OS).

    RESULTS: Samples from 92 patients were analyzed successfully. Drug sensitivity varied considerably between samples. Peritoneal mucinous carcinomatosis (PMCA), compared with PMCA intermediate or disseminated peritoneal adenomucinosis, was slightly more resistant to platinum and 5FU and tumor cells from patients previously treated with chemotherapy were generally less sensitive than those from untreated patients. Multivariate analysis showed patient performance status and completeness of CRS to be prognostic for OS. Among patients with complete CRS (n = 61), PFS tended to be associated with sensitivity to mitomycin C and cisplatin (p ≈ 0.06). At the highest drug concentration tested, the hazard ratio for disease relapse increased stepwise with drug resistance for all drugs.

    CONCLUSIONS: Ex vivo assessment of drug sensitivity in PMP provides prognostic information. The results suggest a role for IPC as therapeutic adjunct to CRS and for individualization of IPC by pretreatment assessment of drug sensitivity.

  • 3.
    Bjersand, Kathrine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Poromaa, Inger Sundström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Pseudomyxoma Peritone: symptoms, treatment, prognosis and sensitivity to cytostatic drugs in vitro2012In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 91, no S159, p. 71-71Article in journal (Other academic)
  • 4.
    Bjersand, Kathrine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Seidal, Tomas
    Department of Pathology, Halmstad Medical Center Hospital, Halmstad, Sweden.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Skírnisdottir, Ingiridur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    The clinical and prognostic correlation of HRNPM and SLC1A5 in pathogenesis and prognosis in epithelial ovarian cancer2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0179363Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To evaluate the prognostic effect of the Heterogeneous nuclear ribonucleoprotein type M (HNRPM) and Solute carrier 1A5 (SLC1A5) in FIGO-stages I-II epithelial ovarian cancer.

    METHODS: A retrospective cohort study was designed to investigate the prognostic effect of HNRPM and SLC1A5, and the association with clinical-pathologic characteristics in 131 patients with FIGO-stages I-II epithelial ovarian cancer. Tissue microarrays were constructed and protein levels were assessed by immunohistochemistry (IHC).

    RESULTS: Positive HRNPM status was associated with positive staining for PUMA (P = 0.04), concomitant PUMA and p21 staining (P = 0.005), and VEGF-R2 (P = 0.003). Positive SLC1A5 staining was associated with positive staining of p27 (P = 0.030), PUMA (P = 0.039), concomitant PUMA and p27 staining, and VEGF-R2 (P = 0.039). In non-serous tumors (n = 72), the SLC1A5 positivity was associated with recurrent disease (P = 0.01). In a multivariable logistic regression analysis FIGO-stage (OR = 12.4), tumor grade (OR = 5.1) and SLC1A5 positivity (OR = 0.1) were independent predictive factors for recurrent disease. Disease-free survival (DFS) in women with SLC1A5-positive non-serous tumors was 92% compared with of 66% in patients with SLC1A5-negative non-serous tumors (Log-rank = 15.343; P = 0.008). In Cox analysis with DFS as endpoint, FIGO-stage (HR = 4.5) and SLC1A5 status (HR = 0.3) were prognostic factors.

    CONCLUSIONS: As the proteins HRNPM and SLC1A5 are associated with the cell cycle regulators p21 or p27, the apoptosis regulators PTEN and PUMA, and the VEGF-R2 it is concluded that both proteins have role in the pathogenesis of ovarian cancer. In patients with non-serous ovarian cancer SLC1A5 protects from recurrent disease, presumably by means of biological mechanisms that are unrelated to cytotoxic drug sensitivity.

  • 5.
    Skirnisdottir, Ingiridur
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Bjersand, Kathrine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Seidal, Tomas
    Napsin A as a marker of clear cell ovarian carcinoma2013In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, no 1, p. 524-Article in journal (Refereed)
    Abstract [en]

    Background: Clear cell carcinomas are aggressive tumors with a distinct biologic behaviour. In a genome-widescreening for genes involved in chemo-resistance, NAPA was over-expressed in cisplatin-resistant cells. The NAPA(protein) Napsin A was described to promote resistance to cisplatin by degradation of the tumor suppressor p53.

    Methods: Totally 131 patients were included in this study all in FIGO-stages I-II; 16 were clear cell tumors which were compared with 40 Type I tumors and 75 type II tumors according to the markers Napsin A, p21, p53 and p27 and some clinical features. For detection of the markers tissue microarrays and immunohistochemistry were used.

    Results: Positivity for Napsin A was detected in 12 (80%) out of the 15 clear cell tumors available for analysis compared with 3 (4%) out of the Type I and II tumors in one group (p < 0.001). Differences in p21 status, p53 status, and p21 + p53- status were striking when clear cell tumors were compared with Type I, Type II, and Type I and II tumors in one group, respectively. The p21 + p53-status was associated to positive staining of Napsin A (p = 0.0015)and clear cell morphology (p = 0.0003). In two separate multivariate logistic regression analyses with Napsin A as endpoint both clear cell carcinoma with OR = 153 (95% C.I. 21–1107); (p < 001) and p21 + p53- status with OR = 5.36(95% C.I. 1.6-17.5); (p = 0.005) were independent predictive factors. ROC curves showed that AUC for Napsin A alone was 0.882, for p21 + p53- it was 0.720 and for p21 + p53-Napsin A + AUC was 0.795. Patients with clear cell tumors had lower (p = 0.013) BMI than Type I patients and were younger (p = 0.046) at diagnosis than Type II patients. Clearcell tumors had a higher frequency (p = 0.039) of capsule rupture at surgery than Type I and II tumors.

    Conclusions: Positivity of Napsin A in an epithelial ovarian tumor might strengthen the morphological diagnosis ofclear cell ovarian carcinoma in the process of differential diagnosis between clear cell ovarian tumors and other histological subtypes.

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