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  • 101.
    Rosell, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Bengtsson, Nils-Olof
    Umeå University Hospital, Sweden .
    Fornander, Tommy
    Karolinska University Hospital, Sweden .
    Hatschek, Thomas
    Karolinska University Hospital, Sweden .
    Lindman, Henrik
    University of Uppsala Hospital, Sweden .
    Malmstrom, Per-Olof
    Skåne University Hospital, Sweden .
    Wallgren, Arne
    Sahlgrens University Hospital, Sweden .
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    Effects of adjuvant tamoxifen therapy on cardiac disease: results from a randomized trial with long-term follow-up2013Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 138, nr 2, s. 467-473Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tamoxifen is associated with a reduced risk of coronary heart disease (CHD). However, there are few reports on long-term effects. Using data from a large Swedish randomized trial of 5 and 2 years of adjuvant tamoxifen in women with early breast cancer, we here present results on morbidity and mortality from cardiac diseases during treatment and long-term after treatment. A total of 4,150 patients were breast cancer recurrence-free after 2 years. Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry were used to define events of disease. Hazard ratios were estimated using Cox regression. Patients assigned to 5 years in comparison with 2 years of postoperative tamoxifen experienced a reduced incidence of CHD [hazard ratio (HR), 0.83; 95 % CI 0.70-1.00], especially apparent during the active treatment period (HR 0.65; 95 % CI 0.43-1.00). The mortality from CHD was significantly reduced (HR 0.72; 95 % CI 0.53-0.97). During the active treatment, the morbidity of other heart diseases was also significantly reduced (HR 0.40; 95 % CI 0.25-0.64) but not after treatment stopped (HR 1.06; 95 % CI 0.87-1.30). Similar results were seen for both heart failure and atrial fibrillation/flutter. As compared to 2 years of therapy, 5 years of postoperative tamoxifen therapy prevents CHD as well as other heart diseases. The risk reduction is most apparent during the active treatment period, and later tends to diminish.

  • 102.
    Rosell, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Nordenskjöld, Bo
    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.
    Bengtsson, Nils-Olof
    Umeå University Hospital, Sweden .
    Fornander, Tommy
    Karolinska University Hospital, Sweden .
    Hatschek, Thomas
    Karolinska University Hospital, Sweden .
    Lindman, Henrik
    University of Uppsala Hospital, Sweden .
    Malmstrom, Per-Olof
    Skåne University Hospital, Sweden .
    Wallgren, Arne
    Sahlgrens University Hospital, Sweden .
    Stål, Olle
    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.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för hälso- och sjukvårdsanalys. Linköpings universitet, Hälsouniversitetet.
    Effects of adjuvant tamoxifen therapy on the incidence of secondary cancer: results from a randomized trial with long term follow-up2014Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    BACKGROUND

    Tamoxifen is a well-established endocrine treatment for breast cancer. We here present results with respect to second primary cancer from a large randomized trial of 5 and 2 years of adjuvant tamoxifen. Breast cancer distant recurrence and mortality are also reported.

    METHODS

    Our study included 4128 postmenopausal patients with early stage breast cancer who were alive and free of breast cancer recurrence after 2 years of tamoxifen therapy. They were randomized to receive three more years of therapy or stop tamoxifen. In the comparison of 5 years versus 2 years of postoperative tamoxifen treatment hazard ratios were estimated using Cox regression for different follow-up periods defined as: During treatment (2-5 years) and after treatment (5-10 years, 10-15 years, > 5 years, > 10 years and > 15 years).

    RESULTS

    In the five years group the incidence of lung cancer was halved (hazard ratio [HR], 0.45, 95% confidence interval [95% CI], 0.27-0.77 [P = .0038]), and lung cancer mortality was decreased. An increased risk was observed for endometrial cancer (HR, 1.83; 95% CI, 1.19-2.81 [P = .0059]), but this risk appeared to decrease over time. The risk of contralateral breast cancer was decreased (HR, 0.73; 95% CI, 0.56-0.96 [P = .022]), also in the period after treatment stopped. In the five years group, the risk of distant recurrence was decreased, and statistically significant reductions were observed both during treatment and in the five year period after treatment stopped. The breast cancer mortality was reduced, especially during the post-treatment phase.

    CONCLUSIONS

    In this randomized study, tamoxifen substantially reduces the risk of new cancer both in contralateral breast and in lung up to 10 years after treatment stopped.

  • 103.
    Sandblom, Gabriel
    et al.
    Karolinska Institute.
    Varenhorst, Eberhard
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Urologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lofman, Owe
    Norwegian University Life Science.
    Carlsson, Per
    Linköpings universitet, Institutionen för medicin och hälsa, Utvärdering och hälsoekonomi. Linköpings universitet, Hälsouniversitetet.
    Letter: PROSTATE CANCER SCREENING Authors reply2011Ingår i: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 342Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 104.
    Sehouli, Jalid
    et al.
    Charite, Germany .
    Pietzner, Klaus
    Charite, Germany .
    Wimberger, Pauline
    Technical University of Dresden, Germany .
    Vergote, Ignace
    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.
    Schneeweiss, Andreas
    University of Heidelberg Hospital, Germany .
    Bokemeyer, Carsten
    University of Medical Centre Hamburg Eppendorf, Germany .
    Salat, Christoph
    Hematol Oncology Clin, Germany .
    Scambia, Giovanni
    Catholic University, Italy .
    Berton-Rigaud, Dominique
    CLCC Rene Gauducheau, France .
    Santoro, Armando
    Humanitas Cancer Centre, Italy .
    Cervantes, Andres
    University of Valencia, Spain .
    Tredan, Olivier
    Centre Leon Berard, France .
    Tournigand, Christophe
    Hop St Antoine, France .
    Colombo, Nicoletta
    University of Milano Bicocca, Italy .
    Dudnichenko, Alexander S.
    Kharkov Medical Academic Postgrad Educ, Ukraine .
    Westermann, Anneke
    University of Amsterdam, Netherlands .
    Friccius-Quecke, Hilke
    Neovu Biotech GmbH, Germany .
    Lordick, Florian
    University of Cancer Centre Leipzig, Germany .
    Catumaxomab with and without prednisolone premedication for the treatment of malignant ascites due to epithelial cancer: results of the randomised phase IIIb CASIMAS study2014Ingår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 31, nr 8, s. 76-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This two-arm, randomised, multicentre, open-label, phase IIIb study investigated the safety and efficacy of a 3-h catumaxomab infusion with/without prednisolone premedication to reduce catumaxomab-related adverse events. Patients with malignant ascites due to epithelial cancer received four 3-h intraperitoneal catumaxomab infusions with/without intravenous prednisolone (25 mg) premedication before each infusion. The primary safety endpoint was a composite safety score calculated from the incidence and intensity of the most frequent catumaxomab-related adverse events (pyrexia, nausea, vomiting and abdominal pain). Puncture-free survival (PuFS) was a co-primary endpoint. Time to next puncture (TTPu) and overall survival (OS) were secondary endpoints. Prednisolone premedication did not result in a significant reduction in the main catumaxomab-related adverse events. The mean composite safety score was comparable in both arms (catumaxomab plus prednisolone, 4.1; catumaxomab, 3.8; p = 0.383). Median PuFS (30 vs. 37 days) and TTPu (78 vs. 102 days) were shorter in the catumaxomab plus prednisolone arm than in the catumaxomab arm, but the differences were not statistically significant (p = 0.402 and 0.599, respectively). Median OS was longer in the catumaxomab plus prednisolone arm than in the catumaxomab arm (124 vs. 86 days), but the difference was not statistically significant (p = 0.186). The superiority of catumaxomab plus prednisolone versus catumaxomab alone could not be proven for the primary endpoint. Prednisolone did not result in a significant reduction in the main catumaxomab-related adverse events. The study confirms the safety and efficacy of catumaxomab administered as four 3-h intraperitoneal infusions for the treatment of malignant ascites.

  • 105.
    Shabo, Ivan
    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, Kirurgiska kliniken US.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Elkarim, Rihab
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    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.
    Svanvik, Joar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Macrophage Infiltration in Tumor Stroma is Related to Tumor Cell Expression of CD163 in Colorectal Cancer2014Ingår i: Cancer Microenvironment, ISSN 1875-2292, E-ISSN 1875-2284, Vol. 7, nr 1, s. 61-69Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The scavenger receptor, CD163, is a macrophage-specific marker. Recent studies have shown that CD163 expression in breast and rectal cancer cells is associated with poor prognosis. This study was conducted to evaluate the relationship between CD163 expression as a macrophage trait in cancer cells, and macrophage infiltration and its clinical significance in colorectal cancer. Immunostaining of CD163 and macrophage infiltration were evaluated in paraffin-embedded specimens, earlier analyzed for CD31, D2-40 and S-phase fraction, from primary tumors and normal colorectal mucosa of 75 patients with colorectal carcinoma. The outcomes were analyzed in relation to clinical-pathological data. CD163 expression was positive in cancer cells in 20 % of colorectal cancer patients and was related to advanced tumor stages (P = 0.008) and unfavorable prognosis (p = 0.001). High macrophage infiltration was related to shorter survival and positive CD163 expression in tumor cells. The prognostic impact of macrophage infiltration was independent of tumor stage and CD163 expression in cancer cells (p = 0.034). The expression of macrophage phenotype in colorectal cancer cells is associated with macrophage density in tumor stroma and lower survival rates. Macrophage infiltration has an independent prognostic impact on mortality in colorectal cancer. In accordance with previous experimental studies, these findings provide new insights into the role of macrophages in colorectal cancer.

  • 106.
    Shabo, Ivan
    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, Kirurgiska kliniken US.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Stål, Olle
    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.
    Svanvik, Joar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Breast Cancer Expression of DAP12 is Associated With Skeletal and Liver Metastases and Poor Survival2013Ingår i: Clinical Breast Cancer, ISSN 1526-8209, E-ISSN 1938-0666, Vol. 13, nr 5, s. 371-377Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Macrophages are an important cellular factor in breast cancer (BRC) progression and metastasis. DNAX activating protein of 12 kD (DAP12) is essential factor for macrophage fusion function. This study was conducted to investigate the expression and significance of DAP12 expression in BRC. DAP12 is expressed in BRC cells and associated with poor survival, liver metastases, and bone metastases. These data provide new insight into the pathophysiology of macrophages in BRC. less thanbrgreater than less thanbrgreater thanBackground: The transmembrane adapter protein, DAP12, transduces activation signals for several arrays of receptors, including human signal-regulatory protein, DAP12-associating lectin-1, triggering receptor expressed on myeloid cells-1, -2, and -3, in natural killer cells, granulocytes, monocytes/macrophages, and dendritic cells. The macrophage-specific antigen, Cluster of Differentiation 163 (CD163), is expressed in breast and colorectal cancers and is associated with early cancer recurrence and poor prognosis. It was recently shown that fusion between intestinal tumor cells and macrophages results in nuclear reprogramming with hybrid transcripts from both cells of origin. The role of DAP12 in the fusion process is not known. This study investigates the expression of DAP12 in BRC cells, and its relation to other macrophage traits and to the clinical progression of disease. Materials and Methods: Immunostaining of DAP12 and CD163 was performed and evaluated in paraffin-embedded specimens from 132 patients with BRC. The outcomes were analyzed in relation to clinicopathological data. Results: DAP12 expression in cancer cells was positive in 66 percent of the cancers and was associated with high tumor grade (P = .015), and with liver (P = .047) and skeletal (P = .067), but not with lung metastases (P = 1.00). Patients with BRC expressing DAP12 had poor prognosis, with higher recurrence rates of skeletal (P = .018) and liver metastases (P = .047), and shorter survival time (P = .0060). Conclusion: We suggest that macrophage traits in BRC cells facilitate the metastatic process and that DAP12 expression might promote metastatic homing to bone and liver tissues.

  • 107.
    Shen, Xiao-Gang
    et al.
    Sichuan University.
    Wang, Cun
    Sichuan University.
    Li, Yuan
    Sichuan University.
    Zhou, Bin
    Sichuan University.
    Xu, Bin
    Sichuan University.
    Yang, Lie
    Sichuan University.
    Zhou, Zong-Guang
    Sichuan University.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Downregulation of caspase-10 predicting poor survival after resection of stage II colorectal cancer2011Ingår i: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 26, nr 12, s. 1519-1524Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose The aim of this study was to evaluate the prevalence and clinical significance of caspase-10 mRNA expression in stage II colorectal cancer. less thanbrgreater than less thanbrgreater thanMethods Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze caspase-10 expression in cancer tissue and corresponding normal mucosa from 120 patients with stage II colorectal cancer. Variables were analyzed by Chi-square test or Fishers exact test. Survival was evaluated with method of Kaplan-Meier. Multivariate analysis was performed with Coxs proportional hazards model. less thanbrgreater than less thanbrgreater thanResults The expression of caspase-10 mRNA was found to be downregulated in cancer tissue compared to normal mucosa (P = 0.001). Poorly differentiated cancer showed lower mRNA expression than cancer with greater differentiation (P = 0.031). Univariate survival curves, estimated using the method of Kaplan-Meier, defined a significant association between caspase-10 expression and both overall survival (P = 0.012) and disease-free survival (P = 0.021). A multivariate analysis, performed by Coxs proportional hazards regression model, confirmed that a low caspase-10 expression was the only significant factor to predict poor prognosis in patients with stage II colorectal cancer. less thanbrgreater than less thanbrgreater thanConclusion Our data indicate that caspase-10 expression, measured by quantitative real-time RT-PCR, is a possible prognostic factor in patients with stage II colorectal cancer.

  • 108.
    Shen, Yang-mei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken i Östergötland.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Overexpression of GLUT1 in colorectal cancer is independently associated with poor prognosis2011Ingår i: International Journal of Biological Markers, ISSN 0393-6155, E-ISSN 1724-6008, Vol. 26, nr 3, s. 166-172Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: To investigate the expression of glucose transporter 1 (GLUT1) in colorectal cancer (CRC) and its relationship to clinicopathological variables. Methods: The expression of GLUT1 in 163 primary tumors together with the corresponding normal mucosa, and 36 liver metastases was examined using real-time PCR. Results: The mean value of GLUT1 was higher in primary tumors (50.390 +/- 68.648) than in the corresponding normal mucosa (20.437 +/- 28.703, p less than 0.0001), while there was no significant difference in GLUT1 expression between CRC and liver metastasis (50.390 +/- 68.648 vs 52.277 +/- 52.482, p = 0.190). In CRCs, GLUT1 expression was higher in poorly differentiated than in well and moderately differentiated tumors (p = 0.022), and higher in stage III + IV than in stage I + II tumors (p = 0.035). The patients with high-expressed GLUT1 had a worse prognosis than those with low-expressed GLUT1 independently of gender, age, tumor site, stage and differentiation (p = 0.026, RR 2.737, 95% CI 1.126-6.651) in stage I-III CRCs. In liver metastasis, GLUT1 expression was higher in larger tumors than in smaller ones (p = 0.025). Conclusions: Overexpression of GLUT1 in stage I-III CRCs was independently associated with poor prognosis.

  • 109.
    Shen, Yang-mei
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken i Östergötland.
    Sandström, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken i Östergötland.
    Gullstrand, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Wei, Yu-Quan
    Sichuan University.
    Zhang, Hong
    University of Skövde.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Peng, Feng
    Sichuan University.
    Yang, Han-Shuo
    Sichuan University.
    Wang, Chun-Ting
    Sichuan University.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Novel gene hBiot2 is an independent prognostic factor in colorectal cancer patients2012Ingår i: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 27, nr 2, s. 376-382Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The present study investigated the expression of the novel gene hBiot2 in colorectal cancer (CRC) and its relationships with clinicopathological variables in CRC patients. The expression of hBiot2 in 163 primary CRCs together with the corresponding normal mucosa, 36 liver metastases and 5 colon cancer cell lines was examined using real-time PCR. In situ hybridization (ISH) was performed to evaluate the localization of hBiot2 expression in CRC and normal mucosa. hBiot2 expression at the RNA level was localized in the nucleus of tumor cells and normal epithelial cells. The mean expression of hBiot2 in the CRCs (243.571 +/- 564.569) was higher compared to the normal mucosa (107.252 +/- 413.635, Pandlt;0.0001) and liver metastasis samples (42.002 +/- 40.809, P=0.0002). hBiot2 expression was increased from stages I + II to III (P=0.047), and no difference in the expression was found in stages III and IV (P=0.452). A high value of hBiot2 was associated with a poorer prognosis compared with a low value independently of gender, age, tumor site, stage and differentiation (P=0.007, RR 7.519, 95% Cl 1.729-32.704). Liver metastasis, smaller tumors, non-local recurrence and primary liver surgery alone were associated with a higher value of hBiot2 compared to larger tumors, local recurrence and repeated liver surgery (P=0.003, 0.044 and 0.026, respectively). An inverse relationship was found between hBiot2 expression and the metastatic potential of the colon cancer cell lines. Thus, increased expression of hBiot2 may be an early and interim event in the development of CRC. A higher expression of hBiot2 in primary CRC patients independently indicates a poorer prognosis.

  • 110.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gunnarsson, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk genetik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Fornander, Tommy
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Skoog, Lambert
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    17β-hydroxysteroid dehydrogenase type 14 is a predictive marker for tamoxifen response in oestrogen receptor positive breast cancer2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 7, s. e40568-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: 17β-hydroxysteroid dehydrogenases (17βHSDs) are important enzymes regulating the pool of bioactive steroids in the breast. The current study was undertaken in order to evaluate implications of 17βHSD14 in breast cancer, measuring 17βHSD14 protein expression in breast tumours.

    Methods: An antibody targeting the 17βHSD14 antigen was generated and validated using HSD17B14-transfected cells and a peptide-neutralising assay. Tissue microarrays with tumours from 912 post-menopausal women diagnosed with lymph node-negative breast cancer, and randomised to adjuvant tamoxifen or no endocrine treatment, were analysed for 17βHSD14 protein expression with immunohistochemistry.

    Results: Results were obtained from 847 tumours. Patients with oestrogen positive tumours with high 17βHSD14 expression had fewer local recurrences when treated with tamoxifen (HR 0.38; 95% C.I. 0.19–0.77, p = 0.007) compared to patients with lower tumoural 17βHSD14 expression, for whom tamoxifen did not reduce the number of local recurrences (HR 1.19; 95% C.I. 0.54–2.59; p = 0.66). No prognostic importance of 17βHSD14 was seen for systemically untreated patients.

    Conclusions: Using a highly specific validated antibody for immunohistochemical analysis of a large number of breast tumours, we have shown that tumoural expression levels of 17βHSD14 can predict the outcome of adjuvant tamoxifen treatment in terms of local recurrence-free survival in patients with lymph node-negative ER+ breast cancer. The results need be verified to confirm any clinical relevance.

  • 111.
    Sjostrom, Martin
    et al.
    Lund University, Sweden .
    Hartman, Linda
    Lund University, Sweden Regional Cancer Centre South, Sweden .
    Grabau, Dorthe
    Lund University, Sweden .
    Fornander, Tommy
    Karolinska University Hospital, Sweden .
    Malmstrom, Per
    Lund University, Sweden Skåne University Hospital, Sweden .
    Nordenskjöld, Bo
    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.
    Sgroi, Dennis C.
    Massachusetts Gen Hospital, MA 02114 USA .
    Skoog, Lambert
    Karolinska University Hospital, Sweden .
    Stål, Olle
    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.
    Fredrik Leeb-Lundberg, L.M.
    Lund University, Sweden .
    Ferno, Marten
    Lund University, Sweden .
    Lack of G protein-coupled estrogen receptor (GPER) in the plasma membrane is associated with excellent long-term prognosis in breast cancer2014Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 145, nr 1, s. 61-71Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    G protein-coupled estrogen receptor (GPER), or GPR30, is a membrane receptor reported to mediate non-genomic estrogen responses. Tamoxifen is a partial agonist at GPER in vitro. Here, we investigated if GPER expression is prognostic in primary breast cancer, if the receptor is treatment-predictive for adjuvant tamoxifen, and if receptor subcellular localization has any impact on the prognostic value. Total and plasma membrane (PM) GPER expression was analyzed by immunohistochemistry in breast tumors from 742 postmenopausal lymph node-negative patients subsequently randomized for tamoxifen treatment for 2-5 years versus no systemic treatment, regardless of estrogen receptor (ER) status, and with a median follow-up of 17 years for patients free of event. PM GPER expression was a strong independent prognostic factor for poor prognosis in breast cancer without treatment-predictive information for tamoxifen. In the tamoxifen-treated ER-positive and progesterone receptor (PgR)-positive patient subgroup, the absence of PM GPER (53 % of all ER-positive tumors) predicted 91 % 20-year distant disease-free survival, compared to 73 % in the presence of GPER (p = 0.001). Total GPER expression showed positive correlations with ER and PgR and negative correlation with histological grade, but the correlations were biphasic. On the other hand, PM GPER expression showed strong negative correlations with ER and PgR, and strong positive correlation with HER2 overexpression and high histological grade. GPER overexpression and PM localization are critical events in breast cancer progression, and lack of GPER in the PM is associated with excellent long-term prognosis in ER-positive and PgR-positive tamoxifen-treated primary breast cancer.

  • 112.
    Sjödahl, Rune
    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, Kirurgiska kliniken US.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Starkhammar, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Causes of death after surgery for colon cancer-impact of other diseases, urgent admittance, and gender2013Ingår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 48, nr 10, s. 1160-1165Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective. In patients with colon cancer, high age and comorbidity is common. In this population-based retrospective study we have investigated causes of death and the influence of urgent operation, and gender on survival. Material and methods. Medical records of 413 patients with verified colon cancer were reviewed. The diagnosis was made during 2000-2006 and operation was performed in 385 patients (93%). Results. The overall 5-year survival after surgery was 48.3%. At the end of the follow-up, 128 patients (54.9%) had verified colon cancer when they died but 105 patients (45.1%) had no signs of colon cancer. Their 5-year survival was 5.5% and 41.9%, respectively (p andlt; 0.0001). Median survival time was significantly shorter after urgent compared with elective admittance, 20.7 months versus 77.9 months, and the 5-year survival 32.4% versus 57.9% (p = 0.0001). The tumor stage at operation was more favorable in patients dying with no signs of colon cancer than in those dying with cancer regarding stage I-II (66.7% versus 16.4%), and stage IV (1.0% versus 53.1%), but not regarding stage III (30.5% versus 29.7%). The overall survival in women who were operated was longer than in men (p = 0.045) as well as survival after elective admittance (p = 0.013). Conclusion. After a median follow-up of 56.1 months almost half of the patients who were dead had died from other causes than colon cancer. Ten percent of those patients had an incorrectly reported diagnosis of colon cancer as cause of death. Urgent admittance was associated with reduced survival time. The median survival time was longer in women than in men.

  • 113.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindqvist Appell, Malin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almér, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Low expression of TPMT wild type alleles in a patient with absent TPMT activity2008Konferensbidrag (Övrigt vetenskapligt)
  • 114.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindqvist Appell, Malin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almér, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Low Expression of TPMT wild type alleles in a patient with absent TPMT activity2008Konferensbidrag (Övrigt vetenskapligt)
  • 115.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindqvist Appell, Malin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Karlgren, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Kidhall, Irene
    Div of Gastroenterology and Hepatology, Danderyd Hospital.
    Almér, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Explaining TPMT Genotype/Phenotype Discrepancy by Identification of a Novel Sequence Variant, TPMT*232007Konferensbidrag (Övrigt vetenskapligt)
  • 116.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Richter, J.
    Department of Hematology and Coagulation, Skåne University Hospital, Lund, Sweden.
    Olsson-Strömberg, U.
    Department of Medical Sciences, Uppsala University and Department of Hematology, University Hospital, Uppsala, Sweden.
    Bergquist, J.
    Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Aluthgedara, W.
    Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Ubhayasekera, K.
    Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Svedberg, A.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Söderlund, S.
    Department of Medical Sciences, Uppsala University and Department of Hematology, University Hospital, Uppsala, Sweden.
    Sandstedt, Anna
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier. Linköpings universitet, Hälsouniversitetet.
    Johnsson, A.
    Department of Internal Medicine, Motala Hospital, Motala, Sweden.
    Aagesen, J.
    Department of Medicine, Ryhov County Hospital, Jönköping, Sweden.
    Alsenhed, J.
    Department of Internal Medicine, Västervik Hospital, Västervik, Sweden.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patientsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Introduction: The hepatic enzymes CYP3A4 and CYP3A5 metabolize the tyrosine kinase inhibitor imatinib into a large number of metabolites including the pharmacologically active N-desmethyl imatinib (CGP74588). Because the metabolic activity of CYP3A varies considerably between individuals and a previous pilot study suggested an inverse association between in vivo CYP3A metabolic activity and therapeutic outcome of imatinib, the primary aim of this study was to investigate the influence of CYP3A metabolic activity on the outcome of imatinib therapy in chronic myeloid leukemia patients.

    Methods: Fifty-five patients were included and CYP3A activity was estimated in vivo using quinine as a probe drug. Imatinib and CGP74588 trough concentrations in the plasma were determined at steady state in 34 patients. Cytogenetic and molecular responses after 12 months of first-line imatinib were retrospectively collected from patients’ medical records.

    Results: Patients with optimal response to imatinib (complete cytogenetic response (CCgR) or molecular response of BCR-ABL <1%) did not have different levels of CYP3A activity compared to non-optimal responders. Similar results were found when analyzing the molecular response and CCgR separately. Neither the imatinib trough concentration nor the CGP74588/imatinib ratio were significantly associated with CYP3A activity.

    Conclusion: CYP3A enzyme activity, as measured by quinine metabolic ratio, does not correlate with the plasma concentrations of imatinib or CGP74588 and is not predictive of imatinib therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the   ratelimiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes such as plasma protein binding or transport protein activity to look for the major contributor to patient variability in imatinib plasma concentration.

  • 117.
    Sorbe, Bengt
    et al.
    University Hospital, Örebro.
    Graflund, Marianne
    University Hospital, Örebro.
    Horvath, Gyorgy
    Sahlgrenska University Hospital.
    Swahn, Marie
    Sahlgrenska University Hospital.
    Boman, Karin
    University Hospital, Umeå.
    Bangshöj, Rene
    Central Hospital Karlstad.
    Lood, Margareta
    Central Hospital Karlstad.
    Malmström, Henric
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Phase II Study of Docetaxel Weekly in Combination With Carboplatin Every 3 Weeks as First-Line Chemotherapy in Stage IIB to Stage IV Epithelial Ovarian Cancer2012Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 22, nr 1, s. 47-53Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: The purpose of this study was to assess the response rate, toxicity, progression-free survival, and overall survival in a series of patients with advanced-stage ovarian carcinoma treated with a first-line weekly docetaxel and 3 weekly carboplatin regimen. less thanbrgreater than less thanbrgreater thanMethods: All eligible patients were treated with intravenous docetaxel (30 mg/m(2)) on days 1, 8, and 15, and carboplatin (area under the curve, 5) on day 1; every 21 days for at least 6 cycles. less thanbrgreater than less thanbrgreater thanResults: One hundred six patients received at least one cycle of primary chemotherapy (median, 6.0; range, 1-9), and they were evaluable for toxicity assessment. Eighty-five patients had evaluable (measurable) disease and received at least 3 courses of chemotherapy and were evaluable for clinical response rate. The overall response rate was 78.8% (95% confidence interval, 70.1%-87.5%), and the biochemical response 92.8% (95% confidence interval, 87.2%-98.4%). The median progression-free survival was 12.0 months and the median overall survival was 35.3 months. Thirty-six patients (34.0%) experienced grades 3 and 4 neutropenia, which resulted in the removal of 3 patients. Six patients (5.7%) experienced grades 3 or 4 thrombocytopenia. No patients experienced grade 3 to grade 4 sensory neuropathy. Epiphora, nail changes, and fatigue were frequently recorded nonhematologic adverse effects. less thanbrgreater than less thanbrgreater thanConclusions: The tolerable hematologic toxicity (no need for colony-stimulating factors) and the low rate of neurotoxicity (only grades 1-2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgerymake this regimen an interesting alternative in selected patients.

  • 118.
    Sorbe, Bengt
    et al.
    University Hospital, Örebro.
    Graflund, Marianne
    University Hospital, Örebro.
    Nygren, Lisa
    University Hospital, Örebro.
    Horvath, Gyorgy
    Sahlgrenska University Hospital.
    Swahn, Marie
    Sahlgrenska University Hospital.
    Boman, Karin
    Umeå University Hospital.
    Bangshoj, Rene
    Central Hospital Karlstad.
    Lood, Margareta
    Central Hospital Karlstad.
    Malmström, Henric
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    A phase II study of docetaxel weekly in combination with carboplatin every three weeks as first line chemotherapy in stage IIB-IV epithelial ovarian cancer: Neurological toxicity and quality-of-life evaluation2012Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 40, nr 3, s. 773-781Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The purpose of this study was to assess the response rate, toxicity, progression-free survival (PFS) and overall survival (OS) in a series of advanced stage ovarian carcinoma patients treated with a first-line weekly docetaxel and three weekly carboplatin regimens. All eligible patients were treated with intravenous docetaxel (30 mg/m(2)) on Days 1, 8 and 15, and carboplatin (area under the curve, 5) on Day 1; Q21 days for at least 6 cycles. Neurological tests, questionnaires, and the EORTC QLQ-C30 and OV28 were used for quality-of-life assessments. One hundred and six patients received at least one cycle of primary chemotherapy (median 6.0; range, 1-9) and they were evaluable for toxicity assessment. Eighty-five patients had evaluable disease and received at least 3 courses of chemotherapy and were evaluable for clinical response rate. The overall response rate was 78.8% (95% CI 70.1-87.5%) and the biochemical response was 92.8% (95% CI 87.2-98.4%). The median PFS was 12.0 months and the median OS was 35.3 months. Thirty-six patients (34.0%) experienced grades 3 and 4 neutropenia, which resulted in the removal of 3 patients. Six patients (5.7%) experienced grades 3 or 4 thrombocytopenia. No patients experienced grade 3-4 sensory neuropathy. Epiphora, nail changes and fatigue were frequently recorded non-hematological side effects. The tolerable hematological toxicity (no need for colony-stimulating factors) and the low rate of severe neurotoxicity (only grade 1-2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgery make this regimen an interesting alternative in selected patients.

  • 119.
    Strand, Carina
    et al.
    Lund University, Skåne University Hospital, Lund, Sweden.
    Bak, Martin
    Odense University Hospital, Denmark.
    Borgquist, Signe
    Lund University, Skåne University Hospital, Lund, Sweden.
    Chebil, Gunilla
    Unilabs, Mammography, Helsingborg, Sweden.
    Falck, Anna-Karin
    Helsingborg Hospital, Sweden.
    Fjällskog, Marie-Louise
    Uppsala University, Sweden.
    Grabau, Dorthe
    Lund University, Skåne University Hospital, Lund, Sweden.
    Hedenfalk, Ingrid
    Lund University, Skåne University Hospital, Lund, Sweden.
    Jirström, Karin
    Lund University, Sweden.
    Klintman, Marie
    Lund University, Skåne University Hospital, Lund, Sweden.
    Malmström, Per
    Lund University, Skåne University Hospital, Lund, Sweden.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Ryden, Lisa
    Lund University, Skåne University Hospital, Lund, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Bendahl, Pär-Ola
    Lund University, Skåne University Hospital, Lund, Sweden.
    Fernö, Mårten
    Lund University, Skåne University Hospital, Lund, Sweden.
    The combination of Ki67, histological grade and estrogen receptor status identifies a low-risk group among 1,854 chemo-naïve women with N0/N1 primary breast cancer2013Ingår i: SpringerPlus, E-ISSN 2193-1801, Vol. 2, nr 111Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:

    The aim was to confirm a previously defined prognostic index, combining a proliferation marker, histological grade, and estrogen receptor (ER) in different subsets of primary N0/N1 chemo-naïve breast cancer patients.

    METHODSDESIGN:

    In the present study, including 1,854 patients, Ki67 was used in the index (KiGE), since it is the generally accepted proliferation marker in clinical routine. The low KiGE-group was defined as histological grade 1 patients and grade 2 patients which were ER-positive and had low Ki67 expression. All other patients made up the high KiGE-group. The KiGE-index separated patients into two groups with different prognosis. In multivariate analysis, KiGE was significantly associated with disease-free survival, when adjusted for age at diagnosis, tumor size and adjuvant endocrine treatment (hazard ratio: 3.5, 95% confidence interval: 2.6-4.7, P<0.0001).

    DISCUSSION:

    We have confirmed a prognostic index based on a proliferation marker (Ki67), histological grade, and ER for identification of a low-risk group of patients with N0/N1 primary breast cancer. For this low-risk group constituting 57% of the patients, with a five-year distant disease-free survival of 92%, adjuvant chemotherapy will have limited effect and may be avoided.

  • 120.
    Stratmann, Johannes
    et al.
    Skovde University.
    Wang, Chaojie
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Gnosa, Sebastian
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Wallin, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Hinselwood, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Zhang, Hong
    Skovde University.
    Dicer and miRNA in relation to clinicopathological variables in colorectal cancer patients2011Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 11, nr 345Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Dicer is aberrantly expressed in several types of cancers. Applying real-time PCR, we detected the expression of Dicer mRNA in normal mucosa (n = 162), primary colorectal cancer (CRC) (n = 162) and liver metastasis (n = 37), and analysed the relationship between Dicer expression and clinicopathological features. We also correlated the expression of Dicer mRNA to the miRNA expression of miR-141, miR-200a, miR-200b, mir-200c and miR-429 in liver metastases. less thanbrgreater than less thanbrgreater thanMethods: RT-PCR and qPCR were used to analyse the Dicer expression in normal mucosa, primary tumour and liver metastasis by using the High Capacity cDNA Reverse Transcription Kit and TaqMan (TM)(R) Gene Expression assays for Dicer and GAPDH. RT-PCR and qPCR were used to detect miRNA expression in liver metastases by utilizing TaqMan (R) MicroRNA Reverse Transcription Kit and TaqMan (R) miRNA Assays. Statistical analyses were performed with STATISTICA. less thanbrgreater than less thanbrgreater thanResults: Dicer expression in rectal cancer (3.146 +/- 0.953) was higher than in colon cancer (2.703 +/- 1.204, P = 0.018). Furthermore the Dicer expression was increased in primary tumours (3.146 +/- 0.952) in comparison to that in normal mucosa from rectal cancer patients (2.816 +/- 1.009, P = 0.034) but this is not evident in colon cancer patients. Dicer expression in liver metastases was decreased in comparison to that of either normal mucosa or primary tumour in both colon and rectal cancers (P andlt; 0.05). Patients with a high Dicer expression in normal mucosa had a worse prognosis compared to those with a low Dicer expression, independently of gender, age, tumour site, stage and differentiation (P andlt; 0.001, RR 3.682, 95% CI 1.749 - 7.750). In liver metastases, Dicer was positively related to miR-141 (R = 0.419, P = 0.015). less thanbrgreater than less thanbrgreater thanConclusion: Dicer is up-regulated in the early development of rectal cancers. An increased expression of Dicer mRNA in normal mucosa from CRC patients is significantly related to poor survival independently of gender, age, tumour site, stage and differentiation.

  • 121.
    Sundquist, M
    et al.
    County Hospital Kalmar.
    Holmberg, E
    ROC, Gothenburg.
    Holmberg, S
    Sahlgrenska University Hospital.
    Kovacs, A
    Sahlgrenska University Hospital.
    Mathe, G
    Sahlgrenska University Hospital.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Tejler, Göran
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Assessments of Proliferation in Breast Cancer in EUROPEAN JOURNAL OF CANCER, vol 47, issue , pp S333-S3332011Ingår i: EUROPEAN JOURNAL OF CANCER, Elsevier , 2011, Vol. 47, s. S333-S333Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 122.
    Suzuki, Chikako
    et al.
    Karolinska University Hospital, Sweden .
    Blomqvist, Lennart
    Karolinska University Hospital, Sweden .
    Hatschek, Thomas
    Karolinska Institute, Sweden .
    Carlsson, Lena
    Sundsvall Gen Hospital, Sweden .
    Einbeigi, Zakaria
    Sahlgrens University Hospital, Sweden .
    Linderholm, Barbro
    Sahlgrens University Hospital, Sweden .
    Lindh, Birgitta
    University of Umeå Hospital, Sweden .
    Loman, Niklas
    Skåne University Hospital, Sweden .
    Malmberg, Martin
    Helsingborg Gen Hospital, Sweden .
    Rotstein, Samuel
    Karolinska University Hospital, Sweden .
    Soderberg, Martin
    Skåne University Hospital, Sweden .
    Sundqvist, Marie
    Kalmar Gen Hospital, Sweden .
    Walz, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Astrom, Gunnar
    Uppsala University, Sweden .
    Fujii, Hirofumi
    National Cancer Centre Hospital East, Japan .
    Jacobsson, Hans
    Karolinska University Hospital, Sweden .
    Glimelius, Bengt
    Karolinska Institute, Sweden .
    Impact of the first tumor response at eight weeks on overall survival in metastatic breast cancer patients treated with first-line combination chemotherapy2013Ingår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 30, nr 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this was to determine whether the change of size observed at the first response evaluation after initiation of first-line combination chemotherapy correlates with overall survival (OS) in patients with metastatic breast cancer (MBC). The change in size of tumors derived from measurements according to Response Evaluation Criteria In Solid Tumors (RECIST) at the first evaluation on computed tomography (CT) was obtained from a multicenter, randomized phase III trial ("TEX trial," n = 287) comparing treatment with a combination of epirubicin and paclitaxel alone or with capecitabine (TEX). Cox regression and Kaplan-Meier analyses were performed to evaluate the correlations between the first change in tumor size, response according to RECIST and OS. Data from CT evaluations of 233 patients were available. Appearance of new lesions or progression of non-target lesions (new/non-target) indicated short OS by univariable regression analysis (HR 3.76, 95 % CI 1.90-7.42, p andlt; 0.001). A decrease by andgt;30 % at this early time point was prognostic favorable (HR 0.69, 95 % CI 0.49-0.98, p = 0.04) and not significantly less than the best overall response according to RECIST. After adjustment for previous adjuvant treatment and the treatment given within the frame of the randomized trial, OS was still significantly shorter in patients with new/non-target lesions after a median 8 weeks of treatment (HR 4.41, 95 % CI 2.74-7.11, p andlt; 0.001). Disease progression at the first evaluation correlates with OS in patients with MBC treated with first-line combination chemotherapy. The main reason for early disease progression was the appearance of new lesions or progression of non-target lesions. These patients had poor OS even though more lines of treatment were available. Thus, these factors should be focused on in the response evaluations besides tumor size changes.

  • 123.
    Söderlund, Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Susanne
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Bendrik, Christina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Robertson, Jennifer
    McMaster University, Hamilton, Ontario, Canada.
    Gauldie, Jack
    McMaster University, Hamilton, Ontario, Canada.
    Olsson, Anna-Karin
    Uppsala University, Sweden .
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer2013Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, nr 8, s. 4420-4430Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Matrix metalloproteinases (MMPs) have been suggested as therapeutic targets in cancer treatment, but broad-spectrum MMP inhibitors have failed in clinical trials. Recent data suggest that several MMPs including MMP-9 exert both pro-and antitumorigenic properties. This is also the case of the natural inhibitors of MMPs, tissue inhibitor of metalloproteinases (TIMPs). The inhibitor of MMP-9 is TIMP-1, and high levels of this enzyme have been associated with decreased survival in breast cancer. Inflammation is one hallmark of cancer progression, and MMPs/TIMPs may be involved in the local immune regulation. We investigated the role of MMP-9/TIMP-1 in regulating innate antitumor immunity in breast cancer. Breast cancers were established in nude mice and treated with intratumoral injections of adenoviruses carrying the human TIMP-1 or MMP-9 gene (AdMMP-9). In vivo microdialysis for sampling of cancer cell-derived (human) and stroma-derived (murine) proteins, immunostainings, as well as cell cultures were performed. We report a dose-dependent decrease of tumor growth and angiogenesis after AdMMP-9 treatment. In addition to increased generation of endostatin, AdMMP-9 promoted an antitumor immune response by inducing massive neutrophil infiltration. Neutrophil depletion prior to gene transfer abolished the therapeutic effects of AdMMP-9. Additionally, AdMMP-9 activated tumor-infiltrating macrophages into a tumor-inhibiting phenotype both in vivo and in vitro. AdMMP-9 also inhibited tumor growth in immune-competent mice bearing breast cancers. Adenoviruses carrying the human TIMP-1 gene had no effect on tumor growth or the immune response. Our novel data identify MMP-9 as a potent player in modulating the innate immune response into antitumor activities. The Journal of Immunology, 2013, 190: 4420-4430.

  • 124.
    Tabar, Laszlo
    et al.
    Falun Central Hospital, Falun.
    Vitak, Bedrich
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Hsiu-Hsi Chen, Tony
    National Taiwan University,Taipei, Taiwan.
    Ming-Fang Yen, Amy
    Taipei Medical University, Taipei, Taiwan.
    Cohen, Anders
    Falun Central Hospital, Falun.
    Tot, Tibor
    Falun Central Hospital, Falun.
    Yueh-Hsia Chiu, Sherry
    Chang Gung University, Taoyuan, Taiwan.
    Li-Sheng Chen, Sam
    Taipei Medical University, Taipei, Taiwan.
    Ching-Yuan Fann, Jean
    Kainan University, Taoyuan, Taiwan.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fohlin, Helena
    Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Smith, Robert A
    American Cancer Society, Atlanta, USA.
    Duffy, Stephen W
    Queen Mary University of London, London, UK.
    Swedish Two-County Trial: Impact of Mammographic Screening on Breast Cancer Mortality during 3 Decades2011Ingår i: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 260, nr 3, s. 658-663Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: To estimate the long-term (29-year) effect of mammographic screening on breast cancer mortality in terms of both relative and absolute effects. less thanbrgreater than less thanbrgreater thanMaterials and Methods: This study was carried out under the auspices of the Swedish National Board of Health and Welfare. The board determined that, because randomization was at a community level and was to invitation to screening, informed verbal consent could be given by the participants when they attended the screening examination. A total of 133 065 women aged 40-74 years residing in two Swedish counties were randomized into a group invited to mammographic screening and a control group receiving usual care. Case status and cause of death were determined by the local trial end point committees and, independently, by an external committee. Mortality analysis was performed by using negative binomial regression. less thanbrgreater than less thanbrgreater thanResults: There was a highly significant reduction in breast cancer mortality in women invited to screening according to both local end point committee data (relative risk [RR] = 0.69; 95% confi dence interval: 0.56, 0.84; P andlt;.0001) and consensus data (RR = 0.73; 95% confi dence interval: 0.59, 0.89; P =.002). At 29 years of follow-up, the number of women needed to undergo screening for 7 years to prevent one breast cancer death was 414 according to local data and 519 according to consensus data. Most prevented breast cancer deaths would have occurred (in the absence of screening) after the first 10 years of follow-up. less thanbrgreater than less thanbrgreater thanConclusion: Invitation to mammographic screening results in a highly significant decrease in breast cancer-specific mortality. Evaluation of the full impact of screening, in particular estimates of absolute benefit and number needed to screen, requires follow-up times exceeding 20 years because the observed number of breast cancer deaths prevented increases with increasing time of follow-up.

  • 125.
    Tandstad, T.
    et al.
    St Olavs University Hospital, Norway.
    Stahl, O.
    Skåne University Hospital, Sweden.
    Hakansson, U.
    Skåne University Hospital, Sweden.
    Dahl, O.
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Haugnes, H. S.
    University of Tromso, Norway; University Hospital North Norway, Norway.
    Klepp, O. H.
    Alesund Hospital, Norway.
    Langberg, C. W.
    Oslo University Hospital, Norway.
    Laurell, A.
    University of Uppsala Hospital, Sweden.
    Oldenburg, J.
    Oslo University Hospital, Norway.
    Solberg, A.
    St Olavs University Hospital, Norway.
    Soderstrom, K.
    Norrland University Hospital, Sweden.
    Cavallin-Stahl, E.
    Skåne University Hospital, Sweden.
    Stierner, U.
    Sahlgrens University Hospital, Sweden.
    Wahlquist, R.
    Oslo University Hospital, Norway.
    Wall, Najme
    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.
    Cohn-Cedermark, G.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group2014Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 25, nr 11, s. 2167-2172Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The SWENOTECA group treated 517 clinical stage I nonseminoma patients with one course of adjuvant BEP in a prospective study. The median follow-up is 7.9 years. One course of adjuvant BEP reduced the risk of relapse by over 90%. The relapse rates were 1.6% in low-risk disease and 3.2% in high-risk disease. One course of adjuvant BEP should be considered a standard adjuvant treatment option.SWENOTECA has since 1998 offered patients with clinical stage I (CS I) nonseminoma, adjuvant chemotherapy with one course of bleomycin, etoposide and cisplatin (BEP). The aim has been to reduce the risk of relapse, sparing patients the need of toxic salvage treatment. Initial results on 312 patients treated with one course of adjuvant BEP, with a median follow-up of 4.5 years, have been previously published. We now report mature and expanded results. In a prospective, binational, population-based risk-adapted treatment protocol, 517 Norwegian and Swedish patients with CS I nonseminoma received one course of adjuvant BEP. Patients with lymphovascular invasion (LVI) in the primary testicular tumor were recommended one course of adjuvant BEP. Patients without LVI could choose between surveillance and one course of adjuvant BEP. Data for patients receiving one course of BEP are presented in this study. At a median follow-up of 7.9 years, 12 relapses have occurred, all with IGCCC good prognosis. The latest relapse occurred 3.3 years after adjuvant treatment. The relapse rate at 5 years was 3.2% for patients with LVI and 1.6% for patients without LVI. Five-year cause-specific survival was 100%. The updated and expanded results confirm a low relapse rate following one course of adjuvant BEP in CS I nonseminoma. One course of adjuvant BEP should be considered a standard treatment in CS I nonseminoma with LVI. For patients with CS I nonseminoma without LVI, one course of adjuvant BEP is also a treatment option.

  • 126.
    Ticha, Ivana
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Gnosa, Sebastian
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Lindblom, Annika
    Karolinska Institute, Sweden .
    Liu, Tao
    Karolinska Institute, Sweden .
    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.
    Variants of the PPARD Gene and Their Clinicopathological Significance in Colorectal Cancer2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. 83952-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Peroxisome proliferator-activated receptor delta (PPARD) is nuclear hormone receptor involved in colorectal cancer (CRC) differentiation and progression. The purpose of this study was to determine prevalence and spectrum of variants in the PPARD gene in CRC, and their contribution to clinicopathological endpoints. Methods and Findings: Direct sequencing of the PPARD gene was performed in 303 primary tumors, in blood samples from 50 patients with greater than= 3 affected first-degree relatives, 50 patients with 2 affected first-degree relatives, 50 sporadic patients, 360 healthy controls, and in 6 colon cancer cell lines. Mutation analysis revealed 22 different transversions, 7 of them were novel. Three of all variants were somatic (c. 548Agreater thanG, p.Y183C, c.425-9Cgreater thanT, and c.628-16Ggreater thanA). Two missense mutations (p.Y183C and p.R258Q) were pathogenic using in silico predictive program. Five recurrent variants were detected in/adjacent to the exons 4 (c.1-87Tgreater thanC, c.1-67Ggreater thanA, c.130+3Ggreater thanA, and c.1-101-8Cgreater thanT) and exon 7 (c.489Tgreater thanC). Variant c.489C/C detected in tumors was correlated to worse differentiation (P=0.0397). Conclusions: We found 7 novel variants among 22 inherited or acquired PPARD variants. Somatic and/or missense variants detected in CRC patients are rare but indicate the clinical importance of the PPARD gene.

  • 127.
    Tobin, N. P.
    et al.
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Harrell, J. C.
    University of N Carolina, NC 27599 USA.
    Lovrot, J.
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Egyhazi Brage, S.
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Frostvik Stolt, M.
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Carlsson, L.
    Sundsvall Gen Hospital, Sweden.
    Einbeigi, Z.
    Sahlgrens University Hospital, Sweden.
    Linderholm, B.
    Karolinska Institute, Sweden; University Hospital, Sweden; Sahlgrens University Hospital, Sweden.
    Loman, N.
    Skåne University Hospital, Sweden.
    Malmberg, M.
    Skåne University Hospital, Sweden.
    Walz, Thomas
    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 Institute, Sweden; University Hospital, Sweden.
    Ferno, M.
    Lund University, Sweden.
    Perou, C. M.
    University of N Carolina, NC 27599 USA.
    Bergh, J.
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Hatschek, T.
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Lindstrom, L. S.
    University Hospital, Sweden; University of Calif San Francisco, CA USA; Karolinska Institute, Sweden.
    Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival2015Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 26, nr 1, s. 81-88Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We and others have recently shown that tumor characteristics are altered throughout tumor progression. These findings emphasize the need for re-examination of tumor characteristics at relapse and have led to recommendations from ESMO and the Swedish Breast Cancer group. Here, we aim to determine whether tumor characteristics and molecular subtypes in breast cancer metastases confer clinically relevant prognostic information for patients. The translational aspect of the Swedish multicenter randomized trial called TEX included 111 patients with at least one biopsy from a morphologically confirmed locoregional or distant breast cancer metastasis diagnosed from December 2002 until June 2007. All patients had detailed clinical information, complete follow-up, and metastasis gene expression information (Affymetrix array GPL10379). We assessed the previously published gene expression modules describing biological processes [proliferation, apoptosis, human epidermal receptor 2 (HER2) and estrogen (ER) signaling, tumor invasion, immune response, and angiogenesis] and pathways (Ras, MAPK, PTEN, AKT-MTOR, PI3KCA, IGF1, Src, Myc, E2F3, and beta-catenin) and the intrinsic subtypes (PAM50). Furthermore, by contrasting genes expressed in the metastases in relation to survival, we derived a poor metastasis survival signature. A significant reduction in post-relapse breast cancer-specific survival was associated with low-ER receptor signaling and apoptosis gene module scores, and high AKT-MTOR, Ras, and beta-catenin module scores. Similarly, intrinsic subtyping of the metastases provided statistically significant post-relapse survival information with the worst survival outcome in the basal-like [hazard ratio (HR) 3.7; 95% confidence interval (CI) 1.3-10.9] and HER2-enriched (HR 4.4; 95% CI 1.5-12.8) subtypes compared with the luminal A subtype. Overall, 25% of the metastases were basal-like, 32% HER2-enriched, 10% luminal A, 28% luminal B, and 5% normal-like. We show that tumor characteristics and molecular subtypes of breast cancer metastases significantly influence post-relapse patient survival, emphasizing that molecular investigations at relapse provide prognostic and clinically relevant information.

  • 128.
    Tonato, M
    et al.
    Policlinico Hospital.
    Clark-Snow, R
    University of Kansas Cancer Center.
    Osoba, D
    West Vancouver.
    Del Favero, A
    University of Perugia.
    Ballatori, E
    University of L’Aquila.
    Börjeson, Sussanne
    Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Emesis induced by low or minimal emetic risk chemotherapy2005Ingår i: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 13, nr 2, s. 109-111Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    For patients treated with low or minimally emetogenic chemotherapy there is little evidence from clinical trials supporting the choice of a given antiemetic therapy or of any treatment at all. The panel recognized the necessity of considering the introduction into clinical practice of new agents in these categories, particularly oral cytotoxic agents and targeted biological agents and also the possibility of over-treatment with antiemetics. There was consensus among panel members regarding the recommended treatment for patients receiving chemotherapy agents with low and minimal emetic risk. Patients without a history of nausea and vomiting for whom minimally emetic risk chemotherapy is prescribed should not routinely receive antiemetic prophylaxis. A single agent such as a low-dose corticosteroid is suggested for patients receiving agents of low emetic risk. If nausea and vomiting occurs during subsequent cycles of chemotherapy, prophylaxis with a single agent such as a substituted benzamide, a corticosteroid, or a phenothiazine should be administered. Only patients with persistent nausea and vomiting despite treatment with these recommended agents should receive a 5-HT3 receptor antagonist in the following cycles.

  • 129.
    Trinks, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Djerf, Emelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Walz, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    The pan-ErbB receptor tyrosine kinase inhibitor canertinib induces ErbB-independent apoptosis in human leukemia (HL-60 and U-937) cells2010Ingår i: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ISSN 0006-291X, Vol. 393, nr 1, s. 6-10Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Epidermal growth factor (EGF) receptor tyrosine kinase inhibitors have recently been shown to display anti-neoplastic effects in human malignant myeloid cells. Our study was initiated in order to determine the effect of the pan-ErbB receptor tyrosine kinase inhibitor, canertinib (CI-1033), on growth and survival of human leukemia (HL-60 and U-937) cells. We show that treatment of HL-60 and U-937 cells with canertinib significantly inhibits growth of both cell lines in a dose-dependent manner; half maximal effective dose (IC50) in HL-60 and U-937 cells was approximately 2.5 mu M and 1.0 mu M, respectively. Treatment with 2 mu M canertinib promoted a G(1) cell cycle arrest, whereas doses of 5 mu M or more induced apoptosis as determined by the Annexin V method and cleavage of poly-(ADP-ribose) polymerase (PARP). HL-60 and U-937 cells lacked EGF-receptor transcript but expressed ErbB2-4 mRNA as determined by RTPCR. However, none of the corresponding ErbB-receptor proteins could be detected by Western blot analysis. We conclude that canertinib induces apoptosis in HL-60 and U-937 cells devoid of functional ErbB1-4 receptors. Our results suggest that canertinib could be of potential clinical interest in the treatment of acute myeloid leukemia.

  • 130.
    Trinks, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Walz, Thomas M.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Human leukemic cell lines express a truncated intracellular 160 kDa ERBB2 receptorManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    It has recently been demonstrated that ERBB specific tyrosine kinase inhibitors display antineoplastic activity in human leukemic cell devoid of functional ERBB receptors. The present study was undertaken in order to identify any putative target for these drugs. Flow cytometry experiments demonstrate the presence of an immunoreactive ERBB2 protein of intracellular localization and Western blot analysis visualized an ERBB2 protein of approximately 160 kDa. Exposing leukemia cells to tunicamycin did not alter the size of the truncated ERBB2 protein. The ERBB2 gene was alternative spliced with an absence of exon 5 containing the start codon for the full-length protein. In conclusion we demonstrate a nonglycosylated 160 kDa ERBB2-receptor protein with an alternative in-frame start codon in human leukemia cell lines.

  • 131.
    Trinks, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Severinsson, Emelie A.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gréen, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Walz, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells2011Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 410, nr 3, s. 422-427Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 mu M caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.

  • 132.
    Tveit, Kjell Magne
    et al.
    Oslo University Hospital, Norway.
    Guren, Tormod
    Uppsala Hospital, Sweden Karolinska Institute, Sweden .
    Pfeiffer, Per
    Odense University Hospital, Denmark .
    Sorbye, Halfdan
    Haukeland Hospital, Norway University of Bergen, Norway .
    Pyrhonen, Seppo
    Turku University Hospital, Finland .
    Sigurdsson, Fridbjorn
    National University Hospital Reykjavik, Iceland .
    Kure, Elin
    University of Oslo, Norway .
    Fokstuen, Tone
    Karolinska Institute, Sweden .
    Hansen, Flemming
    Aarhus University Hospital, Denmark .
    Hofsli, Eva
    St Olavs Hospital, Norway .
    Birkemeyer, Elke
    Stavanger University Hospital, Norway .
    Johnsson, Anders
    University of Lund Hospital, Sweden .
    Starkhammar, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Karen Yilmaz, Mette
    Aalborg University Hospital, Denmark .
    Keldsen, Nina
    Herning Regional Hospital, Denmark .
    Berit Erdal, Anne
    Haukeland Hospital, Norway University of Bergen, Norway .
    Christoffersen, Thoralf
    University of Oslo, Norway .
    Phase III Trial of Cetuximab With Continuous or Intermittent Fluorouracil, Leucovorin, and Oxaliplatin (Nordic FLOX) Versus FLOX Alone in First-Line Treatment of Metastatic Colorectal Cancer: The NORDIC-VII Study2012Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, nr 15, s. 1755-1762Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose less thanbrgreater than less thanbrgreater thanThe NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated. less thanbrgreater than less thanbrgreater thanPatients and Methods less thanbrgreater than less thanbrgreater thanPatients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points. less thanbrgreater than less thanbrgreater thanResults less thanbrgreater than less thanbrgreater thanOf the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients with KRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated. less thanbrgreater than less thanbrgreater thanConclusion less thanbrgreater than less thanbrgreater thanCetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.

  • 133.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Monitoring of thiopurine metabolites - A high-performance liquid chromatography method for clinical use2013Ingår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 75, s. 145-152Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBCs were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials. Ten patient samples were analysed to demonstrate clinical application and to establish pilot ranges for all analytes. less thanbrgreater than less thanbrgreater thanThe method measured thioguanosine mono-(TGMP), di-(TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine). less thanbrgreater than less thanbrgreater thanLOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8 x 10(8) RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 4 degrees C for 8 h after sampling.

  • 134.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Monitoring of thiopurine metabolites: A high-performance liquid chromatography method for clinical useManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBC:s were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials in thiopurine therapy and proven valid by analysis of authentic patient samples.

    The method measured thioguanosine mono- (TGMP), di- (TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine).

    LOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8x10^8 RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 5 °C for 8 hours after sampling.

  • 135.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Andersson, David
    Skåne University Hospital, Sweden; Danderyd Hospital, Sweden.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken. Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Hindorf, Ulf
    Skåne University Hospital, Sweden.
    Novel assay to improve therapeutic drug monitoring of thiopurines in inflammatory bowel disease2014Ingår i: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 8, nr 12, s. 1702-1709Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and aims: The thiopurines are widely used in the treatment of inflammatory bowel disease, but are limited by poor dose effect relationship. The objective was to assess the ability of a novel assay, determining the mono-, di-, and triphosphates, of thioguanine as well as methylthioinosine as individual metabolites in erythrocytes, to predict clinical outcome compared to a routine assay, determining metabolites as sums. Methods: Samples from 79 patients with Crohns disease or ulcerative colitis treated with azathioprine or mercaptopurine were analysed by both assays. Clinical status was determined by the Harvey-Bradshaw and Walmsley indices. The genotypes of thiopurine methyltransferase (TPMT) and inosine triphosphatase were determined. Results: TPMT wild-type patients with thioguanine nucleotide (TGN) levels below the cut-off level were more likely to have active disease when TGN was measured by the novel assay (p = 0.02), and when thioguanosine triphosphate (TGTP) was measured separately (p = 0.01). When TGN was measured by the routine assay the correlation was not evident (p = 0.12). Neither TGN levels nor TGTP correlated to disease activity in TPMT deficient patients. Patients with methyl thioinosine nucleotide (meTIN) levels above 1500 pmol/8 x 10less than^greater than8 RBCs were more likely to have active disease (p = 0.07). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R-2 greater than 0.88). Conclusions: The novel TGN assay was better in predicting clinical outcome compared to the routine assay, while determination of TGTP had no clinical advantage and TGTP ratio was not correlated to disease activity. (C) 2014 European Crohns and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

  • 136.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, David
    Department of Gastroenterology, Skåne University Hospital, Lund, Sweden.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Hindorf, Ulf
    Department of Gastroenterology, Skåne University Hospital, Lund, Sweden.
    Therapeutic drug monitoring of thiopurines in inflammatory bowel disease: Evaluating the benefit of measuring mono-, di-, and triphosphates separatelyManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The thiopurines are widely used in the treatment of inflammatory bowel diseases but are limited by poor dose-effect relationship and large interindividual variability in clinical effects. Many attempts have been made to predict response by therapeutic drug monitoring of phosphorylated and methylated metabolites grouped together as thioguanine nucleotides and methylthioinosine monophosphate. We have developed a method to determine the individual metabolites, thioguanosine mono-, di-, and triphosphates, as well as methylthioinosine mono-, di-, and triphosphates, separately in red blood cells.

    This aim of this study was to assess the ability of our novel method to predict clinical outcome compared to the routine method in 82 patients with inflammatory bowel diseases.

    TPMT wild-type patients with TGN levels below the cut-off level were more likely to have an active disease when TGN was measured by both the routine method (p < 0.05), the novel method (p<0.05), and when TGTP was measured separately (p < 0.01). TGN levels and TGTP were, however, not correlated to disease activity in TPMT defective patients. Patients with meTIN levels above 1500 pmol were more likely to have an active disease (39%, 18/46 vs. 17%, 5/30; p = 0.02). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R2 > 0.88) and the TGTP ratio (TGTP/(TGDP+TGTP)) was not different in patients with active disease or in clinical remission.

    Thiopurine metabolites should still be measured by the routine method, since the novel and technically more challenging method, including determination of TGTP and TGTP ratio, does not offer a clinical advantage compared to the routine method.

  • 137.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Coulthard, S
    Newcastle University, Northern Institute for Cancer Research.
    Josefsson, Martin
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linkoping.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Rapid Method to Measure Thioguanine Incorporation Into DNA2011Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 47, nr Supplement 1, s. S650-S650Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Background: The thiopurine drugs, 6-mercaptopurine, azathioprine, and thioguanine, are used in the treatment of acute lymphoblastic leukaemia (ALL). During treatment the thioguanine nucleotides formed are incorporated into the DNA, causing apoptosis due to the cells inability to repair the resulting damage. This mechanism is believed to be important for the effects of thiopurine drugs. We have developed a novel method for the determination of thioguanine incorporation into DNA which is both faster and cheaper than earlier methods.

    Monitoring the effects of thiopurine treatment by measuring thiopurine metabolites in erythrocytes has proven to be elusive due to the lack of good correlation between measured concentrations and thiopurine effects. If the incorporation is the main mechanism of thiopurine action, a reliable method capable of measuring the incorporation in an ordinary blood sample, such as the method we have developed, should provide a significantly better correlation with treatment effect.

    Material and Methods: Briefly, DNA extracted from buffy coat is degraded using nuclease P1 and alkaline phosphatase to produce free nucleosides which are purified by filtration. Thioguanosine and thymidine are separated and detected using an LC-MS/MS system and the ratio between the bases provides a measurement of the extent of thioguanine incorporation in DNA. The method has been successfully applied to cell culture samples as well as samples from patients treated orally with thiopurines.

    Results: In 8 inflammatory bowel disease patients treated with azathioprine the measured incorporation ranged from 2.2 to 8.4 thioguanine bases for every 10 000 thymidine bases (median 5.2). This is in agreement with earlier reports on incorporation in childhood leukemia patients.

    Conclusions: With the presented method it is possible to determine the incorporation of thioguanine into DNA during thiopurine treatment in a cost effective manner, but further research is needed to determine if there is a place for this type of methods in the monitoring of thiopurine treatment.

    An ongoing study aims to compare the incorporation to treatment effects as well as conventional measurements of erythrocyte metabolite levels. By this study we hope to determine if incorporation is a more reliable measurement to predict treatment effect and if the erythrocyte metabolite levels correlate with the incorporation.

  • 138.
    von Heideman, Anne
    et al.
    Uppsala University, Sweden .
    Tholander, Bengt
    Uppsala University, Sweden .
    Grundmark, Birgitta
    Uppsala University, Sweden .
    Cajander, Stefan
    Karolinska Institute, Sweden .
    Gerdin, Eva
    Uppsala University, Sweden .
    Holm, Leif
    Falun Central Hospital, Sweden .
    Axelsson, Agneta
    Vasteras Hospital, Sweden .
    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.
    Mahteme, Haile
    Uppsala University, Sweden .
    Daniel, Erika
    Uppsala University, Sweden .
    Larsson, Rolf
    Uppsala University, Sweden .
    Nygren, Peter
    Uppsala University, Sweden .
    Chemotherapeutic drug sensitivity of primary cultures of epithelial ovarian cancer cells from patients in relation to tumour characteristics and therapeutic outcome2014Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, nr 2, s. 242-250Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. A number of chemotherapeutic drugs are active in epithelial ovarian cancer (EOC) but so far choice of drugs for treatment is mostly empirically based. Testing of drug activity in tumour cells from patients might provide a rationale for a more individualised approach for drug selection. Material and methods. Sensitivity of EOC to chemotherapeutic drugs was analysed in 125 tumour samples from 112 patients using a short-term primary culture assay based on the concept of total cell kill. Sensitivity was related to tumour histology, treatment status and clinical tumour response. Results. For most EOC standard drugs serous high grade and clear cell EOC were the most sensitive subtypes and the mucinous tumours the most resistant subtype. Docetaxel, however, tended to show the opposite pattern. Samples from previously treated patients tended to be more resistant than those from treatment naive patients. The activity of cisplatin correlated with that of other drugs with the exception of docetaxel. Tumour samples from two sites in the same patient at the same occasion showed similar cisplatin sensitivity in contrast to samples taken at different occasions. Samples from patients responding in the clinic to treatment were more sensitive to most drugs than samples from non-responding patients. At the individual patient level, drug sensitivity in vitro compared with clinical response showed sensitivities and specificities in the 83-100% and 55-83% ranges, respectively. Conclusions. Assessment of EOC tumour cell drug sensitivity in vitro provides clinically relevant and potentially useful information for the optimisation of drug treatment.

  • 139.
    Wang, Chao-Jie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Frånbergh-Karlson, Hanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Wang, Da-Wei
    The Third Hospital of Hebei Medical University, China.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken ViN.
    Zhang, Hong
    Örebro University, Sweden.
    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.
    Clinicopathological significance of BTF3 expression in colorectal cancer2013Ingår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 34, nr 4, s. 2141-2146Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Basic transcription factor 3 (BTF3) is a general RNA polymerase II transcription factor and is also involved in apoptosis regulation. Increasing evidence shows that BTF3 is aberrantly expressed in several kinds of malignancies, but there is no study to analyze BTF3 expression in colorectal cancer (CRC) patients. Applying immunohistochemistry, we detected BTF3 in CRCs (n = 156), the corresponding distant (n = 42), adjacent normal mucosa (n = 96), lymph node metastases (n  = 35), and analyzed its relationships with clinicopathological and biological variables. Our results showed that BTF3 staining significantly increased from distant or adjacent normal mucosa to primary CRCs (p < 0.0001) or metastases (p = 0.002 and p < 0.0001). BTF3 was higher in distal cancers than in proximal cancers (57 % vs. 39 %, p = 0.041). It also showed stronger staining in primary CRCs stage I and II than that in stage III and IV (64 % vs. 35 %, p = 0.0004), or metastases (64 % vs. 29 %, p = 0.004). Cancers with better differentiation had a higher expression than those with worse differentiation (56 % vs. 37 %, p  = 0.031). There were positive correlations of BTF3 expression with nuclear factor kappa B (NF-κB), RAD50, MRE11, NBS1, and AEG-1 (p  < 0.05). In conclusion, BTF3 overexpression may be an early event in CRC development and could be useful biomarker for the early stage of CRCs. BTF3 has positive correlations with NF-κB, RAD50, MRE11, NBS1 and AEG-1, and might influence complex signal pathways in CRC.

  • 140.
    Wang, Mo-Jin
    et al.
    Sichuan University, China.
    Li, Yuan
    Sichuan University, China.
    Wang, Rui
    Sichuan University, China.
    Wang, Cun
    Sichuan University, China.
    Yu, Yong-Yang
    Sichuan University, China.
    Yang, Lie
    Sichuan University, China.
    Zhang, Yi
    Sichuan University, China.
    Zhou, Bin
    Sichuan University, China.
    Zhou, Zong-Guang
    Sichuan University, China.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Downregulation of microRNA-124 is an independent prognostic factor in patients with colorectal cancer2013Ingår i: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 28, nr 2, s. 183-189Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose

    Recently, microRNA-124 (miR-124) has been demonstrated as a potential tumor suppressor in several types of cancers. However, the role of miR-124 in colorectal cancer remains unclear. This study was aimed at investigating the clinicopathological significance of miR-124 expression in colorectal cancer.

    Methods

    Quantitative real-time PCR was used to analyze miR-124 expression in 96 colorectal cancers and individual-matched normal mucosa samples. The expression of miR-124 was assessed for associations with clinicopathological characteristics using chi-square test. The survival curves were calculated by the Kaplan–Meier method. The influence of each variable on survival was examined by the Cox multivariate regression analysis.

    Results

    The miR-124 expression was significantly downregulated in colorectal cancer compared to normal mucosa (P = 0.001). In colorectal cancer, miR-124 decreased expression correlated significantly with the grade of differentiation (P  = 0.021). Univariate survival analysis showed that the downregulated miR-124 was significantly correlated with worse prognosis, both in terms of overall survival (P = 0.017) and disease-free survival (DFS) (P  = 0.014). Further, the downregulated miR-124 was demonstrated as a prognostic factor for overall survival (hazard ratio, HR = 4.634; 95 % confidence interval, CI, 1.731–12.404; P = 0.002) and DFS (HR = 4.533, 95 % CI 1.733–11.856, P = 0.002), independently of gender, age, location, maximum tumor size, depth of invasion, differentiation, and TNM stage.

    Conclusions

    MiR-124 may play a certain role in the development of colorectal cancer. The downregulation expression of miR-124 is an independent prognostic factor in patients with colorectal cancer.

  • 141.
    Wang, Mojin
    et al.
    West China Hospital, Sichuan University, China.
    Zhang, Dan
    West China Hospital, Sichuan University, China.
    Wang, Rui
    West China Hospital, Sichuan University, China.
    Rui, Yuanyi
    West China Hospital, Sichuan University, China.
    Zhou, Jin
    West China Hospital, Sichuan University, China.
    Wang, Rong
    West China Hospital, Sichuan University, China.
    Zhou, Bin
    West China Hospital, Sichuan University, China.
    Huang, Xiaoran
    West China Hospital, Sichuan University, China.
    Yang, Lie
    West China Hospital, Sichuan University, China.
    Li, Yuan
    West China Hospital, Sichuan University, China.
    Hu, Jiankun
    West China Hospital, Sichuan University, China.
    Zhou, Zongguang
    West China Hospital, Sichuan University, China.
    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.
    A-Kinase Anchoring Proteins 10 Expression in Relation to 2073A/G Polymorphism and Tumor Progression in Patients with Colorectal Cancer2013Ingår i: Pathology and Oncology Research, ISSN 1219-4956, E-ISSN 1532-2807, Vol. 19, nr 3, s. 521-527Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The cAMP/PKA signalling events regulated by A-kinase anchoring proteins 10 (AKAP10) is involved in tumorigenesis. Previous study showed that AKAP10 polymorphism (2073 A/G, I646V) was associated with colorectal cancer risk. However, there was no literature reporting the role of AKAP10 in the pathogenesis of colorectal cancer. The aim of the study was to investigate the clinicopathologic significance of A-kinase anchoring proteins 10 (AKAP 10) expression and the relationship with its polymorphism in colorectal cancer. The expression of AKAP10 was determined by immunohistochemical staining (IHC) and western blot assay on colorectal cancer (n = 176), adenoma (n = 87) and distant normal mucosa (n  = 72). 176 patients with colorectal cancer were genotyped for AKAP10 2073A/G polymorphism by TaqMan RT-PCR. We found that the positive expression rate of AKAP10 in colorectal cancer (59 %) was significantly higher than those in adenoma (39 %) and distant normal mucosa (42 %) (P = 0.004). There was no significant difference between adenoma and distant normal mucosa (P = 0.741). Positive AKAP10 staining was correlated with deeper tumor invasion (P < 0.001), lymph nodes metastasis (P = 0.022), advanced tumor stage (P < 0.001) and poorly differentiated degree (P  = 0.003). Compared with AA genotype (52 %), positive expression of AKAP10 was significantly increased in colorectal cancer patients with the variant (AG+GG) genotypes (68 %, P = 0.033). It was concluded that AKAP10 may play an important role in the development and progression of colorectal cancer.

  • 142.
    Wang, Mojin
    et al.
    Sichuan University, Peoples R China.
    Zhang, Peng
    Sichuan University, Peoples R China.
    Li, Yuan
    Sichuan University, Peoples R China .
    Liu, Guanghui
    Sichuan University, Peoples R China.
    Zhou, Bin
    Sichuan University, Peoples R China.
    Zhan, Lan
    Sichuan University, Peoples R China.
    Zhou, Zongguang
    Sichuan University, Peoples R China.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    The quantitative analysis by stem-loop real-time PCR revealed the microRNA-34a, microRNA-155 and microRNA-200c overexpression in human colorectal cancer2012Ingår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 29, nr 5, s. 3113-3118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The recently identified class of microRNAs (miRNAs) provided a new insight in cancer research. As the member of miRNAs family, miR-34a, miR-155 and miR-200c abnormalities have been found in various types of cancer. However, the relationship between these three miRNAs (miR-34a, miR-155 and miR-200c) and colorectal cancer is unclear. In this study, we applied stem-loop real-time PCR to quantitatively detect miR-34a, miR-155 and miR-200c expression in 109 pair-matched human colorectal cancers and the corresponding normal mucosa. MiR-34a (2.2-fold), miR-155 (2.3-fold) and miR-200c (3.1-fold) were all expressed at higher levels in colorectal cancer (P = 0.001, 0.005 and 0.001, respectively). In rectum, miR-34a and miR-200c were significantly upregulated (P = 0.006 and 0.007), while the miR-155 overexpression was not statistically significant (P = 0.083). In colon, the higher expression of three miRNAs was seen, however, without significant difference (P andgt; 0.05). We also found that the miR-34a expression was higher in rectal cancer having more advanced TNM stage (III + IV, P = 0.03). Then miR-200c expression was positively correlated with and sera CEA level of rectal cancer patients (P = 0.04). In conclusion, our results thus suggest that the overexpression of miR-34a, miR-155 and miR-200c be associated with the development of colorectal cancer, meanwhile miR-34a may be involved in the development and progression of rectal cancer. The more deeply and larger scale research are required to prove the correlation.

  • 143.
    Wang, Y.
    et al.
    Sichuan University, Peoples R China.
    Li, Y.
    Sichuan University, Peoples R China.
    Zhou, B.
    Sichuan University, Peoples R China.
    Zhang, W. Y.
    Sichuan University, Peoples R China.
    Guan, J. T.
    Sichuan University, Peoples R China.
    Wang, R.
    Sichuan University, Peoples R China.
    Yang, L.
    Sichuan University, Peoples R China.
    Xia, Q. J.
    Sichuan University, Peoples R China.
    Zhou, Z. G.
    Sichuan University, Peoples R China.
    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.
    Expression of the apoptosis inhibitor livin in colorectal adenoma-carcinoma sequence: correlations with pathology and outcome2014Ingår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, nr 12, s. 11791-11798Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The inhibitor of apoptosis family member livin is expressed in several types of cancer but not in most benign tissues, and it has been considered to be a poor prognostic mark in various malignancies. However, livin expression and its prognostic relevance have not been evaluated in colorectal adenoma-carcinoma sequence. In this study, we analyzed the difference of livin expression among normal mucosa, adenoma, and adenocarcinoma and investigated the relationship of livin expression in carcinomas with clinicopathological variables using immunohistochemistry and real-time reverse transcription-PCR. We observed that the expression of livin protein was mainly present on base of colorectal crypts in adenoma and throughout the epithelium in carcinoma, whereas did not present in accompanying normal mucosa, and the expression of livin messenger RNA (mRNA) in adenocarcinomas was significantly higher than in adenomas and in normalmucosa (P= 0.001, respectively), whereas, compared with normal mucosa, the expression level of livin mRNA was up-regulated in adenomas but no significant difference (P= 0.196). We also found that the expression levels of livin mRNA in rectal cancer was significantly higher than those in colonic cancer, and livin mRNA expression was strongly related to colorectal cancer invasive depth but not to clinical tumor stage, differentiation, lymph node metastasis, tumor morphological category and pathological type, and patients age and gender. These findings support the possibility that the livin gene may play a role in colorectal tumorigenesis, and increased expression of livin mRNA may serve as a new target for colorectal cancer treatment.

  • 144.
    Wang, Zongwei
    et al.
    Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    Dabrosin, Charlotta
    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.
    Yin, Xin
    Medicine and Research Services, Veterans Affairs San Diego Healthcare System & University of California, San Diego, San Diego, CA, USA.
    Fuster, Mark M
    Medicine and Research Services, Veterans Affairs San Diego Healthcare System & University of California, San Diego, San Diego, CA, USA.
    Arreola, Alexandra
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
    Rathmell, W Kimryn
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
    Generali, Daniele
    Molecular Therapy and Pharmacogenomics Unit, AO Isituti Ospitalieri di Cremona, Cremona, Italy.
    Nagaraju, Ganji P
    Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.
    El-Rayes, Bassel
    Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.
    Ribatti, Domenico
    Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy, National Cancer Institute Giovanni Paolo II, Bari, Italy.
    Chen, Yi Charlie
    Department of Biology, Alderson Broaddus University, Philippi, WV, USA.
    Honoki, Kanya
    Department of Orthopedic Surgery, Arthroplasty and Regenerative Medicine, Nara Medical University, Nara, Japan.
    Fujii, Hiromasa
    Department of Orthopedic Surgery, Arthroplasty and Regenerative Medicine, Nara Medical University, Nara, Japan.
    Georgakilas, Alexandros G
    Physics Department, School of Applied Mathematics and Physical Sciences, National Technical University of Athens, Athens, Greece.
    Nowsheen, Somaira
    Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN, USA.
    Amedei, Amedeo
    Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
    Niccolai, Elena
    Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
    Amin, Amr
    Department of Biology, College of Science, United Arab Emirate University, United Arab EmiratesFaculty of Science, Cairo University, Cairo, Egypt.
    Ashraf, S Salman
    Department of Chemistry, College of Science, United Arab Emirate University, United Arab Emirates.
    Helferich, Bill
    University of Illinois at Urbana Champaign, Urbana, IL, USA.
    Yang, Xujuan
    University of Illinois at Urbana Champaign, Urbana, IL, USA.
    Guha, Gunjan
    School of Chemical and Bio Technology, SASTRA University, Thanjavur, India.
    Bhakta, Dipita
    School of Chemical and Bio Technology, SASTRA University, Thanjavur, India.
    Ciriolo, Maria Rosa
    Department of Biology, University of Rome “Tor Vergata”, Rome, Italy.
    Aquilano, Katia
    Department of Biology, University of Rome “Tor Vergata”, Rome, Italy.
    Chen, Sophie
    Ovarian and Prostate Cancer Research Trust Laboratory, Guilford, Surrey, UK.
    Halicka, Dorota
    New York Medical College, New York City, NY, USA.
    Mohammed, Sulma I
    Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN, USA.
    Azmi, Asfar S
    School of Medicine, Wayne State University, Detroit, MI, USA.
    Bilsland, Alan
    Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
    Keith, W Nicol
    Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
    Jensen, Lasse D
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Broad targeting of angiogenesis for cancer prevention and therapy2015Ingår i: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. S1044-579X, nr 15, s. 00002-00004Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Deregulation of angiogenesis - the growth of new blood vessels from an existing vasculature - is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding "the most important target" may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the "Halifax Project" within the "Getting to know cancer" framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the "hallmarks" of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.

  • 145.
    Weiner, Maria
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Skoog, L
    Karolinska Institute, Sweden.
    Fornander, T
    Karolinska Institute, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Sgroi, D C.
    Massachusetts General Hospital, Boston, USA.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Oestrogen receptor co-activator AIB1 is a marker of tamoxifen benefit in postmenopausal breast cancer2013Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, nr 8, s. 1994-1999Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background The oestrogen receptor (ER) co-activator amplified in breast cancer 1 (AIB1) has been suggested as a treatment predictive and prognostic marker in breast cancer. Studies have however not been unanimous.

    Patients and methods AIB1 protein expression was analysed by immunohistochemistry on tissue micro-arrays with tumour samples from 910 postmenopausal women randomised to tamoxifen treatment or no adjuvant treatment. Associations between AIB1 expression, clinical outcome in the two arms and other clinicopathological variables were examined.

    Results In patients with ER-positive breast cancer expressing low tumour levels of AIB1 (<75%), we found no significant difference in recurrence-free survival (RFS) or breast cancer-specific survival (BCS) between tamoxifen treated and untreated patients. In patients with high AIB1 expression (>75%), there was a significant decrease in recurrence rate (HR 0.40, 95% CI 0.26–0.61, P < 0.001) and breast cancer mortality rate (HR 0.38, 95% CI 0.21–0.69, P = 0.0015) with tamoxifen treatment. In the untreated arm, we found high expression of AIB1 to be significantly associated with lower RFS (HR 1.74, 95% CI 1.20–2.53, P = 0.0038).

    Conclusion Our results suggest that high AIB1 is a predictive marker of good response to tamoxifen treatment in postmenopausal women and a prognostic marker of decreased RFS in systemically untreated patients.

  • 146.
    Yang, Lie
    et al.
    Sichuan University, Peoples R China; Sichuan University, Peoples R China.
    Ma, Qin
    Sichuan University, Peoples R China; Sichuan University, Peoples R China.
    Yu, Yong-Yang
    Sichuan University, Peoples R China; Sichuan University, Peoples R China.
    Wang, Cun
    Sichuan University, Peoples R China; Sichuan University, Peoples R China.
    Meng, Wen-Jian
    Sichuan University, Peoples R China; Sichuan University, Peoples R China.
    Adell, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken ViN.
    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.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken ViN.
    Jarlsfelt, Ingvar
    Jonköping Hospital, Sweden.
    Peng, Zhi-Hai
    Shanghai Jiao Tong University, Peoples R China.
    Li, Yuan
    Sichuan University, Peoples R China; Sichuan University, Peoples R China.
    Zhou, Zong-Guang
    Sichuan University, Peoples R China; Sichuan University, Peoples R China.
    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. Sichuan University, Peoples R China; Sichuan University, Peoples R China.
    Efficacy of Surgery and Adjuvant Therapy in Older Patients With Colorectal Cancer A STROBE-compliant article2014Ingår i: Medicine (Baltimore, Md.), ISSN 0025-7974, E-ISSN 1536-5964, Vol. 93, nr 28Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The present study aimed to assess the efficacy of surgery and adjuvant therapy in older patients (age greater than= 70 years) with colorectal cancer (CRC). Older CRC patients are under-represented in available clinical trials, and therefore their outcomes after receiving surgery and adjuvant therapy are unclear. From two prospective Swedish databases, we assessed a cohort of 1021 patients who underwent curative surgery for stage I, II, or III primary CRC, with or without adjuvant chemotherapy/ radiotherapy. Of the patients with colon cancer (n = 467), 182 (39%) were aged less than70 years, 162 (35%) aged 70 to 80 years, and 123 (26%) were aged greater than= 80 years. Of rectal cancer patients (n = 554), 264 (48%) were aged less than70 years, 234 (42%) aged 70 to 80 years, and 56 (10%) aged greater than= 80 years. Older patients with either colon or rectal cancer had higher comorbidity than did younger patients. Older patients with colon cancer had equivalent postoperative morbidity and 30-day mortality to younger patients. Rectal cancer patients aged greater than= 80 years had a higher 30-day mortality than younger patients (odds ratio OR], 2.37; 95% confidence interval CI], 1.6-4.55; P = 0.03). For either colon or rectal cancer, adjuvant chemotherapy compromised the 5-year overall survival (OS) of older patients with stage II disease and had no effect on those with stage III disease. Receiving adjuvant chemotherapy was a poor factor of OS for older patients with either colon (HR 1.88, 95% CI: 1.20-4.35, P = 0.03) or rectal cancer (HR 1.72, 95% CI: 1.052.26, P = 0.004). Preoperative short-course radiotherapy improved both OS and local control for older patients with stage III rectal cancer and had no effect on those with stage II disease. Radiotherapy was a favorable factor for the OS of the older patients with rectal cancer (HR 0.42, 95% CI: 0.21-3.57, P = 0.01). In conclusion, Older CRC patients had equal safety of surgery as younger patients, except rectal cancer patients aged greater than= 80 years that had a higher mortality. Adjuvant 5FU-based chemotherapy did not benefit older CRC patient, while neoadjuvant radiotherapy improved the prognosis of older patients with stage III rectal cancer.

  • 147.
    Yang, Lie
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Zhang, Hong
    University of Skovde.
    Zhou, Zong-Guang
    Sichuan University.
    Yan, Hui
    Sichuan University.
    Adell, G
    Karolinska University Hospital.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Biological Function and Prognostic Significance of Peroxisome Proliferator-Activated Receptor delta in Rectal Cancer2011Ingår i: CLINICAL CANCER RESEARCH, ISSN 1078-0432, Vol. 17, nr 11, s. 3760-3770Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: To investigate the expression significance of PPAR beta/delta in relation to radiotherapy (RT), clinicopathologic, and prognostic variables of rectal cancer patients. Experimental Design: We included 141 primary rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. Tissue microarray samples from the excised rectal cancers and the adjacent or distant normal mucosa and lymph node metastases were stained with PPAR delta antibody. Survival probability was computed by the Kaplan-Meier method and Cox regression model. The proliferation of colon cancer cell lines KM12C, KM12SM, and KM12L4a was assayed after PPAR delta knockdown. Results: PPAR delta was increased from adjacent or distant normal mucosa to primary cancers, whereas it decreased from primary cancers to lymph node metastases. After RT, PPAR delta was increased in normal mucosa, whereas it decreased in primary cancers and lymph node metastases. In primary cancers, the high expression of PPAR delta was related to higher frequency of stage I cases, lower lymph node metastasis rate, and low expression of Ki-67 in the unirradiated cases, and related to favorable survival in the cases either with or without RT. The proliferation of the KM12C, KM12SM, or KM12L4a cells was significantly accelerated after PPAR delta knockdown. Conclusions: RT decreases the PPAR delta expression in primary rectal cancers and lymph node metastases. PPAR delta is related to the early development of rectal cancer and inhibits the proliferation of colorectal cancer cells. Increase of PPAR delta predicts favorable survival in the rectal cancer patients either with or without preoperative

  • 148.
    Yang, Lie
    et al.
    West China Hospital, Sichuan University, China.
    Zhou, Jin
    West China Hospital, Sichuan University, China.
    Ma, Qin
    West China Hospital, Sichuan University, China.
    Wang, Cun
    West China Hospital, Sichuan University, China.
    Chen, Keling
    West China Hospital, Sichuan University, China.
    Meng, Wenjian
    West China Hospital, Sichuan University, China.
    Yu, Yongyang
    West China Hospital, Sichuan University, China.
    Zhou, Zongguang
    West China Hospital, Sichuan University, China.
    Sun, Xiaofeng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Knockdown of PPAR δ Gene Promotes the Growth of Colon Cancer and Reduces the Sensitivity to Bevacizumab in Nude Mice Model2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The role of peroxisome proliferator – activated receptor- δ (PPAR δ) gene in colon carcinogenesis remains highly controversial. Here, we established nude mice xenograft model using a human colon cancer cell line KM12C either with PPAR δ silenced or normal. The xenografts in PPAR δ-silenced group grew significantly larger and heavier with less differentiation, promoted cell proliferation, increased expression of vascular endothelial growth factor (VEGF) and similar apoptosis index compared with those of PPAR δ-normal group. After treated with the specific VEGF inhibitor bevacizumab, the capacities of growth and proliferation of xenografts were decreased in both groups while still significantly higher in PPAR δ-silenced group than in PPAR δ-normal group. Administration of PPAR δ agonist significantly decreased VEGF expression in PPAR δ-normal KM12C cells but not in PPAR δ-silenced cells. These findings demonstrate that, knockdown of PPAR δ promotes the growth of colon cancer by inducing less differentiation, accelerating the proliferation and VEGF expression of tumor cells in vivo, and reduces tumor sensitivity to bevacizumab. This study indicates that PPAR δ attenuates colon carcinogenesis.

  • 149.
    Yngman-Uhlin, Pia
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad.
    Edéll-Gustafsson, Ulla
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad.
    Börjeson, Sussanne
    Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fernström, Anders
    Östergötlands Läns Landsting, Medicincentrum, Njurmedicinska kliniken US. Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Uhlin, Fredrik
    Östergötlands Läns Landsting, Medicincentrum, Njurmedicinska kliniken US. Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Fatique and depression in PD and HD patients2009Ingår i: ASN (TH-PO152), 2009Konferensbidrag (Refereegranskat)
  • 150.
    Zhang, Dan
    et al.
    Sichuan University, Chengdu, Sichuan Province, China.
    Zhou, Bin
    Sichuan University, Chengdu, Sichuan Province, China.
    Li, Yuan
    Sichuan University, Chengdu, Sichuan Province, China.
    Wang, Mojin
    Sichuan University, Chengdu, Sichuan Province, China.
    Wang, Cun
    Sichuan University, Chengdu, Sichuan Province, China.
    Zhou, Zongguang
    Sichuan University, Chengdu, Sichuan Province, China.
    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.
    Polymorphisms of Glucose-Regulated Protein 78 and Risk of Colorectal Cancer: A Case-Control Study in Southwest China2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glucose-regulated protein 78 (GRP78), an endoplasmic reticulum chaperone, up-regulation serves as an efficient mechanism to promote malignant transformation of colorectal cancer (CRC) and protect CRC cells against apoptosis. Recently, the analysis of GRP78 polymorphisms has already determined that GRP78 rs391957 polymorphism could predict clinical outcome in CRC patients. Thus, we tested whether GRP78 polymorphisms are related to the risk of CRC. In this study, we detected two GRP78 polymorphisms (rs391957 (C>T) and rs430397 (G>A)) in 414 CRC cases and 502 hospital-based cancer-free healthy controls in Southwest China using a polymerase chain reaction–restriction fragment length polymorphism technique. Compared with the CC genotype, carriers of CT and TT genotypes of rs391957 polymorphism had higher risks of CRC (odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.06–1.83 for CT genotype and OR = 2.10, 95% CI = 1.06–4.14 for TT genotype, respectively). In CRC cases, the variant T allele was significantly associated with tumor invasion stage (P = 0.030), but not with status of lymph nodes metastasis (P = 0.052). Compared with the GG genotype, carriers of GA and AA genotypes of rs430397 polymorphism had higher risks of CRC (OR = 1.63, 95% CI = 1.23–2.15 for GA genotype and OR = 2.92, 95% CI = 1.23–6.94 for AA genotype, respectively). The rs430397 polymorphism was not associated with the clinicopathological characteristics of CRC. These data provide the first evidence that GRP78 rs391957 and rs430397 polymorphisms could serve as markers to predict the risk of CRC.

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