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  • 151.
    Sandblom, Gabriel
    et al.
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Dufmats, Monika
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Kerstin
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Prostate carcinoma trends in three counties in Sweden 1987–19962000In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 88, no 6, p. 1445-1453Article in journal (Refereed)
    Abstract [en]

    BACKGROUND To detect changes in the incidence rate and management of prostate carcinoma, all cases of the disease diagnosed in the southeast region of Sweden between 1987–1996 were recorded.

    METHODS The register is based on Swedish personal registration numbers, thereby minimizing the number of dropouts. All cases of prostate carcinoma detected in the southeast region have been recorded according to a defined protocol that has been updated successively to match recent views regarding the disease. To ensure a high number of presented cases, the National Cancer Register was checked for missing cases.

    RESULTS Six thousand seven hundred eighty-two cases of prostate carcinoma were registered in the region between 1987–1996. The age-adjusted incidence rate reached a peak in 1993, followed by a slight decrease. The mean age at diagnosis throughout the period was 74.2 years, with a peak age of 74.8 years in 1992. The number of incidental tumors followed the development of the number of transurethral resections of the prostate performed in the region, with a peak in 1991. The percentage of patients receiving gonadotropin-releasing hormone (GnRH) analogues increased from 3.9% to 37.8% whereas the percentage of patients treated with orchiectomy decreased from 40.0% to 12.8% and the percentage of those treated with radical prostatectomy decreased from 11.1% to 2.5%.

    CONCLUSIONS A diminishing pool of latent tumors may explain the decreasing incidence rate and lower age at diagnosis observed after 1993. Orchiectomy is rapidly being superceded by GnRH analogues. In contrast to trends reported in the U.S., the percentage of men with prostate carcinoma undergoing total prostatectomy appears to be declining in Sweden.

  • 152.
    Sandblom, Gabriel
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Dufmats, Monika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Olsson, Mats
    Varenhorst, Eberhard
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Validity of a population-based cancer register in Sweden - An assessment of data reproducibility in the South-East Region prostate cancer register2003In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 37, no 2, p. 112-119Article in journal (Refereed)
    Abstract [en]

    Background: With a population-based setting, high coverage and accurately recorded data, the validity of a register is guaranteed. The South-East Region Prostate Cancer relies on the National Cancer Register as a basic source of data, thereby ensuring a high coverage of the corresponding geographic area. To assess the reproducibility of the data recorded a random sample of the cases were reviewed a second time and compared to the original recording. Material and methods: The South-East Region Prostate Cancer Register was started in 1987. In addition to the basic data acquired from the Swedish National Register, it also includes tumour stage, grade, treatment and, since 1992, PSA. In the first stage of quality assessment 10 cases for each of the years 1987-1996 from Link÷ping University Hospital were randomly selected for two independent recodings according to the same protocol as the original registration. In the second step 10 cases each for the same years from the remaining 8 hospitals in the region were selected for a single recoding. Results: No systematic deviations were seen between the two independent recodings from Link÷ping, a single recoding was therefore considered sufficient for assessing the reproducibility of the data from the remaining hospitals in the region. The Kappa values for agreement between the original registration and the single recoding ranged from 0.589 to 0.869. Conclusion: The population-based setting and high coverage guarantees the external validity of the register. The internal validity is ensured by the high reproducibility shown in the present study.

  • 153.
    Sandblom, Gabriel
    et al.
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Dufmats, Monika
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Long-term survival in a swedish population-based cohort of men with prostate cancer2000In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 56, no 3, p. 442-447Article in journal (Refereed)
    Abstract [en]

    Objectives. To study the long-term survival of patients with prostate cancer, determine the risk factors for prostate cancer death, and investigate the outcome of initially untreated localized prostate cancer and incidentally detected tumors.

    Methods. The survival of 813 patients in a population-based cohort of patients with prostate cancer in Linköping, Sweden, diagnosed from 1974 to 1986, was analyzed.

    Results. At 10, 15, and 20 years after diagnosis, the prostate cancer-specific survival rate of men with localized, initially untreated, prostate cancer was 85.0% (95% confidence interval [CI], 79.0% to 91.0%), 80.0% (95% CI, 72.5% to 87.5%), and 62.6% (95% CI, 43.0% to 82.2%). Age 70 years or older, advanced stage, and poor differentiation were risk factors associated with an increased risk of prostate cancer death. At 10 years, the prostate cancer-specific survival rate among men with localized tumors treated by expectancy was 90% (95% CI, 84% to 97%) for grade 1 tumors, 74% (95% CI, 60% to 89%) for grade 2 tumors, and 59% (95% CI, 29% to 90%) for grade 3 tumors. For patients with incidentally detected tumors, the grade of malignancy was a more important risk factor than tumor volume.

    Conclusions. Patients with localized tumors have a favorable prognosis, even without initial treatment. However, when deciding on therapy, the grade of malignancy should be taken into account, as it has a great influence on survival. We did not see a tendency toward increased mortality when the patients were followed up for longer than 10 years after diagnosis.

  • 154.
    Sandblom, Gabriel
    et al.
    Department of Surgery, Uppsala Akademiska Hospital, Akademiska Sjukhuset, Uppsala, Sweden.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Löfman, Owe
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Rosell, Johan
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Carlsson, Per
    Linköping University, Department of Department of Health and Society, Center for Medical Technology Assessment. Linköping University, Faculty of Health Sciences.
    Clinical consequences of screening for prostate cancer: 15 Years follow-up of a randomised controlled trial in Sweden2004In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 46, no 6, p. 717-723Article in journal (Refereed)
    Abstract [en]

    Objective:

    To test the feasibility of a population-based prostate cancer screening programme in general practice and explore the outcome after a 15-year follow-up period.

    Methods:

    From the total population of men aged 50–69 years in Norrköping (n = 9026) every sixth man (n = 1494) was randomly selected to be screened for prostate cancer every third year over a 12-year period. The remaining 7532 men were treated as controls. In 1987 and 1990 only digital rectal examination (DRE) was performed, in1993 and 1996 DRE was combined with a test for Prostate-Specific Antigen (PSA). TNM categories, grade of malignancy, management and cause of death were recorded in the South-East Region Prostate Cancer Register.

    Results:

    There were 85 (5.7%) cancers detected in the screened group (SG), 42 of these in the interval between screenings, and 292 (3.8%) in the unscreened group (UG). In the SG 48 (56.5%) of the tumours and in the UG 78 (26.7%) were localised at diagnosis (p < 0.001). In the SG 21 (25%) and in the UG 41 (14%) received curative treatment. There was no significant difference in total or prostate cancer-specific survival between the groups.

    Conclusions:

    Although PSA had not been introduced in the clinical practice at the start of the study, we were still able to show that it is possible to perform a long-term population-based randomised controlled study with standardised management and that screening in general practice is an efficient way of detecting prostate cancer whilst it is localised. Complete data on stage, treatment and mortality for both groups was obtained from a validated cancer register, which is a fundamental prerequisite when assessing screening programmes.

  • 155.
    Schöier, Johan
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Kvarnström, Maria
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Söderlund, Gustaf
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Kihlström, Erik
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Chlamydia trachomatis -induced apoptosis occurs in uninfected McCoy cells late in the developmental cycle and is regulated by the intracellular redox state2001In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 31, no 4, p. 173-184Article in journal (Refereed)
    Abstract [en]

    Infections with the obligate intracellular bacterium Chlamydia trachomatis are characterized by avoidance of fusion between chlamydia-containing endosomes and lysosomes, bacterial persistence and development of post-infectious sequelae. In this report we show that C. trachomatis induces apoptosis in McCoy and HeLa cells. Apoptosis was monitored by three different techniques; enzyme-linked immunoassay (EIA) of fragmented nucleosomes, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) and flow cytometry of propidium iodide-stained cells. Apoptosis occurred in uninfected cells, was induced late in the chlamydial developmental cycle, beyond 24 h post-infection and was dependent on bacterial protein synthesis. Apoptosis was not significantly increased in infected, inclusion-containing cells. Treatment of cells with the antioxidants ascorbic acid (10 μM) and α-tocopherol (10 μM) reduced the degree of apoptosis. These results suggest that host cells infected with C. trachomatis generate proapoptotic stimuli that induce apoptosis in uninfected, neighbouring cells and that the redox state of the cell is a regulator in chlamydia-induced apoptosis.

  • 156. Schüle, Jana
    et al.
    Bergkvist, Leif
    Håkansson, Leif
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Håkansson, Annika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Down-regulation of the CD3-? chain in sentinel node biopsies from breast cancer patients2002In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 74, no 1, p. 33-40Article in journal (Refereed)
    Abstract [en]

    Background. In several neoplastic diseases, immunosuppression has been shown to correlate with disease stage, progression, and outcome. As the prognosis for metastatic breast cancer is still pessimistic, additional strategies are being sought to improve survival. Local immunosuppression in sentinel node biopsies from 24 evaluable breast cancer patients was studied as a possible way of selecting patients for immunotherapy. Method. Sentinel node biopsy was performed in 24 out of 25 women operated on for primary breast cancer (one was not evaluable). Specimens were snap-frozen and double-stained for the ?-chain of the T-cell receptor. The degree of down-regulation of the ?-chain was evaluated in three different lymph-node areas: primary follicles, secondary follicles, and paracortex. Results. Down-regulation of varying degrees was noted in all 24 sentinel node biopsies. A high degree of down-regulation (more than 50% of T-cells not expressing ?-chain) was seen in the primary follicles in six patients (25%), in the secondary follicles in 13 patients (72%), and in the paracortex in 19 patients (79%). Conclusion. Local down-regulation of an immune function parameter was seen in sentinel node biopsies from breast cancer patients. In addition to possible prognostic implications, the sentinel node might be an appropriate location for detecting early-stage immunological down-regulation, which might open a possibility of selecting patients who could benefit from immunotherapy.

  • 157. Schüle, Jana M
    et al.
    Bergkvist, Leif
    Håkansson, Leif
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Håkansson, Annika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    CD28 expression in sentinel node biopsies from breast cancer patients in comparison with CD3-ζ chain expression2004In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 2Article in journal (Refereed)
    Abstract [en]

    Background: Immunosuppression is documented in several malignant diseases, including breast cancer. Subsequently, future therapeutic concepts might include immunological approaches. However, detailed knowledge about tumor immunogenicity and host immunoreactivity, and how to assess these adequately, is still limited. We studied CD28 and CD3-ζ expression in sentinel node biopsies (SNB) from breast cancer patients to analyze tumor-related changes in T cell activity. Method: 25 women underwent surgery for primary breast cancer, including SNB. Frozen sections from 21 sentinel nodes could be analyzed with a double-staining technique. CD28 expression was studied in CD4+ and CD8+ T-lymphocyte subsets and compared with CD3-ζ expression in three specified nodal regions. Results: The degree of CD28 expression varied between the different lymph node areas. The lowest degree of CD28 expression was observed in CD4+ T-lymphocytes in the paracortex and germinal centers. Here, a good agreement with CD3-ζ expression was found. A higher CD28 expression was noted in CD4+ T-cells in the primary follicles, where concordance with CD3-ζ expression was weaker. The CD8+ T-lymphocyte subset displayed generally a higher degree of CD28 expression than the CD4+ subset. Conclusion: Sentinel lymph nodes from breast cancer patients displayed local immunosuppression of varying extent. In the areas with the lowest degree of CD28 expression an accordingly low CD3-ζ expression was found. The SNB might prove an important diagnostic tool for the evaluation of interactions between tumor and the host immune system, helping to select patients who might benefit from adjuvant immunotherapy.

  • 158.
    Shabo, Ivan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Nordenskjöld, Kerstin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Svanvik, Joar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Incidensen av gallblåsecancer i Sverige har minskat. Den dåliga prognosen kan möjligen förbättras genom radikal kirurgi. [The incidence of gallbladder cancer in Sweden has decreased. The poor prognosis can possibly be improved by radical surgery.]2001In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 98, no 42, p. 4584-4589Article in journal (Other academic)
    Abstract [sv]

    Gallblåsecancer är en relativt sällsynt sjukdom som har dålig prognos med kort överlevnadstid. Sjukdomen drabbar framför allt kvinnor. Vi har inhämtat registerdata från cancerregistret och dödsorsaksregistret och studerat utvecklingen i Sverige mellan 1988 och 1997. Under de senaste åren har incidensen minskat, vilket möjligen kan förklaras av en hög kolecystektomifrekvens under 1950- och 1970-talen. Prognosen vid erhållen diagnos har tidigare varit dålig, med en medianöverlevnad på 3,5 månader, vilket beror på att diagnosen ofta har ställts först när sjukdomen blivit avancerad. Epidemiologiska data visar att dessa siffror kan ha förbättrats de senaste åren. I flera aktuella studier, framför allt från Japan, rapporteras bättre resultat och längre överlevnadstid efter utvidgad kirurgi. I ett material av elva patienter med gallblåsecancer, grad II–V enligt Nevin, som opererats med utvidgad kirurgi i Linköping finns hos tio inga tecken på recidiv efter en uppföljningstid på 1–8 år.

  • 159. Simonsson, Bengt
    et al.
    Öberg, Gunnar
    Björeman, Mats
    Björkholm, Magnus
    Carneskog, Jan
    Karlsson, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Gahrton, Gösta
    Grimfors, Gunnar
    Hast, Robert
    Karle, Hans
    Linder, Olle
    Ljungman, Per
    Nielsen, Johan L
    Nilsson, Jonas
    Löfvenberg, Eva
    Malm, Claes
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Olsson, Karin
    Olsson-Strömberg, Ulla
    Paul, Christer
    Stenke, Leif
    Stentoft, Jesper
    Turesson, Ingemar
    Udén, Ann-Marie
    Wahlin, Anders
    Vilén, Lars
    Weis-Bjerrum, Ole
    Intensive treatment and stem cell transplantation in chronic myelogenous leukemia: Long-term follow-up2005In: Acta Haematologica, ISSN 0001-5792, E-ISSN 1421-9662, Vol. 113, no 3, p. 155-162Article in journal (Refereed)
    Abstract [en]

    In the present study we combined interferon (IFN) and hydroxyurea (HU) treatment, intensive chemotherapy and autologous stem cell transplantation (SCT) in newly diagnosed chronic myelogenous leukemia patients aged below 56 years, not eligible for allogeneic SCT. Patients who had an HLA-identical sibling donor and no contraindication went for an allogeneic SCT (related donor, RD). After diagnosis, patients not allotransplanted received HU and IFN to keep WBC and platelet counts low. After 6 months patients with Ph-positive cells still present in the bone marrow received 1-3 courses of intensive chemotherapy. Those who became Ph-negative after IFN + HU or after 1-3 chemotherapy courses underwent autologous SCT. Some patients with poor cytogenetic response were allotransplanted with an unrelated donor (URD). IFN + HU reduced the percentage of Ph-positive metaphases in 56% of patients, and 1 patient became Ph-negative. After one or two intensive cytotherapies 86 and 88% had a Ph reduction, and 34 and 40% became Ph-negative, respectively. In patients receiving a third intensive chemotherapy 92% achieved a Ph reduction and 8% became Ph-negative. The median survival after auto-SCT (n = 46) was 7.5 years. The chance of remaining Ph-negative for up to 10 years after autologous SCT was around 20%. The overall survival for allo-SCT RD (n = 91) and URD (n = 28) was almost the same, i.e. ≈ 60% at 10 years. The median survival for all 251 patients registered was 8 years (historical controls 3.5 years). The role of the treatment schedule presented in the imatinib era is discussed. Copyright © 2005 S. Karger AG.

  • 160. Skoglund, Johanna
    et al.
    Emterling, Anna
    Arbman, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Anglard, Patrick
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Clinicopathological significance of stromelysin-3 expression in colorectal cancer2004In: Oncology, ISSN 0890-9091, Vol. 67, no 1, p. 67-72Article in journal (Refereed)
    Abstract [en]

    Objective: Stromelysin-3 (ST3) is a member of the matrix metalloproteinases and suggested to play a role in tissue remodeling observed in growth and metastasis of tumors. ST3 overexpression in breast cancer is associated with a worse outcome. Our aims were to analyze ST3 expression in primary colorectal tumors and metastases, and further to identify relationships of the expression to clinicopathological factors. Materials and Methods: ST3 expression was immunohistochemically analyzed in 200 primary colorectal adenocarcinomas and 36 corresponding lymph node metastases. Results: Scoring was performed by counting the percentages of positive cells and the percentages of positive areas. One hundred and one (51%) cases showed ≤5% positive cells and 99 (49%) >5% positive cells. One hundred and two (51%) cases showed ≤30% positive area and 98 (49%) >30% positive area. ST3 expression determined by both scoring methods was individually related to females, distally located tumors, infiltrative growth pattern and microsatellite stability. No relationship was found with age, Dukes' stage, differentiation and survival. Conclusions: These results suggest that ST3 protein was more involved in the pathway of colorectal cancer development in females, distal locations, infiltrative growth patterns and microsatellite stability. Copyright © 2004 S. Karger AG, Basel.

  • 161. Stenmark Askmalm, Marie
    et al.
    Carstensen, John
    Linköping University, Department of Department of Health and Society.
    Nordenskjöld, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Olsson, Birgit
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Rutqvist, Lars Erik
    Skoog, Lambert
    Stål, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Mutation and accumulation of p53 related to results of adjuvant therapy of postmenopausal breast cancer patients2004In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 43, no 3, p. 235-244Article in journal (Refereed)
    Abstract [en]

    p53 protein accumulation and gene mutation have been implicated in resistance to cytotoxic treatment. This study was performed to further assess the predictive value of p53 in breast cancer. Postmenopausal patients were randomized to adjuvant chemotherapy with cyclophosphamide, metothrexate, or 5-fluorouracil (CMF) vs. Postoperative radiotherapy. The patients were also randomized to adjuvant tamoxifen vs. No endocrine treatment. Immunohistochemistry (IHC) and single-strand conformation polymorphism (SSCP), followed by direct sequencing, was performed. The p53 altered group, regarded as positive for p53 gene mutation and/or p53 protein accumulation, tended to benefit more from CMF than from radiotherapy as compared with others regarding distant recurrences. In the group lacking p53 alteration there was a significantly decreased local recurrence rate in the radiotherapy group as compared with the CMF group (RR = 0.24, 95% CI = 0.083-0.62), whereas no benefit from radiotherapy was found for patients snowing p53 alterations. Tamoxifen significantly decreased the rate of distant recurrence for estrogen receptor-positive patients with no apparent difference in relation to p53 alteration. It is suggested that p53 alteration indicates benefit from CMF compared with radiotherapy regarding distant recurrence-free survival and the best local control with radiotherapy is achieved in the absence of p53 alteration. Finally, altered p53 status is probably not a marker of resistance to tamoxifen.

  • 162.
    Stenmark-Askmalm, Askmalm Marie
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    p53 Alterations in Breast Cancer Related to Prognosis and Results of Therapy1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Breast cancer is the most common malignant tumour disease and also the main cause of cancer-related deaths among women. The lifetime risk in western countries is 10%. The basic treatment for a patient with a localised tumour is surgery. In addition, different pathobiological variables are considered and an estimation of the risk of recurrence is made before deciding whether adjuvant therapy should be recommended. This therapy can be chemotherapy, which mainly prevents distant recurrence, or radiotherapy, which is effective against local recurrence. The treatment can be combined with anti-oestrogen, which prevents distant recurrence among patients exhibiting an oestrogen-receptor-positive tumour. However, breast cancer remains the chief cause of cancerrelated deaths and there is a need· for further pathobiologica! variables that, at an early stage, both can be prognostic and predict the outcome of adjuvant therapy.

    The p53 gene and its product p53 have been shown to play a central role in tumour suppression by regulating the cell cycle or initiating apoptosis. Certain mutations are associated with a stabilisation of the protein, leading to an accumulation that is detectable by immunohistochemistry.

    The main purposes of this study were to analyse p53 protein accumulation and gene mutation in exons 5-8 and to investigate the prognostic and predictive role of p53.

    p53 protein accumulation was investigated with immunohistochemistry in frozen tumour samples from 776 patients; 164 patients with stage U, 205 patients with stage I and 407 patients with either lymph node metastases and/or a tumour diameter exceeding 30mm. Of the latter, 139 were premenopausal and 268 were postmenopausal. These 407 patients had been randomiscd to adjuvant CMF chemotherapy or postoperative radiotherapy. Gene analyses with PCR-SSCP followed by direct sequencing were performed in the 268 postmenopausal patients. The predictive value of p53 was only analysed in the randomised patient material.

    The results showed that nuclear p53 accumulation ranged between 9% and 25%. p53 accumulation was significantly associated with several pathobiological variables, "indicating an aggressive tumour, which was more likely to be oestrogen receptor negative, DNA aneuploid, and have a high S-phase fraction. p53 accumulation was also significantly correlated with an increased rate of distant recurrence, whereas mutations that were found in 16% of the 268 cases investigated were not significantly correlated with an increased risk of distant recurrence. However, the investigation of both protein accumulation and gene mutation in exons 5-8 contributed further information than was achieved with one of the methods alone. The protein accumulation reflected to a certain extent mutations of the gene, mainly missense mutations. A majority of the severe mutations that included alteration of the reading frame did not lead to any protein accumulation. Sixty-one per cent of the tumours exhibiting protein accumulation did not show any mutation in exons 5-8. Subgroups of different p53 alteration patterns seemed to be related to different prognoses.

    The patients with p53 altered tumours, either showing protein accumulation, gene mutation or both, benefited significantly from CMF chemotherapy compared with the radiotherapy group. This benefit could not be seen among the patients without p53 alterations. The test for interaction between p53 status and relative rate was significant. This response was most pronounced among premenopausal patients. Postmenopausal patients seemed to benefit although not significantly.

    In conclusion, the present study suggests that p53 accumulation is a prognostic factor associated with an increased risk of distant recurrence. p53 alteration defined as protein accumulation, gene mutation in exons 5-8, or both, was a predictor of good response to CMF chemotherapy as compared to postoperative radiotherapy. This benefit could not be seen among patients without p53-altered tumours.

  • 163.
    Stenmark-Askmalm, Askmalm Marie
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Gentile, Massimiliano
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Arnesson, Lars-Gunnar
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Protein accumulation and gene mutation of p53 in bilateral breast cancer2001In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 40, no 1, p. 56-62Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the frequency of p53 alterations in bilateral breast cancer and to evaluate a possible clonal relationship between the paired tumours regarding p53 alteration and other pathobiological variables. Tumours from 34 patients were investigated with immunohistochemistry, single strand conformation polymorphism analysis and DNA-sequence analysis applied to exons 5-8. Fifteen percent of the 68 tumours showed positive immunoreaction and/or presence of mutation. The occurrence of p53 accumulation was 9% and the prevalence of gene mutation 10%. No significant concordance was found between the tumours in the same patient for p53 alterations, progesterone receptor status or DNA ploidy. S-phase fraction showed a weak correlation, not statistically significant. Oestrogen receptor status was the only variable that exhibited a significant concordance. No convincing evidence was found for other associations between the paired tumours or for a high prevalence of p53 alterations in bilateral breast cancer.

  • 164. Storlazzi, Clelia T
    et al.
    Fioretos, Thoas
    Paulsson, Kajsa
    Strömbeck, Bodil
    Lassen, Carin
    Ahlgren, Tomas
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Mitelman, Felix
    Rocchi, Mariano
    Johansson, Bertil
    Identification of a commonly amplified 4.3 Mb region with overexpression of C8FW, but not MYC in MYC-containing double minutes in myeloid malignancies2004In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 13, no 14, p. 1479-1485Article in journal (Refereed)
    Abstract [en]

    Double minutes (dmin), the cytogenetic hallmark of genomic amplification, are found in ∼1% of karyotypically abnormal acute myelold leukemias (AML) and myelodysplastic syndromes (MDS). The MYC gene at 8q24 has been reported to be amplified in the majority of the cases, and generally it has been assumed that MYC is the target gene. However, only a few studies have focused on the extent of the amplicon or on the expression patterns of the amplified genes. We have studied six cases (five AML and one MDS) with MYC-containing dmin. Detailed fluorescence in situ hybridization analyses identified a common 4.3 Mb amplicon, with clustered proximal and distal breakpoints, harboring eight known genes (C8FW, NSE2, POU5FLC20, MYC, PVT1, AK093424, MGC27434 and MLZE). The corresponding region was deleted in one of the chromosome 8 homologues in five of the six cases, suggesting that the dmin originated through extra replication (or loop-formation)-excision-amplification. Northern blot analysis revealed that MYC was not overexpressed. Instead, the C8FW gene, encoding a phosphoprotein regulated by mitogenic pathways, displayed increased expression. These results exclude MYC as the target gene and indicate that overexpression of C8FW may be the functionally important consequence of 8q24 amplicons in AML and MDS. © Oxford University Press 2004, all rights reserved.

  • 165.
    Stål, Olle
    Linköping University, Department of Biomedical Engineering. Linköping University, The Institute of Technology. Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Static and flow cytometry for tumor DNA analysis1989Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The analysis of cellular DNA content in human tumors has shown to be of prognostic importance. The techniques used involve measurements in slide preparations by absorption cytophotometry and static cytofluorometry as well as the analysis of cell suspensions by flow cytometry. The aim of this work has been to improve these techniques by the development of computer aided systems in order to facilitate the use in a larger scale for clinical purposes. Another aim has been to study the prognostic significance of DNA analysis in breast cancer.

    Software for determination of DNA content and nuclear area by scanning absorption cytophotometry was developed. The system, HISTOSCAN, is insensitive to light scattering and may therefore be used in tissue sections. Thus, measurements in morphologically well-defined areas may be performed, but the method is less suitable for extensive use due to the slow procedure of the mechanical scanning.

    More rapid analyses are achieved by the system developed for static cytofluorometry in cytocentrifuged specimens. Cells to be measured are not positioned in the ordinary way, but are just passed through the excitation light beam as the specimen is visually scanned. DNA content and nuclear size are estimated simultaneously from the fluorescence recorded. For estimation of proliferative activity a sufficient number of cells may be analysed within a reasonable time.

    Similar results were obtained by static cytofluorometry and flow cytometry in a series of primary breast cancers. A close correlation was found for DNA index and, if 200 cells or more were measured, the same was true for S-phase fraction.

    Tumors from 472 women with primary breast cancer were analysed by flow cytometry. DNA ploidy showed significant association with disease recurrence and mortality but did not show a prognostic value in addition to that of traditional factors. The prognostic significance of S-phase fraction was independent of nodal status, tumor size and estrogen receptor content concerning early relapse and mortality. The survival of 116 women with recurrent breast cancer was correlated with both DNA ploidy and S-phase fraction in a multivariate analysis including nodal status, tumor size, ER content and site of recurrence.

  • 166.
    Stål, Olle
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Borg, Å
    Department of Oncology, University Hospital Lund, Sweden.
    Fernö, M
    Department of Oncology, University Hospital Lund, Sweden.
    Källström, Ann-Christine
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Malmström, P
    Department of Oncology, University Hospital Lund, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer2000In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 11, no 12, p. 1545-1550Article in journal (Refereed)
    Abstract [en]

    Aim:We aimed to study the importance of erbB2 status in early stage postmenopausal breast cancer for patients who participated in a trial of five vs. two years of adjuvant tamoxifen.

    Patients and methods: We analysed the erbB2 status of the tumours from 577 patients participating in the trial, either by a DNA amplification assay (n=181) or by measurement of the protein level with flow cytometry (n=396).

    Results: ErbB2 was overexpressed or gene amplified in 102 of the patients (18%). Overall, erbB2-positive patients had a significantly lower recurrence-free probability than others, 62% at five years as compared to 83%, and showed a significantly decreased breast cancer survival rate (P=0.0007). ErbB2 status was significantly associated with recurrence and death in Cox multivariate analysis, adjusting for nodal status, tumour size and estrogen receptor status. The relative risk of recurrence (RR) for five vs. two years of tamoxifen was analysed in relation to erbB2 status for patients still disease-free two years after surgery. Whereas erbB2-negative patients showed significant benefit from prolonged treatment (RR=0.62, 95% confidence interval (95% CI): 0.42–0.93), no benefit was evident for erbB2-positive patients (RR=1.1, 95% CI: 0.41–3.2). When the same analysis was restricted to ER-positive patients a similar difference in relative hazard was obtained but the difference was not strictly significant (P=0.065).

    Conclusions: For early stage breast cancer patients treated with adjuvant tamoxifen, overexpression of erbB2 is an independent marker of poor prognosis. The results suggest that overexpression decreases the benefit from prolonged tamoxifen treatment.

  • 167.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Clinicopathological and biological features of DNA tetraploid colorectal cancers2006In: Cancer Journal, ISSN 0765-7846, E-ISSN 1292-8658, Vol. 12, no 6, p. 501-506Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Most studies of colorectal cancers focus on a comparison of DNA diploid to non-diploid tumors consisting of tetraploid and aneuploid tumors. Tetraploid tumors alone have not been well studied. In the present study, clinicopathological and biological features of tetraploid colorectal cancers in contrast to those of diploid and aneuploid ones were investigated. PATIENTS AND METHODS: DNA ploidy in 278 primary colorectal adenocarcinomas was determined by flow cytometry. RESULTS: Among 278 cases, 8% of the cases were tetraploidy, 44% were aneuploidy, and 48% were diploidy. Compared to diploid tumors, tetraploid tumors were more frequent in advanced stage, high index of S-phase fraction and apoptosis, higher expression of Cox-2, c-erbB-2 and heat shock protein, but had decreased inflammatory infiltration (P < 0.05). Compared to aneuploid tumors, tetraploid tumors had a high frequency of microsatellite instability, high expression of Cox-2 and heat shock protein (P < 0.05). Unlike tetraploid tumors, aneuploid tumors had increased p53 expression but did not have microsatellite instability (P < 0.05). Tetraploidy and aneploidy predicted a worse prognosis in the subgroups of stages A-C, proximal colon, p53 negative expression and higher S-phase fraction (P < 0.05). CONCLUSIONS: DNA tetraploid tumors seem, to some extent, to exhibit distinct characteristics of clinicopathology and biology compared with aneuploid or diploid colorectal cancers. Copyright © 2006 Jones and Bartlett Publishers, Inc.

  • 168.
    Sun, Xiao-Feng
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Expression of ras and p53, DNA ploidy and 5-phase fraction in human colorectal adenocarcinoma1993Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The accumulation of oncogene and anti-oncogene alterations play an important role in the development of colorectal adenocarcinomas. These specific gene alterations cause changes of DNA ploidy and cell proliferation and, in turn, DNA instability might lead to more genetic changes. In the present work, the expression of ras p21 (79 cases) and p53 protein (293 cases) was investigated by immunohistochemistry, and DNA ploidy and S-phase fraction (279 cases) were measured by flow cytometry on colorectal adenocarcinomas.

    Overexpression of ras p21, nuclear and cytoplasmic p53 were found in 58%, 39% and 25% of the tumours, respectively, while in normal colorectal cases, only 35% were ras positive and no case showed p53 staining. Overexpression of ras was significantly associated with a high S-phase fraction. The frequencies of ras and nuclear p53 staining tended to be increased in DNA non-diploid tumours compared with diploid tumours. Cytoplasmic p53 positive tumours were more common in the proximal colon, while DNA non-diploid tumours were more frequent in the distal colon and rectum. The intensity of ras staining was significantly related to grade of differentiation and increased from Dukes' stage A to C tumours. Cytoplasmic p53 staining increased from Dukes' stage A to D tumours. In multivtiriate survival analyses of patients with Dukes' stage A-C tumours, the prognosticsignificance of ras expression remained even after adjustment for both stage and DNA ploidy. Nuclear p53 and cytoplasmic p53 staining prognosticated clinical Outcome independent of stage, DNA ploidy and each other. DNA non-diploidy predicted an unfavourable survival irrespective of stage, nuclear and cytoplasmic p53 expression. A highS-phase fraction was significantly associated with poor survival in univariate analysis but not after adjustment for other prognostic factors. Analyses in subgroups of tumours showed that the prognostic importance of cytoplasmic p53 expressionwas greater in patients with DNA diploid tumours than in those with non·diploid tumours, and that DNA ploidy exhibited prognostic effect in patients with Dukes' stage B tumours as well as in those with stage C tumours. We conclude that immunohistochemistry and flow cytometry may be used to detect overexpression ofras p21, nuclear p53 and cytoplasmic p53 as wellas abnormal DNA content, and that these alterations may be implicated in different biological mechanisms of colorectal adenocarcinomas and provide important prognostic information.

  • 169.
    Sun, Xiao-Feng
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Ahmadi, Ahmad
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Arbman, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Wallin, Åsa
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Asklid, Daniel
    Zhang, Hong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology.
    Polymorphisms in sulfotransferase 1A1 and glutathione S-transferase P1 genes in relation to colorectal cancer risk and patients' survival2005In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 11, no 43, p. 6875-6879Article in journal (Refereed)
    Abstract [en]

    Aim: To examine whether polymorphisms in SULT1A1 and GSTP1 genes contribute to colorectal cancer development and whether they are associated with clinicopathological variables are not well identified. Methods: We examined the genotypes of 125 colorectal cancer patients and 666 healthy controls in a Swedish population by using PCR restriction fragment length polymorphism (RFLP). Results: SULT1A1 *2/*2 genotype (OR = 2.49, 95%CI = 1.48-4.19, P = 0.0002) and *2 allele (OR = 1.56, 95%CI = 1.16-2.10, P = 0.002) had an effect on colorectal cancer susceptibility, while GSTP1 genotype was without effect. However, GSTP1 G-type predicted a worse prognosis in the patients independently of gender, age, Dukes' stage, growth pattern, and differentiation (P = 0.03). Conclusion: Polymorphism in SULT1A1 may predispose to colorectal cancer and GSTP1 may be a biological indicator of prognosis in the patients. © 2005 The WJG Press and Elsevier Inc. All rights reserved.

  • 170.
    Sun, Xiao-Feng
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Bartik, Zsuzsa
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Zhang, Hong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Dermatology.
    Bcl-2 expression is a prognostic factor in the subgroups of patients with colorectal cancer.2003In: International Journal of Oncology, ISSN 1019-6439, Vol. 23, no 5, p. 1439-1443Article in journal (Refereed)
    Abstract [en]

    The prognostic significance of Bcl-2 expression in colorectal cancer has been intensively studied, however, the results were controversial in the whole group of colorectal cancer patients. We proposed that one of the main reasons for such controversial results may be that Bcl-2 played variable roles in the subgroup of patients. We, therefore, investigated the prognostic importance of Bcl-2 expression by using immunohistochemistry in the various subgroups of 147 patients with colorectal cancer. Among these tumours, 85 (58%) expressed Bcl-2 protein and 62 (42%) were negative. Bcl-2 expression was positively related to DCC expression (p=0.0002). Survival analyses in the subgroups of the patients showed that lack of Bcl-2 expression was related to a worse prognosis in the male patients (p=0.02) but not in female patients (p=0.53), in the patients with DNA diploid tumours (p=0.005) not in the patients with non-diploid tumours (p=0.46), and in the patients with ras negative tumours (p=0.01) not in the patients with ras positive tumours (p=0.25). Bcl-2 expression was not related to prognosis in the total group of the patients (p=0.20). In conclusion, Bcl-2 protein may play variable prognostic roles in the subgroups of the patients with colorectal cancer. Analysis of Bcl-2 expression in the tumour may be of value in predicting prognosis and therapeutic response.

  • 171.
    Sun, Xiao-Feng
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Ekberg, Hanna
    Zhang, Hong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology.
    Carstensen, John
    Linköping University, Faculty of Arts and Sciences. Linköping University, The Tema Institute.
    Nordenskjöld, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Overexpression of ras is an independent prognostic factor in colorectal adenocarcinoma1998In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 106, no 6, p. 657-664Article in journal (Refereed)
  • 172.
    Sun, Xiao-Feng
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Rütten, Sabine
    Zhang, Hong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Nordenskjöld, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Expression of the deleted in colorectal cancer gene is related to prognosis in DNA diploid and low proliferative colorectal adenocarcinoma.1999In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 17, p. 1745-1750Article in journal (Refereed)
  • 173.
    Sun, Xiao-Feng
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Zhang, Hong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology.
    Clinicopathological significance of stromal variables: Angiogenesis, lymphangiogenesis, inflammatory infiltration, MMP and PINCH in colorectal carcinomas2006In: Molecular Cancer, ISSN 1476-4598, E-ISSN 1476-4598, Vol. 5Article in journal (Refereed)
    Abstract [en]

    Cancer research has mainly focused on alterations of genes and proteins in cancer cells themselves that result in either gain-of-function in oncogenes or loss-of-function in tumour-suppressor genes. However, stromal variables within or around tumours, including blood and lymph vessels, stromal cells and various proteins, have also important impacts on tumour development and progression. It has been shown that disruption of stromal-epithelial interactions influences cellular proliferation, differentiation, death, motility, genomic integrity, angiogenesis, and other phenotypes in various tissues. Moreover, stromal variables are also critical to therapy in cancer patients. In this review, we mainly focus on the clinicopathological significance of stromal variables including angiogenesis, lymphangiogenesis, inflammatory infiltration, matrix metalloproteinase (MMP), and the particularly interesting new cysteine-histidine rich protein (PINCH) in colorectal cancer (CRC). © 2006 Sun and Zhang, licensee BioMed Central Ltd.

  • 174.
    Sun, Xiao-Feng
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Zhang, Hong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology.
    NFKB and NFKBI polymorphisms in relation to susceptibility of tumour and other diseases2007In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 22, no 10-12, p. 1387-1398Article in journal (Refereed)
    Abstract [en]

    Nuclear factor-κB (NF-κB) is responsible for the expression by regulating many genes for immune response, cell adhesion, differentiation, proliferation, angiogenesis and apoptosis. The function of NF-κB is inhibited by binding to NF-κB inhibitor (IκB), and imbalance of NF-κB and IκB has been associated with development of many diseases, including tumours. In this review, we focus on polymorphisms of the NFKB and NFKBI genes in relation to development of common inflammatory diseases including ulcerative colitis (UC), Crohn's disease (CD), rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, giant cell arthritis, type 1 diabetes, multiple sclerosis, celiac disease, and Parkinson's disease, as well as susceptibility of several cancers, such as oral squamous cell carcinoma, colorectal cancer (CRC), hepatocellular carcinoma, breast cancer and myeloma.

  • 175.
    Sundquist, Marie
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Prognostic Factors in Breast Cancer2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Breast cancer is increasing in the industrialised countries. Due to early detection and adjuvaut treatment with radiotherapy, hormones and chemotherapy, mortality has decreased. The different adjuvant treatments have adverse effects. It is an important task is to estimate the risk of recurrence for the individual patient in order to tailor her individual treatment. This thesis aims at identifying predictors for disease development in primary and disseminated breast cancer.

    Histologic grade was strongly correlated to breast cancer mortality in 630 patients with primary breast cancer. The combination of grade, tumour size and lymph node status in the Nottingham Prognostic Index provides a powerful instrument separating patients in groups with excellent, good, intermediate and poor prognosis.

    Grade was more sensitive than S-phase fraction in identifying high risk patients and patients with very good prognosis.

    Presence of cancer cells in blood- and lymph vessels close to the tumour in patients with grade 3 tumours increased the risk oflocoregional recurrence 6-fold as compared to patients with grade 1 or 2 tumours without such vascular invasion.

    The mortality of young women with breast cancer has decreased very little since 1960. Women under 37 years of age had increased tumour size, more metastatic lymph nodes and doubled rate of high grade tumours as compared to older women.

    Disease-free interval and survival in patients with distant recurrence were strongly associated to histologic grade and hormone receptor content. Patients with grade 3, hormone receptor negative tumours had a median survival of 10 months after recurrence while only 15 % of women with receptor positive, grade 1 tumours have so far died after a median follow-up time of 5 years after recurrence.

    The Nottingham Prognostic Index and assessments of presence of tmnour cells in vessels provide important information about the risk oflocoregional and distant recurrence in breast cancer. Treatment decisions, counselling and follow-up programmes should be based on such assessments. For patients with metastatic breast cancer, tumour grade, estrogen receptor status and serum-c-erbB-2 predict the course of the disease.

    List of papers
    1. Applying the Nottingham Prognostic Index to a Swedish breast cancer population
    Open this publication in new window or tab >>Applying the Nottingham Prognostic Index to a Swedish breast cancer population
    1999 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 53, no 1, p. 1-8Article in journal (Refereed) Published
    Abstract [en]

    The aim of this study was to assess the applicability of histopathological grading according to the protocol of Elston/Ellis and the Nottingham Prognostic Index (NPI) to a defined breast cancer population. The NPI is the sum of the individual scores concerning grade, tumour size, and lymph node status, each weighted according to regression coefficients of a Cox proportional hazard analysis and calculated for each individual breast cancer patient. 630 consecutive patients with invasive breast cancer diagnosed 1988–91 were retrospectively followed up and their tumours reviewed and graded. A Cox proportional hazard analysis was performed. Grade, lymph node status, and tumour size were statistically significant predictors of survival within the follow up period (median 7.2 years). Similar to NPI, a temporary index (Kalmar Prognostic Index, KPI) was derived and normalised to NPI for comparison (KPI(norm)). NPI and KPI(norm) gave similar prognostic power in spite of the differences of the patient populations from which the 2 indices were derived. Patients with NPI 4 or less had 0.66% breast cancer specific mortality during the follow up time. 14% of the patients with NPI 4.1–5 and 32% of those with an index sum 5.1–6 died from breast cancer during this time. Younger patients tended to have higher grade tumours. We advocate the common use of grade and the NPI in order to increase the comparability of groups of patients receiving different therapies.

    Keywords
    breast cancer, histopathological grade, Nottingham Prognostic Index, prognosis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25294 (URN)10.1023/A:1006052115874 (DOI)9734 (Local ID)9734 (Archive number)9734 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    2. A comparison between flow cytometric assessment of S-phase fraction and Nottingham histologic grade as prognostic instruments in breast cancer
    Open this publication in new window or tab >>A comparison between flow cytometric assessment of S-phase fraction and Nottingham histologic grade as prognostic instruments in breast cancer
    Show others...
    2000 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 63, no 1, p. 11-15Article in journal (Refereed) Published
    Abstract [en]

    Flow cytometric DNA analysis with assessment of S-phase fraction and DNA ploidy was compared to Nottingham histologic grade. The study population consisted of 654 patients who presented between 1987 and 1996 with primary operable breast cancer and whose tumours had been analysed for S-phase fraction and DNA ploidy at the time of surgery. Grade, tumour size, node status, steroid receptor status, age, S-phase fraction and DNA ploidy were analysed univariately and multi-variately in a Cox proportional hazard analysis. In the univariate analyses all parameters were statistically significantly associated with breast cancer mortality during the follow-up period of 2–11 years. The most powerful predictor of death from breast cancer in the multiple regression analysis was grade. Patients with grade 1 tumours have excellent prognosis. We conclude that tumour grade is a strong prognostic indicator applicable to all breast cancer patients, regardless of size and nodal status, and advocate its general use.

    Keywords
    breast cancer, prognosis, Nottingham histologic grade, S-phase fraction
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25288 (URN)10.1023/A:1006494625644 (DOI)9728 (Local ID)9728 (Archive number)9728 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    3. Indicators of loco-regional recurrence in breast cancer
    Open this publication in new window or tab >>Indicators of loco-regional recurrence in breast cancer
    Show others...
    2000 (English)In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 26, no 4, p. 357-362Article in journal (Refereed) Published
    Abstract [en]

    Aim: The aim of the investigation was to contribute to the identification of patients who have increased or decreased risk of loco-regional recurrence.

    Methods: Six hundred and twenty-nine consecutive patients with primary breast cancer diagnosed between 1988 and 1990 were studied. Two-thirds of the patients underwent mastectomy. Radiotherapy was administered if patients were node positive or breast conserved. The Nottingham histological grading protocol was used and presence of lymphovascular invasion was assessed. Investigated parameters were: age, size, grade, steroid receptor content, surgical radicality, vascular invasion and nodal status. Statistically significant risk factors for loco-regional recurrence using univariate or Cox proportional hazard analysis were grade and lymphovascular invasion.

    Results: Women with grade 1-2, node-negative tumours without vascular invasion had a very low loco-regional recurrence rate - 3.1%. Seventeen percent of patients with grade 3 tumours and vessel invasion had loco-regional recurrence.

    Conclusions: Our findings, and those of others, indicate that the use of adjuvant radiotherapy should be influenced to a greater extent by grade and lymphovascular invasion.

    Keywords
    breast cancer, recurrence, lymphovascular invasion, Nottingham histological grade
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25179 (URN)10.1053/ejso.1999.0898 (DOI)9616 (Local ID)9616 (Archive number)9616 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    4. Incidence and prognosis in early onset breast cancer
    Open this publication in new window or tab >>Incidence and prognosis in early onset breast cancer
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    2002 (English)In: Breast, ISSN 0960-9776, E-ISSN 1532-3080, Vol. 11, no 1, p. 30-35Article in journal (Refereed) Published
    Abstract [en]

    The aim of this study was to assess the incidence and prognosis in early onset breast cancer. Age-adjusted incidence and death rate for the 5394 Swedish women diagnosed with breast cancer under the age of 40 between 1960 and 1996 was studied using data from the Swedish Cancer Registry and Swedish Death Cause Registry. A total of 107 consecutive young patients with invasive breast cancer undergoing surgery during 1980–1993 in the Southeast Swedish health care region were retrospectively followed up and their cancers reviewed and graded blindly. The median follow-up time was 11.2 years. The applicability of the Nottingham Prognostic Index (NPI) as a prognostic tool was investigated. Grade, age, node status, tumour size, S-phase fraction and steroid receptor content were related to survival univariately and multivariately in a Cox proportional hazard analysis.

    The incidence of early onset breast cancer has increased moderately and the survival rate has not improved during the last 35 years. When young women are diagnosed with breast cancer their tumours are larger, their lymph nodes more often involved, and the median grade higher than in older with 64% having grade 3 tumours. Lymph node status was the strongest sole prognostic indicator but the use of NPI gave more accurate prognostic information than node status alone.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-28170 (URN)10.1054/brst.2001.0358 (DOI)12986 (Local ID)12986 (Archive number)12986 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    5. Disease free interval and survival after dissemination of breast cancer
    Open this publication in new window or tab >>Disease free interval and survival after dissemination of breast cancer
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Tumour and patients characteristics were analysed and correlated to disease development in 184 women who were consecutively diagnosed with systemic breast cancer. Nottingham histologic grade (NHG) and steroid receptor content were significantly associated with disease-free interval and survival after dissemination. In the multiple regression analysis, NHG was the strongest predictor. Patients with tumours of grade 1 had median disease-free interval of 8,9 years; tumours of grade 2 4,4 years and patients with grade 3 tumours 1,8 years. Grade 2 patients had a median survival after dissemination of 2,6 years and patients with grade 3 tumours 1,2 years. Only 1 of the 12 grade 1 patients are so far diseased. 85 patients participated in a prospective trial assessing the value of serum cerbb-2 as prognostic indicator. Patients with high serum-cerbb-2 levels when distant disease was diagnosed had a more rapid disease development.

    Tumour grade was associated with disease-free interval and post-recurrence survival. Follow up progranunes could be differentiated according to tumour grade.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79570 (URN)
    Available from: 2012-08-09 Created: 2012-08-09 Last updated: 2012-08-09Bibliographically approved
  • 176.
    Sundquist, Marie
    et al.
    Department of Surgery, County Hospital, Kalmar, Sweden.
    Nilsson, I.
    Department of Clinical Chemistry, County Hospital, Kalmar, Sweden.
    Thorstenson, Sten
    Department of Cytology and Pathology, County Hospital, Kalmar, Sweden.
    Brudin, Lars
    Department of Physiology, County Hospital, Kalmar, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Disease free interval and survival after dissemination of breast cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Tumour and patients characteristics were analysed and correlated to disease development in 184 women who were consecutively diagnosed with systemic breast cancer. Nottingham histologic grade (NHG) and steroid receptor content were significantly associated with disease-free interval and survival after dissemination. In the multiple regression analysis, NHG was the strongest predictor. Patients with tumours of grade 1 had median disease-free interval of 8,9 years; tumours of grade 2 4,4 years and patients with grade 3 tumours 1,8 years. Grade 2 patients had a median survival after dissemination of 2,6 years and patients with grade 3 tumours 1,2 years. Only 1 of the 12 grade 1 patients are so far diseased. 85 patients participated in a prospective trial assessing the value of serum cerbb-2 as prognostic indicator. Patients with high serum-cerbb-2 levels when distant disease was diagnosed had a more rapid disease development.

    Tumour grade was associated with disease-free interval and post-recurrence survival. Follow up progranunes could be differentiated according to tumour grade.

  • 177.
    Sundquist, Marie
    et al.
    Department of Surgery, County Hospital, Kalmar, Sweden.
    Thorstenson, Sten
    Department of Cytology and Pathology, County Hospital, Kalmar, Sweden.
    Brudin, Lars
    Department of Physiology, County Hospital, Kalmar, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Applying the Nottingham Prognostic Index to a Swedish breast cancer population1999In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 53, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to assess the applicability of histopathological grading according to the protocol of Elston/Ellis and the Nottingham Prognostic Index (NPI) to a defined breast cancer population. The NPI is the sum of the individual scores concerning grade, tumour size, and lymph node status, each weighted according to regression coefficients of a Cox proportional hazard analysis and calculated for each individual breast cancer patient. 630 consecutive patients with invasive breast cancer diagnosed 1988–91 were retrospectively followed up and their tumours reviewed and graded. A Cox proportional hazard analysis was performed. Grade, lymph node status, and tumour size were statistically significant predictors of survival within the follow up period (median 7.2 years). Similar to NPI, a temporary index (Kalmar Prognostic Index, KPI) was derived and normalised to NPI for comparison (KPI(norm)). NPI and KPI(norm) gave similar prognostic power in spite of the differences of the patient populations from which the 2 indices were derived. Patients with NPI 4 or less had 0.66% breast cancer specific mortality during the follow up time. 14% of the patients with NPI 4.1–5 and 32% of those with an index sum 5.1–6 died from breast cancer during this time. Younger patients tended to have higher grade tumours. We advocate the common use of grade and the NPI in order to increase the comparability of groups of patients receiving different therapies.

  • 178.
    Sundquist, Marie
    et al.
    Department of Surgery, County Hospital, Kalmar, Sweden.
    Thorstenson, Sten
    Department of Cytology and Pathology, County Hospital, Kalmar, Sweden.
    Brudin, Lars
    Department of Physiology, County Hospital, Kalmar, Sweden.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    A comparison between flow cytometric assessment of S-phase fraction and Nottingham histologic grade as prognostic instruments in breast cancer2000In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 63, no 1, p. 11-15Article in journal (Refereed)
    Abstract [en]

    Flow cytometric DNA analysis with assessment of S-phase fraction and DNA ploidy was compared to Nottingham histologic grade. The study population consisted of 654 patients who presented between 1987 and 1996 with primary operable breast cancer and whose tumours had been analysed for S-phase fraction and DNA ploidy at the time of surgery. Grade, tumour size, node status, steroid receptor status, age, S-phase fraction and DNA ploidy were analysed univariately and multi-variately in a Cox proportional hazard analysis. In the univariate analyses all parameters were statistically significantly associated with breast cancer mortality during the follow-up period of 2–11 years. The most powerful predictor of death from breast cancer in the multiple regression analysis was grade. Patients with grade 1 tumours have excellent prognosis. We conclude that tumour grade is a strong prognostic indicator applicable to all breast cancer patients, regardless of size and nodal status, and advocate its general use.

  • 179.
    Sundquist, Marie
    et al.
    Department of Surgery, County Hospital, Kalmar, Sweden.
    Thorstenson, Sten
    Department of Cytology and Pathology, County Hospital, Kalmar, Sweden.
    Brudin, Lars
    Department of Cytology and Pathology, County Hospital, Kalmar, Sweden.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Incidence and prognosis in early onset breast cancer2002In: Breast, ISSN 0960-9776, E-ISSN 1532-3080, Vol. 11, no 1, p. 30-35Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to assess the incidence and prognosis in early onset breast cancer. Age-adjusted incidence and death rate for the 5394 Swedish women diagnosed with breast cancer under the age of 40 between 1960 and 1996 was studied using data from the Swedish Cancer Registry and Swedish Death Cause Registry. A total of 107 consecutive young patients with invasive breast cancer undergoing surgery during 1980–1993 in the Southeast Swedish health care region were retrospectively followed up and their cancers reviewed and graded blindly. The median follow-up time was 11.2 years. The applicability of the Nottingham Prognostic Index (NPI) as a prognostic tool was investigated. Grade, age, node status, tumour size, S-phase fraction and steroid receptor content were related to survival univariately and multivariately in a Cox proportional hazard analysis.

    The incidence of early onset breast cancer has increased moderately and the survival rate has not improved during the last 35 years. When young women are diagnosed with breast cancer their tumours are larger, their lymph nodes more often involved, and the median grade higher than in older with 64% having grade 3 tumours. Lymph node status was the strongest sole prognostic indicator but the use of NPI gave more accurate prognostic information than node status alone.

  • 180.
    Sundquist, Marie
    et al.
    Department of Surgery, County Hospital, Kalmar, Sweden.
    Thorstenson, Sten
    Department of Cytology and Pathology, County Hospital, Kalmar, Sweden.
    Klintenberg, Claes
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Brudin, Lars
    Department of Physiology, County Hospital, Kalmar, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Indicators of loco-regional recurrence in breast cancer2000In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 26, no 4, p. 357-362Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of the investigation was to contribute to the identification of patients who have increased or decreased risk of loco-regional recurrence.

    Methods: Six hundred and twenty-nine consecutive patients with primary breast cancer diagnosed between 1988 and 1990 were studied. Two-thirds of the patients underwent mastectomy. Radiotherapy was administered if patients were node positive or breast conserved. The Nottingham histological grading protocol was used and presence of lymphovascular invasion was assessed. Investigated parameters were: age, size, grade, steroid receptor content, surgical radicality, vascular invasion and nodal status. Statistically significant risk factors for loco-regional recurrence using univariate or Cox proportional hazard analysis were grade and lymphovascular invasion.

    Results: Women with grade 1-2, node-negative tumours without vascular invasion had a very low loco-regional recurrence rate - 3.1%. Seventeen percent of patients with grade 3 tumours and vessel invasion had loco-regional recurrence.

    Conclusions: Our findings, and those of others, indicate that the use of adjuvant radiotherapy should be influenced to a greater extent by grade and lymphovascular invasion.

  • 181. Sörensen, Peter
    et al.
    Höjer, Morten
    Jakobsen, Anders
    Malmström, Henric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Havsteen, Hanne
    Bertelsen, Kamma
    Phase II study of vinorelbine in the treatment of platinum-resistant ovarian carcinoma2001In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 81, no 1, p. 58-62Article in journal (Refereed)
    Abstract [en]

    Objective. The purpose of this phase II study was to evaluate on an intent-to-treat basis the activity and toxicity of single-agent vinorelbine (VRL) as second-line chemotherapy of patients with platinum-resistant ovarian cancer. Platinum-resistant disease was defined as disease refractory to or relapsing within 12 months after finishing platinum-containing chemotherapy. Methods. VRL (30 mg/m2) was administered intravenously as a bolus injection days 1 and 8 every 21 days. Initially, four courses of VRL were given. Patients with responding or stable disease received four more courses of VRL to a maximum of eight courses. Results. Twenty-eight of 33 eligible patients were considered evaluable for response. The overall response rate was 21% (7/33) (95% CI: 7-35). Median time to progression was 3.1 months and median survival was 10.1 months. Toxicity was generally mild. Leukopenia was the dose-limiting toxicity. CALGB grade III/IV infection was observed in 15/0% of patients. The most important nonhematologic toxicities were nausea and constipation. Grade III/IV nausea was observed in 6/0% and grade III/IV constipation in 3/3% of patients. Peripheral neurotoxicity was only a minor problem with no grade III/IV toxicity. No patients stopped treatment because of toxicity and no toxic death was reported. Conclusion. VRL was generally well tolerated, but the activity in platinum-resistant ovarian cancer was only modest, although fully comparable to other second-line treatments. Further studies are required to define the role of VRL in combination chemotherapy for ovarian cancer.

  • 182. Taube, A
    et al.
    Högberg, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Med P: n som i "programpaket" - om studier av prognostiska faktorer2002In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 99, p. 3302-3305Article in journal (Other academic)
  • 183. Tejler, G
    et al.
    Norberg, B
    Dufmats, Monika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Nordenskjöld, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Arnesson, Lars-Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Survival after treatment for breast cancer in a geographically defined population2004In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 91, no 10, p. 1307-1312Article in journal (Refereed)
    Abstract [en]

    Background: South East Sweden with 976000 inhabitants is served by nine hospitals with specialized breast surgeons. Population-based mammographic screening was introduced in 1986 for women aged 40-74 years. Patients with primary breast cancer were treated according to a joint management programme. Methods: All patients were reported to a regional cancer registry from which breast cancer incidence, treatment and survival in this defined population were reported. Results: A total of 7892 women had their first invasive breast cancer diagnosed between 1986 and 1999. The median tumour size was 17 mm and 29.9 per cent had axillary metastases. Some 49.8 per cent of these women had a modified radical mastectomy and 31.9 per cent had a segmental resection with axillary clearance. Postoperative radiotherapy was given to 40.3 per cent of the women after mastectomy and to 87.1 per cent after breast-conserving surgery. Tamoxifen and chemotherapy were used as adjuvant treatment except in low-risk patients. Breast cancer-specific survival rate for all stages was 83.5 per cent at 5 years and 74.0 per cent at 10 years. Respective values were 95.8 and 90.9 per cent for patients with stage T1 N0 M0 tumours, and 77.7 and 62.4 per cent for those with T1-2 N1 M0 tumours. Conclusion: Breast specialists treating women with breast cancer according to a joint management programme have achieved very good survival rates.

  • 184. Tian, Chao
    et al.
    Zhou, Zong-Guang
    Meng, Wen-Jian
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Yu, Yong-Yang
    Li, Li
    Luo, Hong-Zhi
    Yang, Lie
    Zhou, Bin
    Gu, Jun
    Overexpression of connective tissue growth factor WISP-1 in Chinese primary rectal cancer patients2007In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 13, no 28, p. 3878-3882Article in journal (Refereed)
    Abstract [en]

    Aim: To clarify the expression change of Wnt-induced secreted protein-1 (WISP-1) in human rectal cancer and to determine whether it is correlated with invasion and metastasis of human rectal cancer. Methods: Eighty-six paired samples of rectal cancer and surgically resected distant normal rectal tissue were collected and allocated into cancer group and control group respectively. WISP-1 mRNA was detected by relative quantitative real-time RT-PCR and WISP-1 protein was examined by immunohistochemical staining. Results: WISP-1 gene overexpression was found in 65% (56/86) primary rectal cancers, 2-30 times that of the level in normal matched rectal tissues (P = 0.001). The mRNA expression level was correlated with Duke's staging, histological differentiation grade and lymph node status. The WISP-1 protein expression was in accordance with mRNA expression level. The positive degree of immunohistochemical staining in the cancer group (1.40 ± 0.35) was different from that in control group (1.04 ± 0.08, P < 0.001). Moreover, in cancer group the positive staining degree in high-level mRNA cancers (1.46 ± 0.37, n = 56) was higher than that in low-level mRNA (1.28 ± 0.28, n = 30, P = 0.018). Conclusion: Aberrant levels of WISP-1 expression may play a role in rectal tumorigenesis. WISP-1 may be used as a specific clinical diagnosis and prognosis marker in rectal cancer. © 2007 WJG. All rights reserved.

  • 185. Tobin, Gerard
    et al.
    Thunberg, Ulf
    Karlsson, Karin
    Murray, Fiona
    Laurell, Anna
    Willander, Kerstin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Enblad, Gunilla
    Merup, Mats
    Vilpo, Juhani
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Sundström, Christer
    Söderberg, Ola
    Roos, Göran
    Rosenquist, Richard
    Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia2004In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 104, p. 2879-2885Article in journal (Refereed)
  • 186. Tobin, Gerard
    et al.
    Thunberg, Ulf
    Laurell, Anna
    Karlsson, Karin
    Åleskog, Anna
    Willander, Kerstin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Söderberg, Ola
    Merup, Mats
    Vilpo, Juhani
    Hultdin, Magnus
    Sundström, Christer
    Roos, Göran
    Rosenquist, Richard
    Patients with chronic lymphocytic leukemia with mutated VH genes presenting with Binet stage B or C form a subgroup with a poor outcome2005In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 90, no 4, p. 465-469Article in journal (Refereed)
    Abstract [en]

    Background and Objectives. The immunoglobulin VH gene mutation status is a strong prognostic indicator in B-cell chronic lymphocytic leukemia (CLL), since unmutated VH genes are correlated with short survival. However, the traditional cut-off level dividing mutated and unmutated cases, i.e. more or less than 2% mutations, has been questioned and other cut-offs have been suggested. We investigated whether an alternative cut-off should be applied and the relation of mutational status to another prognostic marker, Binet staging. Design and Methods. VH gene mutation status was assessed in 332 CLL cases by polymerase chain reaction amplification and nucleotide sequencing and was further correlated with overall survival using different VH mutation cut-offs (1-7%) and Binet stage. Results. After testing different mutation borders, the 2% cut-off remained the best discriminative level for determining prognosis. Interestingly, prognostic stratification was improved by combining the information on VH gene mutation status with that of Binet stage: unmutated cases (all stages, n=151, mutated cases with stage A (n=77), and mutated cases with stage B or C (n=37) had a median survival of 82, 179 and 74 months, respectively. Interpretation and Conclusions. CLL cases displaying mutated VH genes with Binet stage B or C had a survival similar to that of unmutated cases and significantly shorter than that of mutated stage A CLL. Our result reveals clinical heterogeneity within the VH mutated CLL group by inclusion of Binet stage data, a finding which is of importance when considering surrogate marker(s) for VH mutation status. ©2005 Ferrata Storti Foundation.

  • 187. Tropé, C
    et al.
    Kaern, J
    Hogberg, T
    Abeler, V
    Hagen, B
    Kristensen, G
    Onsrud, M
    Pettersen, E
    Rosenberg, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Sandvei, R
    Sundfor, K
    Vergote, I
    Randomized study on adjuvant chemotherapy in stage I high-risk ovarian cancer with evaluation of DNA-ploidy as prognostic instrument.2000In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 11, p. 281-288Article in journal (Refereed)
  • 188. Tropé, C
    et al.
    Nordal, R
    Himmelmann, A
    Kjörstad, K
    Onsrud, M
    Simonsen, E
    Högberg, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Einhorn, N
    Pettersson, F
    Frankendal, B
    Pettersson, B
    Tholander, B
    Svanberg, L
    Consolidation treatment of advanced (FIGO stage III) ovarian carcinoma in complete surgical remission after induction chemotherapy: A randomized, controlled, clinical trial comparing whole abdominal radiotherapy, chemotherapy, and no further treatment2003In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 13, p. 278-286Article in journal (Refereed)
  • 189. Tågsjö, E-B
    et al.
    Andreescu, Gheorghe
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Rosenberg, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Jacobs index - enkelt sätt att avgöra om bäckentumör hos kvinna är malign.2003In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 100, p. 3231-3233Article in journal (Other academic)
  • 190.
    Vavruch, Ludek
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    DNA content, proliferation markers and histopathology as prognostic factors in Astrocytic tumours1996Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The DNA index and S-phase fractions obtained from freshly frozen and paraffin-embedded specimens of 49 primary intracranial tumors showed significant correlation. Very similar results were obtained when a subgroup of astrocytomas was analyzed. Thus, the feasibility of DNA-flow cytometry for retrospective studies of archival tumor specimens was confirmed.

    In a study of 134 astrocytomas a strong correlation between grade of malignancy, S-phase fraction and DNA ploidy type was seen. In multivariate Cox regression analysis of 60 cases with grade II or Ill astrocytomas, age, grade of malignancy, DNA ploidy and S-phase were independent prognostic factors. An age of under 50, grade II, low S-phase and tetraploid DNA pattern correlated with long survival.

    Twenty-two recurrent astrocytomas were investigated after primary and repeated surgery. The grade of malignancy had significantly increased at the time of re-operation. The S-phase also tended to increase while the DNA-index was essentially unchanged. In recurrent astrocytomas the original_grade of malignancy was the most important prognostic parameter, which significantly correlated with time to recurrence and with survival after reoperation. The recurrence-free interval was significantly shorter in patients over 50 years of age and patients with an aneuploid DNA pattern at the time of the first surgery. However, when DNA ploidy, histopathological grade and age were evaluated simultaneously in a multivariale analysis, DNA ploidy was not an independent prognostic indicator.

    A strong correlation was found between the cell replication measured as Ki-67 labeling index and grades of malignancy at primary and repealed surgery. When less than 10 percent of cells were stained by Ki-67 after primary surgery, patient survival was prolonged approximately three times compared to survival of patients with a high Ki-67 labeling index.

  • 191.
    Vitak, B
    et al.
    Linköping University, Department of Medicine and Care, Radiology. Linköping University, Faculty of Health Sciences.
    Olsen, K E
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Cytology. Linköping University, Faculty of Health Sciences.
    Månson, Jan-Christer
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Cytology. Linköping University, Faculty of Health Sciences.
    Arnesson, Lars-Gunnar
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Tumour characteristics and survival in patients with invasive interval breast cancer classified according to mammographic findings at the latest screening: a comparison of true interval and missed interval cancers1999In: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 9, no 3, p. 460-469Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate whether different mammographic categories of interval cancer classified according to findings at the latest screening are associated with different distributions of prognostic factors or with different survival rates. The series consisted of all patients with invasive interval cancer detected from May 1978 to August 1995 (n = 544). The tumours were evaluated with regard to age, radiological category, interval between the latest screen and diagnosis and tumour characteristics at the time of diagnosis. We investigated possible relationships between the survival rate of patients with interval cancer and the interval between the latest screen and diagnosis, tumour characteristics and radiological category of the interval tumours. The study focused on comparison of patients with true interval and missed interval cancer. Women with mammographically occult tumours were younger than those in the other radiological categories. Comparisons of true interval cancers with overlooked or misinterpreted tumours showed equal distributions of age, tumour size, TNM stage and lymph node status. The overlooked or misinterpreted tumours showed significantly higher proportions of grade-I tumours (22 vs 11 %), tumours with low S-phase fraction (SPF; 44 vs 24 %) and oestrogen receptor (ER) positive tumours (72 vs 57 %). However, analyses of survival rates disclosed no clear differences between the two radiological categories. Radiological category and interval between the latest screen and diagnosis were not genuine predictors of the prognosis in patients with invasive interval breast cancer. No certain prognostic difference existed between true interval cancers and overlooked or misinterpreted interval breast cancers, despite higher proportions of grade-I tumours, ER positive tumours and tumours with low SPF in the latter group.

  • 192.
    Vitak, Bedrich
    Linköping University, Department of Medicine and Care, Medical Radiology. Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Interval cancers, positive predictive value for malignance and other early quality indicators in mammographic screening for breast cancer1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The study was designed to evaluate early quality indicators in screening for breast cancer. lt comprised, (i) investigations of compliance, recall, referral, cancer detection, and interval cancer rates in the Östergötland screening programme of women aged 40-74 years; (ii) evaluation of the three-stage diagnostic procedure for pre-operative assessment of women with suspicious mammographic findings; (iii) comprehensive analysis of all invasive interval cancers detected; and (iv) investigation into how to reduce the number of interval cancers without a concomitant increase in false positives.

    The attendance rates were 85.5% at the initial screen and 81.3% at subsequent screens. The referral rates for further examination at subsequent screens were roughly half of th'lt at the initial screen. The cancer detection rates were 6.4/1000 at the initial and 2.6/1000 at subsequent screens. The positive predictive value for malignancy at surgery was 96% for ages 50-74 years. Apart from the tumour grade (not analysed) the diagnostic outcome tallied with the quality targets stipulated by Tabár et al.

    The study confirmed the less favourable prognosis for interval cancer patients and cancers in non-attenders compared to screen-detected patients, but the mode of detection was not an independent predictor of metastatic capacity (hazard rate ratio [RR] of distant recurrence /adjusted for other variables/ RR=1.39, 95%confidence interval [95%CI] 0.78-2.46 for interval cancers; and RR=1.6, 95%CI 0.76-3.36 for non-attenders). The higher metastatic potential in these tumours could be explained by the differences in tumour characteristics at the time of diagnosis.

    The incidence risk of interval cancer was 0.46/1000 for tumours detected within 1 year of the latest screen, and 1.2/1000 for tumours detected within 2 years of the latest screen. Despite the lower age-specific breast cancer incidence in women aged 40-49 years, these women ran roughly the same risk of interval cancer after a negative screen as did the other age groups in the screening programme.

    Patients with potential iatrogenic delay in diagnosis (overlooked or misinterpreted cancers) constituted 25% of all patients with invasive interval cancer, and patients with true interval cancer 49%. The radiological category of interval cancer had no significant influence on the survival (overall comparison, p=0.1202; comparison of true interval with missed interval cancers, p=0.3175). In the present study there was no clear evidence of difference in prognosis between true interval and overlooked or misinterpreted interval cancers.

    The interval between the latest screen and diagnosis was not an independent prognostic factor in patients with true interval cancers (RR=0.47, 95%CI 0.16-1.35 for tumours detected 21 year after the latest screen), and there was no significant difference in survival according to this interval (comparison of tumours detected <1 year with tumours detected 21 year of the latest screen, p=0.3844).

    The study confirmed the association of criteria for referral for further examination with number of false positives. Efforts to reduce the number of interval cancers by lowering the mammographic threshold for recall are likely to be counterproductive. The early quality indicators constitute. an excellent means of monitoring of the quality of screening.

  • 193. Waage, Anders
    et al.
    Gimsing, Peter
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Turesson, Ingemar
    Gulbrandsen, Nina
    Eriksson, Tommy
    Hjorth, Martin
    Lanng Nielsen, Johan
    Lenhoff, Stig
    Westin, Jan
    Wislöff, Finn
    Early response predicts thalidomide efficiency in patients with advanced multiple myeloma2004In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 125, no 2, p. 149-155Article in journal (Refereed)
    Abstract [en]

    Sixty-five patients who were primary or secondary refractory to melphalan/ prednisone or other type of chemotherapy, or relapsed within 6 months after high dose chemotherapy with stem cell support, were given thalidomide at a dose of 200 mg/d escalating to 800 mg. The patients were followed for a median of 2 years and 22 weeks. Response was evaluated according to M-protein reduction combined with improvement of haemoglobin (Hb) concentration, renal function and pain. Altogether, 14% of patients had a minor response, 14% partial response and 6% complete response. Median survival was 12 months and 29% were alive at last contact. Decline of M protein started early and a minimum 25% reduction of M protein was detected in 14 of 20 responders (70%) after 3 weeks, and in 20 of 22 responders (91%) after 5 weeks of treatment. Reduction of M protein continued for 3 months and further decline was observed in only four patients. The Hb concentration showed a different time course, with a significant increase after 3 months and further increases continued for up to 12 months. Blood concentration levels of thalidomide from 40 patients were used to evaluate the pharmacokinetics of the drug. Rate of absorption, rate of elimination, volume of distribution, clearance and elimination half-life were calculated to be 0.200/h, 0.140/h, 0.886 l/kg, 0.126 l/h/kg and 4.98 h respectively. We found no relationship between thalidomide concentration and effect after 12 weeks.

  • 194.
    Wall, Najme
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Starkhammar, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Chemotherapy of soft tissue sarcoma: A clinical evaluation of treatment over ten years2003In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 42, no 1, p. 55-61Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to evaluate the effect of palliative chemotherapy on soft tissue sarcomas given outside controlled trials. Therapy and response rates of 77 patients with non-resectable sarcoma treated with different regimens between 1991 and 2000 were reviewed. Thirty-six patients were treated with first-line chemotherapy comprising cyclophosphamide+vincristine+doxorubicin+dacarbazine (CYVADIC), with a response rate of 28% (median response duration 5.5 months). Etoposide and ifosfamide (IVP, or VIG, which also includes granulocyte colony-stimulating factor (G-CSF)) were used in the treatment of 18 patients. The response rate was 22% (median response duration 4.5 months), Nineteen patients were treated with doxorubicin+ifosfamide and one patient responded. Four patients received other first-line treatments. Thirty-eight patients were given second-line chemotherapy and 4 (10%) patients responded. Thirteen patients were given third-line treatment and 5 patients received fourth-line treatment, but without any response. Disease progression was the dominant reason for discontinuation of therapy. The response rate in the present study was lower than the best published results, probably due to the fact that our soft tissue sarcoma patient material was unselected. Treatment with CYVADIC yields at least as high a response rate as the more recently described doxorubicin+ifosfamide combination, but third- and fourth-line therapy is not beneficial. Clinical trials with more active drugs are needed, as are more predictive and prognostic tests and a better selection of patient groups suited for different treatment options for soft tissue sarcomas.

  • 195. Wang, Ming-Wei
    et al.
    Gu, Ping
    Zhang, Zhi-Yong
    Zhu, Zhen-Long
    Li, Yan-Min
    Zhao, Hui-Xin
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Expression of PINCH protein in gliomas and its clinicopathological significance2007In: Oncology, ISSN 0890-9091, Vol. 72, no 5-6, p. 343-346Article in journal (Refereed)
    Abstract [en]

    Objectives: Particularly interesting new cysteine-histidine-rich protein (PINCH), as a LIM domain adapter protein, functions in the integrin and growth factor signal transduction pathway, and is upregulated in tumor-associated stroma in several types of cancers. However, no study of PINCH has been carried out in gliomas, therefore we examined PINCH expression in gliomas and its clinicopathological significance. Methods: PINCH expression was immunohistochemically examined in 82 gliomas, along with 26 matched adjacent normal brain samples and 10 recurred gliomas. Results: PINCH was strongly expressed in the primary (35%, p = 0.0001) or recurred tumors (40%, p = 0.004) and weak in normal brain tissue. PINCH expression was significantly increased in high-grade gliomas (55 vs. 24%, high- vs. low-grade gliomas, p = 0.004). There was no association of PINCH expression with gender, age, tumor number, size, histological type and tumor location (p > 0.05). Conclusions: PINCH expression may be involved in glioma development and differentiation. Copyright © 2008 S. Karger AG.

  • 196. Wang, Xiao-Ling
    et al.
    Wu, Guo-Xiang
    Zhang, Ming-Dao
    Guo, Ming
    Zhang, Hong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    A favourable impact of preoperative FPLC chemotherapy on patients with gastric cardia cancer.2000In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 7, p. 241-244Article in journal (Refereed)
  • 197.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    DNA flow cytometry of cytokeratin selected breast cancer cells as prognostic indicator1994Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    DNA flow cytometry is used for the estimation of cell proliferation (S-phase fraction) and abnormalities in cellular DNA content (DNA ploidy), parameters which yield prognostic information in breast carcinomas. However, stromal, inflammatory, and residual non-neoplastic epithelial cells overlap cancer cells in the DNA histogram and complicate the calculation of DNA ploidy and S-phase fraction. In the present thesis, the cell-specific intermediary filament of epithelial tissue, cytokeratin, has been used for flow cytometric selection of the epithelial cell population in order to reduce the influence from nonepithelial cells.

    S-phase fractions with and without flow cytometric selection of cytokeratin-containing cells were analysed in 507 breast cancers. The association between S-phase fraction and distant recurrence was evaluated. Using univariate analysis, S-phase fraction of the epithelial cell population predicted recurrence more effectively than S-phase fraction from the unselected cell population. In multivariate analysis, S-phase fraction of the cytokeratin-containing population added significant prognostic infonnation to the S-phase from non-selected cells, tumor size, and hormone receptor content. Also, the cytokeratin method increased the ability to identify minor aneuploid populations, However, we obtained decreased separation of adjacent peaks in the DNA histogram, due to slightly increased coefficients of variation with the cytokeratin method. Also, there was a reduced proportion of cytokeratin positive cells registered with flow cytometry compared with immunohistochemistry. In experiments with endometrial carcinomas, S-phase estimates with and without selection of epithelial cells were closely correlated for cell populations with a high proportion of cancer cells but not for populations with a low proportion.

  • 198. Wolfraim, Larence A
    et al.
    Walz, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    James, Zakiya
    Fernandez, Tania
    Letterio, John J
    p21Cip1 and p27Kip1 act in synergy to alter the sensitivy of naive T cells to TGF-beta-mediated G1 arrest through modulation of IL-2 responsiveness2004In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 173, p. 3093-3102Article in journal (Refereed)
  • 199. Wolfraim, Lawrence A
    et al.
    Fernandez, Tania M
    Mamura, Mizuko
    Fuller, Walter L
    Kumar, Rajesh
    Cole, Diane E
    Byfield, Stacey
    Felici, Angelina
    Flanders, Kathleen C
    Walz, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Roberts, Anita B
    Aplan, Peter D
    Balis, Frank M
    Letterio, John J
    Loss of Smad3 in acute T-cell lymphoblastic leukemia2004In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 351, no 6, p. 552-559Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The receptors for transforming growth factor β (TGF-β) and their signaling intermediates make up an important tumor-suppressor pathway. The role of one of these intermediates - Smad3 - in the pathogenesis of lymphoid neoplasia is unknown. METHODS: We measured Smad3 messenger RNA (mRNA) and protein in leukemia cells obtained at diagnosis from 19 children with acute leukemia, including 10 with T-cell acute lymphoblastic leukemia (ALL), 7 with pre-B-cell ALL, and 2 with acute nonlymphoblastic leukemia (ANLL). All nine exons of the SMAD3 gene (MADH3) were sequenced. Mice in which one or both alleles of Smad3 were inactivated were used to evaluate the role of Smad3 in the response of normal T cells to TGF-β and in the susceptibility to spontaneous leukemogenesis in mice in which both alleles of the tumor suppressor p27Kip1 were deleted. RESULTS: Smad3 protein was absent in T-cell ALL but present in pre-B-cell ALL and ANLL. No mutations were found in the MADH3 gene in T-cell ALL, and Smad3 mRNA was present in T-cell ALL and normal T cells at similar levels. In mice, the loss of one allele for Smad3 impairs the inhibitory effect of TGF-β on the proliferation of normal T cells and works in tandem with the homozygous inactivation of p27Kip1 to promote T-cell leukemogenesis. CONCLUSIONS: Loss of Smad3 protein is a specific feature of pediatric T-cell ALL. A reduction in Smad3 expression and the loss of p27Kip1 work synergistically to promote T-cell leukemogenesis in mice.

  • 200.
    Yu, Qunyan
    et al.
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts.
    Sicinska, Ewa
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts.
    Geng, Yan
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts.
    Ahnström, Marie
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Zagozdzon, Agnieszka
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts.
    Kong, Yinxin
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts.
    Gardner, Humphrey
    Department of Research Pathology, Biogen Idec, Cambridge, Massachusetts.
    Kiyokawa, Hiroaki
    Department of Molecular Pharmacology and Biochemical Chemistry, Northwestern University, Chicago, Illinois.
    Harris, Lyndsay N
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts and Department of Medical Oncology, Dana-Farber Cancer Institute, and Brigham and Women's Hospital, Boston, Massachusetts.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Sicinski, Piotr
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts.
    Requirement for CDK4 kinase function in breast cancer2006In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 9, no 1, p. 23-32Article in journal (Refereed)
    Abstract [en]

    Cyclin D1 is overexpressed in the majority of human breast cancers. We previously found that mice lacking cyclin D1 are resistant to mammary carcinomas triggered by the ErbB-2 oncogene. In this study, we investigated which function of cyclin D1 is required for ErbB-2-driven mammary oncogenesis. We report that the ability of cyclin D1 to activate cyclin-dependent kinase CDK4 underlies the critical role for cyclin D1 in breast cancer formation. We also found that the continued presence of CDK4-associated kinase activity is required to maintain breast tumorigenesis. We analyzed primary human breast cancers and found high cyclin D1 levels in a subset (∼25%) of ErbB-2-overexpressing tumors. We propose that this subset of breast cancer patients might benefit from inhibiting CDK4 kinase.

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