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  • 51.
    Blockhuys, S.
    et al.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Celauro, E.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Hildesjö, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Feizi, A.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fierro-González, J.C.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Wittung-Stafshede, P.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Defining the human copper proteome and analysis of its expression variation in cancers.2017Ingår i: Metallomics : integrated biometal science, ISSN 1756-591X, Vol. 9, nr 2, s. 112-123Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Copper (Cu) is essential for living organisms, and acts as a cofactor in many metabolic enzymes. To avoid the toxicity of free Cu, organisms have specific transport systems that 'chaperone' the metal to targets. Cancer progression is associated with increased cellular Cu concentrations, whereby proliferative immortality, angiogenesis and metastasis are cancer hallmarks with defined requirements for Cu. The aim of this study is to gather all known Cu-binding proteins and reveal their putative involvement in cancers using the available database resources of RNA transcript levels. Using the database along with manual curation, we identified a total of 54 Cu-binding proteins (named the human Cu proteome). Next, we retrieved RNA expression levels in cancer versus normal tissues from the TCGA database for the human Cu proteome in 18 cancer types, and noted an intricate pattern of up- and downregulation of the genes in different cancers. Hierarchical clustering in combination with bioinformatics and functional genomics analyses allowed for the prediction of cancer-related Cu-binding proteins; these were specifically inspected for the breast cancer data. Finally, for the Cu chaperone ATOX1, which is the only Cu-binding protein proposed to have transcription factor activities, we validated its predicted over-expression in patient breast cancer tissue at the protein level. This collection of Cu-binding proteins, with RNA expression patterns in different cancers, will serve as an excellent resource for mechanistic-molecular studies of Cu-dependent processes in cancer.

  • 52.
    Blom, René
    Linköpings universitet, Institutionen för biomedicin och kirurgi. Linköpings universitet, Hälsouniversitetet.
    Sarcoma of the female genital tract: Histopathology, DNA cytometry, p53 and mdm-2 analysis related to prognosis1999Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Sarcomas of the female genital tract are rare tumors and account for less than 5% of gynecologic malignancies. Traditionally, gynecologic sarcomas have been divided into different tumor types according to their histopathological features. The most common are leiomyosarcoma (LMS), malignant mixed Müllerian tumors (MMMT), endometrial stromal sarcoma (ESS) and (Müllerian) adenosarcoma. The different tumor types are highly aggressive with early lymphatic and/or hematogenous spread. Treatment is difficult and it is believed that sarcomas have a low radio-and chemosensitivity, and the mainstay in treatment is surgical removal of the tumor. The most important prognostic feature has been tumor stage. Nevertheless, there are some early-stage tumors that run a biological course different from that expected and additional prognostic factors indicating high-risk tumors are desirable.

    The study cohort consists of 49 uterine LMS, 44 uterine MMMTs, 17 uterine ESS, 11 uterine adenosarcomas and 26 ovarian MMMTs. The tumors were analyzed in a retrospective manner for DNA ploidy, S-phase fraction (SPF), p53 and mdm-2 expression, as well as traditional clinical and pathological prognostic factors, such as tumor stage. grade, atypia and mitotic index.

    Of the 49 LMS, 36 (86%) were non-diploid and 13 (27%) were p53-positive. Among the 44 uterine MMMTs, 30 (68%) were non-diploid and 27 (61%) had an SPF>10%. Twenty-seven (61%) overexpressed p53 and 11 (25%) were mdm-2 positive. Furthermore, 40 (91%) of the uterine MMMTs had a high mitotic count and 42 (95%) had high grade cytologic atypia. All low-grade ESS were DNA diploid and had a low SPF. Among the four high-grade ESS, three (75%) were DNA aneuploid and three (75%) were p53-positive. Among 1 1 adenosarcomas, eight (73%) were non-diploid. All ovarian MMMTs were non-diploid and all but two had an SPF>10%. 19 (73%) ovarian MMMTs were p53positive.

    The 5-year survival rate was 33% for LMS, 38% for uterine MMMT, 57% for ESS, 69% for adenosarcoma and 30% for ovarian MMMT.

    Thirty-five (71%) patients with LMS died of disease and two of intercurrent disease. Stage was found to be the most important factor for survival (p=0.007); in addition DNA ploidy (p=0.045) and SPF (p=0.041) had prognostic significance.

    Twenty-seven (61%) patients with uterine MMMT died of disease and six (14%) died of intercurrent disease. Stage was the only prognostic factor for survival.

    Nine (53%) patients with ESS died of disease. There was a significant correlation of survival to tumor grade (p=0.007), DNA ploidy (p=0.026), SPF (p=0.048) and stage (p=0.026).

    Of the 11 patients with adenosarcoma, four (36%) patients died of disease and three (27%) patients died of intercurrent disease. There were no variables that correlated with survival.

    Eighteen (69%) patients with ovarian MMMT died of disease and two (8%) patients died of intercurrent disease. In a multivariate analysis, only stage reached independent prognostic significance for survival (p=0.023).

    In summary, stage represents the most important prognostic factor for survival for uterine and ovarian sarcomas. DNA flow cytometry is useful in gaining additional prognostic information for LMS and ESS. P53-and mdm-2 overexpression had no prognostic value for survival rate. Most of the MMMT overexpressed p53 and were non-diploid. Treatment of sarcomatous neoplasms is difficult and the mainstay remains surgical removal of the tumor. For patients with early stage sarcoma there was a high recurrence rate, which suggests that a large proportion of patients may have systemic micrometastasic disease at the time of diagnosis. Recurrent and metastatic uterine sarcoma remains an incurable disease, and treatment must be considered palliative.

    Delarbeten
    1. Leiomyosarcoma of the uterus: A clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 49 cases
    Öppna denna publikation i ny flik eller fönster >>Leiomyosarcoma of the uterus: A clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 49 cases
    Visa övriga...
    1998 (Engelska)Ingår i: Gynecologic Oncology, ISSN 0090-8258, Vol. 68, nr 1, s. 54-61Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    AIM: The authors analyzed in a retrospective manner the prognostic significance of p53 and mdm-2 expression, DNA ploidy, S-phase fraction (SPF), and traditional clinical and pathological prognostic factors in patients with uterine leiomyosarcomas. MATERIAL: Forty-nine patients were diagnosed with uterine leiomyosarcoma (25 stage I, 4 stage II, 8 stage III, and 12 stage IV). DNA flow cytometric analysis and immunohistochemical staining for p53 and mdm-2 were performed on paraffin-embedded archival tissue from the uterine tumors. RESULTS: Of the 49 patients, 35 (71%) died of disease and 2 died of intercurrent disease. The 5-year survival rate was 33%. FIGO surgical stage, DNA ploidy, SPF, mitotic index, cellular atypia, and tumor grade obtained significance (P < 0.05) in a univariate survival analysis of the leiomyosarcomas. In a multivariate analysis with survival as the end point, stage was found to be the most important factor (P = 0.007); DNA ploidy (P = 0. 045) and SPF (P = 0.041) also had independent prognostic significance. For FIGO stage I tumors, DNA ploidy (P = 0.04) and tumor grade (P = 0.01) were statistically significant in a univariate analysis, while only grade had independent prognostic significance (P = 0.01) in a multivariate analysis. In a univariate analysis including only FIGO stage I and II tumors with disease-free survival as the end point, p53 overexpression (P = 0.0016), DNA ploidy (P = 0.042), and tumor grade (P = 0.008) obtained significance. In a multivariate analysis, only p53 had independent statistical significance (P = 0.01). All p53 immunopositive stage I-II tumors recurred within 28 months from diagnosis. CONCLUSION: This study found that stage represents the most important prognostic factor for uterine leiomyosarcomas. DNA ploidy and SPF had independent prognostic value. DNA flow cytometry is useful in gaining additional prognostic information. In stage I patients, tumor grade gives significant information regarding clinical outcome. In addition, p53 overexpression may predict a higher risk of recurrence in early stage leiomyosarcomas.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13510 (URN)
    Tillgänglig från: 1999-02-26 Skapad: 1999-02-26 Senast uppdaterad: 2009-02-09
    2. Malignant mixed Mullerian tumors of the uterus: a clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 44 cases
    Öppna denna publikation i ny flik eller fönster >>Malignant mixed Mullerian tumors of the uterus: a clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 44 cases
    Visa övriga...
    1998 (Engelska)Ingår i: Gynecologic Oncology, ISSN 0090-8258, Vol. 68, nr 1, s. 18-24Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    AIM: The authors retrospectively analyzed the prognostic significance of p53, mdm-2, DNA ploidy, S-phase fraction (SPF), and traditional clinical and pathologic factors in patients with malignant mixed Müllerian tumors (MMMT) of the uterus. METHODS: Between 1970 and 1995, 44 uterine tumors were diagnosed as MMMT (21 stage I, 2 stage II, 10 stage III, and 11 stage IV). Thirty-two were homologous type and 12 were heterologous type. DNA flow cytometry and immunohistochemical analysis for p53 and mdm-2 overexpression were performed on paraffin-embedded archival tissue. RESULTS: 68% of the tumors were nondiploid and 61% had an SPF greater than 10%. Sixty-one percent overexpressed p53 and 25% were mdm-2-positive. Furthermore, 91% of the tumors had a mitotic count greater than 10/10 hpf and 95% had high-grade cytologic atypia. Twenty-seven (61%) patients died of tumor and 6 (14%) died of intercurrent disease. Eleven (25%) patients are alive with no evidence of disease. The median follow-up for patients still alive was 59 months (range, 28-178 months). The overall 5-year survival rate was 38%. In a univariate analysis that included stage, histologic type, DNA ploidy, SPF, p53, mdm-2, mitotic index, and age, and with survival as the end point, only stage reached statistically prognostic significance. CONCLUSION: The majority of the tumors had obvious signs of aggressiveness such as high grade, high mitotic count, nondiploid pattern, high SPF, and overexpression of p53. This study found that stage is the most important prognostic factor for survival in MMMTs of the uterus.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13511 (URN)
    Tillgänglig från: 1999-02-26 Skapad: 1999-02-26 Senast uppdaterad: 2009-02-09
    3. Endometrial stromal sarcoma of the uterus: a clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 17 cases
    Öppna denna publikation i ny flik eller fönster >>Endometrial stromal sarcoma of the uterus: a clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 17 cases
    1999 (Engelska)Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, Vol. 9, nr 2, s. 98-104Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Seventeen patients with endometrial stromal sarcoma (ESS) diagnosed between 1970 and 1996 were evaluated according to DNA ploidy, S-phase fraction (SPF), p53, and mdm-2 expression, as well as traditional clinical and pathologic prognostic factors, such as tumor stage, grade, and mitotic index. DNA flow cytometric analysis and immunohistochemical staining for p53 and mdm-2 were performed on paraffin-embedded archival tissue from the uterine tumors. Flow cytometric DNA histograms were obtained from 16 patients.

    The patients ranged in age from 41 to 78 years (median, 57 years). Seven (41%) patients were premenopausal. Thirteen low-grade ESS were DNA diploid and had a low SPF. Of these, two overexpressed p53, while only one was mdm-2 positive. Among the four high-grade ESS we found one (25%) DNA diploid tumor and three (75%) DNA aneuploid tumors. Two (50%) had an SPF greater than 10%, three (75%) were p53-positive, and two (50%) overexpressed mdm-2. During the observation period, nine (53%) patients (five with low-grade and four with high-grade tumors) died of disease. The 5-year survival rate for patients with low-grade ESS was 74%, while all four patients with high-grade ESS died of disease within 14 months of diagnosis. Using the log-rank test, we found a significant correlation between survival and tumor grade (P = 0.007), DNA ploidy (P = 0.026), SPF (P = 0.048), and FIGO surgical stage (P = 0.026).

    In conclusion, we found that tumor grade was a strong predictor of clinical outcome in ESS. In addition, a worse prognosis was found for those ESS patients with advanced disease, DNA aneuploidy, and a high SPF. There was no difference between the recurrent and nonrecurrent group of early stage (surgical stage I), low-grade ESS with regard to clinicopathological features, DNA ploidy, SPF, p53, and mdm-2 expression. All patients with high-grade ESS died of disease within 14 months of diagnosis. In contrast, only three of the 11 patients with early stage, low-grade ESS died of disease.

    Nyckelord
    DNA ploidy, endometrial stromal sarcoma, mdm-2, p53
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13512 (URN)10.1046/j.1525-1438.1999.09870.x (DOI)
    Tillgänglig från: 1999-02-26 Skapad: 1999-02-26 Senast uppdaterad: 2009-04-28
    4. Adenosarcoma of the uterus: a clinicopathologic, DNA flow cytometric, p53 and mdm-2 analysis of 11 cases
    Öppna denna publikation i ny flik eller fönster >>Adenosarcoma of the uterus: a clinicopathologic, DNA flow cytometric, p53 and mdm-2 analysis of 11 cases
    1999 (Engelska)Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, Vol. 9, nr 1, s. 37-43Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Eleven patients with uterine adenosarcoma diagnosed between 1970 and 1995 were evaluated according to DNA ploidy, S-phase fraction, p53 and mdm-2 expression, and traditional clinical and pathological prognostic factors, such as tumor stage, grade and mitotic index. DNA flow cytometric analysis and immunohistochemical staining for p53 and mdm-2 were performed on paraffin-embedded archival tissue from the uterine tumors. The patients ranged in age from 41 to 90 years (median, 76 years). Only one patient was premenopausal at the time of diagnosis and five (45%) were nulliparous. One patient had received previous pelvic irradiation for anal squamous carcinoma. Six of the tumors (55%) were pure adenosarcoma and five (45%) were adenosarcoma with sarcomatous overgrowth. Nine patients had a stage I tumor and two had a stage II tumor. Among the six adenosarcomas we found three DNA diploid tumors, two DNA aneuploid tumors, and one DNA multiploid tumor. All adenosarcomas had an S-phase fraction less than 10%, except one that was not assessable. None was p53 positive and only one overexpressed mdm-2. All five adenosarcomas with sarcomatous overgrowth were DNA aneuploid, three (60%) had an S-phase fraction > 10%, two (40%) were p53 positive, and one (20%) overexpressed mdm-2. Five of the eleven patients suffered recurrences, and three (60%) of these developed lung metastases. During the observation period four (36%) patients (2 adenosarcomas and 2 adenosarcoma with sarcomatous overgrowth) died of disease, three patients died of intercurrent disease without recurrence, and the remaining four are alive with no evidence of disease. The overall five-year survival rate for all stages was 69%; for patients with AS it was 80%, while for those with adenosarcoma with sarcomatous overgrowth it was 50%. There were no variables which correlated with survival. In conclusion, we found hat the typical adenosarcoma had a tendency to be of low stage, have a lower mitotic rate and an S-phase fraction <10%. On the other hand, adenosarcomas with sarcomatous overgrowth were of high grade, had a high mitotic rate, and were DNA aneuploid with an S-phase fraction >10%. None of the variables studied correlated with survival. Tumors that were p53-positive or overexpressed mdm-2 did not behave worse than their negative counterpart. All patients who recurred with distant metastases died of disease.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13513 (URN)
    Tillgänglig från: 1999-02-26 Skapad: 1999-02-26 Senast uppdaterad: 2009-02-09
    5. Malignant mixed Müllerian tumors of the ovary: A clinicopathologic, DNA ploidy and p53 study of 26 cases
    Öppna denna publikation i ny flik eller fönster >>Malignant mixed Müllerian tumors of the ovary: A clinicopathologic, DNA ploidy and p53 study of 26 cases
    1999 (Engelska)Artikel i tidskrift (Refereegranskat) Submitted
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13514 (URN)
    Tillgänglig från: 1999-02-26 Skapad: 1999-02-26
  • 53.
    Blomstrand, Hakon
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Ryhov Cty Hosp, Sweden.
    Scheibling, Ursula
    Ryhov Cty Hosp, Sweden.
    Bratthall, Charlotte
    Kalmar Cty Hosp, Sweden.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
    Elander, Nils
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Real world evidence on gemcitabine and nab-paclitaxel combination chemotherapy in advanced pancreatic cancer2019Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, artikel-id 40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundIn the recent phase III trial MPACT the combination of gemcitabine and nab-paclitaxel (Gem/NabP) showed increased overall survival compared to gemcitabine alone in the treatment of advanced pancreatic ductal adenocarcinoma (aPDA). Until now there has been limited information on the clinical benefit and toxicity of the combination regimen in a real world setting. In addition the value for patients with locally advanced rather than metastatic aPDA has been unclear, since the former category of patients was not included in the MPACT trial.MethodsA multicentre retrospective observational study in the South Eastern Region of Sweden was performed, with the first 75 consecutive patients diagnosed with aPDA (both locally advanced and metastatic disease) who received first-line treatment with Gem/NabP.ResultsIn the overall population median progression free survival (PFS) and overall survival (OS) were 5.2 (3.4-7.0 95% CI) and 10.9 (7.8-14.0 95% CI) months, respectively. Patients with metastatic disease displayed a median OS of 9.4 (4.9-13.9) and a median PFS of 4.5 (3.3-5.7) months whereas the same parameters in the locally advanced subgroup were 17.1 (7.6-26.6) and 6.8 (5.2-8.4) months, respectively. Grade 3-4 hematologic toxicity was recorded: Neutropenia, leukopenia, thrombocytopenia, and anaemia were observed in 23, 20, 5, and 4% of patients, respectively. Dose reductions were performed in 80% of the patients.ConclusionThis study confirms the effectiveness and safety of first-line Gem/NabP in both locally advanced and metastatic PDA in a real world setting.

  • 54.
    Bogoeva, Vanya
    et al.
    Bulgarian Academic Science, Bulgaria.
    Siksjö, Monica
    Norwegian University of Science and Technology, Norway.
    Säterbo, Kristin G.
    Norwegian University of Science and Technology, Norway.
    Melo, Thor Bernt
    Norwegian University of Science and Technology, Norway.
    Björköy, Astrid
    Norwegian University of Science and Technology, Norway.
    Lindgren, Mikael
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. Norwegian University of Science and Technology, Norway.
    Gederaas, Odrun A.
    Norwegian University of Science and Technology, Norway.
    Ruthenium porphyrin-induced photodamage in bladder cancer cells2016Ingår i: Photodiagnosis and Photodynamic Therapy, ISSN 1572-1000, E-ISSN 1873-1597, Vol. 14Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Photodynamic therapy (PDT) is a noninvasive treatment for solid malignant and flat tumors. Light activated sensitizers catalyze photochemical reactions that produce reactive oxygen species which can cause cancer cell death. In this work we investigated the photophysical properties of the photosensitizer ruthenium(II) porphyrin (RuP), along with its PDT efficiency onto rat bladder cancer cells (AY27). Optical spectroscopy verified that RuP is capable to activate singlet oxygen via blue and red absorption bands and inter system crossing (ISC) to the triplet state. In vitro experiments on AY27 indicated increased photo-toxicity of RuP (20 mu M, 1811 incubation) after cell illumination (at 435 nm), as a function of blue light exposure. Cell survival fraction was significantly reduced to 14% after illumination of 20 mu M RuP with 15.6 J/cm(2), whereas the "dark toxicity" of 20 mu M RuP was 17%. Structural and morphological changes of cells were observed, due to RuP accumulation, as well as light-dependent cell death was recorded by confocal microscopy. Flow cytometry verified that PDT-RuP (50 mu M) triggered significant photo-induced cellular destruction with a photoxicity of (93% +/- 0.9%). Interestingly, the present investigation of RuP-PDT showed that the dominating mode of cell death is necrosis. RuP "dark toxicity" compared to the conventional chemotherapeutic drug cisplatin was higher, both evaluated by the MIT assay (24 h). In conclusion, the present investigation shows that RuP with or without photoactivation induces cell death of bladder cancer cells. (C) 2016 Elsevier B.V. All rights reserved.

  • 55.
    Bojmar, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Metastatic Mechanisms in Malignant Tumors2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The ultimate cause of cancer related deaths is metastasis. This thesis is about three of the main human cancers; breast, colorectal and pancreatic cancer, that together account for more than 25% of the cancer-related deaths worldwide. The focus of the thesis is the spread of cancer, metastasis, and the aim was to investigate mechanisms that can be of importance for this process. We analyzed patient samples to validate the role of epithelialto-mesenchymal transition in vivo and found regulations of many related factors. However, these changes tend to fluctuate along the metastatic process, something which makes targeting complicated. We, moreover, focused on the influence of the tumor microenvironment for metastatic spread. In pancreatic cancer, the stroma constitutes the main part of many tumors. We analyzed the crosstalk between tumor and stromal cell and focused on the mediating inflammatory factor interleukin-1 (IL-1) and regulation of microRNAs. The results showed that the most commonly mutated factor in pancreatic cancer, KRAS, associates with the expression of IL-1 and subsequent activation of stromal cells. Blocking KRAS signaling together with IL-1 blockage give a more pronounced effect on in vitro proliferation and migration of cancer cells and suggests the use of a combination therapy. The cancer-associated activation of the stroma was found to be related to changes in microRNA expression. microRNA was analyzed separately in epithelial cells and stromal cells after microdissection of matched samples of primary and secondary tumors of breast and colorectal cancers. miR-214 and miR-199a were upregulated in stroma associated with progressive tumors and in pancreatic cancer stroma we could show that their expression alters the activation of stromal cells and thereby the growth and migratory ability of associated pancreatic tumor cells. In  breast and colorectal cancers we found several common microRNAs to be up- or downregulated in line with progression. We could show that one of these candidates, miR-18a, had a prognostic value in metastatic breast cancer. To further develop these studies we analyzed this microRNA in circulating microvesicles, i.e. exosomes, and investigated their role in the preparation of a pre-metastatic niche. MicroRNAs are stable biomarkers in the circulation, especially protected in exosomes, which can moreover specifically deliver their message to recipient cells. These studies facilitate the understanding of metastatic behavior and suggest new targets to stop cancer metastasis.

    Delarbeten
    1. The Role of MicroRNA-200 in Progression of Human Colorectal and Breast Cancer
    Öppna denna publikation i ny flik eller fönster >>The Role of MicroRNA-200 in Progression of Human Colorectal and Breast Cancer
    Visa övriga...
    2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. 84815-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The role of the epithelial-mesenchymal transition (EMT) in cancer has been studied extensively in vitro, but involvement of the EMT in tumorigenesis in vivo is largely unknown. We investigated the potential of microRNAs as clinical markers and analyzed participation of the EMT-associated microRNA-200 ZEB E-cadherin pathway in cancer progression. Expression of the microRNA-200 family was quantified by real-time RT-PCR analysis of fresh-frozen and microdissected formalin-fixed paraffin-embedded primary colorectal tumors, normal colon mucosa, and matched liver metastases. MicroRNA expression was validated by in situ hybridization and after in vitro culture of the malignant cells. To assess EMT as a predictive marker, factors considered relevant in colorectal cancer were investigated in 98 primary breast tumors from a treatment-randomized study. Associations between the studied EMTmarkers were found in primary breast tumors and in colorectal liver metastases. MicroRNA-200 expression in epithelial cells was lower in malignant mucosa than in normal mucosa, and was also decreased in metastatic compared to non-metastatic colorectal cancer. Low microRNA-200 expression in colorectal liver metastases was associated with bad prognosis. In breast cancer, low levels of microRNA-200 were related to reduced survival and high expression of microRNA-200 was predictive of benefit from radiotheraphy. MicroRNA-200 was associated with ER positive status, and inversely correlated to HER2 and overactivation of the PI3K/AKT pathway, that was associated with high ZEB1 mRNA expression. Our findings suggest that the stability of microRNAs makes them suitable as clinical markers and that the EMT-related microRNA-200 - ZEB - E-cadherin signaling pathway is connected to established clinical characteristics and can give useful prognostic and treatment-predictive information in progressive breast and colorectal cancers.

    Ort, förlag, år, upplaga, sidor
    Public Library of Science, 2013
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-103717 (URN)10.1371/journal.pone.0084815 (DOI)000328745100188 ()
    Tillgänglig från: 2014-01-24 Skapad: 2014-01-24 Senast uppdaterad: 2019-02-11
    2. IL-1α Expression in Pancreatic Ductal Adenocarcinoma Affects the Tumor Cell Migration and Is Regulated by the p38MAPK Signaling Pathway
    Öppna denna publikation i ny flik eller fönster >>IL-1α Expression in Pancreatic Ductal Adenocarcinoma Affects the Tumor Cell Migration and Is Regulated by the p38MAPK Signaling Pathway
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    2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 8Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The interplay between the tumor cells and the surrounding stroma creates inflammation, which promotes tumor growth and spread. The inflammation is a hallmark for pancreatic adenocarcinoma (PDAC) and is to high extent driven by IL-1α. IL-1α is expressed and secreted by the tumor cells and exerting its effect on the stroma, i.e. cancer associated fibroblasts (CAF), which in turn produce massive amount of inflammatory and immune regulatory factors. IL-1 induces activation of transcription factors such as nuclear factor-κβ (NF-κβ), but also activator protein 1 (AP-1) via the small G-protein Ras. Dysregulation of Ras pathways are common in cancer as this oncogene is the most frequently mutated in many cancers. In contrast, the signaling events leading up to the expression of IL-1α by tumor cells are not well elucidated. Our aim was to examine the signaling cascade involved in the induction of IL-1α expression in PDAC. We found p38MAPK, activated by the K-Ras signaling pathway, to be involved in the expression of IL-1α by PDAC as blocking this pathway decreased both the gene and protein expression of IL-1α. Blockage of the P38MAPK signaling in PDAC also dampened the ability of the tumor cell to induce inflammation in CAFs. In addition, the IL-1α autocrine signaling regulated the migratory capacity of PDAC cells. Taken together, the blockage of signaling pathways leading to IL-1α expression and/or neutralization of IL-1α in the PDAC microenvironment should be taken into consideration as possible treatment or complement to existing treatment of this cancer.

    Ort, förlag, år, upplaga, sidor
    Public Library of Science, 2013
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-97445 (URN)10.1371/journal.pone.0070874 (DOI)000323097300061 ()
    Anmärkning

    Funding Agencies|Swedish Research Council|AI52731|VINNMER (Vinnova)||Medical Research Council of Southeast Sweden||Swedish Society of Medicine||

    Tillgänglig från: 2013-09-12 Skapad: 2013-09-12 Senast uppdaterad: 2017-12-06
    3. MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor
    Öppna denna publikation i ny flik eller fönster >>MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor
    Visa övriga...
    2016 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 13, s. 16396-16408Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Pancreatic stellate cells (PSCs) are the key precursor cells for cancer-associated fibroblasts (CAFs) in pancreatic tumor stroma. Although depletion of tumor stroma is debatable, attenuation of PSC activity is still an interesting strategy to treat pancreatic cancer. In this study, we explored miRNA as therapeutic targets in tumor stroma and found miR-199a-3p and miR-214-3p induced in patient-derived pancreatic CAFs as well as in TGF-β-activated human PSCs (hPSCs). Inhibition of miR-199a or miR-214 using their hairpin inhibitors in hPSCs significantly inhibited their TGFβ-induced differentiation (gene and protein levels of α-SMA, Collagen, PDGFβR), migration and proliferation. Furthermore, heterospheroids of Panc-1 and hPSCs were prepared, which attained smaller size when hPSCs were transfected with anti-miR-199a or -214 than those transfected with control anti-miR. The conditioned medium obtained from TGFβ-activated hPSCs induced tumor cell proliferation and endothelial cell tube formation, but these effects were abrogated when hPSCs were transfected with anti-miR-199a or miR-214. Moreover, IPA analyses revealed signaling pathways related to miR-199a (TP53, mTOR, Smad1) and miR-214 (PTEN, Bax, ING4). Taken together, this study reveals miR-199a-3p and miR-214-3p as major regulators of PSC activation and PSC-induced pro-tumoral effects, representing them as key therapeutic targets in PSCs in pancreatic cancer.

    Ort, förlag, år, upplaga, sidor
    Impact press, 2016
    Nationell ämneskategori
    Cancer och onkologi Cell- och molekylärbiologi Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
    Identifikatorer
    urn:nbn:se:liu:diva-122828 (URN)10.18632/oncotarget.7651 (DOI)000375692900085 ()
    Anmärkning

    Funding agencies: Swedish Research Council, Stockholm, Sweden [K7/60501283]

    Vid tiden för disputationen förelåg publikationen endast som manuskript

    Tillgänglig från: 2015-11-26 Skapad: 2015-11-26 Senast uppdaterad: 2018-01-10
    4. miR-18a is regulated between progressive compartments of cancers, and incorporated in exosomes with the potential of creating premetastatic niches and predict cancer outcome
    Öppna denna publikation i ny flik eller fönster >>miR-18a is regulated between progressive compartments of cancers, and incorporated in exosomes with the potential of creating premetastatic niches and predict cancer outcome
    Visa övriga...
    2015 (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The ultimate cause of death for many cancer patients is the spread of the cancer via metastasis. Even so, there are still a lack of knowledge regarding the metastasis process. This study was performed to investigate the role of metastamirs in exosomes and their metastatic patterns. We used the well-established isogeneic murine cancer model of low metastatic 67NR cells, mimicking luminal/basal breast tumors, and highly metastatic 4T1 cells with characteristics of basal breast  tumors. We studied the exosomal properties and pre-metastatic effects in this metastasis model and compared human materials and exosomes of several other tumor types. Our data clearly demonstrated that exosomes from the highly metastatic cells home to the metastatic organs of their parental cells whereas exosomes from cells with low metastatic potential mostly located to lymph nodes. The exosome protein cargos also resembled their parental cells and potentially affects their target organs, and cells, differently. Furthermore, the exosomes from the highly metastatic cells had a more pronounced effect on tumor growth and pre-metastatic changes than the low metastatic exosomes. The microRNA-18a, a predictor of metastasis, was present to a higher extent in metastatic exosomes as compared to low metastatic exosomes, and altered the tumor progressive properties. Our findings support the role of exomirs as important players in the metastatic process, the value as biomarkers and potential therapeutic targets.

    Nationell ämneskategori
    Cancer och onkologi Cell- och molekylärbiologi Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
    Identifikatorer
    urn:nbn:se:liu:diva-122829 (URN)
    Tillgänglig från: 2015-11-26 Skapad: 2015-11-26 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
  • 56.
    Bojmar, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Zhang, Haiying
    Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
    Costa da Silva, Bruno
    Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
    Karlsson, Elin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Vincent, Theresa
    Departments of Physiology and Biophysics and Cell and Developmental Biology, Weill Cornell Medical College, New York, USA / Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lyden, David
    Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
    Sandström, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    miR-18a is regulated between progressive compartments of cancers, and incorporated in exosomes with the potential of creating premetastatic niches and predict cancer outcome2015Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The ultimate cause of death for many cancer patients is the spread of the cancer via metastasis. Even so, there are still a lack of knowledge regarding the metastasis process. This study was performed to investigate the role of metastamirs in exosomes and their metastatic patterns. We used the well-established isogeneic murine cancer model of low metastatic 67NR cells, mimicking luminal/basal breast tumors, and highly metastatic 4T1 cells with characteristics of basal breast  tumors. We studied the exosomal properties and pre-metastatic effects in this metastasis model and compared human materials and exosomes of several other tumor types. Our data clearly demonstrated that exosomes from the highly metastatic cells home to the metastatic organs of their parental cells whereas exosomes from cells with low metastatic potential mostly located to lymph nodes. The exosome protein cargos also resembled their parental cells and potentially affects their target organs, and cells, differently. Furthermore, the exosomes from the highly metastatic cells had a more pronounced effect on tumor growth and pre-metastatic changes than the low metastatic exosomes. The microRNA-18a, a predictor of metastasis, was present to a higher extent in metastatic exosomes as compared to low metastatic exosomes, and altered the tumor progressive properties. Our findings support the role of exomirs as important players in the metastatic process, the value as biomarkers and potential therapeutic targets.

  • 57.
    Borgström, Annelie
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Analysis of tumour infiltrating leukocytes in colon cancer carcinoma in a syngeneic rat model2010Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Tumour immunity is a balance between immune mediators that promote tumor progression versus mediators that promote tumor rejection. Infiltrating lymphocytes in human colorectal cancer tissues are independent prognostic factors for a better survival and a high number of cytotoxic CD8+ T-cells have been associated with a better prognosis in terms of a longer and disease free survival for the patient. In our syngeneic rat model we induce colon carcinoma subperitoneally by injecting a colon cancer cell line BN7005, a cell line expressing the epitope (Lewis Y) for the BR96 antibody. Tumours are dissected out and treated with different fixatives and then either frozen, snap-frozen or embedded in paraffin followed by sectioning. Immunohistochemistry using monoclonal antibodies against the tumour infiltrating leukocytes was performed on the tissue.

    The results were seen as an infiltration of different leukocytes in the tumours.

     

  • 58.
    Borner, Tito
    et al.
    University of Zurich, Switzerland.
    Arnold, Myrtha
    Swiss Federal Institute Technology, Switzerland.
    Ruud, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Breit, Samuel N.
    University of New South Wales, Australia.
    Langhans, Wolfgang
    University of Zurich, Switzerland; Swiss Federal Institute Technology, Switzerland.
    Lutz, Thomas A.
    University of Zurich, Switzerland.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Riediger, Thomas
    University of Zurich, Switzerland.
    Anorexia-cachexia syndrome in hepatoma tumour-bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC-1/GDF152017Ingår i: Journal of Cachexia, Sarcopenia and Muscle, ISSN 2190-5991, E-ISSN 2190-6009, Vol. 8, nr 3, s. 417-427Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background The cancer-anorexia-cachexia syndrome (CACS) negatively affects survival and therapy success in cancer patients. Inflammatory mediators and tumour-derived factors are thought to play an important role in the aetiology of CACS. However, the central and peripheral mechanisms contributing to CACS are insufficiently understood. The area postrema (AP) and the nucleus tractus solitarii are two important brainstem centres for the control of eating during acute sickness conditions. Recently, the tumour-derived macrophage inhibitory cytokine-1 (MIC-1) emerged as a possible mediator of cancer anorexia because lesions of these brainstem areas attenuated the anorectic effect of exogenous MIC-1 in mice. Methods Using a rat hepatoma tumour model, we examined the roles of the AP and of vagal afferents in the mediation of CACS. Specifically, we investigated whether a lesion of the AP (APX) or subdiaphragmatic vagal deafferentation (SDA) attenuate anorexia, body weight, muscle, and fat loss. Moreover, we analysed MIC-1 levels in this tumour model and their correlation with tumour size and the severity of the anorectic response. Results In tumour-bearing sham-operated animals mean daily food intake significantly decreased. The anorectic response was paralleled by a significant loss of body weight and muscle mass. APX rats were protected against anorexia, body weight loss, and muscle atrophy after tumour induction. In contrast, subdiaphragmatic vagal deafferentation did not attenuate cancer-induced anorexia or body weight loss. Tumour-bearing rats had substantially increased MIC-1 levels, which positively correlated with tumour size and cancer progression and negatively correlated with food intake. Conclusions These findings demonstrate the importance of the AP in the mediation of cancer-dependent anorexia and body weight loss and support a pathological role of MIC-1 as a tumour-derived factor mediating CACS, possibly via an AP-dependent action.

  • 59.
    Bose, Tanima
    et al.
    Leibniz Inst Neurobiol, D-39 Magdeburg, Germany.
    Cieślar-Pobuda, Artur
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Silesian Tech Univ, Inst Automat Control, Biosyst Grp, PL-44100 Gliwice, Poland.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Role of ion channels in regulating Ca2+ homeostasis during the interplay between immune and cancer cells.2015Ingår i: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 19, nr 6, artikel-id e1648Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Ion channels are abundantly expressed in both excitable and non-excitable cells, thereby regulating the Ca2+ influx and downstream signaling pathways of physiological processes. The immune system is specialized in the process of cancer cell recognition and elimination, and is regulated by different ion channels. In comparison with the immune cells, ion channels behave differently in cancer cells by making the tumor cells more hyperpolarized and influence cancer cell proliferation and metastasis. Therefore, ion channels comprise an important therapeutic target in anti-cancer treatment. In this review, we discuss the implication of ion channels in regulation of Ca2+ homeostasis during the crosstalk between immune and cancer cell as well as their role in cancer progression.

  • 60.
    Bostner, Josefine
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Alayev, Anya
    Yeshiva Univ, NY 10033 USA.
    Berman, Adi Y.
    Yeshiva Univ, NY 10033 USA.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Holz, Marina K.
    Yeshiva Univ, NY 10033 USA; Albert Einstein Coll Med, NY 10467 USA; Albert Einstein Coll Med, NY 10467 USA.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer2018Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 168, nr 1, s. 17-27Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Deregulated PI3K/mTOR signals can promote the growth of breast cancer and contribute to endocrine treatment resistance. This report aims to investigate raptor and its intracellular localization to further understand its role in ER-positive breast cancer. Raptor protein expression was evaluated by immunohistochemistry in 756 primary breast tumors from postmenopausal patients randomized to tamoxifen or no tamoxifen. In vitro, the MCF7 breast cancer cell line and tamoxifen-resistant MCF7 cells were studied to track the raptor signaling changes upon resistance, and raptor localization in ER alpha-positive cell lines was compared with that in ER alpha-negative cell lines. Raptor protein expression in the nucleus was high in ER/PgR-positive and HER2-negative tumors with low grade, features associated with the luminal A subtype. Presence of raptor in the nucleus was connected with ER alpha signaling, here shown by a coupled increase of ER alpha phosphorylation at S167 and S305 with accumulation of nuclear raptor. In addition, the expression of ER alpha-activated gene products correlated with nuclear raptor. Similarly, in vitro we observed raptor in the nucleus of ER alpha-positive, but not of ER-negative cells. Interestingly, raptor localized to the nucleus could still be seen in tamoxifen-resistant MCF7 cells. The clinical benefit from tamoxifen was inversely associated with an increase of nuclear raptor. High cytoplasmic raptor expression indicated worse prognosis on long-term follow-up. We present a connection between raptor localization to the nucleus and ER alpha-positive breast cancer, suggesting raptor as a player in stimulating the growth of the luminal A subtype and a possible target along with endocrine treatment.

  • 61.
    Burek, C. J.
    et al.
    University of Münster, Germany.
    Roth, J.
    University of Münster, Germany.
    Koch, H. G.
    University of Münster, Germany.
    Harzer, K.
    University of Tübingen, Germany.
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Münster, Germany.
    Schulze-Osthoff, Klaus
    University of Münster, Germany .
    The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells2001Ingår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 20, nr 45, s. 6493-6502Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The activation of sphingomyelinases leading to the generation of ceramide has been implicated in various apoptotic pathways. However, the role of ceramide as an essential death mediator remains highly controversial. In the present study, we investigated the functional relevance of ceramide in a genetic model by using primary cells from a Farber disease patient. These cells accumulate ceramide as the result of an inherited deficiency of acidic ceramidase. We demonstrate that Farber disease lymphocytes and fibroblasts underwent apoptosis induced by various stress stimuli, including staurosporine, anticancer drugs and gamma -irradiation, equally as normal control cells. In addition, caspase activation by these proapoptotic agents occurred rather similarly in Farber disease and control fibroblasts. Interestingly, Farber disease lymphoid cells underwent apoptosis induced by the CD95 death receptor more rapidly than control cells. Our data therefore suggest that ceramide does not play an essential role as a second messenger in stress-induced apoptosis. However, in accordance with a role in lipid-rich microdomains, ceramide by altering membrane composition may function as an amplifier in CD95-mediated apoptosis.

  • 62.
    Burek, M.
    et al.
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Maddika, Subbareddy
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics,University of Manitoba, Winnipeg, Canada .
    Burek, C. J.
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Daniel, P. T.
    Department of Hematology, Oncology and Tumor Immunology, Charité, Berlin, Germany.
    Schulze-Osthoff, Klaus
    nstitute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Apoptin-induced cell death is modulated by Bcl-2 family members and is Apaf-1dependent2006Ingår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 25, nr 15, s. 2213-2222Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Apoptin, a chicken anemia virus-derived protein, selectively induces apoptosis in transformed but not in normal cells, thus making it a promising candidate as a novel anticancer therapeutic. The mechanism of apoptin-induced apoptosis is largely unknown. Here, we report that contrary to previous assumptions, Bcl-2 and Bcl-x(L) inhibit apoptin-induced cell death in several tumor cell lines. In contrast, deficiency of Bax conferred resistance, whereas Bax expression sensitized cells to apoptin-induced death. Cell death induction by apoptin was associated with cytochrome c release from mitochondria as well as with caspase-3 and -7 activation. Benzyloxy-carbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad spectrum caspase inhibitor, was highly protective against apoptin-induced cell death. Apoptosis induced by apoptin required Apaf-1, as immortalized Apaf-1-deficient fibroblasts as well as tumor cells devoid of Apaf-1 were strongly protected. Thus, our data indicate that apoptin-induced apoptosis is not only Bcl-2- and caspase dependent, but also engages an Apaf-1 apoptosome-mediated mitochondrial death pathway.

  • 63.
    Burger, Gerard
    et al.
    Symbiant Pathol Expert Centre, Netherlands; University of Amsterdam, Netherlands.
    Abu-Hanna, Ameen
    University of Amsterdam, Netherlands.
    de Keizer, Nicolette
    University of Amsterdam, Netherlands.
    Cornet, Ronald
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatik. Linköpings universitet, Tekniska fakulteten. University of Amsterdam, Netherlands.
    Natural language processing in pathology: a scoping review2016Ingår i: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 69, nr 11, s. 949-955Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Background Encoded pathology data are key for medical registries and analyses, but pathology information is often expressed as free text. Objective We reviewed and assessed the use of NLP (natural language processing) for encoding pathology documents. Materials and methods Papers addressing NLP in pathology were retrieved from PubMed, Association for Computing Machinery (ACM) Digital Library and Association for Computational Linguistics (ACL) Anthology. We reviewed and summarised the study objectives; NLP methods used and their validation; software implementations; the performance on the dataset used and any reported use in practice. Results The main objectives of the 38 included papers were encoding and extraction of clinically relevant information from pathology reports. Common approaches were word/phrase matching, probabilistic machine learning and rule-based systems. Five papers (13%) compared different methods on the same dataset. Four papers did not specify the method(s) used. 18 of the 26 studies that reported F-measure, recall or precision reported values of over 0.9. Proprietary software was the most frequently mentioned category (14 studies); General Architecture for Text Engineering (GATE) was the most applied architecture overall. Practical system use was reported in four papers. Most papers used expert annotation validation. Conclusions Different methods are used in NLP research in pathology, and good performances, that is, high precision and recall, high retrieval/removal rates, are reported for all of these. Lack of validation and of shared datasets precludes performance comparison. More comparative analysis and validation are needed to provide better insight into the performance and merits of these methods.

  • 64.
    Carlsson, Marianne
    et al.
    Department of Public Health and Caring Sciences, Section of Caring Sciences, Uppsala University, Sweden.
    Arman, Maria
    Department of Caring Sciences, Åbo Akademi University, Vasa, Finland and Blekinge Institute of Technology, Karlskrona, Sweden.
    Backman, Marie
    The Swedish Red Cross University College of Nursing, Stockholm, SwedenRed Cross Univ. Coll. Nursing, Stockholm, Sweden.
    Flatters, Ursula
    The Vidar Clinic, Järna, Sweden.
    Hatschek, Thomas
    The Department of Oncology (Radiumhemmet), Karolinska Hospital and Institute, Stockholm, Sweden.
    Hamrin, Elisabeth
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Evaluation of Quality of Life/Life Satisfaction in Women with Breast Cancer in Complementary and Conventional Care2004Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 43, nr 1, s. 27-34Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim was to study the perceived quality of life/life satisfaction in a sample of women with breast cancer who were treated in a hospital with alternative/complementary care and the same variables in individually matched patients who received only conventional medical treatment. A non-randomized controlled trial design with repeated measurements was used. Sixty women with breast cancer treated with anthroposophic medicine (ABCW) and 60 with conventional medicine (CBCW) were included and 36 matched pairs took part on all occasions. The quality of life was measured by the EORTC QLQ-C30 and the Life Satisfaction Questionnaire (LSQ). The comparisons were calculated as effect sizes (ES). The women in the ABCW group reported small or moderate effects, expressed as ES, on their quality of life/life satisfaction compared to their matched "twins" in the CBCW group at the 1-year follow-up in 15 out of 21 scales/factors. It was concluded that the women who had chosen anthroposophic care increased their perceived quality of life/life satisfaction according to the methodology of the study.

  • 65.
    Cheng, Dantong
    et al.
    Shanghai Jiao Tong University, Peoples R China.
    Zhao, Senlin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Shanghai Jiao Tong University, Peoples R China.
    Tang, Huamei
    Shanghai Jiao Tong University, Peoples R China.
    Zhang, Dongyuan
    Shanghai Jiao Tong University, Peoples R China.
    Sun, Hongcheng
    Shanghai Jiao Tong University, Peoples R China.
    Yu, Fudong
    Shanghai Jiao Tong University, Peoples R China.
    Jiang, Weiliang
    Shanghai Jiao Tong University, Peoples R China.
    Yue, Ben
    Shanghai Jiao Tong University, Peoples R China.
    Wang, Jingtao
    Shanghai Jiao Tong University, Peoples R China.
    Zhang, Meng
    Fudan University, Peoples R China.
    Yu, Yang
    Shanghai Jiao Tong University, Peoples R China.
    Liu, Xisheng
    Shanghai Jiao Tong University, Peoples R China.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Zhou, Zongguang
    Sichuan University, Peoples R China.
    Qin, Xuebin
    Temple University, PA 19122 USA.
    Zhang, Xin
    Zhejiang Prov Peoples Hospital, Peoples R China.
    Yan, Dongwang
    Shanghai Jiao Tong University, Peoples R China.
    Wen, Yugang
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Shanghai Jiao Tong University, Peoples R China.
    Peng, Zhihai
    Shanghai Jiao Tong University, Peoples R China.
    MicroRNA-20a-5p promotes colorectal cancer invasion and metastasis by downregulating Smad42016Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 29, s. 45199-45213Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Tumor metastasis is one of the leading causes of poor prognosis for colorectal cancer (CRC) patients. Loss of Smad4 contributes to aggression process in many human cancers. However, the underlying precise mechanism of aberrant Smad4 expression in CRC development is still little known. Results: miR-20a-5p negatively regulated Smad4 by directly targeting its 3UTR in human colorectal cancer cells. miR-20a-5p not only promoted CRC cells aggression capacity in vitro and liver metastasis in vivo, but also promoted the epithelial-to-mesenchymal transition process by downregulating Smad4 expression. In addition, tissue microarray analysis obtained from 544 CRC patients clinical characters showed that miR-20a-5p was upregulated in human CRC tissues, especially in the tissues with metastasis. High level of miR-20a-5p predicted poor prognosis in CRC patients. Methods: Five miRNA target prediction programs were applied to identify potential miRNA(s) that target(s) Smad4 in CRC. Luciferase reporter assay and transfection technique were used to validate the correlation between miR-20a-5p and Smad4 in CRC. Wound healing, transwell and tumorigenesis assays were used to explore the function of miR-20a-5p and Smad4 in CRC progression in vitro and in vivo. The association between miR-20a-5p expression and the prognosis of CRC patients was evaluated by Kaplan-Meier analysis and multivariate cox proportional hazard analyses based on tissue microarray data. Conclusions: miR-20a-5p, as an onco-miRNA, promoted the invasion and metastasis ability by suppressing Smad4 expression in CRC cells, and high miR-20a-5p predicted poor prognosis for CRC patients, providing a novel and promising therapeutic target in human colorectal cancer.

  • 66.
    Cibula, David
    et al.
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Poetter, Richard
    Med Univ Vienna, Austria.
    Planchamp, Francois
    Inst Bergoni, France.
    Åvall-Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fischerova, Daniela
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Haie-Meder, Christine
    Inst Gustave Roussy, France.
    Koehler, Christhardt
    Asklepios Hambourg Altona and Univ Cologne, Germany.
    Landoni, Fabio
    Univ Milano Bicocca, Italy.
    Lax, Sigurd
    Gen Hosp Graz Sued West, Austria.
    Lindegaard, Jacob Christian
    Aarhus Univ, Denmark.
    Mahantshetty, Umesh
    Tata Mem Hosp, India.
    Mathevet, Patrice
    Lausanne Univ, Switzerland.
    McCluggage, W. Glenn
    Belfast Hlth and Social Care Trust, North Ireland.
    McCormack, Mary
    Univ Coll London Hosp, England.
    Naik, Raj
    Queen Elizabeth Hosp, England.
    Nout, Remi
    Leiden Univ, Netherlands.
    Pignata, Sandro
    IRCCS, Italy.
    Ponce, Jordi
    Univ Hosp Bellvitge IDIBELL, Spain.
    Querleu, Denis
    Inst Bergoni, France.
    Raspagliesi, Francesco
    Fdn IRCCS Ist Nazl Tumori, Italy.
    Rodolakis, Alexandros
    Univ Athens, Greece.
    Tamussino, Karl
    Med Univ Graz, Austria.
    Wimberger, Pauline
    Dresden Univ, Germany.
    Raspollini, Maria Rosaria
    Univ Hosp, Italy.
    Correction: The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology Guidelines for the Management of Patients with Cervical Cancer (vol 472, pg 919, 2018)2018Ingår i: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 472, nr 6, s. 937-938Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 67.
    Cibula, David
    et al.
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Poetter, Richard
    Med Univ Vienna, Austria.
    Planchamp, Francois
    Inst Bergonie, France.
    Åvall-Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fischerova, Daniela
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Haie-Meder, Christine
    Inst Gustave Roussy, France.
    Koehler, Christhardt
    Asklepios Hambourg Altona, Germany; Univ Cologne, Germany.
    Landoni, Fabio
    Univ Milano Bicocca, Italy.
    Lax, Sigurd
    Gen Hosp Graz Sued West, Austria.
    Lindegaard, Jacob Christian
    Aarhus Univ, Denmark.
    Mahantshetty, Umesh
    Tata Mem Hosp, India.
    Mathevet, Patrice
    Lausanne Univ, Switzerland.
    McCluggage, W. Glenn
    Belfast Hlth and Social Care Trust, North Ireland.
    McCormack, Mary
    Univ Coll London Hosp, England.
    Naik, Raj
    Queen Elizabeth Hosp, England.
    Nout, Remi
    Leiden Univ, Netherlands.
    Pignata, Sandro
    IRCCS, Italy.
    Ponce, Jordi
    Univ Hosp Bellvitge IDIBELL, Spain.
    Querleu, Denis
    Inst Bergonie, France.
    Raspagliesi, Francesco
    Fdn IRCCS Ist Nazl Tumori, Italy.
    Rodolakis, Alexandros
    Univ Athens, Greece.
    Tamussino, Karl
    Med Univ Graz, Austria.
    Wimberger, Pauline
    Dresden Univ, Germany.
    Raspollini, Maria Rosaria
    Univ Hosp, Italy.
    Correction to: Correction: The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology Guidelines for the Management of Patients with Cervical Cancer (vol 472, pg 919, 2018)2018Ingår i: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 473, nr 3, s. 391-391Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 68.
    Cibula, David
    et al.
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Poetter, Richard
    Med Univ Vienna, Austria.
    Planchamp, Francois
    Inst Bergoni, France.
    Åvall-Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fischerova, Daniela
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Haie-Meder, Christine
    Inst Gustave Roussy, France.
    Koehler, Christhardt
    Asklepios Hambourg Altona and Univ Cologne, Germany.
    Landoni, Fabio
    Univ Milano Bicocca, Italy.
    Lax, Sigurd
    Gen Hosp Graz Sued West, Austria.
    Lindegaard, Jacob Christian
    Aarhus Univ, Denmark.
    Mahantshetty, Umesh
    Tata Mem Hosp, India.
    Mathevet, Patrice
    Lausanne Univ, Switzerland.
    McCluggage, W. Glenn
    Belfast Hlth and Social Care Tmst, North Ireland.
    McCormack, Mary
    Univ Coll London Hosp, England.
    Naik, Raj
    Queen Elizabeth Hosp, England.
    Nout, Remi
    Leiden Univ, Netherlands.
    Pignata, Sandro
    IRCCS, Italy.
    Ponce, Jordi
    Univ Hosp Bellvitge IDIBELL, Spain.
    Querleu, Denis
    Inst Bergoni, France.
    Raspagliesi, Francesco
    Fdn IRCCS Ist Nazl Tumori, Italy.
    Rodolakis, Alexandros
    Univ Athens, Greece.
    Tamussino, Karl
    Med Univ Graz, Austria.
    Wimberger, Pauline
    Dresden Univ, Germany.
    Raspollini, Maria Rosaria
    Univ Hosp, Italy.
    The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology Guidelines for the Management of Patients with Cervical Cancer2018Ingår i: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 472, nr 6, s. 919-936Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The European Society of Gynecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide. The ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives. The guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined.

  • 69.
    Cibula, David
    et al.
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Poetter, Richard
    Med Univ Vienna, Austria.
    Planchamp, Francois
    Inst Bergonie, France.
    Åvall-Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fischerova, Daniela
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Meder, Christine Haie
    Inst Gustave Roussy, France.
    Koehler, Christhardt
    Asklepios Hambourg Altona, Germany; Univ Cologne, Germany.
    Landoni, Fabio
    Univ Milano Bicocca, Italy.
    Lax, Sigurd
    Gen Hosp Graz Sued West, Austria.
    Lindegaard, Jacob Christian
    Aarhus Univ, Denmark.
    Mahantshetty, Umesh
    Tata Mem Hosp, India.
    Mathevet, Patrice
    Lausanne Univ, Switzerland.
    McCluggage, W. Glenn
    Belfast Hlth and Social Care Trust, North Ireland.
    McCormack, Mary
    Univ Coll London Hosp, England.
    Naik, Raj
    Queen Elizabeth Hosp, England.
    Nout, Remi
    Leiden Univ, Netherlands.
    Pignata, Sandro
    Ist Nazl Studio and Cura Tumori, Italy.
    Ponce, Jordi
    Univ Hosp Bellvitge IDIBELL, Spain.
    Querleu, Denis
    Inst Bergonie, France.
    Raspagliesi, Francesco
    Not Found:[Cibula, David; Fischerova, Daniela] Charles Univ Prague, Fac Med 1, Gynecol Oncol Ctr, Dept Obstet and Gynecol, Prague, Czech Republic; [Cibula, David; Fischerova, Daniela] Gen Univ Hosp, Prague, Czech Republic; [Poetter, Richard] Med Univ Vienna, Dept Radiotherapy, Vienna, Austria; [Planchamp, Francois; Querleu, Denis] Inst Bergonie, Bordeaux, France; [Avall-Lundqvist, Elisabeth] Linkoping Univ, Linkoping, Sweden; [Meder, Christine Haie] Inst Gustave Roussy, Dept Radiotherapy, Villejuif, France; [Koehler, Christhardt] Asklepios Hambourg Altona, Hamburg, Germany; [Koehler, Christhardt] Univ Cologne, Med Fac, Dept Gynecol, Cologne, Germany; [Landoni, Fabio] Univ Milano Bicocca, Monza, Italy; [Lax, Sigurd] Gen Hosp Graz Sued West, Graz, Austria; [Lindegaard, Jacob Christian] Aarhus Univ, Dept Oncol, Aarhus, Denmark; [Mahantshetty, Umesh] Tata Mem Hosp, Dept Radiat Oncol, Mumbai, Maharashtra, India; [Mathevet, Patrice] Lausanne Univ, Lausanne, Switzerland; [McCluggage, W. Glenn] Belfast Hlth and Social Care Trust, Dept Pathol, Belfast, Antrim, North Ireland; [McCormack, Mary] Univ Coll London Hosp, London, England; [Naik, Raj] Queen Elizabeth Hosp, Gateshead, England; [Nout, Remi] Leiden Univ, Dept Radiat Oncol, Leiden, Netherlands; [Pignata, Sandro] Ist Nazl Studio and Cura Tumori, IRCCS, Fdn G Pascale, Naples, Italy; [Ponce, Jordi] Univ Hosp Bellvitge IDIBELL, Barcelona, Spain; [Rodolakis, Alexandros] Ist Nazl Tumori, Fdn IRCCS, Milan, Italy; [Tamussino, Karl] Univ Athens, Athens, Greece; [Wimberger, Pauline] Med Univ Graz, Graz, Austria; [Wimberger, Pauline] Dresden Univ, TU Dresden, Dresden, Germany; [Raspollini, Maria Rosaria] Univ Hosp, Florence, Italy;.
    Rodolakis, Alexandros
    Ist Nazl Tumori, Italy.
    Tamussino, Karl
    Univ Athens, Greece.
    Wimberger, Pauline
    Med Univ Graz, Austria; Dresden Univ, Germany.
    Raspollini, Maria Rosaria
    Univ Hosp, Italy.
    The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology Guidelines for the Management of Patients With Cervical Cancer2018Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 28, nr 4, s. 641-655Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Despite significant advances in the screening, detection, and treatment of preinvasive cervical lesions, invasive cervical cancer is the fifth most common cancer in European women. There are large disparities in Europe and worldwide in the incidence, management, and mortality of cervical cancer. Objective The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide. Methods The ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives. Results The guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined.

  • 70.
    Cibula, David
    et al.
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Poetter, Richard
    Med Univ Vienna, Austria.
    Planchamp, Francois
    Inst Bergonie, France.
    Åvall-Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fischerova, Daniela
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Meder, Christine Haie
    Inst Gustave Roussy, France.
    Koehler, Christhardt
    Asklepios Hambourg Altona, Germany; Univ Cologne, Germany.
    Landoni, Fabio
    Univ Milano Bicocca, Italy.
    Lax, Sigurd
    Gen Hosp Graz Sued West, Austria.
    Lindegaard, Jacob Christian
    Aarhus Univ, Denmark.
    Mahantshetty, Umesh
    Tata Mem Hosp, India.
    Mathevet, Patrice
    Lausanne Univ, Switzerland.
    McCluggage, W. Glenn
    Belfast Hlth and Social Care Trust, North Ireland.
    McCormack, Mary
    Univ Coll Hosp London, England.
    Naik, Raj
    Queen Elizabeth Hosp, England.
    Nout, Remi
    Leiden Univ, Netherlands.
    Pignata, Sandro
    IRCCS, Italy.
    Ponce, Jordi
    Univ Hosp Bellvitge IDIBELL, Spain.
    Querleu, Denis
    Inst Bergonie, France.
    Raspagliesi, Francesco
    Fdn IRCCS Ist Nazl Tumori, Italy.
    Rodolakis, Alexandros
    Univ Athens, Greece.
    Tamussino, Karl
    Med Univ Graz, Austria.
    Wimberger, Pauline
    Tech Univ Dresden, Germany.
    Raspollini, Maria Rosaria
    Univ Hosp, Italy.
    The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines for the management of patients with cervical cancer2018Ingår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 127, nr 3, s. 404-416Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Despite significant advances in the screening, detection, and treatment of preinvasive cervical lesions, invasive cervical cancer is the fifth most common cancer in European women. There are large disparities in Europe and worldwide in the incidence, management, and mortality of cervical cancer. Objective: The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide. Methods: The ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives. Results: The guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined. (C) 2018 European Society for Gynaecological Oncology, European Society for Radiotherapy and Oncology, and the European Society of Pathology. Published by Elsevier B.V. All rights reserved.

  • 71.
    Clarke, Emily L.
    et al.
    Univ Leeds, England; Leeds Teaching Hosp NHS Trust, England.
    Brettle, David
    Leeds Teaching Hosp NHS Trust, England.
    Sykes, Alexander
    Univ Leeds, England.
    Wright, Alexander
    Univ Leeds, England.
    Boden, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Treanor, Darren
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi. Univ Leeds, England.
    Development and Evaluation of a Novel Point-of-Use Quality Assurance Tool for Digital Pathology2019Ingår i: Archives of Pathology & Laboratory Medicine, ISSN 0003-9985, E-ISSN 1543-2165, Vol. 143, nr 10, s. 1246-1255Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context.-Flexible working at diverse or remote sites is a major advantage when reporting using digital pathology, but currently there is no method to validate the clinical diagnostic setting within digital microscopy. Objective.-To develop a preliminary Point-of-Use Quality Assurance (POUQA) tool designed specifically to validate the diagnostic setting for digital microscopy. Design.-We based the POUQA tool on the red, green, and blue (RGB) values of hematoxylin-eosin. The tool used 144 hematoxylin-eosin-colored, 5x5-cm patches with a superimposed random letter with subtly lighter RGB values from the background color, with differing levels of difficulty. We performed an initial evaluation across 3 phases within 2 pathology departments: 1 in the United Kingdom and 1 in Sweden. Results.-In total, 53 experiments were conducted across all phases resulting in 7632 test images viewed in all. Results indicated that the display, the users visual system, and the environment each independently impacted performance. Performance was improved with reduction in natural light and through use of medical-grade displays. Conclusions.-The use of a POUQA tool for digital microscopy is essential to afford flexible working while ensuring patient safety. The color-contrast test provides a standardized method of comparing diagnostic settings for digital microscopy. With further planned development, the color-contrast test may be used to create a "Verified Login" for diagnostic setting validation.

  • 72.
    Coomans, Marijke B.
    et al.
    Leiden Univ, Netherlands.
    Dirven, Linda
    Leiden Univ, Netherlands; Haaglanden Med Ctr, Netherlands.
    Aaronson, Neil K.
    Netherlands Canc Inst, Netherlands.
    Baumert, Brigitta G.
    Univ Hosp Bonn, Germany; Maastricht Univ, Netherlands; Maastricht Univ, Netherlands.
    Van Den Bent, Martin
    Erasmus MC Canc Inst, Netherlands.
    Bottomley, Andrew
    European Org Res Treatment Canc, Belgium.
    Brandes, Alba A.
    Azienda USL IRCCS, Italy.
    Chinot, Olivier
    Aix Marseille Univ, France.
    Coens, Corneel
    European Org Res Treatment Canc, Belgium.
    Gorlia, Thierry
    European Org Res and Treatment Canc Headquarters, Belgium.
    Herrlinger, Ulrich
    Univ Bonn, Germany.
    Keime-Guibert, Florence
    Pitie Salpetriere Hosp Grp, France.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, LAH Linköping.
    Martinelli, Francesca
    European Org Res Treatment Canc, Belgium.
    Stupp, Roger
    Northwestern Univ, IL 60611 USA.
    Talacchi, Andrea
    San Giovanni Addolorata Hosp, Italy.
    Weller, Michael
    Univ Hosp, Switzerland; Univ Zurich, Switzerland.
    Wick, Wolfgang
    Univ Hosp Heidelberg, Germany; Univ Hosp Heidelberg, Germany; German Canc Res Ctr, Germany.
    Reijneveld, Jaap C.
    Univ Amsterdam, Netherlands.
    Taphoorn, Martin J. B.
    Leiden Univ, Netherlands; Haaglanden Med Ctr, Netherlands.
    Symptom clusters in newly diagnosed glioma patients: which symptom clusters are independently associated with functioning and global health status?2019Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 21, nr 11, s. 1447-1457Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. Symptom management in glioma patients remains challenging, as patients suffer from various concurrently occurring symptoms. This study aimed to identify symptom clusters and examine the association between these symptom clusters and patients functioning. Methods. Data of the CODAGLIO project was used, including individual patient data from previously published international randomized controlled trials (RCTs) in glioma patients. Symptom prevalence and level of functioning were assessed with European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQ-C30 and QLQ-BN20 self-report questionnaires. Associations between symptoms were examined with Spearman correlation coefficients and partial correlation networks. Hierarchical cluster analyses were performed to identify symptom clusters. Multivariable regression analyses were performed to determine independent associations between the symptom clusters and functioning, adjusted for possible confounders. Results. Included in the analysis were 4307 newly diagnosed glioma patients from 11 RCTs who completed the EORTC questionnaires before randomization. Many patients (44%) suffered from 5-10 symptoms simultaneously. Four symptom clusters were identified: a motor cluster, a fatigue cluster, a pain cluster, and a gastrointestinal/seizures/bladder control cluster. Having symptoms in the motor cluster was associated with decreased (amp;gt;= 10 points difference) physical, role, and social functioning (betas ranged from -11.3 to -15.9, all P amp;lt; 0.001), independent of other factors. Similarly, having symptoms in the fatigue cluster was found to negatively influence role functioning (beta of -12.3, P amp;lt; 0.001), independent of other factors. Conclusions. Two symptom clusters, the fatigue and motor cluster, were frequently affected in glioma patients and were found to independently have a negative association with certain aspects of patients functioning as measured with a self-report questionnaire.

  • 73.
    Couch, Fergus J.
    et al.
    Mayo Clin, MN 55905 USA; Mayo Clin, MN 55905 USA.
    Kuchenbaecker, Karoline B.
    University of Cambridge, England.
    Michailidou, Kyriaki
    University of Cambridge, England.
    Mendoza-Fandino, Gustavo A.
    University of S Florida, FL 33612 USA.
    Nord, Silje
    Radiumhosp, Norway.
    Lilyquist, Janna
    Mayo Clin, MN 55905 USA.
    Olswold, Curtis
    Mayo Clin, MN 55905 USA.
    Hallberg, Emily
    Mayo Clin, MN 55905 USA.
    Agata, Simona
    IRCCS, Italy.
    Ahsan, Habibul
    University of Chicago, IL 60637 USA; University of Chicago, IL 60637 USA; University of Chicago, IL 60637 USA.
    Aittomaeki, Kristiina
    University of Helsinki, Finland.
    Ambrosone, Christine
    Roswell Pk Cancer Institute, NY 14263 USA.
    Andrulis, Irene L.
    Mt Sinai Hospital, Canada; University of Toronto, Canada; University of Toronto, Canada.
    Anton-Culver, Hoda
    University of Calif Irvine, CA 92697 USA.
    Arndt, Volker
    German Cancer Research Centre, Germany.
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Arver, Brita
    Karolinska University Hospital, Sweden.
    Barile, Monica
    Ist Europeo Oncol, Italy.
    Barkardottir, Rosa B.
    Landspitali University Hospital, Iceland; University of Iceland, Iceland.
    Barrowdale, Daniel
    University of Cambridge, England.
    Beckmann, Lars
    Institute Qual and Efficiency Health Care IQWiG, Germany.
    Beckmann, Matthias W.
    University of Erlangen Nurnberg, Germany.
    Benitez, Javier
    Spanish National Cancer Centre CNIO, Spain; Spanish National Cancer Centre CNIO, Spain; Biomed Network Rare Disease CIBERER, Spain.
    Blank, Stephanie V.
    NYU, NY 10016 USA.
    Blomqvist, Carl
    University of Helsinki, Finland; University of Helsinki, Finland.
    Bogdanova, Natalia V.
    Hannover Medical Sch, Germany.
    Bojesen, Stig E.
    Copenhagen University Hospital, Denmark.
    Bolla, Manjeet K.
    University of Cambridge, England.
    Bonanni, Bernardo
    Ist Europeo Oncol, Italy.
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany; University of Tubingen, Germany.
    Brenner, Hermann
    German Cancer Research Centre, Germany; German Cancer Research Centre, Germany; National Centre Tumor Disease NCT, Germany.
    Burwinkel, Barbara
    Heidelberg University, Germany.
    Buys, Saundra S.
    University of Utah, UT 84112 USA.
    Caldes, Trinidad
    IdISSC, Spain.
    Caligo, Maria A.
    University of Pisa, Italy; University Hospital Pisa, Italy.
    Canzian, Federico
    German Cancer Research Centre, Germany.
    Carpenter, Jane
    University of Sydney, Australia.
    Chang-Claude, Jenny
    German Cancer Research Centre, Germany.
    Chanock, Stephen J.
    NCI, MD 20850 USA.
    Chung, Wendy K.
    Columbia University, NY 10032 USA; Columbia University, NY 10032 USA.
    Claes, Kathleen B. M.
    University of Ghent, Belgium.
    Cox, Angela
    University of Sheffield, England.
    Cross, Simon S.
    University of Sheffield, England.
    Cunningham, Julie M.
    Mayo Clin, MN 55905 USA.
    Czene, Kamila
    Karolinska Institute, Sweden.
    Daly, Mary B.
    Fox Chase Cancer Centre, PA 19111 USA.
    Damiola, Francesca
    University of Lyon, France.
    Darabi, Hatef
    Karolinska Institute, Sweden.
    de la Hoya, Miguel
    IdISSC, Spain.
    Devilee, Peter
    Leiden University, Netherlands.
    Diez, Orland
    University Hospital Vall dHebron, Spain; University of Autonoma Barcelona, Spain.
    Ding, Yuan C.
    City Hope National Medical Centre, CA 91010 USA.
    Dolcetti, Riccardo
    CRO Aviano National Cancer Institute, Italy.
    Domchek, Susan M.
    University of Penn, PA 19104 USA.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    dos-Santos-Silva, Isabel
    University of London London School Hyg and Trop Med, England.
    Dumont, Martine
    Centre Hospital University of Quebec, Canada; University of Laval, Canada.
    Dunning, Alison M.
    University of Cambridge, England.
    Eccles, Diana M.
    University of Southampton, England.
    Ehrencrona, Hans
    Uppsala University, Sweden; University of Lund Hospital, Sweden.
    Ekici, Arif B.
    University of Erlangen Nurnberg, Germany; Comprehens Cancer Centre EMN, Germany.
    Eliassen, Heather
    Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Ellis, Steve
    University of Cambridge, England.
    Fasching, Peter A.
    University of Erlangen Nurnberg, Germany.
    Figueroa, Jonine
    NCI, MD 20850 USA.
    Flesch-Janys, Dieter
    University of Clin Hamburg Eppendorf, Germany; University of Clin Hamburg Eppendorf, Germany.
    Foersti, Asta
    German Cancer Research Centre, Germany; Lund University, Sweden.
    Fostira, Florentia
    National Centre Science Research Demokritos, Greece.
    Foulkes, William D.
    McGill University, Canada.
    Friebel, Tara
    University of Philadelphia, PA 19104 USA.
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel.
    Frost, Debra
    University of Cambridge, England.
    Gabrielson, Marike
    Karolinska Institute, Sweden.
    Gammon, Marilie D.
    University of N Carolina, NC 27599 USA.
    Ganz, Patricia A.
    Jonsson Comprehens Cancer Centre, CA 90095 USA; Jonsson Comprehens Cancer Centre, CA 90095 USA.
    Gapstur, Susan M.
    Amer Cancer Soc, GA 30303 USA.
    Garber, Judy
    Dana Farber Cancer Institute, MA 02215 USA.
    Gaudet, Mia M.
    Amer Cancer Soc, GA 30303 USA.
    Gayther, Simon A.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Gerdes, Anne-Marie
    Copenhagen University Hospital, Denmark.
    Ghoussaini, Maya
    University of Cambridge, England.
    Giles, Graham G.
    Cancer Council Victoria, Australia.
    Glendon, Gord
    Mt Sinai Hospital, Canada.
    Godwin, Andrew K.
    University of Kansas, KS 66205 USA.
    Goldberg, Mark S.
    McGill University, Canada; McGill University, Canada.
    Goldgar, David E.
    University of Utah, UT 84132 USA.
    Gonzalez-Neira, Anna
    Spanish National Cancer Research Centre CNIO, Spain.
    Greene, Mark H.
    NCI, MD 20850 USA.
    Gronwald, Jacek
    Pomeranian Medical University, Poland.
    Guenel, Pascal
    CESP Centre Research Epidemiol and Populat Heatlh, France.
    Gunter, Marc
    University of London Imperial Coll Science Technology and Med, England.
    Haeberle, Lothar
    University of Erlangen Nurnberg, Germany.
    Haiman, Christopher A.
    University of So Calif, CA 90033 USA.
    Hamann, Ute
    German Cancer Research Centre, Germany.
    Hansen, Thomas V. O.
    Copenhagen University Hospital, Denmark.
    Hart, Steven
    Mayo Clin, MN 55905 USA.
    Healey, Sue
    QIMR Berghofer Medical Research Institute, Australia.
    Heikkinen, Tuomas
    Heidelberg University, Germany; University of Helsinki, Finland.
    Henderson, Brian E.
    University of So Calif, CA 90033 USA.
    Herzog, Josef
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, Netherlands.
    Hollestelle, Antoinette
    Erasmus MC Cancer Institute, Netherlands.
    Hooning, Maartje J.
    Erasmus University, Netherlands.
    Hoover, Robert N.
    NCI, MD 20850 USA.
    Hopper, John L.
    University of Melbourne, Australia.
    Humphreys, Keith
    Karolinska Institute, Sweden.
    Hunter, David J.
    Harvard University, MA 02115 USA.
    Huzarski, Tomasz
    Pomeranian Medical University, Poland.
    Imyanitov, Evgeny N.
    NN Petrov Oncology Research Institute, Russia.
    Isaacs, Claudine
    Georgetown University, DC 20007 USA.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    James, Paul
    Peter MacCallum Cancer Centre, Australia; University of Melbourne, Australia.
    Janavicius, Ramunas
    State Research Institute, Lithuania.
    Birk Jensen, Uffe
    Aarhus University Hospital, Denmark.
    John, Esther M.
    Cancer Prevent Institute Calif, CA 94538 USA.
    Jones, Michael
    Institute Cancer Research, England.
    Kabisch, Maria
    German Cancer Research Centre, Germany.
    Kar, Siddhartha
    University of Cambridge, England.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Khan, Sofia
    University of Helsinki, Finland; University of Helsinki, Finland.
    Khaw, Kay-Tee
    University of Cambridge, England.
    Kibriya, Muhammad G.
    University of Chicago, IL 60637 USA.
    Knight, Julia A.
    Mt Sinai Hospital, Canada.
    Ko, Yon-Dschun
    Evangel Kliniken Bonn gGmbH, Germany.
    Konstantopoulou, Irene
    National Centre Science Research Demokritos, Greece.
    Kosma, Veli-Matti
    University of Eastern Finland, Finland.
    Kristensen, Vessela
    Radiumhosp, Norway.
    Kwong, Ava
    Hong Kong Hereditary Breast Cancer Family Registry, Peoples R China; University of Hong Kong, Peoples R China.
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel.
    Lambrechts, Diether
    VIB, Belgium.
    Lazaro, Conxi
    IDIBELL Catalan Institute Oncol, Spain.
    Lee, Eunjung
    University of So Calif, CA 90032 USA.
    Le Marchand, Loic
    University of Cancer Centre, HI 96813 USA.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Lindblom, Annika
    Karolinska Institute, Sweden.
    Lindor, Noralane
    Mayo Clin, AZ 85259 USA.
    Lindstrom, Sara
    Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Liu, Jianjun
    Genome Institute Singapore, Singapore.
    Long, Jirong
    Vanderbilt University, TN 37203 USA; Vanderbilt University, TN 37203 USA.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Mai, Phuong L.
    NCI, MD 20850 USA.
    Makalic, Enes
    University of Melbourne, Australia.
    Malone, Kathleen E.
    Fred Hutchinson Cancer Research Centre, WA 98109 USA; University of Washington, WA 98195 USA.
    Mannermaa, Arto
    University of Eastern Finland, Finland.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Margolin, Sara
    Karolinska University Hospital, Sweden.
    Marme, Frederik
    Heidelberg University, Germany.
    Martens, John W. M.
    Erasmus MC Cancer Institute, Netherlands.
    McGuffog, Lesley
    University of Cambridge, England.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Miller, Austin
    Roswell Pk Cancer Institute, NY 14263 USA.
    Milne, Roger L.
    Cancer Council Victoria, Australia.
    Miron, Penelope
    Case Western Reserve University, OH 44106 USA.
    Montagna, Marco
    IRCCS, Italy.
    Mazoyer, Sylvie
    University of Lyon, France.
    Mulligan, Anna M.
    University of Health Network, Canada; University of Toronto, Canada.
    Muranen, Taru A.
    Heidelberg University, Germany; University of Helsinki, Finland.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA.
    Neuhausen, Susan L.
    City Hope National Medical Centre, CA 91010 USA.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Nordestgaard, Borge G.
    Copenhagen University Hospital, Denmark.
    Nussbaum, Robert L.
    Invitae Corp, CA 94107 USA.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Olah, Edith
    National Institute Oncol, Hungary.
    Olopade, Olufunmilayo I.
    University of Chicago, IL 60637 USA.
    Olson, Janet E.
    Mayo Clin, MN 55905 USA.
    Osorio, Ana
    Spanish National Cancer Centre CNIO, Spain.
    Park, Sue K.
    Seoul National University, South Korea; Seoul National University, South Korea.
    Peeters, Petra H.
    University of Medical Centre, Netherlands; University of London Imperial Coll Science Technology and Med, England.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Peterlongo, Paolo
    Fdn Ist FIRC Oncology Mol, Italy.
    Peto, Julian
    University of London London School Hyg and Trop Med, England.
    Phelan, Catherine M.
    University of S Florida, FL 33612 USA.
    Pilarski, Robert
    Ohio State University, OH 43210 USA.
    Poppe, Bruce
    University of Ghent, Belgium.
    Pylkaes, Katri
    University of Oulu, Finland; University of Oulu, Finland; University of Oulu, Finland.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Rahman, Nazneen
    Institute Cancer Research, England.
    Rantala, Johanna
    Karolinska University Hospital, Sweden.
    Rappaport, Christine
    Medical University of Vienna, Austria.
    Rennert, Gad
    Clalit National Israeli Cancer Control Centre, Israel; Carmel Hospital, Israel; B Rappaport Fac Med, Israel.
    Richardson, Andrea
    Johns Hopkins University, MD 21205 USA.
    Robson, Mark
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Romieu, Isabelle
    Int Agency Research Canc, France.
    Rudolph, Anja
    German Cancer Research Centre, Germany.
    Rutgers, Emiel J.
    Antoni van Leeuwenhoek Hospital, Netherlands.
    Sanchez, Maria-Jose
    University of Granada, Spain; CIBER Epidemiol and Salud Public CIBERESP, Spain.
    Santella, Regina M.
    Columbia University, NY 10032 USA.
    Sawyer, Elinor J.
    Kings Coll London, England.
    Schmidt, Daniel F.
    University of Melbourne, Australia.
    Schmidt, Marjanka K.
    Antoni van Leeuwenhoek Hospital, Netherlands.
    Schmutzler, Rita K.
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Schumacher, Fredrick
    University of So Calif, CA 90033 USA.
    Scott, Rodney
    John Hunter Hospital, Australia.
    Senter, Leigha
    Ohio State University, OH 43210 USA.
    Sharma, Priyanka
    University of Kansas, KS 66205 USA.
    Simard, Jacques
    University of Laval, Canada.
    Singer, Christian F.
    Medical University of Vienna, Austria.
    Sinilnikova, Olga M.
    University of Lyon, France; Hospital Civils Lyon, France.
    Soucy, Penny
    University of Laval, Canada.
    Southey, Melissa
    University of Melbourne, Australia.
    Steinemann, Doris
    Hannover Medical Sch, Germany.
    Stenmark-Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; University of Paris 05, France.
    Swerdlow, Anthony
    Institute Cancer Research, England.
    Szabo, Csilla I.
    NHGRI, MD 20892 USA.
    Tamimi, Rulla
    Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Tapper, William
    University of Southampton, England.
    Teixeira, Manuel R.
    Portuguese Oncology Institute, Portugal; University of Porto, Portugal.
    Teo, Soo-Hwang
    Cancer Research Initiat Fdn, Malaysia; University of Malaya, Malaysia.
    Terry, Mary B.
    Columbia University, NY 10032 USA.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Thompson, Deborah
    University of Cambridge, England.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Latvia.
    Toland, Amanda E.
    Ohio State University, OH 43210 USA.
    Tollenaar, Robert A. E. M.
    Leiden University, Netherlands.
    Tomlinson, Ian
    University of Oxford, England; University of Oxford, England.
    Truong, Therese
    CESP Centre Research Epidemiol and Populat Heatlh, France.
    Tsimiklis, Helen
    University of Melbourne, Australia.
    Teule, Alex
    IDIBELL Catalan Institute Oncol, Spain.
    Tumino, Rosario
    Civ MP Arezzo Hospital, Italy; Civ MP Arezzo Hospital, Italy.
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA 02215 USA.
    Turnbull, Clare
    Institute Cancer Research, England.
    Ursin, Giski
    Institute Populat Based Cancer Research, Norway.
    van Deurzen, Carolien H. M.
    Erasmus University, Netherlands.
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Varon-Mateeva, Raymonda
    Charite, Germany.
    Wang, Zhaoming
    NCI, MD 20877 USA.
    Wang-Gohrke, Shan
    University Hospital Ulm, Germany.
    Weiderpass, Elisabete
    Karolinska Institute, Sweden; Institute Populat Based Cancer Research, Norway; University of Tromso, Norway; Folkhalsan Research Centre, Finland.
    Weitzel, Jeffrey N.
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Whittemore, Alice
    Stanford University, CA 94305 USA.
    Wildiers, Hans
    University Hospital, Belgium.
    Winqvist, Robert
    University of Oulu, Finland; University of Oulu, Finland; University of Oulu, Finland.
    Yang, Xiaohong R.
    NCI, MD 20892 USA.
    Yannoukakos, Drakoulis
    National Centre Science Research Demokritos, Greece.
    Yao, Song
    Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.
    Pilar Zamora, M.
    Hospital University of La Paz, Spain.
    Zheng, Wei
    Vanderbilt University, TN 37203 USA; Vanderbilt University, TN 37203 USA.
    Hall, Per
    Karolinska Institute, Sweden.
    Kraft, Peter
    Harvard University, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Vachon, Celine
    Mayo Clin, MN 55905 USA.
    Slager, Susan
    Mayo Clin, MN 55905 USA.
    Chenevix-Trench, Georgia
    QIMR Berghofer Medical Research Institute, Australia.
    Pharoah, Paul D. P.
    University of Cambridge, England.
    Monteiro, Alvaro A. N.
    University of S Florida, FL 33612 USA.
    Garcia-Closas, Montserrat
    NCI, MD 20850 USA.
    Easton, Douglas F.
    University of Cambridge, England.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, nr 11375, s. 1-13Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P&lt;5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P&lt;0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

  • 74.
    Dasu, Alexandru
    Norrlands University Hospital.
    Is the alpha/beta value for prostate tumours low enough to be safely used in clinical trials?2007Ingår i: Clinical Oncology, ISSN 0936-6555, E-ISSN 1433-2981, Vol. 19, nr 5, s. 289-301Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    There has been an intense debate over the past several years on the relevant alpha/beta value that could be used to describe the fractionation response of prostate tumours. Previously it has been assumed that prostate tumours have high alpha/beta values, similar to most other tumours and the early reacting normal tissues. However, the proliferation behaviour of the prostate tumours is more like that of the late reacting tissues, with slow doubling times and low alpha/beta values. The analyses of clinical results carried out in the past few years have indeed suggested that the alpha/beta value that characterises the fractionation response of the prostate is low, possibly even below the 3 Gy commonly assumed for most late complications, and hence that hypofractionation of the radiation treatment might improve the therapeutic ratio (better control at the same or lower complication rate). However, hypofractionation might also increase the complication rates in the surrounding late responding tissues and if their alpha/beta value is not larger that of prostate tumours it could even lead to a decrease in the therapeutic ratio. Therefore, the important question is whether the alpha/beta value for the prostate is lower than the alpha/beta values of the surrounding late responding tissues at risk. This paper reviews the clinical and experimental data regarding the radiobiological differential that might exist between prostate tumours and the late normal tissues around them. Several prospective hypofractionated trials that have been initiated recently in order to determine the alpha/beta value or the range of values that describe the fractionation response of prostate tumours are also reviewed. In spite of several confounding factors that interfere with the derivation of a precise value, it seems that most data support a trend towards lower alpha/beta values for prostate tumours than for rectum or bladder.

  • 75.
    Dasu, Alexandru
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper.
    Radiobiology of prostate cancer2012Ingår i: Robotic Radiosurgery. Treating Prostate Cancer and Related Genitourinary Applications / [ed] Ponsky LE, Fuller DB, Meier RM, Ma C-MC, Springer Berlin/Heidelberg, 2012, s. 79-101Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    The 1999 proposal of Brenner and Hall of an alpha/beta value of 1.5 Gy for prostate tumors has rekindled the interest in the traditional radiobiological aspects of time, dose, and fractionation as effective means of modulating the therapeutic window in radiation therapy. It is well established that, depending on the fractionation sensitivity of normal and tumor tissues, one could depart from the usual fractionation pattern and devise schedules that lead to the same tumor results with less complications, or better tumor control with the same level of complications. Nevertheless, radiobiology experience indicates that the success of any fractionation schedule depends on the temporal pattern of dose delivery. From this perspective, the present chapter aims to review the radiobiological aspects that may be relevant for the design of treatment schedules for prostate tumors.

  • 76.
    Dasu, Alexandru
    Norrlands University Hospital, Umeå.
    Treatment planning optimisation based on imaging tumour proliferation and cell density2008Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, nr 7, s. 1221-1228Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Functional imaging could provide valuable information on the distribution of biological factors that influence the outcome of radiation therapy. Tumour proliferation and cell density in particular could be imaged with dedicated metabolic tracers and could thus be used for the biological optimisation of the treatment plans. The feasibility of individualising treatment planning using proliferation and density information has been investigated through simulations of heterogeneous tumours taking into account the cell density and proliferation rates. The predicted outcome was used to estimate the success of the individualisation of dose distributions. The results have shown that tumour control could be increased through the escalation of doses to proliferating foci with a relative reduction of doses to slowly proliferating regions of the tumour. This suggests that individualisation of treatment planning taking into account proliferation information creates the premises for further reduction of the doses to the surrounding regions which would consequently lead to an increased sparing of the normal tissues. Cell density has been shown to be another important factor that could be used for optimisation, albeit of a lower weight than proliferation. However, associated with proliferation it could lead to treatment failure if the trouble foci are underdosed. In conclusion, treatment optimisation based on imaged proliferation could improve both tumour control and normal tissue sparing.

  • 77.
    Dasu, Alexandru
    et al.
    The Skandion Clinic, Uppsala, Sweden.
    Flejmer, Anna M.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. The Skandion Clinic, Uppsala, Sweden.
    Edvardsson, Anneli
    Medical Radiation Physics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
    Witt Nyström, Petra
    The Skandion Clinic, Uppsala, Sweden.
    Normal tissue sparing potential of scanned proton beams with and without respiratory gating for the treatment of internal mammary nodes in breast cancer radiotherapy2018Ingår i: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 52, s. 81-85Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Proton therapy has shown potential for reducing doses to normal tissues in breast cancer radiotherapy. However data on the impact of protons when including internal mammary nodes (IMN) in the target for breast radiotherapy is comparatively scarce. This study aimed to evaluate normal tissue doses when including the IMN in regional RT with scanned proton beams, with and without respiratory gating. The study cohort was composed of ten left-sided breast patients CT-scanned during enhanced inspiration gating (EIG) and free-breathing (FB). Proton plans were designed for the target including or excluding the IMN. Targets and organs-at-risk were delineated according to RTOG guidelines. Comparison was performed between dosimetric parameters characterizing target coverage and OAR radiation burden. Statistical significance of differences was tested using a paired, two-tailed Student’s t-test. Inclusion of the IMN in the target volume led to a small increase of the cardiopulmonary burden. The largest differences were seen for the ipsilateral lung where the mean dose increased from 6.1 to 6.6 Gy (RBE) (P < 0.0001) in FB plans and from 6.9 to 7.4 Gy (RBE) (P = 0.003) in EIG plans. Target coverage parameters were very little affected by the inclusion of IMN into the treatment target. Radiotherapy with scanned proton beams has the potential of maintaining low cardiovascular burden when including the IMN into the target, irrespective of whether respiratory gating is used or not.

  • 78.
    Dasu, Alexandru
    et al.
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Dose painting by numbers - do the practical limitations of the technique decrease or increase the probability of controlling tumours?2013Ingår i: IFMBE Proceedings / [ed] Long Mian, Springer, 2013, Vol. 39, s. 1731-1734Konferensbidrag (Refereegranskat)
    Abstract [en]

    One of the important questions regarding the feasibility of dose-painting-by-numbers approaches for treatment planning concerns the influence of the averaging of the imaging techniques used and the resolution of the planned and achieved dose distributions. This study investigates the impact of these aspects on the probability of controlling dynamic tumours. The effectiveness of dose painting approaches to target tumour hypoxia has been investigated in terms of the predicted tumour control probabilities (TCP) for tumours with dynamic oxygenations. Several levels of resolution for the resistance of the tumour or the planned dose distributions have been investigated. A very fine heterogeneous dose distribution ideally calculated at voxel level for a high target TCP would fail to control a tumour with dynamic oxygenation during the course of fractionated radiotherapy as mismatches between hotspots in the dose distribution and resistant hypoxic foci would lead to a significant loss in TCP. Only adaptive treatment would lead to reasonably high TCP. A coarse resolution for imaging or for dose distributions might compensate microscale mismatches in dynamic tumours, but the resulting tumour control could still be below the target levels. These results indicate that there is a complex relationship between the resolution of the dose-painting-by-numbers approaches and the dynamics of tumour oxygenation. Furthermore, the clinical success of hypoxia targeting strategies in the absence of adaptive approaches might be explained by changes in tumour radiation resistance through reoxygenation.

  • 79.
    Dasu, Alexandru
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Toma-Dasu, Iuliana
    Stockholm University, Sweden.
    Impact of increasing irradiation time on the treatment of prostate cancers2015Ingår i: World Congress on Medical Physics and Biomedical Engineering, June 7-12, 2015, Toronto, Canada / [ed] Jaffray David A., Springer, 2015, Vol. 51, s. 490-493Konferensbidrag (Refereegranskat)
    Abstract [en]

    This study aimed to investigate the expected impact of intrafraction repair during increasing irradiation times for the treatment of prostate cancers. Lengthy sessions are indeed expected for some advanced irradiation techniques capable to deliver the large fractional doses required by the increased fractionation sensitivity of the prostates. For this purpose, clinically-derived parameters characterizing repair rates and dose response curves for prostate tumors have been used to calculate the expected loss of effectiveness when increasing the irradiation time. The results have shown that treatment sessions lasting more than about 20 to 40 minutes could reduce the probability of biochemical control of prostate tumors by more than 20 to 30 percentage points. These results are in agreement with some observed clinical results and therefore they suggest that treatment durations in prostate radiation therapy should be carefully recorded in order to explicitly account for intrafraction repair, especially when irradiation techniques make use of multiple beams and imaging sessions. Failure to do so might overestimate the expected effectiveness of the treatment and could lead to disappointing clinical results precisely from the demanding treatment modalities expected to increase the therapeutic gain in prostate radiotherapy.

  • 80.
    Dasu, Alexandru
    et al.
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Impact of variable RBE on proton fractionation2013Ingår i: Medical physics (Lancaster), ISSN 0094-2405, Vol. 40, nr 1, s. Article ID 011705-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: To explore the impact of variable proton RBE on dose fractionation for clinically-relevant situations. A generic RBE=1.1 is generally used for isoeffect calculations, while experimental studies showed that proton RBE varies with tissue type, dose and LET.

    Material and methods: An analytical expression for the LET and α/β dependence of the LQ model has been used for proton simulations in parallel with the assumption of a generic RBE=1.1. Calculations have been performed for ranges of LET values and fractionation sensitivities to describe clinically-relevant cases, like the treatment of H&N and prostate tumors. Isoeffect calculations were compared with predictions from a generic RBE value and reported clinical results.

    Results: The generic RBE=1.1 appears to be a reasonable estimate for the proton RBE of rapidly growing tissues irradiated with low LET radiation. However, the use of a variable RBE predicts larger differences for tissues with low α/β (both tumor and normal) and at low doses per fraction. In some situations these differences may appear in contrast to the findings from photon studies highlighting the importance of accurate accounting for the radiobiological effectiveness of protons. Furthermore, the use of variable RBE leads to closer predictions to clinical results.

    Conclusions: The LET dependence of the RBE has a strong impact on the predicted effectiveness of fractionated proton radiotherapy. The magnitude of the effect is modulated by the fractionation sensitivity and the fractional dose indicating the need for accurate analyses both in the target and around it. Care should therefore be employed for changing clinical fractionation patterns or when analyzing results from clinical studies for this type of radiation.

  • 81.
    Dasu, Alexandru
    et al.
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet, Stockholm, Sweden.
    Long-term effects and secondary tumors2014Ingår i: Comprehensive Biomedical Physics, Volume 9: Radiation Therapy Physics and Treatment Optimization / [ed] Anders Brahme, Amsterdam: Elsevier, 2014, s. 223-233Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    The issue of secondary tumours as long-term effects of radiation therapy has gained increased importance as the life expectancy of cancer patients has increased due to improvements in detecting and treating their primary tumours. Current knowledge indicates that radiotherapy leads to a small but significant risk of inducing cancers which is often referred to as the price to pay for the effectiveness of this treatment modality. Nevertheless, the levels of incidence for the long-term effects of radiation therapy may be influenced by many factors that could be both treatment-related and patient-related and therefore proposals have been made to include risk estimations in the process of treatment optimisation. This chapter summarises the current knowledge concerning the induction of secondary cancers after radiotherapy and discusses their consequences for the therapeutic use of ionising radiation.

  • 82.
    Dasu, Alexandru
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. The Skandion Clinic, Uppsala, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Sweden; Karolinska Institutet, Sweden .
    Models for the risk of secondary cancers from radiation therapy2017Ingår i: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 42, s. 232-238Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The interest in the induction of secondary tumours following radiotherapy has greatly increased as developments in detecting and treating the primary tumours have improved the life expectancy of cancer patients. However, most of the knowledge on the current levels of risk comes from patients treated many decades ago. As developments of irradiation techniques take place at a much faster pace than the progression of the carcinogenesis process, the earlier results could not be easily extrapolated to modern treatments. Indeed, the patterns of irradiation from historically-used orthovoltage radiotherapy and from contemporary techniques like conformal radiotherapy with megavoltage radiation, intensity modulated radiation therapy with photons or with particles are quite different. Furthermore, the increased interest in individualised treatment options raises the question of evaluating and ranking the different treatment plan options from the point of view of the risk for cancer induction, in parallel with the quantification of other long-term effects. It is therefore inevitable that models for risk assessment will have to be used to complement the knowledge from epidemiological studies and to make predictions for newer forms of treatment for which clinical evidence is not yet available. This work reviews the mathematical models that could be used to predict the risk of secondary cancers from radiotherapy-relevant dose levels, as well as the approaches and factors that have to be taken into account when including these models in the clinical evaluation process. These include the effects of heterogeneous irradiation, secondary particles production, imaging techniques, interpatient variability and other confounding factors.

  • 83.
    Dasu, Alexandru
    et al.
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Prostate alpha/beta revisited – an analysis of clinical results from 14168 patients2012Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, nr 8, s. 963-974Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Purpose: To determine the dose response parameters and the fractionation sensitivity of prostate tumours from clinical results of patients treated with external beam radiotherapy.

    Material and methods: The study was based on 5-year biochemical results from 14168 patients treated with external beam radiotherapy. Treatment data from 11330 patients treated with conventional fractionation have been corrected for overall treatment time and fitted with a logit equation. The results have been used to determine the optimum α/β values that minimise differences in predictions from 2838 patients treated with hypofractionated schedules.

    Results: Conventional fractionation data yielded logit dose response parameters for all risk groups and for all definitions of biochemical failures. The analysis of hypofractionation data led to very low α/β values (1-1.7 Gy) in all mentioned cases. Neglecting the correction for overall treatment time has little impact on the derivation of α/β values for prostate cancers.

    Conclusions: These results indicate that the high fractionation sensitivity is an intrinsic property of prostate carcinomas and they support the use of hypofractionation to increase the therapeutic gain for these tumours.

  • 84.
    Dasu, Alexandru
    et al.
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper.
    Toma-Dasu, Iuliana
    Stockholm University.
    Will intrafraction repair have negative consequences on extreme hypofractionation in prostate radiation therapy?2015Ingår i: British Journal of Radiology, ISSN 0007-1285, E-ISSN 1748-880X, Vol. 88, nr 1056, s. Article ID 20150588-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: The aim of the present study was to investigate the impact of increasing fraction delivery time on the outcome of hypofractionated radiation therapy for prostate cancer.

    Methods: Monoexponential and biexponential repair models have been used for patients with prostate cancer to study the loss of biochemical control at 5 years for several clinically relevant irradiation times. The theoretical predictions were compared with newly reported clinical results from 4607 patients undergoing conventionally fractionated and hypofractionated prostate radiation therapy.

    Results: Time-demanding irradiation techniques appear to lead to biochemical control rates that sometimes are about 10–20 percentage points below predictions that neglect intrafraction repair. This difference appears to be of the same order of magnitude as that predicted by moderately slow to slow repair taking place during the irradiation time. The impact is largest for the patient risk groups receiving doses corresponding to the steepest part of the dose–response curve. By contrast, for treatment techniques requiring irradiation times shorter than about 20 min, the impact of intrafraction repair appears to be much smaller and probably difficult to be observed in the light of other sources of uncertainty in clinical data.

    Conclusion: Neglecting intrafraction repair might overestimate the effectiveness of some treatment schedules and could also influence any subsequent estimations of fractionation sensitivity for prostate tumours.

    Advances in knowledge: The effect of intrafraction repair for prostate cancer should be taken into account for long irradiation sessions as might be expected from scanned beams and/or from multiple intrafraction imaging sessions to check the positioning of the patient.

  • 85.
    Daşu, Alexandru
    et al.
    Umeå University.
    Denekamp, Juliana
    Umeå University.
    Inducible repair and intrinsic radiosensitivity: a complex but predictable relationship?2000Ingår i: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 153, nr 3, s. 279-288Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two groups have proposed a simple linear relationship between inducible radioresistance in a variety of mammalian cells and their intrinsic radiosensitivity at 2 Gy (Lambin et al., Int.J. Radiat. Biol. 69, 279-290, 1996; Alsbeih and Raaphorst, unpublished results, 1997). The inducible repair response (IRR) is quantified as a ratio, alpha(S)/alpha(R), i.e. the slope in the hypersensitive low-dose region, alpha(S), relative to the alpha(R) term of the classical linear-quadratic formula. These proposals imply that the intrinsic radiosensitivity at clinically relevant doses is directly linked to the cell's ability to mount an adaptive response as a result of exposure to very low doses of radiation. We have re-examined this correlation and found that the more extensive data set now available in the literature does not support the contention of a simple linear relationship. The two parameters are correlated, but by a much more complex relationship. A more logical fit is obtained with a log-linear equation. A series of log-linear curves are needed to describe the correlation between IRR and SF2, because of the spectrum of alpha/beta ratios among the cell lines and hence the confounding effect of the beta term at a dose of 2 Gy. The degree of repair competence before irradiation starts could also be a major factor in the apparent magnitude of the amount of repair induced. There appears to be a systematic difference in the data sets from different series of cell lines that have been obtained using flow cytometry techniques in the laboratory in Vancouver and using dynamic microscope imaging at the Gray Laboratory. We suggest that the use of a brief exposure to a laser beam in flow cytometry before the cells are irradiated might itself partially induce a stress response and change the DNA repair capacity of the cells. The clinical consequences of the relationship for predicting the benefits of altered fractionation schedules are discussed. [ru5]

  • 86.
    Daşu, Alexandru
    et al.
    Umeå University.
    Denekamp, Juliana
    Umeå University.
    New insights into factors influencing the clinically relevant oxygen enhancement ratio1998Ingår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 46, nr 3, s. 269-277Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND PURPOSE: This paper deals with the variations in the oxygen enhancement ratios that could be observed (OER') when comparing oxic and hypoxic cells in different types of fractionated experiments as a consequence of the non-linearity of the underlying cell survival curves. Calculations have been made of the OER' that would be obtained for fractionated irradiations with a series of small doses to allow the comparison of isoeffective doses in oxic and hypoxic conditions. Two styles of fractionated experiment were modelled. In one, the dose per fraction was kept constant in the oxic and hypoxic arms of the experiment, necessitating more fractions in hypoxia to achieve the same level of cell kill. In the other the number of fractions was kept constant and the fraction size was varied to obtain equal levels of damage. The first is the relevant design for the clinic, whereas the second is the design most commonly used in animal studies.

    MATERIALS AND METHODS: Three models of the survival curve were used to simulate the response of cells to radiation injury, all based on the linear quadratic model, but with various added assumptions. A simple classical LQ model is compared with two models in which the concept of inducible repair is added. In one of these the induction dose for 'switching on' the more resistant response is assumed to be increased in hypoxia and in the other it is assumed to be independent of the oxygen tension.

    RESULTS: These calculations show a clear and previously unsuspected dependence of the measured OER' on the design of the fractionated experiment. The values obtained in the clinical and animal types of study differ considerably with all three models. The direction and magnitude of that difference depends critically on the assumptions about the fine structure of the survival curve shape. The authors suggest that the inducible repair version with an oxygen-dependent induction dose is probably the most relevant model. Using this, the measured OER' is reduced at doses around 2 Gy for the clinically relevant design of constant sized fractions to the oxic and hypoxic cells. It may even, in certain model assumptions, fall below unity resulting in an increased sensitivity, not resistance, from the hypoxia.

    CONCLUSIONS: These calculations indicate the urgent need for more knowledge about the fine structure of the low dose region of the survival curves for human tumour cells and especially for comparisons in the presence and absence of oxygen. The extent of the hypersensitivity at very low doses, the trigger dose needed to induce the repair and its oxygen modification may be dominant factors in determining the response of tumour cells to clinically relevant fractionation schedules.

  • 87.
    Daşu, Alexandru
    et al.
    Umeå University.
    Denekamp, Juliana
    Umeå University.
    Superfractionation as a potential hypoxic cell radiosensitizer: prediction of an optimum dose per fraction1999Ingår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 43, nr 5, s. 1083-1094Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: A dose "window of opportunity" has been identified in an earlier modeling study (1) if the inducible repair variant of the LQ model is adopted instead of the pure LQ model, and if all survival curve parameters are equally modified by the presence or absence of oxygen. In this paper we have extended the calculations to consider survival curve parameters from 15 sets of data obtained for cells tested at low doses using clonogenic assays.

    METHODS AND MATERIALS: A simple computer model has been used to simulate the response of each cell line to various doses per fraction in multifraction schedules, with oxic and hypoxic cells receiving the same fractional dose. We have then used pairs of simulated survival curves to estimate the effective hypoxic protection (OER') as a function of the dose per fraction.

    RESULTS: The resistance of hypoxic cells is reduced by using smaller doses per fraction than 2 Gy in all these fractionated clinical simulations, whether using a simple LQ model, or the more complex LQ/IR model. If there is no inducible repair, the optimum dose is infinitely low. If there is inducible repair, there is an optimum dose per fraction at which hypoxic protection is minimized. This is usually around 0.5 Gy. It depends on the dose needed to induce repair being higher in hypoxia than in oxygen. The OER' may even go below unity, i.e. hypoxic cells may be more sensitive than oxic cells.

    CONCLUSIONS: If oxic and hypoxic cells are repeatedly exposed to doses of the same magnitude, as occurs in clinical radiotherapy, the observed hypoxic protection varies with the fractional dose. The OER' is predicted to diminish at lower doses in all cell lines. The loss of hypoxic resistance with superfractionation is predicted to be proportional to the capacity of the cells to induce repair, i.e. their intrinsic radioresistance at a dose of 2 Gy.

  • 88.
    Daşu, Alexandru
    et al.
    Umeå University.
    Denekamp, Juliana
    Umeå University.
    The impact of tissue microenvironment on treatment simulation2003Ingår i: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 510, s. 63-67Artikel i tidskrift (Refereegranskat)
  • 89.
    Daşu, Alexandru
    et al.
    Umeå University.
    Fowler, Jack F
    University of Wisconsin Medical School, USA.
    Comments on "Comparison of in vitro and in vivo alpha/beta ratios for prostate cancer"2005Ingår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 50, nr 6, s. L1-4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    n/a

  • 90.
    Daşu, Alexandru
    et al.
    Umeå University.
    Löfroth, Per-Olov
    Umeå University.
    Wickman, Göran
    Umeå University.
    Liquid ionization chamber measurements of dose distributions in small 6 MV photon beams1998Ingår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 43, nr 1, s. 21-36Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new liquid ionization chamber (LIC) design optimized for high spatial resolution was used for measurements of dose distributions in radiation fields intended for stereotactic radiosurgery (SRS). This work was mainly focused on the properties of this detector in radiation fields from linear accelerators for clinical radiotherapy (pulsed radiation with dose rates from approximately 0.5 to 5 Gy min-1 and beam diameters down to 8 mm). The narrow beams used in stereotactic radiosurgery require detectors with small sizes in order to provide a good spatial resolution. The LIC is investigated to see whether it can be used as a detector for dose measurements in beams currently used for stereotactic radiosurgery. Its properties are compared with those of silicon diodes. The comparisons include output factor (OF), depth dose and profile measurements in 6 MV photon fields of different sizes. For OF measurements, an NACP air ionization chamber was also used in the comparison. The dependence of the response on the detector orientation in the photon beam is also investigated for the diodes and the LIC. The results suggest that LICs can provide better properties than diodes for measuring dose distributions in narrow photon beams.

  • 91.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Umeå University.
    Dose-effect models for risk - relationship to cell survival parameters2005Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 44, nr 8, s. 829-835Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There is an increased interest in estimating the induction of cancers following radiotherapy as the patients have nowadays a much longer life expectancy following the treatment. Clinical investigations have shown that the dose response relationship for cancer induction following radiotherapy has either of two main characteristics: an increase of the risk with dose to a maximum effect followed by a decrease or an increase followed by a levelling-off of the risk. While these behaviours have been described qualitatively, there is no mathematical model that can explain both of them on mechanistic terms. This paper investigates the relationship between the shape of the dose-effect curve and the cell survival parameters of a single risk model. Dose response relationships were described with a competition model which takes into account the probability to induce DNA mutations and the probability of cell survival after irradiation. The shape of the curves was analysed in relation to the parameters that have been used to obtain them. It was found that the two main appearances of clinical data for the induction of secondary cancer following radiotherapy could be the manifestations of the particular sets of parameters that describe the induction of mutations and cell kill for fractionated irradiations. Thus, the levelling off appearance of the dose response curve could be either a sign of moderate to high inducible repair effect in cell survival (but weak for DNA mutations) or the effect of heterogeneity, or both. The bell-shaped appearance encompasses all the other cases. The results also stress the importance of taking into account the details of the clinical delivery of dose in radiotherapy, mainly the fractionated character, as the findings of our study did not appear for single dose models. The results thus indicate that the shapes of clinically observed dose response curves for the induction of secondary cancers can be described by using one single competition model. It was also found that data for cancer induction may be linked to in vivo cell survival parameters that may be used for other modelling applications.

  • 92.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    In response to Dr. Karger et al.2008Ingår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 70, nr 5, s. 1614-1615Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    n/a

  • 93.
    Daşu, Alexandru
    et al.
    Norrland University Hospital, Umeå.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    The relationship between vascular oxygen distribution and tissue oxygenation2009Ingår i: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, s. 255-260Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tumour oxygenation could be investigated through several methods that use various measuring principles and can therefore highlight its different aspects. The results have to be subsequently correlated, but this might not be straightforward due to intrinsic limitations of the measurement methods. This study describes an analysis of the relationship between vascular and tissue oxygenations that may help the interpretation of results. Simulations have been performed with a mathematical model that calculates the tissue oxygenation for complex vascular arrangements by taking into consideration the oxygen diffusion into the tissue and its consumption at the cells. The results showed that while vascular and tissue oxygenations are deterministically related, the relationship between them is not unequivocal and this could lead to uncertainties when attempting to correlate them. However, theoretical simulation could bridge the gap between the results obtained with various methods.

  • 94.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Umeå University.
    Theoretical simulation of tumour oxygenation--practical applications2006Ingår i: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 578, nr 12, s. 357-362Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Theoretical simulation of tissue oxygenation is a robust method that can be used to quantify the tissue oxygenation for a variety of applications. However, it is necessary that the relevant input parameters are used for the model describing the tumour microenvironment. The results of the simulations presented in this article suggest that the accuracy of the simulations depends very much on the method of calculation of the effects of the temporal change of the hypoxic pattern due to the opening and the closure of blood vessels. Thus, the use of average oxygenations might lead to dangerous overestimations of the treatment response. This indicates that care should be taken when incorporating hypoxia information into the biological modelling of tumour response.

  • 95.
    Daşu, Alexandru
    et al.
    Norrland University Hospital.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    Treatment modelling: the influence of micro-environmental conditions2008Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, nr 5, s. 896-905Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The interest in theoretical modelling of radiation response has grown steadily from a fast method to estimate the gain of new treatment strategies to an individualisation tool that may be used as part of the treatment planning algorithms. While the advantages of biological optimisation of plans are obvious, accurate theoretical models and realistic information about the micro-environmental conditions in tissues are needed. This paper aimed to investigate the clinical implications of taking into consideration the details of the tumour microenvironmental conditions. The focus was on the availability of oxygen and other nutrients to tumour cells and the relationship between cellular energy reserves and DNA repair ability as this is thought to influence the response of the various hypoxic cells. The choice of the theoretical models for predicting the response (the linear quadratic model or the inducible repair model) was also addressed. The modelling performed in this project has shown that the postulated radiobiological differences between acute and chronic hypoxia have some important clinical implications which may help to understand the mechanism behind the current success rates of radiotherapy. The results also suggested that it is important to distinguish between the two types of hypoxia in predictive assays and other treatment simulations.

  • 96.
    Daşu, Alexandru
    et al.
    Norrland University Hospital.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    Vascular oxygen content and the tissue oxygenation--a theoretical analysis2008Ingår i: Medical physics (Lancaster), ISSN 0094-2405, Vol. 35, nr 2, s. 539-545Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several methods exist for evaluating tumor oxygenation as hypoxia is an important prognostic factor for cancer patients. They use different measuring principles that highlight various aspects of oxygenation. The results could be empirically correlated, but it has been suspected that there could be discordances in some cases. This study describes an analysis of the relationship between vascular and tissue oxygenations. Theoretical simulation has been employed to characterize tissue oxygenations for a broad range of distributions of intervessel distances and vascular oxygenations. The results were evaluated with respect to the implications for practical measurements of tissue oxygenations. The findings showed that although the tissue oxygenation is deterministically related to vascular oxygenation, the relationship between them is not unequivocal. Variability also exists between the fractions of values below the sensitivity thresholds of various measurement methods which in turn could be reflected in the power of correlations between results from different methods or in the selection of patients for prognostic studies. The study has also identified potential difficulties that may be encountered at the quantitative evaluation of the results from oxygenation measurements. These could improve the understanding of oxygenation measurements and the interpretation of comparisons between results from various measurement methods.

  • 97.
    Daşu, Alexandru
    et al.
    Norrland University Hospital, Umeå.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    What is the clinically relevant relative biologic effectiveness? A warning for fractionated treatments with high linear energy transfer radiation2008Ingår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 70, nr 3, s. 867-874Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: To study the clinically relevant relative biologic effectiveness (RBE) of fractionated treatments with high linear energy transfer (LET) radiation and to identify the important factors that might influence the transfer of tolerance and curative levels from low LET radiation. These are important questions in the light of the growing interest for the therapeutic use of radiation with higher LET than electrons or photons.

    METHODS AND MATERIALS: The RBE of various fractionated schedules was analyzed with theoretical models for radiation effect, and the resulting predictions were compared with the published clinical and experimental data regarding fractionated irradiation with high LET radiation.

    RESULTS: The clinically relevant RBE increased for greater doses per fraction, in contrast to the predictions from single-dose experiments. Furthermore, the RBE for late-reacting tissues appeared to modify more quickly than that for early-reacting tissues. These aspects have quite important clinical implications, because the increased biologic effectiveness reported for this type of radiation would otherwise support the use of hypofractionation. Thus, the differential between acute and late-reacting tissues could put the late-reacting normal tissues at more risk from high LET irradiation; however, at the same time, it could increase the therapeutic window for slow-growing tumors.

    CONCLUSIONS: The modification of the RBE with the dose per fraction must be carefully taken into consideration when devising fractionated treatments with high LET radiation. Neglecting to do so might result in an avalanche of complications that could obscure the potential advantages of the therapeutic use of this type of radiation.

  • 98.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Umeå University.
    Fowler, Jack F.
    University of Wisconsin Hospital.
    Should single or distributed parameters be used to explain the steepness of tumour control probability curves?2003Ingår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 48, nr 3, s. 387-397Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Linear quadratic (LQ) modelling allows easy comparison of different fractionation schedules in radiotherapy. However, estimating the radiation effect of a single fractionated treatment introduces many questions with respect to the parameters to be used in the modelling process. Several studies have used tumour control probability (TCP) curves in order to derive the values for the LQ parameters that may be used further for the analysis and ranking of treatment plans. Unfortunately, little attention has been paid to the biological relevance of these derived parameters, either for the initial number of cells or their intrinsic radiosensitivity, or both. This paper investigates the relationship between single values for the TCP parameters and the resulting dose-response curve. The results of this modelling study show how clinical observations for the position and steepness of the TCP curve can be explained only by the choice of extreme values for the parameters, if they are single values. These extreme values are in contradiction with experimental observations. This contradiction suggests that single values for the parameters are not likely to explain reasonably the clinical observations and that some distributions of input parameters should be taken into consideration.

  • 99.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    Franzén, Lars
    Umeå University.
    Widmark, Anders
    Umeå University.
    Nilsson, Per
    Umeå University.
    Secondary malignancies from prostate cancer radiation treatment: a risk analysis of the influence of target margins and fractionation patterns2011Ingår i: International journal of radiation oncology, biology, physics, ISSN 1879-355X, Vol. 79, nr 3, s. 738-746Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: This study explores the implications for cancer induction of treatment details such as fractionation, planning target volume (PTV) definition, and interpatient variations, which are relevant for the radiation treatment of prostate carcinomas.

    METHODS AND MATERIALS: Treatment planning data from 100 patients have been analyzed with a risk model based on the United Nations Scientific Committee on the Effects of Atomic Radiation competition model. The risk model can account for dose heterogeneity and fractionation effects characteristic for modern radiotherapy. Biologically relevant parameters from clinical and experimental data have been used with the model.

    RESULTS: The results suggested that changes in prescribed dose could lead to a modification of the risks for individual organs surrounding the clinical target volume (CTV) but that the total risk appears to be less affected by changes in the target dose. Larger differences are observed for modifications of the margins between the CTV and the PTV because these have direct impact onto the dose level and dose heterogeneity in the healthy tissues surrounding the CTV. Interpatient anatomic variations also have to be taken into consideration for studies of the risk for cancer induction from radiotherapy.

    CONCLUSIONS: The results have shown the complex interplay between the risk for secondary malignancies, the details of the treatment delivery, and the patient heterogeneity that may influence comparisons between the long-term effects of various treatment techniques. Nevertheless, absolute risk levels seem very small and comparable to mortality risks from surgical interventions, thus supporting the robustness of radiation therapy as a successful treatment modality for prostate carcinomas.

  • 100.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    Franzén, Lars
    Umeå University.
    Widmark, Anders
    Umeå University.
    Nilsson, Per
    Umeå University.
    The risk for secondary cancers in patients treated for prostate carcinoma – an analysis with the competition dose response model2009Ingår i: IFMBE Proceedings, Vol. 25/III, s. 237-240Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The risk for radiation-induced cancers has become increasingly important as patient survival following radiotherapy has increased due to the advent of new methods for early detection and advanced treatment. Attempts have been made to quantify the risk of cancer that may be associated with various treatment approaches, but the accuracy of predictions is rather low due to the influence of many confounding factors. It is the aim of this paper to investigate the impact of dose heterogeneity and inter-patient anatomical heterogeneity that may be encountered in a population of patients undergoing radiotherapy and are thought to influence risk predictions. Dose volume histograms from patients treated with radiation for the carcinoma of the prostate have been used to calculate the risk for secondary malignancies using a competition dose-response model previously developed. Biologically-relevant parameters derived from clinical and experimental data have been used for the model. The results suggested that dose heterogeneity plays an important role in predicting the risk for secondary cancer and that it should be taken into account through the use of dose volume histograms. Consequently, dose-response relationships derived for uniform relationships should be used with care to predict the risk for secondary malignancies in heterogeneously irradiated tissues. Inter-patient differences could lead to considerable uncertainties in the shape of the relationship between predicted risk and average tissue dose, as seen in epidemiological studies. They also lead to rather weak correlations between the risk for secondary malignancies and target volumes. The results stress the importance of taking into account the details of the clinical delivery of dose in radiotherapy for treatment plan evaluation or for retrospective analyses of the induction of secondary cancers. Nevertheless, the levels of risks are generally low and they could be regarded as the price of success for the advances in the radiotherapy of the prostate.

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